WorldWideScience

Sample records for understanding disease pathogenesis

  1. Understanding rare disease pathogenesis: a grand challenge for model organisms.

    Science.gov (United States)

    Hieter, Philip; Boycott, Kym M

    2014-10-01

    In this commentary, Philip Hieter and Kym Boycott discuss the importance of model organisms for understanding pathogenesis of rare human genetic diseases, and highlight the work of Brooks et al., "Dysfunction of 60S ribosomal protein L10 (RPL10) disrupts neurodevelopment and causes X-linked microcephaly in humans," published in this issue of GENETICS. Copyright © 2014 by the Genetics Society of America.

  2. [Understanding and treatment strategy of the pathogenesis of periodontal disease based on chronic inflammation].

    Science.gov (United States)

    Murakami, Tomohiko

    2016-05-01

    Prolonged inflammation continuously promotes the infiltration of macrophages in the organization and chronically induces the production of pro-inflammatory cytokines such as TNF and IL-1. In periodontal tissues, these inflammatory cytokines enhance the differentiation and activity of osteoclasts, which cause destruction of the alveolar bone. Therefore, inhibition of inflammatory cytokine production leads to the prevention or treatment of periodontal disease. IL-1 is a pro-inflammatory cytokine that strongly enhances the bone-resorbing activity of osteoclasts. Elucidation of mechanisms for the production of IL-1 is critical for understanding the pathogenesis of periodontal disease. This paper reviews recent findings of the molecular mechanisms regulating IL-1 production and focuses on inflammasome.

  3. Pathogenesis of Parkinson's disease

    OpenAIRE

    Riederer, Peter; Lange, Klaus W.

    1992-01-01

    The importance of genetic aspects, ageing, environmental factors, head trauma, defective mitochondrial respiration, altered iron metabolism, oxidative stress and glutamatergic overactivity of the basal ganglia in the pathogenesis of Parkinson's disease (PD) are considered in this review.

  4. Huntington disease: pathogenesis and treatment.

    Science.gov (United States)

    Dayalu, Praveen; Albin, Roger L

    2015-02-01

    Huntington disease (HD) is an autosomal dominant inherited neurodegenerative disease characterized by progressive motor, behavioral, and cognitive decline, culminating in death. It is caused by an expanded CAG repeat in the huntingtin gene. Even years before symptoms become overt, mutation carriers show subtle but progressive striatal and cerebral white matter atrophy by volumetric MRI. Although there is currently no direct treatment of HD, management options are available for several symptoms. A better understanding of HD pathogenesis, and more sophisticated clinical trials using newer biomarkers, may lead to meaningful treatments. This article reviews the current knowledge of HD pathogenesis and treatment. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Basal Cell Carcinoma: From the Molecular Understanding of the Pathogenesis to Targeted Therapy of Progressive Disease

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    Daniela Göppner

    2011-01-01

    Full Text Available Due to intensified research over the past decade, the Hedgehog (HH pathway has been identified as a pivotal defect implicated in roughly 25% of all cancers. As one of the most frequent cancer worldwide, the development of Basal cell carcinoma (BCC due to activation of the HH pathway has been convincingly demonstrated. Thus the discovery of this central tumor-promoting signalling pathway has not only revolutionized the understanding of BCC carcinogenesis but has also enabled the development of a completely novel therapeutic approach. Targeting just a few of several potential mutations, HH inhibitors such as GDC-0449 achieved already the first promising results in metastatic or locally advanced BCC. This paper summarizes the current understanding of BCC carcinogenesis and describes the current “mechanism-based” therapeutic strategies.

  6. [Achieving pathogenesis understanding of ocular diseases by deciphering the underlying molecular pathways].

    Science.gov (United States)

    Huang, Qian

    2005-10-01

    The field of ophthalmology research has experienced a revolution since the 1970's, when molecular biology techniques were gradually and widely adopted. Many of the developments generated impact that went far beyond the field of ophthalmology. A classic case was the identification and characterization of the Retinoblastoma susceptibility gene (Rb), whose impact went far beyond the rare and obscure disease, as it provides key evidence for the concept of tumor suppressor gene and the "two hit" theory of tumor formation. The identification of scores of genes involved in retinitis pigmentosum (pigmentosa), on the other hand, show cases the complexity of multi-factorial diseases. Ophthalmology researchers in China have been quick in integrating these novel tools into their research. However, the field still lags behind in the effective use of these technologies to carry out in-depth inquiries into key disease mechanisms. The advent of "omics" technologies heralded a new era in biomedical research that allows for the global and rapid survey of genetic and biochemical profiles. Effective integration of these novel technologies into ophthalmology research will have far-reaching impact for the whole field.

  7. Current understanding in pathogenesis of atopic dermatitis

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    Tess McPherson

    2016-01-01

    Full Text Available There have been advances in our understanding of the complex pathogenesis of atopic eczema over the past few decades. This article examines the multiple factors which are implicated in this process.

  8. From genome-wide association studies to Mendelian randomization: Novel opportunities for understanding cardiovascular disease causality, pathogenesis, prevention, and treatment.

    Science.gov (United States)

    Benn, Marianne; Nordestgaard, Børge G

    2018-02-19

    The Mendelian randomization approach is an epidemiologic study design incorporating genetic information into traditional epidemiologic studies to infer causality of biomarkers, risk factors, or lifestyle factors on disease risk. Mendelian randomization studies often draw on novel information generated in genome-wide association studies on causal associations between genetic variants and a risk factor or lifestyle factor. Such information can then be used in a largely unconfounded study design free of reverse causation to understand if and how risk factors and lifestyle factors cause cardiovascular disease. If causation is demonstrated, an opportunity for prevention of disease is identified; importantly however, before prevention or treatment can be implemented, randomized intervention trials altering risk factor levels or improving deleterious lifestyle factors needs to document reductions in cardiovascular disease in a safe and side-effect sparse manner. Documentation of causality can also inform on potential drug targets, more likely to be successful than prior approaches often relying on animal or cell studies mainly.The present review summarizes the history and background of Mendelian randomization, the study design, assumptions for using the design, and the most common caveats, followed by a discussion on advantages and disadvantages of different types of Mendelian randomization studies using one or more samples and different levels of information on study participants. The review also provides an overview of results on many of the risk factors and lifestyle factors for cardiovascular disease examined to date using the Mendelian randomization study design.

  9. Recent advances in understanding the role of adipocytokines during non-alcoholic fatty liver disease pathogenesis and their link with hepatokines.

    Science.gov (United States)

    Panera, Nadia; Della Corte, Claudia; Crudele, Annalisa; Stronati, Laura; Nobili, Valerio; Alisi, Anna

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is currently considered the main cause of chronic liver disease worldwide. Mechanisms leading to the development and progression of this disease are topics of great interest for researchers and clinicians. The current multi-hit hypothesis has thrown the crosstalk between liver and adipose tissue into sharp focus. It is well known that adipose tissue produces circulating factors, known as adipocytokines, which exert several effects on liver cells, promoting the onset of NAFLD and its progression to non-alcoholic steatohepatitis in obese subjects. In a similar way, hepatocytes may also respond to obesogenic stimuli by producing and releasing hepatokines into the circulation. Here, the authors provide an overview of recent advances in our understanding of the role of the most relevant adipocytokines and hepatokines in NAFLD pathogenesis, highlighting their possible molecular and functional interactions.

  10. Immunological pathogenesis of inflammatory bowel disease

    Directory of Open Access Journals (Sweden)

    Seung Hoon Lee

    2018-01-01

    Full Text Available Inflammatory bowel disease (IBD is a chronic inflammatory state of the gastrointestinal tract and can be classified into 2 main clinical phenomena: Crohn's disease (CD and ulcerative colitis (UC. The pathogenesis of IBD, including CD and UC, involves the presence of pathogenic factors such as abnormal gut microbiota, immune response dysregulation, environmental changes, and gene variants. Although many investigations have tried to identify novel pathogenic factors associated with IBD that are related to environmental, genetic, microbial, and immune response factors, a full understanding of IBD pathogenesis is unclear. Thus, IBD treatment is far from optimal, and patient outcomes can be unsatisfactory. As result of massive studying on IBD, T helper 17 (Th17 cells and innate lymphoid cells (ILCs are investigated on their effects on IBD. A recent study of the plasticity of Th17 cells focused primarily on colitis. ILCs also emerging as novel cell family, which play a role in the pathogenesis of IBD. IBD immunopathogenesis is key to understanding the causes of IBD and can lead to the development of IBD therapies. The aim of this review is to explain the pathogenesis of IBD, with a focus on immunological factors and therapies.

  11. Recent advances in understanding ichthyosis pathogenesis

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    Marukian, Nareh V.; Choate, Keith A.

    2016-01-01

    The ichthyoses, also known as disorders of keratinization (DOK), encompass a heterogeneous group of skin diseases linked by the common finding of abnormal barrier function, which initiates a default compensatory pathway of hyperproliferation, resulting in the characteristic clinical manifestation of localized and/or generalized scaling. Additional cutaneous findings frequently seen in ichthyoses include generalized xerosis, erythroderma, palmoplantar keratoderma, hypohydrosis, and recurrent infections. In 2009, the Ichthyosis Consensus Conference established a classification consensus for DOK based on pathophysiology, clinical manifestations, and mode of inheritance. This nomenclature system divides DOK into two main groups: nonsyndromic forms, with clinical findings limited to the skin, and syndromic forms, with involvement of additional organ systems. Advances in next-generation sequencing technology have allowed for more rapid and cost-effective genetic analysis, leading to the identification of novel, rare mutations that cause DOK, many of which represent phenotypic expansion. This review focuses on new findings in syndromic and nonsyndromic ichthyoses, with emphasis on novel genetic discoveries that provide insight into disease pathogenesis. PMID:27408699

  12. Understanding Anaplasmataceae pathogenesis using ‘Omics’ approaches

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    Ludovic ePruneau

    2014-07-01

    Full Text Available This paper examines how Omics approaches improve our understanding of Anaplasmataceae pathogenesis, through a global and integrative strategy to identify genes and proteins involved in biochemical pathways key for pathogen-host-vector interactions.The Anaplasmataceae family comprises obligate intracellular bacteria mainly transmitted by arthropods. These bacteria are responsible for major human and animal endemic and emerging infectious diseases with important economic and public health impacts. In order to improve disease control strategies, it is essential to better understand their pathogenesis. Our work focused on four Anaplasmataceae, which cause important animal, human and zoonotic diseases: Anaplasma marginale, A. phagocytophilum, Ehrlichia chaffeensis and E. ruminantium. Wolbachia spp. an endosymbiont of arthropods was also included in this review as a model of a non-pathogenic Anaplasmataceae.A gap analysis on Omics approaches on Anaplasmataceae was performed, which highlighted a lack of studies on the genes and proteins involved in the infection of hosts and vectors. Furthermore, most of the studies have been done on the pathogen itself, mainly on infectious free-living forms and rarely on intracellular forms. In order to perform a transcriptomic analysis of the intracellular stage of development, researchers developed methods to enrich bacterial transcripts from infected cells. These methods are described in this paper. Bacterial genes encoding outer membrane proteins, post-translational modifications, eukaryotic repeated motif proteins, proteins involved in osmotic and oxidative stress and hypothetical proteins have been identified to play a key role in Anaplasmataceae pathogenesis. Further investigations on the function of these outer membrane proteins and hypothetical proteins will be essential to confirm their role in the pathogenesis. Our work underlines the need for further studies in this domain and on host and vector responses

  13. Progress towards understanding the pathogenesis of dengue hemorrhagic fever.

    Science.gov (United States)

    Pang, Xiaojing; Zhang, Rudian; Cheng, Gong

    2017-02-01

    Dengue virus (DENV) is a mosquito-borne virus belonging to the Flaviviridae family. There are 4 serotypes of DENV that cause human disease through transmission by mosquito vectors. DENV infection results in a broad spectrum of clinical symptoms, ranging from mild fever to dengue hemorrhagic fever (DHF), the latter of which can progress to dengue shock syndrome (DSS) and death. Researchers have made unremitting efforts over the last half-century to understand DHF pathogenesis. DHF is probably caused by multiple factors, such as virus-specific antibodies, viral antigens and host immune responses. This review summarizes the current progress of studies on DHF pathogenesis, which may provide important information for achieving effective control of dengue in the future.

  14. Pathogenic Leptospira: Advances in understanding the molecular pathogenesis and virulence

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    Ciamak Ghazaei

    2018-01-01

    Full Text Available Leptospirosis is a common zoonotic disease has emerged as a major public health problem, with developing countries bearing disproportionate burdens. Although the diverse range of clinical manifestations of the leptospirosis in humans is widely documented, the mechanisms through which the pathogen causes disease remain undetermined. In addition, leptospirosis is a much-neglected life-threatening disease although it is one of the most important zoonoses occurring in a diverse range of epidemiological distribution. Recent advances in molecular profiling of pathogenic species of the genus Leptospira have improved our understanding of the evolutionary factors that determine virulence and mechanisms that the bacteria employ to survive. However, a major impediment to the formulation of intervention strategies has been the limited understanding of the disease determinants. Consequently, the association of the biological mechanisms to the pathogenesis of Leptospira, as well as the functions of numerous essential virulence factors still remain implicit. This review examines recent advances in genetic screening technologies, the underlying microbiological processes, the virulence factors and associated molecular mechanisms driving pathogenesis of Leptospira species.

  15. Pathogenic Leptospira: Advances in understanding the molecular pathogenesis and virulence

    Science.gov (United States)

    Ghazaei, Ciamak

    2018-01-01

    Leptospirosis is a common zoonotic disease has emerged as a major public health problem, with developing countries bearing disproportionate burdens. Although the diverse range of clinical manifestations of the leptospirosis in humans is widely documented, the mechanisms through which the pathogen causes disease remain undetermined. In addition, leptospirosis is a much-neglected life-threatening disease although it is one of the most important zoonoses occurring in a diverse range of epidemiological distribution. Recent advances in molecular profiling of pathogenic species of the genus Leptospira have improved our understanding of the evolutionary factors that determine virulence and mechanisms that the bacteria employ to survive. However, a major impediment to the formulation of intervention strategies has been the limited understanding of the disease determinants. Consequently, the association of the biological mechanisms to the pathogenesis of Leptospira, as well as the functions of numerous essential virulence factors still remain implicit. This review examines recent advances in genetic screening technologies, the underlying microbiological processes, the virulence factors and associated molecular mechanisms driving pathogenesis of Leptospira species. PMID:29445617

  16. Autophagy in lung disease pathogenesis and therapeutics

    Directory of Open Access Journals (Sweden)

    Stefan W. Ryter

    2015-04-01

    Full Text Available Autophagy, a cellular pathway for the degradation of damaged organelles and proteins, has gained increasing importance in human pulmonary diseases, both as a modulator of pathogenesis and as a potential therapeutic target. In this pathway, cytosolic cargos are sequestered into autophagosomes, which are delivered to the lysosomes where they are enzymatically degraded and then recycled as metabolic precursors. Autophagy exerts an important effector function in the regulation of inflammation, and immune system functions. Selective pathways for autophagic degradation of cargoes may have variable significance in disease pathogenesis. Among these, the autophagic clearance of bacteria (xenophagy may represent a crucial host defense mechanism in the pathogenesis of sepsis and inflammatory diseases. Our recent studies indicate that the autophagic clearance of mitochondria, a potentially protective program, may aggravate the pathogenesis of chronic obstructive pulmonary disease by activating cell death programs. We report similar findings with respect to the autophagic clearance of cilia components, which can contribute to airways dysfunction in chronic lung disease. In certain diseases such as pulmonary hypertension, autophagy may confer protection by modulating proliferation and cell death. In other disorders, such as idiopathic pulmonary fibrosis and cystic fibrosis, impaired autophagy may contribute to pathogenesis. In lung cancer, autophagy has multiple consequences by limiting carcinogenesis, modulating therapeutic effectiveness, and promoting tumor cell survival. In this review we highlight the multiple functions of autophagy and its selective autophagy subtypes that may be of significance to the pathogenesis of human disease, with an emphasis on lung disease and therapeutics.

  17. The Pathogenesis of Ebola Virus Disease.

    Science.gov (United States)

    Baseler, Laura; Chertow, Daniel S; Johnson, Karl M; Feldmann, Heinz; Morens, David M

    2017-01-24

    For almost 50 years, ebolaviruses and related filoviruses have been repeatedly reemerging across the vast equatorial belt of the African continent to cause epidemics of highly fatal hemorrhagic fever. The 2013-2015 West African epidemic, by far the most geographically extensive, most fatal, and longest lasting epidemic in Ebola's history, presented an enormous international public health challenge, but it also provided insights into Ebola's pathogenesis and natural history, clinical expression, treatment, prevention, and control. Growing understanding of ebolavirus pathogenetic mechanisms and important new clinical observations of the disease course provide fresh clues about prevention and treatment approaches. Although viral cytopathology and immune-mediated cell damage in ebolavirus disease often result in severe compromise of multiple organs, tissue repair and organ function recovery can be expected if patients receive supportive care with fluids and electrolytes; maintenance of oxygenation and tissue perfusion; and respiratory, renal, and cardiovascular support. Major challenges for managing future Ebola epidemics include establishment of early and aggressive epidemic control and earlier and better patient care and treatment in remote, resource-poor areas where Ebola typically reemerges. In addition, it will be important to further develop Ebola vaccines and to adopt policies for their use in epidemic and pre-epidemic situations.

  18. Understanding the Pathogenesis of Angelman Syndrome through Animal Models

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    Nihar Ranjan Jana

    2012-01-01

    Full Text Available Angelman syndrome (AS is a neurodevelopmental disorder characterized by severe mental retardation, lack of speech, ataxia, susceptibility to seizures, and unique behavioral features such as easily provoked smiling and laughter and autistic features. The disease is primarily caused by deletion or loss-of-function mutations of the maternally inherited UBE3A gene located within chromosome 15q11-q13. The UBE3A gene encodes a 100 kDa protein that functions as ubiquitin ligase and transcriptional coactivator. Emerging evidence now indicates that UBE3A plays a very important role in synaptic function and in regulation of activity-dependent synaptic plasticity. A number of animal models for AS have been generated to understand the disease pathogenesis. The most widely used model is the UBE3A-maternal-deficient mouse that recapitulates most of the essential features of AS including cognitive and motor abnormalities. This paper mainly discusses various animal models of AS and how these models provide fundamental insight into understanding the disease biology for potential therapeutic intervention.

  19. Understanding the Pathogenesis of Angelman Syndrome through Animal Models

    Science.gov (United States)

    Jana, Nihar Ranjan

    2012-01-01

    Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe mental retardation, lack of speech, ataxia, susceptibility to seizures, and unique behavioral features such as easily provoked smiling and laughter and autistic features. The disease is primarily caused by deletion or loss-of-function mutations of the maternally inherited UBE3A gene located within chromosome 15q11-q13. The UBE3A gene encodes a 100 kDa protein that functions as ubiquitin ligase and transcriptional coactivator. Emerging evidence now indicates that UBE3A plays a very important role in synaptic function and in regulation of activity-dependent synaptic plasticity. A number of animal models for AS have been generated to understand the disease pathogenesis. The most widely used model is the UBE3A-maternal-deficient mouse that recapitulates most of the essential features of AS including cognitive and motor abnormalities. This paper mainly discusses various animal models of AS and how these models provide fundamental insight into understanding the disease biology for potential therapeutic intervention. PMID:22830052

  20. [Anatomy and pathogenesis of diverticular disease].

    Science.gov (United States)

    Wedel, T; Böttner, M

    2014-04-01

    Although diverticular disease is one of the most frequent gastrointestinal disorders the pathogenesis is not yet sufficiently clarified. The aim is to define the anatomy and pathogenesis of diverticular disease considering the risk factors and description of structural and functional alterations of the bowel wall. This article gives an appraisal of the literature, presentation and evaluation of classical etiological factors, analysis and discussion of novel pathogenetic concepts. Colonic diverticulosis is defined as an acquired out-pouching of multiple and initially asymptomatic pseudodiverticula through muscular gaps in the colon wall. Diverticular disease is characterized by diverticular bleeding and/or inflammatory processes (diverticulitis) with corresponding complications (e.g. abscess formation, fistula, covered and open perforation, peritonitis and stenosis). Risk factors for diverticular disease include increasing age, genetic predisposition, congenital connective tissue diseases, low fiber diet, high meat consumption and pronounced overweight. Alterations of connective tissue cause a weakening of preformed exit sites of diverticula and rigidity of the bowel wall with reduced flexibility. It is assumed that intestinal innervation disorders and structural alterations of the musculature induce abnormal contractile patterns with increased intraluminal pressure, thereby promoting the development of diverticula. Moreover, an increased release of pain-mediating neurotransmitters is considered to be responsible for persistent pain in chronic diverticular disease. According to the present data the pathogenesis of diverticular disease cannot be attributed to a single factor but should be considered as a multifactorial event.

  1. Pathogenesis of biliary atresia: defining biology to understand clinical phenotypes

    Science.gov (United States)

    Asai, Akihiro; Miethke, Alexander; Bezerra, Jorge A.

    2016-01-01

    Biliary atresia is a severe cholangiopathy of early infancy that destroys extrahepatic bile ducts and disrupts bile flow. With a poorly defined disease pathogenesis, treatment consists of the surgical removal of duct remnants followed by hepatoportoenterostomy. Although this approach can improve the short-term outcome, the liver disease progresses to end-stage cirrhosis in most children. Further improvement in outcome will require a greater understanding of the mechanisms of biliary injury and fibrosis. Here, we review progress in the field, which has been fuelled by collaborative studies in larger patient cohorts and the development of cell culture and animal model systems to directly test hypotheses. Advances include the identification of phenotypic subgroups and stages of disease based on clinical, pathological and molecular features. Stronger evidence exists for viruses, toxins and gene sequence variations in the aetiology of biliary atresia, triggering a proinflammatory response that injures the duct epithelium and produces a rapidly progressive cholangiopathy. The immune response also activates the expression of type 2 cytokines that promote epithelial cell proliferation and extracellular matrix production by nonparenchymal cells. These advances provide insight into phenotype variability and might be relevant to the design of personalized trials to block progression of liver disease. PMID:26008129

  2. Etiology and pathogenesis of periodontal diseases.

    Science.gov (United States)

    Tatakis, Dimitris N; Kumar, Purnima S

    2005-07-01

    The two most prevalent and most investigated periodontal diseases are dental plaque-induced gingivitis and chronic periodontitis. The last 10 to 15 years have seen the emergence of several important new findings and concepts regarding the etiopathogenesis of periodontal diseases. These findings include the recognition of dental bacterial plaque as a biofilm, identification and characterization of genetic defects that predispose individuals to periodontitis, host-defense mechanisms implicated in periodontal tissue destruction, and the interaction of risk factors with host defenses and bacterial plaque. This article reviews current aspects of the etiology and pathogenesis of periodontal diseases.

  3. [The etiology and pathogenesis of Sprengel's disease].

    Science.gov (United States)

    Skopichenko, D N

    1999-01-01

    Basing on the analysis of clinico-radiological and functional signs, electromyographic and histological changes in the shoulder girdle (SG) upper extremities muscles, macro- and microscopic investigations of omovertebral formations in the patients with Sprengel disease, and the literature data there was formulated the scheme of etiology and pathogenesis of the inborn high position of shoulder blade. The leading role in the Sprengel disease etiology plays teratogenic exo- or endogenous harmful agent, affecting mesenchymal tissue in the moment of the vertebral column and SG inlay on the 4-5th week of embryogenesis. Underdevelopment and degeneration of the SG muscles, creation of fibrous, fibrous-cartilaginous and osteal tissues due to the embryogenesis disorder occurrence, are playing essential role in pathogenesis of anatomic-functional disorders, causing occurrence of the inborn high position of shoulder blade.

  4. Advances in understanding the pathogenesis of pneumococcal otitis media.

    NARCIS (Netherlands)

    Tonnaer, E.L.G.M.; Graamans, K.; Sanders, E.A.M.; Curfs, J.H.A.J.

    2006-01-01

    In this review, a state of the art on otitis media research is provided with emphasis on the role of Streptococcus pneumoniae in the pathogenesis of this disease. Articles have been selected by MEDLINE search supplemented with a manual crosscheck of bibliographies. Pathogenic mechanisms in middle

  5. Diverticular Disease: An Update on Pathogenesis and Management.

    Science.gov (United States)

    Rezapour, Mona; Ali, Saima; Stollman, Neil

    2018-03-15

    Diverticular disease is one of the most common conditions in the Western world and one of the most common findings identified at colonoscopy. Recently, there has been a significant paradigm shift in our understanding of diverticular disease and its management. The pathogenesis of diverticular disease is thought to be multifactorial and include both environmental and genetic factors in addition to the historically accepted etiology of dietary fiber deficiency. Symptomatic uncomplicated diverticular disease (SUDD) is currently considered a type of chronic diverticulosis that is perhaps akin to irritable bowel syndrome. Mesalamine, rifaximin and probiotics may achieve symptomatic relief in some patients with SUDD, although their role(s) in preventing complications remain unclear. Antibiotic use for acute diverticulitis and elective prophylactic resection surgery are considered more individualized treatment modalities that take into account the clinical status, comorbidities and lifestyle of the patient. Our understanding of the pathogenesis of diverticular disease continues to evolve and is likely to be diverse and multifactorial. Paradigm shifts in several areas of the pathogenesis and management of diverticular disease are explored in this review.

  6. Inflammatory Bowel Disease: Genetics, Epigenetics and Pathogenesis

    Directory of Open Access Journals (Sweden)

    Italia eLoddo

    2015-11-01

    Full Text Available Inflammatory Bowel Diseases (IBDs are complex, multifactorial disorders characterized by chronic relapsing intestinal inflammation. Although aetiology remains largely unknown, recent research has suggested that genetic factors, environment, microbiota and immune response are involved in the pathogenesis.Epidemiological evidence for a genetic contribution is defined: 15% of patients with Crohn’s Disease (CD have an affected family member with IBD, and twin studies for CD have shown 50% concordance in monozygotic twins compared to less than 10% in dizygotics. The most recent and largest genetic association studies, which employed genome-wide association data for over 75,000 patients and controls, identified 163 susceptibility loci for IBD. More recently, a trans-ethnic analysis, including over 20,000 individuals, identified an additional 38 new IBD loci.Although most cases are correlated with polygenic contribution toward genetic susceptibility, there is a spectrum of rare genetic disorders that can contribute to early onset IBD (before 5 years or very early IBD (before 2 years. Genetic variants that cause these disorders have a wide effect on gene function. These variants are so rare in allele frequency that the genetic signals are not detected in genome-wide association studies of patients with IBD. With recent advances in sequencing techniques, approximately 50 genetic disorders have been identified and associated with IBD-like immunopathology. Monogenic defects have been found to alter intestinal immune homeostasis through many mechanisms. Candidate gene resequencing should be carried out in early-onset patients in clinical practice.The evidence that genetic factors contribute in small part to disease pathogenesis confirms the important role of microbial and environmental factors. Epigenetic factors can mediate interactions between environment and genome. Epigenetic mechanisms could affect development and progression of IBD. Epigenomics is

  7. Multiple pathways contribute to the pathogenesis of Huntington disease

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    Li Xiao-Jiang

    2006-12-01

    Full Text Available Abstract Huntington disease (HD is caused by expansion of a polyglutamine (polyQ domain in the protein known as huntingtin (htt, and the disease is characterized by selective neurodegeneration. Expansion of the polyQ domain is not exclusive to HD, but occurs in eight other inherited neurodegenerative disorders that show distinct neuropathology. Yet in spite of the clear genetic defects and associated neurodegeneration seen with all the polyQ diseases, their pathogenesis remains elusive. The present review focuses on HD, outlining the effects of mutant htt in the nucleus and neuronal processes as well as the role of cell-cell interactions in HD pathology. The widespread expression and localization of mutant htt and its interactions with a variety of proteins suggest that mutant htt engages multiple pathogenic pathways. Understanding these pathways will help us to elucidate the pathogenesis of HD and to target therapies effectively.

  8. [The pathogenesis of periodontal disease: a paradigm shift].

    Science.gov (United States)

    Ekstein, J; Shapira, L; Van Dyke, T E

    2010-07-01

    Periodontitis is a family of related diseases that differ in etiology, natural history, disease progression and response to therapy, but have a common underlying chain of events, thatareinfluenced by disease modifiers. The clinical manifestations observed are a result of the complex interplay of these factors. The pathogenesis of human periodontitis was placed on a rational footing for the first time by Page & Schroeder in 1976 and the general principles and the overall conclusions reached in that article are still largely acceptable today. Still, an enormous amount has been learned about all aspects of human periodontitis, including its pathogenesis, since 1976. A critical evaluation of the literature regarding the complex relationship between the microbial factor, the host factor and the occurrence of a disease, might be leading us over a surge of a paradigm shift in our understanding the pathogenesis of the disease. It is well acknowledged that while the etiology of periodontitis is bacterial, the pathogenesis is inflammatory. The understanding of regulation of inflammation in periodontitis is far from complete; however, as the understanding of periodontal inflammation increases, the current understanding of the microbiology of periodontitis becomes less clear. While we think we know that bacteria initiate the disease, the role of specific bacteria is still unknown. The current knowledge of the microbiology of periodontitis is based on large cross-sectional and association studies. Periodontitis is seen as the direct consequence of bacterial invasion and is regarded as an infectious disease. It is however, not possible to draw cause and- effect inferences from these studies. One might state that the inflammation precedes the overgrowth of the bacteria. In this scenario, the initiator of the disease might be early, gram-positive colonizers that elicit a profound inflammatory response in the susceptible host. The implication of that paradigm shift outlined above

  9. Neonatal respiratory distress: recent progress in understanding pathogenesis and treatment outcomes

    OpenAIRE

    So Young Kim

    2010-01-01

    Transient tachypnea of the newborn (TTN), respiratory distress syndrome (RDS), and persistent pulmonary hypertension (PPHN) are the three most common disorders that cause respiratory distress after birth. An understanding of the pathophysiology of these disorders and the development of effective therapeutic strategies is required to control these conditions. Here, we review recent papers on the pathogenesis and treatment of neonatal respiratory disease.

  10. Pathogenesis of diverticulosis and diverticular disease.

    Science.gov (United States)

    Walker, Marjorie M; Harris, Angela K

    2017-06-01

    Diverticulosis is defined by the presence of diverticula due to herniation of mucosa and muscularis mucosa through the muscularis propria at sites of vascular penetration in the colon and is asymptomatic in the vast majority affected. There are global differences of distribution, in Western industrialized societies, the most common site is in the left colon, but in Asia right sided diverticulosis predominates. Whilst present in 17.5% of a general population and 42% of all comers at endoscopy it is seen in 71% of those aged ≥80 years. Diverticular disease is defined as clinically significant and symptomatic diverticulosis, which may have an absence of macroscopically overt colitis and in true diverticulitis there is macroscopic inflammation of diverticula with related acute or chronic complications. Whilst overall, diverticulitis affects only 4% of those with diverticulosis, in younger patients (aged 40-49 years) this peaks at 11%. Diverticulosis is one of the most common chronic diseases, yet research in this field on pathogenesis has lagged behind other common conditions such as diabetes mellitus. However, in the last decade there have been major advances in taxonomy that can be used to relate to patients' outcome and treatment in both medicine and surgery. It has been shown there is an association with age, diet, drugs and smoking. Genetic studies have shown a familial association and a specific gene, TNFSF 15 may predict severity of disease. The role of the microbiome has been explored and microbial and metabolomic signatures are also important in predicting disease severity. That diverticulosis is a chronic disease is shown by mucosal pathology with subtle chronic inflammation present in those with asymptomatic diverticulosis and inflammation may lead to muscular hypertrophy, enteric nerve remodeling with disordered motility. The diverticulitis quality of life instrument shows that this condition impacts markedly on patients' well-being and prevention and

  11. Genes, autoimmunity and pathogenesis of rheumatic heart disease

    International Nuclear Information System (INIS)

    Guilherme, L; Köhler, K F; Postol, E; Kalil, J

    2011-01-01

    Pathogenesis of rheumatic heart disease (RHD) remains incompletely understood. Several genes associated with RHD have been described; most of these are involved with immune responses. Single nucleotide polymorphisms in a number of genes affect patients with RHD compared to controls. Molecular mimicry between streptococcal antigens and human proteins, including cardiac myosin epitopes, vimentin and other intracellular proteins is central to the pathogenesis of RHD. Autoreactive T cells migrate from the peripheral blood to the heart and proliferate in the valves in response to stimulation with specific cytokines. The types of cells involved in the inflammation as well as different cytokine profiles in these patients are being investigated. High TNF alpha, interferon gamma, and low IL4 are found in the rheumatic valve suggesting an imbalance between Th1 and Th2 cytokines and probably contributing to the progressive and permanent valve damage. Animal model of ARF in the Lewis rat may further contribute towards understanding the ARF

  12. Understanding cardiovascular disease

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/patientinstructions/000759.htm Understanding cardiovascular disease To use the sharing features on this page, ... lead to heart attack or stroke. Types of Cardiovascular Disease Coronary heart disease (CHD) is the most common ...

  13. Research advances in the pathogenesis of nonalcoholic fatty liver disease

    Directory of Open Access Journals (Sweden)

    WANG Hu

    2017-04-01

    Full Text Available Nonalcoholic fatty liver disease (NAFLD has been developing rapidly in recent years and has become one of the most common liver diseases. However, its pathogenesis remains unclear, and there are no widely accepted therapeutic regimens. NAFLD has a complex pathogenesis with multiple factors involved, including insulin resistance, oxidative stress, bile acid metabolic disorders, and autophagy. This article reviews the pathogenesis of NAFLD in order to provide a reference for further research and clinical treatment in the future.

  14. Coronary heart disease: dietary links and pathogenesis.

    Science.gov (United States)

    Renaud, S; Lanzmann-Petithory, D

    2001-04-01

    For decades it has been postulated that the main environmental factor for coronary heart disease (CHD) was the intake of saturated fatty acids (SFA). Nevertheless, confirmation of the role of SFA in CHD through intervention trials has been disappointing. It was only when the diet was enriched in n-3 fatty acids that CHD was significantly prevented, especially cardiac death. In addition to n-3 fatty acids, many other foodstuffs or nutrients such as fibers, antioxidants, folic acid, calcium and even alcohol contribute to prevent CHD. Thus the relationship between diet and CHD morbidity and mortality appears to be much more complex than formerly suspected considering as key factors only SFA, linoleic acid, cholesterol and atherosclerosis. Some of the mechanisms are briefly described, but many additional nutrients (or non nutrients) may also play an important role in the pathogenesis of CHD. Finally, as a result of the most recent epidemiologic studies the ideal diet may comprise: 8% energy from SFA, 5% from polyunsaturated fatty acids with a ratio 5/1 of linoleic/alpha-linolenic acid+longer chains n-3, oleic acid as desired, large intake of cereals, vegetables, legumes and fruits, fish twice a week, cheese and yogurt as dairy products, rapeseed and olive oils as edible fat. Without side effects, such a diet can be highly palatable, easily enjoyed by many populations and may prevent effectively and rapidly (within a few weeks or months) CHD.

  15. MicroRNAs in the pathogenesis of cystic kidney disease.

    Science.gov (United States)

    Phua, Yu Leng; Ho, Jacqueline

    2015-04-01

    Cystic kidney diseases are common renal disorders characterized by the formation of fluid-filled epithelial cysts in the kidneys. The progressive growth and expansion of the renal cysts replace existing renal tissue within the renal parenchyma, leading to reduced renal function. While several genes have been identified in association with inherited causes of cystic kidney disease, the molecular mechanisms that regulate these genes in the context of post-transcriptional regulation are still poorly understood. There is increasing evidence that microRNA (miRNA) dysregulation is associated with the pathogenesis of cystic kidney disease. In this review, recent studies that implicate dysregulation of miRNA expression in cystogenesis will be discussed. The relationship of specific miRNAs, such as the miR-17∼92 cluster and cystic kidney disease, miR-92a and von Hippel-Lindau syndrome, and alterations in LIN28-LET7 expression in Wilms tumor will be explored. At present, there are no specific treatments available for patients with cystic kidney disease. Understanding and identifying specific miRNAs involved in the pathogenesis of these disorders may have the potential to lead to the development of novel therapies and biomarkers.

  16. Cytokines in Gaucher disease: Role in the pathogenesis of bone ...

    African Journals Online (AJOL)

    Azza A.G. Tantawy

    2015-03-03

    Mar 3, 2015 ... Cytokines in Gaucher disease: Role in the pathogenesis of bone and pulmonary ... Studies are increasingly recognizing the role of immune dysregulation and inflammation in the pathogenesis of Gaucher disease. ..... by various other cells of the immune system [11]. Recent work in a murine model of ...

  17. Metabolic Syndrome: Genetic Insights into Disease Pathogenesis

    Science.gov (United States)

    Ziki, Maen D. Abou; Mani, Arya

    2016-01-01

    Purpose of review Metabolic syndrome (MetS) is a cluster of inter-related and heritable metabolic traits, which collectively impart unsurpassed risk for atherosclerotic cardiovascular disease and type 2 diabetes. Considerable work has been done to understand the underlying disease mechanisms by elucidating its genetic etiology. Recent findings Genome-wide association studies (GWAS) have been widely utilized albeit with modest success in identifying variants that are associated with more than two metabolic traits. Another limitation of this approach is the inherent small effect of the common variants, a major barrier for dissecting their cognate pathways. Modest advances in this venue have been also made by genetic studies of kindreds at the extreme ends of quantitative distributions. These efforts have led to the discovery of a number of disease genes with large effects that underlie the association of diverse traits of this syndrome. Summary Substantial progress has been made over the last decade in identification of genetic risk factors associated with the various traits of MetS. The heterogeneity and multifactorial heritability of MetS, however, has been a challenge towards understanding the factors underlying the association of these traits. Genetic investigations of outlier kindreds or homogenous populations with high prevalence for the disease can potentially improve our knowledge of the disease pathophysiology. PMID:26825138

  18. Epigenetic mechanisms underlying the pathogenesis of neurogenetic diseases.

    Science.gov (United States)

    Qureshi, Irfan A; Mehler, Mark F

    2014-10-01

    There have been considerable advances in uncovering the complex genetic mechanisms that underlie nervous system disease pathogenesis, particularly with the advent of exome and whole genome sequencing techniques. The emerging field of epigenetics is also providing further insights into these mechanisms. Here, we discuss our understanding of the interplay that exists between genetic and epigenetic mechanisms in these disorders, highlighting the nascent field of epigenetic epidemiology-which focuses on analyzing relationships between the epigenome and environmental exposures, development and aging, other health-related phenotypes, and disease states-and next-generation research tools (i.e., those leveraging synthetic and chemical biology and optogenetics) for examining precisely how epigenetic modifications at specific genomic sites affect disease processes.

  19. Neonatal respiratory distress: recent progress in understanding pathogenesis and treatment outcomes

    Directory of Open Access Journals (Sweden)

    So Young Kim

    2010-01-01

    Full Text Available Transient tachypnea of the newborn (TTN, respiratory distress syndrome (RDS, and persistent pulmonary hypertension (PPHN are the three most common disorders that cause respiratory distress after birth. An understanding of the pathophysiology of these disorders and the development of effective therapeutic strategies is required to control these conditions. Here, we review recent papers on the pathogenesis and treatment of neonatal respiratory disease.

  20. Diet, gut microbes, and the pathogenesis of inflammatory bowel diseases.

    Science.gov (United States)

    Dolan, Kyle T; Chang, Eugene B

    2017-01-01

    The rising incidence of inflammatory bowel diseases in recent decades has notably paralleled changing lifestyle habits in Western nations, which are now making their way into more traditional societies. Diet plays a key role in IBD pathogenesis, and there is a growing appreciation that the interaction between diet and microbes in a susceptible person contributes significantly to the onset of disease. In this review, we examine what is known about dietary and microbial factors that promote IBD. We summarize recent findings regarding the effects of diet in IBD epidemiology from prospective population cohort studies, as well as new insights into IBD-associated dysbiosis. Microbial metabolism of dietary components can influence the epithelial barrier and the mucosal immune system, and understanding how these interactions generate or suppress inflammation will be a significant focus of IBD research. Our knowledge of dietary and microbial risk factors for IBD provides important considerations for developing therapeutic approaches through dietary modification or re-shaping the microbiota. We conclude by calling for increased sophistication in designing studies on the role of diet and microbes in IBD pathogenesis and disease resolution in order to accelerate progress in response to the growing challenge posed by these complex disorders. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Recent Progress in Understanding Coxsackievirus Replication, Dissemination, and Pathogenesis

    Science.gov (United States)

    Sin, Jon; Mangale, Vrushali; Thienphrapa, Wdee; Gottlieb, Roberta A.; Feuer, Ralph

    2015-01-01

    Coxsackieviruses (CVs) are relatively common viruses associated with a number of serious human diseases, including myocarditis and meningo-encephalitis. These viruses are considered cytolytic yet can persist for extended periods of time within certain host tissues requiring evasion from the host immune response and a greatly reduced rate of replication. A member of Picornaviridae family, CVs have been historically considered non-enveloped viruses – although recent evidence suggest that CV and other picornaviruses hijack host membranes and acquire an envelope. Acquisition of an envelope might provide distinct benefits to CV virions, such as resistance to neutralizing antibodies and efficient nonlytic viral spread. CV exhibits a unique tropism for progenitor cells in the host which may help to explain the susceptibility of the young host to infection and the establishment of chronic disease in adults. CVs have also been shown to exploit autophagy to maximize viral replication and assist in unconventional release from target cells. In this article, we review recent progress in clarifying virus replication and dissemination within the host cell, identifying determinants of tropism, and defining strategies utilized by the virus to evade the host immune response. Also, we will highlight unanswered questions and provide future perspectives regarding the potential mechanisms of CV pathogenesis. PMID:26142496

  2. Review: Cytokines in Gaucher disease: Role in the pathogenesis of ...

    African Journals Online (AJOL)

    Review: Cytokines in Gaucher disease: Role in the pathogenesis of bone and pulmonary disease. AAG Tantawy. Abstract. Gaucher disease (GD) is the most frequently encountered lysosomal storage disease caused by inborn defects of themembrane-bound lysosomal enzyme, acid b-glucosidase or glucocerebrosidase.

  3. MHC restriction to T-cell autoaggression: an emerging understanding of IDDM pathogenesis.

    Science.gov (United States)

    Choudhuri, K; Vergani, D

    1998-12-01

    The Nobel prize-winning discovery of MHC restriction by Zinkernagel and Doherty has led to some of the most exciting advances in immunology over the past two decades. The ongoing progress in our conceptual understanding of the processes governing the immunology to infection, tolerance to self and consequently the immune dysregulation in autoimmunity have all assimilated the laws of restriction as a central tenet. The focus of much of this research has been the T-cell and its interactions. Refinement of the paradigm of MHC restriction at the molecular level has allowed a view of the pathogenesis of insulin-dependent diabetes mellitus (IDDM), a prototypic autoimmune disease, unprecedented in its detail. This article discusses the impact of MHC restriction on the central themes of immunology, and focuses on its utility as a framework in understanding the role of the T-cell in the pathogenesis of IDDM.

  4. Pathogenesis of hyperinflation in chronic obstructive pulmonary disease

    Science.gov (United States)

    Gagnon, Philippe; Guenette, Jordan A; Langer, Daniel; Laviolette, Louis; Mainguy, Vincent; Maltais, François; Ribeiro, Fernanda; Saey, Didier

    2014-01-01

    Chronic obstructive pulmonary disease (COPD) is a preventable and treatable lung disease characterized by airflow limitation that is not fully reversible. In a significant proportion of patients with COPD, reduced lung elastic recoil combined with expiratory flow limitation leads to lung hyperinflation during the course of the disease. Development of hyperinflation during the course of COPD is insidious. Dynamic hyperinflation is highly prevalent in the advanced stages of COPD, and new evidence suggests that it also occurs in many patients with mild disease, independently of the presence of resting hyperinflation. Hyperinflation is clinically relevant for patients with COPD mainly because it contributes to dyspnea, exercise intolerance, skeletal muscle limitations, morbidity, and reduced physical activity levels associated with the disease. Various pharmacological and nonpharmacological interventions have been shown to reduce hyperinflation and delay the onset of ventilatory limitation in patients with COPD. The aim of this review is to address the more recent literature regarding the pathogenesis, assessment, and management of both static and dynamic lung hyperinflation in patients with COPD. We also address the influence of biological sex and obesity and new developments in our understanding of hyperinflation in patients with mild COPD and its evolution during progression of the disease. PMID:24600216

  5. Therapeutics in Osteoarthritis Based on an Understanding of Its Molecular Pathogenesis

    Directory of Open Access Journals (Sweden)

    Ju-Ryoung Kim

    2018-02-01

    Full Text Available Osteoarthritis (OA is the most prevalent joint disease in older people and is characterized by the progressive destruction of articular cartilage, synovial inflammation, changes in subchondral bone and peri-articular muscle, and pain. Because our understanding of the aetiopathogenesis of OA remains incomplete, we haven’t discovered a cure for OA yet. This review appraises novel therapeutics based on recent progress in our understanding of the molecular pathogenesis of OA, including pro-inflammatory and pro-catabolic mediators and the relevant signalling mechanisms. The changes in subchondral bone and peri-articular muscle accompanying cartilage damage are also reviewed.

  6. [Advances in the pathogenesis of non alcoholic fatty liver disease].

    Science.gov (United States)

    Pár, Alajos; Pár, Gabriella

    2017-06-01

    Non alcoholic fatty liver disease is the hepatic manifestation of metabolic syndrome, and the most common liver disease. Its more aggressive form is the non alcoholic steatohepatitis. Multiple genetic and environmental factors lead to the accumulation of triglicerides and the inflammatory cascade. High fat diet, obesity, adipocyte dysfunction with cytokine production, insulin resistance and increased lipolysis with free fatty acid flux into the liver - all are the drivers of liver cell injury. Activation of inflammasome by damage- or pathogen-associated molecular patterns results in "steril inflammation" and immune response, while the hepatic stellate cells and progenitor cells lead to fibrogenesis. Small intestinal bacterial overgrowth and gut dysbiosis are also of pivotal importance in the inflammation. Among the susceptible genetic factors, mutations of patatin-like phospholipase domain containing 3 and the transmembrane 6 superfamily 2 genes play a role in the development and progression of the disease, similarly as do epigenetic regulators such as microRNAs and extracellular vesicles. Better understanding of the pathogenesis of non alcoholic fatty liver disease may identify novel therapeutic agents that improve the outcome of the disease. Orv Hetil. 2017; 158(23): 882-894.

  7. The epidemiology, pathogenesis and histopathology of fatty liver disease.

    Science.gov (United States)

    Levene, Adam P; Goldin, Robert D

    2012-08-01

    Fatty liver disease includes non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD), each of which is increasing in prevalence. Each represents a histological spectrum that extends from isolated steatosis to steatohepatitis and cirrhosis. NAFLD is associated with obesity, diabetes, and insulin resistance, and is considered to be the liver manifestation of the metabolic syndrome. The pathogenesis of NAFLD and ALD involves cytokines, adipokines, oxidative stress, and apoptosis. Histopathology is the gold standard for assessing the severity of liver damage in NAFLD and ALD. We have reviewed the literature, and described and compared the epidemiology, natural disease history, pathogenesis and histopathology of NAFLD and ALD. © 2012 Blackwell Publishing Ltd.

  8. [New knowledge of the pathogenesis of Crohn's disease].

    Science.gov (United States)

    Ambrůzová, B; Rédová, M; Michálek, J; Sachlová, M; Slabý, O

    2012-04-01

    Crohns disease is a complex chronic inflammatory disease of the gastrointestinal tract with multifactorial pathogenesis. Over the recent years, there has been rather a sharp increase in the incidence of Crohn's disease and, even though this disease had been known for some time, the cause remains unknown. Studies exploring genetic basis of Crohn's disease have provided new knowledge of the pathogenesis of this disease, suggesting that this may be associated with a failure of mechanisms behind symbiosis of gut microflora and intestinal mucosal immune system. Crohn's disease seems to be caused by inadequate immune response to intestinal flora in genetically predisposed individuals. Crohn's disease has been linked to a number of genes. Many of them are related to the modulation of non-specific immune response, defects of which are considered to be key in Crohn's disease pathogenesis. The aim of this review paper is to summarize the new knowledge on the pathogenesis of Crohn's disease at the level of polymorphisms of the NOD2, ATG16L1 genes and the IL23-Th17-lymfocytes signalling pathway genes and to consider further research directions in this disease.

  9. Sickle cell disease : Pathogenesis and biomarkers

    NARCIS (Netherlands)

    Schimmel, M.

    2017-01-01

    Sickle cell disease (SCD) is a monogenetic disease wherein the haemoglobin complex of erythrocytes is affected, resulting in sickle haemoglobin. Sickle cell patients suffer from haemolytic anaemia, recurrent painful (micro)-vascular occlusions, secondary organ damage and early death. The

  10. Pilonidal sinus disease - Etiological factors, pathogenesis and clinical features

    Directory of Open Access Journals (Sweden)

    Kazim Duman

    2016-12-01

    Full Text Available and lsquo;Pilonidal sinus' disease, which is most commonly seen in reproductive populations, such as young adults - mostly in males who are in their twenties - is actually a controversial disease in that there is no consensus on its many facets. It is sometimes seen as an infected abscess draining from an opening or a lesion extending to the perineum. It may also present as a draining fistula opening to skin. In terms of etiological factors, various theories (main theories being congenital and acquired have been established since it was first described, no universal understanding achieved. A long and significant post-operative care period with different lengths of recovery depending on the type of operation are quite prevalent with regards to recurrence and complication status. In order to prevent recurrence and improve the quality of life, etiological and predisposing factors as well as clinical features of sacrococcygeal pilonidal disease should be well known, a detailed differential diagnosis should be made, and a suitable and timely intervention should be performed. It was aimed here to explain the etiological factors, pathogenesis and clinical features of the disease that may present with various clinical symptoms. [Arch Clin Exp Surg 2016; 5(4.000: 228-232

  11. Pathogenesis of hyperinflation in chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Gagnon P

    2014-02-01

    Full Text Available Philippe Gagnon,1,2 Jordan A Guenette,3,4 Daniel Langer,5 Louis Laviolette,2 Vincent Mainguy,1 François Maltais,1,2 Fernanda Ribeiro,1,2 Didier Saey1,2 1Faculté de Médecine, Université Laval, 2Centre de Recherche, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec, QC, 3Centre for Heart Lung Innovation, University of British Columbia, St Paul's Hospital, 4Department of Physical Therapy, University of British Columbia, Vancouver, BC, Canada; 5Department of Kinesiology and Rehabilitation Sciences, KU Leuven, Leuven, Belgium Abstract: Chronic obstructive pulmonary disease (COPD is a preventable and treatable lung disease characterized by airflow limitation that is not fully reversible. In a significant proportion of patients with COPD, reduced lung elastic recoil combined with expiratory flow limitation leads to lung hyperinflation during the course of the disease. Development of hyperinflation during the course of COPD is insidious. Dynamic hyperinflation is highly prevalent in the advanced stages of COPD, and new evidence suggests that it also occurs in many patients with mild disease, independently of the presence of resting hyperinflation. Hyperinflation is clinically relevant for patients with COPD mainly because it contributes to dyspnea, exercise intolerance, skeletal muscle limitations, morbidity, and reduced physical activity levels associated with the disease. Various pharmacological and nonpharmacological interventions have been shown to reduce hyperinflation and delay the onset of ventilatory limitation in patients with COPD. The aim of this review is to address the more recent literature regarding the pathogenesis, assessment, and management of both static and dynamic lung hyperinflation in patients with COPD. We also address the influence of biological sex and obesity and new developments in our understanding of hyperinflation in patients with mild COPD and its evolution during

  12. Pathogenesis: common pathways between hidradenitis suppurativa and Crohn disease.

    Science.gov (United States)

    García Martínez, F J; Menchén, L

    2016-09-01

    Both hidradenitis suppurativa and Crohn disease are considered chronic inflammatory diseases due to immune dysregulation. The high prevalence of Crohn disease patients diagnosed with hidradenitis suppurativa suggests the existence of common pathogenic links. The present literature review analyses the similarities and differences in the pathogenesis of the two diseases, in the search for new research and knowledge targets. Copyright © 2016 Elsevier España, S.L.U. y AEDV. All rights reserved.

  13. Autoimmune pathogenesis of Chagas heart disease: looking back, looking ahead.

    Science.gov (United States)

    Bonney, Kevin M; Engman, David M

    2015-06-01

    Chagas heart disease is an inflammatory cardiomyopathy that develops in approximately one-third of individuals infected with the protozoan parasite Trypanosoma cruzi. Since the discovery of T. cruzi by Carlos Chagas >100 years ago, much has been learned about Chagas disease pathogenesis; however, the outcome of T. cruzi infection is highly variable and difficult to predict. Many mechanisms have been proposed to promote tissue inflammation, but the determinants and the relative importance of each have yet to be fully elucidated. The notion that some factor other than the parasite significantly contributes to the development of myocarditis was hypothesized by the first physician-scientists who noted the conspicuous absence of parasites in the hearts of those who succumbed to Chagas disease. One of these factors-autoimmunity-has been extensively studied for more than half a century. Although questions regarding the functional role of autoimmunity in the pathogenesis of Chagas disease remain unanswered, the development of autoimmune responses during infection clearly occurs in some individuals, and the implications that this autoimmunity may be pathogenic are significant. In this review, we summarize what is known about the pathogenesis of Chagas heart disease and conclude with a view of the future of Chagas disease diagnosis, pathogenesis, therapy, and prevention, emphasizing recent advances in these areas that aid in the management of Chagas disease. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  14. Role of proximal tubules in the pathogenesis of kidney disease.

    Science.gov (United States)

    Nakhoul, Nazih; Batuman, Vecihi

    2011-01-01

    The proximal tubules make up a significant portion of the kidneys; proximal tubule epithelial cells are the most populous cell type in the kidney, and carry out diverse regulatory and endocrine functions where numerous transporters are located. Under normal circumstances, more than two thirds of filtered salt and water, and all filtered bicarbonate is reabsorbed in the proximal tubule. A number of inherited and acquired acid-base and tubule disorders are linked to impaired transporters in the proximal tubule cells. Equally important is the intrinsic immune characteristics of proximal tubule cells that give them the ability to also function as immune responders to a wide range of immunologic, ischemic or toxic injury. It is therefore not surprising that proximal tubule-related phenomena are closely related to the pathogenesis of a vast array of kidney diseases. Many kidney diseases, acute and chronic, first manifest with proximal tubule disorders. Recent insight into molecular characteristics of transport functions in the proximal tubules, and the recognition that proximal tubule cells possess intrinsic immune responses have contributed to an improved understanding of important areas in nephrology, such as Fanconi's syndrome, renal tubular acidosis, phosphate wasting syndromes, Dent's disease, cystinuria and other amino acid transport disorders, acute kidney injury, and the role of proximal tubules in progressive kidney disease. Megalin/ cubilin-mediated endocytosis by proximal tubule cells of increased quantities of filtered proteins (protein overloading) in glomerular diseases appears to evoke cell stress responses resulting in increased inflammatory cytokines leading to tubulointerstitial inflammation and fibrosis. Finally, the proximal tubule may be the site of both active vitamin D synthesis through the action of 1-α-hydroxylase, and the site where erythropoietin synthesis takes place. Thus, proximal tubule injury also contributes to two distressing

  15. Clinical studies on the pathogenesis of ischemic cerebrovascular disease

    International Nuclear Information System (INIS)

    Kodama, Shin-ichi

    1991-01-01

    Ischemic cerebrovascular disease represents an annually increasing percentage of cerebral apoplexy. Approaches to the improvement in its functional prognosis and the prevention of its recurrence are important in its treatment. Since the international joint researches in 1985 gave a denial to the predominance of surgical operation for ischemic cerebrovascular disease, its indications for surgery are now under re-examination. In this study, cerebral blood flow was mainly examined in order to have a good understanding of the essentials of ischemic cerebrovascular disease and also to find out the index of decision of its indications for surgery. First, normal blood flow was examined by age group via a measurement of cerebral blood flow according to 133 Xe inhalation method. Next, five types of ischemic cerebrovascular disease divided on the above basis were examined mainly for the relationship between the time-course of cerebral blood flow and the prognosis. Normal cerebral blood flow was decreased with age, with a good negative correlation. TIA, as examined for its etiology in terms of cerebral blood flow was considered to be supported by both of the thrombo-embolic theory and the hemodynamic theory rather than single. RIND, which is essentially similar to TIA, was considered to be different from only in symptomatic duration. The group of established infarction having cerebral blood flow < 30 ml/100 g/min showed very poor prognosis. Limit blood flow, as examined in terms of functional prognosis, was regarded as 40 ml/100 g/min, and this value was considered to be an important index of searching for the indication for the circulatory reconstruction. The above results suggest that a measurement of cerebral blood flow plays an important role in grasping the pathogenesis of ischemic cerebrovascular disease, thus provides us with an important index of its indications for surgery. (author) 81 refs

  16. PATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE

    Directory of Open Access Journals (Sweden)

    Snezana Cekic

    2006-01-01

    Full Text Available Chronic obstructive pulmonary disease (COPD is an obstructive pulmonary disorder which is characterized by limitation of expiratory airflow that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. The inflammatory process associated with COPD is characterized by increased number of activated alveolar macrophages, neutrophils, CD8+ cytotoxic T lymphocytes, B lymphocytes and CD4+ T lymphocytes, and the release of numerous inflammatory mediators (leukotrienes, cytokines, growth factors, chemokines, oxidants and proteases. Chronic inflammation causes remodeling of the small airways with the luminal obstruction due to increased mucus production and thickened walls due to edema and collagen formation that cause fibrosis and narrowing of small airways. Persistent inflammation also leads to destruction of lung tissue, loss of alveolar attachment to the small airways, and decreased lung elastic recoil. Although COPD affects the lungs, it also produces significant systemic consequences.

  17. On the Pathogenesis of Alzheimer's Disease: The MAM Hypothesis.

    Science.gov (United States)

    Area-Gomez, Estela; Schon, Eric A

    2017-03-01

    The pathogenesis of Alzheimer's disease (AD) is currently unclear and is the subject of much debate. The most widely accepted hypothesis designed to explain AD pathogenesis is the amyloid cascade, which invokes the accumulation of extracellular plaques and intracellular tangles as playing a fundamental role in the course and progression of the disease. However, besides plaques and tangles, other biochemical and morphological features are also present in AD, often manifesting early in the course of the disease before the accumulation of plaques and tangles. These include altered calcium, cholesterol, and phospholipid metabolism; altered mitochondrial dynamics; and reduced bioenergetic function. Notably, these other features of AD are associated with functions localized to a subdomain of the endoplasmic reticulum (ER), known as mitochondria-associated ER membranes (MAMs). The MAM region of the ER is a lipid raft-like domain closely apposed to mitochondria in such a way that the 2 organelles are able to communicate with each other, both physically and biochemically, thereby facilitating the functions of this region. We have found that MAM-localized functions are increased significantly in cellular and animal models of AD and in cells from patients with AD in a manner consistent with the biochemical findings noted above. Based on these and other observations, we propose that increased ER-mitochondrial apposition and perturbed MAM function lie at the heart of AD pathogenesis.-Area-Gomez, E., Schon, E. A. On the pathogenesis of Alzheimer's disease: the MAM hypothesis. © FASEB.

  18. Elastin in lung development and disease pathogenesis.

    Science.gov (United States)

    Mecham, Robert P

    2018-01-11

    Elastin is expressed in most tissues that require elastic recoil. The protein first appeared coincident with the closed circulatory system, and was critical for the evolutionary success of the vertebrate lineage. Elastin is expressed by multiple cell types in the lung, including mesothelial cells in the pleura, smooth muscle cells in airways and blood vessels, endothelial cells, and interstitial fibroblasts. This highly crosslinked protein associates with fibrillin-containing microfibrils to form the elastic fiber, which is the physiological structure that functions in the extracellular matrix. Elastic fibers can be woven into many different shapes depending on the mechanical needs of the tissue. In large pulmonary vessels, for example, elastin forms continuous sheets, or lamellae, that separate smooth muscle layers. Outside of the vasculature, elastic fibers form an extensive fiber network that originates in the central bronchi and inserts into the distal airspaces and visceral pleura. The fibrous cables form a looping system that encircle the alveolar ducts and terminal air spaces and ensures that applied force is transmitted equally to all parts of the lung. Normal lung function depends on proper secretion and assembly of elastin, and either inhibition of elastin fiber assembly or degradation of existing elastin results in lung dysfunction and disease. Copyright © 2018 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.

  19. A potential role of Chlamydia pneumoniae in the pathogenesis of periodontal disease in adolescents and adults.

    Science.gov (United States)

    Ajonuma, Louis Chukwuemeka

    2010-01-01

    Periodontal diseases are among the most common human infections that not only impact oral health but also are associated with adverse systemic diseases such as cardiovascular diseases, stroke, diabetes, and respiratory diseases. Periodontal diseases is a chronic severe inflammatory process of the gingiva leading to the destruction of tooth-supporting structures, alveolar bone, and subsequently tooth loss due to bacteria infection. While it has been reported that several oral biofilm-forming bacteria might be involved, the role of C. pneumoniae infection in the pathogenesis of periodontal disease remains unknown. The present hypothesis proposes that C. pneumoniae is involved in the pathogenesis of periodontal diseases. This will lead to a better understanding of the etiopathogenesis of periodontal disease, better treatment strategy and savings on total health care costs.

  20. Understanding Autoimmune Diseases

    Science.gov (United States)

    ... What are they? Points To Remember About Autoimmune Diseases Autoimmune diseases refer to problems with the immune system, ... Infectious Diseases Website: https://www.niaid.nih.gov/diseases-conditions/autoimmune-diseases American Autoimmune Related Diseases Association Website: https:// ...

  1. Correlation between mitochondrial dysfunction and the pathogenesis of Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Xiao-yu LIU

    2014-02-01

    Full Text Available Parkinson's disease (PD is a progressive neurodegenerative disease. A growing number of studies have shown that mitochondrial dysfunction plays an important role in the pathogenesis of PD. Therefore, this review will mainly discuss the research progress on the correlation between PD and abnormal mitochondrial dynamics, mitochondrial autophapy as well as mitochondrial DNA mutations and mitochondrial complex Ⅰ inhibition.doi:10.3969/j.issn.1672-6731.2014.02.012

  2. Genetic and genomic perspective to understand the molecular pathogenesis of keratoconus

    Science.gov (United States)

    Jeyabalan, Nallathambi; Shetty, Rohit; Ghosh, Anuprita; Anandula, Venkata Ramana; Ghosh, Arka Subhra; Kumaramanickavel, Govindasamy

    2013-01-01

    Keratoconus (KC; Mendelian Inheritance in Man (OMIM) 14830) is a bilateral, progressive corneal defect affecting all ethnic groups around the world. It is the leading cause of corneal transplantation. The age of onset is at puberty, and the disorder is progressive until the 3rd–4th decade of life when it usually arrests. It is one of the major ocular problems with significant social and economic impacts as the disease affects young generation. Although genetic and environmental factors are associated with KC, but the precise etiology is still elusive. Results from complex segregation analysis suggests that genetic abnormalities may play an essential role in the susceptibility to KC. Due to genetic heterogeneity, a recent study revealed 17 different genomic loci identified in KC families by linkage mapping in various populations. The focus of this review is to provide a concise update on the current knowledge of the genetic basis of KC and genomic approaches to understand the disease pathogenesis. PMID:23925319

  3. Genetic and genomic perspective to understand the molecular pathogenesis of keratoconus

    Directory of Open Access Journals (Sweden)

    Nallathambi Jeyabalan

    2013-01-01

    Full Text Available Keratoconus (KC; Mendelian Inheritance in Man (OMIM 14830 is a bilateral, progressive corneal defect affecting all ethnic groups around the world. It is the leading cause of corneal transplantation. The age of onset is at puberty, and the disorder is progressive until the 3 rd -4 th decade of life when it usually arrests. It is one of the major ocular problems with significant social and economic impacts as the disease affects young generation. Although genetic and environmental factors are associated with KC, but the precise etiology is still elusive. Results from complex segregation analysis suggests that genetic abnormalities may play an essential role in the susceptibility to KC. Due to genetic heterogeneity, a recent study revealed 17 different genomic loci identified in KC families by linkage mapping in various populations. The focus of this review is to provide a concise update on the current knowledge of the genetic basis of KC and genomic approaches to understand the disease pathogenesis.

  4. Understanding the genetic and molecular pathogenesis of Friedreich’s ataxia through animal and cellular models

    Science.gov (United States)

    Martelli, Alain; Napierala, Marek; Puccio, Hélène

    2012-01-01

    In 1996, a link was identified between Friedreich’s ataxia (FRDA), the most common inherited ataxia in men, and alterations in the gene encoding frataxin (FXN). Initial studies revealed that the disease is caused by a unique, most frequently biallelic, expansion of the GAA sequence in intron 1 of FXN. Since the identification of this link, there has been tremendous progress in understanding frataxin function and the mechanism of FRDA pathology, as well as in developing diagnostics and therapeutic approaches for the disease. These advances were the subject of the 4th International Friedreich’s Ataxia Conference held on 5th–7th May in the Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France. More than 200 scientists gathered from all over the world to present the results of research spanning all areas of investigation into FRDA (including clinical aspects, FRDA pathogenesis, genetics and epigenetics of the disease, development of new models of FRDA, and drug discovery). This review provides an update on the understanding of frataxin function, developments of animal and cellular models of the disease, and recent advances in trying to uncover potential molecules for therapy. PMID:22382366

  5. Microbiome in interstitial lung disease: from pathogenesis to treatment target.

    Science.gov (United States)

    Salisbury, Margaret L; Han, MeiLan K; Dickson, Robert P; Molyneaux, Philip L

    2017-09-01

    This review summarizes current knowledge of the role of the lung microbiome in interstitial lung disease and poses considerations of the microbiome as a therapeutic target. Although historically considered sterile, bacterial communities have now been well documented in lungs in health and disease. Studies in idiopathic pulmonary fibrosis (IPF) suggest that increased bacterial burden and/or abundance of potentially pathogenic bacteria may drive disease progression, acute exacerbations, and mortality. More recent work has highlighted the interaction between the lung microbiome and the innate immune system in IPF, strengthening the argument for the role of both host and environment interaction in disease pathogenesis. In support of this, studies of interstitial lung diseases other than IPF suggest that it may be the host immune response, which shapes the microbiome in these diseases. Some clinical and mouse model data also suggest that the lung microbiome may represent a therapeutic target, via antibiotic administration, immunization against pathogenic organisms, or treatment directed at gastroesophageal reflux. Evidence suggests that the lung microbiome may serve as a prognostic biomarker, a therapeutic target, or provide an explanation for disease pathogenesis in IPF.

  6. Immuno-pathogenesis of Periodontal Disease: Current and Emerging Paradigms.

    Science.gov (United States)

    Huang, Nasi; Gibson, Frank C

    2014-06-01

    Periodontal disease (PD) is a highly complex disease involving many factors; however, two principal facets central to initiation and progression of the majority of PD are the composition of the microbes in the sub-gingival plaque, and the host immune response to these organisms. Numerous studies point to the complexity of PD, and to the fact that despite innate and adaptive immune activation, and resultant inflammation, our immune response fails to cure disease. Stunning new findings have begun to clarify several complexities of the host-pathogen interaction of PD pointing to key roles for microbial dysboisis and immune imbalance in the pathogenesis of disease. Furthermore, these investigations have identified novel translational opportunities to intercede in PD treatment. In this review we will highlight a select few recent findings in innate and adaptive immunity, and host pathogen interactions of PD at a micro-environmental level that may have profound impact on PD progression.

