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Sample records for fibrosis current usefulness

  1. Liver Fibrosis: Current Principles of Diagnosis

    Directory of Open Access Journals (Sweden)

    A.K. Duda

    2014-09-01

    Full Text Available Liver fibrosis — a natural consequence of almost all liver diseases of any origin. We are faced with a number of standard stereotype processes that take place in the liver tissue. Mostly it is the processes of chronic inflammation, which oppose the processes of liver tissue regeneration. The basis of imbalance between the processes of fibrosis and regeneration is an accumulation of extracellular matrix. Liver fibrosis in its development leads to liver cirrhosis, hepatocellular carcinoma, and the increase in morbidity rate is observed worldwide. Furthermore, the process is genetically determined, but modifiable factors play an important role in the progression of this disease. Current data indicate the possibility of reversible liver fibrosis.

  2. Current Understanding of the Pathophysiology of Myocardial Fibrosis and Its Quantitative Assessment in Heart Failure

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    Tong Liu

    2017-04-01

    Full Text Available Myocardial fibrosis is an important part of cardiac remodeling that leads to heart failure and death. Myocardial fibrosis results from increased myofibroblast activity and excessive extracellular matrix deposition. Various cells and molecules are involved in this process, providing targets for potential drug therapies. Currently, the main detection methods of myocardial fibrosis rely on serum markers, cardiac magnetic resonance imaging, and endomyocardial biopsy. This review summarizes our current knowledge regarding the pathophysiology, quantitative assessment, and novel therapeutic strategies of myocardial fibrosis.

  3. Current Strategies for Quantitating Fibrosis in Liver Biopsy

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    Yan Wang

    2015-01-01

    Full Text Available Objective: The present mini-review updated the progress in methodologies based on using liver biopsy. Data Sources: Articles for study of liver fibrosis, liver biopsy or fibrosis assessment published on high impact peer review journals from 1980 to 2014. Study Selection: Key articles were selected mainly according to their levels of relevance to this topic and citations. Results: With the recently mounting progress in chronic liver disease therapeutics, comes by a pressing need for precise, accurate, and dynamic assessment of hepatic fibrosis and cirrhosis in individual patients. Histopathological information is recognized as the most valuable data for fibrosis assessment. Conventional histology categorical systems describe the changes of fibrosis patterns in liver tissue; but the simplified ordinal digits assigned by these systems cannot reflect the fibrosis dynamics with sufficient precision and reproducibility. Morphometric assessment by computer assist digital image analysis, such as collagen proportionate area (CPA, detects change of fibrosis amount in tissue section in a continuous variable, and has shown its independent diagnostic value for assessment of advanced or late-stage of fibrosis. Due to its evident sensitivity to sampling variances, morphometric measurement is feasible to be taken as a reliable statistical parameter for the study of a large cohort. Combining state-of-art imaging technology and fundamental principle in Tissue Engineering, structure-based quantitation was recently initiated with a novel proof-of-concept tool, qFibrosis. qFibrosis showed not only the superior performance to CPA in accurately and reproducibly differentiating adjacent stages of fibrosis, but also the possibility for facilitating analysis of fibrotic regression and cirrhosis sub-staging. Conclusions: With input from multidisciplinary innovation, liver biopsy assessment as a new "gold standard" is anticipated to substantially support the accelerated

  4. Current protocols in the management of oral submucous fibrosis: An update.

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    Arakeri, Gururaj; Rai, Kirthi Kumar; Boraks, George; Patil, Shekar Gowda; Aljabab, Abdulsalam S; Merkx, M A W; Carrozzo, Marco; Brennan, Peter A

    2017-07-01

    Oral submucous fibrosis (OSMF) is a debilitating condition of oral cavity which has significant potential for malignant transformation. In spite of over 20 years of research, the pathogenesis of the condition is still obscure and no single management modality is effective. Many OSMF treatment protocols have been proposed to alleviate the signs and symptoms of the disorder and there is overwhelming evidence that as areca nut is primary cause, stopping its use may have a considerable effect on symptoms rather than reversing pre-existing fibrosis. We present a review of the current protocols for managing OSMF. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Fibrosis imaging : Current concepts and future directions

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    Baues, Maike; Dasgupta, Anshuman; Ehling, Josef; Prakash, Jai; Boor, Peter; Tacke, Frank; Kiessling, Fabian; Lammers, Twan

    2017-01-01

    Fibrosis plays an important role in many different pathologies. It results from tissue injury, chronic inflammation, autoimmune reactions and genetic alterations, and it is characterized by the excessive deposition of extracellular matrix components. Biopsies are routinely employed for fibrosis

  6. Recent progress in translational cystic fibrosis research using precision medicine strategies.

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    Cholon, Deborah M; Gentzsch, Martina

    2018-03-01

    Significant progress has been achieved in developing precision therapies for cystic fibrosis; however, highly effective treatments that target the ion channel, CFTR, are not yet available for many patients. As numerous CFTR therapeutics are currently in the clinical pipeline, reliable screening tools capable of predicting drug efficacy to support individualized treatment plans and translational research are essential. The utilization of bronchial, nasal, and rectal tissues from individual cystic fibrosis patients for drug testing using in vitro assays such as electrophysiological measurements of CFTR activity and evaluation of fluid movement in spheroid cultures, has advanced the prediction of patient-specific responses. However, for precise prediction of drug effects, in vitro models of CFTR rescue should incorporate the inflamed cystic fibrosis airway environment and mimic the complex tissue structures of airway epithelia. Furthermore, novel assays that monitor other aspects of successful CFTR rescue such as restoration of mucus characteristics, which is important for predicting mucociliary clearance, will allow for better prognoses of successful therapies in vivo. Additional cystic fibrosis treatment strategies are being intensively explored, such as development of drugs that target other ion channels, and novel technologies including pluripotent stem cells, gene therapy, and gene editing. The multiple therapeutic approaches available to treat the basic defect in cystic fibrosis combined with relevant precision medicine models provide a framework for identifying optimal and sustained treatments that will benefit all cystic fibrosis patients. Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

  7. Imaging of Myocardial Fibrosis in Patients with End-Stage Renal Disease: Current Limitations and Future Possibilities

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    M. P. M. Graham-Brown

    2017-01-01

    Full Text Available Cardiovascular disease in patients with end-stage renal disease (ESRD is driven by a different set of processes than in the general population. These processes lead to pathological changes in cardiac structure and function that include the development of left ventricular hypertrophy and left ventricular dilatation and the development of myocardial fibrosis. Reduction in left ventricular hypertrophy has been the established goal of many interventional trials in patients with chronic kidney disease, but a recent systematic review has questioned whether reduction of left ventricular hypertrophy improves cardiovascular mortality as previously thought. The development of novel imaging biomarkers that link to cardiovascular outcomes and that are specific to the disease processes in ESRD is therefore required. Postmortem studies of patients with ESRD on hemodialysis have shown that the extent of myocardial fibrosis is strongly linked to cardiovascular death and accurate imaging of myocardial fibrosis would be an attractive target as an imaging biomarker. In this article we will discuss the current imaging methods available to measure myocardial fibrosis in patients with ESRD, the reliability of the techniques, specific challenges and important limitations in patients with ESRD, and how to further develop the techniques we have so they are sufficiently robust for use in future clinical trials.

  8. Pulmonary Hypertension Associated with Idiopathic Pulmonary Fibrosis: Current and Future Perspectives

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    Scott D. Collum

    2017-01-01

    Full Text Available Pulmonary hypertension (PH is commonly present in patients with chronic lung diseases such as Chronic Obstructive Pulmonary Disease (COPD or Idiopathic Pulmonary Fibrosis (IPF where it is classified as Group III PH by the World Health Organization (WHO. PH has been identified to be present in as much as 40% of patients with COPD or IPF and it is considered as one of the principal predictors of mortality in patients with COPD or IPF. However, despite the prevalence and fatal consequences of PH in the setting of chronic lung diseases, there are limited therapies available for patients with Group III PH, with lung transplantation remaining as the most viable option. This highlights our need to enhance our understanding of the molecular mechanisms that lead to the development of Group III PH. In this review we have chosen to focus on the current understating of PH in IPF, we will revisit the main mediators that have been shown to play a role in the development of the disease. We will also discuss the experimental models available to study PH associated with lung fibrosis and address the role of the right ventricle in IPF. Finally we will summarize the current available treatment options for Group III PH outside of lung transplantation.

  9. A review of current and novel therapies for idiopathic pulmonary fibrosis

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    Rafii, Rokhsara; Juarez, Maya M.; Albertson, Timothy E.

    2013-01-01

    Idiopathic pulmonary fibrosis (IPF) is a progressively fibrotic interstitial lung disease that is associated with a median survival of 2-3 years from initial diagnosis. To date, there is no treatment approved for IPF in the United States, and only one pharmacological agent has been approved outside of the United States. Nevertheless, research over the past 10 years has provided us with a wealth of information on its histopathology, diagnostic work-up, and a greater understanding of its pathophysiology. Specifically, IPF is no longer thought to be a predominantly pro-inflammatory disorder. Rather, the fibrosis in IPF is increasingly understood to be the result of a fibroproliferative and aberrant wound healing cascade. The development of therapeutic targets has shifted in accord with this paradigm change. This review highlights the current understanding of IPF, and the recent as well as novel therapeutics being explored in clinical trials for the treatment of this devastating disease. PMID:23372951

  10. Proteome analysis of Radiation-induced pulmonary fibrosis

    International Nuclear Information System (INIS)

    Song, Jie Young; Lim, Hee Soon; Kim, Hyung Doo; Shim, Ji Young; Han, Young Soo; Son, Hyeog Jin Son; Yun, Yeon Sook

    2005-01-01

    Pulmonary fibrosis is perhaps the most universal late effect of organ damage after both chemical insult and irradiation in the treatment of lung cancer. The use chemotherapy and radiation therapy, alone or combined, can be associated with clinically significant pulmonary toxicity, which leads to pneumonia and pulmonary fibrosis. It is also reported that about 100,000 people in the United States are suffered from pulmonary fibrosis. Therefore, pulmonary fibrosis will be more focused by medicinal researchers. Because current therapies, aimed at inhibiting pulmonary inflammation that often precedes fibrosis, are effective only in a minority of suffered patients, novel therapeutic methods are highly needed. Some researchers have used bleomycininduced pulmonary fibrosis as a basis for looking at the molecular mechanisms of fibrosis, and total gene expression was monitored using genomics method. However, radiation-induced pulmonary fibrosis has not been fully focused and investigated. Here, we have analyzed changes in gene expression in response to γ- irradiation by using proteomic analysis

  11. Experimental models of liver fibrosis.

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    Yanguas, Sara Crespo; Cogliati, Bruno; Willebrords, Joost; Maes, Michaël; Colle, Isabelle; van den Bossche, Bert; de Oliveira, Claudia Pinto Marques Souza; Andraus, Wellington; Alves, Venâncio Avancini Ferreira; Leclercq, Isabelle; Vinken, Mathieu

    2016-05-01

    Hepatic fibrosis is a wound healing response to insults and as such affects the entire world population. In industrialized countries, the main causes of liver fibrosis include alcohol abuse, chronic hepatitis virus infection and non-alcoholic steatohepatitis. A central event in liver fibrosis is the activation of hepatic stellate cells, which is triggered by a plethora of signaling pathways. Liver fibrosis can progress into more severe stages, known as cirrhosis, when liver acini are substituted by nodules, and further to hepatocellular carcinoma. Considerable efforts are currently devoted to liver fibrosis research, not only with the goal of further elucidating the molecular mechanisms that drive this disease, but equally in view of establishing effective diagnostic and therapeutic strategies. The present paper provides a state-of-the-art overview of in vivo and in vitro models used in the field of experimental liver fibrosis research.

  12. Nanoparticles for the treatment of liver fibrosis

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    Poilil Surendran S

    2017-09-01

    Full Text Available Suchithra Poilil Surendran, Reju George Thomas, Myeong Ju Moon, Yong Yeon Jeong Department of Radiology, BioMolecular Theranostics (BiT Lab, Chonnam National University Medical School, Chonnam National University Hwasun Hospital (CNUHH, South Korea Abstract: Chronic liver diseases represent a global health problem due to their high prevalence worldwide and the limited available curative treatment options. They can result from various causes, both infectious and noninfectious diseases. The application of nanoparticle (NP systems has emerged as a rapidly evolving area of interest for the safe delivery of various drugs and nucleic acids for chronic liver diseases. This review presents the pathogenesis, diagnosis and the emerging nanoparticulate systems used in the treatment of chronic liver diseases caused by liver fibrosis. Activated hepatic stellate cell (HSC is considered to be the main mechanism for liver fibrosis. Ultrasonography and magnetic resonance imaging techniques are widely used noninvasive diagnostic methods for hepatic fibrosis. A variety of nanoparticulate systems are mainly focused on targeting HSC in the treatment of hepatic fibrosis. As early liver fibrosis is reversible by current NP therapy, it is being studied in preclinical as well as clinical trials. Among various nanoparticulate systems, inorganic NPs, liposomes and nanomicelles have been widely studied due to their distinct properties to deliver drugs as well as other therapeutic moieties. Liposomal NPs in clinical trials is considered to be a milestone in the treatment of hepatic fibrosis. Currently, NP therapy for liver fibrosis is updating fast, and hopefully, it can be the future remedy for liver fibrosis. Keywords: liver fibrosis, inorganic nanoparticles, liposomes, micelles

  13. Current status of nephrogenic systemic fibrosis

    International Nuclear Information System (INIS)

    Daftari Besheli, L.; Aran, S.; Shaqdan, K.; Kay, J.; Abujudeh, H.

    2014-01-01

    Nephrogenic systemic fibrosis (NSF) occurs in patients with advanced chronic kidney disease (CKD) or acute renal failure, most commonly following exposure to gadolinium-based contrast agents (GBCAs). NSF can be debilitating and associated with increased mortality. The putative association of NSF with GBCAs prompted the development of guidelines to limit the use of these contrast agents in at-risk patients. Indeed, the incidence of NSF has decreased dramatically following application of these guidelines, which appears to be the only effective means of decreasing NSF incidence. Thus, increasing clinician awareness of these updated guidelines is important. The present review introduces and compares updated guidelines for GBCA use and discusses the latest advances in the understanding of the pathogenic mechanisms and treatment of NSF

  14. Molecular basis of hepatic fibrosis and current status of its diagnosis and treatment

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    LI Yan

    2018-01-01

    Full Text Available During the process of acute or chronic liver injury, hepatic stellate cells interact with various types of cells such as hepatic parenchymal cells, Kupffer cells, and liver sinusoidal endothelial cells to mediate extracellular matrix deposition and sinusoid capillarization and thus initiate the process of hepatic fibrosis. The nature of hepatic fibrosis is repair response after liver injury. Liver biopsy is regarded as the gold standard for the diagnosis of hepatic fibrosis; however, it is generally associated with the risk of bleeding and even death. Noninvasive diagnostic methods for liver fibrosis mainly include serum biomarkers, imaging techniques, and predictive statistical model, but such methods cannot completely replace liver biopsy. At present, the treatment of hepatic fibrosis focuses on the research and development of new drugs targeting primary disease, hepatic stellate cells, or balance of extracellular matrix synthesis/degradation. The research on the molecular mechanism of hepatic fibrosis provides a solid theoretical basis for exploring the treatment of hepatic fibrosis.

  15. Therapeutic targets in liver fibrosis.

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    Fallowfield, Jonathan A

    2011-05-01

    Detailed analysis of the cellular and molecular mechanisms that mediate liver fibrosis has provided a framework for therapeutic approaches to prevent, slow down, or even reverse fibrosis and cirrhosis. A pivotal event in the development of liver fibrosis is the activation of quiescent hepatic stellate cells (HSCs) to scar-forming myofibroblast-like cells. Consequently, HSCs and the factors that regulate HSC activation, proliferation, and function represent important antifibrotic targets. Drugs currently licensed in the US and Europe for other indications target HSC-related components of the fibrotic cascade. Their deployment in the near future looks likely. Ultimately, treatment strategies for liver fibrosis may vary on an individual basis according to etiology, risk of fibrosis progression, and the prevailing pathogenic milieu, meaning that a multiagent approach could be required. The field continues to develop rapidly and starts to identify exciting potential targets in proof-of-concept preclinical studies. Despite this, no antifibrotics are currently licensed for use in humans. With epidemiological predictions for the future prevalence of viral, obesity-related, and alcohol-related cirrhosis painting an increasingly gloomy picture, and a shortfall in donors for liver transplantation, the clinical urgency for new therapies is high. There is growing interest from stakeholders keen to exploit the market potential for antifibrotics. However, the design of future trials for agents in the developmental pipeline will depend on strategies that enable equal patient stratification, techniques to reliably monitor changes in fibrosis over time, and the definition of clinically meaningful end points.

  16. Noninvasive diagnosis of hepatic fibrosis in chronic hepatitis C

    OpenAIRE

    Stauber, Rudolf E; Lackner, Carolin

    2007-01-01

    Assessment of hepatic fibrosis is important for determining prognosis, guiding management decisions, and monitoring disease. Histological evaluation of liver biopsy specimens is currently considered the reference test for staging hepatic fibrosis. Since liver biopsy carries a small but significant risk, noninvasive tests to assess hepatic fibrosis are desirable. This editorial gives an overview on noninvasive methods currently available to determine hepatic fibrosis and their diagnostic accur...

  17. Ivacaftor: A Novel Gene-Based Therapeutic Approach for Cystic Fibrosis

    OpenAIRE

    Condren, Michelle E.; Bradshaw, Marquita D.

    2013-01-01

    Ivacaftor is a new therapeutic agent that acts at the cystic fibrosis transmembrane conductance regulator (CFTR) channel to alter activity. It is approved for use in patients 6 years and older with cystic fibrosis who have at least 1 G551D mutation in the CFTR gene. It is unlike any other current pharmacologic agent for cystic fibrosis in that it specifically targets the gene defect associated with cystic fibrosis as opposed to treating resulting symptomology. Mucoactive agents, antibiotics, ...

  18. Pathological assessment of liver fibrosis regression

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    WANG Bingqiong

    2017-03-01

    Full Text Available Hepatic fibrosis is the common pathological outcome of chronic hepatic diseases. An accurate assessment of fibrosis degree provides an important reference for a definite diagnosis of diseases, treatment decision-making, treatment outcome monitoring, and prognostic evaluation. At present, many clinical studies have proven that regression of hepatic fibrosis and early-stage liver cirrhosis can be achieved by effective treatment, and a correct evaluation of fibrosis regression has become a hot topic in clinical research. Liver biopsy has long been regarded as the gold standard for the assessment of hepatic fibrosis, and thus it plays an important role in the evaluation of fibrosis regression. This article reviews the clinical application of current pathological staging systems in the evaluation of fibrosis regression from the perspectives of semi-quantitative scoring system, quantitative approach, and qualitative approach, in order to propose a better pathological evaluation system for the assessment of fibrosis regression.

  19. Current approaches to the management of idiopathic pulmonary fibrosis.

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    Raghu, Ganesh; Richeldi, Luca

    2017-08-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal lung disease associated with dyspnoea, cough and impaired quality of life. Currently, the aims of patient care are to improve outcomes for patients by slowing the progression of the disease, extending life, and improving quality of life. A prompt, accurate diagnosis is important to enable patients to receive treatment early in the course of the disease and to be considered for lung transplantation. Two anti-fibrotic drugs, nintedanib and pirfenidone, have been shown to reduce decline in lung function in patients with IPF. In addition to pharmacological therapy, optimal management of IPF includes treatment of comorbidities, symptom relief, pulmonary rehabilitation, and palliative care. Patient education is important to enable patients to make decisions about their care and to help them manage their disease and the side-effects of anti-fibrotic drugs. Research continues into new treatments and combinations of treatments that may improve outcomes for patients with this devastating disease. Copyright © 2017. Published by Elsevier Ltd.

  20. Complementary and alternative medicine use in children with cystic fibrosis.

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    Giangioppo, Sandra; Kalaci, Odion; Radhakrishnan, Arun; Fleischer, Erin; Itterman, Jennifer; Lyttle, Brian; Price, April; Radhakrishnan, Dhenuka

    2016-11-01

    To estimate the overall prevalence of complementary and alternative medicine use among children with cystic fibrosis, determine specific modalities used, predictors of use and subjective helpfulness or harm from individual modalities. Of 53 children attending the cystic fibrosis clinic in London, Ontario (100% recruitment), 79% had used complementary and alternative medicine. The most commonly used modalities were air purifiers, humidifiers, probiotics, and omega-3 fatty acids. Family complementary and alternative medicine use was the only independent predictor of overall use. The majority of patients perceived benefit from specific modalities for cystic fibrosis symptoms. Given the high frequency and number of modalities used and lack of patient and disease characteristics predicting use, we recommend that health care providers should routinely ask about complementary and alternative medicine among all pediatric cystic fibrosis patients and assist patients in understanding the potential benefits and risks to make informed decisions about its use. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Idiopathic pulmonary fibrosis: current understanding of the pathogenesis and the status of treatment.

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    Khalil, Nasreen; O'Connor, Robert

    2004-07-20

    Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal pulmonary fibrotic lung disease. The diagnostic histological changes are called usual interstitial pneumonia and are characterized by histological temporal heterogeneity, whereby normal lung tissue is interspersed with interstitial fibrosis, honeycomb cysts and fibroblast foci. Pulmonary functions show restricted volumes and capacities, preserved flows and evidence of decreased gas exchange. High-resolution computed axial tomography demonstrates evidence of fibrosis and lung remodelling such as honeycomb cysts and traction bronchiectasis. There is no known effective treatment for IPF, but lung transplantation improves survival.

  2. Noninvasive imaging of experimental lung fibrosis.

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    Zhou, Yong; Chen, Huaping; Ambalavanan, Namasivayam; Liu, Gang; Antony, Veena B; Ding, Qiang; Nath, Hrudaya; Eary, Janet F; Thannickal, Victor J

    2015-07-01

    Small animal models of lung fibrosis are essential for unraveling the molecular mechanisms underlying human fibrotic lung diseases; additionally, they are useful for preclinical testing of candidate antifibrotic agents. The current end-point measures of experimental lung fibrosis involve labor-intensive histological and biochemical analyses. These measures fail to account for dynamic changes in the disease process in individual animals and are limited by the need for large numbers of animals for longitudinal studies. The emergence of noninvasive imaging technologies provides exciting opportunities to image lung fibrosis in live animals as often as needed and to longitudinally track the efficacy of novel antifibrotic compounds. Data obtained by noninvasive imaging provide complementary information to histological and biochemical measurements. In addition, the use of noninvasive imaging in animal studies reduces animal usage, thus satisfying animal welfare concerns. In this article, we review these new imaging modalities with the potential for evaluation of lung fibrosis in small animal models. Such techniques include micro-computed tomography (micro-CT), magnetic resonance imaging, positron emission tomography (PET), single photon emission computed tomography (SPECT), and multimodal imaging systems including PET/CT and SPECT/CT. It is anticipated that noninvasive imaging will be increasingly used in animal models of fibrosis to gain insights into disease pathogenesis and as preclinical tools to assess drug efficacy.

  3. Syndecans in heart fibrosis.

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    Lunde, Ida G; Herum, Kate M; Carlson, Cathrine C; Christensen, Geir

    2016-09-01

    Heart disease is a deadly syndrome affecting millions worldwide. It reflects an unmet clinical need, and the disease mechanisms are poorly understood. Cardiac fibrosis is central to heart disease. The four-membered family of transmembrane proteoglycans, syndecan-1 to -4, is believed to regulate fibrosis. We review the current literature concerning syndecans in cardiac fibrosis. Syndecan expression is up-regulated in response to pro-inflammatory stimuli in various forms of heart disease with fibrosis. Mice lacking syndecan-1 and -4 show reduced activation of pro-fibrotic signaling and increased cardiac rupture upon infarction indicating an important role for these molecules. Whereas the short cytoplasmic tail of syndecans regulates signaling, their extracellular part, substituted with heparan sulfate glycosaminoglycan chains, binds a plethora of extracellular matrix (ECM) molecules involved in fibrosis, e.g., collagens, growth factors, cytokines, and immune cell adhesion proteins. Full-length syndecans induce pro-fibrotic signaling, increasing the expression of collagens, myofibroblast differentiation factors, ECM enzymes, growth factors, and immune cell adhesion molecules, thereby also increasing cardiac stiffness and preventing cardiac rupture. Upon pro-inflammatory stimuli, syndecan ectodomains are enzymatically released from heart cells (syndecan shedding). Shed ectodomains affect the expression of ECM molecules, promoting ECM degradation and cardiac rupture upon myocardial infarction. Blood levels of shed syndecan-1 and -4 ectodomains are associated with hospitalization, mortality, and heart remodeling in patients with heart failure. Improved understanding of syndecans and their modifying enzymes in cardiac fibrosis might contribute to the development of compounds with therapeutic potential, and enzymatically shed syndecan ectodomains might constitute a future prognostic tool for heart diseases with fibrosis. Graphical Abstract Graphical abstract summarizing

  4. Fibrosis in nonalcoholic fatty liver disease: Noninvasive assessment using computed tomography volumetry.

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    Fujita, Nobuhiro; Nishie, Akihiro; Asayama, Yoshiki; Ishigami, Kousei; Ushijima, Yasuhiro; Takayama, Yukihisa; Okamoto, Daisuke; Shirabe, Ken; Yoshizumi, Tomoharu; Kotoh, Kazuhiro; Furusyo, Norihiro; Hida, Tomoyuki; Oda, Yoshinao; Fujioka, Taisuke; Honda, Hiroshi

    2016-10-28

    To evaluate the diagnostic performance of computed tomography (CT) volumetry for discriminating the fibrosis stage in patients with nonalcoholic fatty liver disease (NAFLD). A total of 38 NAFLD patients were enrolled. On the basis of CT imaging, the volumes of total, left lateral segment (LLS), left medial segment, caudate lobe, and right lobe (RL) of the liver were calculated with a dedicated liver application. The relationship between the volume percentage of each area and fibrosis stage was analyzed using Spearman's rank correlation coefficient. A receiver operating characteristic (ROC) curve analysis was performed to determine the accuracy of CT volumetry for discriminating fibrosis stage. The volume percentages of the caudate lobe and the LLS significantly increased with the fibrosis stage ( r = 0.815, P volumetry is a useful diagnostic parameter for staging fibrosis in NAFLD patients.

  5. Lung function imaging methods in Cystic Fibrosis pulmonary disease.

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    Kołodziej, Magdalena; de Veer, Michael J; Cholewa, Marian; Egan, Gary F; Thompson, Bruce R

    2017-05-17

    Monitoring of pulmonary physiology is fundamental to the clinical management of patients with Cystic Fibrosis. The current standard clinical practise uses spirometry to assess lung function which delivers a clinically relevant functional readout of total lung function, however does not supply any visible or localised information. High Resolution Computed Tomography (HRCT) is a well-established current 'gold standard' method for monitoring lung anatomical changes in Cystic Fibrosis patients. HRCT provides excellent morphological information, however, the X-ray radiation dose can become significant if multiple scans are required to monitor chronic diseases such as cystic fibrosis. X-ray phase-contrast imaging is another emerging X-ray based methodology for Cystic Fibrosis lung assessment which provides dynamic morphological and functional information, albeit with even higher X-ray doses than HRCT. Magnetic Resonance Imaging (MRI) is a non-ionising radiation imaging method that is garnering growing interest among researchers and clinicians working with Cystic Fibrosis patients. Recent advances in MRI have opened up the possibilities to observe lung function in real time to potentially allow sensitive and accurate assessment of disease progression. The use of hyperpolarized gas or non-contrast enhanced MRI can be tailored to clinical needs. While MRI offers significant promise it still suffers from poor spatial resolution and the development of an objective scoring system especially for ventilation assessment.

  6. A prediction model for the grade of liver fibrosis using magnetic resonance elastography.

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    Mitsuka, Yusuke; Midorikawa, Yutaka; Abe, Hayato; Matsumoto, Naoki; Moriyama, Mitsuhiko; Haradome, Hiroki; Sugitani, Masahiko; Tsuji, Shingo; Takayama, Tadatoshi

    2017-11-28

    Liver stiffness measurement (LSM) has recently become available for assessment of liver fibrosis. We aimed to develop a prediction model for liver fibrosis using clinical variables, including LSM. We performed a prospective study to compare liver fibrosis grade with fibrosis score. LSM was measured using magnetic resonance elastography in 184 patients that underwent liver resection, and liver fibrosis grade was diagnosed histologically after surgery. Using the prediction model established in the training group, we validated the classification accuracy in the independent test group. First, we determined a cut-off value for stratifying fibrosis grade using LSM in 122 patients in the training group, and correctly diagnosed fibrosis grades of 62 patients in the test group with a total accuracy of 69.3%. Next, on least absolute shrinkage and selection operator analysis in the training group, LSM (r = 0.687, P prediction model. This prediction model applied to the test group correctly diagnosed 32 of 36 (88.8%) Grade I (F0 and F1) patients, 13 of 18 (72.2%) Grade II (F2 and F3) patients, and 7 of 8 (87.5%) Grade III (F4) patients in the test group, with a total accuracy of 83.8%. The prediction model based on LSM, ICGR15, and platelet count can accurately and reproducibly predict liver fibrosis grade.

  7. Idiopathic pulmonary fibrosis: treatment update.

    LENUS (Irish Health Repository)

    O'Connell, Oisin J

    2011-11-01

    Idiopathic pulmonary fibrosis (IPF) is the most common of the idiopathic interstitial pneumonias. Despite multiple recent clinical trials, there is no strong evidence supporting a survival advantage for any agent in the management of patients with IPF. The limited effectiveness of current treatment regimes has led to a search for novel therapies including antifibrotic strategies. This article reviews the evidence supporting the treatments currently used in the management of IPF.

  8. Idiopathic pulmonary fibrosis: current understanding of the pathogenesis and the status of treatment

    OpenAIRE

    Khalil, Nasreen; O'Connor, Robert

    2004-01-01

    IDIOPATHIC PULMONARY FIBROSIS (IPF) is a progressive and lethal pulmonary fibrotic lung disease. The diagnostic histological changes are called usual interstitial pneumonia and are characterized by histological temporal heterogeneity, whereby normal lung tissue is interspersed with interstitial fibrosis, honeycomb cysts and fibroblast foci. Pulmonary functions show restricted volumes and capacities, preserved flows and evidence of decreased gas exchange. High-resolution computed axial tomogra...

  9. Adeno-associated virus for cystic fibrosis gene therapy

    Directory of Open Access Journals (Sweden)

    S.V. Martini

    2011-11-01

    Full Text Available Gene therapy is an alternative treatment for genetic lung disease, especially monogenic disorders such as cystic fibrosis. Cystic fibrosis is a severe autosomal recessive disease affecting one in 2500 live births in the white population, caused by mutation of the cystic fibrosis transmembrane conductance regulator (CFTR. The disease is classically characterized by pancreatic enzyme insufficiency, an increased concentration of chloride in sweat, and varying severity of chronic obstructive lung disease. Currently, the greatest challenge for gene therapy is finding an ideal vector to deliver the transgene (CFTR to the affected organ (lung. Adeno-associated virus is the most promising viral vector system for the treatment of respiratory disease because it has natural tropism for airway epithelial cells and does not cause any human disease. This review focuses on the basic properties of adeno-associated virus and its use as a vector for cystic fibrosis gene therapy.

  10. Accuracy of FibroScan for diagnosing liver fibrosis

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    Jian ZHANG

    2011-11-01

    Full Text Available Objective To evaluate the accuracy of transient elastometry(FibroScan for the detection of liver fibrosis.Methods A total of 323 patients diagnosed with chronic liver disease based on pathological examination in the 302 Hospital of the People’s Liberation Army from April to December of 2009 were involved in the current study.Among them,141 patients were subjected to liver biopsy.Their liver function,coagulant index,B-ultrasound and blood cell count were examined clinically.Four examinations related to liver fibrosis were done on some of the patients.Meanwhile,FibroScan was used for liver stiffness measurement(LSM of every patient.The correlation between liver stiffness and the serologic index and liver fibrosis degree was analyzed.The Receive Operating Characteristic(ROC curve was adopted to analyze the accuracy of FibroScan for diagnosing liver fibrosis.Results Each serologic index was significantly correlated with liver stiffness(P < 0.001,and liver stiffness was closely related to the stage of liver fibrosis(r=0.74,P < 0.001.The statistical results of the 141 patients who underwent pathologic examination show that the areas under the ROC curve were 0.97(0.94,1.00 for patients with portal fibrosis(F1,0.96(0.93,0.99 for patients with significant fibrosis(F2,0.99(0.98,1.00 for patients with severe fibrosis(F3,and 0.97(0.94,0.99 for patients with cirrhosis(F4.The cutoff values were 4.4KPa,6.8KPa,9.7KPa,and 10.0KPa,respectively.Conclusion FibroScan is valuable for the diagnosis of liver fibrosis.It can be used as the basis for follow-up and management of patients with chronic liver diseases.

  11. Oral submucous fibrosis: An update on current theories of pathogenesis

    NARCIS (Netherlands)

    Arakeri, G.; Rai, K.K.; Hunasgi, S.; Merkx, M.A.W.; Gao, S.; Brennan, P.A.

    2017-01-01

    Over the last 40 years, many theories linking oral submucous fibrosis (OSMF) to various risk factors have been proposed. Spicy, pungent foods and irritants such as supari (areca nut), paan (betel leaves), tobacco (through chewing or smoking)-the common Asian habits of chewing the aforementioned

  12. MFAP4: a candidate biomarker for hepatic and pulmonary fibrosis?

    Science.gov (United States)

    Mölleken, Christian; Poschmann, Gereon; Bonella, Francesco; Costabel, Ulrich; Sitek, Barbara; Stühler, Kai; Meyer, Helmut E; Schmiegel, Wolff H; Marcussen, Niels; Helmer, Michael; Nielsen, Ole; Hansen, Søren; Schlosser, Anders; Holmskov, Uffe; Sorensen, Grith Lykke

    2016-03-29

    Several comparable mechanisms have been identified for hepatic and pulmonary fibrosis. The human microfibrillar associated glycoprotein 4 (MFAP4), produced by activated myofibroblasts, is a ubiquitous protein playing a potential role in extracellular matrix (ECM) turnover and was recently identified as biomarker for hepatic fibrosis in hepatitis C patients. The current study aimed to evaluate serum levels of MFAP4 in patients with pulmonary fibrosis in order to test its potential as biomarker in clinical practice. A further aim was to determine whether MFAP4 deficiency in mice affects the formation of pulmonary fibrosis in the bleomycin model of lung fibrosis. 91 patients with idiopathic pulmonary fibrosis (IPF), 23 with hypersensitivity pneumonitis (HP) and 31 healthy subjects were studied. In the mouse model, C57BL/6 Mfap4+/+ and Mfap4-/- mice between 6-8 weeks of age were studied. Serum levels of MFAP4 were measured by ELISA in patients and in mice. Surfactant protein D (SP-D) and LDH were measured as comparison biomarkers in patients with pulmonary fibrosis. Morphometric assessment and the Sircol kit were used to determine the amount of collagen in the lung tissue in the mouse model. Serum levels of MFAP4 were not elevated in lung fibrosis - neither in the patients with IPF or HP nor in the animal model. Furthermore no significant correlations with pulmonary function tests of IPF patients could be found for MFAP4. MFAP4 levels were increased in BAL of bleomycin treated mice with pulmonary fibrosis. MFAP4 is not elevated in sera of patients with pulmonary fibrosis or bleomycin treated mice with pulmonary fibrosis. This may be due to different pathogenic mechanisms of liver and lung fibrogenesis. MFAP4 seems to be useful as serum biomarker for hepatic but not for lung fibrosis.

  13. Combined Pulmonary Fibrosis and Emphysema Syndrome

    Science.gov (United States)

    Rounds, Sharon I. S.

    2012-01-01

    There is increasing clinical, radiologic, and pathologic recognition of the coexistence of emphysema and pulmonary fibrosis in the same patient, resulting in a clinical syndrome known as combined pulmonary fibrosis and emphysema (CPFE) that is characterized by dyspnea, upper-lobe emphysema, lower-lobe fibrosis, and abnormalities of gas exchange. This syndrome frequently is complicated by pulmonary hypertension, acute lung injury, and lung cancer. The CPFE syndrome typically occurs in male smokers, and the mortality associated with this condition, especially if pulmonary hypertension is present, is significant. In this review, we explore the current state of the literature and discuss etiologic factors and clinical characteristics of the CPFE syndrome. PMID:22215830

  14. Cardiovascular magnetic resonance imaging to assess myocardial fibrosis in valvular heart disease.

    Science.gov (United States)

    Podlesnikar, Tomaz; Delgado, Victoria; Bax, Jeroen J

    2018-01-01

    The left ventricular (LV) remodeling process associated with significant valvular heart disease (VHD) is characterized by an increase of myocardial interstitial space with deposition of collagen and loss of myofibers. These changes occur before LV systolic function deteriorates or the patient develops symptoms. Cardiovascular magnetic resonance (CMR) permits assessment of reactive fibrosis, with the use of T1 mapping techniques, and replacement fibrosis, with the use of late gadolinium contrast enhancement. In addition, functional consequences of these structural changes can be evaluated with myocardial tagging and feature tracking CMR, which assess the active deformation (strain) of the LV myocardium. Several studies have demonstrated that CMR techniques may be more sensitive than the conventional measures (LV ejection fraction or LV dimensions) to detect these structural and functional changes in patients with severe left-sided VHD and have shown that myocardial fibrosis may not be reversible after valve surgery. More important, the presence of myocardial fibrosis has been associated with lesser improvement in clinical symptoms and recovery of LV systolic function. Whether assessment of myocardial fibrosis may better select the patients with severe left-sided VHD who may benefit from surgery in terms of LV function and clinical symptoms improvement needs to be demonstrated in prospective studies. The present review article summarizes the current status of CMR techniques to assess myocardial fibrosis and appraises the current evidence on the use of these techniques for risk stratification of patients with severe aortic stenosis or regurgitation and mitral regurgitation.

  15. [Combination of NAFLD Fibrosis Score and liver stiffness measurement for identification of moderate fibrosis stages (II & III) in non-alcoholic fatty liver disease].

    Science.gov (United States)

    Drolz, Andreas; Wehmeyer, Malte; Diedrich, Tom; Piecha, Felix; Schulze Zur Wiesch, Julian; Kluwe, Johannes

    2018-01-01

    Non-alcoholic fatty liver disease (NAFLD) has become one of the most frequent causes of chronic liver disease. Currently, therapeutic options for NAFLD patients are limited, but new pharmacologic agents are being investigated in the course of clinical trials. Because most of these studies are focusing on patients with fibrosis stages II and III (according to Kleiner), non-invasive identification of patients with intermediate fibrosis stages (II and III) is of increasing interest. Evaluation of NAFLD Fibrosis Score (NFS) and liver stiffness measurement (LSM) for prediction of fibrosis stages II/III. Patients with histologically confirmed NAFLD diagnosis were included in the study. All patients underwent a clinical and laboratory examination as well as a LSM prior to liver biopsy. Predictive value of NFS and LSM with respect to identification of fibrosis stages II/III was assessed. 134 NAFLD patients were included and analyzed. Median age was 53 (IQR 36 - 60) years, 55 patients (41 %) were female. 82 % of our patients were overweight/obese with typical aspects of metabolic syndrome. 84 patients (66 %) had liver fibrosis, 42 (50 %) advanced fibrosis. LSM and NFS correlated with fibrosis stage (r = 0.696 and r = 0.685, respectively; p stages II/III. If both criteria were met, probability of fibrosis stage II/III was 61 %. If none of the two criteria was met, chance for fibrosis stage II/III was only 6 % (negative predictive value 94 %). Combination of LSM and NFS enables identification of patients with significant probability of fibrosis stage II/III. Accordingly, these tests, especially in combination, may be a suitable screening tool for fibrosis stages II/III in NAFLD. The use of these non-invasive methods might also help to avoid unnecessary biopsies. © Georg Thieme Verlag KG Stuttgart · New York.

  16. Clinical usefulness of biochemical markers of liver fibrosis in patients with nonalcoholic fatty liver disease

    Institute of Scientific and Technical Information of China (English)

    Hiroshi Sakugawa; Fukunori Kinjo; Atsushi Saito; Tomofumi Nakayoshi; Kasen Kobashigawa; Tsuyoshi Yamashiro; Tatsuji Maeshiro; Satoru Miyagi; Joji Shiroma; Akiyo Toyama; Tomokuni Nakayoshi

    2005-01-01

    AIM: Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD), and progresses to the end stage of liver disease. Biochemical markers of liver fibrosis are strongly associated with the degree of histological liver fibrosis in patients with chronic liver disease.However, data are few on the usefulness of markers in NAFLD patients. The aim of this study was to identify better noninvasive predictors of hepatic fibrosis, with special focus on markers of liver fibrosis, type Ⅵ collagen 7S domain and hyaluronic acid.METHODS: One hundred and twelve patients with histologically proven NAFLD were studied.RESULTS: The histological stage of NAFLD correlated with several clinical and biochemical variables, the extent of hepatic fibrosis and the markers of liver fibrosis were relatively strong associated. The best cutoff values to detect NASH were assessed by using receiver operating characteristic analysis: type Ⅵ collagen 7S domain ≥5.0 ng/mL, hyaluronic acid ≥43 ng/mL. Both markers had a high positive predictive value: type Ⅵ collagen 7S domain, 86% and hyaluronic acid,92%. Diagnostic accuracies of these markers were evaluated to detect severe fibrosis. Both markers showed high negative predictive values: type Ⅵ collagen 7S domain (≥5.0 ng/mL),84% and hyaluronic acid (≥50 ng/mL), 78%, and were significantly and independently associated with the presence of NASH or severe fibrosis by logistic regression analysis.CONCLUSION: Both markers of liver fibrosis are useful in discriminating NASH from fatty liver alone or patients with severe fibrosis from patients with non-severe fibrosis.

  17. Cystic fibrosis-related diabetes: a distinct condition.

    Science.gov (United States)

    Cano Megías, Marta; González Albarrán, Olga

    2015-01-01

    Cystic fibrosis is the most common fatal inherited autosomal recessive disease in Caucasians, affecting approximately one out of every 2,000 births. Survival of patients with cystic fibrosis has significantly improved due to advances in respiratory and nutritional care, and their current average life expectancy is 30-40 years. Development of cystic fibrosis-related diabetes is a comorbidity that increases with age and may reach a prevalence up to 50% in adults. Its development is associated to impaired lung function and nutritional status, and early diagnosis and treatment are therefore essential to improve quality of life and performance status. Insulin therapy for diabetes and other early carbohydrate metabolism disorders may improve lung function and nutritional status of patients with cystic fibrosis. Copyright © 2014 SEEN. Published by Elsevier Espana. All rights reserved.

  18. Introduction to Pulmonary Fibrosis

    Science.gov (United States)

    ... page: Introduction to Pulmonary Fibrosis What Is Pulmonary Fibrosis? Pulmonary fibrosis is a disease where there is scarring ... of pulmonary fibrosis. Learn more How Is Pulmonary Fibrosis Diagnosed? Pulmonary fibrosis can be difficult to diagnose, so it ...

  19. Pulmonary Fibrosis Foundation

    Science.gov (United States)

    ... submissions. MORE We Imagine a World Without Pulmonary Fibrosis The Pulmonary Fibrosis Foundation mobilizes people and resources to provide ... its battle against the deadly lung disease, pulmonary fibrosis (PF). PULMONARY FIBROSIS WALK SURPASSES PARTICIPATION AND FUNDRAISING GOALS Nearly ...

  20. Current protocols in the management of oral submucous fibrosis: An update

    NARCIS (Netherlands)

    Arakeri, G.; Rai, K.K.; Boraks, G.; Patil, S.G.; Aljabab, A.S.; Merkx, M.A.W.; Carrozzo, M.; Brennan, P.A.

    2017-01-01

    Oral submucous fibrosis (OSMF) is a debilitating condition of oral cavity which has significant potential for malignant transformation. In spite of over 20 years of research, the pathogenesis of the condition is still obscure and no single management modality is effective. Many OSMF treatment

  1. Identification and Fibrosis Staging of Hepatitis C Patients Using the Electronic Medical Record System.

    Science.gov (United States)

    Anand, Vijay; Hyun, Christian; Khan, Qasim M; Hall, Curtis; Hessefort, Norbert; Sonnenberg, Amnon; Fimmel, Claus J

    2016-09-01

    The aim of this study was to noninvasively assess the severity of chronic hepatitis C virus (HCV) in large patient populations. It would be helpful if fibrosis scores could be calculated solely on the basis of data contained in the patients' electronic medical records (EMR). We performed a pilot study to identify all HCV-infected patients in a large health care system, and predict their fibrosis stage on the basis of demographic and laboratory data using common data from their EMR. HCV-infected patients were identified using the EMR. The liver biopsies of 191 HCV patients were graded using the Ishak and Metavir scoring systems. Demographic and laboratory data were extracted from the EMR and used to calculate the aminotransferase to platelet ratio index, Fib-4, Fibrosis Index, Forns, Göteborg University Cirrhosis Index, Lok Index, and Vira-HepC. In total, 869 HCV-infected patients were identified from a population of over 1 million. In the subgroup of patients with liver biopsies, all 7 algorithms were significantly correlated with the fibrosis stage. The degree of correlation was moderate, with correlation coefficients ranging from 0.22 to 0.60. For the detection of advanced fibrosis (Metavir 3 or 4), the areas under the receiver operating characteristic curve ranged from 0.71 to 0.84, with no significant differences between the individual scores. Sensitivities, specificities, and positive and negative predictive values were within the previously reported range. All scores tended to perform better for higher fibrosis stages. Our study demonstrates that HCV-infected patients can be identified and their fibrosis staged using commonly available EMR-based algorithms.

  2. Reversal of liver fibrosis: From fiction to reality.

    Science.gov (United States)

    Zoubek, Miguel Eugenio; Trautwein, Christian; Strnad, Pavel

    2017-04-01

    In chronic liver diseases, an ongoing hepatocellular injury together with inflammatory reaction results in activation of hepatic stellate cells (HSCs) and increased deposition of extracellular matrix (ECM) termed as liver fibrosis. It can progress to cirrhosis that is characterized by parenchymal and vascular architectural changes together with the presence of regenerative nodules. Even at late stage, liver fibrosis is reversible and the underlying mechanisms include a switch in the inflammatory environment, elimination or regression of activated HSCs and degradation of ECM. While animal models have been indispensable for our understanding of liver fibrosis, they possess several important limitations and need to be further refined. A better insight into the liver fibrogenesis resulted in a large number of clinical trials aiming at reversing liver fibrosis, particularly in patients with non-alcoholic steatohepatitis. Collectively, the current developments demonstrate that reversal of liver fibrosis is turning from fiction to reality. Copyright © 2017. Published by Elsevier Ltd.

  3. Addressing liver fibrosis with Liposomes targeted to hepatic stellate cells

    NARCIS (Netherlands)

    Adrian, Joanna E.; Poelstra, Klaas; Kamps, Jan A. A. M.

    2007-01-01

    Liver fibrosis is a chronic disease that results from hepatitis B and C infections, alcohol abuse or metabolic and genetic disorders. Ultimately, progression of fibrosis leads to cirrhosis, a stage of the disease characterized by failure of the normal liver functions. Currently, the treatment of

  4. State-of-the-art imaging of liver fibrosis and cirrhosis: A comprehensive review of current applications and future perspectives

    Directory of Open Access Journals (Sweden)

    Adrian Huber

    2015-01-01

    Conclusion: MR elastography (MRE appears to be the most reliable method for grading liver fibrosis, although the CT fibrosis score derived from the combination of caudate-to-right-lobe ratio and the diameters of the liver veins significantly correlates with the stage of fibrosis.

  5. Microengineered in vitro model of cardiac fibrosis through modulating myofibroblast mechanotransduction

    International Nuclear Information System (INIS)

    Zhao, Hui; Li, Xiaokang; Zhao, Shan; Zeng, Yang; Ding, Haiyan; Du, Yanan; Zhao, Long; Sun, Wei

    2014-01-01

    Cardiac fibrosis greatly impairs normal heart function post infarction and there is no effective anti-fibrotic drug developed at present. The current therapies for cardiac infarction mainly take effect by eliminating occlusion in coronary artery by thrombolysis drugs, vascular stent grafting or heart bypass operation, which are capable to provide sufficient blood flow for intact myocardium yet showed subtle efficacy in ameliorating fibrosis condition. The advances of in vitro cell/tissue models open new avenues for drug assessment due to the low cost, good controllability and availability as well as the convenience for operation as compared to the animal models. To our knowledge, no proper biomimetic in vitro cardiac fibrosis model has been reported yet. Here we engineered an in vitro cardiac fibrosis model using heart-derived fibroblasts, and the fibrogenesis was recapitulated by patterning the substrate rigidity which mimicked the mechanical heterogeneity of myocardium post-infarction. Various biomarkers for cardiac fibrosis were assayed to validate the biomimicry of the engineered platform. Subsequent addition of Rho-associated protein kinase (ROCK) pathway inhibitor reduced the ratio of myofibroblasts, indicating the feasibility of applying this platform in screening anti-fibrosis drugs. (paper)

  6. Laboratory Diagnosis and Characterization of Fungal Disease in Patients with Cystic Fibrosis (CF): A Survey of Current UK Practice in a Cohort of Clinical Microbiology Laboratories.

    Science.gov (United States)

    Boyle, Maeve; Moore, John E; Whitehouse, Joanna L; Bilton, Diana; Downey, Damian G

    2018-03-02

    There is much uncertainty as to how fungal disease is diagnosed and characterized in patients with cystic fibrosis (CF). A 19-question anonymous electronic questionnaire was developed and distributed to ascertain current practice in clinical microbiology laboratories providing a fungal laboratory service to CF centres in the UK. Analyses of responses identified the following: (1) current UK laboratory practice, in general, follows the current guidelines, but the scope and diversity of what is currently being delivered by laboratories far exceeds what is detailed in the guidelines; (2) there is a lack of standardization of fungal tests amongst laboratories, outside of the current guidelines; (3) both the UK CF Trust Laboratory Standards for Processing Microbiological Samples from People with Cystic Fibrosis and the US Cumulative Techniques and Procedures in Clinical Microbiology (Cumitech) Guidelines 43 Cystic Fibrosis Microbiology need to be updated to reflect both new methodological innovations, as well as better knowledge of fungal disease pathophysiology in CF; (4) there is a need for clinical medicine to decide upon a stratification strategy for the provision of new fungal assays that will add value to the physician in the optimal management of CF patients; (5) there is also a need to rationale what assays should be performed at local laboratory level and those which are best served at National Mycology Reference Laboratory level; and (6) further research is required in developing laboratory assays, which will help ascertain the clinical importance of 'old' fungal pathogens, as well as 'emerging' fungal pathogens.

  7. Enhanced liver fibrosis test using ELISA assay accurately discriminates advanced stage of liver fibrosis as determined by transient elastography fibroscan in treatment naïve chronic HCV patients.

    Science.gov (United States)

    Omran, Dalia; Yosry, Ayman; Darweesh, Samar K; Nabeel, Mohammed M; El-Beshlawey, Mohammed; Saif, Sameh; Fared, Azza; Hassany, Mohamed; Zayed, Rania A

    2018-02-01

    Evaluation of liver fibrosis stage is crucial in the assessment of chronic HCV patients, regarding decision to start treatment and during follow-up. Our aim was to assess the validity of the enhanced liver fibrosis (ELF) score in discrimination of advanced stage of liver fibrosis in naïve chronic HCV patients. We prospectively evaluated liver fibrosis stage in one hundred eighty-one naïve chronic HCV Egyptian patients by transient elastography (TE)-FibroScan. Patients were categorized into mild to moderate fibrosis (≤F2) group and advanced fibrosis (≥F3) group. The ELF score components, hyaluronic acid (HA), amino-terminal propeptide of type-III-procollagen (PIIINP) and tissue inhibitor of metalloproteinase type-1 (TIMP-1), were done using ELISA test. The mean values of ELF and its individual components significantly correlated with the hepatic fibrosis stage as measured by TE-FibroScan (P value 0.001). ELF cutoff value of 9.8 generated a sensitivity of 77.8%, specificity of 67.1%, area under the receiver operator characteristic curve (AUROC) of 0.76 with 95% confidence interval [CI] (0.68-0.83) for detecting advanced fibrosis (F ≥ 3). ELF panel is a good, reliable noninvasive test and showed comparable results to TE-FibroScan in detecting liver fibrosis stage in treatment naïve chronic HCV patients.

  8. Type IV collagen as marker of fibrosis in nonalcoholic liver disease

    Directory of Open Access Journals (Sweden)

    Alvina Alvina

    2016-02-01

    Full Text Available Currently nonalcoholic fatty liver disease (NAFLD and nonalcoholic steatohepatitis (NASH are medical problems associated with the increasing prevalence of diabetes mellitus, obesity, hypertension and hypertriglyceridemia, usually designated as the metabolic syndrome associated with insulin resistance. One study demonstrated an increase in NAFLD prevalence of around 17-33% and in NASH prevalence of 5.7-16.5%. NAFLD comprises a range of mild to severe conditions, from simple steatosis to steatohepatitis, hepatic fibrosis and cirrhosis. The diagnosis of hepatic fibrosis is important for prognosis, stratification for treatment, and monitoring of treatment efficacy. Ultrasonography (USG is a simple method for detecting fatty infiltrates in the liver. USG has a sensitivity of 82-89% and a specificity of 93%, but cannot differentiate between hepatic steatosis and fibrosis. The gold standard for evaluation of hepatic fibrosis is liver biopsy, which however is a painful and invasive procedure. Currently determination of serum type IV collagen has been suggested as an alternative to liver biopsy among the non-invasive methods for evaluation of hepatic fibrosis, as its serum concentration is closely correlated with advanced hepatic fibrosis in NASH. Type IV collagen is one of the components of basement membrane and its serum concentration is indicative of degradation of the extracellular matrix.

  9. Type IV collagen as marker of fibrosis in nonalcoholic liver disease

    Directory of Open Access Journals (Sweden)

    Alvina

    2010-08-01

    Full Text Available Currently nonalcoholic fatty liver disease (NAFLD and nonalcoholic steatohepatitis (NASH are medical problems associated with the increasing prevalence of diabetes mellitus, obesity, hypertension and hypertriglyceridemia, usually designated as the metabolic syndrome associated with insulin resistance. One study demonstrated an increase in NAFLD prevalence of around 17-33% and in NASH prevalence of 5.7-16.5%. NAFLD comprises a range of mild to severe conditions, from simple steatosis to steatohepatitis, hepatic fibrosis and cirrhosis. The diagnosis of hepatic fibrosis is important for prognosis, stratification for treatment, and monitoring of treatment efficacy. Ultrasonography (USG is a simple method for detecting fatty infiltrates in the liver. USG has a sensitivity of 82-89% and a specificity of 93%, but cannot differentiate between hepatic steatosis and fibrosis. The gold standard for evaluation of hepatic fibrosis is liver biopsy, which however is a painful and invasive procedure. Currently determination of serum type IV collagen has been suggested as an alternative to liver biopsy among the non-invasive methods for evaluation of hepatic fibrosis, as its serum concentration is closely correlated with advanced hepatic fibrosis in NASH. Type IV collagen is one of the components of basement membrane and its serum concentration is indicative of degradation of the extracellular matrix.

  10. The Processes and Mechanisms of Cardiac and Pulmonary Fibrosis

    Directory of Open Access Journals (Sweden)

    Lucy A. Murtha

    2017-10-01

    Full Text Available Fibrosis is the formation of fibrous connective tissue in response to injury. It is characterized by the accumulation of extracellular matrix components, particularly collagen, at the site of injury. Fibrosis is an adaptive response that is a vital component of wound healing and tissue repair. However, its continued activation is highly detrimental and a common final pathway of numerous disease states including cardiovascular and respiratory disease. Worldwide, fibrotic diseases cause over 800,000 deaths per year, accounting for ~45% of total deaths. With an aging population, the incidence of fibrotic disease and subsequently the number of fibrosis-related deaths will rise further. Although, fibrosis is a well-recognized cause of morbidity and mortality in a range of disease states, there are currently no viable therapies to reverse the effects of chronic fibrosis. Numerous predisposing factors contribute to the development of fibrosis. Biological aging in particular, interferes with repair of damaged tissue, accelerating the transition to pathological remodeling, rather than a process of resolution and regeneration. When fibrosis progresses in an uncontrolled manner, it results in the irreversible stiffening of the affected tissue, which can lead to organ malfunction and death. Further investigation into the mechanisms of fibrosis is necessary to elucidate novel, much needed, therapeutic targets. Fibrosis of the heart and lung make up a significant proportion of fibrosis-related deaths. It has long been established that the heart and lung are functionally and geographically linked when it comes to health and disease, and thus exploring the processes and mechanisms that contribute to fibrosis of each organ, the focus of this review, may help to highlight potential avenues of therapeutic investigation.

  11. The Role of PPARs in Lung Fibrosis

    Directory of Open Access Journals (Sweden)

    Heather F. Lakatos

    2007-01-01

    wound healing. PPARβ/δ agonists inhibit lung fibroblast proliferation and enhance the antifibrotic properties of PPARγ agonists. PPARγ ligands oppose the profibrotic effect of TGF-β, which induces differentiation of fibroblasts to myofibroblasts, a critical effector cell in fibrosis. PPARγ ligands, including the thiazolidinedione class of antidiabetic drugs, effectively inhibit lung fibrosis in vitro and in animal models. The clinical availability of potent and selective PPARα and PPARγ agonists should facilitate rapid development of successful treatment strategies based on current and ongoing research.

  12. Non-invasive Markers of Liver Fibrosis: Adjuncts or Alternatives to Liver Biopsy?

    Science.gov (United States)

    Chin, Jun L.; Pavlides, Michael; Moolla, Ahmad; Ryan, John D.

    2016-01-01

    Liver fibrosis reflects sustained liver injury often from multiple, simultaneous factors. Whilst the presence of mild fibrosis on biopsy can be a reassuring finding, the identification of advanced fibrosis is critical to the management of patients with chronic liver disease. This necessity has lead to a reliance on liver biopsy which itself is an imperfect test and poorly accepted by patients. The development of robust tools to non-invasively assess liver fibrosis has dramatically enhanced clinical decision making in patients with chronic liver disease, allowing a rapid and informed judgment of disease stage and prognosis. Should a liver biopsy be required, the appropriateness is clearer and the diagnostic yield is greater with the use of these adjuncts. While a number of non-invasive liver fibrosis markers are now used in routine practice, a steady stream of innovative approaches exists. With improvement in the reliability, reproducibility and feasibility of these markers, their potential role in disease management is increasing. Moreover, their adoption into clinical trials as outcome measures reflects their validity and dynamic nature. This review will summarize and appraise the current and novel non-invasive markers of liver fibrosis, both blood and imaging based, and look at their prospective application in everyday clinical care. PMID:27378924

  13. Familial Pulmonary Fibrosis

    Science.gov (United States)

    ... Education & Training Home Conditions Familial Pulmonary Fibrosis Familial Pulmonary Fibrosis Make an Appointment Find a Doctor Ask a ... more members within the same family have Idiopathic Pulmonary Fibrosis (IPF) or any other form of Idiopathic Interstitial ...

  14. Cystic Fibrosis-Related Diabetes

    Directory of Open Access Journals (Sweden)

    Kayani Kayani

    2018-02-01

    Full Text Available Cystic fibrosis (CF is the most common autosomal recessive disorder in Caucasian populations. Individuals with CF have seen significant increases in life expectancy in the last 60 years. As a result, previously rare complications are now coming to light. The most common of these is cystic fibrosis-related diabetes (CFRD, which affects 40–50% of CF adults. CFRD significantly impacts the pulmonary function and longevity of CF patients, yet a lack of consensus on the best methods to diagnose and treat CFRD remains. We begin by reviewing our understanding of the pathogenesis of CFRD, as emerging evidence shows the cystic fibrosis transmembrane conductance regulator (CFTR also has important roles in the release of insulin and glucagon and in the protection of β cells from oxidative stress. We then discuss how current recommended methods of CFRD diagnosis are not appropriate, as continuous glucose monitoring becomes more effective, practical, and cost-effective. Finally, we evaluate emerging treatments which have narrowed the mortality gap within the CF patient group. In the future, pharmacological potentiators and correctors directly targeting CFTR show huge promise for both CFRD and the wider CF patient groups.

  15. Serum markers of liver fibrosis

    DEFF Research Database (Denmark)

    Veidal, Sanne Skovgård; Bay-Jensen, Anne-Christine; Tougas, Gervais

    2010-01-01

    -epitopes, may be targeted for novel biochemical marker development in fibrosis. We used the recently proposed BIPED system (Burden of disease, Investigative, Prognostic, Efficacy and Diagnostic) to characterise present serological markers. METHODS: Pubmed was search for keywords; Liver fibrosis, neo......, a systematic use of the neo-epitope approach, i.e. the quantification of peptide epitopes generated from enzymatic cleavage of proteins during extracellular remodeling, may prove productive in the quest to find new markers of liver fibrosis....

  16. Non-invasive measurement of liver and pancreas fibrosis in patients with cystic fibrosis.

    Science.gov (United States)

    Friedrich-Rust, Mireen; Schlueter, Nina; Smaczny, Christina; Eickmeier, Olaf; Rosewich, Martin; Feifel, Kirstin; Herrmann, Eva; Poynard, Thierry; Gleiber, Wolfgang; Lais, Christoph; Zielen, Stefan; Wagner, Thomas O F; Zeuzem, Stefan; Bojunga, Joerg

    2013-09-01

    Patients with cystic fibrosis (CF) have a relevant morbidity and mortality caused by CF-related liver-disease. While transient elastography (TE) is an established elastography method in hepatology centers, Acoustic-Radiation-Force-Impulse (ARFI)-Imaging is a novel ultrasound-based elastography method which is integrated in a conventional ultrasound-system. The aim of the present study was to evaluate the prevalence of liver-fibrosis in patients with CF using TE, ARFI-imaging and fibrosis blood tests. 106 patients with CF were prospectively included in the present study and received ARFI-imaging of the left and right liver-lobe, ARFI of the pancreas TE of the liver and laboratory evaluation. The prevalence of liver-fibrosis according to recently published best practice guidelines for CFLD was 22.6%. Prevalence of significant liver-fibrosis assessed by TE, ARFI-right-liver-lobe, ARFI-left-liver-lobe, Fibrotest, Fibrotest-corrected-by-haptoglobin was 17%, 24%, 40%, 7%, and 16%, respectively. The best agreement was found for TE, ARFI-right-liver-lobe and Fibrotest-corrected-by-haptoglobin. Patients with pancreatic-insufficiency had significantly lower pancreas-ARFI-values as compared to patients without. ARFI-imaging and TE seem to be promising non-invasive methods for detection of liver-fibrosis in patients with CF. Copyright © 2013 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

  17. Combined pulmonary fibrosis and emphysema: an increasingly recognized condition

    Directory of Open Access Journals (Sweden)

    Olívia Meira Dias

    2014-06-01

    Full Text Available Combined pulmonary fibrosis and emphysema (CPFE has been increasingly recognized in the literature. Patients with CPFE are usually heavy smokers or former smokers with concomitant lower lobe fibrosis and upper lobe emphysema on chest HRCT scans. They commonly present with severe breathlessness and low DLCO, despite spirometry showing relatively preserved lung volumes. Moderate to severe pulmonary arterial hypertension is common in such patients, who are also at an increased risk of developing lung cancer. Unfortunately, there is currently no effective treatment for CPFE. In this review, we discuss the current knowledge of the pathogenesis, clinical characteristics, and prognostic factors of CPFE. Given that most of the published data on CPFE are based on retrospective analysis, more studies are needed in order to address the role of emphysema and its subtypes; the progression of fibrosis/emphysema and its correlation with inflammation; treatment options; and prognosis.

  18. Non-invasive assessment of liver fibrosis using two-dimensional shear wave elastography in patients with autoimmune liver diseases.

    Science.gov (United States)

    Zeng, Jie; Huang, Ze-Ping; Zheng, Jian; Wu, Tao; Zheng, Rong-Qin

    2017-07-14

    To determine the diagnostic accuracy of two-dimensional shear wave elastography (2D-SWE) for the non-invasive assessment of liver fibrosis in patients with autoimmune liver diseases (AILD) using liver biopsy as the reference standard. Patients with AILD who underwent liver biopsy and 2D-SWE were consecutively enrolled. Receiver operating characteristic (ROC) curves were constructed to assess the overall accuracy and to identify optimal cut-off values. The characteristics of the diagnostic performance were determined for 114 patients with AILD. The areas under the ROC curves for significant fibrosis, severe fibrosis, and cirrhosis were 0.85, 0.85, and 0.86, respectively, and the optimal cut-off values associated with significant fibrosis (≥ F2), severe fibrosis (≥ F3), and cirrhosis (F4) were 9.7 kPa, 13.2 kPa and 16.3 kPa, respectively. 2D-SWE showed sensitivity values of 81.7% for significant fibrosis, 83.0% for severe fibrosis, and 87.0% for cirrhosis, and the respective specificity values were 81.3%, 74.6%, and 80.2%. The overall concordance rate of the liver stiffness measurements obtained using 2D-SWE vs fibrosis stages was 53.5%. 2D-SWE showed promising diagnostic performance for assessing liver fibrosis stages and exhibited high cut-off values in patients with AILD. Low overall concordance rate was observed in the liver stiffness measurements obtained using 2D-SWE vs fibrosis stages.

  19. Growth factors in idiopathic pulmonary fibrosis: relative roles

    Directory of Open Access Journals (Sweden)

    Allen Jeremy T

    2001-11-01

    Full Text Available Abstract Treatment of idiopathic pulmonary fibrosis patients has evolved very slowly; the fundamental approach of corticosteroids alone or in combination with other immunosuppressive agents has had little impact on long-term survival. The continued use of corticosteroids is justified because of the lack of a more effective alternative. Current research indicates that the mechanisms driving idiopathic pulmonary fibrosis reflect abnormal, dysregulated wound healing within the lung, involving increased activity and possibly exaggerated responses by a spectrum of profibrogenic growth factors. An understanding of the roles of these growth factors, and the way in which they modulate events at cellular level, could lead to more targeted therapeutic strategies, improving patients' quality of life and survival.

  20. PECULIARITIES OF ENT-DAMAGE IN CHILDREN WITH CYSTIC FIBROSIS

    Directory of Open Access Journals (Sweden)

    I.V. Martynova

    2011-01-01

    Full Text Available Traditional approach to cystic fibrosis patients treatment doesn’t involve upper respiratory tract assessment, though abnormal changes — consequences of the cystic fibrosis transmembrane conductivity regulator gene mutation- do affect nasal and paranasal mucosa to the same extent. Approximately half of cystic fibrosis patients suffer from chronic rhinosinusitis and/or nasal polyposis that worsens the clinical course of already severe disease. Chronic hyperplasia in paranasal cavities can be quite extensive, recurrent and can lead to destruction of osseous walls of the cavity and of nasal septum. Thus increasing the amount of hospital admissions and and their duration. Low awareness of ENT-specialists working in polyclinics and in hospitals of ENT-pathology in cystic fibrosis patients leads to belated diagnostics, excessive manipulations, ineffective treatment, including surgery. All these lays grounds to implication of the early screening diagnostic program and development of proper treatment methods of ENT-complications of cystic fibrosis — therapeutic as well as surgical, with strict specification of indications and contraindications. Key words: cystic fibrosis, chronic rhino sinusitis, nasal polyposis. (Voprosy sovremennoi pediatrii — Current Pediatrics. — 2011; 10 (5: 49–53.

  1. Update on diagnosis and treatment of idiopathic pulmonary fibrosis

    Science.gov (United States)

    Baddini-Martinez, José; Baldi, Bruno Guedes; da Costa, Cláudia Henrique; Jezler, Sérgio; Lima, Mariana Silva; Rufino, Rogério

    2015-01-01

    Idiopathic pulmonary fibrosis is a type of chronic fibrosing interstitial pneumonia, of unknown etiology, which is associated with a progressive decrease in pulmonary function and with high mortality rates. Interest in and knowledge of this disorder have grown substantially in recent years. In this review article, we broadly discuss distinct aspects related to the diagnosis and treatment of idiopathic pulmonary fibrosis. We list the current diagnostic criteria and describe the therapeutic approaches currently available, symptomatic treatments, the action of new drugs that are effective in slowing the decline in pulmonary function, and indications for lung transplantation. PMID:26578138

  2. Update on diagnosis and treatment of idiopathic pulmonary fibrosis

    Directory of Open Access Journals (Sweden)

    José Baddini-Martinez

    2015-10-01

    Full Text Available Idiopathic pulmonary fibrosis is a type of chronic fibrosing interstitial pneumonia, of unknown etiology, which is associated with a progressive decrease in pulmonary function and with high mortality rates. Interest in and knowledge of this disorder have grown substantially in recent years. In this review article, we broadly discuss distinct aspects related to the diagnosis and treatment of idiopathic pulmonary fibrosis. We list the current diagnostic criteria and describe the therapeutic approaches currently available, symptomatic treatments, the action of new drugs that are effective in slowing the decline in pulmonary function, and indications for lung transplantation.

  3. Nephrogenic systemic fibrosis

    DEFF Research Database (Denmark)

    Marckmann, Peter; Skov, Lone; Rossen, Kristian

    2006-01-01

    Nephrogenic systemic fibrosis is a new, rare disease of unknown cause that affects patients with renal failure. Single cases led to the suspicion of a causative role of gadodiamide that is used for magnetic resonance imaging. This study therefore reviewed all of the authors' confirmed cases...... of nephrogenic systemic fibrosis (n = 13) with respect to clinical characteristics, gadodiamide exposure, and subsequent clinical course. It was found that all had been exposed to gadodiamide before the development of nephrogenic systemic fibrosis. The delay from exposure to first sign of the disease was 2 to 75...... d (median 25 d). Odds ratio for acquiring the disease when gadodiamide exposed was 32.5 (95% confidence interval 1.9 to 549.2; P

  4. Ursodeoxycholic acid for cystic fibrosis-related liver disease.

    Science.gov (United States)

    Cheng, Katharine; Ashby, Deborah; Smyth, Rosalind L

    2017-09-11

    Abnormal biliary secretion leads to the thickening of bile and the formation of plugs within the bile ducts; the consequent obstruction and abnormal bile flow ultimately results in the development of cystic fibrosis-related liver disease. This condition peaks in adolescence with up to 20% of adolescents with cystic fibrosis developing chronic liver disease. Early changes in the liver may ultimately result in end-stage liver disease with people needing transplantation. One therapeutic option currently used is ursodeoxycholic acid. This is an update of a previous review. To analyse evidence that ursodeoxycholic acid improves indices of liver function, reduces the risk of developing chronic liver disease and improves outcomes in general in cystic fibrosis. We searched the Cochrane CF and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. We also contacted drug companies and searched online trial registries.Date of the most recent search of the Group's trials register: 09 April 2017. Randomised controlled trials of the use of ursodeoxycholic acid for at least three months compared with placebo or no additional treatment in people with cystic fibrosis. Two authors independently assessed trial eligibility and quality. The authors used GRADE to assess the quality of the evidence. Twelve trials have been identified, of which four trials involving 137 participants were included; data were only available from three of the trials (118 participants) since one cross-over trial did not report appropriate data. The dose of ursodeoxycholic acid ranged from 10 to 20 mg/kg/day for up to 12 months. The complex design used in two trials meant that data could only be analysed for subsets of participants. There was no significant difference in weight change, mean difference -0.90 kg (95% confidence interval -1.94 to 0.14) based on 30

  5. Pulmonary fibrosis

    International Nuclear Information System (INIS)

    Yamakido, Michio; Okuzaki, Takeshi

    1992-01-01

    When the chest is exposed to x radiation and Co-60 gamma radiation, radiation damage may occur in the lungs 2 to 10 weeks after irradiation. This condition is generally referred to as radiation pneumonitis, with the incidence ranging from 5.4% to 91.8% in the literature. Then radiation pneumonitis may develop into pulmonary fibrosis associated with roentgenologically diffuse linear and ring-like shadows and strong contraction 6 months to one year after irradiation. Until recently, little attention has been paid to pulmonary pneumonitis as a delayed effect of A-bomb radiation. The recent study using the population of 9,253 A-bomb survivors have suggested that the prevalence of pulmonary fibrosis tended to be high in heavily exposed A-bomb survivors. Two other studies using the cohort of 16,956 and 42,728 A-bomb survivors, respectively, have shown that the prevalence of roentgenologically proven pulmonary fibrosis was higher in men than women (1.82% vs 0.41%), was increased with aging and had a higher tendency in heavily exposed A-bomb survivors. (N.K.)

  6. Smoking-related emphysema is associated with idiopathic pulmonary fibrosis and rheumatoid lung.

    Science.gov (United States)

    Antoniou, Katerina M; Walsh, Simon L; Hansell, David M; Rubens, Michael R; Marten, Katharina; Tennant, Rachel; Hansel, Trevor; Desai, Sujal R; Siafakas, Nikolaos M; du Bois, Roland M; Wells, Athol U

    2013-11-01

    A combined pulmonary fibrosis/emphysema syndrome has been proposed, but the basis for this syndrome is currently uncertain. The aim was to evaluate the prevalence of emphysema in idiopathic pulmonary fibrosis (IPF) and rheumatoid lung (rheumatoid arthritis-interstitial lung disease (RA-ILD)), and to compare the morphological features of lung fibrosis between smokers and non-smokers. Using high-resolution computed tomography, the prevalence of emphysema and the pack-year smoking histories associated with emphysema were compared between current/ex-smokers with IPF (n = 186) or RA-ILD (n = 46), and non-chronic obstructive pulmonary disease (COPD) controls (n = 103) and COPD controls (n = 34). The coarseness of fibrosis was compared between smokers and non-smokers. Emphysema, present in 66/186 (35%) patients with IPF and 22/46 (48%) smokers with RA-ILD, was associated with lower pack-year smoking histories than in control groups (P emphysema in IPF was positively linked to the pack-year smoking history (odds ratio 1.04, 95% confidence interval (CI) 1.02-1.06, P emphysema but did not differ significantly between smokers and non-smokers. In IPF and RA-ILD, a high prevalence of concurrent emphysema, in association with low pack-year smoking histories, and an association between coarser pulmonary fibrosis and a history of smoking in IPF together provide support for possible pathogenetic linkage to smoking in both diseases. © 2013 The Authors. Respirology © 2013 Asian Pacific Society of Respirology.

  7. Automated biphasic morphological assessment of hepatitis B-related liver fibrosis using second harmonic generation microscopy

    Science.gov (United States)

    Wang, Tong-Hong; Chen, Tse-Ching; Teng, Xiao; Liang, Kung-Hao; Yeh, Chau-Ting

    2015-08-01

    Liver fibrosis assessment by biopsy and conventional staining scores is based on histopathological criteria. Variations in sample preparation and the use of semi-quantitative histopathological methods commonly result in discrepancies between medical centers. Thus, minor changes in liver fibrosis might be overlooked in multi-center clinical trials, leading to statistically non-significant data. Here, we developed a computer-assisted, fully automated, staining-free method for hepatitis B-related liver fibrosis assessment. In total, 175 liver biopsies were divided into training (n = 105) and verification (n = 70) cohorts. Collagen was observed using second harmonic generation (SHG) microscopy without prior staining, and hepatocyte morphology was recorded using two-photon excitation fluorescence (TPEF) microscopy. The training cohort was utilized to establish a quantification algorithm. Eleven of 19 computer-recognizable SHG/TPEF microscopic morphological features were significantly correlated with the ISHAK fibrosis stages (P 0.82 for liver cirrhosis detection. Since no subjective gradings are needed, interobserver discrepancies could be avoided using this fully automated method.

  8. Impact of a CXCL12/CXCR4 Antagonist in Bleomycin (BLM Induced Pulmonary Fibrosis and Carbon Tetrachloride (CCl4 Induced Hepatic Fibrosis in Mice.

    Directory of Open Access Journals (Sweden)

    Leola N Chow

    Full Text Available Modulation of chemokine CXCL12 and its receptor CXCR4 has been implicated in attenuation of bleomycin (BLM-induced pulmonary fibrosis and carbon tetrachloride (CCl4-induced hepatic injury. In pulmonary fibrosis, published reports suggest that collagen production in the injured lung is derived from fibrocytes recruited from the circulation in response to release of pulmonary CXCL12. Conversely, in hepatic fibrosis, resident hepatic stellate cells (HSC, the key cell type in progression of fibrosis, upregulate CXCR4 expression in response to activation. Further, CXCL12 induces HSC proliferation and subsequent production of collagen I. In the current study, we evaluated AMD070, an orally bioavailable inhibitor of CXCL12/CXCR4 in alleviating BLM-induced pulmonary and CCl4-induced hepatic fibrosis in mice. Similar to other CXCR4 antagonists, treatment with AMD070 significantly increased leukocyte mobilization. However, in these two models of fibrosis, AMD070 had a negligible impact on extracellular matrix deposition. Interestingly, our results indicated that CXCL12/CXCR4 signaling has a role in improving mortality associated with BLM induced pulmonary injury, likely through dampening an early inflammatory response and/or vascular leakage. Together, these findings indicate that the CXCL12-CXCR4 signaling axis is not an effective target for reducing fibrosis.

  9. Diagnosis of cystic fibrosis

    NARCIS (Netherlands)

    H.J. Veeze

    1995-01-01

    textabstractApplying the sweat-test as the first choice of test when a diagnosis of cystic fibrosis is suspected is still common practice and advisable. Since the cloning of the CFTR gene more than 400 different cystic fibrosis (CF) mutations have already been identified. The use of CF mutation

  10. Breakthrough Therapies: Cystic Fibrosis (CF) Potentiators and Correctors

    Science.gov (United States)

    Solomon, George M.; Marshall, Susan G.; Ramsey, Bonnie W.; Rowe, Steven M.

    2015-01-01

    Cystic Fibrosis is caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene resulting in abnormal protein function. Recent advances of targeted molecular therapies and high throughput screening have resulted in multiple drug therapies that target many important mutations in the CFTR protein. In this review, we provide the latest results and current progress of CFTR modulators for the treatment of cystic fibrosis, focusing on potentiators of CFTR channel gating and Phe508del processing correctors for the Phe508del CFTR mutation. Special emphasis is placed on the molecular basis underlying these new therapies and emerging results from the latest clinical trials. The future directions for augmenting the rescue of Phe508del with CFTR modulators is also emphasized. PMID:26097168

  11. Diagnostic Usefulness of Real-Time Elastography for Liver Fibrosis in Chronic Viral Hepatitis B and C

    Directory of Open Access Journals (Sweden)

    Young Woon Kim

    2014-01-01

    Full Text Available The aim of this study was to investigate the diagnostic usefulness of real-time elastography (RTE for liver fibrosis in chronic viral hepatitis B (CHB and C (CHC. Fifty-one and thirty-two of the patients were diagnosed with CHB and CHC, respectively. Enrolled patients underwent liver biopsy and RTE. The FIB-4 index and aspartate transaminase-to-platelet ratio index (APRI were also measured. The liver fibrosis index (LFI by RTE increased significantly with the Knodell fibrosis stage: 3.14±0.62 for F0, 3.28 ± 0.42 for F1, 3.43 ± 0.53 for F3, and 4.09 ± 1.03 for F4 (P=0.000. LFI as well as APRI, FIB-4, platelet, albumin, and prothrombin time showed the difference in patients with advanced fibrosis (≥F3 and those with mild fibrosis (≤F1. In addition, RTE had better discrimination power between ≥F3 and F4 than between FIB-4 and APRI. In CHC patients, the area under receiver operating characteristic curves of RTE for advanced fibrosis was higher than that in CHB patients (0.795 versus 0.641. RTE is useful for the assessment of advanced fibrosis in patients with CHB and CHC and has better discrimination power than other serologic markers.

  12. An ROC study detecting ability of idiopathic pulmonary fibrosis using digital radiography

    International Nuclear Information System (INIS)

    Chung, Eun Chul; Im, Jung Gi; Han, Man Chung; Kim, Jong Hyo

    1991-01-01

    One potential advantage of the digital radiography system is its ability to enhance image quality by various types of processing. Digital unsharp masking is one of the simplest and most useful forms of enhancing processes. The efficacy of unsharp masking in radiological diagnosis has not been investigated thoroughly. To evaluate the effects of unsharp masking in film-digital chest images, 3 observers were shown 150 test radiographs. These test radiographs consisted of 50 unprocessed images (25 normals and 25 patients with idiopathic pulmonary fibrosis with honey combing) and their 100 processed images by using 450 and 15-sized masks respectively. An ROC analysis of these data suggests that unsharp masking is more effective in detecting idiopathic pulmonary fibrosis than unprocessed image (ρ < 0.05), and so it may improve diagnostic accuracy for interstitial fibrosis. In addition, the smaller mask size (15) is more effective than the larger one (mask size 45) (ρ < 0.05). By using this analytic approach, an optimal parameter in digital chest radiography may be investigated in many other forms of pulmonary disease such as pulmonary nodule or mediastinal mass

  13. An ROC study detecting ability of idiopathic pulmonary fibrosis using digital radiography

    Energy Technology Data Exchange (ETDEWEB)

    Chung, Eun Chul; Im, Jung Gi; Han, Man Chung; Kim, Jong Hyo [College of Medicine, Ewha Womens University, Seoul (Korea, Republic of)

    1991-03-15

    One potential advantage of the digital radiography system is its ability to enhance image quality by various types of processing. Digital unsharp masking is one of the simplest and most useful forms of enhancing processes. The efficacy of unsharp masking in radiological diagnosis has not been investigated thoroughly. To evaluate the effects of unsharp masking in film-digital chest images, 3 observers were shown 150 test radiographs. These test radiographs consisted of 50 unprocessed images (25 normals and 25 patients with idiopathic pulmonary fibrosis with honey combing) and their 100 processed images by using 450 and 15-sized masks respectively. An ROC analysis of these data suggests that unsharp masking is more effective in detecting idiopathic pulmonary fibrosis than unprocessed image ({rho} < 0.05), and so it may improve diagnostic accuracy for interstitial fibrosis. In addition, the smaller mask size (15) is more effective than the larger one (mask size 45) ({rho} < 0.05). By using this analytic approach, an optimal parameter in digital chest radiography may be investigated in many other forms of pulmonary disease such as pulmonary nodule or mediastinal mass.

  14. Cystic Fibrosis (CF): Chloride Sweat Test

    Science.gov (United States)

    ... on this topic for: Parents Kids Teens Cystic Fibrosis Cystic Fibrosis and Nutrition Cystic Fibrosis (CF) Respiratory Screen: Sputum Cystic Fibrosis: Diet and Nutrition Cystic Fibrosis Cystic Fibrosis: Diet and Nutrition View more Partner Message ...

  15. Cystic fibrosis chronic rhinosinusitis: A comprehensive review

    Science.gov (United States)

    Chaaban, Mohamad R.; Kejner, Alexandra; Rowe, Steven M.

    2013-01-01

    Background: Advances in the care of patients with cystic fibrosis (CF) have improved pulmonary outcomes and survival. In addition, rapid developments regarding the underlying genetic and molecular basis of the disease have led to numerous novel targets for treatment. However, clinical and basic scientific research focusing on therapeutic strategies for CF-associated chronic rhinosinusitis (CRS) lags behind the evidence-based approaches currently used for pulmonary disease. Methods: This review evaluates the available literature and provides an update concerning the pathophysiology, current treatment approaches, and future pharmaceutical tactics in the management of CRS in patients with CF. Results: Optimal medical and surgical strategies for CF CRS are lacking because of a dearth of well-performed clinical trials. Medical and surgical interventions are supported primarily by level 2 or 3 evidence and are aimed at improving clearance of mucus, infection, and inflammation. A number of novel therapeutics that target the basic defect in the cystic fibrosis transmembrane conductance regulator channel are currently under investigation. Ivacaftor, a corrector of the G551D mutation, was recently approved by the Food and Drug Administration. However, sinonasal outcomes using this and other novel drugs are pending. Conclusion: CRS is a lifelong disease in CF patients that can lead to substantial morbidity and decreased quality of life. A multidisciplinary approach will be necessary to develop consistent and evidence-based treatment paradigms. PMID:24119602

  16. The pathogenesis of bleomycin-induced lung injury in animals and its applicability to human idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Williamson, James D; Sadofsky, Laura R; Hart, Simon P

    2015-03-01

    Idiopathic pulmonary fibrosis (IPF) is a devastating disease of unknown etiology, for which there is no curative pharmacological therapy. Bleomycin, an anti-neoplastic agent that causes lung fibrosis in human patients has been used extensively in rodent models to mimic IPF. In this review, we compare the pathogenesis and histological features of human IPF and bleomycin-induced pulmonary fibrosis (BPF) induced in rodents by intratracheal delivery. We discuss the current understanding of IPF and BPF disease development, from the contribution of alveolar epithelial cells and inflammation to the role of fibroblasts and cytokines, and draw conclusions about what we have learned from the intratracheal bleomycin model of lung fibrosis.