  7. Contribution of pertussis toxin to the pathogenesis of pertussis disease

    Science.gov (United States)

    Carbonetti, Nicholas H.

    2015-01-01

    Pertussis toxin (PT) is a multisubunit protein toxin secreted by Bordetella pertussis, the bacterial agent of the disease pertussis or whooping cough. PT in detoxified form is a component of all licensed acellular pertussis vaccines, since it is considered to be an important virulence factor for this pathogen. PT inhibits G protein-coupled receptor signaling through Gi proteins in mammalian cells, an activity that has led to its widespread use as a cell biology tool. But how does this activity of PT contribute to pertussis, including the severe respiratory symptoms of this disease? In this minireview, the contribution of PT to the pathogenesis of pertussis disease will be considered based on evidence from both human infections and animal model studies. Although definitive proof of the role of PT in humans is lacking, substantial evidence supports the idea that PT is a major contributor to pertussis pathology, including the severe respiratory symptoms associated with this disease. PMID:26394801

  8. Pathogenesis of Paget's disease based on viral etiology.

    Science.gov (United States)

    Mirra, J M

    1987-04-01

    It has been slightly over 100 years since Sir James Paget's classic descriptions of "osteitis deformans" first appeared. He had described the mid- to late stages of patients with the chronic, debilitating, rare, and polyostotic forms of the disease. It is now known that the milder forms of the disease are quite common particularly in those of Anglo-Saxon ancestry. He believed the condition to be a chronic inflammation of unknown etiology because of its asymmetrical skeletal distribution, chronicity, and the gross appearance of the bones. With regard to the possible etiology of Paget's disease of bone, nothing worthy of note had been discovered until 1974 when viral-like inclusions were reported within the osteoclasts of all Paget's disease patients. In the ensuing decade, a great deal more circumstantial evidence from electron microscopic and immunologic studies supports the view that Paget's disease represents a slow virus infection. This article deals with the possible to probable viral etiology of Paget's disease with respect to its pathogenesis and its potential for eventual eradication. For many years Paget's disease was considered a disease almost exclusively confined to adulthood. Evidence now suggests that "familial chronic hyperphosphatasemia" represents the childhood form of Paget's disease.

  9. Pulmonary hypertension in rheumatic diseases: epidemiology and pathogenesis.

    Science.gov (United States)

    Shahane, Anupama

    2013-07-01

    The focus of this review is to increase awareness of pulmonary arterial hypertension (PAH) in patients with rheumatic diseases. Epidemiology and pathogenesis of PAH in rheumatic diseases is reviewed, with recommendations for early screening and diagnosis and suggestion of possible role of immunosuppressive therapy in treatment for PAH in rheumatic diseases. A MEDLINE search for articles published between January 1970 and June 2012 was conducted using the following keywords: pulmonary hypertension, scleroderma, systemic sclerosis, pulmonary arterial hypertension, connective tissues disease, systemic lupus erythematosus, mixed connective tissue disease, rheumatoid arthritis, Sjogren's syndrome, vasculitis, sarcoidosis, inflammatory myopathies, dermatomyositis, ankylosing spondylitis, spondyloarthropathies, diagnosis and treatment. Pathogenesis and disease burden of PAH in rheumatic diseases was highlighted, with emphasis on early consideration and workup of PAH. Screening recommendations and treatment were touched upon. PAH is most commonly seen in systemic sclerosis and may be seen in isolation or in association with interstitial lung disease. Several pathophysiologic processes have been identified including an obliterative vasculopathy, veno-occlusive disease, formation of microthrombi and pulmonary fibrosis. PAH in systemic lupus erythematosus is associated with higher prevalence of antiphospholipid and anticardiolipin antibodies and the presence of Raynaud's phenomenon. Endothelial proliferation with vascular remodeling, abnormal coagulation with thrombus formation and immune-mediated vasculopathy are the postulated mechanisms. Improvement with immunosuppressive medications has been reported. Pulmonary fibrosis, extrinsic compression of pulmonary arteries and granulomatous vasculitis have been reported in patients with sarcoidosis. Intimal and medial hyperplasia with luminal narrowing has been observed in Sjogren's syndrome, mixed connective tissue disease and

  10. Pathogenesis of thyroid autoimmune disease: the role of cellular mechanisms.

    Science.gov (United States)

    Ramos-Leví, Ana Maria; Marazuela, Mónica

    2016-10-01

    Hashimoto's thyroiditis (HT) and Graves' disease (GD) are two very common organ-specific autoimmune diseases which are characterized by circulating antibodies and lymphocyte infiltration. Although humoral and cellular mechanisms have been classically considered separately in the pathogenesis of autoimmune thyroid diseases (AITD), recent research suggests a close reciprocal relationship between these two immune pathways. Several B- and T-cell activation pathways through antigen-presenting cells (APCs) and cytokine production lead to specific differentiation of T helper (Th) and T regulatory (Treg) cells. This review will focus on the cellular mechanisms involved in the pathogenesis of AITD. Specifically, it will provide reasons for discarding the traditional simplistic dichotomous view of the T helper type 1 and 2 pathways (Th1/Th2) and will focus on the role of the recently characterized T cells, Treg and Th17 lymphocytes, as well as B lymphocytes and APCs, especially dendritic cells (DCs). Copyright © 2016 SEEN. Publicado por Elsevier España, S.L.U. All rights reserved.

  11. Amyloid cascade hypothesis: Pathogenesis and therapeutic strategies in Alzheimer's disease.

    Science.gov (United States)

    Barage, Sagar H; Sonawane, Kailas D

    2015-08-01

    Alzheimer's disease is an irreversible, progressive neurodegenerative disorder. Various therapeutic approaches are being used to improve the cholinergic neurotransmission, but their role in AD pathogenesis is still unknown. Although, an increase in tau protein concentration in CSF has been described in AD, but several issues remains unclear. Extensive and accurate analysis of CSF could be helpful to define presence of tau proteins in physiological conditions, or released during the progression of neurodegenerative disease. The amyloid cascade hypothesis postulates that the neurodegeneration in AD caused by abnormal accumulation of amyloid beta (Aβ) plaques in various areas of the brain. The amyloid hypothesis has continued to gain support over the last two decades, particularly from genetic studies. Therefore, current research progress in several areas of therapies shall provide an effective treatment to cure this devastating disease. This review critically evaluates general biochemical and physiological functions of Aβ directed therapeutics and their relevance. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Selected Aspects in the Pathogenesis of Autoimmune Diseases

    Directory of Open Access Journals (Sweden)

    György Nagy

    2015-01-01

    Full Text Available Autoimmune processes can be found in physiological circumstances. However, they are quenched with properly functioning regulatory mechanisms and do not evolve into full-blown autoimmune diseases. Once developed, autoimmune diseases are characterized by signature clinical features, accompanied by sustained cellular and/or humoral immunological abnormalities. Genetic, environmental, and hormonal defects, as well as a quantitative and qualitative impairment of immunoregulatory functions, have been shown in parallel to the relative dominance of proinflammatory Th17 cells in many of these diseases. In this review we focus on the derailed balance between regulatory and Th17 cells in the pathogenesis of autoimmune diseases. Additionally, we depict a cytokine imbalance, which gives rise to a biased T-cell homeostasis. The assessment of Th17/Treg-cell ratio and the simultaneous quantitation of cytokines, may give a useful diagnostic tool in autoimmune diseases. We also depict the multifaceted role of dendritic cells, serving as antigen presenting cells, contributing to the development of the pathognomonic cytokine signature and promote cellular and humoral autoimmune responses. Finally we describe the function and role of extracellular vesicles in particular autoimmune diseases. Targeting these key players of disease progression in patients with autoimmune diseases by immunomodulating therapy may be beneficial in future therapeutic strategies.

  13. Inflammatory Bowel Disease: Autoimmune or Immune-mediated Pathogenesis?

    Directory of Open Access Journals (Sweden)

    Zhonghui Wen

    2004-01-01

    Full Text Available The pathogenesis of Crohn's disease (CD and ulcerative colitis (UC, the two main forms of inflammatory bowel disease (IBD, is still unclear, but both autoimmune and immune-mediated phenomena are involved. Autoimmune phenomena include the presence of serum and mucosal autoantibodies against intestinal epithelial cells in either form of IBD, and against human tropomyosin fraction five selectively in UC. In addition, perinuclear antineutrophil cytoplasmic antibodies (pANCA are common in UC, whereas antibodies against Saccharomyces cerevisiae (ASCA are frequently found in CD. Immune-mediate phenomena include a variety of abnormalities of humoral and cell-mediated immunity, and a generalized enhanced reactivity against intestinal bacterial antigens in both CD and UC. It is currently believed that loss of tolerance against the indigenous enteric flora is the central event in IBD pathogenesis. Various complementary factors probably contribute to the loss of tolerance to commensal bacteria in IBD. They include defects in regulatory T-cell function, excessive stimulation of mucosal dendritic cells, infections or variants of proteins critically involved in bacterial antigen recognition, such as the products of CD-associated NOD2/CARD15 mutations.

  14. Molecular Mechanisms of Disease Pathogenesis Differ in Krabbe Disease Variants

    DEFF Research Database (Denmark)

    Spratley, Samantha J; Hill, Chris H; Viuff, Agnete H

    2016-01-01

    Krabbe disease is a severe, fatal neurodegenerative disorder caused by defects in the lysosomal enzyme galactocerebrosidase (GALC). The correct targeting of GALC to the lysosome is essential for the degradation of glycosphingolipids including the primary lipid component of myelin. Over 100...... different mutations have been identified in GALC that cause Krabbe disease but the mechanisms by which they cause disease remain unclear. We have generated monoclonal antibodies against full-length human GALC and used these to monitor the trafficking and processing of GALC variants in cell-based assays...... to cause disease due to protein misfolding and should be targeted for pharmacological chaperone therapies. Other GALC variants can be correctly secreted by cells and cause disease due to catalytic defects in the enzyme active site, inappropriate post-translational modification or a potential inability...

  15. Liver injury and disease pathogenesis in chronic hepatitis C.

    Science.gov (United States)

    Yamane, Daisuke; McGivern, David R; Masaki, Takahiro; Lemon, Stanley M

    2013-01-01

    Chronic hepatitis C virus (HCV) infection is a leading cause of liver-specific morbidity and mortality in humans, including progressive liver fibrosis, cirrhosis, and hepatocellular carcinoma. It has also been associated with altered function in other organs, including those of the endocrine, hematopoietic, and nervous systems. Disease results from both direct regulation of cellular metabolism and signaling pathways by viral proteins as well as indirect consequences of the host response to HCV infection, including inflammatory responses stemming from immune recognition of the virus. Recent in vitro studies have begun to reveal molecular mechanisms responsible for virus-induced changes in cell metabolism and cellular kinase cascades that culminate in pathologic consequences in the liver, such as steatosis, insulin resistance, and carcinogenesis. Here we discuss how these findings may be relevant to disease pathogenesis in patients, and suggest future directions in the field.

  16. Pathogenesis of Chagas' Disease: Parasite Persistence and Autoimmunity

    Science.gov (United States)

    Teixeira, Antonio R. L.; Hecht, Mariana M.; Guimaro, Maria C.; Sousa, Alessandro O.; Nitz, Nadjar

    2011-01-01

    Summary: Acute Trypanosoma cruzi infections can be asymptomatic, but chronically infected individuals can die of Chagas' disease. The transfer of the parasite mitochondrial kinetoplast DNA (kDNA) minicircle to the genome of chagasic patients can explain the pathogenesis of the disease; in cases of Chagas' disease with evident cardiomyopathy, the kDNA minicircles integrate mainly into retrotransposons at several chromosomes, but the minicircles are also detected in coding regions of genes that regulate cell growth, differentiation, and immune responses. An accurate evaluation of the role played by the genotype alterations in the autoimmune rejection of self-tissues in Chagas' disease is achieved with the cross-kingdom chicken model system, which is refractory to T. cruzi infections. The inoculation of T. cruzi into embryonated eggs prior to incubation generates parasite-free chicks, which retain the kDNA minicircle sequence mainly in the macrochromosome coding genes. Crossbreeding transfers the kDNA mutations to the chicken progeny. The kDNA-mutated chickens develop severe cardiomyopathy in adult life and die of heart failure. The phenotyping of the lesions revealed that cytotoxic CD45, CD8+ γδ, and CD8α+ T lymphocytes carry out the rejection of the chicken heart. These results suggest that the inflammatory cardiomyopathy of Chagas' disease is a genetically driven autoimmune disease. PMID:21734249

  17. Cardiac Hemodynamics in the Pathogenesis of Congenital Heart Disease and Aortic Valve Calcification

    Science.gov (United States)

    Nigam, Vishal

    2011-11-01

    An improved understanding of the roles of hemodynamic forces play in cardiac development and the pathogenesis of cardiac disease will have significant scientific and clinical impact. I will focus on the role of fluid dynamics in congenital heart disease and aortic valve calcification. Congenital heart defects are the most common form of birth defect. Aortic valve calcification/stenosis is the third leading cause of adult heart disease and the most common form of acquired valvular disease in developed countries. Given the high incidence of these diseases and their associated morbidity and mortality, the potential translational impact of an improved understanding of cardiac hemodynamic forces is very large. Division of Pediatric Cardiology, Rady Children's Hospital, San Diego

  18. Current concepts of the pathogenesis of inflammatory bowel disease.

    LENUS (Irish Health Repository)

    Shanahan, F

    2012-02-03

    Although the cause of inflammatory bowel disease is not known, the pathogenesis involves an immune-mediated tissue damage that is the result of an interaction among genetic predisposing factors, exogenous triggers and endogenous modifying influences. Multiple genes are involved and operate at the level of the immune response and at the target organ. Exogenous triggers include the enteric microflora which might stimulate the mucosal immune system in genetically predisposed individuals. Endogenous modifying factors such as the psychoneuroendocrine system have regulatory effects on the immune system and the inflammatory response, and may influence the course of the disease. While autoimmune phenomena do occur, particularly in ulcerative colitis, there is no evidence that they are directly responsible for the tissue damage. It appears more likely, particularly in Crohn\\'s disease, that tissue injury may occur as an indirect or "bystander" effect of mucosal T-cell hyperactivation, perhaps in response to a normal enteric microbial antigen. Most of the immunologic and histologic features of Crohn\\'s disease can be explained by the effects of T-cell derived and other cytokines on the epithelium, the local immune system, the microvasculature, and the recruitment of auxiliary effector cells such as neutrophils.

  19. Role of HLA typing on Crohn's disease pathogenesis

    Directory of Open Access Journals (Sweden)

    Batool Mutar Mahdi

    2015-09-01

    Full Text Available Crohn's disease (CD is the main type of chronic inflammatory bowel disease of unknown etiology. Evidence from family and twin studies suggests that genetics plays a significant role in predisposing an individual to develop Crohn's disease. A susceptibility locus for Crohn's disease has been mapped 3 to chromosome 16: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators which is expressed in hematopoietic compartment cells and intestinal epithelial cells as well as in paneth cells, where NOD2 may play an important role in the pathogenesis of Crohn disease in the gastrointestinal system. This leads to alteration the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has two functions, first an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. Thus, NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in intestinal epithelial cells as well as in paneth cells. Further confirmation of a genetic predisposition comes from studies of the association between the human leukocyte antigen (HLA system and CD. The immunogenetic predisposition may be considered an important requirement for the development of CD, as several alleles of human major histocompatibility complex had an association with CD. Although it is difficult to estimate the importance of this region in determining overall genetic susceptibility in a population, studies of HLA allele sharing within families suggest that this region contributes between 10% and 33% of the total genetic risk of Crohn's disease.

  20. Huntington Disease: Linking Pathogenesis to the Development of Experimental Therapeutics.

    Science.gov (United States)

    Mestre, Tiago A; Sampaio, Cristina

    2017-02-01

    Huntington disease (HD) is an autosomal dominant neurodegenerative condition caused by a CAG trinucleotide expansion in the huntingtin gene. At present, the HD field is experiencing exciting times with the assessment for the first time in human subjects of interventions aimed at core disease mechanisms. Out of a portfolio of interventions that claim a potential disease-modifying effect in HD, the target huntingtin has more robust validation. In this review, we discuss the spectrum of huntingtin-lowering therapies that are currently being considered. We provide a critical appraisal of the validation of huntingtin as a drug target, describing the advantages, challenges, and limitations of the proposed therapeutic interventions. The development of these new therapies relies strongly on the knowledge of HD pathogenesis and the ability to translate this knowledge into validated pharmacodynamic biomarkers. Altogether, the goal is to support a rational drug development that is ethical and cost-effective. Among the pharmacodynamic biomarkers under development, the quantification of mutant huntingtin in the cerebral spinal fluid and PET imaging targeting huntingtin or phosphodiesterase 10A deserve special attention. Huntingtin-lowering therapeutics are eagerly awaited as the first interventions that may be able to change the course of HD in a meaningful way.

  1. Metabolism-Centric Overview of the Pathogenesis of Alzheimer's Disease.

    Science.gov (United States)

    Kang, Somang; Lee, Yong Ho; Lee, Jong Eun

    2017-05-01

    Alzheimer's disease (AD) is a degenerative brain disease and the most common cause of dementia. AD is characterized by the extracellular amyloid beta (Aβ) plaques and intraneuronal deposits of neurofibrillary tangles (NFTs). Recently, as aging has become a familiar phenomenon around the world, patients with AD are increasing in number. Thus, many researchers are working toward finding effective therapeutics for AD focused on Aβ hypothesis, although there has been no success yet. In this review paper, we suggest that AD is a metabolic disease and that we should focus on metabolites that are affected by metabolic alterations to find effective therapeutics for AD. Aging is associated with not only AD but also obesity and type 2 diabetes (T2DM). AD, obesity, and T2DM share demographic profiles, risk factors, and clinical and biochemical features in common. Considering AD as a kind of metabolic disease, we suggest insulin, adiponectin, and antioxidants as mechanistic links among these diseases and targets for AD therapeutics. Patients with AD show reduced insulin signal transductions in the brain, and intranasal injection of insulin has been found to have an effect on AD treatment. In addition, adiponectin is decreased in the patients with obesity and T2DM. This reduction induces metabolic dysfunction both in the body and the brain, leading to AD pathogenesis. Oxidative stress is known to be induced by Aβ and NFTs, and we suggest that oxidative stress caused by metabolic alterations in the body induce brain metabolic alterations, resulting in AD. © Copyright: Yonsei University College of Medicine 2017.

  2. Recent Advances in the Pathogenesis of Autoimmune Hair Loss Disease Alopecia Areata

    Directory of Open Access Journals (Sweden)

    Taisuke Ito

    2013-01-01

    Full Text Available Alopecia areata is considered to be a cell-mediated autoimmune disease, in which autoreactive cytotoxic T cells recognize melanocyte-associated proteins such as tyrosinase. This review discusses recent advances in the understanding of the pathogenesis of alopecia areata, focusing on immunobiology and hormonal aspects of hair follicles (HFs. The HF is a unique “miniorgan” with its own immune and hormonal microenvironment. The immunosuppressive milieu of the anagen hair bulb modulated by immunosuppressive factors is known as “hair follicle immune privilege.” The collapse of the hair follicle immune privilege leads to autoimmune reactions against hair follicle autoantigens. Alopecia areata is sometimes triggered by viral infections such as influenza that causes excess production of interferons (IFN. IFN-γ is one of the key factors that lead to the collapse of immune privilege. This paper reviews the interactions between the endocrine and immune systems and hair follicles in the pathogenesis of alopecia areata.

  3. Current roles of specific bacteria in the pathogenesis of inflammatory bowel disease

    Directory of Open Access Journals (Sweden)

    Lucy McMullen

    2015-12-01

    Full Text Available The relevance of alterations in gut microbiota in the pathogenesis of inflammatory bowel disease (IBD remains unclear. Currently there is conflicting evidence with regards to the roles of specific bacterial species. Escherichia coli (particularly the adherent invasive strain are more prevalent in those with IBD and are associated with higher risk of IBD. However, the organisms are also present in healthy individuals and colonisation does not correlate with the degree of inflammation in IBD. Campylobacter concisus is more prevalent in those with IBD and higher levels of C. concisus specific IgG antibodies are found in the serum of those with IBD compared to healthy controls. Further, C. concisus has immunogenic properties that stimulate an antibody response suggesting the bacteria might trigger or exacerbate disease. Conversely most mycobacteria are unlikely to be causative as they are not presentin microbial stool cultures early in disease. In various studies,Mycobacterium aviumparatuberculosishas been detected both more frequently and not at all in individuals with Crohn's disease. Similar conflict exists with respect to Yersinia enterocolitica,Bacteroidesvulgatus and Helicobacter hepaticus, which are also more prevalent in IBD. However, these organisms appear more likely to contribute to disease persistence than initial disease development. This review aims to summarise the current understanding of key bacterial species implicated in the pathogenesis of IBD.

  4. Novel lipid signaling pathways in Alzheimer's disease pathogenesis.

    Science.gov (United States)

    Giannopoulos, Phillip F; Joshi, Yash B; Praticò, Domenico

    2014-04-15

    Alzheimer's disease (AD) is the most common cause of dementia in the elderly. With an increasing longevity and the absence of a cure, AD has become not only a major health problem but also a heavy social and economic burden worldwide. In addition to the presence of abundant intra- and extra-cellular neurotoxic amyloid β (Aβ) peptides, which form the amyloid plaques, and intracellular hyperphosphorylated tau protein, the main component of neurofibrillary tangles, consistent evidence indicates that the AD brain is characterized by extensive neuroinflammatory processes. The 5-lipoxygenase (5LO) is a pro-inflammatory enzymatic pathway widely distributed within the central nervous system and is up-regulated in AD. In the last five years our group has been involved in unraveling the neurobiology of this protein and investigating its relationship with cellular and molecular events of functional importance in AD pathogenesis. By using a combination of in vitro and in vivo experimental tools and implementing genetic as well as pharmacological approaches today we know that 5LO is likely an endogenous regulator of Aβ formation via the modulation of the γ-secretase complex, and tau metabolism by modulating its phosphorylation state at specific epitopes via the cyclin-dependent kinase-5 (cdk-5). In addition, 5LO influences synaptic function and integrity and by doing so significantly affects learning and memory in the Tg2576 and 3xTg AD transgenic mouse models. Taken together our data establish this protein as a pleiotropic contributor to the development of the full spectrum of the AD-like phenotype in these mouse models of the disease, making it a viable therapeutic target for the treatment of AD in humans. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Foam Cells and the Pathogenesis of Kidney Disease

    Science.gov (United States)

    Eom, Minseob; Hudkins, Kelly L.; Alpers, Charles E.

    2015-01-01

    Purpose of review Foam cells in human glomeruli can be encountered in various renal diseases including focal segmental glomerulosclerosis and diabetic nephropathy. Although foam cells are a key participant in atherosclerosis, surprisingly little is known about their pathogenicity in the kidney. We review our understanding (or lack thereof) of foam cells in the kidney as well as insights gained in studies of foam cells and macrophages involved in atherosclerosis, to suggest areas of investigation that will allow better characterization of the role of these cells in renal disease. Recent findings There is a general dearth of animal models of disease with renal foam cell accumulation, limiting progress in our understanding of the pathobiology of these cells. Recent genetic modifications of hyperlipidemic mice have resulted in some new disease models with renal foam cell accumulation. Recent studies have challenged older paradigms by findings that indicate many tissue macrophages are derived from cells permanently residing in the tissue from birth rather than circulating monocytes. Summary Renal foam cells remain an enigma. Extrapolating from studies of atherosclerosis suggests that therapeutics targeting mitochondrial ROS production or modulating cholesterol and lipoprotein uptake or egress from these cells may prove beneficial for kidney diseases in which foam cells are present. PMID:25887903

  6. Possible Role of the Transglutaminases in the Pathogenesis of Alzheimer's Disease and Other Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Antonio Martin

    2011-01-01

    Full Text Available Transglutaminases are ubiquitous enzymes which catalyze posttranslational modifications of proteins. Recently, transglutaminase-catalyzed post-translational modification of proteins has been shown to be involved in the molecular mechanisms responsible for human diseases. Transglutaminase activity has been hypothesized to be involved also in the pathogenetic mechanisms responsible for several human neurodegenerative diseases. Alzheimer's disease and other neurodegenerative diseases, such as Parkinson's disease, supranuclear palsy, Huntington's disease, and other polyglutamine diseases, are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains. This paper focuses on the possible molecular mechanisms by which transglutaminase activity could be involved in the pathogenesis of Alzheimer's disease and other neurodegenerative diseases, and on the possible therapeutic effects of selective transglutaminase inhibitors for the cure of patients with diseases characterized by aberrant transglutaminase activity.

  7. MicroRNAs in inflammatory bowel disease--pathogenesis, diagnostics and therapeutics

    DEFF Research Database (Denmark)

    Coskun, Mehmet; Bjerrum, Jacob Tveiten; Seidelin, Jakob Benedict

    2012-01-01

    The pathogenesis of inflammatory bowel disease (IBD) is complex and largely unknown. Until recently, research has focused on the study of protein regulators in inflammation to reveal the cellular and molecular networks in the pathogenesis of IBD. However, in the last few years, new and promising...... diagnosis of IBD, and in the development of personalized therapies. Here, we provide a short review of the current state-of-the-art of miRNAs in IBD pathogenesis, diagnostics and therapeutics....

  8. Understanding the role of cytokines in the pathogenesis of rheumatoid arthritis.

    Science.gov (United States)

    Mateen, Somaiya; Zafar, Atif; Moin, Shagufta; Khan, Abdul Qayyum; Zubair, Swaleha

    2016-04-01

    Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease of unknown etiology. It is characterized by the presence of rheumatoid factor and anti-citrullinated peptide antibodies. Initial phase of RA involves the activation of both T and B cells. Cytokines have a crucial role in the pathophysiology of RA as pro-inflammatory cytokines such as TNFα, IL-1, IL-17 stimulates inflammation and degradation of bone and cartilage. There occurs an imbalance between the pro- and anti-inflammatory cytokine activities which leads to multisystem immune complications. There occurs a decline in the number of Treg cells which may also play an important role in pathophysiology of the disease. In RA patients, serum or plasma level of cytokines may indicate the severity of disease. Cytokine gene polymorphism could be used as markers of susceptibility and severity of RA. Anti-cytokine agents seem to emerge as potent drug molecules to treat RA. Many clinical trials are ongoing and several positive results have been obtained. There is a need to develop potential anti-cytokine agents that target numerous pathways involved in the pathogenesis of RA. This review article describes the effector functions of pro- and anti-inflammatory cytokines and the role of cytokine gene polymorphism in the pathogenesis of RA. Anti-cytokine agents that are currently available and those that are still in clinical trials have also been summarized. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Analysis of phenotype–genotype connection: the story of dissecting disease pathogenesis in genomic era in China, and beyond

    OpenAIRE

    Shen, Yan; Xu, Qi; Han, Zeguang; Liu, Han; Zhou, Guang-Biao

    2007-01-01

    DNA is the ultimate depository of biological complexity. Thus, in order to understand life and gain insights into disease pathogenesis, genetic information embedded in the sequence of DNA base pairs comprising chromosomes should be deciphered. The stories of investigating the association between phenotype and genotype in China and other countries further demonstrate that genomics can serve as a probe for disease biology. We now know that in Mendelian disorders, one gene is not only a dictator...

  10. Functional impacts of the intestinal microbiome in the pathogenesis of inflammatory bowel disease.

    Science.gov (United States)

    Li, Jennifer; Butcher, James; Mack, David; Stintzi, Alain

    2015-01-01

    : The human intestinal microbiome plays a critical role in human health and disease, including the pathogenesis of inflammatory bowel disease (IBD). Numerous studies have identified altered bacterial diversity and abundance at varying taxonomic levels through biopsies and fecal samples of patients with IBD and diseased model animals. However, inconsistent observations regarding the microbial compositions of such patients have hindered the efforts in assessing the etiological role of specific bacterial species in the pathophysiology of IBD. These observations highlight the importance of minimizing the confounding factors associated with IBD and the need for a standardized methodology to analyze well-defined microbial sampling sources in early IBD diagnosis. Furthermore, establishing the linkage between microbiota compositions with their function within the host system can provide new insights on the pathogenesis of IBD. Such research has been greatly facilitated by technological advances that include functional metagenomics coupled with proteomic and metabolomic profiling. This review provides updates on the composition of the microbiome in IBD and emphasizes microbiota dysbiosis-involved mechanisms. We highlight functional roles of specific bacterial groups in the development and management of IBD. Functional analyses of the microbiome may be the key to understanding the role of microbiota in the development and chronicity of IBD and reveal new strategies for therapeutic intervention.

  11. Periodontal disease and subgingival microbiota as contributors for rheumatoid arthritis pathogenesis: modifiable risk factors?

    Science.gov (United States)

    Scher, Jose U; Bretz, Walter A; Abramson, Steven B

    2014-07-01

    Since the early 1900s, the role of periodontal disease in the pathogenesis of rheumatoid arthritis has been a matter of intense research. The last decade has witnessed many advances supporting a link between periodontitis, the presence of specific bacterial species (i.e. Porphyromonas gingivalis) and their effects in immune response. This review will examine available evidence on the individuals. Epidemiological studies have stressed the commonalities shared by periodontal disease and rheumatoid arthritis. Many groups have focused their attention toward understanding the periodontal microbiota and its alterations in states of health and disease. The presence of circulating antibodies against periodontopathic bacteria and associated inflammatory response has been found in both rheumatoid arthritis (RA) patients and individuals at-risk for disease development. Most recently, the periodontal microbiota of smokers and patients with RA has been elucidated, revealing profound changes in the bacterial communities compared with those of healthy controls. This has led to several small clinical trials of progressive disease treatment as adjuvant for disease-modifying therapy in RA. Smoking and periodontal disease are emerging risk factors for the development of RA. Epidemiological, clinical, and basic research has further strengthened this association, pointing toward changes in the oral microbiota as possible contributors to systemic inflammation and arthritis.

  12. Proteome Analysis—A Novel Approach to Understand the Pathogenesis of Type 1 Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Allan E. Karlsen

    2001-01-01

    Full Text Available Type 1 (insulin-dependent diabetes mellitus (T1DM is associated with a specific destruction of the insulin-producing beta-cells in the islets of Langerhans. Several factors, e.g. genetic, environmental and immunologial, may be involved in the etiology and pathogenesis of T1DM. Autoreactive Tand B-lymphocytes, together with macrophages infiltrate the islets during the pathogenesis, releasing a mixture of cytokines, demonstrated to be specifically toxic to the beta-cells within the islets. Our goal is to understand the molecular mechanisms responsible for the beta-cell specific toxicity enabling us to design novel intervention strategies in T1DM. The proteome approach allows us to get a detailed picture of the beta-cell proteins, which change expression level or are post-translationally modified in different in vitro and in vivo models of T1DM-associated beta-cell destruction. Combining the information obtained from this extended proteome approach, with that of genetic-, transcriptome- and candidategene approaches, we believe that it is possible to reach this goal.

  13. Peripheral Ulcerative Keratitis Associated with Autoimmune Disease: Pathogenesis and Treatment

    Directory of Open Access Journals (Sweden)

    Yan Cao

    2017-01-01

    Full Text Available Peripheral ulcerative keratitis (PUK is type of crescent-shaped inflammatory damage that occurs in the limbal region of the cornea. PUK is always combined with an epithelial defect and the destruction of the peripheral corneal stroma. PUK may have a connection to systemic conditions, such as long-standing rheumatoid arthritis (RA, systemic lupus erythematosus (SLE, Wegener granulomatosis (WG, relapsing polychondritis, classic polyarteritis nodosa and its variants, microscopic polyangiitis, and Churg-Strauss syndrome. However, the most common connection is with RA, which is also the focus of this review. The pathogenesis of PUK is still unclear. It is thought that circulating immune complexes and cytokines exert an important influence on the progression of this syndrome. Treatment is applied to inhibit certain aspects of PUK pathogenesis.

  14. Peripheral Ulcerative Keratitis Associated with Autoimmune Disease: Pathogenesis and Treatment

    Science.gov (United States)

    Cao, Yan; Zhang, Wensong; Wu, Jie; Zhang, Hong

    2017-01-01

    Peripheral ulcerative keratitis (PUK) is type of crescent-shaped inflammatory damage that occurs in the limbal region of the cornea. PUK is always combined with an epithelial defect and the destruction of the peripheral corneal stroma. PUK may have a connection to systemic conditions, such as long-standing rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Wegener granulomatosis (WG), relapsing polychondritis, classic polyarteritis nodosa and its variants, microscopic polyangiitis, and Churg-Strauss syndrome. However, the most common connection is with RA, which is also the focus of this review. The pathogenesis of PUK is still unclear. It is thought that circulating immune complexes and cytokines exert an important influence on the progression of this syndrome. Treatment is applied to inhibit certain aspects of PUK pathogenesis. PMID:28785483

  15. Clinical implications of shared genetics and pathogenesis in autoimmune diseases

    NARCIS (Netherlands)

    Zhernakova, Alexandra; Withoff, Sebo; Wijmenga, Cisca

    2013-01-01

    Many endocrine diseases, including type 1 diabetes mellitus, Graves disease, Addison disease and Hashimoto disease, originate as an autoimmune reaction that affects disease-specific target organs. These autoimmune diseases are characterized by the development of specific autoantibodies and by the

  16. Pathogenesis of salivary gland disease and xerostomia. The conception of Mikulicz's disease based on new knowledge

    International Nuclear Information System (INIS)

    Himi, Tetsuo; Kanaizumi, Etsuko; Ogasawara, Noriko; Yamamoto, Motohisa; Takahashi, Hiroki

    2007-01-01

    This review focuses on two topics of salivary gland diseases regarding xerostomia. First, the pathogenesis and treatment of xerostomia after radiotherapy against head and neck cancer is discussed. It is well known that the extent of radiation-induced salivary dysfunction and mucositis depends on the radiation dose and field. Moreover, the balance in the defense system of oropharyngeal cavity alters after radiotherapy. This altered balance may impair the ability to maintain the stable immunological control mechanism. Second, the newly established concept about Mikulicz's disease is discussed. Recently, elevated IgG4 concentration in serum and prominent infiltrating by plasmacytes expressing IgG4 in the salivary glands in Mikulicz's disease were revealed. Mikulicz's disease is different from Sjoegren's syndrome, and may be a systemic IgG4-related plasmacytic disease. (author)

  17. Inflammatory bowel diseases (IBD) - critical discussion of etiology, pathogenesis, diagnostics, and therapy

    International Nuclear Information System (INIS)

    Ochsenkuehn, T.; Sackmann, M.; Goeke, B.

    2003-01-01

    Aims Crohn's disease and ulcerative colitis are the most frequent inflammatory bowel diseases (IBD) with a prevalence of approximately one out of 500.Cytokine research opened new and potent treatment options and thus stimulated clinical and basic research.However, the IBD still remain a challenge for patients and physicians,demanding close cooperation between gastroenterologists,radiologists and surgeons.The basic understanding of IBD,which is necessary for efficient diagnostic and therapeutic concepts is reviewed. Based upon recent publications and our clinical experience we discuss aspects of etiology,pathogenesis,diagnostics,and therapy of Crohn's disease and ulcerative colitis. A genetically influenced, exaggerated and sustained immune response against the own gut flora seems to be one of the most important factors in the pathogenesis of IBD.Not less important are environmental influences.For instance, cigarette smoking had been judged to have some negative influence on the natural course of Crohn's disease.Now,however, recent studies show that smoking is even a significant independent risk factor in the pathogenesis of IBD. Since IBD and especially Crohn's disease can effect the whole body, detailed analysis of inflammatory organ involvement is necessary before therapy.For instance, the MRIenteroclysis technique adds a necessary diagnostic tool for the exploration of those parts of the small bowel that cannot been reached by routine endoscopy like the upper ileum and the lower jejunum. In terms of therapy, a change of paradigms can be observed: patients will no longer be treated only when symptoms arise, but will early be integrated into a therapeutic concept, which is determined by site and extent of the disease and adapted to the abilities and needs of the patient.Furthermore,immunosuppressive agents like azathioprine and 6-mercaptopurine will establish as central concept in the medical treatment of IBD.Discussion IBD-therapy should rather be adapted to the

  18. Analysis of phenotype-genotype connection: the story of dissecting disease pathogenesis in genomic era in China, and beyond.

    Science.gov (United States)

    Shen, Yan; Xu, Qi; Han, Zeguang; Liu, Han; Zhou, Guang-Biao

    2007-06-29

    DNA is the ultimate depository of biological complexity. Thus, in order to understand life and gain insights into disease pathogenesis, genetic information embedded in the sequence of DNA base pairs comprising chromosomes should be deciphered. The stories of investigating the association between phenotype and genotype in China and other countries further demonstrate that genomics can serve as a probe for disease biology. We now know that in Mendelian disorders, one gene is not only a dictator of one phenotype but also a dictator of two or more distinct disorders. Dissecting genetic abnormalities of complex diseases, including diabetes, hypertension, mental diseases, coronary heart disease and cancer, may unravel the complicated networks and crosstalks, and help to simplify the complexity of the disease. The transcriptome and proteomic analysis for medicine not only deepen our understanding of disease pathogenesis, but also provide novel diagnostic and therapeutic strategies. Taken together, genomic research offers a new opportunity for determining how diseases occur, by taking advantage of experiments of nature and a growing array of sophisticated research tools to identify the molecular abnormalities underlying disease processes. We should be ready for the advent of genomic medicine, and put the genome into the doctors' bag, so that we can help patients to conquer diseases.

  19. Mechanisms of hybrid oligomer formation in the pathogenesis of combined Alzheimer's and Parkinson's diseases.

    Directory of Open Access Journals (Sweden)

    Igor F Tsigelny

    Full Text Available BACKGROUND: Misfolding and pathological aggregation of neuronal proteins has been proposed to play a critical role in the pathogenesis of neurodegenerative disorders. Alzheimer's disease (AD and Parkinson's disease (PD are frequent neurodegenerative diseases of the aging population. While progressive accumulation of amyloid beta protein (Abeta oligomers has been identified as one of the central toxic events in AD, accumulation of alpha-synuclein (alpha-syn resulting in the formation of oligomers and protofibrils has been linked to PD and Lewy body Disease (LBD. We have recently shown that Abeta promotes alpha-syn aggregation and toxic conversion in vivo, suggesting that abnormal interactions between misfolded proteins might contribute to disease pathogenesis. However the molecular characteristics and consequences of these interactions are not completely clear. METHODOLOGY/PRINCIPAL FINDINGS: In order to understand the molecular mechanisms involved in potential Abeta/alpha-syn interactions, immunoblot, molecular modeling, and in vitro studies with alpha-syn and Abeta were performed. We showed in vivo in the brains of patients with AD/PD and in transgenic mice, Abeta and alpha-synuclein co-immunoprecipitate and form complexes. Molecular modeling and simulations showed that Abeta binds alpha-syn monomers, homodimers, and trimers, forming hybrid ring-like pentamers. Interactions occurred between the N-terminus of Abeta and the N-terminus and C-terminus of alpha-syn. Interacting alpha-syn and Abeta dimers that dock on the membrane incorporated additional alpha-syn molecules, leading to the formation of more stable pentamers and hexamers that adopt a ring-like structure. Consistent with the simulations, under in vitro cell-free conditions, Abeta interacted with alpha-syn, forming hybrid pore-like oligomers. Moreover, cells expressing alpha-syn and treated with Abeta displayed increased current amplitudes and calcium influx consistent with the

  20. Viral subversion mechanisms in chronic kidney disease pathogenesis.

    Science.gov (United States)

    Bruggeman, Leslie A

    2007-07-01

    Viruses cannot autonomously replicate but must rely on the host cellular machinery to support their life cycle. Through natural selection, viruses have evolved strategies to co-opt the host organism to be a better site for their propagation. Some of these strategies are directed at the cellular machinery and involve complicated and ingenious solutions to optimize infection, replication, viral gene expression, and new virion assembly and shedding. Other strategies are directed at the host's innate and adaptive immune systems that permit the virus to evade clearance mechanisms. The more common pathogenic viral infections in nephrology-cytomegalovirus, HIV-1, hepatitis C virus, polyomavirus BK, and parvovirus B19-all have acquired subversion strategies that benefit the virus but because they interfere with normal cellular and immune processes also have become pathogenic to the host. In addition, the highly prevalent viruses cytomegalovirus, BK, and B19 cause severe disease only in the setting of immunosuppression, revealing the very delicate balance that some viruses have achieved with their host's immune system. Thus, selective pressure for survival drives both the evolution of more sophisticated viruses and the host immune system as it evolves to combat the environment of adapting and emerging infectious agents. Understanding the molecular mechanisms of these viral subversion strategies may reveal new targets for the development of highly specific antiviral therapies and also aid vaccine development.

  1. Proteomic and genomic studies of non-alcoholic fatty liver disease - clues in the pathogenesis

    Science.gov (United States)

    Lim, Jun Wei; Dillon, John; Miller, Michael

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a widely prevalent hepatic disorder that covers wide spectrum of liver pathology. NAFLD is strongly associated with liver inflammation, metabolic hyperlipidaemia and insulin resistance. Frequently, NAFLD has been considered as the hepatic manifestation of metabolic syndrome. The pathophysiology of NAFLD has not been fully elucidated. Some patients can remain in the stage of simple steatosis, which generally is a benign condition; whereas others can develop liver inflammation and progress into non-alcoholic steatohepatitis, fibrosis, cirrhosis and hepatocellular carcinoma. The mechanism behind the progression is still not fully understood. Much ongoing proteomic researches have focused on discovering the unbiased circulating biochemical markers to allow early detection and treatment of NAFLD. Comprehensive genomic studies have also begun to provide new insights into the gene polymorphism to understand patient-disease variations. Therefore, NAFLD is considered a complex and mutifactorial disease phenotype resulting from environmental exposures acting on a susceptible polygenic background. This paper reviewed the current status of proteomic and genomic studies that have contributed to the understanding of NAFLD pathogenesis. For proteomics section, this review highlighted functional proteins that involved in: (1) transportation; (2) metabolic pathway; (3) acute phase reaction; (4) anti-inflammatory; (5) extracellular matrix; and (6) immune system. In the genomic studies, this review will discuss genes which involved in: (1) lipolysis; (2) adipokines; and (3) cytokines production. PMID:25024592

  2. Insights into Mechanisms of Transmission and Pathogenesis from Transgenic Mouse Models of Prion Diseases.

    Science.gov (United States)

    Moreno, Julie A; Telling, Glenn C

    2017-01-01

    Prions represent a new paradigm of protein-mediated information transfer. In the case of mammals, prions are the cause of fatal, transmissible neurodegenerative diseases, sometimes referred to as transmissible spongiform encephalopathies (TSEs), which frequently occur as epidemics. An increasing body of evidence indicates that the canonical mechanism of conformational corruption of cellular prion protein (PrP C ) by the pathogenic isoform (PrP Sc ) that is the basis of prion formation in TSEs is common to a spectrum of proteins associated with various additional human neurodegenerative disorders, including the more common Alzheimer's and Parkinson's diseases. The peerless infectious properties of TSE prions, and the unparalleled tools for their study, therefore enable elucidation of mechanisms of template-mediated conformational propagation that are generally applicable to these related disease states. Many unresolved issues remain including the exact molecular nature of the prion, the detailed cellular and molecular mechanisms of prion propagation, and the means by which prion diseases can be both genetic and infectious. In addition, we know little about the mechanism by which neurons degenerate during prion diseases. Tied to this, the physiological role of the normal form of the prion protein remains unclear and it is uncertain whether or not loss of this function contributes to prion pathogenesis. The factors governing the transmission of prions between species remain unclear, in particular the means by which prion strains and PrP primary structure interact to affect interspecies prion transmission. Despite all these unknowns, advances in our understanding of prions have occurred because of their transmissibility to experimental animals, and the development of transgenic (Tg) mouse models has done much to further our understanding about various aspects of prion biology. In this review, we will focus on advances in our understanding of prion biology that occurred

  3. Pathogenesis of non-alcoholic fatty liver disease

    OpenAIRE

    Dowman, J. K.; Tomlinson, J.W.; Newsome, P.N.

    2009-01-01

    Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of disease ranging from hepatocellular steatosis through steatohepatitis to fibrosis and irreversible cirrhosis. The prevalence of NAFLD has risen rapidly in parallel with the dramatic rise in obesity and diabetes, and is rapidly becoming the most common cause of liver disease in Western countries. Indeed, NAFLD is now recognized to be the aetiology in many cases previously labelled as cryptogenic cirrhosis.

  4. Osteoarthritis: pathogenesis and therapeutic interventions for a whole joint disease

    NARCIS (Netherlands)

    M. Siebelt (Michiel)

    2015-01-01

    markdownabstract__Abstract__ Osteoarthritis (OA) is an invalidating disease characterized by progressive cartilage degradation. OA is the most prevalent arthritic disease and leading cause of disability that effects approximately 34% of the population in the United states over age 65. Also in

  5. Postoperative recurrence of Crohn's disease: pathogenesis and prevention

    NARCIS (Netherlands)

    D'Haens, G. R.; Rutgeerts, P. J.

    1994-01-01

    Postoperative recurrence of Crohn's disease is very common and almost invariably appears at the ileal side of the ileocolonic anastomosis. Luminal factors are believed to play an essential role in triggering the earliest inflammatory events. The characteristics of recurrent disease are often very

  6. Pathogenesis, diagnosis, and management of severe pelvic inflammatory disease and tuboovarian abscess.

    Science.gov (United States)

    Chappell, Catherine A; Wiesenfeld, Harold C

    2012-12-01

    Severe pelvic inflammatory disease and tuboovarian abscesses (TOAs) are common pelvic infections requiring inpatient admission. There are few large randomized trials guiding appropriate clinical management of TOA, including antibiotic selection and timing of surgical management and drainage. The pathogenesis, diagnosis, and management of severe pelvic inflammatory disease and TOA are summarized and reviewed from the most current literature.

  7. The role of cytomegalovirus infection in the pathogenesis of periodontal diseases.

    Science.gov (United States)

    Beader, Natasa; Ivić-Kardum, Marija

    2011-03-01

    The main characteristic ofperiodontal disease is chronic inflammation that leads to progressive destruction of the connective tissues and bone with subsequent tooth mobility and finally tooth loss. Traditionally, the pathogenesis of periodontitis was based on the infection caused by bacteria that colonize tooth surface and gingival sulcus. Accumulated evidence show that host response factors such as inflammatory reaction and activation of the innate immune system are critical to the pathogenesis of periodontal disease. Periodontal disease has been widely recognized as a chronic disease but the nature of chronicity remains unclear. The question is whether periodontal disease is a continuous process or consists of episodes of exacerbations and remissions. Maybe cytomegalovirus infection of the periodontium, depending on the latent or active phase of infection, can partly explain the episodic progressive nature of periodontal disease. Cytomegalovirus infection impairs periodontal defense and permits overgrowth of periodontopathogenic bacteria. Owing to advances in new technologies, experimental evidence show the influence and interrelatedness of genomic, epigenetic, proteomic and metabolic factors in the pathogenesis of periodontal disease. Data on the pathogenesis of periodontal disease are reviewed.

  8. Global foot-and-mouth disease research update and gap analysis: 7 - pathogenesis and molecular biology

    Science.gov (United States)

    In 2014, the GFRA (Global Foot-and-mouth disease Research Alliance) conducted a gap analysis of FMD (Foot-and-Mouth Disease) research. This work has been updated and reported in a series of papers, in this article we report findings in the fields of 1) pathogenesis and 2) molecular biology. The arti...

  9. The epidemiology and the pathogenesis of inflammatory bowel disease

    International Nuclear Information System (INIS)

    Karlinger, Kinga; Gyoerke, Tamas; Makoe, Erno; Mester, Adam; Tarjan, Zsolt

    2000-01-01

    The etiology of inflammatory bowel disease (IBD) is still unknown. However, a satisfactory solution cannot be far away. IBD actually encompasses two diseases, i.e. Crohn's disease (CD) and ulcerous colitis (UC). These diseases resemble each other so closely that they cannot be distinguished even pathologically, but differ from each other sufficiently to regard them as independent entities. Epidemiological observations may be helpful in identifying the true causative factors of this evasive disease. Geographically, the prevalence of the disease has a slope from North to South and, to a lesser degree, from West to East. The Western-Eastern discrepancy can be attributed to a difference in Western life styles. The incidence of the disease has been increasing world-wide of late, but its spread has been slowing down in highly affected countries. Racial and ethnic relations in different populations and immigration studies offer interesting data which can reflect genetic, inherited, environmental and behavioural factors. The disease seems to have a characteristic racial-ethnic distribution: the Jewish population is highly susceptible everywhere, but its prevalence in that population nears that of the domestic society in which they live. In Hungary, the Roma (Gypsies) have a considerably lower prevalence than the average population. This can be attributed to a genetic or environmental influence. According to age, the onset of the disease occurs more often in the second or the third decade of life, but there also is another peak in the 60s. Regarding sexual distribution, there is a slight preponderance of colitis ulcerosa in men and of Crohn's disease in women. It may correspond to the stronger auto-immune affection in the process of Crohn's disease. Environmental factors and behavioural influences also are investigated. Diet, the role of the early ages, smoking habits and the influence of hormonal status and drugs are viewed as useful contributing factors in the

  10. The epidemiology and the pathogenesis of inflammatory bowel disease

    Energy Technology Data Exchange (ETDEWEB)

    Karlinger, Kinga E-mail: karlking@radi.sote.hu; Gyoerke, Tamas; Makoe, Erno; Mester, Adam; Tarjan, Zsolt

    2000-09-01

    The etiology of inflammatory bowel disease (IBD) is still unknown. However, a satisfactory solution cannot be far away. IBD actually encompasses two diseases, i.e. Crohn's disease (CD) and ulcerous colitis (UC). These diseases resemble each other so closely that they cannot be distinguished even pathologically, but differ from each other sufficiently to regard them as independent entities. Epidemiological observations may be helpful in identifying the true causative factors of this evasive disease. Geographically, the prevalence of the disease has a slope from North to South and, to a lesser degree, from West to East. The Western-Eastern discrepancy can be attributed to a difference in Western life styles. The incidence of the disease has been increasing world-wide of late, but its spread has been slowing down in highly affected countries. Racial and ethnic relations in different populations and immigration studies offer interesting data which can reflect genetic, inherited, environmental and behavioural factors. The disease seems to have a characteristic racial-ethnic distribution: the Jewish population is highly susceptible everywhere, but its prevalence in that population nears that of the domestic society in which they live. In Hungary, the Roma (Gypsies) have a considerably lower prevalence than the average population. This can be attributed to a genetic or environmental influence. According to age, the onset of the disease occurs more often in the second or the third decade of life, but there also is another peak in the 60s. Regarding sexual distribution, there is a slight preponderance of colitis ulcerosa in men and of Crohn's disease in women. It may correspond to the stronger auto-immune affection in the process of Crohn's disease. Environmental factors and behavioural influences also are investigated. Diet, the role of the early ages, smoking habits and the influence of hormonal status and drugs are viewed as useful contributing factors in

  11. Association of periodontal pathogenesis and cardiovascular diseases: a literature review.

    Science.gov (United States)

    Ahmed, Umair; Tanwir, Farzeen

    2015-01-01

    To present a short review of recent literature available on the association of periodontal and cardiovascular diseases (CVD) and the role of peridontal disease as a risk factor to exacerbate CVD. A thorough search of articles was carried out on the databases PUBMED and MEDLINE on the association of periodontal and cardiovascular diseases (CVD). The selected literature included review articles, observational and case-control studies as well as randomised control trials. While selecting articles, priority was placed on papers published within the last 12 years. A brief description of periodontal diseases, atherosclerosis, underlying pathophysiology and oral bacteria has been included. There is growing evidence of the association of periodontal diseases and CVD, as reviewed by the epidemiological studies. The in vitro studies also highlight a potential link between oral bacteria and atherosclerosis. Thus, there is urgent need for proper case controls and efficient interventional trials to analyse how such interventions can produce a positive outcome on cardiovascular diseases. Some recent interventional trials have shown that periodontal treatment can decrease markers of systemic inflammation. The relationship between periodontal diseases and CVD deserves further research because of its consequences for public health.

  12. Understanding the impact of infection, inflammation and their persistence in the pathogenesis of bronchopulmonary dysplasia

    Directory of Open Access Journals (Sweden)

    Jherna eBalany

    2015-12-01

    Full Text Available The concerted interaction of genetic and environmental factors act on the preterm human immature lung with inflammation being the common denominator leading to the multifactorial origin of the most common chronic lung disease in infants – bronchopulmonary dysplasia or BPD. Adverse perinatal exposure to infection/inflammation with added insults like invasive mechanical ventilation, exposure to hyperoxia and sepsis causes persistent immune dysregulation. In this review article we have attempted to analyze and consolidate current knowledge about the role played by persistent prenatal and postnatal inflammation in the pathogenesis of BPD. While some parameters of the early inflammatory response (neutrophils, cytokines etc. may not be detectable after days to weeks of exposure to noxious stimuli, they have already initiated the signaling pathways of the inflammatory process / immune cascade and have affected permanent defects structurally and functionally in the BPD lungs. Hence translational research aimed at prevention / amelioration of BPD needs to focus on dampening the inflammatory response at an early stage to prevent the cascade of events leading to lung injury with impaired healing resulting in the pathologic pulmonary phenotype of alveolar simplification and dysregulated vascularization characteristic of BPD.

  13. Understanding the Impact of Infection, Inflammation, and Their Persistence in the Pathogenesis of Bronchopulmonary Dysplasia.

    Science.gov (United States)

    Balany, Jherna; Bhandari, Vineet

    2015-01-01

    The concerted interaction of genetic and environmental factors acts on the preterm human immature lung with inflammation being the common denominator leading to the multifactorial origin of the most common chronic lung disease in infants - -bronchopulmonary dysplasia (BPD). Adverse perinatal exposure to infection/inflammation with added insults like invasive mecha nical ventilation, exposure to hyperoxia, and sepsis causes persistent immune dysregulation. In this review article, we have attempted to analyze and consolidate current knowledge about the role played by persistent prenatal and postnatal inflammation in the pathogenesis of BPD. While some parameters of the early inflammatory response (neutrophils, cytokines, etc.) may not be detectable after days to weeks of exposure to noxious stimuli, they have already initiated the signaling pathways of the inflammatory process/immune cascade and have affected permanent defects structurally and functionally in the BPD lungs. Hence, translational research aimed at prevention/amelioration of BPD needs to focus on dampening the inflammatory response at an early stage to prevent the cascade of events leading to lung injury with impaired healing resulting in the pathologic pulmonary phenotype of alveolar simplification and dysregulated vascularization characteristic of BPD.

  14. Parkinson’s Disease – the Debate on the Clinical Phenomenology, Aetiology, Pathology and Pathogenesis

    Science.gov (United States)

    Jenner, Peter; Morris, Huw R.; Robbins, Trevor W.; Goedert, Michel; Hardy, John; Ben-Shlomo, Yoav; Bolam, Paul; Burn, David; Hindle, John V.; Brooks, David

    2014-01-01

    The definition of Parkinson’s disease (PD) is changing with the expansion of clinical phenomenology and improved understanding of environmental and genetic influences that impact on the pathogenesis of the disease at the cellular and molecular level. This had led to debate and discussion with as yet, no general acceptance of the direction that change should take either at the level of diagnosis or of what should and should not be sheltered under an umbrella of PD. This article is one contribution to this on-going discussion. There are two different themes running through the article - widening the definition of PD/LBD/synucleinopathies and the heterogeneity that exists within PD itself from a clinical, pathological and genetic per-spective. The conclusion reached is that in the future, further diagnostic categories will need to be recognized. These are likely to include - Parkinson’s syndrome, Parkinson’s syndrome likely to be Lewy body PD, clinical PD (defined by QSBB criteria), Lewy body disease (PD, LBD, REM SBD) and synucleinopathies (including LBD, MSA). PMID:23938306

  15. Parkinson's disease--the debate on the clinical phenomenology, aetiology, pathology and pathogenesis.

    Science.gov (United States)

    Jenner, Peter; Morris, Huw R; Robbins, Trevor W; Goedert, Michel; Hardy, John; Ben-Shlomo, Yoav; Bolam, Paul; Burn, David; Hindle, John V; Brooks, David

    2013-01-01

    The definition of Parkinson's disease (PD) is changing with the expansion of clinical phenomenology and improved understanding of environmental and genetic influences that impact on the pathogenesis of the disease at the cellular and molecular level. This had led to debate and discussion with as yet, no general acceptance of the direction that change should take either at the level of diagnosis or of what should and should not be sheltered under an umbrella of PD. This article is one contribution to this on-going discussion. There are two different themes running through the article--widening the definition of PD/LBD/synucleinopathies and the heterogeneity that exists within PD itself from a clinical, pathological and genetic perspective. The conclusion reached is that in the future, further diagnostic categories will need to be recognized. These are likely to include--Parkinson's syndrome, Parkinson's syndrome likely to be Lewy body PD, clinical PD (defined by QSBB criteria), Lewy body disease (PD, LBD, REM SBD) and synucleinopathies (including LBD, MSA).

  16. Glial cell inclusions and the pathogenesis of neurodegenerative diseases

    OpenAIRE

    Miller, David W.; Cookson, Mark R.; Dickson, Dennis W.

    2004-01-01

    In this review, we discuss examples that show how glial-cell pathology is increasingly recognized in several neurodegenerative diseases. We also discuss the more provocative idea that some of the disorders that are currently considered to be neurodegenerative diseases might, in fact, be due to primary abnormalities in glia. Although the mechanism of glial pathology (i.e. modulating glutamate excitotoxicity) might be better established for amyotrophic lateral sclerosis (ALS), a role for neuron...

  17. Caroli's Disease: Current Knowledge of Its Biliary Pathogenesis Obtained from an Orthologous Rat Model

    Directory of Open Access Journals (Sweden)

    Yasunori Sato

    2012-01-01

    Full Text Available Caroli's disease belongs to a group of hepatic fibropolycystic diseases and is a hepatic manifestation of autosomal recessive polycystic kidney disease (ARPKD. It is a congenital disorder characterized by segmental saccular dilatations of the large intrahepatic bile duct and is frequently associated with congenital hepatic fibrosis (CHF. The most viable theory explaining its pathogenesis suggests that it is related to ductal plate malformation. The development of the polycystic kidney (PCK rat, an orthologous rodent model of Caroli's disease with CHF as well as ARPKD, has allowed the molecular pathogenesis of the disease and the therapeutic options for its treatment to be examined. The relevance of the findings of studies using PCK rats and/or the cholangiocyte cell line derived from them to the pathogenesis of human Caroli's disease is currently being analyzed. Fibrocystin/polyductin, the gene product responsible for ARPKD, is normally localized to primary cilia, and defects in the fibrocystin from primary cilia are observed in PCK cholangiocytes. Ciliopathies involving PCK cholangiocytes (cholangiociliopathies appear to be associated with decreased intracellular calcium levels and increased cAMP concentrations, causing cholangiocyte hyperproliferation, abnormal cell matrix interactions, and altered fluid secretion, which ultimately result in bile duct dilatation. This article reviews the current knowledge about the pathogenesis of Caroli's disease with CHF, particularly focusing on studies of the mechanism responsible for the biliary dysgenesis observed in PCK rats.

  18. Blood pressure gradients in cerebral arteries: a clue to pathogenesis of cerebral small vessel disease.

    Science.gov (United States)

    Blanco, Pablo J; Müller, Lucas O; Spence, J David

    2017-09-01

    The role of hypertension in cerebral small vessel disease is poorly understood. At the base of the brain (the 'vascular centrencephalon'), short straight arteries transmit blood pressure directly to small resistance vessels; the cerebral convexity is supplied by long arteries with many branches, resulting in a drop in blood pressure. Hypertensive small vessel disease (lipohyalinosis) causes the classically described lacunar infarctions at the base of the brain; however, periventricular white matter intensities (WMIs) seen on MRI and WMI in subcortical areas over the convexity, which are often also called 'lacunes', probably have different aetiologies. We studied pressure gradients from proximal to distal regions of the cerebral vasculature by mathematical modelling. Blood flow/pressure equations were solved in an Anatomically Detailed Arterial Network (ADAN) model, considering a normotensive and a hypertensive case. Model parameters were suitably modified to account for structural changes in arterial vessels in the hypertensive scenario. Computations predict a marked drop in blood pressure from large and medium-sized cerebral vessels to cerebral peripheral beds. When blood pressure in the brachial artery is 192/113 mm Hg, the pressure in the small arterioles of the posterior parietal artery bed would be only 117/68 mm Hg. In the normotensive case, with blood pressure in the brachial artery of 117/75 mm Hg, the pressure in small parietal arterioles would be only 59/38 mm Hg. These findings have important implications for understanding small vessel disease. The marked pressure gradient across cerebral arteries should be taken into account when evaluating the pathogenesis of small WMIs on MRI. Hypertensive small vessel disease, affecting the arterioles at the base of the brain should be distinguished from small vessel disease in subcortical regions of the convexity and venous disease in the periventricular white matter.

  19. Alternative RNA Splicing in the Pathogenesis of Liver Disease

    Directory of Open Access Journals (Sweden)

    Nicholas J. G. Webster

    2017-06-01

    Full Text Available Non-alcoholic fatty liver disease (NAFLD is becoming increasingly prevalent due to the worldwide obesity epidemic and currently affects one-third of adults or about one billion people worldwide. NAFLD is predicted to affect over 50% of the world’s population by the end of the next decade. It is the most common form of liver disease and is associated with increased risk for progression to a more severe form non-alcoholic steatohepatitis, as well as insulin resistance, type 2 diabetes mellitus, cirrhosis, and eventually hepatocellular carcinoma. This review article will focus on the role of alternative splicing in normal liver physiology and dysregulation in liver disease.

  20. Pathogenesis and potential therapy of autosomal dominant polycystic kidney disease

    Directory of Open Access Journals (Sweden)

    O.O. Melnyk

    2017-10-01

    Full Text Available Autosomal dominant polycystic kidney disease (ADPKD is a hereditary disease characterized by progressive growth of the cyst and an increase in the total volume of the kidneys which leads to kidney failure. The main causes of ADPKD are mutations in the genes PKD1 and PKD2 which encode the formation of polycystin-1 and polycystin-2 proteins. There is a connection between structural and functional defects in the primary cilia with the ADPKD. The most promising drugs for the treatment of ADPKD today are vasopressin-2 receptor antagonists, m-TOR and c-AMP inhibitors.

  1. Parkinson's disease : The syndrome, the pathogenesis and pathophysiology

    NARCIS (Netherlands)

    Bartels, Anna L.; Leenders, Klaus L.

    Parkinson's disease (PD) is characterised by a slowly expanding degeneration of neurons particularly in the mesencephalon. The causes are unknown although risk factors in the genetic and toxic domain are being discovered. An important pathophysiological feature in PD is the loss of part of the

  2. Involvement of morbilliviruses in the pathogenesis of demyelinating disease

    NARCIS (Netherlands)

    Sips, G. J.; Chesik, D.; Glazenburg, L.; Wilschut, J.; De Keyser, J.; Wilczak, N.

    2007-01-01

    Two members of the morbillivirus genus of the family Paramyxoviridae, canine distemper virus (CDV) and measles virus (MV), are well-known for their ability to cause a chronic demyelinating disease of the CNS in their natural hosts, dogs and humans, respectively. Both viruses have been studied for

  3. Potential Celiac Patients : A Model of Celiac Disease Pathogenesis

    NARCIS (Netherlands)

    Sperandeo, Maria Pia; Tosco, Antonella; Izzo, Valentina; Tucci, Francesca; Troncone, Riccardo; Auricchio, Renata; Romanos, Jihane; Trynka, Gosia; Auricchio, Salvatore; Jabri, Bana; Greco, Luigi

    2011-01-01

    Background and Aim: Potential celiacs have the 'celiactype' HLA, positive anti-transglutaminase antibodies but no damage at small intestinal mucosa. Only a minority of them develops mucosal lesion. More than 40 genes were associated to Celiac Disease (CD) but we still do not know how those pathways

  4. Astrogliosis : An integral player in the pathogenesis of Alzheimer's disease

    NARCIS (Netherlands)

    Osborn, Lana M.; Kamphuis, Willem; Wadman, Wytse J.; Hol, Elly M.

    Alzheimer's disease is the main cause of dementia in the elderly and begins with a subtle decline in episodic memory followed by a more general decline in overall cognitive abilities. Though the exact trigger for this cascade of events remains unknown the presence of the misfolded amyloid-beta

  5. Imaging lymphoid tissues in nonhuman primates to understand SIV pathogenesis and persistence.

    Science.gov (United States)

    Deleage, Claire; Turkbey, Baris; Estes, Jacob D

    2016-08-01

    CD4+ T cells are the primary HIV-1 target cell, with the vast majority of these cells residing within lymphoid tissue compartments throughout the body. Predictably, HIV-1 infection, replication, localization, reservoir establishment and persistence, as well as associated host immune and inflammatory responses and disease pathology principally take place within the tissues of the immune system. By virture of the fact that the virus-host struggle is played out within lymphoid and additional tissues compartments in HIV-1 infected individuals it is critical to understand HIV-1 infection and disease within these relevant tissue sites; however, there are obvious limitations to studying these dynamic processes in humans. Nonhuman primate (NHP) research has provided a vital bridge between basic and preclinical research and clinical studies, with experimental SIV infection of NHP models offering unique opportunities to understand key processes of HIV-1 infection and disease that are either not practically feasible or ethical in HIV-1 infected humans. In this review we will discuss current approaches to studying the tissue based immunopathogenesis of AIDS virus infection in NHPs, including both analyses of tissues obtained at biopsy or necropsy and complementary non-invasive imaging approaches that may have practical utility in monitoring HIV-1 disease in the clinical setting. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Parkinson’s Disease: From Pathogenesis to Pharmacogenomics

    Directory of Open Access Journals (Sweden)

    Ramón Cacabelos

    2017-03-01

    Full Text Available Parkinson’s disease (PD is the second most important age-related neurodegenerative disorder in developed societies, after Alzheimer’s disease, with a prevalence ranging from 41 per 100,000 in the fourth decade of life to over 1900 per 100,000 in people over 80 years of age. As a movement disorder, the PD phenotype is characterized by rigidity, resting tremor, and bradykinesia. Parkinson’s disease -related neurodegeneration is likely to occur several decades before the onset of the motor symptoms. Potential risk factors include environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular damage, and genomic defects. Parkinson’s disease neuropathology is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta, with widespread involvement of other central nervous system (CNS structures and peripheral tissues. Pathogenic mechanisms associated with genomic, epigenetic and environmental factors lead to conformational changes and deposits of key proteins due to abnormalities in the ubiquitin–proteasome system together with dysregulation of mitochondrial function and oxidative stress. Conventional pharmacological treatments for PD are dopamine precursors (levodopa, l-DOPA, l-3,4 dihidroxifenilalanina, and other symptomatic treatments including dopamine agonists (amantadine, apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, ropinirole, rotigotine, monoamine oxidase (MAO inhibitors (selegiline, rasagiline, and catechol-O-methyltransferase (COMT inhibitors (entacapone, tolcapone. The chronic administration of antiparkinsonian drugs currently induces the “wearing-off phenomenon”, with additional psychomotor and autonomic complications. In order to minimize these clinical complications, novel compounds have been developed. Novel drugs and bioproducts for the treatment of PD should address dopaminergic neuroprotection to reduce premature neurodegeneration in

  7. IMMUNOGLOBULINS IN DEFENSE, PATHOGENESIS AND THERAPY OF FUNGAL DISEASES

    OpenAIRE

    Casadevall, Arturo; Pirofski, Liise-anne

    2012-01-01

    Only two decades ago antibodies to fungi were thought to have little or no role in protection against fungal diseases. However, subsequent research has provided convincing evidence that certain antibodies can modify the course of fungal infection to the benefit or detriment of the host. Hybridoma technology was the breakthrough that enabled the characterization of antibodies to fungi, illuminating some of the requirements for antibody efficacy. As discussed in this review, fungal specific ant...