  17. The role of anaerobic bacteria in the cystic fibrosis airway.

    Science.gov (United States)

    Sherrard, Laura J; Bell, Scott C; Tunney, Michael M

    2016-11-01

    Anaerobic bacteria are not only normal commensals, but are also considered opportunistic pathogens and have been identified as persistent members of the lower airway community in people with cystic fibrosis of all ages and stages of disease. Currently, the role of anaerobic bacteria in cystic fibrosis lower airway disease is not well understood. Therefore, this review describes the recent studies relating to the potential pathophysiological role(s) of anaerobes within the cystic fibrosis lungs. The most frequently identified anaerobic bacteria in the lower airways are common to both cystic fibrosis and healthy lungs. Studies have shown that in cystic fibrosis, the relative abundance of anaerobes fluctuates in the lower airways with reduced lung function and increased inflammation associated with a decreased anaerobic load. However, anaerobes found within the lower airways also produce virulence factors, may cause a host inflammatory response and interact synergistically with recognized pathogens. Anaerobic bacteria are potentially members of the airway microbiota in health but could also contribute to the pathogenesis of lower airway disease in cystic fibrosis via both direct and indirect mechanisms. A personalized treatment strategy that maintains a normal microbial community may be possible in the future.

  18.  Usefulness of acoustic radiation force impulse and fibrotest in liver fibrosis assessment after liver transplant.

    Science.gov (United States)

    Bignulin, Sara; Falleti, Edmondo; Cmet, Sara; Cappello, Dario; Cussigh, Annarosa; Lenisa, Ilaria; Dissegna, Denis; Pugliese, Fabio; Vivarelli, Cinzia; Fabris, Carlo; Fabris, Carlo; Toniutto, Pierluigi

    2016-01-01

     Background and rationale. Acoustic radiation force impulse (ARFI) is a non-invasive tool used in the evaluation of liver fibrosis in HCV positive immune-competent patients. This study aimed to assess the accuracy of ARFI in discriminating liver transplanted patients with different graft fibrosis severity and to verify whether ARFI, eventually combined with non-invasive biochemical tests, could spare liver biopsies. This prospective study included 51 HCV positive liver transplanted patients who consecutively underwent to annual liver biopsy concomitantly with ARFI and blood chemistry tests measurements needed to calculate several non-invasive liver fibrosis tests. Overall ARFI showed an AUC of 0.885 in discriminating between patients without or with significant fibrosis (Ishak score 0-2vs. 3-6). Using a cut-off of 1.365 m/s, ARFI possesses a negative predictive value of 100% in identifying patients without significant fibrosis. AUC for Fibrotest was 0.848 in discriminating patients with Ishak fibrosis score 0-2 vs. 3-6. The combined assessment of ARFI and Fibro-test did not improve the results obtained by ARFI alone. ARFI measurement in HCV positive liver transplanted patients can be considered an easy and accurate non-invasive tool in identify patients with a benign course of HCV recurrence.

  19. Cystic Fibrosis Related Liver Disease—Another Black Box in Hepatology

    Directory of Open Access Journals (Sweden)

    Katharina Staufer

    2014-08-01

    Full Text Available Due to improved medical care, life expectancy in patients with cystic fibrosis (CF has veritably improved over the last decades. Importantly, cystic fibrosis related liver disease (CFLD has become one of the leading causes of morbidity and mortality in CF patients. However, CFLD might be largely underdiagnosed and diagnostic criteria need to be refined. The underlying pathomechanisms are largely unknown, and treatment strategies with proven efficacy are lacking. This review focuses on current invasive and non-invasive diagnostic standards, the current knowledge on the pathophysiology of CFLD, treatment strategies, and possible future developments.

  20. Relaxin suppresses atrial fibrillation in aged rats by reversing fibrosis and upregulating Na+ channels.

    Science.gov (United States)

    Henry, Brian L; Gabris, Beth; Li, Qiao; Martin, Brian; Giannini, Marianna; Parikh, Ashish; Patel, Divyang; Haney, Jamie; Schwartzman, David S; Shroff, Sanjeev G; Salama, Guy

    2016-04-01

    Atrial fibrillation (AF) contributes significantly to morbidity and mortality in elderly patients and has been correlated with enhanced age-dependent atrial fibrosis. Reversal of atrial fibrosis has been proposed as therapeutic strategy to suppress AF. To test the ability of relaxin to reverse age-dependent atrial fibrosis and suppress AF. Aged F-344 rats (24 months old) were treated with subcutaneous infusion of vehicle or relaxin (0.4 mg/kg/day) for 2 weeks. Rat hearts were excised, perfused on a Langendorff apparatus, and stained with voltage and Ca(2+) indicator dyes. Optical mapping and programmed electrical stimulation was used to test arrhythmia vulnerability and changes in electrophysiological characteristics. Changes in protein expression and Na(+) current density (INa) were measured by tissue immunofluorescence and whole-cell patch clamp technique. In aged rats, sustained AF was readily induced with a premature pulse (n = 7/8) and relaxin treatment suppressed sustained AF by a premature impulse or burst pacing (n = 1/6) (P atrial action potential conduction velocity and decreased atrial fibrosis. Relaxin treatment increased Nav1.5 expression (n = 6; 36% ± 10%) and decreased total collagen and collagen I (n = 5-6; 55%-66% ± 15%) in aged atria (P atrial INa by 46% ± 4% (n = 12-13/group, P atrial conduction velocity by decreasing atrial fibrosis and increasing INa. These data provide compelling evidence that relaxin may serve as an effective therapy to manage AF in geriatric patients by reversing fibrosis and modulating cardiac ionic currents. Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

  1. A stepwise algorithm using an at-a-glance first-line test for the non-invasive diagnosis of advanced liver fibrosis and cirrhosis.

    Science.gov (United States)

    Boursier, Jérôme; de Ledinghen, Victor; Leroy, Vincent; Anty, Rodolphe; Francque, Sven; Salmon, Dominique; Lannes, Adrien; Bertrais, Sandrine; Oberti, Frederic; Fouchard-Hubert, Isabelle; Calès, Paul

    2017-06-01

    Chronic liver diseases (CLD) are common, and are therefore mainly managed by non-hepatologists. These physicians lack access to the best non-invasive tests of liver fibrosis, and consequently cannot accurately determine the disease severity. Referral to a hepatologist is then needed. We aimed to implement an algorithm, comprising a new first-line test usable by all physicians, for the detection of advanced liver fibrosis in all CLD patients. Diagnostic study: 3754 CLD patients with liver biopsy were 2:1 randomized into derivation and validation sets. Prognostic study: longitudinal follow-up of 1275 CLD patients with baseline fibrosis tests. Diagnostic study: the easy liver fibrosis test (eLIFT), an "at-a-glance" sum of points attributed to age, gender, gamma-glutamyl transferase, aspartate aminotransferase (AST), platelets and prothrombin time, was developed for the diagnosis of advanced fibrosis. In the validation set, eLIFT and fibrosis-4 (FIB4) had the same sensitivity (78.0% vs. 76.6%, p=0.470) but eLIFT gave fewer false positive results, especially in patients ≥60years old (53.8% vs. 82.0%, ptest. FibroMeter with vibration controlled transient elastography (VCTE) was the most accurate among the eight fibrosis tests evaluated. The sensitivity of the eLIFT-FM VCTE algorithm (first-line eLIFT, second-line FibroMeter VCTE ) was 76.1% for advanced fibrosis and 92.1% for cirrhosis. Prognostic study: patients diagnosed as having "no/mild fibrosis" by the algorithm had excellent liver-related prognosis with thus no need for referral to a hepatologist. The eLIFT-FM VCTE algorithm extends the detection of advanced liver fibrosis to all CLD patients and reduces unnecessary referrals of patients without significant CLD to hepatologists. Blood fibrosis tests and transient elastography accurately diagnose advanced liver fibrosis in the large population of patients having chronic liver disease, but these non-invasive tests are only currently available in specialized

  2. Vitamin A supplementation for cystic fibrosis.

    Science.gov (United States)

    Bonifant, Catherine M; Shevill, Elizabeth; Chang, Anne B

    2014-05-14

    People with cystic fibrosis and pancreatic insufficiency are at risk of fat soluble vitamin deficiency as these vitamins (A, D, E and K) are co-absorbed with fat. Thus, some cystic fibrosis centres routinely administer these vitamins as supplements but the centres vary in their approach of addressing the possible development of deficiencies in these vitamins. Vitamin A deficiency causes predominantly eye and skin problems while supplementation of vitamin A to excessive levels may cause harm to the respiratory and skeletal systems in children. Thus a systematic review on vitamin A supplementation in people with cystic fibrosis would help guide clinical practice. To determine if vitamin A supplementation in children and adults with cystic fibrosis:1. reduces the frequency of vitamin A deficiency disorders;2. improves general and respiratory health;3. increases the frequency of vitamin A toxicity. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of the most recent search of the Group's Cystic Fibrosis Trials Register: 07 April 2014. All randomised or quasi-randomised controlled trials comparing all preparations of oral vitamin A used as a supplement compared to either no supplementation (or placebo) at any dose and for any duration, in children or adults with cystic fibrosis (defined by sweat tests or genetic testing) with and without pancreatic insufficiency. No relevant studies for inclusion were identified in the search. No studies were included in this review. As there were no randomised or quasi-randomised controlled trials identified, we cannot draw any conclusions on the benefits (or otherwise) of regular administration of vitamin A in people with cystic fibrosis. Until further data are available, country or region specific guidelines on the use of

  3. CYSTIC FIBROSIS: MICROBIOLOGY AND HOST RESPONSE

    Science.gov (United States)

    Zemanick, Edith T.

    2016-01-01

    THE EARLIEST DESCRIPTIONS OF LUNG DISEASE IN PEOPLE WITH CYSTIC FIBROSIS (CF) DEMONSTRATED THE INVOLVEMENT OF THREE INTERACTING PATHOPHYSIOLOGICAL ELEMENTS IN CF AIRWAYS: MUCUS OBSTRUCTION, INFLAMMATION, AND INFECTION. OVER THE PAST 7 DECADES, OUR UNDERSTANDING OF CF RESPIRATORY MICROBIOLOGY AND INFLAMMATION HAS EVOLVED WITH THE INTRODUCTION OF NEW TREATMENTS, WITH INCREASED LONGEVITY, AND WITH INCREASINGLY SOPHISTICATED LABORATORY TECHNIQUES. IN THIS CHAPTER, WE WILL REVIEW THE CURRENT STATE OF UNDERSTANDING OF THE ROLES OF INFECTION AND INFLAMMATION AND THEIR ROLES IN DRIVING LUNG DISEASE. WE WILL ALSO DISCUSS HOW THIS CONSTANTLY EVOLVING INFORMATION IS USED TO INFORM CURRENT THERAPEUTIC STRATEGIES, MEASURES AND PREDICTORS OF DISEASE SEVERITY, AND RESEARCH PRIORITIES. PMID:27469179

  4. The pediatric NAFLD fibrosis index: a predictor of liver fibrosis in children with non-alcoholic fatty liver disease

    Directory of Open Access Journals (Sweden)

    Pietrobattista Andrea

    2009-05-01

    Full Text Available Abstract Background Liver fibrosis is a stage of non-alcoholic fatty liver disease (NAFLD which is responsible for liver-related morbidity and mortality in adults. Accordingly, the search for non-invasive markers of liver fibrosis has been the subject of intensive efforts in adults with NAFLD. Here, we developed a simple algorithm for the prediction of liver fibrosis in children with NAFLD followed at a tertiary care center. Methods The study included 136 male and 67 female children with NAFLD aged 3.3 to 18.0 years; 141 (69% of them had fibrosis at liver biopsy. On the basis of biological plausibility, readily availability and evidence from adult studies, we evaluated the following potential predictors of liver fibrosis at bootstrapped stepwise logistic regression: gender, age, body mass index, waist circumference, alanine transaminase, aspartate transaminase, gamma-glutamyl-transferase, albumin, prothrombin time, glucose, insulin, triglycerides and cholesterol. A final model was developed using bootstrapped logistic regression with bias-correction. We used this model to develop the 'pediatric NAFLD fibrosis index' (PNFI, which varies between 0 and 10. Results The final model was based on age, waist circumference and triglycerides and had a area under the receiver operating characteristic curve of 0.85 (95% bootstrapped confidence interval (CI with bias correction 0.80 to 0.90 for the prediction of liver fibrosis. A PNFI ≥ 9 (positive likelihood ratio = 28.6, 95% CI 4.0 to 201.0; positive predictive value = 98.5, 95% CI 91.8 to 100.0 could be used to rule in liver fibrosis without performing liver biopsy. Conclusion PNFI may help clinicians to predict liver fibrosis in children with NAFLD, but external validation is needed before it can be employed for this purpose.

  5. Cystic fibrosis: case report

    International Nuclear Information System (INIS)

    Park, Si Hyun; Lee, Hyun Ju; Kim, Ji Hye; Park, Chol Heui

    2002-01-01

    Cystic fibrosis is an autosomal recessive genetic disease. Among Caucasians, it is the most common cause of pulmonary insufficiency during the first three decades of life. The prevalence of cystic fibrosis varies according to ethnic origin: it is common among Caucasians but rare among Asians. We report a case in which cystic fibrosis with bronchiectasis and hyperaeration was revealed by high-resolution CT, and mutation of the cystic fibrosis conductance transmembrane regulator gene (CFTR) by DNA analysis

  6. Cystic fibrosis: case report

    International Nuclear Information System (INIS)

    Park, Si Hyun; Lee, Hyun Ju; Kim, Ji Hye; Park, Chol Heui

    2002-01-01

    Cystic fibrosis is a autosomal recessive genetic disease. Among caucasians, it is the most common cause of pulmonary insufficiency during the first three decades of life. The prevalence of cystic fibrosis varies according to ethnic origin: it is common among caucasians but rare among Asians. We report a case in which cystic fibrosis with bronchiectasis and hyperaeration was revealed by high-resolution CT, and mutation of the cystic fibrosis conductance transmembrane regulator gene (CFTR) by DNA analysis

  7. A single blood test adjusted for different liver fibrosis targets improves fibrosis staging and especially cirrhosis diagnosis.

    Science.gov (United States)

    Calès, Paul; Boursier, Jérôme; Oberti, Frédéric; Moal, Valérie; Fouchard Hubert, Isabelle; Bertrais, Sandrine; Hunault, Gilles; Rousselet, Marie Christine

    2018-04-01

    Fibrosis blood tests are usually developed using significant fibrosis, which is a unique diagnostic target; however, these tests are employed for other diagnostic targets, such as cirrhosis. We aimed to improve fibrosis staging accuracy by simultaneously targeting biomarkers for several diagnostic targets. A total of 3,809 patients were included, comprising 1,012 individuals with chronic hepatitis C (CHC) into a derivation population and 2,797 individuals into validation populations of different etiologies (CHC, chronic hepatitis B, human immunodeficiency virus/CHC, nonalcoholic fatty liver disease, alcohol) using Metavir fibrosis stages as reference. FibroMeter biomarkers were targeted for different fibrosis-stage combinations into classical scores by logistic regression. Independent scores were combined into a single score reflecting Metavir stages by linear regression and called Multi-FibroMeter Version Second Generation (V2G). The primary objective was to combine the advantages of a test targeted for significant fibrosis (FibroMeter V2G ) with those of a test targeted for cirrhosis (CirrhoMeter V2G ). In the derivation CHC population, we first compared Multi-FibroMeter V2G to FibroMeter V2G and observed significant increases in the cirrhosis area under the receiver operating characteristic curve (AUROC), Obuchowski index (reflecting all fibrosis-stage AUROCs), and classification metric (six classes expressed as a correctly classified percentage) and a nonsignificant increase in significant fibrosis AUROC. Thereafter, we compared it to CirroMeter V2G and observed a nonsignificant increase in the cirrhosis AUROC. In all 3,809 patients, respective accuracies for Multi-FibroMeter V2G and FibroMeter V2G were the following: cirrhosis AUROC, 0.906 versus 0.878 ( P fibrosis AUROC, 0.833 versus 0.832 ( P = 0.366). Multi-FibroMeter V2G had the highest correlation with the area of portoseptal fibrosis and the highest reproducibility over time. Correct classification rates

  8. Association of High-Dose Ibuprofen Use, Lung Function Decline, and Long-Term Survival in Children with Cystic Fibrosis.

    Science.gov (United States)

    Konstan, Michael W; VanDevanter, Donald R; Sawicki, Gregory S; Pasta, David J; Foreman, Aimee J; Neiman, Evgueni A; Morgan, Wayne J

    2018-04-01

    Cystic fibrosis deaths result primarily from lung function loss, so chronic respiratory therapies, intended to preserve lung function, are cornerstones of cystic fibrosis care. Although treatment-associated reduction in rate of lung function loss should ultimately improve cystic fibrosis survival, no such relationship has been described for any chronic cystic fibrosis therapy. In part, this is because the ages of most rapid lung function decline-early adolescence-precede the median age of cystic fibrosis deaths by more than a decade. To study associations of high-dose ibuprofen treatment with the rate of forced expiratory volume in 1 second decline and mortality among children followed in the Epidemiologic Study of Cystic Fibrosis and subsequently in the U.S. Cystic Fibrosis Foundation Patient Registry. We performed a matched cohort study using data from Epidemiologic Study of Cystic Fibrosis. Exposure was defined as high-dose ibuprofen use reported at ≥80% of encounters over 2 years. Unexposed children were matched to exposed children 5:1 using propensity scores on the basis of demographic, clinical, and treatment covariates. The rate of decline of percent predicted forced expiratory volume in 1 second during the 2-year follow-up period was estimated by mixed-effects modeling with random slopes and intercepts. Survival over 16 follow-up years in the U.S. Cystic Fibrosis Foundation Patient Registry was compared between treatment groups by using proportional hazards modeling controlling for matching and covariates. We included 775 high-dose ibuprofen users and 3,665 nonusers who were well matched on demographic, clinical, and treatment variables. High-dose ibuprofen users declined on average 1.10 percent predicted forced expiratory volume in 1 second/yr (95% confidence interval; 0.51, 1.69) during the 2-year treatment period, whereas nonusers declined at a rate of 1.76% percent predicted forced expiratory volume in 1 second/yr (95% confidence interval; 1.48, 2

  9. Assessment of Myocardial Fibrosis in Mice Using a T2*-Weighted 3D Radial Magnetic Resonance Imaging Sequence.

    Directory of Open Access Journals (Sweden)

    Bastiaan J van Nierop

    Full Text Available Myocardial fibrosis is a common hallmark of many diseases of the heart. Late gadolinium enhanced MRI is a powerful tool to image replacement fibrosis after myocardial infarction (MI. Interstitial fibrosis can be assessed indirectly from an extracellular volume fraction measurement using contrast-enhanced T1 mapping. Detection of short T2* species resulting from fibrotic tissue may provide an attractive non-contrast-enhanced alternative to directly visualize the presence of both replacement and interstitial fibrosis.To goal of this paper was to explore the use of a T2*-weighted radial sequence for the visualization of fibrosis in mouse heart.C57BL/6 mice were studied with MI (n = 20, replacement fibrosis, transverse aortic constriction (TAC (n = 18, diffuse fibrosis, and as control (n = 10. 3D center-out radial T2*-weighted images with varying TE were acquired in vivo and ex vivo (TE = 21 μs-4 ms. Ex vivo T2*-weighted signal decay with TE was analyzed using a 3-component model. Subtraction of short- and long-TE images was used to highlight fibrotic tissue with short T2*. The presence of fibrosis was validated using histology and correlated to MRI findings.Detailed ex vivo T2*-weighted signal analysis revealed a fast (T2*fast, slow (T2*slow and lipid (T2*lipid pool. T2*fast remained essentially constant. Infarct T2*slow decreased significantly, while a moderate decrease was observed in remote tissue in post-MI hearts and in TAC hearts. T2*slow correlated with the presence of diffuse fibrosis in TAC hearts (r = 0.82, P = 0.01. Ex vivo and in vivo subtraction images depicted a positive contrast in the infarct co-localizing with the scar. Infarct volumes from histology and subtraction images linearly correlated (r = 0.94, P<0.001. Region-of-interest analysis in the in vivo post-MI and TAC hearts revealed significant T2* shortening due to fibrosis, in agreement with the ex vivo results. However, in vivo contrast on subtraction images was rather poor

  10. Macrophage recruitment by fibrocystin-defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis.

    Science.gov (United States)

    Locatelli, Luigi; Cadamuro, Massimiliano; Spirlì, Carlo; Fiorotto, Romina; Lecchi, Silvia; Morell, Carola Maria; Popov, Yury; Scirpo, Roberto; De Matteis, Maria; Amenduni, Mariangela; Pietrobattista, Andrea; Torre, Giuliano; Schuppan, Detlef; Fabris, Luca; Strazzabosco, Mario

    2016-03-01

    Congenital hepatic fibrosis (CHF) is a disease of the biliary epithelium characterized by bile duct changes resembling ductal plate malformations and by progressive peribiliary fibrosis, in the absence of overt necroinflammation. Progressive liver fibrosis leads to portal hypertension and liver failure; however, the mechanisms leading to fibrosis in CHF remain elusive. CHF is caused by mutations in PKHD1, a gene encoding for fibrocystin, a ciliary protein expressed in cholangiocytes. Using a fibrocystin-defective (Pkhd1(del4/del4)) mouse, which is orthologous of CHF, we show that Pkhd1(del4/del4) cholangiocytes are characterized by a β-catenin-dependent secretion of a range of chemokines, including chemokine (C-X-C motif) ligands 1, 10, and 12, which stimulate bone marrow-derived macrophage recruitment. We also show that Pkhd1(del4/del4) cholangiocytes, in turn, respond to proinflammatory cytokines released by macrophages by up-regulating αvβ6 integrin, an activator of latent local transforming growth factor-β1. While the macrophage infiltrate is initially dominated by the M1 phenotype, the profibrogenic M2 phenotype increases with disease progression, along with the number of portal myofibroblasts. Consistent with these findings, clodronate-induced macrophage depletion results in a significant reduction of portal fibrosis and portal hypertension as well as of liver cysts. Fibrosis can be initiated by an epithelial cell dysfunction, leading to low-grade inflammation, macrophage recruitment, and collagen deposition; these findings establish a new paradigm for biliary fibrosis and represent a model to understand the relationship between cell dysfunction, parainflammation, liver fibrosis, and macrophage polarization over time. © 2015 by the American Association for the Study of Liver Diseases.

  11. Idiopathic Pulmonary Fibrosis: Diagnosis and Clinical Manifestations

    Science.gov (United States)

    Nakamura, Yutaro; Suda, Takafumi

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is a parenchymal lung disease characterized by progressive interstitial fibrosis. The clinical course of IPF can be unpredictable and may be punctuated by acute exacerbations. Although much progress is being made in unraveling the mechanisms underlying IPF, effective therapy for improving survival remains elusive. Longitudinal disease profiling, especially in terms of clinical manifestations in a large cohort of patients, should lead to proper management of the patients and development of new treatments for IPF. Appropriate multidisciplinary assessment in ongoing registries is required to achieve this. This review summarizes the current status of the diagnosis and clinical manifestations of IPF. PMID:27625576

  12. Diagnosis of Fibrosis and Activity by a Combined Use of Strain and Shear Wave Imaging in Patients with Liver Disease.

    Science.gov (United States)

    Yada, Norihisa; Tamaki, Nobuhura; Koizumi, Yohei; Hirooka, Masashi; Nakashima, Osamu; Hiasa, Yoichi; Izumi, Namiki; Kudo, Masatoshi

    2017-01-01

    Performing shear wave imaging is simple, but can be difficult when inflammation, jaundice, and congestion are present. Therefore, the correct diagnosis of liver fibrosis using shear wave imaging alone might be difficult in mild-to-moderate fibrosis cases. Strain imaging can diagnose liver fibrosis without the influence of inflammation. Therefore, the combined use of strain and shear wave imaging (combinational elastography) for cases without jaundice and congestion might be useful for evaluating fibrosis and inflammation. We enrolled consecutive patients with liver disease, without jaundice or liver congestion. Strain and shear wave imaging, blood tests, and liver biopsy were performed on the same day. The liver fibrosis index (LF index) was calculated by strain imaging; real-time tissue elastography, and the shear wave velocity (Vs) was calculated by shear wave imaging. Fibrosis index (F index) and activity index (A index) were calculated as a multiple regression equation for determining hepatic fibrosis and inflammation using histopathological diagnosis as the gold standard. The diagnostic ability of F index for fibrosis and A index for inflammation were compared using LF index and Vs. The total number of enrolled cases was 388. The area under the receiver operating characteristic (AUROC) was 0.87, 0.80, 0.83, and 0.80, at diagnosis of fibrosis stage with an F index of F1 or higher, F2 or higher, F3 or higher, and F4, respectively. The AUROC was 0.94, 0.74, and 0.76 at diagnosis of activity grade with an A index of A1 or higher, A2 or higher, and A3, respectively. The diagnostic ability of F index for liver fibrosis and A index for inflammation was higher than for other conventional diagnostic values. The combined use of strain and shear wave imaging (combinational elastography) might increase the positive diagnosis of liver fibrosis and inflammation. © 2017 S. Karger AG, Basel.

  13. Role of histone deacetylases(HDACs) in progression and reversal of liver fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Li, Xing; Wu, Xiao-Qin; Xu, Tao; Li, Xiao-Feng; Yang, Yang; Li, Wan-Xia; Huang, Cheng; Meng, Xiao-Ming; Li, Jun, E-mail: lijun@ahmu.edu.cn

    2016-09-01

    Liver fibrosis refers to a reversible wound healing process response to chronic liver injuries. Activation of hepatic stellate cells (HSCs) is closely correlated with the development of liver fibrosis. Histone deacetylases(HDACs) determine the acetylation levels of core histones to modulate expression of genes. To demonstrate the link between HDACs and liver fibrosis, CCl4-induced mouse liver fibrosis model and its spontaneous reversal model were established. Results of the current study demonstrated that deregulation of liver HDACs may involved in the development of liver fibrosis. Among 11 HDACs tested in our study (Class I, II, and IV HDACs), expression of HDAC2 was maximally increased in CCl4-induced fibrotic livers but decreased after spontaneous recovery. Moreover, expression of HDAC2 was elevated in human liver fibrotic tissues. In this regard, the potential role of HDAC2 in liver fibrosis was further evaluated. Our results showed that administration of HSC-T6 cells with transforming growth factor-beta1 (TGF-β1) resulted in an increase of HDAC2 protein expression in dose- and time-dependent manners. Moreover, HDAC2 deficiency inhibited HSC-T6 cell proliferation and activation induced by TGF-β1. More importantly, the present study showed HDAC2 may regulate HSCs activation by suppressing expression of Smad7, which is a negative modulator in HSCs activation and liver fibrosis. Collectively, these observations revealed that HDAC2 may play a pivotal role in HSCs activation and liver fibrosis while deregulation of HDACs may serve as a novel mechanism underlying liver fibrosis. - Highlights: • This is the first report to systematically examine expressions of HDACs during liver fibrosis and fibrosis reversal. • Aberrant expression of HDAC2 contributes to the development of liver fibrosis. • Provided important foundation for further liver fibrosis conversion studies.

  14. Pharmacoeconomic review of recombinant human DNase in the management of cystic fibrosis

    NARCIS (Netherlands)

    Zijlstra, Gerrit; Boersma, Cornelis; Frijlink, Henderik W.; Postma, Maarten J.

    For the treatment of patients with cystic fibrosis, recombinant human deoxyribonuclease I is widely used. Deoxyribonuclease I has a positive effect on lung function and the number of hospitalizations. Deoxyribonuclease I is currently administered by nebulization, which is an inefficient

  15. An American Thoracic Society Official Research Statement: Future Directions in Lung Fibrosis Research.

    Science.gov (United States)

    White, Eric S; Borok, Zea; Brown, Kevin K; Eickelberg, Oliver; Guenther, Andreas; Jenkins, R Gisli; Kolb, Martin; Martinez, Fernando J; Roman, Jesse; Sime, Patricia

    2016-04-01

    Pulmonary fibrosis encompasses a group of lung-scarring disorders that occur owing to known or unknown insults and accounts for significant morbidity and mortality. Despite intense investigation spanning decades, much remains to be learned about the natural history, pathophysiology, and biologic mechanisms of disease. To identify the most pressing research needs in the lung fibrosis community and to provide a roadmap of priorities to investigators, funding agencies, patient advocacy groups, and other interested stakeholders. An ad hoc international working group of the American Thoracic Society with experience in clinical, translational, and bench-based research in fibrotic lung diseases was convened. The group used an iterative consensus process to identify successes and challenges in pulmonary fibrosis research. The group identified five main priority areas in which substantial resources should be invested to advance our understanding and to develop novel therapies for patients with pulmonary fibrosis. These priorities include develop newer models of human lung fibrosis, engage current and new stakeholders to provide sustained funding for the initiatives, create a global infrastructure for storing patient-derived materials, establish collaborative preclinical and clinical research networks in fibrotic lung disease, and create a global lung fibrosis initiative that unites these multifaceted efforts into a single virtual umbrella structure. Despite recent advances in the treatment of some forms of lung fibrosis, many gaps in knowledge about natural history, pathophysiology, and treatment remain. Investment in the research priorities enumerated above will help address these shortcomings and enhance patient care worldwide.

  16. Dual core quantum dots for highly quantitative ratiometric detection of trypsin activity in cystic fibrosis patients

    Science.gov (United States)

    Castelló Serrano, Iván; Stoica, Georgiana; Matas Adams, Alba; Palomares, Emilio

    2014-10-01

    We present herein two colour encoded silica nanospheres (2nanoSi) for the fluorescence quantitative ratiometric determination of trypsin in humans. Current detection methods for cystic fibrosis diagnosis are slow, costly and suffer from false positives. The 2nanoSi proved to be a highly sensitive, fast (minutes), and single-step approach nanosensor for the screening and diagnosis of cystic fibrosis, allowing the quantification of trypsin concentrations in a wide range relevant for clinical applications (25-350 μg L-1). Furthermore, as trypsin is directly related to the development of cystic fibrosis (CF), different human genotypes, i.e. CF homozygotic, CF heterozygotic, and unaffected, respectively, can be determined using our 2nanoSi nanospheres. We anticipate the 2nanoSi system to be a starting point for non-invasive, easy-to-use and cost effective ratiometric fluorescent biomarkers for recessive genetic diseases like human cystic fibrosis. In a screening program in which the goal is to detect disease and also the carrier status, early diagnosis could be of great help.We present herein two colour encoded silica nanospheres (2nanoSi) for the fluorescence quantitative ratiometric determination of trypsin in humans. Current detection methods for cystic fibrosis diagnosis are slow, costly and suffer from false positives. The 2nanoSi proved to be a highly sensitive, fast (minutes), and single-step approach nanosensor for the screening and diagnosis of cystic fibrosis, allowing the quantification of trypsin concentrations in a wide range relevant for clinical applications (25-350 μg L-1). Furthermore, as trypsin is directly related to the development of cystic fibrosis (CF), different human genotypes, i.e. CF homozygotic, CF heterozygotic, and unaffected, respectively, can be determined using our 2nanoSi nanospheres. We anticipate the 2nanoSi system to be a starting point for non-invasive, easy-to-use and cost effective ratiometric fluorescent biomarkers for

  17. Nephrogenic systemic fibrosis and gadolinium-based contrast media

    DEFF Research Database (Denmark)

    Thomsen, Henrik S; Morcos, Sameh K; Almén, Torsten

    2012-01-01

    PURPOSE: To update the guidelines of the Contrast Media Safety Committee (CMSC) of the European Society of Urogenital Radiology (ESUR) on nephrogenic systemic fibrosis and gadolinium-based contrast media. AREAS COVERED: Topics reviewed include the history, clinical features and prevalence of neph...... guidelines regarding gadolinium contrast agents minimises the risk of NSF • Potential long-term harm from gadolinium accumulation in the body is discussed.......PURPOSE: To update the guidelines of the Contrast Media Safety Committee (CMSC) of the European Society of Urogenital Radiology (ESUR) on nephrogenic systemic fibrosis and gadolinium-based contrast media. AREAS COVERED: Topics reviewed include the history, clinical features and prevalence...... of nephrogenic systemic fibrosis and the current understanding of its pathophysiology. The risk factors for NSF are discussed and prophylactic measures are recommended. The stability of the different gadolinium-based contrast media and the potential long-term effects of gadolinium in the body have also been...

  18. A new model using routinely available clinical parameters to predict significant liver fibrosis in chronic hepatitis B.

    Directory of Open Access Journals (Sweden)

    Wai-Kay Seto

    Full Text Available OBJECTIVE: We developed a predictive model for significant fibrosis in chronic hepatitis B (CHB based on routinely available clinical parameters. METHODS: 237 treatment-naïve CHB patients [58.4% hepatitis B e antigen (HBeAg-positive] who had undergone liver biopsy were randomly divided into two cohorts: training group (n = 108 and validation group (n = 129. Liver histology was assessed for fibrosis. All common demographics, viral serology, viral load and liver biochemistry were analyzed. RESULTS: Based on 12 available clinical parameters (age, sex, HBeAg status, HBV DNA, platelet, albumin, bilirubin, ALT, AST, ALP, GGT and AFP, a model to predict significant liver fibrosis (Ishak fibrosis score ≥3 was derived using the five best parameters (age, ALP, AST, AFP and platelet. Using the formula log(index+1 = 0.025+0.0031(age+0.1483 log(ALP+0.004 log(AST+0.0908 log(AFP+1-0.028 log(platelet, the PAPAS (Platelet/Age/Phosphatase/AFP/AST index predicts significant fibrosis with an area under the receiving operating characteristics (AUROC curve of 0.776 [0.797 for patients with ALT <2×upper limit of normal (ULN] The negative predictive value to exclude significant fibrosis was 88.4%. This predictive power is superior to other non-invasive models using common parameters, including the AST/platelet/GGT/AFP (APGA index, AST/platelet ratio index (APRI, and the FIB-4 index (AUROC of 0.757, 0.708 and 0.723 respectively. Using the PAPAS index, 67.5% of liver biopsies for patients being considered for treatment with ALT <2×ULN could be avoided. CONCLUSION: The PAPAS index can predict and exclude significant fibrosis, and may reduce the need for liver biopsy in CHB patients.

  19. Protein S is protective in pulmonary fibrosis.

    Science.gov (United States)

    Urawa, M; Kobayashi, T; D'Alessandro-Gabazza, C N; Fujimoto, H; Toda, M; Roeen, Z; Hinneh, J A; Yasuma, T; Takei, Y; Taguchi, O; Gabazza, E C

    2016-08-01

    Essentials Epithelial cell apoptosis is critical in the pathogenesis of idiopathic pulmonary fibrosis. Protein S, a circulating anticoagulant, inhibited apoptosis of lung epithelial cells. Overexpression of protein S in lung cells reduced bleomycin-induced pulmonary fibrosis. Intranasal therapy with exogenous protein S ameliorated bleomycin-induced pulmonary fibrosis. Background Pulmonary fibrosis is the terminal stage of interstitial lung diseases, some of them being incurable and of unknown etiology. Apoptosis plays a critical role in lung fibrogenesis. Protein S is a plasma anticoagulant with potent antiapoptotic activity. The role of protein S in pulmonary fibrosis is unknown. Objectives To evaluate the clinical relevance of protein S and its protective role in pulmonary fibrosis. Methods and Results The circulating level of protein S was measured in patients with pulmonary fibrosis and controls by the use of enzyme immunoassays. Pulmonary fibrosis was induced with bleomycin in transgenic mice overexpressing human protein S and wild-type mice, and exogenous protein S or vehicle was administered to wild-type mice; fibrosis was then compared in both models. Patients with pulmonary fibrosis had reduced circulating levels of protein S as compared with controls. Inflammatory changes, the levels of profibrotic cytokines, fibrosis score, hydroxyproline content in the lungs and oxygen desaturation were significantly reduced in protein S-transgenic mice as compared with wild-type mice. Wild-type mice treated with exogenous protein S showed significant decreases in the levels of inflammatory and profibrotic markers and fibrosis in the lungs as compared with untreated control mice. After bleomycin infusion, mice overexpressing human protein S showed significantly low caspase-3 activity, enhanced expression of antiapoptotic molecules and enhanced Akt and Axl kinase phosphorylation as compared with wild-type counterparts. Protein S also inhibited apoptosis of alveolar

  20. Analysis of disease-associated protein expression using quantitative proteomics—fibulin-5 is expressed in association with hepatic fibrosis.

    Science.gov (United States)

    Bracht, Thilo; Schweinsberg, Vincent; Trippler, Martin; Kohl, Michael; Ahrens, Maike; Padden, Juliet; Naboulsi, Wael; Barkovits, Katalin; Megger, Dominik A; Eisenacher, Martin; Borchers, Christoph H; Schlaak, Jörg F; Hoffmann, Andreas-Claudius; Weber, Frank; Baba, Hideo A; Meyer, Helmut E; Sitek, Barbara

    2015-05-01

    Hepatic fibrosis and cirrhosis are major health problems worldwide. Until now, highly invasive biopsy remains the diagnostic gold standard despite many disadvantages. To develop noninvasive diagnostic assays for the assessment of liver fibrosis, it is urgently necessary to identify molecules that are robustly expressed in association with the disease. We analyzed biopsied tissue samples from 95 patients with HBV/HCV-associated hepatic fibrosis using three different quantification methods. We performed a label-free proteomics discovery study to identify novel disease-associated proteins using a subset of the cohort (n = 27). Subsequently, gene expression data from all available clinical samples were analyzed (n = 77). Finally, we performed a targeted proteomics approach, multiple reaction monitoring (MRM), to verify the disease-associated expression in samples independent from the discovery approach (n = 68). We identified fibulin-5 (FBLN5) as a novel protein expressed in relation to hepatic fibrosis. Furthermore, we confirmed the altered expression of microfibril-associated glycoprotein 4 (MFAP4), lumican (LUM), and collagen alpha-1(XIV) chain (COL14A1) in association to hepatic fibrosis. To our knowledge, no tissue-based quantitative proteomics study for hepatic fibrosis has been performed using a cohort of comparable size. By this means, we add substantial evidence for the disease-related expression of the proteins examined in this study.

  1. Microencapsulation of Lefty-secreting engineered cells for pulmonary fibrosis therapy in mice.

    Science.gov (United States)

    Ma, Hongge; Qiao, Shupei; Wang, Zeli; Geng, Shuai; Zhao, Yufang; Hou, Xiaolu; Tian, Weiming; Chen, Xiongbiao; Yao, Lifen

    2017-05-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive disease that causes unremitting deposition of extracellular matrix proteins, thus resulting in distortion of the pulmonary architecture and impaired gas exchange. Associated with high morbidity and mortality, IPF is generally refractory to current pharmacological therapies. Lefty A, a potent inhibitor of transforming growth factor-β signaling, has been shown to have promising antifibrotic ability in vitro for the treatment of renal fibrosis and other potential organ fibroses. Here, we determined whether Lefty A can attenuate bleomycin (BLM)-induced pulmonary fibrosis in vivo based on a novel therapeutic strategy where human embryonic kidney 293 (HEK293) cells are genetically engineered with the Lefty A-associated GFP gene. The engineered HEK293 cells were encapsulated in alginate microcapsules and then subcutaneously implanted in ICR mice that had 1 wk earlier been intratracheally administered BLM to induce pulmonary fibrosis. The severity of fibrosis in lung tissue was assessed using pathological morphology and collagen expression to examine the effect of Lefty A released from the microencapsulated cells. The engineered HEK293 cells with Lefty A significantly reduced the expression of connective tissue growth factor and collagen type I mRNA, lessened the morphological fibrotic effects induced by BLM, and increased the expression of matrix metalloproteinase-9. This illustrates that engineered HEK293 cells with Lefty A can attenuate pulmonary fibrosis in vivo, thus providing a novel method to treat human pulmonary fibrotic disease and other organ fibroses. Copyright © 2017 the American Physiological Society.

  2. A pilot study on the use of optical spectroscopy to detection of liver fibrosis

    International Nuclear Information System (INIS)

    Fabila, A; La Rosa, J. de; Stolik, S.; Escobedo, C.; Suarez Alvarez, K.; Lopez Navarrete, G.

    2012-01-01

    In this paper we present the preliminary study to evaluate the use of optical spectroscopy as a tool to detect liver fibrosis. In vivo fluorescence and diffuse reflectance spectra were acquired from male rats in which fibrosis were induced by means of carbon tetrachloride. Spectral measurements were obtained using a portable system with an excitation source of 365 nm and a fiber-optic probe. The livers from rats with fibrosis showed an increase in fluorescence and diffuse reflectance intensity when compared to normal liver tissue. A support vector machine discrimination algorithm based on fluorescence and diffuse reflectance intensities at 493 and 365 nm was developed. This algorithm yields a sensitivity and specificity of 88% and 94%, respectively, in differentiating fibrotic liver from normal liver tissue. the results obtained in this study suggest that optical spectroscopy could be worthy of further exploration in patients. (Author)

  3. Can early hepatic fibrosis stages be discriminated by combining ultrasonic parameters?

    Science.gov (United States)

    Bouzitoune, Razika; Meziri, Mahmoud; Machado, Christiano Bittencourt; Padilla, Frédéric; Pereira, Wagner Coelho de Albuquerque

    2016-05-01

    In this study, we put forward a new approach to classify early stages of fibrosis based on a multiparametric characterization using backscatter ultrasonic signals. Ultrasonic parameters, such as backscatter coefficient (Bc), speed of sound (SoS), attenuation coefficient (Ac), mean scatterer spacing (MSS), and spectral slope (SS), have shown their potential to differentiate between healthy and pathologic samples in different organs (eye, breast, prostate, liver). Recently, our group looked into the characterization of stages of hepatic fibrosis using the parameters cited above. The results showed that none of them could individually distinguish between the different stages. Therefore, we explored a multiparametric approach by combining these parameters in two and three, to test their potential to discriminate between the stages of liver fibrosis: F0 (normal), F1, F3, and/without F4 (cirrhosis), according to METAVIR Score. Discriminant analysis showed that the most relevant individual parameter was Bc, followed by SoS, SS, MSS, and Ac. The combination of (Bc, SoS) along with the four stages was the best in differentiating between the stages of fibrosis and correctly classified 85% of the liver samples with a high level of significance (p<0.0001). Nevertheless, when taking into account only stages F0, F1, and F3, the discriminant analysis showed that the parameters (Bc, SoS) and (Bc, Ac) had a better classification (93%) with a high level of significance (p<0.0001). The combination of the three parameters (Bc, SoS, and Ac) led to a 100% correct classification. In conclusion, the current findings show that the multiparametric approach has great potential in differentiating between the stages of fibrosis, and thus could play an important role in the diagnosis and follow-up of hepatic fibrosis. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Relationship between Fibrosis and Ventricular Arrhythmias in Chagas Heart Disease Without Ventricular Dysfunction

    Energy Technology Data Exchange (ETDEWEB)

    Tassi, Eduardo Marinho, E-mail: etassi@ibest.com.br [Instituto de Cardiologia Edson Saad - Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ (Brazil); Continentino, Marcelo Abramoff [Hospital Frei Galvão, Guaratinguetá, SP (Brazil); Nascimento, Emília Matos do; Pereira, Basílio de Bragança [Instituto de Cardiologia Edson Saad - Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ (Brazil); Coppe - Instituto Alberto Luiz Coimbra de Pós-Graduação e Pesquisa de Engenharia - UFRJ, Rio de Janeiro, RJ (Brazil); Pedrosa, Roberto Coury [Instituto de Cardiologia Edson Saad - Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ (Brazil)

    2014-05-15

    Patients with Chagas disease and segmental wall motion abnormality (SWMA) have worse prognosis independent of left ventricular ejection fraction (LVEF). Cardiac magnetic resonance (CMR) is currently the best method to detect SWMA and to assess fibrosis. To quantify fibrosis by using late gadolinium enhancement CMR in patients with Chagas disease and preserved or minimally impaired ventricular function (> 45%), and to detect patterns of dependence between fibrosis, SWMA and LVEF in the presence of ventricular arrhythmia. Electrocardiogram, treadmill exercise test, Holter and CMR were carried out in 61 patients, who were divided into three groups as follows: (1) normal electrocardiogram and CMR without SWMA; (2) abnormal electrocardiogram and CMR without SWMA; (3) CMR with SWMA independently of electrocardiogram. The number of patients with ventricular arrhythmia in relation to the total of patients, the percentage of fibrosis, and the LVEF were, respectively: Group 1, 4/26, 0.74% and 74.34%; Group 2, 4/16, 3.96% and 68.5%; and Group 3, 11/19, 14.07% and 55.59%. Ventricular arrhythmia was found in 31.1% of the patients. Those with and without ventricular arrhythmia had mean LVEF of 59.87% and 70.18%, respectively, and fibrosis percentage of 11.03% and 3.01%, respectively. Of the variables SWMA, groups, age, LVEF and fibrosis, only the latter was significant for the presence of ventricular arrhythmia, with a cutoff point of 11.78% for fibrosis mass (p < 0.001). Even in patients with Chagas disease and preserved or minimally impaired ventricular function, electrical instability can be present. Regarding the presence of ventricular arrhythmia, fibrosis is the most important variable, its amount being proportional to the complexity of the groups.

  5. Relationship between Fibrosis and Ventricular Arrhythmias in Chagas Heart Disease Without Ventricular Dysfunction

    International Nuclear Information System (INIS)

    Tassi, Eduardo Marinho; Continentino, Marcelo Abramoff; Nascimento, Emília Matos do; Pereira, Basílio de Bragança; Pedrosa, Roberto Coury

    2014-01-01

    Patients with Chagas disease and segmental wall motion abnormality (SWMA) have worse prognosis independent of left ventricular ejection fraction (LVEF). Cardiac magnetic resonance (CMR) is currently the best method to detect SWMA and to assess fibrosis. To quantify fibrosis by using late gadolinium enhancement CMR in patients with Chagas disease and preserved or minimally impaired ventricular function (> 45%), and to detect patterns of dependence between fibrosis, SWMA and LVEF in the presence of ventricular arrhythmia. Electrocardiogram, treadmill exercise test, Holter and CMR were carried out in 61 patients, who were divided into three groups as follows: (1) normal electrocardiogram and CMR without SWMA; (2) abnormal electrocardiogram and CMR without SWMA; (3) CMR with SWMA independently of electrocardiogram. The number of patients with ventricular arrhythmia in relation to the total of patients, the percentage of fibrosis, and the LVEF were, respectively: Group 1, 4/26, 0.74% and 74.34%; Group 2, 4/16, 3.96% and 68.5%; and Group 3, 11/19, 14.07% and 55.59%. Ventricular arrhythmia was found in 31.1% of the patients. Those with and without ventricular arrhythmia had mean LVEF of 59.87% and 70.18%, respectively, and fibrosis percentage of 11.03% and 3.01%, respectively. Of the variables SWMA, groups, age, LVEF and fibrosis, only the latter was significant for the presence of ventricular arrhythmia, with a cutoff point of 11.78% for fibrosis mass (p < 0.001). Even in patients with Chagas disease and preserved or minimally impaired ventricular function, electrical instability can be present. Regarding the presence of ventricular arrhythmia, fibrosis is the most important variable, its amount being proportional to the complexity of the groups

  6. Anabolic agent use in adults with cystic fibrosis.

    Science.gov (United States)

    Green, Heather D; Barry, Peter J; Jones, Andrew M

    2015-10-01

    The use of non-prescribed anabolic agents amongst non-athletes is increasing with young, adult males with cystic fibrosis (CF) in the highest risk demographic. There is evidence that anabolic agents increase weight and muscle mass in adults with a variety of catabolic conditions but there is no evidence for their use in hormone sufficient adults with CF. We report a case of anabolic agent use in a male adult with CF and review the clinical features of anabolic agent use with a focus on adults with CF. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Voice Disorder in Cystic Fibrosis Patients

    Science.gov (United States)

    Lourenço, Bruna Mendes; Costa, Kauê Machado; da Silva Filho, Manoel

    2014-01-01

    Cystic fibrosis is a common autosomal recessive disorder with drastic respiratory symptoms, including shortness of breath and chronic cough. While most of cystic fibrosis treatment is dedicated to mitigating the effects of respiratory dysfunction, the potential effects of this disease on vocal parameters have not been systematically studied. We hypothesized that cystic fibrosis patients, given their characteristic respiratory disorders, would also present dysphonic symptoms. Given that voice disorders can severely impair quality of life, the identification of a potential cystic fibrosis-related dysphonia could be of great value for the clinical evaluation and treatment of this disease. We tested our hypothesis by measuring vocal parameters, using both objective physical measures and the GRBAS subjective evaluation method, in male and female cystic fibrosis patients undergoing conventional treatment and compared them to age and sex matched controls. We found that cystic fibrosis patients had a significantly lower vocal intensity and harmonic to noise ratio, as well as increased levels of jitter and shimmer. In addition, cystic fibrosis patients also showed higher scores of roughness, breathiness and asthenia, as well as a significantly altered general grade of dysphonia. When we segregated the results according to sex, we observed that, as a group, only female cystic fibrosis patients had significantly lower values of harmonic to noise ratio and an abnormal general grade of dysphonia in relation to matched controls, suggesting that cystic fibrosis exerts a more pronounced effect on vocal parameters of women in relation to men. Overall, the dysphonic characteristics of CF patients can be explained by dysfunctions in vocal fold movement and partial upper airway obstruction, potentially caused by the accumulation of mucus and chronic cough characteristic of CF symptomatology. Our results show that CF patients exhibit significant dysphonia and suggest they may

  8. Molecular biomarkers in idiopathic pulmonary fibrosis

    Science.gov (United States)

    Ley, Brett; Brown, Kevin K.

    2014-01-01

    Molecular biomarkers are highly desired in idiopathic pulmonary fibrosis (IPF), where they hold the potential to elucidate underlying disease mechanisms, accelerated drug development, and advance clinical management. Currently, there are no molecular biomarkers in widespread clinical use for IPF, and the search for potential markers remains in its infancy. Proposed core mechanisms in the pathogenesis of IPF for which candidate markers have been offered include alveolar epithelial cell dysfunction, immune dysregulation, and fibrogenesis. Useful markers reflect important pathological pathways, are practically and accurately measured, have undergone extensive validation, and are an improvement upon the current approach for their intended use. The successful development of useful molecular biomarkers is a central challenge for the future of translational research in IPF and will require collaborative efforts among those parties invested in advancing the care of patients with IPF. PMID:25260757

  9. Experimental liver fibrosis research: update on animal models, legal issues and translational aspects

    Science.gov (United States)

    2013-01-01

    Liver fibrosis is defined as excessive extracellular matrix deposition and is based on complex interactions between matrix-producing hepatic stellate cells and an abundance of liver-resident and infiltrating cells. Investigation of these processes requires in vitro and in vivo experimental work in animals. However, the use of animals in translational research will be increasingly challenged, at least in countries of the European Union, because of the adoption of new animal welfare rules in 2013. These rules will create an urgent need for optimized standard operating procedures regarding animal experimentation and improved international communication in the liver fibrosis community. This review gives an update on current animal models, techniques and underlying pathomechanisms with the aim of fostering a critical discussion of the limitations and potential of up-to-date animal experimentation. We discuss potential complications in experimental liver fibrosis and provide examples of how the findings of studies in which these models are used can be translated to human disease and therapy. In this review, we want to motivate the international community to design more standardized animal models which might help to address the legally requested replacement, refinement and reduction of animals in fibrosis research. PMID:24274743

  10. Thoracic periaortal fibrosis and Ormond's disease

    International Nuclear Information System (INIS)

    Kacl, G.M.; Bino, M.; Salomon, F.; Risti, B.; Marincek, B.

    1995-01-01

    Two cases of thoracic periaortal fibrosis as a manifestation of retroperitoneal fibrosis (Ormond's disease) are shown on CT and MRI. Thoracic periaortal fibrosis can result in an inflammatory aneurysmo with chronic dissection. Manifestation of thoracic periaortal fibrosis may typically occur intermittently over decades. (orig.) [de

  11. Idiopathic pulmonary fibrosis: evolving concepts.

    Science.gov (United States)

    Ryu, Jay H; Moua, Teng; Daniels, Craig E; Hartman, Thomas E; Yi, Eunhee S; Utz, James P; Limper, Andrew H

    2014-08-01

    Idiopathic pulmonary fibrosis (IPF) occurs predominantly in middle-aged and older adults and accounts for 20% to 30% of interstitial lung diseases. It is usually progressive, resulting in respiratory failure and death. Diagnostic criteria for IPF have evolved over the years, and IPF is currently defined as a disease characterized by the histopathologic pattern of usual interstitial pneumonia occurring in the absence of an identifiable cause of lung injury. Understanding of the pathogenesis of IPF has shifted away from chronic inflammation and toward dysregulated fibroproliferative repair in response to alveolar epithelial injury. Idiopathic pulmonary fibrosis is likely a heterogeneous disorder caused by various interactions between genetic components and environmental exposures. High-resolution computed tomography can be diagnostic in the presence of typical findings such as bilateral reticular opacities associated with traction bronchiectasis/bronchiolectasis in a predominantly basal and subpleural distribution, along with subpleural honeycombing. In other circumstances, a surgical lung biopsy may be needed. The clinical course of IPF can be unpredictable and may be punctuated by acute deteriorations (acute exacerbation). Although progress continues in unraveling the mechanisms of IPF, effective therapy has remained elusive. Thus, clinicians and patients need to reach informed decisions regarding management options including lung transplant. The findings in this review were based on a literature search of PubMed using the search terms idiopathic pulmonary fibrosis and usual interstitial pneumonia, limited to human studies in the English language published from January 1, 2000, through December 31, 2013, and supplemented by key references published before the year 2000. Copyright © 2014 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

  12. Performance of transient elastography and serum fibrosis biomarkers for non-invasive evaluation of recurrent fibrosis after liver transplantation: A meta-analysis.

    Science.gov (United States)

    Bhat, Mamatha; Tazari, Mahmood; Sebastiani, Giada

    2017-01-01

    Recurrent fibrosis after liver transplantation (LT) impacts on long-term graft and patient survival. We performed a meta-analysis to compare the accuracy of non-invasive methods to diagnose significant recurrent fibrosis (stage F2-F4) following LT. Studies comparing serum fibrosis biomarkers, namely AST-to-platelet ratio index (APRI), fibrosis score 4 (FIB-4), or transient elastography (TE) with liver biopsy in LT recipients were systematically identified through electronic databases. In the meta-analysis, we calculated the weighted pooled odds ratio and used a fixed effect model, as there was no significant heterogeneity between studies. Eight studies were included for APRI, four for FIB-4, and twelve for TE. The mean prevalence of significant liver fibrosis was 37.4%. The summary odds ratio was significantly higher for TE (21.17, 95% CI confidence interval 14.10-31.77, p = 1X10-30) as compared to APRI (9.02, 95% CI 5.79-14.07; p = 1X10-30) and FIB-4 (7.08, 95% CI 4.00-12.55; p = 1.93X10-11). In conclusion, TE performs best to diagnose recurrent fibrosis in LT recipients. APRI and FIB-4 can be used as an estimate of significant fibrosis at centres where TE is not available. Longitudinal assessment of fibrosis by means of these non-invasive tests may reduce the need for liver biopsy.

  13. Modeling the mechanical properties of liver fibrosis in rats.

    Science.gov (United States)

    Zhu, Ying; Chen, Xin; Zhang, Xinyu; Chen, Siping; Shen, Yuanyuan; Song, Liang

    2016-06-14

    The progression of liver fibrosis changes the biomechanical properties of liver tissue. This study characterized and compared different liver fibrosis stages in rats in terms of viscoelasticity. Three viscoelastic models, the Voigt, Maxwell, and Zener models, were applied to experimental data from rheometer tests and then the elasticity and viscosity were estimated for each fibrosis stage. The study found that both elasticity and viscosity are correlated with the various stages of liver fibrosis. The study revealed that the Zener model is the optimal model for describing the mechanical properties of each fibrosis stage, but there is no significant difference between the Zener and Voigt models in their performance on liver fibrosis staging. Therefore the Voigt model can still be effectively used for liver fibrosis grading. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Pentoxifylline and vitamin E for treatment or prevention of radiation-induced fibrosis in patients with breast cancer.

    Science.gov (United States)

    Kaidar-Person, Orit; Marks, Lawrence B; Jones, Ellen L

    2018-04-23

    Radiation therapy (RT) plays an important role in the management of breast cancer. Radiation-induced fibrosis is a side effect of radiation therapy and may occur in up to 13% of the cases in patients (Radiother Oncol, 2009;90:80), fortunately usually is modest/localized and not associated with marked symptoms. However, occasionally, fibrosis can be moderate-to-severe, and cause clinically-meaningful symptoms. The current review summarizes the use of pentoxifylline and vitamin E of treatment or prevention of radiation-induced fibrosis in breast cancer patients. Even though data are limited, this regimen may reduce RT-associated toxicity. © 2018 Wiley Periodicals, Inc.

  15. Automatic liver volume segmentation and fibrosis classification

    Science.gov (United States)

    Bal, Evgeny; Klang, Eyal; Amitai, Michal; Greenspan, Hayit

    2018-02-01

    In this work, we present an automatic method for liver segmentation and fibrosis classification in liver computed-tomography (CT) portal phase scans. The input is a full abdomen CT scan with an unknown number of slices, and the output is a liver volume segmentation mask and a fibrosis grade. A multi-stage analysis scheme is applied to each scan, including: volume segmentation, texture features extraction and SVM based classification. Data contains portal phase CT examinations from 80 patients, taken with different scanners. Each examination has a matching Fibroscan grade. The dataset was subdivided into two groups: first group contains healthy cases and mild fibrosis, second group contains moderate fibrosis, severe fibrosis and cirrhosis. Using our automated algorithm, we achieved an average dice index of 0.93 ± 0.05 for segmentation and a sensitivity of 0.92 and specificity of 0.81for classification. To the best of our knowledge, this is a first end to end automatic framework for liver fibrosis classification; an approach that, once validated, can have a great potential value in the clinic.

  16. Viral infection drives tissue fibrosis in vitro

    Directory of Open Access Journals (Sweden)

    Andrea P. Malizia

    2008-04-01

    Full Text Available Idiopathic Pulmonary Fibrosis (IPF is a refractory and lethal interstitial lung disease characterized by loss of alveolar epithelial cells, fibroblast proliferation and extra-cellular matrix protein deposition. EBV, localised to alveolar epithelial cells of pulmonary fibrosis patients is associated with a poor prognosis. In this study we utilised a microarray-based differential gene expression analysis strategy to identify molecular drivers of EBV associated with lung fibrosis. A549 cells and an alveolar epithelial cell line infected with EBV (VAAK were used to identify genes whose expression was altered by EBV reactivation. EBV reactivation by TGFbeta1 drives alterations in expression of non-canonical Wnt pathway mediators, implicating it in epithelial mesenchymal transition (EMT, the molecular event underpinning scar production in tissue fibrosis. Cell invasion, EMT correlated transcripts expression, GSK-3b and c-Jun activation were altered in response to non-canonical Wnt pathway regulation. The role of EBV in promoting fibrosis can be attenuated by antiviral strategies and inhibition of Wnt signalling. Activation of non-canonical Wnt signalling pathway by EBV in epithelial cells suggests a novel mechanism of tissue fibrosis. These data present a framework for further description of the link between infectious agents and fibrosis, a significant disease burden.

  17. From bad to worse: when lung cancer complicates idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Strock, Stephen B; Alder, Jonathan K; Kass, Daniel J

    2018-04-01

    Patients with idiopathic pulmonary fibrosis have a significantly increased risk for the development of lung cancer. The morbidity and mortality of this disease combination are substantial, and, unfortunately, there are currently few data to help guide clinicians in its diagnosis and treatment. In a recent issue of this journal, Hwang et al presented one of the first studies to evaluate lung cancer in patients with idiopathic pulmonary fibrosis at the molecular level. They demonstrate variants in regulators of the cell cycle, which are known to be important in malignant transformation and may also be important in the pathogenesis of idiopathic pulmonary fibrosis. Further understanding of the pathogenic overlap between lung cancer and idiopathic pulmonary fibrosis could help point the direction to specific diagnostic modalities and targeted treatment of both conditions in the future. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  18. Individual radiosensitivity measured with lymphocytes may be used to predict the risk of fibrosis after radiotherapy for breast cancer

    International Nuclear Information System (INIS)

    Hoeller, Ulrike; Borgmann, Kerstin; Bonacker, Michael; Kuhlmey, Antje; Bajrovic, Amira; Jung, Horst; Alberti, Winfried; Dikomey, Ekkehard

    2003-01-01

    Background and purpose: To analyse the relationship of individual cellular radiosensitivity and fibrosis after breast conserving therapy. A new model was used describing the percentage of patients developing fibrosis per year and per patient at risk. Patients and methods: In a retrospective study, 86 patients were included, who had undergone breast conserving surgery and irradiation of the breast with a median dose of 55 Gy (54-55 Gy) given at 2.5 Gy/fraction (n=57) or 2 Gy/fraction (n=29). Median age was 62 years (range 44-86) and median follow-up was 7.5 years (range 5-17). Patients were examined for fibrosis according to the LENT/SOMA score. For analysis, fibrosis was classified as grade 0 and grade 1 (G0-1) or present grade 2 and grade 3 (G2-3). The time to complete development of fibrosis was determined by analysis of yearly mammograms. Individual cellular radiosensitivity was determined by scoring lethal chromosomal aberrations in in vitro irradiated (6 Gy) lymphocytes using metaphase technique. Patients with low/intermediate cellular radiosensitivity were compared with patients with high cellular radiosensitivity using actuarial methods. Results: Ten patients developed fibrosis at 1-8 years after radiotherapy. Individual cellular radiosensitivity was described by normal distribution of lethal chromosomal aberrations, the average was 5.47 lethal aberrations per cell (standard deviation (SD) 0.71). Cellular radiosensitivity was defined as low/intermediate (≤6.18 lethal aberrations) in 73 patients and high (>6.18 lethal aberrations; mean+SD) in 13 patients. In both groups, the actuarial rate of fibrosis-free patients decreased exponentially with time after radiotherapy. Patients with high cellular radiosensitivity showed a 2.3-fold higher annual rate for fibrosis than patients with intermediate and low radiosensitivity (3.6 versus 1.6% per year). Conclusions: In breast cancer patients, high individual cellular radiosensitivity as determined by the number of

  19. Smoking and Pulmonary Fibrosis: Novel Insights

    Directory of Open Access Journals (Sweden)

    Katerina D. Samara

    2011-01-01

    Full Text Available The relationship between smoking and pulmonary fibrosis is under debate and intense investigation. The aim of this paper is to review the existing literature and identify further areas of research interest. Recently the negative influence of cigarette smoking on IPF outcome was highlighted, as non-smokers exhibit a better survival than ex-smokers and combined current- and ex-smokers. In patients with non-specific interstitial pneumonia (NSIP, a high prevalence of emphysema was recently demonstrated, providing an indirect support for a smoking pathogenetic hypothesis in NSIP. The coexistence of pulmonary fibrosis and emphysema has been extensively described in a syndrome termed combined pulmonary fibrosis and emphysema (CPFE. Connective tissue disorders (CTDs are a group of autoimmune diseases which affect the lung, as one of the most common and severe manifestations. However, the relationship between smoking and autoimmune disorders is still conflicting. Rheumatoid arthritis results from the interaction between genetic and environmental factors, while the best established environmental factor is tobacco smoking. Smoking has also a negative impact on the response of the RA patients to treatment. The aforementioned smoking-related implications give rise to further research questions and certainly provide one more important reason for physicians to advocate smoking cessation and smoke-free environment.

  20. Imaging pulmonary fibrosis

    International Nuclear Information System (INIS)

    Brauner, M.W.; Rety, F.; Naccache, J.M.; Girard, F.; Valeyre, D.F.

    2001-01-01

    Localized fibrosis of the lung is usually scar tissue while diffuse pulmonary fibrosis is more often a sign of active disease. Chronic infiltrative lung disease may be classified into four categories: idiopathic pneumonitis, collagen diseases, granulomatosis (sarcoidosis), and caused by known diseases (pneumoconiosis, hypersensitivity pneumonitis, drug-induced lung disease, radiation). (authors)

  1. IDENTIFICATION OF SPONTANEOUS FELINE IDIOPATHIC PULMONARY FIBROSIS: MORPHOLOGY AND ULTRASTRUCTURAL EVIDENCE FOR A TYPE II PNEUMOCYTE DEFECT

    Science.gov (United States)

    AbstractIdiopathic pulmonary fibrosis currently lacks an animal model that develops the persistent, progressive lung fibrosis characteristic of the disease. Sixteen domestic cats developed dyspnea that was not responsive to therapy and which rapidly progressed until death/eu...

  2. Intra-abdominal fibrosis in a recent cohort of patients with neuroendocrine ('carcinoid') tumours of the small bowel.

    Science.gov (United States)

    Druce, M R; Bharwani, N; Akker, S A; Drake, W M; Rockall, A; Grossman, A B

    2010-03-01

    Fibrosis is a hallmark of neuroendocrine tumours (NETs) arising in the jejunum and ileum and may manifest in the mesentery and elsewhere. It is clinically important and once-established, there are few effective therapies. To examine the frequency, radiological manifestations and clinical significance of intra-abdominal fibrosis in a patient cohort using modern cross-sectional imaging. Current prevalence is compared to historical series and correlation with cardiac fibrosis evaluated. Cross-sectional, retrospective survey of a cohort of patients with mid-gut NETs from a single centre. Review of clinical features, biochemistry and imaging of patients with sporadic mid-gut NET and available imaging between 2002 and 2008. Thirty-one patients were included: 26 (83.9%) had liver metastases and 11 (35.4%) had small-bowel wall thickening; 17 patients (55%) had mesenteric involvement, with a mass, which contained coarse calcification in seven patients and fine calcification in a further two. There was soft-tissue stranding in 13 patients (plus in a further patient with no mass) and 'indrawing' of tissues in 11 patients. Two patients had a 'misty' mesentery and two had early retroperitoneal fibrosis. Mesenteric involvement was unrelated to gender and urinary 5HIAA excretion. Intra-abdominal fibrosis can be detected radiologically in around half of patients with mid-gut NET using contemporary cross-sectional imaging. Although not statistically significant, small-bowel obstruction was seen more frequently in the group with fibrosis. There was no relationship with cardiac fibrosis. Prospective studies are needed to evaluate predictors of fibrosis onset and clinical course and determine optimal methods of prevention and treatment.

  3. Cadmium stimulates myofibroblast differentiation and mouse lung fibrosis

    International Nuclear Information System (INIS)

    Hu, Xin; Fernandes, Jolyn; Jones, Dean P.; Go, Young-Mi

    2017-01-01

    Highlights: • Low-dose Cd stimulates differentiation of human lung fibroblast to myofibroblast. • Cd-stimulated fibrosis signaling involves activation of SMAD transcription factor. • Low-dose Cd intake in mice activates myofibroblast differentiation. - Abstract: Increasing evidence suggests that Cd at levels found in the human diet can cause oxidative stress and activate redox-sensitive transcription factors in inflammatory signaling. Following inflammation, tissue repair often involves activation of redox-sensitive transcription factors in fibroblasts. In lungs, epithelial barrier remodeling is required to restore gas exchange and barrier function, and aberrant myofibroblast differentiation leads to pulmonary fibrosis. Contributions of exogenous exposures, such as dietary Cd, to pulmonary fibrosis remain inCompletely defined. In the current study, we tested whether Cd activates fibrotic signaling in human fetal lung fibroblasts (HFLF) at micromolar and submicromolar Cd concentrations that do not cause cell death. Exposure of HFLF to low-dose Cd (≤1.0 μM) caused an increase in stress fibers and increased protein levels of myofibroblast differentiation markers, including α-smooth muscle actin (α-SMA) and extra-domain-A-containing fibronectin (ED-A-FN). Assay of transcription factor (TF) activity using a 45-TF array showed that Cd increased activity of 12 TF, including SMAD2/3/4 (mothers against decapentaplegic homolog) signaling differentiation and fibrosis. Results were confirmed by real-time PCR and supported by increased expression of target genes of SMAD2/3/4. Immunocytochemistry of lungs of mice exposed to low-dose Cd (0.3 and 1.0 mg/L in drinking water) showed increased α-SMA protein level with lung Cd accumulation similar to lung Cd in non-smoking humans. Together, the results show that relatively low Cd exposures stimulate pulmonary fibrotic signaling and myofibroblast differentiation by activating SMAD2/3/4-dependent signaling. The results

  4. Always cleave up your mess: targeting collagen degradation to treat tissue fibrosis

    Science.gov (United States)

    McKleroy, William; Lee, Ting-Hein

    2013-01-01

    Pulmonary fibrosis is a vexing clinical problem with no proven therapeutic options. In the normal lung there is continuous collagen synthesis and collagen degradation, and these two processes are precisely balanced to maintain normal tissue architecture. With lung injury there is an increase in the rate of both collagen production and collagen degradation. The increase in collagen degradation is critical in preventing the formation of permanent scar tissue each time the lung is exposed to injury. In pulmonary fibrosis, collagen degradation does not keep pace with collagen production, resulting in extracellular accumulation of fibrillar collagen. Collagen degradation occurs through both extracellular and intracellular pathways. The extracellular pathway involves cleavage of collagen fibrils by proteolytic enzyme including the metalloproteinases. The less-well-described intracellular pathway involves binding and uptake of collagen fragments by fibroblasts and macrophages for lysosomal degradation. The relationship between these two pathways and their relevance to the development of fibrosis is complex. Fibrosis in the lung, liver, and skin has been associated with an impaired degradative environment. Much of the current scientific effort in fibrosis is focused on understanding the pathways that regulate increased collagen production. However, recent reports suggest an important role for collagen turnover and degradation in regulating the severity of tissue fibrosis. The objective of this review is to evaluate the roles of the extracellular and intracellular collagen degradation pathways in the development of fibrosis and to examine whether pulmonary fibrosis can be viewed as a disease of impaired matrix degradation rather than a disease of increased matrix production. PMID:23564511

  5. Gastroesophageal Reflux and Idiopathic Pulmonary Fibrosis: A Review

    Directory of Open Access Journals (Sweden)

    Ahmed Fahim

    2011-01-01

    Full Text Available The histological counterpart of idiopathic pulmonary fibrosis is usual interstitial pneumonia, in which areas of fibrosis of various ages are interspersed with normal lung. This pattern could be explained by repeated episodes of lung injury followed by abnormal wound healing responses. The cause of the initiating alveolar epithelial injury is unknown, but postulated mechanisms include immunological, microbial, or chemical injury, including aspirated gastric refluxate. Reflux is promoted by low basal pressure in the lower oesophageal sphincter and frequent relaxations, potentiated by hiatus hernia or oesophageal dysmotility. In susceptible individuals, repeated microaspiration of gastric refluxate may contribute to the pathogenesis of IPF. Microaspiration of nonacid or gaseous refluxate is poorly detected by current tests for gastroesophageal reflux which were developed for investigating oesophageal symptoms. Further studies using pharyngeal pH probes, high-resolution impedance manometry, and measurement of pepsin in the lung should clarify the impact of reflux and microaspiration in the pathogenesis of IPF.

  6. Identification of key metabolic changes in renal interstitial fibrosis rats using metabonomics and pharmacology.

    Science.gov (United States)

    Zhao, Liangcai; Dong, Minjian; Liao, Shixian; Du, Yao; Zhou, Qi; Zheng, Hong; Chen, Minjiang; Ji, Jiansong; Gao, Hongchang

    2016-06-03

    Renal fibrosis is one of the important pathways involved in end-stage renal failure. Investigating the metabolic changes in the progression of disease may enhance the understanding of its pathogenesis and therapeutic information. In this study, (1)H-nuclear magnetic resonance (NMR)-based metabonomics was firstly used to screen the metabolic changes in urine and kidney tissues of renal interstitial fibrotic rats induced by unilateral ureteral obstruction (UUO), at 7, 14, 21, and 28 days after operation, respectively. The results revealed that reduced levels of bioenergy synthesis and branched chain amino acids (BCAAs), as well as elevated levels of indoxyl sulfate (IS) are involved in metabolic alterations of renal fibrosis rats. Next, by pharmacological treatment we found that reduction of IS levels could prevent the renal fibrotic symptoms. Therefore, we suggested that urinary IS may be used as a potential biomarker for the diagnosis of renal fibrosis, and a therapeutic target for drugs. Novel attempt combining metabonomics and pharmacology was established that have ability to provide more systematic diagnostic and therapeutic information of diseases.

  7. Serum hyaluronic acid as a marker of hepatic fibrosis

    International Nuclear Information System (INIS)

    Khan, J.A.; Khan, F.A.; Ijaz, A.; Khan, N.A.; Mehmood, T.

    2007-01-01

    To determine the serum hyaluronic acid (HA) levels as biochemical marker of hepatic fibrosis and cirrhosis and correlate it with the degree of hepatic fibrosis and cirrhosis. This study was performed on 100 patients of chronic liver disease whose liver biopsies had been carried out. Fifty healthy controls were also included in the study. Routine liver function tests, hepatitis serology and serum hyaluronic acid levels were carried out on patients and controls. Liver biopsy of 100 patients revealed that 21 were in stage 0 fibrosis, 38 in stage 1 fibrosis, 26 in stage 3 fibrosis and 15 in stage 4 fibrosis. Mean Serum HA (mean +- SD) concentration in patients were 189 +- 98 mg/L vs. 21 +- 10 mg/L of healthy controls. The difference observed was statistically significant (p < 0.001). Patients in stage 4 fibrosis had significantly higher (p <0.001) mean serum HA concentration as compared to other stages of liver fibrosis. Diagnostic accuracy of serum HA at marginally elevated level of 60 mg/L determined the sensitivity 78.4 %, specificity 80.9%, positive predicted value 93.9% and negative predicted value of 50%. Serum HA is a useful non-invasive marker of liver fibrosis. There is a strong positive correlation between serum HA levels and degree of liver fibrosis. The concentration of serum HA rises according to progression of liver fibrosis and levels are highest in patients with liver cirrhosis. (author)

  8. Automated evaluation of liver fibrosis in thioacetamide, carbon tetrachloride, and bile duct ligation rodent models using second-harmonic generation/two-photon excited fluorescence microscopy.

    Science.gov (United States)

    Liu, Feng; Chen, Long; Rao, Hui-Ying; Teng, Xiao; Ren, Ya-Yun; Lu, Yan-Qiang; Zhang, Wei; Wu, Nan; Liu, Fang-Fang; Wei, Lai

    2017-01-01

    Animal models provide a useful platform for developing and testing new drugs to treat liver fibrosis. Accordingly, we developed a novel automated system to evaluate liver fibrosis in rodent models. This system uses second-harmonic generation (SHG)/two-photon excited fluorescence (TPEF) microscopy to assess a total of four mouse and rat models, using chemical treatment with either thioacetamide (TAA) or carbon tetrachloride (CCl 4 ), and a surgical method, bile duct ligation (BDL). The results obtained by the new technique were compared with that using Ishak fibrosis scores and two currently used quantitative methods for determining liver fibrosis: the collagen proportionate area (CPA) and measurement of hydroxyproline (HYP) content. We show that 11 shared morphological parameters faithfully recapitulate Ishak fibrosis scores in the models, with high area under the receiver operating characteristic (ROC) curve (AUC) performance. The AUC values of 11 shared parameters were greater than that of the CPA (TAA: 0.758-0.922 vs 0.752-0.908; BDL: 0.874-0.989 vs 0.678-0.966) in the TAA mice and BDL rat models and similar to that of the CPA in the TAA rat and CCl 4 mouse models. Similarly, based on the trends in these parameters at different time points, 9, 10, 7, and 2 model-specific parameters were selected for the TAA rats, TAA mice, CCl 4 mice, and BDL rats, respectively. These parameters identified differences among the time points in the four models, with high AUC accuracy, and the corresponding AUC values of these parameters were greater compared with those of the CPA in the TAA rat and mouse models (rats: 0.769-0.894 vs 0.64-0.799; mice: 0.87-0.93 vs 0.739-0.836) and similar to those of the CPA in the CCl 4 mouse and BDL rat models. Similarly, the AUC values of 11 shared parameters and model-specific parameters were greater than those of HYP in the TAA rats, TAA mice, and CCl 4 mouse models and were similar to those of HYP in the BDL rat models. The automated

  9. Effects and mechanisms of pirfenidone, prednisone and acetylcysteine on pulmonary fibrosis in rat idiopathic pulmonary fibrosis models.

    Science.gov (United States)

    Yu, Wencheng; Guo, Fang; Song, Xiaoxia

    2017-12-01

    Previous studies have reported that caveolin-1 (Cav-1) is associated with lung fibrosis. However, the role of Cav-1 expression in pirfenidone-treated idiopathic pulmonary fibrosis (IPF) is unknown. This study investigated Cav-1 expression in pirfenidone-treated IPF, and compared the effects of pirfenidone with acetylcysteine and prednisone on IPF. Rat IPF model was established by endotracheal injection of 5 mg/kg bleomycin A5 into the specific pathogen-free Wistar male rats. Pirfenidone (P, 100 mg/kg once daily), prednisone (H, 5 mg/kg once daily) and acetylcysteine (N, 4 mg/kg 3 times per day) were used to treat the rat model by intragastric administration for 45 consecutive days, respectively. The normal rats without IPF were used as the controls. After 15, 30 and 45 days of drug treatment, lung histopathology was assessed. The expression of Cav-1 was determined using real-time quantitative PCR and Western blot; the expression of tumour necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1) and platelet-derived growth factor (PDGF) was determined by enzyme-linked immunosorbent assay. After 15, 30 and 45 days of drug treatment, comparison of the three drug-treated groups with the model group showed significantly lower (p fibrosis scores of lung tissues, as well as expression of TGF-β1, TNF-α and PDGF, but the expression of Cav-1 was higher (p fibrosis score was significantly lower and the protein expression of Cav-1 was significantly higher in the P group (p fibrosis scores (r = -0.506, p pulmonary fibrosis in rat IPF models, which may be related with enhanced caveolin-1, reduced TNF-α, TGF-β1, PDGF.

  10. Fibrosis and Cancer

    DEFF Research Database (Denmark)

    Cox, Thomas R.; Erler, Janine T.

    2016-01-01

    The relation between fibrosis and cancer has long been debated, specifically whether desmoplasia precedes, accompanies, or succeeds tumourigenesis, progression, and metastasis. Recent reports have published opposing data, adding to the perplexity. However, what is emerging is that it is likely th...... the specific properties of the extracellular matrix (ECM) that determine the paradoxical nature of cancer-associated fibrosis....

  11. Endoscopic Ultrasound Elastography: Current Clinical Use in Pancreas.

    Science.gov (United States)

    Mondal, Utpal; Henkes, Nichole; Patel, Sandeep; Rosenkranz, Laura

    2016-08-01

    Elastography is a newer technique for the assessment of tissue elasticity using ultrasound. Cancerous tissue is known to be stiffer (hence, less elastic) than corresponding healthy tissue, and as a result, could be identified in an elasticity-based imaging. Ultrasound elastography has been used in the breast, thyroid, and cervix to differentiate malignant from benign neoplasms and to guide or avoid unnecessary biopsies. In the liver, elastography has enabled a noninvasive and reliable estimate of fibrosis. Endoscopic ultrasound has become a robust diagnostic and therapeutic tool for the management of pancreatic diseases. The addition of elastography to endoscopic ultrasound enabled further characterization of pancreas lesions, and several European and Asian studies have reported encouraging results. The current clinical role of endoscopic ultrasound elastography in the management of pancreas disorders and related literature are reviewed.

  12. Ormond's disease or secondary retroperitoneal fibrosis? An overview of retroperitoneal fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Heckmann, M.; Uder, M.; Kuefner, M.A.; Heinrich, M.C. [Universitaetsklinikum Erlangen (Germany). Radiologisches Inst.

    2009-04-15

    Retroperitoneal fibrosis represents a rare inflammatory disease. About two thirds of all cases seem to be idiopathic (= Ormond's disease). The remaining one third is secondary and may be ascribed to infections, trauma, radiation therapy, malignant diseases, and the use of certain drugs. Up to 15 % of patients have additional fibrotic processes outside the retroperitoneum. The clinical symptoms of retroperitoneal fibrosis are non-specific. In sonography retroperitoneal fibrosis appears as a retroperitoneal hypoechoic mass which can involve the ureters and thus cause hydronephrosis. Intravenous urography and MR urography can demonstrate the typical triad of medial deviation and extrinsic compression of the ureters and hydronephrosis. CT and MRI are the modalities of choice for the diagnosis and follow-up of this disease. The lesion typically begins at the level of the fourth or fifth lumbar vertebra and appears as a plaque, encasing the aorta and the inferior vena cava and often enveloping and medially displacing the ureters. In unenhanced CT, retroperitoneal fibrosis appears as a mass that is isodense with muscle. When using MRI, the mass is hypointense in T1-weighted images and of variable intensity in T2-weighted images according to its stage: it may be hyperintense in early stages, while the tissue may have a low signal in late stages. After the administration of contrast media, enhancement is greatest in the early inflammatory phase and minimal in the late fibrotic phase. Dynamic gadolinium enhancement can be useful for assessing disease activity, monitoring response to treatment, and detecting relapse. To differentiate retroperitoneal masses, diffusion-weighted MRI may provide useful information. (orig.)

  13. Cystic Fibrosis Gene Therapy in the UK and Elsewhere

    Science.gov (United States)

    Pytel, Kamila M.; Alton, Eric W.F.W.

    2015-01-01

    Abstract The cystic fibrosis transmembrane conductance regulator (CFTR) gene was identified in 1989. This opened the door for the development of cystic fibrosis (CF) gene therapy, which has been actively pursued for the last 20 years. Although 26 clinical trials involving approximately 450 patients have been carried out, the vast majority of these trials were short and included small numbers of patients; they were not designed to assess clinical benefit, but to establish safety and proof-of-concept for gene transfer using molecular end points such as the detection of recombinant mRNA or correction of the ion transport defect. The only currently published trial designed and powered to assess clinical efficacy (defined as improvement in lung function) administered AAV2-CFTR to the lungs of patients with CF. The U.K. Cystic Fibrosis Gene Therapy Consortium completed, in the autumn of 2014, the first nonviral gene therapy trial designed to answer whether repeated nonviral gene transfer (12 doses over 12 months) can lead to clinical benefit. The demonstration that the molecular defect in CFTR can be corrected with small-molecule drugs, and the success of gene therapy in other monogenic diseases, is boosting interest in CF gene therapy. Developments are discussed here. PMID:25838137

  14. Radiation pneumonitis and fibrosis: Mechanisms underlying its pathogenesis and implications for future research

    International Nuclear Information System (INIS)

    Tsoutsou, Pelagia G.; Koukourakis, Michael I.

    2006-01-01

    Radiation pneumonitis and subsequent radiation pulmonary fibrosis are the two main dose-limiting factors when irradiating the thorax that can have severe implications for patients' quality of life. In this article, the current concepts about the pathogenetic mechanisms underlying radiation pneumonitis and fibrosis are presented. The clinical course of fibrosis, a postulated acute inflammatory stage, and a late fibrotic and irreversible stage are discussed. The interplay of cells and the wide variety of molecules orchestrating the immunologic response to radiation, their interactions with specific receptors, and the cascade of events they trigger are elucidated. Finally, the implications of this knowledge with respect to the therapeutic interventions are critically presented

  15. IGFBP-1 and IGF-I as markers for advanced fibrosis in NAFLD - a pilot study.

    Science.gov (United States)

    Hagström, Hannes; Stål, Per; Hultcrantz, Rolf; Brismar, Kerstin; Ansurudeen, Ishrath

    2017-12-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease globally. Advanced fibrosis (stage 3-4) is the most robust marker for future mortality, but diagnosis requires liver biopsy. Current non-invasive scoring systems aimed to identify advanced fibrosis are imperfect. Insulin-like growth factor I (IGF-I) and its binding protein IGFBP-1 are liver derived proteins, that are involved in various liver disorders. The aim of this study was to examine the possible association between advanced fibrosis and IGF-I and IGFBP-1 in NAFLD. Fasting blood samples were obtained from 52 patients diagnosed with NAFLD by liver biopsy. Total IGF-I and IGFBP-1 concentrations were determined in serum by in-house radio-immuno-assays. IGF-I levels were age-standardized (IGF-SD). A logistic regression model was used to investigate the association of IGF-SD and IGFBP-1 with advanced fibrosis (stage 3-4). Patients with advanced fibrosis (stage 3-4 vs. 0-2) had lower IGF-SD (-1.17 vs. 0.11, p = .01) and higher mean levels of IGFBP-1 (29.9 vs. 18.8 µg/l, p = .02). IGFBP-1 was associated with presence of advanced fibrosis (OR 1.04 per unit increase, 95%CI 1.0-1.07, p = .05), while IGF-1 was negatively associated with advanced fibrosis (OR 0.63 per standard deviation, 95%CI 0.44-0.92, p = .02). This pilot study suggests an association between serum IGFBP-1 and IGF-I levels with advanced fibrosis in NAFLD patients. IGFBP1 and IGF-1 could be of interest as future biomarkers. Similar studies in larger cohorts are needed.

  16. Advances in ultrasound-targeted microbubble-mediated gene therapy for liver fibrosis.

    Science.gov (United States)

    Huang, Cuiyuan; Zhang, Hong; Bai, Ruidan

    2017-07-01

    Hepatic fibrosis develops as a wound-healing scar in response to acute and chronic liver inflammation and can lead to cirrhosis in patients with chronic hepatitis B and C. The condition arises due to increased synthesis and reduced degradation of extracellular matrix (ECM) and is a common pathological sequela of chronic liver disease. Excessive deposition of ECM in the liver causes liver dysfunction, ascites, and eventually upper gastrointestinal bleeding as well as a series of complications. However, fibrosis can be reversed before developing into cirrhosis and has thus been the subject of extensive researches particularly at the gene level. Currently, therapeutic genes are imported into the damaged liver to delay or prevent the development of liver fibrosis by regulating the expression of exogenous genes. One technique of gene delivery uses ultrasound targeting of microbubbles combined with therapeutic genes where the time and intensity of the ultrasound can control the release process. Ultrasound irradiation of microbubbles in the vicinity of cells changes the permeability of the cell membrane by its cavitation effect and enhances gene transfection. In this paper, recent progress in the field is reviewed with emphasis on the following aspects: the types of ultrasound microbubbles, the construction of an ultrasound-mediated gene delivery system, the mechanism of ultrasound microbubble-mediated gene transfer and the application of ultrasound microbubbles in the treatment of liver fibrosis.

  17. Advances in ultrasound-targeted microbubble-mediated gene therapy for liver fibrosis

    Directory of Open Access Journals (Sweden)

    Cuiyuan Huang

    2017-07-01

    Full Text Available Hepatic fibrosis develops as a wound-healing scar in response to acute and chronic liver inflammation and can lead to cirrhosis in patients with chronic hepatitis B and C. The condition arises due to increased synthesis and reduced degradation of extracellular matrix (ECM and is a common pathological sequela of chronic liver disease. Excessive deposition of ECM in the liver causes liver dysfunction, ascites, and eventually upper gastrointestinal bleeding as well as a series of complications. However, fibrosis can be reversed before developing into cirrhosis and has thus been the subject of extensive researches particularly at the gene level. Currently, therapeutic genes are imported into the damaged liver to delay or prevent the development of liver fibrosis by regulating the expression of exogenous genes. One technique of gene delivery uses ultrasound targeting of microbubbles combined with therapeutic genes where the time and intensity of the ultrasound can control the release process. Ultrasound irradiation of microbubbles in the vicinity of cells changes the permeability of the cell membrane by its cavitation effect and enhances gene transfection. In this paper, recent progress in the field is reviewed with emphasis on the following aspects: the types of ultrasound microbubbles, the construction of an ultrasound-mediated gene delivery system, the mechanism of ultrasound microbubble–mediated gene transfer and the application of ultrasound microbubbles in the treatment of liver fibrosis.

  18. Exploring the need for Transition Readiness Scales within cystic fibrosis services: A qualitative descriptive study.

    Science.gov (United States)

    Bourke, Mary; Houghton, Catherine

    2018-07-01

    To explore healthcare professionals' and patients' perceptions of the potential use of a Transition Readiness Scale in cystic fibrosis care. This included an examination of barriers and facilitators to its implementation along with the identification of key items to include in a Transition Readiness Scale. Due to increasing life expectancy and improved quality of life, more adolescents with cystic fibrosis are transitioning from paediatric to adult health care. To assess and correctly manage this transition, a more structured approach to transition is advocated. This can be achieved using a Transition Readiness Scale to potentially identify or target areas of care in which the adolescent may have poor knowledge. These key items include education, developmental readiness taking into account relationships, reproduction, future plans and self-management skills. Existing tools to gauge readiness concentrate mainly on education and self-care needs assessment as their key items. Currently, there is no specific cystic fibrosis Transition Readiness Scale in use in Ireland or internationally. The study used a descriptive qualitative design. Data were collected using semi-structured interviews (n = 8) and analysed using a thematic approach. The findings identified the potential benefits of this tool and second the resources which need to be in place before its development and implementation into cystic fibrosis services. Transition Readiness Scales have substantial relevance with cystic fibrosis services emphasising the importance of establishing the necessary resources prior to its implementation. These were identified as more staff, a dedicated private space and staff training and education. Significant resources are needed to fully integrate Transition Readiness Scales in practice. The study findings suggest multidisciplinary collaborations, and patient engagement is pivotal in planning and easing the transition process for adolescents with cystic fibrosis. © 2018 The

  19. Individual radiosensitivity measured with lymphocytes can be used to predict the risk of fibrosis after radiotherapy of breast cancer patients

    International Nuclear Information System (INIS)

    Hoeller, U.; Borgmann, K.; Alberti, W.; Dikomey, E.

    2003-01-01

    To analyse the relationship of individual cellular radiosensitivity and fibrosis after breast conserving therapy. A new model was used describing the percentage of patients developing fibrosis per year per patients at risk . In a retrospective study, 86 patients were included, who had undergone breast conserving surgery and irradiation of the breast with a median dose of 55 Gy (54-55Gy), 2.5 Gy/fraction (n=57) or 2 Gy/fraction (n=29). Median age was 62 years (range: 44-86) and median follow up was 7.5 years (range 5-16). Patients were examined for fibrosis according to the LENT/SOMA score. For analysis, fibrosis was classified as none (G0-1) or present (G2-3). The time to complete development of fibrosis was determined by analysis of yearly mammograms. Individual cellular radiosensitivity was determined by scoring lethal chromosomal aberrations in in vitro irradiated (6 Gy) lymphocytes using metaphase technique. Patients with low/intermediate cellular radiosensitivity were compared with patients with high cellular radiosensitivity with actuarial methods. Ten patients developed fibrosis at 1-8 years after radiotherapy. Individual cellular radiosensitivity was described by normal distribution of lethal chromosomal aberrations, average 5.47 lethal aberrations per cell (standard deviation 0.71). Cellular radiosensitivity was defined as low/intermediate (le 6.18 lethal aberrations) in 73 patients and as high (> 6.18 lethal aberrations ) in 13 patients. In both groups the actuarial rate of fibrosis-free patients declined exponentially with time after radiotherapy. Patients with high cellular radiosensitivity showed a 2.3 fold higher annual rate for fibrosis than patients with intermediate and low radiosensitivity (3.6±0.1 vs. 1.6±0.3). In breast cancer patients, high individual cellular radiosensitivity as determined by the number of lethal chromosome aberrations in in vitro irradiated lymphocytes was correlated with an enhanced annual rate of fibrosis

  20. Vitamin D deficiency as a risk factor for cystic fibrosis-related diabetes in the Scandinavian Cystic Fibrosis Nutritional Study

    DEFF Research Database (Denmark)

    Pincikova, T; Nilsson, Kristine Kahr; Moen, I E

    2011-01-01

    Many cystic fibrosis patients are vitamin D-insufficient. Cystic fibrosis-related diabetes is a major complication of cystic fibrosis. The literature suggests that vitamin D might possess certain glucose-lowering properties. We aimed to assess the relationship between vitamin D and cystic fibrosis...

  1. Algorithm of Golgi protein 73 and liver stiffness accurately diagnoses significant fibrosis in chronic HBV infection.

    Science.gov (United States)

    Cao, Zhujun; Li, Ziqiang; Wang, Hui; Liu, Yuhan; Xu, Yumin; Mo, Ruidong; Ren, Peipei; Chen, Lichang; Lu, Jie; Li, Hong; Zhuang, Yan; Liu, Yunye; Wang, Xiaolin; Zhao, Gangde; Tang, Weiliang; Xiang, Xiaogang; Cai, Wei; Liu, Longgen; Bao, Shisan; Xie, Qing

    2017-11-01

    Serum Golgi protein 73 (GP73) is a potential biomarker for fibrosis assessment. We aimed to develop an algorithm based on GP73 and liver stiffness (LS) for further improvement of accuracy for significant fibrosis in patients with antiviral-naïve chronic hepatitis B virus (HBV) infection. Diagnostic accuracy evaluation of GP73 and development of GP73-LS algorithm was performed in training cohort (n = 267) with an independent cohort (n = 133) for validation. A stepwise increasing pattern of serum GP73 was observed across fibrosis stages in patients with antiviral-naïve chronic HBV infection. Serum GP73 significantly correlated (rho = 0.48, P 73, accuracy: 63.6%). Using GP73-LS algorithm, GP73 < 63 in agreement with LS < 8.5 provided accuracy of 81.7% to excluded significant fibrosis. GP73 ≥ 63 in agreement with LS ≥ 8.5 provided accuracy of 93.3% to confirm significant fibrosis. Almost 64% or 68% of patients in the training or validation cohort could be accurately classified. Serum GP73 is a robust biomarker for significant fibrosis diagnosis. GP73-LS algorithm provided better diagnostic accuracy than currently available approaches. More than 60% antiviral naïve CHB patients could use this algorithm without resorting to liver biopsy. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Assessment of disease activity of idiopathic pulmonary fibrosis (IPF) using FDG PET and high-resolution computed tomography (HRCT)

    International Nuclear Information System (INIS)

    Kim, Bom Sahn; Kang, Won Jun; Oh, So Won; Lee, Jeong Won; Kang, Ji Yeon; Lee, Dong Soo; Chung, June Key; Lee, Myung Chul

    2007-01-01

    Idiopathic pulmonary fibrosis (lPF) is induced by an uncontrolled accumulation and an activation of fibroblasts. The activity of IPF can be assessed according to the degrees of fibrosis and ground glass opacity (GGO) on HRCT. However, it has been thought that FDG PET reflects activity of inflammatory disease. The aim of this study was to compare the HRCT score and FDG uptake in patients with IPF. Six patients with IPF (M: F=4: 2, age 66.513.8 y) who underwent both FDG PET-CT and HRCT were enrolled (interval=33.042.6 d). The activity of IPF was scored at the level of the 1 cm above the diaphragm on HRCT, which was thought to be standard level of lower lobe. The degree of fibrosis was scored from 0 to 5 (0: no fibrosis, 1: interlobular septal wall thickening, 2: 75%). GGO was quantified from 0 to 5 (0: no GGO, 1: = 5 % of the lobe, 2: 5- 75%). Total score of HRCT was defined as the summed score of fibrosis and GGO. Standardized uptake value (SUV) was measured on same plane of FDG PET-CT by manual drawing of region of interest (ROI). SUV ratio of lung to liver was used as a metabolic marker of IPF activity. SUV ratio had a positive correlation with fibrosis score of HRCT (r=0.727, p=0.027), but did not have a significant correlation with GGO score (r=0.228, p=0.556). SUV ratio had a better correlation with total score of HRCT (r=0.895 and p<0.001). We demonstrated that SUV ratio might reflect disease activity of IPF. SUV ratio had a positive correlation with fibrosis score or total score on HRCT. FDG PET could be used to assess disease activity of IPF

  3. Ultrasound Elastography Is Useful for Evaluation of Liver Fibrosis in Children

    DEFF Research Database (Denmark)

    Andersen, Sofie Bech; Ewertsen, Caroline; Carlsen, Jonathan Frederik

    2016-01-01

    OBJECTIVES: Adult studies have proven ultrasound elastography as a validated measure of liver fibrosis. The present study aimed to review the available literature on ultrasound elastography in children to evaluate the ability of the method to distinguish healthy from fibrotic liver tissue...... and investigate whether cutoff values for liver fibrosis in children have been established. METHODS: A literature search was performed in MEDLINE, EMBASE, the Cochrane Library, and Web of Science to identify studies on ultrasound elastography of the liver in children. Only original research articles in English...

  4. Vitamin K supplementation for cystic fibrosis.

    Science.gov (United States)

    Jagannath, Vanitha A; Thaker, Vidhu; Chang, Anne B; Price, Amy I

    2017-08-22

    Cystic fibrosis is a genetic disorder which can lead to multiorgan dysfunction. Malabsorption of fat and fat-soluble vitamins (A, D, E, K) may occur and can cause subclinical deficiencies of some of these vitamins. Vitamin K is known to play an important role in both blood coagulation and bone formation. Supplementation with vitamin K appears to be one way of addressing the deficiency, but there is very limited agreement on the appropriate dose and frequency of use of these supplements. This is an updated version of the review. To assess the effects of vitamin K supplementation in people with cystic fibrosis and to determine the optimal dose and route of administration of vitamin K for both routine and therapeutic use. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Most recent search: 30 January 2017. Randomised and quasi-randomised controlled trials of all preparations of vitamin K used as a supplement compared to either no supplementation (or placebo) at any dose or route and for any duration, in children or adults diagnosed with cystic fibrosis (by sweat test or genetic testing). Two authors independently screened papers, extracted trial details and assessed their risk of bias. Two trials (total of 32 participants) each lasting one month were included in the review and were assessed as having a moderate risk of bias. One was a dose-ranging parallel group trial in children (aged 8 to 18 years); and the other (with an older cohort) had a cross-over design comparing supplements to no treatment, but no separate data were reported for the first intervention period. Neither of the trials addressed any of the primary outcomes (coagulation, bone formation and quality of life). Both trials reported the restoration of serum vitamin K and undercarboxylated osteocalcin

  5. Validation of Shear Wave Elastography Cutoff Values on the Supersonic Aixplorer for Practical Clinical Use in Liver Fibrosis Staging.

    Science.gov (United States)

    Dhyani, Manish; Grajo, Joseph R; Bhan, Atul K; Corey, Kathleen; Chung, Raymond; Samir, Anthony E

    2017-06-01

    The purpose of this study was to determine the validity of previously established ultrasound shear wave elastography (SWE) cut-off values (≥F2 fibrosis) on an independent cohort of patients with chronic liver disease. In this cross-sectional study, approved by the institutional review board and compliant with the Health Insurance Portability and Accountability Act, 338 patients undergoing liver biopsy underwent SWE using an Aixplorer ultrasound machine (SuperSonic Imagine, Aix-en-Provence, France). Median SWE values were calculated from sets of 10 elastograms. A single blinded pathologist evaluated METAVIR fibrosis staging as the gold standard. The study analyzed 277 patients with a mean age of 48 y. On pathologic examination, 212 patients (76.5%) had F0-F1 fibrosis, whereas 65 (23.5%) had ≥F2 fibrosis. Spearman's correlation of fibrosis with SWE was 0.456 (p Aixplorer SWE system. Copyright © 2017 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

  6. Vaccines for preventing infection with Pseudomonas aeruginosa in cystic fibrosis

    DEFF Research Database (Denmark)

    Johansen, H.K.; Gøtzsche, Peter C.; Johansen, Helle Krogh

    2008-01-01

    BACKGROUND: Chronic pulmonary infection in cystic fibrosis results in progressive lung damage. Once colonisation of the lungs with Pseudomonas aeruginosa occurs, it is almost impossible to eradicate. Vaccines, aimed at reducing infection with Pseudomonas aeruginosa, have been developed. OBJECTIVES......: To assess the effectiveness of vaccination against Pseudomonas aeruginosa in cystic fibrosis. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register using the terms vaccines AND pseudomonas (last search May 2008) and PubMed using the terms vaccin* AND cystic...... fibrosis (last search May 2008). SELECTION CRITERIA: Randomised trials (published or unpublished) comparing Pseudomonas aeruginosa vaccines (oral, parenteral or intranasal) with control vaccines or no intervention in cystic fibrosis. DATA COLLECTION AND ANALYSIS: The authors independently selected trials...

  7. Angiogenesis in liver fibrosis

    NARCIS (Netherlands)

    Adlia, Amirah

    2017-01-01

    Angiogenesis emerges in parallel with liver fibrosis, but it is still unclear whether angiogenesis is a defense mechanism of the body in response to fibrosis, or whether it aggravates the fibrotic condition. In this thesis, Amirah Adlia applied different approaches to elucidate the role of

  8. Role of the renin-angiotensin system in hepatic fibrosis and portal hypertension.

    Science.gov (United States)

    Shim, Kwang Yong; Eom, Young Woo; Kim, Moon Young; Kang, Seong Hee; Baik, Soon Koo

    2018-05-01

    The renin-angiotensin system (RAS) is an important regulator of cirrhosis and portal hypertension. As hepatic fibrosis progresses, levels of the RAS components angiotensin (Ang) II, Ang-(1-7), angiotensin-converting enzyme (ACE), and Ang II type 1 receptor (AT1R) are increased. The primary effector Ang II regulates vasoconstriction, sodium homoeostasis, fibrosis, cell proliferation, and inflammation in various diseases, including liver cirrhosis, through the ACE/Ang II/AT1R axis in the classical RAS. The ACE2/Ang-(1-7)/Mas receptor and ACE2/Ang-(1-9)/AT2R axes make up the alternative RAS and promote vasodilation, antigrowth, proapoptotic, and anti-inflammatory effects; thus, countering the effects of the classical RAS axis to reduce hepatic fibrogenesis and portal hypertension. Patients with portal hypertension have been treated with RAS antagonists such as ACE inhibitors, Ang receptor blockers, and aldosterone antagonists, with very promising hemodynamic results. In this review, we examine the RAS, its roles in hepatic fibrosis and portal hypertension, and current therapeutic approaches based on the use of RAS antagonists in patients with portal hypertension.

  9. Oral submucous fibrosis: An update on current theories of pathogenesis.

    Science.gov (United States)

    Arakeri, Gururaj; Rai, Kirthi Kumar; Hunasgi, Santosh; Merkx, M A W; Gao, Shan; Brennan, Peter A

    2017-07-01

    Over the last 40 years, many theories linking oral submucous fibrosis (OSMF) to various risk factors have been proposed. Spicy, pungent foods and irritants such as supari (areca nut), paan (betel leaves), tobacco (through chewing or smoking)-the common Asian habits of chewing the aforementioned agents-have all been incriminated as causative agents. Systemic factors such as nutritional deficiency, genetic predisposition and autoimmunity have also been proposed in the pathogenesis of OSMF. However, the precise aetiology of OSMF is still unknown, and no conclusive evidence has been found despite many extensive investigations on implicated factors. Most of the ideas proposed have been derived from the existing clinical and epidemiological data. We present a comprehensive review of the various theories regarding the pathogenesis of the condition, but have not concentrated on malignant transformation in this article. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. Independent predictors of fibrosis in patients with nonalcoholic fatty liver disease.

    Science.gov (United States)

    Hossain, Noreen; Afendy, Arian; Stepanova, Maria; Nader, Fatema; Srishord, Manirath; Rafiq, Nila; Goodman, Zachary; Younossi, Zobair

    2009-11-01

    Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease. We investigated factors associated with advanced fibrosis in NAFLD. The study included 432 patients with histologically proven NAFLD (26.8% with nonalcoholic steatohepatitis [NASH] and 17.4% with moderate-to severe fibrosis). NASH was defined as steatosis, lobular inflammation, and ballooning degeneration with or without Mallory-Denk bodies and/or fibrosis. Fibrosis was classified into 2 groups: those with no or minimal fibrosis and those with moderate-to-severe fibrosis. Groups were compared using Mann-Whitney and chi-square method analyses. A model was constructed using a stepwise bidirectional method; its predictive power was measured using a 10-fold cross-validation technique. Patients with NASH were more likely to be male (P < .0001); have lower hip-to-waist ratios (P = .03); were less likely to be African American (P = .06); have higher levels of alanine aminotransferase (ALT; P < .0001), aspartate aminotransferase (AST; P < .0001), and serum triglycerides (P = .0154), but lower levels of high-density lipoprotein cholesterol (P < .0001). Patients with moderate-to-severe fibrosis were older (P = .0245); more likely to be male (P = .0189), Caucasian (P = .0382), have diabetes mellitus (P = .0238), and hypertension (P = .0375); and have a lower hip-to-waist ratio (P = .0077) but higher serum AST (P < .0001) and ALT (P < .0001) levels. The multivariate analysis model to predict moderate-to-severe fibrosis included male sex, Caucasian ethnicity, diabetes mellitus, and increased AST and ALT levels (model P value < .0001). In patients with NAFLD, diabetes mellitus and aminotransferase levels are independent predictors of moderate-to-severe fibrosis. They can be used to identify NAFLD patients at risk for advanced fibrosis.

  11. Evaluation of the aspartate aminotransferase/platelet ratio index and enhanced liver fibrosis tests to detect significant fibrosis due to chronic hepatitis C.

    Science.gov (United States)

    Petersen, John R; Stevenson, Heather L; Kasturi, Krishna S; Naniwadekar, Ashutosh; Parkes, Julie; Cross, Richard; Rosenberg, William M; Xiao, Shu-Yuan; Snyder, Ned

    2014-04-01

    The assessment of liver fibrosis in chronic hepatitis C patients is important for prognosis and making decisions regarding antiviral treatment. Although liver biopsy is considered the reference standard for assessing hepatic fibrosis in patients with chronic hepatitis C, it is invasive and associated with sampling and interobserver variability. Serum fibrosis markers have been utilized as surrogates for a liver biopsy. We completed a prospective study of 191 patients in which blood draws and liver biopsies were performed on the same visit. Using liver biopsies the sensitivity, specificity, and negative and positive predictive values for both aspartate aminotransferase/platelet ratio index (APRI) and enhanced liver fibrosis (ELF) were determined. The patients were divided into training and validation patient sets to develop and validate a clinically useful algorithm for differentiating mild and significant fibrosis. The area under the ROC curve for the APRI and ELF tests for the training set was 0.865 and 0.880, respectively. The clinical sensitivity in separating mild (F0-F1) from significant fibrosis (F2-F4) was 80% and 86.0% with a clinical specificity of 86.7% and 77.8%, respectively. For the validation sets the area under the ROC curve for the APRI and ELF tests was, 0.855 and 0.780, respectively. The clinical sensitivity of the APRI and ELF tests in separating mild (F0-F1) from significant (F2-F4) fibrosis for the validation set was 90.0% and 70.0% with a clinical specificity of 73.3% and 86.7%, respectively. There were no differences between the APRI and ELF tests in distinguishing mild from significant fibrosis for either the training or validation sets (P=0.61 and 0.20, respectively). Using APRI as the primary test followed by ELF for patients in the intermediate zone, would have decreased the number of liver biopsies needed by 40% for the validation set. Overall, use of our algorithm would have decreased the number of patients who needed a liver biopsy

  12. Neonatal cystic fibrosis screening test

    Science.gov (United States)

    Cystic fibrosis screening - neonatal; Immunoreactive trypsinogen; IRT test; CF - screening ... Cystic fibrosis is a disease passed down through families. CF causes thick, sticky mucus to build up in ...

  13. Radiation pneumonitis and fibrosis

    International Nuclear Information System (INIS)

    Shopova, V.; Salovsky, P.; Dancheva, V.

    2001-01-01

    The likelihood of toxic pulmonary lesions development as the result of radiation therapy for pulmonary carcinoma and breast cancer is discussed. Two possible forms of radiation induced changes are described, namely: classical radiation pneumonitis (RP) terminating with lung fibrosis circumscribed in the radiation zone, and sporadic RP giving rise to bilateral lymphatic alveolitis and manifestations outside the irradiation field. Attention is called to the fact that chemotherapy augments the risk of toxic lung damage occurrence. A number of markers for early RP diagnosis, including lactate dehydrogenase activity, KL-6, procollagen III, transforming growth factor β, C-reactive protein and partial oxygen pressure are listed. Therapeutic possibilities in coping with RP and pulmonary fibrosis are assayed. Apart from the standard therapeutic approach using corticosteroids and azatioprin, ideas are set forth concerning the application of some antioxidants, angiotensin converting enzyme inhibitors and γ-interferon. It is pointed out that radiation pneumonitis and pulmonary fibrosis treatment has an essential practical bearing on life expectancy and quality of life in a great number of cancer patients. (author)

  14. Monocyte Subsets in Schistosomiasis Patients with Periportal Fibrosis

    Directory of Open Access Journals (Sweden)

    Jamille Souza Fernandes

    2014-01-01

    Full Text Available A major issue with Schistosoma mansoni infection is the development of periportal fibrosis, which is predominantly caused by the host immune response to egg antigens. Experimental studies have pointed to the participation of monocytes in the pathogenesis of liver fibrosis. The aim of this study was to characterize the subsets of monocytes in individuals with different degrees of periportal fibrosis secondary to schistosomiasis. Monocytes were classified into classical (CD14++CD16−, intermediate (CD14++CD16+, and nonclassical (CD14+CD16++. The expressions of monocyte markers and cytokines were assessed using flow cytometry. The frequency of classical monocytes was higher than the other subsets. The expression of HLA-DR, IL-6, TNF-α, and TGF-β was higher in monocytes from individuals with moderate to severe fibrosis as compared to other groups. Although no differences were observed in receptors expression (IL-4R and IL-10R between groups of patients, the expression of IL-12 was lower in monocytes from individuals with moderate to severe fibrosis, suggesting a protective role of this cytokine in the development of fibrosis. Our data support the hypothesis that the three different monocyte populations participate in the immunopathogenesis of periportal fibrosis, since they express high levels of proinflammatory and profibrotic cytokines and low levels of regulatory markers.

  15. Fibrosis of Two: Epithelial Cell-Fibroblast Interactions in Pulmonary Fibrosis

    Science.gov (United States)

    Sakai, Norihiko; Tager, Andrew M.

    2013-01-01

    Idiopathic pulmonary fibrosis (IPF) is characterized by the progressive and ultimately fatal accumulation of fibroblasts and extracellular matrix in the lung that distorts its architecture and compromises its function. IPF is now thought to result from wound-healing processes that, although initiated to protect the host from injurious environmental stimuli, lead to pathological fibrosis due to these processes becoming aberrant or over-exuberant. Although the environmental stimuli that trigger IPF remain to be identified, recent evidence suggests that they initially injure the alveolar epithelium. Repetitive cycles of epithelial injury and resultant alveolar epithelial cell death provoke the migration, proliferation, activation and myofibroblast differentiation of fibroblasts, causing the accumulation of these cells and the extracellular matrix that they synthesize. In turn, these activated fibroblasts induce further alveolar epithelial cell injury and death, thereby creating a vicious cycle of pro-fibrotic epithelial cell-fibroblast interactions. Though other cell types certainly make important contributions, we focus here on the “pas de deux” (steps of two), or perhaps more appropriate to IPF pathogenesis, the “folie à deux” (madness of two) of epithelial cells and fibroblasts that drives the progression of pulmonary fibrosis. We describe the signaling molecules that mediate the interactions of these cell types in their “fibrosis of two”, including transforming growth factor-β, connective tissue growth factor, sonic hedgehog, prostaglandin E2, angiotensin II and reactive oxygen species. PMID:23499992

  16. Breakdown in Breathing: The Complexities of Cystic Fibrosis

    Science.gov (United States)

    ... Healthier Lungs in Kids Wise Choices Living with Cystic Fibrosis In between checkups, practice good self-care and ... Links What Is Cystic Fibrosis? Learning About Cystic Fibrosis NIH Cystic Fibrosis Fact Sheet Genetic and Rare Diseases Information ...

  17. Innovating cystic fibrosis clinical trial designs in an era of successful standard of care therapies.

    Science.gov (United States)

    VanDevanter, Donald R; Mayer-Hamblett, Nicole

    2017-11-01

    Evolving cystic fibrosis 'standards of care' have influenced recent cystic fibrosis clinical trial designs for new therapies; care additions/improvements will require innovative trial designs to maximize feasibility and efficacy detection. Three cystic fibrosis therapeutic areas (pulmonary exacerbations, Pseudomonas aeruginosa airway infections, and reduced cystic fibrosis transmembrane conductance regulator [CFTR] protein function) differ with respect to the duration for which recognized 'standards of care' have been available. However, developers of new therapies in all the three areas are affected by similar challenges: standards of care have become so strongly entrenched that traditional placebo-controlled studies in cystic fibrosis populations likely to benefit from newer therapies have become less and less feasible. Today, patients/clinicians are more likely to entertain participation in active-comparator trial designs, that have substantial challenges of their own. Foremost among these are the selection of 'valid' active comparator(s), estimation of a comparator's current clinical efficacy (required for testing noninferiority hypotheses), and effective blinding of commercially available comparators. Recent and future cystic fibrosis clinical trial designs will have to creatively address this collateral result of successful past development of effective cystic fibrosis therapies: patients and clinicians are much less likely to accept simple, placebo-controlled studies to evaluate future therapies.

  18. Phosphoproteomic biomarkers predicting histologic nonalcoholic steatohepatitis and fibrosis.

    Science.gov (United States)

    Younossi, Zobair M; Baranova, Ancha; Stepanova, Maria; Page, Sandra; Calvert, Valerie S; Afendy, Arian; Goodman, Zachary; Chandhoke, Vikas; Liotta, Lance; Petricoin, Emanuel

    2010-06-04

    The progression of nonalcoholic fatty liver disease (NAFLD) has been linked to deregulated exchange of the endocrine signaling between adipose and liver tissue. Proteomic assays for the phosphorylation events that characterize the activated or deactivated state of the kinase-driven signaling cascades in visceral adipose tissue (VAT) could shed light on the pathogenesis of nonalcoholic steatohepatitis (NASH) and related fibrosis. Reverse-phase protein microarrays (RPMA) were used to develop biomarkers for NASH and fibrosis using VAT collected from 167 NAFLD patients (training cohort, N = 117; testing cohort, N = 50). Three types of models were developed for NASH and advanced fibrosis: clinical models, proteomics models, and combination models. NASH was predicted by a model that included measurements of two components of the insulin signaling pathway: AKT kinase and insulin receptor substrate 1 (IRS1). The models for fibrosis were less reliable when predictions were based on phosphoproteomic, clinical, or the combination data. The best performing model relied on levels of the phosphorylation of GSK3 as well as on two subunits of cyclic AMP regulated protein kinase A (PKA). Phosphoproteomics technology could potentially be used to provide pathogenic information about NASH and NASH-related fibrosis. This information can lead to a clinically relevant diagnostic/prognostic biomarker for NASH.

  19. The cost-effectiveness of neonatal screening for Cystic Fibrosis: an analysis of alternative scenarios using a decision model

    Directory of Open Access Journals (Sweden)

    Tu Karen

    2005-08-01

    Full Text Available Abstract Background The use of neonatal screening for cystic fibrosis is widely debated in the United Kingdom and elsewhere, but the evidence available to inform policy is limited. This paper explores the cost-effectiveness of adding screening for cystic fibrosis to an existing routine neonatal screening programme for congenital hypothyroidism and phenylketonuria, under alternative scenarios and assumptions. Methods The study is based on a decision model comparing screening to no screening in terms of a number of outcome measures, including diagnosis of cystic fibrosis, life-time treatment costs, life years and QALYs gained. The setting is a hypothetical UK health region without an existing neonatal screening programme for cystic fibrosis. Results Under initial assumptions, neonatal screening (using an immunoreactive trypsin/DNA two stage screening protocol costs £5,387 per infant diagnosed, or £1.83 per infant screened (1998 costs. Neonatal screening for cystic fibrosis produces an incremental cost-effectiveness of £6,864 per QALY gained, in our base case scenario (an assumed benefit of a 6 month delay in the emergence of symptoms. A difference of 11 months or more in the emergence of symptoms (and mean survival means neonatal screening is both less costly and produces better outcomes than no screening. Conclusion Neonatal screening is expensive as a method of diagnosis. Neonatal screening may be a cost-effective intervention if the hypothesised delays in the onset of symptoms are confirmed. Implementing both antenatal and neonatal screening would undermine potential economic benefits, since a reduction in the birth incidence of cystic fibrosis would reduce the cost-effectiveness of neonatal screening.

  20. Blood Gene Expression Profiling of Breast Cancer Survivors Experiencing Fibrosis

    International Nuclear Information System (INIS)

    Landmark-Hoyvik, Hege; Dumeaux, Vanessa; Reinertsen, Kristin V.; Edvardsen, Hege; Fossa, Sophie D.; Borresen-Dale, Anne-Lise

    2011-01-01

    Purpose: To extend knowledge on the mechanisms and pathways involved in maintenance of radiation-induced fibrosis (RIF) by performing gene expression profiling of whole blood from breast cancer (BC) survivors with and without fibrosis 3-7 years after end of radiotherapy treatment. Methods and Materials: Gene expression profiles from blood were obtained for 254 BC survivors derived from a cohort of survivors, treated with adjuvant radiotherapy for breast cancer 3-7 years earlier. Analyses of transcriptional differences in blood gene expression between BC survivors with fibrosis (n = 31) and BC survivors without fibrosis (n = 223) were performed using R version 2.8.0 and tools from the Bioconductor project. Gene sets extracted through a literature search on fibrosis and breast cancer were subsequently used in gene set enrichment analysis. Results: Substantial differences in blood gene expression between BC survivors with and without fibrosis were observed, and 87 differentially expressed genes were identified through linear analysis. Transforming growth factor-β1 signaling was identified as the most significant gene set, showing a down-regulation of most of the core genes, together with up-regulation of a transcriptional activator of the inhibitor of fibrinolysis, Plasminogen activator inhibitor 1 in the BC survivors with fibrosis. Conclusion: Transforming growth factor-β1 signaling was found down-regulated during the maintenance phase of fibrosis as opposed to the up-regulation reported during the early, initiating phase of fibrosis. Hence, once the fibrotic tissue has developed, the maintenance phase might rather involve a deregulation of fibrinolysis and altered degradation of extracellular matrix components.

  1. Accuracy of the Enhanced Liver Fibrosis Test vs FibroTest, Elastography, and Indirect Markers in Detection of Advanced Fibrosis in Patients With Alcoholic Liver Disease.

    Science.gov (United States)

    Thiele, Maja; Madsen, Bjørn Stæhr; Hansen, Janne Fuglsang; Detlefsen, Sönke; Antonsen, Steen; Krag, Aleksander

    2018-04-01

    Alcohol is the leading cause of cirrhosis and liver-related mortality, but we lack serum markers to detect compensated disease. We compared the accuracy of the Enhanced Liver Fibrosis test (ELF), the FibroTest, liver stiffness measurements (made by transient elastography and 2-dimensional shear-wave elastography), and 6 indirect marker tests in detection of advanced liver fibrosis (Kleiner stage ≥F3). We performed a prospective study of 10 liver fibrosis markers (patented and not), all performed on the same day. Patients were recruited from primary centers (municipal alcohol rehabilitation, n = 128; 6% with advanced fibrosis) and secondary health care centers (hospital outpatient clinics, n = 161; 36% with advanced fibrosis) in the Region of Southern Denmark from 2013 through 2016. Biopsy-verified fibrosis stage was used as the reference standard. The primary aim was to validate ELF in detection of advanced fibrosis in patients with alcoholic liver disease recruited from primary and secondary health care centers, using the literature-based cutoff value of 10.5. Secondary aims were to assess the diagnostic accuracy of ELF for significant fibrosis and cirrhosis and to determine whether combinations of fibrosis markers increase diagnostic yield. The ELF identified patients with advanced liver fibrosis with an area under the receiver operating characteristic curve (AUROC) of 0.92 (95% confidence interval 0.89-0.96); findings did not differ significantly between patients from primary vs secondary care (P = .917). ELF more accurately identified patients with advanced liver fibrosis than indirect marker tests, but ELF and FibroTest had comparable diagnostic accuracies (AUROC of FibroTest, 0.90) (P = .209 for comparison with ELF). Results from the ELF and FibroTest did not differ significantly from those of liver stiffness measurement in intention-to-diagnose analyses (AUROC for transient elastography, 0.90), but did differ in the per-protocol analysis (AUROC for

  2. Nephrogenic systemic fibrosis

    DEFF Research Database (Denmark)

    Marckmann, Peter

    2008-01-01

    PURPOSE OF REVIEW: The aim of this article is to outline the history of nephrogenic systemic fibrosis, a new and serious disease of patients with renal failure, and to give an update on its aetiology and prevalence. RECENT FINDINGS: Epidemiological and histochemical studies demonstrated....... Increasingly poor renal function, aberrations in calcium-phosphate metabolism and erythropoietin treatment seem to increase the risk of the disease and its severity. Up to 25-30% of patients with renal failure exposed to gadolinium-based contrast agents may develop nephrogenic systemic disease. The figure...... that gadolinium-containing contrast agents used for magnetic resonance imaging have an essential causative role in most, if not all, cases of nephrogenic systemic fibrosis. One particular agent, gadodiamide, caused the majority of cases, but gadopentetate dimeglumine has also been implicated in several cases...

  3. Prediction of liver-related events using fibroscan in chronic hepatitis B patients showing advanced liver fibrosis.

    Directory of Open Access Journals (Sweden)

    Seung Up Kim

    Full Text Available Liver stiffness measurement (LSM using transient elastography (FibroScan® can assess liver fibrosis noninvasively. This study investigated whether LSM can predict the development of liver-related events (LREs in chronic hepatitis B (CHB patients showing histologically advanced liver fibrosis.Between March 2006 and April 2010, 128 CHB patients with who underwent LSM and liver biopsy (LB before starting nucleot(side analogues and showed histologically advanced fibrosis (≥F3 with a high viral loads [HBV DNA ≥2,000 IU/mL] were enrolled. All patients were followed regularly to detect LRE development, including hepatic decompensation (variceal bleeding, ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome and hepatocellular carcinoma (HCC.The mean age of the patient (72 men, 56 women was 52.2 years. During the median follow-up period [median 27.8 (12.6-61.6 months], LREs developed in 19 (14.8% patients (five with hepatic decompensation, 13 with HCC, one with both. Together with age, multivariate analysis identified LSM as an independent predictor of LRE development [P19 kPa were at significantly greater risk than those with LSM≤19 kPa for LRE development (HR, 7.176; 95% CI, 2.257-22.812; P = 0.001.LSM can be a useful predictor of LRE development in CHB patients showing histologically advanced liver fibrosis.

  4. Taurine attenuates radiation-induced lung fibrosis in C57/Bl6 fibrosis prone mice.

    LENUS (Irish Health Repository)

    Robb, W B

    2010-03-01

    The amino acid taurine has an established role in attenuating lung fibrosis secondary to bleomycin-induced injury. This study evaluates taurine\\'s effect on TGF-beta1 expression and the development of lung fibrosis after single-dose thoracic radiotherapy.

  5. Assessment of disease activity of idiopathic pulmonary fibrosis (IPF) using FDG PET and high-resolution computed tomography (HRCT)

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Bom Sahn; Kang, Won Jun; Oh, So Won; Lee, Jeong Won; Kang, Ji Yeon; Lee, Dong Soo; Chung, June Key; Lee, Myung Chul [Seoul National Univ. College of Medicine, Seoul (Korea, Republic of)

    2007-07-01

    Idiopathic pulmonary fibrosis (lPF) is induced by an uncontrolled accumulation and an activation of fibroblasts. The activity of IPF can be assessed according to the degrees of fibrosis and ground glass opacity (GGO) on HRCT. However, it has been thought that FDG PET reflects activity of inflammatory disease. The aim of this study was to compare the HRCT score and FDG uptake in patients with IPF. Six patients with IPF (M: F=4: 2, age 66.513.8 y) who underwent both FDG PET-CT and HRCT were enrolled (interval=33.042.6 d). The activity of IPF was scored at the level of the 1 cm above the diaphragm on HRCT, which was thought to be standard level of lower lobe. The degree of fibrosis was scored from 0 to 5 (0: no fibrosis, 1: interlobular septal wall thickening, 2: <25 % of the lobe, 3: 25-49 %, 4: 50-75 %, 5: >75%). GGO was quantified from 0 to 5 (0: no GGO, 1: = 5 % of the lobe, 2: 5-<25 %, 3: 25-49 %, 4: 50-75%, 5: >75%). Total score of HRCT was defined as the summed score of fibrosis and GGO. Standardized uptake value (SUV) was measured on same plane of FDG PET-CT by manual drawing of region of interest (ROI). SUV ratio of lung to liver was used as a metabolic marker of IPF activity. SUV ratio had a positive correlation with fibrosis score of HRCT (r=0.727, p=0.027), but did not have a significant correlation with GGO score (r=0.228, p=0.556). SUV ratio had a better correlation with total score of HRCT (r=0.895 and p<0.001). We demonstrated that SUV ratio might reflect disease activity of IPF. SUV ratio had a positive correlation with fibrosis score or total score on HRCT. FDG PET could be used to assess disease activity of IPF.

  6. MicroRNA mimicry blocks pulmonary fibrosis

    Science.gov (United States)

    Montgomery, Rusty L; Yu, Guoying; Latimer, Paul A; Stack, Christianna; Robinson, Kathryn; Dalby, Christina M; Kaminski, Naftali; van Rooij, Eva

    2014-01-01

    Over the last decade, great enthusiasm has evolved for microRNA (miRNA) therapeutics. Part of the excitement stems from the fact that a miRNA often regulates numerous related mRNAs. As such, modulation of a single miRNA allows for parallel regulation of multiple genes involved in a particular disease. While many studies have shown therapeutic efficacy using miRNA inhibitors, efforts to restore or increase the function of a miRNA have been lagging behind. The miR-29 family has gained a lot of attention for its clear function in tissue fibrosis. This fibroblast-enriched miRNA family is downregulated in fibrotic diseases which induces a coordinate increase of many extracellular matrix genes. Here, we show that intravenous injection of synthetic RNA duplexes can increase miR-29 levels in vivo for several days. Moreover, therapeutic delivery of these miR-29 mimics during bleomycin-induced pulmonary fibrosis restores endogenous miR-29 function whereby decreasing collagen expression and blocking and reversing pulmonary fibrosis. Our data support the feasibility of using miRNA mimics to therapeutically increase miRNAs and indicate miR-29 to be a potent therapeutic miRNA for treating pulmonary fibrosis. PMID:25239947

  7. Grape seed extract ameliorates bleomycin-induced mouse pulmonary fibrosis.

    Science.gov (United States)

    Liu, Qi; Jiang, Jun-Xia; Liu, Ya-Nan; Ge, Ling-Tian; Guan, Yan; Zhao, Wei; Jia, Yong-Liang; Dong, Xin-Wei; Sun, Yun; Xie, Qiang-Min

    2017-05-05

    Pulmonary fibrosis is common in a variety of inflammatory lung diseases, such as interstitial pneumonia, chronic obstructive pulmonary disease, and silicosis. There is currently no effective clinical drug treatment. It has been reported that grape seed extracts (GSE) has extensive pharmacological effects with minimal toxicity. Although it has been found that GSE can improve the lung collagen deposition and fibrosis pathology induced by bleomycin in rat, its effects on pulmonary function, inflammation, growth factors, matrix metalloproteinases and epithelial-mesenchymal transition remain to be researched. In the present study, we studied whether GSE provided protection against bleomycin (BLM)-induced mouse pulmonary fibrosis. ICR strain mice were treated with BLM in order to establish pulmonary fibrosis models. GSE was given daily via intragastric administration for three weeks starting at one day after intratracheal instillation. GSE at 50 or 100mg/kg significantly reduced BLM-induced inflammatory cells infiltration, proinflammatory factor protein expression, and hydroxyproline in lung tissues, and improved pulmonary function in mice. Additionally, treatment with GSE also significantly impaired BLM-induced increases in lung fibrotic marker expression (collagen type I alpha 1 and fibronectin 1) and decreases in an anti-fibrotic marker (E-cadherin). Further investigation indicated that the possible molecular targets of GSE are matrix metalloproteinases-9 (MMP-9) and TGF-β1, given that treatment with GSE significantly prevented BLM-induced increases in MMP-9 and TGF-β1 expression in the lungs. Together, these results suggest that supplementation with GSE may improve the quality of life of lung fibrosis patients by inhibiting MMP-9 and TGF-β1 expression in the lungs. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Pathogenic aspects and therapeutic avenues of intestinal fibrosis in Crohn's disease.

    Science.gov (United States)

    Zorzi, Francesca; Calabrese, Emma; Monteleone, Giovanni

    2015-12-01

    In Crohn's disease, one of the two major forms of inflammatory bowel diseases in human beings, persistent and chronic inflammation promotes fibrotic processes thereby facilitating formation of strictures, the most common indication for surgical intervention in this disorder. The pathogenesis of Crohn's disease-associated fibrosis is not fully understood, but variants of genes involved in the recognition of microbial components/products [e.g. CARD15 (caspase-activating recruitment domain 15) and ATG16L1 (autophagy-related 16-like 1)] are associated with this phenotype, and experimental evidence suggests that intestinal fibrosis results from an altered balance between deposition of ECM (extracellular matrix) and degradation of ECM by proteases. Studies have also contributed to identify the main phenotypic and functional alterations of cells involved in the fibrogenic process, as well as molecules that stimulate such cells to produce elevated amounts of collagen and other ECM-related proteins. In the present review, we assess the current knowledge about cellular and molecular mediators of intestinal fibrosis and describe results of recent studies aimed at testing the preventive/therapeutic effect of compounds in experimental models of intestinal fibrosis. © 2015 Authors; published by Portland Press Limited.

  9. Serum adiponectin is increased in advancing liver fibrosis and declines with reduction in fibrosis in chronic hepatitis B.

    Science.gov (United States)

    Hui, Chee-Kin; Zhang, Hai-Ying; Lee, Nikki P; Chan, Weng; Yueng, Yui-Hung; Leung, Kar-Wai; Lu, Lei; Leung, Nancy; Lo, Chung-Mau; Fan, Sheung-Tat; Luk, John M; Xu, Aimin; Lam, Karen S; Kwong, Yok-Lam; Lau, George K K

    2007-08-01

    Despite the possible role of adiponectin in the pathogenesis of liver cirrhosis, few data have been collected from patients in different stages of liver fibrosis. We studied the role of adiponectin in 2 chronic hepatitis B (CHB)-patient cohorts. Serum adiponectin was quantified by enzyme-linked immunosorbent assay. One-hundred liver biopsy specimens from CHB patients with different stages of fibrosis and 38 paired liver biopsies from hepatitis B e antigen-positive patients randomized to lamivudine (n=15), pegylated interferon alfa-2a (n=15) or pegylated interferon alfa-2a plus lamivudine (n=8) therapy for 48 weeks were assessed. Serum adiponectin was detected at levels ranging over fourfold magnitude with advancing fibrosis stage and correlated positively with fibrosis stage [r=0.45, p<0.001]. CHB patients with stage 0-1 fibrosis had higher composition of high molecular weight (HMW) form of adiponectin when compared with CHB patients with liver cirrhosis [mean+/-SEM 51.2+/-2.1% vs. 40.9+/-1.7%, respectively, p=0.001]. After antiviral therapy, patients with fibrosis reduction had marked decline in serum adiponectin level and increase in HMW form of adiponectin [mean+/-SEM 43.5+/-1.2% vs. 37.0+/-3.0%, respectively, p=0.04]. Serum adiponectin may have a role in fibrosis progression in CHB infection. A marked decline in serum adiponectin after antiviral therapy is associated with fibrosis reduction.

  10. Endomyocardial fibrosis in infancy

    Directory of Open Access Journals (Sweden)

    Jatene Marcelo Biscegli

    2003-01-01

    Full Text Available The patient was a 4-month-old infant, who underwent persistent ductus arteriosus interruption with titanium clips at the age of 13 days and, since the age of 2 months, had crises of hypoxia and hypertonicity. After clinical investigation, the presence of pulmonary hypertension was confirmed and left ventricular inflow tract obstruction was suspected. The patient underwent surgical treatment at the age of 4 months, during which right and left ventricular endocardial fibrosis was identified. The fibrosis was resected, but the infant had an unfavorable clinical evolution with significant diastolic restriction and died on the sixth postoperative day. Anatomicopathological and surgical findings suggested endomyocardial fibrosis, although that pathology is very rare at the patient's age.

  11. Basigin/CD147 promotes renal fibrosis after unilateral ureteral obstruction.

    Science.gov (United States)

    Kato, Noritoshi; Kosugi, Tomoki; Sato, Waichi; Ishimoto, Takuji; Kojima, Hiroshi; Sato, Yuka; Sakamoto, Kazuma; Maruyama, Shoichi; Yuzawa, Yukio; Matsuo, Seiichi; Kadomatsu, Kenji

    2011-02-01

    Regardless of their primary causes, progressive renal fibrosis and tubular atrophy are the main predictors of progression to end-stage renal disease. Basigin/CD147 is a multifunctional molecule-it induces matrix metalloproteinases and hyaluronan, for example-and has been implicated in organ fibrosis. However, the relationship between basigin and organ fibrosis has been poorly studied. We investigated basigin's role in renal fibrosis using a unilateral ureteral obstruction model. Basigin-deficient mice (Bsg(-/-)) demonstrated significantly less fibrosis after surgery than Bsg(+/+) mice. Fewer macrophages had infiltrated in Bsg(-/-) kidneys. Consistent with these in vivo data, primary cultured tubular epithelial cells from Bsg(-/-) mice produced less matrix metalloproteinase and exhibited less motility on stimulation with transforming growth factor β. Furthermore, Bsg(-/-) embryonic fibro blasts produced less hyaluronan and α-smooth muscle actin after transforming growth factor β stimulation. Together, these results demonstrate for the first time that basigin is a key regulator of renal fibrosis. Basigin could be a candidate target molecule for the prevention of organ fibrosis. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  12. Gastrointestinal Manifestations of Cystic Fibrosis

    Science.gov (United States)

    2016-01-01

    Cystic fibrosis has historically been considered a pulmonary disease, but with the increasing life expectancy of these patients, gastrointestinal manifestations are becoming more important. Furthermore, nutritional status is closely linked to pulmonary function and, thus, overall mortality. This article discusses gastrointestinal manifestations (which involve nutritional, pancreatic, hepatobiliary, and, in particular, gastrointestinal tract issues) of cystic fibrosis as well as management of the disease. In addition, the article discusses studies that have been critical to our understanding of gastrointestinal manifestations of cystic fibrosis. PMID:27330503

  13. Prediction of fibrosis progression in chronic viral hepatitis

    Directory of Open Access Journals (Sweden)

    Grace Lai-Hung Wong

    2014-09-01

    Full Text Available Prediction of liver fibrosis progression has a key role in the management of chronic viral hepatitis, as it will be translated into the future risk of cirrhosis and its various complications including hepatocellular carcinoma. Both hepatitis B and C viruses mainly lead to fibrogenesis induced by chronic inflammation and a continuous wound healing response. At the same time direct and indirect profibrogenic responses are also elicited by the viral infection. There are a handful of well-established risk factors for fibrosis progression including older age, male gender, alcohol use, high viral load and co-infection with other viruses. Metabolic syndrome is an evolving risk factor of fibrosis progression. The new notion of regression of advanced fibrosis or even cirrhosis is now strongly supported various clinical studies. Even liver biopsy retains its important role in the assessment of fibrosis progression, various non-invasive assessments have been adopted widely because of their non-invasiveness, which facilitates serial applications in large cohorts of subjects. Transient elastography is one of the most validated tools which has both diagnostic and prognostic role. As there is no single perfect test for liver fibrosis assessment, algorithms combining the most validated noninvasive methods should be considered as initial screening tools.

  14. Origin and function of myofibroblasts in kidney fibrosis.

    Science.gov (United States)

    LeBleu, Valerie S; Taduri, Gangadhar; O'Connell, Joyce; Teng, Yingqi; Cooke, Vesselina G; Woda, Craig; Sugimoto, Hikaru; Kalluri, Raghu

    2013-08-01

    Myofibroblasts are associated with organ fibrosis, but their precise origin and functional role remain unknown. We used multiple genetically engineered mice to track, fate map and ablate cells to determine the source and function of myofibroblasts in kidney fibrosis. Through this comprehensive analysis, we identified that the total pool of myofibroblasts is split, with 50% arising from local resident fibroblasts through proliferation. The nonproliferating myofibroblasts derive through differentiation from bone marrow (35%), the endothelial-to-mesenchymal transition program (10%) and the epithelial-to-mesenchymal transition program (5%). Specific deletion of Tgfbr2 in α-smooth muscle actin (αSMA)(+) cells revealed the importance of this pathway in the recruitment of myofibroblasts through differentiation. Using genetic mouse models and a fate-mapping strategy, we determined that vascular pericytes probably do not contribute to the emergence of myofibroblasts or fibrosis. Our data suggest that targeting diverse pathways is required to substantially inhibit the composite accumulation of myofibroblasts in kidney fibrosis.

  15. Immunoreactive trypsin and neonatalscreening for cystic fibrosis

    International Nuclear Information System (INIS)

    Travert, G.; Laroche, D.; Blandin, C.; Pasquet, C.

    1988-01-01

    Immunoreactive trypsin (IRT) was measured in dried blood spots from 160.822 five-day-old babies as a part of a regionwide neonatal screening program for cystic fibrosis. A second test was performed for 492 babies in whom blood IRT levels were found greater than 900 μg/l; retesting revealed persistent elevation in 55. Sweat testing confirmed cystic fibrosis in 43 babies, but results were normal in 12. During the course of this study, a total of 51 cystic fibrosis babies were identified: 43 by newborn screening, 6 because they had meconium ileus; so, early diagnosis was achieved in 49 cases out of 51. Two newborn babies did not have elevated IRT and they were missed by the screening test. Our results confirm that elevated blood IRT is characteristic of newborn babies with cystic fibrosis and show that this test has an excellent specificity (99.7%) and a good sensitivity (95%) when used as a neonatal screening test [fr

  16. Molecular Mechanisms of Liver Fibrosis in HIV/HCV Coinfection

    Directory of Open Access Journals (Sweden)

    Claudio M. Mastroianni

    2014-05-01

    Full Text Available Chronic hepatitis C virus (HCV infection is an important cause of morbidity and mortality in people coinfected with human immunodeficiency virus (HIV. Several studies have shown that HIV infection promotes accelerated HCV hepatic fibrosis progression, even with HIV replication under full antiretroviral control. The pathogenesis of accelerated hepatic fibrosis among HIV/HCV coinfected individuals is complex and multifactorial. The most relevant mechanisms involved include direct viral effects, immune/cytokine dysregulation, altered levels of matrix metalloproteinases and fibrosis biomarkers, increased oxidative stress and hepatocyte apoptosis, HIV-associated gut depletion of CD4 cells, and microbial translocation. In addition, metabolic alterations, heavy alcohol use, as well drug use, may have a potential role in liver disease progression. Understanding the pathophysiology and regulation of liver fibrosis in HIV/HCV co-infection may lead to the development of therapeutic strategies for the management of all patients with ongoing liver disease. In this review, we therefore discuss the evidence and potential molecular mechanisms involved in the accelerated liver fibrosis seen in patients coinfected with HIV and HCV.

  17. Non-Invasive Evaluation of Cystic Fibrosis Related Liver Disease in Adults with ARFI, Transient Elastography and Different Fibrosis Scores

    OpenAIRE

    Karlas, Thomas; Neuschulz, Marie; Oltmanns, Annett; Güttler, Andrea; Petroff, David; Wirtz, Hubert; Mainz, Jochen G.; Mössner, Joachim; Berg, Thomas; Tröltzsch, Michael; Keim, Volker; Wiegand, Johannes

    2012-01-01

    BACKGROUND: Cystic fibrosis-related liver disease (CFLD) is present in up to 30% of cystic fibrosis patients and can result in progressive liver failure. Diagnosis of CFLD is challenging. Non-invasive methods for staging of liver fibrosis display an interesting diagnostic approach for CFLD detection. AIM: We evaluated transient elastography (TE), acoustic radiation force impulse imaging (ARFI), and fibrosis indices for CFLD detection. METHODS: TE and ARFI were performed in 55 adult CF patient...

  18. Amifostine Analog, DRDE-30, Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice

    Directory of Open Access Journals (Sweden)

    Aastha Arora

    2018-04-01

    Full Text Available Bleomycin (BLM is an effective curative option in the management of several malignancies including pleural effusions; but pulmonary toxicity, comprising of pneumonitis and fibrosis, poses challenge in its use as a front-line chemotherapeutic. Although Amifostine has been found to protect lungs from the toxic effects of radiation and BLM, its application is limited due to associated toxicity and unfavorable route of administration. Therefore, there is a need for selective, potent, and safe anti-fibrotic drugs. The current study was undertaken to assess the protective effects of DRDE-30, an analog of Amifostine, on BLM-induced lung injury in C57BL/6 mice. Whole body micro- computed tomography (CT was used to non-invasively observe tissue damage, while broncheo-alveolar lavage fluid (BALF and lung tissues were assessed for oxidative damage, inflammation and fibrosis. Changes in the lung density revealed by micro-CT suggested protection against BLM-induced lung injury by DRDE-30, which correlated well with changes in lung morphology and histopathology. DRDE-30 significantly blunted BLM-induced oxidative stress, inflammation and fibrosis in the lungs evidenced by reduced oxidative damage, endothelial barrier dysfunction, Myeloperoxidase (MPO activity, pro-inflammatory cytokine release and protection of tissue architecture, that could be linked to enhanced anti-oxidant defense system and suppression of redox-sensitive pro-inflammatory signaling cascades. DRDE-30 decreased the BLM-induced augmentation in BALF TGF-β and lung hydroxyproline levels, as well as reduced the expression of the mesenchymal marker α-smooth muscle actin (α-SMA, suggesting the suppression of epithelial to mesenchymal transition (EMT as one of its anti-fibrotic effects. The results demonstrate that the Amifostine analog, DRDE-30, ameliorates the oxidative injury and lung fibrosis induced by BLM and strengthen its potential use as an adjuvant in alleviating the side effects of

  19. Nephrogenic systemic fibrosis (NSF) and gadolinium-based contrast ...

    African Journals Online (AJOL)

    Nephrogenic systemic fibrosis (NSF), unknown before March 1997 and first described in 2000, is a systemic disorder characterised by widespread tissue fibrosis. The first known case occurred in 1997, after the use of gadolinium-based contrast agents (GBCAs) at high doses in patients with renal failure had become routine.

  20. Transcellular sodium transport in cultured cystic fibrosis human nasal epithelium

    DEFF Research Database (Denmark)

    Willumsen, Niels J.; Boucher, Richard C.

    1991-01-01

    Cystic fibrosis (CF) airway epithelia exhibit raised transepithelial Na+ transport rates, as determined by open-circuit isotope fluxes and estimates of the amiloride-sensitive equivalent short-circuit current (Ieq). To study the contribution of apical and basolateral membrane paths to raised Na+ ...

  1. Utility of diffusion-weighted imaging in the evaluation of liver fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Bakan, Ayse Ahsen; Inci, Ercan; Cimilli, Tan [Istanbul Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Department of Radiology, Istanbul (Turkey); Bakan, Selim [Istanbul University, Faculty of Medicine, Deparment of Radiology, Istanbul (Turkey); Gokturk, Suut [Istanbul University, Faculty of Medicine, Department of Internal Medicine, Division of Gastroenterohepatology, Istanbul (Turkey)

    2012-03-15

    To evaluate the usefulness of diffusion- weighted MRI (DWI) in the detection and staging of liver fibrosis and inflammation. DWI was performed with b-factors of 0, 500 and 1000 s/mm{sup 2}. ADC values were obtained by placing circular regions of interest in four segments of the liver. Differences between the study (n = 34) and control groups' (n = 25) ADC values were examined. Further, this study investigated if and how ADC values were related to fibrosis stages and histological activity index (HAI) scores. The mean ADC value of the liver was smaller in the study group compared with the control group (P < 0.001). Spearman rho correlation analyses showed lower ADC values were associated with higher fibrosis and HAI scores (P < 0.01). There were statistically significant differences in liver ADC values between each combination of fibrosis stages (e.g. stages 0 and 1, 0 and 2) except for stages 1 and 2. ADC values prove to be a valuable technique for the diagnosis of liver fibrosis and inflammation. They can also be useful in fibrosis staging, particularly in distinguishing later stages of fibrosis from intermediate and early stages. (orig.)

  2. Novel algorithm for non-invasive assessment of fibrosis in NAFLD.

    Directory of Open Access Journals (Sweden)

    Jan-Peter Sowa

    Full Text Available INTRODUCTION: Various conditions of liver disease and the downsides of liver biopsy call for a non-invasive option to assess liver fibrosis. A non-invasive score would be especially useful to identify patients with slow advancing fibrotic processes, as in Non-Alcoholic Fatty Liver Disease (NAFLD, which should undergo histological examination for fibrosis. PATIENTS/METHODS: Classic liver serum parameters, hyaluronic acid (HA and cell death markers of 126 patients undergoing bariatric surgery for morbid obesity were analyzed by machine learning techniques (logistic regression, k-nearest neighbors, linear support vector machines, rule-based systems, decision trees and random forest (RF. Specificity, sensitivity and accuracy of the evaluated datasets to predict fibrosis were assessed. RESULTS: None of the single parameters (ALT, AST, M30, M60, HA did differ significantly between patients with a fibrosis score 1 or 2. However, combining these parameters using RFs reached 79% accuracy in fibrosis prediction with a sensitivity of more than 60% and specificity of 77%. Moreover, RFs identified the cell death markers M30 and M65 as more important for the decision than the classic liver parameters. CONCLUSION: On the basis of serum parameters the generation of a fibrosis scoring system seems feasible, even when only marginally fibrotic tissue is available. Prospective evaluation of novel markers, i.e. cell death parameters, should be performed to identify an optimal set of fibrosis predictors.

  3. Natural Killer cells and liver fibrosis

    Directory of Open Access Journals (Sweden)

    Frank eFasbender

    2016-01-01

    Full Text Available In the 40 years since the discovery of Natural Killer (NK cells it has been well established that these innate lymphocytes are important for early and effective immune responses against transformed cells and infections with different pathogens. In addition to these classical functions of NK cells, we now know that they are part of a larger family of innate lymphoid cells and that they can even mediate memory-like responses. Additionally, tissue resident NK cells with distinct phenotypical and functional characteristics have been identified. Here we focus on the phenotype of different NK cell subpopulations that can be found in the liver and summarize the current knowledge about the functional role of these cells with a special emphasis on liver fibrosis. NK cell cytotoxicity can contribute to liver damage in different forms of liver disease. However, NK cells can limit liver fibrosis by killing hepatic stellate cell-derived myofibroblasts, which play a key role in this pathogenic process. Therefore, liver NK cells need to be tightly regulated in order to balance these beneficial and pathological effects.

  4. Appetite stimulants for people with cystic fibrosis.

    Science.gov (United States)

    Chinuck, Ruth; Dewar, Jane; Baldwin, David R; Hendron, Elizabeth

    2014-07-27

    Chronic loss of appetite in cystic fibrosis concerns both individuals and families. Appetite stimulants have been used to help cystic fibrosis patients with chronic anorexia attain optimal body mass index and nutritional status. However, these may have adverse effects on clinical status. The aim of this review is to systematically search for and evaluate evidence on the beneficial effects of appetite stimulants in the management of CF-related anorexia and synthesize reports of any side-effects. Trials were identified by searching the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register, MEDLINE, Embase, CINAHL, handsearching reference lists and contacting local and international experts.Last search of online databases: 01 April 2014.Last search of the Cystic Fibrosis Trials Register: 08 April 2014. Randomised and quasi-randomised controlled trials of appetite stimulants, compared to placebo or no treatment for at least one month in adults and children with cystic fibrosis. Authors independently extracted data and assessed the risk of bias within eligible trials. Meta-analyses were performed. Three trials (total of 47 recruited patients) comparing appetite stimulants (cyproheptadine hydrochloride and megesterol acetate) to placebo were included; the numbers of adults or children within each trial were not always reported. The risk of bias of the included trials was graded as moderate.A meta-analysis of all three trials showed appetite stimulants produced a larger increase in weight z score at three months compared to placebo, mean difference 0.61 (95% confidence interval 0.29 to 0.93) (P children, appetite stimulants improved only two of the outcomes in this review - weight (or weight z score) and appetite; and side effects were insufficiently reported to determine the full extent of their impact. Whilst the data may suggest the potential use of appetite stimulants in treating anorexia in adults and children with cystic fibrosis

  5. [Bacterial prostatitis and prostatic fibrosis: modern view on the treatment and prophylaxis].

    Science.gov (United States)

    Zaitsev, A V; Pushkar, D Yu; Khodyreva, L A; Dudareva, A A

    2016-08-01

    Treatments of chronic bacterial prostatitis (CP) remain difficult problem. Bacterial prostatitis is a disease entity diagnosed clinically and by evidence of inflammation and infection localized to the prostate. Risk factors for UTI in men include urological interventions, such as transrectal prostate biopsy. Ensuing infections after prostate biopsy, such as UTI and bacterial prostatitis, are increasing due to increasing rates of fluoroquinolone resistance. The increasing global antibiotic resistance also significantly affects management of UTI in men, and therefore calls for alternative strategies. Prostatic inflammation has been suggested to contribute to the etiology of lower urinary tract symptoms (LUTS) by inducing fibrosis. Several studies have shown that prostatic fibrosis is strongly associated with impaired urethral function and LUTS severity. Fibrosis resulting from excessive deposition of collagen is traditionally recognized as a progressive irreversible condition and an end stage of inflammatory diseases; however, there is compelling evidence in both animal and human studies to support that the development of fibrosis could potentially be a reversible process. Prostate inflammation may induce fibrotic changes in periurethral prostatic tissues, promote urethral stiffness and LUTS. Patients experiencing CP and prostate-related LUTS could benefit from anti-inflammatory therapies, especially used in combination with the currently prescribed enzyme treatment with Longidase. Treatment results showed that longidase is highly effective in bacterial and abacterial CP. Longidase addition to standard therapeutic methods significantly reduced the disease symptoms and regression of inflammatory-proliferative alterations in the prostate.

  6. Noninvasive Assessment of Fibrosis in Patients with Nonalcoholic Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Elena Buzzetti

    2015-01-01

    Full Text Available Nonalcoholic fatty liver disease (NAFLD is prevalent in 20–25% of the general population and is associated with metabolic risk factors such as obesity, diabetes mellitus, and dyslipidemia. Histologically, NAFLD ranges from simple steatosis to nonalcoholic steatohepatitis (NASH, fibrosis, and cirrhosis. As NASH develops in only 10–15% of patients with NAFLD, it is not practical to biopsy all patients who present with NAFLD. Noninvasive fibrosis tests have been extensively developed recently and offer alternatives for staging fibrosis. Despite their increasing use, such tests cannot adequately differentiate simple steatosis from NASH. At present, such tests can be used as first line tests to rule out patients without advanced fibrosis and thus prevent unnecessary secondary care referrals in a significant number of patients. In this review we present the evidence for the use of noninvasive fibrosis tests in patients with NAFLD.

  7. Role of Magnetic Resonance Elastography as a Noninvasive Measurement Tool of Fibrosis in a Renal Allograft: A Case Report.

    Science.gov (United States)

    Kim, J K; Yuen, D A; Leung, G; Jothy, S; Zaltzman, J; Ramesh Prasad, G V; Prabhudesai, V; Mnatzakanian, G; Kirpalani, A

    2017-09-01

    A major reason for poor long-term kidney transplant outcomes is the development of chronic allograft injury, characterized by interstitial fibrosis and tubular atrophy. Currently, an invasive biopsy that samples only tool of allograft fibrosis in a kidney transplant patient at 2 time points. The MRE whole-kidney stiffness values reflected the changes in fibrosis of the kidney allograft as assessed by histologic examination. To our knowledge, this technique is the first observation of change over time in MRE-derived whole-kidney stiffness in an allograft that is consistent with changes in histology-derived fibrosis scores in a single patient. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Assessment of renal fibrosis in chronic kidney disease using diffusion-weighted MRI

    International Nuclear Information System (INIS)

    Zhao, J.; Wang, Z.J.; Liu, M.; Zhu, J.; Zhang, X.; Zhang, T.; Li, S.; Li, Y.

    2014-01-01

    Aim: To assess the performance of diffusion-weighted magnetic resonance imaging (MRI) for the assessment of renal fibrosis in chronic kidney disease (CKD), with histopathology as a reference standard. Materials and methods: Forty patients with CKD and 30 healthy volunteers were recruited for the study. All participants underwent diffusion-weighted MRI. Renal biopsy was performed in 25 patients with CKD. Mean renal medullary and cortical apparent diffusion coefficient (ADC) values were compared between CKD patients and the healthy volunteers. Pearson's correlation coefficient was calculated to investigate the relationship between ADC values, serum creatinine (SCr), estimated glomerular filtration rate (eGFR), 24 h urinary protein (24h-UPRO), and renal histopathological scores. Results: Cortical and medullary ADC values in the CKD group were significantly lower compared to those in the healthy controls. In the CKD group, a significant negative correlation was found between cortical ADC values and SCr/24h-UPRO, and significant positive correlation was found between cortical ADC and eGFR. There was also a significant negative correlation between medullary ADC values and SCr. Both cortical and medullary ADC values were significantly correlated with histopathological fibrosis score. Conclusion: Renal ADC values strongly correlate with histological measures of fibrosis, and have the potential to enhance the non-invasive monitoring of chronic kidney disease. - Highlights: • Renal ADC values in the CKD patients were lower than those in controls. • Renal ADC values were strongly correlated with histological fibrosis score. • Renal ADC values have the potential to enhance the noninvasive monitoring of CKD

  9. Recent advances in understanding idiopathic pulmonary fibrosis

    Science.gov (United States)

    Daccord, Cécile; Maher, Toby M.

    2016-01-01

    Despite major research efforts leading to the recent approval of pirfenidone and nintedanib, the dismal prognosis of idiopathic pulmonary fibrosis (IPF) remains unchanged. The elaboration of international diagnostic criteria and disease stratification models based on clinical, physiological, radiological, and histopathological features has improved the accuracy of IPF diagnosis and prediction of mortality risk. Nevertheless, given the marked heterogeneity in clinical phenotype and the considerable overlap of IPF with other fibrotic interstitial lung diseases (ILDs), about 10% of cases of pulmonary fibrosis remain unclassifiable. Moreover, currently available tools fail to detect early IPF, predict the highly variable course of the disease, and assess response to antifibrotic drugs. Recent advances in understanding the multiple interrelated pathogenic pathways underlying IPF have identified various molecular phenotypes resulting from complex interactions among genetic, epigenetic, transcriptional, post-transcriptional, metabolic, and environmental factors. These different disease endotypes appear to confer variable susceptibility to the condition, differing risks of rapid progression, and, possibly, altered responses to therapy. The development and validation of diagnostic and prognostic biomarkers are necessary to enable a more precise and earlier diagnosis of IPF and to improve prediction of future disease behaviour. The availability of approved antifibrotic therapies together with potential new drugs currently under evaluation also highlights the need for biomarkers able to predict and assess treatment responsiveness, thereby allowing individualised treatment based on risk of progression and drug response. This approach of disease stratification and personalised medicine is already used in the routine management of many cancers and provides a potential road map for guiding clinical care in IPF. PMID:27303645

  10. Regional quantification of lung function in cystic fibrosis using hyperpolarized xenon-129 and chemical shift imaging

    OpenAIRE

    Fernandes, Carolina Campanha

    2012-01-01

    Tese de mestrado em Engenharia Biomédica e Biofísica (Radiações em Diagnóstico e Terapia), apresentada à Universidade de Lisboa, através da Faculdade de Ciências, 2012 Cystic fibrosis (CF) is a genetic disorder in which the defective gene causes the production of unusually thick and viscous mucus that builds-up in the airways, leading to impaired ventilation and infection of lung structures. Currently, there is a lack of methods capable of routinely assessing, in a regional manner, basic p...

  11. Contemporary use of elastography in liver fibrosis and portal hypertension

    DEFF Research Database (Denmark)

    Thiele, Maja; Kjærgaard, Maria; Thielsen, Peter

    2017-01-01

    significant portal hypertension, techniques and limitations. Four types of ultrasound elastography exist, but there is scarce evidence comparing the different techniques. The majority of experience concern transient elastography for diagnosing fibrosis and cirrhosis in patients with chronic viral hepatitis C...

  12. Vaccines for preventing infection with Pseudomonas aeruginosa in cystic fibrosis

    DEFF Research Database (Denmark)

    Johansen, Helle Krogh; Gøtzsche, Peter C

    2015-01-01

    BACKGROUND: Chronic pulmonary infection in cystic fibrosis results in progressive lung damage. Once colonisation of the lungs with Pseudomonas aeruginosa occurs, it is almost impossible to eradicate. Vaccines, aimed at reducing infection with Pseudomonas aeruginosa, have been developed....... This is an update of a previously published review. OBJECTIVES: To assess the effectiveness of vaccination against Pseudomonas aeruginosa in cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register using the terms vaccines AND pseudomonas (last search 30...... March 2015). We previously searched PubMed using the terms vaccin* AND cystic fibrosis (last search 30 May 2013). SELECTION CRITERIA: Randomised trials (published or unpublished) comparing Pseudomonas aeruginosa vaccines (oral, parenteral or intranasal) with control vaccines or no intervention in cystic...

  13. Lung cancer in patients with idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Karampitsakos, Theodoros; Tzilas, Vasilios; Tringidou, Rodoula; Steiropoulos, Paschalis; Aidinis, Vasilis; Papiris, Spyros A; Bouros, Demosthenes; Tzouvelekis, Argyris

    2017-08-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic lung disease of unknown etiology. With a gradually increasing worldwide prevalence and a mortality rate exceeding that of many cancers, IPF diagnosis and management are critically important and require a comprehensive multidisciplinary approach. This approach also involves assessment of comorbid conditions, such as lung cancer, that exerts a dramatic impact on disease survival. Emerging evidence suggests that progressive lung scarring in the context of IPF represents a risk factor for lung carcinogenesis. Both disease entities present with major similarities in terms of pathogenetic pathways, as well as potential causative factors, such as smoking and viral infections. Besides disease pathogenesis, anti-cancer agents, including nintedanib, have been successfully applied in the treatment of patients with IPF while an oncologic approach with a cocktail of several pleiotropic anti-fibrotic agents is currently in the therapeutic pipeline of IPF. Nevertheless, epidemiologic association between IPF and lung cancer does not prove causality. Currently there is significant lack of knowledge supporting a direct association between lung fibrosis and cancer reflecting to disappointing therapeutic algorithms. An optimal therapeutic strategy for patients with both IPF and lung cancer represents an amenable need. This review article synthesizes the current state of knowledge regarding pathogenetic commonalities between IPF and lung cancer and focuses on clinical and therapeutic data that involve both disease entities. Copyright © 2017. Published by Elsevier Ltd.

  14. Loss of Matrix Metalloproteinase-13 Attenuates Murine Radiation-Induced Pulmonary Fibrosis

    International Nuclear Information System (INIS)

    Flechsig, Paul; Hartenstein, Bettina; Teurich, Sybille; Dadrich, Monika; Hauser, Kai; Abdollahi, Amir; Groene, Hermann-Josef; Angel, Peter; Huber, Peter E.

    2010-01-01

    Purpose: Pulmonary fibrosis is a disorder of the lungs with limited treatment options. Matrix metalloproteinases (MMPs) constitute a family of proteases that degrade extracellular matrix with roles in fibrosis. Here we studied the role of MMP13 in a radiation-induced lung fibrosis model using a MMP13 knockout mouse. Methods and Materials: We investigated the role of MMP13 in lung fibrosis by investigating the effects of MMP13 deficiency in C57Bl/6 mice after 20-Gy thoracic irradiation (6-MV Linac). The morphologic results in histology were correlated with qualitative and quantitative results of volume computed tomography (VCT), magnetic resonance imaging (MRI), and clinical outcome. Results: We found that MMP13 deficient mice developed less pulmonary fibrosis than their wildtype counterparts, showed attenuated acute pulmonary inflammation (days after irradiation), and a reduction of inflammation during the later fibrogenic phase (5-6 months after irradiation). The reduced fibrosis in MMP13 deficient mice was evident in histology with reduced thickening of alveolar septi and reduced remodeling of the lung architecture in good correlation with reduced features of lung fibrosis in qualitative and quantitative VCT and MRI studies. The partial resistance of MMP13-deficient mice to fibrosis was associated with a tendency towards a prolonged mouse survival. Conclusions: Our data indicate that MMP13 has a role in the development of radiation-induced pulmonary fibrosis. Further, our findings suggest that MMP13 constitutes a potential drug target to attenuate radiation-induced lung fibrosis.

  15. Otorhinolaryngologic manifestations of cystic fibrosis: literature review

    Directory of Open Access Journals (Sweden)

    Carvalho, Carolina Pimenta

    2008-12-01

    Full Text Available Introduction: Cystic Fibrosis is the most common recessive autosomic genetic disease among Caucasians. It's caused by mutations in the gene that decodes regulatory protein for transmembrane conductance, resulting in defective transport of chlorine. Objective: Review the literature about Cystic Fibrosis, with emphasis on otorhinolaryngologic manifestations. Method: The online Pub Med databases were researched and we applied the following search terms Fibrosis Cystic and Sinusitis, and Mucoviscidosis and Sinusitis. Conclusions: Although it is not the main cause of death, the otorhinolaryngologic manifestations of the Cystic Fibrosis bring important morbidity to these patients.

  16. Chemoprotective effect of omega-3 fatty acids on thioacetamide induced hepatic fibrosis in male rats

    Directory of Open Access Journals (Sweden)

    Atef M. Al-Attar

    2017-05-01

    Full Text Available The current study was designed to investigate the possible protective effect of omega-3 fatty acids from fish oil on hepatic fibrosis induced by thioacetamide (TAA in male rats. The experimental animals were divided into four groups. The first group was received saline solution and served as control. The second group was given 250 mg/kg body weight of TAA. The third group was treated with omega-3 fatty acids and TAA. The fourth group was given saline solution and supplemented with omega-3 fatty acids. Treatment of rats with TAA for three and six weeks resulted in a significant decrease in body weight gain, while the value of liver/body weight ratio was statistically increased. Furthermore, the levels of serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transferase and total bilirubin were significantly increased. After three weeks of exposure to only TAA, liver sections showed an abnormal morphology characterized by noticeable fibrosis with the extracellular matrix collagen contents and damage of liver cells’ structure. Liver sections from rats treated with only TAA for six weeks revealed an obvious increase in extracellular matrix collagen content and bridging fibrosis. Treating TAA-intoxicated rats with omega-3 fatty acids significantly attenuated the severe physiological and histopathological changes. Finally, the present investigation suggests that omega-3 fatty acids could act against hepatic fibrosis induced by TAA due to its antioxidant properties, thus supporting its use in hepatic fibrosis therapy.

  17. Adiponectin attenuates lung fibroblasts activation and pulmonary fibrosis induced by paraquat.

    Science.gov (United States)

    Yao, Rong; Cao, Yu; He, Ya-rong; Lau, Wayne Bond; Zeng, Zhi; Liang, Zong-an

    2015-01-01

    Pulmonary fibrosis is one of the most common complications of paraquat (PQ) poisoning, which demands for more effective therapies. Accumulating evidence suggests adiponectin (APN) may be a promising therapy against fibrotic diseases. In the current study, we determine whether the exogenous globular APN isoform protects against pulmonary fibrosis in PQ-treated mice and human lung fibroblasts, and dissect the responsible underlying mechanisms. BALB/C mice were divided into control group, PQ group, PQ + low-dose APN group, and PQ + high-dose APN group. Mice were sacrificed 3, 7, 14, and 21 days after PQ treatment. We compared pulmonary histopathological changes among different groups on the basis of fibrosis scores, TGF-β1, CTGF and α-SMA pulmonary content via Western blot and real-time quantitative fluorescence-PCR (RT-PCR). Blood levels of MMP-9 and TIMP-1 were determined by ELISA. Human lung fibroblasts WI-38 were divided into control group, PQ group, APN group, and APN receptor (AdipoR) 1 small-interfering RNA (siRNA) group. Fibroblasts were collected 24, 48, and 72 hours after PQ exposure for assay. Cell viability and apoptosis were determined via Kit-8 (CCK-8) and fluorescein Annexin V-FITC/PI double labeling. The protein and mRNA expression level of collagen type III, AdipoR1, and AdipoR2 were measured by Western blot and RT-PCR. APN treatment significantly decreased the lung fibrosis scores, protein and mRNA expression of pulmonary TGF-β1, CTGF and α-SMA content, and blood MMP-9 and TIMP-1 in a dose-dependent manner (ppulmonary fibrosis in a dose-dependent manner, via suppression of lung fibroblast activation. Functional AdipoR1 are expressed by human WI-38 lung fibroblasts, suggesting potential future clinical applicability of APN against pulmonary fibrosis.

  18. Review of drug treatment of oral submucous fibrosis.

    Science.gov (United States)

    Chole, Revant H; Gondivkar, Shailesh M; Gadbail, Amol R; Balsaraf, Swati; Chaudhary, Sudesh; Dhore, Snehal V; Ghonmode, Sumeet; Balwani, Satish; Mankar, Mugdha; Tiwari, Manish; Parikh, Rima V

    2012-05-01

    This study undertook a review of the literature on drug treatment of oral submucous fibrosis. An electronic search was carried out for articles published between January 1960 to November 2011. Studies with high level of evidence were included. The levels of evidence of the articles were classified after the guidelines of the Oxford Centre for Evidence-Based Medicine. The main outcome measures used were improvement in oral ulceration, burning sensation, blanching and trismus. Only 13 publications showed a high level of evidence (3 randomized controlled trials and 10 clinical trials/controlled clinical trials), with a total of 1157 patients. Drugs like steroids, hyaluronidase, human placenta extracts, chymotrypsin and collagenase, pentoxifylline, nylidrin hydrochloride, iron and multivitamin supplements including lycopene, have been used. Only systemic agents were associated with few adverse effects like gastritis, gastric irritation and peripheral flushing with pentoxifylline, and flushingly warm skin with nylidrin hydrochloride; all other side-effects were mild and mainly local. Few studies with high levels of evidence were found. The drug treatment that is currently available for oral submucous fibrosis is clearly inadequate. There is a need for high-quality randomized controlled trials with carefully selected and standardized outcome measures. Copyright © 2011 Elsevier Ltd. All rights reserved.

  19. PROFILEing idiopathic pulmonary fibrosis: rethinking biomarker discovery

    Directory of Open Access Journals (Sweden)

    Toby M. Maher

    2013-06-01

    Full Text Available Despite major advances in the understanding of the pathogenesis of idiopathic pulmonary fibrosis (IPF, diagnosis and management of the condition continue to pose significant challenges. Clinical management of IPF remains unsatisfactory due to limited availability of effective drug therapies, a lack of accurate indicators of disease progression, and an absence of simple short-term measures of therapeutic response. The identification of more accurate predictors of prognosis and survival in IPF would facilitate counseling of patients and their families, aid communication among clinicians, and would guide optimal timing of referral for transplantation. Improvements in molecular techniques have led to the identification of new disease pathways and a more targeted approach to the development of novel anti-fibrotic agents. However, despite an increased interest in biomarkers of IPF disease progression there are a lack of measures that can be used in early phase clinical trials. Careful longitudinal phenotyping of individuals with IPF together with the application of novel omics-based technology should provide important insights into disease pathogenesis and should address some of the major issues holding back drug development in IPF. The PROFILE (Prospective Observation of Fibrosis in the Lung Clinical Endpoints study is a currently enrolling, prospective cohort study designed to tackle these issues.

  20. Lysyl oxidase‑like 2 is expressed in kidney tissue and is associated with the progression of tubulointerstitial fibrosis.

    Science.gov (United States)

    Choi, Sung-Eun; Jeon, Nara; Choi, Hoon Young; Shin, Jae Il; Jeong, Hyeon Joo; Lim, Beom Jin

    2017-09-01

    Tubulointerstitial fibrosis is a common end point of chronic kidney diseases, and preventing its progression is key to avoiding renal failure. Transforming growth factor‑β (TGF‑β) and associated molecules promote tubulointerstitial fibrosis; however, effective therapies targeting these molecules have yet to be developed. Lysyl oxidase‑like 2 (LOXL2), which is involved in invasive growth and metastasis of malignant neoplasms, has recently been reported to serve a key role in hepatic and pulmonary fibrosis. However, little is currently known regarding LOXL2 expression in the kidney and its involvement in tubulointerstitial fibrosis. The present study evaluated LOXL2 expression in human and mouse kidney tissues, as well as in cultured renal cells. LOXL2 protein expression was detected in glomerular capillary loops and tubular epithelial cells in human and mouse kidneys. Glomerular LOXL2 was localized to the cytoplasm of podocytes, as determined by double immunofluorescence microscopy using a podocyte marker (synaptopodin). This result was supported by western blot analysis, which demonstrated that LOXL2 protein expression is present in cultured human podocytes and HK‑2 human proximal tubular cells. In addition, the mRNA and protein expression levels of LOXL2 were higher in a mouse model of tubulointerstitial fibrosis compared with in control mice. In addition, immunohistochemistry results demonstrated that LOXL2 is present in the fibrous interstitium and infiltrating mononuclear cells in a mouse model of tubulointerstitial fibrosis. The present study demonstrated that LOXL2 is expressed in compartments of renal tissue, where it appears to contribute to the progression of tubulointerstitial fibrosis.