  8. Edema in renal diseases – current view on pathogenesis

    Directory of Open Access Journals (Sweden)

    Irina Bobkova

    2016-10-01

    Full Text Available Edema is a common complication of numerous renal disease. In the recent past several aspects of the pathophysiology of this condition have been elucidated. We herein present a case of nephrotic syndrome in a 30 year-old men. The discussion revolves around the following key questions on fluid accumulation in renal disease: 1. What is edema? What diseases can cause edema? 2. What are the mechanisms of edema in nephrotic syndrome?   2a. The “underfill” theory   2b. The “overfill” theory   2c. Tubulointerstitial inflammation   2d. Vascular permeability 3. What are the mechanisms of edema in nephritic syndrome? 4. How can the volume status be assessed in patients with nephrotic syndrome? 5. What are therapeutic strategies for edema management? 6. What are the factors affecting response to diuretics? 7. How can we overcome the diuretics resistance?   7a. Effective doses of loop diuretics   7b. Combined diuretic therapy   7c. Intravenous administration of diuretics   7d. Albumin infusions   7e. Alternative methods of edema management 8. Conclusion.

  9. Intestinal Microbiota and the Innate Immune System – A Crosstalk in Crohn’s Disease Pathogenesis

    OpenAIRE

    Haag, Lea-Maxie; Siegmund, Britta

    2015-01-01

    Crohn’s disease (CD) is a chronic, relapsing inflammatory disorder that can occur anywhere along the gastrointestinal tract. The precise etiology of CD is still unclear but it is widely accepted that a complex series of interactions between susceptibility genes, the immune system and environmental factors are implicated in the onset and perpetuation of the disease. Increasing evidence from experimental and clinical studies implies the intestinal microbiota in disease pathogenesis, thereby sup...

  10. Crohn’s Disease – The Pathogenesis of a Granulomatous Vasculitis: A Hypothesis

    OpenAIRE

    Andrew J Wakefield

    1995-01-01

    Dissatisfied with traditional approaches to studying the pathogenesis of Crohn’s disease, the author and colleagues proposed and developed the hypothesis that Crohn’s disease is a granulomatous vasculitis mediated by a persistent viral infection of the mesenteric microvascular endothelium. Employing a range of techniques, the mesenteric vascular anatomy of intestine affected by Crohn’s disease was studied and the presence of a widespread multifocal vasculitis was demonstrated. Based upon cert...

  11. Pathogenesis of Renal Disease in Systemic Lupus Erythematosus—The Role of Autoantibodies and Lymphocytes Subset Abnormalities

    Directory of Open Access Journals (Sweden)

    Desmond Y. H. Yap

    2015-04-01

    Full Text Available Lupus nephritis (LN is a common and severe organ manifestation of systemic lupus erythematosus (SLE, and is associated with significant patient morbidity and mortality. Autoantibodies and aberrations in lymphocyte subsets have putative roles in the pathogenesis of SLE and LN, and might reflect disease activity and are amenable to immunosuppressive treatments. Anti-DNA is one of the well-studied autoantibodies, which correlates with disease activity and has direct nephritogenic effects on resident renal cells and various glomerular components. Other important autoantibodies in the pathogenesis of LN include anti-C1q, anti-α-actinin and anti-nucleosome antibodies. Changes in naive and memory B cells and plasma cells have been observed in SLE and LN patients. These B cell subsets exert diverse effects during pathogenesis of LN such as production of autoantibodies, secretion of proinflammatory and anti-inflammatory cytokines and presentation of auto-antigens to effector cells. Aberration of T lymphocytes, especially the T-helper subsets, is also highly pertinent in the development of LN. In this context, important T helper subsets include Th1, Th2, Th9, Th17, TReg and follicular T-helper cells. The growing knowledge on these autoantibodies and lymphocyte subset abnormalities will enhance our understanding of SLE and LN, and hence help devise better strategies for disease monitoring and treatment.

  12. Telomeres and Telomerase: Role in Marek’s Disease Virus Pathogenesis, Integration and Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Ahmed Kheimar

    2017-07-01

    Full Text Available Telomeres protect the ends of vertebrate chromosomes from deterioration and consist of tandem nucleotide repeats (TTAGGGn that are associated with a number of proteins. Shortening of the telomeres occurs during genome replication, thereby limiting the replication potential of somatic cells. To counteract this shortening, vertebrates encode the telomerase complex that maintains telomere length in certain cell types via de novo addition of telomeric repeats. Several herpesviruses, including the highly oncogenic alphaherpesvirus Marek’s disease virus (MDV, harbor telomeric repeats (TMR identical to the host telomere sequences at the ends of their linear genomes. These TMR facilitate the integration of the MDV genome into host telomeres during latency, allowing the virus to persist in the host for life. Integration into host telomeres is critical for disease and tumor induction by MDV, but also enables efficient reactivation of the integrated virus genome. In addition to the TMR, MDV also encodes a telomerase RNA subunit (vTR that shares 88% sequence identity with the telomerase RNA in chicken (chTR. vTR is highly expressed during all stages of the virus lifecycle, enhances telomerase activity and plays an important role in MDV-induced tumor formation. This review will focus on the recent advances in understanding the role of viral TMR and vTR in MDV pathogenesis, integration and tumorigenesis.

  13. Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease

    Directory of Open Access Journals (Sweden)

    A.P. Bastos

    2011-07-01

    Full Text Available Autosomal dominant polycystic kidney disease (ADPKD is one of the most common human life-threatening monogenic disorders. The disease is characterized by bilateral, progressive renal cystogenesis and cyst and kidney enlargement, often leading to end-stage renal disease, and may include extrarenal manifestations. ADPKD is caused by mutation in one of two genes, PKD1 and PKD2, which encode polycystin-1 (PC1 and polycystin-2 (PC2, respectively. PC2 is a non-selective cation channel permeable to Ca2+, while PC1 is thought to function as a membrane receptor. The cyst cell phenotype includes increased proliferation and apoptosis, dedifferentiation, defective planar polarity, and a secretory pattern associated with extracellular matrix remodeling. The two-hit model for cyst formation has been recently extended by the demonstration that early gene inactivation leads to rapid and diffuse development of renal cysts, while inactivation in adult life is followed by focal and late cyst formation. Renal ischemia/reperfusion, however, can function as a third hit, triggering rapid cyst development in kidneys with Pkd1 inactivation induced in adult life. The PC1-PC2 complex behaves as a sensor in the primary cilium, mediating signal transduction via Ca2+ signaling. The intracellular Ca2+ homeostasis is impaired in ADPKD, being apparently responsible for the cAMP accumulation and abnormal cell proliferative response to cAMP. Activated mammalian target for rapamycin (mTOR and cell cycle dysregulation are also significant features of PKD. Based on the identification of pathways altered in PKD, a large number of preclinical studies have been performed and are underway, providing a basis for clinical trials in ADPKD and helping the design of future trials.

  14. Ebola virus disease - pathogenesis, clinical presentation and management.

    Science.gov (United States)

    Bociaga-Jasik, Monika; Piatek, Anna; Garlicki, Aleksander

    2014-01-01

    On March 2014 the WHO notified the outbreak of Ebola virus disease (EVD) in Guinea, and infection quickly spread to another West African countries including Sierra Leone, Liberia and Nigeria. Current outbreak is the largest in the history, since discovery of the virus in 1976. Imported cases and infection among healthcare workers in Europe and United States have elucidated necessity of better education of medical staff. Clinicians must be familiar with clinical picture of EVD, differential diagnosis and therapeutic approach, as rapid diagnosis and prompt introduction of supportive therapy can have a significant impact on the survival.

  15. Pathogenesis and Treatment of Sole Ulcers and White Line Disease.

    Science.gov (United States)

    Shearer, J K; van Amstel, Sarel R

    2017-07-01

    Sole ulcers and white line disease are 2 of the most common claw horn lesions in confined dairy cattle. Predisposing causes include unbalanced weight bearing, and metabolic, enzymatic, and hormonal changes. The white line serves as the junction between the sole and axial and abaxial wall. It is vulnerable to trauma and separation, permitting organic matter to become entrapped. Colonization contributes to retrograde movement of the infection to the solar and perioplic corium, where an abscess forms resulting in pain and lameness. Successful treatment requires an orthopedic foot block to the healthy claw and corrective trimming of the lesion. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Molecular and cellular pathogenesis of hemoglobin SC disease.

    OpenAIRE

    Bunn, H F; Noguchi, C T; Hofrichter, J; Schechter, G P; Schechter, A N; Eaton, W A

    1982-01-01

    Solution and cell studies were performed to ascertain why individuals with hemoglobin (Hb) SC have disease whereas those with Hb AS do not. The polymerization of deoxygenated mixtures containing sickle cell Hb (Hb S; alpha 2 beta 2(6)Glu leads to Val) and Hb C (alpha 2 beta 2(6)Glu leads to Lys) was investigated by measurements of delay times and solubilities. In mixtures containing more than 40% Hb S, polymerization takes place by the same mechanism as in solutions of Hb S alone, with no evi...

  17. Microparticles as players in the pathogenesis of cardiovascular disease

    Energy Technology Data Exchange (ETDEWEB)

    Alexandru, N.; Georgescu, A.

    2015-07-01

    Cardiovascular diseases (CVD) are the largest cause of morbidity and mortality in the world and include all diseases and conditions of the heart and blood vessels. The main cause of most CVD is atherosclerosis, which is an abnormal build-up of fat and other substances which form plaque inside the arteries. Atherosclerosis is most serious when it leads to reduced or blocked blood supply to the heart (causing angina or heart attack) or to the brain (causing a stroke). The majority of CVD is caused by risk factors that can be controlled, treated or modified. Microparticles (MPs) are now recognized as potential biomarkers and key elements in the development of CVD. Although MP generation is a physiological phenomenon, their shedding from a variety of cell types into body fluid is intensified in response to cellular activation, high shear stress, as well as cellular apoptosis. In this review we outline distinct aspect of MP generation and their side as players n the CVD development.

  18. Biology and pathogenesis of cytomegalovirus in periodontal disease.

    Science.gov (United States)

    Contreras, Adolfo; Botero, Javier Enrique; Slots, Jørgen

    2014-02-01

    Human periodontitis is associated with a wide range of bacteria and viruses and with complex innate and adaptive immune responses. Porphyromonas gingivalis, Tannerella forsythia, Aggregatibacter actinomycetemcomitans, Treponema denticola, cytomegalovirus and other herpesviruses are major suspected pathogens of periodontitis, and a combined herpesvirus-bacterial periodontal infection can potentially explain major clinical features of the disease. Cytomegalovirus infects periodontal macrophages and T-cells and elicits a release of interleukin-1β and tumor necrosis factor-α. These proinflammatory cytokines play an important role in the host defense against the virus, but they also have the potential to induce alveolar bone resorption and loss of periodontal ligament. Gingival fibroblasts infected with cytomegalovirus also exhibit diminished collagen production and release of an increased level of matrix metalloproteinases. This article reviews innate and adaptive immunity to cytomegalovirus and suggests that immune responses towards cytomegalovirus can play roles in controlling, as well as in exacerbating, destructive periodontal disease. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Cardiovascular dysautonomia in Parkinson disease: from pathophysiology to pathogenesis.

    Science.gov (United States)

    Jain, Samay; Goldstein, David S

    2012-06-01

    Signs or symptoms of impaired autonomic regulation of circulation often attend Parkinson disease (PD). This review covers biomarkers and mechanisms of autonomic cardiovascular abnormalities in PD and related alpha-synucleinopathies. The clearest clinical laboratory correlate of dysautonomia in PD is loss of myocardial noradrenergic innervation, detected by cardiac sympathetic neuroimaging. About 30-40% of PD patients have orthostatic hypotension (OH), defined as a persistent, consistent fall in systolic blood pressure of at least 20 mmHg or diastolic blood pressure of at least 10 mmHg within 3 min of change in position from supine to standing. Neuroimaging evidence of cardiac sympathetic denervation is universal in PD with OH (PD+OH). In PD without OH about half the patients have diffuse left ventricular myocardial sympathetic denervation, a substantial minority have partial denervation confined to the inferolateral or apical walls, and a small number have normal innervation. Among patients with partial denervation the neuronal loss invariably progresses over time, and in those with normal innervation at least some loss eventually becomes evident. Thus, cardiac sympathetic denervation in PD occurs independently of the movement disorder. PD+OH also entails extra-cardiac noradrenergic denervation, but this is not as severe as in pure autonomic failure. PD+OH patients have failure of both the parasympathetic and sympathetic components of the arterial baroreflex. OH in PD therefore seems to reflect a "triple whammy" of cardiac and extra-cardiac noradrenergic denervation and baroreflex failure. In contrast, most patients with multiple system atrophy, which can resemble PD+OH clinically, do not have evidence for cardiac or extra-cardiac noradrenergic denervation. Catecholamines in the neuronal cytoplasm are potentially toxic, via spontaneous and enzyme-catalyzed oxidation. Normally cytoplasmic catecholamines are efficiently taken up into vesicles via the vesicular

  20. Genetic Variations of PTPN2 and PTPN22: Role in the Pathogenesis of Type 1 Diabetes and Crohn's Disease.

    Science.gov (United States)

    Sharp, Robert C; Abdulrahim, Muna; Naser, Ebraheem S; Naser, Saleh A

    2015-01-01

    Genome wide association studies have identified several genes that might be associated with increase susceptibility to Type 1 Diabetes (T1D) and Crohn's disease. Both Crohn's disease and T1D have a profound impact on the lives of patients and it is pivotal to investigate the genetic role in patients acquiring these diseases. Understanding the effect of single nucleotide polymorphisms (SNP's) in key genes in patients suffering from T1D and Crohn's disease is crucial to finding an effective treatment and generating novel therapeutic drugs. This review article is focused on the impact of SNP's in PTPN2 (protein tyrosine phosphatase, non-receptor type 2) and PTPN22 (protein tyrosine phosphatase non-receptor type 22) on the development of Crohn's disease and T1D. The PTPN2 gene mutation in T1D patients play a direct role in the destruction of beta cells while in Crohn's disease patients, it modulates the innate immune responses. The PTPN22 gene mutations also play a role in both diseases by modulating intracellular signaling. Examining the mechanism through which these genes increase the susceptibility to both diseases and gaining a better understanding of their structure and function is of vital importance to understand the etiology and pathogenesis of Type 1 Diabetes and Crohn's disease.

  1. Understanding anemia of chronic disease.

    Science.gov (United States)

    Fraenkel, Paula G

    2015-01-01

    The anemia of chronic disease is an old disease concept, but contemporary research in the role of proinflammatory cytokines and iron biology has shed new light on the pathophysiology of the condition. Recent epidemiologic studies have connected the anemia of chronic disease with critical illness, obesity, aging, and kidney failure, as well as with the well-established associations of cancer, chronic infection, and autoimmune disease. Functional iron deficiency, mediated principally by the interaction of interleukin-6, the iron regulatory hormone hepcidin, and the iron exporter ferroportin, is a major contributor to the anemia of chronic disease. Although anemia is associated with adverse outcomes, experimental models suggest that iron sequestration is desirable in the setting of severe infection. Experimental therapeutic approaches targeting interleukin-6 or the ferroportin-hepcidin axis have shown efficacy in reversing anemia in either animal models or human patients, although these agents have not yet been approved for the treatment of the anemia of chronic disease. © 2015 by The American Society of Hematology. All rights reserved.

  2. Cytosolic phospholipase A2 as a mediator of disease pathogenesis.

    Science.gov (United States)

    Linkous, Amanda; Yazlovitskaya, Eugenia

    2010-10-01

    As efficient catalysts, enzymes help maintain a variety of biological and chemical transformations necessary for cellular metabolism and normal physiology. Unfortunately, pathogenic microbes can also exploit enzymatic reactions in an attempt to spread infection. Cytosolic phospholipase A2 (cPLA(2) ) is an enzyme that is responsible for the hydrolysis of membrane phospholipids such as phosphatidylcholine. Following activation, cPLA(2) cleaves phosphatidylcholine to yield free fatty acid and lysophosphatidylcholine. Both of these products and their downstream metabolites initiate a network of signalling cascades that influence cellular viability and inflammation. Recent observations have shown that viral and bacterial agents often target this intricate organization of signalling molecules. This review briefly discusses the role of cPLA(2) in the biological response to disease-causing pathogens and injury, the immunological process and tumour progression. © 2010 Blackwell Publishing Ltd.

  3. Immunoglobulins in defense, pathogenesis, and therapy of fungal diseases.

    Science.gov (United States)

    Casadevall, Arturo; Pirofski, Liise-Anne

    2012-05-17

    Only two decades ago antibodies to fungi were thought to have little or no role in protection against fungal diseases. However, subsequent research has provided convincing evidence that certain antibodies can modify the course of fungal infection to the benefit or detriment of the host. Hybridoma technology was the breakthrough that enabled the characterization of antibodies to fungi, illuminating some of the requirements for antibody efficacy. As discussed in this review, fungal-specific antibodies mediate protection through direct actions on fungal cells and through classical mechanisms such as phagocytosis and complement activation. Although mechanisms of antibody-mediated protection are often species-specific, numerous fungal antigens can be targeted to generate vaccines and therapeutic immunoglobulins. Furthermore, the study of antibody function against medically important fungi has provided fresh immunological insights into the complexity of humoral immunity that are likely to apply to other pathogens. Copyright © 2012 Elsevier Inc. All rights reserved.

  4. Pelvic inflammatory disease: current concepts in pathogenesis, diagnosis and treatment.

    Science.gov (United States)

    Mitchell, Caroline; Prabhu, Malavika

    2013-12-01

    Pelvic inflammatory disease (PID) is characterized by infection and inflammation of the upper genital tract in women and can cause significant reproductive health sequelae for women. Although a definitive diagnosis of PID is made by laparoscopic visualization of inflamed, purulent fallopian tubes, PID is generally a clinical diagnosis and thus represents a diagnostic challenge. Therefore, diagnosis and treatment algorithms advise a high index of suspicion for PID in any woman of reproductive age with pelvic or abdominal pain. Antibiotic therapy should be started early, and given for an adequate period of time to reduce the risk of complications. Coverage for anaerobic organisms should be considered in most cases. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Genomic analysis of a ginger pathogen Bacillus pumilus providing the understanding to the pathogenesis and the novel control strategy.

    Science.gov (United States)

    Yuan, Yihui; Gao, Meiying

    2015-05-19

    Bacillus pumilus has been widely identified as a pathogen of plant and human, while the genetic information is rarely available for pathogenic B. pumilus strains. B. pumilus GR8 is a pathogen that causes ginger rhizome rot disease by invading ginger rhizome parenchymatous tissues, growing in the extracellular space, and producing plant cell wall-degrading enzymes to destroy ginger cells. In this study, the genome of GR8 was sequenced and characterized. This genome was the third completely sequenced genome of the B. pumilus species, and it exhibited high similarity to the genome of the B. pumilus strain B6033. The genome of GR8 was 3.67 Mb in length and encoded 3,713 putative ORFs. Among these predicted proteins, numerous plant cell wall-degrading enzymes and several proteins associated with invading and adapting to the environment in the extracellular space of the ginger rhizome parenchymatous tissue were found. The GR8 genome contained only one restriction-modification system and no CRISPR/Cas system. The lack of phage-resistant system suggested that phages might be potential agents for the control of GR8. The genomic analysis of GR8 provided the understanding to the pathogenesis and the phage-control strategy of pathogenic B. pumilus strains.

  6. Inflammatory bowel disease. Current concepts of pathogenesis and implications for therapy.

    Science.gov (United States)

    Fiocchi, C

    2002-09-01

    Inflammatory bowel disease (IBD) still presents major challenges to the understanding of its cause, mechanisms of inflammation, and therapeutic choices to control the damaged tissue. Both types of IBD, ulcerative colitis and Crohn's disease, have been known and investigated for over half century but neither one is fully understood nor can be satisfactorily managed. While many gaps in our knowledge still exist, the last two decades have witnessed an unprecedented progress not only in the etiology but mainly in the mechanisms underlying the chronic inflammatory response. The pattern of IBD epidemiology has drastically changed since World War II, with an increased frequency in countries that have adopted a ''westernized'' life style. A parallel and important phenomenon is the continuous drop in age of onset in children. Unfortunately, only few epidemiological clues are available, with the exception of smoking and diet. What in smoking alters the course of IBD is still a mystery and which, among thousands of additives, could represent a risk factor will remain unknown for the foreseeable future. The current emphasis on the study of the enteric flora as the source of potential antigens against which the mucosal immune system reacts appear well justified. The data from animal models appears particularly convincing. Thus, after decades of relying almost exclusively on patient-derived information, numerous animal models are generating precious new information on IBD pathogenesis. In experimental IBD the genetic background of the animal markedly influences the course of the disease, and the same is probably true in humans. The identification of NOD2 as the first mutated gene associated with a subgroup of Crohn's disease patients is the first evidence that genetics are pointing to the right direction for understanding how the environment interacts with genes to cause IBD. For many years immunology has been the main source of scientific information on mechanisms of IBD

  7. Nutritional factors in the pathogenesis of ear disease in children: a systematic review

    NARCIS (Netherlands)

    Elemraid, M. A.; Mackenzie, I. J.; Fraser, W. D.; Brabin, B. J.

    2009-01-01

    Background: Ear disease is a major health problem in poorly resourced countries. The role of nutritional deficiencies in its pathogenesis and in relation to chronic suppurative otitis media (CSOM) has not been reviewed previously. Methods: A systematic review was undertaken using Pubmed, SCOPUS,

  8. Implications for the pathogenesis of non-alcoholic fatty liver disease

    African Journals Online (AJOL)

    Aim. Explore the possibility that increased gastrointestinal alcohol production may play a role in the pathogenesis of non-alcoholic fatty liver disease in patients with the metabolic syndrome. Methods. Blood, urine and breath levels of alcohol measured in 20 patients with the metabolic syndrome were compared with those of ...

  9. Small animal models to understand pathogenesis of osteoarthritis and use of stem cell in cartilage regeneration.

    Science.gov (United States)

    Piombo, Virginia

    2017-01-01

    Osteoarthritis (OA) is one of the most common diseases, which affect the correct functionality of synovial joints and is characterized by articular cartilage degradation. Limitation in the treatment of OA is mostly due to the very limited regenerative characteristic of articular cartilage once is damaged. Small animal models are of particular importance for mechanistic analysis to understand the processes that affect cartilage degradation. Combination of joint injury techniques with the use of stem cells has been shown to be an important tool for understanding the processes of cartilage degradation and regeneration. Implementation of stem cells and small animal models are important tools to help researchers to find a solution that could ameliorate and prevent the symptoms of OA. Copyright © 2017 John Wiley & Sons, Ltd.

  10. Progress in understanding the pathogenesis of BPD using the baboon and sheep models.

    Science.gov (United States)

    Albertine, Kurt H

    2013-04-01

    Bronchopulmonary dysplasia (BPD) is among the most common chronic lung diseases in infants in the US. Improved survival of preterm infants who developed BPD is becoming increasingly important because of the high risk for persistent pulmonary morbidities such as poor respiratory gas exchange, pulmonary hypertension, and excess airway expiratory resistance later in life. This review focuses on unique insights provided by the two large-animal, physiological models of neonatal chronic lung disease: preterm baboons and preterm lambs. The models' are valuable because they contribute to better understanding of the underlying molecular pathogenic mechanisms. An epigenetic hypothesis is proposed as a pathogenic mechanism for BPD and its persistent pulmonary morbidities. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. Intestinal Microbiota and the Innate Immune System - A Crosstalk in Crohn's Disease Pathogenesis.

    Science.gov (United States)

    Haag, Lea-Maxie; Siegmund, Britta

    2015-01-01

    Crohn's disease (CD) is a chronic, relapsing inflammatory disorder that can occur anywhere along the gastrointestinal tract. The precise etiology of CD is still unclear but it is widely accepted that a complex series of interactions between susceptibility genes, the immune system and environmental factors are implicated in the onset and perpetuation of the disease. Increasing evidence from experimental and clinical studies implies the intestinal microbiota in disease pathogenesis, thereby supporting the hypothesis that chronic intestinal inflammation arises from an abnormal immune response against the microorganisms of the intestinal flora in genetically susceptible individuals. Given that CD patients display changes in their gut microbiota composition, collectively termed "dysbiosis," the question raises whether the altered microbiota composition is a cause of disease or rather a consequence of the inflammatory state of the intestinal environment. This review will focus on the crosstalk between the gut microbiota and the innate immune system during intestinal inflammation, thereby unraveling the role of the microbiota in CD pathogenesis.

  12. Antibody transfection into neurons as a tool to study disease pathogenesis.

    Science.gov (United States)

    Douglas, Joshua N; Gardner, Lidia A; Lee, Sangmin; Shin, Yoojin; Groover, Chassidy J; Levin, Michael C

    2012-09-26

    hydrophobic interactions and delivering them inside cells. Thus chemical and genetic couplings are not necessary for delivery of functional antibodies into living cells. This method has enabled us to perform various antibody tracing and protein localization experiments, as well as the analyses of the molecular consequences of intracellular antibody:protein interactions. In this protocol, we will show how to transfect antibodies into neurons rapidly, reproducibly and with a high degree of transfection efficiency. As an example, we will use anti-hnRNP A1 and anti-IgG antibodies. For easy quantification of transfection efficiency we used anti-hnRNP A1 antibodies labelled with Atto-550-NHS and FITC-labeled IgG. Atto550 NHS is a new label with high molecular absorbtion and quantum yield. Excitation source and fluorescent filters for Atto550 are similar to Cy3 (Ex. 556 Em. 578). In addition, Atto550 has high photostability. FITC-labeled IgG were used as a control to show that this method is versatile and not dye dependent. This approach and the data that is generated will assist in understanding of the role that antibodies to intracellular target antigens might play in the pathogenesis of human diseases.

  13. Report of the ECCO pathogenesis workshop on anti-TNF therapy failures in inflammatory bowel diseases: definitions, frequency and pharmacological aspects

    DEFF Research Database (Denmark)

    Allez, Matthieu; Karmiris, Konstantinos; Louis, Edouard

    2010-01-01

    The first ECCO pathogenesis workshop focused on anti-TNF therapy failures in inflammatory bowel diseases (IBDs). The overall objective was to better understand and explore primary non response and loss of response to anti-TNF agents in IBD. The outcome of this workshop is presented into two parts...

  14. The Pathogenesis of Alzheimer's Disease: A Reevaluation of the “Amyloid Cascade Hypothesis”

    Directory of Open Access Journals (Sweden)

    R. A. Armstrong

    2011-01-01

    Full Text Available The most influential theory to explain the pathogenesis of Alzheimer's disease (AD has been the “Amyloid Cascade Hypothesis” (ACH first formulated in 1992. The ACH proposes that the deposition of β-amyloid (Aβ is the initial pathological event in AD leading to the formation of senile plaques (SPs and then to neurofibrillary tangles (NFTs death of neurons, and ultimately dementia. This paper examines two questions regarding the ACH: (1 is there a relationship between the pathogenesis of SPs and NFTs, and (2 what is the relationship of these lesions to disease pathogenesis? These questions are examined in relation to studies of the morphology and molecular determinants of SPs and NFTs, the effects of gene mutation, degeneration induced by head injury, the effects of experimentally induced brain lesions, transgenic studies, and the degeneration of anatomical pathways. It was concluded that SPs and NFTs develop independently and may be the products rather than the causes of neurodegeneration in AD. A modification to the ACH is proposed which may better explain the pathogenesis of AD, especially of late-onset cases of the disease.

  15. Oxidative damage and the pathogenesis of menopause related disturbances and diseases.

    Science.gov (United States)

    Cervellati, Carlo; Bergamini, Carlo M

    2016-05-01

    The postmenopausal phase of life is frequently associated in women with subjective symptoms (e.g. vasomotor) and real diseases (atherosclerosis with coronary ischemia, osteoporosis, Alzheimer-type neurodegeneration, urogenital dystrophy), which together determine the post-menopausal syndrome. Observations that oxidative damage by reactive oxygen/nitrogen species in experimental models can contribute to the pathogenesis of these disturbances stimulated research on the relationships between menopause, its endocrine deficiency, oxidative balance and the "wellness" in postmenopausal life. The connection among these events is probably due to the loss of protective actions exerted by estrogens during the fertile life. Most recent studies have revealed that estrogens exert an antioxidant action not by direct chemical neutralization of reactants as it was expected until recently but by modulating the expression of antioxidant enzymes that control levels of biological reducing agents. Also nutritional antioxidants apparently act by a similar mechanism. From this perspective it is conceivable that a cumulative control of body oxidant challenges and biological defenses could help in monitoring between "normal" and "pathological" menopause. However, as clinical studies failed to confirm this scenario in vivo, we have decided to review the existing literature to understand the causes of this discrepancy and whether this was due to methodologic reasons or to real failure of the basic hypothesis.

  16. Intestinal Epithelial Cell Endoplasmic Reticulum Stress and Inflammatory Bowel Disease Pathogenesis: An Update Review

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    Xiaoshi Ma

    2017-10-01

    Full Text Available The intestinal epithelial cells serve essential roles in maintaining intestinal homeostasis, which relies on appropriate endoplasmic reticulum (ER function for proper protein folding, modification, and secretion. Exogenous or endogenous risk factors with an ability to disturb the ER function can impair the intestinal barrier function and activate inflammatory responses in the host. The last decade has witnessed considerable progress in the understanding of the functional role of ER stress and unfolded protein response (UPR in the gut homeostasis and its significant contribution to the pathogenesis of inflammatory bowel disease (IBD. Herein, we review recent evidence supporting the viewpoint that deregulation of ER stress and UPR signaling in the intestinal epithelium, including the absorptive cells, Paneth cells, goblet cells, and enteroendocrine cells, mediates the action of genetic or environmental factors driving colitis in experimental animals and IBD patients. In addition, we highlight pharmacologic application of chaperones or small molecules that enhance protein folding and modification capacity or improve the function of the ER. These molecules represent potential therapeutic strategies in the prevention or treatment of IBD through restoring ER homeostasis in intestinal epithelial cells.

  17. The role of bile acids in the pathogenesis of bowel diseases

    Directory of Open Access Journals (Sweden)

    Magdalena Panek-Jeziorna

    2017-08-01

    Full Text Available Bile acids not only play a cardinal role in the digestion and absorption of fat and fat-soluble vitamins, but also significantly affect gastrointestinal motor, sensory and secretory functions, intestinal barrier permeability and the regulation of the inflammatory response. The results of recent studies have revealed complex interactions between bile acids and the gut microbiota. In addition, bile acids also play a role of signaling molecules regulating the activity of lipid and glucose metabolic pathways, as well as a role of ligands for transcription factors. Genetic factors associated with the regulation of bile acid synthesis, transport and action may significantly influence gastrointestinal function and predispose to diarrhea resulting from bile acid malabsorption. Methods used in the diagnosis of bile acid malabsorption include 75selenium-homotaurocholic acid test, serum C4 and fibroblast growth factor 19 (FGF19, as well as fecal bile acid levels. The paper presents the latest data on the role of bile acid in the pathogenesis of irritable bowel syndrome, inflammatory bowel diseases and colorectal cancer. Advances in the treatment of disturbances in bile acids absorption and synthesis are also presented. A better understanding of molecular mechanisms regulating bile acid action may have implication for colorectal cancer prevention.

  18. Proteomics in veterinary medicine: applications and trends in disease pathogenesis and diagnostics.

    Science.gov (United States)

    Ceciliani, F; Eckersall, D; Burchmore, R; Lecchi, C

    2014-03-01

    Advancement in electrophoresis and mass spectrometry techniques along with the recent progresses in genomics, culminating in bovine and pig genome sequencing, widened the potential application of proteomics in the field of veterinary medicine. The aim of the present review is to provide an in-depth perspective about the application of proteomics to animal disease pathogenesis, as well as its utilization in veterinary diagnostics. After an overview on the various proteomic techniques that are currently applied to veterinary sciences, the article focuses on proteomic approaches to animal disease pathogenesis. Included as well are recent achievements in immunoproteomics (ie, the identifications through proteomic techniques of antigen involved in immune response) and histoproteomics (ie, the application of proteomics in tissue processed for immunohistochemistry). Finally, the article focuses on clinical proteomics (ie, the application of proteomics to the identification of new biomarkers of animal diseases).

  19. Deregulation of protein translation control, a potential game-changing hypothesis for Parkinson's disease pathogenesis.

    Science.gov (United States)

    Taymans, Jean-Marc; Nkiliza, Aurore; Chartier-Harlin, Marie-Christine

    2015-08-01

    Protein translation is one of the most fundamental and exquisitely controlled processes in biology, and is energetically demanding. The deregulation of this process is deleterious to cells, as demonstrated by several diseases caused by mutations in protein translation machinery. Emerging evidence now points to a role for protein translation in the pathogenesis of Parkinson's disease (PD); a debilitating neurodegenerative movement disorder. In this paper, we propose a hypothesis that protein translation machinery, PD-associated proteins and PD pathology are connected in a functional network linking cell survival to protein translation control. This hypothesis is a potential game changer in the field of the molecular pathogenesis of PD, with implications for the development of PD diagnostics and disease-modifying therapies. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Is Behçet's disease a 'class 1-opathy'? The role of HLA-B*51 in the pathogenesis of Behçet's disease.

    Science.gov (United States)

    Giza, M; Koftori, D; Chen, L; Bowness, P

    2018-01-01

    The association between carriage of the human leucocyte antigen (HLA)-B*51 allele and development of Behçet's disease (BD) has been known since the early 1970s, but the exact mechanisms responsible for its role in pathogenesis remain much-debated. In an effort to explain the disease process, it has been suggested that BD constitutes one of a newly termed group of diseases, the 'MHC-I-opathies'. Other MHC-I-opathies include ankylosing spondylitis and HLA-B*27-associated spondyloarthropathies and HLA-C*0602-associated skin psoriasis. Recent work analysing the peptidome of HLA-B*51 suggests that altered peptide presentation by HLA-B*51 is vital to the disease process. In this review, we argue that immune receptor interactions with HLA-B*51 or the HLA-B*51-peptide complex could lead to development of inflammation in BD. The evidence for CD8 + T cell involvement is weak, and based on emerging studies it seems more likely that natural killer (NK) or other cell interactions, perhaps mediated by leucocyte immunoglobulin-like receptor (LILR) or killer immunoglobulin-like receptor (KIR) receptors, are culpable in pathogenesis. HLA misfolding leading directly to inflammation is another hypothesis for BD pathogenesis that deserves greater investigation. Ultimately, greater understanding of HLA-B*51's unique role in BD will probably lead to improved development of therapeutic strategies. © 2017 British Society for Immunology.

  1. The "soft collagen" hypothesis in the pathogenesis of the inflammatory bowel disease and the seronegative spondylarthritides.

    Science.gov (United States)

    Vounotrypidis, Periklis; Kouklakis, Georgios

    2010-09-01

    Seronegative spondylarthritides (SpAs) and inflammatory bowel disease (IBD) are disorders with a complex and elusive etiology. Current research has focused on downstream events and mechanisms of autoimmunity and inflammation but the primary etiologic factor is still unknown. We present a new hypothesis for the role of collagen into the pathogenesis of SpAs and IBD based on the assumption that they represent deferent phenotypes of the same disease. We gathered information on humans and animals which fit to the current evidence based concepts into their pathogenesis. We developed a logical hypothesis for the contribution of the individual's connective tissue profile among with the well known contribution of other genetic factors. The presence of a specific collagen or tissue matrix, which for abbreviation will be called the "soft collagen" (SC) is the basis for the pathogenesis of SpAs and the IBD. It seems that a triplet consisted of the "soft collagen", the genetic predisposition (such as the presence of HLA-B27, PSORS1 genes, NOD2/CARD mutations) and the triggering event (trauma or infection) are necessary for the development of these particular disorders. The "soft collagen" hypothesis may explain the pathogenesis as well as the various clinical aspects of these particular disorders which affect mostly young individuals. (c) 2010 Elsevier Ltd. All rights reserved.

  2. Pathogenesis of myasthenia gravis: update on disease types, models, and mechanisms [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    William D. Phillips

    2016-06-01

    Full Text Available Myasthenia gravis is an autoimmune disease of the neuromuscular junction (NMJ caused by antibodies that attack components of the postsynaptic membrane, impair neuromuscular transmission, and lead to weakness and fatigue of skeletal muscle. This can be generalised or localised to certain muscle groups, and involvement of the bulbar and respiratory muscles can be life threatening. The pathogenesis of myasthenia gravis depends upon the target and isotype of the autoantibodies. Most cases are caused by immunoglobulin (IgG1 and IgG3 antibodies to the acetylcholine receptor (AChR. They produce complement-mediated damage and increase the rate of AChR turnover, both mechanisms causing loss of AChR from the postsynaptic membrane. The thymus gland is involved in many patients, and there are experimental and genetic approaches to understand the failure of immune tolerance to the AChR. In a proportion of those patients without AChR antibodies, antibodies to muscle-specific kinase (MuSK, or related proteins such as agrin and low-density lipoprotein receptor-related protein 4 (LRP4, are present. MuSK antibodies are predominantly IgG4 and cause disassembly of the neuromuscular junction by disrupting the physiological function of MuSK in synapse maintenance and adaptation. Here we discuss how knowledge of neuromuscular junction structure and function has fed into understanding the mechanisms of AChR and MuSK antibodies. Myasthenia gravis remains a paradigm for autoantibody-mediated conditions and these observations show how much there is still to learn about synaptic function and pathological mechanisms.

  3. Pathogenesis of myasthenia gravis: update on disease types, models, and mechanisms

    Science.gov (United States)

    Phillips, William D.; Vincent, Angela

    2016-01-01

    Myasthenia gravis is an autoimmune disease of the neuromuscular junction (NMJ) caused by antibodies that attack components of the postsynaptic membrane, impair neuromuscular transmission, and lead to weakness and fatigue of skeletal muscle. This can be generalised or localised to certain muscle groups, and involvement of the bulbar and respiratory muscles can be life threatening. The pathogenesis of myasthenia gravis depends upon the target and isotype of the autoantibodies. Most cases are caused by immunoglobulin (Ig)G1 and IgG3 antibodies to the acetylcholine receptor (AChR). They produce complement-mediated damage and increase the rate of AChR turnover, both mechanisms causing loss of AChR from the postsynaptic membrane. The thymus gland is involved in many patients, and there are experimental and genetic approaches to understand the failure of immune tolerance to the AChR. In a proportion of those patients without AChR antibodies, antibodies to muscle-specific kinase (MuSK), or related proteins such as agrin and low-density lipoprotein receptor-related protein 4 (LRP4), are present. MuSK antibodies are predominantly IgG4 and cause disassembly of the neuromuscular junction by disrupting the physiological function of MuSK in synapse maintenance and adaptation. Here we discuss how knowledge of neuromuscular junction structure and function has fed into understanding the mechanisms of AChR and MuSK antibodies. Myasthenia gravis remains a paradigm for autoantibody-mediated conditions and these observations show how much there is still to learn about synaptic function and pathological mechanisms. PMID:27408701

  4. Disordered glycometabolism involved in pathogenesis of Kashin–Beck disease, an endemic osteoarthritis in China

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Cuiyan, E-mail: xj.cy.69@stu.xjtu.edu.cn [School of Public Health, Health Science Centre of Xi' an Jiaotong University, No. 76 Yanta West Road, Xi' an, Shaanxi 710061 (China); Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education (China); Key Laboratory of Trace elements and Endemic Diseases, Ministry of Health, Xi' an, Shaanxi 710061 (China); Lei, Ronghui, E-mail: leirh@mail.xjtu.edu.cn [School of Public Health, Health Science Centre of Xi' an Jiaotong University, No. 76 Yanta West Road, Xi' an, Shaanxi 710061 (China); Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education (China); Key Laboratory of Trace elements and Endemic Diseases, Ministry of Health, Xi' an, Shaanxi 710061 (China); Tiainen, Mika, E-mail: mika.tiainen@uef.fi [School of Pharmacy, University of Eastern Finland, Kuopio (Finland); Wu, Shixun, E-mail: wushixun313@stu.xjtu.edu.cn [School of Public Health, Health Science Centre of Xi' an Jiaotong University, No. 76 Yanta West Road, Xi' an, Shaanxi 710061 (China); Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education (China); Key Laboratory of Trace elements and Endemic Diseases, Ministry of Health, Xi' an, Shaanxi 710061 (China); Zhang, Qiang, E-mail: wdrr@163.com [Department of Kashin–Beck Disease, Qinghai Institute for Endemic Disease Control and Prevention, Xining, Qinghai 811602 (China); Pei, Fuxing, E-mail: peifuxing@vip.163.com [Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041 (China); Guo, Xiong, E-mail: guox@mail.xjtu.edu.cn [School of Public Health, Health Science Centre of Xi' an Jiaotong University, No. 76 Yanta West Road, Xi' an, Shaanxi 710061 (China); Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education (China); Key Laboratory of Trace elements and Endemic Diseases, Ministry of Health, Xi' an, Shaanxi 710061 (China)

    2014-08-15

    Kashin–Beck disease (KBD) is a chronic endemic osteoarthritis in China. Previous studies have suggested a role of metabolic dysfunction in causation of this disease. In this investigation, the metabolomics approach and cell experiments were used to discover the metabolic changes and their effects on KBD chondrocytes. Nuclear magnetic resonance ({sup 1}H NMR) spectroscopy was used to examine serum samples from both the KBD patients and normal controls. The pattern recognition multivariate analysis (OSC–PLS) and quantitative analysis (QMTLS iterator) revealed altered glycometabolism in KBD, with increased glucose and decreased lactate and citrate levels. IPA biological analysis showed the centric location of glucose in the metabolic network. Massive glycogen deposits in chondrocytes and increased uptake of glucose by chondrocytes further confirmed disordered glycometabolism in KBD. An in vitro study showed the effects of disordered glycometabolism in chondrocytes. When chondrocytes were treated with high glucose, expression of type II collagen and aggrecan were decreased, while TNF-α expression, the level of cellular reactive oxygen species and cell apoptosis rates all were increased. Therefore, our results demonstrated that disordered glycometabolism in patients with KBD was linked to the damage of chondrocytes. This may provide a new basis for understanding the pathogenesis of KBD. - Highlights: • Disordered glycometabolism in KBD was demonstrated by combining serum metabolomics and chondrocyte studies. • Glucose and TNF-α were key molecules linked to altered metabolism and inflammation in the pathophysiology of KBD. • The glycometabolism disorder was linked to expression of type II collagen and aggrecan, ROS and apoptosis of KBD chondrocytes.

  5. The role of gut microbiota in the pathogenesis of rheumatic diseases.

    Science.gov (United States)

    Zhong, Danli; Wu, Chanyuan; Zeng, Xiaofeng; Wang, Qian

    2018-01-01

    Rheumatic diseases refer to many diseases with a loss of immune self-tolerance, leading to a chronic inflammation, degeneration, or metabolic derangement in multiple organs or tissues. The cause of rheumatic diseases remains to be elucidated, though both environmental and genetic factors are required for the development of rheumatic diseases. Over the past decades, emerging studies suggested that alteration of intestinal microbiota, known as gut dysbiosis, contributed to the occurrence or development of a range of rheumatic diseases, including rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, and Sjogren's syndrome, through profoundly affecting the balance between pro- and anti-inflammatory immune responses. In this article, we discussed the role of gut microbiota in the pathogenesis of rheumatic diseases based on a large number of experimental and clinical materials, thereby providing a new insight for microbiota-targeted therapies to prevent or cure rheumatic diseases.

  6. A review of the role of oxidative stress in the pathogenesis of eye diseases

    Directory of Open Access Journals (Sweden)

    O. A. Oduntan

    2011-12-01

    Full Text Available Free radicals, referred to as oxidants are molecules in the body with unpaired electrons, hence are unstable and ready to bond with other molecules with unpaired electrons.  They include Reactive Oxygen Species (ROS such as superoxide anion radicals (·O¯, hydrogen peroxide (H202, and hydroxyl free radicals (·OH.  Endogenous sources of ROS include metabolic and other organic processes, while exogenous sources include ultraviolet radiation and environmental toxins such as smoke.  Antioxidants (oxidant scavengers such as ascorbate, alpha-tocopherol and glutathione as well as various enzymatic compounds such as superoxide dismutase (SOD, catalase and glutathione reductase are also present in the body and in manyfoods or food supplements.  An imbalance between oxidants and antioxidants in favour of oxidantsis termed oxidative stress and can lead to cell or tissue damage and aging. Oxidative stress has been implicated in the pathogenesis of many serious systemic diseases such as diabetes, cancer and neurological disorders.  Also, laboratory and epidemiological studies have implicated oxidative stress in the pathogenesis of the majority of common serious eye diseases such as cataract, primary open angle glaucoma and age-related macular degeneration. In this article, we reviewed the current information on the roles of oxidative stress in the pathogenesis of various eye diseases and the probable roles of antioxidants.  Eye care practitioners will find this article useful as it provides information on the pathogenesis of common eye diseases. (S Afr Optom 2011 70(4 182-190

  7. Metabolic reprogramming in the pathogenesis of chronic lung diseases including BPD, COPD, and pulmonary fibrosis.

    Science.gov (United States)

    Zhao, Haifeng; Dennery, Phyllis A; Yao, Hongwei

    2018-01-04

    The metabolism of nutrient substrates including glucose, glutamine and fatty acids provides acetyl-CoA for the tricarboxylic acid cycle to generate energy, and metabolites for the biosynthesis of biomolecules including nucleotides, proteins, and lipids. It has been shown that metabolism of glucose, fatty acid, and glutamine plays important roles in modulating cellular proliferation, differentiation, apoptosis, autophagy, senescence, and inflammatory responses. All these cellular processes contribute to the pathogenesis of chronic lung diseases, including bronchopulmonary dysplasia, chronic obstructive pulmonary disease, and pulmonary fibrosis. Recent studies demonstrate that metabolic reprogramming occurs in patients with and animal models of chronic lung diseases, suggesting that metabolic dysregulation may participate in the pathogenesis and progression of these diseases. In this review, we briefly discuss the catabolic pathways for glucose, glutamine and fatty acids, and focus on how metabolic reprogramming of these pathways impacts cellular functions and leads to the development of these chronic lung diseases. We also highlight how targeting metabolic pathways can be utilized in the prevention and treatment of these diseases.

  8. Understanding mechanisms and the role of differentiation in pathogenesis of Toxoplasma gondii: a review

    Directory of Open Access Journals (Sweden)

    William J Sullivan Jr

    2009-03-01

    Full Text Available Parasite differentiation from proliferating tachyzoites into latent bradyzoites is central to pathogenesis and transmission of the intracellular protozoan pathogen Toxoplasma gondii. The presence of bradyzoite-containing cysts in human hosts and their subsequent rupture can cause life-threatening recrudescence of acute infection in the immunocompromised and cyst formation in other animals contributes to zoonotic transmission and widespread dissemination of the parasite. In this review, we discuss the evidence showing how the clinically relevant process of bradyzoite differentiation is regulated at both transcriptional and post-transcriptional levels. Specific regulatory factors implicated in modulating bradyzoite differentiation include promoter-based cis-elements, epigenetic modifications and protein translation control through eukaryotic initiation factor -2 (eIF2. In addition to a summary of the current state of knowledge in these areas we discuss the pharmacological ramifications and pose some questions for future research.

  9. Latest developments in our understanding of the pathogenesis of mesothelioma and the design of targeted therapies.

    Science.gov (United States)

    Bononi, Angela; Napolitano, Andrea; Pass, Harvey I; Yang, Haining; Carbone, Michele

    2015-10-01

    Malignant mesothelioma is an aggressive cancer whose pathogenesis is causally linked to occupational exposure to asbestos. Familial clusters of mesotheliomas have been observed in settings of genetic predisposition. Mesothelioma incidence is anticipated to increase worldwide in the next two decades. Novel treatments are needed, as current treatment modalities may improve the quality of life, but have shown modest effects in improving overall survival. Increasing knowledge on the molecular characteristics of mesothelioma has led to the development of novel potential therapeutic strategies, including: molecular targeted approaches, that is the inhibition of vascular endothelial growth factor with bevacizumab; immunotherapy with chimeric monoclonal antibody, immunotoxin, antibody drug conjugate, vaccine and viruses; inhibition of asbestos-induced inflammation, that is aspirin inhibition of HMGB1 activity may decrease or delay mesothelioma onset and/or growth. We elaborate on the rationale behind new therapeutic strategies, and summarize available preclinical and clinical results, as well as efforts still ongoing.

  10. Circulating microbial products and acute phase proteins as markers of pathogenesis in lymphatic filarial disease.

    Directory of Open Access Journals (Sweden)

    R Anuradha

    Full Text Available Lymphatic filariasis can be associated with development of serious pathology in the form of lymphedema, hydrocele, and elephantiasis in a subset of infected patients. Dysregulated host inflammatory responses leading to systemic immune activation are thought to play a central role in filarial disease pathogenesis. We measured the plasma levels of microbial translocation markers, acute phase proteins, and inflammatory cytokines in individuals with chronic filarial pathology with (CP Ag+ or without (CP Ag- active infection; with clinically asymptomatic infections (INF; and in those without infection (endemic normal [EN]. Comparisons between the two actively infected groups (CP Ag+ compared to INF and those without active infection (CP Ag- compared to EN were used preliminarily to identify markers of pathogenesis. Thereafter, we tested for group effects among all the four groups using linear models on the log transformed responses of the markers. Our data suggest that circulating levels of microbial translocation products (lipopolysaccharide and LPS-binding protein, acute phase proteins (haptoglobin and serum amyloid protein-A, and inflammatory cytokines (IL-1β, IL-12, and TNF-α are associated with pathogenesis of disease in lymphatic filarial infection and implicate an important role for circulating microbial products and acute phase proteins.

  11. Online testable concept maps: benefits for learning about the pathogenesis of disease.

    Science.gov (United States)

    Ho, Veronica; Kumar, Rakesh K; Velan, Gary

    2014-07-01

    Concept maps have been used to promote meaningful learning and critical thinking. Although these are crucially important in all disciplines, evidence for the benefits of concept mapping for learning in medicine is limited. We performed a randomised crossover study to assess the benefits of online testable concept maps for learning in pathology by volunteer junior medical students. Participants (n = 65) were randomly allocated to either of two groups with equivalent mean prior academic performance, in which they were given access to either online maps or existing online resources for a 2-week block on renal disease. Groups then crossed over for a 2-week block on hepatic disease. Outcomes were assessed using timed online quizzes, which included questions unrelated to topics in the pathogenesis maps as an internal control. Questionnaires were administered to evaluate students' acceptance of the maps. In both blocks, the group with access to pathogenesis maps achieved significantly higher average scores than the control group on quiz questions related to topics covered by the maps (Block 1: p online testable pathogenesis maps are well accepted and can improve learning of concepts in pathology by medical students. © 2014 John Wiley & Sons Ltd.

  12. Novel players in coeliac disease pathogenesis: role of the gut microbiota

    Science.gov (United States)

    Verdu, Elena F.; Galipeau, Heather J.; Jabri, Bana

    2016-01-01

    Several studies point towards alteration in gut microbiota composition and function in coeliac disease, some of which can precede the onset of disease and/or persist when patients are on a gluten-free diet. Evidence also exists that the gut microbiota might promote or reduce coeliac-disease-associated immunopathology. However, additional studies are required in humans and in mice (using gnotobiotic technology) to determine cause–effect relationships and to identify agents for modulating the gut microbiota as a therapeutic or preventative approach for coeliac disease. In this Review, we summarize the current evidence for altered gut microbiota composition in coeliac disease and discuss how the interplay between host genetics, environmental factors and the intestinal microbiota might contribute to its pathogenesis. Moreover, we highlight the importance of utilizing animal models and long-term clinical studies to gain insight into the mechanisms through which host–microbial interactions can influence host responses to gluten. PMID:26055247

  13. Multi-platform ’Omics Analysis of Human Ebola Virus Disease Pathogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Eisfeld, Amie J.; Halfmann, Peter J.; Wendler, Jason P.; Kyle, Jennifer E.; Burnum-Johnson, Kristin E.; Peralta, Zuleyma; Maemura, Tadashi; Walters, Kevin B.; Watanabe, Tokiko; Fukuyama, Satoshi; Yamashita, Makoto; Jacobs, Jon M.; Kim, Young-Mo; Casey, Cameron P.; Stratton, Kelly G.; Webb-Robertson, Bobbie-Jo M.; Gritsenko, Marina A.; Monroe, Matthew E.; Weitz, Karl K.; Shukla, Anil K.; Tian, Mingyuan; Neumann, Gabriele; Reed, Jennifer L.; van Bakel, Harm; Metz, Thomas O.; Smith, Richard D.; Waters, Katrina M.; N' jai, Alhaji; Sahr, Foday; Kawaoka, Yoshihiro

    2017-12-01

    The pathogenesis of human Ebola virus disease (EVD) is complex. EVD is characterized by high levels of virus replication and dissemination, dysregulated immune responses, extensive virus- and host-mediated tissue damage, and disordered coagulation. To clarify how host responses contribute to EVD pathophysiology, we performed multi-platform ’omics analysis of peripheral blood mononuclear cells and plasma from EVD patients. Our results indicate that EVD molecular signatures overlap with those of sepsis, imply that pancreatic enzymes contribute to tissue damage in fatal EVD, and suggest that Ebola virus infection may induce aberrant neutrophils whose activity could explain hallmarks of fatal EVD. Moreover, integrated biomarker prediction identified putative biomarkers from different data platforms that differentiated survivors and fatalities early after infection. This work reveals insight into EVD pathogenesis, suggests an effective approach for biomarker identification, and provides an important community resource for further analysis of human EVD severity.

  14. A tale of two maladies? Pathogenesis of depression with and without the Huntington’s disease gene mutation

    Directory of Open Access Journals (Sweden)

    Xin eDu

    2013-07-01

    Full Text Available Huntington’s disease (HD is an autosomal dominant disorder caused by a tandem repeat expansion encoding an expanded tract of glutamines in the huntingtin protein. HD is progressive and manifests as psychiatric symptoms (including depression, cognitive deficits (culminating in dementia and motor abnormalities (including chorea. Having reached the 20th anniversary of the discovery of the ‘genetic stutter’ which causes HD, we still lack sophisticated insight into why so many HD patients exhibit affective disorders such as depression at very early stages, prior to overt appearance of motor deficits. In this review, we will focus on depression as the major psychiatric manifestation of HD, discuss potential mechanisms of pathogenesis identified from animal models, and compare depression in HD patients with that of the wider gene-negative population. The discovery of depressive-like behaviours as well as cellular and molecular correlates of depression in transgenic HD mice has added strong support to the hypothesis that the HD mutation adds significantly to the genetic load for depression. A key question is whether HD-associated depression differs from that in the general population. Whilst preclinical studies, clinical data and treatment responses suggest striking similarities, there are also some apparent differences. We discuss various molecular and cellular mechanisms which may contribute to depression in HD, and whether they may generalise to other depressive disorders. The autosomal dominant nature of HD and the existence of models with excellent construct validity provide a unique opportunity to understand the pathogenesis of depression and associated gene-environment interactions. Thus, understanding the pathogenesis of depression in HD may not only facilitate tailored therapeutic approaches for HD sufferers, but may also translate to the clinical depression which devastates the lives of so many people.

  15. Historical aspects of studies on roles of the inflammasome in the pathogenesis of periodontal diseases.

    Science.gov (United States)

    Shibata, K

    2018-01-23

    The proinflammatory cytokine interleukin-1β (IL-1β) is produced as inactive proIL-1β and then processed by caspase-1 to become active. In 2002, it was demonstrated that the intracellular multiprotein complex known as the inflammasome functions as a molecular platform to trigger activation of caspase-1. Inflammasomes are known to function as intracellular sensors for a broad spectrum of various pathogen-associated and damage-associated molecular patterns. In 1985, it was demonstrated that Porphyromonas gingivalis, a representative bacterium causing chronic periodontitis, induces IL-1 production by murine peritoneal macrophages. Since then, many studies have suggested that IL-1, particularly IL-1β plays key roles in the pathogenesis of periodontal diseases. However, the term "inflammasome" was not used until the involvement of inflammasomes in periodontal disease was suggested in 2009. Several subsequent studies on the roles of the inflammasome in the pathogenesis of periodontal diseases have been published. Interestingly, two contradictory reports on the modulation of inflammasomes by P. gingivalis have been published. Some papers have described how P. gingivalis activates the inflammasome to produce IL-1β whereas some stated that P. gingivalis inhibits inflammasome activation to subvert immune responses. Several lines of evidence have suggested that the inflammasome activation is modulated by periodontopathic bacteria other than P. gingivalis. Hence, studies on the roles of inflammasomes in the pathogenesis of periodontal diseases began only 8 years ago and many pathological roles of inflammasomes remain to be clarified. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Roles of abnormal lipid metabolism in pathogenesis of non-alcoholic fatty liver disease

    Directory of Open Access Journals (Sweden)

    LU Ran

    2015-07-01

    Full Text Available The prevalence of non-alcoholic fatty liver disease (NAFLD keeps rising worldwide along with the increasing prevalence of metabolic diseases such as obesity, type 2 diabetes, and dyslipidemia. Although most NAFLD patients present with simple steatosis of hepatocytes, some patients progress to non-alcoholic steatohepatitis, liver cirrhosis, and even cancer. In the Western world, NAFLD is the most common cause of elevated liver enzymes, and hence there has been a growing interest in this disease. Given that fat deposition in the liver is the hallmark of NAFLD, we review the roles and the underlying mechanism of disturbed lipid metabolism in the development of NAFLD and suggest that more insights into the pathogenesis of NAFLD will help develop targeted strategies for the prevention and treatment of this disease.

  17. Intestinal Microbiota and the Innate Immune System – A Crosstalk in Crohn’s Disease Pathogenesis

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    Haag, Lea-Maxie; Siegmund, Britta

    2015-01-01

    Crohn’s disease (CD) is a chronic, relapsing inflammatory disorder that can occur anywhere along the gastrointestinal tract. The precise etiology of CD is still unclear but it is widely accepted that a complex series of interactions between susceptibility genes, the immune system and environmental factors are implicated in the onset and perpetuation of the disease. Increasing evidence from experimental and clinical studies implies the intestinal microbiota in disease pathogenesis, thereby supporting the hypothesis that chronic intestinal inflammation arises from an abnormal immune response against the microorganisms of the intestinal flora in genetically susceptible individuals. Given that CD patients display changes in their gut microbiota composition, collectively termed “dysbiosis,” the question raises whether the altered microbiota composition is a cause of disease or rather a consequence of the inflammatory state of the intestinal environment. This review will focus on the crosstalk between the gut microbiota and the innate immune system during intestinal inflammation, thereby unraveling the role of the microbiota in CD pathogenesis. PMID:26441993

  18. Microbial Sensing by the Intestinal Epithelium in the Pathogenesis of Inflammatory Bowel Disease

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    Michael Scharl

    2010-01-01

    Full Text Available Recent years have raised evidence that the intestinal microbiota plays a crucial role in the pathogenesis of chronic inflammatory bowels diseases. This evidence comes from several observations. First, animals raised under germ-free conditions do not develop intestinal inflammation in several different model systems. Second, antibiotics are able to modulate the course of experimental colitis. Third, genetic polymorphisms in a variety of genes of the innate immune system have been associated with chronic intestinal inflammatory diseases. Dysfunction of these molecules results in an inappropriate response to bacterial and antigenic stimulation of the innate immune system in the gastrointestinal tract. Variants of pattern recognition receptors such as NOD2 or TLRs by which commensal and pathogenic bacteria can be detected have been shown to be involved in the pathogenesis of IBD. But not only pathways of microbial detection but also intracellular ways of bacterial processing such as autophagosome function are associated with the risk to develop Crohn's disease. Thus, the “environment concept” and the “genetic concept” of inflammatory bowel disease pathophysiology are converging via the intestinal microbiota and the recognition mechanisms for an invasion of members of the microbiota into the mucosa.

  19. Role of gut microbiota and nutrients in amyloid formation and pathogenesis of Alzheimer disease.

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    Pistollato, Francesca; Sumalla Cano, Sandra; Elio, Iñaki; Masias Vergara, Manuel; Giampieri, Francesca; Battino, Maurizio

    2016-10-01

    It has been hypothesized that alterations in the composition of the gut microbiota might be associated with the onset of certain human pathologies, such as Alzheimer disease, a neurodegenerative syndrome associated with cerebral accumulation of amyloid-β fibrils. It has been shown that bacteria populating the gut microbiota can release significant amounts of amyloids and lipopolysaccharides, which might play a role in the modulation of signaling pathways and the production of proinflammatory cytokines related to the pathogenesis of Alzheimer disease. Additionally, nutrients have been shown to affect the composition of the gut microbiota as well as the formation and aggregation of cerebral amyloid-β. This suggests that modulating the gut microbiome and amyloidogenesis through specific nutritional interventions might prove to be an effective strategy to prevent or reduce the risk of Alzheimer disease. This review examines the possible role of the gut in the dissemination of amyloids, the role of the gut microbiota in the regulation of the gut-brain axis, the potential amyloidogenic properties of gut bacteria, and the possible impact of nutrients on modulation of microbiota composition and amyloid formation in relation to the pathogenesis of Alzheimer disease. © The Author(s) 2016. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  20. Understanding Neurological Disease Mechanisms in the Era of Epigenetics

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    Qureshi, Irfan A.; Mehler, Mark F.

    2015-01-01

    The burgeoning field of epigenetics is making a significant impact on our understanding of brain evolution, development, and function. In fact, it is now clear that epigenetic mechanisms promote seminal neurobiological processes, ranging from neural stem cell maintenance and differentiation to learning and memory. At the molecular level, epigenetic mechanisms regulate the structure and activity of the genome in response to intracellular and environmental cues, including the deployment of cell type–specific gene networks and those underlying synaptic plasticity. Pharmacological and genetic manipulation of epigenetic factors can, in turn, induce remarkable changes in neural cell identity and cognitive and behavioral phenotypes. Not surprisingly, it is also becoming apparent that epigenetics is intimately involved in neurological disease pathogenesis. Herein, we highlight emerging paradigms for linking epigenetic machinery and processes with neurological disease states, including how (1) mutations in genes encoding epigenetic factors cause disease, (2) genetic variation in genes encoding epigenetic factors modify disease risk, (3) abnormalities in epigenetic factor expression, localization, or function are involved in disease pathophysiology, (4) epigenetic mechanisms regulate disease-associated genomic loci, gene products, and cellular pathways, and (5) differential epigenetic profiles are present in patient-derived central and peripheral tissues. PMID:23571666

  1. Amyloid-β diurnal pattern: possible role of sleep in Alzheimer's disease pathogenesis.

    Science.gov (United States)

    Lucey, Brendan P; Bateman, Randall J

    2014-09-01

    Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline that is a growing public health crisis with a prevalence projected to more than double in the next 20 years. Sleep is frequently impaired in individuals with AD. Further, recent studies have linked numerous age-related sleep disturbances such as poor sleep efficiency and sleep apnea, to future risk of cognitive impairment. Aggregation of amyloid-β (Aβ) into extracellular plaques in the brain is a key step in AD pathogenesis and likely begins 20 years before the onset of dementia. Aβ concentrations in both humans and mouse models show Aβ concentrations rise during wakefulness and fall during sleep, that is, an Aβ diurnal pattern. There is evidence in animal models that changes in sleep time alter Aβ deposition, suggesting that sleep may play a role in AD pathogenesis. A hypothetical model for the role of sleep and the Aβ diurnal pattern in AD pathogenesis is proposed. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Inclusion-body myositis, a multifactorial muscle disease associated with aging: current concepts of pathogenesis.

    Science.gov (United States)

    Askanas, Valerie; Engel, W King

    2007-11-01

    Sporadic inclusion-body myositis, the most common muscle disease of older persons, has no known cause or persistently beneficial treatment. The unfolding pathogenesis could lead to new treatment strategies and it is now of growing interest among clinicians and basic scientists. About 100 papers related to the subject were published in 2006 and the first part of 2007 (we cite only articles most relevant to this review). This review focuses on the current concepts of the pathogenesis of sporadic inclusion-body myositis. Both degeneration and mononuclear-cell inflammation are components of the pathology, but how each relates to the pathogenesis remains unclear. We suggest that an intramuscle fiber degenerative component is primary, leading to muscle-fiber destruction, while the lymphocytic inflammatory component may only slightly contribute to sporadic inclusion-body myositis muscle-fiber damage. Intracellular accumulation of amyloid-beta precursor protein, amyloid-beta, and amyloid-beta oligomers in an aging muscle-fiber cellular milieu, and other abnormalities, appear to be key pathogenic factors. We summarize intracellular molecular events and their consequences, and correlate findings in sporadic inclusion-body myositis muscle biopsies with inclusion-body myositis experimental models in tissue culture and in transgenic mice. Treatment of sporadic inclusion-body myositis remains a challenge. Antiinflammatory approaches used so far are without major or enduring benefit. Possible new treatment avenues are suggested.

  3. Liver mitochondrial dysfunction and oxidative stress in the pathogenesis of experimental nonalcoholic fatty liver disease

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    Oliveira C.P.M.S.

    2006-01-01

    Full Text Available Oxidative stress and hepatic mitochondria play a role in the pathogenesis of nonalcoholic fatty liver disease. The aim of the present study was to evaluate the role of hepatic mitochondrial dysfunction and oxidative stress in the pathogenesis of the disease. Fatty liver was induced in Wistar rats with a choline-deficient diet (CD; N = 7 or a high-fat diet enriched with PUFAs-omega-3 (H; N = 7 for 4 weeks. The control group (N = 7 was fed a standard diet. Liver mitochondrial oxidation and phosphorylation were measured polarographically and oxidative stress was estimated on the basis of malondialdehyde and glutathione concentrations. Moderate macrovacuolar liver steatosis was observed in the CD group and mild liver steatosis was observed in the periportal area in the H group. There was an increase in the oxygen consumption rate by liver mitochondria in respiratory state 4 (S4 and a decrease in respiratory control rate (RCR in the CD group (S4: 32.70 ± 3.35; RCR: 2.55 ± 0.15 ng atoms of O2 min-1 mg protein-1 when compared to the H and control groups (S4: 23.09 ± 1.53, 17.04 ± 2.03, RCR: 3.15 ± 0.15, 3.68 ± 0.15 ng atoms of O2 min-1 mg protein-1, respectively, P < 0.05. Hepatic lipoperoxide concentrations were significantly increased and the concentration of reduced glutathione was significantly reduced in the CD group. A choline-deficient diet causes moderate steatosis with disruption of liver mitochondrial function and increased oxidative stress. These data suggest that lipid peroxidation products can impair the flow of electrons along the respiratory chain, causing overreduction of respiratory chain components and enhanced mitochondrial reactive oxygen species. These findings are important in the pathogenesis of nonalcoholic fatty liver disease.

  4. The Gut-Associated Lymphoid Tissues in the Small Intestine, Not the Large Intestine, Play a Major Role in Oral Prion Disease Pathogenesis.