  1. Clinical application of noninvasive diagnosis of liver fibrosis

    Directory of Open Access Journals (Sweden)

    ZHU Chuanlong

    2015-03-01

    Full Text Available Hepatic fibrosis is the common outcome of chronic liver diseases of various causes. At present, liver biopsy is the “gold standard” for the diagnosis of liver fibrosis, but it has limitations and is invasive, which leads to the development of noninvasive assessment of liver fibrosis. The article mainly introduces the technology and application of noninvasive diagnosis of liver fibrosis from the aspects of clinical manifestation, serology, and radiology. It has pointed out the clinical value of these noninvasive diagnosis techniques, and it discusses the progress in clinical research and its limitations for noninvasive diagnosis of liver fibrosis.

  2. Imaging findings in idiopathic pelvic fibrosis

    International Nuclear Information System (INIS)

    Wiesner, W.; Bongartz, G.; Stoffel, F.

    2001-01-01

    Two patients presented with ureteric obstruction, and voiding symptoms and constipation, respectively, and were examined by means of intravenous urography and computed tomography. One patient was additionally examined by means of MR tomography. After CT (performed in both patients) and MRT (performed in one patient) had shown a diffuse, contrast-enhancing, infiltrating process in the small pelvis with infiltration of adjacent organs and vessels, surgical biopsy proved the diagnosis of idopathic pelvic fibrosis. Extension of retroperitoneal fibrosis below the pelvic rim is very rare. Clinical symptoms of pelvic fibrosis are variable and imaging findings may lead to a broad list of differential diagnoses. We present two patients with idiopathic pelvic fibrosis and discuss radiological findings and differential diagnoses of this rare disease. (orig.)

  3. Imaging findings in idiopathic pelvic fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Wiesner, W.; Bongartz, G. [Inst. of Diagnostic Radiology University Hospital Basel (Switzerland); Stoffel, F. [Inst. of Urology, University Hospital Basel (Switzerland)

    2001-04-01

    Two patients presented with ureteric obstruction, and voiding symptoms and constipation, respectively, and were examined by means of intravenous urography and computed tomography. One patient was additionally examined by means of MR tomography. After CT (performed in both patients) and MRT (performed in one patient) had shown a diffuse, contrast-enhancing, infiltrating process in the small pelvis with infiltration of adjacent organs and vessels, surgical biopsy proved the diagnosis of idopathic pelvic fibrosis. Extension of retroperitoneal fibrosis below the pelvic rim is very rare. Clinical symptoms of pelvic fibrosis are variable and imaging findings may lead to a broad list of differential diagnoses. We present two patients with idiopathic pelvic fibrosis and discuss radiological findings and differential diagnoses of this rare disease. (orig.)

  4. Idiopathic Pulmonary Fibrosis: The Association between the Adaptive Multiple Features Method and Fibrosis Outcomes.

    Science.gov (United States)

    Salisbury, Margaret L; Lynch, David A; van Beek, Edwin J R; Kazerooni, Ella A; Guo, Junfeng; Xia, Meng; Murray, Susan; Anstrom, Kevin J; Yow, Eric; Martinez, Fernando J; Hoffman, Eric A; Flaherty, Kevin R

    2017-04-01

    Adaptive multiple features method (AMFM) lung texture analysis software recognizes high-resolution computed tomography (HRCT) patterns. To evaluate AMFM and visual quantification of HRCT patterns and their relationship with disease progression in idiopathic pulmonary fibrosis. Patients with idiopathic pulmonary fibrosis in a clinical trial of prednisone, azathioprine, and N-acetylcysteine underwent HRCT at study start and finish. Proportion of lung occupied by ground glass, ground glass-reticular (GGR), honeycombing, emphysema, and normal lung densities were measured by AMFM and three radiologists, documenting baseline disease extent and postbaseline change. Disease progression includes composite mortality, hospitalization, and 10% FVC decline. Agreement between visual and AMFM measurements was moderate for GGR (Pearson's correlation r = 0.60, P fibrosis (as measured by GGR densities) is independently associated with elevated hazard for disease progression. Postbaseline change in AMFM-measured and visually measured GGR densities are modestly correlated with change in FVC. AMFM-measured fibrosis is an automated adjunct to existing prognostic markers and may allow for study enrichment with subjects at increased disease progression risk.

  5. Evolutionary-driven support vector machines for determining the degree of liver fibrosis in chronic hepatitis C.

    Science.gov (United States)

    Stoean, Ruxandra; Stoean, Catalin; Lupsor, Monica; Stefanescu, Horia; Badea, Radu

    2011-01-01

    Hepatic fibrosis, the principal pointer to the development of a liver disease within chronic hepatitis C, can be measured through several stages. The correct evaluation of its degree, based on recent different non-invasive procedures, is of current major concern. The latest methodology for assessing it is the Fibroscan and the effect of its employment is impressive. However, the complex interaction between its stiffness indicator and the other biochemical and clinical examinations towards a respective degree of liver fibrosis is hard to be manually discovered. In this respect, the novel, well-performing evolutionary-powered support vector machines are proposed towards an automated learning of the relationship between medical attributes and fibrosis levels. The traditional support vector machines have been an often choice for addressing hepatic fibrosis, while the evolutionary option has been validated on many real-world tasks and proven flexibility and good performance. The evolutionary approach is simple and direct, resulting from the hybridization of the learning component within support vector machines and the optimization engine of evolutionary algorithms. It discovers the optimal coefficients of surfaces that separate instances of distinct classes. Apart from a detached manner of establishing the fibrosis degree for new cases, a resulting formula also offers insight upon the correspondence between the medical factors and the respective outcome. What is more, a feature selection genetic algorithm can be further embedded into the method structure, in order to dynamically concentrate search only on the most relevant attributes. The data set refers 722 patients with chronic hepatitis C infection and 24 indicators. The five possible degrees of fibrosis range from F0 (no fibrosis) to F4 (cirrhosis). Since the standard support vector machines are among the most frequently used methods in recent artificial intelligence studies for hepatic fibrosis staging, the

  6. Angiotensin II type 1 and 2 receptors and lymphatic vessels modulate lung remodeling and fibrosis in systemic sclerosis and idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Parra, Edwin Roger; Ruppert, Aline Domingos Pinto; Capelozzi, Vera Luiza

    2014-01-01

    To validate the importance of the angiotensin II receptor isotypes and the lymphatic vessels in systemic sclerosis and idiopathic pulmonary fibrosis. We examined angiotensin II type 1 and 2 receptors and lymphatic vessels in the pulmonary tissues obtained from open lung biopsies of 30 patients with systemic sclerosis and 28 patients with idiopathic pulmonary fibrosis. Their histologic patterns included cellular and fibrotic non-specific interstitial pneumonia for systemic sclerosis and usual interstitial pneumonia for idiopathic pulmonary fibrosis. We used immunohistochemistry and histomorphometry to evaluate the number of cells in the alveolar septae and the vessels stained by these markers. Survival curves were also used. We found a significantly increased percentage of septal and vessel cells immunostained for the angiotensin type 1 and 2 receptors in the systemic sclerosis and idiopathic pulmonary fibrosis patients compared with the controls. A similar percentage of angiotensin 2 receptor positive vessel cells was observed in fibrotic non-specific interstitial pneumonia and usual interstitial pneumonia. A significantly increased percentage of lymphatic vessels was present in the usual interstitial pneumonia group compared with the non-specific interstitial pneumonia and control groups. A Cox regression analysis showed a high risk of death for the patients with usual interstitial pneumonia and a high percentage of vessel cells immunostained for the angiotensin 2 receptor in the lymphatic vessels. We concluded that angiotensin II receptor expression in the lung parenchyma can potentially control organ remodeling and fibrosis, which suggests that strategies aimed at preventing high angiotensin 2 receptor expression may be used as potential therapeutic target in patients with pulmonary systemic sclerosis and idiopathic pulmonary fibrosis.

  7. Noninvasive assessment of hepatic fibrosis in patients with chronic hepatic B viral Infection using magnetic resonance elastography

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    Lee, Jeong Eun [Dept. of Radiology, Chungnam National University Hospital, Daejeon (Korea, Republic of); Lee, Jeong Min; Yoon, Jeong Hee; Shin, Cheong Il; Han, Joon Koo; Choi, Byung Ihn [Seoul National University College of Medicine, Seoul (Korea, Republic of); Lee, Kyung Bun [Dept. of Pathology, Seoul National University Hospital, Seoul (Korea, Republic of)

    2014-04-15

    To evaluate the diagnostic performance of magnetic resonance elastography (MRE) for staging hepatic fibrosis in patients with chronic hepatitis B virus (HBV) infection. Patients with chronic HBV infection who were suspected of having focal or diffuse liver diseases (n = 195) and living donor candidates (n = 166) underwent MRE as part of the routine liver MRI examination. We measured liver stiffness (LS) values on quantitative shear stiffness maps. The technical success rate of MRE was then determined. Liver cell necroinflammatory activity and fibrosis were assessed using histopathologic examinations as the reference. Areas under the receiver operating characteristic curve (Az) were calculated in order to predict the liver fibrosis stage. The technical success rate of MRE was 92.5% (334/361). The causes of technical failure were poor wave propagation (n = 12), severe respiratory motion (n = 3), or the presence of iron deposits in the liver (n = 12). The mean LS values, as measured by MRE, increased significantly along with an increase in the fibrosis stage (r = 0.901, p < 0.001); however, the mean LS values did not increase significantly along with the degree of necroinflammatory activity. The cutoff values of LS for ≥ F1, ≥ F2, ≥ F3, and F4 were 2.45 kPa, 2.69 kPa, 3.0 kPa, and 3.94 kPa, respectively, and with Az values of 0.987-0.988. MRE has a high technical success rate and excellent diagnostic accuracy for staging hepatic fibrosis in patients with chronic HBV infection.

  8. Factors Promoting Development of Fibrosis in Crohn’s Disease

    Directory of Open Access Journals (Sweden)

    Gerhard Rogler

    2017-07-01

    Full Text Available The concepts on the pathophysiology of intestinal fibrosis in Crohn’s disease (CD have changed in recent years. Some years ago fibrosis was regarded to be a consequence of long-standing inflammation with subsequent destruction of the gut wall matrix followed by scar formation and collagen deposition. Fibrosis in CD patients appeared to be an irreversible process that could hardly be influenced. Therefore, the main target in CD therapy was to control inflammation to avoid fibrosis development. Many of these assumptions seem to be only partially true. Inflammation may be a necessary prerequisite for the initiation of fibrosis. However, when the pathophysiologic processes that lead to fibrosis in CD patients have been initiated fibrosis development may be independent of inflammation and may continue even when inflammation is under good medical control. Fibrosis in CD also may be reversible. After strictureplasty local collagen deposits decrease or even disappear. With new animal models for intestinal fibrosis on the horizon, we need to spend more efforts on understanding the factors influencing fibrosis in CD patients to finally find specific therapies. In this context, it will be as important to find markers and quantitative imaging tools to have reliable endpoints for clinical trials in fibrosing CD.

  9. Recommendations for quality improvement in genetic testing for cystic fibrosis European Concerted Action on Cystic Fibrosis

    NARCIS (Netherlands)

    Dequeker, E; Cuppens, H; Dodge, J; Estivill, [No Value; Goossens, M; Pignatti, PF; Scheffer, H; Schwartz, M; Schwarz, M; Tummler, B; Cassiman, JJ

    These recommendations for quality improvement of cystic fibrosis genetic diagnostic testing provide general guidelines for the molecular genetic testing of cystic fibrosis in patients/individuals. General strategies for testing as well as guidelines for laboratory procedures, internal and external

  10. A European regulatory perspective on cystic fibrosis: current treatments, trends in drug development and translational challenges for CFTR modulators.

    Science.gov (United States)

    Ponzano, Stefano; Nigrelli, Giulia; Fregonese, Laura; Eichler, Irmgard; Bertozzi, Fabio; Bandiera, Tiziano; Galietta, Luis J V; Papaluca, Marisa

    2018-06-30

    In this article we analyse the current authorised treatments and trends in early drug development for cystic fibrosis (CF) in the European Union for the time period 2000-2016. The analysis indicates a significant improvement in the innovation and development of new potential medicines for CF, shifting from products that act on the symptoms of the disease towards new therapies targeting the cause of CF. However, within these new innovative medicines, results for CF transmembrane conductance regulator (CFTR) modulators indicate that one major challenge for turning a CF concept product into an actual medicine for the benefit of patients resides in the fact that, although pre-clinical models have shown good predictability for certain mutations, a good correlation to clinical end-points or biomarkers ( e.g. forced expiratory volume in 1 s and sweat chloride) for all mutations has not yet been achieved. In this respect, the use of alternative end-points and innovative nonclinical models could be helpful for the understanding of those translational discrepancies. Collaborative endeavours to promote further research and development in these areas as well as early dialogue with the regulatory bodies available at the European competent authorities are recommended. Copyright ©ERS 2018.

  11. Deep learning for staging liver fibrosis on CT: a pilot study.

    Science.gov (United States)

    Yasaka, Koichiro; Akai, Hiroyuki; Kunimatsu, Akira; Abe, Osamu; Kiryu, Shigeru

    2018-05-14

    To investigate whether liver fibrosis can be staged by deep learning techniques based on CT images. This clinical retrospective study, approved by our institutional review board, included 496 CT examinations of 286 patients who underwent dynamic contrast-enhanced CT for evaluations of the liver and for whom histopathological information regarding liver fibrosis stage was available. The 396 portal phase images with age and sex data of patients (F0/F1/F2/F3/F4 = 113/36/56/66/125) were used for training a deep convolutional neural network (DCNN); the data for the other 100 (F0/F1/F2/F3/F4 = 29/9/14/16/32) were utilised for testing the trained network, with the histopathological fibrosis stage used as reference. To improve robustness, additional images for training data were generated by rotating or parallel shifting the images, or adding Gaussian noise. Supervised training was used to minimise the difference between the liver fibrosis stage and the fibrosis score obtained from deep learning based on CT images (F DLCT score) output by the model. Testing data were input into the trained DCNNs to evaluate their performance. The F DLCT scores showed a significant correlation with liver fibrosis stage (Spearman's correlation coefficient = 0.48, p deep learning model based on CT images, with moderate performance. • Liver fibrosis can be staged by a deep learning model based on magnified CT images including the liver surface, with moderate performance. • Scores from a trained deep learning model showed moderate correlation with histopathological liver fibrosis staging. • Further improvement are necessary before utilisation in clinical settings.

  12. Probiotic supplementation in children with cystic fibrosis-a systematic review.

    Science.gov (United States)

    Ananthan, Anitha; Balasubramanian, Haribalakrishna; Rao, Shripada; Patole, Sanjay

    2016-10-01

    Probiotics may benefit in cystic fibrosis (CF) as gut dysbiosis is associated with gastrointestinal symptoms and exacerbation of respiratory symptoms in CF. We conducted a systematic review of randomized controlled trials (RCTs) and non-RCTs of probiotic supplementation in children with CF, using the Cochrane methodology, preferred reporting items for systematic reviews (PRISMA) statement, and meta-analysis of observational studies in epidemiology (MOOSE) guidelines. Primary outcomes were pulmonary exacerbations, duration of hospitalization and antibiotics, and all-cause mortality. Secondary outcomes included gastrointestinal symptoms, markers of gut inflammation, and intestinal microbial balance. A total of nine studies (RCTs, 6, non-RCTs, 3; N = 275) with some methodological weaknesses were included in the review. The pooled estimate showed significant reduction in the rate of pulmonary exacerbation (fixed effects model, two parallel group RCTs and one cross-over trial: relative risk (RR) 0.25, (95 % confidence interval (95 % CI) 0.15,0.41); p probiotic supplementation. Probiotic supplementation significantly improved gastrointestinal symptoms (one RCT, one non-RCT) and gut microbial balance (decreased Proteobacteria, increased Firmicutes, and Bacteroides in one RCT, one non-RCT). Limited low-quality evidence exists on the effects of probiotics in children with CF. Well-designed adequately powered RCTs assessing clinically meaningful outcomes are required to study this important issue. • Gut dysbiosis is frequent in children with cystic fibrosis due to frequent exposure to pathogens and antibiotics. • Probiotics decrease gut dysbiosis and improve gut maturity and function. What is New: • This comprehensive systematic review shows that current evidence on the safety and efficacy of probiotics in children with cystic fibrosis is limited and of low quality. • Well-designed and adequately powered trials assessing clinically important outcomes are

  13. Usefulness of an index score as a predictor of hepatic fibrosis in obese patients undergoing bariatric surgery Utilidad de un índice de puntuación como predictor de fibrosis hepática en pacientes obesos sometidos a cirugía bariátrica

    Directory of Open Access Journals (Sweden)

    R. Díez Rodríguez

    2009-08-01

    Full Text Available Objective: to evaluate the usefulness of a non-invasive clinical score to predict liver fibrosis in the steatosis associated with morbid obesity. Patients and methods: we included 88 patients, who underwent bariatric surgery in the Sanitary Area of León, Spain, and who showed a liver biopsy with steatosis greater than 5%. This is a retrospective study in which the rate of fibrosis is calculated from tests performed during the preoperative period, and is then compared to data from intraoperative hepatic biopsies. The analysis population was grouped according to the presence of advanced fibrosis in the liver biopsy (grade 3-4 or its absence (grade 0-2. The cutoff used for diagnosing advanced fibrosis was 0.676 (high cutoff point, and the cutoff point to exclude advanced fibrosis was -1.455 (low cutoff. Results: the prevalence of advanced fibrosis in the histological samples was 5.5%, and 65.9% of patients had no fibrosis. The cutoff for a low negative predictive value was 100%, and sensitivity was 100%. The cutoff point for a high positive predictive value was 1.7%, and specificity was 31.3%. Conclusions: this scoring system for morbidly obese patients eligible for bariatric surgery allows to identify those without advanced fibrosis, but cannot predict who may have advanced fibrosis.Objetivo: evaluar la utilidad de un índice de puntuación clínica no invasivo para predecir fibrosis hepática en la esteatosis asociada a la obesidad mórbida. Pacientes y métodos: se incluyeron 88 pacientes, intervenidos de cirugía bariátrica en el área sanitaria de León, que presentaron en la biopsia hepática una esteatosis mayor del 5%. Se trata de un estudio retrospectivo en el que se calculó el índice de fibrosis a partir de los datos analíticos del preoperatorio, y se comparó su resultado con los datos de la biopsia hepática intraoperatoria realizada. Para el análisis los pacientes fueron agrupados según presentaban en la biopsia hep

  14. Traditional Herbal Medicine Use Associated with Liver Fibrosis in Rural Rakai, Uganda

    Science.gov (United States)

    2012-11-27

    Traditional Herbal Medicine Use Associated with Liver Fibrosis in Rural Rakai, Uganda Brandon J. Auerbach1,2*, Steven J. Reynolds3,4, Mohammed...Background: Traditional herbal medicines are commonly used in sub-Saharan Africa and some herbs are known to be hepatotoxic. However little is known...about the effect of herbal medicines on liver disease in sub-Saharan Africa. Methods: 500 HIV-infected participants in a rural HIV care program in Rakai

  15. Targeting Interleukin-13 with Tralokinumab Attenuates Lung Fibrosis and Epithelial Damage in a Humanized SCID Idiopathic Pulmonary Fibrosis Model

    Science.gov (United States)

    Zhang, Huilan; Oak, Sameer R.; Coelho, Ana Lucia; Herath, Athula; Flaherty, Kevin R.; Lee, Joyce; Bell, Matt; Knight, Darryl A.; Martinez, Fernando J.; Sleeman, Matthew A.; Herzog, Erica L.; Hogaboam, Cory M.

    2014-01-01

    The aberrant fibrotic and repair responses in the lung are major hallmarks of idiopathic pulmonary fibrosis (IPF). Numerous antifibrotic strategies have been used in the clinic with limited success, raising the possibility that an effective therapeutic strategy in this disease must inhibit fibrosis and promote appropriate lung repair mechanisms. IL-13 represents an attractive target in IPF, but its disease association and mechanism of action remains unknown. In the present study, an overexpression of IL-13 and IL-13 pathway markers was associated with IPF, particularly a rapidly progressive form of this disease. Targeting IL-13 in a humanized experimental model of pulmonary fibrosis using tralokinumab (CAT354) was found to therapeutically block aberrant lung remodeling in this model. However, targeting IL-13 was also found to promote lung repair and to restore epithelial integrity. Thus, targeting IL-13 inhibits fibrotic processes and enhances repair processes in the lung. PMID:24325475

  16. Characteristic patterns in the fibrotic lung. Comparing idiopathic pulmonary fibrosis with chronic lung allograft dysfunction.

    Science.gov (United States)

    Fernandez, Isis E; Heinzelmann, Katharina; Verleden, Stijn; Eickelberg, Oliver

    2015-03-01

    Tissue fibrosis, a major cause of death worldwide, leads to significant organ dysfunction in any organ of the human body. In the lung, fibrosis critically impairs gas exchange, tissue oxygenation, and immune function. Idiopathic pulmonary fibrosis (IPF) is the most detrimental and lethal fibrotic disease of the lung, with an estimated median survival of 50% after 3-5 years. Lung transplantation currently remains the only therapeutic alternative for IPF and other end-stage pulmonary disorders. Posttransplant lung function, however, is compromised by short- and long-term complications, most importantly chronic lung allograft dysfunction (CLAD). CLAD affects up to 50% of all transplanted lungs after 5 years, and is characterized by small airway obstruction with pronounced epithelial injury, aberrant wound healing, and subepithelial and interstitial fibrosis. Intriguingly, the mechanisms leading to the fibrotic processes in the engrafted lung exhibit striking similarities to those in IPF; therefore, antifibrotic therapies may contribute to increased graft function and survival in CLAD. In this review, we focus on these common fibrosis-related mechanisms in IPF and CLAD, comparing and contrasting clinical phenotypes, the mechanisms of fibrogenesis, and biomarkers to monitor, predict, or prognosticate disease status.

  17. Targeting coagulation factor receptors - protease-activated receptors in idiopathic pulmonary fibrosis

    NARCIS (Netherlands)

    Lin, C.; Borensztajn, K.; Spek, C. A.

    2017-01-01

    Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease with a 5-year mortality rate of > 50% and unknown etiology. Treatment options remain limited and, currently, only two drugs are available, i.e. nintedanib and pirfenidone. However, both of these antifibrotic agents only slow down the

  18. Ultrasound based evaluation of hepatic steatosis and fibrosis in hepatitis c non-responders

    International Nuclear Information System (INIS)

    Sohail, S.; Aziz, S.

    2013-01-01

    To determine the accuracy of ultrasound in the diagnosis and grading of steatosis and fibrosis in Hepatitis C (HCV) patients not responding to ribavarin-interferon therapy. Study Design: A cross-sectional, analytical study. Place and Duration of Study: Radiology Department, Civil Hospital, Karachi, from March 2008 to August 2010. Methodology: Patients with positive HCV RNA despite 24 weeks ribavarin-interferon therapy (non-responders) were subjected to ultrasound and biopsy prior to institution of pegylated interferon therapy for detection and grading of steatosis and fibrosis. Using histopathology as the gold standard, sensitivity, specificity, negative and positive predictive values for ultrasound were determined. Results: The sensitivity of ultrasound for hepatic steatosis was 90.9% for no steatosis (NS), 100% for moderate and gross steatosis and 84.4% for mild steatosis with 100% specificity. The senitivity for fibrosis was 25% for no fibrosis, 100% for mild fibrosis, 89.74% for moderate fibrosis and 100% for gross fibrosis. The overall accuracy for detection of steatosis was 95.39% and that for fibrosis was 98.02%. Hepatic vein showed increased dampening of flow with advancing grades of steatosis and fibrosis. Conclusion: Ultrasound has a high accuracy in the diagnosis and grading of steatosis and fibrosis in HCV nonresponders. Mild fibrosis may confound the diagnosis of mild steatosis. (author)

  19. Higher Anti-Liver Fibrosis Effect of Cordyceps militaris-Fermented Product Cultured with Deep Ocean Water via Inhibiting Proinflammatory Factors and Fibrosis-Related Factors Expressions

    Directory of Open Access Journals (Sweden)

    Yu-Ping Hung

    2017-06-01

    Full Text Available Deep ocean water (DOW has been shown to enhance the functional components of fungi, resulting in increased health benefits. Therefore, using DOW for culturing fungi can enhance the cordycepin and adenosine of Cordyceps militaris (CM and its protective effects on the liver. In this study, the antiliver fibrosis effects and mechanisms of ultrapure water-cultured CM (UCM, DOW-cultured CM (DCM, synthetic water-cultured CM, DOW, cordycepin, and adenosine were compared in the liver fibrosis mice induced by intraperitoneal injections of thioacetamide (TAA. The results indicated that DCM exhibited superior performance in reducing liver collagen accumulation, mitigating liver injuries, inhibiting proinflammatory factors and fibrosis-related factor (TGF-β1, Smad2/3, α-SMA, COL1A1 expression compared with UCM. DOW, cordycepin, and adenosine also performed antiliver fibrosis effect. Therefore, because DCM is rich in DOW and functional components, it can achieve anti-liver fibrosis effects through multiple pathways. These ameliorative effects are considerably superior to those of UCM.

  20. Higher Anti-Liver Fibrosis Effect of Cordyceps militaris-Fermented Product Cultured with Deep Ocean Water via Inhibiting Proinflammatory Factors and Fibrosis-Related Factors Expressions.

    Science.gov (United States)

    Hung, Yu-Ping; Lee, Chun-Lin

    2017-06-08

    Deep ocean water (DOW) has been shown to enhance the functional components of fungi, resulting in increased health benefits. Therefore, using DOW for culturing fungi can enhance the cordycepin and adenosine of Cordyceps militaris (CM) and its protective effects on the liver. In this study, the antiliver fibrosis effects and mechanisms of ultrapure water-cultured CM (UCM), DOW-cultured CM (DCM), synthetic water-cultured CM, DOW, cordycepin, and adenosine were compared in the liver fibrosis mice induced by intraperitoneal injections of thioacetamide (TAA). The results indicated that DCM exhibited superior performance in reducing liver collagen accumulation, mitigating liver injuries, inhibiting proinflammatory factors and fibrosis-related factor (TGF-β1, Smad2/3, α-SMA, COL1A1) expression compared with UCM. DOW, cordycepin, and adenosine also performed antiliver fibrosis effect. Therefore, because DCM is rich in DOW and functional components, it can achieve anti-liver fibrosis effects through multiple pathways. These ameliorative effects are considerably superior to those of UCM.

  1. Assessment of myocardial fibrosis with T1 mapping MRI

    International Nuclear Information System (INIS)

    Everett, R.J.; Stirrat, C.G.; Semple, S.I.R.; Newby, D.E.; Dweck, M.R.; Mirsadraee, S.

    2016-01-01

    Myocardial fibrosis can arise from a range of pathological processes and its presence correlates with adverse clinical outcomes. Cardiac magnetic resonance (CMR) can provide a non-invasive assessment of cardiac structure, function, and tissue characteristics, which includes late gadolinium enhancement (LGE) techniques to identify focal irreversible replacement fibrosis with a high degree of accuracy and reproducibility. Importantly the presence of LGE is consistently associated with adverse outcomes in a range of common cardiac conditions; however, LGE techniques are qualitative and unable to detect diffuse myocardial fibrosis, which is an earlier form of fibrosis preceding replacement fibrosis that may be reversible. Novel T1 mapping techniques allow quantitative CMR assessment of diffuse myocardial fibrosis with the two most common measures being native T1 and extracellular volume (ECV) fraction. Native T1 differentiates normal from infarcted myocardium, is abnormal in hypertrophic cardiomyopathy, and may be particularly useful in the diagnosis of Anderson–Fabry disease and amyloidosis. ECV is a surrogate measure of the extracellular space and is equivalent to the myocardial volume of distribution of the gadolinium-based contrast medium. It is reproducible and correlates well with fibrosis on histology. ECV is abnormal in patients with cardiac failure and aortic stenosis, and is associated with functional impairment in these groups. T1 mapping techniques promise to allow earlier detection of disease, monitor disease progression, and inform prognosis; however, limitations remain. In particular, reference ranges are lacking for T1 mapping values as these are influenced by specific CMR techniques and magnetic field strength. In addition, there is significant overlap between T1 mapping values in healthy controls and most disease states, particularly using native T1, limiting the clinical application of these techniques at present.

  2. Assessment of myocardial fibrosis with T1 mapping MRI.

    Science.gov (United States)

    Everett, R J; Stirrat, C G; Semple, S I R; Newby, D E; Dweck, M R; Mirsadraee, S

    2016-08-01

    Myocardial fibrosis can arise from a range of pathological processes and its presence correlates with adverse clinical outcomes. Cardiac magnetic resonance (CMR) can provide a non-invasive assessment of cardiac structure, function, and tissue characteristics, which includes late gadolinium enhancement (LGE) techniques to identify focal irreversible replacement fibrosis with a high degree of accuracy and reproducibility. Importantly the presence of LGE is consistently associated with adverse outcomes in a range of common cardiac conditions; however, LGE techniques are qualitative and unable to detect diffuse myocardial fibrosis, which is an earlier form of fibrosis preceding replacement fibrosis that may be reversible. Novel T1 mapping techniques allow quantitative CMR assessment of diffuse myocardial fibrosis with the two most common measures being native T1 and extracellular volume (ECV) fraction. Native T1 differentiates normal from infarcted myocardium, is abnormal in hypertrophic cardiomyopathy, and may be particularly useful in the diagnosis of Anderson-Fabry disease and amyloidosis. ECV is a surrogate measure of the extracellular space and is equivalent to the myocardial volume of distribution of the gadolinium-based contrast medium. It is reproducible and correlates well with fibrosis on histology. ECV is abnormal in patients with cardiac failure and aortic stenosis, and is associated with functional impairment in these groups. T1 mapping techniques promise to allow earlier detection of disease, monitor disease progression, and inform prognosis; however, limitations remain. In particular, reference ranges are lacking for T1 mapping values as these are influenced by specific CMR techniques and magnetic field strength. In addition, there is significant overlap between T1 mapping values in healthy controls and most disease states, particularly using native T1, limiting the clinical application of these techniques at present. Copyright © 2016 The Royal College

  3. Computed tomography of cystic pancreatic fibrosis

    International Nuclear Information System (INIS)

    Brachlow, M.; Zaunbauer, W.; Haertel, M.

    1984-01-01

    The computer tomographic appearances of atrophic and lipomatous degeneration of the pancreas in cystic pancreatic fibrosis are described. CT exploration of the pancreas in recommended, particularly in differential diagnostic aspects of cystic fibrosis. (orig.) [de

  4. Effect of Ganfukang on liver function and serum hepatic fibrosis markers levels in SD rats with experimental hepatic fibrosis

    International Nuclear Information System (INIS)

    Che Ying; Wang Shanju; Xu Tingting; Jiang Miaona; Jia Yujie

    2004-01-01

    Objective: To observe the effect of Ganfukang on liver function and serum hepatic fibrosis markers levels in SD rats with experimental hepatic fibrosis. Methods: SD rat models of liver fibrosis was induced by CCl 4 (n=57). Liver function (GPT, GOT) and serum hepatic fibrosis markers levels (HA, LN, C-IV, PC-III, with RIA) were tested in these models and 10 control rats. Eleven model rats were left untreated, the others were treated with Ganfukang of different concentrations and the above hepatic parameters were again determined after completion of treatment. Results: Lever function was much deteriorated and serum markers levels significantly increased in the model rats (vs controls, P<0.01). After treatment with Ganfukang, the improvement was significant (vs untreated models, P<0.01). Conclusion: Ganfukang is of definite therapeutic value for experimental hepatic fibrosis in rat models. (authors)

  5. Treatment and education reduce the severity of schistosomiasis periportal fibrosis

    Directory of Open Access Journals (Sweden)

    Paula Carolina Valenca Silva

    2013-07-01

    Full Text Available Introduction This study evaluates the factors associated with the development of severe periportal fibrosis in patients with Schistosoma mansoni. Methods A cross-sectional study was conducted from April to December 2012 involving 178 patients infected with S. mansoni who were treated in the Hospital das Clínicas of Pernambuco, Brazil. Information regarding risk factors was obtained using a questionnaire. Based on the patients' epidemiological history, clinical examination, and upper abdomen ultrasound evaluation, patients were divided into 2 groups: 137 with evidence of severe periportal fibrosis and 41 patients without fibrosis or with mild or moderate periportal fibrosis. Univariate and multivariate analyses were conducted using EpiInfo software version 3.5.5. Results Illiterate individuals (30.1% and patients who had more frequent contact with contaminated water in towns in the Zona da Mata of Pernambuco (33.2% were at greater risk for severe periportal fibrosis. Based on multivariate analysis, it was determined that an education level of up to 11 years of study and specific prior treatment for schistosomiasis were preventive factors for severe periportal fibrosis. Conclusions The prevailing sites of the severe forms of periportal fibrosis are still within the Zona da Mata of Pernambuco, although there has been an expansion to urban areas and the state coast. Specific treatment and an increased level of education were identified as protective factors, indicating the need for implementing social, sanitary, and health education interventions aimed at schistosomiasis to combat the risk factors for this major public health problem.

  6. Nutrient Status of Adults with Cystic Fibrosis

    Science.gov (United States)

    GORDON, CATHERINE M.; ANDERSON, ELLEN J.; HERLYN, KAREN; HUBBARD, JANE L.; PIZZO, ANGELA; GELBARD, RONDI; LAPEY, ALLEN; MERKEL, PETER A.

    2011-01-01

    Nutrition is thought to influence disease status in patients with cystic fibrosis (CF). This cross-sectional study sought to evaluate nutrient intake and anthropometric data from 64 adult outpatients with cystic fibrosis. Nutrient intake from food and supplements was compared with the Dietary Reference Intakes for 16 nutrients and outcomes influenced by nutritional status. Attention was given to vitamin D and calcium given potential skeletal implications due to cystic fibrosis. Measurements included weight, height, body composition, pulmonary function, and serum metabolic parameters. Participants were interviewed about dietary intake, supplement use, pulmonary function, sunlight exposure, and pain. The participants’ mean body mass index (±standard deviation) was 21.8±4.9 and pulmonary function tests were normal. Seventy-eight percent used pancreatic enzyme replacement for malabsorption. Vitamin D deficiency [25-hydroxyvitamin D (25OHD)<37.5 nmol/L] was common: 25 (39%) were deficient despite adequate vitamin D intake. Lipid profiles were normal in the majority, even though total and saturated fat consumption represented 33.0% and 16.8% of energy intake, respectively. Reported protein intake represented 16.9% of total energy intake (range 10%–25%). For several nutrients, including vitamin D and calcium, intake from food and supplements in many participants exceeded recommended Tolerable Upper Intake Levels. Among adults with cystic fibrosis, vitamin D deficiency was common despite reported adequate intake, and lipid profiles were normal despite a relatively high fat intake. Mean protein consumption was adequate, but the range of intake was concerning, as both inadequate or excessive intake may have deleterious skeletal effects. These findings call into question the applicability of established nutrient thresholds for patients with cystic fibrosis. PMID:18060897

  7. Quantification of lung fibrosis and emphysema in mice using automated micro-computed tomography.

    Directory of Open Access Journals (Sweden)

    Ellen De Langhe

    Full Text Available BACKGROUND: In vivo high-resolution micro-computed tomography allows for longitudinal image-based measurements in animal models of lung disease. The combination of repetitive high resolution imaging with fully automated quantitative image analysis in mouse models of lung fibrosis lung benefits preclinical research. This study aimed to develop and validate such an automated micro-computed tomography analysis algorithm for quantification of aerated lung volume in mice; an indicator of pulmonary fibrosis and emphysema severity. METHODOLOGY: Mice received an intratracheal instillation of bleomycin (n = 8, elastase (0.25 U elastase n = 9, 0.5 U elastase n = 8 or saline control (n = 6 for fibrosis, n = 5 for emphysema. A subset of mice was scanned without intervention, to evaluate potential radiation-induced toxicity (n = 4. Some bleomycin-instilled mice were treated with imatinib for proof of concept (n = 8. Mice were scanned weekly, until four weeks after induction, when they underwent pulmonary function testing, lung histology and collagen quantification. Aerated lung volumes were calculated with our automated algorithm. PRINCIPAL FINDINGS: Our automated image-based aerated lung volume quantification method is reproducible with low intra-subject variability. Bleomycin-treated mice had significantly lower scan-derived aerated lung volumes, compared to controls. Aerated lung volume correlated with the histopathological fibrosis score and total lung collagen content. Inversely, a dose-dependent increase in lung volume was observed in elastase-treated mice. Serial scanning of individual mice is feasible and visualized dynamic disease progression. No radiation-induced toxicity was observed. Three-dimensional images provided critical topographical information. CONCLUSIONS: We report on a high resolution in vivo micro-computed tomography image analysis algorithm that runs fully automated and allows quantification of aerated lung volume in mice. This

  8. Clinical application of noninvasive diagnosis of liver fibrosis

    OpenAIRE

    ZHU Chuanlong

    2015-01-01

    Hepatic fibrosis is the common outcome of chronic liver diseases of various causes. At present, liver biopsy is the “gold standard” for the diagnosis of liver fibrosis, but it has limitations and is invasive, which leads to the development of noninvasive assessment of liver fibrosis. The article mainly introduces the technology and application of noninvasive diagnosis of liver fibrosis from the aspects of clinical manifestation, serology, and radiology. It has pointed out the clinical value o...

  9. Prevalence and progression of combined pulmonary fibrosis and emphysema in asymptomatic smokers: A case-control study

    Energy Technology Data Exchange (ETDEWEB)

    Chae, Kum Ju; Jin, Gong Yong; Han, Young Min; Kim, Yong Seek; Chon, Su Bin; Lee, Young Sun [Chonbuk National University Medical School and Hospital, Department of Radiology, Institute of Medical Science, Research Institute of Clinical Medicine, Jeonju, Jeonbuk (Korea, Republic of); Kwon, Keun Sang [Chonbuk National University Medical School, Department of Preventive Medicine, Research Institute of Clinical Medicine, Jeonju, Jeonbuk (Korea, Republic of); Choi, Hye Mi [Chonbuk National University, Department of Statistics and Institute of Applied Statistics, Jeonju, Jeonbuk (Korea, Republic of); Lynch, David [National Jewish Health, Department of Radiology, Denver, CO (United States)

    2015-08-15

    We aimed to estimate the prevalence of combined pulmonary fibrosis and emphysema (CPFE) and describe the follow-up CT results of CPFE in asymptomatic smokers. This study was retrospective, and approved by an institutional review board. CT images of 2,016 current or previous male smokers who underwent low-dose chest CT at our healthcare centre were reviewed. Quantitative CT analysis was used to assess the extent of emphysema, and two radiologists visually analyzed the extent of fibrosis. Changes in fibrosis (no change, improvement, or progression) were evaluated on follow-up CT imaging (n = 42). Kaplan-Meier survival analysis, multivariate logistic regression and its ROC curve were used for survival and progression analysis. The prevalence of CPFE among asymptomatic male smokers was 3.1 % (63/2,016). The median follow-up period was 50.4 months, and 72.7 % (16/22) of continued smoker had progressing fibrosis on follow-up CT. CPFE progressed more rapidly in continuous smokers than in former smokers (p = 0.002). The 3.5-year follow-up period after initial CPFE diagnosis maximized the sum of sensitivity and specificity of CPFE progression prediction in continuous smokers. The prevalence of CPFE turned out not to be inconsiderable in asymptomatic male smokers, but serial CT follow-up would be helpful in recognizing disease progression. (orig.)

  10. Prevalence and progression of combined pulmonary fibrosis and emphysema in asymptomatic smokers: A case-control study

    International Nuclear Information System (INIS)

    Chae, Kum Ju; Jin, Gong Yong; Han, Young Min; Kim, Yong Seek; Chon, Su Bin; Lee, Young Sun; Kwon, Keun Sang; Choi, Hye Mi; Lynch, David

    2015-01-01

    We aimed to estimate the prevalence of combined pulmonary fibrosis and emphysema (CPFE) and describe the follow-up CT results of CPFE in asymptomatic smokers. This study was retrospective, and approved by an institutional review board. CT images of 2,016 current or previous male smokers who underwent low-dose chest CT at our healthcare centre were reviewed. Quantitative CT analysis was used to assess the extent of emphysema, and two radiologists visually analyzed the extent of fibrosis. Changes in fibrosis (no change, improvement, or progression) were evaluated on follow-up CT imaging (n = 42). Kaplan-Meier survival analysis, multivariate logistic regression and its ROC curve were used for survival and progression analysis. The prevalence of CPFE among asymptomatic male smokers was 3.1 % (63/2,016). The median follow-up period was 50.4 months, and 72.7 % (16/22) of continued smoker had progressing fibrosis on follow-up CT. CPFE progressed more rapidly in continuous smokers than in former smokers (p = 0.002). The 3.5-year follow-up period after initial CPFE diagnosis maximized the sum of sensitivity and specificity of CPFE progression prediction in continuous smokers. The prevalence of CPFE turned out not to be inconsiderable in asymptomatic male smokers, but serial CT follow-up would be helpful in recognizing disease progression. (orig.)

  11. Rosiglitazone attenuates pulmonary fibrosis and radiation-induced intestinal damage

    International Nuclear Information System (INIS)

    Mangoni, M.; Gerini, C.; Sottili, M.; Cassani, S.; Stefania, G.; Biti, G.; Castiglione, F.; Vanzi, E.; Bottoncetti, A.; Pupi, A.

    2011-01-01

    Full text of publication follows: Purpose.-The aim of the study was to evaluate radioprotective effect of rosiglitazone (RGZ) on a murine model of late pulmonary damage and of acute intestinal damage. Methods.- Lung fibrosis: C57 mice were treated with the radiomimetic agent bleomycin, with or without rosiglitazone (5 mg/kg/day). To obtain an independent qualitative and quantitative measure for lung fibrosis we used high resolution CT, performed twice a week during the entire observation period. Hounsfield Units (HU) of section slides from the upper and lower lung region were determined. On day 31 lungs were collected for histological analysis. Acute intestinal damage: mice underwent 12 Gy total body irradiation with or without rosiglitazone. Mice were sacrificed 24 or 72 h after total body irradiation and ileum and colon were collected. Results.- Lung fibrosis: after bleomycin treatment, mice showed typical CT features of lung fibrosis, including irregular septal thickening and patchy peripheral reticular abnormalities. Accordingly, HU lung density was dramatically increased. Rosiglitazone markedly attenuated the radiological signs of fibrosis and strongly inhibited HU lung density increase (60% inhibition at the end of the observation period). Histological analysis revealed that in bleomycin-treated mice, fibrosis involved 50-55% of pulmonary parenchyma and caused an alteration of the alveolar structures in 10% of parenchyma, while in rosiglitazone-treated mice, fibrosis involved only 20-25% of pulmonary parenchyma, without alterations of the alveolar structures. Acute intestinal damage: 24 h after 12 Gy of total body irradiation intestinal mucosa showed villi shortening, mucosal thickness and crypt necrotic changes. Rosiglitazone showed a histological improvement of tissue structure, with villi and crypts normalization and oedema reduction. Conclusion.- These results demonstrate that rosiglitazone displays a protective effect on pulmonary fibrosis and radiation

  12. Rosiglitazone attenuates pulmonary fibrosis and radiation-induced intestinal damage

    Energy Technology Data Exchange (ETDEWEB)

    Mangoni, M.; Gerini, C.; Sottili, M.; Cassani, S.; Stefania, G.; Biti, G. [Radiotherapy Unit, Clinical Physiopathology Department, University of Florence, Firenze (Italy); Castiglione, F. [Department of Human Pathology and Oncology, University of Florence, Firenze (Italy); Vanzi, E.; Bottoncetti, A.; Pupi, A. [Nuclear Medicine Unit, Clinical Physiopathology Department, University of Florence, Firenze (Italy)

    2011-10-15

    Full text of publication follows: Purpose.-The aim of the study was to evaluate radioprotective effect of rosiglitazone (RGZ) on a murine model of late pulmonary damage and of acute intestinal damage. Methods.- Lung fibrosis: C57 mice were treated with the radiomimetic agent bleomycin, with or without rosiglitazone (5 mg/kg/day). To obtain an independent qualitative and quantitative measure for lung fibrosis we used high resolution CT, performed twice a week during the entire observation period. Hounsfield Units (HU) of section slides from the upper and lower lung region were determined. On day 31 lungs were collected for histological analysis. Acute intestinal damage: mice underwent 12 Gy total body irradiation with or without rosiglitazone. Mice were sacrificed 24 or 72 h after total body irradiation and ileum and colon were collected. Results.- Lung fibrosis: after bleomycin treatment, mice showed typical CT features of lung fibrosis, including irregular septal thickening and patchy peripheral reticular abnormalities. Accordingly, HU lung density was dramatically increased. Rosiglitazone markedly attenuated the radiological signs of fibrosis and strongly inhibited HU lung density increase (60% inhibition at the end of the observation period). Histological analysis revealed that in bleomycin-treated mice, fibrosis involved 50-55% of pulmonary parenchyma and caused an alteration of the alveolar structures in 10% of parenchyma, while in rosiglitazone-treated mice, fibrosis involved only 20-25% of pulmonary parenchyma, without alterations of the alveolar structures. Acute intestinal damage: 24 h after 12 Gy of total body irradiation intestinal mucosa showed villi shortening, mucosal thickness and crypt necrotic changes. Rosiglitazone showed a histological improvement of tissue structure, with villi and crypts normalization and oedema reduction. Conclusion.- These results demonstrate that rosiglitazone displays a protective effect on pulmonary fibrosis and radiation

  13. Nephrogenic systemic fibrosis: UK survey of the use of gadolinium-based contrast media

    International Nuclear Information System (INIS)

    Rees, O.; Agarwal, S.K.

    2010-01-01

    Aim: To identify the current practice of administration of gadolinium-based contrast media (Gd-CM) within the UK with respect to the European Society of Urogenital Radiology (ESUR) guidelines on nephrogenic systemic fibrosis (NSF). Materials and methods: One hundred and fifty-two institutions were contacted to request details regarding the use of Gd-CM at their institution, their awareness of NSF, and of the ESUR guidelines, and their departmental policy on the administration of Gd-CM agents associated with NSF (high-risk agents) in patients with diminished renal function. Results: Of the 100 institutions that replied, 72% used a cyclic agent as a first-line Gd-CM. The majority of institutions used more than one Gd-CM, and 57% used a high-risk Gd-CM. Seventy percent were aware of the ESUR guidelines, and of the 57% that used a high-risk Gd-CM, 9% did not check renal function at all prior to administration. The course of action of the remaining 48% was varied in patients with diminished renal function with some changing to a low-risk Gd-CM and others electing not to use Gd-CM at all. Five percent continued to use a high-risk Gd-CM with an estimated glomerular filtration rate <30 ml/min. Conclusion: The present survey shows that the majority of institutions use a low-risk Gd-CM as a first-line agent; however, a number of institutions do use a high-risk Gd-CM and their course of action for patients with diminished renal function is varied. Given current evidence, it is advisable to use a low-risk Gd-CM, such as a cyclic agent, in patients with diminished renal function.

  14. Lung adenocarcinoma mimicking pulmonary fibrosis-a case report

    International Nuclear Information System (INIS)

    Mehić, Bakir; Duranović Rayan, Lina; Bilalović, Nurija; Dohranović Tafro, Danina; Pilav, Ilijaz

    2016-01-01

    Lung cancer is usually presented with cough, dyspnea, pain and weight loss, which is overlapping with symptoms of other lung diseases such as pulmonary fibrosis. Pulmonary fibrosis shows characteristic reticular and nodular pattern, while lung cancers are mostly presented with infiltrative mass, thick-walled cavitations or a solitary nodule with spiculated borders. If the diagnosis is established based on clinical symptoms and CT findings, it would be a misapprehension. We report a case of lung adenocarcinoma whose symptoms as well as clinical images overlapped strongly with pulmonary fibrosis. The patient’s non-productive cough, progressive dyspnea, restrictive pattern of pulmonary function test and CT scans (showing reticular interstitial opacities) were all indicative of pulmonary fibrosis. The patient underwent a treatment consisting of corticosteroids and antibiotics, to no avail. Histopathology of the lung showed that the patient suffered from mucinous adenocarcinoma. Albeit the immunohistochemical staining was not consistent with lung adenocarcinoma, tumor’s morphological characteristics were consistent, and were used to make the definitive diagnosis. Given the fact that radiography cannot always make a clear-cut difference between pulmonary fibrosis and lung adenocarcinomas, and that clinical symptoms often overlap, histological examination should be considered as gold standard for diagnosis of lung adenocarcinoma

  15. Glycyrrhizic acid alleviates bleomycin-induced pulmonary fibrosis in rats

    Directory of Open Access Journals (Sweden)

    Lili eGao

    2015-10-01

    Full Text Available Idiopathic pulmonary fibrosis is a progressive and lethal form of interstitial lung disease that lacks effective therapies at present. Glycyrrhizic acid (GA, a natural compound extracted from a traditional Chinese herbal medicine Glycyrrhiza glabra, was recently reported to benefit lung injury and liver fibrosis in animal models, yet whether GA has a therapeutic effect on pulmonary fibrosis is unknown. In this study, we investigated the potential therapeutic effect of GA on pulmonary fibrosis in a rat model with bleomycin (BLM-induced pulmonary fibrosis. The results indicated that GA treatment remarkably ameliorated BLM-induced pulmonary fibrosis and attenuated BLM-induced inflammation, oxidative stress, epithelial-mesenchymal transition and activation of tansforming growth factor-beta signaling pathway in the lungs. Further, we demonstrated that GA treatment inhibited proliferation of 3T6 fibroblast cells, induced cell cycle arrest and promoted apoptosis in vitro, implying that GA-mediated suppression of fibroproliferation may contribute to the anti-fibrotic effect against BLM-induced pulmonary fibrosis. In summary, our study suggests a therapeutic potential of GA in the treatment of pulmonary fibrosis.

  16. Multicenter study of quantitative computed tomography analysis using a computer-aided three-dimensional system in patients with idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Iwasawa, Tae; Kanauchi, Tetsu; Hoshi, Toshiko; Ogura, Takashi; Baba, Tomohisa; Gotoh, Toshiyuki; Oba, Mari S

    2016-01-01

    To evaluate the feasibility of automated quantitative analysis with a three-dimensional (3D) computer-aided system (i.e., Gaussian histogram normalized correlation, GHNC) of computed tomography (CT) images from different scanners. Each institution's review board approved the research protocol. Informed patient consent was not required. The participants in this multicenter prospective study were 80 patients (65 men, 15 women) with idiopathic pulmonary fibrosis. Their mean age was 70.6 years. Computed tomography (CT) images were obtained by four different scanners set at different exposures. We measured the extent of fibrosis using GHNC, and used Pearson's correlation analysis, Bland-Altman plots, and kappa analysis to directly compare the GHNC results with manual scoring by radiologists. Multiple linear regression analysis was performed to determine the association between the CT data and forced vital capacity (FVC). For each scanner, the extent of fibrosis as determined by GHNC was significantly correlated with the radiologists' score. In multivariate analysis, the extent of fibrosis as determined by GHNC was significantly correlated with FVC (p < 0.001). There was no significant difference between the results obtained using different CT scanners. Gaussian histogram normalized correlation was feasible, irrespective of the type of CT scanner used.

  17. Segmental Difference of the Hepatic Fibrosis from Chronic Viral Hepatitis due to Hepatitis B versus C Virus Infection: Comparison Using Dual Contrast Material-Enhanced MRI

    International Nuclear Information System (INIS)

    Shin, Jae Ho; Yu, Jeong Sik; Chung, Jae Joon; Kim, Joo Hee; Kim, Ki Whang

    2011-01-01

    We wanted to identify the geographic differences in hepatic fibrosis and their associations with the atrophy-hypertrophy complex in patients with chronic viral hepatitis using the dual-contrast material-enhanced MRI (DC-MRI) with gadopentetate dimeglumine and ferucarbotran. Patients with chronic C (n = 22) and B-viral hepatitis (n = 35) were enrolled for determining the subjective grade of fibrosis (the extent and thickness of fibrotic reticulations) in the right lobe (RL), the caudate lobe (CL), the medial segment (MS) and the lateral segment (LS) of the liver, with using a 5-grade scale, on the gradient echo T2-weighted images of DC-MRI. The fibrosis grades of different segments were compared using the Kruskal-Wallis test followed by post-hoc analysis to establish the segment-by-segment differences. The incidences of two pre-established morphologic signs of cirrhosis were also compared with each other between the two groups of patients. There were significant intersegmental differences in fibrosis grades of the C-viral group (p = 0.005), and the CL showed lower fibrosis grades as compared with the grades of the RL and MS, whereas all lobes were similarly affected in the B-viral group (p = 0.221). The presence of a right posterior hepatic notch was significantly higher in the patients with intersegmental differences of fibrosis between the RL and the CL (19 out of 25, 76%) than those without such differences (6 out of 32, 19%) (p < 0.001). An expanded gallbladder fossa showed no significant relationship (p = 0.327) with the segmental difference of the fibrosis grades between the LS and the MS. The relative lack of fibrosis in the CL with more advanced fibrosis in the RL can be a distinguishing feature to differentiate chronic C-viral hepatitis from chronic B-viral hepatitis and this is closely related to the presence of a right posterior hepatic notch.

  18. Segmental Difference of the Hepatic Fibrosis from Chronic Viral Hepatitis due to Hepatitis B versus C Virus Infection: Comparison Using Dual Contrast Material-Enhanced MRI

    Energy Technology Data Exchange (ETDEWEB)

    Shin, Jae Ho; Yu, Jeong Sik; Chung, Jae Joon; Kim, Joo Hee; Kim, Ki Whang [Gangnam Severance Hospital, Yensei University College of Medicine, Seoul (Korea, Republic of)

    2011-08-15

    We wanted to identify the geographic differences in hepatic fibrosis and their associations with the atrophy-hypertrophy complex in patients with chronic viral hepatitis using the dual-contrast material-enhanced MRI (DC-MRI) with gadopentetate dimeglumine and ferucarbotran. Patients with chronic C (n = 22) and B-viral hepatitis (n = 35) were enrolled for determining the subjective grade of fibrosis (the extent and thickness of fibrotic reticulations) in the right lobe (RL), the caudate lobe (CL), the medial segment (MS) and the lateral segment (LS) of the liver, with using a 5-grade scale, on the gradient echo T2-weighted images of DC-MRI. The fibrosis grades of different segments were compared using the Kruskal-Wallis test followed by post-hoc analysis to establish the segment-by-segment differences. The incidences of two pre-established morphologic signs of cirrhosis were also compared with each other between the two groups of patients. There were significant intersegmental differences in fibrosis grades of the C-viral group (p = 0.005), and the CL showed lower fibrosis grades as compared with the grades of the RL and MS, whereas all lobes were similarly affected in the B-viral group (p = 0.221). The presence of a right posterior hepatic notch was significantly higher in the patients with intersegmental differences of fibrosis between the RL and the CL (19 out of 25, 76%) than those without such differences (6 out of 32, 19%) (p < 0.001). An expanded gallbladder fossa showed no significant relationship (p = 0.327) with the segmental difference of the fibrosis grades between the LS and the MS. The relative lack of fibrosis in the CL with more advanced fibrosis in the RL can be a distinguishing feature to differentiate chronic C-viral hepatitis from chronic B-viral hepatitis and this is closely related to the presence of a right posterior hepatic notch.

  19. Thrombin and factor Xa link the coagulation system with liver fibrosis.

    Science.gov (United States)

    Dhar, Ameet; Sadiq, Fouzia; Anstee, Quentin M; Levene, Adam P; Goldin, Robert D; Thursz, Mark R

    2018-05-08

    Thrombin activates hepatic stellate cells via protease-activated receptor-1. The role of Factor Xa (FXa) in hepatic fibrosis has not been elucidated. We aimed to evaluate the impact of FXa and thrombin in vitro on stellate cells and their respective inhibition in vivo using a rodent model of hepatic fibrosis. HSC-LX2 cells were incubated with FXa and/or thrombin in cell culture, stained for αSMA and relative gene expression and gel contraction calculated. C57BL/6 J mice were administered thioacetamide (TAA) for 8 weeks with Rivaroxaban (n = 15) or Dabigatran (n = 15). Control animals received TAA alone (n = 15). Fibrosis was scored and quantified using digital image analysis and hepatic tissue hydroxyproline estimated. Stellate cells treated with FXa and thrombin demonstrated upregulation of procollagen, TGF-beta, αSMA and significant cell contraction (43.48%+/- 4.12) compared to culturing with FXa or thrombin alone (26.90%+/- 8.90, p = 0.02; 13.1%+/- 9.84, p < 0.001). Mean fibrosis score, percentage area of fibrosis and hepatic hydroxyproline content (2.46 vs 4.08, p = 0.008; 2.02% vs 3.76%, p = 0.012; 276.0 vs 651.3, p = 0.0001) were significantly reduced in mice treated with the FXa inhibitor compared to control mice. FXa inhibition was significantly more effective than thrombin inhibition in reducing percentage area of fibrosis and hepatic hydroxyproline content (2.02% vs 3.70%,p = 0.031; 276.0 vs 413.1,p = 0.001). FXa promotes stellate cell contractility and activation. Early inhibition of coagulation using a FXa inhibitor significantly reduces TAA induced murine liver fibrosis and may be a viable treatment for liver fibrosis in patients.

  20. Effects of Angiotensin Converting Enzyme Inhibitors on Liver Fibrosis in HIV and Hepatitis C Coinfection

    Directory of Open Access Journals (Sweden)

    Lindsey J. Reese

    2012-01-01

    Full Text Available Background. Liver fibrosis is accelerated in HIV and hepatitis C coinfection, mediated by profibrotic effects of angiotensin. The objective of this study was to determine if angiotensin converting enzyme inhibitors (ACE-Is attenuate liver fibrosis in coinfection. Methods. A retrospective review of 156 coinfected subjects was conducted to analyze the association between exposure to ACE-Is and liver fibrosis. Noninvasive indices of liver fibrosis (APRI, FIB-4, Forns indices were compared between subjects who had taken ACE-Is and controls who had not taken them. Linear regression was used to evaluate ACE-I use as an independent predictor of fibrosis. Results. Subjects taking ACE-Is for three years were no different than controls on the APRI and the FIB-4 but had significantly higher scores than controls on the Forns index, indicating more advanced fibrosis. The use of ACE-Is for three years remained independently associated with an elevated Forns score when adjusted for age, race, and HIV viral load (P<0.001. There were significant associations between all of the indices and significant fibrosis, as determined clinically and radiologically. Conclusions. There was not a protective association between angiotensin inhibition and liver fibrosis in coinfection. These noninvasive indices may be useful for ruling out significant fibrosis in coinfection.

  1. Guidelines for the medical treatment of idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Xaubet, Antoni; Molina-Molina, María; Acosta, Orlando; Bollo, Elena; Castillo, Diego; Fernández-Fabrellas, Estrella; Rodríguez-Portal, José Antonio; Valenzuela, Claudia; Ancochea, Julio

    2017-05-01

    Idiopathic pulmonary fibrosis is defined as chronic fibrosing interstitial pneumonia limited to the lung, with poor prognosis. The incidence has been rising in recent years probably due to improved diagnostic methods and increased life expectancy. In 2013, the SEPAR guidelines for the diagnosis and treatment for idiopathic pulmonary fibrosis were published. Since then, clinical trials and meta-analyses have shown strong scientific evidence for the use of pirfenidone and nintedanib in the treatment of idiopathic pulmonary fibrosis. In 2015, the international consensus of 2011 was updated and new therapeutic recommendations were established, prompting us to update our recommendation for the medical treatment of idiopathic pulmonary fibrosis accordingly. Diagnostic aspects and non-pharmacological treatment will not be discussed as no relevant developments have emerged since the 2013 guidelines. Copyright © 2017 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.

  2. Fibrosis and carcinoid syndrome: from causation to future therapy.

    Science.gov (United States)

    Druce, Maralyn; Rockall, Andrea; Grossman, Ashley B

    2009-05-01

    Carcinoid tumors are part of a heterogeneous group of gastrointestinal and pancreatic endocrine tumors that are characterized by their capacity to produce and secrete hormones, 5-hydroxytryptamine, tachykinins and other mediators. These substances are thought to be responsible for the collection of symptoms, which include diarrhea, flushing and wheezing, that is known as carcinoid syndrome. Fibrosis that occurs either local to or distant from the primary tumor is one of the hallmarks of carcinoid tumors that originate from the midgut. The fibrotic process can occur in the mesentery as a desmoplastic response and may lead to obstruction of the small bowel, but it can also occur in the lungs, skin or retroperitoneum. Importantly, up to one-third of patients develop cardiac valvulopathy. One or more products that are secreted by the tumor and enter into the circulation are likely to have a role in this process. This Review discusses the incidence and prevalence of fibrosis in carcinoid syndrome and explores evidence to date for causative agents, in particular the roles of 5-hydroxytryptamine and elements of the downstream signaling pathway. Improved understanding of the etiology of carcinoid-tumor-related fibrosis may lead to better treatments for this condition than those we currently have.

  3. Routine blood tests to predict liver fibrosis in chronic hepatitis C.

    Science.gov (United States)

    Hsieh, Yung-Yu; Tung, Shui-Yi; Lee, Kamfai; Wu, Cheng-Shyong; Wei, Kuo-Liang; Shen, Chien-Heng; Chang, Te-Sheng; Lin, Yi-Hsiung

    2012-02-28

    To verify the usefulness of FibroQ for predicting fibrosis in patients with chronic hepatitis C, compared with other noninvasive tests. This retrospective cohort study included 237 consecutive patients with chronic hepatitis C who had undergone percutaneous liver biopsy before treatment. FibroQ, aspartate aminotransferase (AST)/alanine aminotransferase ratio (AAR), AST to platelet ratio index, cirrhosis discriminant score, age-platelet index (API), Pohl score, FIB-4 index, and Lok's model were calculated and compared. FibroQ, FIB-4, AAR, API and Lok's model results increased significantly as fibrosis advanced (analysis of variance test: P fibrosis score in chronic hepatitis C compared with other noninvasive tests. FibroQ is a simple and useful test for predicting significant fibrosis in patients with chronic hepatitis C.

  4. Transient elastography for liver fibrosis diagnosis

    DEFF Research Database (Denmark)

    Andersen, Ellen Sloth; Christensen, Peer Brehm; Weis, Nina

    2008-01-01

    Liver biopsy is considered the "golden standard" for assessment of hepatic fibrosis. However, the procedure has limitations because of inconvenience and rare but serious complications as bleeding. Furthermore, sampling errors are frequent, and interobserver variability often poses problems....... Recently, a modified ultrasound scanner (transient elastography) has been developed to assess fibrosis. The device measures liver elasticity, which correlates well with the degree of fibrosis. Studies have shown that transient elastography is more accurate in diagnosing cirrhosis than minor to moderate...... to be a valuable diagnostic procedure and follow-up of patients with chronic liver diseases....

  5. Transient elastography for liver fibrosis diagnosis

    DEFF Research Database (Denmark)

    Andersen, Ellen Sloth; Christensen, Peer Brehm; Weis, Nina

    2009-01-01

    Liver biopsy is considered the "golden standard" for assessment of hepatic fibrosis. However, the procedure has limitations because of inconvenience and rare but serious complications as bleeding. Furthermore, sampling errors are frequent, and interobserver variability often poses problems....... Recently, a modified ultrasound scanner (transient elastography) has been developed to assess fibrosis. The device measures liver elasticity, which correlates well with the degree of fibrosis. Studies have shown that transient elastography is more accurate in diagnosing cirrhosis than minor to moderate...... to be a valuable diagnostic procedure and follow-up of patients with chronic liver diseases....

  6. Comparison of serological assessments in the diagnosis of liver fibrosis in bile duct ligation mice.

    Science.gov (United States)

    Xie, Chengxia; Ma, Bo; Wang, Ning; Wan, Lin

    2017-08-01

    Liver fibrosis assessment is essential to make a prognosis and to determine the appropriate anti-fibrosis treatment. Non-invasive serum markers are widely studied in patients to assess liver fibrosis due to the limitations of liver biopsy. When using animal models to study the mechanism and intervention of hepatic fibrosis, serum markers might be useful for the continuous assessment of liver fibrosis in individual animals, which could avoid the influence of biological differences between individuals. However, it is unclear whether serum markers can assess hepatic fibrosis in the animal model. In the present study, we evaluated and compared the ability of four serum markers to assess liver fibrosis in bile duct ligation mice. According to the stages of liver fibrosis assessed by pathological changes, mice in this study were divided into five groups (F0, F1, F2, F3, and F4). Subsequently, four serum markers, aspartate aminotransferase-to-alanine aminotransferase ratio (AAR), aspartate aminotransferase-to-platelet ratio index (APRI), fibrosis index based on the 4 factors (FIB-4), and Forns Index, were calculated for each group. Furthermore, the correlations between serum markers and pathological stages and the ability of serological markers to evaluate liver fibrosis were analyzed. AAR, APRI, FIB-4, and Forns Index could significantly distinguish F0-2 from F3-4 mice. APRI, FIB-4, and Forns Index could detect F0-3 from F4 mice. Among these four markers, FIB-4 was the best able to distinguish ≥F2 and ≥F3, with area under the curve values of 0.882 and 0.92, respectively. Forns Index was best for diagnosing F4 with area under the curve value of 0.879. These results demonstrated that serum markers could be used for assessing liver fibrosis in bile duct ligation mice, and therefore, these markers might lead to more accurate diagnostic and therapeutic studies through continuous monitoring in individual animals. Impact statement The assessment of liver fibrosis is

  7. Exploring Cystic Fibrosis Using Bioinformatics Tools: A Module Designed for the Freshman Biology Course

    Science.gov (United States)

    Zhang, Xiaorong

    2011-01-01

    We incorporated a bioinformatics component into the freshman biology course that allows students to explore cystic fibrosis (CF), a common genetic disorder, using bioinformatics tools and skills. Students learn about CF through searching genetic databases, analyzing genetic sequences, and observing the three-dimensional structures of proteins…

  8. A biomarker panel for non-alcoholic steatohepatitis (NASH) and NASH-related fibrosis.

    Science.gov (United States)

    Younossi, Zobair M; Page, Sandra; Rafiq, Nila; Birerdinc, Aybike; Stepanova, Maria; Hossain, Noreen; Afendy, Arian; Younoszai, Zahra; Goodman, Zachary; Baranova, Ancha

    2011-04-01

    Patients with biopsy-proven NASH and especially those with fibrosis are at risk for progressive liver disease, emphasizing the clinical importance of developing non-invasive biomarkers for NASH and NASH-related fibrosis. This study examines the performance of a new biomarker panel for NASH and NASH-related fibrosis with a combination of clinical and laboratory variables. Enrolled patients had biopsy-proven NAFLD. Clinical data, laboratory data, and serum samples were collected at the time of biopsy. Fasting serum was assayed for adiponectin, resistin, glucose, M30, M65, Tissue inhibitor of metalloproteinases-1 (Timp-1), ProCollagen 3 N-terminal peptide (PIIINP), and hyaluronic acid (HA). Regression models predictive of NASH, NASH-related fibrosis, and NASH-related advanced fibrosis were designed and cross-validated. Of the 79 enrolled NAFLD patients, 40 had biopsy-proven NASH and 39 had non-NASH NAFLD. Clinical and laboratory data were from this cohort were used to develop a NAFLD Diagnostic Panel that includes three models (models for NASH, NASH-related fibrosis, and NASH-related advanced fibrosis). The model for predicting NASH includes diabetes, gender, BMI, triglycerides, M30 (apoptosis), and M65-M30 (necrosis) [AUC: 0.81, 95% CI, 0.70-0.89, 300 p value <9E 301 (-06)]. The NASH-related fibrosis prediction model includes the same predictors [AUC: 0.80, 95% CI 0.68-0.88, 307 p value <0.00014]. Finally, the NASH-related advanced fibrosis model includes type 2 diabetes, serum triglycerides, Timp-1, and AST [AUC: 0.81, 95% CI, 0.70-0.89; p value, 0.000062]. This NAFLD Diagnostic Panel based on a clinical and laboratory data has good performance characteristics and is easy to use. This biomarker panel could become useful in the management of patients with NAFLD.

  9. Pregnancy and cystic fibrosis: Approach to contemporary management

    Science.gov (United States)

    Tay, George; Callaway, Leonie; Bell, Scott C

    2014-01-01

    Over the previous 50 years survival of patients with cystic fibrosis has progressively increased. As a result of improvements in health care, increasing numbers of patients with cystic fibrosis are now considering starting families of their own. For the health care professionals who look after these patients, the assessment of the potential risks, and the process of guiding prospective parents through pregnancy and beyond can be both challenging and rewarding. To facilitate appropriate discussions about pregnancy, health care workers must have a detailed understanding of the various important issues that will ultimately need to be considered for any patient with cystic fibrosis considering parenthood. This review will address these issues. In particular, it will outline pregnancy outcomes for mothers with cystic fibrosis, issues that need to be taken into account when planning a pregnancy and the management of pregnancy for mothers with cystic fibrosis or mothers who have undergone organ transplantation as a result of cystic fibrosis. PMID:27512443

  10. Idiopathic pulmonary fibrosis: current treatment options and critical appraisal of nintedanib

    Directory of Open Access Journals (Sweden)

    Bonella F

    2015-12-01

    Full Text Available Francesco Bonella,1 Susanne Stowasser,2 Lutz Wollin3 1Interstitial and Rare Lung Disease Unit, Ruhrlandklinik, University Hospital, University of Duisburg-Essen, Essen, 2Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, 3Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany Abstract: Idiopathic pulmonary fibrosis (IPF is the most common type of idiopathic interstitial pneumonia and is characterized by a poor prognosis, with an estimated 5-year survival of approximately 20%. Progressive and irreversible lung functional impairment leads to chronic respiratory insufficiency with a severely impaired quality of life. In the last 2 decades, novel treatments for IPF have been developed as a consequence of an increasing understanding of disease pathogenesis and pathobiology. In IPF, injured dysfunctional alveolar epithelial cells promote fibroblast recruitment and proliferation, resulting in scarring of the lung tissue. Recently, pirfenidone and nintedanib have been approved for the treatment of IPF, having shown efficacy to slow functional decline and disease progression. This article focuses on the pharmacologic characteristics and clinical evidence supporting the use of nintedanib, a potent small-molecule tyrosine kinase inhibitor, as therapy for IPF. After introducing the mechanism of action and pharmacokinetics, an overview of the safety and efficacy results from the most recent clinical trials of nintedanib in IPF is presented. Keywords: tyrosine kinase, disease progression, treatment outcome, usual interstitial pneumonia, therapeutics

  11. Genetics Home Reference: idiopathic pulmonary fibrosis

    Science.gov (United States)

    ... these health problems has idiopathic pulmonary fibrosis . Other respiratory diseases, some of which are less serious, can cause similar signs and symptoms. In people with idiopathic pulmonary fibrosis , scarring of the lungs increases over time until the lungs can no longer ...

  12. Coefficient of Variance as Quality Criterion for Evaluation of Advanced Hepatic Fibrosis Using 2D Shear-Wave Elastography.

    Science.gov (United States)

    Lim, Sanghyeok; Kim, Seung Hyun; Kim, Yongsoo; Cho, Young Seo; Kim, Tae Yeob; Jeong, Woo Kyoung; Sohn, Joo Hyun

    2018-02-01

    To compare the diagnostic performance for advanced hepatic fibrosis measured by 2D shear-wave elastography (SWE), using either the coefficient of variance (CV) or the interquartile range divided by the median value (IQR/M) as quality criteria. In this retrospective study, from January 2011 to December 2013, 96 patients, who underwent both liver stiffness measurement by 2D SWE and liver biopsy for hepatic fibrosis grading, were enrolled. The diagnostic performances of the CV and the IQR/M were analyzed using receiver operating characteristic curves with areas under the curves (AUCs) and were compared by Fisher's Z test, based on matching the cutoff points in an interactive dot diagram. All P values less than 0.05 were considered significant. When using the cutoff value IQR/M of 0.21, the matched cutoff point of CV was 20%. When a cutoff value of CV of 20% was used, the diagnostic performance for advanced hepatic fibrosis ( ≥ F3 grade) with CV of less than 20% was better than that in the group with CV greater than or equal to 20% (AUC 0.967 versus 0.786, z statistic = 2.23, P = .025), whereas when the matched cutoff value IQR/M of 0.21 showed no difference (AUC 0.918 versus 0.927, z statistic = -0.178, P = .859). The validity of liver stiffness measurements made by 2D SWE for assessing advanced hepatic fibrosis may be judged using CVs, and when the CV is less than 20% it can be considered "more reliable" than using IQR/M of less than 0.21. © 2017 by the American Institute of Ultrasound in Medicine.

  13. Psychological interventions for individuals with cystic fibrosis and their families.

    Science.gov (United States)

    Goldbeck, Lutz; Fidika, Astrid; Herle, Marion; Quittner, Alexandra L

    2014-06-18

    cover interventions with generic approaches, as well as interventions developed specifically to target disease-specific symptoms and problems in people with cystic fibrosis. These include cognitive behavioural interventions to improve adherence to nutrition or psychosocial adjustment, cognitive interventions to improve adherence or those associated with decision making in lung transplantation, a community-based support intervention and other interventions, such as self-hypnosis, respiratory muscle biofeedback, music therapy, dance and movement therapy, and a tele-medicine intervention to support patients awaiting transplantation.A substantial proportion of outcomes relate to adherence, changes in physical status or other specific treatment concerns during the chronic phase of the disease.There is some evidence that behavioural interventions targeting nutrition and growth in children (4 to 12 years) with cystic fibrosis are effective in the short term. Evidence was found that providing a structured decision-making tool for patients considering lung transplantation improves patients' knowledge of and expectations about the transplant, and reduces decisional conflict in the short term. One study about training in biofeedback-assisted breathing demonstrated some evidence that it improved some lung function measurements. Currently there is insufficient evidence for interventions aimed at other aspects of the disease process. Currently, insufficient evidence exists on psychological interventions or approaches to support people with cystic fibrosis and their caregivers, although some of the studies were promising. Due to the heterogeneity between studies, more of each type of intervention are needed to support preliminary evidence. Multicentre studies, with consequent funding implications, are needed to increase the sample size of these studies and enhance the statistical power and precision to detect important findings. In addition, multicentre studies could improve the

  14. Acute exacerbation of idiopathic pulmonary fibrosis triggered by Aspergillus empyema

    Directory of Open Access Journals (Sweden)

    Atsushi Suzuki

    Full Text Available Acute exacerbation (AE is a severe and life-threatening complication of idiopathic pulmonary fibrosis (IPF. In 2016, the definition and diagnostic criteria for AE-IPF were updated by an international working group. The new definition includes any acute, clinically significant respiratory deterioration (both idiopathic and triggered events characterized by evidence of new widespread alveolar abnormality in patients with IPF. There are no currently proven beneficial management strategies for idiopathic and triggered AE-IPF. This is the first report describing AE-IPF triggered by Aspergillus empyema, which was improved by a combination of corticosteroid, systemic antifungal therapy, local antifungal therapy, and additional pharmacological therapies. Future research may reveal optimal strategies for both idiopathic and triggered AE-IPF. Keywords: Idiopathic pulmonary fibrosis, Acute exacerbation, AE-IPF, Triggered AE, Aspergillus infection

  15. Systems Level Analysis and Identification of Pathways and Networks Associated with Liver Fibrosis

    Science.gov (United States)

    2014-11-07

    Affymetrix GeneChip Rat Genome 230 2.0 Arrays. In GSE13747, liver fibrosis was produced by bile duct ligation [60]. Six replicates of liver fibrosis...fibrosis produced by bile duct ligation. B) GSE6929 represents sunitinib (SU11248) treatment in liver cirrhosis. doi:10.1371/journal.pone.0112193...respectively. In the study associated with the GSE13747 dataset, liver fibrosis was induced using bile duct ligation. We observed the predicted positive

  16. Laparoscopic cholecystectomy in adult cystic fibrosis.

    LENUS (Irish Health Repository)

    McGrath, D S

    2012-02-03

    Two female patients with Cystic Fibrosis, attending the Adult Regional Cystic Fibrosis centre at the Cork University Hospital, were investigated for upper abdominal pain and found to have gallstones at ultrasonography. Laparoscopic cholecystectomy was performed successfully and, without complication, in both patients.

  17. Prognostic durability of liver fibrosis tests and improvement in predictive performance for mortality by combining tests.

    Science.gov (United States)

    Bertrais, Sandrine; Boursier, Jérôme; Ducancelle, Alexandra; Oberti, Frédéric; Fouchard-Hubert, Isabelle; Moal, Valérie; Calès, Paul

    2017-06-01

    There is currently no recommended time interval between noninvasive fibrosis measurements for monitoring chronic liver diseases. We determined how long a single liver fibrosis evaluation may accurately predict mortality, and assessed whether combining tests improves prognostic performance. We included 1559 patients with chronic liver disease and available baseline liver stiffness measurement (LSM) by Fibroscan, aspartate aminotransferase to platelet ratio index (APRI), FIB-4, Hepascore, and FibroMeter V2G . Median follow-up was 2.8 years during which 262 (16.8%) patients died, with 115 liver-related deaths. All fibrosis tests were able to predict mortality, although APRI (and FIB-4 for liver-related mortality) showed lower overall discriminative ability than the other tests (differences in Harrell's C-index: P fibrosis, 1 year in patients with significant fibrosis, and liver disease (MELD) score testing sets. In the training set, blood tests and LSM were independent predictors of all-cause mortality. The best-fit multivariate model included age, sex, LSM, and FibroMeter V2G with C-index = 0.834 (95% confidence interval, 0.803-0.862). The prognostic model for liver-related mortality included the same covariates with C-index = 0.868 (0.831-0.902). In the testing set, the multivariate models had higher prognostic accuracy than FibroMeter V2G or LSM alone for all-cause mortality and FibroMeter V2G alone for liver-related mortality. The prognostic durability of a single baseline fibrosis evaluation depends on the liver fibrosis level. Combining LSM with a blood fibrosis test improves mortality risk assessment. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  18. [Pancreatic infringement exocrine and endocrine in cystic fibrosis].

    Science.gov (United States)

    Kessler, L; Abély, M

    2016-12-01

    The exocrine pancreatic insufficiency affects more than 80% of cystic fibrosis (CF) infants. Pancreatic insufficiency is diagnosed by low levels of fecal elastase. An optimal caloric intake, a pancreatic enzyme treatment are the keys to maintain a good nutritional status. The fat soluble vitamins supplementation will be associated with pancreatic enzymes treatment and will be adapted to plasma levels. Iron and oligo-element deficiency such as zinc is common. The pancreatic enzymes function is not optimal in the proximal bowel: the intraluminal intestinal pH is low because of the absence of bicarbonate release by the pancreas. The use of proton pump inhibitors may improve the functionality of pancreatic enzymes treatment. New therapies such as ivacaftor in patients with a G551D mutation allows a weight gain in particular by restoring intestinal pH similar to controls. Lengthening of the life expectancy of patients with CF is accompanied by the emergence new aspects of the disease, especially diabetes, favored by pancreatic cystic fibrosis resulting in an anatomical destruction of pancreatic islets. Currently, diabetes affects a third of the patients after 20 years, and half after 30 years. Cystic fibrosis-related diabetes is a major factor of morbidity-mortality in all stages of the disease and is characterized by a preclinical phase of glucose intolerance particularly long reaching up to 10 years. Its pathophysiology combines a lack of insulin secretion, an insulin resistance secondary to chronic infection, and a decrease in the production of the GIP and GLP-1. The insulin secretion depending on the channel chlorine (Cystic Fibrosis Transmembrane conductance Regulator [CFTR]) activity at the membrane surface of insulin cell is reduced prior to the occurrence of pancreatic histological lesions. At the stage of diabetes, obtaining a normoglycemia by insulin treatment began very early allows to slow the decline of lung function and nutritional status. Given the silent

  19. PEDICLE TONGUE FLAP SURGERY IN ORAL SUBMUCOUS FIBROSIS

    Directory of Open Access Journals (Sweden)

    Muthubabu K

    2016-09-01

    Full Text Available BACKGROUND Oral submucous fibrosis is a disease of unknown aetiology and is a legacy of Indians. It has been variously treated both medically and surgically but neither has been found to be rewarding. Various groups have been studying the therapy schedules and aetiological association, but the conclusions have remained unclear. AIM The study aims to focus on newer surgical therapy stressing on the mechanics and use of pedicle tongue flap in the management of this condition. METHODS AND MATERIALS The study comprised of 40 patients from our outpatient department suffering from oral submucous fibrosis in the age group of 11 to 70 years. The contributory factors of oral submucous fibrosis and the symptoms of the disease were evaluated and the role of pedicle tongue flap surgery in the management of this disease which is a premalignant condition is discussed. RESULTS AND CONCLUSION Pedicle tongue flap surgery has given promising results in the treatment of trismus due to oral submucous fibrosis. After the surgery, none of our patients developed any malignant change.

  20. TGF-β/Smad signaling in renal fibrosis

    Directory of Open Access Journals (Sweden)

    Xiao-Ming eMeng

    2015-03-01

    Full Text Available TGF-β (transforming growth factor-β is well identified as a central mediator in renal fibrosis. TGF-β initiates canonical and non-canonical pathways to exert multiple biological effects. Among them, Smad signaling is recognized as a major pathway of TGF- signaling in progressive renal fibrosis. During fibrogenesis, Smad3 is highly activated, which is associated with the down-regulation of an inhibitory Smad7 via an ubiquitin E3-ligases-dependent degradation mechanism. The equilibrium shift between Smad3 and Smad7 leads to accumulation and activation of myofibroblasts, overproduction of ECM (extracellular matrix, and reduction in ECM degradation in the diseased kidney. Therefore, overexpression of Smad7 has been shown to be a therapeutic agent for renal fibrosis in various models of kidney diseases. In contrast, another downstream effecter of TGF-β/Smad signaling pathway, Smad2, exerts its renal protective role by counter-regulating the Smad3. Furthermore, recent studies demonstrated that Smad3 mediates renal fibrosis by down-regulating miR-29 and miR-200 but up-regulating miR-21 and miR-192. Thus, overexpression of miR-29 and miR-200 or down-regulation of miR-21 and miR-192 is capable of attenuating Smad3-mediated renal fibrosis in various mouse models of chronic kidney diseases. Taken together, TGF-/Smad signaling plays an important role in renal fibrosis. Targeting TGF-β/Smad3 signaling may represent a specific and effective therapy for chronic kidney diseases associated with renal fibrosis.

  1. Retroperitoneal fibrosis with pancreatic involvement – radiological appearance

    International Nuclear Information System (INIS)

    Zielonko, Joanna; Obołończyk, Łukasz

    2011-01-01

    Retroperitoneal fibrosis or Ormond’s disease is an uncommon process characterized by fibrous tissue proliferation in the retroperitoneum, usually involving the aorta, inferior vena cava and iliac vessels. Obstructive hydronephrosis is often observed due to ureteral entrapment. This report presents a case of the peripancreatic location of the disease. The role of CT and MRI in establishing diagnosis of retroperitoneal fibrosis in an atypical site is discussed. A 52-year-old woman with Hashimoto’s thyroiditis was admitted to hospital because of pain suggesting renal colic. The patient was subjected to ultrasound, CT, and MRI which did not confirm urolithiasis but revealed pancreatic infiltration. Partial pancreatectomy, left-sided adrenalectomy and splenectomy were performed. Retroperitoneal fibrosis was diagnosed in the histopathological examination. A few weeks after surgery, a complication such as pancreatitis developed. Repeat CT confirmed it and showed right hydronephrosis secondary to ureteral involvement by a mass adjacent to the common iliac artery (defined as a typical manifestation of retroperitoneal fibrosis). Nephrostomy and conservative treatment improved the clinical state of the patient. No progression of the process was observed in the follow-up examinations. Atypical retroperitoneal fibrosis remains a diagnostic challenge. Imaging techniques CT and MRI are useful tools for evaluating the extent of Ormond’s disease. An unusual distribution of the process (e.g. peripancreatic location reported in this study) requires histopathological assessment to establish the final diagnosis

  2. Evaluation of Liver Fibrosis Using Texture Analysis on Combined-Contrast-Enhanced Magnetic Resonance Images at 3.0T

    Directory of Open Access Journals (Sweden)

    Takeshi Yokoo

    2015-01-01

    Full Text Available Purpose. To noninvasively assess liver fibrosis using combined-contrast-enhanced (CCE magnetic resonance imaging (MRI and texture analysis. Materials and Methods. In this IRB-approved, HIPAA-compliant prospective study, 46 adults with newly diagnosed HCV infection and recent liver biopsy underwent CCE liver MRI following intravenous administration of superparamagnetic iron oxides (ferumoxides and gadolinium DTPA (gadopentetate dimeglumine. The image texture of the liver was quantified in regions-of-interest by calculating 165 texture features. Liver biopsy specimens were stained with Masson trichrome and assessed qualitatively (METAVIR fibrosis score and quantitatively (% collagen stained area. Using L1 regularization path algorithm, two texture-based multivariate linear models were constructed, one for quantitative and the other for quantitative histology prediction. The prediction performance of each model was assessed using receiver operating characteristics (ROC and correlation analyses. Results. The texture-based predicted fibrosis score significantly correlated with qualitative (r=0.698, P<0.001 and quantitative (r=0.757, P<0.001 histology. The prediction model for qualitative histology had 0.814–0.976 areas under the curve (AUC, 0.659–1.000 sensitivity, 0.778–0.930 specificity, and 0.674–0.935 accuracy, depending on the binary classification threshold. The prediction model for quantitative histology had 0.742–0.950 AUC, 0.688–1.000 sensitivity, 0.679–0.857 specificity, and 0.696–0.848 accuracy, depending on the binary classification threshold. Conclusion. CCE MRI and texture analysis may permit noninvasive assessment of liver fibrosis.

  3. Congenital hepatic fibrosis associated with von Recklinghausen's disease Fibrosis hepática congénita asociada a enfermedad de von Recklinghausen

    Directory of Open Access Journals (Sweden)

    O. A. Jorge

    2006-09-01

    Full Text Available Congenital hepatic fibrosis is characterized by a ductal plate malformation with duct-like structures and fibrosis. It manifests clinically with portal hypertension and may be associated with multiple congenital defects. We present the case of a 16-year-old male with splenomegaly, leukopenia and thrombocytopenia, esophageal varices, and a histopathological diagnosis of congenital hepatic fibrosis. He exhibits "café au lait' spots and "Lisch' nodules, with a diagnosis of von Recklinghausen's disease. Congenital hepatic fibrosis belongs to the so-called fibropolycystic diseases, in which there is a disordered interaction between cells and the extracellular matrix. Von Recklinghausen's disease affects tissues derived from the neural crest and its diagnosis is based on clinical criteria. It is associated with multiple diseases. We describe its association with congenital hepatic fibrosis for the first time.La fibrosis hepática congénita se origina como consecuencia de una malformación de la placa ductal con estructuras tipo ductales acompañadas de fibrosis. Se manifiesta con hipertensión portal y puede asociarse a múltiples defectos congénitos. Presentamos un varón de 16 años con esplenomegalia, leuco- y plaquetopenia, varices esofágicas y diagnóstico histopatológico de fibrosis hepática congénita. La exploración física mostraba la existencia de manchas de "café con leche' y nódulos de "Lisch' con diagnóstico de enfermedad de von Recklinghausen. La fibrosis hepática congénita forma parte de las enfermedades fibropoliquísticas donde existiría una alteración en la interacción entre las células y la matriz extracelular. La enfermedad de von Recklinghausen afecta a los tejidos derivados de la cresta neural y su diagnóstico se basa en criterios clínicos. Se asocia a múltiples patologías. Presentamos por primera vez su asociación con fibrosis hepática congénita.

  4. Genetics and Early Detection in Idiopathic Pulmonary Fibrosis

    Science.gov (United States)

    Putman, Rachel K.; Rosas, Ivan O.

    2014-01-01

    Genetic studies hold promise in helping to identify patients with early idiopathic pulmonary fibrosis (IPF). Recent studies using chest computed tomograms (CTs) in smokers and in the general population have demonstrated that imaging abnormalities suggestive of an early stage of pulmonary fibrosis are not uncommon and are associated with respiratory symptoms, physical examination abnormalities, and physiologic decrements expected, but less severe than those noted in patients with IPF. Similarly, recent genetic studies have demonstrated strong and replicable associations between a common promoter polymorphism in the mucin 5B gene (MUC5B) and both IPF and the presence of abnormal imaging findings in the general population. Despite these findings, it is important to note that the definition of early-stage IPF remains unclear, limited data exist to definitively connect abnormal imaging findings to IPF, and genetic studies assessing early-stage pulmonary fibrosis remain in their infancy. In this perspective we provide updated information on interstitial lung abnormalities and their connection to IPF. We summarize information on the genetics of pulmonary fibrosis by focusing on the recent genetic findings of MUC5B. Finally, we discuss the implications of these findings and suggest a roadmap for the use of genetics in the detection of early IPF. PMID:24547893

  5. Lack of the serum- and glucocorticoid-inducible kinase SGK1 improves muscle force characteristics and attenuates fibrosis in dystrophic mdx mouse muscle

    DEFF Research Database (Denmark)

    Steinberger, Martin; Föller, Michael; Vogelgesang, Silke

    2015-01-01

    Duchenne muscular dystrophy (DMD) is a human genetic disease characterized by fibrosis and severe muscle weakness. Currently, there is no effective treatment available to prevent progressive fibrosis in skeletal muscles. The serum- and glucocorticoid-inducible kinase SGK1 regulates a variety...... of physiological functions and participates in fibrosis stimulation. Here, we investigated whether SGK1 influences structure, function and/or fibrosis of the muscles from the mdx mouse, an animal model for DMD. As expected, mdx muscles showed the typical pathological features of muscular dystrophy including fiber...... size variations, central nuclei of muscle fibers, fibrosis in the diaphragm, and force reduction by 30–50 %. Muscles from sgk1 -/- mice were histologically overall intact and specific force was only slightly reduced compared to wild-type muscles. Surprisingly, soleus and diaphragm muscles of mdx/sgk1...

  6. Challenges with current inhaled treatments for chronic Pseudomonas aeruginosa infection in patients with cystic fibrosis.

    LENUS (Irish Health Repository)

    Greally, Peter

    2012-06-01

    Pseudomonas aeruginosa (Pa) is the predominant pathogen infecting the airways of patients with cystic fibrosis (CF). Initial colonization is usually transient and associated with non-mucoid strains, which can be eradicated if identified early. This strategy can prevent, or at least delay, chronic Pa infection, which eventually develops in the majority of patients by their late teens or early adulthood. This article discusses the management and latest treatment developments of Pa lung infection in patients with CF, with a focus on nebulized antibiotic therapy.

  7. Effect of iron, taurine and arginine on rat hepatic fibrosis

    International Nuclear Information System (INIS)

    Song Liangwen; Wang Dewen; Cui Xuemei

    1997-01-01

    Objective: The promotion role of iron on pathogenesis of hepatic fibrosis and the protective role of taurine and L-arginine against hepatic fibrosis were studied. Method: The model of rat radiation hepatic fibrosis was used. Experimental rats were divided into 0 Gy, 30 Gy, 30 Gy + iron, 30 Gy + taurine and 30 Gy + L-arginine groups. Serum iron, liver tissue hydroxyproline (Hyp) and malondialdehyde (MDA) were measured one and three months respectively after irradiation of hepatic tissue, production and distribution characteristics of hepatic tissue type I and III collagen were observed with a polarizing microscope. Results: Administration of iron agent could significantly increase hepatic tissue MDA content and serum iron concentration, one month after irradiation, hepatic tissue Hyp in 30 Gy + iron group began to increase, and collagen in hepatic tissue obviously increased. Taurine and L-arginine could reduce serum iron concentration and decrease production of hepatic fissure Hyp. Conclusion: Exogenous iron agent could promote early development of radiation hepatic fibrosis; taurine and arginine could diminish pathologic alteration of hepatic fibrosis to a certain extent

  8. Oral calorie supplements for cystic fibrosis.

    Science.gov (United States)

    Smyth, Rosalind L; Rayner, Oli

    2017-05-04

    Poor nutrition occurs frequently in people with cystic fibrosis and is associated with other adverse outcomes. Oral calorie supplements are used to increase total daily calorie intake and improve weight gain. However, they are expensive and there are concerns they may reduce the amount of food eaten and not improve overall energy intake. This is an update of a previously published review. To establish whether in people with cystic fibrosis, oral calorie supplements: increase daily calorie intake; and improve overall nutritional intake, nutritional indices, lung function, survival and quality of life. To assess adverse effects associated with using these supplements. We searched the Cochrane Cystic Fibrosis Trials Register comprising references from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. We contacted companies marketing oral calorie supplements.Last search: 18 October 2016. Randomised or quasi-randomised controlled trials comparing use of oral calorie supplements for at least one month to increase calorie intake with no specific intervention or additional nutritional advice in people with cystic fibrosis. We independently selected the included trials, assessed risk of bias and extracted data. We contacted the authors of included trials and obtained additional information for two trials. We identified 21 trials and included three, reporting results from 131 participants lasting between three months and one year. Two trials compared supplements to additional nutritional advice and one to no intervention. Two of the included trials recruited only children. In one trial the risk of bias was low across all domains, in a second trial the risk of bias was largely unclear and in the third mainly low. Blinding of participants was unclear in two of the trials. Also, in one trial the clinical condition of groups appeared to be unevenly balanced at baseline and in another trial there were

  9. Novel non-invasive biological predictive index for liver fibrosis in hepatitis C virus genotype 4 patients

    Science.gov (United States)

    Khattab, Mahmoud; Sakr, Mohamed Amin; Fattah, Mohamed Abdel; Mousa, Youssef; Soliman, Elwy; Breedy, Ashraf; Fathi, Mona; Gaber, Salwa; Altaweil, Ahmed; Osman, Ashraf; Hassouna, Ahmed; Motawea, Ibrahim

    2016-01-01

    AIM To investigate the diagnostic ability of a non-invasive biological marker to predict liver fibrosis in hepatitis C genotype 4 patients with high accuracy. METHODS A cohort of 332 patients infected with hepatitis C genotype 4 was included in this cross-sectional study. Fasting plasma glucose, insulin, C-peptide, and angiotensin-converting enzyme serum levels were measured. Insulin resistance was mathematically calculated using the homeostasis model of insulin resistance (HOMA-IR). RESULTS Fibrosis stages were distributed based on Metavir score as follows: F0 = 43, F1 = 136, F2 = 64, F3 = 45 and F4 = 44. Statistical analysis relied upon reclassification of fibrosis stages into mild fibrosis (F0-F) = 179, moderate fibrosis (F2) = 64, and advanced fibrosis (F3-F4) = 89. Univariate analysis indicated that age, log aspartate amino transaminase, log HOMA-IR and log platelet count were independent predictors of liver fibrosis stage (P < 0.0001). A stepwise multivariate discriminant functional analysis was used to drive a discriminative model for liver fibrosis. Our index used cut-off values of ≥ 0.86 and ≤ -0.31 to diagnose advanced and mild fibrosis, respectively, with receiving operating characteristics of 0.91 and 0.88, respectively. The sensitivity, specificity, positive predictive value, negative predictive value and positive likelihood ratio were: 73%, 91%, 75%, 90% and 8.0 respectively for advanced fibrosis, and 67%, 88%, 84%, 70% and 4.9, respectively, for mild fibrosis. CONCLUSION Our predictive model is easily available and reproducible, and predicted liver fibrosis with acceptable accuracy. PMID:27917265

  10. Novel non-invasive biological predictive index for liver fibrosis in hepatitis C virus genotype 4 patients.

    Science.gov (United States)

    Khattab, Mahmoud; Sakr, Mohamed Amin; Fattah, Mohamed Abdel; Mousa, Youssef; Soliman, Elwy; Breedy, Ashraf; Fathi, Mona; Gaber, Salwa; Altaweil, Ahmed; Osman, Ashraf; Hassouna, Ahmed; Motawea, Ibrahim

    2016-11-18

    To investigate the diagnostic ability of a non-invasive biological marker to predict liver fibrosis in hepatitis C genotype 4 patients with high accuracy. A cohort of 332 patients infected with hepatitis C genotype 4 was included in this cross-sectional study. Fasting plasma glucose, insulin, C-peptide, and angiotensin-converting enzyme serum levels were measured. Insulin resistance was mathematically calculated using the homeostasis model of insulin resistance (HOMA-IR). Fibrosis stages were distributed based on Metavir score as follows: F0 = 43, F1 = 136, F2 = 64, F3 = 45 and F4 = 44. Statistical analysis relied upon reclassification of fibrosis stages into mild fibrosis (F0-F) = 179, moderate fibrosis (F2) = 64, and advanced fibrosis (F3-F4) = 89. Univariate analysis indicated that age, log aspartate amino transaminase, log HOMA-IR and log platelet count were independent predictors of liver fibrosis stage ( P < 0.0001). A stepwise multivariate discriminant functional analysis was used to drive a discriminative model for liver fibrosis. Our index used cut-off values of ≥ 0.86 and ≤ -0.31 to diagnose advanced and mild fibrosis, respectively, with receiving operating characteristics of 0.91 and 0.88, respectively. The sensitivity, specificity, positive predictive value, negative predictive value and positive likelihood ratio were: 73%, 91%, 75%, 90% and 8.0 respectively for advanced fibrosis, and 67%, 88%, 84%, 70% and 4.9, respectively, for mild fibrosis. Our predictive model is easily available and reproducible, and predicted liver fibrosis with acceptable accuracy.

  11. Matrix Metalloproteinases as Therapeutic Targets for Idiopathic Pulmonary Fibrosis

    OpenAIRE

    Craig, Vanessa J.; Zhang, Li; Hagood, James S.; Owen, Caroline A.

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is a restrictive lung disease that is associated with high morbidity and mortality. Current medical therapies are not fully effective at limiting mortality in patients with IPF, and new therapies are urgently needed. Matrix metalloproteinases (MMPs) are proteinases that, together, can degrade all components of the extracellular matrix and numerous nonmatrix proteins. MMPs and their inhibitors, tissue inhibitors of MMPs (TIMPs), have been implicated in the p...

  12. Non-invasive Imaging of Idiopathic Pulmonary Fibrosis Using Cathepsin Protease Probes

    NARCIS (Netherlands)

    Withana, N.P.; Ma, X.W.; McGuire, H.M.; Verdoes, M.; Linden, W.A. van der; Ofori, L.O.; Zhang, R.P.; Li, H.; Sanman, L.E.; Wei, K.; Yao, S.B.; Wu, P.L.; Li, F.; Huang, H.; Xu, Z.J.; Wolters, P.J.; Rosen, G.D.; Collard, H.R.; Zhu, Z.H.; Cheng, Z.; Bogyo, M.

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is a lethal, chronic, progressive disease characterized by formation of scar tissue within the lungs. Because it is a disease of unknown etiology, it is difficult to diagnose, to predict disease course and to devise treatment strategies. Recent evidence suggests

  13. Inhalable Antimicrobials for Treatment of Bacterial Biofilm-Associated Sinusitis in Cystic Fibrosis Patients

    DEFF Research Database (Denmark)

    Klodzinska, Sylvia Natalie; Priemel, Petra Alexandra; Rades, Thomas

    2016-01-01

    Bacterial biofilm-associated chronic sinusitis in cystic fibrosis (CF) patients caused by Pseudomonas aeruginosa infections and the lack of available treatments for such infections constitute a critical aspect of CF disease management. Currently, inhalation therapies to combat P. aeruginosa infec...... and management of biofilm infections caused by P. aeruginosa and discusses critical issues related to novel antimicrobial drug formulation design approaches.......Bacterial biofilm-associated chronic sinusitis in cystic fibrosis (CF) patients caused by Pseudomonas aeruginosa infections and the lack of available treatments for such infections constitute a critical aspect of CF disease management. Currently, inhalation therapies to combat P. aeruginosa....... aeruginosa from the respiratory tract after a first infection has been shown to delay chronic pulmonary infection with the bacteria for up to two years. The challenges with providing a suitable treatment for bacterial sinusitis include: (i) identifying a suitable antimicrobial compound; (ii) selecting...

  14. Arginine metabolism by macrophages promotes cardiac and muscle fibrosis in mdx muscular dystrophy.

    Directory of Open Access Journals (Sweden)

    Michelle Wehling-Henricks

    2010-05-01

    Full Text Available Duchenne muscular dystrophy (DMD is the most common, lethal disease of childhood. One of 3500 new-born males suffers from this universally-lethal disease. Other than the use of corticosteroids, little is available to affect the relentless progress of the disease, leading many families to use dietary supplements in hopes of reducing the progression or severity of muscle wasting. Arginine is commonly used as a dietary supplement and its use has been reported to have beneficial effects following short-term administration to mdx mice, a genetic model of DMD. However, the long-term effects of arginine supplementation are unknown. This lack of knowledge about the long-term effects of increased arginine metabolism is important because elevated arginine metabolism can increase tissue fibrosis, and increased fibrosis of skeletal muscles and the heart is an important and potentially life-threatening feature of DMD.We use both genetic and nutritional manipulations to test whether changes in arginase metabolism promote fibrosis and increase pathology in mdx mice. Our findings show that fibrotic lesions in mdx muscle are enriched with arginase-2-expressing macrophages and that muscle macrophages stimulated with cytokines that activate the M2 phenotype show elevated arginase activity and expression. We generated a line of arginase-2-null mutant mdx mice and found that the mutation reduced fibrosis in muscles of 18-month-old mdx mice, and reduced kyphosis that is attributable to muscle fibrosis. We also observed that dietary supplementation with arginine for 17-months increased mdx muscle fibrosis. In contrast, arginine-2 mutation did not reduce cardiac fibrosis or affect cardiac function assessed by echocardiography, although 17-months of dietary supplementation with arginine increased cardiac fibrosis. Long-term arginine treatments did not decrease matrix metalloproteinase-2 or -9 or increase the expression of utrophin, which have been reported as beneficial

  15. Heterogenic transplantation of bone marrow-derived rhesus macaque mesenchymal stem cells ameliorates liver fibrosis induced by carbon tetrachloride in mouse

    Directory of Open Access Journals (Sweden)

    Xufeng Fu

    2018-02-01

    Full Text Available Liver fibrosis is a disease that causes high morbidity and has become a major health problem. Liver fibrosis can lead to the end stage of liver diseases (livercirrhosisand hepatocellularcarcinoma. Currently, liver transplantation is the only effective treatment for end-stage liver disease. However, the shortage of organ donors, high cost of medical surgery, immunological rejection and transplantation complications severely hamper liver transplantation therapy. Mesenchymal stem cells (MSCs have been regarded as promising cells for clinical applications in stem cell therapy in the treatment of liver diseases due to their unique multipotent differentiation capacity, immunoregulation and paracrine effects. Although liver fibrosis improvements by MSC transplantation in preclinical experiments as well as clinical trials have been reported, the in vivo fate of MSCs after transportation and their therapeutic mechanisms remain unclear. In this present study, we isolated MSCs from the bone marrow of rhesus macaques. The cells exhibited typical MSC markers and could differentiate into chondrocytes, osteocytes, and adipocytes, which were not affected by labeling with enhanced green fluorescent protein (EGFP. The harvested MSCs respond to interferon-γ stimulation and have the ability to inhibit lymphocyte proliferation in vitro. EGFP-labeled MSCs (1 × 106 cells were transplanted into mice with carbon tetrachloride-induced liver fibrosis via tail vein injection. The ability of the heterogenic MSC infusion to ameliorate liver fibrosis in mice was evaluated by a blood plasma chemistry index, pathological examination and liver fibrosis-associated gene expression. Additionally, a small number of MSCs that homed and engrafted in the mouse liver tissues were evaluated by immunofluorescence analysis. Our results showed that the transplantation of heterogenic MSCs derived from monkey bone marrow can be used to treat liver fibrosis in the mouse model and that the

  16. Combined pulmonary fibrosis and emphysema: The many aspects of a cohabitation contract.

    Science.gov (United States)

    Papaioannou, Andriana I; Kostikas, Konstantinos; Manali, Effrosyni D; Papadaki, Georgia; Roussou, Aneza; Kolilekas, Likurgos; Borie, Raphaël; Bouros, Demosthenis; Papiris, Spyridon A

    2016-08-01

    Combined pulmonary fibrosis and emphysema (CPFE) is a clinical entity characterized by the coexistence of upper lobe emphysema and lower lobe fibrosis. Patients with this condition experience severe dyspnea and impaired gas exchange with preserved lung volumes. The diagnosis of the CPFE syndrome is based on HRCT imaging, showing the coexistence of emphysema and pulmonary fibrosis both in varying extent and locations within the lung parenchyma. Individual genetic background seem to predispose to the development of the disease. The risk of the development of pulmonary hypertension in patients with CPFE is high and related to poor prognosis. CPFE patients also present a high risk of lung cancer. Mortality is significant in patients with CPFE and median survival is reported between 2.1 and 8.5 years. Currently, no specific recommendations are available regarding the management of patients with CPFE. In this review we provide information on the existing knowledge on CPFE regarding the pathophysiology, clinical manifestations, imaging, complications, possible therapeutic interventions and prognosis of the disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Physical exercise training for cystic fibrosis.

    Science.gov (United States)

    Radtke, Thomas; Nevitt, Sarah J; Hebestreit, Helge; Kriemler, Susi

    2017-11-01

    Physical exercise training may form an important part of regular care for people with cystic fibrosis. This is an update of a previously published review. To assess the effects of physical exercise training on exercise capacity by peak oxygen consumption, pulmonary function by forced expiratory volume in one second, health-related quality of life and further important patient-relevant outcomes in people with cystic fibrosis. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of the most recent search: 04 May 2017.We searched ongoing trials registers (clinicaltrials.gov and the WHO ICTRP). Date of most recent search: 10 August 2017. All randomised and quasi-randomised controlled clinical trials comparing exercise training of any type and a minimum duration of two weeks with conventional care (no training) in people with cystic fibrosis. Two authors independently selected studies for inclusion, assessed methodological quality and extracted data. The quality of the evidence was assessed using the GRADE system. Of the 83 studies identified, 15 studies which included 487 participants, met the inclusion criteria. The numbers in each study ranged from nine up to 72 participants; two studies were in adults, seven were in children and adolescents and six studies included all age ranges. Four studies of hospitalised participants lasted less than one month and 11 studies were outpatient-based, lasting between two months and three years. The studies included participants with a wide range of disease severity and employed differing levels of supervision with a mixture of types of training. There was also wide variation in the quality of the included studies.This systematic review shows very low- to low-quality evidence from both short- and long-term studies that in people

  18. Performance of 2-D shear wave elastography in liver fibrosis assessment compared with serologic tests and transient elastography in clinical routine.

    Science.gov (United States)

    Bota, Simona; Paternostro, Rafael; Etschmaier, Alexandra; Schwarzer, Remy; Salzl, Petra; Mandorfer, Mattias; Kienbacher, Christian; Ferlitsch, Monika; Reiberger, Thomas; Trauner, Michael; Peck-Radosavljevic, Markus; Ferlitsch, Arnulf

    2015-09-01

    Liver stiffness values assessed with 2-D shear wave elastography (SWE), transient elastography (TE) and simple serologic tests were compared with respect to non-invasive assessment in a cohort of 127 consecutive patients with chronic liver diseases. The rate of reliable liver stiffness measurements was significantly higher with 2-D SWE than with TE: 99.2% versus 74.8%, p < 0.0001 (different reliability criteria used, according to current recommendations). In univariate analysis, liver stiffness measured with 2-D SWE correlated best with fibrosis stage estimated with TE (r = 0.699, p < 0.0001), followed by Forns score (r = 0.534, p < 0.0001) and King's score (r = 0.512, p < 0.0001). However, in multivariate analysis, only 2-D SWE-measured values remained correlated with fibrosis stage (p < 0.0001). The optimal 2-D SWE cutoff values for predicting significant fibrosis were 8.03 kPa for fibrosis stage ≥2 (area under the receiver operating characteristic curve = 0.832) and 13.1 kPa for fibrosis stage 4 (area under the receiver operating characteristic curve = 0.915), respectively. In conclusion, 2-D SWE can be used to obtain reliable liver stiffness measurements in almost all patients and performs very well in predicting the presence of liver cirrhosis. Copyright © 2015 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

  19. FibroMeters: a family of blood tests for liver fibrosis.

    Science.gov (United States)

    Calès, P; Boursier, J; Oberti, F; Hubert, I; Gallois, Y; Rousselet, M-C; Dib, N; Moal, V; Macchi, L; Chevailler, A; Michalak, S; Hunault, G; Chaigneau, J; Sawadogo, A; Lunel, F

    2008-09-01

    FibroMeters are blood tests for liver fibrosis with several specificities: two main diagnostic targets (fibrosis stage and area of fibrosis); adaptation to specific causes; and results confirmed by an expert system. Thus, FibroMeters comprise six different tests: one for staging and one for quantitation of liver fibrosis in each of the three main causes of chronic liver disease-chronic viral hepatitis, alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). FibroMeters display a high overall diagnostic accuracy and are the only tests to correctly classify 100% of HCV patients without fibrosis or with cirrhosis. They have 90% predictive values in a higher proportion of patients than with other usual blood tests. A 90% correct classification is available in 100% of HCV patients with the following reliable diagnostic intervals: F0/1, F1/2, F2+/-1, F3+/-1. In real-life conditions, the reproducibility of FibroMeters is higher than that of liver biopsy or ultrasonographic elastometry. FibroMeters are robust tests with the most stable diagnostic performance across different centers. Optional tests are also available, such as a specific one for cirrhosis, which has a diagnostic accuracy of 93.0% (AUROC: 0.92) and a 100% positive predictive value for diagnosis of HCV cirrhosis. Determination by FibroMeters of the area of fibrosis - the only direct, non-invasive, quantitative measurement of liver fibrosis - are especially useful for following-up cirrhosis as it correlates well with clinical events. FibroMeters are also very accurate in HVB or HIV-HCV co-infected patients. The tests specific for ALD and NAFLD also have a high diagnostic accuracy (AUROCs: 0.96 and 0.94, respectively, for significant fibrosis).

  20. Vitamin D bioavailability in cystic fibrosis: a cause for concern?

    Science.gov (United States)

    Mailhot, Geneviève

    2012-05-01

    Despite the inclusion of extra vitamin D in their regimen of fat-soluble vitamin supplementation, cystic fibrosis patients remain chronically depleted of vitamin D. The persistence of suboptimal vitamin D status is often blamed on the maldigestion and malabsorption of fat. However, the mitigated success of recent clinical trials with high-dose vitamin D supplementation suggests that vitamin D bioavailability might be impaired in these patients. Given the growing understanding of the importance of this vitamin in the regulation of multiple biological functions beyond skeletal health, the present review analyzes the current literature by addressing each step of vitamin D metabolism and action in the context of this life-limiting pathology. In addition, it highlights the importance of vitamin D in relation to organs and or conditions affected by cystic fibrosis. © 2012 International Life Sciences Institute.

  1. Vitamin A intake and serum retinol levels in children and adolescents with cystic fibrosis

    NARCIS (Netherlands)

    Woestenenk, JW; Broos, Nancy; Stellato, Rebecca K; Arets, Hubertus G M; van der Ent, Cornelis K.; Houwen, RHJ

    2016-01-01

    BACKGROUND: Pancreatic insufficient cystic fibrosis (CF) patients receive vitamin A supplementation according to CF-specific recommendations to prevent deficiencies. Whether current recommendations are optimal for preventing both deficiency and toxicity is a subject of debate. We assessed the

  2. Biochemical and radio-immunological studies on HCV-induced liver fibrosis

    International Nuclear Information System (INIS)

    Abdel-Mageed, M.E.A.

    2010-01-01

    Hepatitis C virus infection is now becoming a common health problem in Egypt. Liver biopsy is the gold standard for this diagnosis. However, liver biopsy is invasive and is associated with complications with chronic hepatitis C patients. There is a clinical need for noninvasive measurement of liver fibrosis. Noninvasive bio markers such as Collagen III was identified in serum samples of patients with HCV induced liver fibrosis at 70 kDa using SDS-PAGE and western blot, measured by ELISA and purified using electro elution . Hyaluronic acid also can be used to differentiate between liver fibrosis patients and healthy individuals using radioimmunoassay .we have developed noninvasive diagnosis that can be applied to patients who either have contraindications or refuse liver biopsy for the management of their HCV infection.

  3. Impaired Lymphocyte Profile in Schistosomiasis Patients with Periportal Fibrosis

    Directory of Open Access Journals (Sweden)

    Luciana Santos Cardoso

    2013-01-01

    Full Text Available The Th2 immune response in chronic schistosomiasis is associated with the development of periportal fibrosis. However, little is known about the phenotype and activation status of T cells in the process. Objective. To evaluate the profile of T cells in schistosomiasis patients with periportal fibrosis. Methods. It was a cross-sectional study, conducted in the village of Agua Preta, Bahia, Brazil, which included 37 subjects with periportal fibrosis determined by ultrasound. Peripheral blood mononuclear cells were obtained by the Ficcol-hypaque gradient and the frequency of T cells expressing the surface markers CD28, CD69, CD25, and CTLA-4 was determined by flow cytometry. Results. The frequency of CD4+CD28+ T lymphocytes was higher in individuals with moderate to severe fibrosis compared to patients with incipient fibrosis. We did not observe any significant difference in the frequency of CD4+ T cells expressing CD69 among groups of individuals. There was also no significant difference in the frequency of CD8+ T cells expressing CD28 or CD69 among the studied groups. Individuals with moderate to severe fibrosis presented a lower frequency of CD8+ T cells, CD4+CD25high T cells, and CD4+CTLA-4+ T cells when compared to patients without fibrosis or incipient fibrosis. The frequency of CD4+CD25low cells did not differ between groups. Conclusion. The high frequency of activated T cells coinciding with a low frequency of putative Treg cells may account for the development of periportal fibrosis in human schistosomiasis.

  4. Nephrogenic Systemic Fibrosis in Denmark

    DEFF Research Database (Denmark)

    Elmholdt, Tina Rask; Olesen, Anne; J�rgensen, Bettina

    2013-01-01

    Nephrogenic systemic fibrosis is a debilitating and painful disorder with an increased stimulation of the connective tissue in the skin and systemic tissues. The disease is associated with exposure to gadolinium-based contrast agent used in magnetic resonance imaging in patients with renal...

  5. Treating Radiation Induced Skin Injury and Fibrosis Using Small Molecule Thiol Modifying Agents

    Science.gov (United States)

    2016-10-01

    necrosis after the animals were sacrificed 1 week postop. Findings confirmed RTA-408 when delivered during radiation resulted in significant...irradiation induces extensive flap necrosis at the distal end of the skin flap 5 . In all experiments irradiation was performed using external beam...collagen deposition, vascular density, and mRNA expression of mediators of chronic inflammation and fibrosis. Figure1: A) Initial wound at

  6. Management of the Upper Airway in Cystic Fibrosis

    Science.gov (United States)

    Illing, Elisa A.; Woodworth, Bradford A.

    2015-01-01

    Purpose of Review Upper airway disease engenders significant morbidity for patients with cystic fibrosis and is increasingly recognized as having a much greater role in pulmonary outcomes and quality of life than originally believed. Widespread disparate therapeutic strategies for cystic fibrosis chronic rhinosinusitis underscore the absence of a standardized treatment paradigm. This review outlines the most recent evidence-based trends in the management of upper airway disease in cystic fibrosis. Recent Findings The unified airway theory proposes that the sinuses are a focus of initial bacterial colonization which seeds the lower airway and may play a large role in maintaining lung infections. Mounting evidence suggests more aggressive treatment of the sinuses may confer significant improvement in pulmonary disease and quality of life outcomes in cystic fibrosis patients. However, there is a lack of high-level evidence regarding medical and surgical management of cystic fibrosis chronic rhinosinusitis that makes generalizations difficult. Summary Well designed clinical trials with long-term follow-up concerning medical and surgical interventions for cystic fibrosis sinus disease are required to establish standardized treatment protocols, but increased interest in the sinuses as a bacterial reservoir for pulmonary infections has generated considerable attention. PMID:25250804

  7. MRI in mucoviscidosis (cystic fibrosis)

    International Nuclear Information System (INIS)

    Eichinger, M.; Puderbach, M.; Kauczor, H.-U.; Heussel, C.-P.

    2006-01-01

    Cystic fibrosis (CF) is a multi-systemic disease with major impact on the lungs. Pulmonary manifestation is crucial for the prognosis and life expectancy of patients. Imaging modalities and lung function tests reflect the pulmonary status in these patients. The standard imaging modality for diagnosis and follow-up of pulmonary changes is chest x-ray. The gold standard for the detection of parenchymal lung changes remains high resolution computed tomography (HRCT), but this is not used routinely for CF-patients due to radiation exposure. Magnetic resonance imaging (MRI) used to be of no importance in monitoring cystic fibrosis lung disease, as shown in studies from the 1980s and early 1990s. The continuing improvement of MRI techniques, however, has allowed for an adequate application of this non-radiation method in diagnosing the major pulmonary findings in CF, in addition to the assessment of lung function. (orig.) [de

  8. Cystic Fibrosis-Related Diabetes (CFRD): Daily Management

    Science.gov (United States)

    Cystic Fibrosis-Related Diabetes (CFRD): Daily Management September 20, 2011 This Web cast is supported by an unrestricted ... Moran, MD Professor, Pediatric Endocrinology University of Minnesota Cystic Fibrosis-Related Diabetes (CFRD): Daily Management September 20, 2011 ...

  9. Outcome in cystic fibrosis liver disease.

    LENUS (Irish Health Repository)

    Rowland, Marion

    2011-01-01

    Evidence suggests that cystic fibrosis liver disease (CFLD) does not affect mortality or morbidity in patients with cystic fibrosis (CF). The importance of gender and age in outcome in CF makes selection of an appropriate comparison group central to the interpretation of any differences in mortality and morbidity in patients with CFLD.

  10. [Genetic counseling in cystic fibrosis].

    Science.gov (United States)

    Julia, S; Bieth, E

    2000-08-01

    Genetic counseling is an important part of health care in patients with cystic fibrosis or respiratory diseases associated with the CFTR (cystic fibrosis transmembrane conductance regulator) gene, including certain types of allergic bronchopulmonary aspergilloses or bronchial diseases (diffuse bronchiectasia). The basic goal is to provide patients with information on the transmission of cystic fibrosis and to asses the risk of recurrence. This risk is determined from molecular biology analyses examining the CFTR gene. Genotyping is the only means of screening for the heterozygous state, frequent in the French population (about 1/30). Because of the large number of mutated alleles not covered entirely by the genetic tests, there remains a question of probability expressed as a residual risk of a heterozygous state. A prenatal genotype diagnosis should be proposed to heterozygous couples who have a 25% risk of having a diseased child. Technically, this is almost always possible and the results are highly reliable. Nevertheless, there remains the risks related to sample taking and the ethical issue about which the patients must be informed. Management of these at risk couples who desire a child must be based on a multidisciplinary approach, particularly important when one of the parents has overt cystic fibrosis.

  11. Radiation-induced pulmonary fibrosis: examination of chemokine and chemokine receptor families.

    Science.gov (United States)

    Johnston, Carl J; Williams, Jacqueline P; Okunieff, Paul; Finkelstein, Jacob N

    2002-03-01

    Fibrosis is a common outcome of chronic inflammation or injury. Pulmonary fibrosis may be the result of abnormal repair after an acute inflammatory response. The process of repair initiated by a tissue insult is largely a function of the activation of cells to produce important biological mediators such as cytokines, growth factors and chemokines, which orchestrate most aspects of the inflammatory response. Consequently, altered regulation of the production of inflammatory cell cytokines and chemokines after injury and repair likely contributes to the fibrosis. Our hypothesis is that chronic expression of specific chemokine and chemokine receptors during the fibrotic phase induced by thoracic irradiation may perpetuate the recruitment and activation of lymphocytes and macrophages, which may contribute to the development of fibrosis. Fibrosis-sensitive (C57BL/6) and fibrosis-resistant (C3H/HeJ) mice were irradiated with a single dose of 12.5 Gy to the thorax. Total lung RNA was prepared and hybridized using microarray analysis and RNase protection assays. At 26 weeks postirradiation, messages encoding the chemokines BLC (now known as Scyb13), C10 (now known as Scya6), IP-10 (now known as Scyb10), MCP-1 (now known as Scya2), MCP-3 (now known as Scya7), MIP-1gamma (now known as Scya9), and RANTES (now known as Scya5) and the chemokine receptors Ccr1, Ccr2, Ccr5 and Ccr6 were elevated in fibrosis-sensitive (C57BL/6) mice. In contrast, only the messages encoding SDF-1alpha (now known as Sdf1) and Ccr1 were elevated 26 weeks postirradiation in fibrosis-resistant (C3H/HeJ) mice. Our results point to the CC and CCR family members as the predominant chemokine responders during the development of fibrosis. These studies suggest that monocyte/macrophage and lymphocyte recruitment and activation are key components of radiation-induced fibrosis.

  12. Radiotherapy of breast fibrosis

    International Nuclear Information System (INIS)

    Heibel, J.H.

    1979-01-01

    In a retrospective study radiotherapy of breast fibrosis in hormone-treated men with histologically confirmed prostate carcinoma was examined. 10 patients had received hormones even before irradiation, 113 obtained hormone administration only after irradiation. The objective size of the glandular body and the overall size of the breast were measured with a special method developed by the author. 46 patients indicated complaints. With hypertrophic mamma and hypertrophic mamilla in 67 examined patients, 127 different symptoms resulted in total. Four patients of the group who had obtained hormones before irradiation, suffered from subjective symptoms. It resulted that radiotherapy of breast fibrosis carried out during hormone treatment is no gynecomastia prophylaxis, that already existent mamma hypertrophies are irreversible, but that existent sensations were notably reduced within 6 months after irradiation therapy. These results indicate the necessity of a radiotherapy of the mamma fibrosis before the hormone treatment is begun. Particularly in cases of higher operative risks, also the possibility of preferring radiotherapy to mastectomy should be fully utilized, in view of adequate or even better therapeutic results. (orig./MG) [de

  13. Laboratory confirmation of the diagnosis of cystic fibrosis.

    Science.gov (United States)

    Tocci, P M; McKey, R M

    1976-11-01

    The recent commercial introduction of a method for detecting albumin in meconium makes screening for cystic fibrosis feasible for many hospitals. If the tests is adopted, confirmatory tests should be available. Quantitative analyses of sweat for sodium by flame photometry and for chloride by silver titration and ion-sleective electrodes are now used as confirmatory tests. We compare results of these confirmatory methods applied to presons with cystic fibrosis, respiratory disorders, or digestive disorders, and to control subjects.

  14. Pancreatic fibrosis correlates with exocrine pancreatic insufficiency after pancreatoduodenectomy.

    Science.gov (United States)

    Tran, T C K; van 't Hof, G; Kazemier, G; Hop, W C; Pek, C; van Toorenenbergen, A W; van Dekken, H; van Eijck, C H J

    2008-01-01

    Obstruction of the pancreatic duct can lead to pancreatic fibrosis. We investigated the correlation between the extent of pancreatic fibrosis and the postoperative exocrine and endocrine pancreatic function. Fifty-five patients who were treated for pancreatic and periampullary carcinoma and 19 patients with chronic pancreatitis were evaluated. Exocrine pancreatic function was evaluated by fecal elastase-1 test, while endocrine pancreatic function was assessed by plasma glucose level. The extent of fibrosis, duct dilation and endocrine tissue loss was examined histopathologically. A strong correlation was found between pancreatic fibrosis and elastase-1 level less than 100 microg/g (p pancreatic insufficiency. A strong correlation was found between pancreatic fibrosis and endocrine tissue loss (p pancreatic fibrosis nor endocrine tissue loss were correlated with the development of postoperative diabetes mellitus. Duct dilation alone was neither correlated with exocrine nor with endocrine function loss. The majority of patients develop severe exocrine pancreatic insufficiency after pancreatoduodenectomy. The extent of exocrine pancreatic insufficiency is strongly correlated with preoperative fibrosis. The loss of endocrine tissue does not correlate with postoperative diabetes mellitus. Preoperative dilation of the pancreatic duct per se does not predict exocrine or endocrine pancreatic insufficiency postoperatively. Copyright 2008 S. Karger AG, Basel.

  15. "Tipping" extracellular matrix remodeling towards regression of liver fibrosis

    DEFF Research Database (Denmark)

    Magdaleno, Fernando; Schierwagen, Robert; Uschner, Frank E

    2018-01-01

    Fibrosis development was initially conceived as an incessant progressive condition. Nowadays, it has become evident that fibrotic tissue undergoes a continuous two-way process: fibrogenesis and fibrinolysis, characterizing the remodeling of extracellular matrix (ECM). However, in established...... fibrosis, this two-way process is tipped towards fibrogenesis and this leads to a self-perpetuating accumulation of ECM, a distinct metabolic unit, together with other cells and processes promoting fibrosis deposition. Several mechanisms promote fibrosis regression, such as degradation of ECM, infiltration...

  16. Phosphocalcic Markers and Calcification Propensity for Assessment of Interstitial Fibrosis and Vascular Lesions in Kidney Allograft Recipients.

    Directory of Open Access Journals (Sweden)

    Lena Berchtold

    Full Text Available Renal interstitial fibrosis and arterial lesions predict loss of function in chronic kidney disease. Noninvasive estimation of interstitial fibrosis and vascular lesions is currently not available. The aim of the study was to determine whether phosphocalcic markers are associated with, and can predict, renal chronic histological changes. We included 129 kidney allograft recipients with an available transplant biopsy in a retrospective study. We analyzed the associations and predictive values of phosphocalcic markers and serum calcification propensity (T50 for chronic histological changes (interstitial fibrosis and vascular lesions. PTH, T50 and vitamin D levels were independently associated to interstitial fibrosis. PTH elevation was associated with increasing interstitial fibrosis severity (r = 0.29, p = 0.001, while T50 and vitamin D were protective (r = -0.20, p = 0.025 and r = -0.23, p = 0.009 respectively. On the contrary, fibroblast growth factor 23 (FGF23 and Klotho correlated only modestly with interstitial fibrosis (p = 0.045 whereas calcium and phosphate did not. PTH, vitamin D and T50 were predictors of extensive fibrosis (AUC: 0.73, 0.72 and 0.68 respectively, but did not add to renal function prediction. PTH, FGF23 and T50 were modestly predictive of low fibrosis (AUC: 0.63, 0.63 and 0.61 but did not add to renal function prediction. T50 decreased with increasing arterial lesions (r = -0.21, p = 0.038. The discriminative performance of T50 in predicting significant vascular lesions was modest (AUC 0.61. In summary, we demonstrated that PTH, vitamin D and T50 are associated to interstitial fibrosis and vascular lesions in kidney allograft recipients independently of renal function. Despite these associations, mineral metabolism indices do not show superiority or additive value to fibrosis prediction by eGFR and proteinuria in kidney allograft recipients, except for vascular lesions where T50 could be of relevance.

  17. Inhibiting core fucosylation attenuates glucose-induced peritoneal fibrosis in rats.

    Science.gov (United States)

    Li, Longkai; Shen, Nan; Wang, Nan; Wang, Weidong; Tang, Qingzhu; Du, Xiangning; Carrero, Juan Jesus; Wang, Keping; Deng, Yiyao; Li, Zhitong; Lin, Hongli; Wu, Taihua

    2018-06-01

    Ultrafiltration failure is a major complication of long-term peritoneal dialysis, resulting in dialysis failure. Peritoneal fibrosis induced by continuous exposure to high glucose dialysate is the major contributor of ultrafiltration failure, for which there is no effective treatment. Overactivation of several signaling pathways, including transforming growth factor-β1 (TGF-β1) and platelet-derived growth factor (PDGF) pathways, contribute to the development of peritoneal fibrosis. Therefore, simultaneously blocking multiple signaling pathways might be a potential novel method of treating peritoneal fibrosis. Previously, we showed that core fucosylation, an important posttranslational modification of the TGF-β1 receptors, can regulate the activation of TGF-β1 signaling in renal interstitial fibrosis. However, it remains unclear whether core fucosylation affects the progression of peritoneal fibrosis. Herein, we show that core fucosylation was enriched in the peritoneal membrane of rats accompanied by peritoneal fibrosis induced by a high glucose dialysate. Blocking core fucosylation dramatically attenuated peritoneal fibrosis in the rat model achieved by simultaneously inactivating the TGF-β1 and PDGF signaling pathways. Next the protective effects of blocking core fucosylation and imatinib (a selective PDGF receptor inhibitor) on peritoneal fibrosis were compared and found to exhibit a greater inhibitory effect over imatinib alone, suggesting that blocking activation of multiple signaling pathways may have superior inhibitory effects on the development of peritoneal fibrosis. Thus, core fucosylation is essential for the development of peritoneal fibrosis by regulating the activation of multiple signaling pathways. This may be a potential novel target for drug development to treat peritoneal fibrosis. Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  18. Novel and optimized strategies for inducing fibrosis in vivo: focus on Duchenne Muscular Dystrophy

    Science.gov (United States)

    2014-01-01

    Background Fibrosis, an excessive collagen accumulation, results in scar formation, impairing function of vital organs and tissues. Fibrosis is a hallmark of muscular dystrophies, including the lethal Duchenne muscular dystrophy (DMD), which remains incurable. Substitution of muscle by fibrotic tissue also complicates gene/cell therapies for DMD. Yet, no optimal models to study muscle fibrosis are available. In the widely used mdx mouse model for DMD, extensive fibrosis develops in the diaphragm only at advanced adulthood, and at about two years of age in the ‘easy-to-access’ limb muscles, thus precluding fibrosis research and the testing of novel therapies. Methods We developed distinct experimental strategies, ranging from chronic exercise to increasing muscle damage on limb muscles of young mdx mice, by myotoxin injection, surgically induced trauma (laceration or denervation) or intramuscular delivery of profibrotic growth factors (such as TGFβ). We also extended these approaches to muscle of normal non-dystrophic mice. Results These strategies resulted in advanced and enhanced muscle fibrosis in young mdx mice, which persisted over time, and correlated with reduced muscle force, thus mimicking the severe DMD phenotype. Furthermore, increased fibrosis was also obtained by combining these procedures in muscles of normal mice, mirroring aberrant repair after severe trauma. Conclusions We have developed new and improved experimental strategies to accelerate and enhance muscle fibrosis in vivo. These strategies will allow rapidly assessing fibrosis in the easily accessible limb muscles of young mdx mice, without necessarily having to use old animals. The extension of these fibrogenic regimes to the muscle of non-dystrophic wild-type mice will allow fibrosis assessment in a wide array of pre-existing transgenic mouse lines, which in turn will facilitate understanding the mechanisms of fibrogenesis. These strategies should improve our ability to combat fibrosis

  19. Nephrogenic systemic fibrosis: epidemiology update

    DEFF Research Database (Denmark)

    Marckmann, P.

    2008-01-01

    Purpose of review The aim of this article is to outline the history of nephrogenic systemic fibrosis, a new and serious disease of patients with renal failure, and to give an update on its aetiology and prevalence. Recent findings Epidemiological and histochemical studies demonstrated....... Increasingly poor renal function, aberrations in calcium-phosphate metabolism and erythropoietin treatment seem to increase the risk of the disease and its severity. Up to 25-30% of patients with renal failure exposed to gadolinium-based contrast agents may develop nephrogenic systemic disease. The figure...... that gadolinium-containing contrast agents used for magnetic resonance imaging have an essential causative role in most, if not all, cases of nephrogenic systemic fibrosis. One particular agent, gadodiamide, caused the majority of cases, but gadopentetate dimeglumine has also been implicated in several cases...

  20. Simultaneous Administration of ADSCs-Based Therapy and Gene Therapy Using Ad-huPA Reduces Experimental Liver Fibrosis.

    Science.gov (United States)

    Meza-Ríos, Alejandra; García-Benavides, Leonel; García-Bañuelos, Jesus; Salazar-Montes, Adriana; Armendáriz-Borunda, Juan; Sandoval-Rodríguez, Ana

    2016-01-01

    hADSCs transplantation in cirrhosis models improves liver function and reduces fibrosis. In addition, Ad-huPA gene therapy diminished fibrosis and increased hepatocyte regeneration. In this study, we evaluate the combination of these therapies in an advanced liver fibrosis experimental model. hADSCs were expanded and characterized before transplantation. Ad-huPA was simultaneously administrated via the ileac vein. Animals were immunosuppressed by CsA 24 h before treatment and until sacrifice at 10 days post-treatment. huPA liver expression and hADSCs biodistribution were evaluated, as well as the percentage of fibrotic tissue, hepatic mRNA levels of Col-αI, TGF-β1, CTGF, α-SMA, PAI-I, MMP2 and serum levels of ALT, AST and albumin. hADSCs homed mainly in liver, whereas huPA expression was similar in Ad-huPA and hADSCs/Ad-huPA groups. hADSCs, Ad-huPA and hADSCs/Ad-huPA treatment improves albumin levels, reduces liver fibrosis and diminishes Collagen α1, CTGF and α-SMA mRNA liver levels. ALT and AST serum levels showed a significant decrease exclusively in the hADSCs group. These results showed that combinatorial effect of cell and gene-therapy does not improve the antifibrogenic effects of individual treatments, whereas hADSCs transplantation seems to reduce liver fibrosis in a greater proportion.

  1. The Interplay between Inflammation and Fibrosis in Kidney Transplantation

    Directory of Open Access Journals (Sweden)

    Irina B. Torres

    2014-01-01

    Full Text Available Serial surveillance renal allograft biopsies have shown that early subclinical inflammation constitutes a risk factor for the development of interstitial fibrosis. More recently, it has been observed that persistent inflammation is also associated with fibrosis progression and chronic humoral rejection, two histological conditions associated with poor allograft survival. Treatment of subclinical inflammation with steroid boluses prevents progression of fibrosis and preserves renal function in patients treated with a cyclosporine-based regimen. Subclinical inflammation has been reduced after the introduction of tacrolimus based regimens, and it has been shown that immunosuppressive schedules that are effective in preventing acute rejection and subclinical inflammation may prevent the progression of fibrosis and chronic humoral rejection. On the other hand, minimization protocols are associated with progression of fibrosis, and noncompliance with the immunosuppressive regime constitutes a major risk factor for chronic humoral rejection. Thus, adequate immunosuppressive treatment, avoiding minimization strategies and reinforcing educational actions to prevent noncompliance, is at present an effective approach to combat the progression of fibrosis.

  2. Cystic fibrosis Delta F508 heterozygotes, smoking, and reproduction

    DEFF Research Database (Denmark)

    Dahl, Morten; Tybjaerg-Hansen, A; Wittrup, H H

    1998-01-01

    Cystic fibrosis is the most common fatal autosomal recessive disease affecting Caucasian populations. It remains a puzzle how this disease is maintained at such a remarkably high incidence, however, it could be due to a reproductive advantage in cystic fibrosis heterozygotes. We tested this hypot......Cystic fibrosis is the most common fatal autosomal recessive disease affecting Caucasian populations. It remains a puzzle how this disease is maintained at such a remarkably high incidence, however, it could be due to a reproductive advantage in cystic fibrosis heterozygotes. We tested.......001). In conclusion, overall these results do not support a reproductive advantage for cystic fibrosis DeltaF508 heterozygotes. However, the data cannot totally exclude the possibility that nonsmoking DeltaF508 heterozygotes experience a reproductive advantage while smoking DeltaF508 heterozygotes experience...... the opposite, a reproductive disadvantage. Accordingly, the data suggest a previously undocumented role of smoking on fecundity among cystic fibrosis heterozygotes....

  3. Role of Receptor Tyrosine Kinase Signaling in Renal Fibrosis

    Directory of Open Access Journals (Sweden)

    Feng Liu

    2016-06-01

    Full Text Available Renal fibrosis can be induced in different renal diseases, but ultimately progresses to end stage renal disease. Although the pathophysiologic process of renal fibrosis have not been fully elucidated, it is characterized by glomerulosclerosis and/or tubular interstitial fibrosis, and is believed to be caused by the proliferation of renal inherent cells, including glomerular epithelial cells, mesangial cells, and endothelial cells, along with defective kidney repair, renal interstitial fibroblasts activation, and extracellular matrix deposition. Receptor tyrosine kinases (RTKs regulate a variety of cell physiological processes, including metabolism, growth, differentiation, and survival. Many studies from in vitro and animal models have provided evidence that RTKs play important roles in the pathogenic process of renal fibrosis. It is also showed that tyrosine kinases inhibitors (TKIs have anti-fibrotic effects in basic research and clinical trials. In this review, we summarize the evidence for involvement of specific RTKs in renal fibrosis process and the employment of TKIs as a therapeutic approach for renal fibrosis.

  4. Liver Disease in Cystic Fibrosis: an Update

    Science.gov (United States)

    Parisi, Giuseppe Fabio; Di Dio, Giovanna; Franzonello, Chiara; Gennaro, Alessia; Rotolo, Novella; Lionetti, Elena; Leonardi, Salvatore

    2013-01-01

    Context Cystic fibrosis (CF) is the most widespread autosomal recessive genetic disorder that limits life expectation amongst the Caucasian population. As the median survival has increased related to early multidisciplinary intervention, other manifestations of CF have emergedespecially for the broad spectrum of hepatobiliary involvement. The present study reviews the existing literature on liver disease in cystic fibrosis and describes the key issues for an adequate clinical evaluation and management of patients, with a focus on the pathogenetic, clinical and diagnostic-therapeutic aspects of liver disease in CF. Evidence Acquisition A literature search of electronic databases was undertaken for relevant studies published from 1990 about liver disease in cystic fibrosis. The databases searched were: EMBASE, PubMed and Cochrane Library. Results CF is due to mutations in the gene on chromosome 7 that encodes an amino acidic polypeptide named CFTR (cystic fibrosis transmembrane regulator). The hepatic manifestations include particular changes referring to the basic CFTR defect, iatrogenic lesions or consequences of the multisystem disease. Even though hepatobiliary disease is the most common non-pulmonary cause ofmortalityin CF (the third after pulmonary disease and transplant complications), only about the 33%ofCF patients presents clinically significant hepatobiliary disease. Conclusions Liver disease will have a growing impact on survival and quality of life of cystic fibrosis patients because a longer life expectancy and for this it is important its early recognition and a correct clinical management aimed atdelaying the onset of complications. This review could represent an opportunity to encourage researchers to better investigate genotype-phenotype correlation associated with the development of cystic fibrosis liver disease, especially for non-CFTR genetic polymorphisms, and detect predisposed individuals. Therapeutic trials are needed to find strategies of

  5. Liver fibrosis: in vivo evaluation using intravoxel incoherent motion-derived histogram metrics with histopathologic findings at 3.0 T.

    Science.gov (United States)

    Hu, Fubi; Yang, Ru; Huang, Zixing; Wang, Min; Zhang, Hanmei; Yan, Xu; Song, Bin

    2017-12-01

    To retrospectively determine the feasibility of intravoxel incoherent motion (IVIM) imaging based on histogram analysis for the staging of liver fibrosis (LF) using histopathologic findings as the reference standard. 56 consecutive patients (14 men, 42 women; age range, 15-76, years) with chronic liver diseases (CLDs) were studied using IVIM-DWI with 9 b-values (0, 25, 50, 75, 100, 150, 200, 500, 800 s/mm 2 ) at 3.0 T. Fibrosis stage was evaluated using the METAVIR scoring system. Histogram metrics including mean, standard deviation (Std), skewness, kurtosis, minimum (Min), maximum (Max), range, interquartile (Iq) range, and percentiles (10, 25, 50, 75, 90th) were extracted from apparent diffusion coefficient (ADC), true diffusion coefficient (D), pseudo-diffusion coefficient (D*), and perfusion fraction (f) maps. All histogram metrics among different fibrosis groups were compared using one-way analysis of variance or nonparametric Kruskal-Wallis test. For significant parameters, receivers operating characteristic curve (ROC) analyses were further performed for the staging of LF. Based on their METAVIR stage, the 56 patients were reclassified into three groups as follows: F0-1 group (n = 25), F2-3 group (n = 21), and F4 group (n = 10). The mean, Iq range, percentiles (50, 75, and 90th) of D* maps between the groups were significant differences (all P histogram metrics of ADC, D, and f maps demonstrated no significant difference among the groups (all P > 0.05). Histogram analysis of D* map derived from IVIM can be used to stage liver fibrosis in patients with CLDs and provide more quantitative information beyond the mean value.

  6. Cystic fibrosis with normal sweat chloride concentration: case report

    Directory of Open Access Journals (Sweden)

    Silva Filho Luiz Vicente Ferreira da

    2003-01-01

    Full Text Available Cystic fibrosis is a genetic disease usually diagnosed by abnormal sweat testing. We report a case of an 18-year-old female with bronchiectasis, chronic P. aeruginosa infection, and normal sweat chloride concentrations who experienced rapid decrease of lung function and clinical deterioration despite treatment. Given the high suspicion ofcystic fibrosis, broad genotyping testing was performed, showing a compound heterozygous with deltaF508 and 3849+10kb C->T mutations, therefore confirming cystic fibrosis diagnosis. Although the sweat chloride test remains the gold standard for the diagnosis of cystic fibrosis, alternative diagnostic tests such as genotyping and electrophysiologic measurements must be performed if there is suspicion of cystic fibrosis, despite normal or borderline sweat chloride levels.

  7. Cytokine levels as biomarkers of radiation fibrosis in patients treated with breast radiotherapy

    International Nuclear Information System (INIS)

    Westbury, Charlotte B; Yarnold, John R; Haviland, Joanne; Davies, Sue; Gothard, Lone; Abdi, Bahja Ahmed; Sydenham, Mark; Bowen, Jo; Stratton, Richard; Short, Susan C

    2014-01-01

    Radiation fibrosis is not easily measurable although clinical scores have been developed for this purpose. Biomarkers present an alternative more objective approach to quantification, and estimation in blood provides accessible samples. We investigated if blood cytokines could be used to measure established fibrosis in patients who have undergone radiotherapy for breast cancer. We studied two cohorts treated by breast-conserving surgery and radiotherapy in the UK START Trial A, one with breast fibrosis (cases) and one with no or minimal fibrosis (controls). Two candidate cytokines, plasma connective tissue growth factor (CTGF) and serum interleukin-6 (IL6) were estimated by ELISA. Comparisons between cases and controls used the t-test or Mann–Whitney test and associations between blood concentration and clinical factors were assessed using the Spearman rank correlation coefficient. Seventy patients were included (26 cases, 44 controls). Mean time since radiotherapy was 9.9 years (range 8.3-12.0). No statistically significant differences between cases and controls in serum IL6 (median (IQR) 0.84 pg/ml (0.57-1.14), 0.75 pg/ml (0.41-1.43) respectively) or plasma CTGF (331.4 pg/ml (234.8-602.9), 334.5 pg/ml (270.0-452.8) were identified. There were no significant associations between blood cytokine concentration and age, fibrosis severity, breast size or time since radiotherapy. No significant difference in IL6 or CTGF concentrations was detected between patients with breast fibrosis and controls with minimal or no fibrosis

  8. Diagnostic Usefulness of APRI and FIB-4 for the Prediction of Liver Fibrosis After Liver Transplantation in Patients Infected with Hepatitis C Virus.

    Science.gov (United States)

    Imai, H; Kamei, H; Onishi, Y; Ishizu, Y; Ishigami, M; Goto, H; Ogura, Y

    2018-06-01

    Aspartate transaminase-to-platelet ratio index (APRI) and fibrosis-4 (FIB-4) are well known as representative indirect serum biomarkers related to liver fibrosis. The usefulness of these markers for the diagnosis of liver fibrosis after liver transplantation (LT) in hepatitis C virus (HCV)-infected patients and the influence of splenectomy were investigated. From June 2003 to May 2014, 31 HCV-infected patients who underwent LT and postoperative follow-up liver biopsies were included in this study. The association between liver fibrosis and serum biomarkers and the influence of splenectomy on APRI and FIB-4 were also investigated. A total of 195 biopsy specimens were collected, and liver fibrosis was identified as: F0, 59.7%; F1, 34.1%; and F2, 6.3%. Both APRI and FIB-4 were significantly higher in patients who showed F1 and F2 in liver biopsy specimen than F0 (P values, .009 and .022, respectively); sensitivity and specificity of APRI were, respectively, 63.4% and 66.7%, and those of FIB-4 were 57.7% and 69.6%. In 11 patients (35.5%) who underwent splenectomy at the time of LT, the cutoff values for APRI and FIB-4 were 0.61 and 1.41, which were significantly lower than the corresponding values (1.00 and 3.64) of patients without splenectomy. APRI and FIB-4 could effectively estimate liver fibrosis after LT for HCV-related liver disease. For LT patients with splenectomy, APRI and FIB-4 were also useful to estimate liver fibrosis, but the standard values should be adjusted lower than those for patients without splenectomy. Copyright © 2018 Elsevier Inc. All rights reserved.

  9. Inhibition of the Unfolded Protein Response Mechanism Prevents Cardiac Fibrosis.

    Directory of Open Access Journals (Sweden)

    Jody Groenendyk

    Full Text Available Cardiac fibrosis attributed to excessive deposition of extracellular matrix proteins is a major cause of heart failure and death. Cardiac fibrosis is extremely difficult and challenging to treat in a clinical setting due to lack of understanding of molecular mechanisms leading to cardiac fibrosis and effective anti-fibrotic therapies. The objective in this study was to examine whether unfolded protein response (UPR pathway mediates cardiac fibrosis and whether a pharmacological intervention to modulate UPR can prevent cardiac fibrosis and preserve heart function.We demonstrate here that the mechanism leading to development of fibrosis in a mouse with increased expression of calreticulin, a model of heart failure, stems from impairment of endoplasmic reticulum (ER homeostasis, transient activation of the unfolded protein response (UPR pathway and stimulation of the TGFβ1/Smad2/3 signaling pathway. Remarkably, sustained pharmacologic inhibition of the UPR pathway by tauroursodeoxycholic acid (TUDCA is sufficient to prevent cardiac fibrosis, and improved exercise tolerance.We show that the mechanism leading to development of fibrosis in a mouse model of heart failure stems from transient activation of UPR pathway leading to persistent remodelling of cardiac tissue. Blocking the activation of the transiently activated UPR pathway by TUDCA prevented cardiac fibrosis, and improved prognosis. These findings offer a window for additional interventions that can preserve heart function.

  10. Self-management education for cystic fibrosis.

    LENUS (Irish Health Repository)

    Savage, Eileen

    2011-01-01

    Self-management education may help patients with cystic fibrosis and their families to choose, monitor and adjust treatment requirements for their illness, and also to manage the effects of illness on their lives. Although self-management education interventions have been developed for cystic fibrosis, no previous systematic review of the evidence of effectiveness of these interventions has been conducted.

  11. Exhaled breath analysis using electronic nose in cystic fibrosis and primary ciliary dyskinesia patients with chronic pulmonary infections

    DEFF Research Database (Denmark)

    Joensen, Odin; Paff, Tamara; Haarman, Eric G

    2014-01-01

    The current diagnostic work-up and monitoring of pulmonary infections may be perceived as invasive, is time consuming and expensive. In this explorative study, we investigated whether or not a non-invasive exhaled breath analysis using an electronic nose would discriminate between cystic fibrosis...... (CF) and primary ciliary dyskinesia (PCD) with or without various well characterized chronic pulmonary infections. We recruited 64 patients with CF and 21 with PCD based on known chronic infection status. 21 healthy volunteers served as controls. An electronic nose was employed to analyze exhaled......, this method significantly discriminates CF patients suffering from a chronic pulmonary P. aeruginosa (PA) infection from CF patients without a chronic pulmonary infection. Further studies are needed for verification and to investigate the role of electronic nose technology in the very early diagnostic workup...

  12. Cost-Effectiveness Analysis: Risk Stratification of Nonalcoholic Fatty Liver Disease (NAFLD by the Primary Care Physician Using the NAFLD Fibrosis Score.

    Directory of Open Access Journals (Sweden)

    Elliot B Tapper

    Full Text Available The complications of Nonalcoholic Fatty Liver Disease (NAFLD are dependent on the presence of advanced fibrosis. Given the high prevalence of NAFLD in the US, the optimal evaluation of NAFLD likely involves triage by a primary care physician (PCP with advanced disease managed by gastroenterologists.We compared the cost-effectiveness of fibrosis risk-assessment strategies in a cohort of 10,000 simulated American patients with NAFLD performed in either PCP or referral clinics using a decision analytical microsimulation state-transition model. The strategies included use of vibration-controlled transient elastography (VCTE, the NAFLD fibrosis score (NFS, combination testing with NFS and VCTE, and liver biopsy (usual care by a specialist only. NFS and VCTE performance was obtained from a prospective cohort of 164 patients with NAFLD. Outcomes included cost per quality adjusted life year (QALY and correct classification of fibrosis.Risk-stratification by the PCP using the NFS alone costs $5,985 per QALY while usual care costs $7,229/QALY. In the microsimulation, at a willingness-to-pay threshold of $100,000, the NFS alone in PCP clinic was the most cost-effective strategy in 94.2% of samples, followed by combination NFS/VCTE in the PCP clinic (5.6% and usual care in 0.2%. The NFS based strategies yield the best biopsy-correct classification ratios (3.5 while the NFS/VCTE and usual care strategies yield more correct-classifications of advanced fibrosis at the cost of 3 and 37 additional biopsies per classification.Risk-stratification of patients with NAFLD primary care clinic is a cost-effective strategy that should be formally explored in clinical practice.

  13. Lymphoplasmacytic Sclerosing Pancreatitis and Retroperitoneal Fibrosis

    Directory of Open Access Journals (Sweden)

    Nigel K. F. Koo Ng

    2008-01-01

    Full Text Available Although cases of lymphoplasmacytic sclerosing pancreatitis (LSP associated with idiopathic retroperitoneal fibrosis have been reported, the association is rare. We describe a 74-year-old man who presented with obstructive jaundice and weight loss. Nineteen months earlier, he had been diagnosed with idiopathic retroperitoneal fibrosis and treated with bilateral ureteric stents. Initial investigations were suggestive of a diagnosis of LSP, however, a malignant cause could not be ruled out. He underwent an exploratory laparotomy and frozen sections confirmed the diagnosis of LSP. An internal biliary bypass was performed using a Roux loop of jejunum, and the patient made an uneventful recovery. This case illustrates the difficulty in distinguishing LSP from pancreatic carcinoma preoperatively.

  14. Abdominal CT predictors of fibrosis in patients with chronic pancreatitis undergoing surgery

    Energy Technology Data Exchange (ETDEWEB)

    Sinha, Amitasha; Afghani, Elham [Johns Hopkins Medical Institutions, Division of Gastroenterology, Baltimore, MD (United States); Singh, Vikesh K. [Johns Hopkins Medical Institutions, Division of Gastroenterology, Baltimore, MD (United States); Johns Hopkins Medical Institutions, Pancreatitis Center, Baltimore, MD (United States); Cruise, Michael; Matsukuma, Karen [Johns Hopkins Medical Institutions, Department of Pathology, Baltimore, MD (United States); Ali, Sumera; Raman, Siva P.; Fishman, Elliot K. [Johns Hopkins Medical Institutions, The Russel H. Morgan Department of Radiology and Radiological Science, Baltimore, MD (United States); Andersen, Dana K. [National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD (United States); Makary, Martin A. [Johns Hopkins Medical Institutions, Department of Surgery, Baltimore, MD (United States); Johns Hopkins Medical Institutions, Pancreatitis Center, Baltimore, MD (United States); Zaheer, Atif [Johns Hopkins Medical Institutions, The Russel H. Morgan Department of Radiology and Radiological Science, Baltimore, MD (United States); Johns Hopkins Medical Institutions, Pancreatitis Center, Baltimore, MD (United States); Johns Hopkins Medical Institutions, Baltimore, MD (United States)

    2015-05-01

    To determine which abdominal CT findings predict severe fibrosis and post-operative pain relief in chronic pancreatitis (CP). Pre-operative abdominal CTs of 66 patients (mean age 52 ± 12 years, 53 % males) with painful CP who underwent the Whipple procedure (n = 32), Frey procedure (n = 32) or pancreatic head biopsy (n = 2), between 1/2003-3/2014, were evaluated. CT was evaluated for parenchymal calcifications, intraductal calculi, main pancreatic duct dilation (>5 mm), main pancreatic duct stricture, and abnormal side branch(es). The surgical histopathology was graded for fibrosis. CT findings were evaluated as predictors of severe fibrosis and post-operative pain relief using regression and area under receiver operating curve (AUC) analysis. Thirty-eight (58 %) patients had severe fibrosis. Parenchymal calcification(s) were an independent predictor of severe fibrosis (p = 0.03), and post-operative pain relief over a mean follow-up of 1-year (p = 0.04). Presence of >10 parenchymal calcifications had higher predictive accuracy for severe fibrosis than 1-10 parenchymal calcification(s) (AUC 0.88 vs. 0.59, p = 0.003). The predictive accuracy of >10 versus 1-10 parenchymal calcifications increased after adjusting for all other CT findings (AUC 0.89 vs. 0.63, p = 0.01). Parenchymal calcification(s) independently predict severe fibrosis and are significantly associated with post-operative pain relief in CP. The presence of >10 parenchymal calcifications is a better predictor of severe fibrosis than 1-10 parenchymal calcification(s). (orig.)

  15. Abdominal CT predictors of fibrosis in patients with chronic pancreatitis undergoing surgery

    International Nuclear Information System (INIS)

    Sinha, Amitasha; Afghani, Elham; Singh, Vikesh K.; Cruise, Michael; Matsukuma, Karen; Ali, Sumera; Raman, Siva P.; Fishman, Elliot K.; Andersen, Dana K.; Makary, Martin A.; Zaheer, Atif

    2015-01-01

    To determine which abdominal CT findings predict severe fibrosis and post-operative pain relief in chronic pancreatitis (CP). Pre-operative abdominal CTs of 66 patients (mean age 52 ± 12 years, 53 % males) with painful CP who underwent the Whipple procedure (n = 32), Frey procedure (n = 32) or pancreatic head biopsy (n = 2), between 1/2003-3/2014, were evaluated. CT was evaluated for parenchymal calcifications, intraductal calculi, main pancreatic duct dilation (>5 mm), main pancreatic duct stricture, and abnormal side branch(es). The surgical histopathology was graded for fibrosis. CT findings were evaluated as predictors of severe fibrosis and post-operative pain relief using regression and area under receiver operating curve (AUC) analysis. Thirty-eight (58 %) patients had severe fibrosis. Parenchymal calcification(s) were an independent predictor of severe fibrosis (p = 0.03), and post-operative pain relief over a mean follow-up of 1-year (p = 0.04). Presence of >10 parenchymal calcifications had higher predictive accuracy for severe fibrosis than 1-10 parenchymal calcification(s) (AUC 0.88 vs. 0.59, p = 0.003). The predictive accuracy of >10 versus 1-10 parenchymal calcifications increased after adjusting for all other CT findings (AUC 0.89 vs. 0.63, p = 0.01). Parenchymal calcification(s) independently predict severe fibrosis and are significantly associated with post-operative pain relief in CP. The presence of >10 parenchymal calcifications is a better predictor of severe fibrosis than 1-10 parenchymal calcification(s). (orig.)

  16. Respiratory muscle training for cystic fibrosis.

    Science.gov (United States)

    Hilton, Nathan; Solis-Moya, Arturo

    2018-05-24

    Cystic fibrosis is the most common autosomal recessive disease in white populations, and causes respiratory dysfunction in the majority of individuals. Numerous types of respiratory muscle training to improve respiratory function and health-related quality of life in people with cystic fibrosis have been reported in the literature. Hence a systematic review of the literature is needed to establish the effectiveness of respiratory muscle training (either inspiratory or expiratory muscle training) on clinical outcomes in cystic fibrosis. This is an update of a previously published review. To determine the effectiveness of respiratory muscle training on clinical outcomes in people with cystic fibrosis. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials register comprising of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of most recent search: 17 April 2018.A hand search of the Journal of Cystic Fibrosis and Pediatric Pulmonology was performed, along with an electronic search of online trial databases up until 07 May 2018. Randomised controlled studies comparing respiratory muscle training with a control group in people with cystic fibrosis. Review authors independently selected articles for inclusion, evaluated the methodological quality of the studies, and extracted data. Additional information was sought from trial authors where necessary. The quality of the evidence was assessed using the GRADE system MAIN RESULTS: Authors identified 19 studies, of which nine studies with 202 participants met the review's inclusion criteria. There was wide variation in the methodological and written quality of the included studies. Four of the nine included studies were published as abstracts only and lacking concise details, thus limiting the information available. Seven studies were parallel studies and two of a cross-over design. Respiratory

  17. Not All Children with Cystic Fibrosis Have Abnormal Esophageal Neutralization during Chemical Clearance of Acid Reflux.

    Science.gov (United States)

    Woodley, Frederick W; Moore-Clingenpeel, Melissa; Machado, Rodrigo Strehl; Nemastil, Christopher J; Jadcherla, Sudarshan R; Hayes, Don; Kopp, Benjamin T; Kaul, Ajay; Di Lorenzo, Carlo; Mousa, Hayat

    2017-09-01

    Acid neutralization during chemical clearance is significantly prolonged in children with cystic fibrosis, compared to symptomatic children without cystic fibrosis. The absence of available reference values impeded identification of abnormal findings within individual patients with and without cystic fibrosis. The present study aimed to test the hypothesis that significantly more children with cystic fibrosis have acid neutralization durations during chemical clearance that fall outside the physiological range. Published reference value for acid neutralization duration during chemical clearance (determined using combined impedance/pH monitoring) was used to assess esophageal acid neutralization efficiency during chemical clearance in 16 children with cystic fibrosis (3 to chemical clearance exceeded the upper end of the physiological range in 9 of 16 (56.3%) children with and in 3 of 16 (18.8%) children without cystic fibrosis ( p =0.0412). The likelihood ratio for duration indicated that children with cystic fibrosis are 2.1-times more likely to have abnormal acid neutralization during chemical clearance, and children with abnormal acid neutralization during chemical clearance are 1.5-times more likely to have cystic fibrosis. Significantly more (but not all) children with cystic fibrosis have abnormally prolonged esophageal clearance of acid. Children with cystic fibrosis are more likely to have abnormal acid neutralization during chemical clearance. Additional studies involving larger sample sizes are needed to address the importance of genotype, esophageal motility, composition and volume of saliva, and gastric acidity on acid neutralization efficiency in cystic fibrosis children.

  18. Idiopathic Pulmonary Fibrosis: Data-driven Textural Analysis of Extent of Fibrosis at Baseline and 15-Month Follow-up.

    Science.gov (United States)

    Humphries, Stephen M; Yagihashi, Kunihiro; Huckleberry, Jason; Rho, Byung-Hak; Schroeder, Joyce D; Strand, Matthew; Schwarz, Marvin I; Flaherty, Kevin R; Kazerooni, Ella A; van Beek, Edwin J R; Lynch, David A

    2017-10-01

    Purpose To evaluate associations between pulmonary function and both quantitative analysis and visual assessment of thin-section computed tomography (CT) images at baseline and at 15-month follow-up in subjects with idiopathic pulmonary fibrosis (IPF). Materials and Methods This retrospective analysis of preexisting anonymized data, collected prospectively between 2007 and 2013 in a HIPAA-compliant study, was exempt from additional institutional review board approval. The extent of lung fibrosis at baseline inspiratory chest CT in 280 subjects enrolled in the IPF Network was evaluated. Visual analysis was performed by using a semiquantitative scoring system. Computer-based quantitative analysis included CT histogram-based measurements and a data-driven textural analysis (DTA). Follow-up CT images in 72 of these subjects were also analyzed. Univariate comparisons were performed by using Spearman rank correlation. Multivariate and longitudinal analyses were performed by using a linear mixed model approach, in which models were compared by using asymptotic χ 2 tests. Results At baseline, all CT-derived measures showed moderate significant correlation (P pulmonary function. At follow-up CT, changes in DTA scores showed significant correlation with changes in both forced vital capacity percentage predicted (ρ = -0.41, P pulmonary function (P fibrosis at CT yields an index of severity that correlates with visual assessment and functional change in subjects with IPF. © RSNA, 2017.

  19. Endocytosis and intracellular protein degradation in cystic fibrosis fibroblasts

    International Nuclear Information System (INIS)

    Jessup, W.; Dean, R.T.

    1983-01-01

    Normal rates of pinocytosis of [ 3 H]sucrose were measured in cystic fibrosis fibroblasts, and were not affected by the addition of cystic fibrosis serum. Bulk protein degradation (a significant proportion of which occurs intralysosomally following autophagy) and its regulation by growth state were apparently identical in normal and cystic fibrosis cultures. (Auth.)

  20. The features of radiation induced lung fibrosis related with dosimetric parameters

    International Nuclear Information System (INIS)

    Oh, Young-Taek; Noh, O Kyu; Jang, Hyunsoo; Chun, Mison; Park, Kyung Joo; Park, Kwang Joo; Kim, Mi-Hwa; Park, Hae-Jin

    2012-01-01

    Background and purpose: Radiation induced lung fibrosis (RILF) is a major complication after lung irradiation and is very important for long term quality of life and could result in fatal respiratory insufficiency. However, there has been little information on dosimetric parameters for radiotherapy planning in the aspect of RILF. The features of RILF related with dosimetric parameters were evaluated. Methods and materials: Forty-eight patients with non-small cell lung carcinoma who underwent post-operative radiation therapy (PORT) without adjuvant chemotherapy were analyzed. The degree of lung fibrosis was estimated by fibrosis volume and the dosimetric parameters were calculated from the plan of 3-dimensional conformal radiotherapy. Results: The fibrosis volume and V-dose as dosimetric parameters showed significant correlation and the correlation coefficient ranged from 0.602 to 0.683 (P < 0.01). The degree of the correlation line was steeper as the dose increase and threshold dose was not found. Mean lung dose (MLD) showed strong correlation with fibrosis volume (correlation coefficient = 0.726, P < 0.01). Conclusions: The fibrosis volume is continuously increased with V-dose as the reference dose increases. MLD is useful as a single parameter for comparing rival plans in the aspect of RILF.

  1. Adiponectin attenuates lung fibroblasts activation and pulmonary fibrosis induced by paraquat.

    Directory of Open Access Journals (Sweden)

    Rong Yao

    Full Text Available Pulmonary fibrosis is one of the most common complications of paraquat (PQ poisoning, which demands for more effective therapies. Accumulating evidence suggests adiponectin (APN may be a promising therapy against fibrotic diseases. In the current study, we determine whether the exogenous globular APN isoform protects against pulmonary fibrosis in PQ-treated mice and human lung fibroblasts, and dissect the responsible underlying mechanisms. BALB/C mice were divided into control group, PQ group, PQ + low-dose APN group, and PQ + high-dose APN group. Mice were sacrificed 3, 7, 14, and 21 days after PQ treatment. We compared pulmonary histopathological changes among different groups on the basis of fibrosis scores, TGF-β1, CTGF and α-SMA pulmonary content via Western blot and real-time quantitative fluorescence-PCR (RT-PCR. Blood levels of MMP-9 and TIMP-1 were determined by ELISA. Human lung fibroblasts WI-38 were divided into control group, PQ group, APN group, and APN receptor (AdipoR 1 small-interfering RNA (siRNA group. Fibroblasts were collected 24, 48, and 72 hours after PQ exposure for assay. Cell viability and apoptosis were determined via Kit-8 (CCK-8 and fluorescein Annexin V-FITC/PI double labeling. The protein and mRNA expression level of collagen type III, AdipoR1, and AdipoR2 were measured by Western blot and RT-PCR. APN treatment significantly decreased the lung fibrosis scores, protein and mRNA expression of pulmonary TGF-β1, CTGF and α-SMA content, and blood MMP-9 and TIMP-1 in a dose-dependent manner (p<0.05. Pretreatment with APN significantly attenuated the reduced cell viability and up-regulated collagen type III expression induced by PQ in lung fibroblasts, (p<0.05. APN pretreatment up-regulated AdipoR1, but not AdipoR2, expression in WI-38 fibroblasts. AdipoR1 siRNA abrogated APN-mediated protective effects in PQ-exposed fibroblasts. Taken together, our data suggests APN protects against PQ-induced pulmonary fibrosis in a

  2. Macrolide resistance of Staphylococcus aureus and Haemophilus species associated with long-term azithromycin use in cystic fibrosis

    NARCIS (Netherlands)

    S.J. Phaff (Sonja); H.A.W.M. Tiddens (Harm); H.A. Verbrugh (Henri); A. Ott (Alewijn)

    2006-01-01

    textabstractOBJECTIVES: Azithromycin is used to modulate exuberant inflammatory response in patients with cystic fibrosis (CF). The purpose of this study was to determine the association between long-term use of azithromycin in CF patients and change over time in macrolide susceptibility of

  3. Hepatic fibrosis: Concept to treatment.

    Science.gov (United States)

    Trautwein, Christian; Friedman, Scott L; Schuppan, Detlef; Pinzani, Massimo

    2015-04-01

    Understanding the molecular mechanisms underlying liver fibrogenesis is fundamentally relevant to developing new treatments that are independent of the underlying etiology. The increasing success of antiviral treatments in blocking or reversing the fibrogenic progression of chronic liver disease has unearthed vital information about the natural history of fibrosis regression, and has established important principles and targets for antifibrotic drugs. Although antifibrotic activity has been demonstrated for many compounds in vitro and in animal models, none has been thoroughly validated in the clinic or commercialized as a therapy for fibrosis. In addition, it is likely that combination therapies that affect two or more key pathogenic targets and/or pathways will be needed. To accelerate the preclinical development of these combination therapies, reliable single target validation is necessary, followed by the rational selection and systematic testing of combination approaches. Improved noninvasive tools for the assessment of fibrosis content, fibrogenesis and fibrolysis must accompany in vivo validation in experimental fibrosis models, and especially in clinical trials. The rapidly changing landscape of clinical trial design for liver disease is recognized by regulatory agencies in the United States (FDA) and Western Europe (EMA), who are working together with the broad range of stakeholders to standardize approaches to testing antifibrotic drugs in cohorts of patients with chronic liver diseases. Copyright © 2015. Published by Elsevier B.V.

  4. Interleukin-22 Inhibits Bleomycin-Induced Pulmonary Fibrosis

    Directory of Open Access Journals (Sweden)

    Minrui Liang

    2013-01-01

    Full Text Available Pulmonary fibrosis is a progressive and fatal fibrotic disease of the lungs with unclear etiology. Recent insight has suggested that early injury/inflammation of alveolar epithelial cells could lead to dysregulation of tissue repair driven by multiple cytokines. Although dysregulation of interleukin- (IL- 22 is involved in various pulmonary pathophysiological processes, the role of IL-22 in fibrotic lung diseases is still unclear and needs to be further addressed. Here we investigated the effect of IL-22 on alveolar epithelial cells in the bleomycin- (BLM- induced pulmonary fibrosis. BLM-treated mice showed significantly decreased level of IL-22 in the lung. IL-22 produced γδT cells were also decreased significantly both in the tissues of lungs and spleens. Administration of recombinant human IL-22 to alveolar epithelial cell line A549 cells ameliorated epithelial to mesenchymal transition (EMT and partially reversed the impaired cell viability induced by BLM. Furthermore, blockage of IL-22 deteriorated pulmonary fibrosis, with elevated EMT marker (α-smooth muscle actin (α-SMA and overactivated Smad2. Our results indicate that IL-22 may play a protective role in the development of BLM-induced pulmonary fibrosis and may suggest IL-22 as a novel immunotherapy tool in treating pulmonary fibrosis.

  5. [Endomyocardial fibrosis with massive calcification of the left ventricle].

    Science.gov (United States)

    Trigo, Joana; Camacho, Ana; Gago, Paula; Candeias, Rui; Santos, Walter; Marques, Nuno; Matos, Pedro; Brandão, Victor; Gomes, Veloso

    2010-03-01

    Endomyocardial fibrosis is a rare disease, endemic in tropical countries. It is characterized by fibrosis of the endocardium that can extend to myocardium. Important calcification of the endocardium is rare with only a few cases reported in the literature. We report a case of endomyocardial fibrosis in a european caucasian patient, associated with massive calcification of left ventricle.

  6. State of progress in treating cystic fibrosis respiratory disease

    Directory of Open Access Journals (Sweden)

    Flume Patrick A

    2012-08-01

    Full Text Available Abstract Since the discovery of the gene associated with cystic fibrosis (CF, there has been tremendous progress in the care of patients with this disease. New therapies have entered the market and are part of the standard treatment of patients with CF, and have been associated with marked improvement in survival. Now there are even more promising therapies directed at different components of the pathophysiology of this disease. In this review, our current knowledge of the pathophysiology of lung disease in patients with CF is described, along with the current treatment of CF lung disease, and the therapies in development that offer great promise to our patients.