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    Donaldson, David S; Else, Kathryn J; Mabbott, Neil A

    2015-09-01

    Prion diseases are infectious neurodegenerative disorders characterized by accumulations of abnormally folded cellular prion protein in affected tissues. Many natural prion diseases are acquired orally, and following exposure, the early replication of some prion isolates upon follicular dendritic cells (FDC) within gut-associated lymphoid tissues (GALT) is important for the efficient spread of disease to the brain (neuroinvasion). Prion detection within large intestinal GALT biopsy specimens has been used to estimate human and animal disease prevalence. However, the relative contributions of the small and large intestinal GALT to oral prion pathogenesis were unknown. To address this issue, we created mice that specifically lacked FDC-containing GALT only in the small intestine. Our data show that oral prion disease susceptibility was dramatically reduced in mice lacking small intestinal GALT. Although these mice had FDC-containing GALT throughout their large intestines, these tissues were not early sites of prion accumulation or neuroinvasion. We also determined whether pathology specifically within the large intestine might influence prion pathogenesis. Congruent infection with the nematode parasite Trichuris muris in the large intestine around the time of oral prion exposure did not affect disease pathogenesis. Together, these data demonstrate that the small intestinal GALT are the major early sites of prion accumulation and neuroinvasion after oral exposure. This has important implications for our understanding of the factors that influence the risk of infection and the preclinical diagnosis of disease. Many natural prion diseases are acquired orally. After exposure, the accumulation of some prion diseases in the gut-associated lymphoid tissues (GALT) is important for efficient spread of disease to the brain. However, the relative contributions of GALT in the small and large intestines to oral prion pathogenesis were unknown. We show that the small intestinal

  5. THE CONCEPT OF BARRIER ORGAN DISEASE IN THE PATHOGENESIS OF SPONDYLOARTHRITIS

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    E. A. Galushko

    2016-01-01

    Full Text Available There have been now prerequisites for changing the scientific view of the etiology and pathogenesis of spondyloarthritis (SpA. An important role is assigned to the dysfunction and disintegration of the so-called barrier organs that make protection of man between his internal milieu and the environment. An update on cellular and molecular mechanisms in the pathogenesis of SpA permits rheumatologists to offer a hypothesis of the concept of barrier organ disease as a preclinical stage of the diseases included in the SpA group. There is reason to think that this process involves individual genetic and immune factors leading to damage of the superficial epithelium of the mucosal membranes and epidermis that serves as the first protective barrier for innate immunity and is in contact with huge numbers of microorganisms (a microbiome and with the pathogen-associated molecular patterns. The microbiome may affect the preclinical phase of the disease in several ways, including those to change the composition of the microflora (dysbiosis and to act as targets for immunological dysregulation. 

  6. The role of interleukin 16 in the pathogenesis of selected skin diseases

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    Dorota Purzycka-Bohdan

    2014-03-01

    Full Text Available Interleukin-16 (IL-16 is a proinflammatory cytokine with a pleiotropic impact on cells of the immune system. Based on its biological properties including activation of CD4+ T cell migration and proliferation and also stimulation of proinflammatory cytokine synthesis, it could be postulated that IL-16 may play an important role in the pathogenesis of many diseases associated with immunological disturbances. Interleukin-16 acts as a chemoattractant not only for T CD4+ lymphocytes, but also for other cells, which have specific receptors on their surface. Moreover, IL-16 acts as a cell cycle regulator. This cytokine is produced by cells of the immune system, i.e. T CD4+ and T CD8+ lymphocytes, eosinophils, mast cells, dendritic cells and also fibroblasts and epithelial cells. The mechanism of action of IL-16 may suggest its significant role in the pathogenesis of skin disorders associated with an inflammatory reaction and infiltration composed of T CD4+ lymphocytes. Both this interleukin and anti-IL-16 antibodies may be useful in diagnosis and therapy of many skin diseases. Further detailed studies on the release of IL-16 and its biological functions are needed to reveal the role of this cytokine in the complex immunological process. The aim of this article is a current literature review of the relationship between IL-16 and the development of selected skin diseases: atopic dermatitis, systemic lupus erythematosus, bullous pemphigoid, cutaneous T-cell lymphomas and psoriasis.

  7. [Role of the endocrine system in the pathogenesis of non-alcoholic fatty liver disease].

    Science.gov (United States)

    Hagymási, Krisztina; Reismann, Péter; Rácz, Károly; Tulassay, Zsolt

    2009-11-29

    The most frequent liver disorder in metabolic syndrome is the nonalcoholic fatty liver disease. Its pathogenesis is a complex, multifactorial process, characterized by insulin resistance and involvement of the endocrine system. Hypothyroidism may lead to nonalcoholic steatohepatitis via hyperlipidemia and obesity. Adult patients with growth hormone deficiency have a metabolic syndrome-like phenotype with obesity and many characteristic metabolic alterations. The chronic activation of the hypothalamic-pituitary-adrenal axis results in metabolic syndrome as well. Cushing's syndrome has also features of metabolic syndrome. Mild elevation of transaminase activities is commonly seen in patients with adrenal failure. Non-alcoholic steatosis is twice as common in postmenopusal as in premenopausal women and hormonal replacement therapy decreases the risk of steatosis. Insulin resistance, diabetes mellitus type 2, sleeping apnoe syndrome, cardiovascular disorders and non-alcoholic fatty liver disease are more frequent in polycystic ovary syndrome. Hypoandrogenism in males and hyperandrogenism in females may lead to fatty liver via obesity and insulin resistance. Adipokines (leptin, acylation stimulating protein, adiponectin) have a potential role in the pathogenesis of nonalcoholic fatty liver. The alterations of endocrine system must be considered in the background of cryptogenic liver diseases. The endocrine perspective may help the therapeutic approaches in the future.

  8. Research progress on the pathogenesis of rapid eye movement sleep behavior disorder and neurodegenerative diseases

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    Hai-yang JIANG

    2017-10-01

    Full Text Available Rapid eye movement sleep behavior disorder (RBD is a sleep disorder characterized by the disappearance of muscle relaxation and enacting one's dreams during rapid eye movement (REM, with most of the dreams being violent or aggressive. Prevalence of RBD, based on population, is 0.38%-2.01%, but it becomes much higher in patients with neurodegenerative diseases, especially α - synucleinopathies. RBD may herald the emergence of α-synucleinopathies by decades, thus it may be used as an effective early marker of neurodegenerative diseases. In this review, we summarized the progress on the pathogenesis of RBD and its relationship with neurodegenerative diseases. DOI: 10.3969/j.issn.1672-6731.2017.10.003

  9. Pathogenesis, Molecular Genetics, and Genomics of Mycobacterium avium subsp. paratuberculosis, the Etiologic Agent of Johne’s Disease

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    Govardhan Rathnaiah

    2017-11-01

    Full Text Available Mycobacterium avium subsp. paratuberculosis (MAP is the etiologic agent of Johne’s disease in ruminants causing chronic diarrhea, malnutrition, and muscular wasting. Neonates and young animals are infected primarily by the fecal–oral route. MAP attaches to, translocates via the intestinal mucosa, and is phagocytosed by macrophages. The ensuing host cellular immune response leads to granulomatous enteritis characterized by a thick and corrugated intestinal wall. We review various tissue culture systems, ileal loops, and mice, goats, and cattle used to study MAP pathogenesis. MAP can be detected in clinical samples by microscopy, culturing, PCR, and an enzyme-linked immunosorbent assay. There are commercial vaccines that reduce clinical disease and shedding, unfortunately, their efficacies are limited and may not engender long-term protective immunity. Moreover, the potential linkage with Crohn’s disease and other human diseases makes MAP a concern as a zoonotic pathogen. Potential therapies with anti-mycobacterial agents are also discussed. The completion of the MAP K-10 genome sequence has greatly improved our understanding of MAP pathogenesis. The analysis of this sequence has identified a wide range of gene functions involved in virulence, lipid metabolism, transcriptional regulation, and main metabolic pathways. We also review the transposons utilized to generate random transposon mutant libraries and the recent advances in the post-genomic era. This includes the generation and characterization of allelic exchange mutants, transcriptomic analysis, transposon mutant banks analysis, new efforts to generate comprehensive mutant libraries, and the application of transposon site hybridization mutagenesis and transposon sequencing for global analysis of the MAP genome. Further analysis of candidate vaccine strains development is also provided with critical discussions on their benefits and shortcomings, and strategies to develop a highly

  10. MicroRNAs in inflammatory bowel disease - pathogenesis, diagnostics and therapeutics

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    Coskun, Mehmet; Bjerrum, Jacob Tveiten; Seidelin, Jakob Benedict; Nielsen, Ole Haagen

    2012-01-01

    The pathogenesis of inflammatory bowel disease (IBD) is complex and largely unknown. Until recently, research has focused on the study of protein regulators in inflammation to reveal the cellular and molecular networks in the pathogenesis of IBD. However, in the last few years, new and promising insights have been generated from studies describing an association between an altered expression of a specific class of non-coding RNAs, called microRNAs (miRs or miRNAs) and IBD. The short (approximately 22 nucleotides), endogenous, single-stranded RNAs are evolutionary conserved in animals and plants, and regulate specific target mRNAs at the post-transcriptional level. MiRNAs are involved in several biological processes, including development, cell differentiation, proliferation and apoptosis. Furthermore, it is estimated that miRNAs may be responsible for regulating the expression of nearly one-third of the genes in the human genome. Thus, miRNA deregulation often results in an impaired cellular function, and a disturbance of downstream gene regulation and signaling cascades, suggesting their implication in disease etiology. Despite the identification of more than 1900 mature human miRNAs, very little is known about their biological functions and functional targets. Recent studies have identified dysregulated miRNAs in tissue samples of IBD patients and have demonstrated similar differences in circulating miRNAs in the serum of IBD patients. Thus, there is great promise that miRNAs will aid in the early diagnosis of IBD, and in the development of personalized therapies. Here, we provide a short review of the current state-of-the-art of miRNAs in IBD pathogenesis, diagnostics and therapeutics. PMID:23002331

  11. Advances in our understanding of the pathogenesis of hemolytic uremic syndromes.

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    Bowen, E E; Coward, R J

    2018-03-01

    Hemolytic uremic syndrome (HUS) is major global health care issue as it is the leading cause of acute kidney injury in children. It is a triad of acute kidney injury, microangiopathic hemolytic anemia, and thrombocytopenia. In recent years, major advances in our understanding of complement-driven inherited rare forms of HUS have been achieved. However, in children 90% of cases of HUS are associated with a Shiga toxin-producing enteric pathogen. The precise pathological mechanisms in this setting are yet to be elucidated. The purpose of this review is to discuss advances in our understanding of the pathophysiology underlying HUS and identify the key questions yet to be answered by the scientific community.

  12. The role of human endogenous retroviruses in the pathogenesis of autoimmune diseases.

    Science.gov (United States)

    Brodziak, Andrzej; Ziółko, Ewa; Muc-Wierzgoń, Małgorzata; Nowakowska-Zajdel, Ewa; Kokot, Teresa; Klakla, Katarzyna

    2012-06-01

    This paper presents a new, recently formulated theory, which concerns the etiopathological process of autoimmune diseases. This theory takes into account the existence in the human genome, since approximately 40 million years, of so-called human endogenous retroviruses (HERVs), which are transmitted to descendants "vertically" by the germ cells. It was recently established that these generally silent sequences perform some physiological roles, but occasionally become active and influence the development of some chronic diseases like diabetes, some neoplasms, chronic diseases of the nervous system (eg, sclerosis multiplex), schizophrenia and autoimmune diseases. We present a short synopsis of immunological processes involved in the pathogenesis of autoimmune diseases, such as molecular mimicry, epitope spreading and activation of the superantigen. We then focus on experimental findings related to systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome and some diseases of hepar and otorhinal tissues. We conclude the outline of this new model of the development of chronic diseases and indicate the conclusions important for the teaching of the basis of pathology.

  13. Human Hemorrhagic Fever Causing Arenaviruses: Molecular Mechanisms Contributing to Virus Virulence and Disease Pathogenesis

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    Junjie Shao

    2015-05-01

    Full Text Available Arenaviruses include multiple human pathogens ranging from the low-risk lymphocytic choriomeningitis virus (LCMV to highly virulent hemorrhagic fever (HF causing viruses such as Lassa (LASV, Junin (JUNV, Machupo (MACV, Lujo (LUJV, Sabia (SABV, Guanarito (GTOV, and Chapare (CHPV, for which there are limited preventative and therapeutic measures. Why some arenaviruses can cause virulent human infections while others cannot, even though they are isolated from the same rodent hosts, is an enigma. Recent studies have revealed several potential pathogenic mechanisms of arenaviruses, including factors that increase viral replication capacity and suppress host innate immunity, which leads to high viremia and generalized immune suppression as the hallmarks of severe and lethal arenaviral HF diseases. This review summarizes current knowledge of the roles of each of the four viral proteins and some known cellular factors in the pathogenesis of arenaviral HF as well as of some human primary cell-culture and animal models that lend themselves to studying arenavirus-induced HF disease pathogenesis. Knowledge gained from these studies can be applied towards the development of novel therapeutics and vaccines against these deadly human pathogens.

  14. Towards Better Understanding of the Pathogenesis of Neuronal Respiratory Network in Sudden Perinatal Death

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    Riffat Mehboob

    2017-07-01

    Full Text Available Sudden perinatal death that includes the victims of sudden infant death syndrome, sudden intrauterine death syndrome, and stillbirth are heartbreaking events in the life of parents. Most of the studies about sudden perinatal death were reported from Italy, highlighting two main etiological factors: prone sleeping position and smoking. Other probable contributory factors are prematurity, male gender, lack of breastfeeding, respiratory tract infections, use of pacifiers, infant botulism, extensive use of pesticides and insecticides, etc. However, extensive studies across the world are required to establish the role of these factors in a different subset of populations. Previous studies confirmed the widely accepted hypothesis that neuropathology of the brainstem is one of the main cause of sudden perinatal death. This study is an effort to summarize the neuropathological evaluation of the brainstems and their association to sudden perinatal death. Brainstem nuclei in vulnerable infants undergo certain changes that may alter the sleep arousal cycle, cardiorespiratory control, and ultimately culminate in death. This review focuses on the roles of different brainstem nuclei, their pathologies, and the established facts in this regard in terms of it’s link to such deaths. This study will also help to understand the role of brainstem nuclei in controlling the cardiorespiratory cycles in sudden perinatal death and may provide a better understanding to resolve the mystery of these deaths in future. It is also found that a global initiative to deal with perinatal death is required to facilitate the diagnosis and prevention in developed and as well as developing countries.

  15. Porphyromonas gingivalis mediated periodontal disease and atherosclerosis: disparate diseases with commonalities in pathogenesis through TLRs.

    Science.gov (United States)

    Gibson, Frank C; Genco, Caroline A

    2007-01-01

    Toll-like receptors (TLRs) are a group of pathogen-associated molecular pattern receptors, which play an important role in innate immune signaling in response to microbial infection. It has been demonstrated that TLRs are differentially up regulated in response to microbial infection and chronic inflammatory diseases such as atherosclerosis. Furthermore hyperlipidemic mice deficient in TLR2, TLR4, and MyD88 signaling exhibit diminished inflammatory responses and decreased atherosclerosis. Accumulating evidence has implicated specific infectious agents including the periodontal disease pathogen Porphyromonas gingivalis in the progression of atherosclerosis. Evidence in humans suggesting that periodontal infection predisposes to atherosclerosis is derived from studies demonstrating that the periodontal pathogen P. gingivalis resides in the wall of atherosclerotic vessels and seroepidemiological studies demonstrating an association between pathogen-specific IgG antibodies and atherosclerosis. We have established that the inflammatory signaling pathways that P. gingivalis utilizes is dependent on the cell type and this specificity clearly influences innate immune signaling in the context of local and distant chronic inflammation induced by this pathogen. We have demonstrated that P. gingivalis requires TLR2 to induce oral inflammatory bone lose in mice. Furthermore, we have demonstrated that P. gingivalis infection accelerates atherosclerosis in hyperlipidemic mice with an associated increase in expression of TLR2 and TLR4 in atherosclerotic lesions. Our recent work with P. gingivalis has demonstrated the effectiveness of specific intervention strategies (immunization) in the prevention of pathogen-accelerated atherosclerosis. Improved understanding of the mechanisms driving infection, and chronic inflammation during atherosclerosis may ultimately provide new targets for therapy.

  16. PERIODONTAL DISEASE AND BONE PATHOGENESIS: THE CROSSTALK BETWEEN CYTOKINES AND PORPHYROMONAS GINGIVALIS.

    Science.gov (United States)

    Ballini, A; Cantore, S; Farronato, D; Cirulli, N; Inchingolo, F; Papa, F; Malcangi, G; Inchingolo, A D; Dipalma, G; Sardaro, N; Lippolis, R; Santacroce, L; Coscia, M F; Pettini, F; De Vito, D; Scacco, S

    2015-01-01

    Periodontal disease is the most frequent cause of tooth loss among adults. It is defined as a plaque-induced inflammation of the periodontal tissues that results in a loss of support of the affected teeth. This process is characterized by destruction of the periodontal attachment apparatus, increased bone resorption with loss of crestal alveolar bone, apical migration of the epithelial attachment, and formation of periodontal pockets. Although the presence of periodontal pathogens such as Porphyromonas gingivalis is a prerequisite, the progression of periodontal disease is dependent on the host response to pathogenic bacteria that colonize the tooth surface. Nowadays, a growing body of literature has accumulated to investigate the association between bone diseases, periodontal pathogens and periodontal diseases. The integration of pathogen-associated molecular patterns from microorganisms with their surface receptors in the immune cells, induces the production of several cytokines and chemokines that present either a pro- and/or anti-inflammatory role and the activation of mechanisms of controlling this and the related disease, such as osteoporosis and rheumatoid arthritis. This review focuses on the evidence and significance of bone host cell invasion by Porphyromonas gingivalis in the pathogenesis of bone disorders, as well as the different lines of evidence supporting the role of cytokines in bone diseases.

  17. Transgenic animal models for study of the pathogenesis of Huntington’s disease and therapy

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    Chang RB

    2015-04-01

    Full Text Available Renbao Chang,1 Xudong Liu,1 Shihua Li,2 Xiao-Jiang Li1,2 1State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, People’s Republic of China; 2Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA Abstract: Huntington’s disease (HD is caused by a genetic mutation that results in polyglutamine expansion in the N-terminal regions of huntingtin. As a result, this polyQ expansion leads to the misfolding and aggregation of mutant huntingtin as well as age-dependent neurodegeneration. The genetic mutation in HD allows for generating a variety of animal models that express different forms of mutant huntingtin and show differential pathology. Studies of these animal models have provided an important insight into the pathogenesis of HD. Mouse models of HD include transgenic mice, which express N-terminal or full-length mutant huntingtin ubiquitously or selectively in different cell types, and knock-in mice that express full-length mutant Htt at the endogenous level. Large animals, such as pig, sheep, and monkeys, have also been used to generate animal HD models. This review focuses on the different features of commonly used transgenic HD mouse models as well as transgenic large animal models of HD, and also discusses how to use them to identify potential therapeutics. Since HD shares many pathological features with other neurodegenerative diseases, identification of therapies for HD would also help to develop effective treatment for different neurodegenerative diseases that are also caused by protein misfolding and occur in an age-dependent manner. Keywords: transgenic animal models, Huntington’s disease, pathogenesis, therapy

  18. Possible Role of the Transglutaminases in the Pathogenesis of Alzheimer's Disease and Other Neurodegenerative Diseases

    OpenAIRE

    Martin, Antonio; De Vivo, Giulia; Gentile, Vittorio

    2011-01-01

    Transglutaminases are ubiquitous enzymes which catalyze posttranslational modifications of proteins. Recently, transglutaminase-catalyzed post-translational modification of proteins has been shown to be involved in the molecular mechanisms responsible for human diseases. Transglutaminase activity has been hypothesized to be involved also in the pathogenetic mechanisms responsible for several human neurodegenerative diseases. Alzheimer's disease and other neurodegenerative diseases, such as Pa...

  19. Shank synaptic scaffold proteins: keys to understanding the pathogenesis of autism and other synaptic disorders.

    Science.gov (United States)

    Sala, Carlo; Vicidomini, Cinzia; Bigi, Ilaria; Mossa, Adele; Verpelli, Chiara

    2015-12-01

    Shank/ProSAP proteins are essential to synaptic formation, development, and function. Mutations in the family of SHANK genes are strongly associated with autism spectrum disorders (ASD) and other neurodevelopmental and neuropsychiatric disorders, such as intellectual disability (ID), and schizophrenia. Thus, the term 'Shankopathies' identifies a number of neuronal diseases caused by alteration of Shank protein expression leading to abnormal synaptic development. With this review we want to summarize the major genetic, molecular, behavior and electrophysiological studies that provide new clues into the function of Shanks and pave the way for the discovery of new therapeutic drugs targeted to treat patients with SHANK mutations and also patients affected by other neurodevelopmental and neuropsychiatric disorders. Shank/ProSAP proteins are essential to synaptic formation, development, and function. Mutations in the family of SHANK genes are strongly associated with autism spectrum disorders (ASD) and other neurodevelopmental and neuropsychiatric disorders, such as intellectual disability (ID), and schizophrenia (SCZ). With this review we want to summarize the major genetic, molecular, behavior and electrophysiological studies that provide new clues into the function of Shanks and pave the way for the discovery of new therapeutic drugs targeted to treat patients with SHANK mutations. © 2015 International Society for Neurochemistry.

  20. Molecular insights into the pathogenesis of Alzheimer's disease and its relationship to normal aging.

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    Alexei A Podtelezhnikov

    Full Text Available Alzheimer's disease (AD is a complex neurodegenerative disorder that diverges from the process of normal brain aging by unknown mechanisms. We analyzed the global structure of age- and disease-dependent gene expression patterns in three regions from more than 600 brains. Gene expression variation could be almost completely explained by four transcriptional biomarkers that we named BioAge (biological age, Alz (Alzheimer, Inflame (inflammation, and NdStress (neurodegenerative stress. BioAge captures the first principal component of variation and includes genes statistically associated with neuronal loss, glial activation, and lipid metabolism. Normally BioAge increases with chronological age, but in AD it is prematurely expressed as if some of the subjects were 140 years old. A component of BioAge, Lipa, contains the AD risk factor APOE and reflects an apparent early disturbance in lipid metabolism. The rate of biological aging in AD patients, which cannot be explained by BioAge, is associated instead with NdStress, which includes genes related to protein folding and metabolism. Inflame, comprised of inflammatory cytokines and microglial genes, is broadly activated and appears early in the disease process. In contrast, the disease-specific biomarker Alz was selectively present only in the affected areas of the AD brain, appears later in pathogenesis, and is enriched in genes associated with the signaling and cell adhesion changes during the epithelial to mesenchymal (EMT transition. Together these biomarkers provide detailed description of the aging process and its contribution to Alzheimer's disease progression.

  1. Gliadin is a good substrate of several transglutaminases: possible implication in the pathogenesis of coeliac disease.

    Science.gov (United States)

    Skovbjerg, H; Norén, O; Anthonsen, D; Moller, J; Sjöström, H

    2002-07-01

    Deamidation of distinct glutamines in HLA-DQ2 restricted gliadin epitopes, considered critical in the pathogenesis of coeliac disease (CD), can be mediated by tissue transglutaminase (tTG). To elucidate the possible role of other transglutaminases in CD we investigated whether different mammalian, microbial and vegetable transglutaminases can use gliadin as substrate. Studies in which small amounts of transglutaminase have been measured have led to our modifying a microtitre plate assay. We used proteolytically digested gliadin as solid phase substrate and Europium-labelled streptavidine to quantify the biotinylated product covalently linked by the enzyme to the plate. The modified assay is ultrasensitive and quantitative, measuring guinea pig liver transglutaminase concentrations between 0.5 and 50 ng/well. The specific activities of the enzymes (counts/min/mg) against gliadin and N,N-dimethylcasein, respectively, are: tTG 9800/4900, Factor XIII 97330/55620, epidermal transglutaminase 47650/50770, streptoverticillium transglutaminase 4290/2200, phytophora cactorum transglutaminase 6910/4110. For the first time, we have detected transglutaminase activity in bean sprouts, spinach leaves and green peas, which are commonly used Vegetables. Gliadin is a good substrate for endogenous, microbial and plant transglutaminases. An interesting altemative is that gliadins are deamidated by microbial or food transglutaminases in the intestinal lumen. The assay described provides an ultrasensitive method for measuring small amounts of transglutaminase and is considered a helpful tool in further studies of the possible role of transglutaminases in the pathogenesis of CD.

  2. Evaluation of circulating zonulin as a potential marker in the pathogenesis of nonalcoholic fatty liver disease.

    Science.gov (United States)

    Hendy, Olfat M; Elsabaawy, Maha M; Aref, Mona M; Khalaf, Fatma M; Oda, Abdel Moaty A; El Shazly, Helmy M

    2017-07-01

    Nonalcoholic fatty liver disease (NAFLD) is a spectrum of liver disorders ranging from simple hepatic steatosis up to nonalcoholic steatohepatitis (NASH) evolving to cirrhosis and hepatocellular carcinoma (HCC). Liver biopsy is still the gold standard modality for diagnosing and staging NAFLD. The linkage between intestinal microbiota and NAFLD, might suggest a potential role of serum zonulin in NAFLD diagnosis. To appraise the role of circulating zonulin in NAFLD pathogenesis, 56 subjects with proved NAFLD by ultrasonography and liver biopsy, as well as 20 healthy controls were tested. Liver function tests, serum glucose, fasting insulin, C peptide, lipid profile, homeostasis model assessment of insulin resistance (HOMA-IR), IL-6, and circulating zonulin were performed to all subjects. Aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (GGT), triglycerides, HDL-c, fasting insulin, C peptide, HOMA-IR, IL-6, and serum zonulin were higher in NAFLD group than in controls (p Zonulin was positively correlated with body mass index (BMI), ALT, triglycerides, fasting insulin, HOMA-IR, liver histopathology, and serum IL-6 (p zonulin was found to be of diagnostic value of NASH occurrence with 100% sensitivity and specificity (AUR = 1.000, p-value = zonulin levels in NAFLD patients with steep rise in NASH group denotes a possible role in pathogenesis of NAFLD occurrence and progression. This could open a new avenue of implicating zonulin antagonists as targeted therapies in NAFLD prevention. © 2017 APMIS. Published by John Wiley & Sons Ltd.

  3. Neuroinflammation and neurohormesis in the pathogenesis of Alzheimer's disease and Alzheimer-linked pathologies: modulation by nutritional mushrooms.

    Science.gov (United States)

    Trovato Salinaro, Angela; Pennisi, Manuela; Di Paola, Rosanna; Scuto, Maria; Crupi, Rosalia; Cambria, Maria Teresa; Ontario, Maria Laura; Tomasello, Mario; Uva, Maurizio; Maiolino, Luigi; Calabrese, Edward J; Cuzzocrea, Salvatore; Calabrese, Vittorio

    2018-01-01

    Human life develops and expands not only in time and space, but also in the retrograde permanent recollection and interweaving of memories. Therefore, individual human identity depends fully on a proper access to the autobiographical memory. Such access is hindered or lost under pathological conditions such as Alzheimer's disease, including recently associated oxidant pathologies, such as ocular neural degeneration occurring in glaucoma or neurosensorial degeneration occurring in Menière's disease. Oxidative stress and altered antioxidant systems have been suggested to play a role in the aetiology of major neurodegenerative disorders, and altered expression of genes sensing oxidative stress, as well as decreased cellular stress response mechanisms could synergistically contribute to the course of these oxidant disorders. Thus, the theory that low levels of stress can produce protective responses against the pathogenic processes is a frontier area of neurobiological research focal to understanding and developing therapeutic approaches to neurodegenerative disorders. Herein, we discuss cellular mechanisms underlying AD neuroinflammatory pathogenesis that are contributory to Alzheimer's disease. We describe endogenous cellular defence mechanism modulation and neurohormesis as a potentially innovative approach to therapeutics for AD and other neurodegenerative conditions that are associated with mitochondrial dysfunction and neuroinflammation. Particularly, we consider the emerging role of the inflammasome as an important component of the neuroprotective network, as well as the importance of Coriolus and Hericium nutritional mushrooms in redox stress responsive mechanisms and neuroprotection.

  4. Osteoarthritis and age. Role of aging in the etiology and pathogenesis of the disease

    Directory of Open Access Journals (Sweden)

    L. V. Luchikhina

    2017-01-01

    Full Text Available The paper considers current views on the mechanisms for the development and progression of osteoarthritis (OA and gives the definition of the disease. It describes the processes underlying aging and OA at the molecular and cellular level, with emphasis on the role of chronic nonspecific inflammation. The possible mechanisms of chronic age-related inflammation (inflammaging, the mainstay of which is systemic aging of the immune system, are characterized. On the basis of the data available in the literature, it is concluded that aging and OA have common intracellular transcription cascades and pathophysiological mechanisms: chronic nonspecific inflammation and metabolic disorders are substantially implicated in the pathogenesis of these conditions. Metabolic and structural changes occurring in the cartilage and other tissues of the locomotor apparatus with aging are noted to serve as a favorable platform for the further development and progression of OA.

  5. Foot-and-mouth disease virus infection in young lambs: pathogenesis and tissue tropism

    DEFF Research Database (Denmark)

    Ryan, Eoin; Horsington, Jacquelyn; Durand, Stephanie

    2008-01-01

    Foot-and-mouth disease (FMD) in adult sheep usually causes milder clinical signs than in cattle or pigs, and is often subtle enough to go undiagnosed. In contrast, FMD in lambs has been reported to cause high mortality during field outbreaks. In order to investigate the pathogenesis of FMD in lambs...... examined for histopathological lesions, and in situ hybridisation (ISH) was used to localise viral RNA within histological sections. The contact-infected lambs became infected approximately 24 h after the ewes were inoculated. Vesicular lesions developed on the feet of all lambs and on the caudo......-lateral part of the tongues of six of the eight inoculated lambs and three of the four contact-infected lambs. Although no lambs developed severe clinical signs, one of the contact-infected lambs died acutely at 5 days post-exposure. Histological examination of the heart from this lamb showed multi-focal areas...

  6. Contributions of PHOX2B in the pathogenesis of Hirschsprung disease.

    Directory of Open Access Journals (Sweden)

    Raquel María Fernández

    Full Text Available Hirschsprung disease (HSCR is a congenital malformation of the hindgut resulting from a disruption of neural crest cell migration during embryonic development. It has a complex genetic aetiology with several genes involved in its pathogenesis. PHOX2B plays a key function in the development of neural crest derivatives, and heterozygous mutations cause a complex dysautonomia associating HSCR, Congenital Central Hypoventilation Syndrome (CCHS and neuroblastoma (NB in various combinations. In order to determine the role of PHOX2B in isolated HSCR, we performed a mutational screening in a cohort of 207 Spanish HSCR patients. Our most relevant finding has been the identification of a de novo and novel deletion (c.393_410del18 in a patient with HSCR. Results of in silico and functional assays support its pathogenic effect related to HSCR. Therefore our results support that PHOX2B loss-of-function is a rare cause of HSCR phenotype.

  7. High fat diet accelerates pathogenesis of murine Crohn's disease-like ileitis independently of obesity.

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    Lisa Gruber

    Full Text Available BACKGROUND: Obesity has been associated with a more severe disease course in inflammatory bowel disease (IBD and epidemiological data identified dietary fats but not obesity as risk factors for the development of IBD. Crohn's disease is one of the two major IBD phenotypes and mostly affects the terminal ileum. Despite recent observations that high fat diets (HFD impair intestinal barrier functions and drive pathobiont selection relevant for chronic inflammation in the colon, mechanisms of high fat diets in the pathogenesis of Crohn's disease are not known. The aim of this study was to characterize the effect of HFD on the development of chronic ileal inflammation in a murine model of Crohn's disease-like ileitis. METHODS: TNF(ΔARE/WT mice and wildtype C57BL/6 littermates were fed a HFD compared to control diet for different durations. Intestinal pathology and metabolic parameters (glucose tolerance, mesenteric tissue characteristics were assessed. Intestinal barrier integrity was characterized at different levels including polyethylene glycol (PEG translocation, endotoxin in portal vein plasma and cellular markers of barrier function. Inflammatory activation of epithelial cells as well as immune cell infiltration into ileal tissue were determined and related to luminal factors. RESULTS: HFD aggravated ileal inflammation but did not induce significant overweight or typical metabolic disorders in TNF(ΔARE/WT. Expression of the tight junction protein Occludin was markedly reduced in the ileal epithelium of HFD mice independently of inflammation, and translocation of endotoxin was increased. Epithelial cells showed enhanced expression of inflammation-related activation markers, along with enhanced luminal factors-driven recruitment of dendritic cells and Th17-biased lymphocyte infiltration into the lamina propria. CONCLUSIONS: HFD feeding, independently of obesity, accelerated disease onset of small intestinal inflammation in Crohn's disease

  8. Long Non-Coding RNA Profiling in a Non-Alcoholic Fatty Liver Disease Rodent Model: New Insight into Pathogenesis

    Directory of Open Access Journals (Sweden)

    Yi Chen

    2017-01-01

    Full Text Available Non-alcoholic fatty liver disease (NAFLD is one of the most prevalent chronic liver diseases worldwide with an unclear mechanism. Long non-coding RNAs (lncRNAs have recently emerged as important regulatory molecules. To better understand NAFLD pathogenesis, lncRNA and messenger RNA (mRNA microarrays were conducted in an NAFLD rodent model. Potential target genes of significantly changed lncRNA were predicted using cis/trans-regulatory algorithms. Gene Ontology (GO analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG pathway enrichment analysis were then performed to explore their function. In the current analysis, 89 upregulated and 177 downregulated mRNAs were identified, together with 291 deregulated lncRNAs. Bioinformatic analysis of these RNAs has categorized these RNAs into pathways including arachidonic acid metabolism, circadian rhythm, linoleic acid metabolism, peroxisome proliferator-activated receptor (PPAR signaling pathway, sphingolipid metabolism, steroid biosynthesis, tryptophan metabolism and tyrosine metabolism were compromised. Quantitative polymerase chain reaction (qPCR of representative nine mRNAs and eight lncRNAs (named fatty liver-related lncRNA, FLRL was conducted and this verified previous microarray results. Several lncRNAs, such as FLRL1, FLRL6 and FLRL2 demonstrated to be involved in circadian rhythm targeting period circadian clock 3 (Per3, Per2 and aryl hydrocarbon receptor nuclear translocator-like (Arntl, respectively. While FLRL8, FLRL3 and FLRL7 showed a potential role in PPAR signaling pathway through interaction with fatty acid binding protein 5 (Fabp5, lipoprotein lipase (Lpl and fatty acid desaturase 2 (Fads2. Functional experiments showed that interfering of lncRNA FLRL2 expression affected the expression of predicted target, circadian rhythm gene Arntl. Moreover, both FLRL2 and Arntl were downregulated in the NAFLD cellular model. The current study identified lncRNA and corresponding mRNA in NAFLD

  9. Immunohistochemical analysis of TGF-β1 and VEGF in gingival and periodontal tissues: a role of these biomarkers in the pathogenesis of scleroderma and periodontal disease.

    Science.gov (United States)

    Matarese, Giovanni; Isola, Gaetano; Anastasi, Giuseppe Pio; Favaloro, Angelo; Milardi, Demetrio; Vermiglio, Giovanna; Vita, Giuseppe; Cordasco, Giancarlo; Cutroneo, Giuseppina

    2012-09-01

    Periodontal disease is characterized by inflammation and bone loss. The balance between inflammatory mediators and their counter-regulatory molecules may be fundamental for determining the outcome of the immune pathology of periodontal disease. Transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF) represent a family of polypeptide proteins involved in the inflammation and regulation of immune responses, especially in rheumatic disease. The relationship between these growth factors and periodontitis has resulted in a new field of osteoimmunology and provides a context for better understanding the pathogenesis of periodontal disease. Therefore, the aim of this study was to compare the protein expression profile of these inflammatory mediators in 90 patients divided in three groups: healthy control, chronic periodontitis and in rheumatic disease, scleroderma. The findings presented here highlight that biomarkers, such as TGF-β1 and VEGF, play a key role in the evolution of the immune response, which in turn influences the outcome of disease establishment.

  10. The Significance of the Psychosocial Factors Influence in Pathogenesis of Cardiovascular Disease

    Science.gov (United States)

    Masic, Izet; Alajbegovic, Jasmin

    2013-01-01

    Background: Cardiovascular diseases (CVD) are the leading cause of death in the world today. Risk factors are those factors that influence the development of CVD. Risk factors can be divided into materialistic (genetic predisposition, smoking, alcohol) and non-materialistic (psychosocial factors). Our goal is to note the role of the health system, to emphasize the importance of psychosocial factors in the pathogenesis of CVD, explain the relationship between psychosocial factors and other risk factors, stress the importance of prevention through the provision of management of the cardiovascular system (CVS) diseases. Methods: A descriptive analysis was performed on scientific studies in several published articles in journals on CVS: Public Health Reviews, CVD, European Heart Journal, Materia Socio Medica and other indexed journals that publish articles on CVS. Results and Conclusions: The importance and role of the health system in the early detection, diagnosis, therapy and CVS disease prevention is presented through three thematic areas: (a) The incidence and prevalence of CVS diseases; (b) treatment of CVS diseases and (c) promotion of health in patients with CVS disease and those the risk of their occurrence. Health promotion is the most important aspect of the health system monitoring. Health promotion is adequately implemented ifthe management ofCVD is proper. The main objectives of CVD management are: Preventing or delaying the occurrence of CVD, reducing the number and severity of worsening and complications of CVD. Management Includes: Individual and family, the health system and the community. Materialistic and non-materialistic risk factors together contribute to the development of CVD. PMID:24404370

  11. RAGE and its emerging role in the pathogenesis of Parkinson's disease.

    Science.gov (United States)

    Jiang, Xiuli; Wang, Xiaoli; Tuo, Miao; Ma, Jiangnan; Xie, Anmu

    2018-02-22

    Receptor for advanced glycation end products (RAGE) is a multiligand receptor belonging to the immunoglobulin superfamily and plays crucial roles in the development of many human diseases such as neurodegenerative diseases, diabetes, cardiovascular diseases, osteoarthritis and cancer. RAGE involves in a number of cell processes such as neuroinflammation, apoptosis, proliferation and autophagy. In CNS, RAGE was primarily expressed in neurons, microglia and vascular endothelial cells. Interacting with ligands, RAGE induces a series of signal transduction cascades and leads to the activation of transcription factor NF-κB as well as increased expression of cytokines like TNF-α, IL-1. Moreover, binding to RAGE can also stimulate the generation of reactive oxygen species (ROS), which is implicated in neuron death. It was reported that RAGE were highly expressed in PD patients when compared to age-matched controls. And RAGE ablation protected nigral dopaminergic neurons against cell death in MPTP treated mice. Here we review this article to elucidate the role of RAGE in PD pathogenesis and highlight the anti-RAGE strategies in the treatment of PD. Copyright © 2018 Elsevier B.V. All rights reserved.

  12. Is spinal muscular atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications?

    Science.gov (United States)

    Simone, Chiara; Ramirez, Agnese; Bucchia, Monica; Rinchetti, Paola; Rideout, Hardy; Papadimitriou, Dimitra; Re, Diane B; Corti, Stefania

    2016-03-01

    Spinal muscular atrophy (SMA) is a genetic neurological disease that causes infant mortality; no effective therapies are currently available. SMA is due to homozygous mutations and/or deletions in the survival motor neuron 1 gene and subsequent reduction of the SMN protein, leading to the death of motor neurons. However, there is increasing evidence that in addition to motor neurons, other cell types are contributing to SMA pathology. In this review, we will discuss the involvement of non-motor neuronal cells, located both inside and outside the central nervous system, in disease onset and progression. Even if SMN restoration in motor neurons is needed, it has been shown that optimal phenotypic amelioration in animal models of SMA requires a more widespread SMN correction. It has been demonstrated that non-motor neuronal cells are also involved in disease pathogenesis and could have important therapeutic implications. For these reasons it will be crucial to take this evidence into account for the clinical translation of the novel therapeutic approaches.

  13. Transgenic animal models for study of the pathogenesis of Huntington's disease and therapy.

    Science.gov (United States)

    Chang, Renbao; Liu, Xudong; Li, Shihua; Li, Xiao-Jiang

    2015-01-01

    Huntington's disease (HD) is caused by a genetic mutation that results in polyglutamine expansion in the N-terminal regions of huntingtin. As a result, this polyQ expansion leads to the misfolding and aggregation of mutant huntingtin as well as age-dependent neurodegeneration. The genetic mutation in HD allows for generating a variety of animal models that express different forms of mutant huntingtin and show differential pathology. Studies of these animal models have provided an important insight into the pathogenesis of HD. Mouse models of HD include transgenic mice, which express N-terminal or full-length mutant huntingtin ubiquitously or selectively in different cell types, and knock-in mice that express full-length mutant Htt at the endogenous level. Large animals, such as pig, sheep, and monkeys, have also been used to generate animal HD models. This review focuses on the different features of commonly used transgenic HD mouse models as well as transgenic large animal models of HD, and also discusses how to use them to identify potential therapeutics. Since HD shares many pathological features with other neurodegenerative diseases, identification of therapies for HD would also help to develop effective treatment for different neurodegenerative diseases that are also caused by protein misfolding and occur in an age-dependent manner.

  14. When aging-onset diabetes is coming across with Alzheimer disease: comparable pathogenesis and therapy.

    Science.gov (United States)

    Tang, Jun; Pei, Yijin; Zhou, Guangji

    2013-08-01

    Diabetes mellitus is a metabolic disorder that is characterized by high blood glucose because of the insulin-resistance and insulin-deficiency in Type 2, while the insulin deficiency due to destruction of islet cells in the pancreas in Type 1. The development of Type 2 diabetes is caused by a combination of lifestyle and genetic factors. Aging patients with diabetes are at increased risk of developing cognitive and memory dysfunctions, which is one of the significant symptoms of Alzheimer disease (AD). Also, over 2/3 of AD patients were clinically indentified with impairment of glucose. Cognitive dysfunction would be associated with poor self-care ability in diabetes patients. This review will briefly summarize the current knowledge of the pathogenesis of these two diseases and highlight similarities in their pathophysiologies. Furthermore, we will shortly discuss recent progress in the insulin-targeted strategy, aiming to explore the inner linkage between these two diseases in aging populations. Copyright © 2013 Elsevier Inc. All rights reserved.

  15. Bridging Lung Development with Chronic Obstructive Pulmonary Disease. Relevance of Developmental Pathways in Chronic Obstructive Pulmonary Disease Pathogenesis.

    Science.gov (United States)

    Boucherat, Olivier; Morissette, Mathieu C; Provencher, Steeve; Bonnet, Sébastien; Maltais, François

    2016-02-15

    Chronic obstructive pulmonary disease (COPD) is characterized by chronic airflow limitation. This generic term encompasses emphysema and chronic bronchitis, two common conditions, each having distinct but also overlapping features. Recent epidemiological and experimental studies have challenged the traditional view that COPD is exclusively an adult disease occurring after years of inhalational insults to the lungs, pinpointing abnormalities or disruption of the pathways that control lung development as an important susceptibility factor for adult COPD. In addition, there is growing evidence that emphysema is not solely a destructive process because it is also characterized by a failure in cell and molecular maintenance programs necessary for proper lung development. This leads to the concept that tissue regeneration required stimulation of signaling pathways that normally operate during development. We undertook a review of the literature to outline the contribution of developmental insults and genes in the occurrence and pathogenesis of COPD, respectively.

  16. Recent insights into the molecular pathogenesis of Crohn's disease: a review of emerging therapeutic targets

    Directory of Open Access Journals (Sweden)

    Manuc TE

    2016-03-01

    Full Text Available Teodora-Ecaterina M Manuc,1 Mircea M Manuc,2 Mircea M Diculescu2 1Fundeni Clinical Institute, 2University of Medicine and Pharmacy "Carol Davila", Bucharest, Romania Abstract: Chronic inflammatory bowel diseases (IBDs are a subject of great interest in gastroenterology, due to a pathological mechanism that is difficult to explain and an optimal therapeutic approach still undiscovered. Crohn's disease (CD is one of the main entities in IBD, characterized by clinical polymorphism and great variability in the treatment response. Modern theories on the pathogenesis of CD have proven that gut microbiome and environmental factors lead to an abnormal immune response in a genetically predisposed patient. Genome-wide association studies in patients with CD worldwide revealed several genetic mutations that increase the risk of IBD and that predispose to a more severe course of disease. Gut microbiota is considered a compulsory and an essential part in the pathogenesis of CD. Intestinal dysmicrobism with excessive amounts of different bacterial strains can be found in all patients with IBD. The discovery of Escherichia coli entero-invasive on resection pieces in patients with CD now increases the likelihood of antimicrobial or vaccine-type treatments. Recent studies targeting intestinal immunology and its molecular activation pathways provide new possibilities for therapeutics. In addition to antitumor necrosis factor molecules, which were a breakthrough in IBD, improving mucosal healing and resection-free survival rate, other classes of therapeutic agents come to focus. Leukocyte adhesion inhibitors block the leukocyte homing mechanism and prevent cellular immune response. In addition to anti-integrin antibodies, chemokine receptor antagonists and SMAD7 antisense oligonucleotides have shown encouraging results in clinical trials. Micro-RNAs have demonstrated their role as disease biomarkers but it could also become useful for the treatment of IBD

  17. Toward molecular pathogenesis of an autoimmune disease: Refined genetic mapping of autoimmune polyglandular disease type I (APECED)

    Energy Technology Data Exchange (ETDEWEB)

    Aaltonen, J.; Bjoerses, P.; Peltonen, L. [National Public Health Institute, Helsinki (Finland)] [and others

    1994-09-01

    Autoimmune reactions encoupled to many human diseases are still only partially understood. Unravelling the molecular pathogenesis of inherited diseases with a strong autoimmune component in their clinical expression could help to dissect individual components in the molecular background of abnormal immune response. One such genetic disorder is autosomal recessive autoimmune polyglandular disease type I (PGD I), also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, MIM 240300). The disease is especially enriched in the genetically isolated population of Finland and we have assigned the APECED locus to human chromosome 21q22.3 in 14 Finnish families by linkage analyses. The best positional lod score of 6.49 was observed with marker D21S49. Based on the history of the Finns, the gene pool of this population clearly demonstrates the consequences of a founder effect and consequent isolation. In the Finnish population, we can take advantage of linkage disequilibrium and allelic association studies to more precisely define the critical DNA region for our disease gene of interest than would be possible by linkage analyses alone. We are now able to define the chromosomal region of interest between two flanking markers locating 1 cM apart. Linkage disequilibrium is observed with three of the markers used in the analyses and this suggests a distance of less than 500 kb to the disease locus, well approachable with molecular cloning techniques. Overlapping YAC and cosmid clones spanning our region of interest will facilitate the cloning of APECED gene in the near future.

  18. Genetic prion disease: no role for the immune system in disease pathogenesis?

    Science.gov (United States)

    Friedman-Levi, Yael; Binyamin, Orli; Frid, Kati; Ovadia, Haim; Gabizon, Ruth

    2014-08-01

    Prion diseases, which can manifest by transmissible, sporadic or genetic etiologies, share several common features, such as a fatal neurodegenerative outcome and the aberrant accumulation of proteinase K (PK)-resistant PrP forms in the CNS. In infectious prion diseases, such as scrapie in mice, prions first replicate in immune organs, then invade the CNS via ascending peripheral tracts, finally causing death. Accelerated neuroinvasion and death occurs when activated prion-infected immune cells infiltrate into the CNS, as is the case for scrapie-infected mice induced for experimental autoimmune encephalomyelitis (EAE), a CNS inflammatory insult. To establish whether the immune system plays such a central role also in genetic prion diseases, we induced EAE in TgMHu2ME199K mice, a line mimicking for late onset genetic Creutzfeldt Jacob disease (gCJD), a human prion disease. We show here that EAE induction of TgMHu2ME199K mice neither accelerated nor aggravated prion disease manifestation. Concomitantly, we present evidence that PK-resistant PrP forms were absent from CNS immune infiltrates, and most surprisingly also from lymph nodes and spleens of TgMHu2ME199K mice at all ages and stages of disease. These results imply that the mechanism of genetic prion disease differs widely from that of the infectious presentation, and that the conversion of mutant PrPs into PK resistant forms occurs mostly/only in the CNS. If the absence of pathogenic PrP forms form immune organs is also true for gCJD patients, it may suggest their blood is devoid of prion infectivity. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  19. Importance of indoor dust biological ultrafine particles in the pathogenesis of chronic inflammatory lung diseases

    Directory of Open Access Journals (Sweden)

    Jinho Yang

    2017-11-01

    Full Text Available The role of infectious agents in the etiology of inflammatory diseases once believed to be non-infectious is increasingly being recognized. Many bacterial components in the indoor dust can evoke inflammatory lung diseases. Bacteria secrete nanometer-sized vesicles into the extracellular milieu, so-called extracellular vesicles (EV. which are pathophysiologically related to inflammatory diseases. Microbiota compositions in the indoor dust revealed the presence of both Gram-negative and Gram-positive bacteria. Escherichia coli is a model organism of Gram-negative Enterobacteriaceae. The repeated inhalation of E. coli-derived EVs caused neutrophilic inflammation and emphysema in a dose-dependent manner. The emphysema induced by E. coli-derived EVs was partially eliminated by the absence of Interferon-gamma or interleukin-17, suggesting that Th1 and/or Th17 cell responses are important in the emphysema development. Meanwhile, the repeated inhalation of Staphylococcus aureus-derived EVs did not induce emphysema, although they induced neutrophilic inflammation in the lung. In terms of microbial EV compositions in the indoor dust, genera Pseudomonas, Acinetobacter, Enterobacter, and Staphylococcus were dominant. As for the clinical significance of sensitization to EVs in the indoor dust, EV sensitization was closely associated with asthma, chronic obstructive pulmonary disorder (COPD, and lung cancer. These data indicate that biological ultrafine particles in the indoor dust, which are mainly composed of microbial EVs, are important in the pathogenesis of chronic lung diseases associated with neutrophilic inflammation. Taken together, microbial EVs in the indoor dust are an important diagnostic and therapeutic target for the control of chronic lung diseases, such as asthma, COPD, and lung cancer.

  20. Soluble CD40 ligand: a novel biomarker in the pathogenesis of periodontal disease.

    Science.gov (United States)

    Chaturvedi, Rashi; Gupta, Mili; Jain, Ashish; Das, Tarun; Prashar, Savita

    2015-01-01

    Periodontitis involves a complex interplay of micro-organisms and host immune response via numerous mediator molecules playing strategic roles in its pathogenesis. Soluble CD40L (sCD40L) is one such co-stimulatory molecule which is essential for T-helper cell activation and is a well-known risk indicator of cardiovascular diseases. The levels of this marker in crevicular fluid of patients of chronic periodontitis have been explored in the present study for the first time along with an analysis of its association with levels in serum in otherwise systemically healthy patients. Sixty patients 20 healthy and 40 of chronic periodontitis (18 moderate and 22 severe) participated in the study. Patients of the diseased group underwent non-surgical periodontal therapy. Clinical evaluation and collection of gingival crevicular fluid (GCF) and serum samples was done at baseline, and 6 weeks after phase I periodontal therapy. sCD40L levels were quantified in the fluids using ELISA. Levels of sCD40L in GCF were significantly higher in the diseased group (p ≤ 0.001) and strongly correlated not only with increasing severity of disease but also with levels in serum. In post-treatment, the levels decreased significantly in both the biological fluids (p ≤ 0.001). The present study brings to light the role of sCD40L as a novel marker in mediating periodontal destruction and disease progression. Evaluation of local treatment outcomes seems promising in minimizing these effects. Positive association of its local levels with those in serum further implicates the possibility of widespread systemic effects of this infection.

  1. Molecular Mechanisms for Herpes Simplex Virus Type 1 Pathogenesis in Alzheimer’s Disease

    Science.gov (United States)

    Harris, Steven A.; Harris, Elizabeth A.

    2018-01-01

    This review focuses on research in the areas of epidemiology, neuropathology, molecular biology and genetics that implicates herpes simplex virus type 1 (HSV-1) as a causative agent in the pathogenesis of sporadic Alzheimer’s disease (AD). Molecular mechanisms whereby HSV-1 induces AD-related pathophysiology and pathology, including neuronal production and accumulation of amyloid beta (Aβ), hyperphosphorylation of tau proteins, dysregulation of calcium homeostasis, and impaired autophagy, are discussed. HSV-1 causes additional AD pathologies through mechanisms that promote neuroinflammation, oxidative stress, mitochondrial damage, synaptic dysfunction, and neuronal apoptosis. The AD susceptibility genes apolipoprotein E (APOE), phosphatidylinositol binding clathrin assembly protein (PICALM), complement receptor 1 (CR1) and clusterin (CLU) are involved in the HSV lifecycle. Polymorphisms in these genes may affect brain susceptibility to HSV-1 infection. APOE, for example, influences susceptibility to certain viral infections, HSV-1 viral load in the brain, and the innate immune response. The AD susceptibility gene cholesterol 25-hydroxylase (CH25H) is upregulated in the AD brain and is involved in the antiviral immune response. HSV-1 interacts with additional genes to affect cognition-related pathways and key enzymes involved in Aβ production, Aβ clearance, and hyperphosphorylation of tau proteins. Aβ itself functions as an antimicrobial peptide (AMP) against various pathogens including HSV-1. Evidence is presented supporting the hypothesis that Aβ is produced as an AMP in response to HSV-1 and other brain infections, leading to Aβ deposition and plaque formation in AD. Epidemiologic studies associating HSV-1 infection with AD and cognitive impairment are discussed. Studies are reviewed supporting subclinical chronic reactivation of latent HSV-1 in the brain as significant in the pathogenesis of AD. Finally, the rationale for and importance of clinical

  2. Host immune response and acute disease in a zebrafish model of francisella pathogenesis

    Science.gov (United States)

    Vojtech, L.N.; Sanders, G.E.; Conway, C.; Ostland, V.; Hansen, J.D.

    2009-01-01

    Members of the bacterial genus Francisella are highly virulent and infectious pathogens. New models to study Francisella pathogenesis in evolutionarily distinct species are needed to provide comparative insight, as the mechanisms of host resistance and pathogen virulence are not well understood. We took advantage of the recent discovery of a novel species of Francisella to establish a zebrafish/Francisella comparative model of pathogenesis and host immune response. Adult zebraflsh were susceptible to acute Francisella-induced disease and suffered mortality in a dose-dependent manner. Using immunohistochemical analysis, we localized bacterial antigens primarily to lymphoid tissues and livers of zebraflsh following infection by intraperitoneal injection, which corresponded to regions of local cellular necrosis. Francisella sp. bacteria replicated rapidly in these tissues beginning 12 h postinfection, and bacterial titers rose steadily, leveled off, and then decreased by 7 days postinfection. Zebraflsh mounted a significant tissue-specific proinflammatory response to infection as measured by the upregulation of interleukin-l?? (IL-1??), gamma interferon, and tumor necrosis factor alpha mRNA beginning by 6 h postinfection and persisting for up to 7 days postinfection. In addition, exposure of zebraflsh to heat-killed bacteria demonstrated that the significant induction of IL-?? was highly specific to live bacteria. Taken together, the pathology and immune response to acute Francisella infection in zebraflsh share many features with those in mammals, highlighting the usefulness of this new model system for addressing both general and specific questions about Francisella host-pathogen interactions via an evolutionary approach. Copyright ?? 2009, American Society for Microbiology. All Rights Reserved.

  3. Dysfunction of autophagy and endosomal-lysosomal pathways: Roles in pathogenesis of Down syndrome and Alzheimer's Disease.

    Science.gov (United States)

    Colacurcio, Daniel J; Pensalfini, Anna; Jiang, Ying; Nixon, Ralph A

    2018-01-01

    Individuals with Down syndrome (DS) have an increased risk of early-onset Alzheimer's Disease (AD), largely owing to a triplication of the APP gene, located on chromosome 21. In DS and AD, defects in endocytosis and lysosomal function appear at the earliest stages of disease development and progress to widespread failure of intraneuronal waste clearance, neuritic dystrophy and neuronal cell death. The same genetic factors that cause or increase AD risk are also direct causes of endosomal-lysosomal dysfunction, underscoring the essential partnership between this dysfunction and APP metabolites in AD pathogenesis. The appearance of APP-dependent endosome anomalies in DS beginning in infancy and evolving into the full range of AD-related endosomal-lysosomal deficits provides a unique opportunity to characterize the earliest pathobiology of AD preceding the classical neuropathological hallmarks. Facilitating this characterization is the authentic recapitulation of this endosomal pathobiology in peripheral cells from people with DS and in trisomy mouse models. Here, we review current research on endocytic-lysosomal dysfunction in DS and AD, the emerging importance of APP/βCTF in initiating this dysfunction, and the potential roles of additional trisomy 21 genes in accelerating endosomal-lysosomal impairment in DS. Collectively, these studies underscore the growing value of investigating DS to probe the biological origins of AD as well as to understand and ameliorate the developmental disability of DS. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. The gnotobiotic piglet as a model for studies of disease pathogenesis and immunity to human rotaviruses.

    Science.gov (United States)

    Saif, L J; Ward, L A; Yuan, L; Rosen, B I; To, T L

    1996-01-01

    Gnotobiotic piglets serve as a useful animal model for studies of human rotavirus infections, including disease pathogenesis and immunity. An advantage of piglets over laboratory animal models is their prolonged susceptibility to human rotavirus-induced disease, permitting cross-protection studies and an analysis of active immunity. Major advances in rotavirus research resulting from gnotobiotic piglet studies include: 1) the adaptation of the first human rotavirus to cell culture after passage and amplification in piglets; 2) delineation of the independent roles of the two rotavirus outer capsid proteins (VP4 and VP7) in induction of neutralizing antibodies and cross-protection; and 3) recognition of a potential role for a nonstructural protein (NSP4) in addition to VP4 and VP7, in rotavirus virulence. Current studies of the pathogenesis of group A human rotavirus infections in gnotobiotic piglets in our laboratory have confirmed that villous atrophy is induced in piglets given virulent but not cell culture attenuated human rotavirus (G1, P1A, Wa strain) and have revealed that factors other than villous atrophy may contribute to the early diarrhea induced. A comprehensive examination of these factors, including a proposed role for NSP4 in viral-induced cytopathology, may reveal new mechanisms for induction of viral diarrhea. Finally, to facilitate and improve rotavirus vaccination strategies, our current emphasis is on the identification of correlates of protective active immunity in the piglet model of human rotavirus-induced diarrhea. Comparison of cell-mediated and antibody immune responses induced by infection with a virulent human rotavirus (to mimic host response to natural infection) with those induced by a live attenuated human rotavirus (to mimic attenuated oral vaccines) in the context of homotypic protection has permitted an analysis of correlates of protective immunity. Results of these studies have indicated that the magnitude of the immune response

  5. The TRIPS (Toll-like receptors in immuno-inflammatory pathogenesis) Hypothesis: a novel postulate to understand schizophrenia.

    Science.gov (United States)

    Venkatasubramanian, Ganesan; Debnath, Monojit

    2013-07-01

    Mounting evidence indicates that immune activation and/or immuno-inflammatory reactions during neurodevelopment apparently contribute to the pathogenesis and progression of schizophrenia. One of the important environmental factors that is known to trigger immune activation/inflammatory responses during early pregnancy is prenatal infection. Recent understanding from animal studies suggests that prenatal infection induced maternal immune activation (MIA)/inflammation in congruence with oxidative/nitrosative stress can lead to neurodevelopmental damage and behavioral abnormalities in the offspring. Although the underlying precise mechanistic processes of MIA/inflammation are yet to be completely elucidated, it is being increasingly recognized that Toll-like receptors (TLRs) that form the first line of defense against invading microorganisms could participate in the prenatal infection induced immune insults. Interestingly, some of the TLRs, especially TLR3 and TLR4 that modulate neurodevelopment, neuronal survival and neuronal plasticity by regulating the neuro-immune cross-talk in the developing and adult brain could also be affected by prenatal infection. Importantly, sustained activation of TLR3/TLR4 due to environmental factors including infection and stress has been found to generate excessive reactive oxygen species (ROS)/reactive nitrogen species (RNS) as well as pro-inflammatory mediators during embryogenesis, which result into neuronal damage by necrosis/apoptosis. In recent times, ROS/RNS and immuno-inflammatory mediators are being increasingly linked to progressive brain changes in schizophrenia. Although a significant role of TLR3/TLR4 in neurodegeneration is gaining certainty, their importance in establishing a causal link between prenatal infection and immuno-inflammatory, oxidative and nitrosative stress (IO&NS) responses and influence on adult presentation of schizophrenia is yet to be ascertained. We review here the current knowledge generated from

  6. Perivascular adipose tissue as a regulator of vascular disease pathogenesis: identifying novel therapeutic targets.

    Science.gov (United States)

    Akoumianakis, Ioannis; Tarun, Akansha; Antoniades, Charalambos

    2017-10-01

    Adipose tissue (AT) is an active endocrine organ with the ability to dynamically secrete a wide range of adipocytokines. Importantly, its secretory profile is altered in various cardiovascular disease states. AT surrounding vessels, or perivascular AT (PVAT), is recognized in particular as an important local regulator of vascular function and dysfunction. Specifically, PVAT has the ability to sense vascular paracrine signals and respond by secreting a variety of vasoactive adipocytokines. Due to the crucial role of PVAT in regulating many aspects of vascular biology, it may constitute a novel therapeutic target for the prevention and treatment of vascular disease pathogenesis. Signalling pathways in PVAT, such as those using adiponectin, H 2 S, glucagon-like peptide 1 or pro-inflammatory cytokines, are among the potential novel pharmacological therapeutic targets of PVAT. This article is part of a themed section on Molecular Mechanisms Regulating Perivascular Adipose Tissue - Potential Pharmacological Targets? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.20/issuetoc. © 2016 The British Pharmacological Society.

  7. Microglial Scavenger Receptors and Their Roles in the Pathogenesis of Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Kim Wilkinson

    2012-01-01

    Full Text Available Alzheimer’s disease (AD is increasing in prevalence with the aging population. Deposition of amyloid-β (Aβ in the brain of AD patients is a hallmark of the disease and is associated with increased microglial numbers and activation state. The interaction of microglia with Aβ appears to play a dichotomous role in AD pathogenesis. On one hand, microglia can phagocytose and clear Aβ, but binding of microglia to Aβ also increases their ability to produce inflammatory cytokines, chemokines, and neurotoxic reactive oxygen species (ROS. Scavenger receptors, a group of evolutionally conserved proteins expressed on the surface of microglia act as receptors for Aβ. Of particular interest are SCARA-1 (scavenger receptor A-1, CD36, and RAGE (receptor for advanced glycation end products. SCARA-1 appears to be involved in the clearance of Aβ, while CD36 and RAGE are involved in activation of microglia by Aβ. In this review, we discuss the roles of various scavenger receptors in the interaction of microglia with Aβ and propose that these receptors play complementary, nonredundant functions in the development of AD pathology. We also discuss potential therapeutic applications for these receptors in AD.

  8. Genetic variations of PTPN2 and PTPN22: Role in the Pathogenesis of Type 1 Diabetes and Crohn’s Disease

    Directory of Open Access Journals (Sweden)

    Muna eAbdulrahim

    2015-12-01

    Full Text Available Genome wide association studies have identified several genes that might be associated with increase susceptibility to Type 1 Diabetes (T1D and Crohn’s disease. Both Crohn’s disease and T1D have a profound impact on the lives of patients and it is pivotal to investigate the genetic role in patients acquiring these diseases. Understanding the effect of single nucleotide polymorphisms (SNP’s in key genes in patients suffering from T1D and Crohn’s disease is crucial to finding an effective treatment and generating novel therapeutic drugs. This review article is focused on the impact of SNP’s in PTPN2 (protein tyrosine phosphatase, non-receptor type 2 and PTPN22 (protein tyrosine phosphatase non-receptor type 22 on the development of Crohn’s disease T1D. The PTPN2 gene mutation in T1D patients play a direct role in the destruction of beta cells while in Crohn’s disease patients, it modulates the innate immune responses. The PTPN22 gene mutations also play a role in both diseases by modulating intracellular signaling. Examining the mechanism through which these genes increase the susceptibility to both diseases and gaining a better understanding of their structure and function is of vital importance to understand the etiology and pathogenesis of Type 1 Diabetes and Crohn’s disease.

  9. The Role of Environmental Factors in the Pathogenesis of Inflammatory Bowel Diseases: A Review.

    Science.gov (United States)

    Shouval, Dror S; Rufo, Paul A

    2017-10-01

    Inflammatory bowel diseases (IBD), such as Crohn disease and ulcerative colitis, are chronic relapsing conditions that affect a growing number of children worldwide. The pathogenesis of these disorders is complex and thought to be mediated by the interplay between genetic susceptibility, microbial dysbiosis, and environmental factors that result in a dysregulated immune system. This dysregulation ultimately mediates intestinal inflammation and clinical symptoms typically observed in patients with IBD including abdominal pain, diarrhea, and poor growth. A dramatic increase in the incidence of IBD has been observed in the past 2 decades, mainly in developed countries but also in developing regions. This increased incidence has paralleled changes in diet, sanitation conditions, and lifestyle habits. The increased incidence of IBD can likely be attributed to more than evolving genetic diversity alone and strongly suggests that environmental factors are playing an increasingly critical role in the development of these disorders and in the modulation of IBD clinical phenotypes over time. Here, we review the data suggesting how different environmental factors may modulate the risk of developing IBD including diets, smoking, lifestyle choices, enteric infections, appendectomy, air pollution, and the use of medications, with an emphasis on antibiotics. We will also discuss how early-life events can influence the subsequent likelihood of developing one of these diseases and suggest directions that can help decrease the risk of IBD in particularly high-risk populations. Dramatic lifestyle changes in the last century have substantially improved the quality of life but are also associated with increased risk of various diseases. Pediatricians should be aware of the changing epidemiology of IBD and environmental factors that modulate the risk of developing these conditions.

  10. PENDING ISSUES OF PATHOGENESIS IN CHILDREN’S INFLAMMATORY INTESTINAL DISEASES. THE ROLE OF INTESTINAL PARIETAL MICROFLORA

    Directory of Open Access Journals (Sweden)

    P.V. Shumilov

    2010-01-01

    Full Text Available Inflammatory intestinal diseases are among the critical issues in modern pediatrics. The article discusses the specific nature of genetic predisposition and immune mechanisms of this pathology, as well as the impact of intestinal microflora on the development and evolution of inflammatory intestinal diseases in children. It outlines current views on pathogenesis of Crohn’s disease and non-specific ulcerative colitis. It describes in detail the local immune system functioning mechanism of the digestive tract system and functions of its individual components. It explains the phenomenon of food tolerance. It demonstrates the results of modern research and further problem study prospects.Key words: inflammatory intestinal diseases, non-specific ulcerative colitis, Crohn’s disease, pathogenesis, intestinal microflora, children. (Pediatric Pharmacology. – 2010; 7(5:54-58

  11. The Intimate Relationship between Vestibular Migraine and Meniere Disease: A Review of Pathogenesis and Presentation

    Directory of Open Access Journals (Sweden)

    Yuan F. Liu

    2016-01-01

    Full Text Available Vestibular migraine (VM has only recently been recognized as a distinct disease entity. One reason is that its symptoms overlap greatly with those of other vestibular disorders, especially Meniere disease (MD. The pathophysiology of neither VM nor MD is entirely elucidated. However, there are many theories linking migraine to both disorders. We reviewed the current understanding of migraine, VM, and MD and described how VM and MD are similar or different from each other in terms of pathophysiology and presentation, including hypotheses that the two share a common etiology and/or are variants of the same disease.

  12. Role of TGFβ signaling in the pathogenesis of Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Rommy eVon Bernhardi

    2015-10-01

    Full Text Available Aging is the main risk factor for Alzheimer’s disease (AD; being associated with conspicuous changes on microglia activation. Aged microglia exhibit an increased expression of cytokines, exacerbated reactivity to various stimuli, oxidative stress, and reduced phagocytosis of Aβ. Whereas normal inflammation is protective, it becomes dysregulated in the presence of a persistent stimulus, or in the context of an inflammatory environment, as observed in aging. Thus, neuroinflammation can be a self-perpetuating deleterious response, becoming a source of additional injury to host cells in neurodegenerative diseases. In aged individuals, although TGFβ is upregulated, its canonical Smad3 signaling is greatly reduced and neuroinflammation persists. This age-related Smad3 impairment reduces protective activation while facilitating cytotoxic activation of microglia through several cellular mechanisms, potentiating microglia-mediated neurodegeneration. Here, we critically discuss the role of TGFβ-Smad signaling on the cytotoxic activation of microglia and its relevance in the pathogenesis of AD. Other protective functions, such as phagocytosis, although observed in aged animals, are not further induced by inflammatory stimuli and TGFβ1. Analysis in silico revealed that increased expression of receptor SR-A, involved in Aβ uptake and cell activation, by microglia exposed to TGFβ, through a Smad3-dependent mechanism could be mediated by transcriptional co-factors Smad2/3 over the MSR1 gene. We discuss that changes of TGFβ-mediated regulation could at least partially mediate age-associated microglia changes, and, together with other changes on inflammatory response, could result in the reduction of protective activation and the potentiation of cytotoxicity of microglia, resulting in the promotion of neurodegenerative diseases.

  13. Understanding lack of understanding : Invalidation in rheumatic diseases

    NARCIS (Netherlands)

    Kool, M.B.

    2012-01-01

    The quality of life of patients with chronic rheumatic diseases is negatively influenced by symptoms such as pain, fatigue, and stiffness, and secondary symptoms such as physical limitations and depressive mood. On top of this burden, some patients experience negative responses from others, such as

  14. Gasotransmitters: Physiological Role and Involvement in the Pathogenesis of the Diseases.

    Science.gov (United States)

    Sukmansky, O I; Reutov, V P

    2016-01-01

    In recent decades, it has been found the existence of a new class of biologically active substances - gaseous mediators (gasotransmitters), performing in the cells the signaling function and with high specificity involved in the intercellular and intracellular communication. This review characterizes the main gasotransmitters: nitric oxide, carbon monoxide, hydrogen sulfide, sulfur dioxide and polysulfides. Their physiological role and involvement in the pathogenesis of diseases is described. Basic information about main gasotransmitters is generalized in the original table. Nitrate-Nitrite background, which is a chemical background of the existence of modern man, affects the intra- and intercellular signaling system, alters the ultrastructure of neurons, neuron-neuron and neuron-glia interaction, eliminates the effects of endogenous gasotransmitters and affects the average life expectancy. In accordance with the principle of cyclicity is proposed and substantiated the hypothesis of the existence of “hydrogen sulfide cycle”, combining three sulfur-containing gasotransmitters. It is suggested that the cyclic organization of gasotransmitters in the cells and the whole body can be due to the existence of a global principle of cyclicity, which can spread its influence on almost all the structural and functional levels in the animate and inanimate nature.

  15. Unintended effects of cardiovascular drugs on the pathogenesis of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Jun Wang

    Full Text Available Alzheimer's disease (AD is rapidly becoming one of the leading causes of disability and mortality in the elderly. As life-expectancy increases, an increasing number of people will rely on modern medicines to treat age-associated disorders. Among these medications, some might benefit, while others might exacerbate, the pathogenesis of AD. We screened 1,600 FDA approved drugs for β-amyloid (Aβ-modifying activity and identified drugs that can potentially influence amyloid precursor protein processing. In this study, we focused on cardiovascular drugs and demonstrated that some hypertensive medication can differentially modulate Aβ, both in vitro and in vivo. Our study suggests that some commonly prescribed drugs might exert unintended effects and modulate AD and provides the basis for continuing investigation of the role of individual drugs on a case-by-case basis. This line of investigation will lead to the identification of common medications that are potentially beneficial or detrimental to AD as a reference for physicians to consider when prescribing the most appropriate drugs for their patients, particularly for treating chronic disorders among the growing geriatric population.

  16. Atherosclerotic lesions and mitochondria DNA deletions in brain microvessels: implication in the pathogenesis of Alzheimer's disease.

    Science.gov (United States)

    Aliev, Gjumrakch; Gasimov, Eldar; Obrenovich, Mark E; Fischbach, Kathryn; Shenk, Justin C; Smith, Mark A; Perry, George

    2008-01-01

    The pathogenesis that is primarily responsible for Alzheimer's disease (AD) and cerebrovascular accidents (CVA) appears to involve chronic hypoperfusion. We studied the ultrastructural features of vascular lesions and mitochondria in brain vascular wall cells from human AD biopsy samples and two transgenic mouse models of AD, yeast artificial chromosome (YAC) and C57B6/SJL Tg (+), which overexpress human amyloid beta precursor protein (AbetaPP). In situ hybridization using probes for normal and 5 kb deleted human and mouse mitochondrial DNA (mtDNA) was performed along with immunocytochemistry using antibodies against the Abeta peptide processed from AbetaPP, 8-hydroxy-2'-guanosine (8OHG), and cytochrome c oxidase (COX). More amyloid deposition, oxidative stress markers as well as mitochondrial DNA deletions and structural abnormalities were present in the vascular walls of the human AD samples and the AbetaPP-YAC and C57B6/SJL Tg (+) transgenic mice compared to age-matched controls. Ultrastructural damage in perivascular cells highly correlated with endothelial lesions in all samples. Therefore, pharmacological interventions, directed at correcting the chronic hypoperfusion state, may change the natural course of the development of dementing neurodegeneration.

  17. Intestinal microbiota pathogenesis and fecal microbiota transplantation for inflammatory bowel disease

    Science.gov (United States)

    Wang, Zi-Kai; Yang, Yun-Sheng; Chen, Ye; Yuan, Jing; Sun, Gang; Peng, Li-Hua

    2014-01-01

    The intestinal microbiota plays an important role in inflammatory bowel disease (IBD). The pathogenesis of IBD involves inappropriate ongoing activation of the mucosal immune system driven by abnormal intestinal microbiota in genetically predisposed individuals. However, there are still no definitive microbial pathogens linked to the onset of IBD. The composition and function of the intestinal microbiota and their metabolites are indeed disturbed in IBD patients. The special alterations of gut microbiota associated with IBD remain to be evaluated. The microbial interactions and host-microbe immune interactions are still not clarified. Limitations of present probiotic products in IBD are mainly due to modest clinical efficacy, few available strains and no standardized administration. Fecal microbiota transplantation (FMT) may restore intestinal microbial homeostasis, and preliminary data have shown the clinical efficacy of FMT on refractory IBD or IBD combined with Clostridium difficile infection. Additionally, synthetic microbiota transplantation with the defined composition of fecal microbiota is also a promising therapeutic approach for IBD. However, FMT-related barriers, including the mechanism of restoring gut microbiota, standardized donor screening, fecal material preparation and administration, and long-term safety should be resolved. The role of intestinal microbiota and FMT in IBD should be further investigated by metagenomic and metatranscriptomic analyses combined with germ-free/human flora-associated animals and chemostat gut models. PMID:25356041

  18. Understanding HIV infection for the design of a therapeutic vaccine. Part I: Epidemiology and pathogenesis of HIV infection.

    Science.gov (United States)

    de Goede, A L; Vulto, A G; Osterhaus, A D M E; Gruters, R A

    2015-03-01

    HIV infection leads to a gradual loss CD4+ T lymphocytes comprising immune competence and progression to AIDS. Effective treatment with combined antiretroviral drugs (cART) decreases viral load below detectable levels but is not able to eliminate the virus from the body. The success of cART is frustrated by the requirement of expensive life-long adherence, accumulating drug toxicities and chronic immune activation resulting in increased risk of several non-AIDS disorders, even when viral replication is suppressed. Therefore there is a strong need for therapeutic strategies as an alternative to cART. Immunotherapy, or therapeutic vaccination, aims to increase existing immune responses against HIV or induce de novo immune responses. These immune responses should provide a functional cure by controlling viral replication and preventing disease progression in the absence of cART. The key difficulty in the development of an HIV vaccine is our ignorance of the immune responses that control of viral replication, and thus how these responses can be elicited and how they can be monitored. Part one of this review provides an extensive overview of the (patho-) physiology of HIV infection. It describes the structure and replication cycle of HIV, the epidemiology and pathogenesis of HIV infection and the innate and adaptive immune responses against HIV. Part two of this review discusses therapeutic options for HIV. Prevention modalities and antiretroviral therapy are briefly touched upon, after which an extensive overview on vaccination strategies for HIV is provided, including the choice of immunogens and delivery strategies. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  19. Report of the ECCO pathogenesis workshop on anti-TNF therapy failures in inflammatory bowel diseases: definitions, frequency and pharmacological aspects

    DEFF Research Database (Denmark)

    Allez, Matthieu; Karmiris, Konstantinos; Louis, Edouard

    2010-01-01

    The first ECCO pathogenesis workshop focused on anti-TNF therapy failures in inflammatory bowel diseases (IBDs). The overall objective was to better understand and explore primary non response and loss of response to anti-TNF agents in IBD. The outcome of this workshop is presented into two parts....... This first section addresses definitions, frequency and pharmacological aspects of anti-TNF therapy failure, including pharmacokinetics of anti-TNF monoclonal antibodies and immune and non-immune mediated clearance of anti-TNF mAbs. The second section concerns the biological roles of TNF and TNF antagonists...

  20. Is Oxidative Stress Associated with Activation and Pathogenesis of Inflammatory Bowel Disease?

    Directory of Open Access Journals (Sweden)

    Yuksel Mahmut

    2017-08-01

    Full Text Available Background: We aimed to determine the levels of total antioxidant status (TAS, total oxidant status (TOS, oxidative stress index (OSI and paraoxonase1/arylesterase levels in inflammatory bowel disease (IBD, and the relation be - tween these molecules and the activity index of the disease. Methods: Eighty IBD patients (ulcerative colitis (UC/Crohn disease (CD 40/40 and 80 control group participants were included in the study. Oxidative stress parameters were measured using the colorimetric method. As disease activity indexes, the endoscopic activity index (EAI was used for UC and the CD activity index (CDAI was used for CD. Results: In IBD patients, mean TAS (1.3±0.2 vs 1.9±0.2, respectively; p<0.001 and arylesterase (963.9±232.2 vs 1252.9±275, respectively; p<0.001 levels were found to be lower and TOS level (5.6±1.6 vs 4.0±1.0, respectively; p<0.001 and OSI rate (4.5±1.6 vs 2.2±0.8, respectively; p<0.001 were found to be higher compared to the control group. A strong positive correlation was found between EAI and TOS levels (r=0.948, p<0.001 and OSI rate (r=0.894, p<0.001 for UC patients. A very strong positive correlation was found between EAI and TOS levels (r=0.964, p<0.001 and OSI rate (r=0.917, p<0.001 for CD patients. It was found in a stepwise regression model that C-reactive protein, OSI and arylesterase risk factors were predictors of IBD compared to the control group. Conclusion: Increased oxidative stress level in IBD patients and the detection of OSI rate as an independent predictor for disease activity indexes lead to the idea that oxidative stress might be related to the pathogenesis of IBD.

  1. Mast Cell Activation in Brain Injury, Stress, and Post-traumatic Stress Disorder and Alzheimer's Disease Pathogenesis

    Directory of Open Access Journals (Sweden)

    Duraisamy Kempuraj

    2017-12-01

    Full Text Available Mast cells are localized throughout the body and mediate allergic, immune, and inflammatory reactions. They are heterogeneous, tissue-resident, long-lived, and granulated cells. Mast cells increase their numbers in specific site in the body by proliferation, increased recruitment, increased survival, and increased rate of maturation from its progenitors. Mast cells are implicated in brain injuries, neuropsychiatric disorders, stress, neuroinflammation, and neurodegeneration. Brain mast cells are the first responders before microglia in the brain injuries since mast cells can release prestored mediators. Mast cells also can detect amyloid plaque formation during Alzheimer's disease (AD pathogenesis. Stress conditions activate mast cells to release prestored and newly synthesized inflammatory mediators and induce increased blood-brain barrier permeability, recruitment of immune and inflammatory cells into the brain and neuroinflammation. Stress induces the release of corticotropin-releasing hormone (CRH from paraventricular nucleus of hypothalamus and mast cells. CRH activates glial cells and mast cells through CRH receptors and releases neuroinflammatory mediators. Stress also increases proinflammatory mediator release in the peripheral systems that can induce and augment neuroinflammation. Post-traumatic stress disorder (PTSD is a traumatic-chronic stress related mental dysfunction. Currently there is no specific therapy to treat PTSD since its disease mechanisms are not yet clearly understood. Moreover, recent reports indicate that PTSD could induce and augment neuroinflammation and neurodegeneration in the pathogenesis of neurodegenerative diseases. Mast cells play a crucial role in the peripheral inflammation as well as in neuroinflammation due to brain injuries, stress, depression, and PTSD. Therefore, mast cells activation in brain injury, stress, and PTSD may accelerate the pathogenesis of neuroinflammatory and neurodegenerative diseases

  2. Mast Cell Activation in Brain Injury, Stress, and Post-traumatic Stress Disorder and Alzheimer's Disease Pathogenesis.

    Science.gov (United States)

    Kempuraj, Duraisamy; Selvakumar, Govindhasamy P; Thangavel, Ramasamy; Ahmed, Mohammad E; Zaheer, Smita; Raikwar, Sudhanshu P; Iyer, Shankar S; Bhagavan, Sachin M; Beladakere-Ramaswamy, Swathi; Zaheer, Asgar

    2017-01-01

    Mast cells are localized throughout the body and mediate allergic, immune, and inflammatory reactions. They are heterogeneous, tissue-resident, long-lived, and granulated cells. Mast cells increase their numbers in specific site in the body by proliferation, increased recruitment, increased survival, and increased rate of maturation from its progenitors. Mast cells are implicated in brain injuries, neuropsychiatric disorders, stress, neuroinflammation, and neurodegeneration. Brain mast cells are the first responders before microglia in the brain injuries since mast cells can release prestored mediators. Mast cells also can detect amyloid plaque formation during Alzheimer's disease (AD) pathogenesis. Stress conditions activate mast cells to release prestored and newly synthesized inflammatory mediators and induce increased blood-brain barrier permeability, recruitment of immune and inflammatory cells into the brain and neuroinflammation. Stress induces the release of corticotropin-releasing hormone (CRH) from paraventricular nucleus of hypothalamus and mast cells. CRH activates glial cells and mast cells through CRH receptors and releases neuroinflammatory mediators. Stress also increases proinflammatory mediator release in the peripheral systems that can induce and augment neuroinflammation. Post-traumatic stress disorder (PTSD) is a traumatic-chronic stress related mental dysfunction. Currently there is no specific therapy to treat PTSD since its disease mechanisms are not yet clearly understood. Moreover, recent reports indicate that PTSD could induce and augment neuroinflammation and neurodegeneration in the pathogenesis of neurodegenerative diseases. Mast cells play a crucial role in the peripheral inflammation as well as in neuroinflammation due to brain injuries, stress, depression, and PTSD. Therefore, mast cells activation in brain injury, stress, and PTSD may accelerate the pathogenesis of neuroinflammatory and neurodegenerative diseases including AD. This

  3. Pathogenesis and management issues for non-alcoholic fatty liver disease

    Science.gov (United States)

    Duvnjak, Marko; Lerotić, Ivan; Baršić, Neven; Tomašić, Vedran; Jukić, Lucija Virović; Velagić, Vedran

    2007-01-01

    Nonalcoholic fatty liver disease (NAFLD) has, although it is a very common disorder, only relatively recently gained broader interest among physicians and scientists. Fatty liver has been documented in up to 10 to 15 percent of normal individuals and 70 to 80 percent of obese individuals. Although the pathophysiology of NAFLD is still subject to intensive research, several players and mechanisms have been suggested based on the substantial evidence. Excessive hepatocyte triglyceride accumulation resulting from insulin resistance is the first step in the proposed ‘two hit’ model of the pathogenesis of NAFLD. Oxidative stress resulting from mitochondrial fatty acids oxidation, NF-κB-dependent inflammatory cytokine expression and adipocytokines are all considered to be the potential factors causing second hits which lead to hepatocyte injury, inflammation and fibrosis. Although it was initially believed that NAFLD is a completely benign disorder, histologic follow-up studies have showed that fibrosis progression occurs in about a third of patients. A small number of patients with NAFLD eventually ends up with end-stage liver disease and even hepatocellular carcinoma. Although liver biopsy is currently the only way to confirm the NAFLD diagnosis and distinguish between fatty liver alone and NASH, no guidelines or firm recommendations can still be made as for when and in whom it is necessary. Increased physical activity, gradual weight reduction and in selected cases bariatric surgery remain the mainstay of NAFLD therapy. Studies with pharmacologic agents are showing promising results, but available data are still insufficient to make specific recommendations; their use therefore remains highly individual. PMID:17729403

  4. The Involvement of Immune Semaphorins in the Pathogenesis of Inflammatory Bowel Diseases (IBDs.

    Directory of Open Access Journals (Sweden)

    Zahava Vadasz

    Full Text Available Immune semaphorins are a large family of proteins involved in the pathogenesis of inflammatory diseases through the regulation of immune homeostasis and tissue inflammation. We aim to assess the possible involvement of semaphorin3A (sema3A and 4A (sema4A in peripheral immune responses and bowel tissue inflammation of patients suffering from Crohn's disease (CD and ulcerative colitis (UC.Twenty-seven CD patients and 10 UC patients were studied and compared to 10 patients followed for acute diverticulitis (disease control and 12 healthy individuals. All were evaluated for sema3A expression on T regulatory cells (Tregs, serum levels of sema3A and sema4A, and tissue expression of sema3A and sema4A in bowel biopsies.The percentage (% of T regulatory cells (Tregs expressing sema3A in patients with active CD (64.5% ± 14.49% and active UC (49.8% ± 16.45% was significantly lower when compared to that of healthy controls (88.7% ± 3.6%, p< 0.001 and p< 0.0001, respectively. This expression was seen to be in negative correlation with CD activity. Serum levels of Sema4A were significantly lower in patients with CD and UC when compared to that of controls (5.69 ± 1 .48 ng\\ml for CD, 5.26 ± 1.23 ng/ml for UC patients vs 9.74 ± 2.73 ng/ml for normal controls, P<0.001. Sema4A was highly expressed in lymphocytes of the lamina propria of CD and UC patients but absent in patients with diverticulitis or in normal individuals.Altered % of Tregs expressing sema3A in patients with inflammatory bowel diseases (IBD is partially responsible for their failure in preventing CD4+ effector T cell induced inflammation in IBD in peripheral blood. The increased expression of sema4A in bowel biopsies from CD and UC patients is suggestive of its central role in regulating local tissue inflammation in the bowel.

  5. Assessing neuronal networks: understanding Alzheimer's disease.

    LENUS (Irish Health Repository)

    Bokde, Arun L W

    2012-02-01

    Findings derived from neuroimaging of the structural and functional organization of the human brain have led to the widely supported hypothesis that neuronal networks of temporally coordinated brain activity across different regional brain structures underpin cognitive function. Failure of integration within a network leads to cognitive dysfunction. The current discussion on Alzheimer\\'s disease (AD) argues that it presents in part a disconnection syndrome. Studies using functional magnetic resonance imaging, positron emission tomography and electroencephalography demonstrate that synchronicity of brain activity is altered in AD and correlates with cognitive deficits. Moreover, recent advances in diffusion tensor imaging have made it possible to track axonal projections across the brain, revealing substantial regional impairment in fiber-tract integrity in AD. Accumulating evidence points towards a network breakdown reflecting disconnection at both the structural and functional system level. The exact relationship among these multiple mechanistic variables and their contribution to cognitive alterations and ultimately decline is yet unknown. Focused research efforts aimed at the integration of both function and structure hold great promise not only in improving our understanding of cognition but also of its characteristic progressive metamorphosis in complex chronic neurodegenerative disorders such as AD.

  6. Recent advances in understanding autoimmune thyroid disease

    DEFF Research Database (Denmark)

    Bliddal, Sofie; Nielsen, Claus Henrik; Feldt-Rasmussen, Ulla

    2017-01-01

    Autoimmune thyroid disease (AITD) is often observed together with other autoimmune diseases. The coexistence of two or more autoimmune diseases in the same patient is referred to as polyautoimmunity, and AITD is the autoimmune disease most frequently involved. The occurrence of polyautoimmunity has...... led to the hypothesis that the affected patients suffer from a generalized dysregulation of their immune system. The present review summarizes recent discoveries unravelling the immunological mechanisms involved in autoimmunity, ranging from natural autoimmunity to disease-specific autoimmunity...

  7. MicroRNAs located in the Hox gene clusters are implicated in huntington's disease pathogenesis.

    Directory of Open Access Journals (Sweden)

    Andrew G Hoss

    2014-02-01

    Full Text Available Transcriptional dysregulation has long been recognized as central to the pathogenesis of Huntington's disease (HD. MicroRNAs (miRNAs represent a major system of post-transcriptional regulation, by either preventing translational initiation or by targeting transcripts for storage or for degradation. Using next-generation miRNA sequencing in prefrontal cortex (Brodmann Area 9 of twelve HD and nine controls, we identified five miRNAs (miR-10b-5p, miR-196a-5p, miR-196b-5p, miR-615-3p and miR-1247-5p up-regulated in HD at genome-wide significance (FDR q-value<0.05. Three of these, miR-196a-5p, miR-196b-5p and miR-615-3p, were expressed at near zero levels in control brains. Expression was verified for all five miRNAs using reverse transcription quantitative PCR and all but miR-1247-5p were replicated in an independent sample (8HD/8C. Ectopic miR-10b-5p expression in PC12 HTT-Q73 cells increased survival by MTT assay and cell viability staining suggesting increased expression may be a protective response. All of the miRNAs but miR-1247-5p are located in intergenic regions of Hox clusters. Total mRNA sequencing in the same samples identified fifteen of 55 genes within the Hox cluster gene regions as differentially expressed in HD, and the Hox genes immediately adjacent to the four Hox cluster miRNAs as up-regulated. Pathway analysis of mRNA targets of these miRNAs implicated functions for neuronal differentiation, neurite outgrowth, cell death and survival. In regression models among the HD brains, huntingtin CAG repeat size, onset age and age at death were independently found to be inversely related to miR-10b-5p levels. CAG repeat size and onset age were independently inversely related to miR-196a-5p, onset age was inversely related to miR-196b-5p and age at death was inversely related to miR-615-3p expression. These results suggest these Hox-related miRNAs may be involved in neuroprotective response in HD. Recently, miRNAs have shown promise as

  8. THE ROLE OF MICROBIAL COMMUNITIES OF AIRWAYS IN PATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE

    Directory of Open Access Journals (Sweden)

    S. V. Fedosenko

    2014-01-01

    Full Text Available This review summarizes the results of studies on the composition of microbial communities in the airways of healthy subjects and in patients with chronic obstructive pulmonary disease. Modern technologies of molecular-genetic identification methods of microorganisms allow to perform a deep analysis  of  the  respiratory  microbiom.  It  is  of  considerable  interest  to  determine  the  role  of  the microbiome in the development of human diseases of the bronchopulmonary system, and to understand the impact of the microbes communities as a course of disease and the important factor for the efficacy of current therapy.

  9. When Blood Cells Bend: Understanding Sickle Cell Disease

    Science.gov (United States)

    ... Subscribe April 2012 Print this issue When Blood Cells Bend Understanding Sickle Cell Disease Send us your ... Diabetes? Sound Health Wise Choices Living with Sickle Cell Disease See a sickle cell disease expert regularly. ...

  10. The Role of Inflammatory Mediators in the Pathogenesis of Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Gholamreza Azizi

    2015-08-01

    Full Text Available Alzheimer’s disease (AD, a neurodegenerative disorder associated with advanced age, is the most common cause of dementia globally. AD is characterised by cognitive dysfunction, deposition of amyloid plaques, neurofibrillary tangles and neuro-inflammation. Inflammation of the brain is a key pathological hallmark of AD. Thus, clinical and immunopathological evidence of AD could be potentially supported by inflammatory mediators, including cytokines, chemokines, the complement system, acute phase proteins and oxidative mediators. In particular, oxidative mediators may actively contribute to the progression of AD and on-going inflammation in the brain. This review provides an overview of the functions and activities of inflammatory mediators in AD. An improved understanding of inflammatory processes and their role in AD is needed to improve therapeutic research aims in the field of AD and similar diseases.

  11. Unexpected relevance of the hallmarks of cancer to the pathogenesis of polycystic kidney disease

    Science.gov (United States)

    Seeger-Nukpezah, Tamina; Geynisman, Daniel M.; Nikonova, Anna S.; Benzing, Thomas; Golemis, Erica A.

    2018-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a progressive inherited disorder in which renal tissue is gradually replaced with fluid-filled cysts, giving rise to chronic kidney disease (CKD) and progressive loss of renal function. ADPKD is also associated with liver ductal cysts, hypertension, chronic pain and extrarenal problems such as cerebral aneurysms. Intriguingly, improved understanding of the signalling and pathological derangements characteristic of ADPKD has revealed marked similarities to those of solid tumours, even though the gross presentation of tumours and the greater morbidity and mortality associated with tumour invasion and metastasis would initially suggest an entirely different disease processes. The commonalities between ADPKD and cancer are provocative, particularly in the context of recent preclinical and clinical studies of ADPKD that have shown promise with drugs that were originally developed for cancer. The potential therapeutic benefit of such repurposing has led us to review in detail the pathological features of ADPKD through the lens of the defined, classic hallmarks of cancer. In addition, we have evaluated features typical of ADPKD, and determined whether evidence supports the presence of such features in cancer cells. This analysis, which places pathological processes in the context of defined signalling pathways and approved signalling inhibitors, highlights potential avenues for further research and therapeutic exploitation in both diseases. PMID:25870008

  12. Role of microbial communities in the pathogenesis of periodontal diseases and caries.

    Science.gov (United States)

    Mira, Alex; Simon-Soro, A; Curtis, M A

    2017-03-01

    The microbiological characteristics of both caries and periodontal disease show significant change from those in health. In both instances, there is evidence of co-association of different organisms into consortia. We review and summarize a number of issues pertinent to the community organization and functional activity of the bacterial populations resident on supra- and subgingival tooth surface and the influence of these populations on disease. A literature review was undertaken with a particular emphasis on recent publications involving high-throughput, deep sequencing approaches to the analysis of microbial populations and their functional activity. There is increasing evidence to suggest that both caries and periodontal disease represent dysbiotic states of the oral microbiome. The mode of acquisition of the oral microbial communities may be less passive than previously recognized but once established remains relatively stable within an individual although there are very significant site variations. A repertoire of stable dysbiotic states may occur in both caries and periodontitis involving different microbial community structures with potentially similar functional properties. The processes which underlie the development and stability of microbial populations in the healthy mouth are fundamental to understanding how these populations are transformed into a dysbiotic state in disease. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Epigenetics: The missing link to understanding β-cell dysfunction in the pathogenesis of type 2 diabetes

    OpenAIRE

    Gilbert, Elizabeth R.; Liu, Dongmin

    2012-01-01

    Type 2 diabetes (T2D) is a growing health problem worldwide. While peripheral insulin resistance is common during obesity and aging in both animals and people, progression to T2D is largely due to insulin secretory dysfunction and significant apoptosis of functional β-cells, leading to an inability to compensate for insulin resistance. It is recognized that environmental factors and nutrition play an important role in the pathogenesis of diabetes. However, our knowledge surrounding molecular ...

  14. Crohn’s Disease: a Role of Gut Microbiota and Nod2 Gene Polymorphisms in Disease Pathogenesis

    Directory of Open Access Journals (Sweden)

    Lucia Hrnčířová

    2014-01-01

    Full Text Available Crohn’s disease is a chronic immune-mediated intestinal inflammation targeted against a yet incompletely defined subset of commensal gut microbiota and occurs on the background of a genetic predisposition under the influence of environmental factors. Genome-wide association studies have identified about 70 genetic risk loci associated with Crohn’s disease. The greatest risk for Crohn’s disease represent polymorphisms affecting the CARD15 gene encoding nucleotide-binding oligomerization domain 2 (NOD2 which is an intracellular sensor for muramyl dipeptide, a peptidoglycan constituent of bacterial cell wall. The accumulated evidence suggests that gut microbiota represent an essential, perhaps a central factor in the induction and maintaining of Crohn’s disease where dysregulation of normal co-evolved homeostatic relationships between intestinal microbiota and host mucosal immune system leads to intestinal inflammation. Taken together, these findings identify Crohn’s disease as a syndrome of overlapping phenotypes that involves variable influences of genetic and environmental factors. A deeper understanding of different genetic abnormalities underlying Crohn’s disease together with the identification of beneficial and harmful components of gut microbiota and their interactions are essential conditions for the categorization of Crohn’s disease patients, which enable us to design more effective, preferably causative, individually tailored therapy.

  15. Evaluation of the oxidant and antioxidant balance in the pathogenesis of chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    C. Cristóvão

    2013-03-01

    Full Text Available Chronic obstructive pulmonary disease (COPD is one of the most common chronic diseases and a major cause of morbidity and mortality. An imbalance between oxidants and antioxidants (oxidative stress has been proposed as a critical event in the pathogenesis of COPD. The increased oxidative stress in patients with COPD is the result of exogenous oxidants namely pollutants and cigarette smoke as well as endogenous oxidant production during inflammation. The aim of the present study was to clarify the hypothesis about the presence of an imbalance between oxidants and the antioxidant defences associated to COPD. In this study, we evaluated a biomarker of oxidative stress (malondialdehyde, a lipid peroxidation derived product and non-enzymatic antioxidants (vitamin C and the sulphydryl groups in COPD patients and healthy controls. The marker of oxidative stress was found to be significantly (p < 0.001 higher in COPD patients when compared with control group. No age dependent changes in the plasma levels of lipid peroxidation products were found. COPD patients had a significant (p < 0.001 decrease in antioxidant status as compared with control group. Our results show that oxidative stress is an important pathophysiologic change in COPD. Resumo: A doença pulmonar obstrutiva crónica (DPOC é uma das doenças crónicas mais comuns e representa uma importante causa de morbilidade e mortalidade. Um desequilíbrio entre oxidantes e antioxidantes (stress oxidativo tem sido proposto como um acontecimento importante na patogénese da DPOC. O aumento do stress oxidativo em doentes com DPOC é o resultado da presença de oxidantes exógenos, nomeadamente, poluentes e fumo do tabaco, assim como oxidantes endógenos produzidos durante a inflamação. O objetivo do presente estudo consistiu em clarificar a hipótese sobre a existência de um desequilíbrio entre oxidantes e as defesas antioxidantes associado à DPOC. Neste estudo, avaliou-se um biomarcador do

  16. Role of peroxisome proliferators-activated receptors in the pathogenesis and treatment of nonalcoholic fatty liver disease.

    Science.gov (United States)

    Kallwitz, Eric R; McLachlan, Alan; Cotler, Scott J

    2008-01-07

    Nonalcoholic fatty liver disease (NAFLD) is highly prevalent and can result in nonalcoholic steatohepatitis (NASH) and progressive liver disease including cirrhosis and hepatocellular carcinoma. A growing body of literature implicates the peroxisome proliferators-activated receptors (PPARs) in the pathogenesis and treatment of NAFLD. These nuclear hormone receptors impact on hepatic triglyceride accumulation and insulin resistance. The aim of this review is to describe the data linking PPAR alpha and PPAR gamma to NAFLD/NASH and to discuss the use of PPAR ligands for the treatment of NASH.

  17. Molecular Pathogenesis of NASH

    Directory of Open Access Journals (Sweden)

    Alessandra Caligiuri

    2016-09-01

    Full Text Available Nonalcoholic steatohepatitis (NASH is the main cause of chronic liver disease in the Western world and a major health problem, owing to its close association with obesity, diabetes, and the metabolic syndrome. NASH progression results from numerous events originating within the liver, as well as from signals derived from the adipose tissue and the gastrointestinal tract. In a fraction of NASH patients, disease may progress, eventually leading to advanced fibrosis, cirrhosis and hepatocellular carcinoma. Understanding the mechanisms leading to NASH and its evolution to cirrhosis is critical to identifying effective approaches for the treatment of this condition. In this review, we focus on some of the most recent data reported on the pathogenesis of NASH and its fibrogenic progression, highlighting potential targets for treatment or identification of biomarkers of disease progression.

  18. Hydrogen sulphide and the kidney: important roles in renal physiology and pathogenesis and treatment of kidney injury and disease.

    Science.gov (United States)

    Lobb, I; Sonke, E; Aboalsamh, G; Sener, A

    2015-04-30

    The kidney is an essential mammalian organ that serves to filter toxins and metabolic by-products out of the blood, which are then excreted through urine. Hydrogen sulphide (H2S) is a recently characterized, endogenous gaseous molecule with important physiological roles. Many interesting roles continue to be identified for H2S related specifically to the kidney. The current review discusses how production and action of H2S influences normal physiology of the kidney. We investigate as well the many roles H2S plays in the pathogenesis and treatment of kidney injury and disease, such as chronic kidney disease (CKD), ureteral obstruction (UO), hyperhomocysteinaemia (HHcy), drug-induced nephrotoxicity (DIN) and renal ischaemia reperfusion injury (IRI). We suggest that H2S plays a complex and essential role in the normal function of the kidney and dysregulation of H2S production can directly or indirectly contribute to the pathogenesis of renal disease and injury. Also, H2S could be a promising potential therapeutic treatment to decrease the severity of several renal diseases. Further research will identify increasingly important and complex roles for H2S in renal physiology and how H2S can be effectively utilized to improve clinical outcomes of renal disease. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Illness understanding in children and adolescents with heart disease

    OpenAIRE

    Veldtman, G; Matley, S; Kendall, L; Quirk, J; Gibbs, J; Parsons, J; Hewison, J

    2000-01-01

    AIMS—To evaluate illness knowledge and understanding in children and adolescents with congenital and acquired heart disease, and whether the degree of understanding is related to age, sex, or complexity of the heart disease.
DESIGN—Prospective cohort study.
SETTING—Tertiary paediatric cardiac centre.
METHODS—Patients' understanding of their congenital heart disease was assessed in a representative sample of volunteers aged between 7-18 years using semistructured interviews based upon Leventha...

  20. Illness understanding in children and adolescents with heart disease

    OpenAIRE

    Veldtman, G R; Matley, S L; Kendall, L; Quirk, J; Gibbs, J L; Parsons, J M; Hewison, J

    2001-01-01

    Aims To evaluate illness knowledge and understanding in children and adolescents with congenital and acquired heart disease and to assess whether the degree of understanding is related to age, sex, or complexity of the heart disease. Design Prospective cohort study. Setting Tertiary pediatric cardiac center. Methods Patients' understanding of their congenital heart disease was assessed in a representative sample of volunteers aged between 7 and 18 years using semistructured interviews based o...

  1. Defining Kidney Biology to Understand Renal Disease

    Science.gov (United States)

    Little, Melissa H.; Brown, Dennis; Humphreys, Benjamin D.; McMahon, Andrew P.; Miner, Jeffrey H.; Sands, Jeff M.; Weisz, Ora A.; Mullins, Chris

    2014-01-01

    The Kidney Research National Dialogue represents a novel effort by the National Institute of Diabetes and Digestive and Kidney Diseases to solicit and prioritize research objectives from the renal research and clinical communities. The present commentary highlights selected scientific opportunities specific to the study of renal development, physiology, and cell biology. Describing such fundamental kidney biology serves as a necessary foundation for translational and clinical studies that will advance disease care and prevention. It is intended that these objectives foster and focus scientific efforts in these areas in the coming decade and beyond. PMID:24370769

  2. Understanding the sensory irregularities of esophageal disease.

    Science.gov (United States)

    Farmer, Adam D; Brock, Christina; Frøkjaer, Jens Brøndum; Gregersen, Hans; Khan, Sheeba; Lelic, Dina; Lottrup, Christian; Drewes, Asbjørn Mohr

    2016-08-01

    Symptoms relating to esophageal sensory abnormalities can be encountered in the clinical environment. Such sensory abnormalities may be present in demonstrable disease, such as erosive esophagitis, and in the ostensibly normal esophagus, such as non-erosive reflux disease or functional chest pain. In this review, the authors discuss esophageal sensation and the esophageal pain system. In addition, the authors provide a primer concerning the techniques that are available for investigating the autonomic nervous system, neuroimaging and neurophysiology of esophageal sensory function. Such technological advances, whilst not readily available in the clinic may facilitate the stratification and individualization of therapy in disorders of esophageal sensation in the future.

  3. Necrotizing enterocolitis. New thoughts about pathogenesis and potential treatments.

    Science.gov (United States)

    MacKendrick, W; Caplan, M

    1993-10-01

    Necrotizing enterocolitis (NEC) remains a major cause of morbidity and mortality in premature infants. An incomplete understanding of its pathogenesis has hampered efforts to devise an effective preventative strategy. New insights into the pathogenesis of NEC, particularly at the cellular and biochemical level, however, offer a rational basis for the development of new approaches to this disease.

  4. Development of in vitro models for a better understanding of the early pathogenesis of Batrachochytrium dendrobatidis infections in amphibians.

    Science.gov (United States)

    Van Rooij, Pascale; Martel, An; Brutyn, Melanie; Maes, Sofie; Chiers, Koen; Van Waeyenberghe, Lieven; Croubels, Siska; Haesebrouck, Freddy; Pasmans, Frank

    2010-12-01

    Batrachochytrium dendrobatidis, the causal agent of chytridiomycosis, is implicated in the global decline of amphibians. This chytrid fungus invades keratinised epithelial cells, and infection is mainly associated with epidermal hyperplasia and hyperkeratosis. Since little is known about the pathogenesis of chytridiomycosis, this study was designed to optimise the conditions under which primary keratinocytes and epidermal explants of amphibian skin could be maintained ex vivo for several days. The usefulness of the following set-ups for pathogenesis studies was investigated: a) cultures of primary keratinocytes; b) stripped epidermal (SE) explants; c) full-thickness epidermal (FTE) explants on Matrigel™; d) FTE explants in cell culture inserts; and e) FTE explants in Ussing chambers. SE explants proved most suitable for short-term studies, since adherence of fluorescently-labelled zoospores to the superficial epidermis could be observed within one hour of infection. FTE explants in an Ussing chamber set-up are most suitable for the study of the later developmental stages of B. dendrobatidis in amphibian skin up to five days post-infection. These models provide a good alternative for in vivo experiments, and reduce the number of experimental animals needed. 2010 FRAME.

  5. Distinct Roles of Wnt/β-Catenin Signaling in the Pathogenesis of Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis

    Science.gov (United States)

    Shi, Juan; Li, Feng; Luo, Meihui; Wei, Jun

    2017-01-01

    Wnt signaling pathways are tightly controlled under a physiological condition, under which they play key roles in many biological functions, including cell fate specification and tissue regeneration. Increasing lines of evidence recently demonstrated that a dysregulated activation of Wnt signaling, particularly the Wnt/β-catenin signaling, was involved in the pathogenesis of chronic pulmonary diseases, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). In this respect, Wnt signaling interacts with other cellular signaling pathways to regulate the initiation and pathogenic procedures of airway inflammation and remodeling, pulmonary myofibroblast proliferation, epithelial-to-mesenchymal transition (EMT), and development of emphysema. Intriguingly, Wnt/β-catenin signaling is activated in IPF; an inhibition of this signaling leads to an alleviation of pulmonary inflammation and fibrosis in experimental models. Conversely, Wnt/β-catenin signaling is inactivated in COPD tissues, and its reactivation results in an amelioration of airspace enlargement with a restored alveolar epithelial structure and function in emphysema models. These studies thus imply distinct mechanisms of Wnt/β-catenin signaling in the pathogenesis of these two chronic pulmonary diseases, indicating potential targets for COPD and IPF treatments. This review article aims to summarize the involvement and pathogenic roles of Wnt signaling pathways in the COPD and IPF, with a focus on the implication of Wnt/β-catenin signaling as underlying mechanisms and therapeutic targets in these two incurable diseases. PMID:28588349

  6. Making headway in understanding pine wilt disease: what do we perceive in the postgenomic era?

    Science.gov (United States)

    Shinya, Ryoji; Morisaka, Hironobu; Takeuchi, Yuko; Futai, Kazuyoshi; Ueda, Mitsuyoshi

    2013-07-01

    The advent of next generation sequencing has revolutionized research approaches to biology by making entire genome sequences available and marking a new age in biology that has the potential to open innovative research avenues in various fields. Genome sequencing is now being applied in the fields of forest ecology and forest pathology, which previously had limited access to molecular techniques. One of the most advanced areas of progress is the study of "pine wilt disease", which is caused by the parasitic nematode, Bursaphelenchus xylophilus. The entire genome sequence of B. xylophilus was determined in 2011, and since then, proteomic studies have been conducted to understand the molecular basis of the parasitism and pathogenicity of B. xylophilus. These postgenomic studies have provided numerous molecular insights and greatly changed our understanding of the pathogenesis of pine wilt disease. Here, we review the recent advances in genomic and proteomic approaches that address some of the longstanding questions behind the pathogenesis of pine wilt disease and have identified future questions and directions in this regard. Copyright © 2013 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

  7. Understanding nutrition and immunity in disease management.

    Science.gov (United States)

    Cooper, Edwin L; Ma, Melissa J

    2017-10-01

    As we search for answers to modern medicine's most prevalent and challenging problems, the relationship between nutrition, immunity, and biological function of various natural compounds are preimminent. Nutritional research involving genomics provides rational capabilities for preventing disease. Scientific advances in genomic sequencing reveal opportunities for exploring diet-health relationships and potential for individual, genotype based dietary recommendations. Utilizing molecular and genetic technology to analyze impact of nutrition on genomics and metabolism reveals that nutrients may influence certain innate and/or acquired immune functions. By analyzing immune mechanisms including their cells and complex molecules, animal models have offered relevant insight that clarifies interrelations between immunity and nutrition. Plant products also provide numerous resources through bioengineering for designing novel pharmaceuticals. Having long been employed successfully in traditional and folk medicines, plant compounds exhibit anti-inflammatory, antimicrobial, and angiogenic activity. As a result, we now have a promising arsenal for successful application of bioactive compounds.

  8. Possible role of histamine in pathogenesis of autoimmune diseases: implications for immunotherapy with histamine-2 receptor antagonists

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen; Hammer, J H

    1992-01-01

    The immunosuppressive chemical drugs cyclosporine A (CsA) and methotrexate (Mx) have recently been shown to be of benefit in several different diseases of autoimmune origin. Cellular immune responses may play a major role in autoimmunity as autoreactive T lymphocytes appear to recognize...... autoantigens and major histocompatibility complex (MHC) class II restriction molecules presented by non-immune, aberrant cells, subsequently leading to damage on healthy tissues. Psoriasis is suggested to be an autoimmune disease and in severe, uncontrollable psoriasis CsA and Mx are of value in reducing...... the possibility, that histamine is one of the molecules involved in pathogenesis of autoimmune diseases. T cell mediated regulation and suppression of autoreactive T cells seem to be ineffective in controlling the enhanced immune reaction in patients where the discrimination between self and non-self is changed...

  9. Possible role of histamine in pathogenesis of autoimmune diseases: implications for immunotherapy with histamine-2 receptor antagonists

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen; Hammer, J H

    1992-01-01

    The immunosuppressive chemical drugs cyclosporine A (CsA) and methotrexate (Mx) have recently been shown to be of benefit in several different diseases of autoimmune origin. Cellular immune responses may play a major role in autoimmunity as autoreactive T lymphocytes appear to recognize autoantig......The immunosuppressive chemical drugs cyclosporine A (CsA) and methotrexate (Mx) have recently been shown to be of benefit in several different diseases of autoimmune origin. Cellular immune responses may play a major role in autoimmunity as autoreactive T lymphocytes appear to recognize...... the possibility, that histamine is one of the molecules involved in pathogenesis of autoimmune diseases. T cell mediated regulation and suppression of autoreactive T cells seem to be ineffective in controlling the enhanced immune reaction in patients where the discrimination between self and non-self is changed...

  10. Diffuse neuroendocrine system and mitochondrial diseases: molecular and cellular bases of pathogenesis, new approaches to diagnosis and therapy.

    Science.gov (United States)

    Kvetnoy, Igor M.; Hernández-Yago, José; Hernández, José Miguel; Kvetnaia, Tatiana V.; Reiter, Russel J.; Khavinson, Vladimir Kh.

    2000-01-01

    Structural and functional alterations of mitochondria have been shown to be responsible for a wide variety of clinical disorders that are referred to as "mitochondrial diseases." It is now obvious that many factors are involved in transport of mitochondrial proteins including cytokines, chaperones, chemokines, neurosteroids, ubiquitin and many others. At the same time the participation and the role of biogenic amines and peptide hormones (which are produced by the diffuse neuroendocrine system cells located in different organs) in endogenous mechanisms of mitochondrial diseases are still unknown. Taking into account the wide spectrum of biological effects of biogenic amines and peptide hormones, and especially their regulatory role for intercellular communication, it seems important to analyze the possible participation of these molecules in the pathogenesis of mitochondrial disorders as well as to draw up new ways for elaboration of new markers for lifetime diagnosis, definition of prognosis and efficiency of specific therapy in neurodegenerative diseases.

  11. Gliadin is a Good Substrate of Several Transglutaminases: Possible Implication in the Pathogenesis of Coeliac Disease

    DEFF Research Database (Denmark)

    Skovbjerg, Hanne; Norén, Ove; Anthonsen, Dorit

    2002-01-01

    Coeliac disease, enzymatic assay, Europium, gliadin, human, microbial, microtitre plate, patogenesis, transglutaminase, vegetable......Coeliac disease, enzymatic assay, Europium, gliadin, human, microbial, microtitre plate, patogenesis, transglutaminase, vegetable...

  12. Role of the Innate Immune System in the Pathogenesis of Inflammatory Bowel Disease

    NARCIS (Netherlands)

    van Lierop, Pieter P. E.; Samsom, Janneke N.; Escher, Johanna C.; Nieuwenhuis, Edward E. S.

    Crohn disease and ulcerative colitis are chronic inflammatory diseases of the intestinal tract commonly denoted as inflammatory bowel diseases. It has been proposed that these diseases result from aberrant mucosal immune responses to nonpathogenic microbial residents of the intestines. Recently, it

  13. Pathogenesis of microbial keratitis.

    Science.gov (United States)

    Lakhundi, Sahreena; Siddiqui, Ruqaiyyah; Khan, Naveed Ahmed

    2017-03-01

    Microbial keratitis is a sight-threatening ocular infection caused by bacteria, fungi, and protist pathogens. Epithelial defects and injuries are key predisposing factors making the eye susceptible to corneal pathogens. Among bacterial pathogens, the most common agents responsible for keratitis include Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus pneumonia and Serratia species. Fungal agents of corneal infections include both filamentous as well as yeast, including Fusarium, Aspergillus, Phaeohyphomycetes, Curvularia, Paecilomyces, Scedosporium and Candida species, while in protists, Acanthamoeba spp. are responsible for causing ocular disease. Clinical features include redness, pain, tearing, blur vision and inflammation but symptoms vary depending on the causative agent. The underlying molecular mechanisms associated with microbial pathogenesis include virulence factors as well as the host factors that aid in the progression of keratitis, resulting in damage to the ocular tissue. The treatment therefore should focus not only on the elimination of the culprit but also on the neutralization of virulence factors to minimize the damage, in addition to repairing the damaged tissue. A complete understanding of the pathogenesis of microbial keratitis will lead to the rational development of therapeutic interventions. This is a timely review of our current understanding of the advances made in this field in a comprehensible manner. Coupled with the recently available genome sequence information and high throughput genomics technology, and the availability of innovative approaches, this will stimulate interest in this field. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Relationship between adipose tissue dysfunction, vitamin D deficiency and the pathogenesis of non-alcoholic fatty liver disease

    Science.gov (United States)

    Cimini, Flavia A; Barchetta, Ilaria; Carotti, Simone; Bertoccini, Laura; Baroni, Marco G; Vespasiani-Gentilucci, Umberto; Cavallo, Maria-Gisella; Morini, Sergio

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Its pathogenesis is complex and not yet fully understood. Over the years many studies have proposed various pathophysiological hypotheses, among which the currently most widely accepted is the “multiple parallel hits” theory. According to this model, lipid accumulation in the hepatocytes and insulin resistance increase the vulnerability of the liver to many factors that act in a coordinated and cooperative manner to promote hepatic injury, inflammation and fibrosis. Among these factors, adipose tissue dysfunction and subsequent chronic low grade inflammation play a crucial role. Recent studies have shown that vitamin D exerts an immune-regulating action on adipose tissue, and the growing wealth of epidemiological data is demonstrating that hypovitaminosis D is associated with both obesity and NAFLD. Furthermore, given the strong association between these conditions, current findings suggest that vitamin D may be involved in the relationship between adipose tissue dysfunction and NAFLD. The purpose of this review is to provide an overview of recent advances in the pathogenesis of NAFLD in relation to adipose tissue dysfunction, and in the pathophysiology linking vitamin D deficiency with NAFLD and adiposity, together with an overview of the evidence available on the clinical utility of vitamin D supplementation in cases of NAFLD. PMID:28596677

  15. Relationship between adipose tissue dysfunction, vitamin D deficiency and the pathogenesis of non-alcoholic fatty liver disease.

    Science.gov (United States)

    Cimini, Flavia A; Barchetta, Ilaria; Carotti, Simone; Bertoccini, Laura; Baroni, Marco G; Vespasiani-Gentilucci, Umberto; Cavallo, Maria-Gisella; Morini, Sergio

    2017-05-21

    Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Its pathogenesis is complex and not yet fully understood. Over the years many studies have proposed various pathophysiological hypotheses, among which the currently most widely accepted is the "multiple parallel hits" theory. According to this model, lipid accumulation in the hepatocytes and insulin resistance increase the vulnerability of the liver to many factors that act in a coordinated and cooperative manner to promote hepatic injury, inflammation and fibrosis. Among these factors, adipose tissue dysfunction and subsequent chronic low grade inflammation play a crucial role. Recent studies have shown that vitamin D exerts an immune-regulating action on adipose tissue, and the growing wealth of epidemiological data is demonstrating that hypovitaminosis D is associated with both obesity and NAFLD. Furthermore, given the strong association between these conditions, current findings suggest that vitamin D may be involved in the relationship between adipose tissue dysfunction and NAFLD. The purpose of this review is to provide an overview of recent advances in the pathogenesis of NAFLD in relation to adipose tissue dysfunction, and in the pathophysiology linking vitamin D deficiency with NAFLD and adiposity, together with an overview of the evidence available on the clinical utility of vitamin D supplementation in cases of NAFLD.

  16. Overstimulation of the inhibitory nervous system plays a role in the pathogenesis of neuromuscular and neurological diseases: a novel hypothesis [version 2; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Bert Tuk

    2016-08-01

    Full Text Available Based upon a thorough review of published clinical observations regarding the inhibitory system, I hypothesize that this system may play a key role in the pathogenesis of a variety of neuromuscular and neurological diseases. Specifically, excitatory overstimulation, which is commonly reported in neuromuscular and neurological diseases, may be a homeostatic response to inhibitory overstimulation. Involvement of the inhibitory system in disease pathogenesis is highly relevant, given that most approaches currently being developed for treating neuromuscular and neurological diseases focus on reducing excitatory activity rather than reducing inhibitory activity.

  17. Understanding Aspects of Aluminum Exposure in Alzheimer's Disease Development.

    Science.gov (United States)

    Kandimalla, Ramesh; Vallamkondu, Jayalakshmi; Corgiat, Edwin B; Gill, Kiran Dip

    2016-03-01

    Aluminum is a ubiquitously abundant nonessential element. Aluminum has been associated with neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis, and dialysis encephalopathy. Many continue to regard aluminum as controversial although increasing evidence supports the implications of aluminum in the pathogenesis of AD. Aluminum causes the accumulation of tau protein and Aβ protein in the brain of experimental animals. Aluminum induces neuronal apoptosis in vivo and in vitro, either by endoplasmic stress from the unfolded protein response, by mitochondrial dysfunction, or a combination of them. Some, people who are exposed chronically to aluminum, either from through water and/or food, have not shown any AD pathology, apparently because their gastrointestinal barrier is more effective. This article is written keeping in mind mechanisms of action of aluminum neurotoxicity with respect to AD. © 2015 International Society of Neuropathology.

  18. Plaque hemorrhage in carotid artery disease: Pathogenesis, clinical and biomechanical considerations

    Science.gov (United States)

    Teng, Zhongzhao; Sadat, Umar; Brown, Adam J.; Gillard, Jonathan H.

    2014-01-01

    Stroke remains the most prevalent disabling illness today, with internal carotid artery luminal stenosis due to atheroma formation responsible for the majority of ischemic cerebrovascular events. Severity of luminal stenosis continues to dictate both patient risk stratification and the likelihood of surgical intervention. But there is growing evidence to suggest that plaque morphology may help improve pre-existing risk stratification criteria. Plaque components such a fibrous tissue, lipid rich necrotic core and calcium have been well investigated but plaque hemorrhage (PH) has been somewhat overlooked. In this review we discuss the pathogenesis of PH, its role in dictating plaque vulnerability, PH imaging techniques, marterial properties of atherosclerotic tissues, in particular, those obtained based on in vivo measurements and effect of PH in modulating local biomechanics. PMID:24485514

  19. Understanding the Function of Genes Involved in Inherited Retinal Degeneration-Insights into the Pathogenesis and Function of C8ORF37

    Science.gov (United States)

    Sharif, Ali Sakawa

    Inherited retinal degenerative diseases (IRD) are a group of disorders that lead to progressive deterioration of mainly the photoreceptors. Retinitis pigmentosa (RP) and cone-rod dystrophy (CRD) are two forms of IRDs. RP is the most common form of IRD and is due to rod photoreceptor degeneration followed by cone photoreceptor loss. CRD, on the other hand, is characterized by the loss of cones or the concurrent degeneration of both cones and rods. Both RP and CRD are presently incurable. More than 200 genes have been identified to cause IRDs and the functions of many of these genes remain unclear. Mutations in a novel gene, C8ORF37, were identified to cause recessive, severe, and early-onset RP and CRD. I, therefore, pioneered in characterizing the role of C8ORF37 in the retina. This dissertation is comprised of four chapters that is organized as follows: (1) summary of an ocular disorder (2) a genetic model of a retinal disorder (3) biochemical/proteomic analysis of C8ORF37 (4) potential clinical applications. A summary of ocular disorders is discussed in Chapter 1, with an emphasis on CRD. Chapter 2 focuses on the generation and characterization of C8orf37 mutant mouse models that recapitulate the retinal pathologies observed in human patients. In C8orf37 knockout retinas, the outer segment (OS) was nonuniform, swollen, and wider in width when compared to the controls. Moreover, many OS membrane proteins were reduced in the retina of C8orf37 knockout, including CNGB1 and RDS, proteins essential for OS disc morphogenesis and alignment. Our findings shed new light on the pathogenesis underlying retinal dysfunction and degeneration in C8ORF37-deficient patients. To determine the function of a novel protein, a powerful approach is by identifying its binding partners. In Chapter 3, I discuss GST pull-down using bovine retinal lysates, yeast-two-hybrid, and immunoprecipitation with mouse retinal lysate in order to identify C8ORF37-interacting proteins. Our pull

  20. Characterization and pathogenesis of anemia in glycogen storage disease type Ia and Ib.

    Science.gov (United States)

    Wang, David Q; Carreras, Caroline T; Fiske, Laurie M; Austin, Stephanie; Boree, Danielle; Kishnani, Priya S; Weinstein, David A

    2012-09-01

    The aim of this study was to characterize the frequency and causes of anemia in glycogen storage disease type I. Hematologic data and iron studies were available from 202 subjects (163 with glycogen storage disease Ia and 39 with glycogen storage disease Ib). Anemia was defined as hemoglobin concentrations less than the 5th percentile for age and gender; severe anemia was defined as presence of a hemoglobin glycogen storage disease Ia, 68/163 patients were anemic at their last follow-up. Preadolescent patients tended to have milder anemia secondary to iron deficiency, but anemia of chronic disease predominated in adults. Severe anemia was present in 8/163 patients, of whom 75% had hepatic adenomas. The anemia improved or resolved in all 10 subjects who underwent resection of liver lesions. Anemia was present in 72% of patients with glycogen storage disease Ib, and severe anemia occurred in 16/39 patients. Anemia in patients with glycogen storage disease Ib was associated with exacerbations of glycogen storage disease enterocolitis, and there was a significant correlation between C-reactive protein and hemoglobin levels (P = 0.036). Anemia is a common manifestation of both glycogen storage disease Ia and Ib, although the pathophysiology appears to be different between these conditions. Those with severe anemia and glycogen storage disease Ia likely have hepatic adenomas, whereas glycogen storage disease enterocolitis should be considered in those with glycogen storage disease Ib.

  1. Vascular toxicity of urea, a new "old player" in the pathogenesis of chronic renal failure induced cardiovascular diseases.

    Science.gov (United States)

    Giardino, Ida; D'Apolito, Maria; Brownlee, Michael; Maffione, Angela Bruna; Colia, Anna Laura; Sacco, Michele; Ferrara, Pietro; Pettoello-Mantovani, Massimo

    2017-12-01

    Chronic kidney disease in children is an irreversible process that may lead to end-stage renal disease. The mortality rate in children with end-stage renal disease who receive dialysis increased dramatically in the last decade, and it is significantly higher compared with the general pediatric population. Furthermore, dialysis and transplant patients, who have developed end-stage renal disease during childhood, live respectively far less as compared with age/race-matched populations. Different reports show that cardiovascular disease is the leading cause of death in children with end-stage renal disease and in adults with childhood-onset chronic kidney disease, and that children with chronic kidney disease are in the highest risk group for the development of cardiovascular disease. Urea, which is generated in the liver during catabolism of amino acids and other nitrogenous metabolites, is normally excreted into the urine by the kidneys as rapidly as it is produced. When renal function is impaired, increasing concentrations of blood urea will steadily accumulate. For a long time, urea has been considered to have negligible toxicity. However, the finding that plasma urea is the only significant predictor of aortic plaque area fraction in an animal model of chronic renal failure -accelerated atherosclerosis, suggests that the high levels of urea found in chronic dialysis patients might play an important role in accelerated atherosclerosis in this group of patients. The aim of this review was to provide novel insights into the role played by urea in the pathogenesis of accelerated cardiovascular disease in renal failure.

  2. Understanding Parkinson Disease: A Complex and Multifaceted Illness.

    Science.gov (United States)

    Gopalakrishna, Apoorva; Alexander, Sheila A

    2015-12-01

    Parkinson disease is an incredibly complex and multifaceted illness affecting millions of people in the United States. Parkinson disease is characterized by progressive dopaminergic neuronal dysfunction and loss, leading to debilitating motor, cognitive, and behavioral symptoms. Parkinson disease is an enigmatic illness that is still extensively researched today to search for a better understanding of the disease, develop therapeutic interventions to halt or slow progression of the disease, and optimize patient outcomes. This article aims to examine in detail the normal function of the basal ganglia and dopaminergic neurons in the central nervous system, the etiology and pathophysiology of Parkinson disease, related signs and symptoms, current treatment, and finally, the profound impact of understanding the disease on nursing care.

  3. The Role of Oxidative Stress on the Pathogenesis of Graves' Disease

    OpenAIRE

    ?arkovi?, Milo?

    2011-01-01

    Graves' disease is a most common cause of hyperthyroidism. It is an autoimmune disease, and autoimmune process induces an inflammatory reaction, and reactive oxygen species (ROSs) are among its products. When balance between oxidants and antioxidants is disturbed, in favour of the oxidants it is termed “oxidative stress” (OS). Increased OS characterizes Graves' disease. It seems that the level of OS is increased in subjects with Graves' ophthalmopathy compared to the other subjects with Grave...

  4. The emerging role of interleukin (IL)-1 in the pathogenesis and treatment of inflammatory and degenerative eye diseases.

    Science.gov (United States)

    Fabiani, Claudia; Sota, Jurgen; Tosi, Gian Marco; Franceschini, Rossella; Frediani, Bruno; Galeazzi, Mauro; Rigante, Donato; Cantarini, Luca

    2017-10-01

    Interleukin (IL)-1 plays a key role in the pathogenesis and thereafter in the search for specific treatments of different inflammatory and degenerative eye diseases. Indeed, an overactivity of IL-1 might be an initiating factor for many immunopathologic sceneries in the eye, as proven by the efficacy of the specific IL-1 blockade in different ocular diseases. For instance, the uveitis in monogenic autoinflammatory disorders, such as Blau syndrome and cryopyrin-associated periodic syndrome, or in complex polygenic autoinflammatory disorders, such as Behçet's disease, has been successfully treated with IL-1 blockers. Similarly, therapy with the IL-1 receptor antagonist anakinra has proven successful also in scleritis and episcleritis in the context of different rheumatic conditions. Moreover, interesting findings deriving from animal models of ocular disease have set a rational basis from a therapeutic viewpoint to manage patients also with dry eye disease and a broadening number of ocular inflammatory and degenerative conditions, which start from an imbalance between IL-1 and its receptor antagonist.

  5. A Perspective on the Maillard Reaction and the Analysis of Protein Glycation by Mass Spectrometry: Probing the Pathogenesis of Chronic Disease

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    Zhang, Qibin; Ames, Jennifer M.; Smith, Richard D.; Baynes, John; Metz, Thomas O.

    2008-12-18

    The Maillard reaction, starting from the glycation of protein and progressing to the formation of advanced glycation end-products (AGEs), is implicated in the development of complications of diabetes mellitus, as well as in the pathogenesis of cardiovascular, renal, and neurodegenerative diseases. In this perspective review, we provide on overview on the relevance of the Maillard reaction in the pathogenesis of chronic disease and discuss traditional approaches and recent developments in the analysis of glycated proteins by mass spectrometry. We propose that proteomics approaches, particularly bottom-up proteomics, will play a significant role in analyses of clinical samples leading to the identification of new markers of disease development and progression.

  6. Experimental infection of the pig with Mycobacterium ulcerans: a novel model for studying the pathogenesis of Buruli ulcer disease.

    Directory of Open Access Journals (Sweden)

    Miriam Bolz

    2014-07-01

    Full Text Available Buruli ulcer (BU is a slowly progressing, necrotising disease of the skin caused by infection with Mycobacterium ulcerans. Non-ulcerative manifestations are nodules, plaques and oedema, which may progress to ulceration of large parts of the skin. Histopathologically, BU is characterized by coagulative necrosis, fat cell ghosts, epidermal hyperplasia, clusters of extracellular acid fast bacilli (AFB in the subcutaneous tissue and lack of major inflammatory infiltration. The mode of transmission of BU is not clear and there is only limited information on the early pathogenesis of the disease available.For evaluating the potential of the pig as experimental infection model for BU, we infected pigs subcutaneously with different doses of M. ulcerans. The infected skin sites were excised 2.5 or 6.5 weeks after infection and processed for histopathological analysis. With doses of 2 × 10(7 and 2 × 10(6 colony forming units (CFU we observed the development of nodular lesions that subsequently progressed to ulcerative or plaque-like lesions. At lower inoculation doses signs of infection found after 2.5 weeks had spontaneously resolved at 6.5 weeks. The observed macroscopic and histopathological changes closely resembled those found in M. ulcerans disease in humans.Our results demonstrate that the pig can be infected with M. ulcerans. Productive infection leads to the development of lesions that closely resemble human BU lesions. The pig infection model therefore has great potential for studying the early pathogenesis of BU and for the development of new therapeutic and prophylactic interventions.

  7. Experimental Infection of the Pig with Mycobacterium ulcerans: A Novel Model for Studying the Pathogenesis of Buruli Ulcer Disease

    Science.gov (United States)

    Bolz, Miriam; Ruggli, Nicolas; Ruf, Marie-Thérèse; Ricklin, Meret E.; Zimmer, Gert; Pluschke, Gerd

    2014-01-01

    Background Buruli ulcer (BU) is a slowly progressing, necrotising disease of the skin caused by infection with Mycobacterium ulcerans. Non-ulcerative manifestations are nodules, plaques and oedema, which may progress to ulceration of large parts of the skin. Histopathologically, BU is characterized by coagulative necrosis, fat cell ghosts, epidermal hyperplasia, clusters of extracellular acid fast bacilli (AFB) in the subcutaneous tissue and lack of major inflammatory infiltration. The mode of transmission of BU is not clear and there is only limited information on the early pathogenesis of the disease available. Methodology/Principal Findings For evaluating the potential of the pig as experimental infection model for BU, we infected pigs subcutaneously with different doses of M. ulcerans. The infected skin sites were excised 2.5 or 6.5 weeks after infection and processed for histopathological analysis. With doses of 2×107 and 2×106 colony forming units (CFU) we observed the development of nodular lesions that subsequently progressed to ulcerative or plaque-like lesions. At lower inoculation doses signs of infection found after 2.5 weeks had spontaneously resolved at 6.5 weeks. The observed macroscopic and histopathological changes closely resembled those found in M. ulcerans disease in humans. Conclusion/Significance Our results demonstrate that the pig can be infected with M. ulcerans. Productive infection leads to the development of lesions that closely resemble human BU lesions. The pig infection model therefore has great potential for studying the early pathogenesis of BU and for the development of new therapeutic and prophylactic interventions. PMID:25010421

  8. Pros and cons of a prion-like pathogenesis in Parkinson's disease

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    Brotchie Jonathan M

    2011-06-01

    Full Text Available Abstract Background Parkinson's disease (PD is a slowly progressive neurodegenerative disorder which affects widespread areas of the brainstem, basal ganglia and cerebral cortex. A number of proteins are known to accumulate in parkinsonian brains including ubiquitin and α-synuclein. Prion diseases are sporadic, genetic or infectious disorders with various clinical and histopathological features caused by prion proteins as infectious proteinaceous particles transmitting a misfolded protein configuration through brain tissue. The most important form is Creutzfeldt-Jakob disease which is associated with a self-propagating pathological precursor form of the prion protein that is physiologically widely distributed in the central nervous system. Discussion It has recently been found that α-synuclein may behave similarly to the prion precursor and propagate between cells. The post-mortem proof of α-synuclein containing Lewy bodies in embryonic dopamine cells transplants in PD patient suggests that the misfolded protein might be transmitted from the diseased host to donor neurons reminiscent of prion behavior. The involvement of the basal ganglia and brainstem in the degenerative process are other congruencies between Parkinson's and Creutzfeldt-Jakob disease. However, a number of issues advise caution before categorizing Parkinson's disease as a prion disorder, because clinical appearance, brain imaging, cerebrospinal fluid and neuropathological findings exhibit fundamental differences between both disease entities. Most of all, infectiousness, a crucial hallmark of prion diseases, has never been observed in PD so far. Moreover, the cellular propagation of the prion protein has not been clearly defined and it is, therefore, difficult to assess the molecular similarities between the two disease entities. Summary At the current state of knowledge, the molecular pathways of transmissible pathogenic proteins are not yet fully understood. Their exact

  9. The Demise of Poskanzer and Schwab's Influenza Theory on the Pathogenesis of Parkinson's Disease.

    Science.gov (United States)

    Estupinan, Danny; Nathoo, Sunina; Okun, Michael S

    2013-01-01

    In 1961, David C. Poskanzer and Robert S. Schwab presented a paper, "Studies in the epidemiology of Parkinson's disease predicting its disappearance as a major clinical entity by 1980." This paper introduced the hypothesis that Parkinson's disease was derived from a single aetiology, the influenza virus. We review the original Poskanzer and Schwab hypothesis that Parkinson's disease was based on the association between the 1918-19 influenza epidemic and the later observation of Parkinsonism in some influenza sufferers. We also further explore the prediction that Parkinson's disease would totally disappear as an entity once original influenza victims were all deceased. Current research has revealed that there are many potential causes and factors important in the occurrence of Parkinson's disease, postencephalitic Parkinsonism, and encephalitis lethargica. Poskanzer and Schwab presented a novel hypothesis; however, it was proven false by a combination of research and time.