  7. T2 relaxation time is related to liver fibrosis severity

    Science.gov (United States)

    Siqueira, Luiz; Uppal, Ritika; Alford, Jamu; Fuchs, Bryan C.; Yamada, Suguru; Tanabe, Kenneth; Chung, Raymond T.; Lauwers, Gregory; Chew, Michael L.; Boland, Giles W.; Sahani, Duhyant V.; Vangel, Mark; Hahn, Peter F.; Caravan, Peter

    2016-01-01

    Background The grading of liver fibrosis relies on liver biopsy. Imaging techniques, including elastography and relaxometric, techniques have had varying success in diagnosing moderate fibrosis. The goal of this study was to determine if there is a relationship between the T2-relaxation time of hepatic parenchyma and the histologic grade of liver fibrosis in patients with hepatitis C undergoing both routine, liver MRI and liver biopsy, and to validate our methodology with phantoms and in a rat model of liver fibrosis. Methods This study is composed of three parts: (I) 123 patients who underwent both routine, clinical liver MRI and biopsy within a 6-month period, between July 1999 and January 2010 were enrolled in a retrospective study. MR imaging was performed at 1.5 T using dual-echo turbo-spin echo equivalent pulse sequence. T2 relaxation time of liver parenchyma in patients was calculated by mono-exponential fit of a region of interest (ROI) within the right lobe correlating to histopathologic grading (Ishak 0–6) and routine serum liver inflammation [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)]. Statistical comparison was performed using ordinary logistic and ordinal logistic regression and ANOVA comparing T2 to Ishak fibrosis without and using AST and ALT as covariates; (II) a phantom was prepared using serial dilutions of dextran coated magnetic iron oxide nanoparticles. T2 weighed imaging was performed by comparing a dual echo fast spin echo sequence to a Carr-Purcell-Meigboom-Gill (CPMG) multi-echo sequence at 1.5 T. Statistical comparison was performed using a paired t-test; (III) male Wistar rats receiving weekly intraperitoneal injections of phosphate buffer solution (PBS) control (n=4 rats); diethylnitrosamine (DEN) for either 5 (n=5 rats) or 8 weeks (n=4 rats) were MR imaged on a Bruker Pharmascan 4.7 T magnet with a home-built bird-cage coil. T2 was quantified by using a mono-exponential fitting algorithm on multi-slice multi

  8. Archetypal analysis of diverse Pseudomonas aeruginosa transcriptomes reveals adaptation in cystic fibrosis airways

    Science.gov (United States)

    2013-01-01

    Background Analysis of global gene expression by DNA microarrays is widely used in experimental molecular biology. However, the complexity of such high-dimensional data sets makes it difficult to fully understand the underlying biological features present in the data. The aim of this study is to introduce a method for DNA microarray analysis that provides an intuitive interpretation of data through dimension reduction and pattern recognition. We present the first “Archetypal Analysis” of global gene expression. The analysis is based on microarray data from five integrated studies of Pseudomonas aeruginosa isolated from the airways of cystic fibrosis patients. Results Our analysis clustered samples into distinct groups with comprehensible characteristics since the archetypes representing the individual groups are closely related to samples present in the data set. Significant changes in gene expression between different groups identified adaptive changes of the bacteria residing in the cystic fibrosis lung. The analysis suggests a similar gene expression pattern between isolates with a high mutation rate (hypermutators) despite accumulation of different mutations for these isolates. This suggests positive selection in the cystic fibrosis lung environment, and changes in gene expression for these isolates are therefore most likely related to adaptation of the bacteria. Conclusions Archetypal analysis succeeded in identifying adaptive changes of P. aeruginosa. The combination of clustering and matrix factorization made it possible to reveal minor similarities among different groups of data, which other analytical methods failed to identify. We suggest that this analysis could be used to supplement current methods used to analyze DNA microarray data. PMID:24059747

  9. TRIF Differentially Regulates Hepatic Steatosis and Inflammation/Fibrosis in MiceSummary

    Directory of Open Access Journals (Sweden)

    Ling Yang

    2017-05-01

    Full Text Available Background & Aims: Toll-like receptor 4 (TLR4 signaling is activated through 2 adaptor proteins: MyD88 and TIR-domain containing adaptor-inducing interferon-β (TRIF. TLR4 and MyD88 are crucial in nonalcoholic steatohepatitis (NASH and fibrosis. However, the role of TRIF in TLR4-mediated NASH and fibrosis has been elusive. This study investigated the differential roles of TRIF in hepatic steatosis and inflammation/fibrosis. Methods: A choline-deficient amino acid defined (CDAA diet was used for the mouse NASH model. On this diet, the mice develop hepatic steatosis, inflammation, and fibrosis. TLR4 wild-type and TLR4-/- bone marrow chimeric mice and TRIF-/- mice were fed CDAA or a control diet for 22 weeks. Hepatic steatosis, inflammation, and fibrosis were examined. Results: In the CDAA diet–induced NASH, the mice with wild-type bone marrow had higher alanine aminotransferase and hepatic tumor necrosis factor levels than the mice with TLR4-/- bone marrow. The nonalcoholic fatty liver disease activity score showed that both wild-type and TLR4-/- bone marrow chimeras had reduced hepatic steatosis, and that both types of chimeras had similar levels of inflammation and hepatocyte ballooning to whole-body wild-type mice. Notably, wild-type recipients showed more liver fibrosis than TLR4-/- recipients. Although TRIF-/- mice showed reduced hepatic steatosis, these mice showed more liver injury, inflammation, and fibrosis than wild-type mice. TRIF-/- stellate cells and hepatocytes produced more C-X-C motif chemokine ligand 1 (CXCL1 and C-C motif chemokine ligand than wild-type cells in response to lipopolysaccharide. Consistently, TRIF-/- mice showed increased CXCL1 and CCL3 expression along with neutrophil and macrophage infiltration, which promotes liver inflammation and injury. Conclusions: In TLR4-mediated NASH, different liver cells have distinct roles in hepatic steatosis, inflammation, and fibrosis. TRIF promotes hepatic

  10. European Cystic Fibrosis Society Standards of Care

    DEFF Research Database (Denmark)

    Stern, Martin; Bertrand, Dominique Pougheon; Bignamini, Elisabetta

    2014-01-01

    Since the earliest days of cystic fibrosis (CF) treatment, patient data have been recorded and reviewed in order to identify the factors that lead to more favourable outcomes. Large data repositories, such as the US Cystic Fibrosis Registry, which was established in the 1960s, enabled successful ...... to indicators of health, the role of CF Centres, regional networks, national health policy, and international data registration and comparisons.......Since the earliest days of cystic fibrosis (CF) treatment, patient data have been recorded and reviewed in order to identify the factors that lead to more favourable outcomes. Large data repositories, such as the US Cystic Fibrosis Registry, which was established in the 1960s, enabled successful...... therapies, approaches to care and indeed data recording. The quality of care for individuals with CF has become a focus at several levels: patient, centre, regional, national and international. This paper reviews the quality management and improvement issues at each of these levels with particular reference...

  11. Molecular and cellular mechanisms of pulmonary fibrosis

    Science.gov (United States)

    2012-01-01

    Pulmonary fibrosis is a chronic lung disease characterized by excessive accumulation of extracellular matrix (ECM) and remodeling of the lung architecture. Idiopathic pulmonary fibrosis is considered the most common and severe form of the disease, with a median survival of approximately three years and no proven effective therapy. Despite the fact that effective treatments are absent and the precise mechanisms that drive fibrosis in most patients remain incompletely understood, an extensive body of scientific literature regarding pulmonary fibrosis has accumulated over the past 35 years. In this review, we discuss three broad areas which have been explored that may be responsible for the combination of altered lung fibroblasts, loss of alveolar epithelial cells, and excessive accumulation of ECM: inflammation and immune mechanisms, oxidative stress and oxidative signaling, and procoagulant mechanisms. We discuss each of these processes separately to facilitate clarity, but certainly significant interplay will occur amongst these pathways in patients with this disease. PMID:22824096

  12. Drug- and radiation-induced pulmonary fibrosis

    International Nuclear Information System (INIS)

    Uthgenannt, H.

    1976-01-01

    These two forms of pulmonary fibrosis which according to their type have nothing to do with one another, are presented as they are well suited to clarify the problems of the diagnosis of pulmonary fibrosis which is not a fixed concept for the pathologists. The frequent discrepancy found between the subjective clinical symptoms, clinical findings and X-ray and morphological pictures is indicated. (MG) [de

  13. Intestinal fibrosis is reduced by early elimination of inflammation in a mouse model of IBD: impact of a "Top-Down" approach to intestinal fibrosis in mice.

    Science.gov (United States)

    Johnson, Laura A; Luke, Amy; Sauder, Kay; Moons, David S; Horowitz, Jeffrey C; Higgins, Peter D R

    2012-03-01

    The natural history of Crohn's disease follows a path of progression from an inflammatory to a fibrostenosing disease, with most patients requiring surgical resection of fibrotic strictures. Potent antiinflammatory therapies reduce inflammation but do not appear to alter the natural history of intestinal fibrosis. The aim of this study was to determine the relationship between intestinal inflammation and fibrogenesis and the impact of a very early "top-down" interventional approach on fibrosis in vivo. In this study we removed the inflammatory stimulus from the Salmonella typhimurium mouse model of intestinal fibrosis by eradicating the S. typhimurium infection with levofloxacin at sequential timepoints during the infection. We evaluated the effect of this elimination of the inflammatory stimulus on the natural history of inflammation and fibrosis as determined by gross pathology, histopathology, mRNA expression, and protein expression. Fibrogenesis is preceded by inflammation. Delayed eradication of the inflammatory stimulus by antibiotic treatment represses inflammation without preventing fibrosis. Early intervention significantly ameliorates but does not completely prevent subsequent fibrosis. This study demonstrates that intestinal fibrosis develops despite removal of an inflammatory stimulus and elimination of inflammation. Early intervention ameliorates but does not abolish subsequent fibrosis, suggesting that fibrosis, once initiated, is self-propagating, suggesting that a very early top-down interventional approach may have the most impact on fibrostenosing disease. Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.

  14. Experimental induction of pulmonary fibrosis in horses with the gammaherpesvirus equine herpesvirus 5.

    Directory of Open Access Journals (Sweden)

    Kurt J Williams

    Full Text Available Gammaherpesviruses (γHV are implicated in the pathogenesis of pulmonary fibrosis in humans and murine models of lung fibrosis, however there is little direct experimental evidence that such viruses induce lung fibrosis in the natural host. The equine γHV EHV 5 is associated with equine multinodular pulmonary fibrosis (EMPF, a progressive fibrosing lung disease in its natural host, the horse. Experimental reproduction of EMPF has not been attempted to date. We hypothesized that inoculation of EHV 5 isolated from cases of EMPF into the lungs of clinically normal horses would induce lung fibrosis similar to EMPF. Neutralizing antibody titers were measured in the horses before and after inoculation with EHV 5. PCR and virus isolation was used to detect EHV 5 in antemortem blood and BAL samples, and in tissues collected postmortem. Nodular pulmonary fibrosis and induction of myofibroblasts occurred in EHV 5 inoculated horses. Mean lung collagen in EHV 5 inoculated horses (80 µg/mg was significantly increased compared to control horses (26 µg/mg (p < 0.5, as was interstitial collagen (32.6% ± 1.2% vs 23% ± 1.4% (mean ± SEM; p < 0.001. Virus was difficult to detect in infected horses throughout the experiment, although EHV 5 antigen was detected in the lung by immunohistochemistry. We conclude that the γHV EHV 5 can induce lung fibrosis in the horse, and hypothesize that induction of fibrosis occurs while the virus is latent within the lung. This is the first example of a γHV inducing lung fibrosis in the natural host.

  15. Experimental induction of pulmonary fibrosis in horses with the gammaherpesvirus equine herpesvirus 5.

    Science.gov (United States)

    Williams, Kurt J; Robinson, N Edward; Lim, Ailam; Brandenberger, Christina; Maes, Roger; Behan, Ashley; Bolin, Steven R

    2013-01-01

    Gammaherpesviruses (γHV) are implicated in the pathogenesis of pulmonary fibrosis in humans and murine models of lung fibrosis, however there is little direct experimental evidence that such viruses induce lung fibrosis in the natural host. The equine γHV EHV 5 is associated with equine multinodular pulmonary fibrosis (EMPF), a progressive fibrosing lung disease in its natural host, the horse. Experimental reproduction of EMPF has not been attempted to date. We hypothesized that inoculation of EHV 5 isolated from cases of EMPF into the lungs of clinically normal horses would induce lung fibrosis similar to EMPF. Neutralizing antibody titers were measured in the horses before and after inoculation with EHV 5. PCR and virus isolation was used to detect EHV 5 in antemortem blood and BAL samples, and in tissues collected postmortem. Nodular pulmonary fibrosis and induction of myofibroblasts occurred in EHV 5 inoculated horses. Mean lung collagen in EHV 5 inoculated horses (80 µg/mg) was significantly increased compared to control horses (26 µg/mg) (p < 0.5), as was interstitial collagen (32.6% ± 1.2% vs 23% ± 1.4%) (mean ± SEM; p < 0.001). Virus was difficult to detect in infected horses throughout the experiment, although EHV 5 antigen was detected in the lung by immunohistochemistry. We conclude that the γHV EHV 5 can induce lung fibrosis in the horse, and hypothesize that induction of fibrosis occurs while the virus is latent within the lung. This is the first example of a γHV inducing lung fibrosis in the natural host.

  16. Shear wave elastography results correlate with liver fibrosis histology and liver function reserve.

    Science.gov (United States)

    Feng, Yan-Hong; Hu, Xiang-Dong; Zhai, Lin; Liu, Ji-Bin; Qiu, Lan-Yan; Zu, Yuan; Liang, Si; Gui, Yu; Qian, Lin-Xue

    2016-05-07

    To evaluate the correlation of shear wave elastography (SWE) results with liver fibrosis histology and quantitative function reserve. Weekly subcutaneous injection of 60% carbon tetrachloride (1.5 mL/kg) was given to 12 canines for 24 wk to induce experimental liver fibrosis, with olive oil given to 2 control canines. At 24 wk, liver condition was evaluated using clinical biochemistry assays, SWE imaging, lidocaine metabolite monoethylglycine-xylidide (MEGX) test, and histologic fibrosis grading. Clinical biochemistry assays were performed at the institutional central laboratory for routine liver function evaluation. Liver stiffness was measured in triplicate from three different intercostal spaces and expressed as mean liver stiffness modulus (LSM). Plasma concentrations of lidocaine and its metabolite MEGX were determined using high-performance liquid chromatography repeated in duplicate. Liver biopsy samples were fixed in 10% formaldehyde, and liver fibrosis was graded using the modified histological activity index Knodell score (F0-F4). Correlations among histologic grading, LSM, and MEGX measures were analyzed with the Pearson linear correlation coefficient. At 24 wk liver fibrosis histologic grading was as follows: F0, n = 2 (control); F1, n = 0; F2, n = 3; F3, n = 7; and F4, n = 2. SWE LSM was positively correlated with histologic grading (r = 0.835, P function reserve in experimental severe fibrosis and cirrhosis.

  17. Chronic hepatitis C and fibrosis: evidences for possible estrogen benefits

    Directory of Open Access Journals (Sweden)

    Liana Codes

    Full Text Available The main injury caused by hepatitis C virus is the hepatic fibrosis, as a result of a chronic inflammatory process in the liver characterized by the deposit of components from the extracellular matrix. The fibrosis development leads to the modification of the hepatic architecture, of the hepatocellular function and to irregularities in the microcirculation. The tissue remodeling process observed in fibrosis has stellate cells, located at the space of Disse, as main acting agents. These cells, in response to a harmful stimulus, undergo phenotypic changes from non-proliferating cells to proliferating cells that express a- smooth-muscle actin (a-SMA, a process called as transdifferentiation. There are evidences that the oxidative stress is involved in the chronic liver disease and serves as bond between the injury and the hepatic fibrosis. A number of studies suggest that the estrogen, at physiological levels, presents an antifibrogenic action probably through an antioxidant effect, decreasing the levels of lipid peroxidation products in the liver and blood, thus inhibiting the myofibroblastic transformation of stellate cells and contributing for gender-associated differences in relation to the fibrosis development. The aim of this paper was to describe data from literature concerning the interaction between chronic hepatitis C and estrogens, pregnancy, use of oral contraceptives, menopause and hormone reposition therapy.

  18. Asthma and cystic fibrosis: a tangled web.

    Science.gov (United States)

    Kent, Brian D; Lane, Stephen J; van Beek, Edwin J; Dodd, Jonathan D; Costello, Richard W; Tiddens, Harm A W M

    2014-03-01

    Successfully diagnosing concomitant asthma in people with cystic fibrosis (CF) is a challenging proposition, and the utility of conventional diagnostic criteria of asthma in CF populations remains uncertain. Nonetheless, the accurate identification of individuals with CF and asthma allows appropriate tailoring of therapy, and should reduce the unnecessary use of asthma medication in broader CF cohorts. In this review, we discuss the diagnostic challenge posed by asthma in CF, both in terms of clinical evaluation, and of interpretation of pulmonary function testing and non-invasive markers of airway inflammation. We also examine how the role of cross-sectional thoracic imaging in CF and asthma can assist in the diagnosis of asthma in these patients. Finally, we critically appraise the evidence base behind the use of asthma medications in CF populations, with a particular focus on the use of inhaled corticosteroids and bronchodilators. As shall be discussed, the gaps in the current literature make further high-quality research in this field imperative. © 2014 Wiley Periodicals, Inc.

  19. Hepatosplenic volumetric assessment at MDCT for staging liver fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Pickhardt, Perry J.; Malecki, Kyle; Hunt, Oliver F.; Beaumont, Claire; Kloke, John; Ziemlewicz, Timothy J.; Lubner, Meghan G. [University of Wisconsin School of Medicine and Public Health, Department of Radiology, Madison, WI (United States)

    2017-07-15

    To investigate hepatosplenic volumetry at MDCT for non-invasive prediction of hepatic fibrosis. Hepatosplenic volume analysis in 624 patients (mean age, 48.8 years; 311 M/313 F) at MDCT was performed using dedicated software and compared against pathological fibrosis stage (F0 = 374; F1 = 48; F2 = 40; F3 = 65; F4 = 97). The liver segmental volume ratio (LSVR) was defined by Couinaud segments I-III over segments IV-VIII. All pre-cirrhotic fibrosis stages (METAVIR F1-F3) were based on liver biopsy within 1 year of MDCT. LSVR and total splenic volumes increased with stage of fibrosis, with mean(±SD) values of: F0: 0.26 ± 0.06 and 215.1 ± 88.5 mm{sup 3}; F1: 0.25 ± 0.08 and 294.8 ± 153.4 mm{sup 3}; F2: 0.331 ± 0.12 and 291.6 ± 197.1 mm{sup 3}; F3: 0.39 ± 0.15 and 509.6 ± 402.6 mm{sup 3}; F4: 0.56 ± 0.30 and 790.7 ± 450.3 mm{sup 3}, respectively. Total hepatic volumes showed poor discrimination (F0: 1674 ± 320 mm{sup 3}; F4: 1631 ± 691 mm{sup 3}). For discriminating advanced fibrosis (≥F3), the ROC AUC values for LSVR, total liver volume, splenic volume and LSVR/spleen combined were 0.863, 0.506, 0.890 and 0.947, respectively. Relative changes in segmental liver volumes and total splenic volume allow for non-invasive staging of hepatic fibrosis, whereas total liver volume is a poor predictor. Unlike liver biopsy or elastography, these CT volumetric biomarkers can be obtained retrospectively on routine scans obtained for other indications. (orig.)

  20. Imaging pulmonary fibrosis; Imagerie des fibroses pulmonaires

    Energy Technology Data Exchange (ETDEWEB)

    Brauner, M.W.; Rety, F.; Naccache, J.M.; Girard, F.; Valeyre, D.F. [Hopital Avicenne, 93 - Bobigny (France). Service de radiologie et de pneumologie

    2001-02-01

    Localized fibrosis of the lung is usually scar tissue while diffuse pulmonary fibrosis is more often a sign of active disease. Chronic infiltrative lung disease may be classified into four categories: idiopathic pneumonitis, collagen diseases, granulomatosis (sarcoidosis), and caused by known diseases (pneumoconiosis, hypersensitivity pneumonitis, drug-induced lung disease, radiation). (authors)

  1. Effect of Green Tea Extract Encapsulated Into Chitosan Nanoparticles on Hepatic Fibrosis Collagen Fibers Assessed by Atomic Force Microscopy in Rat Hepatic Fibrosis Model.

    Science.gov (United States)

    Safer, Abdel-Majeed A; Hanafy, Nomany A; Bharali, Dhruba J; Cui, Huadong; Mousa, Shaker A

    2015-09-01

    The present study examined the effect of Green Tea Extract (GTE) encapsulated into Chitosan Nanoparticles (CS-NPs) on hepatic fibrosis in rat model as determined by atomic force microscopy (AFM). The bioactive compounds in GTE encapsulated into CS-NPs were determined using LC-MS/MS method. Additionally, the uptake of GTE-CS NPs in HepG2 cells showed enhanced uptake. In experimental fibrosis model, AFM was used as a high resolution microscopic tool to investigate collagen fibers as an indicator of hepatic fibrosis induced by treatment with CCl4. Paraffin sections of fibrotic liver tissues caused by CC4 treatment of rats and the effect of GTE-CS NPs treatment with or without CCl4 on hepatic fibrosis were examined. Liver tissues from the different groups of animals were de-waxed and processed as for normal H/E staining and Masson's trichrome staining to locate the proper area of ECM collagen in the CCl4 group versus collagen in liver tissues treated with the GTE-CS NPs with or without CCl4. Selected areas of paraffin sections were trimmed off and fixed flat on top of mica and inserted in the AFM stage. H/E staining, Masson's trichrome stained slides, and AFM images revealed that collagen fibers of 250 to 300 nm widths were abundant in the fibrotic liver samples while those of GTE-CS NPs were clear as in the control group. Data confirmed the hypothesis that GTE-CS NPs are effective in removing all the extracellular collagen caused by CCl4 in the hepatic fibrosis rat liver.

  2. Radiation Fibrosis of the Vocal Fold: From Man to Mouse

    Science.gov (United States)

    Johns, Michael M.; Kolachala, Vasantha; Berg, Eric; Muller, Susan; Creighton, Frances X.; Branski, Ryan C.

    2013-01-01

    Objectives To characterize fundamental late tissue effects in the human vocal fold following radiation therapy. To develop a murine model of radiation fibrosis to ultimately develop both treatment and prevention paradigms. Design Translational study using archived human and fresh murine irradiated vocal fold tissue. Methods 1) Irradiated vocal fold tissue from patients undergoing laryngectomy for loss of function from radiation fibrosis were identified from pathology archives. Histomorphometry, immunohistochemistry, and whole-genome microarray as well as real-time transcriptional analyses was performed. 2) Focused radiation to the head and neck was delivered to mice in a survival fashion. One month following radiation, vocal fold tissue was analyzed with histomorphometry, immunohistochemistry, and real-time PCR transcriptional analysis for selected markers of fibrosis. Results Human irradiated vocal folds demonstrated increased collagen transcription with increased deposition and disorganization of collagen in both the thyroarytenoid muscle and the superficial lamina propria. Fibronectin were increased in the superficial lamina propria. Laminin decreased in the thyroarytenoid muscle. Whole genome microarray analysis demonstrated increased transcription of markers for fibrosis, oxidative stress, inflammation, glycosaminoglycan production and apoptosis. Irradiated murine vocal folds demonstrated increases in collagen and fibronectin transcription and deposition in the lamina propria. Transforming growth factor (TGF)-β increased in the lamina propria. Conclusion Human irradiated vocal folds demonstrate molecular changes leading to fibrosis that underlie loss of vocal fold pliability that occurs in patients following laryngeal irradiation. Irradiated murine tissue demonstrates similar findings, and this mouse model may have utility in creating prevention and treatment strategies for vocal fold radiation fibrosis. PMID:23242839

  3. Diagnostic value of fibronectin discriminant score for predicting liver fibrosis stages in chronic hepatitis C virus patients.

    Science.gov (United States)

    Attallah, Abdelfattah M; Abdallah, Sanaa O; Attallah, Ahmed A; Omran, Mohamed M; Farid, Khaled; Nasif, Wesam A; Shiha, Gamal E; Abdel-Aziz, Abdel-Aziz F; Rasafy, Nancy; Shaker, Yehia M

    2013-01-01

    Several noninvasive predictive models were developed to substitute liver biopsy for fibrosis assessment. To evaluate the diagnostic value of fibronectin which reflect extracellular matrix metabolism and standard liver functions tests which reflect alterations in hepatic functions. Chronic hepatitis C (CHC) patients (n = 145) were evaluated using ROC curves and stepwise multivariate discriminant analysis (MDA) and was validated in 180 additional patients. Liver biochemical profile including transaminases, bilirubin, alkaline phosphatase, albumin, complete blood count were estimated. Fibronectin concentration was determined using monoclonal antibody and ELISA. A novel index named fibronectin discriminant score (FDS) based on fibronectin, APRI and albumin was developed. FDS produced areas under ROC curves (AUC) of 0.91 for significant fibrosis and 0.81 for advanced fibrosis. The FDS correctly classified 79% of the significant liver fibrosis patients (F2-F4) with 87% sensitivity and 75% specificity. The relative risk [odds ratio (OR)] of having significant liver fibrosis using the cut-off values determined by ROC curve analyses were 6.1 for fibronectin, 4.9 for APRI, and 4.2 for albumin. FDS predicted liver fibrosis with an OR of 16.8 for significant fibrosis and 8.6 for advanced fibrosis. The FDS had similar AUC and OR in the validation group to the estimation group without statistically significant difference. FDS predicted liver fibrosis with high degree of accuracy, potentially decreasing the number of liver biopsy required.

  4. Intrinsic pro-angiogenic status of cystic fibrosis airway epithelial cells

    International Nuclear Information System (INIS)

    Verhaeghe, Catherine; Tabruyn, Sebastien P.; Oury, Cecile; Bours, Vincent; Griffioen, Arjan W.

    2007-01-01

    Cystic fibrosis is a common genetic disorder characterized by a severe lung inflammation and fibrosis leading to the patient's death. Enhanced angiogenesis in cystic fibrosis (CF) tissue has been suggested, probably caused by the process of inflammation, as similarly described in asthma and chronic bronchitis. The present study demonstrates an intrinsic pro-angiogenic status of cystic fibrosis airway epithelial cells. Microarray experiments showed that CF airway epithelial cells expressed several angiogenic factors such as VEGF-A, VEGF-C, bFGF, and PLGF at higher levels than control cells. These data were confirmed by real-time quantitative PCR and, at the protein level, by ELISA. Conditioned media of these cystic fibrosis cells were able to induce proliferation, migration and sprouting of cultured primary endothelial cells. This report describes for the first time that cystic fibrosis epithelial cells have an intrinsic angiogenic activity. Since excess of angiogenesis is correlated with more severe pulmonary disease, our results could lead to the development of new therapeutic applications

  5. Variation in Cilia Protein Genes and Progression of Lung Disease in Cystic Fibrosis.

    Science.gov (United States)

    Blue, Elizabeth; Louie, Tin L; Chong, Jessica X; Hebbring, Scott J; Barnes, Kathleen C; Rafaels, Nicholas M; Knowles, Michael R; Gibson, Ronald L; Bamshad, Michael J; Emond, Mary J

    2018-04-01

    Cystic fibrosis, like primary ciliary dyskinesia, is an autosomal recessive disorder characterized by abnormal mucociliary clearance and obstructive lung disease. We hypothesized that genes underlying the development or function of cilia may modify lung disease severity in persons with cystic fibrosis. To test this hypothesis, we compared variants in 93 candidate genes in both upper and lower tertiles of lung function in a large cohort of children and adults with cystic fibrosis with those of a population control dataset. Variants within candidate genes were tested for association using the SKAT-O test, comparing cystic fibrosis cases defined by poor (n = 127) or preserved (n = 127) lung function with population controls (n = 3,269 or 3,148, respectively). Associated variants were then tested for association with related phenotypes in independent datasets. Variants in DNAH14 and DNAAF3 were associated with poor lung function in cystic fibrosis, whereas variants in DNAH14 and DNAH6 were associated with preserved lung function in cystic fibrosis. Associations between DNAH14 and lung function were replicated in disease-related phenotypes characterized by obstructive lung disease in adults. Genetic variants within DNAH6, DNAH14, and DNAAF3 are associated with variation in lung function among persons with cystic fibrosis.

  6. Ciprofloxacin-loaded PLGA nanoparticles against Cystic Fibrosis P. aeruginosa Lung Infections.

    OpenAIRE

    Günday Türeli, Nazende; Torge, Afra; Juntke, Jenny; Schwarz, Bianca C; Schneider-Daum, Nicole; Türeli, Akif Emre; Lehr, Claus-Michael; Schneider, Marc

    2017-01-01

    Current pulmonary treatments against Pseudomonasaeruginosa infections in cystic fibrosis (CF) lung suffer from deactivation of the drug and immobilization in thick and viscous biofilm/mucus blend, along with the general antibiotic resistance. Administration of nanoparticles (NPs) with high antibiotic load capable of penetrating the tight mesh of biofilm/mucus can be an advent to overcome the treatment bottlenecks. Biodegradable and biocompatible polymer nanoparticles efficiently loaded with c...

  7. Fibrosis quística que simula un síndrome de Bartter Cystic fibrosis mimicking Bartter syndrome

    Directory of Open Access Journals (Sweden)

    Neri G Campañá Cobas

    2008-12-01

    Full Text Available La fibrosis quística es una enfermedad que se hereda como trastorno autosómico recesivo. La presentación clásica está caracterizada por enfermedad pulmonar crónica, deficiencia pancreática y concentraciones altas de electrolitos en sudor. En algunos pacientes la presentación puede ser monosíntomatica, por ejemplo, la depleción de electrolitos en sangre. El propósito de este informe es comunicar el caso de una lactante de 2 meses de edad diagnosticada de fibrosis quística, que inicialmente pareció ser un síndrome de Bartter. El motivo de ingreso fue un vómito, decaimiento y signos de deshidratación. Se realizó gasometría, estudio de electrolitos en sangre, determinación de concentración de electrolitos en la orina, prueba de electrolitos en sudor y estudio genético para fibrosis quística. La concentración de potasio (28 mEeq/L hizo pensar en un síndrome de Bartter y se comenzó tratamiento con indometacina y cloruro de potasio; se normalizaron todos los parámetros. Dos meses después reingresó con deshidratación ligera por un vómito, trastornos mixtos del equilibrio ácido-base, hiponatremia, hipocloremia y ligera hiperpotasemia. Se realizaron electrolitos en sudor en 3 ocasiones y fueron positivos, y el estudio genético para fibrosis quística demostró una mutación delta F508.Cystic fibrosis is a disease that is inherited as a recessive autosomal disorder. The classical presentation is characterized by chronic lung disease, pancreatic deficiency and high concentrations of electrolytes in sweat. In some patients, the presentation may be monosymptomatic as, for example, the depletion of electrolytes in blood. The objective of this paper is to report the case of a 2-months-old female infant with diagnosis of cystic fibrosis that initially seemed to be a Bartter syndrome. The reason to be admitted was vomit, dwindles and dehydration signs. Gasometry, study of electrolytes in blood, determination of concentration of

  8. Therapy of experimental NASH and fibrosis with galectin inhibitors.

    Directory of Open Access Journals (Sweden)

    Peter G Traber

    Full Text Available Non-alcoholic steatohepatitis (NASH and resultant liver fibrosis is a major health problem without effective therapy. Some data suggest that galectin-3 null mice are resistant to the development of NASH with fibrosis. We examined the ability of two complex carbohydrate drugs that bind galectin-3, GM-CT-01 and GR-MD-02, to treat NASH with fibrosis in a murine model. GR-MD-02 treatment resulted in marked improvement in liver histology with significant reduction in NASH activity and collagen deposition. Treatments seemed also to improve both glomerulopathy and interstitial fibrosis observed in kidneys. The improvement in liver histology was evident when animals were treated early in disease or after establishment of liver fibrosis. In all measures, GM-CT-01 had an intermediate effect between vehicle and GR-MD-02. Galectin-3 protein expression was increased in NASH with highest expression in macrophages surrounding lipid laden hepatocytes, and reduced following treatment with GR-MD-02, while the number of macrophages was unchanged. Treatment with GR-MD-02 also reduced the expression of pathological indicators including iNOS, an important TH1 inflammatory mediator, CD36, a scavenger receptor for lipoproteins on macrophages, and α-smooth muscle actin, a marker for activated stellate cells which are the primary collagen producing cells in liver fibrosis. We conclude that treatment with these galectin-3 targeting drugs improved histopathological findings of NASH and markedly reduced fibrosis in a murine model of NASH. While the mechanisms require further investigation, the treatment effect is associated with a reduction of galectin-3 expressed by activated macrophages which was associated with regression of NASH, including hepatocellular fat accumulation, hepatocyte ballooning, intra-portal and intra-lobular inflammatory infiltrate, and deposition of collagen. Similar effects were found with GM-CT-01, but with approximately four-fold lower potency than

  9. Living with Cystic Fibrosis: A Guide for the Young Adult.

    Science.gov (United States)

    Cystic Fibrosis Foundation, Atlanta, GA.

    Intended for the young adult with cystic fibrosis, the booklet provides information on dealing with problems and on advances in treatment and detection related to the disease. Addressed are the following topics: description of cystic fibrosis; inheritance of cystic fibrosis; early diagnosis; friends, careers, and other matters; treatment;…

  10. Unusual Presentation Of Idiopathic Retroperitoneal Fibrosis: Case ...

    African Journals Online (AJOL)

    Idiopathic retroperitoneal fibrosis (IRF) is an uncommon entity described as progressive proliferation of connective tissues leading to a fibrous plaque-like lesions that encases the aorta and inferior vena cava inferior to the level of the renal arteries. Mass forming retroperitoneal fibrosis is rare. We present a rare case of a ...

  11. INHALATION ANTIBIOTICS ARE ESSENTIAL FOR THE CONTROL OF INFECTION IN CHILDREN WITH CYSTIC FIBROSIS

    Directory of Open Access Journals (Sweden)

    O.I. Simonova

    2011-01-01

    Full Text Available The article discusses the problem of basis therapy in patients with chronic Pseudomonas aeruginosa infection and cystic fibrosis. Authors showed the safety, good tolerance and high efficacy of constant treatment with special tobramycin solution delivered by nebulizer (Tobi in children including ones under 6 years old. Even first inhalations of tobramycin result in decrease of Pseudomonas aeruginosa rate in bacterial inoculation or to it complete removal. The drug helps stabilization of clinical and functional state of patients, improvement of airflow and common state, and to clinical remission.Key words: children, cystic fibrosis, chronic Pseudomonas aeruginosa infection, tobramycin, nebulizer therapy.(Voprosy sovremennoi pediatrii — Current Pediatrics. 2011; 10 (3: 119–123

  12. Insulin-like growth factors and leucine kinetics during exercise training in children with cystic fibrosis

    NARCIS (Netherlands)

    Gulmans, [No Value; van der Laag, J; Wattimena, D; van Doorn, J; Oostveen, D; Berger, R; van de Meer, K

    Background: Little is known about the metabolic effects of exercise training in children with cystic fibrosis. The hypothesis for the current study was that in patients with declining clinical status, exercise increases circulating insulin-like growth factors (IGFs) and improves protein kinetics.

  13. Inhalation of antibiotics in cystic fibrosis

    NARCIS (Netherlands)

    Touw, D J; Brimicombe, R W; Hodson, M E; Heijerman, H G; Bakker, W

    Aerosol administration of antipseudomonal antibiotics is commonly used in cystic fibrosis. However, its contribution to the improvement of lung function, infection and quality of life is not well-established. All articles published from 1965 until the present time concerning the inhalation of

  14. Pulmonary tuberculosis in patients with idiopathic pulmonary fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Chung, Myung Jin; Goo, Jin Mo E-mail: jmgoo@plaza.snu.ac.kr; Im, Jung-Gi

    2004-11-01

    Objectives: Patients with idiopathic pulmonary fibrosis (IPF) have an increased risk of pulmonary tuberculosis. However, detecting pulmonary tuberculosis may be difficult due to the underlying fibrosis. The aim of this report is to describe the radiological and clinical findings of pulmonary tuberculosis in patients with idiopathic pulmonary fibrosis. Materials and methods: We reviewed 143 consecutive patients in whom IPF was diagnosed by either the histological or radio-clinical criteria. Among them, nine patients were histologically (n=2) or bacteriologically (n=7) confirmed to have active pulmonary tuberculosis. The location and patterns of pulmonary tuberculosis were examined on a thin section CT scan. Results: The most common thin section CT findings were subpleural nodules (n=6; mean diameter, 3.2 cm) and a lobar or segmental consolidation (n=3). The lesions were located most commonly in the right lower lobe (n=4). The incidence of tuberculosis in patients with idiopathic pulmonary fibrosis was more than five times higher than that of the general population. Conclusion: The atypical manifestation of pulmonary tuberculosis is common in patients with idiopathic pulmonary fibrosis, which may mimic lung cancer or bacterial pneumonia.

  15. Pulmonary tuberculosis in patients with idiopathic pulmonary fibrosis

    International Nuclear Information System (INIS)

    Chung, Myung Jin; Goo, Jin Mo; Im, Jung-Gi

    2004-01-01

    Objectives: Patients with idiopathic pulmonary fibrosis (IPF) have an increased risk of pulmonary tuberculosis. However, detecting pulmonary tuberculosis may be difficult due to the underlying fibrosis. The aim of this report is to describe the radiological and clinical findings of pulmonary tuberculosis in patients with idiopathic pulmonary fibrosis. Materials and methods: We reviewed 143 consecutive patients in whom IPF was diagnosed by either the histological or radio-clinical criteria. Among them, nine patients were histologically (n=2) or bacteriologically (n=7) confirmed to have active pulmonary tuberculosis. The location and patterns of pulmonary tuberculosis were examined on a thin section CT scan. Results: The most common thin section CT findings were subpleural nodules (n=6; mean diameter, 3.2 cm) and a lobar or segmental consolidation (n=3). The lesions were located most commonly in the right lower lobe (n=4). The incidence of tuberculosis in patients with idiopathic pulmonary fibrosis was more than five times higher than that of the general population. Conclusion: The atypical manifestation of pulmonary tuberculosis is common in patients with idiopathic pulmonary fibrosis, which may mimic lung cancer or bacterial pneumonia

  16. US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis.

    Science.gov (United States)

    Floto, R Andres; Olivier, Kenneth N; Saiman, Lisa; Daley, Charles L; Herrmann, Jean-Louis; Nick, Jerry A; Noone, Peadar G; Bilton, Diana; Corris, Paul; Gibson, Ronald L; Hempstead, Sarah E; Koetz, Karsten; Sabadosa, Kathryn A; Sermet-Gaudelus, Isabelle; Smyth, Alan R; van Ingen, Jakko; Wallace, Richard J; Winthrop, Kevin L; Marshall, Bruce C; Haworth, Charles S

    2016-01-01

    Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms that can cause chronic pulmonary infection, particularly in individuals with pre-existing inflammatory lung disease such as cystic fibrosis (CF). Pulmonary disease caused by NTM has emerged as a major threat to the health of individuals with CF but remains difficult to diagnose and problematic to treat. In response to this challenge, the US Cystic Fibrosis Foundation (CFF) and the European Cystic Fibrosis Society (ECFS) convened an expert panel of specialists to develop consensus recommendations for the screening, investigation, diagnosis and management of NTM pulmonary disease in individuals with CF. Nineteen experts were invited to participate in the recommendation development process. Population, Intervention, Comparison, Outcome (PICO) methodology and systematic literature reviews were employed to inform draft recommendations. An anonymous voting process was used by the committee to reach consensus. All committee members were asked to rate each statement on a scale of: 0, completely disagree, to 9, completely agree; with 80% or more of scores between 7 and 9 being considered 'good' agreement. Additionally, the committee solicited feedback from the CF communities in the USA and Europe and considered the feedback in the development of the final recommendation statements. Three rounds of voting were conducted to achieve 80% consensus for each recommendation statement. Through this process, we have generated a series of pragmatic, evidence-based recommendations for the screening, investigation, diagnosis and treatment of NTM infection in individuals with CF as an initial step in optimising management for this challenging condition. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  17. Gastroenterological endpoints in drug trials for cystic fibrosis

    NARCIS (Netherlands)

    Bodewes, Frank A. J. A.; Verkade, Henkjan J.; Wilschanski, Micheal

    2016-01-01

    The phenotype of cystic fibrosis includes a wide variety of clinical and biochemical gastrointestinal presentations. These gastrointestinal characteristics of the disease have come under renewed interest as potential outcome measures and clinical endpoints for therapeutic trials in cystic fibrosis.

  18. Pulmonary CCR2+CD4+ T cells are immune regulatory and attenuate lung fibrosis development.

    Science.gov (United States)

    Milger, Katrin; Yu, Yingyan; Brudy, Eva; Irmler, Martin; Skapenko, Alla; Mayinger, Michael; Lehmann, Mareike; Beckers, Johannes; Reichenberger, Frank; Behr, Jürgen; Eickelberg, Oliver; Königshoff, Melanie; Krauss-Etschmann, Susanne

    2017-11-01

    Animal models have suggested that CCR2-dependent signalling contributes to the pathogenesis of pulmonary fibrosis, but global blockade of CCL2 failed to improve the clinical course of patients with lung fibrosis. However, as levels of CCR2 + CD4 + T cells in paediatric lung fibrosis had previously been found to be increased, correlating with clinical symptoms, we hypothesised that distinct CCR2 + cell populations might either increase or decrease disease pathogenesis depending on their subtype. To investigate the role of CCR2 + CD4 + T cells in experimental lung fibrosis and in patients with idiopathic pulmonary fibrosis and other fibrosis. Pulmonary CCR2 + CD4 + T cells were analysed using flow cytometry and mRNA profiling, followed by in silico pathway analysis, in vitro assays and adoptive transfer experiments. Frequencies of CCR2 + CD4 + T cells were increased in experimental fibrosis-specifically the CD62L - CD44 + effector memory T cell phenotype, displaying a distinct chemokine receptor profile. mRNA profiling of isolated CCR2 + CD4 + T cells from fibrotic lungs suggested immune regulatory functions, a finding that was confirmed in vitro using suppressor assays. Importantly, adoptive transfer of CCR2 + CD4 + T cells attenuated fibrosis development. The results were partly corroborated in patients with lung fibrosis, by showing higher percentages of Foxp3 + CD25 + cells within bronchoalveolar lavage fluid CCR2 + CD4 + T cells as compared with CCR2 - CD4 + T cells. Pulmonary CCR2 + CD4 + T cells are immunosuppressive, and could attenuate lung inflammation and fibrosis. Therapeutic strategies completely abrogating CCR2-dependent signalling will therefore also eliminate cell populations with protective roles in fibrotic lung disease. This emphasises the need for a detailed understanding of the functions of immune cell subsets in fibrotic lung disease. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights

  19. Production site of radiation-induced pulmonary fibrosis

    International Nuclear Information System (INIS)

    Song Liangwen; Cui Xuemei; Gao Yabing; Yang Ruibiao; Xia Guowei; Wang Dewen

    1997-01-01

    Production site development and alterations of early pulmonary fibrosis were studied. Single irradiation was made at right thorax of rats with 0, 15 and 30 Gy of γ-irradiation, respectively. The rats were divided into three groups which were sacrificed 1, 3, 5 months post irradiation. Hydroxyproline in lungs was measured by biochemical method. Pulmonary type I and III collagens were measured by polarization method. Distribution of angiotensin II (A II) in pulmonary tissues was displayed by immunohistochemical method. Extent of pulmonary fibrosis relatively increased with irradiation dose and time elapse after irradiation. Ratio of type I to type III collagens increased with increasing fibrosis. Proliferating collagen fibers mainly came from fibroblasts of pulmonary bronchial and arterial adventitia, and extended into pulmonary parenchyma. Meanwhile, type I collagen substituted for type III collagen in interstitium of pulmonary alveoli. A II was positive for fibroblasts and macrophages in pulmonary interstitium. Irradiation can stimulate fibroblasts in interstitium proliferation, and type I collagen substitutes for type III collagen. Expression and synthesis of A II in interstitium may promote the course of pulmonary fibrosis

  20. DeltaF508 heterozygosity in cystic fibrosis and susceptibility to asthma

    DEFF Research Database (Denmark)

    Dahl, Morten; Tybjaerg-Hansen, A; Lange, P

    1998-01-01

    Cystic fibrosis is a recessive disorder mainly characterised by lung disease. We tested the hypothesis that individuals heterozygous for the common cystic fibrosis deltaF508 mutation are at risk of obstructive pulmonary disease.......Cystic fibrosis is a recessive disorder mainly characterised by lung disease. We tested the hypothesis that individuals heterozygous for the common cystic fibrosis deltaF508 mutation are at risk of obstructive pulmonary disease....

  1. Matrix Remodeling in Pulmonary Fibrosis and Emphysema

    Science.gov (United States)

    O’Reilly, Philip; Antony, Veena B.; Gaggar, Amit

    2016-01-01

    Pulmonary fibrosis and emphysema are chronic lung diseases characterized by a progressive decline in lung function, resulting in significant morbidity and mortality. A hallmark of these diseases is recurrent or persistent alveolar epithelial injury, typically caused by common environmental exposures such as cigarette smoke. We propose that critical determinants of the outcome of the injury-repair processes that result in fibrosis versus emphysema are mesenchymal cell fate and associated extracellular matrix dynamics. In this review, we explore the concept that regulation of mesenchymal cells under the influence of soluble factors, in particular transforming growth factor-β1, and the extracellular matrix determine the divergent tissue remodeling responses seen in pulmonary fibrosis and emphysema. PMID:26741177

  2. Intestinal permeability to [51Cr]EDTA in children with cystic fibrosis

    International Nuclear Information System (INIS)

    Leclercq-Foucart, J.; Forget, P.; Sodoyez-Goffaux, F.; Zappitelli, A.

    1986-01-01

    Intestinal permeability was investigated in 14 children with cystic fibrosis making use of [ 51 Cr]EDTA as probe molecule. Ten normal young adults and 11 children served as controls. After oral administration of [ 51 Cr]EDTA, 24 h urine was collected. Urinary radioactivity was calculated and results expressed as percentage of oral dose excreted in 24 h urine. Mean and SEM were as follows: 2.51 +/- 0.21, 2.35 +/- 0.24, and 13.19 +/- 1.72 for control children, normal adults, and cystic fibrosis patients, respectively. The permeability differences between cystic fibrosis patients and either control children or control adults are significant (p less than 0.001)

  3. Pathogenic mechanism in lung fibrosis

    International Nuclear Information System (INIS)

    Witschi, H.; Haschek, W.M.; Meyer, K.R.; Ullrich, R.L.; Dalbey, W.E.

    1979-01-01

    The purpose of the study was to examine whether an interaction between two agents causing alveolar epithelial damage would produce lung fibrosis. In mouse lung, intraperitoneal injection of the antioxidant butylated hydroxytoluene causes diffuse alveolar type I cell necrosis, followed by proliferation of type II alveolar cells. In animals exposed to 70% O 2 or 100-200 rad x rays during the phase of type II cell proliferation following BHT, diffuse interstitial lung fibrosis developed within 2 weeks. Quantitative analysis of the lungs for hydroxyproline showed that the interaction between BHT and O 2 or x rays was synergistic. If exposure to O 2 or x rays was delayed until epithelial recovery was complete, no fibrosis was seen. Abnormally high levels of lung collagen persisted up to 6 months after one single treatment with BHT and 100 rad x rays. A commonly seen form of chronic lung damage may thus be caused by an acute interaction between a bloodborne agent which damages the alveolar cell and a toxic inhalant or x rays, provided a critically ordered sequence of exposure is observed

  4. Central Nervous System Fibrosis Is Associated with Fibrocyte-Like Infiltrates

    Science.gov (United States)

    Aldrich, Amy; Kielian, Tammy

    2011-01-01

    Fibrotic wall formation is essential for limiting pathogen dissemination during brain abscess development. However, little is known about the regulation of fibrotic processes in the central nervous system (CNS). Most CNS injury responses are associated with hypertrophy of resident astrocytes, a process termed reactive gliosis. Studies of fibrosis outside the CNS have identified two bone marrow–derived cell types, fibrocytes and alternatively activated M2 macrophages, as key mediators of fibrosis. The current study used bone marrow chimeras generated from green fluorescent protein transgenic mice to evaluate the appearance of these cell types and whether bone marrow–derived cells were capable of acquiring fibrotic characteristics during brain abscess development. Immunofluorescence staining revealed partial overlap between green fluorescent protein, α-smooth muscle actin, and procollagen, suggesting that a population of cells forming the brain abscess capsule originate from a bone marrow precursor. In addition, the influx of fibrocyte-like cells into brain abscesses immediately preceded the onset of fibrotic encapsulation. Fibrotic wall formation was also associated with increased numbers of alternatively activated M2 microglia and macrophages. To our knowledge, this is the first study demonstrating that bone marrow–derived infiltrates are capable of expressing fibrotic molecules during CNS inflammation. PMID:22015460

  5. Protective role of NKT cells and macrophage M2-driven phenotype in bleomycin-induced pulmonary fibrosis.

    Science.gov (United States)

    Grabarz, Felipe; Aguiar, Cristhiane Favero; Correa-Costa, Matheus; Braga, Tárcio Teodoro; Hyane, Meire I; Andrade-Oliveira, Vinícius; Landgraf, Maristella Almeida; Câmara, Niels Olsen Saraiva

    2018-04-01

    Pulmonary fibrosis is a result of an abnormal wound healing in lung tissue triggered by an excessive accumulation of extracellular matrix proteins, loss of tissue elasticity, and debit of ventilatory function. NKT cells are a major source of Th1 and Th2 cytokines and may be crucial in the polarization of M1/M2 macrophages in pulmonary fibrogenesis. Although there appears to be constant scientific progress in that field, pulmonary fibrosis still exhibits no current cure. From these facts, we hypothesized that NKT cells could influence the development of pulmonary fibrosis via modulation of macrophage activation. Wild type (WT) and NKT type I cell-deficient mice (Jα18 -/- ) were subjected to the protocol of bleomycin-induced pulmonary fibrosis with or without treatment with NKT cell agonists α-galactosylceramide and sulfatide. The participation of different cell populations, collagen deposition, and protein levels of different cytokines involved in inflammation and fibrosis was evaluated. The results indicate a benign role of NKT cells in Jα18 -/- mice and in wild-type α-galactosylceramide-sulfatide-treated groups. These animals presented lower levels of collagen deposition, fibrogenic molecules such as TGF-β and vimentin and improved survival rates. In contrast, WT mice developed a Th2-driven response augmenting IL-4, 5, and 13 protein synthesis and increased collagen deposition. Furthermore, the arginase-1 metabolic pathway was downregulated in wild-type NKT-activated and knockout mice indicating lower activity of M2 macrophages in lung tissue. Hence, our data suggest that NKT cells play a protective role in this experimental model by down modulating the Th2 milieu, inhibiting M2 polarization and finally preventing fibrosis.

  6. Assessment of cutaneous radiation fibrosis by 20 MHz-sonography

    International Nuclear Information System (INIS)

    Gottloeber, P.; Braun-Falco, B.; Plewig, G.; Kerscher, M.; Peter, R.U.; Nadeshina, N.

    1996-01-01

    Radiation fibrosis is the cardinal symptom of the chronicle stage of the cutaneous radiation syndrome. The degree of cutaneous fibrosis can clinically be estimated by palpation. High-frequency 20 MHz-sonography is an established, noninvasive procedure, which renders an exact determination of skin thickness and additionally densitometry is possible. We investigated 15 survivors of the Chernobyl accident in 1986, who developed symptoms of the chronic stage of the cutaneous radiation syndrome. We determined skin thickness and echogenicity of skin areas clinically suggestive of radiation fibrosis before, during and after treatment. 20 MHz-sonography showed a distinct enlargement of the echorich corium and a reduction of the subcutaneous fatty tissue in comparison with the unaffected, contralateral skin, here demonstrating typical features of radiation fibrosis, namely dermal fibrosis and reactive pseudoatrophy and fatty tissue. The histology presented an increase and swelling of the collagen fibers and atypical fibroblastic cells. The patients received treatment with low-dose interferon y (Polyfcron R , 3 x 50μg s.C., three times per week) up to 30 months. A marked reduction of skin thickness and echogenicity reaching nearly normal values could be observed. We conclude that 20 MHz-sonography is an easy to apply, noninvasive, well established procedure to quantify cutaneous radiation fibrosis and to assess therapeutic outcome

  7. Cost-Effectiveness of Screening Individuals With Cystic Fibrosis for Colorectal Cancer.

    Science.gov (United States)

    Gini, Andrea; Zauber, Ann G; Cenin, Dayna R; Omidvari, Amir-Houshang; Hempstead, Sarah E; Fink, Aliza K; Lowenfels, Albert B; Lansdorp-Vogelaar, Iris

    2017-12-27

    Individuals with cystic fibrosis are at increased risk of colorectal cancer (CRC) compared to the general population, and risk is higher among those who received an organ transplant. We performed a cost-effectiveness analysis to determine optimal CRC screening strategies for patients with cystic fibrosis. We adjusted the existing Microsimulation Screening Analysis-Colon microsimulation model to reflect increased CRC risk and lower life expectancy in patients with cystic fibrosis. Modeling was performed separately for individuals who never received an organ transplant and patients who had received an organ transplant. We modeled 76 colonoscopy screening strategies that varied the age range and screening interval. The optimal screening strategy was determined based on a willingness to pay threshold of $100,000 per life-year gained. Sensitivity and supplementary analyses were performed, including fecal immunochemical test (FIT) as an alternative test, earlier ages of transplantation, and increased rates of colonoscopy complications, to assess whether optimal screening strategies would change. Colonoscopy every 5 years, starting at age 40 years, was the optimal colonoscopy strategy for patients with cystic fibrosis who never received an organ transplant; this strategy prevented 79% of deaths from CRC. Among patients with cystic fibrosis who had received an organ transplant, optimal colonoscopy screening should start at an age of 30 or 35 years, depending on the patient's age at time of transplantation. Annual FIT screening was predicted to be cost-effective for patients with cystic fibrosis. However, the level of accuracy of the FIT in population is not clear. Using a Microsimulation Screening Analysis-Colon microsimulation model, we found screening of patients with cystic fibrosis for CRC to be cost-effective. Due to the higher risk in these patients for CRC, screening should start at an earlier age with a shorter screening interval. The findings of this study

  8. Diagnosis of different liver fibrosis characteristics by blood tests in non-alcoholic fatty liver disease.

    Science.gov (United States)

    Calès, Paul; Boursier, Jérôme; Chaigneau, Julien; Lainé, Fabrice; Sandrini, Jeremy; Michalak, Sophie; Hubert, Isabelle; Dib, Nina; Oberti, Frédéric; Bertrais, Sandrine; Hunault, Gilles; Cavaro-Ménard, Christine; Gallois, Yves; Deugnier, Yves; Rousselet, Marie C

    2010-10-01

    Our aim was to develop an accurate, non-invasive, blood-test-based method for identifying the main characteristics of liver fibrosis in non-alcoholic fatty liver disease (NAFLD). Fibrosis was staged according to NASH-CRN and Metavir systems in 226 patients with NAFLD. A fully automated algorithm measured the fractal dimension (FD) and the area of fibrosis (AOF). Independent predictors of diagnostic targets were determined using bootstrap methods. (i) Development. Significant fibrosis defined by NASH-CRN F ≥2 was diagnosed by weight, glycaemia, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and prothrombin index [area under the receiver operating characteristic (AUROC)=0.867]; significant fibrosis defined by Metavir F ≥2 was diagnosed by weight, age, glycaemia, AST, ALT, ferritin and platelets (FibroMeter AUROC=0.941, Pfibrosis staging, Metavir staging was a better reference for blood test. Thus, the patient rate with predictive values ≥90% by tests was 97.3% with Metavir reference vs. 66.5% with NASH-CRN reference (Pfibrosis score for significant fibrosis, but not for severe fibrosis or cirrhosis, with both staging systems. Relationships between fibrosis lesions were well reflected by blood tests, e.g., the correlation between histological area and FD of fibrosis (r(s) =0.971, Pblood tests (r(s) =0.852, Pfibrosis in NAFLD can be diagnosed and quantified by blood tests with excellent accuracy. © 2010 John Wiley & Sons A/S.

  9. Noninvasive Assessment of Advanced Fibrosis Based on Hepatic Volume in Patients with Nonalcoholic Fatty Liver Disease.

    Science.gov (United States)

    Hayashi, Tatsuya; Saitoh, Satoshi; Fukuzawa, Kei; Tsuji, Yoshinori; Takahashi, Junji; Kawamura, Yusuke; Akuta, Norio; Kobayashi, Masahiro; Ikeda, Kenji; Fujii, Takeshi; Miyati, Tosiaki; Kumada, Hiromitsu

    2017-09-15

    Noninvasive liver fibrosis evaluation was performed in patients with nonalcoholic fatty liver disease (NAFLD). We used a quantitative method based on the hepatic volume acquired from gadoxetate disodium-enhanced (Gd-EOB-DTPA-enhanced) magnetic resonance imaging (MRI) for diagnosing advanced fibrosis in patients with NAFLD. A total of 130 patients who were diagnosed with NAFLD and underwent Gd-EOB-DTPA-enhanced MRI were retrospectively included. Histological data were available for 118 patients. Hepatic volumetric parameters, including the left hepatic lobe to right hepatic lobe volume ratio (L/R ratio), were measured. The usefulness of the L/R ratio for diagnosing fibrosis ≥F3-4 and F4 was assessed using the area under the receiver operating characteristic (AUROC) curve. Multiple regression analysis was performed to identify variables (age, body mass index, serum fibrosis markers, and histological features) that were associated with the L/R ratio. The L/R ratio demonstrated good performance in differentiating advanced fibrosis (AUROC, 0.80; 95% confidence interval, 0.72 to 0.88) from cirrhosis (AUROC, 0.87; 95% confidence interval, 0.75 to 0.99). Multiple regression analysis showed that only fibrosis was significantly associated with the L/R ratio (coefficient, 0.121; p<0.0001). The L/R ratio, which is not influenced by pathological parameters other than fibrosis, is useful for diagnosing cirrhosis in patients with NAFLD.

  10. A comparative study on the hepatoprotective action of bear bile and Coptidis Rhizoma aqueous extract on experimental liver fibrosis in rats.

    Science.gov (United States)

    Wang, Ning; Feng, Yibin; Cheung, Fan; Chow, Oi-Yee; Wang, Xuanbin; Su, Weiwei; Tong, Yao

    2012-11-29

    Bear bile and Coptidis Rhizoma have been used in Chinese medicine with a long tradition in treating heat-diseases. Both bear bile and Coptidis Rhizoma are used to treat liver diseases in clinical practice of Chinese Medicine. Since bears are currently endangered, it raises the question whether the use of bear bile is ethical. To look for substitute for bear bile, the aim of this study is to compare the anti-fibrotic effects of Coptidis Rhizoma and its major component berberine with the actions of bear bile and its major compound tauroursodeoxycholic acid on experimental liver fibrosis in rats. Quality assessment was conducted with high performance liquid chromatography. The experimental liver fibrosis in rats was induced by carbon tetrachloride, alcohol, and bile duct ligation respectively. The biochemical criteria in the blood and tissue samples were measured to evaluate the anti-fibrotic properties and underlying mechanisms of the drugs. Coptidis Rhizoma Aqueous Extract (CRAE), berberine, and bear bile exerted anti-fibrotic properties on various liver fibrosis models in rats. CRAE and berberine significantly reduced the peroxidative stress in liver through increasing the superoxide dismutase enzyme activity. CRAE and berberine were able to excrete bilirubin products from the liver and protect hepatocytes from cholestatic damage. The effect of CRAE and berberine are comparable to that of bear bile. Instead of using bear bile, CRAE and berberine can be potential substitutes in treating liver fibrosis.

  11. A new compound heterozygous CFTR mutation in a Chinese family with cystic fibrosis.

    Science.gov (United States)

    Xie, Yingjun; Huang, Xueqiong; Liang, Yujian; Xu, Lingling; Pei, Yuxin; Cheng, Yucai; Zhang, Lidan; Tang, Wen

    2017-11-01

    Cystic fibrosis (CF) is the most common autosomal recessive disease among Caucasians but is rarer in the Chinese population, because mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. To elucidate the causative role of a novel compound heterozygous mutation of CF. In this study, clinical samples were obtained from two siblings with recurrent airway infections, clubbed fingers, salt-sweat and failure to gain weight in a non-consanguineous Chinese family. Next-generation sequencing was performed on the 27 coding exons of CFTR in both children, with confirmation by Sanger sequencing. Next-generation sequencing showed the same compound heterozygous CFTR mutation (c.865A>T p.Arg289X and c.3651_3652insAAAT p.Tyr1219X) in both children. As this mutation is consistent with the clinical manifestations of CF and no other mutations were detected after scanning the gene sequence, we suggest that the CF phenotype is caused by compound heterozygosity for c.865A>T and c.3651_3652insAAAT. As c865A>T is not currently listed in the "Cystic Fibrosis Mutation Database", this information about CF in a Chinese population is of interest. © 2015 John Wiley & Sons Ltd.

  12. Functional and prognostic effects when emphysema complicates idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Jacob, Joseph; Bartholmai, Brian J; Rajagopalan, Srinivasan; Kokosi, Maria; Maher, Toby M; Nair, Arjun; Karwoski, Ronald; Renzoni, Elisabetta; Walsh, Simon L F; Hansell, David M; Wells, Athol U

    2017-07-01

    This study aimed to investigate whether the combination of fibrosis and emphysema has a greater effect than the sum of its parts on functional indices and outcome in idiopathic pulmonary fibrosis (IPF), using visual and computer-based (CALIPER) computed tomography (CT) analysis.Consecutive patients (n=272) with a multidisciplinary IPF diagnosis had the extent of interstitial lung disease (ILD) scored visually and by CALIPER. Visually scored emphysema was subcategorised as isolated or mixed with fibrotic lung. The CT scores were evaluated against functional indices forced vital capacity (FVC), diffusing capacity of the lungs for carbon monoxide ( D LCO ), transfer coefficient of the lung for carbon monoxide ( K CO ), composite physiologic index (CPI)) and mortality.The presence and extent of emphysema had no impact on survival. Results were maintained following correction for age, gender, smoking status and baseline severity using D LCO , and combined visual emphysema and ILD extent. Visual emphysema quantitation indicated that relative preservation of lung volumes (FVC) resulted from tractionally dilated airways within fibrotic lung, ventilating areas of admixed emphysema (pemphysema. Conversely, only isolated emphysema (pemphysema in IPF, beyond that explained by the additive extents of both fibrosis and emphysema. With respect to the location of pulmonary fibrosis, emphysema distribution determines the functional effects of emphysema. Copyright ©ERS 2017.

  13. Young patients with cystic fibrosis demonstrate subtle alterations of the cardiovascular system.

    Science.gov (United States)

    Eising, Jacobien B; van der Ent, Cornelis K; Teske, Arco J; Vanderschuren, Maaike M; Uiterwaal, Cuno S P M; Meijboom, Folkert J

    2018-02-02

    As life expectancy increases in patients with cystic fibrosis, it is important to pay attention to extra-pulmonary comorbidities. Several studies have shown signs of myocardial dysfunction in adult patients, but little is known about onset and development of these changes over time. In this prospective study, cardiac function in children with cystic fibrosis was compared to that of healthy children. 33 children, aged 3-12years, with cystic fibrosis were recruited from the Wilhelmina Children's hospital and 33 age-matched healthy children were selected from the WHISTLER study, a population-based cohort study. Measurements of lung function, arterial stiffness, and echocardiography (conventional measures and myocardial deformation imaging) were performed. There were no differences in anthropometrics, lung function and blood pressure between the two groups. The cystic fibrosis children had a higher arterial stiffness compared to the healthy children (pulse wave velocity respectively 5.76±0.57m/s versus 5.43±0.61m/s, p-value 0.049). Using conventional echocardiographic parameters for right ventricular function, Tricuspid Annular Plane Systolic Excursion) and Tissue Doppler Imaging, cystic fibrosis children had a reduced right ventricular systolic function when compared to the healthy children. After adjustment for lung function, global strains of both right and left ventricles were significantly lower in the cystic fibrosis group than in healthy children (linear regression coefficient 1.45% left ventricle, p-value 0.022 and 4.42% right ventricle, p-value cystic fibrosis children than in healthy controls. Our study suggests that already at a very young age, children with cystic fibrosis show an increased arterial stiffness and some signs of diminished both right and left ventricular function. Copyright © 2018. Published by Elsevier B.V.

  14. Shared genetic effects between hepatic steatosis and fibrosis: A prospective twin study

    Science.gov (United States)

    Cui, Jeffrey; Chen, Chi-Hua; Lo, Min-Tzu; Schork, Nicholas; Bettencourt, Ricki; Gonzalez, Monica P; Bhatt, Archana; Hooker, Jonathan; Shaffer, Katherine; Nelson, Karen E; Long, Michelle T; Brenner, David A; Sirlin, Claude B; Loomba, Rohit

    2016-01-01

    Introduction Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic risk factors including hypertension and dyslipidemia, and may progress to liver fibrosis. Previous studies have shown that hepatic steatosis and fibrosis are heritable but whether they have a significant shared gene effect is unknown. This study aimed to examine the shared gene effects between hepatic steatosis, fibrosis, and their associations with metabolic risk factors. Methods This is a cross-sectional analysis of a prospective cohort of well-characterized, community-dwelling twins (45 monozygotic, 20 dizygotic twin pairs, 130 total subjects) from Southern California. Hepatic steatosis was assessed with MRI-proton density fat fraction (MRI-PDFF) and hepatic fibrosis was assessed with magnetic resonance elastography (MRE). A standard bivariate twin AE model was used to estimate the proportion of phenotypic variance between two phenotypes accounted for by additive genetic effects (A) and individual-specific environmental effects (E). Genetic correlations (rG) estimated from this model represent the degree to which the genetic determinants of two phenotypes overlap. Results The mean (±SD) age and BMI were 47.1 (±21.9) years and 26.9 (±6.5) kg/m2, respectively. 20% (26/130) of the cohort had hepatic steatosis (MRI-PDFF ≥5%) and 8.2% (10/122) had hepatic fibrosis (MRE ≥3Kpa). Blood pressure (systolic and diastolic), triglycerides, glucose, homeostatic model assessment of insulin resistance (HOMA-IR), insulin, hemoglobin A1c (HbA1c), and low high-density lipoprotein (HDL) had significant shared gene effects with hepatic steatosis. Triglycerides, glucose, HOMA-IR, insulin, HbA1c, and low HDL had significant shared gene effects with hepatic fibrosis. Hepatic steatosis and fibrosis had a highly significant shared gene effect of 0.756 (95% CI: 0.716–1, psteatosis pathogenesis may also be involved with fibrosis pathogenesis. PMID:27315352

  15. Differentiation state of skin fibroblast cultures versus risk of subcutaneous fibrosis after radiotherapy

    International Nuclear Information System (INIS)

    Herskind, C.; Bamberg, M.; Rodemann, H.P.; Bentzen, S.M.; Overgaard, J.; Overgaard, M.

    1998-01-01

    Background and purpose: There is increasing evidence for patient-to-patient variation in the response of normal tissue to radiotherapy. Recently, it has been suggested that accumulation of functional fibrocytes may be a key step in the development of radiation-induced fibrosis. Therefore, we have examined a possible relationship between the differentiation state of untreated fibroblasts and the risk of radiation-induced subcutaneous fibrosis in individual patients. Materials and methods: We used skin fibroblast cultures isolated from eight postmastectomy radiotherapy patients whose individual clinical radiosensitivity was assessed by the mean excess risk of fibrosis. Different types of potentially mitotic progenitor fibroblasts (MF) and postmitotic functional fibrocytes (PMF) in the terminal differentiation lineage (MFI approaches MFII approaches MFIII approaches PMF) were scored morphologically in clonal culture. Progression of differentiation was quantified by the ratio L/E of colony-forming late (MFIII and late MFII) and early (MFI and early MFII) progenitors. Results: We observed a correlation between the ratio L/E and the mean risk of fibrosis (r S =0.743, P=0.03), indicating an approximately 10-fold increase in L/E with an increasing risk of fibrosis. This was paralleled by a decreasing trend in the absolute numbers of early progenitor types. By contrast, there was no significant correlation between the plating efficiency and the risk of fibrosis. Conclusions: The data suggest that the risk of fibrosis increases with the progression of the differentiation of untreated progenitor fibroblasts, indicating that the progression of fibroblast differentiation may be a co-factor in the development of radiation-induced fibrosis. If this hypothesis is validated, it provides a rationale for a novel predictive test to identify patients with an increased risk of subcutaneous fibrosis. (Copyright (c) 1998 Elsevier Science B.V., Amsterdam. All rights reserved.)

  16. Quantitative Differentiation of LV Myocardium with and without Layer-Specific Fibrosis Using MRI in Hypertrophic Cardiomyopathy and Layer-Specific Strain TTE Analysis.

    Science.gov (United States)

    Funabashi, Nobusada; Takaoka, Hiroyuki; Ozawa, Koya; Kamata, Tomoko; Uehara, Masae; Komuro, Issei; Kobayashi, Yoshio

    2018-05-30

    To achieve further risk stratification in hypertrophic cardiomyopathy (HCM) patients, we localized and quantified layer-specific LVM fibrosis on MRI in HCM patients using regional layer-specific peak longitudinal strain (PLS) and peak circumferential strain (PCS) in LV myocardium (LVM) on speckle tracking transthoracic echocardiography (TTE). A total of 18 HCM patients (14 males; 58 ± 17 years) underwent 1.5T-MRI and TTE. PLS and PCS in each layer of the LVM (endocardium, epicardium, and whole-layer myocardium) were calculated for 17 AHA-defined lesions. MRI assessment showed that fibrosis was classified as endocardial, epicardial, or whole-layer (= either or both of these). Regional PLS was smaller in fibrotic endocardial lesions than in non-fibrotic endocardial lesions (P = 0.004). To detect LV endocardial lesions with fibrosis, ROC curves of regional PLS revealed an area under the curve (AUC) of 0.609 and a best cut-off point of 13.5%, with sensitivity of 65.3% and specificity of 54.3%. Regional PLS was also smaller in fibrotic epicardial lesions than in non-fibrotic epicardial lesions (P layer myocardium analysis, PLS was smaller in fibrotic lesions than in non-fibrotic lesions (P layer LV lesions with fibrosis, ROC curves of regional PLS revealed an AUC of 0.674 and a best cut-off point of 12.5%, with sensitivity of 79.0% and specificity of 50.7%. There were no significant differences in PCS of LV myocardium (endocardium, epicardium, and whole-layer) between fibrotic and non-fibrotic lesions. Quantitative regional PLS but not PCS in LV endocardium, epicardium, and whole-layer myocardium provides useful non-invasive information for layer-specific localization of fibrosis in HCM patients.

  17. Targeted Sterically Stabilized Phospholipid siRNA Nanomedicine for Hepatic and Renal Fibrosis

    Directory of Open Access Journals (Sweden)

    Fatima Khaja

    2016-01-01

    Full Text Available Since its discovery, small interfering RNA (siRNA has been considered a potent tool for modulating gene expression. It has the ability to specifically target proteins via selective degradation of messenger RNA (mRNA not easily accessed by conventional drugs. Hence, RNA interference (RNAi therapeutics have great potential in the treatment of many diseases caused by faulty protein expression such as fibrosis and cancer. However, for clinical application siRNA faces a number of obstacles, such as poor in vivo stability, and off-target effects. Here we developed a unique targeted nanomedicine to tackle current siRNA delivery issues by formulating a biocompatible, biodegradable and relatively inexpensive nanocarrier of sterically stabilized phospholipid nanoparticles (SSLNPs. This nanocarrier is capable of incorporating siRNA in its core through self-association with a novel cationic lipid composed of naturally occuring phospholipids and amino acids. This overall assembly protects and delivers sufficient amounts of siRNA to knockdown over-expressed protein in target cells. The siRNA used in this study, targets connective tissue growth factor (CTGF, an important regulator of fibrosis in both hepatic and renal cells. Furthermore, asialoglycoprotein receptors are targeted by attaching the galactosamine ligand to the nanocarries which enhances the uptake of nanoparticles by hepatocytes and renal tubular epithelial cells, the major producers of CTGF in fibrosis. On animals this innovative nanoconstruct, small interfering RNA in sterically stabilized phospholipid nanoparticles (siRNA-SSLNP, showed favorable pharmacokinetic properties and accumulated mostly in hepatic and renal tissues making siRNA-SSLNP a suitable system for targeting liver and kidney fibrotic diseases.

  18. Higher Anti-Liver Fibrosis Effect of Cordyceps militaris-Fermented Product Cultured with Deep Ocean Water via Inhibiting Proinflammatory Factors and Fibrosis-Related Factors Expressions

    OpenAIRE

    Hung, Yu-Ping; Lee, Chun-Lin

    2017-01-01

    Deep ocean water (DOW) has been shown to enhance the functional components of fungi, resulting in increased health benefits. Therefore, using DOW for culturing fungi can enhance the cordycepin and adenosine of Cordyceps militaris (CM) and its protective effects on the liver. In this study, the antiliver fibrosis effects and mechanisms of ultrapure water-cultured CM (UCM), DOW-cultured CM (DCM), synthetic water-cultured CM, DOW, cordycepin, and adenosine were compared in the liver fibrosis mic...

  19. A comparison of MR elastography and {sup 31}P MR spectroscopy with histological staging of liver fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Godfrey, Edmund M. [St James' Hospital, Leeds (United Kingdom); St James' Hospital, Department of Radiology, Leeds (United Kingdom); Patterson, Andrew J.; Priest, Andrew N.; Davies, Susan E.; Joubert, Ilse; Krishnan, Anant S.; Shaw, Ashley S.; Alexander, Graeme J.; Allison, Michael E.; Griffiths, William J.H.; Gimson, Alexander E.S. [Addenbrooke' s Hospital, Cambridge (United Kingdom); Griffin, Nyree [St Thomas' s Hospital, London (United Kingdom); Lomas, David J. [University of Cambridge, Department of Radiology, Cambridge (United Kingdom)

    2012-12-15

    Conventional imaging techniques are insensitive to liver fibrosis. This study assesses the diagnostic accuracy of MR elastography (MRE) stiffness values and the ratio of phosphomonoesters (PME)/phosphodiesters (PDE) measured using {sup 31}P spectroscopy against histological fibrosis staging. The local research ethics committee approved this prospective, blinded study. A total of 77 consecutive patients (55 male, aged 49 {+-} 11.5 years) with a clinical suspicion of liver fibrosis underwent an MR examination with a liver biopsy later the same day. Patients underwent MRE and {sup 31}P spectroscopy on a 1.5 T whole body system. The liver biopsies were staged using an Ishak score for chronic hepatitis or a modified NAS fibrosis score for fatty liver disease. MRE increased with and was positively associated with fibrosis stage (Spearman's rank = 0.622, P < 0.001). PME/PDE was not associated with fibrosis stage (Spearman's rank = -0.041, p = 0.741). Area under receiver operating curves for MRE stiffness values were high (range 0.75-0.97). The diagnostic utility of PME/PDE was no better than chance (range 0.44-0.58). MRE-estimated liver stiffness increases with fibrosis stage and is able to dichotomise fibrosis stage groupings. We did not find a relationship between {sup 31}P MR spectroscopy and fibrosis stage. circle Magnetic resonance elastography (MRE) and MR spectroscopy can both assess the liver. (orig.)

  20. Non-invasive evaluation of cystic fibrosis related liver disease in adults with ARFI, transient elastography and different fibrosis scores.

    Directory of Open Access Journals (Sweden)

    Thomas Karlas

    Full Text Available BACKGROUND: Cystic fibrosis-related liver disease (CFLD is present in up to 30% of cystic fibrosis patients and can result in progressive liver failure. Diagnosis of CFLD is challenging. Non-invasive methods for staging of liver fibrosis display an interesting diagnostic approach for CFLD detection. AIM: We evaluated transient elastography (TE, acoustic radiation force impulse imaging (ARFI, and fibrosis indices for CFLD detection. METHODS: TE and ARFI were performed in 55 adult CF patients. In addition, AST/Platelets-Ratio-Index (APRI, and Forns' score were calculated. Healthy probands and patients with alcoholic liver cirrhosis served as controls. RESULTS: Fourteen CF patients met CFLD criteria, six had liver cirrhosis. Elastography acquisition was successful in >89% of cases. Non-cirrhotic CFLD individuals showed elastography values similar to CF patients without liver involvement. Cases with liver cirrhosis differed significantly from other CFLD patients (ARFI: 1.49 vs. 1.13 m/s; p = 0.031; TE: 7.95 vs. 4.16 kPa; p = 0.020 and had significantly lower results than individuals with alcoholic liver cirrhosis (ARFI: 1.49 vs. 2.99 m/s; p = 0.002. APRI showed the best diagnostic performance for CFLD detection (AUROC 0.815; sensitivity 85.7%, specificity 70.7%. CONCLUSIONS: ARFI, TE, and laboratory based fibrosis indices correlate with each other and reliably detect CFLD related liver cirrhosis in adult CF patients. CF specific cut-off values for cirrhosis in adults are lower than in alcoholic cirrhosis.

  1. Non-Invasive Evaluation of Cystic Fibrosis Related Liver Disease in Adults with ARFI, Transient Elastography and Different Fibrosis Scores

    Science.gov (United States)

    Oltmanns, Annett; Güttler, Andrea; Petroff, David; Wirtz, Hubert; Mainz, Jochen G.; Mössner, Joachim; Berg, Thomas; Tröltzsch, Michael; Keim, Volker; Wiegand, Johannes

    2012-01-01

    Background Cystic fibrosis-related liver disease (CFLD) is present in up to 30% of cystic fibrosis patients and can result in progressive liver failure. Diagnosis of CFLD is challenging. Non-invasive methods for staging of liver fibrosis display an interesting diagnostic approach for CFLD detection. Aim We evaluated transient elastography (TE), acoustic radiation force impulse imaging (ARFI), and fibrosis indices for CFLD detection. Methods TE and ARFI were performed in 55 adult CF patients. In addition, AST/Platelets-Ratio-Index (APRI), and Forns' score were calculated. Healthy probands and patients with alcoholic liver cirrhosis served as controls. Results Fourteen CF patients met CFLD criteria, six had liver cirrhosis. Elastography acquisition was successful in >89% of cases. Non-cirrhotic CFLD individuals showed elastography values similar to CF patients without liver involvement. Cases with liver cirrhosis differed significantly from other CFLD patients (ARFI: 1.49 vs. 1.13 m/s; p = 0.031; TE: 7.95 vs. 4.16 kPa; p = 0.020) and had significantly lower results than individuals with alcoholic liver cirrhosis (ARFI: 1.49 vs. 2.99 m/s; p = 0.002). APRI showed the best diagnostic performance for CFLD detection (AUROC 0.815; sensitivity 85.7%, specificity 70.7%). Conclusions ARFI, TE, and laboratory based fibrosis indices correlate with each other and reliably detect CFLD related liver cirrhosis in adult CF patients. CF specific cut-off values for cirrhosis in adults are lower than in alcoholic cirrhosis. PMID:22848732

  2. Establishment of a Radiation-Induced Fibrosis Model in BALB/c Mice

    Energy Technology Data Exchange (ETDEWEB)

    Ryu, Seung Hee; Lee, Sang Wook; Moon, Soo Young; Oh, Jeong Yoon; Yang, Youn Joo; Park, Jin Hong [Dept. of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of)

    2010-11-15

    Although radiation-induced fibrosis is one of the common sequelae occurring after irradiation of skin and soft tissues, the treatment methods are not well standardized. This study aimed to establish the skin fibrosis mouse model by fractionated radiation for the further mechanism studies or testing the efficacy of therapeutic candidates. The right hind limbs of BALB/c mice received two fractions of 20 Gy using a therapeutic linear accelerator. Early skin damages were scored and tissue fibrosis was assessed by the measurement of a leg extension. Morphological changes were assessed by H and E staining and by Masson's Trichrome staining. TGF-{beta}1 expression from soft tissues was also detected by immunohistochemistry and PCR. Two fractions of 20 Gy irradiation were demonstrated as being enough to induce early skin damage effects such as erythema, mild skin dryness, dry and wet desquamation within several weeks of radiation. After 13 weeks of irradiation, the average radiation-induced leg contraction was 11.1 {+-} 6.2 mm. Morphologic changes in irradiated skin biopsies exhibited disorganized collagen and extracellular matrix fibers, as well as the accumulation of myofibroblasts compared to the non-irradiated skin. Moreover, TGF-{beta}1 expression in tissue was increased by radiation. These results show that two fractions of 20 Gy irradiation can induce skin fibrosis in BALB/c mice accompanied by other common characteristics of skin damages. This animal model can be a useful tool for studying skin fibrosis induced by radiation.

  3. Non-invasive evaluation of liver stiffness after splenectomy in rabbits with CCl4-induced liver fibrosis.

    Science.gov (United States)

    Wang, Ming-Jun; Ling, Wen-Wu; Wang, Hong; Meng, Ling-Wei; Cai, He; Peng, Bing

    2016-12-14

    To investigate the diagnostic performance of liver stiffness measurement (LSM) by elastography point quantification (ElastPQ) in animal models and determine the longitudinal changes in liver stiffness by ElastPQ after splenectomy at different stages of fibrosis. Liver stiffness was measured in sixty-eight rabbits with CCl 4 -induced liver fibrosis at different stages and eight healthy control rabbits by ElastPQ. Liver biopsies and blood samples were obtained at scheduled time points to assess liver function and degree of fibrosis. Thirty-one rabbits with complete data that underwent splenectomy at different stages of liver fibrosis were then included for dynamic monitoring of changes in liver stiffness by ElastPQ and liver function according to blood tests. LSM by ElastPQ was significantly correlated with histologic fibrosis stage ( r = 0.85, P fibrosis, moderate fibrosis, and cirrhosis, respectively. Longitudinal monitoring of the changes in liver stiffness by ElastPQ showed that early splenectomy (especially F1) may delay liver fibrosis progression. ElastPQ is an available, convenient, objective and non-invasive technique for assessing liver stiffness in rabbits with CCl 4 -induced liver fibrosis. In addition, liver stiffness measurements using ElastPQ can dynamically monitor the changes in liver stiffness in rabbit models, and in patients, after splenectomy.

  4. Multicentre chest computed tomography standardisation in children and adolescents with cystic fibrosis

    DEFF Research Database (Denmark)

    Kuo, Wieying; Kemner-van de Corput, Mariette P. C.; Perez-Rovira, Adria

    2016-01-01

    Progressive cystic fibrosis (CF) lung disease is the main cause of mortality in CF patients. CF lung disease starts in early childhood. With current standards of care, respiratory function remains largely normal in children and more sensitive outcome measures are needed to monitor early CF lung...... disease. Chest CT is currently the most sensitive imaging modality to monitor pulmonary structural changes in children and adolescents with CF. To quantify structural lung disease reliably among multiple centres, standardisation of chest CT protocols is needed. SCIFI CF (Standardised Chest Imaging...

  5. Up-to-date and projected estimates of survival for people with cystic fibrosis using baseline characteristics: A longitudinal study using UK patient registry data.

    Science.gov (United States)

    Keogh, Ruth H; Szczesniak, Rhonda; Taylor-Robinson, David; Bilton, Diana

    2018-03-01

    Cystic fibrosis (CF) is the most common inherited disease in Caucasians, affecting around 10,000 individuals in the UK today. Prognosis has improved considerably over recent decades with ongoing improvements in treatment and care. Providing up-to-date survival predictions is important for patients, clinicians and health services planning. Flexible parametric survival modelling of UK CF Registry data from 2011 to 2015, capturing 602 deaths in 10,428 individuals. Survival curves were estimated from birth; conditional on reaching older ages; and projected under different assumptions concerning future mortality trends, using baseline characteristics of sex, CFTR genotype (zero, one, two copies of F508del) and age at diagnosis. Male sex was associated with better survival, as was older age at diagnosis, but only in F508del non-homozygotes. Survival did not differ by genotype among individuals diagnosed at birth. Median survival ages at birth in F508del homozygotes were 46years (males) and 41years (females), and similar in non-homozygotes diagnosed at birth. F508del heterozygotes diagnosed aged 5 had median survival ages of 57 (males) and 51 (females). Conditional on survival to 30, median survival age rises to 52 (males) and 49 (females) in homozygotes. Mortality rates decreased annually by 2% during 2006-2015. Future improvements at this rate suggest median survival ages for F508del homozygous babies of 65 (males) and 56 (females). Over half of babies born today, and of individuals aged 30 and above today, can expect to survive into at least their fifth decade. Evidence before this study We searched PubMed with terms "(cystic fibrosis survival) and (projection OR model OR registry OR United Kingdom OR UK)" to identify relevant studies on survival estimates for individuals with cystic fibrosis (CF). We also considered the most recent annual report from the UK Cystic Fibrosis Registry (Cystic Fibrosis Trust, 2016), a review by Buzzetti and colleagues (2009), the chapter

  6. Uncovering a Predictive Molecular Signature for the Onset of NASH-Related Fibrosis in a Translational NASH Mouse Model.