  10. Chronic Granulomatous Disease; fundamental stages in our understanding of CGD.

    Science.gov (United States)

    Assari, Tracy

    2006-09-21

    It has been 50 years since chronic granulomatous disease was first reported as a disease which fatally affected the ability of children to survive infections. Various milestone discoveries from the insufficient ability of patients' leucocytes to destroy microbial particles to the underlying genetic predispositions through which the disease is inherited have had important consequences. Longterm antibiotic prophylaxis has helped to fight infections associated with chronic granulomatous disease while the steady progress in bone marrow transplantation and the prospect of gene therapy are hailed as long awaited permanent treatment options. This review unearths the important findings by scientists that have led to our current understanding of the disease.

  11. Pathogenesis of Takotsubo syndrome

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    Daniele Masarone

    2017-01-01

    Full Text Available Takotsubo syndrome (TTS is an enigmatic disease with a multifactorial and still unresolved pathogenesis. Postulated mechanisms include catecholamine excess, coronary artery spasm, and microvascular dysfunction, however catecholamines seem to play a central role in the pathophysiology of TTS. In facts catecholamines have relevant effects on the vasculature and myocardium. Toxic direct effects of catecholamine on myocardium are mediated by multiple pathway including functional hypoxia, metabolic changes and changes in membrane permeability leading to various electrolytic imbalances. Recently report of familial cases has suggested a genetic component. Further research is required to help clarify the proposed hypotheses and to increase our understanding of the cardiovascular responses to acute stress and the pathophysiology underpinning TTS.

  12. Gains and losses on the road to understanding Alzheimer's disease.

    Science.gov (United States)

    Konietzko, Uwe

    2015-01-01

    Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause for dementia, which affects approximately 120 thousand people in Switzerland and 35 million worldwide. Aging is a major risk factor for developing AD and thus, as our societies are growing older, we face great challenges to find treatment strategies. The disease is characterised by loss of memory, deposition of extracellular amyloid plaques containing Aβ peptides and intraneuronal tangles of the tau protein. To date, there is no effective treatment and the cause of the disease is still debated. The Schweizerische Alzheimervereinigung states that we need "continuous manifold research" into all possible causes of AD to find a cure for this disease. Fitting this proposition, a recent publication by Xia et al. (2015) described a novel mouse model that for the first time reproduces cortical neuron death as observed in human AD cases. At the same time, this publication questions the major theory of AD pathogenesis and points towards different treatment avenues that should be followed to find a cure for AD.

  13. Roles of abnormal lipid metabolism in pathogenesis of non-alcoholic fatty liver disease

    OpenAIRE

    LU Ran; HONG Tianpei

    2015-01-01

    The prevalence of non-alcoholic fatty liver disease (NAFLD) keeps rising worldwide along with the increasing prevalence of metabolic diseases such as obesity, type 2 diabetes, and dyslipidemia. Although most NAFLD patients present with simple steatosis of hepatocytes, some patients progress to non-alcoholic steatohepatitis, liver cirrhosis, and even cancer. In the Western world, NAFLD is the most common cause of elevated liver enzymes, and hence there has been a growing interest in this disea...

  14. Pathogenesis of hepatic steatosis: The link between hypercortisolism and non-alcoholic fatty liver disease

    OpenAIRE

    Tarantino, Giovanni; Finelli, Carmine

    2013-01-01

    Based on the available literature, non alcoholic fatty liver disease or generally speaking, hepatic steatosis, is more frequent among people with diabetes and obesity, and is almost universally present amongst morbidly obese diabetic patients. Non alcoholic fatty liver disease is being increasingly recognized as a common liver condition in the developed world, with non alcoholic steatohepatitis projected to be the leading cause of liver transplantation. Previous data report that only 20% of p...

  15. The Role of Oxidative Damage in the Pathogenesis and Progression of Alzheimer’s Disease and Vascular Dementia

    Directory of Open Access Journals (Sweden)

    Maria Luca

    2015-01-01

    Full Text Available Oxidative stress (OS has been demonstrated to be involved in the pathogenesis of the two major types of dementia: Alzheimer’s disease (AD and vascular dementia (VaD. Evidence of OS and OS-related damage in AD is largely reported in the literature. Moreover, OS is not only linked to VaD, but also to all its risk factors. Several researches have been conducted in order to investigate whether antioxidant therapy exerts a role in the prevention and treatment of AD and VaD. Another research field is that pertaining to the heat shock proteins (Hsps, that has provided promising findings. However, the role of OS antioxidant defence system and more generally stress responses is very complex. Hence, research on this topic should be improved in order to reach further knowledge and discover new therapeutic strategies to face a disorder with such a high burden which is dementia.

  16. A review on the cause-effect relationship between oxidative stress and toxic proteins in the pathogenesis of neurodegenerative diseases.

    Science.gov (United States)

    Borza, Liana Rada

    2014-01-01

    Protein aggregates are the defining pathological feature of human neurodegenerative diseases. Studies have revealed that mutant huntingtin, polyglutamine-expanded ataxin-1 and ataxin-3 can cause elevated levels of reactive oxygen species in neuronal cells. It has also been indicated that the normal host prion protein behaves as an antioxidant, while the neurotoxic peptide based on the sequence of the scrapie isoform increases hydrogen peroxide toxicity in neuronal cultures. Additionally, not only can oxidative stress contribute to the aggregation of beta-amyloid and alpha-synuclein, but both beta-amyloid and alpha-synuclein can induce oxidative damage. Furthermore, oxidative stressors have been shown to play a critical role in neurofibrillary pathology leading to tau hyperphosphorylation. In conclusion, the present review supports a cause-effect relationship between oxidative stress and toxic proteins in the pathogenesis of neurodegenerative disorders.

  17. Partial regulatory T cell depletion prior to acute feline immunodeficiency virus infection does not alter disease pathogenesis.

    Directory of Open Access Journals (Sweden)

    S Rochelle Mikkelsen

    2011-02-01

    Full Text Available Feline immunodeficiency virus (FIV infection in cats follows a disease course similar to HIV-1, including a short acute phase characterized by high viremia, and a prolonged asymptomatic phase characterized by low viremia and generalized immune dysfunction. CD4(+CD25(hiFoxP3(+ immunosuppressive regulatory T (Treg cells have been implicated as a possible cause of immune dysfunction during FIV and HIV-1 infection, as they are capable of modulating virus-specific and inflammatory immune responses. Additionally, the immunosuppressive capacity of feline Treg cells has been shown to be increased during FIV infection. We have previously shown that transient in vivo Treg cell depletion during asymptomatic FIV infection reveals FIV-specific immune responses suppressed by Treg cells. In this study, we sought to determine the immunological influence of Treg cells during acute FIV infection. We asked whether Treg cell depletion prior to infection with the highly pathogenic molecular clone FIV-C36 in cats could alter FIV pathogenesis. We report here that partial Treg cell depletion prior to FIV infection does not significantly change provirus, viremia, or CD4(+ T cell levels in blood and lymphoid tissues during the acute phase of disease. The effects of anti-CD25 mAb treatment are truncated in cats acutely infected with FIV-C36 as compared to chronically infected cats or FIV-naïve cats, as Treg cell levels were heightened in all treatment groups included in the study within two weeks post-FIV infection. Our findings suggest that the influence of Treg cell suppression during FIV pathogenesis is most prominent after Treg cells are activated in the environment of established FIV infection.

  18. Partial regulatory T cell depletion prior to acute feline immunodeficiency virus infection does not alter disease pathogenesis.

    Science.gov (United States)

    Mikkelsen, S Rochelle; Long, Julie M; Zhang, Lin; Galemore, Erin R; VandeWoude, Sue; Dean, Gregg A

    2011-02-25

    Feline immunodeficiency virus (FIV) infection in cats follows a disease course similar to HIV-1, including a short acute phase characterized by high viremia, and a prolonged asymptomatic phase characterized by low viremia and generalized immune dysfunction. CD4(+)CD25(hi)FoxP3(+) immunosuppressive regulatory T (Treg) cells have been implicated as a possible cause of immune dysfunction during FIV and HIV-1 infection, as they are capable of modulating virus-specific and inflammatory immune responses. Additionally, the immunosuppressive capacity of feline Treg cells has been shown to be increased during FIV infection. We have previously shown that transient in vivo Treg cell depletion during asymptomatic FIV infection reveals FIV-specific immune responses suppressed by Treg cells. In this study, we sought to determine the immunological influence of Treg cells during acute FIV infection. We asked whether Treg cell depletion prior to infection with the highly pathogenic molecular clone FIV-C36 in cats could alter FIV pathogenesis. We report here that partial Treg cell depletion prior to FIV infection does not significantly change provirus, viremia, or CD4(+) T cell levels in blood and lymphoid tissues during the acute phase of disease. The effects of anti-CD25 mAb treatment are truncated in cats acutely infected with FIV-C36 as compared to chronically infected cats or FIV-naïve cats, as Treg cell levels were heightened in all treatment groups included in the study within two weeks post-FIV infection. Our findings suggest that the influence of Treg cell suppression during FIV pathogenesis is most prominent after Treg cells are activated in the environment of established FIV infection.

  19. Cellular senescence and autophagy in the pathogenesis of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF).

    Science.gov (United States)

    Kuwano, Kazuyoshi; Araya, Jun; Hara, Hiromichi; Minagawa, Shunsuke; Takasaka, Naoki; Ito, Saburo; Kobayashi, Kenji; Nakayama, Katsutoshi

    2016-11-01

    Aging is associated with impairments in homeostasis. Although aging and senescence are not equivalent, the number of senescent cells increases with aging. Cellular senescence plays important roles in tissue repair or remodeling, as well as embryonic development. Autophagy is a process of lysosomal self-degradation that maintains a homeostatic balance between the synthesis, degradation, and recycling of cellular proteins. Autophagy diminishes with aging; additionally, accelerated aging can be attributed to reduced autophagy. Cellular senescence has been widely implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD), a disease of accelerated lung aging, presumably by impairing cell repopulation and by aberrant cytokine secretion in the senescence-associated secretory phenotype. The possible participation of autophagy in the pathogenic sequence of COPD has been extensively explored. Although it has been reported that increased autophagy may induce epithelial cell death, an insufficient reserve of autophagy can induce cellular senescence in bronchial epithelial cells of COPD. Furthermore, advanced age is one of the most important risk factors for the development of idiopathic pulmonary fibrosis (IPF). Telomere shortening is found in blood leukocytes and alveolar epithelial cells from patients with IPF. Accelerated senescence of epithelial cells plays a role in IPF pathogenesis by perpetuating abnormal epithelial-mesenchymal interactions. Insufficient autophagy may be an underlying mechanism of accelerated epithelial cell senescence and myofibroblast differentiation in IPF. Herein, we review the molecular mechanisms of cellular senescence and autophagy and summarize the role of cellular senescence and autophagy in both COPD and IPF. Copyright © 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

  20. Unmet Needs in the Pathogenesis and Treatment of Cardiovascular Comorbidities in Chronic Inflammatory Diseases.

    Science.gov (United States)

    Panico, Cristina; Condorelli, Gianluigi

    2017-07-24

    The developments that have taken place in recent decades in the diagnosis and therapy of a number of diseases have led to improvements in prognosis and life expectancy. As a consequence, there has been an increase in the number of patients affected by chronic diseases and who can face new pathologies during their lifetime. The prevalence of chronic heart failure, for example, is approximately 1-2% of the adult population in developed countries, rising to ≥10% among people >70 years of age; in 2015, more than 85 million people in Europe were living with some sort of cardiovascular disease (CVD) (Lubrano and Balzan World J Exp Med 5:21-32, 5; Takahashi et al. Circ J 72:867-72, 8; Kaptoge et al. Lancet 375:132-40, 9). Chronic disease can become, in turn, a major risk factor for other diseases. Furthermore, several new drugs have entered clinical practice whose adverse effects on multiple organs are still to be evaluated. All this necessarily involves a multidisciplinary vision of medicine, where the physician must view the patient as a whole and where collaboration between the various specialists plays a key role. An example of what has been said so far is the relationship between CVD and chronic inflammatory diseases (CIDs). Patients with chronic CVD may develop a CID within their lifetime, and, vice versa, a CID can be a risk factor for the development of CVD. Moreover, drugs used for the treatment of CIDs may have side effects involving the cardiovascular system and thus may be contraindicated. The purpose of this paper is to investigate the close relationship between these two groups of diseases and to provide recommendations on the diagnostic approach and treatments in light of the most recent scientific data available.

  1. ALLERGIC EYE DISEASES IN CHILDREN. MODERN VIEW ON PATHOGENESIS AND TREATMENT

    Directory of Open Access Journals (Sweden)

    E. Y. Markova

    2017-01-01

    Full Text Available The prevalence off allergic diseases has  been  significantly increased among  adults  and children during last 30-40 years. International study has  shown  that  the  frequency  of atopy  in developed  countries, including Russia,   is higher  than  in developing.  Often atopic dermatitis, started in infancy, can develop into an “allergic march”  — food allergy, followed by the formation of allergic rhinitis, allergic conjunctivitis and  other  allergic diseases. The problem  of prophylaxis and  treatment of allergic pathology  becomes actual  for these reasons. An opinion according some  preventive  measures has  changed in recent. It was  noted  that  in families  with many children, where  children  were  often  sick  with respiratory infections,  the  incidence  of allergic  diseases was  lower  than  among  rarely sick children.  It is explained by the  “hygienic theory” — insufficient “training” of the  Th1 response in rarely sick children.  Allergic diseases, which are  based on IgE-mediated inflammation,  have a common  pathogenetic nature and,  consequently, general  principles of therapy, in which, as  is well known,  antihistamines take  a significant  place.  This is cased by the  mandatory involvement of histamine  in the mechanism of development of the main symptoms of allergic diseases. Current  capabilities  of local ophthalmologic  antiallergic therapy includes medicines  with multiple action mechanisms, such as mast cell stabilizers, antihistamines, combined  agents, steroids and nonsteroidal anti-inflammatory effects. The latest generation antihistamine drug — olopatadine hydrochloride  0.2% is a new form of the molecule of olopatadine, which is intended  to increase the duration  of the action.  The article considers the main modern directions in prevention  and treatment of allergic diseases, including allergic eye diseases, which are  a

  2. Visible aging signs as risk markers for ischemic heart disease: Epidemiology, pathogenesis and clinical implications.

    Science.gov (United States)

    Christoffersen, Mette; Tybjærg-Hansen, Anne

    2016-01-01

    Association of common aging signs (i.e., male pattern baldness, hair graying, and facial wrinkles) as well as other age-related appearance factors (i.e., arcus corneae, xanthelasmata, and earlobe crease) with increased risk of ischemic heart disease was initially described in anecdotal reports from clinicians observing trends in the physical appearance of patients with ischemic heart disease. Following these early observations numerous epidemiological studies have reported these associations. Since the prevalences of both visible aging signs and ischemic heart disease have a strong correlation with increasing age, it has been extensively debated whether the observed associations could be entirely explained by a common association with age. Furthermore, the etiologies of the visible aging signs are rarely fully understood, and pathophysiological explanations for these associations remain controversial, and are mostly speculative. As a consequence of inconsistent findings and lack of mechanistic explanations for the observed associations with ischemic heart disease, consensus on the clinical importance of these visible aging signs has been lacking. The aim of this review is for each of the visible aging signs to (i) review the etiology, (ii) to discuss the current epidemiological evidence for an association with risk of ischemic heart disease, and (iii) to present possible pathophysiological explanations for these associations. Finally this review discusses the potential clinical implications of these findings. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. An alkaline phosphatase transport mechanism in the pathogenesis of Alzheimer's disease and neurodegeneration.

    Science.gov (United States)

    Pike, Adrianne F; Kramer, Nynke I; Blaauboer, Bas J; Seinen, Willem; Brands, Ruud

    2015-01-25

    Systemic inflammation is associated with loss of blood-brain barrier integrity and neuroinflammation that lead to the exacerbation of neurodegenerative diseases. It is also associated specifically with the characteristic amyloid-β and tau pathologies of Alzheimer's disease. We have previously proposed an immunosurveillance mechanism for epithelial barriers involving negative feedback-regulated alkaline phosphatase transcytosis as an acute phase anti-inflammatory response that hangs in the balance between the resolution and the progression of inflammation. We now extend this model to endothelial barriers, particularly the blood-brain barrier, and present a literature-supported mechanistic explanation for Alzheimer's disease pathology with this system at its foundation. In this mechanism, a switch in the role of alkaline phosphatase from its baseline duties to a stopgap anti-inflammatory function results in the loss of alkaline phosphatase from cell membranes into circulation, thereby decreasing blood-brain barrier integrity and functionality. This occurs with impairment of both amyloid-β efflux and tau dephosphorylating activity in the brain as alkaline phosphatase is replenished at the barrier by receptor-mediated transport. We suggest systemic alkaline phosphatase administration as a potential therapy for the resolution of inflammation and the prevention of Alzheimer's disease pathology as well as that of other inflammation-related neurodegenerative diseases. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  4. The genetic basis of ankylosing spondylitis: new insights into disease pathogenesis

    Science.gov (United States)

    Tsui, Florence WL; Tsui, Hing Wo; Akram, Ali; Haroon, Nigil; Inman, Robert D

    2014-01-01

    Ankylosing spondylitis (AS) is a complex disease involving multiple risk factors, both genetic and environmental. AS patients are predominantly young men, and the disease is characterized by inflammation and ankylosis, mainly at the cartilage–bone interface and enthesis. HLA-B27 has been known to be the major AS-susceptibility gene for more than 40 years. Despite advances made in the past few years, progress in the search for non-human leukocyte antigen susceptibility genes has been hampered by the heterogeneity of the disease. Compared to other complex diseases, such as inflammatory bowel disease (IBD), fewer susceptibility loci have been identified in AS. Furthermore, non-major histocompatibility-complex susceptibility loci discovered, such as ERAP1 and IL23R, are likely contributors to joint inflammation. Identification and confirmation of functional variants remains a significant challenge of investigations involving genome-wide association studies (GWAS). It remains unclear why none of the AS-susceptibility genes identified in GWAS appear to be directly involved in the ankylosing process. Numerous reviews have recently been published on the genetics of AS. Therefore, aside from a brief summary of what AS GWAS has successfully achieved thus far, this review will focus on directions that could address unanswered questions raised by GWAS. PMID:24971029

  5. On the Pathogenesis Trail: What Marker B Cell Clones Tell Us about Inflammatory Bowel Disease

    Directory of Open Access Journals (Sweden)

    Jonathan Braun

    1996-01-01

    Full Text Available Clonal patterns of B cell activity have been recognized in inflammatory bowel disease, most notably in the immunogenetic relationship of perinuclear-antineutrophil cytoplasmic antibodies to ulcerative colitis. Conceptually, this most likely reflects the B cell response to antigens predominating at these sites of mucosal inflammation. Identification of these B cell clones and their antigenic targets may be of pathogenetic and practical importance to diagnosis and treatment. The authors describe strategies to identify such clones, based on recent advances in the characterization and detection of antibody gene products. As an example of this strategy, a clonal detection system was used to identify new marker antibodies potentially useful in the laboratory diagnosis of Crohn’s disease and ulcerative colitis. One surprising outcome of such studies is the unexpected and specific association of the B cell clonal response in Campylobacter jejuni enterocolitis and inflammatory bowel disease. By analogy to the pathogenetic role of Helicobacter pylori-induced mucositis in peptic ulcer disease, this evidence renews attention to the role of C jejuni in the initiation of ulcerative colitis and Crohn’s disease.

  6. Phosphorylated α-Synuclein-Copper Complex Formation in the Pathogenesis of Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Juan Antonio Castillo-Gonzalez

    2017-01-01

    Full Text Available Parkinson’s disease is the second most important neurodegenerative disorder worldwide. It is characterized by the presence of Lewy bodies, which are mainly composed of α-synuclein and ubiquitin-bound proteins. Both the ubiquitin proteasome system (UPS and autophagy-lysosomal pathway (ALS are altered in Parkinson’s disease, leading to aggregation of proteins, particularly α-synuclein. Interestingly, it has been observed that copper promotes the protein aggregation process. Additionally, phosphorylation of α-synuclein along with copper also affects the protein aggregation process. The interrelation among α-synuclein phosphorylation and its capability to interact with copper, with the subsequent disruption of the protein degradation systems in the neurodegenerative process of Parkinson’s disease, will be analyzed in detail in this review.

  7. Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management

    NARCIS (Netherlands)

    Cnossen, W.R.; Drenth, J.P.H.

    2014-01-01

    Polycystic liver disease (PLD) is the result of embryonic ductal plate malformation of the intrahepatic biliary tree. The phenotype consists of numerous cysts spread throughout the liver parenchyma. Cystic bile duct malformations originating from the peripheral biliary tree are called Von Meyenburg

  8. Investigation of the pathogenesis of transplacental transmission of Aleutian mink disease parvovirus in experimentally infected mink

    DEFF Research Database (Denmark)

    Broll, S.; Alexandersen, Søren

    1996-01-01

    The transplacental transmission of Aleutian mink disease parvovirus (ADV) was studied in experimental infection of 1-year-old female non-Aleutian mink. The ADV-seronegative female mink were inoculated,vith ADV prior to mating or after the expected implantation of the embryos during pregnancy...

  9. New insights in the pathogenesis of non-alcoholic fatty liver disease

    NARCIS (Netherlands)

    Gaemers, Ingrid C.; Groen, Albert K.

    2006-01-01

    PURPOSE OF REVIEW: The hallmark of non-alcoholic fatty liver disease is hepatic steatosis. This is mostly a benign condition, but for largely unknown reasons it progresses to liver fibrosis, cirrhosis, and ultimately hepatocellular carcinoma in about 10% of patients. In this review we discuss recent

  10. Interleukin-11 and IL-17 and the pathogenesis of periodontal disease.

    Science.gov (United States)

    Johnson, R B; Wood, N; Serio, F G

    2004-01-01

    Interleukin (IL)-11 and IL-17 are cytokines that modulate the inflammatory process and have not been assessed within normal or inflamed gingival tissues. Our purpose was to compare concentrations of human IL-11 and IL-17 within healthy and diseased human gingiva to determine their possible role in the initiation or progression of periodontal diseases. Biopsies from healthy (non-hemorrhagic gingiva adjacent to a or = 3 mm periodontal pocket) were studied. IL-11, IL-17, RANTES, and IL-6 concentrations were assessed within solubilized gingival biopsies by enzyme-linked immunosorbent assay. Data were compared by factorial analysis of variance and a post-hoc Tukey honestly significant difference (HSD) test. Regression analysis and partial correlation analysis (adjusted for sample weight) were also used to determine correlations between the variables. Interleukin-11 concentrations were highest within gingiva adjacent to 3 mm diseased pockets (P or = 6 mm pocket. RANTES concentrations were significantly greater in gingiva adjacent to > or = 6 mm pockets than in tissues derived from other sites (P or = 6 mm pockets, suggesting that their concentrations change as a consequence of the progression of gingivitis to periodontitis and that both cytokines could have a significant role in this progression. These data may be useful for the design of procedures for prevention of periodontal disease.

  11. The Elements Steering Pathogenesis in IgG-Mediated Alloimmune Diseases

    NARCIS (Netherlands)

    Sonneveld, Myrthe E.; van der Schoot, C. Ellen; Vidarsson, Gestur

    2016-01-01

    Alloimmune diseases can occur in pregnancy and after blood transfusions, where antibodies are formed, targeting foreign cells and tissues for destruction by myeloid cells through IgG Fc-receptors (FcγR). In pregnancy, antibodies against human blood group or platelet antigens (e.g. HPA1-a) cause

  12. A New Decision Tree to Solve the Puzzle of Alzheimer's Disease Pathogenesis Through Standard Diagnosis Scoring System.

    Science.gov (United States)

    Kumar, Ashwani; Singh, Tiratha Raj

    2017-03-01

    Alzheimer's disease (AD) is a progressive, incurable and terminal neurodegenerative disorder of the brain and is associated with mutations in amyloid precursor protein, presenilin 1, presenilin 2 or apolipoprotein E, but its underlying mechanisms are still not fully understood. Healthcare sector is generating a large amount of information corresponding to diagnosis, disease identification and treatment of an individual. Mining knowledge and providing scientific decision-making for the diagnosis and treatment of disease from the clinical dataset are therefore increasingly becoming necessary. The current study deals with the construction of classifiers that can be human readable as well as robust in performance for gene dataset of AD using a decision tree. Models of classification for different AD genes were generated according to Mini-Mental State Examination scores and all other vital parameters to achieve the identification of the expression level of different proteins of disorder that may possibly determine the involvement of genes in various AD pathogenesis pathways. The effectiveness of decision tree in AD diagnosis is determined by information gain with confidence value (0.96), specificity (92 %), sensitivity (98 %) and accuracy (77 %). Besides this functional gene classification using different parameters and enrichment analysis, our finding indicates that the measures of all the gene assess in single cohorts are sufficient to diagnose AD and will help in the prediction of important parameters for other relevant assessments.

  13. Link between Aluminum and the Pathogenesis of Alzheimer's Disease: The Integration of the Aluminum and Amyloid Cascade Hypotheses

    Directory of Open Access Journals (Sweden)

    Masahiro Kawahara

    2011-01-01

    Full Text Available Whilst being environmentally abundant, aluminum is not essential for life. On the contrary, aluminum is a widely recognized neurotoxin that inhibits more than 200 biologically important functions and causes various adverse effects in plants, animals, and humans. The relationship between aluminum exposure and neurodegenerative diseases, including dialysis encephalopathy, amyotrophic lateral sclerosis and Parkinsonism dementia in the Kii Peninsula and Guam, and Alzheimer's disease (AD has been suggested. In particular, the link between aluminum and Alzheimer's disease has been the subject of scientific debate for several decades. However, the complex characteristics of aluminum bioavailability make it difficult to evaluate its toxicity and therefore, the relationship remains to be established. Mounting evidence has suggested that significance of oligomerization of β-amyloid protein and neurotoxicity in the molecular mechanism of AD pathogenesis. Aluminum may play crucial roles as a cross-linker in β-amyloid oligomerization. Here, we review the detailed characteristics of aluminum neurotoxicity based on our own studies and the recent literatures. Our aim is to revisit the link between aluminum and AD and to integrate aluminum and amyloid cascade hypotheses in the context of β-amyloid oligomerization and the interactions with other metals.

  14. [The importance of folic acid deficiency in the pathogenesis of vascular, mixed and Alzheimer's disease dementia].

    Science.gov (United States)

    Marzena, Zboch; Jerzy, Leszek

    2013-10-01

    Alzheimer's disease (AD), vascular dementia (VaD) and mixed dementia (MD) are the most common dementia diseases among the elderly. Currently, there is no effective treatment of these diseases and, therefore, it seems justified to develop the principles of prevention, taking into account the elimination of risk factors. Among them folic acid deficiency may play an important role. To evaluate possible relationship of folate deficiency with the development of selected dementia diseases: vascular dementia (VaD), Alzheimer's disease (AD), mixed dementia (MD). The study involved 166 people, including 47 people with the diagnosis of AD, 41 with VaD and 36 with MD. The control group consisted of 42 persons without cognitive impairment. All patients underwent a general physical, neurological, psychiatric and extensive neuropsychological examination, as well as routine blood and biochemical screening tests and neuroimaging. The level of serum folate (Fol) was measured by electrochemiluminescence immunoassay. To assess the correlation of Fol level with the cognitive impairment neuropsychometric scales: Mini Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) were used. In patients with dementia, compared with the control group, there were significantly lower levels of folic acid (p = 0.04). There was no difference in the concentration of Fol in groups of patients (p = 0.0889). In people without cognitive impairment (CDR 0) levels of folic acid were significantly higher compared to the group with moderate dementia (CDR 2, p = 0.0475). The results may suggest that folic acid deficiency is one of the possible causes of dementia, but does not determine its type. Determination of serum Fol in the elderly and supplementation of this vitamin deficiency may play an important role in the prevention of the most common dementias.

  15. Possible pathophysiological roles of transglutaminase-catalyzed reactions in the pathogenesis of human neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Enrica Serretiello

    2015-09-01

    Full Text Available Transglutaminases (TG, E.C. 2.3.2.13 are related and ubiquitous enzymes that catalyze the cross linking of a glutaminyl residue of a protein/peptide substrate to a lysyl residue of a protein/peptide co-substrate. These enzymes are also capable of catalyzing other post-translational reactions important for cell life. The distribution and the physiological roles of human TGs have been widely studied in numerous cell types and tissues and recently their roles in several diseases have begun to be identified. It has been hypothesized that transglutaminase activity is directly involved in the pathogenetic mechanisms responsible for several human diseases. In particular, tissue TG (tTG, TG2, a member of the TG enzyme family, has been recently shown to be involved in the molecular mechanisms responsible for a very widespread human pathology, Celiac Disease (CD, one of the most common food intolerances described in the western population. The main food agent that provokes the strong and diffuse clinical symptoms has been known for several years to be gliadin, a protein present in a very large number of human foods derived from vegetables. Recently, some biochemical and immunological aspects of this very common disease have been clarified, and “tissue” transglutaminase, a multifunctional and ubiquitous enzyme, has been identified as one of the major factors. The aim of this review is to summarize the most recent findings concerning the relationships between the biochemical properties of the transglutaminase activity and the basic molecular mechanisms responsible for some human diseases, with particular reference to neuropsychiatric disorders. Possible molecular links between CD and neuropsychiatric disorders, and the use of transglutaminase inhibitors are also discussed.

  16. Mesenchymal stromal cells and rheumatic diseases: new tools from pathogenesis to regenerative therapies.

    Science.gov (United States)

    Cipriani, Paola; Ruscitti, Piero; Di Benedetto, Paola; Carubbi, Francesco; Liakouli, Vasiliki; Berardicurti, Onorina; Ciccia, Francesco; Triolo, Giovanni; Giacomelli, Roberto

    2015-07-01

    In recent years, mesenchymal stromal cells (MSCs) have been largely investigated and tested as a new therapeutic tool for several clinical applications, including the treatment of different rheumatic diseases. MSCs are responsible for the normal turnover and maintenance of adult mesenchymal tissues as the result of their multipotent differentiation abilities and their secretion of a variety of cytokines and growth factors. Although initially derived from bone marrow, MSCs are present in many different tissues such as many peri-articular tissues. MSCs may exert immune-modulatory properties, modulating different immune cells in both in vitro and in vivo models, and they are considered immune-privileged cells. At present, these capacities are considered the most intriguing aspect of their biology, introducing the possibility that these cells may be used as effective therapy in autoimmune diseases. Therefore, stem cell therapies may represent an innovative approach for the treatment of rheumatic diseases, especially for the forms that are not responsive to standard treatments or alternatively still lacking a definite therapy. At present, although the data from scientific literature appear to suggest that such treatments might be more effective whether administered as soon as possible, the use of MSCs in clinical practice is likely to be restricted to patients with a long history of a severe refractory disease. Further results from larger clinical trials are needed to corroborate preclinical findings and human non-controlled studies, and advancement in the knowledge of MSCs might provide information about the therapeutic role of these cells in the treatment of many rheumatic diseases. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  17. The experimental autoimmune encephalomyelitis (EAE) model of MS: utility for understanding disease pathophysiology and treatment

    Science.gov (United States)

    ROBINSON, ANDREW P.; HARP, CHRISTOPHER T.; NORONHA, AVERTANO; MILLER, STEPHEN D.

    2014-01-01

    While no single model can exactly recapitulate all aspects of multiple sclerosis (MS), animal models are essential in understanding the induction and pathogenesis of the disease and to develop therapeutic strategies that limit disease progression and eventually lead to effective treatments for the human disease. Several different models of MS exist, but by far the best understood and most commonly used is the rodent model of experimental autoimmune encephalomyelitis (EAE). This model is typically induced by either active immunization with myelin-derived proteins or peptides in adjuvant or by passive transfer of activated myelin-specific CD4+ T lymphocytes. Mouse models are most frequently used because of the inbred genotype of laboratory mice, their rapid breeding capacity, the ease of genetic manipulation, and availability of transgenic and knockout mice to facilitate mechanistic studies. Although not all therapeutic strategies for MS have been developed in EAE, all of the current US Food and Drug Administration (FDA)-approved immunomodulatory drugs are effective to some degree in treating EAE, a strong indicator that EAE is an extremely useful model to study potential treatments for MS. Several therapies, such as glatiramer acetate (GA: Copaxone), and natalizumab (Tysabri), were tested first in the mouse model of EAE and then went on to clinical trials. Here we discuss the usefulness of the EAE model in understanding basic disease pathophysiology and developing treatments for MS as well as the potential drawbacks of this model. PMID:24507518

  18. Non-Alcocholic Fatty Liver Disease: Modern View on Pathogenesis, Diagnosis and Treatment

    Directory of Open Access Journals (Sweden)

    V.B. Yagmur

    2013-09-01

    Full Text Available The article describes the modern views on the causes, mechanisms of development and treatment of nonalcoholic fatty liver disease (NAFLD. The main mechanisms for the accumulation of fat in the liver are an excess intake, synthesis, and their lack of their excretion. Besides numerous adipocytokines, the progression of fatty liver disease with cirrhosis is influenced by oxidative stress. For the diagnosis of NAFLD, modern instrumental and laboratory methods are being used, but the most sensitive method is a morphological study. The main objective in treating NAFLD — prevention of its progression. Treatment strategies are based on therapy of associated metabolic disorders (diabetes, hyperlipidemia and includes lifestyle modification, use of insulin sensitizers. The article is also discussed new trends in the pathogenetic treatment of hepatic steatosis.

  19. 311 Pathogenesis of Radiation-induced Pneumonitis in Patients with Chronic Obstructive Pulmonary Disease

    OpenAIRE

    Politi, Ekaterini; Tolia, Maria; Makrilia, Nektaria; Psarros, Fotis; Dannos, Ioannis; Syrigos, Kostas N.; Syrigou, Ekaterini

    2012-01-01

    Background Chest radiation is a common therapeutic approach in the management of lung cancer, as well as in other malignancies, rendering radiation-induced pneumonitis a rather commonly reported adverse event. A large proportion of patients undergoing radiation have underlying chronic obstructive pulmonary disease (COPD). We aim to elucidate the pathogenetic pathways implicated in radiation-induced pneumonitis particularly in this subgroup of patients. Methods A literature search was performe...

  20. Modeling HCV disease in animals: virology, immunology and pathogenesis of HCV and GBV-B infections

    OpenAIRE

    Manickam, Cordelia; Reeves, R. Keith

    2014-01-01

    Hepatitis C virus (HCV) infection has become a global public health burden costing billions of dollars in health care annually. Even with rapidly advancing scientific technologies this disease still poses a significant threat due to a lack of vaccines and affordable treatment options. The immune correlates of protection and predisposing factors toward chronicity remain major obstacles to development of HCV vaccines and immunotherapeutics due, at least in part, to lack of a tangible infection ...

  1. Insulin resistance: an additional risk factor in the pathogenesis of cardiovascular disease in type 2 diabetes.

    Science.gov (United States)

    Patel, Tushar P; Rawal, Komal; Bagchi, Ashim K; Akolkar, Gauri; Bernardes, Nathalia; Dias, Danielle da Silva; Gupta, Sarita; Singal, Pawan K

    2016-01-01

    Sedentary life style and high calorie dietary habits are prominent leading cause of metabolic syndrome in modern world. Obesity plays a central role in occurrence of various diseases like hyperinsulinemia, hyperglycemia and hyperlipidemia, which lead to insulin resistance and metabolic derangements like cardiovascular diseases (CVDs) mediated by oxidative stress. The mortality rate due to CVDs is on the rise in developing countries. Insulin resistance (IR) leads to micro or macro angiopathy, peripheral arterial dysfunction, hampered blood flow, hypertension, as well as the cardiomyocyte and the endothelial cell dysfunctions, thus increasing risk factors for coronary artery blockage, stroke and heart failure suggesting that there is a strong association between IR and CVDs. The plausible linkages between these two pathophysiological conditions are altered levels of insulin signaling proteins such as IR-β, IRS-1, PI3K, Akt, Glut4 and PGC-1α that hamper insulin-mediated glucose uptake as well as other functions of insulin in the cardiomyocytes and the endothelial cells of the heart. Reduced AMPK, PFK-2 and elevated levels of NADP(H)-dependent oxidases produced by activated M1 macrophages of the adipose tissue and elevated levels of circulating angiotensin are also cause of CVD in diabetes mellitus condition. Insulin sensitizers, angiotensin blockers, superoxide scavengers are used as therapeutics in the amelioration of CVD. It evidently becomes important to unravel the mechanisms of the association between IR and CVDs in order to formulate novel efficient drugs to treat patients suffering from insulin resistance-mediated cardiovascular diseases. The possible associations between insulin resistance and cardiovascular diseases are reviewed here.

  2. New Twists to an Old Story: Novel Concepts in the Pathogenesis of Allergic Eye Disease

    OpenAIRE

    Saban, Daniel R.; Calder, Virginia; Kuo, Chuan-Hui; Reyes, Nancy J.; Dartt, Darlene A.; Ono, Santa J.; Niederkorn, Jerry Y.

    2013-01-01

    The prevalence of allergy is rising globally at an alarming rate, which is currently at 20-40% of individuals in westernized nations. In the eye, allergic conditions can take on the acute form such as in seasonal and perennial allergic conjunctivitis, or a more severe and debilitating chronic form such as in vernal and atopic keratoconjunctivitis. Indeed, some key aspects of allergic eye disease pathophysiology are understood, such as the chief role of mast cells in the acute allergic reactio...

  3. Radical Roles for RAGE in the Pathogenesis of Oxidative Stress in Cardiovascular Diseases and Beyond

    Science.gov (United States)

    Daffu, Gurdip; del Pozo, Carmen Hurtado; O’Shea, Karen M.; Ananthakrishnan, Radha; Ramasamy, Ravichandran; Schmidt, Ann Marie

    2013-01-01

    Oxidative stress is a central mechanism by which the receptor for advanced glycation endproducts (RAGE) mediates its pathological effects. Multiple experimental inquiries in RAGE-expressing cultured cells have demonstrated that ligand-RAGE interaction mediates generation of reactive oxygen species (ROS) and consequent downstream signal transduction and regulation of gene expression. The primary mechanism by which RAGE generates oxidative stress is via activation of NADPH oxidase; amplification mechanisms in the mitochondria may further drive ROS production. Recent studies indicating that the cytoplasmic domain of RAGE binds to the formin mDia1 provide further support for the critical roles of this pathway in oxidative stress; mDia1 was required for activation of rac1 and NADPH oxidase in primary murine aortic smooth muscle cells treated with RAGE ligand S100B. In vivo, in multiple distinct disease models in animals, RAGE action generates oxidative stress and modulates cellular/tissue fate in range of disorders, such as in myocardial ischemia, atherosclerosis, and aneurysm formation. Blockade or genetic deletion of RAGE was shown to be protective in these settings. Indeed, beyond cardiovascular disease, evidence is accruing in human subjects linking levels of RAGE ligands and soluble RAGE to oxidative stress in disorders such as doxorubicin toxicity, acetaminophen toxicity, neurodegeneration, hyperlipidemia, diabetes, preeclampsia, rheumatoid arthritis and pulmonary fibrosis. Blockade of RAGE signal transduction may be a key strategy for the prevention of the deleterious consequences of oxidative stress, particularly in chronic disease. PMID:24084731

  4. Pathogenesis, diagnosis and treatment of non-alcoholic fatty liver disease

    Directory of Open Access Journals (Sweden)

    Verónica Martín-Domínguez

    2013-08-01

    Full Text Available Non-alcoholic fatty liver disease (NAFLD includes a broad spectrum of alterations that go from simple steatosis to steatohepatitis and cirrhosis. Type 2 diabetes mellitus (DM-2 and obesity are the principle factors associated to NAFLD. A 20-30 % prevalence in general population has been described. The survival of this type of patient is lower than the general population's, showing a higher incidence of hepatic and cardiovascular complications. The aetiopathogenesis is still unclear, but we know the intervention of different factors that produce fatty-acid accumulation in hepatic parenchyma, causing oxidative stress, oxygen-free radicals and the synthesis of an inflammatory cascade, that determine the progression of this disease from steatosis up to advanced fibrosis. The diagnostic gold-standard is still the liver biopsy, even though the development of newer non-invasive techniques, like serological and imaging (radiology, have opened a new field for research that allows bloodless testing of these patients and better study of the natural history of this disease. Nowadays, there is still no specific treatment for NAFLD. The development of healthy life habits and moderate exercise continue to be the pillars of treatment. Different pharmacological approaches have been studied and applied, such as the control of insulin resistance, lowering cholesterol levels, antioxidants, and other alternatives in experimental trials.

  5. Modeling HCV Disease in Animals: Virology, Immunology and Pathogenesis of HCV and GBV-B Infections

    Directory of Open Access Journals (Sweden)

    Cordelia eManickam

    2014-12-01

    Full Text Available Hepatitis C virus (HCV infection has become a global public health burden costing billions of dollars in health care annually. Even with rapidly advancing scientific technologies, this disease still looms large due to a lack of vaccines and affordable treatment options. The immune correlates of protection and predisposing factors towards chronicity remain major obstacles to development of HCV vaccines and immunotherapeutics due, at least in part, to lack of a tangible infection animal model. This review discusses the currently available animal models for HCV disease, with a primary focus on GB virus B (GBV-B infection of New World primates that recapitulates the dual hepacivirus phenotypes of acute viral clearance and chronic pathologic disease. HCV and GBV-B are also closely phylogenetically related, and advances in characterization of the immune systems of New World primates have already led to the use of this model for drug testing and vaccine trials. Herein, we discuss the benefits and caveats of the GBV-B infection model and discuss potential avenues for future development of novel vaccines and immunotherapies.

  6. Pathogenesis of hepatic steatosis: the link between hypercortisolism and non-alcoholic fatty liver disease.

    Science.gov (United States)

    Tarantino, Giovanni; Finelli, Carmine

    2013-10-28

    Based on the available literature, non alcoholic fatty liver disease or generally speaking, hepatic steatosis, is more frequent among people with diabetes and obesity, and is almost universally present amongst morbidly obese diabetic patients. Non alcoholic fatty liver disease is being increasingly recognized as a common liver condition in the developed world, with non alcoholic steatohepatitis projected to be the leading cause of liver transplantation. Previous data report that only 20% of patients with Cushing's syndrome have hepatic steatosis. Aiming at clarifying the reasons whereby patients suffering from Cushing's syndrome - a condition characterized by profound metabolic changes - present low prevalence of hepatic steatosis, the Authors reviewed the current concepts on the link between hypercortisolism and obesity/metabolic syndrome. They hypothesize that this low prevalence of fat accumulation in the liver of patients with Cushing's syndrome could result from the inhibition of the so-called low-grade chronic-inflammation, mainly mediated by Interleukin 6, due to an excess of cortisol, a hormone characterized by an anti-inflammatory effect. The Cushing's syndrome, speculatively considered as an in vivo model of the hepatic steatosis, could also help clarify the mechanisms of non alcoholic fatty liver disease.

  7. Hypoxia-regulated mechanisms in the pathogenesis of obesity and non-alcoholic fatty liver disease.

    Science.gov (United States)

    Lefere, Sander; Van Steenkiste, Christophe; Verhelst, Xavier; Van Vlierberghe, Hans; Devisscher, Lindsey; Geerts, Anja

    2016-09-01

    The pandemic rise in obesity has resulted in an increased incidence of metabolic complications. Non-alcoholic fatty liver disease is the hepatic manifestation of the metabolic syndrome and has become the most common chronic liver disease in large parts of the world. The adipose tissue expansion and hepatic fat accumulation characteristics of these disorders compromise local oxygen homeostasis. The resultant tissue hypoxia induces adaptive responses to restore oxygenation and tissue metabolism and cell survival. Hypoxia-inducible factors (HIFs) function as master regulators of this hypoxia adaptive response, and are in turn hydroxylated by prolyl hydroxylases (PHDs). PHDs are the main cellular oxygen sensors and regulate HIF proteasomal degradation in an oxygen-dependent manner. HIFs and PHDs are implicated in numerous physiological and pathological conditions. Extensive research using genetic models has revealed that hypoxia signaling is also a key mechanism in adipose tissue dysfunction, leading to adipose tissue fibrosis, inflammation and insulin resistance. Moreover, hypoxia affects liver lipid metabolism and deranges hepatic lipid accumulation. This review summarizes the molecular mechanisms through which the hypoxia adaptive response affects adipocyte and hepatic metabolism, and the therapeutic possibilities of modulating HIFs and PHDs in obesity and fatty liver disease.

  8. The human gastric microbiota: Is it time to rethink the pathogenesis of stomach diseases?

    Science.gov (United States)

    Nardone, Gerardo; Compare, Debora

    2015-06-01

    Although long thought to be a sterile organ, due to its acid production, the human stomach holds a core microbiome. To provide an update of findings related to gastric microbiota and its link with gastric diseases. We conducted a systematic review of the literature. The development of culture-independent methods facilitated the identification of many bacteria. Five major phyla have been detected in the stomach: Firmicutes, Bacteroidites, Actinobacteria, Fusobacteria and Proteobacteria. At the genera level, the healthy human stomach is dominated by Prevotella, Streptococcus, Veillonella, Rothia and Haemophilus; however, the composition of the gastric microbiota is dynamic and affected by such factors as diet, drugs and diseases. The interaction between the pre-existing gastric microbiota and Helicobacter pylori infection might influence an individual's risk of gastric disease, including gastric cancer. The maintenance of bacterial homeostasis could be essential for the stomach's health and highlights the chance for therapeutic interventions targeting the gastric microbiota, even if gastric pH, peristalsis and the mucus layer may prevent bacteria colonization; and the definition of gastric microbiota of the healthy stomach is still an ongoing challenging task.

  9. Host genetics role in the pathogenesis of periodontal disease and caries.

    Science.gov (United States)

    Nibali, Luigi; Di Iorio, Anna; Tu, Yu-Kang; Vieira, Alexandre R

    2017-03-01

    This study aimed to produce the latest summary of the evidence for association of host genetic variants contributing to both periodontal diseases and caries. Two systematic searches of the literature were conducted in Ovid Medline, Embase, LILACS and Cochrane Library for large candidate gene studies (CGS), systematic reviews and genome-wide association studies reporting data on host genetic variants and presence of periodontal disease and caries. A total of 124 studies were included in the review (59 for the periodontitis outcome and 65 for the caries outcome), from an initial search of 15,487 titles. Gene variants associated with periodontitis were categorized based on strength of evidence and then compared with gene variants associated with caries. Several gene variants showed moderate to strong evidence of association with periodontitis, although none of them had also been associated with the caries trait. Despite some potential aetiopathogenic similarities between periodontitis and caries, no genetic variants to date have clearly been associated with both diseases. Further studies or comparisons across studies with large sample size and clear phenotype definition could shed light into possible shared genetic risk factors for caries and periodontitis. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. Calcium Nutrition and Extracellular Calcium Sensing: Relevance for the Pathogenesis of Osteoporosis, Cancer and Cardiovascular Diseases

    Science.gov (United States)

    Peterlik, Meinrad; Kállay, Enikoe; Cross, Heide S.

    2013-01-01

    Through a systematic search in Pubmed for literature, on links between calcium malnutrition and risk of chronic diseases, we found the highest degree of evidence for osteoporosis, colorectal and breast cancer, as well as for hypertension, as the only major cardiovascular risk factor. Low calcium intake apparently has some impact also on cardiovascular events and disease outcome. Calcium malnutrition can causally be related to low activity of the extracellular calcium-sensing receptor (CaSR). This member of the family of 7-TM G-protein coupled receptors allows extracellular Ca2+ to function as a “first messenger” for various intracellular signaling cascades. Evidence demonstrates that Ca2+/CaSR signaling in functional linkage with vitamin D receptor (VDR)-activated pathways (i) promotes osteoblast differentiation and formation of mineralized bone; (ii) targets downstream effectors of the canonical and non-canonical Wnt pathway to inhibit proliferation and induce differentiation of colorectal cancer cells; (iii) evokes Ca2+ influx into breast cancer cells, thereby activating pro-apoptotic intracellular signaling. Furthermore, Ca2+/CaSR signaling opens Ca2+-sensitive K+ conductance channels in vascular endothelial cells, and also participates in IP3-dependent regulation of cytoplasmic Ca2+, the key intermediate of cardiomyocyte functions. Consequently, impairment of Ca2+/CaSR signaling may contribute to inadequate bone formation, tumor progression, hypertension, vascular calcification and, probably, cardiovascular disease. PMID:23340319

  11. Radical Roles for RAGE in the Pathogenesis of Oxidative Stress in Cardiovascular Diseases and Beyond

    Directory of Open Access Journals (Sweden)

    Radha Ananthakrishnan

    2013-10-01

    Full Text Available Oxidative stress is a central mechanism by which the receptor for advanced glycation endproducts (RAGE mediates its pathological effects. Multiple experimental inquiries in RAGE-expressing cultured cells have demonstrated that ligand-RAGE interaction mediates generation of reactive oxygen species (ROS and consequent downstream signal transduction and regulation of gene expression. The primary mechanism by which RAGE generates oxidative stress is via activation of NADPH oxidase; amplification mechanisms in the mitochondria may further drive ROS production. Recent studies indicating that the cytoplasmic domain of RAGE binds to the formin mDia1 provide further support for the critical roles of this pathway in oxidative stress; mDia1 was required for activation of rac1 and NADPH oxidase in primary murine aortic smooth muscle cells treated with RAGE ligand S100B. In vivo, in multiple distinct disease models in animals, RAGE action generates oxidative stress and modulates cellular/tissue fate in range of disorders, such as in myocardial ischemia, atherosclerosis, and aneurysm formation. Blockade or genetic deletion of RAGE was shown to be protective in these settings. Indeed, beyond cardiovascular disease, evidence is accruing in human subjects linking levels of RAGE ligands and soluble RAGE to oxidative stress in disorders such as doxorubicin toxicity, acetaminophen toxicity, neurodegeneration, hyperlipidemia, diabetes, preeclampsia, rheumatoid arthritis and pulmonary fibrosis. Blockade of RAGE signal transduction may be a key strategy for the prevention of the deleterious consequences of oxidative stress, particularly in chronic disease.

  12. Review article: the role of oxidative stress in pathogenesis and treatment of inflammatory bowel diseases.

    Science.gov (United States)

    Piechota-Polanczyk, Aleksandra; Fichna, Jakub

    2014-07-01

    In this review, we focus on the role of oxidative stress in the aetiology of inflammatory bowel diseases (IBD) and colitis-associated colorectal cancer and discuss free radicals and free radical-stimulated pathways as pharmacological targets for anti-IBD drugs. We also suggest novel anti-oxidative agents, which may become effective and less-toxic alternatives in IBD and colitis-associated colorectal cancer treatment. A Medline search was performed to identify relevant bibliography using search terms including: 'free radicals,' 'antioxidants,' 'oxidative stress,' 'colon cancer,' 'ulcerative colitis,' 'Crohn's disease,' 'inflammatory bowel disease.' Several therapeutics commonly used in IBD treatment, among which are immunosuppressants, corticosteroids and anti-TNF-α antibodies, could also affect the IBD progression by interfering with cellular oxidative stress and cytokine production. Experimental data shows that these drugs may effectively scavenge free radicals, increase anti-oxidative capacity of cells, influence multiple signalling pathways, e.g. MAPK and NF-kB, and inhibit pro-oxidative enzyme and cytokine concentration. However, their anti-oxidative and anti-inflammatory effectiveness still needs further investigation. A highly specific antioxidative activity may be important for the clinical treatment and relapse of IBD. In the future, a combination of currently used pharmaceutics, together with natural and synthetic anti-oxidative compounds, like lipoic acid or curcumine, could be taken into account in the design of novel anti-IBD therapies.

  13. Gene expression signature for biliary atresia and a role for Interleukin-8 in pathogenesis of experimental disease

    Science.gov (United States)

    Bessho, Kazuhiko; Mourya, Reena; Shivakumar, Pranavkumar; Walters, Stephanie; Magee, John C; Rao, Marepalli; Jegga, Anil G; Bezerra, Jorge A

    2014-01-01

    Biliary atresia is a progressive fibroinflammatory obstruction of extrahepatic bile ducts that presents as neonatal cholestasis. Due to the overlap in clinical, biochemical, and histological features with other causes of cholestasis, the diagnosis requires an intraoperative cholangiogram. Thus, we determined whether diseased livers express a gene expression signature unique to biliary atresia. Applying stringent statistical analysis to a genome-wide liver expression platform of 64 infants with biliary atresia at the time of diagnosis, 14 age-appropriate subjects with intrahepatic cholestasis as diseased controls, and 7 normal controls, we identified 15 genes uniquely expressed in biliary atresia with an accuracy of 92.3%. Among these genes, IL8 and LAMC2 were sufficient to classify subjects with biliary atresia distinctly from diseased controls with an area under the curve of 0.934 (95%CI: 0.84-1.03), sensitivity of 96.9%, and specificity of 85.7% using their combined first principal component. Direct measurement of IL8 protein in the serum, however, was not different between the two groups. To investigate whether the liver-restricted increase in IL8 was relevant to disease pathogenesis, we inactivated the signaling of IL8 homologs by genetic targeting of the Cxcr2 receptor in a murine model of experimental biliary atresia. Disruption of Cxcr2 shortened the duration of cholestasis, decreased the incidence of bile duct obstruction, and improved survival above wild-type neonatal mice. Conclusion: The hepatic expression of IL8 and LAMC2 has high sensitivity for biliary atresia at diagnosis and may serve as a biomarker of disease, with an important role for the IL8 signaling in experimental biliary atresia. PMID:24493287

  14. Chronic obstructive pulmonary disease (COPD): evaluation from clinical, immunological and bacterial pathogenesis perspectives.

    Science.gov (United States)

    Hassett, Daniel J; Borchers, Michael T; Panos, Ralph J

    2014-03-01

    Chronic obstructive pulmonary disease (COPD), a disease manifested by significantly impaired airflow, afflicts ∼14.2 million cases in the United States alone with an estimated 63 million people world-wide. Although there are a number of causes, the predominant cause is excessive tobacco smoke. In fact, in China, there have been estimates of 315,000,000 people that smoke. Other less frequent causes are associated with indirect cigarette smoke, air pollutants, biomass fuels, and genetic mutations. COPD is often associated with heart disease, lung cancer, osteoporosis and conditions can worsen in patients with sudden falls. COPD also affects both innate and adaptive immune processes. Cigarette smoke increases the expression of matrix metalloproteases and proinflammatory chemokines and increases lung titers of natural killer cells and neutrophils. Yet, neutrophil reactive oxygen species (ROS) mediated by the phagocytic respiratory burst and phagocytosis is impaired by nicotine. In contrast to innate immunity in COPD, dendritic cells represent leukocytes recruited to the lung that link the innate immune responses to adaptive immune responses by activating naïve T cells through antigen presentation. The autoimmune process that is also a significant part of inflammation associated with COPD. Moreover, coupled with restricted FEV1 values, are the prevalence of patients with single or multiple infections by bacteria, viruses and fungi. Finally, we focus on one of the more problematic infectious agents, the Gram-negative opportunistic pathogenic bacterium, Pseudomonas aeruginosa. Specifically, we delve into the development of highly problematic biofilm infections that are highly refractory to conventional antibiotic therapies in COPD. We offer a non-conventional, biocidal treatment that may be effective for COPD airway infections as well as with combinations of current antibiotic regimens for more effective treatment outcomes and relief for patients with COPD.

  15. Irritable bowel syndrome: A disease still searching for pathogenesis, diagnosis and therapy

    Science.gov (United States)

    Bellini, Massimo; Gambaccini, Dario; Stasi, Cristina; Urbano, Maria Teresa; Marchi, Santino; Usai-Satta, Paolo

    2014-01-01

    Irritable bowel syndrome (IBS) is the most frequently diagnosed functional gastrointestinal disorder in primary and secondary care. It is characterised by abdominal discomfort, pain and changes in bowel habits that can have a serious impact on the patient’s quality of life. The pathophysiology of IBS is not yet completely clear. Genetic, immune, environmental, inflammatory, neurological and psychological factors, in addition to visceral hypersensitivity, can all play an important role, one that most likely involves the complex interactions between the gut and the brain (gut-brain axis). The diagnosis of IBS can only be made on the basis of the symptoms of the Rome III criteria. Because the probability of organic disease in patients fulfilling the IBS criteria is very low, a careful medical history is critical and should pay particular attention to the possible comorbidities. Nevertheless, the severity of the patient’s symptoms or concerns sometimes compels the physician to perform useless and/or expensive diagnostic tests, transforming IBS into a diagnosis of exclusion. The presence of alarming symptoms (fever, weight loss, rectal bleeding, significant changes in blood chemistry), the presence of palpable abdominal masses, any recent onset of symptoms in patient aged over 50 years, the presence of symptoms at night, and a familial history of celiac disease, colorectal cancer and/or inflammatory bowel diseases all warrant investigation. Treatment strategies are based on the nature and severity of the symptoms, the degree of functional impairment of the bowel habits, and the presence of psychosocial disorders. This review examines and discusses the pathophysiological aspects and the diagnostic and therapeutic approaches available for patients with symptoms possibly related to IBS, pointing out controversial issues and the strengths and weaknesses of the current knowledge. PMID:25083055

  16. New clues in celiac disease epidemiology, pathogenesis, clinical manifestations, and treatment.

    Science.gov (United States)

    Lionetti, Elena; Catassi, Carlo

    2011-08-01

    Celiac disease (CD) is an immune-mediated enteropathy triggered by the ingestion of gluten in genetically susceptible individuals. It is one of the most common lifelong disorders on a worldwide basis. Celiac enteropathy is the final consequence of an abnormal immune reaction, showing features of both an innate and an adaptive response to gluten prolamins. The clinical spectrum is wide, including cases with either typical intestinal or atypical extraintestinal features, and silent forms. The only available treatment consists in dietary exclusion of grains containing gluten. New pharmacological treatment are currently under scrutiny.

  17. The physical approximation of APP and BACE-1: A key event in alzheimer's disease pathogenesis.

    Science.gov (United States)

    Sun, Jichao; Roy, Subhojit

    2018-03-01

    Alzheimer's disease (AD) is characterized by the accumulation of insoluble deposits of Amyloid β (Aβ) in brains. Aβ is derived by sequential cleavage of the amyloid precursor protein (APP) by β-site secretase enzyme (BACE-1) and γ-secretase. Proteolytic processing of APP by BACE-1 is the rate-limiting step in Aβ production, and this pathway is a prime target for AD drug development. Both APP and BACE-1 are membrane-spanning proteins, transported via secretory and endocytic pathways; and the physical interaction of APP and BACE-1 during trafficking is a key cell biological event initiating the amyloidogenic pathway. Here, we highlight recent research on intracellular trafficking/sorting of APP and BACE-1, and discuss how dysregulation of these pathways might lead to enhanced convergence of APP and BACE-1, and subsequent β-cleavage of APP. © 2018 Wiley Periodicals, Inc. Develop Neurobiol 78: 340-347, 2018. © 2018 Wiley Periodicals, Inc.

  18. Seronegative Neuromyelitis Optica Spectrum - The challenges on disease definition and pathogenesis

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    Douglas Kazutoshi Sato

    2014-06-01

    Full Text Available Neuromyelitis optica spectrum disorders (NMOSD are characterized by severe optic neuritis and/or longitudinally extensive transverse myelitis, and some brain lesions are also unique to NMOSD. Serum autoantibodies against aquaporin-4 (AQP4 are detected in most cases of NMOSD. However, some patients with NMOSD remain seronegative despite repetitive testing during attacks with highly sensitive cell-based assays. The differential diagnosis of NMOSD is not restricted to multiple sclerosis and it includes many diseases that can produce longitudinally extensive myelitis and/or optic neuritis. We review the clinical features, imaging, and laboratory findings that can be helpful on the diagnostic work-up, discuss the differences between AQP4 antibody positive and negative patients with NMOSD, including features of NMOSD with antibodies against myelin oligodendrocyte glycoprotein.

  19. Oxidative stress mediated mitochondrial and vascular lesions as markers in the pathogenesis of Alzheimer disease.

    Science.gov (United States)

    Aliev, G; Priyadarshini, M; Reddy, V P; Grieg, N H; Kaminsky, Y; Cacabelos, R; Ashraf, G Md; Jabir, N R; Kamal, M A; Nikolenko, V N; Zamyatnin, A A; Benberin, V V; Bachurin, S O

    2014-01-01

    Mitochondrial dysfunction plausibly underlies the aging-associated brain degeneration. Mitochondria play a pivotal role in cellular bioenergetics and cell-survival. Oxidative stress consequent to chronic hypoperfusion induces mitochondrial damage, which is implicated as the primary cause of cerebrovascular accidents (CVA) mediated Alzheimer's disease (AD). The mitochondrial function deteriorates with aging, and the mitochondrial damage correlates with increased intracellular production of oxidants and pro-oxidants. The prolonged oxidative stress and the resultant hypoperfusion in the brain tissues stimulate the expression of nitric oxide synthase (NOS) enzymes, which further drives the formation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The ROS and RNS collectively contributes to the dysfunction of the blood-brain barrier (BBB) and damage to the brain parenchymal cells. Delineating the molecular mechanisms of these processes may provide clues for the novel therapeutic targets for CVA and AD patients.

  20. Research advances in susceptibility genes and their role in the pathogenesis of nonalcoholic fatty liver disease

    Directory of Open Access Journals (Sweden)

    XUAN Shiying

    2016-03-01

    Full Text Available Currently the incidence of nonalcoholic fatty liver disease (NAFLD is increasing, and the age of onset is getting younger worldwide, resulting in a heavy economic burden for both individuals and the society. Since NAFLD is closely related to heredity, metabolism, and the environment, genetic factors play an important role in the development and progression of NAFLD. With the development and wide application of the techniques from the genome-wide association studies, new research advances have been achieved in the susceptibility genes of NAFLD. This review summarizes the related research findings at home and abroad, and investigates the pathogenic factors for NAFLD and related mechanisms with a focus on the polymorphisms of susceptibility genes.

  1. Mitochondria and α-Synuclein: Friends or Foes in the Pathogenesis of Parkinson's Disease?

    Science.gov (United States)

    Faustini, Gaia; Bono, Federica; Valerio, Alessandra; Pizzi, Marina; Spano, PierFranco; Bellucci, Arianna

    2017-12-08

    Parkinson's disease (PD) is a movement disorder characterized by dopaminergic nigrostriatal neuron degeneration and the formation of Lewy bodies (LB), pathological inclusions containing fibrils that are mainly composed of α-synuclein. Dopaminergic neurons, for their intrinsic characteristics, have a high energy demand that relies on the efficiency of the mitochondria respiratory chain. Dysregulations of mitochondria, deriving from alterations of complex I protein or oxidative DNA damage, change the trafficking, size and morphology of these organelles. Of note, these mitochondrial bioenergetics defects have been related to PD. A series of experimental evidence supports that α-synuclein physiological action is relevant for mitochondrial homeostasis, while its pathological aggregation can negatively impinge on mitochondrial function. It thus appears that imbalances in the equilibrium between the reciprocal modulatory action of mitochondria and α-synuclein can contribute to PD onset by inducing neuronal impairment. This review will try to highlight the role of physiological and pathological α-synuclein in the modulation of mitochondrial functions.

  2. PATHOGENESIS OF HEPATOCELLULAR CARCINOMA DEVELOPMENT IN NON ALCOHOLIC FATTY LIVER DISEASE.

    Science.gov (United States)

    Shetty, Kirti; Chen, Jian; Shin, Ji-Hyun; Jogunoori, Wilma; Mishra, Lopa

    2015-06-01

    Non-alcoholic fatty liver disease (NAFLD) is being recognized as an increasingly important contributor to the burden of hepatocellular carcinoma (HCC) worldwide. It is often accompanied by obesity and diabetes mellitus and is believed to be the hepatic representation of the metabolic syndrome. HCC development in NAFLD is multifactorial and complex. It is dependent on not only the well-described mechanisms noted in chronic liver injury, but also on the molecular derangements associated with obesity and dysmetabolism. These include adipocyte remodeling, adipokine secretion, lipotoxicity and insulin resistance. Recent advances focus on the importance of the gut-liver axis in accelerating the process of oncogenesis in NAFLD. The farnesoid X nuclear receptor (FXR) has been demonstrated to have important metabolic effects and its pharmacological activation by obeticholic acid has been recently reported to produce histological improvement in NASH. It is hoped that delineating the mechanisms of hepatic fibrosis and oncogenesis in NASH will lead to enhanced strategies for cancer prevention, surveillance and therapy in this population.

  3. Nonalcoholic Fatty Liver Disease: Pathogenesis and Therapeutics from a Mitochondria-Centric Perspective

    Directory of Open Access Journals (Sweden)

    Aaron M. Gusdon

    2014-01-01

    Full Text Available Nonalcoholic fatty liver disease (NAFLD describes a spectrum of disorders characterized by the accumulation of triglycerides within the liver. The global prevalence of NAFLD has been increasing as the obesity epidemic shows no sign of relenting. Mitochondria play a central role in hepatic lipid metabolism and also are affected by upstream signaling pathways involved in hepatic metabolism. This review will focus on the role of mitochondria in the pathophysiology of NAFLD and touch on some of the therapeutic approaches targeting mitochondria as well as metabolically important signaling pathways. Mitochondria are able to adapt to lipid accumulation in hepatocytes by increasing rates of beta-oxidation; however increased substrate delivery to the mitochondrial electron transport chain (ETC leads to increased reactive oxygen species (ROS production and eventually ETC dysfunction. Decreased ETC function combined with increased rates of fatty acid beta-oxidation leads to the accumulation of incomplete products of beta-oxidation, which combined with increased levels of ROS contribute to insulin resistance. Several related signaling pathways, nuclear receptors, and transcription factors also regulate hepatic lipid metabolism, many of which are redox sensitive and regulated by ROS.

  4. Pathogenesis of Molluscum Contagiosum: A new concept for the spontaneous involution of the disease

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    Khalifa E. Sharquie

    2015-07-01

    Full Text Available Background: Molluscum contagiosum is a common viral skin disease that usually has a self-clearing course. Objectives: to study the process of involution of molluscum contagiosum through utilizing histological examination. Patients and Methods: Different sizes and stages of evolution of lesions from 50 patients with molluscum contagiosum were included. Deep shave biopsies were taken from each patient for histopathological examination. Results: All lesions showed a single punctum and this was confirmed by histopathological examination. Each individual lesion showed an epidermal hyperplasia consisting of many lobes which subdivided into lobules that contain the molluscum bodies. The intra-cytoplasmic molluscum inclusion bodies increase in the number and size as the cells differentiate toward the surface of the epidermis to accumulate at a central meeting point equivalent to the clinical sign of umblication at which the infected cells undergo cytocidal disintegration releasing its viral contents into the skin surface. The general histological architecture resemble that of keratoacanthoma. Conclusion: The central umblication represent the site of the future involution that contains the final growth phase of the infected epidermal cells where it ends by a process of cellular death and disintegration releasing its viral contents into the surface of the skin at the craterform opening which is called punctum. This process of self-involution may resemble that of keratoacanthoma where there are many similar pathological features in both conditions.

  5. Effect of Infectious Diseases on the Pathogenesis of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.

    Science.gov (United States)

    Okamoto-Uchida, Yoshimi; Nakamura, Ryosuke; Sai, Kimie; Imatoh, Takuya; Matsunaga, Kayoko; Aihara, Michiko; Saito, Yoshiro

    2017-01-01

    Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse drug reactions. Recent studies have revealed that the prevalence of SJS/TEN is associated with genetic backgrounds, such as polymorphisms in human leukocyte antigens (HLAs). However, non-genetic factors contributing to the etiology of SJS/TEN are largely unknown. This study aimed to assess the involvement of concurrent infection on the pathological states of SJS/TEN, examining the severity of cutaneous symptoms and ocular involvement as well as the time to onset in drug-induced SJS/TEN patients. We recruited 257 Japanese SJS/TEN patients from June 2006 to September 2013 through a nationwide case collection network and participating hospitals and reviewed the clinical information including patient backgrounds, primary disease and medication status. Association between infection and pathological states of SJS/TEN was assessed using univariate and multivariate analyses. The concurrent infectious group of SJS/TEN patients showed a significantly higher rate of exhibiting severer dermatological and ophthalmological phenotypes and an earlier onset of SJS/TEN than the non-infectious group. Our results suggest that the infection could be a risk factor to cause severer symptoms and earlier onset of SJS/TEN.

  6. Dealing with Stress: Defective Metabolic Adaptation in Chronic Obstructive Pulmonary Disease Pathogenesis.

    Science.gov (United States)

    Michaeloudes, Charalambos; Bhavsar, Pankaj K; Mumby, Sharon; Chung, Kian Fan; Adcock, Ian M

    2017-11-01

    The mitochondrion is the main site of energy production and a hub of key signaling pathways. It is also central in stress-adaptive response due to its dynamic morphology and ability to interact with other organelles. In response to stress, mitochondria fuse into networks to increase bioenergetic efficiency and protect against oxidative damage. Mitochondrial damage triggers segregation of damaged mitochondria from the mitochondrial network through fission and their proteolytic degradation by mitophagy. Post-translational modifications of the mitochondrial proteome and nuclear cross-talk lead to reprogramming of metabolic gene expression to maintain energy production and redox balance. Chronic obstructive pulmonary disease (COPD) is caused by chronic exposure to oxidative stress arising from inhaled irritants, such as cigarette smoke. Impaired mitochondrial structure and function, due to oxidative stress-induced damage, may play a key role in causing COPD. Deregulated metabolic adaptation may contribute to the development and persistence of mitochondrial dysfunction in COPD. We discuss the evidence for deregulated metabolic adaptation and highlight important areas for investigation that will allow the identification of molecular targets for protecting the COPD lung from the effects of dysfunctional mitochondria.

  7. Astrovirus Pathogenesis

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    Cydney Johnson

    2017-01-01

    Full Text Available Astroviruses are a major cause of diarrhea in the young, elderly, and the immunocompromised. Since the discovery of human astrovirus type 1 (HAstV-1 in 1975, the family Astroviridae has expanded to include two more human clades and numerous mammalian and avian-specific genotypes. Despite this, there is still little known about pathogenesis. The following review highlights the current knowledge of astrovirus pathogenesis, and outlines the critical steps needed to further astrovirus research, including the development of animal models of cell culture systems.

  8. Crohn´s disease: a role of gut microbiota and Nod2 gene polymorphisms in disease pathogenesis

    Czech Academy of Sciences Publication Activity Database

    Hrnčířová, Lucia; Krejsek, J.; Šplíchal, Igor; Hrnčíř, Tomáš

    2014-01-01

    Roč. 57, č. 3 (2014), s. 89-96 ISSN 1211-4286 Grant - others:Universita Karlova(CZ) 37/10/906613 Institutional support: RVO:61388971 Keywords : gut * microbiota * Crohn disease Subject RIV: EC - Immunology

  9. The role of the apelinergic and vasopressinergic systems in the regulation of the cardiovascular system and the pathogenesis of cardiovascular disease.

    Science.gov (United States)

    Czarzasta, Katarzyna; Cudnoch-Jedrzejewska, Agnieszka

    2014-01-01

    Research studies indicate a role of the apelinergic and vasopressinergic systems both in the regulation of the cardiovascular system and the pathogenesis of CVD, including in such settings as obesity and stress. Based on these data, it may be suggested that interactions between these systems underlie numerous physiological and pathophysiological processes, some of them related to the cardiovascular system. Better understanding of the role of these systems and their interactions, both physiological and related to the pathogenesis of CVD, will allow further advances in prevention and drug therapy.

  10. Role of iodine in pathogenesis of thyroid disease - is induction of apoptosis consequence of iodine cytotoxicity?

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    Marković Ljiljana

    2017-01-01

    Full Text Available Iodine is one of the best-characterized environmental factors associated with autoimmune thyroid disease (ATD. Epidemiological studies have shown that ATD incidence has increased following the introduction of salt iodination in the 1920s; in addition, ATD patients can improve upon iodine restriction. In animal models such as BioBreeding/Worcester and Buffalo rats, obese chicken strain, and non-obese diabetic H-2h4 mice, excess iodine is associated with autoimmunity. Analyses of Hashimoto thyroiditis (HT have shown enlarged number of apoptotic follicular cells, and the destruction is an effect of death receptormediated apoptosis. Excess of iodine induces rapid apoptosis of goitrogen Wistar pretreated rats, possibly connected with inhibition of polyamine synthesis, inhibitors of DNA fragmentation. Percentage of apoptotic cells was statistically higher in patients with HT than in those with euthyroid goiter, with significant increase of caspase 32. Genes for Bcl-2 and Bax proteins are under the transcriptional control of p53. In TAD-2 cell cultures, apoptosis is p53-independed, suggesting that DNA damage is not primarily evoked by potassium iodide (KI. High concentrations of NaI increase the proportion of apoptotic cells in FTRL5 thyroid cell line. Iodide cytotoxicity is inhibited by a TPO inhibitor and is relieved with an anti-oxidant agent. Chronic iodine excess induces apoptosis and necrosis of thyroid follicular and endothelial cells, leading to thyroglobulin accumulation in connective tissue. Iodide excess requires peroxidase enzymatic activity to induce apoptosis. Ionic iodide is not directly toxic, whereas its molecular form I2 mediates the apoptotic effect of KI. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. OI-175059

  11. Roles of Amyloid β-Peptide-Associated Oxidative Stress and Brain Protein Modifications in the Pathogenesis of Alzheimer's Disease and Mild Cognitive Impairment

    OpenAIRE

    Butterfield, D. Allan; Reed, Tanea; Newman, Shelley F.; Sultana, Rukhsana

    2007-01-01

    Oxidative stress has been implicated to play a crucial role in the pathogenesis of a number of diseases, including neurodegenerative disorders, cancer, and ischemia just to name a few. Alzheimer's disease (AD) is an age-related neurodegenerative disorder that is recognized as the most common form of dementia. AD is histopathologically characterized by the presence of extracellular amyloid plaques, intracellular neurofibrillary tangles, the presence of oligomers of amyloid β-peptide (Aβ), and ...

  12. The Role of the Blood-Brain Barrier in the Pathogenesis of Senile Plaques in Alzheimer’s Disease

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    J. Provias

    2014-01-01

    Full Text Available The accumulation of beta-amyloid [Aβ] within senile plaques [SP] is characteristic of these lesions in Alzheimer’s disease. The accumulation of Aβ42, in particular, in the superior temporal [ST] cortex may result from an inability of the blood brain barrier (BBB to regulate the trans-endothelial transport and clearance of the amyloid. Lipoprotein receptor-related protein [LRP] and P-glycoprotein [P-gp] facilitate the efflux of Aβ out of the brain, whereas receptor for advanced glycation end products [RAGE] facilitates Aβ influx. Additionally, vascular endothelial growth factor [VEGF] and endothelial nitric oxide synthase [eNOS] may influence the trans-BBB transport of Aβ. In this study we examined ST samples and compared SP burden of all types with the capillary expression of LRP, p-gp, RAGE, VEGF, and e-NOS in samples from 15 control and 15 Alzheimer brains. LRP, P-gp, RAGE, VEGF, and eNOS positive capillaries and Aβ42 plaques were quantified and statistical analysis of the nonparametric data was performed using the Mann-Whitney and Kruskal-Wallis tests. In the Alzheimer condition P-gp, VEGF, and eNOS positive capillaries were negatively correlated with SP burden, but LRP and RAGE were positively correlated with SP burden. These results indicate altered BBB function in the pathogenesis of SPs in Alzheimer brains.

  13. Modeling the Pathogenesis of Charcot-Marie-Tooth Disease Type 1A Using Patient-Specific iPSCs

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    Lei Shi

    2018-01-01

    Full Text Available Charcot-Marie-Tooth disease type 1A (CMT1A, one of the most frequent inherited peripheral neuropathies, is associated with PMP22 gene duplication. Previous studies of CMT1A mainly relied on rodent models, and it is not yet clear how PMP22 overexpression leads to the phenotype in patients. Here, we generated the human induced pluripotent stem cell (hiPSC lines from two CMT1A patients as an in vitro cell model. We found that, unlike the normal control cells, CMT1A hiPSCs rarely generated Schwann cells through neural crest stem cells (NCSCs. Instead, CMT1A NCSCs produced numerous endoneurial fibroblast-like cells in the Schwann cell differentiation system, and similar results were obtained in a PMP22-overexpressing iPSC model. Therefore, despite the demyelination-remyelination and/or dysmyelination theory for CMT1A pathogenesis, developmental disabilities of Schwann cells may be considered as an underlying cause of CMT1A. Our results may have important implications for the uncovering of the underlying mechanism and the development of a promising therapeutic strategy for CMT1A neuropathy.

  14. Understanding complexity in neurodegenerative diseases: in silico reconstruction of emergence

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    Alexey eKolodkin

    2012-07-01

    Full Text Available Healthy functioning is an emergent property of the network of interacting biomolecules that comprise an organism. It follows that disease (a network shift that causes malfunction is also an emergent property, emerging from a perturbation of the network. On one hand, the biomolecular network of every individual is unique and this is evident when similar disease-producing agents cause different individual pathologies. Consequently, a personalized model and approach for every patient may be required for therapies to become effective across mankind. On the other hand, diverse combinations of internal and external perturbation factors may cause a similar shift in network functioning. We offer this as an explanation for the multi-factorial nature of most diseases: they are ‘systems biology diseases’, or ‘network diseases’. Here we focus on neurodegenerative diseases, like Parkinson’s disease, as an example. Because of the inherent complexity of these networks, it is difficult to understand multi-factorial diseases using simply our ‘naked brain’. When describing interactions between biomolecules through mathematical equations and integrating those equations into a mathematical model, we try to reconstruct the emergent properties of the system in silico. The reconstruction of emergence from interactions between huge numbers of macromolecules is one of the aims of systems biology. Systems biology approaches enable us to break through the limitation of the human brain to perceive the extraordinarily large number of interactions, but this also means that we delegate the understanding of reality to the computer. We no longer recognize all those essences in the system’s design crucial for important physiological behavior (the so-called ‘design principles’ of the system. In this paper we review evidence that by using more abstract approaches and by experimenting in silico, one may still be able to discover and understand the design

  15. Kaposi sarcoma herpesvirus pathogenesis.

    Science.gov (United States)

    Mariggiò, Giuseppe; Koch, Sandra; Schulz, Thomas F

    2017-10-19

    Kaposi sarcoma herpesvirus (KSHV), taxonomical name human gammaherpesvirus 8, is a phylogenetically old human virus that co-evolved with human populations, but is now only common (seroprevalence greater than 10%) in sub-Saharan Africa, around the Mediterranean Sea, parts of South America and in a few ethnic communities. KSHV causes three human malignancies, Kaposi sarcoma, primary effusion lymphoma, and many cases of the plasmablastic form of multicentric Castleman's disease (MCD) as well as occasional cases of plasmablastic lymphoma arising from MCD; it has also been linked to rare cases of bone marrow failure and hepatitis. As it has colonized humans physiologically for many thousand years, cofactors are needed to allow it to unfold its pathogenic potential. In most cases, these include immune defects of genetic, iatrogenic or infectious origin, and inflammation appears to play an important role in disease development. Our much improved understanding of its life cycle and its role in pathogenesis should now allow us to develop new therapeutic strategies directed against key viral proteins or intracellular pathways that are crucial for virus replication or persistence. Likewise, its limited (for a herpesvirus) distribution and transmission should offer an opportunity for the development and use of a vaccine to prevent transmission.This article is part of the themed issue 'Human oncogenic viruses'. © 2017 The Authors.

  16. A single nucleotide polymorphism in primary-microRNA-146a reduces the expression of mature microRNA-146a in patients with Alzheimer's disease and is associated with the pathogenesis of Alzheimer's disease.

    Science.gov (United States)

    Zhang, Bin; Wang, Aihong; Xia, Cuiping; Lin, Qunfeng; Chen, Chunfu

    2015-09-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common form of dementia among the aging population. Although the incidence of the disease continues to increase, no cure has been developed. Effective treatment is restricted not only due to the lack of curative medicine, but also due to limited understanding of the underlying mechanisms and the difficulties in accurately diagnosing AD in its earliest stages prior to clinical symptoms. Micro (mi) RNAs (miR) have gained increasing attention in the investigation of neurodegenerative diseases. Previous reports have demonstrated that deregulation of miR‑146a‑5p is associated with the pathogenesis of human AD. In the present study, the coding region of primary (pri)‑miR‑146a in patients with AD was scanned and the rare C allele of rs2910164 was found to be associated with AD. Using reverse transcription quantitative polymerase chain reaction, it was demonstrated that site variation reduced the expression of mature miR‑146a‑5p. Notably, a reduction in the expression of miR‑146a‑5p led to less efficient inhibition of target genes, including Toll‑like receptor (TLR)2, which is important in the pathogenesis of AD. Biological function investigations in RAW264.7 cells indicated that, compared with the G allele, the rare C allele upregulated the expression of tumor necrosis factor‑α following stimulation with β‑amyloid. These findings suggested that one common polymorphism in pri‑miR‑146a may contribute to the genetic predisposition to AD by disrupting the production of miR‑146a‑5p and affecting the expression and function of TLR2.

  17. Porphyromonas gingivalis peptidylarginine deiminase, a key contributor in the pathogenesis of experimental periodontal disease and experimental arthritis.

    Science.gov (United States)

    Gully, Neville; Bright, Richard; Marino, Victor; Marchant, Ceilidh; Cantley, Melissa; Haynes, David; Butler, Catherine; Dashper, Stuart; Reynolds, Eric; Bartold, Mark

    2014-01-01

    To investigate the suggested role of Porphyromonas gingivalis peptidylarginine deiminase (PAD) in the relationship between the aetiology of periodontal disease and experimentally induced arthritis and the possible association between these two conditions. A genetically modified PAD-deficient strain of P. gingivalis W50 was produced. The effect of this strain, compared to the wild type, in an established murine model for experimental periodontitis and experimental arthritis was assessed. Experimental periodontitis was induced following oral inoculation with the PAD-deficient and wild type strains of P. gingivalis. Experimental arthritis was induced via the collagen antibody induction process and was monitored by assessment of paw swelling and micro-CT analysis of the radio-carpal joints. Experimental periodontitis was monitored by micro CT scans of the mandible and histological assessment of the periodontal tissues around the mandibular molars. Serum levels of anti-citrullinated protein antibodies (ACPA) and P. gingivalis were assessed by ELISA. The development of experimental periodontitis was significantly reduced in the presence of the PAD-deficient P. gingivalis strain. When experimental arthritis was induced in the presence of the PAD-deficient strain there was less paw swelling, less erosive bone damage to the joints and reduced serum ACPA levels when compared to the wild type P. gingivalis inoculated group. This study has demonstrated that a PAD-deficient strain of P. gingivalis was associated with significantly reduced periodontal inflammation. In addition the extent of experimental arthritis was significantly reduced in animals exposed to prior induction of periodontal disease through oral inoculation of the PAD-deficient strain versus the wild type. This adds further evidence to the potential role for P. gingivalis and its PAD in the pathogenesis of periodontitis and exacerbation of arthritis. Further studies are now needed to elucidate the mechanisms

  18. Trichomonas vaginalis Pathogenesis: a Narrative Review

    Directory of Open Access Journals (Sweden)

    Zahra Arab-Mazar

    2015-07-01

    Full Text Available In the latest articles which were published during 2013-2014, Trichomonas vaginalis (T. vaginalis was mentioned as a neglected sexual transmission disease (STD, while the exact mechanism of its pathogenesis has not been cleared yet. Although trichomonasiasis is easy curable, there is concern that resistance to drug are increasing. This common infection as concerning the important public health implications needs more research to be done for understanding the diagnosis, treatment, immunology and pathogenesis. In this review we searched all valuable and relevant information considering the pathogenesis of T. vaginalis. We referred to the information databases of Medline, PubMed, Scopus and Google scholar. The used keywords were the combinations of T. vaginalis and words associated with pathogenicity. This review discusses the host-parasite interaction and pathogenicity of this parasite.

  19. Framework for Understanding Balance Dysfunction in Parkinson’s Disease

    Science.gov (United States)

    Schoneburg, Bernadette; Mancini, Martina; Horak, Fay; Nutt, John G.

    2013-01-01

    People with Parkinson’s disease (PD) suffer from progressive impairment in their mobility. Locomotor and balance dysfunction that impairs mobility in PD is an important cause of physical and psychosocial disability. The recognition and evaluation of balance dysfunction by the clinician is an essential component of managing PD. In this review, we describe a framework for understanding balance dysfunction in PD to help clinicians recognize patients that are at risk for falling and impaired mobility. PMID:23925954

  20. Disease: H01004 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available disease, learning disabilities, and high rates of psychiatric disorder, especially schizophrenia... syndrome: a model for understanding the genetics and pathogenesis of schizophrenia

  1. Using biological networks to improve our understanding of infectious diseases

    Directory of Open Access Journals (Sweden)

    Nicola J. Mulder

    2014-08-01

    Full Text Available Infectious diseases are the leading cause of death, particularly in developing countries. Although many drugs are available for treating the most common infectious diseases, in many cases the mechanism of action of these drugs or even their targets in the pathogen remain unknown. In addition, the key factors or processes in pathogens that facilitate infection and disease progression are often not well understood. Since proteins do not work in isolation, understanding biological systems requires a better understanding of the interconnectivity between proteins in different pathways and processes, which includes both physical and other functional interactions. Such biological networks can be generated within organisms or between organisms sharing a common environment using experimental data and computational predictions. Though different data sources provide different levels of accuracy, confidence in interactions can be measured using interaction scores. Connections between interacting proteins in biological networks can be represented as graphs and edges, and thus studied using existing algorithms and tools from graph theory. There are many different applications of biological networks, and here we discuss three such applications, specifically applied to the infectious disease tuberculosis, with its causative agent Mycobacterium tuberculosis and host, Homo sapiens. The applications include the use of the networks for function prediction, comparison of networks for evolutionary studies, and the generation and use of host–pathogen interaction networks.

  2. Toxicity of Mineral Dusts and a Proposed Mechanism for the Pathogenesis of Particle-Induced Lung Diseases

    Science.gov (United States)

    Lam, C.-W.; Zeidler-Erdely, P.; Scully, R.R.; Meyers, V.; Wallace, W.; Hunter, R.; Renne, R.; McCluskey, R.; Castranova, V.; Barger, M.; hide

    2015-01-01

    Humans will set foot on the moon again. The lunar surface has been bombarded for 4 billion years by micrometeoroids and cosmic radiation, creating a layer of fine dust having a potentially reactive particle surface. To investigate the impact of surface reactivity (SR) on the toxicity of particles, and in particular, lunar dust (LD), we ground 2 Apollo 14 LD samples to increase their SR and compare their toxicity with those of unground LD, TiO2 and quartz. Intratracheally instilled at 0, 1, 2.5, or 7.5 mg/rat, all dusts caused dose-dependent increases in pulmonary lesions, and enhancement of biomarkers of toxicity assessed in bronchoalveolar lavage fluids (BALF). The toxicity of LD was greater than that of TiO2 but less than that of quartz. Three LDs differed 14-fold in SR but were equally toxic; quartz had the lowest SR but was most toxic. These results show no correlation between particle SR and toxicity. Often pulmonary toxicity of a dust can be attributed to oxidative stress (OS). We further observed dose-dependent and dustcytotoxicity- dependent increases in neutrophils. The oxidative content per BALF cell was also directly proportional to both the dose and cytotoxicity of the dusts. Because neutrophils are short-lived and release of oxidative contents after they die could initiate and promote a spectrum of lesions, we postulate a general mechanism for the pathogenesis of particle-induced diseases in the lung that involves chiefly neutrophils, the source of persistent endogenous OS. This mechanism explains why one dust (e.g., quartz or nanoparticles) is more toxic than another (e.g., micrometer-sized TiO2), why dust-induced lesions progress with time, and why lung cancer occurs in rats but not in mice and hamsters exposed to the same duration and concentration of dust.

  3. Pathogenesis of Hepatic Encephalopathy

    Directory of Open Access Journals (Sweden)

    Irena Ciećko-Michalska

    2012-01-01

    Full Text Available Hepatic encephalopathy can be a serious complication of acute liver failure and chronic liver diseases, predominantly liver cirrhosis. Hyperammonemia plays the most important role in the pathogenesis of hepatic encephalopathy. The brain-blood barrier disturbances, changes in neurotransmission, neuroinflammation, oxidative stress, GABA-ergic or benzodiazepine pathway abnormalities, manganese neurotoxicity, brain energetic disturbances, and brain blood flow abnormalities are considered to be involved in the development of hepatic encephalopathy. The influence of small intestine bacterial overgrowth (SIBO on the induction of minimal hepatic encephalopathy is recently emphasized. The aim of this paper is to present the current views on the pathogenesis of hepatic encephalopathy.

  4. Challenges and issues with streptozotocin-induced diabetes - A clinically relevant animal model to understand the diabetes pathogenesis and evaluate therapeutics.

    Science.gov (United States)

    Goyal, Sameer N; Reddy, Navya M; Patil, Kalpesh R; Nakhate, Kartik T; Ojha, Shreesh; Patil, Chandragouda R; Agrawal, Yogeeta O

    2016-01-25

    Streptozotocin (STZ) has been extensively used over the last three decades to induce diabetes in various animal species and to help screen for hypoglycemic drugs. STZ induces clinical features in animals that resemble those associated with diabetes in humans. For this reason STZ treated animals have been used to study diabetogenic mechanisms and for preclinical evaluation of novel antidiabetic therapies. However, the physiochemical characteristics and associated toxicities of STZ are still major obstacles for researchers using STZ treated animals to investigate diabetes. Another major challenges in STZ-induced diabetes are sustaining uniformity, suitability, reproducibility and induction of diabetes with minimal animal lethality. Lack of appropriate use of STZ was found to be associated with increased mortality and animal suffering. During STZ use in animals, attention should be paid to several factors such as method of preparation of STZ, stability, suitable dose, route of administration, diet regimen, animal species with respect to age, body weight, gender and the target blood glucose level used to represent hyperglycemia. Therefore, protocol for STZ-induced diabetes in experimental animals must be meticulously planned. This review highlights specific skills and strategies involved in the execution of STZ-induced diabetes model. The present review aims to provide insight into diabetogenic mechanisms of STZ, specific toxicity of STZ with its significance and factors responsible for variations in diabetogenic effects of STZ. Further this review also addresses ways to minimize STZ-induced mortality, suggests methods to improve STZ-based experimental models and best utilize them for experimental studies purported to understand diabetes pathogenesis and preclinical evaluation of drugs. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  5. New discoveries in the pathogenesis and classification of vitiligo.

    Science.gov (United States)

    Rodrigues, Michelle; Ezzedine, Khaled; Hamzavi, Iltefat; Pandya, Amit G; Harris, John E

    2017-07-01

    Vitiligo is a common autoimmune disease that progressively destroys melanocytes in the skin, resulting in the appearance of patchy depigmentation. This disfiguring condition frequently affects the face and other visible areas of the body, which can be psychologically devastating. The onset of vitiligo often occurs in younger individuals and progresses for life, resulting in a heavy burden of disease and decreased quality of life. Presentation patterns of vitiligo vary, and recognition of these patterns provides both diagnostic and prognostic clues. Recent insights into disease pathogenesis offer a better understanding of the natural history of the disease, its associations, and potential for future treatments. The first article in this continuing medical education series outlines typical and atypical presentations of vitiligo, how they reflect disease activity, prognosis, and response to treatment. Finally, we discuss disease associations, risk factors, and our current understanding of disease pathogenesis. Copyright © 2016 American Academy of Dermatology, Inc. All rights reserved.

  6. Contribution of β-phenethylamine, a component of chocolate and wine, to dopaminergic neurodegeneration: implications for the pathogenesis of Parkinson’s disease

    OpenAIRE

    Borah, Anupom; Paul, Rajib; Mazumder, Muhammed Khairujjaman; Bhattacharjee, Nivedita

    2013-01-01

    While the cause of dopaminergic neuronal cell death in Parkinson’s disease (PD) is not yet understood, many endogenous molecules have been implicated in its pathogenesis. β-phenethylamine (β-PEA), a component of various food items including chocolate and wine, is an endogenous molecule produced from phenylalanine in the brain. It has been reported recently that long-term administration of β-PEA in rodents causes neurochemical and behavioral alterations similar to that produced by parkinsonian...

  7. An Evaluation of the Training Program: "The Alzheimer's Disease Afflicted: Understanding the Disease and the Resident."

    Science.gov (United States)

    Miah, M. Mizanur Rahman

    This study was undertaken to evaluate a training program on understanding Alzheimer's disease for nursing home caregivers of those with the disease. A pretest/posttest design control group methodology was used to evaluate 81 staff members. Results of the study showed that: (1) staff satisfaction with working with mentally impaired and demented…

  8. Pathogenesis of Idiopathic Pulmonary Fibrosis

    Science.gov (United States)

    Wolters, Paul J.; Collard, Harold R.; Jones, Kirk D.

    2014-01-01

    Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease associated with aging that is characterized by the histopathological pattern of usual interstitial pneumonia. Although an understanding of the pathogenesis of IPF is incomplete, recent advances delineating specific clinical and pathologic features of IPF have led to better definition of the molecular pathways that are pathologically activated in the disease. In this review we highlight several of these advances, with a focus on genetic predisposition to IPF and how genetic changes, which occur primarily in epithelial cells, lead to activation of profibrotic pathways in epithelial cells. We then discuss the pathologic changes within IPF fibroblasts and the extracellular matrix, and we conclude with a summary of how these profibrotic pathways may be interrelated. PMID:24050627

  9. Molecular Pathogenesis of Neuromyelitis Optica

    Directory of Open Access Journals (Sweden)

    Simon A Broadley

    2012-10-01

    Full Text Available Neuromyelitis optica (NMO is a rare autoimmune disorder, distinct from multiple sclerosis, causing inflammatory lesions in the optic nerves and spinal cord. An autoantibody (NMO IgG against aquaporin-4 (AQP4, a water channel expressed on astrocytes is thought to be causative. Peripheral production of the antibody is triggered by an unknown process in genetically susceptible individuals. Anti-AQP4 antibody enters the central nervous system (CNS when the blood brain barrier is made permeable and has high affinity for orthogonal array particles of AQP4. Like other autoimmune diseases, Th17 cells and their effector cytokines (such as interleukin 6 have been implicated in pathogenesis. AQP4 expressing peripheral organs are not affected by NMO IgG, but the antibody causes extensive astrocytic loss in specific regions of the CNS through complement mediated cytotoxicity. Demyelination occurs during the inflammatory process and is probably secondary to oligodendrocyte apoptosis subsequent to loss of trophic support from astrocytes. Ultimately, extensive axonal injury leads to severe disability. Despite rapid advances in the understanding of NMO pathogenesis, unanswered questions remain, particularly with regards to disease mechanisms in NMO IgG seronegative cases. Increasing knowledge of the molecular pathology is leading to improved treatment strategies.

  10. Pathogenesis of growth failure and partial reversal with gene therapy in murine and canine Glycogen Storage Disease type Ia.

    Science.gov (United States)

    Brooks, Elizabeth Drake; Little, Dianne; Arumugam, Ramamani; Sun, Baodong; Curtis, Sarah; Demaster, Amanda; Maranzano, Michael; Jackson, Mark W; Kishnani, Priya; Freemark, Michael S; Koeberl, Dwight D

    2013-06-01

    Glycogen Storage Disease type Ia (GSD-Ia) in humans frequently causes delayed bone maturation, decrease in final adult height, and decreased growth velocity. This study evaluates the pathogenesis of growth failure and the effect of gene therapy on growth in GSD-Ia affected dogs and mice. Here we found that homozygous G6pase (-/-) mice with GSD-Ia have normal growth hormone (GH) levels in response to hypoglycemia, decreased insulin-like growth factor (IGF) 1 levels, and attenuated weight gain following administration of GH. Expression of hepatic GH receptor and IGF 1 mRNAs and hepatic STAT5 (phospho Y694) protein levels are reduced prior to and after GH administration, indicating GH resistance. However, restoration of G6Pase expression in the liver by treatment with adeno-associated virus 8 pseudotyped vector expressing G6Pase (AAV2/8-G6Pase) corrected body weight, but failed to normalize plasma IGF 1 in G6pase (-/-) mice. Untreated G6pase (-/-) mice also demonstrated severe delay of growth plate ossification at 12 days of age; those treated with AAV2/8-G6Pase at 14 days of age demonstrated skeletal dysplasia and limb shortening when analyzed radiographically at 6 months of age, in spite of apparent metabolic correction. Moreover, gene therapy with AAV2/9-G6Pase only partially corrected growth in GSD-Ia affected dogs as detected by weight and bone measurements and serum IGF 1 concentrations were persistently low in treated dogs. We also found that heterozygous GSD-Ia carrier dogs had decreased serum IGF 1, adult body weights and bone dimensions compared to wild-type littermates. In sum, these findings suggest that growth failure in GSD-Ia results, at least in part, from hepatic GH resistance. In addition, gene therapy improved growth in addition to promoting long-term survival in dogs and mice with GSD-Ia. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. Vestibular animal models: contributions to understanding physiology and disease.

    Science.gov (United States)

    Straka, Hans; Zwergal, Andreas; Cullen, Kathleen E

    2016-04-01

    Our knowledge of the vestibular sensory system, its functional significance for gaze and posture stabilization, and its capability to ensure accurate spatial orientation perception and spatial navigation has greatly benefitted from experimental approaches using a variety of vertebrate species. This review summarizes the attempts to establish the roles of semicircular canal and otolith endorgans in these functions followed by an overview of the most relevant fields of vestibular research including major findings that have advanced our understanding of how this system exerts its influence on reflexive and cognitive challenges encountered during daily life. In particular, we highlight the contributions of different animal models and the advantage of using a comparative research approach. Cross-species comparisons have established that the morpho-physiological properties underlying vestibular signal processing are evolutionarily inherent, thereby disclosing general principles. Based on the documented success of this approach, we suggest that future research employing a balanced spectrum of standard animal models such as fish/frog, mouse and primate will optimize our progress in understanding vestibular processing in health and disease. Moreover, we propose that this should be further supplemented by research employing more "exotic" species that offer unique experimental access and/or have specific vestibular adaptations due to unusual locomotor capabilities or lifestyles. Taken together this strategy will expedite our understanding of the basic principles underlying vestibular computations to reveal relevant translational aspects. Accordingly, studies employing animal models are indispensible and even mandatory for the development of new treatments, medication and technical aids (implants) for patients with vestibular pathologies.

  12. Sport and acute coronary syndromes : new observations on the pathogenesis of excercise-related acute cornoray heart disease

    NARCIS (Netherlands)

    R. Ciampricotti (Renzo)

    1992-01-01

    textabstractThe present study was undertaken in order to elucidate the pathogenesis of exercise-related coronary events and to determine whether or not there is a direct cause-effect relationship between sport and these events- A secondary objeCtive was to establish whether or not habitual physical

  13. Aberrant Free Radical Biology Is a Unifying Theme in the Etiology and Pathogenesis of Major Human Diseases

    Directory of Open Access Journals (Sweden)

    Frederick E. Domann

    2013-04-01

    Full Text Available The seemingly disparate areas of oxygen toxicity, radiation exposure, and aging are now recognized to share a common feature—the aberrant production and/or removal of biologically derived free radicals and other reactive oxygen and nitrogen species (ROS/RNS. Advances in our understanding of the effects of free radicals in biology and medicine have been, and continue to be, actively translated into clinically tractable diagnostic and therapeutic applications. This issue is dedicated to recent advances, both basic discoveries and clinical applications, in the field of free radicals in biology and medicine. As more is understood about the proximal biological targets of aberrantly produced or removed reactive species, their sensors, and effectors of compensatory response, a great deal more will be learned about the commonalities in mechanisms underlying seemingly disparate disease states. Together with this deeper understanding, opportunities will arise to devise rational therapeutic interventions to decrease the incidence and severity of these diseases and positively impact the human healthspan.

  14. Interleukin 17A is an immune marker for chlamydial disease severity and pathogenesis in the koala (Phascolarctos cinereus).

    Science.gov (United States)

    Mathew, Marina; Waugh, Courtney; Beagley, Kenneth W; Timms, Peter; Polkinghorne, Adam

    2014-10-01

    The koala (Phascolarctos cinereus) is an iconic Australian marsupial species that is facing many threats to its survival. Chlamydia pecorum infections are a significant contributor to this ongoing decline. A major limiting factor in our ability to manage and control chlamydial disease in koalas is a limited understanding of the koala's cell-mediated immune response to infections by this bacterial pathogen. To identify immunological markers associated with chlamydial infection and disease in koalas, we used koala-specific Quantitative Real Time PCR (qrtPCR) assays to profile the cytokine responses of Peripheral Blood Mononuclear Cells (PBMCs) collected from 41 koalas with different stages of chlamydial disease. Target cytokines included the principal Th1 (Interferon gamma; IFNγ), Th2 (Interleukin 10; IL10), and pro-inflammatory cytokines (Tumor Necrosis Factor alpha; TNFα). A novel koala-specific IL17A qrtPCR assay was also developed as part of this study to quantitate the gene expression of this Th17 cytokine in koalas. A statistically significant higher IL17A gene expression was observed in animals with current chlamydial disease compared to animals with asymptomatic chlamydial infection. A modest up-regulation of pro-inflammatory cytokines, such as TNFα and IFNγ, was also observed in these animals with signs of current chlamydial disease. IL10 gene expression was not evident in the majority of animals from both groups. Future longitudinal studies are now required to confirm the role played by cytokines in pathology and/or protection against C. pecorum infection in the koala. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. Effects of Endobacterium (Stenotrophomonas maltophilia on Pathogenesis-Related Gene Expression of Pine Wood Nematode (Bursaphelenchus xylophilus and Pine Wilt Disease

    Directory of Open Access Journals (Sweden)

    Long-Xi He

    2016-05-01

    Full Text Available Pine wilt disease (PWD caused by the pine wood nematode (PWN, Bursaphelenchus xylophilus, is responsible for devastating epidemics in pine trees in Asia and Europe. Recent studies showed that bacteria carried by the PWN might be involved in PWD. However, the molecular mechanism of the interaction between bacteria and the PWN remained unclear. Now that the whole genome of B. xylophilus (Bursaphelenchus xylophilus is published, transcriptome analysis is a unique method to study the role played by bacteria in PWN. In this study, the transcriptome of aseptic B. xylophilus, B. xylophilus treated with endobacterium (Stenotrophomonas maltophilia NSPmBx03 and fungus B. xylophilus were sequenced. We found that 61 genes were up-regulated and 830 were down-regulated in B. xylophilus after treatment with the endobacterium; 178 genes were up-regulated and 1122 were down-regulated in fungus B. xylophilus compared with aseptic B. xylophilus. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were used to study the significantly changed biological functions and pathways for these differentially expressed genes. Many pathogenesis-related genes, including glutathinone S-transferase, pectate lyase, ATP-binding cassette transporter and cytochrome P450, were up-regulated after B. xylophilus were treated with the endobacterium. In addition, we found that bacteria enhanced the virulence of PWN. These findings indicate that endobacteria might play an important role in the development and virulence of PWN and will improve our understanding of the regulatory mechanisms involved in the interaction between bacteria and the PWN.

  16. Effects of Endobacterium (Stenotrophomonas maltophilia) on Pathogenesis-Related Gene Expression of Pine Wood Nematode (Bursaphelenchus xylophilus) and Pine Wilt Disease

    Science.gov (United States)

    He, Long-Xi; Wu, Xiao-Qin; Xue, Qi; Qiu, Xiu-Wen

    2016-01-01

    Pine wilt disease (PWD) caused by the pine wood nematode (PWN), Bursaphelenchus xylophilus, is responsible for devastating epidemics in pine trees in Asia and Europe. Recent studies showed that bacteria carried by the PWN might be involved in PWD. However, the molecular mechanism of the interaction between bacteria and the PWN remained unclear. Now that the whole genome of B. xylophilus (Bursaphelenchus xylophilus) is published, transcriptome analysis is a unique method to study the role played by bacteria in PWN. In this study, the transcriptome of aseptic B. xylophilus, B. xylophilus treated with endobacterium (Stenotrophomonas maltophilia NSPmBx03) and fungus B. xylophilus were sequenced. We found that 61 genes were up-regulated and 830 were down-regulated in B. xylophilus after treatment with the endobacterium; 178 genes were up-regulated and 1122 were down-regulated in fungus B. xylophilus compared with aseptic B. xylophilus. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were used to study the significantly changed biological functions and pathways for these differentially expressed genes. Many pathogenesis-related genes, including glutathinone S-transferase, pectate lyase, ATP-binding cassette transporter and cytochrome P450, were up-regulated after B. xylophilus were treated with the endobacterium. In addition, we found that bacteria enhanced the virulence of PWN. These findings indicate that endobacteria might play an important role in the development and virulence of PWN and will improve our understanding of the regulatory mechanisms involved in the interaction between bacteria and the PWN. PMID:27231904

  17. Modern views on the pathogenesis of hard dental tissues and periodontium lesions and means of their treatment in children with chronic diseases of the gastrointestinal tract

    Directory of Open Access Journals (Sweden)

    Krupey V.Y.

    2014-09-01

    Full Text Available Changes in the mouth covity often reflect regularities of pathogenesis of a number of disease states, and primarily from the digestive tract. Therefore, the purpose of the study was to clarify pathogenesis of certain lesions of hard dental tissues and periodontal tissues in children with chronic diseases of the gastrointestinal tract and development of schemes for their treatment. The study observed 441 children aged from 7 to 15 years with dental caries and generalized chronic catarrhal gingivitis on the background of chronic gastritis and duodenitis, duodenal ulcer and malabsorption syndrome. All the children were divided into 2 groups - basic and comparison one. The study identified the most dan¬gerous and little-known way of pathogenesis, which passes through the general processes of reducing the production of various proteins (immune system and antiseptics, is a violation of the general and local resistance and, ultimately, mineral metabolism. Such disorders impair complete mineralization of tooth enamel, reduce optimal composition and properties of saliva stimulating glycolysis processes in oral cavity. Prevention of dental caries and generalized chronic catarrhal gingivitis in children with chronic pathology of the gastrointestinal tract is based on the use of developed therapeutic and prophylactic complex, which includes mucosal gel Kvertulin, probiotic Latsidofil and drug Calcium D.

  18. Major histocompatibility complex: its role in the pathogenesis of autoimmune rheumatic diseases - doi:10.5020/18061230.2006.p155

    Directory of Open Access Journals (Sweden)

    Crésio Alves

    2012-01-01

    Full Text Available In order to allow early diagnosis and more efficient treatments, many studies have been trying to define genetic markers of rheumatic diseases. Amongst them, antigens and alleles of the HLA (Human Leukocyte Antigens system are distinguished. Located in the short arm of chromosome 6, the HLA system exerts genetic influence on the susceptibility and severity of these diseases. The discovery of new molecular methods to typify HLA alleles and the recent nomenclature updates have been contributing to a better understanding of this system. Unfortunately, this information has not been adequately published in the clinical literature. The present work aimed at presenting the function, nomenclature and methods of detection of the HLA polymorphism; and to review its associations with rheumatic fever, systemic erythematosus lupus, rheumatoid arthritis, juvenile idiopathic arthritis and spondyloarthropathies. Articles that were published between 1980 and 2005 were searched in the MEDLINE and LILACS data basis. This review demonstrated that although the HLA association is well established for some rheumatic diseases (e.g., HLA-B27 and spondyloarthropathies, HLA DR-3 and HLA-DR4 with rheumatoid arthritis, HLA-DR4 and lupus others vary in different ethnic-racial group and illnesses, due to its polymorphism. It is necessary to study populations from different ethnic backgrounds to identify new associations or to strengthen associations with the ones already identified. This knowledge will contribute to future prophylactic or therapeutic interventions in patients with rheumatic disorders or at risk to develop them.

  19. A Biochemical Approach to Understand the Pathogenesis of Advanced Pulmonary Arterial Hypertension: Metabolomic Profiles of Arginine, Sphingosine-1-Phosphate, and Heme of Human Lung.

    Directory of Open Access Journals (Sweden)

    Yidan D Zhao

    Full Text Available Pulmonary arterial hypertension (PAH is a vascular disease characterized by persistent precapillary pulmonary hypertension (PH, leading to progressive right heart failure and premature death. The pathological mechanisms underlying this condition remain elusive. Analysis of global metabolomics from lung tissue of patients with PAH (n = 8 and control lung tissue (n = 8 leads to a better understanding of disease progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted arginine pathways with increased Nitric oxide (NO and decreased arginine. Our results also showed specific metabolic pathways and genetic profiles with increased Sphingosine-1-phosphate (S1P metabolites as well as increased Heme metabolites with altered oxidative pathways in the advanced stage of the human PAH lung. The results suggest that PAH has specific metabolic pathways contributing to the vascular remodeling in severe pulmonary hypertension. Profiling metabolomic alterations of the PAH lung has provided a new understanding of the pathogenic mechanisms of PAH, which benefits therapeutic targeting to specific metabolic pathways involved in the progression of PAH.

  20. The epigenetic paradigm in periodontitis pathogenesis

    Directory of Open Access Journals (Sweden)

    Vamsi Lavu

    2015-01-01

    Full Text Available Epigenome refers to "epi" meaning outside the "genome." Epigenetics is the field of study of the epigenome. Epigenetic modifications include changes in the promoter CpG Islands, modifications of histone protein structure, posttranslational repression by micro-RNA which contributes to the alteration of gene expression. Epigenetics provides an understanding of the role of gene-environment interactions on disease phenotype especially in complex multifactorial diseases. Periodontitis is a chronic inflammatory disorder that affects the supporting structures of the tooth. The role of the genome (in terms of genetic polymorphisms in periodontitis pathogenesis has been examined in numerous studies, and chronic periodontitis has been established as a polygenic disorder. The potential role of epigenetic modifications in the various facets of pathogenesis of periodontitis is discussed in this paper based on the available literature.

  1. Inflammatory bowel diseases (IBD) - critical discussion of etiology, pathogenesis, diagnostics, and therapy; Chronisch entzuendliche Darmerkrankungen - Kritische Diskussion von Aetiologie, Pathogenese, Diagnostik und Therapie

    Energy Technology Data Exchange (ETDEWEB)

    Ochsenkuehn, T.; Sackmann, M.; Goeke, B. [Medizinische Klinik II, Klinikum der Universitaet Muenchen-Grosshadern (Germany)

    2003-01-01

    Aims Crohn's disease and ulcerative colitis are the most frequent inflammatory bowel diseases (IBD) with a prevalence of approximately one out of 500.Cytokine research opened new and potent treatment options and thus stimulated clinical and basic research.However, the IBD still remain a challenge for patients and physicians,demanding close cooperation between gastroenterologists,radiologists and surgeons.The basic understanding of IBD,which is necessary for efficient diagnostic and therapeutic concepts is reviewed. Based upon recent publications and our clinical experience we discuss aspects of etiology,pathogenesis,diagnostics,and therapy of Crohn's disease and ulcerative colitis. A genetically influenced, exaggerated and sustained immune response against the own gut flora seems to be one of the most important factors in the pathogenesis of IBD.Not less important are environmental influences.For instance, cigarette smoking had been judged to have some negative influence on the natural course of Crohn's disease.Now,however, recent studies show that smoking is even a significant independent risk factor in the pathogenesis of IBD. Since IBD and especially Crohn's disease can effect the whole body, detailed analysis of inflammatory organ involvement is necessary before therapy.For instance, the MRIenteroclysis technique adds a necessary diagnostic tool for the exploration of those parts of the small bowel that cannot been reached by routine endoscopy like the upper ileum and the lower jejunum. In terms of therapy, a change of paradigms can be observed: patients will no longer be treated only when symptoms arise, but will early be integrated into a therapeutic concept, which is determined by site and extent of the disease and adapted to the abilities and needs of the patient.Furthermore,immunosuppressive agents like azathioprine and 6-mercaptopurine will establish as central concept in the medical treatment of IBD.Discussion IBD-therapy should

  2. Immune regulation in T1D and T2D: prospective role of Foxp3+ Treg cells in disease pathogenesis and treatment

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    Mara eKornete

    2013-06-01

    Full Text Available There is increasing evidence that dysregulated immune responses play key roles in the pathogenesis and complications of type 1 but also type 2 diabetes. Indeed, chronic inflammation and autoimmunity, which are salient features of type 1 diabetes, are now believed to actively contribute to the pathogenesis of type 2 diabetes. The accumulation of activated innate and adaptive immune cells in various metabolic tissues results in the release of inflammatory mediators, which promote insulin resistance and β-cell damage. Moreover, these dysregulated immune responses can also mutually influence the prevalence of both type 1 and 2 diabetes. In this review article, we discuss the central role of immune responses in the patho-physiology and complications of type 1 and 2 diabetes, and provide evidence that regulation of these responses, particularly through the action of regulatory T cells, may be a possible therapeutic avenue for the treatment of these disease and their respective complications.

  3. [Interaction of plasma selenium levels and D12S304 gene site in the pathogenesis of Kashin-Beck disease analyzed by multifactor dimensionality reduction software].

    Science.gov (United States)

    Ping, Zhiguang; Liu, Li; Guo, Xiong

    2011-07-01

    To explore the interaction of plasma selenium levels and D12S304 gene site in the pathogenesis of Kashin-Beck disease (KBD). Case-control design was taken to compare the difference of plasma selenium levels and genotype of D12S304 between KBD patients and non-patients, and the interactions were analyzed by MDR software. Plasma selenium levels was lower in the case group than in the control group, while the D12S304 gene site was not different between the two groups, and no interaction between plasma selenium and genotype was observed. There was no interaction between plasma selenium and genotype at D12S304. Enlarging sample size or selecting another gene site might be needed in exploring the gene-environment interactions in the pathogenesis of KBD.

  4. The Pathogenesis of Autism

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    Timothy John Watts

    2008-01-01

    Full Text Available Autism is well known as a complex developmental disorder with a seemingly confusing and uncertain pathogenesis. The definitive mechanisms that promote autism are poorly understood and mostly unknown, yet available theories do appear to focus on the disruption of normal cerebral development and its subsequent implications on the functional brain unit. This mini-review aims solely to discuss and evaluate the most prominent current theories regarding the pathogenesis of autism. The main conclusion is that although there is not a clear pathway of mechanisms directed towards a simple pathogenesis and an established link to autism on the symptomatic level; there are however several important theories (neural connectivity, neural migration, excitatory-inhibitory neural activity, dendritic morphology, neuroimmune; calcium signalling and mirror neurone which appear to offer an explanation to how autism develops. It seems probable that autism's neurodevelopmental defect is ‘multi-domain’ in origin (rather than a single anomaly and is hence distributed across numerous levels of study (genetic, immunopathogenic, etc.. A more definitive understanding of the pathogenesis could facilitate the development of better treatments for this complex psychiatric disorder.

  5. Understanding patients' preferences for surgical management of urethral stricture disease.

    Science.gov (United States)

    Hampson, Lindsay A; Lin, Tracy K; Wilson, Leslie; Allen, Isabel E; Gaither, Thomas W; Breyer, Benjamin N

    2017-11-01

    To understand how prioritization of treatment attributes and treatment choice varies by patient characteristics, we sought to specifically determine how demographic variables affect patient treatment preference. Male patients with urethral stricture disease participated in a choice-based conjoint (CBC) analysis exercise evaluating six treatment attributes associated with internal urethrotomy and urethroplasty. Demographic and past symptom data were collected. Stratified analysis of demographic variables, including age, education, income, was conducted using a mixed effect logistic regression model to evaluate the coefficient size and confidence intervals between the treatments attribute preferences of each strata. 169 patients completed the CBC exercise and were included in our analysis. Overall success of the procedure is the most important treatment attribute to patients and this persists across strata. Older patients (≥65) express preferences for better success rates and fewer future procedures, whereas younger patients prefer a less invasive approach and are more willing to accept additional procedures if needed. Patients with lower levels of education preferred open reconstruction and had a stronger preference against multiple future procedures, whereas those with higher levels of education preferred endoscopic treatment and had a less strong preference against multiple future procedures. Low-income individuals express statistically significant stronger negative preferences against high copay costs compared to high-income individuals. These results can help to inform physicians' counseling about surgical management of urethral stricture disease to better align patient preferences with treatment selection and encourage shared decision making.

  6. The Battle between Infection and Host Immune Responses of Dengue Virus and Its Implication in Dengue Disease Pathogenesis

    Science.gov (United States)

    Sun, Peifang; Kochel, Tadeusz J.

    2013-01-01

    Dengue virus (DENV) is a mosquito-transmitted single stranded RNA virus belonging to genus Flavivirus. The virus is endemic in the tropical and subtropical countries of the world, causing diseases classified according to symptoms and severity (from mild to severe) as dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. Among a variety of human cell types targeted by DENV, monocytes, macrophages, and dendritic cells are members of innate immunity, capable of mounting rapid inflammatory responses. These cells are also major antigen presenting cells, responsible for activating the adaptive immunity for long-term memory. This paper is an overview of the current understanding of the following mutually affected aspects: DENV structure, viral infectivity, cellular receptors, innate immune response, and adaptive immunity. PMID:23476150

  7. Systemic inflammation, blood-brain barrier vulnerability and cognitive / non-cognitive symptoms in Alzheimer disease: Relevance to pathogenesis and therapy

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    Shuko eTakeda

    2014-07-01

    Full Text Available The incidence of dementia is increasing at an alarming rate, and has become a major public health concern. Alzheimer disease (AD is the most common form of dementia and is characterized by progressive cognitive impairment. In addition to classical neuropathological features such as amyloid plaques and neurofibrillary tangles, accumulation of activated immune cells has been documented in the AD brain, suggesting a contribution of neuroinflammation in the pathogenesis of AD. Besides cognitive deterioration, non-cognitive symptoms, such as agitation, aggression, depression and psychosis, are often observed in demented patients, including those with AD, and these neuropsychological symptoms place a heavy burden on caregivers. These symptoms often exhibit sudden onset and tend to fluctuate over time, and in many cases, they are triggered by an infection in peripheral organs, suggesting that inflammation plays an important role in the pathogenesis of these non-cognitive symptoms. However, there is no mechanistic explanation for the relationship between inflammation and neuropsychiatric symptoms. Observations from experimental mouse models indicate that alteration of brain blood vessels, especially blood-brain barrier dysfunction, may contribute to the relationship. The current review summarizes the results from recent studies on the relationship between inflammation and AD, while focusing on cerebrovascular alterations, which might provide an insight into the pathogenesis of cognitive / non-cognitive symptoms in AD patients and suggest a basis for the development of new therapeutic treatments for these conditions.

  8. Pathogenesis of oral FIV infection

    Science.gov (United States)

    Miller, Craig; Boegler, Karen; Carver, Scott; MacMillan, Martha; Bielefeldt-Ohmann, Helle

    2017-01-01

    Feline immunodeficiency virus (FIV) is the feline analogue of human immunodeficiency virus (HIV) and features many hallmarks of HIV infection and pathogenesis, including the development of concurrent oral lesions. While HIV is typically transmitted via parenteral transmucosal contact, recent studies prove that oral transmission can occur, and that saliva from infected individuals contains significant amounts of HIV RNA and DNA. While it is accepted that FIV is primarily transmitted by biting, few studies have evaluated FIV oral infection kinetics and transmission mechanisms over the last 20 years. Modern quantitative analyses applied to natural FIV oral infection could significantly further our understanding of lentiviral oral disease and transmission. We therefore characterized FIV salivary viral kinetics and antibody secretions to more fully document oral viral pathogenesis. Our results demonstrate that: (i) saliva of FIV-infected cats contains infectious virus particles, FIV viral RNA at levels equivalent to circulation, and lower but significant amounts of FIV proviral DNA; (ii) the ratio of FIV RNA to DNA is significantly higher in saliva than in circulation; (iii) FIV viral load in oral lymphoid tissues (tonsil, lymph nodes) is significantly higher than mucosal tissues (buccal mucosa, salivary gland, tongue); (iv) salivary IgG antibodies increase significantly over time in FIV-infected cats, while salivary IgA levels remain static; and, (v) saliva from naïve Specific Pathogen Free cats inhibits FIV growth in vitro. Collectively, these results suggest that oral lymphoid tissues serve as a site for enhanced FIV replication, resulting in accumulation of FIV particles and FIV-infected cells in saliva. Failure to induce a virus-specific oral mucosal antibody response, and/or viral capability to overcome inhibitory components in saliva may perpetuate chronic oral cavity infection. Based upon these findings, we propose a model of oral FIV pathogenesis and suggest

  9. Pathogenesis of oral FIV infection.

    Directory of Open Access Journals (Sweden)

    Craig Miller

    Full Text Available Feline immunodeficiency virus (FIV is the feline analogue of human immunodeficiency virus (HIV and features many hallmarks of HIV infection and pathogenesis, including the development of concurrent oral lesions. While HIV is typically transmitted via parenteral transmucosal contact, recent studies prove that oral transmission can occur, and that saliva from infected individuals contains significant amounts of HIV RNA and DNA. While it is accepted that FIV is primarily transmitted by biting, few studies have evaluated FIV oral infection kinetics and transmission mechanisms over the last 20 years. Modern quantitative analyses applied to natural FIV oral infection could significantly further our understanding of lentiviral oral disease and transmission. We therefore characterized FIV salivary viral kinetics and antibody secretions to more fully document oral viral pathogenesis. Our results demonstrate that: (i saliva of FIV-infected cats contains infectious virus particles, FIV viral RNA at levels equivalent to circulation, and lower but significant amounts of FIV proviral DNA; (ii the ratio of FIV RNA to DNA is significantly higher in saliva than in circulation; (iii FIV viral load in oral lymphoid tissues (tonsil, lymph nodes is significantly higher than mucosal tissues (buccal mucosa, salivary gland, tongue; (iv salivary IgG antibodies increase significantly over time in FIV-infected cats, while salivary IgA levels remain static; and, (v saliva from naïve Specific Pathogen Free cats inhibits FIV growth in vitro. Collectively, these results suggest that oral lymphoid tissues serve as a site for enhanced FIV replication, resulting in accumulation of FIV particles and FIV-infected cells in saliva. Failure to induce a virus-specific oral mucosal antibody response, and/or viral capability to overcome inhibitory components in saliva may perpetuate chronic oral cavity infection. Based upon these findings, we propose a model of oral FIV pathogenesis

  10. The pathogenesis of cardiac fibrosis.

    Science.gov (United States)

    Kong, Ping; Christia, Panagiota; Frangogiannis, Nikolaos G

    2014-02-01

    Cardiac fibrosis is characterized by net accumulation of extracellular matrix proteins in the cardiac interstitium, and contributes to both systolic and diastolic dysfunction in many cardiac pathophysiologic conditions. This review discusses the cellular effectors and molecular pathways implicated in the pathogenesis of cardiac fibrosis. Although activated myofibroblasts are the main effector cells in the fibrotic heart, monocytes/macrophages, lymphocytes, mast cells, vascular cells and cardiomyocytes may also contribute to the fibrotic response by secreting key fibrogenic mediators. Inflammatory cytokines and chemokines, reactive oxygen species, mast cell-derived proteases, endothelin-1, the renin/angiotensin/aldosterone system, matricellular proteins, and growth factors (such as TGF-β and PDGF) are some of the best-studied mediators implicated in cardiac fibrosis. Both experimental and clinical evidence suggests that cardiac fibrotic alterations may be reversible. Understanding the mechanisms responsible for initiation, progression, and resolution of cardiac fibrosis is crucial to design anti-fibrotic treatment strategies for patients with heart disease.

  11. Complement and Viral Pathogenesis

    Science.gov (United States)

    Stoermer, Kristina A.; Morrison, Thomas E.

    2011-01-01

    The complement system functions as an immune surveillance system that rapidly responds to infection. Activation of the complement system by specific recognition pathways triggers a protease cascade, generating cleavage products that function to eliminate pathogens, regulate inflammatory responses, and shape adaptive immune responses. However, when dysregulated, these powerful functions can become destructive and the complement system has been implicated as a pathogenic effector in numerous diseases, including infectious diseases. This review highlights recent discoveries that have identified critical roles for the complement system in the pathogenesis of viral infection. PMID:21292294

  12. The Aldo-Keto Reductase AKR1B10 Is Up-Regulated in Keloid Epidermis, Implicating Retinoic Acid Pathway Dysregulation in the Pathogenesis of Keloid Disease.

    Science.gov (United States)

    Jumper, Natalie; Hodgkinson, Tom; Arscott, Guyan; Har-Shai, Yaron; Paus, Ralf; Bayat, Ardeshir

    2016-07-01

    Keloid disease is a recurrent fibroproliferative cutaneous tumor of unknown pathogenesis for which clinical management remains unsatisfactory. To obtain new insights into hitherto underappreciated aspects of keloid pathobiology, we took a laser capture microdissection-based, whole-genome microarray analysis approach to identify distinct keloid disease-associated gene expression patterns within defined keloid regions. Identification of the aldo-keto reductase enzyme AKR1B10 as highly up-regulated in keloid epidermis suggested that an imbalance of retinoic acid metabolism is likely associated with keloid disease. Here, we show that AKR1B10 transfection into normal human keratinocytes reproduced the abnormal retinoic acid pathway expression pattern we had identified in keloid epidermis. Cotransfection of AKR1B10 with a luciferase reporter plasmid showed reduced retinoic acid response element activity, supporting the hypothesis of retinoic acid synthesis deficiency in keloid epidermis. Paracrine signals released by AKR1B10-overexpressing keratinocytes into conditioned medium resulted in up-regulation of transforming growth factor-β1, transforming growth factor-β2, and collagens I and III in both keloid and normal skin fibroblasts, mimicking the typical profibrotic keloid profile. Our study results suggest that insufficient retinoic acid synthesis by keloid epidermal keratinocytes may contribute to the pathogenesis of keloid disease. We refocus attention on the role of injured epithelium in keloid disease and identify AKR1B10 as a potential new target in future management of keloid disease. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  13. The Current Status of the Disease Caused by Enterovirus 71 Infections: Epidemiology, Pathogenesis, Molecular Epidemiology, and Vaccine Development.

    Science.gov (United States)

    Chang, Ping-Chin; Chen, Shou-Chien; Chen, Kow-Tong

    2016-09-09

    Enterovirus 71 (EV71) infections have a major public health impact in the Asia-Pacific region. We reviewed the epidemiology, pathogenesis, and molecular epidemiology of EV71 infection as well as EV71 vaccine development. Previous studies were found using the search terms "enterovirus 71" and "epidemiology" or "pathogenesis" or "molecular epidemiology" or "vaccine" in Medline and PubMed. Articles that were not published in the English language, manuscripts without an abstract, and opinion articles were excluded from the review. The reported epidemiology of cases caused by EV71 infection varied from country to country; seasonal variations in incidence were observed. Most cases of EV71 infection that resulted in hospitalization for complications occurred in children less than five years old. The brainstem was the most likely major target of EV71 infection. The emergence of the EV71 epidemic in the Asia-Pacific region has been associated with the circulation of different genetic lineages (genotypes B3, B4, C1, C2, and C4) that appear to be undergoing rapid evolutionary changes. The relationship between the gene structure of the EV71 virus and the factors that ensure its survival, circulation, and evasion of immunity is still unknown. EV71 infection has emerged as an important global public health problem. Vaccine development, including the development of inactivated whole-virus live attenuated, subviral particles, and DNA vaccines, has been progressing.

  14. Concepts in viral pathogenesis II

    Energy Technology Data Exchange (ETDEWEB)

    Notkins, A.L.; Oldstone, M.B.A.

    1986-01-01

    This paper contains papers divided among 10 sections. The section titles are: Viral Structure and Function; Viral Constructs; Oncogenes, Transfection, and Differentiation; Viral Tropism and Entry into Cells; Immune Recognition of Viruses; Evolving Concepts in Viral Pathogenesis Illustrated by Selected Plant and Animal Models; Evolving Concepts in Viral Pathogenesis Illustrated by Selected Diseases in Humans; New Trends in Diagnosis and Epidemiology; and Vaccines and Antiviral Therapy.

  15. Hepatitis C Virus-Induced Upregulation of MicroRNA miR-146a-5p in Hepatocytes Promotes Viral Infection and Deregulates Metabolic Pathways Associated with Liver Disease Pathogenesis

    Science.gov (United States)

    Bandiera, Simonetta; Pernot, Sophie; El Saghire, Hussein; Durand, Sarah C.; Thumann, Christine; Crouchet, Emilie; Ye, Tao; Fofana, Isabel; Oudot, Marine A.; Barths, Jochen; Schuster, Catherine; Pessaux, Patrick

    2016-01-01

    induces liver cancer remains poorly understood. There is accumulating evidence that a viral cure does not eliminate the risk for HCC development. Thus, there is an unmet medical need to develop novel approaches to predict and prevent virus-induced HCC. miRNA expression is known to be deregulated in liver disease and cancer. Furthermore, miRNAs are essential for HCV replication, and HCV infection alters miRNA expression. However, how miRNAs contribute to HCV-driven pathogenesis remains elusive. Here we show that HCV induces miRNAs that may contribute to liver injury and carcinogenesis. The miR-146a-5p level was consistently increased in different cell-based models of HCV infection and in HCV patient-derived liver tissue. Furthermore, miR-146a-5p increased HCV infection. Collectively, our data are relevant to understanding viral pathogenesis and may open perspectives for novel biomarkers and prevention of virus-induced liver disease and HCC. PMID:27147737

  16. Gut microbiome in health and disease: Linking the microbiome-gut-brain axis and environmental factors in the pathogenesis of systemic and neurodegenerative diseases.

    Science.gov (United States)

    Ghaisas, Shivani; Maher, Joshua; Kanthasamy, Anumantha

    2016-02-01

    The gut microbiome comprises the collective genome of the trillions of microorganisms residing in our gastrointestinal ecosystem. The interaction between the host and its gut microbiome is a complex relationship whose manipulation could prove critical to preventing or treating not only various gut disorders, like irritable bowel syndrome (IBS) and ulcerative colitis (UC), but also central nervous system (CNS) disorders, such as Alzheimer's and Parkinson's diseases. The purpose of this review is to summarize what is known about the gut microbiome, how it is connected to the development of disease and to identify the bacterial and biochemical targets that should be the focus of future research. Understanding the mechanisms behind the activity and proliferation of the gut microbiome will provide us new insights that may pave the way for novel therapeutic strategies. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Differences in optic nerve structure between individuals of predominantly African and European ancestry: Implications for disease detection and pathogenesis

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    Christopher A Girkin

    2008-03-01

    Full Text Available Christopher A GirkinUniversity of Alabama at Birmingham School of Medicine, Birmingham, AL, USAAbstract: Glaucoma disproportionately affects individual of African ancestry. Additionally, racial differences in the optic nerve head have been well described that may alter the vulnerability to intraocular pressure related injury and, in addition, alter the clinical ability to detect the presence of early optic nerve injury. This paper will review the literature describing racial differences in the optic nerve head between individuals of African and European ancestry with regards to the potential effects of these differences on the ability to detect glaucoma in different racial groups and to potential differences in the pathogenesis of glaucomatous injury.Keywords: primary open angle glaucoma, African American, optic nerve, optic disc, retinal nerve fiber layer

  18. Understanding the biology of bone sarcoma from early initiating events through late events in metastasis and disease progression.

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    Limin eZhu

    2013-09-01

    Full Text Available The two most common primary bone malignancies, osteosarcoma and Ewing sarcoma, are both aggressive, highly metastatic cancers that most often strike teens, though both can be found in younger children and adults. Despite distinct origins and pathogenesis, both diseases share several mechanisms of progression and metastasis, including neovascularization, invasion, anoikis resistance, chemoresistance and evasion of the immune response. Some of these processes are well-studies in more common carcinoma models, and the observation from adult diseases may be readily applied to pediatric bone sarcomas. Neovascularization, which includes angiogenesis and vasculogenesis, is a clear example of a process that is likely to be similar between carcinomas and sarcomas, since the responding cells are the same in each case. Chemoresistance mechanisms also may be similar between other cancers and the bone sarcomas. Since osteosarcoma and Ewing sarcoma are mesenchymal in origin, the process of epithelial-to-mesenchymal transformation is largely absent in bone sarcomas, necessitating different approaches to study progression and metastasis in these diseases. One process that is less well-studied in bone sarcomas is dormancy, which allows micrometastatic disease to remain viable but not growing in distant sites – typically the lungs – for months or years before renewing growth to become overt metastatic disease. By understanding the basic biology of these processes, novel therapeutic strategies may be developed that could improve survival in children with osteosarcoma or Ewing sarcoma.

  19. To understand coral disease, look at coral cells

    Science.gov (United States)

    Work, Thierry M.; Meteyer, Carol U.

    2014-01-01

    Diseases threaten corals globally, but 40 years on their causes remain mostly unknown. We hypothesize that inconsistent application of a complete diagnostic approach to coral disease has contributed to this slow progress. We quantified methods used to investigate coral disease in 492 papers published between 1965 and 2013. Field surveys were used in 65% of the papers, followed by biodetection (43%), laboratory trials (20%), microscopic pathology (21%), and field trials (9%). Of the microscopic pathology efforts, 57% involved standard histopathology at the light microscopic level (12% of the total investigations), with the remainder dedicated to electron or fluorescence microscopy. Most (74%) biodetection efforts focused on culture or molecular characterization of bacteria or fungi from corals. Molecular and immunological tools have been used to incriminate infectious agents (mainly bacteria) as the cause of coral diseases without relating the agent to specific changes in cell and tissue pathology. Of 19 papers that declared an infectious agent as a cause of disease in corals, only one (5%) used microscopic pathology, and none fulfilled all of the criteria required to satisfy Koch’s postulates as applied to animal diseases currently. Vertebrate diseases of skin and mucosal surfaces present challenges similar to corals when trying to identify a pathogen from a vast array of environmental microbes, and diagnostic approaches regularly used in these cases might provide a model for investigating coral diseases. We hope this review will encourage specialists of disease in domestic animals, wildlife, fish, shellfish, and humans to contribute to the emerging field of coral disease.

  20. Recent advances in dengue pathogenesis and clinical management.

    Science.gov (United States)

    Simmons, Cameron P; McPherson, Kirsty; Van Vinh Chau, Nguyen; Hoai Tam, D T; Young, Paul; Mackenzie, Jason; Wills, Bridget

    2015-12-10

    This review describes and commentates on recent advances in the understanding of dengue pathogenesis and immunity, plus clinical research on vaccines and therapeutics. We expand specifically on the role of the dermis in dengue virus infection, the contribution of cellular and humoral immune responses to pathogenesis and immunity, NS1 and mechanisms of virus immune evasion. Additionally we review a series of therapeutic intervention trials for dengue, as well as recent clinical research aimed at improving clinical diagnosis, risk prediction and disease classification. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  1. IL-6 amplifies TLR mediated cytokine and chemokine production: implications for the pathogenesis of rheumatic inflammatory diseases.