    Science.gov (United States)

    van Koppen, Arianne; Verschuren, Lars; van den Hoek, Anita M; Verheij, Joanne; Morrison, Martine C; Li, Kelvin; Nagabukuro, Hiroshi; Costessi, Adalberto; Caspers, Martien P M; van den Broek, Tim J; Sagartz, John; Kluft, Cornelis; Beysen, Carine; Emson, Claire; van Gool, Alain J; Goldschmeding, Roel; Stoop, Reinout; Bobeldijk-Pastorova, Ivana; Turner, Scott M; Hanauer, Guido; Hanemaaijer, Roeland

    2018-01-01

    The incidence of nonalcoholic steatohepatitis (NASH) is increasing. The pathophysiological mechanisms of NASH and the sequence of events leading to hepatic fibrosis are incompletely understood. The aim of this study was to gain insight into the dynamics of key molecular processes involved in NASH and to rank early markers for hepatic fibrosis. A time-course study in low-density lipoprotein-receptor knockout. Leiden mice on a high-fat diet was performed to identify the temporal dynamics of key processes contributing to NASH and fibrosis. An integrative systems biology approach was used to elucidate candidate markers linked to the active fibrosis process by combining transcriptomics, dynamic proteomics, and histopathology. The translational value of these findings were confirmed using human NASH data sets. High-fat-diet feeding resulted in obesity, hyperlipidemia, insulin resistance, and NASH with fibrosis in a time-dependent manner. Temporal dynamics of key molecular processes involved in the development of NASH were identified, including lipid metabolism, inflammation, oxidative stress, and fibrosis. A data-integrative approach enabled identification of the active fibrotic process preceding histopathologic detection using a novel molecular fibrosis signature. Human studies were used to identify overlap of genes and processes and to perform a network biology-based prioritization to rank top candidate markers representing the early manifestation of fibrosis. An early predictive molecular signature was identified that marked the active profibrotic process before histopathologic fibrosis becomes manifest. Early detection of the onset of NASH and fibrosis enables identification of novel blood-based biomarkers to stratify patients at risk, development of new therapeutics, and help shorten (pre)clinical experimental time frames.

  7. Agmatine attenuates silica-induced pulmonary fibrosis.

    Science.gov (United States)

    El-Agamy, D S; Sharawy, M H; Ammar, E M

    2014-06-01

    There is a large body of evidence that nitric oxide (NO) formation is implicated in mediating silica-induced pulmonary fibrosis. As a reactive free radical, NO may not only contribute to lung parenchymal tissue injury but also has the ability to combine with superoxide and form a highly reactive toxic species peroxynitrite that can induce extensive cellular toxicity in the lung tissues. This study aimed to explore the effect of agmatine, a known NO synthase inhibitor, on silica-induced pulmonary fibrosis in rats. Male Sprague Dawley rats were treated with agmatine for 60 days following a single intranasal instillation of silica suspension (50 mg in 0.1 ml saline/rat). The results revealed that agmatine attenuated silica-induced lung inflammation as it decreased the lung wet/dry weight ratio, protein concentration, and the accumulation of the inflammatory cells in the bronchoalveolar lavage fluid. Agmatine showed antifibrotic activity as it decreased total hydroxyproline content of the lung and reduced silica-mediated lung inflammation and fibrosis in lung histopathological specimen. In addition, agmatine significantly increased superoxide dismutase (p Agmatine also reduced silica-induced overproduction of pulmonary nitrite/nitrate as well as tumor necrosis factor α. Collectively, these results demonstrate the protective effects of agmatine against the silica-induced lung fibrosis that may be attributed to its ability to counteract the NO production, lipid peroxidation, and regulate cytokine effects. © The Author(s) 2014.

  8. Improved fibrosis staging by elastometry and blood test in chronic hepatitis C.

    Science.gov (United States)

    Calès, Paul; Boursier, Jérôme; Ducancelle, Alexandra; Oberti, Frédéric; Hubert, Isabelle; Hunault, Gilles; de Lédinghen, Victor; Zarski, Jean-Pierre; Salmon, Dominique; Lunel, Françoise

    2014-07-01

    Our main objective was to improve non-invasive fibrosis staging accuracy by resolving the limits of previous methods via new test combinations. Our secondary objectives were to improve staging precision, by developing a detailed fibrosis classification, and reliability (personalized accuracy) determination. All patients (729) included in the derivation population had chronic hepatitis C, liver biopsy, 6 blood tests and Fibroscan. Validation populations included 1584 patients. The most accurate combination was provided by using most markers of FibroMeter and Fibroscan results targeted for significant fibrosis, i.e. 'E-FibroMeter'. Its classification accuracy (91.7%) and precision (assessed by F difference with Metavir: 0.62 ± 0.57) were better than those of FibroMeter (84.1%, P fibrosis absence (F0) was increased, e.g. from 16.0% with Fibroscan to 75.0% with E-FibroMeter (P test (1.2% of patients) and increasing optimal reliability (accuracy ≥85%) from 80.4% of patients with Fibroscan (accuracy: 90.9%) to 94.2% of patients with E-FibroMeter (accuracy: 92.9%), P test (FibroMeter: 16.2%, P test combination increased: accuracy, globally and especially in patients without fibrosis, staging precision, cirrhosis prediction, and even reliability, thus offering improved fibrosis staging. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. The evaluation of selected insomnia predictors in adolescents and young adults with cystic fibrosis.

    Science.gov (United States)

    Tomaszek, Lucyna; Cepuch, Grazyna; Pawlik, Lidia

    2018-03-21

    The purpose of the study was to assess the incidence of insomnia in adolescents and young adults with cystic fibrosis and its impact on the quality of life, and to examine whether demographic and clinical factors and negative emotional states are predictors of insomnia in these patients. The study was conducted among 95 cystic fibrosis patients aged 14-25 years. The study used a personal questionnaire survey, the Athens Insomnia Scale, the Cystic Fibrosis Quality of Life Questionnaire, the Hospital Anxiety and Depression Scale, and the Numeric Rating Scale. Insomnia was diagnosed in 38% of cystic fibrosis patients. In patients with insomnia, the level of anxiety (Me: 10 vs. 4; P=0.000) and depression (Me: 6.5 vs. 2; P=0.000) was significantly higher than in the good sleep quality group. The risk of insomnia increases as anxiety (OR: 4.31; 95% CI: 2.20 to 8.41) and depressive symptoms exacerbate (OR: 4.98; 95% CI: 1.84 to 13.43). Insomnia significantly worsens the quality of life in cystic fibrosis patients (ß =-0.5, P=0.000). Insomnia affects a large percentage of cystic fibrosis patients, and anxiety and depression are factors that increase the risk of insomnia. Insomnia decreases the quality of life in cystic fibrosis patients.

  10. Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis.

    Science.gov (United States)

    Cao, Zhongwei; Lis, Raphael; Ginsberg, Michael; Chavez, Deebly; Shido, Koji; Rabbany, Sina Y; Fong, Guo-Hua; Sakmar, Thomas P; Rafii, Shahin; Ding, Bi-Sen

    2016-02-01

    Although the lung can undergo self-repair after injury, fibrosis in chronically injured or diseased lungs can occur at the expense of regeneration. Here we study how a hematopoietic-vascular niche regulates alveolar repair and lung fibrosis. Using intratracheal injection of bleomycin or hydrochloric acid in mice, we show that repetitive lung injury activates pulmonary capillary endothelial cells (PCECs) and perivascular macrophages, impeding alveolar repair and promoting fibrosis. Whereas the chemokine receptor CXCR7, expressed on PCECs, acts to prevent epithelial damage and ameliorate fibrosis after a single round of treatment with bleomycin or hydrochloric acid, repeated injury leads to suppression of CXCR7 expression and recruitment of vascular endothelial growth factor receptor 1 (VEGFR1)-expressing perivascular macrophages. This recruitment stimulates Wnt/β-catenin-dependent persistent upregulation of the Notch ligand Jagged1 (encoded by Jag1) in PCECs, which in turn stimulates exuberant Notch signaling in perivascular fibroblasts and enhances fibrosis. Administration of a CXCR7 agonist or PCEC-targeted Jag1 shRNA after lung injury promotes alveolar repair and reduces fibrosis. Thus, targeting of a maladapted hematopoietic-vascular niche, in which macrophages, PCECs and perivascular fibroblasts interact, may help to develop therapy to spur lung regeneration and alleviate fibrosis.

  11. Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis

    Science.gov (United States)

    Cao, Zhongwei; Lis, Raphael; Ginsberg, Michael; Chavez, Deebly; Shido, Koji; Rabbany, Sina Y.; Fong, Guo-Hua; Sakmar, Thomas P.; Rafii, Shahin; Ding, Bi-Sen

    2016-01-01

    Although the lung can undergo self-repair after injury, fibrosis in chronically injured or diseased lungs can occur at the expense of regeneration. Here we study how a hematopoietic-vascular niche regulates alveolar repair and lung fibrosis. Using intratracheal injection of bleomycin or hydrochloric acid in mice, we show that repetitive lung injury activates pulmonary capillary endothelial cells (PCECs) and perivascular macrophages, impeding alveolar repair and promoting fibrosis. Whereas the chemokine receptor CXCR7, expressed on PCECs, acts to prevent epithelial damage and ameliorate fibrosis after a single round of treatment with bleomycin or hydrochloric acid, repeated injury leads to suppression of CXCR7 expression and recruitment of vascular endothelial growth factor receptor 1 (VEGFR1)-expressing perivascular macrophages. This recruitment stimulates Wnt/β-catenin–dependent persistent upregulation of the Notch ligand Jagged1 (encoded by Jag1) in PCECs, which in turn stimulates exuberant Notch signaling in perivascular fibroblasts and enhances fibrosis. Administration of a CXCR7 agonist or PCEC-targeted Jag1 shRNA after lung injury promotes alveolar repair and reduces fibrosis. Thus, targeting of a maladaptbed hematopoietic-vascular niche, in which macrophages, PCECs and perivascular fibroblasts interact, may help to develop therapy to spur lung regeneration and alleviate fibrosis. PMID:26779814

  12. Subclinical anaemia of chronic disease in adult patients with cystic fibrosis.

    LENUS (Irish Health Repository)

    O'connor, T M

    2012-02-03

    Patients with chronic hypoxaemia develop secondary polycythaemia that improves oxygen-carrying capacity. Therefore, normal haemoglobin and haematocrit values in the presence of chronic arterial hypoxaemia in cystic fibrosis constitute \\'relative anaemia\\'. We sought to determine the cause of this relative anaemia in patients with cystic fibrosis. We studied haematological indices and oxygen saturation in healthy volunteers (n=17) and in adult patients with cystic fibrosis (n=15). Patients with cystic fibrosis had lower resting arterial oxygen saturation when compared with normal volunteers (P<0.0001), and exercise led to a greater reduction in arterial oxygen saturation (P<0.0001). However, haemoglobin and haematocrit values in patients with cystic fibrosis did not significantly differ from normal volunteers. Serum iron (P=0.002), transferrin (P=0.02), and total iron-binding capacity (P=0.01) were lower in patients with cystic fibrosis. There were no significant differences in serum ferritin, percentage iron saturation, serum erythropoietin or red cell volume between the groups. The data presented demonstrate a characteristic picture of anaemia of chronic disease in adult patients with cystic fibrosis, except for normal haemoglobin and haematocrit values. Normal haemoglobin and haematocrit values in patients with cystic fibrosis appear to represent a combination of the effects of arterial hypoxaemia promoting polycythaemia, counterbalanced by chronic inflammation promoting anaemia of chronic disease.

  13. Idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Xaubet, Antoni; Ancochea, Julio; Molina-Molina, María

    2017-02-23

    Idiopathic pulmonary fibrosis is a fibrosing interstitial pneumonia associated with the radiological and/or histological pattern of usual interstitial pneumonia. Its aetiology is unknown, but probably comprises the action of endogenous and exogenous micro-environmental factors in subjects with genetic predisposition. Its diagnosis is based on the presence of characteristic findings of high-resolution computed tomography scans and pulmonary biopsies in absence of interstitial lung diseases of other aetiologies. Its clinical evolution is variable, although the mean survival rate is 2-5 years as of its clinical presentation. Patients with idiopathic pulmonary fibrosis may present complications and comorbidities which modify the disease's clinical course and prognosis. In the mild-moderate disease, the treatment consists of the administration of anti-fibrotic drugs. In severe disease, the best therapeutic option is pulmonary transplantation. In this paper we review the diagnostic and therapeutic aspects of the disease. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  14. Fibrosis index based on four factors better predicts advanced fibrosis or cirrhosis than aspartate aminotransferase/platelet ratio index in chronic hepatitis C patients

    Directory of Open Access Journals (Sweden)

    Chia-Chi Wang

    2015-10-01

    Conclusion: FIB-4 could predict hepatic fibrosis in CHC patients. By adding two parameters (age and alanine aminotransferase, FIB-4 better predicts advanced fibrosis and cirrhosis than APRI in CHC patients.

  15. Serologic and ultrasonographic parameters of praziquantel treatment of hepatic fibrosis in Schistosoma japonicum infection.

    Science.gov (United States)

    Ohmae, H; Tanaka, M; Nara, T; Utsunomiya, H; Taguchi, H; Irie, Y; Yasuraoka, K

    1991-09-01

    We describe the parameters useful in evaluating the development of hepatic fibrosis in Schistosoma japonicum infection, as well as its improvement after treatment with praziquantel (PZQ). Various serologic parameters and ultrasonographic images were examined, and their changes were monitored using rabbits infected with 200 or 300 cercariae of S. japonicum. Infected rabbits were administered one oral treatment of PZQ at a dosage of 100 mg/kg at 6, 12, or 24 weeks after infection. Histopathologic examinations revealed that PZQ had a strong and rapid effect, even on damage that developed long after the infection. The improvement of moderate hepatic fibrosis that developed over 24 weeks after infection was also detected by histopathologic examinations. The serum level of total bile acid was the most sensitive parameter in evaluating the severity of hepatic fibrosis and its improvement after treatment with PZQ. The level of serum procollagen-III-peptide was also useful in evaluating the development of hepatic fibrosis, but not in its improvement. Ultrasonography revealed specific echogenic bands and nodules according to the progress of granuloma formation and fibrosis, and the reversal of these changes could also be observed after treatment with PZQ.

  16. Tissue Inhibitor of Matrix Metalloproteinase-1 Promotes Myocardial Fibrosis by Mediating CD63-Integrin β1 Interaction.

    Science.gov (United States)

    Takawale, Abhijit; Zhang, Pu; Patel, Vaibhav B; Wang, Xiuhua; Oudit, Gavin; Kassiri, Zamaneh

    2017-06-01

    Myocardial fibrosis is excess accumulation of the extracellular matrix fibrillar collagens. Fibrosis is a key feature of various cardiomyopathies and compromises cardiac systolic and diastolic performance. TIMP1 (tissue inhibitor of metalloproteinase-1) is consistently upregulated in myocardial fibrosis and is used as a marker of fibrosis. However, it remains to be determined whether TIMP1 promotes tissue fibrosis by inhibiting extracellular matrix degradation by matrix metalloproteinases or via an matrix metalloproteinase-independent pathway. We examined the function of TIMP1 in myocardial fibrosis using Timp1 -deficient mice and 2 in vivo models of myocardial fibrosis (angiotensin II infusion and cardiac pressure overload), in vitro analysis of adult cardiac fibroblasts, and fibrotic myocardium from patients with dilated cardiomyopathy (DCM). Timp1 deficiency significantly reduced myocardial fibrosis in both in vivo models of cardiomyopathy. We identified a novel mechanism for TIMP1 action whereby, independent from its matrix metalloproteinase-inhibitory function, it mediates an association between CD63 (cell surface receptor for TIMP1) and integrin β1 on cardiac fibroblasts, initiates activation and nuclear translocation of Smad2/3 and β-catenin, leading to de novo collagen synthesis. This mechanism was consistently observed in vivo, in cultured cardiac fibroblasts, and in human fibrotic myocardium. In addition, after long-term pressure overload, Timp1 deficiency persistently reduced myocardial fibrosis and ameliorated diastolic dysfunction. This study defines a novel matrix metalloproteinase-independent function of TIMP1 in promoting myocardial fibrosis. As such targeting TIMP1 could prove to be a valuable approach in developing antifibrosis therapies. © 2017 American Heart Association, Inc.

  17. Festival food coma in cystic fibrosis.

    Science.gov (United States)

    Pandit, Chetan; Graham, Christie; Selvadurai, Hiran; Gaskin, Kevin; Cooper, Peter; van Asperen, Peter

    2013-07-01

    Children with cystic fibrosis liver disease and portal hypertension are at risk of developing acute hepatic encephalopathy. Even in the presence of normal synthetic liver function these children may have porto-systemic shunting. We report a case of an adolosecent who had cystic fibrosis liver disease and presented with life threatening hepatinc encephalopathy. This case illustrates that it is necessary to consider an appropriate dietary regimen in adolosecents with liver disease to prevent hepatic decompensation. Copyright © 2012 Wiley Periodicals, Inc.

  18. WE-FG-206-12: Enhanced Laws Textures: A Potential MRI Surrogate Marker of Hepatic Fibrosis in a Murine Model

    International Nuclear Information System (INIS)

    Li, B; Yu, H; Jara, H; Soto, J; Anderson, S

    2016-01-01

    Purpose: To compare enhanced Laws texture derived from parametric proton density (PD) maps to other MRI-based surrogate markers (T2, PD, ADC) in assessing degrees of liver fibrosis in a murine model of hepatic fibrosis using 11.7T scanner. Methods: This animal study was IACUC approved. Fourteen mice were divided into control (n=1) and experimental (n=13). The latter were fed a DDC-supplemented diet to induce hepatic fibrosis. Liver specimens were imaged using an 11.7T scanner; the parametric PD, T2, and ADC maps were generated from spin-echo pulsed field gradient and multi-echo spin-echo acquisitions. Enhanced Laws texture analysis was applied to the PD maps: first, hepatic blood vessels and liver margins were segmented/removed using an automated dual-clustering algorithm; secondly, an optimal thresholding algorithm was applied to reduce the partial volume artifact; next, mean and stdev were corrected to minimize grayscale variation across images; finally, Laws texture was extracted. Degrees of fibrosis was assessed by an experienced pathologist and digital image analysis (%Area Fibrosis). Scatterplots comparing enhanced Laws texture, T2, PD, and ADC values to degrees of fibrosis were generated and correlation coefficients were calculated. Unenhanced Laws texture was also compared to assess the effectiveness of the proposed enhancements. Results: Hepatic fibrosis and the enhanced Laws texture were strongly correlated with higher %Area Fibrosis associated with higher Laws texture (r=0.89). Only a moderate correlation was detected between %Area Fibrosis and unenhanced Laws texture (r=0.70). Strong correlation also existed between ADC and %Area Fibrosis (r=0.86). Moderate correlations were seen between %Area Fibrosis and PD (r=0.65) and T2 (r=0.66). Conclusions: Higher degrees of hepatic fibrosis are associated with increased Laws texture. The proposed enhancements improve the accuracy of Laws texture. Enhanced Laws texture features are more accurate than PD and T2 in

  19. WE-FG-206-12: Enhanced Laws Textures: A Potential MRI Surrogate Marker of Hepatic Fibrosis in a Murine Model

    Energy Technology Data Exchange (ETDEWEB)

    Li, B; Yu, H; Jara, H; Soto, J; Anderson, S [Boston University Medical Center, Boston, MA (United States)

    2016-06-15

    Purpose: To compare enhanced Laws texture derived from parametric proton density (PD) maps to other MRI-based surrogate markers (T2, PD, ADC) in assessing degrees of liver fibrosis in a murine model of hepatic fibrosis using 11.7T scanner. Methods: This animal study was IACUC approved. Fourteen mice were divided into control (n=1) and experimental (n=13). The latter were fed a DDC-supplemented diet to induce hepatic fibrosis. Liver specimens were imaged using an 11.7T scanner; the parametric PD, T2, and ADC maps were generated from spin-echo pulsed field gradient and multi-echo spin-echo acquisitions. Enhanced Laws texture analysis was applied to the PD maps: first, hepatic blood vessels and liver margins were segmented/removed using an automated dual-clustering algorithm; secondly, an optimal thresholding algorithm was applied to reduce the partial volume artifact; next, mean and stdev were corrected to minimize grayscale variation across images; finally, Laws texture was extracted. Degrees of fibrosis was assessed by an experienced pathologist and digital image analysis (%Area Fibrosis). Scatterplots comparing enhanced Laws texture, T2, PD, and ADC values to degrees of fibrosis were generated and correlation coefficients were calculated. Unenhanced Laws texture was also compared to assess the effectiveness of the proposed enhancements. Results: Hepatic fibrosis and the enhanced Laws texture were strongly correlated with higher %Area Fibrosis associated with higher Laws texture (r=0.89). Only a moderate correlation was detected between %Area Fibrosis and unenhanced Laws texture (r=0.70). Strong correlation also existed between ADC and %Area Fibrosis (r=0.86). Moderate correlations were seen between %Area Fibrosis and PD (r=0.65) and T2 (r=0.66). Conclusions: Higher degrees of hepatic fibrosis are associated with increased Laws texture. The proposed enhancements improve the accuracy of Laws texture. Enhanced Laws texture features are more accurate than PD and T2 in

  20. Discrete Microstructural Cues for the Attenuation of Fibrosis Following Myocardial Infarction

    OpenAIRE

    Pinney, James R.; Du, Kim; Ayala, Perla; Fang, Qizhi; Sievers, Rich; Chew, Patrick; Delrosario, Lawrence; Lee, Randall J.; Desai, Tejal A.

    2014-01-01

    Chronic fibrosis caused by acute myocardial infarction (MI) leads to increased morbidity and mortality due to cardiac dysfunction. We have developed a therapeutic materials strategy that aims to mitigate myocardial fibrosis by utilizing injectable polymeric microstructures to mechanically alter the microenvironment. Polymeric microstructures were fabricated using photolithographic techniques and studied in a three-dimensional culture model of the fibrotic environment and by direct injection i...

  1. Pulmonary fibrosis and exposure to steel welding fume.

    Science.gov (United States)

    Cosgrove, M P

    2015-12-01

    Arc welders who have been exposed to high concentrations of steel welding fume for prolonged periods of time may develop pulmonary fibrosis but the nature of the fibrotic changes has been debated over the last 80 years without any clear international consensus. To characterize the nature of the pulmonary fibrosis that develops in response to steel welding fume exposure and to provide a working hypothesis that would explain the findings of the existing research, to provide a platform for future research and to inform future occupational and clinical management of welders with pulmonary effects from welding fume. Review of the world literature on pulmonary fibrosis and welding of steel in all languages using PubMed, with further secondary search of references in the articles found in the primary search. Google and Reference Manager were used as further confirmatory search tools. Only case series and case reports were found but these provided consistent evidence that the consequence of exposure to steel welding fume at high levels for a prolonged period of time is a type of pulmonary fibrosis similar to, and possibly the same as, respiratory bronchiolitis which eventually develops into desquamative interstitial pneumonia with ongoing exposure. Steel welding fume may cause an occupational respiratory bronchiolitis which may develop into de squamative interstitial pneumonia with ongoing exposure. This concept may explain the difficulties in interpreting the wider literature on welding fume and lung function at lower exposures and may also explain the increased risk of lung cancer in welders. © The Author 2015. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  2. The Sociology and Entrenchment. A Cystic Fibrosis Test for Everyone?

    DEFF Research Database (Denmark)

    Koch, Lene; Stemerding, Dirk

    1994-01-01

    Socialmedicine, genetic screening, cystic fibrosis, ethics, political regulation, sociology of technology......Socialmedicine, genetic screening, cystic fibrosis, ethics, political regulation, sociology of technology...

  3. Description and validation of a scoring system for tomosynthesis in pulmonary cystic fibrosis.

    Science.gov (United States)

    Vult von Steyern, Kristina; Björkman-Burtscher, Isabella M; Höglund, Peter; Bozovic, Gracijela; Wiklund, Marie; Geijer, Mats

    2012-12-01

    To design and validate a scoring system for tomosynthesis (digital tomography) in pulmonary cystic fibrosis. A scoring system dedicated to tomosynthesis in pulmonary cystic fibrosis was designed. Three radiologists independently scored 88 pairs of radiographs and tomosynthesis examinations of the chest in 60 patients with cystic fibrosis and 7 oncology patients. Radiographs were scored according to the Brasfield scoring system and tomosynthesis examinations were scored using the new scoring system. Observer agreements for the tomosynthesis score were almost perfect for the total score with square-weighted kappa >0.90, and generally substantial to almost perfect for subscores. Correlation between the tomosynthesis score and the Brasfield score was good for the three observers (Kendall's rank correlation tau 0.68, 0.77 and 0.78). Tomosynthesis was generally scored higher as a percentage of the maximum score. Observer agreements for the total score for Brasfield score were almost perfect (square-weighted kappa 0.80, 0.81 and 0.85). The tomosynthesis scoring system seems robust and correlates well with the Brasfield score. Compared with radiography, tomosynthesis is more sensitive to cystic fibrosis changes, especially bronchiectasis and mucus plugging, and the new tomosynthesis scoring system offers the possibility of more detailed and accurate scoring of disease severity. Tomosynthesis is more sensitive than conventional radiography for pulmonary cystic fibrosis changes. The radiation dose from chest tomosynthesis is low compared with computed tomography. Tomosynthesis may become useful in the regular follow-up of patients with cystic fibrosis.

  4. Blood lipids analysis in patients with hepatitis and hepatic fibrosis

    International Nuclear Information System (INIS)

    Si Jianhong

    2007-01-01

    Objective: To investigate the correlationship between blood hepatic fibrosis markers and blood lipids levels. Methods: Serum hepatic fibrosis markers (HA, PC III, IV-C, LN) levels were determined with RIA and serum lipids (TG, TCh HDL; LDL, apoA1, apoB) were measured with biochemical methods in 98 patients with hepatitis in various stages and 50 controls. Liver biopsy was done in all the hepatitis patients. Results: Hepatic fibrosis was classified into 5 grades (S0-S4) according to the pathology shown in the biopsy specimen. The serum lipid levels decreased along with the increase of severity of fibrosis from S0 to S4. Levels in S4 patients were significantly lower than those in controls (P 0.05). Conclusion: The serum hepatic fibrosis markers levels increased and lipids levels decreased along with the progress of hepatitis from acute to cirrhosis. (authors)

  5. [Effects and mechanisms of ursodeoxycholic acid on isoprenaline-Induced myocardial fibrosis in mice].

    Science.gov (United States)

    Li, X; Han, K Q; Shi, Y N; Men, S Z; Li, S; Sun, M H; Dong, H; Lu, J J; Ma, L J; Zhao, M; Li, D; Liu, W

    2017-02-07

    Objective: To investigate the effects and possible mechanisms of ursodeoxycholic acid (UDCA) on myocardial fibrosis in mice. Method: To observe the expression of transforming growth factor(TGF) -β1, CTGF, MMPs and the degree of myocardial fibrosis, 61 male Kunming mice were randomly divided into normal group, low dose UDCA group, high dose of UDCA group, spironolactone group, and the control group.Isoproterenol (ISO) injection was given subcutaneously (30 d) to make the model of myocardial fibrosis.Corresponding anti-fibrosis drugs (UDCA or spironolactone) were given by gavage.HE staining and Masson staining were performed to explore the inflammation and fibrosis in the myocardium.The expression of collagen Ⅰ and collagen Ⅲ protein was detected by immunohistochemistry to evaluate the degree of fibrosis among the groups.Western blot was used to detect the expression of transforming growth factor, (TGF)-β1, connective tissue growth factor (CTGF), matrix metalloproteinase (MMP)-2, -9, tissue inhibitor of metalloproteinase (TIMP)-4, -1 and anti-phospho-NFKBIA (p-IκB-α) inhibitor of NF-κB (IκB) protein in myocardium. Results: HE and Masson staining results showed that in the normal group, myocardial fibrosis is less, while the control group showed a large amount of fibrotic tissue ( P 0.05). UDCA decrease p-IκB-α expression and increase IκB protein expression dose-dependently. Conclusions: UDCA can relieve isoproterenol induced myocardial fibrosis and reduce the myocardial collagen Ⅰ and collagen Ⅲ deposition in a dose dependent manner.Down-regulating of TGFβ-1 protein expression through the inhibition of TGR5-NF-κB signal transduction pathway might be a potential mechanism underlying UDCA's effects.

  6. Cardiac sympathetic neuronal damage precedes myocardial fibrosis in patients with Anderson-Fabry disease

    International Nuclear Information System (INIS)

    Imbriaco, Massimo; Piscopo, Valentina; Ponsiglione, Andrea; Nappi, Carmela; Puglia, Marta; Dell'Aversana, Serena; Spinelli, Letizia; Cuocolo, Alberto; Pellegrino, Teresa; Petretta, Mario; Riccio, Eleonora; Pisani, Antonio

    2017-01-01

    Cardiac sympathetic denervation may be detectable in patients with Anderson-Fabry disease (AFD), suggesting its usefulness for early detection of the disease. However, the relationship between sympathetic neuronal damage measured by 123 I-metaiodobenzylguanidine (MIBG) imaging with myocardial fibrosis on cardiac magnetic resonance (CMR) is still unclear. Cardiac sympathetic innervation was assessed by 123 I-MIBG single-photon emission computed tomography (SPECT) in 25 patients with genetically proved AFD. Within one month from MIBG imaging, all patients underwent contrast-enhanced CMR. MIBG defect size and fibrosis size on CMR were measured for the left ventricle (LV) and expressed as %LV. Patients were divided into three groups according to MIBG and CMR findings: (1) matched normal, without MIBG defects and without fibrosis on CMR (n = 10); (2) unmatched, with MIBG defect but without fibrosis (n = 5); and (3) matched abnormal, with MIBG defect and fibrosis (n = 10). The three groups did not differ with respect to age, gender, α-galactosidase, proteinuria, glomerular filtration rate, and troponin I, while New York Heart Association class (p = 0.008), LV hypertrophy (p = 0.05), and enzyme replacement therapy (p = 0.02) were different among groups. Although in patients with matched abnormal findings, there was a significant correlation between MIBG defect size and area of fibrosis at CMR (r 2 = 0.98, p < 0.001), MIBG defect size was larger than fibrosis size (26 ± 23 vs. 18 ± 13%LV, p = 0.02). Sympathetic neuronal damage is frequent in AFD patients, and it may precede myocardial damage, such as fibrosis. Thus, 123 I-MIBG imaging can be considered a challenging technique for early detection of cardiac involvement in AFD. (orig.)

  7. Vascular dysfunction by myofibroblast activation in patients with idiopathic pulmonary fibrosis and prognostic significance

    Directory of Open Access Journals (Sweden)

    E.R. Parra

    2012-07-01

    Full Text Available In this study, we demonstrated the importance of telomerase protein expression and determined the relationships among telomerase, endothelin-1 (ET-1 and myofibroblasts during early and late remodeling of parenchymal and vascular areas in usual interstitial pneumonia (UIP using 27 surgical lung biopsies from patients with idiopathic pulmonary fibrosis (IPF. Telomerase+, myofibroblasts α-SMA+, smooth muscle cells caldesmon+, endothelium ET-1+ cellularity, and fibrosis severity were evaluated in 30 fields covering normal lung parenchyma, minimal fibrosis (fibroblastic foci, severe (mural fibrosis, and vascular areas of UIP by the point-counting technique and a semiquantitative score. The impact of these markers was determined in pulmonary functional tests and follow-up until death from IPF. Telomerase and ET-1 expression was significantly increased in normal and vascular areas compared to areas of fibroblast foci. Telomerase and ET-1 expression was inversely correlated with minimal fibrosis in areas of fibroblast foci and directly associated with severe fibrosis in vascular areas. Telomerase activity in minimal fibrosis areas was directly associated with diffusing capacity of the lung for oxygen/alveolar volume and ET-1 expression and indirectly associated with diffusing capacity of the lungs for carbon monoxide and severe fibrosis in vascular areas. Cox proportional hazards regression revealed a low risk of death for females with minimal fibrosis displaying high telomerase and ET-1 expression in normal areas. Vascular dysfunction by telomerase/ET-1 expression was found earlier than vascular remodeling by myofibroblast activation in UIP with impact on IPF evolution, suggesting that strategies aimed at preventing the effect of these mediators may have a greater impact on patient outcome.

  8. Gluteal muscle fibrosis with abduction contracture of the hip.

    Science.gov (United States)

    Al Bayati, Mohammed Ali; Kraidy, Bakir Kadhum

    2016-03-01

    Gluteal muscle fibrosis with hip contracture is a rare condition and causes major disability; literature reports are sparse. The aim of this study is to present, for the first time in Iraq and the region, a case series of gluteal fibrosis and the results of surgical treatment. Seven children--six boys and one girl--diagnosed as having gluteal muscle fibrosis with hip contracture, were investigated and treated by open surgical release of fibrotic bands and physiotherapy. All patients improved dramatically over the subsequent weeks, and were able to sit and squat in the normal position. Gluteal muscle fibrosis with hip contracture is present in Iraq and more awareness is needed for early diagnosis. Surgical treatment provided excellent results. More studies are needed to delineate the aetiology of the condition.

  9. Idiopathic pulmonary fibrosis in a Staffordshire bull terrier with hypothyroidism.

    Science.gov (United States)

    Corcoran, B M; Dukes-McEwan, J; Rhind, S; French, A

    1999-04-01

    Radiographic evidence of chronic interstitial lung changes, usually believed to be attributable to lung fibrosis, is readily recognised in canine practice. Furthermore, there is a body of anecdotal evidence suggesting that a specific clinical entity consistent with chronic lung fibrosis occurs in specific breeds of terrier dogs. However, there is little pathological data to confirm these radiographic and clinical findings and, therefore, chronic interstitial lung disease of dogs is poorly characterised. In this report, a case of chronic pulmonary fibrosis is described in which histopathological confirmation was possible, and suggested that the condition might be analogous to idiopathic pulmonary fibrosis (cryptogenic fibrosing alveolitis) in humans.

  10. Effects of aspirin and enoxaparin in a rat model of liver fibrosis.

    Science.gov (United States)

    Li, Chen-Jie; Yang, Zhi-Hui; Shi, Xiao-Liu; Liu, De-Liang

    2017-09-21

    To examine the effects of aspirin and enoxaparin on liver function, coagulation index and histopathology in a rat model of liver fibrosis. METHODS Forty-five male Sprague-Dawley rats were randomly divided into the control group (n = 5) and model group (n = 40). Thioacetamide (TAA) was used to induce liver fibrosis in the model group. TAA-induced fibrotic rats received TAA continuously (n = 9), TAA + low-dose aspirin (n = 9), TAA + high-dose aspirin (n = 9) or TAA + enoxaparin (n = 9) for 4 wk. All rats were euthanized after 4 wk, and both hematoxylin-eosin and Masson staining were performed to observe pathological changes in liver tissue. Liver fibrosis was assessed according to the METAVIR score. Compared with untreated cirrhotic controls, a significant improvement in fibrosis grade was observed in the low-dose aspirin, high-dose aspirin and enoxaparin treated groups, especially in the high-dose aspirin treated group. Alanine aminotransferase and total bilirubin were higher, albumin was lower and both prothrombin time and international normalized ratio were prolonged in the four treatment groups compared to controls. No significant differences among the four groups were observed. Aspirin and enoxaparin can alleviate liver fibrosis in this rat model.

  11. Pathological and radiological correlation in an autopsy case of combined pulmonary fibrosis and emphysema

    Directory of Open Access Journals (Sweden)

    Karata H

    2015-07-01

    Full Text Available Hiroki Karata,1 Tomonori Tanaka,1 Ryoko Egashira,2 Kazuhiro Tabata,1 Kyoko Otani,3 Ryuji Hayashi,4 Takashi Hori,5 Junya Fukuoka1 1Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; 2Department of Radiology, Faculty of Medicine, Saga University, Saga, Japan; 3Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Japan; 4Department of Internal Medicine, University of Toyama, Faculty of Medicine, Toyama, Japan; 5Laboratory of Pathology, Toyama University Hospital, Toyama, Japan Abstract: We report an educational autopsy case of combined pulmonary fibrosis and emphysema. Radiological patterns of the upper lung were considered as mostly emphysema, but pathological observation revealed significant interstitial fibrosis of usual interstitial pneumonia as a major pathology. The patient eventually developed acute exacerbation of background interstitial pneumonia. Careful radiological and pathological correlation of the current case indicates that regions with distal acinar emphysema on computed tomography image may possess histologically marked dense fibrosis of lethal interstitial pneumonia. Keywords: interstitial pneumonia, CPFE, AEF, smoking, CT

  12. Novel form of miR-29b suppresses bleomycin-induced pulmonary fibrosis.

    Directory of Open Access Journals (Sweden)

    Yuko Yamada

    Full Text Available MicroRNA 29b (miR-29b replacement therapy is effective for suppressing fibrosis in a mouse model. However, to develop clinical applications for miRNA mimics, the side effects of nucleic acid drugs have to be addressed. In this study, we focused on miRNA mimics in order to develop therapies for idiopathic pulmonary fibrosis. We developed a single-stranded RNA, termed "miR-29b Psh-match," that has a unique structure to avoid problems associated with the therapeutic uses of miRNAs. A comparison of miR-29b Psh-match and double-stranded one, termed "miR-29b mimic" indicated that the single-stranded form was significantly effective towards fibrosis according to both in vivo and in vitro experiments. This novel form of miR-29b may become the foundation for developing an effective therapeutic drug for pulmonary fibrosis.

  13. Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis

    Directory of Open Access Journals (Sweden)

    Nico Derichs

    2013-03-01

    Full Text Available Cystic fibrosis (CF is caused by genetic mutations that affect the cystic fibrosis transmembrane conductance regulator (CFTR protein. These mutations can impact the synthesis and transfer of the CFTR protein to the apical membrane of epithelial cells, as well as influencing the gating or conductance of chloride and bicarbonate ions through the channel. CFTR dysfunction results in ionic imbalance of epithelial secretions in several organ systems, such as the pancreas, gastrointestinal tract, liver and the respiratory system. Since discovery of the CFTR gene in 1989, research has focussed on targeting the underlying genetic defect to identify a disease-modifying treatment for CF. Investigated management strategies have included gene therapy and the development of small molecules that target CFTR mutations, known as CFTR modulators. CFTR modulators are typically identified by high-throughput screening assays, followed by preclinical validation using cell culture systems. Recently, one such modulator, the CFTR potentiator ivacaftor, was approved as an oral therapy for CF patients with the G551D-CFTR mutation. The clinical development of ivacaftor not only represents a breakthrough in CF care but also serves as a noteworthy example of personalised medicine.

  14. Fibroblasts in fibrosis: novel roles and mediators

    Directory of Open Access Journals (Sweden)

    Ryan Thomas Kendall

    2014-05-01

    Full Text Available Fibroblasts are the most common cell type of the connective tissues found throughout the body and the principal source of the extensive extracellular matrix (ECM characteristic of these tissues. They are also the central mediators of the pathological fibrotic accumulation of ECM and the cellular proliferation and differentiation that occurs in response to prolonged tissue injury and chronic inflammation. The transformation of the fibroblast cell lineage involves classical developmental signaling programs and includes a surprisingly diverse range of precursor cell types—most notably, myofibroblasts that are the apex of the fibrotic phenotype. Myofibroblasts display exaggerated ECM production; constitutively secrete and are hypersensitive to chemical signals such as cytokines, chemokines, and growth factors; and are endowed with a contractile apparatus allowing them to manipulate the ECM fibers physically to close open wounds. In addition to ECM production, fibroblasts have multiple concomitant biological roles, such as in wound healing, inflammation, and angiogenesis, which are each interwoven with the process of fibrosis. We now recognize many common fibroblast-related features across various physiological and pathological protracted processes. Indeed, a new appreciation has emerged for the role of noncancerous fibroblast interactions with tumors in cancer progression. Although the predominant current clinical treatments of fibrosis involve nonspecific immunosuppressive and anti-proliferative drugs, a variety of potential therapies under investigation specifically target fibroblast biology.

  15. induced pulmonary fibrosis in mice via regulation of IL

    African Journals Online (AJOL)

    TRAF6, IL-33 and ST2 in lung tissue were determined by western blotting assay. Serum levels of ..... facilitate excessive tissue repair and fibrosis [20]. Therefore ... to cancer biology. ... liver regeneration, fibrosis and carcinogenesis. Hepatol.

  16. Fibrocytes in pulmonary fibrosis: a brief synopsis

    Directory of Open Access Journals (Sweden)

    Shyam Maharaj

    2013-12-01

    Full Text Available Fibrocytes are bone marrow-derived, circulating mesenchymal progenitor cells that play a role in several fibrotic disorders, including lung fibrosis. They are attracted to injured tissue by various chemokines. It is likely that fibrocytes play a detrimental role in tissue homeostasis and promote fibrosis, although this paradigm needs further confirmation. This would make fibrocytes a possible novel treatment target for fibrotic disorders. Fibrocytes also have some potential as a biomarker for idiopathic pulmonary fibrosis (IPF and other diseases, but the promising preliminary data from single centre studies still require independent validation. Despite several, as yet, unresolved issues, it has become clear that fibrocytes are more than an incidental finding in lung injury and repair, and may hold great promise for the future of IPF management.

  17. Areca nut and its role in oral submucous fibrosis.

    Science.gov (United States)

    Prabhu, Rachana V; Prabhu, Vishnudas; Chatra, Laxmikanth; Shenai, Prashant; Suvarna, Nithin; Dandekeri, Savita

    2014-12-01

    Areca nut, commonly called as betel nut or supari, is a fruit of areca catechu palm tree, which is native of South Asia and Pacific Islands. The seed or endosperm is consumed fresh, boiled or after sun drying or curing. Chewing areca nut is thought to have central nervous system stimulating effect and along with this it is known to have salivary stimulating and digestive properties. According to the traditional Ayurvedic medicine, chewing areca nut and betel leaf is a good remedy against halitosis. It is also used for its deworming property. Along with these beneficial effects of areca nut one of its most harmful effects on the human body in general and oral cavity in particular is the development of potentially malignant disorder called Oral Submucous Fibrosis. The present paper discusses in detail the effects of the components of areca nut on pathogenesis of Oral Submucous Fibrosis. Key words:Areca nut, oral submucous fibrosis, potentially malignant disorder, supari.

  18. Elucidation of the therapeutic role of mitochondrial biogenesis transducers NRF-1 in the regulation of renal fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Hsieh, Pei-Fang [Graduate Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung, Taiwan (China); Graduate Institute of Medical Laboratory Science and Biotechnology, Chung Hwa University of Medical Technology, Tainan, Taiwan (China); Liu, Shu-Fen [Department of Internal Medicine, Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung, Taiwan (China); Hung, Tsung-Jen [Graduate Institute of Biomedical Science, Chung Hwa University of Medical Technology, Tainan, Taiwan (China); Hung, Chien-Ya [Department of Food Nutrition, Chung Hwa University of Medical Technology, Tainan, Taiwan (China); Liu, Guo-Zheng [Graduate Institute of Medical Laboratory Science and Biotechnology, Chung Hwa University of Medical Technology, Tainan, Taiwan (China); Chuang, Lea-Yea [Department of Biochemistry, Kaohsiung Medical University, Kaohsiung, Taiwan (China); Chen, Mei-Fen [Department of Acupressure Technology, Chung Hwa University of Medical Technology, Tainan, Taiwan (China); Wang, Jue-Long [Department of Physical Medicine and Rehabilitation, Kaohsiung Veterans General Hospital, Taiwan (China); Shi, Ming-Der [Graduate Institute of Medical Laboratory Science and Biotechnology, Chung Hwa University of Medical Technology, Tainan, Taiwan (China); Department of Medical Technology, Kaohsiung Veterans General Hospital Tainan Branch, Tainan, Taiwan (China); Hsu, Chen Hung [Department of Biological Science and Technology, Chung Hwa University of Medical Technology, Tainan, Taiwan (China); Shiue, Yow-Ling, E-mail: shiue.shirley@gmail.com [Graduate Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung, Taiwan (China); Yang, Yu-Lin, E-mail: Call0955443221@gmail.com [Graduate Institute of Medical Laboratory Science and Biotechnology, Chung Hwa University of Medical Technology, Tainan, Taiwan (China); Graduate Institute of Biomedical Science, Chung Hwa University of Medical Technology, Tainan, Taiwan (China)

    2016-11-15

    Background: Mitochondrial dysfunction is a newly established risk factor for the development of renal fibrosis. Cell survival and injury repair is facilitated by mitochondrial biogenesis. Nuclear respiratory factor 1 (NRF-1) is a transcriptional regulation factor that plays a central role in the regulation of mitochondrial biogenesis. However, the transcription factor of this process in renal fibrosis is unknown. Thus, we hereby discussed the correlations of NRF-1 and renal interstitial fibrosis. Materials and methods: In vitro fibrosis model was established by treatment with transforming growth factor-β1 (TGF-β1) in NRK-49F (Normal Rat kidney fibroblast). We investigated the ROS production, mitochondrial biogenesis and fibrogenic marker (e.q. fibronectin) during the progression of renal fibrosis by kit and Western blotting assay. Here, we used that two distinct mechanisms regulate NRF-1 activation and degradation of NRF-1. NRF-1 was transfect by pcDNA-NRF-1 overexpression gene to evaluate the NRF-1 activity of the therapeutic effect in renal fibrosis. In addition, NRF-1 was silenced by shRNA-NRF-1 to evaluate the significance of NRF-1. ELISA was used to evaluate the secreted fibronectin. Immunofluorescence staining was used to assay the in situ expression of proteins (e.g. fibronectin, NRF-1). Results: Under renal fibrosis conditions, TGF-β1 (5 ng/ml) increased ROS. Simultaneously, TGF-β1-induced extracellular fibronectin by ELISA assay. In addition, TGF-β1 decreased expression of mitochondrial biogenesis. This is the first time to demonstrate that expression of NRF-1 is significantly decreased in renal fibrosis. However, NRK49F was a transfection with pcDNA-NRF-1 (2 μg/ml) expression vector dramatically reverse TGF-β1-induced cellular fibrosis concomitantly with the suppression of fibronectin (both intracellular and extracellular fibronectin). More importantly, transfection with shRNA-NRF-1 (2 μg/ml) significantly increased the expression of fibronectin

  19. Magnetic resonance elastography is as accurate as liver biopsy for liver fibrosis staging.

    Science.gov (United States)

    Morisaka, Hiroyuki; Motosugi, Utaroh; Ichikawa, Shintaro; Nakazawa, Tadao; Kondo, Tetsuo; Funayama, Satoshi; Matsuda, Masanori; Ichikawa, Tomoaki; Onishi, Hiroshi

    2018-05-01

    Liver MR elastography (MRE) is available for the noninvasive assessment of liver fibrosis; however, no previous studies have compared the diagnostic ability of MRE with that of liver biopsy. To compare the diagnostic accuracy of liver fibrosis staging between MRE-based methods and liver biopsy using the resected liver specimens as the reference standard. A retrospective study at a single institution. In all, 200 patients who underwent preoperative MRE and subsequent surgical liver resection were included in this study. Data from 80 patients were used to estimate cutoff and distributions of liver stiffness values measured by MRE for each liver fibrosis stage (F0-F4, METAVIR system). In the remaining 120 patients, liver biopsy specimens were obtained from the resected liver tissues using a standard biopsy needle. 2D liver MRE with gradient-echo based sequence on a 1.5 or 3T scanner was used. Two radiologists independently measured the liver stiffness value on MRE and two types of MRE-based methods (threshold and Bayesian prediction method) were applied. Two pathologists evaluated all biopsy samples independently to stage liver fibrosis. Surgically resected whole tissue specimens were used as the reference standard. The accuracy for liver fibrosis staging was compared between liver biopsy and MRE-based methods with a modified McNemar's test. Accurate fibrosis staging was achieved in 53.3% (64/120) and 59.1% (71/120) of patients using MRE with threshold and Bayesian methods, respectively, and in 51.6% (62/120) with liver biopsy. Accuracies of MRE-based methods for diagnoses of ≥F2 (90-91% [108-9/120]), ≥F3 (79-81% [95-97/120]), and F4 (82-85% [98-102/120]) were statistically equivalent to those of liver biopsy (≥F2, 79% [95/120], P ≤ 0.01; ≥F3, 88% [105/120], P ≤ 0.006; and F4, 82% [99/120], P ≤ 0.017). MRE can be an alternative to liver biopsy for fibrosis staging. 3. Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1268-1275. © 2017

  20. Nephrogenic systemic fibrosis

    DEFF Research Database (Denmark)

    Khurram, Misbah; Skov, Lone; Rossen, Kristian

    2007-01-01

    Nephrogenic systemic fibrosis (NSF) is a fibrotic disease seen in renal failure patients that may lead to severe physical disability. It has been demonstrated in recent studies that NSF can be caused by some gadolinium-containing MRI contrast agents. In this report we present one of a total of 26...

  1. PTP1B confers liver fibrosis by regulating the activation of hepatic stellate cells

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Pei-Jie; Cai, Shuang-Peng; Yang, Yang; Li, Wan-Xia; Huang, Cheng; Meng, Xiao-Ming; Li, Jun, E-mail: lj@ahmu.edu.cn

    2016-02-01

    Liver fibrosis is a reversible wound-healing response to chronic hepatic injuries. Activation of hepatic stellate cells (HSCs) plays a pivotal role in the development of hepatic fibrosis. The currently accepted mechanism for the resolution of liver fibrosis is the apoptosis and inactivation of activated HSCs. Protein tyrosine phosphatase 1B (PTP1B), a prototype of non-receptor protein tyrosine phosphatase, is proved to be a vital modulator in cardiac fibrogenesis. However, the precise role of PTP1B on liver fibrosis and HSC activation is still unclear. Our study showed that the expression of PTP1B was elevated in fibrotic liver but reduced after spontaneous recovery. Moreover, stimulation of HSC-T6 cells with transforming growth factor-β1 (TGF-β1) resulted in a dose/time-dependent increase of PTP1B mRNA and protein. Co-incubation of HSC-T6 cells with PTP1B-siRNA inhibited the cell proliferation and activation induced by TGF-β1. Additionally, both mRNA and protein of PTP1B were dramatically decreased in inactivated HSCs after treated with adipogenic differentiation mixture (MDI). Over-expression of PTP1B hindered the inactivation of HSC-T6 cells induced by MDI. These observations revealed a regulatory role of PTP1B in liver fibrosis and implied PTP1B as a potential therapeutic target. - Highlights: • The expression of PTP1B in the fibrotic livers and recovery livers • The expression of PTP1B in activated and inactivated HSCs • Blockade of PTP1B inhibited the TGF-β1-induced proliferation and activation of HSCs. • Over-expression of PTP1B abolished the inactivation of HSCs induced by MDI.

  2. PTP1B confers liver fibrosis by regulating the activation of hepatic stellate cells

    International Nuclear Information System (INIS)

    Chen, Pei-Jie; Cai, Shuang-Peng; Yang, Yang; Li, Wan-Xia; Huang, Cheng; Meng, Xiao-Ming; Li, Jun

    2016-01-01

    Liver fibrosis is a reversible wound-healing response to chronic hepatic injuries. Activation of hepatic stellate cells (HSCs) plays a pivotal role in the development of hepatic fibrosis. The currently accepted mechanism for the resolution of liver fibrosis is the apoptosis and inactivation of activated HSCs. Protein tyrosine phosphatase 1B (PTP1B), a prototype of non-receptor protein tyrosine phosphatase, is proved to be a vital modulator in cardiac fibrogenesis. However, the precise role of PTP1B on liver fibrosis and HSC activation is still unclear. Our study showed that the expression of PTP1B was elevated in fibrotic liver but reduced after spontaneous recovery. Moreover, stimulation of HSC-T6 cells with transforming growth factor-β1 (TGF-β1) resulted in a dose/time-dependent increase of PTP1B mRNA and protein. Co-incubation of HSC-T6 cells with PTP1B-siRNA inhibited the cell proliferation and activation induced by TGF-β1. Additionally, both mRNA and protein of PTP1B were dramatically decreased in inactivated HSCs after treated with adipogenic differentiation mixture (MDI). Over-expression of PTP1B hindered the inactivation of HSC-T6 cells induced by MDI. These observations revealed a regulatory role of PTP1B in liver fibrosis and implied PTP1B as a potential therapeutic target. - Highlights: • The expression of PTP1B in the fibrotic livers and recovery livers • The expression of PTP1B in activated and inactivated HSCs • Blockade of PTP1B inhibited the TGF-β1-induced proliferation and activation of HSCs. • Over-expression of PTP1B abolished the inactivation of HSCs induced by MDI.

  3. IL-10 is significantly involved in HSP70-regulation of experimental subretinal fibrosis.

    Directory of Open Access Journals (Sweden)

    Yang Yang

    Full Text Available Subretinal fibrosis is directly related to severe visual loss, especially if occurs in the macula, and is frequently observed in advanced age-related macular degeneration and other refractory eye disorders such as diabetic retinopathy and uveitis. In this study, we analyzed the immunosuppressive mechanism of subretinal fibrosis using the novel animal model recently demonstrated. Both TLR2 and TLR4 deficient mice showed significant enlargement of subretinal fibrotic area as compared with wild-type mice. A single intraocular administration of heat shock protein 70 (HSP70, which is an endogenous ligand for TLR2 and TLR4, inhibited subretinal fibrosis in wild-type mice but not in TLR2 and TLR4-deficient mice. Additionally, HSP70 induced IL-10 production in eyes from wild-type mice but was impaired in both TLR2- and TLR4-deficient mice, indicating that HSP70-TLR2/TLR4 axis plays an immunomodulatory role in subretinal fibrosis. Thus, these results suggest that HSP70-TLR2/TLR4 axis is a new therapeutic target for subretinal fibrosis due to prognostic CNV.

  4. Non-invasive liver fibrosis score calculated by combination of virtual touch tissue quantification and serum liver functional tests in chronic hepatitis C patients.

    Science.gov (United States)

    Takaki, Shintaro; Kawakami, Yoshiiku; Miyaki, Daisuke; Nakahara, Takashi; Naeshiro, Noriaki; Murakami, Eisuke; Tanaka, Mio; Honda, Yohji; Yokoyama, Satoe; Nagaoki, Yuko; Kawaoka, Tomokazu; Hiramatsu, Akira; Tsuge, Masataka; Hiraga, Nobuhiko; Imamura, Michio; Hyogo, Hideyuki; Aikata, Hiroshi; Takahashi, Shoichi; Arihiro, Koji; Chayama, Kazuaki

    2014-03-01

    Acoustic radiation force impulse (ARFI) technology, involving the shear wave velocity (SWV) with virtual touch tissue quantification (VTTQ), are currently available for the assessment of liver fibrosis, while there is no index derived from the combination of SWV and blood tests. The aim of this study was to develop a new index for assessment of liver fibrosis. The subjects were 176 consecutive patients with hepatitis C (training set [n = 120] and validation set [n = 56]) who underwent liver biopsy in our institution. In the training set, SWV, international normalized ratio (INR) and alanine aminotransferase (ALT) correlated independently and significantly with fibrosis. According to this, we developed the VIA index = -1.282 + 0.965 × SWV + 1.785 INR + 0.00185 ALT. The areas under the receiver-operator curve (AUROC) of the VIA index were 0.838 for the diagnosis of significant fibrosis (≥F2), 0.904 for the severe fibrosis (≥F3) and 0.958 for the cirrhosis (F4) in the training set. While in the validation set, AUROC of the VIA index were 0.917 for F2 or higher, 0.906 for F3 or higher and 1.000 for F4, respectively. AUROC of the VIA index was improved compared to SWV alone, equivalent for VIA for the diagnosis of F2 or higher, and superior to that of FIB-4 index and aspartate aminotransferase-to-platelet ratio index for the diagnosis of F3 or higher and F4. The VIA index is potentially more useful for assessment of liver fibrosis than SWV alone, and easily and accurately measures liver fibrosis stage. © 2013 The Japan Society of Hepatology.

  5. Localized bilateral perirenal fibrosis, a rare cause of idiopathic retroperitoneal fibrosis

    Directory of Open Access Journals (Sweden)

    Maja Kveder

    2014-08-01

    Full Text Available Background: Idiopathic retroperitoneal fibrosis is an infrequent process of unknown aetiology characterised by fibrous tissue proliferation in the retroperitoneum. Even less frequent is a localized form of this disease by a proliferation of fibrous tissue around single or both kidneys.Case report: We describe a case of 46-year old man in whom medical management was started for accidentally discovered arterial hypertension, which turned out to be difficult to control.   During diagnostic work-up of hypertension, an abdominal ultrasound was obtained a year later demonstrating slight bilateral caliectasis without obvious visible cause for it. Laboratory exams have shown significantly impaired renal function, normocytic anaemia, slightly higher sedimentation rate, increased CRP and normal urinalysis. Nephrologist has decided for hospitalisation during which magnetic resonance imaging was performed  showing a few mm wide tissue coats surrounding both kidneys with fluid lying between the coat and kidney capsule. A biopsy of perirenal mass has confirmed a dense cellular lesion consisted of interweaved fascicles of spindle-shaped cells. After exclusion of tumours and other causes, a diagnosis of retroperitoneal fibrosis was confirmed. Clinical picture and laboratory data corresponded to idiopathic form of this disease. A treatment with tamoxifen was started after patient refused treatment with methylprednisolone. During tamoxifen monotherapy, there was gradual significant improvement of general symptoms, notable decline in inflammation markers, improvement of anaemia, normalisation of kidney function, and normalisation of blood pressure. Conclusion: Retroperitoneal fibrosis is still an obscure and multifaceted disease. A proper selection of diagnostic methods is the key to correct and fast diagnosis as well as good grounding for proper treatment.

  6. Asthma and cystic fibrosis: A tangled web.

    LENUS (Irish Health Repository)

    Kent, Brian D

    2014-03-01

    Successfully diagnosing concomitant asthma in people with cystic fibrosis (CF) is a challenging proposition, and the utility of conventional diagnostic criteria of asthma in CF populations remains uncertain. Nonetheless, the accurate identification of individuals with CF and asthma allows appropriate tailoring of therapy, and should reduce the unnecessary use of asthma medication in broader CF cohorts. In this review, we discuss the diagnostic challenge posed by asthma in CF, both in terms of clinical evaluation, and of interpretation of pulmonary function testing and non-invasive markers of airway inflammation. We also examine how the role of cross-sectional thoracic imaging in CF and asthma can assist in the diagnosis of asthma in these patients. Finally, we critically appraise the evidence base behind the use of asthma medications in CF populations, with a particular focus on the use of inhaled corticosteroids and bronchodilators. As shall be discussed, the gaps in the current literature make further high-quality research in this field imperative. Pediatr Pulmonol. 2014; 49:205-213. © 2014 Wiley Periodicals, Inc.

  7. Blunted perception of neural respiratory drive and breathlessness in patients with cystic fibrosis

    Directory of Open Access Journals (Sweden)

    Charles C. Reilly

    2016-03-01

    Full Text Available The electromyogram recorded from the diaphragm (EMGdi and parasternal intercostal muscle using surface electrodes (sEMGpara provides a measure of neural respiratory drive (NRD, the magnitude of which reflects lung disease severity in stable cystic fibrosis. The aim of this study was to explore perception of NRD and breathlessness in both healthy individuals and patients with cystic fibrosis. Given chronic respiratory loading and increased NRD in cystic fibrosis, often in the absence of breathlessness at rest, we hypothesised that patients with cystic fibrosis would be able to tolerate higher levels of NRD for a given level of breathlessness compared to healthy individuals during exercise. 15 cystic fibrosis patients (mean forced expiratory volume in 1 s (FEV1 53.5% predicted and 15 age-matched, healthy controls were studied. Spirometry was measured in all subjects and lung volumes measured in the cystic fibrosis patients. EMGdi and sEMGpara were recorded at rest and during incremental cycle exercise to exhaustion and expressed as a percentage of maximum (% max obtained from maximum respiratory manoeuvres. Borg breathlessness scores were recorded at rest and during each minute of exercise. EMGdi % max and sEMGpara % max and associated Borg breathlessness scores differed significantly between healthy subjects and cystic fibrosis patients at rest and during exercise. The relationship between EMGdi % max and sEMGpara % max and Borg score was shifted to the right in the cystic fibrosis patients, such that at comparable levels of EMGdi % max and sEMGpara % max the cystic fibrosis patients reported significantly lower Borg breathlessness scores compared to the healthy individuals. At Borg score 1 (clinically significant increase in breathlessness from baseline corresponding levels of EMGdi % max (20.2±12% versus 32.15±15%, p=0.02 and sEMGpara % max (18.9±8% versus 29.2±15%, p=0.04 were lower in the healthy individuals compared to the cystic

  8. [Comparison of various noninvasive serum markers of liver fibrosis in chronic viral liver disease].

    Science.gov (United States)

    Kim, Sun Min; Sohn, Joo Hyun; Kim, Tae Yeob; Roh, Young Wook; Eun, Chang Soo; Jeon, Yong Cheol; Han, Dong Soo; Oh, Young Ha

    2009-12-01

    The aim of this study was to determine the clinical performances of noninvasive serum markers for the prediction of liver fibrosis in chronic viral liver diseases. We analyzed a total of 225 patients with chronic viral liver diseases (180 with hepatitis B virus, 43 with hepatitis C virus, and 2 with hepatitis B+C virus) who underwent a liver biopsy procedure at the Hanyang University Guri Hospital between March 2002 and February 2007. Serum was also obtained at the time of liver biopsy. Liver fibrosis was staged according to the scoring system proposed by the Korean Study Group for the Pathology of Digestive Diseases. Various noninvasive serum markers were evaluated, including the aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio (AAR), age-platelet (AP) index, AST/platelet ratio index (APRI), cirrhosis discriminant score (CDS), platelet count, hyaluronic acid (HA), and type IV collagen. There were 17, 40, 61, 74, and 33 patients at stages F0, F1, F2, F3, and F4, respectively. The overall diagnostic accuracies of each marker, as determined by the area under receiver operating characteristics curves, were APRI=0.822, CDS=0.776, platelet count=0.773, AP index=0.756, HA=0.749, type IV collagen=0.718, and AAR=0.642 for predicting significant fibrosis (> or =F2); and CDS=0.835, platelet count=0.795, AP index=0.794, HA=0.766, AAR=0.711, type IV collagen=0.697, and APRI=0.691 for predicting extensive fibrosis (> or =F3). All noninvasive serum markers evaluated in this study were useful for predicting significant or extensive liver fibrosis in chronic viral liver diseases. In particular, APRI was most useful for the prediction of significant fibrosis, and CDS was most useful for the prediction of extensive fibrosis.

  9. A perpetual cascade of cytokines postirradiation leads to pulmonary fibrosis

    International Nuclear Information System (INIS)

    Rubin, Philip; Johnston, Carl J.; Williams, Jacqueline P.; McDonald, Sandra; Finkelstein, Jacob N.

    1995-01-01

    Purpose: Radiation-induced pulmonary reactions have classically been viewed as distinct phases--acute pneumonitis and, later, fibrosis--occurring at different times after irradiation and attributed to different target cell populations. We prefer to view these events as a continuum, with no clear distinction between the temporal sequence of the different pulmonary reactions; the progression is the result of an early activation of an inflammatory reaction, leading to the expression and maintenance of a cytokine cascade. In the current study, we have examined the temporal and spatial expression of cytokine and extracellular matrix messenger ribonucleic acid (mRNA) abundance in fibrosis-sensitive mice after thoracic irradiation. Methods and Materials: Radiation fibrosis-prone ((C57BL(6))) mice received thoracic irradiation of 5 and 12.5 Gy. At Day 1, and 1, 2, 8, 16 and 24 weeks after treatment, animals were killed and lung tissue processed for light microscopy and isolation of RNA. Expression of cytokine and extracellular matrix mRNA abundance was evaluated by slot-blot analysis and cellular localization by in situ hybridization and immunochemistry. Results: One of the cytokines responsible for the inflammatory phase (IL-1α) is elevated at 2 weeks, returns to normal baseline values, then increases at 8 weeks, remaining elevated until 26 weeks when lung fibrosis appears. Transforming growth factor-beta (TGFβ), a proliferative cytokine, is elevated at 2 weeks, persists until 8 weeks, and then returns to baseline values. In parallel with the cytokine cascade, the fibrogenic markers for CI/CIII/IV (collagen genes) correlate by showing a similar early and then later elevation of activity. For instance, the collagen gene expression of CI/CIII is a biphasic response with an initial increase at 1-2 weeks that remits at 8 weeks, remains inactive from 8 to 16 weeks, and then becomes elevated at 6 months when collagen deposition is recognized histopathologically. Conclusion

  10. Chymase: a multifunctional player in pulmonary hypertension associated with lung fibrosis.

    Science.gov (United States)

    Kosanovic, Djuro; Luitel, Himal; Dahal, Bhola Kumar; Cornitescu, Teodora; Janssen, Wiebke; Danser, A H Jan; Garrelds, Ingrid M; De Mey, Jo G R; Fazzi, Gregorio; Schiffers, Paul; Iglarz, Marc; Fischli, Walter; Ghofrani, Hossein Ardeschir; Weissmann, Norbert; Grimminger, Friedrich; Seeger, Werner; Reiss, Irwin; Schermuly, Ralph Theo

    2015-10-01

    Limited literature sources implicate mast-cell mediator chymase in the pathologies of pulmonary hypertension and pulmonary fibrosis. However, there is no evidence on the contribution of chymase to the development of pulmonary hypertension associated with lung fibrosis, which is an important medical condition linked with increased mortality of patients who already suffer from a life-threatening interstitial lung disease.The aim of this study was to investigate the role of chymase in this particular pulmonary hypertension form, by using a bleomycin-induced pulmonary hypertension model.Chymase inhibition resulted in attenuation of pulmonary hypertension and pulmonary fibrosis, as evident from improved haemodynamics, decreased right ventricular remodelling/hypertrophy, pulmonary vascular remodelling and lung fibrosis. These beneficial effects were associated with a strong tendency of reduction in mast cell number and activity, and significantly diminished chymase expression levels. Mechanistically, chymase inhibition led to attenuation of transforming growth factor β1 and matrix-metalloproteinase-2 contents in the lungs. Furthermore, chymase inhibition prevented big endothelin-1-induced vasoconstriction of the pulmonary arteries.Therefore, chymase plays a role in the pathogenesis of pulmonary hypertension associated with pulmonary fibrosis and may represent a promising therapeutic target. In addition, this study may provide valuable insights on the contribution of chymase in the pulmonary hypertension context, in general, regardless of the pulmonary hypertension form. Copyright ©ERS 2015.

  11. Multiple-Breath Washout Outcomes Are Sensitive to Inflammation and Infection in Children with Cystic Fibrosis.

    Science.gov (United States)

    Ramsey, Kathryn A; Foong, Rachel E; Grdosic, Jasmine; Harper, Alana; Skoric, Billy; Clem, Charles; Davis, Miriam; Turkovic, Lidija; Stick, Stephen M; Davis, Stephanie D; Ranganathan, Sarath C; Hall, Graham L

    2017-09-01

    The lung clearance index is a measure of ventilation distribution derived from the multiple-breath washout technique. The lung clearance index is increased in the presence of lower respiratory tract inflammation and infection in infants with cystic fibrosis; however, the associations during the preschool years are unknown. We assessed the ability of the lung clearance index to detect the presence and extent of lower respiratory tract inflammation and infection in preschool children with cystic fibrosis. Ventilation distribution outcomes were assessed at 82 visits with 58 children with cystic fibrosis and at 38 visits with 31 healthy children aged 3-6 years. Children with cystic fibrosis also underwent bronchoalveolar lavage fluid collection for detection of lower respiratory tract inflammation and infection. Associations between multiple-breath washout indices and the presence and extent of airway inflammation and infection were assessed using linear mixed effects models. Lung clearance index was elevated in children with cystic fibrosis (mean [SD], 8.00 [1.45]) compared with healthy control subjects (6.67 [0.56]). In cystic fibrosis, the lung clearance index was elevated in individuals with lower respiratory tract infections (difference compared with uninfected [95% confidence interval], 0.62 [0.06, 1.18]) and correlated with the extent of airway inflammation. These data suggest that the lung clearance index may be a useful surveillance tool for monitoring the presence and extent of lower airway inflammation and infection in preschool children with cystic fibrosis.

  12. Dynamic Contrast-Enhanced Magnetic Resonance Imaging with Gd-EOB-DTPA for the Evaluation of Liver Fibrosis Induced by Carbon Tetrachloride in Rats.

    Directory of Open Access Journals (Sweden)

    Wei Zhang

    Full Text Available To investigate the utility of dynamic contrast-enhanced MRI (DCE-MRI with Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA for detecting liver fibrosis induced by carbon tetrachloride (CCl4 in rats.This study was approved by the institutional animal care and use committee. Liver fibrosis in rats was induced by intraperitoneal injection of 1 mL/kg 50% CCl4 twice a week for 4-13 weeks. Control rats were injected with saline. Liver fibrosis was graded using the Metaviar score: no fibrosis (F0, mild fibrosis (F1-F2 and advanced fibrosis (F3-F4. DCE-MRI with Gd-EOB-DTPA was performed for all rats. Ktrans, Kep, Ve and iAUC of the liver parenchyma were measured. Relative enhancement (RE value of the liver was calculated on T1-weighted images at 15, 20 and 25 min after Gd-EOB-DTPA administration.Thirty-five rats were included: no fibrosis (n=13, mild fibrosis (n=11 and advanced fibrosis (n=11. Ktrans and iAUC values were highest in advanced fibrosis group and lowest in no fibrosis group (P<0.05. The area under the receiver operating characteristic curve (AUROC for fibrosis (stages F1 and greater were 0.773 and 0.882 for Ktrans and iAUC, respectively. AUROC for advanced fibrosis were 0.835 and 0.867 for Ktrans and iAUC, respectively. Kep and RE values were not able to differentiate fibrosis stages (all P>0.05.Ktrans and iAUC obtained from DCE-MRI with Gd-EOB-DTPA are useful for the detection and staging of rat liver fibrosis induced by CCl4.

  13. Cost Effectiveness of Screening Individuals With Cystic Fibrosis for Colorectal Cancer.

    Science.gov (United States)

    Gini, Andrea; Zauber, Ann G; Cenin, Dayna R; Omidvari, Amir-Houshang; Hempstead, Sarah E; Fink, Aliza K; Lowenfels, Albert B; Lansdorp-Vogelaar, Iris

    2018-02-01

    Individuals with cystic fibrosis are at increased risk of colorectal cancer (CRC) compared with the general population, and risk is higher among those who received an organ transplant. We performed a cost-effectiveness analysis to determine optimal CRC screening strategies for patients with cystic fibrosis. We adjusted the existing Microsimulation Screening Analysis-Colon model to reflect increased CRC risk and lower life expectancy in patients with cystic fibrosis. Modeling was performed separately for individuals who never received an organ transplant and patients who had received an organ transplant. We modeled 76 colonoscopy screening strategies that varied the age range and screening interval. The optimal screening strategy was determined based on a willingness to pay threshold of $100,000 per life-year gained. Sensitivity and supplementary analyses were performed, including fecal immunochemical test (FIT) as an alternative test, earlier ages of transplantation, and increased rates of colonoscopy complications, to assess if optimal screening strategies would change. Colonoscopy every 5 years, starting at an age of 40 years, was the optimal colonoscopy strategy for patients with cystic fibrosis who never received an organ transplant; this strategy prevented 79% of deaths from CRC. Among patients with cystic fibrosis who had received an organ transplant, optimal colonoscopy screening should start at an age of 30 or 35 years, depending on the patient's age at time of transplantation. Annual FIT screening was predicted to be cost-effective for patients with cystic fibrosis. However, the level of accuracy of the FIT in this population is not clear. Using a Microsimulation Screening Analysis-Colon model, we found screening of patients with cystic fibrosis for CRC to be cost effective. Because of the higher risk of CRC in these patients, screening should start at an earlier age with a shorter screening interval. The findings of this study (especially those on FIT

  14. The Role of Butylidenephthalide in Targeting Microenvironment Contributes to the Ameliorate of Liver Fibrosis

    Directory of Open Access Journals (Sweden)

    Hong-Meng eChuang

    2016-04-01

    Full Text Available The treatment of liver fibrosis has clinical limitations because of its multiple etiologies, such as epithelial–mesenchymal transition (EMT promotion, cell regeneration and remodeling dysfunction, inflammatory cell activation, and scar tissue deposition. These factors might be considered as a new target for the fibrotic microenvironment, leading to increased fibrogenesis and liver fibrosis. Here, we investigate a small molecule named butylidenephthalide (BP and its multiple effects on liver fibrosis treatment. Thioacetamide was used in vivo to induce chronic liver fibrosis. BP was administered orally in rats for a period of 2 weeks and 4 weeks, which resulted in a significantly reduced fibrosis score (p<0.05 and (p<0.001, respectively. The inflammatory reaction of macrophage infiltration were reduced in the administration of BP, which led to the decrease in the transaminase levels. Moreover, we also found liver functions recovering (due to the increased serum albumin and reduced prothrombin time where liver cells regenerated, which can be seen in the increase of Ki-67 on Oval cell. In addition, the fibrotic scar was also reduced, along with the expression of matrix metalloprotease by hepatic stellate cell. Furthermore, regarding the mechanism/study of EMT reduced by BP, the knockdown of BMP-7, which could reduce α-SMA expression, was mediated by the regulation of TGF-β, which implies its major role on EMT. Finally, in the in vivo study, BP treatment of liver fibrosis was reduced by Bmp7 knockdown in zebrafish, suggesting that BP leads to the reduction of liver fibrosis, which also depends on BMP-7 induction. These results suggest that BP had multiple targets for treating liver fibrosis in the following ways: reduction of EMT, decreasing inflammatory reaction, and liver cell proliferation. This multiple targets approach provided a new mechanism to treat liver injury and fibrosis.

  15. Comparative study of two models of combined pulmonary fibrosis and emphysema in mice.

    Science.gov (United States)

    Zhang, Wan-Guang; Wu, Si-Si; He, Li; Yang, Qun; Feng, Yi-Kuan; Chen, Yue-Tao; Zhen, Guo-Hua; Xu, Yong-Jian; Zhang, Zhen-Xiang; Zhao, Jian-Ping; Zhang, Hui-Lan

    2017-04-01

    Combined pulmonary fibrosis and emphysema (CPFE) is an "umbrella term" encompassing emphysema and pulmonary fibrosis, but its pathogenesis is not known. We established two models of CPFE in mice using tracheal instillation with bleomycin (BLM) or murine gammaherpesvirus 68 (MHV-68). Experimental mice were divided randomly into four groups: A (normal control, n=6), B (emphysema, n=6), C (emphysema+MHV-68, n=24), D (emphysema+BLM, n=6). Group C was subdivided into four groups: C1 (sacrificed on day 367, 7 days after tracheal instillation of MHV-68); C2 (day 374; 14days); C3 (day 381; 21days); C4 (day 388; 28days). Conspicuous emphysema and interstitial fibrosis were observed in BLM and MHV-68 CPFE mouse models. However, BLM induced diffuse pulmonary interstitial fibrosis with severely diffuse pulmonary inflammation; MHV-68 induced relatively modest inflammation and fibrosis, and the inflammation and fibrosis were not diffuse, but instead around bronchioles. Inflammation and fibrosis were detectable in the day-7 subgroup and reached a peak in the day-28 subgroup in the emphysema + MHV-68 group. Levels of macrophage chemoattractant protein-1, macrophage inflammatory protein-1α, interleukin-13, and transforming growth factor-β1 in bronchoalveolar lavage fluid were increased significantly in both models. Percentage of apoptotic type-2 lung epithelial cells was significantly higher; however, all four types of cytokine and number of macrophages were significantly lower in the emphysema+MHV-68 group compared with the emphysema +BLM group. The different changes in pathology between BLM and MHV-68 mice models demonstrated different pathology subtypes of CPFE: macrophage infiltration and apoptosis of type-II lung epithelial cells increased with increasing pathology score for pulmonary fibrosis. Copyright © 2017 Elsevier GmbH. All rights reserved.

  16. Cardiac sympathetic neuronal damage precedes myocardial fibrosis in patients with Anderson-Fabry disease

    Energy Technology Data Exchange (ETDEWEB)

    Imbriaco, Massimo; Piscopo, Valentina; Ponsiglione, Andrea; Nappi, Carmela; Puglia, Marta; Dell' Aversana, Serena; Spinelli, Letizia; Cuocolo, Alberto [University Federico II, Department of Advanced Biomedical Sciences, Naples (Italy); Pellegrino, Teresa [National Council of Research, Institute of Biostructure and Bioimaging, Naples (Italy); Petretta, Mario [University Federico II, Department of Translational Medical Sciences, Naples (Italy); Riccio, Eleonora; Pisani, Antonio [University of Naples Federico II, Department of Public Health, Naples (Italy)

    2017-12-15

    Cardiac sympathetic denervation may be detectable in patients with Anderson-Fabry disease (AFD), suggesting its usefulness for early detection of the disease. However, the relationship between sympathetic neuronal damage measured by {sup 123}I-metaiodobenzylguanidine (MIBG) imaging with myocardial fibrosis on cardiac magnetic resonance (CMR) is still unclear. Cardiac sympathetic innervation was assessed by {sup 123}I-MIBG single-photon emission computed tomography (SPECT) in 25 patients with genetically proved AFD. Within one month from MIBG imaging, all patients underwent contrast-enhanced CMR. MIBG defect size and fibrosis size on CMR were measured for the left ventricle (LV) and expressed as %LV. Patients were divided into three groups according to MIBG and CMR findings: (1) matched normal, without MIBG defects and without fibrosis on CMR (n = 10); (2) unmatched, with MIBG defect but without fibrosis (n = 5); and (3) matched abnormal, with MIBG defect and fibrosis (n = 10). The three groups did not differ with respect to age, gender, α-galactosidase, proteinuria, glomerular filtration rate, and troponin I, while New York Heart Association class (p = 0.008), LV hypertrophy (p = 0.05), and enzyme replacement therapy (p = 0.02) were different among groups. Although in patients with matched abnormal findings, there was a significant correlation between MIBG defect size and area of fibrosis at CMR (r{sup 2} = 0.98, p < 0.001), MIBG defect size was larger than fibrosis size (26 ± 23 vs. 18 ± 13%LV, p = 0.02). Sympathetic neuronal damage is frequent in AFD patients, and it may precede myocardial damage, such as fibrosis. Thus, {sup 123}I-MIBG imaging can be considered a challenging technique for early detection of cardiac involvement in AFD. (orig.)

  17. Cystic fibrosis transmembrane regulator haplotypes in households of patients with cystic fibrosis.

    Science.gov (United States)

    Furgeri, Daniela Tenório; Marson, Fernando Augusto Lima; Correia, Cyntia Arivabeni Araújo; Ribeiro, José Dirceu; Bertuzzo, Carmen Sílvia

    2018-01-30

    Nearly 2000 mutations in the cystic fibrosis transmembrane regulator (CFTR) gene have been reported. The F508del mutation occurs in approximately 50-65% of patients with cystic fibrosis (CF). However, molecular diagnosis is not always possible. Therefore, silent polymorphisms can be used to label the mutant allele in households of patients with CF. To verify the haplotypes of four polymorphisms at the CFTR locus in households of patients with CF for pre-fertilization, pre-implantation, and prenatal indirect mutation diagnosis to provide better genetic counseling for families and patients with CF and to associate the genotypes/haplotypes with the F508del mutation screening. GATT polymorphism analysis was performed using direct polymerase chain reaction amplification, and the MP6-D9, TUB09 and TUB18 polymorphism analyses were performed using restriction fragment length polymorphism. Nine haplotypes were found in 37 CFTR alleles, and of those, 24 were linked with the F508del mutation and 13 with other CFTR mutations. The 6 (GATT), C (MP6-D9), G (TUB09), and C (TUB18) haplotypes showed the highest prevalence (48%) of the mutant CFTR allele and were linked to the F508del mutation (64%). In 43% of households analyzed, at least one informative polymorphism can be used for the indirect diagnostic test. CFTR polymorphisms are genetic markers that are useful for identifying the mutant CFTR alleles in households of patients with CF when it is not possible to establish the complete CFTR genotype. Moreover, the polymorphisms can be used for indirect CFTR mutation identification in cases of pre-fertilization, pre-implantation and prenatal analysis. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Slow conduction in the border zones of patchy fibrosis stabilises the drivers for atrial fibrillation: Insights from multi-scale human atrial modelling

    Directory of Open Access Journals (Sweden)

    Ross Morgan

    2016-10-01

    Full Text Available Introduction. The genesis of atrial fibrillation (AF and success of AF ablation therapy have been strongly linked with atrial fibrosis. Increasing evidence suggests that patient-specific distributions of fibrosis may determine the locations of electrical drivers (rotors sustaining AF, but the underlying mechanisms are incompletely understood. This study aims to elucidate a missing mechanistic link between patient-specific fibrosis distributions and AF drivers. Methods. 3D atrial models integrated human atrial geometry, rule-based fibre orientation, region-specific electrophysiology and AF-induced ionic remodelling. A novel detailed model for an atrial fibroblast was developed, and effects of myocyte-fibroblast (M-F coupling were explored at single-cell, 1D tissue and 3D atria levels. Left atrial LGE MRI datasets from 3 chronic AF patients were segmented to provide the patient-specific distributions of fibrosis. The data was non-linearly registered and mapped to the 3D atria model. Six distinctive fibrosis levels (0 – healthy tissue, 5 – dense fibrosis were identified based on LGE MRI intensity and modelled as progressively increasing M-F coupling and decreasing atrial tissue coupling. Uniform 3D atrial model with diffuse (level 2 fibrosis was considered for comparison.Results. In single cells and tissue, the largest effect of atrial M-F coupling was on the myocyte resting membrane potential, leading to partial inactivation of sodium current and reduction of conduction velocity (CV. In the 3D atria, further to the M-F coupling, effects of fibrosis on tissue coupling greatly reduce atrial CV. AF was initiated by fast pacing in each 3D model with either uniform or patient-specific fibrosis. High variation in fibrosis distributions between the models resulted in varying complexity of AF, with several drivers emerging. In the diffuse fibrosis models, waves randomly meandered through the atria, whereas in each the patient-specific models, rotors

  19. Serum Mac-2 binding protein glycosylation isomer predicts grade F4 liver fibrosis in patients with biliary atresia.

    Science.gov (United States)

    Yamada, Naoya; Sanada, Yukihiro; Tashiro, Masahisa; Hirata, Yuta; Okada, Noriki; Ihara, Yoshiyuki; Urahashi, Taizen; Mizuta, Koichi

    2017-02-01

    Mac-2 Binding Protein Glycosylation Isomer (M2BPGi) is a novel fibrosis marker. We examined the ability of M2BPGi to predict liver fibrosis in patients with biliary atresia. Sixty-four patients who underwent living donor liver transplantation (LDLT) were included [median age, 1.1 years (range 0.4-16.0), male 16 patients (25.0 %)]. We examined M2BPGi levels in serum obtained the day before LDLT, and we compared the value of the preoperative M2BPGi levels with the histological evaluation of fibrosis using the METAVIR fibrosis score. Subsequently, we assessed the ability of M2BPGi levels to predict fibrosis. The median M2BPGi level in patients with BA was 6.02 (range, 0.36-20.0), and 0, 1, 1, 11, and 51 patients had METAVIR fibrosis scores of F0, F1, F2, F3, and F4, respectively. In patients with F4 fibrosis, the median M2BPGi level was 6.88 (quartile; 5.235, 12.10), significantly higher than that in patients with F3 fibrosis who had a median level of 2.42 (quartile; 1.93, 2.895, p F4 fibrosis. M2BPGi is a novel fibrosis marker for evaluating the status of the liver in patients with BA, especially when predicting grade F4 fibrosis.

  20. Preconception risk assessment for thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease.

    Science.gov (United States)

    Hussein, Norita; Weng, Stephen F; Kai, Joe; Kleijnen, Jos; Qureshi, Nadeem

    2018-03-14

    Globally, about five per cent of children are born with congenital or genetic disorders. The most common autosomal recessive conditions are thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease, with higher carrier rates in specific patient populations. Identifying and counselling couples at genetic risk of the conditions before pregnancy enables them to make fully informed reproductive decisions, with some of these choices not being available if genetic counselling is only offered in an antenatal setting. This is an update of a previously published review. To assess the effectiveness of systematic preconception genetic risk assessment to improve reproductive outcomes in women and their partners who are identified as carriers of thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease in healthcare settings when compared to usual care. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Registers. In addition, we searched for all relevant trials from 1970 (or the date at which the database was first available if after 1970) to date using electronic databases (MEDLINE, Embase, CINAHL, PsycINFO), clinical trial databases (National Institutes of Health, Clinical Trials Search portal of the World Health Organization, metaRegister of controlled clinical trials), and hand searching of key journals and conference abstract books from 1998 to date (European Journal of Human Genetics, Genetics in Medicine, Journal of Community Genetics). We also searched the reference lists of relevant articles, reviews and guidelines and also contacted subject experts in the field to request any unpublished or other published trials.Date of latest search of the registers: 20 June 2017.Date of latest search of all other sources: 16 November 2017. Any randomised or quasi-randomised controlled trials (published or unpublished) comparing reproductive outcomes of systematic preconception genetic risk assessment for thalassaemia, sickle

  1. Can acoustic radiation force impulse elastography be a substitute for liver biopsy in predicting liver fibrosis?

    International Nuclear Information System (INIS)

    Jain, V.; Dixit, R.; Chowdhury, V.; Puri, A.S.; Gondal, R.

    2016-01-01

    Aim: To evaluate the clinical feasibility and accuracy of acoustic radiation force impulse (ARFI) elastography for the detection of liver fibrosis in patients with chronic viral hepatitis. Materials and methods: ARFI-based ultrasound elastography was performed in 69 patients with chronic liver disease (CLD) of viral aetiology and 36 healthy volunteers. Fifty-eight patients with CLD also underwent liver biopsy. Results: ARFI was feasible in all 36 healthy volunteers and all 69 CLD patients, while valid measurements were obtained in 65 patients (95.6%) and all healthy volunteers. The mean shear-wave velocity (SWV) in healthy volunteers was 1.12±0.2 m/s. A gradual increase in mean SWV was noted from fibrosis of Grade F0 to F6 (Ishak's score) and a high positive correlation was found between the mean SWV on ARFI and fibrosis scores at liver biopsy (rho=0.789). The difference between the mild (F1 and F2) versus significant fibrosis (F3 and F4) was also statistically significant (p<0.001). The difference in the SWV measurements obtained from consecutive groups (i.e., F1 versus F2, F2 versus F3, and F3 versus F4) was not statistically significant. Using the area under the receiver operating characteristic curve (AUROC), the best calculated cut-off SWVs for the presence of fibrosis (≥F1), significant fibrosis (≥F3), severe fibrosis (≥F4), and cirrhosis (F6) were found to be 1.207, 1.347, 1.513, and 1.92 m/s, respectively. ARFI values were significantly higher in cirrhotic patients than in other patients (p<0.001). Conclusions: ARFI elastography allows valid non-invasive evaluation of liver stiffness and may help to distinguish between no/mild fibrosis and significant fibrosis and guide management decisions. - Highlights: • Our study included healthy volunteer with 28 males and 8 females in a ratio of 3:1 with mean SWV of 1.2±0.20m/s. • A high positive correlation was found between the SWV on ARFI and fibrosis scores. • There was a significantly higher mean

  2. A novel telomerase activator suppresses lung damage in a murine model of idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Le Saux, Claude Jourdan; Davy, Philip; Brampton, Christopher; Ahuja, Seema S; Fauce, Steven; Shivshankar, Pooja; Nguyen, Hieu; Ramaseshan, Mahesh; Tressler, Robert; Pirot, Zhu; Harley, Calvin B; Allsopp, Richard

    2013-01-01

    The emergence of diseases associated with telomere dysfunction, including AIDS, aplastic anemia and pulmonary fibrosis, has bolstered interest in telomerase activators. We report identification of a new small molecule activator, GRN510, with activity ex vivo and in vivo. Using a novel mouse model, we tested the potential of GRN510 to limit fibrosis induced by bleomycin in mTERT heterozygous mice. Treatment with GRN510 at 10 mg/kg/day activated telomerase 2-4 fold both in hematopoietic progenitors ex vivo and in bone marrow and lung tissue in vivo, respectively. Telomerase activation was countered by co-treatment with Imetelstat (GRN163L), a potent telomerase inhibitor. In this model of bleomycin-induced fibrosis, treatment with GRN510 suppressed the development of fibrosis and accumulation of senescent cells in the lung via a mechanism dependent upon telomerase activation. Treatment of small airway epithelial cells (SAEC) or lung fibroblasts ex vivo with GRN510 revealed telomerase activating and replicative lifespan promoting effects only in the SAEC, suggesting that the mechanism accounting for the protective effects of GRN510 against induced lung fibrosis involves specific types of lung cells. Together, these results support the use of small molecule activators of telomerase in therapies to treat idiopathic pulmonary fibrosis.

  3. Pancreatic fibrosis correlates with exocrine pancreatic insufficiency after pancreatoduodenectomy

    NARCIS (Netherlands)

    T.C. Tran; G. van 't Hof; G. Kazemier (Geert); W.C.J. Hop (Wim); C.J. Pek (Chulja); A.W. van Toorenenbergen (Albert); H. van Dekken (Herman); C.H.J. van Eijck (Casper)

    2008-01-01

    textabstractBackground: Obstruction of the pancreatic duct can lead to pancreatic fibrosis. We investigated the correlation between the extent of pancreatic fibrosis and the postoperative exocrine and endocrine pancreatic function. Methods: Fifty-five patients who were treated for pancreatic and

  4. A Multiscale Agent-Based in silico Model of Liver Fibrosis Progression

    International Nuclear Information System (INIS)

    Dutta-Moscato, Joyeeta; Solovyev, Alexey; Mi, Qi; Nishikawa, Taichiro; Soto-Gutierrez, Alejandro; Fox, Ira J.; Vodovotz, Yoram

    2014-01-01

    Chronic hepatic inflammation involves a complex interplay of inflammatory and mechanical influences, ultimately manifesting in a characteristic histopathology of liver fibrosis. We created an agent-based model (ABM) of liver tissue in order to computationally examine the consequence of liver inflammation. Our liver fibrosis ABM (LFABM) is comprised of literature-derived rules describing molecular and histopathological aspects of inflammation and fibrosis in a section of chemically injured liver. Hepatocytes are modeled as agents within hexagonal lobules. Injury triggers an inflammatory reaction, which leads to activation of local Kupffer cells and recruitment of monocytes from circulation. Portal fibroblasts and hepatic stellate cells are activated locally by the products of inflammation. The various agents in the simulation are regulated by above-threshold concentrations of pro- and anti-inflammatory cytokines and damage-associated molecular pattern molecules. The simulation progresses from chronic inflammation to collagen deposition, exhibiting periportal fibrosis followed by bridging fibrosis, and culminating in disruption of the regular lobular structure. The ABM exhibited key histopathological features observed in liver sections from rats treated with carbon tetrachloride (CCl 4 ). An in silico “tension test” for the hepatic lobules predicted an overall increase in tissue stiffness, in line with clinical elastography literature and published studies in CCl 4 -treated rats. Therapy simulations suggested differential anti-fibrotic effects of neutralizing tumor necrosis factor alpha vs. enhancing M2 Kupffer cells. We conclude that a computational model of liver inflammation on a structural skeleton of physical forces can recapitulate key histopathological and macroscopic properties of CCl 4 -injured liver. This multiscale approach linking molecular and chemomechanical stimuli enables a model that could be used to gain translationally relevant insights into

  5. Vitamin K1 attenuates bile duct ligation-induced liver fibrosis in rats.

    Science.gov (United States)

    Jiao, Kun; Sun, Quan; Chen, Baian; Li, Shengli; Lu, Jing

    2014-06-01

    Vitamin K1 is used as a liver protection drug for cholestasis-induced liver fibrosis in China, but the mechanism of vitamin K1's action in liver fibrosis is unclear. In this study, a model of liver fibrosis was achieved via bile duct ligation in rats. The rats were then injected with vitamin K1, and the levels of serum aspartate aminotransferase, alanine transaminase, total bilirubin and the fibrotic grade score, collagen content, the expressions of α-smooth muscle actin (SMA) and cytokeratin 19 (CK19) were measured on day 28 after ligation. The levels of the biochemical parameters, fibrotic score and collagen content were significantly reduced by treatment with vitamin K1 in bile duct-ligated rats. In addition, α-SMA and CK19 expression was significantly reduced by vitamin K1 treatment in bile duct-ligated rats. These results suggested that vitamin K1 may attenuate liver fibrosis by inhibiting hepatic stellate cell activation in bile duct-ligated rats.

  6. Application of Serum Hepatic Fibrosis Indices in the Diagnosis of Hepatic Disease

    International Nuclear Information System (INIS)

    Lu Yanting; Wang Taisong; Gu Xin

    2010-01-01

    To investigate the significance of combined detection of laminin (LN), collagen type IV (CIV), hyaluronic acid (HA) and precollagen type III (PCIII) in the diagnosis of hepatic fibrosis. The serum levels of LN, CIV, HA and PCIII in 143 patients with hepatic disease and 41 healthy controls were measured by radioimmunoassay (RIA). The results showed that the serum levels of LN, CIV, HA and PCIII in patients with hepatic disease were significantly higher than those of the control group (P<0.01), and the serum levels of those markers were related to the severity of the chronic hepatic disease. The highest serum levels were found in serious chronic hepatitis group and hepatic fibrosis group,and the increase of serum HA and PCIII was most remarkable. Combined detection of LN, CIV, HA and PCIII is a sensitive and reliable method in the diagnosis of hepatic fibrosis, but the four serum indices can not be used in differentiating serious chronic hepatitis and hepatic fibrosis. (authors)

  7. Inhaled medication and inhalation devices for lung disease in patients with cystic fibrosis : A European consensus

    NARCIS (Netherlands)

    Heijerman, Harry; Westerman, Elsbeth; Conway, Steven; Touw, Daan; Döring, Gerd; Frijlink, Henderik

    In cystic fibrosis inhalation of drugs for the treatment of CF related lung disease has been proven to be highly effective. Consequently, an increasing number of drugs and devices have been developed for CF lung disease or are currently under development. In this European consensus document we

  8. Current insights into the role of PKA phosphorylation in CFTR channel activity and the pharmacological rescue of cystic fibrosis disease-causing mutants.

    Science.gov (United States)

    Chin, Stephanie; Hung, Maurita; Bear, Christine E

    2017-01-01

    Cystic fibrosis transmembrane conductance regulator (CFTR) channel gating is predominantly regulated by protein kinase A (PKA)-dependent phosphorylation. In addition to regulating CFTR channel activity, PKA phosphorylation is also involved in enhancing CFTR trafficking and mediating conformational changes at the interdomain interfaces of the protein. The major cystic fibrosis (CF)-causing mutation is the deletion of phenylalanine at position 508 (F508del); it causes many defects that affect CFTR trafficking, stability, and gating at the cell surface. Due to the multiple roles of PKA phosphorylation, there is growing interest in targeting PKA-dependent signaling for rescuing the trafficking and functional defects of F508del-CFTR. This review will discuss the effects of PKA phosphorylation on wild-type CFTR, the consequences of CF mutations on PKA phosphorylation, and the development of therapies that target PKA-mediated signaling.

  9. Value of 3 Tesla diffusion-weighted magnetic resonance imaging for assessing liver fibrosis.

    Science.gov (United States)

    Papalavrentios, Lavrentios; Sinakos, Emmanouil; Chourmouzi, Danai; Hytiroglou, Prodromos; Drevelegas, Konstantinos; Constantinides, Manos; Drevelegas, Antonios; Talwalkar, Jayant; Akriviadis, Evangelos

    2015-01-01

    Limited data are available regarding the role of magnetic resonance imaging (MRI), particularly the new generation 3 Tesla technology, and especially diffusion-weighted imaging (DWI) in predicting liver fibrosis. The aim of our pilot study was to assess the clinical performance of the apparent diffusion coefficient (ADC) of liver parenchyma for the assessment of liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). 18 patients with biopsy-proven NAFLD underwent DWI with 3 Tesla MRI. DWI was performed with single-shot echo-planar technique at b values of 0-500 and 0-1000 s/mm 2 . ADC was measured in four locations in the liver and the mean ADC value was used for analysis. Staging of fibrosis was performed according to the METAVIR system. The median age of patients was 52 years (range 23-73). The distribution of patients in different fibrosis stages was: 0 (n=1), 1 (n=7), 2 (n=1), 3 (n=5), 4 (n=4). Fibrosis stage was poorly associated with ADC at b value of 0-500 s/mm 2 (r= -0.30, P=0.27). However it was significantly associated with ADC at b value of 0-1000 s/mm 2 (r= -0.57, P=0.01). For this b value (0-1000 s/mm 2 ) the area under receiver-operating characteristic curve was 0.93 for fibrosis stage ≥3 and the optimal ADC cut-off value was 1.16 ×10 -3 mm 2 /s. 3 Tesla DWI can possibly predict the presence of advanced fibrosis in patients with NAFLD.

  10. Episodic seasonal Pseudo-Bartter syndrome in cystic fibrosis.

    Science.gov (United States)

    Kintu, Brett; Brightwell, Alex

    2014-06-01

    Pseudo-Bartter syndrome (PBS) describes an uncommon but well recognised complication of cystic fibrosis leading to hypochloraemic, hypokalaemic metabolic alkalosis. Pseudo-Bartter syndrome is usually seen at initial presentation or within the first two years of life in children with cystic fibrosis. Risk factors for development of PBS include warm weather conditions, severe respiratory or pancreatic disease and gastrointestinal losses (e.g. vomiting and diarrhoea). PBS is rare in older children and adolescents although epidemics have been associated with heat wave conditions in warmer climates. In this era of climate change, it is crucial that clinicians consider Pseudo-Bartter syndrome when patients with cystic fibrosis present unwell during summer. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Magnetic resonance imaging in chronic liver disease evaluated in relation to hepatic fibrosis

    International Nuclear Information System (INIS)

    Ohno, Akihiko; Ohta, Yasuhiko; Ohtomo, Kuni

    1990-01-01

    In 21 patients with chronic liver disease, the ratio of liver to muscle signal intensity on T 1 -weighted images was negatively correlated with the progression of hepatic fibrosis defined according to findings by laparoscopy and liver biopsy, and differentiated six patients with early chronic hepatitis from eight with liver cirrhosis. On T 2 -weighted images, the number of low intensity nodules comparable in size to regenerating nodules surrounded by connective tissues showed a positive correlation with stage. When hepatic fibrosis with no necrosis or fat infiltration was induced in rats, T 2 values were positively correlated with hepatic hydroxyproline content, though there was no such correlation for T 1 values. These results suggest that MR imaging may be useful for determining the progression of hepatic fibrosis in chronic liver disease. T 2 values may directly reflect hepatic fibrosis. (author)

  12. The Role of Dendritic Cells in Fibrosis Progression in Nonalcoholic Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Paloma Almeda-Valdes

    2015-01-01

    Full Text Available Nonalcoholic fatty liver disease (NAFLD is the most frequent cause of chronic liver disease. NAFLD encompasses a wide range of pathologies, from simple steatosis to steatosis with inflammation to fibrosis. The pathogenesis of NAFLD progression has not been completely elucidated, and different liver cells could be implicated. This review focuses on the current evidence of the role of liver dendritic cells (DCs in the progression from NAFLD to fibrosis. Liver DCs are a heterogeneous population of hepatic antigen-presenting cells; their main function is to induce T-cell mediated immunity by antigen processing and presentation to T cells. During the steady state liver DCs are immature and tolerogenic. However, in an environment of chronic inflammation, DCs are transformed to potent inducers of immune responses. There is evidence about the role of DC in liver fibrosis, but it is not clearly understood. Interestingly, there might be a link between lipid metabolism and DC function, suggesting that immunogenic DCs are associated with liver lipid storage, representing a possible pathophysiological mechanism in NAFLD development. A better understanding of the interaction between inflammatory pathways and the different cell types and the effect on the progression of NAFLD is of great relevance.

  13. Inhibiting aerobic glycolysis suppresses renal interstitial fibroblast activation and renal fibrosis.

    Science.gov (United States)

    Ding, Hao; Jiang, Lei; Xu, Jing; Bai, Feng; Zhou, Yang; Yuan, Qi; Luo, Jing; Zen, Ke; Yang, Junwei

    2017-09-01

    Chronic kidney diseases generally lead to renal fibrosis. Despite great progress having been made in identifying molecular mediators of fibrosis, the mechanism that governs renal fibrosis remains unclear, and so far no effective therapeutic antifibrosis strategy is available. Here we demonstrated that a switch of metabolism from oxidative phosphorylation to aerobic glycolysis (Warburg effect) in renal fibroblasts was the primary feature of fibroblast activation during renal fibrosis and that suppressing renal fibroblast aerobic glycolysis could significantly reduce renal fibrosis. Both gene and protein assay showed that the expression of glycolysis enzymes was upregulated in mouse kidneys with unilateral ureter obstruction (UUO) surgery or in transforming growth factor-β1 (TGF-β1)-treated renal interstitial fibroblasts. Aerobic glycolysis flux, indicated by glucose uptake and lactate production, was increased in mouse kidney with UUO nephropathy or TGF-β1-treated renal interstitial fibroblasts and positively correlated with fibrosis process. In line with this, we found that increasing aerobic glycolysis can remarkably induce myofibroblast activation while aerobic glycolysis inhibitors shikonin and 2-deoxyglucose attenuate UUO-induced mouse renal fibrosis and TGF-β1-stimulated myofibroblast activation. Furthermore, mechanistic study indicated that shikonin inhibits renal aerobic glycolysis via reducing phosphorylation of pyruvate kinase type M2, a rate-limiting glycolytic enzyme associated with cell reliance on aerobic glycolysis. In conclusion, our findings demonstrate the critical role of aerobic glycolysis in renal fibrosis and support treatment with aerobic glycolysis inhibitors as a potential antifibrotic strategy. Copyright © 2017 the American Physiological Society.

  14. Increased circulating miR-21 levels are associated with kidney fibrosis.

    Directory of Open Access Journals (Sweden)

    François Glowacki

    Full Text Available MicroRNAs (miRNAs are a class of noncoding RNA acting at a post-transcriptional level to control the expression of large sets of target mRNAs. While there is evidence that miRNAs deregulation plays a causative role in various complex disorders, their role in fibrotic kidney diseases is largely unexplored. Here, we found a strong up-regulation of miR-21 in the kidneys of mice with unilateral ureteral obstruction and also in the kidneys of patients with severe kidney fibrosis. In addition, mouse primary fibroblasts derived from fibrotic kidneys exhibited higher miR-21 expression level compared to those derived from normal kidneys. Expression of miR-21 in normal primary kidney fibroblasts was induced upon TGFβ exposure, a key growth factor involved in fibrogenesis. Finally, ectopic expression of miR-21 in primary kidney fibroblasts was sufficient to promote myofibroblast differentiation. As circulating miRNAs have been suggested as promising non-invasive biomarkers, we further assess whether circulating miR-21 levels are associated with renal fibrosis using sera from 42 renal transplant recipients, categorized according to their renal fibrosis severity, evaluated on allograft biopsies (Interstitial Fibrosis/Tubular Atrophy (IF/TA. Circulating miR-21 levels are significantly increased in patients with severe IF/TA grade (IF/TA grade 3: 3.0±1.0 vs lower grade of fibrosis: 1.5±1.2; p = 0.001. By contrast, circulating miR-21 levels were not correlated with other renal histological lesions. In a multivariate linear regression model including IF/TA grade and estimated GFR, independent associations were found between circulating miR-21 levels and IF/TA score (ß = 0.307, p = 0.03, and between miR-21 levels and aMDRD (ß = -0.398, p = 0.006. Altogether, these data suggest miR-21 has a key pathogenic role in kidney fibrosis and may represent a novel, predictive and reliable blood marker of kidney fibrosis.

  15. Fibrosis endomiocárdica

    Directory of Open Access Journals (Sweden)

    María Juliana Rodríguez-González

    2017-07-01

    Una de las formas más comunes de miocardiopatía restrictiva es la fibrosis endomiocárdica la cual es endémica en algunas zonas tropicales especialmente en África (países de bajos ingresos, pero en nuestro medio hay pocos reportes de aparición. Su etiología es desconocida, aunque existen diversos mecanismos que han sido involucrados en su fisiopatología. Su diagnóstico se basa en estudios imagenológicos (ecocardiograma transtorácico y resonancia magnética nuclear cardíaca. El pronóstico es muy pobre, y usualmente se diagnostica en etapas muy avanzadas de la enfermedad. Se describe el caso de una paciente femenina, adulta media, que debutó con cardiopatía restrictiva, cuyo diagnóstico final fue fibrosis endomiocárdica.

  16. Treatment with 4-methylpyrazole modulated stellate cells and natural killer cells and ameliorated liver fibrosis in mice.

    Directory of Open Access Journals (Sweden)

    Hyon-Seung Yi

    Full Text Available Accumulating evidence suggests that retinol and its metabolites are closely associated with liver fibrogenesis. Recently, we demonstrated that genetic ablation of alcohol dehydrogenase 3 (ADH3, a retinol metabolizing gene that is expressed in hepatic stellate cells (HSCs and natural killer (NK cells, attenuated liver fibrosis in mice. In the current study, we investigated whether pharmacological ablation of ADH3 has therapeutic effects on experimentally induced liver fibrosis in mice.Liver fibrosis was induced by intraperitoneal injections of carbon tetrachloride (CCl4 or bile duct ligation (BDL for two weeks. To inhibit ADH3-mediated retinol metabolism, 10 μg 4-methylpyrazole (4-MP/g of body weight was administered to mice treated with CCl4 or subjected to BDL. The mice were sacrificed at week 2 to evaluate the regression of liver fibrosis. Liver sections were stained for collagen and α-smooth muscle actin (α-SMA. In addition, HSCs and NK cells were isolated from control and treated mice livers for molecular and immunological studies.Treatment with 4-MP attenuated CCl4- and BDL-induced liver fibrosis in mice, without any adverse effects. HSCs from 4-MP treated mice depicted decreased levels of retinoic acids and increased retinol content than HSCs from control mice. In addition, the expression of α-SMA, transforming growth factor-β1 (TGF-β1, and type I collagen α1 was significantly reduced in the HSCs of 4-MP treated mice compared to the HSCs from control mice. Furthermore, inhibition of retinol metabolism by 4-MP increased interferon-γ production in NK cells, resulting in increased apoptosis of activated HSCs.Based on our data, we conclude that inhibition of retinol metabolism by 4-MP ameliorates liver fibrosis in mice through activation of NK cells and suppression of HSCs. Therefore, retinol and its metabolizing enzyme, ADH3, might be potential targets for therapeutic intervention of liver fibrosis.

  17. Improving care at cystic fibrosis centers through quality improvement.

    Science.gov (United States)

    Kraynack, Nathan C; McBride, John T

    2009-10-01

    Quality improvement (QI) using a clinical microsystems approach provides cystic fibrosis (CF) centers the opportunity to make a significant positive impact on the health of their patients. The availability of center-specific outcomes data and the support of the Cystic Fibrosis Foundation are important advantages for these quality improvement efforts. This article illustrates how the clinical microsystems methodology can improve care delivery and outcomes by describing the gradual application of quality improvement principles over the past 5 years by the CF team at the Lewis Walker Cystic Fibrosis Center at Akron Children's Hospital in Akron, Ohio. Using the example of a project to improve the pulmonary function of the pediatric patients at our center as a framework, we describe the QI process from the initial team-building phase, through the assessment of care processes, standardization of care, and developing a culture of continuous improvement. We outline how enthusiastic commitment from physician leadership, clinical managers and central administration, the availability of coaches, and an appreciation of the importance of measurement, patient involvement, communication, and standardization are critical components for successful process improvement. Copyright Thieme Medical Publishers.

  18. [Historical compilation of cystic fibrosis].

    Science.gov (United States)

    Navarro, Salvador

    2016-01-01

    Cystic fibrosis is the most common life-shortening recessively inherited disorder in the Caucasian population. The genetic mutation that most frequently provokes cystic fibrosis (ΔF508) appeared at least 53,000years ago. For many centuries, the disease was thought to be related to witchcraft and the "evil eye" and it was only in 1938 that Dorothy H. Andersen characterized this disorder and suspected its genetic origin. The present article reviews the pathological discoveries and diagnostic and therapeutic advances made in the last 75 years. The review ends with some considerations for the future. Copyright © 2015 Elsevier España, S.L.U. and AEEH y AEG. All rights reserved.

  19. Systemic sclerosis and localized scleroderma--current concepts and novel targets for therapy.

    Science.gov (United States)

    Distler, Oliver; Cozzio, Antonio

    2016-01-01

    Systemic sclerosis (SSc) is a chronic autoimmune disease with a high morbidity and mortality. Skin and organ fibrosis are key manifestations of SSc, for which no generally accepted therapy is available. Thus, there is a high unmet need for novel anti-fibrotic therapeutic strategies in SSc. At the same time, important progress has been made in the identification and characterization of potential molecular targets in fibrotic diseases over the recent years. In this review, we have selected four targeted therapies, which are tested in clinical trials in SSc, for in depths discussion of their preclinical characterization. Soluble guanylate cyclase (sGC) stimulators such as riociguat might target both vascular remodeling and tissue fibrosis. Blockade of interleukin-6 might be particularly promising for early inflammatory stages of SSc. Inhibition of serotonin receptor 2b signaling links platelet activation to tissue fibrosis. Targeting simultaneously multiple key molecules with the multityrosine kinase-inhibitor nintedanib might be a promising approach in complex fibrotic diseases such as SSc, in which many partially independent pathways are activated. Herein, we also give a state of the art overview of the current classification, clinical presentation, diagnostic approach, and treatment options of localized scleroderma. Finally, we discuss whether the novel targeted therapies currently tested in SSc could be used for localized scleroderma.

  20. Autogenic drainage for airway clearance in cystic fibrosis.

    Science.gov (United States)

    McCormack, Pamela; Burnham, Paul; Southern, Kevin W

    2017-10-06

    Autogenic drainage is an airway clearance technique that was developed by Jean Chevaillier in 1967. The technique is characterised by breathing control using expiratory airflow to mobilise secretions from smaller to larger airways. Secretions are cleared independently by adjusting the depth and speed of respiration in a sequence of controlled breathing techniques during exhalation. The technique requires training, concentration and effort from the individual. It is important to systematically review the evidence demonstrating that autogenic drainage is an effective intervention for people with cystic fibrosis. To compare the clinical effectiveness of autogenic drainage in people with cystic fibrosis with other physiotherapy airway clearance techniques. We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews, as well as two trials registers (31 August 2017).Dtae of most recent search of the Cochrane Cystic Fibrosis Trials Register: 25 September 2017. We identified randomised and quasi-randomised controlled studies comparing autogenic drainage to another airway clearance technique or no therapy in people with cystic fibrosis for at least two treatment sessions. Data extraction and assessments of risk of bias were independently performed by two authors. The authors assessed the quality of the evidence using the GRADE system. The authors contacted two investigators for further information pertinent to their published studies. Searches retrieved 35 references to 21 individual studies, of which seven (n = 208) were eligible for inclusion. One study was of parallel design with the remaining six being cross-over in design; participant numbers ranged from 17 to 75. The total study duration varied between four days and two years. The age of participants ranged between seven and 63 years with a wide

  1. Thermodynamic Aspects and Reprogramming Cellular Energy Metabolism during the Fibrosis Process

    Directory of Open Access Journals (Sweden)

    Alexandre Vallée

    2017-11-01

    Full Text Available Fibrosis is characterized by fibroblast proliferation and fibroblast differentiation into myofibroblasts, which generate a relaxation-free contraction mechanism associated with excessive collagen synthesis in the extracellular matrix, which promotes irreversible tissue retraction evolving towards fibrosis. From a thermodynamic point of view, the mechanisms leading to fibrosis are irreversible processes that can occur through changing the entropy production rate. The thermodynamic behaviors of metabolic enzymes involved in fibrosis are modified by the dysregulation of both transforming growth factor β (TGF-β signaling and the canonical WNT/β-catenin pathway, leading to aerobic glycolysis, called the Warburg effect. Molecular signaling pathways leading to fibrosis are considered dissipative structures that exchange energy or matter with their environment far from the thermodynamic equilibrium. The myofibroblastic cells arise from exergonic processes by switching the core metabolism from oxidative phosphorylation to glycolysis, which generates energy and reprograms cellular energy metabolism to induce the process of myofibroblast differentiation. Circadian rhythms are far-from-equilibrium thermodynamic processes. They directly participate in regulating the TGF-β and WNT/β-catenin pathways involved in energetic dysregulation and enabling fibrosis. The present review focusses on the thermodynamic implications of the reprogramming of cellular energy metabolism, leading to fibroblast differentiation into myofibroblasts through the positive interplay between TGF-β and WNT/β-catenin pathways underlying in fibrosis.

  2. Liver shear-wave velocity and serum fibrosis markers to diagnose hepatic fibrosis in patients with chronic viral hepatitis B

    International Nuclear Information System (INIS)

    Liu, Jian Xue; Ji, Yong Hao; Zhao Junzhi; Zhang, Yao Ren; Dun, Guo Liang; Ning, Bo; Ai, Hong

    2016-01-01

    To compare several noninvasive indices of fibrosis in chronic viral hepatitis B, including liver shear-wave velocity (SWV), hyaluronic acid (HA), collagen type IV (CIV), procollagen type III (PCIII), and laminin (LN). Acoustic radiation force impulse (ARFI) was performed in 157 patients with chronic viral hepatitis B and in 30 healthy volunteers to measure hepatic SWV (m/s) in a prospective study. Serum markers were acquired on the morning of the same day of the ARFI evaluation. Receiver operating characteristic (ROC) analysis was performed to evaluate and compare the accuracies of SWV and serum markers using METAVIR scoring from liver biopsy as a reference standard. The most accurate test for diagnosing fibrosis F ≥ 1 was SWV with the area under the ROC curve (AUC) of 0.913, followed by LN (0.744), HA (0.701), CIV (0.690), and PCIII (0.524). The best test for diagnosing F ≥ 2 was SWV (AUC of 0.851), followed by CIV (0.671), HA (0.668), LN (0.562), and PCIII (0.550). The best test for diagnosing F ≥ 3 was SWV (0.854), followed by CIV (0.693), HA (0.675), PCIII (0.591), and LN (0.548). The best test for diagnosing F = 4 was SWV (0.965), followed by CIV (0.804), PCIII (0.752), HA (0.744), and LN (0.662). SWV combined with HA and CIV did not improve diagnostic accuracy (AUC = 0.931 for F ≥ 1, 0.863 for F ≥ 2, 0.855 for F ≥ 3, 0.960 for F = 4). The performance of SWV in diagnosing liver fibrosis is superior to that of serum markers. However, the combination of SWV, HA, and CIV does not increase the accuracy of diagnosing liver fibrosis and cirrhosis

  3. Liver shear-wave velocity and serum fibrosis markers to diagnose hepatic fibrosis in patients with chronic viral hepatitis B

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Jian Xue; Ji, Yong Hao; Zhao Junzhi; Zhang, Yao Ren; Dun, Guo Liang; Ning, Bo [Dept. of Ultrasonography, Baoji Central Hospital, Baoji (China); Ai, Hong [Dept. of Ultrasonography, The First Affiliated Hospital of Medical College, Xi' an Jiaotong University, Xi' an (China)

    2016-06-15

    To compare several noninvasive indices of fibrosis in chronic viral hepatitis B, including liver shear-wave velocity (SWV), hyaluronic acid (HA), collagen type IV (CIV), procollagen type III (PCIII), and laminin (LN). Acoustic radiation force impulse (ARFI) was performed in 157 patients with chronic viral hepatitis B and in 30 healthy volunteers to measure hepatic SWV (m/s) in a prospective study. Serum markers were acquired on the morning of the same day of the ARFI evaluation. Receiver operating characteristic (ROC) analysis was performed to evaluate and compare the accuracies of SWV and serum markers using METAVIR scoring from liver biopsy as a reference standard. The most accurate test for diagnosing fibrosis F ≥ 1 was SWV with the area under the ROC curve (AUC) of 0.913, followed by LN (0.744), HA (0.701), CIV (0.690), and PCIII (0.524). The best test for diagnosing F ≥ 2 was SWV (AUC of 0.851), followed by CIV (0.671), HA (0.668), LN (0.562), and PCIII (0.550). The best test for diagnosing F ≥ 3 was SWV (0.854), followed by CIV (0.693), HA (0.675), PCIII (0.591), and LN (0.548). The best test for diagnosing F = 4 was SWV (0.965), followed by CIV (0.804), PCIII (0.752), HA (0.744), and LN (0.662). SWV combined with HA and CIV did not improve diagnostic accuracy (AUC = 0.931 for F ≥ 1, 0.863 for F ≥ 2, 0.855 for F ≥ 3, 0.960 for F = 4). The performance of SWV in diagnosing liver fibrosis is superior to that of serum markers. However, the combination of SWV, HA, and CIV does not increase the accuracy of diagnosing liver fibrosis and cirrhosis.

  4. Systematic review of studies on cost-effectiveness of cystic fibrosis carrier testing

    Directory of Open Access Journals (Sweden)

    Ernesto Andrade-Cerquera

    2016-10-01

    Full Text Available Introduction: Cystic fibrosis is considered the most common autosomal disease with multisystem complications in non-Hispanic white population. Objective: To review the available evidence on cost-effectiveness of the cystic fibrosis carrier testing compared to no intervention. Materials and methods: The databases of MEDLINE, Embase, NHS, EBM Reviews - Cochrane Database of Systematic Reviews, LILACS, Health Technology Assessment, Genetests.org, Genetsickkids.org and Web of Science were used to conduct a systematic review of the cost-effectiveness of performing the genetic test in cystic fibrosis patients. Cost-effectiveness studies were included without language or date of publication restrictions. Results: Only 13 studies were relevant for full review. Prenatal, preconception and mixed screening strategies were found. Health perspective was the most used; the discount rate applied was heterogeneous between 3.5% and 5%; the main analysis unit was the cost per detected carrier couple, followed by cost per averted birth with cystic fibrosis. It was evident that the most cost-effective strategy was preconception screening associated with prenatal test. Conclusions: A marked heterogeneity in the methodology was found, which led to incomparable results and to conclude that there are different approaches to this genetic test.

  5. Colchicine for alcoholic and non-alcoholic liver fibrosis or cirrhosis

    DEFF Research Database (Denmark)

    Rambaldi, A; Gluud, C

    2001-01-01

    Colchicine is an anti-inflammatory and anti-fibrotic drug. Several randomized clinical trials have addressed the question whether colchicine has any efficacy in patients with alcoholic as well as non-alcoholic fibrosis and cirrhosis. The objectives were to assess the efficacy of colchicine...... evaluated in randomized trials on mortality, liver related mortality, liver related complications, liver fibrosis markers, liver histology, alcohol consumption, quality of life, and health economics in patients with alcoholic and non-alcoholic fibrosis or cirrhosis....

  6. Hyperleptinemia Exacerbates High-Fat Diet-Mediated Atrial Fibrosis and Fibrillation.

    Science.gov (United States)

    Fukui, Akira; Ikebe-Ebata, Yuki; Kondo, Hidekazu; Saito, Shotaro; Aoki, Kohei; Fukunaga, Naoya; Shinohara, Tetsuji; Masaki, Takayuki; Teshima, Yasushi; Takahashi, Naohiko

    2017-06-01

    Obesity including metabolic syndrome is an independent risk factor of atrial fibrillation (AF). Although hyperleptinemia is usually a characteristic of obese subjects, the relationship with atrial fibrosis and AF is unknown. We tested the hypothesis that high-fat diet (HFD)-induced hyperleptinemia exacerbates atrial fibrosis and AF. Eight-week-old male C57BL/6 (WT) and leptin-deficient ob/ob (Ob) mice were treated with a normal-fat diet (NFD) or 60% HFD. After 8 weeks, transesophageal burst pacing and electrophysiological study using isolated perfused hearts were performed and left atrial (LA) tissues were collected for histological analysis, hydroxyproline assay, and reverse transcription-polymerase chain reaction. HFD treatment increased body weight in both WT and Ob mice compared with NFD (both P atrial fibrosis and AF. Inhibition of leptin signaling may become a novel therapeutic target to prevent obesity-related AF. © 2017 Wiley Periodicals, Inc.

  7. The Processes and Mechanisms of Cardiac and Pulmonary Fibrosis

    NARCIS (Netherlands)

    Murtha, Lucy A.; Schuliga, Michael J.; Mabotuwana, Nishani S.; Hardy, Sean A.; Waters, David W.; Burgess, Janette K.; Knight, Darryl A.; Boyle, Andrew J.

    2017-01-01

    Fibrosis is the formation of fibrous connective tissue in response to injury. It is characterized by the accumulation of extracellular matrix components, particularly collagen, at the site of injury. Fibrosis is an adaptive response that is a vital component of wound healing and tissue repair.

  8. IL-4 Receptor Alpha Signaling through Macrophages Differentially Regulates Liver Fibrosis Progression and Reversal

    Directory of Open Access Journals (Sweden)

    Shih-Yen Weng

    2018-03-01

    Full Text Available Chronic hepatitis leads to liver fibrosis and cirrhosis. Cirrhosis is a major cause of worldwide morbidity and mortality. Macrophages play a key role in fibrosis progression and reversal. However, the signals that determine fibrogenic vs fibrolytic macrophage function remain ill defined. We studied the role of interleukin-4 receptor α (IL-4Rα, a potential central switch of macrophage polarization, in liver fibrosis progression and reversal. We demonstrate that inflammatory monocyte infiltration and liver fibrogenesis were suppressed in general IL-4Rα−/− as well as in macrophage-specific IL-4Rα−/− (IL-4RαΔLysM mice. However, with deletion of IL-4RαΔLysM spontaneous fibrosis reversal was retarded. Results were replicated by pharmacological intervention using IL-4Rα-specific antisense oligonucleotides. Retarded resolution was linked to the loss of M2-type resident macrophages, which secreted MMP-12 through IL-4 and IL-13-mediated phospho-STAT6 activation. We conclude that IL-4Rα signaling regulates macrophage functional polarization in a context-dependent manner. Pharmacological targeting of macrophage polarization therefore requires disease stage-specific treatment strategies. Research in Context: Alternative (M2-type macrophage activation through IL-4Rα promotes liver inflammation and fibrosis progression but speeds up fibrosis reversal. This demonstrates context dependent, opposing roles of M2-type macrophages. During reversal IL-4Rα induces fibrolytic MMPs, especially MMP-12, through STAT6. Liver-specific antisense oligonucleotides efficiently block IL-4Rα expression and attenuate fibrosis progression. Keywords: Fibrosis, IL-4 receptor alpha, Liver, Macrophage, MMP12, Progression, Reversal

  9. Nephrogenic systemic fibrosis

    International Nuclear Information System (INIS)

    Samtleben, W.

    2007-01-01

    A scleromyxedema-like disease was recognized in 1997. In 2000 this disorder was first published and termed nephrogenic fibrosing dermopathy because all patients had advanced renal failure. In 2006 it was discovered that the patients had a history of a preceding contrast-enhanced magnetic resonance imaging (MRI). All patients had acute or chronic severe renal insufficiency with a glomerular filtration rate (GFR) 2 . So far a total of about 215 patients with this new skin disorder have been reported to international registries. The skin thickening has a typical histology and begins in the peripheral extremities and progresses proximally, including also the abdominal wall and the head in some patients. NSF involves not only the skin, but also the muscles and other organs (e.g., lungs, heart, eyes) in some patients. Therefore the term nephrogenic systemic fibrosis (NSF) was introduced. Skin fibrosis and sclerosis are usually progressive with disabling contractures of involved joints (knees, hands, feet). NSF may be lethal in up to 28% of patients. Spontaneous remissions are rare. No generally accepted treatment is available. So far, the pathogenesis is not well understood. One hypothesis supposes a role of gadolinium liberated from the contrast agents. As patients with acute or chronic advanced renal failure (GFR 2 ) including those with hepatorenal dysfunctions are at high risk to develop NSF after exposure to gadolinium-based contrast agents, contrast-enhanced MRI should be avoided in this group and alternative diagnostic procedures should be used whenever possible. (orig.) [de

  10. Correlation of endothelin-1 concentration and angiotensin-converting enzyme activity with the staging of liver fibrosis.

    Science.gov (United States)

    Kardum, Dusko; Fabijanić, Damir; Lukić, Anita; Romić, Zeljko; Petrovecki, Mladen; Bogdanović, Zoran; Jurić, Klara; Urek-Crncević, Marija; Banić, Marko

    2012-06-01

    Increased serum angiotensin-converting enzyme (SACE) activity and serum concentration of endothelin-1 (ET-1) were found in liver cirrhosis. We investigated a correlation between the different stages of liver fibrosis and SACE activity and serum ET-1 concentration. Seventy patients with pathohistologically established chronic liver disease were divided in three groups according to Ishak criteria for liver fibrosis: minimal fibrosis (Ishak score 0-1, n =20), medium fibrosis (Ishak score 2-5, n=20) and cirrhosis (Ishak score 6, n=30). SACE activity and ET-1 concentration were determined using commercial ELISA kits. SACE activity and ET-1 concentrations were proportional to the severity of disease, the highest being in patients with liver cirrhosis. Maximal increase in SACE activity was found between minimal and medium fibrosis while maximal increase in ET-1 concentration was revealed between medium fibrosis and cirrhosis. The analysis of the Receiver Operating Characteristic (ROC) curve for SACE activity suggested a cut-off value to separate minimal from medium fibrosis at 59.00 U/L (sensitivity 100%, specificity 64.7%). The cut-off value for serum ET-1 concentration to separate medium fibrosis from cirrhosis was 12.4 pg/mL (sensitivity 96.8%, specificity 94.4%). A positive correlation between SACE activity and ET-1 concentration was registered (Spearman's ñ = 0.438, p = 0.004). Both SACE activity and ET-1 concentration were increased in all stages of liver fibrosis. Cut-off points for SACE activity and ET-1 concentration could be a biochemical marker for the progression of fibrosis. Positive correlation between SACE activity and ET-1 concentration might indicate their interaction in the development of liver cirrhosis.

  11. Epithelial-mesenchymal transition: An emerging target in tissue fibrosis

    Science.gov (United States)

    Li, Meirong; Luan, Fuxin; Zhao, Yali; Hao, Haojie; Zhou, Yong; Han, Weidong

    2016-01-01

    Epithelial-mesenchymal transition (EMT) is involved in a variety of tissue fibroses. Fibroblasts/myofibroblasts derived from epithelial cells contribute to the excessive accumulation of fibrous connective tissue in damaged tissue, which can lead to permanent scarring or organ malfunction. Therefore, EMT-related fibrosis cannot be neglected. This review highlights the findings that demonstrate the EMT to be a direct contributor to the fibroblast/myofibroblast population in the development of tissue fibrosis and helps to elucidate EMT-related anti-fibrotic strategies, which may enable the development of therapeutic interventions to suppress EMT and potentially reverse organ fibrosis. PMID:26361988

  12. Radiation-induced neck fibrosis in patients with nasopharyngeal carcinoma

    International Nuclear Information System (INIS)

    Li Jian; Wang Rensheng; Gan Langge; Liu Wenqi; Zhang Yong

    2005-01-01

    Objective: To investigate the post-irradiation neck fibrosis in patients with nasopharyngeal carcinoma and its related factors. Methods: A total of 267 patients received conventional fractionated radiotherapy with D T 50-72 Gy on the neck a half year to 10 years ago were observed for the changes of cervical shape and functions. Results: Different degrees of post-irradiation neck fibrosis were seen in all patients. The rate of heavy degree of neck radiation fibrosis was 24.34 %, and it was 2.74% when received preventive dose on the neck. There was a very significant difference between patients who received late course of tangential irradiation on the neck and those who didn't receive (P=0.0001). The incidence of post-irradiation neck fibrosis didn't increase when patients received radiotherapy combined with chemotherapy (P=0.2678). The function of cervical muscles turned weak in patients received radiotherapy delivered by 6 MV accelerator in late course of tangential irradiation, whereas skin damage was severer in patients treated with 60 Co γ-rays. Conclusions: The incidence of heavy degree of post-irradiation neck fibrosis is high ,and is related closely to late course of tangential irradiation. The authors should avoid adopting this sort of irradiation on the neck. (authors)

  13. A new model of progressive pulmonary fibrosis in rats

    Energy Technology Data Exchange (ETDEWEB)

    Last, J.A.; Gelzleichter, T.R.; Pinkerton, K.E.; Walker, R.M.; Witschi, H. (Univ. of California, Davis (United States))

    1993-08-01

    Sprague-Dawley rats were exposed for 6 h daily to 0.8 ppm of ozone and 14.4 ppm of nitrogen dioxide. Approximately 7 to 10 wk after the initiation of exposure, animals began to demonstrate respiratory insufficiency and severe weight loss. About half of the rats died between Days 55 and 78 of exposure; no overt ill effects were observed in animals exposed to filtered air, to ozone alone, or to nitrogen dioxide. Biochemical findings in animals exposed to ozone and nitrogen dioxide included increased lung content of DNA, protein, collagen, and elastin, which was about 300% higher than the control values. The collagen-specific crosslink hydroxy-pyridinium, a biomarker for mature collagen in the lung, was decreased by about 40%. These results are consistent with extensive breakdown and remodeling of the lung parenchyma and its associated vasculature. Histopathologic evaluation showed severe fibrosis, alveolar collapse, honeycombing, macrophage and mast cell accumulation, vascular smooth muscle hypertrophy, and other indications of severe progressive interstitial pulmonary fibrosis and end-stage lung disease. This unique animal model of progressive pulmonary fibrosis resembles the final stages of human idiopathic pulmonary fibrosis and should facilitate studying underlying mechanisms and potential therapy of progressive pulmonary fibrosis.

  14. A mouse model for inherited renal fibrosis associated with endoplasmic reticulum stress

    Directory of Open Access Journals (Sweden)

    Sian E. Piret

    2017-06-01

    Full Text Available Renal fibrosis is a common feature of renal failure resulting from multiple etiologies, including diabetic nephropathy, hypertension and inherited renal disorders. However, the mechanisms of renal fibrosis are incompletely understood and we therefore explored these by establishing a mouse model for a renal tubular disorder, referred to as autosomal dominant tubulointerstitial kidney disease (ADTKD due to missense uromodulin (UMOD mutations (ADTKD-UMOD. ADTKD-UMOD, which is associated with retention of mutant uromodulin in the endoplasmic reticulum (ER of renal thick ascending limb cells, is characterized by hyperuricemia, interstitial fibrosis, inflammation and renal failure, and we used targeted homologous recombination to generate a knock-in mouse model with an ADTKD-causing missense cysteine to arginine uromodulin mutation (C125R. Heterozygous and homozygous mutant mice developed reduced uric acid excretion, renal fibrosis, immune cell infiltration and progressive renal failure, with decreased maturation and excretion of uromodulin, due to its retention in the ER. The ER stress marker 78 kDa glucose-regulated protein (GRP78 was elevated in cells expressing mutant uromodulin in heterozygous and homozygous mutant mice, and this was accompanied, both in vivo and ex vivo, by upregulation of two unfolded protein response pathways in primary thick ascending limb cells from homozygous mutant mice. However, this did not lead to an increase in apoptosis in vivo. Thus, we have developed a novel mouse model for renal fibrosis, which will be a valuable resource to decipher the mechanisms linking uromodulin mutations with ER stress and renal fibrosis.

  15. Pulmonary Artery Occlusion and Mediastinal Fibrosis in a Patient on Dopamine Agonist Treatment for Hyperprolactinemia

    DEFF Research Database (Denmark)

    Su, Junjing; Simonsen, Ulf; Carlsen, Jørn

    2017-01-01

    Unusual forms of pulmonary hypertension include pulmonary hypertension related to mediastinal fibrosis and the use of serotonergic drugs. Here, we describe a patient with diffuse mediastinal fibrosis and pulmonary hypertension while she was on dopamine agonist therapy. A young woman, who...... showed fibrosis and chronic inflammation. Subsequent investigations revealed that diffuse mediastinal fibrosis with concurrent pulmonary hypertension, and not CTEPH, was the most likely diagnosis and cabergoline and bromocriptine may have triggered the fibrotic changes. Both drugs are ergot...... was treated with cabergoline and bromocriptine for hyperprolactinemia, presented with progressive dyspnea over several months. Based on the clinical investigation results, in particular, elevated pulmonary arterial pressures and significant perfusion defects on computed tomography (CT) pulmonary angiography...

  16. Role of NLRC5 in progression and reversal of hepatic fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Xuejiao, E-mail: liuxuejiao0615@163.com [School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032 (China); Institute for Liver Diseases, Anhui Medical University, Hefei 230032 (China); Wu, Yuting; Yang, Yang; Li, Wanxia; Huang, Cheng; Meng, Xiaoming [School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032 (China); Institute for Liver Diseases, Anhui Medical University, Hefei 230032 (China); Li, Jun, E-mail: lj@ahmu.edu.cn [School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032 (China); Institute for Liver Diseases, Anhui Medical University, Hefei 230032 (China); School of Pharmacy, Anhui Medical University, Mei Shan load, Hefei 230032, Anhui Province (China)

    2016-03-01

    Background: NLRC5, as the largest member of NLRs family, has recently been identified as a critical regulator of immune responses through negatively regulating NF-κB which is associated with the development of hepatic fibrosis. However, the expression and potential roles of NLRC5 in hepatic fibrosis and its reversal are still to be defined. Methods: C57BL/6 mice were treatment with carbon tetrachloride (CCl{sub 4}) induce hepatic fibrosis and its reversal. In vitro, models of hepatic fibrosis and its reversal are established by the treatment with TGF-β and MDI. The expression of NLRC5 was determined by RT-PCR, Western blot and immunohistochemistry. Consequently, NLRC5 was overexpressed or knockdown by transfecting PEGFP-C2-NLRC5 or NLRC5-siRNA respectively in the reversal of hepatic fibrosis, and the expression of fibrogenic genes such as α-SMA and Col1α1 was quantified. The NF-κB activity was detected as well. Results: Immunohistochemistry, RT-PCR and Western blot analysis with liver tissues and primary HSCs showed that NLRC5 was highly expressed in hepatic fibrosis and correspondingly decreased in the reversal stage. The differential expression of NLRC5 was confirmed in vitro. Enforced NLRC5 expression increased the expression of α-SMA and Col1α1, and blockade of NLRC5 reduced the fibrotic response. While the opposite expression of phosphorylated NF-kB p65 and phospho-IκBα was found. Conclusion: NLRC5 is differentially expressed in hepatic tissues and hepatic stellate cells during hepatic fibrosis and its reversal. All the data indicated that NLRC5 may play a crucial role in regulating the reversal of hepatic fibrosis through NF-κB signaling pathway. - Highlights: • The activated HSCs can be reverted to quiescent HSCs by MDI treatment. • NLRC5 expressed differentially during different stages of hepatic fibrosis and its reversal. • Enforced NLRC5 in reverted LX-c cells boosted the expression of α-SMA and Col1α1. • Blockade of NLRC5 diminished

  17. Markers of Collagen Remodeling Detect Clinically Significant Fibrosis in Chronic Hepatitis C Patients

    DEFF Research Database (Denmark)

    Nielsen, Mette J; Kazankov, Konstantin; Leeming, Diana J

    2015-01-01

    as potential biomarkers for clinically significant and advanced fibrosis. METHODS: Specific protein fragments of matrix metalloprotease degraded type I, III, IV and VI collagen (C1M, C3M, C4M, C6M) and type III and IV collagen formation (Pro-C3 and P4NP7S) were assessed in plasma from 403 chronic hepatitis C...... patients by specific ELISAs. Patients were stratified according to Metavir Fibrosis stage; F0 (n = 46), F1 (n = 161), F2 (n = 95), F3 (n = 44) and F4 (n = 33) based on liver biopsy. RESULTS: Pro-C3 was significantly elevated in patients with significant fibrosis (≥F2) compared to F0-F1 (p... the markers C3M, C4M, C6M and P4NP7S were significantly elevated in patients with advanced fibrosis (≥F3) compared to F0-F2 (pC1M showed no difference between fibrosis stages. Using Receiver Operating Characteristics analysis, the best marker for detecting ≥F2 and ≥F3 was Pro-C3 with AUC = 0...

  18. Profiling of antioxidant superoxide dismutase in saliva of oral submucous fibrosis patients to categorize its diagnosis in varying stages

    International Nuclear Information System (INIS)

    Sirohi, Y.; Shetty, D.C.; Urs, A.B.; Rai, H.C.

    2011-01-01

    Background: Oral submucous fibrosis is a pre malignant condition in Indian and South-East Asia. Role of oxidant-antioxidant in causation and progression of cancer and pre cancers is known. Reactive oxygen species are generated in the oral cavity during chewing areca nut, the major etiological agent in oral submucous fibrosis. Objectives: To see the alterations in the salivary superoxide dismutase levels in various clinical and histopathological grades of oral submucous fibrosis. Materials and Methods: Unstimulated saliva was collected from 25 oral submucous fibrosis patients and age and gender matched controls. The saliva was assessed for superoxide dismutase value by spectrophotometric method using assay kit (Bio Vision Catalog number K335-100). The oral submucous fibrosis cases were grouped into clinical stages and histopathological grades and superoxide dismutase values were compared in different clinical stages and histopathological grades. Results: The superoxide dismutase levels were reduced in oral submucous fibrosis as compared to controls. A steady decline in the levels was seen as the clinical stage and histopathological grade of oral submucous fibrosis advanced. Conclusions: Salivary superoxide dismutase levels can be alternatively used as a surrogate marker for the diagnosis of oral submucous fibrosis. Policy message: Oral physicians should advise the pan chewers to regularly check their salivary superoxide dismutase levels so as to ease the early diagnosis of oral submucous fibrosis. (author)

  19. Protective role of andrographolide in bleomycin-induced pulmonary fibrosis in mice.

    Science.gov (United States)

    Zhu, Tao; Zhang, Wei; Xiao, Min; Chen, Hongying; Jin, Hong

    2013-12-03

    Idiopathic pulmonary fibrosis (IPF) is a chronic devastating disease with poor prognosis. Multiple pathological processes, including inflammation, epithelial mesenchymal transition (EMT), apoptosis, and oxidative stress, are involved in the pathogenesis of IPF. Recent findings suggested that nuclear factor-κB (NF-κB) is constitutively activated in IPF and acts as a central regulator in the pathogenesis of IPF. The aim of our study was to reveal the value of andrographolide on bleomycin-induced inflammation and fibrosis in mice. The indicated dosages of andrographolide were administered in mice with bleomycin-induced pulmonary fibrosis. On day 21, cell counts of total cells, macrophages, neutrophils and lymphocytes, alone with TNF-α in bronchoalveolar lavage fluid (BALF) were measured. HE staining and Masson's trichrome (MT) staining were used to observe the histological alterations of lungs. The Ashcroft score and hydroxyproline content of lungs were also measured. TGF-β1 and α-SMA mRNA and protein were analyzed. Activation of NF-κB was determined by western blotting and electrophoretic mobility shift assay (EMSA). On day 21 after bleomycin stimulation, andrographolide dose-dependently inhibited the inflammatory cells and TNF-α in BALF. Meanwhile, our data demonstrated that the Ashcroft score and hydroxyproline content of the bleomycin-stimulated lung were reduced by andrographolide administration. Furthermore, andrographloide suppressed TGF-β1 and α-SMA mRNA and protein expression in bleomycin-induced pulmonary fibrosis. Meanwhile, andrographolide significantly dose-dependently inhibited the ratio of phospho-NF-κB p65/total NF-κB p65 and NF-κB p65 DNA binding activities. Our findings indicate that andrographolide compromised bleomycin-induced pulmonary inflammation and fibrosis possibly through inactivation of NF-κB. Andrographolide holds promise as a novel drug to treat the devastating disease of pulmonary fibrosis.

  20. Protective Role of Andrographolide in Bleomycin-Induced Pulmonary Fibrosis in Mice

    Directory of Open Access Journals (Sweden)

    Tao Zhu

    2013-12-01

    Full Text Available Idiopathic pulmonary fibrosis (IPF is a chronic devastating disease with poor prognosis. Multiple pathological processes, including inflammation, epithelial mesenchymal transition (EMT, apoptosis, and oxidative stress, are involved in the pathogenesis of IPF. Recent findings suggested that nuclear factor-κB (NF-κB is constitutively activated in IPF and acts as a central regulator in the pathogenesis of IPF. The aim of our study was to reveal the value of andrographolide on bleomycin-induced inflammation and fibrosis in mice. The indicated dosages of andrographolide were administered in mice with bleomycin-induced pulmonary fibrosis. On day 21, cell counts of total cells, macrophages, neutrophils and lymphocytes, alone with TNF-α in bronchoalveolar lavage fluid (BALF were measured. HE staining and Masson’s trichrome (MT staining were used to observe the histological alterations of lungs. The Ashcroft score and hydroxyproline content of lungs were also measured. TGF-β1 and α-SMA mRNA and protein were analyzed. Activation of NF-κB was determined by western blotting and electrophoretic mobility shift assay (EMSA. On day 21 after bleomycin stimulation, andrographolide dose-dependently inhibited the inflammatory cells and TNF-α in BALF. Meanwhile, our data demonstrated that the Ashcroft score and hydroxyproline content of the bleomycin-stimulated lung were reduced by andrographolide administration. Furthermore, andrographloide suppressed TGF-β1 and α-SMA mRNA and protein expression in bleomycin-induced pulmonary fibrosis. Meanwhile, andrographolide significantly dose-dependently inhibited the ratio of phospho-NF-κB p65/total NF-κB p65 and NF-κB p65 DNA binding activities. Our findings indicate that andrographolide compromised bleomycin-induced pulmonary inflammation and fibrosis possibly through inactivation of NF-κB. Andrographolide holds promise as a novel drug to treat the devastating disease of pulmonary fibrosis.

  1. A Multiscale Agent-Based in silico Model of Liver Fibrosis Progression

    Energy Technology Data Exchange (ETDEWEB)

    Dutta-Moscato, Joyeeta [Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA (United States); Department of Surgery, University of Pittsburgh, Pittsburgh, PA (United States); Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Solovyev, Alexey [Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Department of Mathematics, University of Pittsburgh, Pittsburgh, PA (United States); Mi, Qi [Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Department of Sports Medicine and Nutrition, University of Pittsburgh, Pittsburgh, PA (United States); Nishikawa, Taichiro [McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Department of Surgery, Children’s Hospital of Pittsburgh, Pittsburgh, PA (United States); Soto-Gutierrez, Alejandro [McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Department of Pathology, University of Pittsburgh, Pittsburgh, PA (United States); Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA (United States); Fox, Ira J. [McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Department of Surgery, Children’s Hospital of Pittsburgh, Pittsburgh, PA (United States); Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA (United States); Vodovotz, Yoram, E-mail: vodovotzy@upmc.edu [Department of Surgery, University of Pittsburgh, Pittsburgh, PA (United States); Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA (United States)

    2014-05-30

    Chronic hepatic inflammation involves a complex interplay of inflammatory and mechanical influences, ultimately manifesting in a characteristic histopathology of liver fibrosis. We created an agent-based model (ABM) of liver tissue in order to computationally examine the consequence of liver inflammation. Our liver fibrosis ABM (LFABM) is comprised of literature-derived rules describing molecular and histopathological aspects of inflammation and fibrosis in a section of chemically injured liver. Hepatocytes are modeled as agents within hexagonal lobules. Injury triggers an inflammatory reaction, which leads to activation of local Kupffer cells and recruitment of monocytes from circulation. Portal fibroblasts and hepatic stellate cells are activated locally by the products of inflammation. The various agents in the simulation are regulated by above-threshold concentrations of pro- and anti-inflammatory cytokines and damage-associated molecular pattern molecules. The simulation progresses from chronic inflammation to collagen deposition, exhibiting periportal fibrosis followed by bridging fibrosis, and culminating in disruption of the regular lobular structure. The ABM exhibited key histopathological features observed in liver sections from rats treated with carbon tetrachloride (CCl{sub 4}). An in silico “tension test” for the hepatic lobules predicted an overall increase in tissue stiffness, in line with clinical elastography literature and published studies in CCl{sub 4}-treated rats. Therapy simulations suggested differential anti-fibrotic effects of neutralizing tumor necrosis factor alpha vs. enhancing M2 Kupffer cells. We conclude that a computational model of liver inflammation on a structural skeleton of physical forces can recapitulate key histopathological and macroscopic properties of CCl{sub 4}-injured liver. This multiscale approach linking molecular and chemomechanical stimuli enables a model that could be used to gain translationally relevant

  2. An adult cystic fibrosis patient presenting with persistent dyspnea: case report

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    Farinet Catherine L

    2006-05-01

    Full Text Available Abstract Background Persistent dyspnea is a common finding in the cystic fibrosis patient that typically leads to further work up of an alternative pulmonary etiology. Adult cystic fibrosis patients; however, are growing in numbers and they are living into the ages in which coronary artery disease becomes prevalent. Coronary disease should be included in the consideration of diagnostic possibilities. Case presentation A 52-year-old white male with cystic fibrosis was evaluated for exertional dyspnea associated with vague chest discomfort. Diagnostic testing revealed normal white blood cell, hemoglobin and platelet count, basic metabolic panel, fasting lipid profile, HbA1c, with chest radiograph confirming chronic cystic findings unchanged from prior radiographs and an electrocardiogram that revealed sinus rhythm with left anterior fascicular block. Stress thallium testing demonstrated a reversible anteroseptal perfusion defect with a 55% left ventricular ejection fraction. Heart catheterization found a 99% occlusion of the left anterior descending artery extending into the two diagonal branches, with 100% obstruction of the left anterior descending artery at the trifurcation and 70% lesion affecting the first posterior lateral branch of the circumflex artery. Conclusion This case report represents the first description in the medical literature of a cystic fibrosis patient diagnosed with symptomatic coronary artery disease. Applying a standard clinical practice guide proved useful toward evaluating a differential diagnosis for a cystic fibrosis patient presenting with dyspnea and chest discomfort.

  3. Estimating past hepatitis C infection risk from reported risk factor histories: implications for imputing age of infection and modeling fibrosis progression

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    Busch Michael P

    2007-12-01

    Full Text Available Abstract Background Chronic hepatitis C virus infection is prevalent and often causes hepatic fibrosis, which can progress to cirrhosis and cause liver cancer or liver failure. Study of fibrosis progression often relies on imputing the time of infection, often as the reported age of first injection drug use. We sought to examine the accuracy of such imputation and implications for modeling factors that influence progression rates. Methods We analyzed cross-sectional data on hepatitis C antibody status and reported risk factor histories from two large studies, the Women's Interagency HIV Study and the Urban Health Study, using modern survival analysis methods for current status data to model past infection risk year by year. We compared fitted distributions of past infection risk to reported age of first injection drug use. Results Although injection drug use appeared to be a very strong risk factor, models for both studies showed that many subjects had considerable probability of having been infected substantially before or after their reported age of first injection drug use. Persons reporting younger age of first injection drug use were more likely to have been infected after, and persons reporting older age of first injection drug use were more likely to have been infected before. Conclusion In cross-sectional studies of fibrosis progression where date of HCV infection is estimated from risk factor histories, modern methods such as multiple imputation should be used to account for the substantial uncertainty about when infection occurred. The models presented here can provide the inputs needed by such methods. Using reported age of first injection drug use as the time of infection in studies of fibrosis progression is likely to produce a spuriously strong association of younger age of infection with slower rate of progression.

  4. Fibrosis of the pancreas: the initial tissue damage and the resulting pattern.

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    Klöppel, Günter; Detlefsen, Sönke; Feyerabend, Bernd

    2004-07-01

    Fibrosis in the pancreas is caused by such processes as necrosis/apoptosis, inflammation or duct obstruction. The initial event that induces fibrogenesis in the pancreas is an injury that may involve the interstitial mesenchymal cells, the duct cells and/or the acinar cells. Damage to any one of these tissue compartments of the pancreas is associated with cytokine-triggered transformation of resident fibroblasts/pancreatic stellate cells into myofibroblasts and the subsequent production and deposition of extracellular matrix. Depending on the site of injury in the pancreas and the involved tissue compartment, predominantly inter(peri)lobular fibrosis (as in alcoholic chronic pancreatitis), periductal fibrosis (as in hereditary pancreatitis), periductal and interlobular fibrosis (as in autoimmune pancreatitis) or diffuse inter- and intralobular fibrosis (as in obstructive chronic pancreatitis) develops.

  5. [Cystic fibrosis--initial diagnosis in a 39-year-old patient].

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    Bargon, J; Rickmann, J; Jacobi, V; Straub, R; Arnemann, J; Wagner, T O

    2000-12-15

    Cystic fibrosis is the most common hereditary disorder among Caucasians. Most of the patients are diagnosed as children. However, some cases are going undiagnosed into adulthood and are then often misdiagnosed because the non-pediatricians do not know cystic fibrosis very well and do not consider this diagnosis in adult patients. We present the medical history of a woman, who was diagnosed with cystic fibrosis at the age of 39 years, although she had suffered from bronchiectasis, pancreatic insufficiency and liver cirrhosis since many years. Her medical history was long with some diagnosis, but because of her age nobody considered the final diagnosis. In adult patients with bronchiectasis, liver cirrhosis and pancreatic insufficiency in combination or with only one of these symptoms, cystic fibrosis should be included into the differential diagnosis.

  6. The cystic fibrosis gene: Medical and social implications for heterozygote detection

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    Wilfond, B.S.; Fost, N. (Univ. of Wisconsin School of Medicine, Madison (USA))

    1990-05-23

    The primary goal of mass screening programs for cystic fibrosis carriers should be to allow people to make more informed reproductive decisions. However, previous experience with genetic screening programs, including those for phenylketonuria and sickle cell disease, have revealed complex problems including error, confusion, and stigmatization. These problems could be greater with cystic fibrosis, since more than 8 million Americans may be carriers and entrepreneurial interests can be expected to promote screening in what could become a billion-dollar industry. The present frequency of the detectable mutation ({Delta}F{sub 508}), 75%, will complicate the counseling process. The sensitivity of the test to detect at-risk couples would be 56%. The cost of screening could be as much as $2.2 million for each cystic fibrosis birth avoided. Regardless of improvements in the detection rate, implementation of population screening should be delayed until pilot studies that demonstrate its safety and effectiveness are completed. While studies are in progress, preconception testing should be offered to adult relatives of cystic fibrosis patients as part of a comprehensive program following institutional review board approval for compassionate use.

  7. Lipoxin A4 stimulates calcium-activated chloride currents and increases airway surface liquid height in normal and cystic fibrosis airway epithelia.

    LENUS (Irish Health Repository)

    2012-01-01

    Cystic Fibrosis (CF) is a genetic disease characterised by a deficit in epithelial Cl(-) secretion which in the lung leads to airway dehydration and a reduced Airway Surface Liquid (ASL) height. The endogenous lipoxin LXA(4) is a member of the newly identified eicosanoids playing a key role in ending the inflammatory process. Levels of LXA(4) are reported to be decreased in the airways of patients with CF. We have previously shown that in normal human bronchial epithelial cells, LXA(4) produced a rapid and transient increase in intracellular Ca(2+). We have investigated, the effect of LXA(4) on Cl(-) secretion and the functional consequences on ASL generation in bronchial epithelial cells obtained from CF and non-CF patient biopsies and in bronchial epithelial cell lines. We found that LXA(4) stimulated a rapid intracellular Ca(2+) increase in all of the different CF bronchial epithelial cells tested. In non-CF and CF bronchial epithelia, LXA(4) stimulated whole-cell Cl(-) currents which were inhibited by NPPB (calcium-activated Cl(-) channel inhibitor), BAPTA-AM (chelator of intracellular Ca(2+)) but not by CFTRinh-172 (CFTR inhibitor). We found, using confocal imaging, that LXA(4) increased the ASL height in non-CF and in CF airway bronchial epithelia. The LXA(4) effect on ASL height was sensitive to bumetanide, an inhibitor of transepithelial Cl(-) secretion. The LXA(4) stimulation of intracellular Ca(2+), whole-cell Cl(-) currents, conductances and ASL height were inhibited by Boc-2, a specific antagonist of the ALX\\/FPR2 receptor. Our results provide, for the first time, evidence for a novel role of LXA(4) in the stimulation of intracellular Ca(2+) signalling leading to Ca(2+)-activated Cl(-) secretion and enhanced ASL height in non-CF and CF bronchial epithelia.

  8. The Use of Buccal Fat Pad in the Treatment of Oral Submucous Fibrosis: A Newer Method

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    K. Saravanan

    2012-01-01

    Full Text Available Purpose of the study. This study was to evaluate the use of buccal fat pad as an interpositioning material in surgical management of oral sub mucous fibrosis. Materials and methods. A series of 8 cases with proven oral sub mucous fibrosis, with mouth opening less than 20 mm, involving the buccal mucosa were treated surgically in the Department of Oral and Maxillofacial Surgery, College of Dental Surgery, Saveetha University, Chennai. Pedicled buccal fat pad was used as an interpositioning material to cover the raw areas in the oral cavity after incision and release of fibrous bands. Results. In 8 patients, the range of pre operative mouth opening was 3–18 mm (mean 14 mm. As the result of the successful surgical procedure, the size of the intra operative mouth opening was ranged from 25–38 mm (mean 33.25 mm. The patients were discharged 5–7 days after the operation. The range of the mouth opening at this time was 25–36 mm (mean 30.63 mm. The results were evaluated using student’s t test and found to be statistically significant. The pedicled grafts took up uneventfull.

  9. Identifying and quantifying the stromal fibrosis in muscularis propria of colorectal carcinoma by multiphoton microscopy

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    Chen, Sijia; Yang, Yinghong; Jiang, Weizhong; Feng, Changyin; Chen, Zhifen; Zhuo, Shuangmu; Zhu, Xiaoqin; Guan, Guoxian; Chen, Jianxin

    2014-10-01

    The examination of stromal fibrosis within colorectal cancer is overlooked, not only because the routine pathological examinations seem to focus more on tumour staging and precise surgical margins, but also because of the lack of efficient diagnostic methods. Multiphoton microscopy (MPM) can be used to study the muscularis stroma of normal and colorectal carcinoma tissue at the molecular level. In this work, we attempt to show the feasibility of MPM for discerning the microstructure of the normal human rectal muscle layer and fibrosis colorectal carcinoma tissue practicably. Three types of muscularis propria stromal fibrosis beneath the colorectal cancer infiltration were first observed through the MPM imaging system by providing intercellular microstructural details in fresh, unstained tissue samples. Our approach also presents the capability of quantifying the extent of stromal fibrosis from both amount and orientation of collagen, which may further characterize the severity of fibrosis. By comparing with the pathology analysis, these results show that the MPM has potential advantages in becoming a histological tool for detecting the stromal fibrosis and collecting prognosis evidence, which may guide subsequent therapy procedures for patients into good prognosis.

  10. Targeting miRNA-based medicines to cystic fibrosis airway epithelial cells using nanotechnology

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    McKiernan PJ

    2013-10-01

    Full Text Available Paul J McKiernan,2 Orla Cunninghamm,1,2 Catherine M Greenem,2 Sally-Ann Cryan1,31School of Pharmacy, Royal College of Surgeons in Ireland, 2Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland Education and Research Centre, Beaumont Hospital, 3Trinity Centre for Bioengineering, Trinity College Dublin, Dublin, IrelandAbstract: Cystic fibrosis (CF is an inherited disorder characterized by chronic airway inflammation. microRNAs (miRNAs are endogenous small RNAs which act on messenger (mRNA at a post transcriptional level, and there is a growing understanding that altered expression of miRNA is involved in the CF phenotype. Modulation of miRNA by replacement using miRNA mimics (premiRs presents a new therapeutic paradigm for CF, but effective and safe methods of delivery to the CF epithelium are limiting clinical translation. Herein, polymeric nanoparticles are investigated for delivery of miRNA mimics into CF airway epithelial cells, using miR-126 as a proof-of-concept premiR cargo to determine efficiency. Two polymers, polyethyleneimine (PEI and chitosan, were used to prepare miRNA nanomedicines, characterized for their size, surface (zeta potential, and RNA complexation efficiency, and screened for delivery and cytotoxicity in CFBE41o- (human F508del cystic fibrosis transmembrane conductance regulator bronchial epithelial cells using a novel high content analysis method. RNA extraction was carried out 24 hours post transfection, and miR-126 and TOM1 (target of Myb1 expression (a validated miR-126 target was assessed. Manufacture was optimized to produce small nanoparticles that effectively complexed miRNA. Using high content analysis, PEI-based nanoparticles were more effective than chitosan-based nanoparticles in facilitating uptake of miRNA into CFBE41o- cells and this was confirmed in miR-126 assays. PEI-premiR-126 nanoparticles at low nitrogen/phosphate (N/P ratios resulted in significant knockdown of

  11. Dietary supplementation of blueberry juice enhances hepatic expression of metallothionein and attenuates liver fibrosis in rats.

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    Yuping Wang

    Full Text Available To investigate the effect of blueberry juice intake on rat liver fibrosis and its influence on hepatic antioxidant defense.Rabbiteye blueberry was used to prepare fresh juice to feed rats by daily gastric gavage. Dan-shao-hua-xian capsule (DSHX was used as a positive control for liver fibrosis protection. Liver fibrosis was induced in male Sprague-Dawley rats by subcutaneous injection of CCl4 and feeding a high-lipid/low-protein diet for 8 weeks. Hepatic fibrosis was evaluated by Masson staining. The expression of α-smooth muscle actin (α-SMA and collagen III (Col III were determined by immunohistochemical techniques. The activities of superoxide dismutase (SOD and malondialdehyde (MDA in liver homogenates were determined. Metallothionein (MT expression was detected by real-time RT-PCR and immunohistochemical techniques.Blueberry juice consumption significantly attenuates CCl4-induced rat hepatic fibrosis, which was associated with elevated expression of metallothionein (MT, increased SOD activity, reduced oxidative stress, and decreased levels of α-SMA and Col III in the liver.Our study suggests that dietary supplementation of blueberry juice can augment antioxidative capability of the liver presumably via stimulating MT expression and SOD activity, which in turn promotes HSC inactivation and thus decreases extracellular matrix collagen accumulation in the liver, and thereby alleviating hepatic fibrosis.

  12. Inactivated Orf virus (Parapoxvirus ovis) elicits antifibrotic activity in models of liver fibrosis.

    Science.gov (United States)

    Nowatzky, Janina; Knorr, Andreas; Hirth-Dietrich, Claudia; Siegling, Angela; Volk, Hans-Dieter; Limmer, Andreas; Knolle, Percy; Weber, Olaf

    2013-05-01

    Inactivated Orf virus (ORFV, Parapoxvirus ovis) demonstrates strong antiviral activity in animal models including a human hepatitis B virus (HBV)-transgenic mouse. In addition, expression of interferon (IFN)-γ and interleukin-10 (IL-10) was induced after administration of inactivated ORFV in these mice. IFN-γ and IL-10 are known to elicit antifibrotic activity. We therefore aimed to study antifibrotic activity of inactivated ORFV in models of liver fibrosis. We characterized ORFV-induced hepatic cytokine expression in rats. We then studied ORFV in two models of liver fibrosis in rats, pig serum-induced liver fibrosis and carbon tetrachloride (CCL4 )-induced liver fibrosis. ORFV induced hepatic expression of IFN-γ and IL-10 in rats. ORFV mediated antifibrotic activity when administrated concomitantly with the fibrosis-inducing agents in both models of liver fibrosis. Importantly, when CCL4 -induced liver fibrosis was already established, ORFV application still showed significant antifibrotic activity. In addition, we were able to demonstrate a direct antifibrotic effect of ORFV on stellate cells. These results establish a potential novel antifibrotic therapeutic approach that not only prevents but also resolves established liver fibrosis. Further studies are required to unravel the details of the mechanisms involved. © 2012 The Japan Society of Hepatology.

  13. The Role of Computed Tomography in Monitoring Patients with Cystic Fibrosis

    International Nuclear Information System (INIS)

    Rybacka, Anna; Karmelita-Katulska, Katarzyna

    2016-01-01

    Cystic fibrosis is the most common lethal autosomal recessive disorder in the Caucasian population. Although the survival rate in patients constantly improves, lung damage is still the major cause of morbidity and mortality in patients with cystic fibrosis. In clinical practice, evaluation of patients’ pulmonary state is made by combination of monitoring of lung function and more directly by assessing the lung structure in imaging studies. Studies showed that computed tomography findings are more sensitive as compared to the pulmonary function tests. Computed tomography can identify a wide range of morphological abnormalities in patients with cystic fibrosis, such as bronchiectasis (which is progressive, irreversible and probably the most relevant structural change in cystic fibrosis) peribronchial thickening, mucous plugging and many other disorders that occur in the course of the disease. Computed tomography has a crucial role in the assessment of pulmonary damage over time, detecting complications and monitoring treatment effects in patients with cystic fibrosis

  14. Ketamine induced renal fibrosis in a ketamine addition rat model

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    Mei-Yu Jang

    2017-09-01

    Conclusion: Ketamine treatment not only induced cystitis-like syndrome, but also renal fibrosis. These renal interstitial fibrosis changes may be induced by the TGF-β pathway. These preliminary results can provide valuable information from a clinical perspective.

  15. Second Harmonic Generation Reveals Subtle Fibrosis Differences in Adult and Pediatric Nonalcoholic Fatty Liver Disease.

    Science.gov (United States)

    Liu, Feng; Zhao, Jing-Min; Rao, Hui-Ying; Yu, Wei-Miao; Zhang, Wei; Theise, Neil D; Wee, Aileen; Wei, Lai

    2017-11-20

    Investigate subtle fibrosis similarities and differences in adult and pediatric nonalcoholic fatty liver disease (NAFLD) using second harmonic generation (SHG). SHG/two-photon excitation fluorescence imaging quantified 100 collagen parameters and determined qFibrosis values by using the nonalcoholic steatohepatitis (NASH) Clinical Research Network (CRN) scoring system in 62 adult and 36 pediatric NAFLD liver specimens. Six distinct parameters identified differences among the NASH CRN stages with high accuracy (area under the curve, 0835-0.982 vs 0.885-0.981, adult and pediatric). All portal region parameters showed similar changes across early stages 0, 1C, and 2, in both groups. Parameter values decreased in adults with progression from stage 1A/B to 2 in the central vein region. In children, aggregated collagen parameters decreased, but nearly all distributed collagen parameters increased from stage 1A/B to 2. SHG analysis accurately reproduces NASH CRN staging in NAFLD, as well as reveals differences and similarities between adult and pediatric collagen deposition not captured by currently available quantitative methods. © American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

  16. Novel aspects of acute coronary syndromes, reperfusion injury and post-infarction myocardial fibrosis

    OpenAIRE

    Chan, William

    2017-01-01

    This thesis comprises 4 clinical studies aiming to explore the mechanisms related to coronary plaque destabilization, clinical outcomes of the no-reflow phenomenon, a novel treatment of ischaemia-reperfusion injury, and the pattern and temporal evolution of left ventricular myocardial fibrosis following myocardial infarction. Current risk prediction models for future cardiovascular events are derived from large scale population-based studies (such as that from the Framingham Heart Study),...

  17. Volumetric capnography for the evaluation of pulmonary disease in adult patients with cystic fibrosis and noncystic fibrosis bronchiectasis.

    Science.gov (United States)

    Veronez, L; Moreira, M M; Soares, S T P; Pereira, M C; Ribeiro, M A G O; Ribeiro, J D; Terzi, R G G; Martins, L C; Paschoal, I A

    2010-06-01

    This study was designed to use volumetric capnography to evaluate the breathing pattern and ventilation inhomogeneities in patients with chronic sputum production and bronchiectasis and to correlate the phase 3 slope of the capnographic curve to spirometric measurements. Twenty-four patients with cystic fibrosis (CF) and 21 patients with noncystic fibrosis idiopathic bronchiectasis (BC) were serially enrolled. The diagnosis of cystic fibrosis was based on the finding of at least two abnormal sweat chloride concentrations (iontophoresis sweat test). The diagnosis of bronchiectasis was made when the patient had a complaint of chronic sputum production and compatible findings at high-resolution computed tomography (HRCT) scan of the thorax. Spirometric tests and volumetric capnography were performed. The 114 subjects of the control group for capnographic variables were nonsmoker volunteers, who had no respiratory symptoms whatsoever and no past or present history of lung disease. Compared with controls, patients in CF group had lower SpO(2) (P volumes normalized for weight (V(E)/kg) (P volume (P3Slp/V(E)) (P capacities and both groups had very similar abnormalities. The capnographic variables in the patient group suggest a restrictive respiratory pattern (greater respiratory rates, smaller expiratory times and expiratory volumes, normal peak expiratory flows). Both groups of patients showed increased phase III slopes compared with controls, which probably indicates the presence of diffuse disease of small airways in both conditions leading to inhomogeneities of ventilation.

  18. Extracellular Matrix Molecular Remodeling in Human Liver Fibrosis Evolution.

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    Andrea Baiocchini

    Full Text Available Chronic liver damage leads to pathological accumulation of ECM proteins (liver fibrosis. Comprehensive characterization of the human ECM molecular composition is essential for gaining insights into the mechanisms of liver disease. To date, studies of ECM remodeling in human liver diseases have been hampered by the unavailability of purified ECM. Here, we developed a decellularization method to purify ECM scaffolds from human liver tissues. Histological and electron microscopy analyses demonstrated that the ECM scaffolds, devoid of plasma and cellular components, preserved the three-dimensional ECM structure and zonal distribution of ECM components. This method has been then applied on 57 liver biopsies of HCV-infected patients at different stages of liver fibrosis according to METAVIR classification. Label-free nLC-MS/MS proteomics and computation biology were performed to analyze the ECM molecular composition in liver fibrosis progression, thus unveiling protein expression signatures specific for the HCV-related liver fibrotic stages. In particular, the ECM molecular composition of liver fibrosis was found to involve dynamic changes in matrix stiffness, flexibility and density related to the dysregulation of predominant collagen, elastic fibers and minor components with both structural and signaling properties. This study contributes to the understanding of the molecular bases underlying ECM remodeling in liver fibrosis and suggests new molecular targets for fibrolytic strategies.

  19. The transport of drug in fibrosis. Comment on "Towards a unified approach in the modeling of fibrosis: A review with research perspectives" by Martine Ben Amar and Carlo Bianca

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    Ivancevic, Vladimir

    2016-07-01

    The topic of the review article [1] is the derivation of a multiscale paradigm for the modeling of fibrosis. Firstly, the biological process of the physiological and pathological fibrosis including therapeutical actions is reviewed. Fibrosis can be a consequence of tissue damage, infections and autoimmune diseases, foreign material, tumors. Some questions regarding the pathogenesis, progression and possible regression of fibrosis are lacking. At each scale of observation, different theoretical tools coming from computational, mathematical and physical biology have been proposed. However a complete framework that takes into account the different mechanisms occurring at different scales is still missing. Therefore with the main aim to define a multiscale approach for the modeling of fibrosis, the authors of [1] have presented different top-down and bottom-up approaches that have been developed in the literature. Specifically, their description refers to models for fibrosis diseases based on ordinary and partial differential equation, agents [2], thermostatted kinetic theory [3-5], coarse-grained structures [6-8] and constitutive laws for fibrous collagen networks [9]. A critical analysis has been addressed for all frameworks discussed in the paper. Open problems and future research directions referring to both biological and modeling insight of fibrosis are presented. The paper concludes with the ambitious aim of a multiscale model.

  20. Nanostructured Surfaces for Drug Delivery and Anti-Fibrosis

    Science.gov (United States)

    Kam, Kimberly Renee

    Effective and cost-efficient healthcare is at the forefront of public discussion; on both personal and policy levels, technologies that improve therapeutic efficacy without the use of painful hypodermic needle injections or the use of harsh chemicals would prove beneficial to patients. Nanostructured surfaces as structure-mediated permeability enhancers introduce a potentially revolutionary approach to the field of drug delivery. Parental administration routes have been the mainstay technologies for delivering biologics because these therapeutics are too large to permeate epithelial barriers. However, there is a significant patient dislike for hypodermic needles resulting in reduced patient compliance and poor therapeutic results. We present an alternative strategy to harness the body's naturally occurring biological processes and transport mechanisms to enhance the drug transport of biologics across the epithelium. Our strategy offers a paradigm shift from traditional biochemical drug delivery vehicles by using nanotopography to loosen the epithelial barrier. Herein, we demonstrate that nanotopographical cues can be used to enable biologics > 66 kDa to be transported across epithelial monolayers by increasing paracellular transport. When placed in contact with epithelial cells, nanostructured films significantly increase the transport of albumin, IgG, and a model therapeutic, etanercept. Our work highlights the potential to use drug delivery systems which incorporate nanotopographical cues to increase the transport of biologics across epithelial tissue. Furthermore, we describe current advancements in nano- and microfabrication for applications in anti-fibrosis and wound healing. Influencing cellular responses to biomaterials is crucial in the field of tissue engineering and regenerative medicine. Since cells are surrounded by extracellular matrix features that are on the nanoscale, identifying nanostructures for imparting desirable cellular function could greatly