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    Ivan Caiello

    Full Text Available The role of Interleukin(IL-6 in the pathogenesis of joint and systemic inflammation in rheumatoid arthritis (RA and systemic juvenile idiopathic arthritis (s-JIA has been clearly demonstrated. However, the mechanisms by which IL-6 contributes to the pathogenesis are not completely understood. This study investigates whether IL-6 affects, alone or upon toll like receptor (TLR ligand stimulation, the production of inflammatory cytokines and chemokines in human peripheral blood mononuclear cells (PBMCs, synovial fluid mononuclear cells from JIA patients (SFMCs and fibroblast-like synoviocytes from rheumatoid arthritis patients (RA synoviocytes and signalling pathways involved. PBMCs were pre-treated with IL-6 and soluble IL-6 Receptor (sIL-6R. SFMCs and RA synoviocytes were pre-treated with IL-6/sIL-6R or sIL-6R, alone or in combination with Tocilizumab (TCZ. Cells were stimulated with LPS, S100A8-9, poly(I-C, CpG, Pam2CSK4, MDP, IL-1β. Treatment of PBMCs with IL-6 induced production of TNF-α, CXCL8, and CCL2, but not IL-1β. Addition of IL-6 to the same cells after stimulation with poly(I-C, CpG, Pam2CSK4, and MDP induced a significant increase in IL-1β and CXCL8, but not TNF-α production compared with TLR ligands alone. This enhanced production of IL-1β and CXCL8 paralleled increased p65 NF-κB activation. In contrast, addition of IL-6 to PBMCs stimulated with LPS or S100A8-9 (TLR-4 ligands led to reduction of IL-1β, TNF-α and CXCL8 with reduced p65 NF-κB activation. IL-6/IL-1β co-stimulation increased CXCL8, CCL2 and IL-6 production. Addition of IL-6 to SFMCs stimulated with LPS or S100A8 increased CXCL8, CCL2 and IL-1β production. Treatment of RA synoviocytes with sIL-6R increased IL-6, CXCL8 and CCL2 production, with increased STAT3 and p65 NF-κB phosphorylation. Our results suggest that IL-6 amplifies TLR-induced inflammatory response. This effect may be relevant in the presence of high IL-6 and sIL-6R levels, such as in arthritic

  2. Heart Disease in Women: Understand Symptoms and Risk Factors

    Science.gov (United States)

    ... Some research has found that if you had pregnancy complications such as high blood pressure or diabetes your children may also have an increased risk of heart disease in the future. Women with inflammatory diseases, such as rheumatoid arthritis or lupus, may also have a higher risk of heart ...

  3. Advances in understanding gender difference in cardiometabolic disease risk.

    Science.gov (United States)

    Onat, Altan; Karadeniz, Yusuf; Tusun, Eyyup; Yüksel, Hüsniye; Kaya, Ayşem

    2016-01-01

    Gender differences exist in cardiovascular or metabolic disease risk, beyond the protective effect of estrogens, mostly burdening the postmenopausal female. We aimed to review herein sex differences in pro-inflammatory states, the independence of inflammation from insulin resistance, differences in high-density lipoprotein dysfunction, in gene-environment interactions, and in the influence of current and former smoking on cardiometabolic risk. Sex differences in absorption of long-chain fatty acids are highlighted. Differences exist in the first manifestation of cardiovascular disease, men being more likely to develop coronary heart disease as a first event, compared to women who have cerebrovascular disease or heart failure as a first event. Autoimmune activation resulting from pro-inflammatory states, a fundamental mechanism for numerous chronic diseases in people prone to metabolic syndrome, is much more common in women, and these constitute major determinants. Therapeutic approaches to aspects related to sex difference are briefly reviewed.

  4. Selected mice models based on APP, MAPT and presenilin gene mutations in research on the pathogenesis of Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Magdalena Więdłocha

    2012-06-01

    Full Text Available  The research conducted on animal models of Alzheimer’s disease (AD has provided valuable information about the pathogenesis of this disease and associated behavioral and cognitive deficits as well as the disease-associated anatomical and histopathological lesions of the brain. Transgenic technologies have enabled the creation of animal models based on mutations in APP, MAPT, presenilin genes, tau protein and apoE. Due to economic reasons studies are mainly conducted on mice. Their brain tissue, depending on the mutation, is characterized by histopathological changes, such as the presence of amyloid plaques, tau protein deposits and dystrophic neurites, gliosis, hippocampal atrophy and amyloid accumulation in vessels. Animal cognitive impairment and behavior, which can be demonstrated in behavioral tests, primarily relate to the working and reference memory, alternation and anxiety. Unfortunately, despite the various modifications specific to AD in the genome of animals, scientists have failed to create an animal model characterized by all the pathological changes that can occur in Alzheimer’s disease. Nevertheless, the role of transgenic animals is undeniable, both in research on AD neuropathology and for testing new therapies, such as immunotherapy. Despite the occurrence of abundant Alzheimer’s disease mice models this article is dedicated to selected models with mutations in the APP, MAPT and presenilin genes and their application for behavioral studies.

  5. Chondrocytes damage induced by T-2 toxin via Wnt/β-catenin signaling pathway is involved in the pathogenesis of an endemic osteochondropathy, Kashin-Beck disease.

    Science.gov (United States)

    Wang, Xi; Ning, Yujie; Zhang, Pan; Yang, Lei; Wang, Yingting; Guo, Xiong

    2017-12-01

    Kashin-Beck disease (KBD), an endemic osteochondropathy, is characterized by cartilage degeneration which is caused by abnormal catabolism in the extracellular matrix (ECM). In this study, we investigated the expression of the Wnt/β-catenin signaling pathway in KBD pathogenesis. Among the proteins involved in the Wnt/β-catenin signaling pathway, WNT-3A, FZD1, SOX9, and β-catenin were up-regulated, while FRZB was down-regulated in KBD cartilage. C28/I2 cells were evaluated for cell viability using the MTT assay after exposure to T-2 toxin, a suspicious environmental pathogenic factors of KBD. C28/I2 cells were treated with different intervening concentrations (0.001μg/mL,0.005μg/mL and 0.01μg/mL) of T-2 toxin for 24h. The expression of FZD1 and CTNNB1 (i.e.,β-catenin) was significantly reduced and SOX9 expression was significantly increased in chondrocytes after treatment with different intervening concentrations of T-2 toxin. Our results indicate that alterations in the Wnt/β-catenin signaling pathway in articular cartilage play an important role in the onset and pathogenesis of KBD. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Pathogenesis of type 2 diabetes and cardiovascular disease in South Asians : effects of dietary interventions on metabolism and cardiovascular function

    NARCIS (Netherlands)

    Bakker, Leontine Erica Henriëtte

    2015-01-01

    People of South Asian origin have an increased risk of developing type 2 diabetes (T2D) and cardiovascular disease (CVD) compared to people of Western European descent. Not only is the prevalence of these diseases higher in South Asians, they also occur at a younger age and lower BMI, and have a

  7. Understanding Celiac Disease From Genetics to the Future Diagnostic Strategies

    Directory of Open Access Journals (Sweden)

    Carolina Salazar

    2017-07-01

    Full Text Available Celiac disease (CD is an autoimmune disorder characterized by the permanent inflammation of the small bowel, triggered by the ingestion of gluten. It is associated with a number of symptoms, the most common being gastrointestinal. The prevalence of this illness worldwide is 1%. One of the main problems of CD is its difficulty to be diagnosed due to the various presentations of the disease. Besides, in many cases, CD is asymptomatic. Celiac disease is a multifactorial disease, HLA-DQ2 and HLA-DQ8 haplotypes are predisposition factors. Nowadays, molecular markers are being studied as diagnostic tools. In this review, we explore CD from its basic concept, manifestations, types, current and future methods of diagnosis, and associated disorders. Before addressing the therapeutic approaches, we also provide a brief overview of CD genetics and treatment.

  8. Using Earth Observations to Understand and Predict Infectious Diseases

    Science.gov (United States)

    Soebiyanto, Radina P.; Kiang, Richard

    2015-01-01

    This presentation discusses the processes from data collection and processing to analysis involved in unraveling patterns between disease outbreaks and the surrounding environment and meteorological conditions. We used these patterns to estimate when and where disease outbreaks will occur. As a case study, we will present our work on assessing the relationship between meteorological conditions and influenza in Central America. Our work represents the discovery, prescriptive and predictive aspects of data analytics.

  9. Pathogenesis of Acanthamoeba Keratitis

    Science.gov (United States)

    Panjwani, Noorjahan

    2010-01-01

    Acanthamoeba keratitis (AK) is a serious infection of the cornea. At present, diagnosis of the disease is not straightforward and treatment is very demanding. While contact lens wear is the leading risk factor for AK, Acanthamoeba parasites are increasingly recognized as an important cause of keratitis in non-contact lens wearers. The first critical step in the pathogenesis of infection is the adhesion of the microbe to the surface of the host tissues. Acanthamoebae express a major virulence protein, the mannose-binding protein (MBP), which mediates the adhesion of amoebae to the surface of the cornea. The MBP is a transmembrane protein with characteristics of a typical cell surface receptor. Subsequent to the MBP-mediated adhesion to host cells, the amoebae produce a contact-dependent metalloproteinase and several contact-independent serine proteinases. These proteinases work in concert to produce a potent cytopathic effect (CPE) involving killing of the host cells, degradation of epithelial basement membrane and underlying stromal matrix, and penetration into the deeper layers of the cornea. In the hamster animal model, oral immunization with the recombinant MBP protects against AK, and this protection is associated with an increased level of anti-MBP IgA in tears of protected animals. Normal human tear fluid contains IgA antibodies against Acanthamoeba MBP that is likely to provide protection by inhibiting the adhesion of parasites to host cells. Indeed, in in vitro CPE assays, even a low concentration of tears (10 [MU]μL of undiluted tears per milliliter of media) almost completely inhibits Acanthamoeba-induced CPE. In addition to adherence-inhibiting, IgA-mediated protection, human tears also contain IgA-independent factors that provide protection against Acanthamoeba-induced CPE by inhibiting the activity of cytotoxic proteinases. Characterization of the CPE-inhibitory factors of human tears should lead to a better understanding of the mechanism by which the

  10. Common Mechanism of Pathogenesis in Gastrointestinal Diseases Implied by Consistent Efficacy of Single Chinese Medicine Formula: A PRISMA-Compliant Systematic Review and Meta-Analysis.

    Science.gov (United States)

    Ling, Wei; Li, Yang; Jiang, Wei; Sui, Yi; Zhao, Hai-Lu

    2015-07-01

    Gastrointestinal (GI) disorders often manifest similar symptoms with overlapping clinical diagnosis and unmet medical needs. Traditional Chinese medicine (TCM) has history-proven benefits for GI diseases; albeit language barrier prevents Western readers from accessing the original reports in Chinese. The TCM formula Si-Ni-San (SNS) consists of 4 herbs targeting on homeostatic disturbances characterized by "reflux" and "irritable" problems. Here we used SNS as a therapeutic tool to explore the common mechanisms of pathogenesis in non-neoplastic GI diseases.Data sources from PUBMED, Chinese National Knowledge Infrastructure, and Wanfang databases were searched for clinical trials. Comparisons were SNS as intervention and Western conventional medicine as control, which treat patients with upper GI disorders (gastroesophageal reflux disease, peptic ulcer, chronic gastritis, duodenogastric reflux), lower GI diseases (irritable bowel syndrome, ulcerative colitis), and functional dyspepsia. Participants and studies in accordance with the Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement were eligible. We used the Jadad scale to assess methodological qualities, the fixed or random-effect model to evaluate therapeutic efficacy, and the funnel plots to explore publication bias. Outcome was clinical efficacy defined by symptom relief with normal GI endoscopy, radiology, and pathology.We included 83 studies involving 7762 participants: 1708 versus 1397 of the upper GI disorders in 34 studies, 901 versus 768 of the lower GI diseases in 19 studies, 1641 versus 1348 of functional dyspepsia in 30 studies, and 328 versus 287 of relapse rate in 8 studies. Six studies had a Jadad score >2 points and the rest were <2 points. Pooled data showed significant efficacy of SNS for the upper GI disorders (odds ratio [OR] = 3.9, 95% confidence interval [CI] = 3.09-4.92), lower GI diseases (OR = 4.91, 95% CI = 3.71-6.51), and functional dyspepsia (N

  11. POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDERS: ROLE OF VIRAL INFECTION, GENETIC LESIONS AND ANTIGEN STIMULATION IN THE PATHOGENESIS OF THE DISEASE

    Directory of Open Access Journals (Sweden)

    Daniela Capello

    2009-11-01

    Full Text Available Post-transplant lymphoproliferative disorders (PTLD are a life-threatening complication of solid organ transplantation or, more rarely, hematopoietic stem cell transplantation. The majority of PTLD is of B-cell origin and associated with Epstein–Barr virus (EBV infection. PTLD generally display involvement of extranodal sites, aggressive histology and aggressive clinical behavior. The molecular pathogenesis of PTLD involves infection by oncogenic viruses, namely Epstein-Barr virus, as well as genetic or epigenetic alterations of several cellular genes. At variance with lymphoma arising in immunocompetent hosts, whose genome is relatively stable, a fraction of PTLD are characterized by microsatellite instability as a consequence of defects in the DNA mismatch repair mechanism. Apart from microsatellite instability, molecular alterations of cellular genes recognized in PTLD include alterations of cMYC, BCL6, TP53, DNA hypermethylation, and aberrant somatic hypermutation of protooncogenes. The occurrence of IGV mutations in the overwhelming majority of PTLD documents that malignant transformation targets germinal centre (GC B-cells and their descendants both in EBV–positive and EBV–negative cases. Analysis of phenotypic markers of B-cell histogenesis, namely BCL6, MUM1 and CD138, allows further distinction of PTLD histogenetic categories. PTLD expressing the BCL6+/MUM1+/-/CD138- profile reflect B-cells actively experiencing the GC reaction, and comprise diffuse large B-cell lymphoma (DLBCL centroblastic and Burkitt lymphoma. PTLD expressing the BCL6-/MUM1+/CD138- phenotype putatively derive from B-cells that have concluded the GC reaction, and comprise the majority of polymorphic PTLD and a fraction of DLBCL immunoblastic. A third group of PTLD is reminiscent of post-GC and preterminally differentiated B-cells that show the BCL6-/MUM1+/CD138+ phenotype, and are morphologically represented by either polymorphic PTLD or DLBCL immunoblastic.

  12. The role of autonomic cardiovascular neuropathy in pathogenesis of ischemic heart disease in patients with diabetes mellitus

    OpenAIRE

    Popović-Pejičić Snježana; Todorović-Đilas Ljiljana; Pantelinac Pavle

    2006-01-01

    Introduction. Diabetes is strongly associated with macrovascular complications, among which ischemic heart disease is the major cause of mortality. Autonomic neuropathy increases the risk of complications, which calls for an early diagnosis. The aim of this study was to determine both presence and extent of cardiac autonomic neuropathy, in regard to the type of diabetes mellitus, as well as its correlation with coronary disease and major cardiovascular risk factors. Material and methods. We h...

  13. Link between Aluminum and the Pathogenesis of Alzheimer's Disease: The Integration of the Aluminum and Amyloid Cascade Hypotheses

    OpenAIRE

    Kawahara, Masahiro; Kato-Negishi, Midori

    2011-01-01

    Whilst being environmentally abundant, aluminum is not essential for life. On the contrary, aluminum is a widely recognized neurotoxin that inhibits more than 200 biologically important functions and causes various adverse effects in plants, animals, and humans. The relationship between aluminum exposure and neurodegenerative diseases, including dialysis encephalopathy, amyotrophic lateral sclerosis and Parkinsonism dementia in the Kii Peninsula and Guam, and Alzheimer's disease (AD) has been...

  14. Vitamin D receptor protects glioblastoma A172 cells against Coxsackievirus A16 infection induced cell death in the pathogenesis of hand, foot, and mouth disease.

    Science.gov (United States)

    Qu, Meiling; Di, Shunxiang; Zhang, Shuyun; Xia, Zhiqun; Quan, Guohong

    2017-11-18

    Hand, foot, and mouth disease (HFMD) was one of the most common children illnesses. Coxsackievirus A16 was one of the major pathogens that cause HFMD. However, the role of vitamin D underlying this common illness has not been elucidated. Our study examined that vitamin D levels was significantly lower in 33 HFMD patients, compared to 36 healthy children. Unexpectedly, both mRNA and protein expression of VDR were significantly decreased in CA16 infected glioblastoma A172 cells. And overexpression of VDR or vitamin D treatment in CA16 infected glioblastoma A172 cells could reverse the CA16 infection induced cell death, apoptosis or mitochondrial membrane rupture. Therefore, our study, for the first time, demonstrated that vitamin D and VDR could associate with the pathogenesis of HFMD. Thus might provide useful information for HFMD prevention and treatments. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Roles of silent information regulator 1-serine/arginine-rich splicing factor 10-lipin 1 axis in the pathogenesis of alcohol fatty liver disease.

    Science.gov (United States)

    Li, Yuanyuan; Zhou, Junying

    2017-06-01

    Alcohol exposure is a major reason of morbidity and mortality all over the world, with much of detrimental consequences attributing to alcoholic liver disease (ALD). With the continued ethanol consumption, alcoholic fatty liver disease (AFLD, the earliest and reversible form of ALD) can further develop to more serious forms of alcoholic liver damage, including alcoholic steatohepatitis, fibrosis/cirrhosis, and even eventually progress to hepatocellular carcinoma and liver failure. Furthermore, cell trauma, inflammation, oxidative stress, regeneration, and bacterial translocation are crucial promoters of ethanol-mediated liver lesions. AFLD is characterized by excessive fat deposition in liver induced by excessive drinking, which is related closely to the raised synthesis of fatty acids and triglyceride, reduction of mitochondrial fatty acid β-oxidation, and the aggregation of very-low-density lipoprotein (VLDL). Although little is known about the cellular and molecular mechanisms of AFLD, it seems to be correlated to diverse signal channels. Massive studies have suggested that liver steatosis is closely associated with the inhibition of silent information regulator 1 (SIRT1) and the augment of lipin1 β/α ratio mediated by ethanol. Recently, serine/arginine-rich splicing factor 10 (SFRS10), a specific molecule functioning in alternative splicing of lipin 1 (LPIN1) pre-mRNAs, has emerged as the central connection between SIRT1 and lipin1 signaling. It seems a new signaling axis, SIRT1-SFRS10-LPIN1 axis, acting in the pathogenesis of AFLD exists. This article aims to further explore the interactions among the above three molecules and their influences on the development of AFLD. Impact statement ALD is a major health burden in industrialized countries as well as China. AFLD, the earliest and reversible form of ALD, can progress to hepatitis, fibrosis/cirrhosis, even hepatoma. While the mechanisms, by which ethanol consumption leads to AFLD, are complicated and

  16. Convergent sets of data from in vivo and in vitro methods point to an active role of Hsp60 in chronic obstructive pulmonary disease pathogenesis.

    Directory of Open Access Journals (Sweden)

    Francesco Cappello

    Full Text Available BACKGROUND: It is increasingly clear that some heat shock proteins (Hsps play a role in inflammation. Here, we report results showing participation of Hsp60 in the pathogenesis of chronic obstructive pulmonary diseases (COPD, as indicated by data from both in vivo and in vitro analyses. METHODS AND RESULTS: Bronchial biopsies from patients with stable COPD, smoker controls with normal lung function, and non-smoker controls were studied. We quantified by immunohistochemistry levels of Hsp10, Hsp27, Hsp40, Hsp60, Hsp70, Hsp90, and HSF-1, along with levels of inflammatory markers. Hsp10, Hsp40, and Hsp60 were increased during progression of disease. We found also a positive correlation between the number of neutrophils and Hsp60 levels. Double-immunostaining showed that Hsp60-positive neutrophils were significantly increased in COPD patients. We then investigated in vitro the effect on Hsp60 expression in bronchial epithelial cells (16HBE caused by oxidative stress, a hallmark of COPD mucosa, which we induced with H₂O₂. This stressor determined increased levels of Hsp60 through a gene up-regulation mechanism involving NFkB-p65. Release of Hsp60 in the extracellular medium by the bronchial epithelial cells was also increased after H₂O₂ treatment in the absence of cell death. CONCLUSIONS: This is the first report clearly pointing to participation of Hsps, particularly Hsp60, in COPD pathogenesis. Hsp60 induction by NFkB-p65 and its release by epithelial cells after oxidative stress can have a role in maintaining inflammation, e.g., by stimulating neutrophils activity. The data open new scenarios that might help in designing efficacious anti-inflammatory therapies centered on Hsp60 and applicable to COPD.

  17. Understanding the application of stem cell therapy in cardiovascular diseases

    Directory of Open Access Journals (Sweden)

    Sharma RK

    2012-10-01

    Full Text Available Rakesh K Sharma, Donald J Voelker, Roma Sharma, Hanumanth K ReddyUniversity of Arkansas for Medical Sciences, Medical Center of South Arkansas, El Dorado, AR, USAAbstract: Throughout their lifetime, an individual may sustain many injuries and recover spontaneously over a period of time, without even realizing the injury in the first place. Wound healing occurs due to a proliferation of stem cells capable of restoring the injured tissue. The ability of adult stem cells to repair tissue is dependent upon the intrinsic ability of tissues to proliferate. The amazing capacity of embryonic stem cells to give rise to virtually any type of tissue has intensified the search for similar cell lineage in adults to treat various diseases including cardiovascular diseases. The ability to convert adult stem cells into pluripotent cells that resemble embryonic cells, and to transplant those in the desired organ for regenerative therapy is very attractive, and may offer the possibility of treating harmful disease-causing mutations. The race is on to find the best cells for treatment of cardiovascular disease. There is a need for the ideal stem cell, delivery strategies, myocardial retention, and time of administration in the ideal patient population. There are multiple modes of stem cell delivery to the heart with different cell retention rates that vary depending upon method and site of injection, such as intra coronary, intramyocardial or via coronary sinus. While there are crucial issues such as retention of stem cells, microvascular plugging, biodistribution, homing to myocardium, and various proapoptotic factors in the ischemic myocardium, the regenerative potential of stem cells offers an enormous impact on clinical applications in the management of cardiovascular diseases.Keywords: stem cell therapy, stem cell delivery, cardiovascular diseases, myocardial infarction, cardiomyopathy

  18. Review of Critical Issues in the Pathogenesis of Atopic Dermatitis.

    Science.gov (United States)

    Irvine, Alan D; Eichenfield, Lawrence F; Friedlander, Sheila F; Simpson, Eric L

    2016-06-01

    About a decade age, loss-of-function mutations in the filaggrin molecule were first implicated in the pathogenesis of ichthyosis vulgaris and, subsequently, of atopic dermatitis and other atopic diseases. Since then, intensive study of the role of filaggrin null mutations have led to other milestones in understanding the pathologic pathways in these diseases, including the initiation, maintenance, and promotion of the disease processes. The result has been new and emerging clinical and pharmacologic strategies for early identification of and intervention in atopic diseases. Semin Cutan Med Surg 35(supp5):S89-S91. 2016 published by Frontline Medical Communications.

  19. Acute colonic diverticulitis: modern understanding of pathomechanisms, risk factors, disease burden and severity

    NARCIS (Netherlands)

    Søreide, Kjetil; Boermeester, Marja A.; Humes, David J.; Velmahos, George C.

    2016-01-01

    Conservative, non-antibiotic and non-surgical management of acute diverticulitis is currently being investigated. To better inform clinical decisions, better understanding of disease mechanisms, disease burden and severity is needed. Literature search of risk factors, pathophysiology, epidemiology

  20. Translational Mini-Review Series on B cell subsets in disease. B cells in multiple sclerosis: drivers of disease pathogenesis and Trojan horse for Epstein-Barr virus entry to the central nervous system?

    Science.gov (United States)

    Meier, U-C; Giovannoni, G; Tzartos, J S; Khan, G

    2012-01-01

    The recent success of therapies directed at B cells has highlighted their potential as central players in multiple sclerosis (MS) pathogenesis. Exciting new data showed that B cell depletion led to reduced clinical and magnetic resonance imaging (MRI) evidence of disease activity. However, the mechanisms of action remain unknown, but could involve autoantibody production, antigen presentation and/or cytokine production by B cells. Another exciting line of investigation in the field of MS comes from latent infection of memory B cells by Epstein-Barr virus (EBV). These cells are hijacked as 'Trojan horses' and 'smuggle' the virus into the central nervous system (CNS). Thus, these new anti B cell treatments will also be likely to have anti-viral effects. We briefly review recent findings in the field of MS pathogenesis, and highlight promising new targets for therapeutic intervention in MS. © 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for Immunology.

  1. Transgenic fatal familial insomnia mice indicate prion infectivity-independent mechanisms of pathogenesis and phenotypic expression of disease.

    Directory of Open Access Journals (Sweden)

    Ihssane Bouybayoune

    2015-04-01

    Full Text Available Fatal familial insomnia (FFI and a genetic form of Creutzfeldt-Jakob disease (CJD178 are clinically different prion disorders linked to the D178N prion protein (PrP mutation. The disease phenotype is determined by the 129 M/V polymorphism on the mutant allele, which is thought to influence D178N PrP misfolding, leading to the formation of distinctive prion strains with specific neurotoxic properties. However, the mechanism by which misfolded variants of mutant PrP cause different diseases is not known. We generated transgenic (Tg mice expressing the mouse PrP homolog of the FFI mutation. These mice synthesize a misfolded form of mutant PrP in their brains and develop a neurological illness with severe sleep disruption, highly reminiscent of FFI and different from that of analogously generated Tg(CJD mice modeling CJD178. No prion infectivity was detectable in Tg(FFI and Tg(CJD brains by bioassay or protein misfolding cyclic amplification, indicating that mutant PrP has disease-encoding properties that do not depend on its ability to propagate its misfolded conformation. Tg(FFI and Tg(CJD neurons have different patterns of intracellular PrP accumulation associated with distinct morphological abnormalities of the endoplasmic reticulum and Golgi, suggesting that mutation-specific alterations of secretory transport may contribute to the disease phenotype.

  2. Sickle cell disease, part 1: understanding the condition.

    OpenAIRE

    Addis, Gulen

    2012-01-01

    Sickle cell disease (SCD) is one of the most common genetic blood disorders in the world and affects 12, 500 individuals in the UK. This article looks at the definition of SCD, symptoms and treatments and practical tips to prevent sickle cell crises.

  3. [Diseases and the sick--understanding medical practices in capitalism].

    Science.gov (United States)

    Ornellas, C P

    1999-01-01

    This article discusses the diseases and the sick as well as how the process from which to take care of them became object of medical practices. Based on Donnagelo and Gonçalves contributions, the author discusses the process that explains medical practices appropriation by the capitalism.

  4. Understanding gene expression in coronary artery disease through ...

    Indian Academy of Sciences (India)

    Molecular mechanism underlying the patho-physiology of coronary artery disease (CAD) is complex. We used global expres- sion profiling combined with analysis of biological network to dissect out potential genes and pathways associated with CAD in a representative case–control Asian Indian cohort. We initially ...

  5. Understanding complexity in neurodegenerative diseases: in silico reconstruction of emergence.

    NARCIS (Netherlands)

    Kolodkin, A.; Simeonidis, E.; Balling, R.; Westerhoff, H.V.

    2012-01-01

    Healthy functioning is an emergent property of the network of interacting biomolecules that comprise an organism. It follows that disease (a network shift that causes malfunction) is also an emergent property, emerging from a perturbation of the network. On the one hand, the biomolecular network of

  6. Understanding complexityin neurodegenerative diseases: in silico reconstructionof emergence

    NARCIS (Netherlands)

    Kolodkin, A.N.; Simeonides, E.; Balling, R.; Westerhoff, H.V.

    2012-01-01

    Healthy functioning is an emergent property of the network of interacting biomolecules that comprise an organism. It follows that disease (a network shift that causes malfunction) is also an emergent property, emerging from a perturbation of the network. On the one hand, the biomolecular network of

  7. Understanding the biological mechanisms of Zika virus disease ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    ... as well as via sexual and mother-to-child transmission. It causes a wide spectrum of disease, ranging from symptom-free infections to mild, self-limiting symptoms, to severe infections requiring hospitalization. Additionally, Zika infection in pregnant women has been linked to microcephaly) and other brain abnormalities in ...

  8. POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDERS: ROLE OF VIRAL INFECTION, GENETIC LESIONS AND ANTIGEN STIMULATION IN THE PATHOGENESIS OF THE DISEASE

    Directory of Open Access Journals (Sweden)

    Gianluca Gaidano

    2009-11-01

    Full Text Available

    Post-transplant lymphoproliferative disorders (PTLD are a life-threatening complication of solid organ transplantation or, more rarely, hematopoietic stem cell transplantation. The majority of PTLD is of B-cell origin and associated with Epstein–Barr virus (EBV infection. PTLD generally display involvement of extranodal sites, aggressive histology and aggressive clinical behavior. The molecular pathogenesis of PTLD involves infection by oncogenic viruses, namely Epstein-Barr virus, as well as genetic or epigenetic alterations of several cellular genes. At variance with lymphoma arising in immunocompetent hosts, whose genome is relatively stable, a fraction of PTLD are characterized by microsatellite instability as a consequence of defects in the DNA mismatch repair mechanism. Apart from microsatellite instability, molecular alterations of cellular genes recognized in PTLD include alterations of cMYC, BCL6, TP53, DNA hypermethylation, and aberrant somatic hypermutation of protooncogenes. The occurrence of IGV mutations in the overwhelming majority of PTLD documents that malignant transformation targets germinal centre (GC B-cells and their descendants both in EBV–positive and EBV–negative cases. Analysis of phenotypic markers of B-cell histogenesis, namely BCL6, MUM1 and CD138, allows further distinction of PTLD histogenetic categories. PTLD expressing the BCL6+/MUM1+/-/CD138- profile reflect B-cells actively experiencing the GC reaction, and comprise diffuse large B-cell lymphoma (DLBCL centroblastic and Burkitt lymphoma. PTLD expressing the BCL6-/MUM1+/CD138- phenotype putatively derive from B-cells that have concluded the GC reaction, and comprise the majority of polymorphic PTLD and a fraction of

  9. Pathogenesis of Cardiovascular and Metabolic Diseases: Are Fructose-Containing Sugars More Involved Than Other Dietary Calories?

    Science.gov (United States)

    Rosset, Robin; Surowska, Anna; Tappy, Luc

    2016-06-01

    There is increasing concern that sugar consumption may be linked to the development of metabolic and cardiovascular diseases. There is indeed strong evidence that consumption of energy-dense sugary beverages and foods is associated with increased energy intake and body weight gain over time. It is further proposed that the fructose component of sugars may exert specific deleterious effects due to its propension to stimulate hepatic glucose production and de novo lipogenesis. Excess fructose and energy intake may be associated with visceral obesity, intrahepatic fat accumulation, and high fasting and postprandial blood triglyceride concentrations. Additional effects of fructose on blood uric acid and sympathetic nervous system activity have also been reported, but their link with metabolic and cardiovascular diseases remains hypothetical. There is growing evidence that fructose at physiologically consumed doses may exert important effects on kidney function. Whether this is related to the development of high blood pressure and cardiovascular diseases remains to be further assessed.

  10. [The age-related macular degeneration as a vascular disease/part of systemic vasculopathy: contributions to its pathogenesis].

    Science.gov (United States)

    Fischer, Tamás

    2015-03-01

    The wall of blood vessels including those in choroids may be harmed by several repeated and/or prolonged mechanical, physical, chemical, microbiological, immunologic, and genetic impacts (risk factors), which may trigger a protracted response, the so-called host defense response. As a consequence, pathological changes resulting in vascular injury (e. g. atherosclerosis, age-related macular degeneration) may be evolved. Risk factors can also act directly on the endothelium through an increased production of reactive oxygen species promoting an endothelial activation, which leads to endothelial dysfunction, the onset of vascular disease. Thus, endothelial dysfunction is a link between the harmful stimulus and vascular injury; any kind of harmful stimuli may trigger the defensive chain that results in inflammation that may lead to vascular injury. It has been shown that even early age-related macular degeneration is associated with the presence of diffuse arterial disease and patients with early age-related macular degeneration demonstrate signs of systemic and retinal vascular alterations. Chronic inflammation, a feature of AMD, is tightly linked to diseases associated with ED: AMD is accompanied by a general inflammatory response, in the form of complement system activation, similar to that observed in degenerative vascular diseases such as atherosclerosis. All these facts indicate that age-related macular degeneration may be a vascular disease (or part of a systemic vasculopathy). This recognition could have therapeutic implications because restoration of endothelial dysfunction may prevent the development or improve vascular disease resulting in prevention or improvement of age-related macular degeneration as well.

  11. An overview of history, pathogenesis and treatment of perforated peptic ulcer disease with evaluation of prognostic scoring in adults.

    Science.gov (United States)

    Prabhu, V; Shivani, A

    2014-01-01

    Peptic ulcer disease including both gastric and duodenal ulcer form a substantial part of patients seeking surgical opinion world-wide. The concept of acid in peptic ulcer disease, which was the basis of treatment of peptic ulcer was revolutionized by the discovery of H2-receptor antagonists, that led to the principle of acid suppression therapy for duodenal ulcer which followed decades of preference for surgical interventions in the form of gastric resections, vagotomy etc., After the discovery of Helicobacter pylori organism as the causative factor a triple drug regime was identified to treat peptic disease which was further modified to sequential therapy to avoid antibiotic resistance. This recognition has not concluded the chapter on peptic ulcers. The management of ulcer disease and its complications remain a surgical challenge. All the materials for this review have been accessed from various internet search engines. The references have been narrowed down to 34 by excluding cross references, duplicated citations, pediatric studies, case reports, iatrogenic and malignant perforations and including microbiological, immunohistochemistry references and studies with more than a sample size of ten. Case control, cohort studies, prospective/retrospective, metaanalytical studies were preferred in that order. This article attempts to take an overview of all aspects of the management of peptic ulcer.

  12. Study of the participation of MMP-7, EMMPRIN and cyclophilin A in the pathogenesis of periodontal disease.

    Science.gov (United States)

    de Oliveira Nóbrega, Fernando José; de Oliveira, Denise Hélen Imaculada Pereira; Vasconcelos, Rodrigo Gadelha; Nonaka, Cassiano Francisco Weege; Queiroz, Lélia Maria Guedes

    2016-12-01

    Periodontal disease is an infectious disease resulting from the immunoinflammatory response of the host to microorganisms present in the dental biofilm which causes tissue destruction. The objective of this study was to evaluate the immunohistochemical expression of matrix metalloproteinase 7 (MMP-7), extracellular matrix metalloproteinase inducer (EMMPRIN) and cyclophilin A (CypA) in periodontal disease. Gingival tissue samples were divided as follows: clinically healthy gingiva (n=32), biofilm-induced gingivitis (n=28), and chronic periodontitis (n=30). Histological sections of 3μm were submitted to immunoperoxidase method and undergone quantitative analysis. The results were analyzed statistically by the Mann-Whitney and Spearman correlation tests, with the level of significance set at 0.05 (α=0.05). Immunopositivity for MMP-7, EMMPRIN and CypA differed significantly between the three groups, with higher percentages of staining in chronic periodontitis specimens, followed by chronic gingivitis and healthy gingiva specimens (pperiodontitis (ppathogenesis and progression of periodontal disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Epstein-Barr Virus-Positive Posttransplant Lymphoproliferative Disease After Solid Organ Transplantation: Pathogenesis, Clinical Manifestations, Diagnosis, and Management

    NARCIS (Netherlands)

    Nijland, Marieke L.; Kersten, Marie José; Pals, Steven T.; Bemelman, Frederike J.; ten Berge, Ineke J. M.

    2016-01-01

    Posttransplant lymphoproliferative disease (PTLD) is a potentially fatal complication after (solid organ) transplantation, which is highly associated with Epstein-Barr virus (EBV). The EBV-specific cytotoxic T cell response that is essential in controlling the virus in healthy individuals is

  14. Zika virus genome biology and molecular pathogenesis.

    Science.gov (United States)

    Wang, Anyou; Thurmond, Stephanie; Islas, Leonel; Hui, Kingyung; Hai, Rong

    2017-03-22

    Zika virus (ZIKV) is an emerging RNA virus in the widespread Flavivirus genus. Recently, ZIKV has rapidly spread around the world and has been implicated in human disease, including neurological disorders, triggering public and scientific attention. Understanding how ZIKV causes disease is the highest priority, yet little is known about this virus. Here we examine the currently published data from ZIKV studies to provide the latest understanding of ZIKV genome biology and molecular pathogenesis. The ZIKV genome evolved rapidly from the Flavivirus genus and diverged from the members of this genus, even within the dengue virus cluster to which ZIKV belongs. Genome variations and divergences also exist among ZIKV strains/isolates. These genome divergences might account for the uniqueness of Zika disease. ZIKV infection activates not only the antiviral immune response but also the pro-inflammatory responses associated with disease symptoms. Strikingly, ZIKV activates protein complexes that are functionally associated with disease process, such as glial cell activation and proliferation (for example, Toll-like receptors), apoptosis and cell death, and inflammation. The activation of these complexes may critically contribute to Zika disease. The novel insights into ZIKV genome divergence and disease mechanisms summarized in this review will help accelerate the development of anti-ZIKV strategies.

  15. Understanding Microbial Sensing in Inflammatory Bowel Disease Using Click Chemistry

    Science.gov (United States)

    2017-10-01

    Scale bars, 20 µm. e, Flow cytometry histogram plots of luminal contents from mice given HADA or HALA orally demonstrate decay of fluorescent signal over...Software) and were based on normally distributed data sets with equal variance (Bartlett’s test). Gender- and age-matched mice were randomly assigned to...18643 (2012). 30. Elson, C. O. et al. Experimental models of inflammatory bowel disease reveal innate, adaptive , and regulatory mechanisms of host

  16. Understanding disease control: influence of epidemiological and economic factors.

    Directory of Open Access Journals (Sweden)

    Katarzyna Oleś

    Full Text Available We present a model of disease transmission on a regular and small world network and compare different control options. Comparison is based on a total cost of epidemic, including cost of palliative treatment of ill individuals and preventive cost aimed at vaccination or culling of susceptible individuals. Disease is characterized by pre-symptomatic phase, which makes detection and control difficult. Three general strategies emerge: global preventive treatment, local treatment within a neighborhood of certain size and only palliative treatment with no prevention. While the choice between the strategies depends on a relative cost of palliative and preventive treatment, the details of the local strategy and, in particular, the size of the optimal treatment neighborhood depend on the epidemiological factors. The required extent of prevention is proportional to the size of the infection neighborhood, but depends on time till detection and time till treatment in a non-nonlinear (power law. The optimal size of control neighborhood is also highly sensitive to the relative cost, particularly for inefficient detection and control application. These results have important consequences for design of prevention strategies aiming at emerging diseases for which parameters are not nessecerly known in advance.

  17. The changing understanding of ageing. Part 3: Diseases of ageing

    Directory of Open Access Journals (Sweden)

    Dennis F. Lawler

    2011-09-01

    Full Text Available This third and final paper in this series considers ageing mechanisms across species, with emphasis on conserved metabolic pathways that relate to disease. The growth hormone (GH-insulin-like growth factor (IGF-1-insulin axis continues as an example of how critical pathways might relate to longevity and senescence. Aligning theory, research outcomes and clinical investigations at the levels of the cell, organism and population, is suggested as a means by which to consider the many complexities of the ageing process in an orderly fashion. A contentious debate revolves around whether ageing is purely a combined effect of stochastic events on residual programming relating to reproductive robustness, or whether ageing itself is programmed by natural selection. Emerging data indicate that the influence of genetic programming on specific late-life diseases, and even individual tissue pathologies, will probably need to be reconsidered in the light of newer theoretical possibilities. In particular, the evidence that late life and its diseases are objects of considerable investment of energy challenges theory that couples longevity with reproduction. Furthermore, the author suggests that ageing may have evolved at least partly as a means of niche preservation for contemporaries and for progeny.

  18. Host-induced gene silencing: a tool for understanding fungal host interaction and for developing novel disease control strategies.

    Science.gov (United States)

    Nunes, Cristiano C; Dean, Ralph A

    2012-06-01

    Recent discoveries regarding small RNAs and the mechanisms of gene silencing are providing new opportunities to explore fungal pathogen-host interactions and potential strategies for novel disease control. Plant pathogenic fungi are a constant and major threat to global food security; they represent the largest group of disease-causing agents on crop plants on the planet. An initial understanding of RNA silencing mechanisms and small RNAs was derived from model fungi. Now, new knowledge with practical implications for RNA silencing is beginning to emerge from the study of plant-fungus interactions. Recent studies have shown that the expression of silencing constructs in plants designed on fungal genes can specifically silence their targets in invading pathogenic fungi, such as Fusarium verticillioides, Blumeria graminis and Puccinia striiformis f.sp. tritici. Here, we highlight the important general aspects of RNA silencing mechanisms and emphasize recent findings from plant pathogenic fungi. Strategies to employ RNA silencing to investigate the basis of fungal pathogenesis are discussed. Finally, we address important aspects for the development of fungal-derived resistance through the expression of silencing constructs in host plants as a powerful strategy to control fungal disease. © 2011 The Authors. Molecular Plant Pathology © 2011 BSPP and Blackwell Publishing Ltd.

  19. Molecular pathogenesis of intrahepatic cholangiocarcinoma

    DEFF Research Database (Denmark)

    Andersen, Jesper Bøje

    2014-01-01

    Cholangiocarcinoma (CCA) is an orphan cancer of the hepatobiliary tract, the incidence of which has increased in the past decade. The molecular pathogenesis of this treatment-refractory disease is poorly understood. Desmoplasia is a key causal feature of CCA; however, a majority of tumors develop...

  20. Rheumatoid arthritis - integrated approach to pathogenesis, treatment and care. New opportunities for management of chronic diseases based on synergetic methodology.

    OpenAIRE

    Sidorov, Pavel; Sovershaeva, Evgeniya

    2017-01-01

    Introduction: Rheumatoid arthritis (RA) is the most common chronic systemic autoimmune disease. Chronic and severe course, early disability, social disadaptation as well as the high incidence of psychological problems require the development of an integrated approach to etiopathogenesis, diagnostics, management as well as rehabilitation and preventive care.Theory: We have developed a synergetic bio-psycho-socio-spiritual concept of ontogenesis that is represented by a four-dimensional model c...

  1. Depression in Parkinson Disease: Current Understanding and Treatment

    Directory of Open Access Journals (Sweden)

    Pei-Hao Chen

    2008-12-01

    Full Text Available Depression has a negative impact on activities of daily living, cognitive performance, and quality of life. Despite the high prevalence of depressive symptoms in Parkinson disease (PD, this important clinical feature is under-recognized by physicians. Effective diagnosis, assessment and treatment of depression are, therefore, important aspects of PD management. In this article, we review the literature concerning depression associated with PD, paying specific attention to clinical presentation, diagnosis, etiology, and the principles of management and treatment. The efficacy and safety of antidepressants must rely on empiric assessments of known risks and putative benefits to guide treatment decisions.

  2. Therapeutic implications from the pathogenesis of Raynaud's phenomenon

    OpenAIRE

    Herrick, Ariane L

    2017-01-01

    INTRODUCTION: Raynaud's phenomenon (RP) can be either primary (idiopathic) or secondary to a number of different diseases/conditions, when vasopasm can be superimposed upon structural vascular abnormality or a hyperviscosity state and may then lead to severe ischaemia with tissue damage. Treatment must be tailored to the individual. Areas covered: This review discusses how increased understanding of the pathogenesis of RP has driven and is driving new approaches to therapy, and how we are now...

  3. Involvement of a periodontal pathogen, Porphyromonas gingivalis on the pathogenesis of non-alcoholic fatty liver disease.

    Science.gov (United States)

    Yoneda, Masato; Naka, Shuhei; Nakano, Kazuhiko; Wada, Koichiro; Endo, Hiroki; Mawatari, Hironori; Imajo, Kento; Nomura, Ryota; Hokamura, Kazuya; Ono, Masafumi; Murata, Shogo; Tohnai, Iwai; Sumida, Yoshio; Shima, Toshihide; Kuboniwa, Masae; Umemura, Kazuo; Kamisaki, Yoshinori; Amano, Atsuo; Okanoue, Takeshi; Ooshima, Takashi; Nakajima, Atsushi

    2012-02-16

    Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome that is closely associated with multiple factors such as obesity, hyperlipidemia and type 2 diabetes mellitus. However, other risk factors for the development of NAFLD are unclear. With the association between periodontal disease and the development of systemic diseases receiving increasing attention recently, we conducted this study to investigate the relationship between NAFLD and infection with Porphyromonas gingivalis (P. gingivalis), a major causative agent of periodontitis. The detection frequencies of periodontal bacteria in oral samples collected from 150 biopsy-proven NAFLD patients (102 with non-alcoholic steatohepatitis (NASH) and 48 with non-alcoholic fatty liver (NAFL) patients) and 60 non-NAFLD control subjects were determined. Detection of P. gingivalis and other periodontopathic bacteria were detected by PCR assay. In addition, effect of P. gingivalis-infection on mouse NAFLD model was investigated. To clarify the exact contribution of P. gingivalis-induced periodontitis, non-surgical periodontal treatments were also undertaken for 3 months in 10 NAFLD patients with periodontitis. The detection frequency of P. gingivalis in NAFLD patients was significantly higher than that in the non-NAFLD control subjects (46.7% vs. 21.7%, odds ratio: 3.16). In addition, the detection frequency of P. gingivalis in NASH patients was markedly higher than that in the non-NAFLD subjects (52.0%, odds ratio: 3.91). Most of the P. gingivalis fimbria detected in the NAFLD patients was of invasive genotypes, especially type II (50.0%). Infection of type II P. gingivalis on NAFLD model of mice accelerated the NAFLD progression. The non-surgical periodontal treatments on NAFLD patients carried out for 3 months ameliorated the liver function parameters, such as the serum levels of AST and ALT. Infection with high-virulence P. gingivalis might be an additional risk factor for the

  4. Genes contributing to prion pathogenesis

    DEFF Research Database (Denmark)

    Tamgüney, Gültekin; Giles, Kurt; Glidden, David V

    2008-01-01

    incubation times, indicating that the conversion reaction may be influenced by other gene products. To identify genes that contribute to prion pathogenesis, we analysed incubation times of prions in mice in which the gene product was inactivated, knocked out or overexpressed. We tested 20 candidate genes...... show that many genes previously implicated in prion replication have no discernible effect on the pathogenesis of prion disease. While most genes tested did not significantly affect survival times, ablation of the amyloid beta (A4) precursor protein (App) or interleukin-1 receptor, type I (Il1r1...

  5. The role of disorders in the regional microcirculation and in metabolism in hypertension and inflammatory periodontal disease pathogenesis

    Directory of Open Access Journals (Sweden)

    Yu. A. Sycheva

    2013-01-01

    Full Text Available We have studied interrelation between pathological activation of apoptosis and the state and activity of free radical oxidation, and of regional hemodynamics in 27 patients with essential hypertension (EH and inflammatory periodontal disease. The results show that arterial hypertension is accompanied by tissue hypoxia initiating oxidative modification of proteins and lipids with following pathological activation of apoptosis, that triggers the mechanisms of remodeling of the target organs and results in inflammatory and degenerative forms of periodontal tissue modification as a morphological substrate of remodeling. Therefore periodontium may be looked upon as a target organ of remodeling in EH.

  6. Celiac disease: understanding the gluten-free diet.

    Science.gov (United States)

    Bascuñán, Karla A; Vespa, María Catalina; Araya, Magdalena

    2017-03-01

    The only effective and safe treatment of celiac disease (CD) continues being strict exclusion of gluten for life, the so-called gluten-free diet (GFD). Although this treatment is highly successful, following strict GFD poses difficulties to patients in family, social and working contexts, deteriorating his/her quality of life. We aimed to review main characteristics of GFD with special emphasis on factors that may interfere with adherence to it. We conducted a search of various databases, such as PubMed, Google Scholar, Embase, and Scielo, with focus on key words such as "gluten-free diet", "celiac disease", "gluten" and "gluten-free diet adherence". Available literature has not reached definitive conclusions on the exact amount of gluten that is harmless to celiac patients, although international agreements establish cutoff points for gluten-free products and advise the use of clinical assessment to tailor the diet according to individual needs. Following GFD must include eliminating gluten as ingredient as well as hidden component and potential cross contamination in foods. There are numerous grains to substitute wheat but composition of most gluten-free products tends to include only a small number of them, especially rice. The diet must be not only free of gluten but also healthy to avoid nutrient, vitamins and minerals deficiencies or excess. Overweight/obesity frequency has increased among celiac patients so weight gain deserves attention during follow up. Nutritional education by a trained nutritionist is of great relevance to achieve long-term satisfactory health status and good compliance. A balanced GFD should be based on a combination of naturally gluten-free foods and certified processed gluten-free products. How to measure and improve adherence to GFD is still controversial and deserves further study.

  7. Using iPS Cells toward the Understanding of Parkinson’s Disease

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    Roger Torrent

    2015-03-01

    Full Text Available Cellular reprogramming of somatic cells to human pluripotent stem cells (iPSC represents an efficient tool for in vitro modeling of human brain diseases and provides an innovative opportunity in the identification of new therapeutic drugs. Patient-specific iPSC can be differentiated into disease-relevant cell types, including neurons, carrying the genetic background of the donor and enabling de novo generation of human models of genetically complex disorders. Parkinson’s disease (PD is the second most common age-related progressive neurodegenerative disease, which is mainly characterized by nigrostriatal dopaminergic (DA neuron degeneration and synaptic dysfunction. Recently, the generation of disease-specific iPSC from patients suffering from PD has unveiled a recapitulation of disease-related cell phenotypes, such as abnormal α-synuclein accumulation and alterations in autophagy machinery. The use of patient-specific iPSC has a remarkable potential to uncover novel insights of the disease pathogenesis, which in turn will open new avenues for clinical intervention. This review explores the current Parkinson’s disease iPSC-based models highlighting their role in the discovery of new drugs, as well as discussing the most challenging limitations iPSC-models face today.

  8. Mycobacterium ulcerans causes minimal pathogenesis and colonization in medaka (Oryzias latipes): an experimental fish model of disease transmission.

    Science.gov (United States)

    Mosi, Lydia; Mutoji, Nadine K; Basile, Fritz A; Donnell, Robert; Jackson, Kathrine L; Spangenberg, Thomas; Kishi, Yoshito; Ennis, Don G; Small, Pamela L C

    2012-08-01

    Mycobacterium ulcerans causes Buruli ulcer in humans, a progressive ulcerative epidermal lesion due to the mycolactone toxin produced by the bacterium. Molecular analysis of M. ulcerans reveals it is closely related to Mycobacterium marinum, a pathogen of both fish and man. Molecular evidence from diagnostic PCR assays for the insertion sequence IS2404 suggests an association of M. ulcerans with fish. However, fish infections by M. ulcerans have not been well documented and IS2404 has been found in other mycobacteria. We have thus, employed two experimental approaches to test for M. ulcerans in fish. We show here for the first time that M. ulcerans with or without the toxin does not mount acute or chronic infections in Japanese Medaka "Oryzias latipes" even at high doses. Moreover, M. ulcerans-infected medaka do not exhibit any visible signs of infection nor disease and the bacteria do not appear to replicate over time. In contrast, similar high doses of the wild-type M. marinum or a mycolactone-producing M. marinum "DL" strain are able to mount an acute disease with mortality in medaka. Although these results would suggest that M. ulcerans does not mount infections in fish we have evidence that CLC macrophages from goldfish are susceptible to mycolactones. Copyright © 2012 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

  9. Identification of genetic risk factors in the Chinese population implicates a role of immune system in Alzheimer's disease pathogenesis.

    Science.gov (United States)

    Zhou, Xiaopu; Chen, Yu; Mok, Kin Y; Zhao, Qianhua; Chen, Keliang; Chen, Yuewen; Hardy, John; Li, Yun; Fu, Amy K Y; Guo, Qihao; Ip, Nancy Y

    2018-02-20

    Alzheimer's disease (AD) is a leading cause of mortality among the elderly. We performed a whole-genome sequencing study of AD in the Chinese population. In addition to the variants identified in or around the APOE locus (sentinel variant rs73052335, P = 1.44 × 10 -14 ), two common variants, GCH1 (rs72713460, P = 4.36 × 10 -5 ) and KCNJ15 (rs928771, P = 3.60 × 10 -6 ), were identified and further verified for their possible risk effects for AD in three small non-Asian AD cohorts. Genotype-phenotype analysis showed that KCNJ15 variant rs928771 affects the onset age of AD, with earlier disease onset in minor allele carriers. In addition, altered expression level of the KCNJ15 transcript can be observed in the blood of AD subjects. Moreover, the risk variants of GCH1 and KCNJ15 are associated with changes in their transcript levels in specific tissues, as well as changes of plasma biomarkers levels in AD subjects. Importantly, network analysis of hippocampus and blood transcriptome datasets suggests that the risk variants in the APOE , GCH1 , and KCNJ15 loci might exert their functions through their regulatory effects on immune-related pathways. Taking these data together, we identified common variants of GCH1 and KCNJ15 in the Chinese population that contribute to AD risk. These variants may exert their functional effects through the immune system. Copyright © 2018 the Author(s). Published by PNAS.

  10. Sucrose-mediated priming of plant defense responses and broad-spectrum disease resistance by overexpression of the maize pathogenesis-related PRms protein in rice plants.

    Science.gov (United States)

    Gómez-Ariza, Jorge; Campo, Sonia; Rufat, Mar; Estopà, Montserrat; Messeguer, Joaquima; San Segundo, Blanca; Coca, María

    2007-07-01

    Expression of pathogenesis-related (PR) genes is part of the plant's natural defense response against pathogen attack. The PRms gene encodes a fungal-inducible PR protein from maize. Here, we demonstrate that expression of PRms in transgenic rice confers broad-spectrum protection against pathogens, including fungal (Magnaporthe oryzae, Fusarium verticillioides, and Helminthosporium oryzae) and bacterial (Erwinia chrysanthemi) pathogens. The PRms-mediated disease resistance in rice plants is associated with an enhanced capacity to express and activate the natural plant defense mechanisms. Thus, PRms rice plants display a basal level of expression of endogenous defense genes in the absence of the pathogen. PRms plants also exhibit stronger and quicker defense responses during pathogen infection. We also have found that sucrose accumulates at higher levels in leaves of PRms plants. Sucrose responsiveness of rice defense genes correlates with the pathogen-responsive priming of their expression in PRms rice plants. Moreover, pretreatment of rice plants with sucrose enhances resistance to M. oryzae infection. Together, these results support a sucrose-mediated priming of defense responses in PRms rice plants which results in broad-spectrum disease resistance.

  11. Involvement of a periodontal pathogen, Porphyromonas gingivalis on the pathogenesis of non-alcoholic fatty liver disease

    Directory of Open Access Journals (Sweden)

    Yoneda Masato

    2012-02-01

    Full Text Available Abstract Background Non-alcoholic fatty liver disease (NAFLD is a hepatic manifestation of metabolic syndrome that is closely associated with multiple factors such as obesity, hyperlipidemia and type 2 diabetes mellitus. However, other risk factors for the development of NAFLD are unclear. With the association between periodontal disease and the development of systemic diseases receiving increasing attention recently, we conducted this study to investigate the relationship between NAFLD and infection with Porphyromonas gingivalis (P. gingivalis, a major causative agent of periodontitis. Methods The detection frequencies of periodontal bacteria in oral samples collected from 150 biopsy-proven NAFLD patients (102 with non-alcoholic steatohepatitis (NASH and 48 with non-alcoholic fatty liver (NAFL patients and 60 non-NAFLD control subjects were determined. Detection of P. gingivalis and other periodontopathic bacteria were detected by PCR assay. In addition, effect of P. gingivalis-infection on mouse NAFLD model was investigated. To clarify the exact contribution of P. gingivalis-induced periodontitis, non-surgical periodontal treatments were also undertaken for 3 months in 10 NAFLD patients with periodontitis. Results The detection frequency of P. gingivalis in NAFLD patients was significantly higher than that in the non-NAFLD control subjects (46.7% vs. 21.7%, odds ratio: 3.16. In addition, the detection frequency of P. gingivalis in NASH patients was markedly higher than that in the non-NAFLD subjects (52.0%, odds ratio: 3.91. Most of the P. gingivalis fimbria detected in the NAFLD patients was of invasive genotypes, especially type II (50.0%. Infection of type II P. gingivalis on NAFLD model of mice accelerated the NAFLD progression. The non-surgical periodontal treatments on NAFLD patients carried out for 3 months ameliorated the liver function parameters, such as the serum levels of AST and ALT. Conclusions Infection with high-virulence P

  12. Morbillivirus Experimental Animal Models: Measles Virus Pathogenesis Insights from Canine Distemper Virus.

    Science.gov (United States)

    da Fontoura Budaszewski, Renata; von Messling, Veronika

    2016-10-11

    Morbilliviruses share considerable structural and functional similarities. Even though disease severity varies among the respective host species, the underlying pathogenesis and the clinical signs are comparable. Thus, insights gained with one morbillivirus often apply to the other members of the genus. Since the Canine distemper virus (CDV) causes severe and often lethal disease in dogs and ferrets, it is an attractive model to characterize morbillivirus pathogenesis mechanisms and to evaluate the efficacy of new prophylactic and therapeutic approaches. This review compares the cellular tropism, pathogenesis, mechanisms of persistence and immunosuppression of the Measles virus (MeV) and CDV. It then summarizes the contributions made by studies on the CDV in dogs and ferrets to our understanding of MeV pathogenesis and to vaccine and drugs development.

  13. Morbillivirus Experimental Animal Models: Measles Virus Pathogenesis Insights from Canine Distemper Virus

    Directory of Open Access Journals (Sweden)

    Renata da Fontoura Budaszewski

    2016-10-01

    Full Text Available Morbilliviruses share considerable structural and functional similarities. Even though disease severity varies among the respective host species, the underlying pathogenesis and the clinical signs are comparable. Thus, insights gained with one morbillivirus often apply to the other members of the genus. Since the Canine distemper virus (CDV causes severe and often lethal disease in dogs and ferrets, it is an attractive model to characterize morbillivirus pathogenesis mechanisms and to evaluate the efficacy of new prophylactic and therapeutic approaches. This review compares the cellular tropism, pathogenesis, mechanisms of persistence and immunosuppression of the Measles virus (MeV and CDV. It then summarizes the contributions made by studies on the CDV in dogs and ferrets to our understanding of MeV pathogenesis and to vaccine and drugs development.

  14. Small RNA sequencing revealed dysregulated piRNAs in Alzheimer's disease and their probable role in pathogenesis.

    Science.gov (United States)

    Roy, Jyoti; Sarkar, Arijita; Parida, Sibun; Ghosh, Zhumur; Mallick, Bibekanand

    2017-02-28

    PIWI-interacting RNAs (piRNAs), ∼23-36 nucleotide-long small non-coding RNAs, earlier believed to be germline-specific, have now been identified in somatic cells including neural cells. However, piRNAs have not yet been studied in the human brain (HB) and Alzheimer's disease (AD)-affected brain. In this study, by next-generation small RNA sequencing, 564 and 451 piRNAs were identified in the HB and AD-affected brain respectively. The majority of the neuronal piRNAs have intronic origin wherein primary piRNAs are mostly from the negative strand. piRNAs originating from the coding sequence of mRNAs and tRNAs are highly conserved compared to other genomic contexts. We found 1923 mRNAs significantly down-regulated in AD as the predicted targets of 125 up-regulated piRNAs. The filtering of targets based on our criteria coupled with pathway enrichment analysis of all the predicted targets resulted in five most significant AD-associated pathways enriched with four genes (CYCS, LIN7C, KPNA6, and RAB11A) found to be regulated by four piRNAs. The qRT-PCR study verified the reciprocal expression of piRNAs and their targets. This study provides the first evidence of piRNAs in the HB and AD which will provide the foundation for future studies to unravel the regulatory role of piRNAs in the human brain and associated diseases. The sequencing data have been submitted to the GEO database (Accession no. GSE85075).

  15. Substitutions of PrP N-terminal histidine residues modulate scrapie disease pathogenesis and incubation time in transgenic mice.

    Directory of Open Access Journals (Sweden)

    Sabina Eigenbrod

    Full Text Available Prion diseases have been linked to impaired copper homeostasis and copper induced-oxidative damage to the brain. Divalent metal ions, such as Cu2+ and Zn2+, bind to cellular prion protein (PrPC at octapeptide repeat (OR and non-OR sites within the N-terminal half of the protein but information on the impact of such binding on conversion to the misfolded isoform often derives from studies using either OR and non-OR peptides or bacterially-expressed recombinant PrP. Here we created new transgenic mouse lines expressing PrP with disrupted copper binding sites within all four histidine-containing OR's (sites 1-4, H60G, H68G, H76G, H84G, "TetraH>G" allele or at site 5 (composed of residues His-95 and His-110; "H95G" allele and monitored the formation of misfolded PrP in vivo. Novel transgenic mice expressing PrP(TetraH>G at levels comparable to wild-type (wt controls were susceptible to mouse-adapted scrapie strain RML but showed significantly prolonged incubation times. In contrast, amino acid replacement at residue 95 accelerated disease progression in corresponding PrP(H95G mice. Neuropathological lesions in terminally ill transgenic mice were similar to scrapie-infected wt controls, but less severe. The pattern of PrPSc deposition, however, was not synaptic as seen in wt animals, but instead dense globular plaque-like accumulations of PrPSc in TgPrP(TetraH>G mice and diffuse PrPSc deposition in (TgPrP(H95G mice, were observed throughout all brain sections. We conclude that OR and site 5 histidine substitutions have divergent phenotypic impacts and that cis interactions between the OR region and the site 5 region modulate pathogenic outcomes by affecting the PrP globular domain.

  16. Substitutions of PrP N-terminal histidine residues modulate scrapie disease pathogenesis and incubation time in transgenic mice.

    Science.gov (United States)

    Eigenbrod, Sabina; Frick, Petra; Bertsch, Uwe; Mitteregger-Kretzschmar, Gerda; Mielke, Janina; Maringer, Marko; Piening, Niklas; Hepp, Alexander; Daude, Nathalie; Windl, Otto; Levin, Johannes; Giese, Armin; Sakthivelu, Vignesh; Tatzelt, Jörg; Kretzschmar, Hans; Westaway, David

    2017-01-01

    Prion diseases have been linked to impaired copper homeostasis and copper induced-oxidative damage to the brain. Divalent metal ions, such as Cu2+ and Zn2+, bind to cellular prion protein (PrPC) at octapeptide repeat (OR) and non-OR sites within the N-terminal half of the protein but information on the impact of such binding on conversion to the misfolded isoform often derives from studies using either OR and non-OR peptides or bacterially-expressed recombinant PrP. Here we created new transgenic mouse lines expressing PrP with disrupted copper binding sites within all four histidine-containing OR's (sites 1-4, H60G, H68G, H76G, H84G, "TetraH>G" allele) or at site 5 (composed of residues His-95 and His-110; "H95G" allele) and monitored the formation of misfolded PrP in vivo. Novel transgenic mice expressing PrP(TetraH>G) at levels comparable to wild-type (wt) controls were susceptible to mouse-adapted scrapie strain RML but showed significantly prolonged incubation times. In contrast, amino acid replacement at residue 95 accelerated disease progression in corresponding PrP(H95G) mice. Neuropathological lesions in terminally ill transgenic mice were similar to scrapie-infected wt controls, but less severe. The pattern of PrPSc deposition, however, was not synaptic as seen in wt animals, but instead dense globular plaque-like accumulations of PrPSc in TgPrP(TetraH>G) mice and diffuse PrPSc deposition in (TgPrP(H95G) mice), were observed throughout all brain sections. We conclude that OR and site 5 histidine substitutions have divergent phenotypic impacts and that cis interactions between the OR region and the site 5 region modulate pathogenic outcomes by affecting the PrP globular domain.

  17. The role of iron-induced fibrin in the pathogenesis of Alzheimer's disease and the protective role of magnesium.

    Science.gov (United States)

    Lipinski, Boguslaw; Pretorius, Etheresia

    2013-10-29

    Amyloid hypothesis of Alzheimer's disease (AD) has recently been challenged by the increasing evidence for the role of vascular and hemostatic components that impair oxygen delivery to the brain. One such component is fibrin clots, which, when they become resistant to thrombolysis, can cause chronic inflammation. It is not known, however, why some cerebral thrombi are resistant to the fibrinolytic degradation, whereas fibrin clots formed at the site of vessel wall injuries are completely, although gradually, removed to ensure proper wound healing. This phenomenon can now be explained in terms of the iron-induced free radicals that generate fibrin-like polymers remarkably resistant to the proteolytic degradation. It should be noted that similar insoluble deposits are present in AD brains in the form of aggregates with Abeta peptides that are resistant to fibrinolytic degradation. In addition, iron-induced fibrin fibers can irreversibly trap red blood cells (RBCs) and in this way obstruct oxygen delivery to the brain and induce chronic hypoxia that may contribute to AD. The RBC-fibrin aggregates can be disaggregated by magnesium ions and can also be prevented by certain polyphenols that are known to have beneficial effects in AD. In conclusion, we argue that AD can be prevented by: (1) limiting the dietary supply of trivalent iron contained in red and processed meat; (2) increasing the intake of chlorophyll-derived magnesium; and (3) consumption of foods rich in polyphenolic substances and certain aliphatic and aromatic unsaturated compounds. These dietary components are present in the Mediterranean diet known to be associated with the lower incidence of AD and other degenerative diseases.

  18. The enduring importance of animal models in understanding periodontal disease.

    Science.gov (United States)

    Hajishengallis, George; Lamont, Richard J; Graves, Dana T

    2015-01-01

    Whereas no single animal model can reproduce the complexity of periodontitis, different aspects of the disease can be addressed by distinct models. Despite their limitations, animal models are essential for testing the biological significance of in vitro findings and for establishing cause-and-effect relationships relevant to clinical observations, which are typically correlative. We provide evidence that animal-based studies have generated a durable framework for dissecting the mechanistic basis of periodontitis. These studies have solidified the etiologic role of bacteria in initiating the inflammatory response that leads to periodontal bone loss and have identified key mediators (IL-1, TNF, prostaglandins, complement, RANKL) that induce inflammatory breakdown. Moreover, animal studies suggest that dysbiosis, rather than individual bacterial species, are important in initiating periodontal bone loss and have introduced the concept that organisms previously considered commensals can play important roles as accessory pathogens or pathobionts. These studies have also provided insight as to how systemic conditions, such as diabetes or leukocyte adhesion deficiency, contribute to tissue destruction. In addition, animal studies have identified and been useful in testing therapeutic targets.

  19. A case of insulinoma with non-alcoholic fatty liver disease: Roles of hyperphagia and hyperinsulinemia in pathogenesis of the disease.

    Science.gov (United States)

    Rokutan, Mariyo; Yabe, Daisuke; Komoto, Izumi; Kurose, Takeshi; Kawai, Jun; Nakamura, Takefumi; Imamura, Masayuki; Seino, Yutaka

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a serious health-related condition all over the world; the number of patients is increasing in Asian countries including Japan. Better understanding of its pathophysiology is required to develop effective therapeutics, as patients may go on to develop non-alcoholic steatohepatitis and hepatocellular carcinomas. While NAFLD is believed to be associated with metabolic risk factors such as obesity, diabetes, and dyslipidemia, its etiology remains largely unknown and the development or co-existence of NAFLD in patients with insulinoma has not been investigated. A 33-year-old male with an insulinoma, who had been hypoglycemic during the previous four years, developed abnormally elevated levels of liver enzymes and histological fatty liver characteristic of NAFLD by the time of admission to our hospital for resection of an insulinoma. His medical records for the previous eight years revealed that his bodyweight had increased gradually from 60 kg to 71 kg for seven years and then acutely increased to 79 kg in the latest one-year period. This sudden increase was thought to be due to the patient's self-described overeating of fruits to forestall hypoglycemia. Fresh fruits are rich in fructose, and the patient's triglycerides, alanine and aspartate transaminases showed an acute increase in the previous one-year period. After resection of the insulinoma, the levels of these parameters all were mostly restored, which suggests that hyperinsulinemia and subsequent hyperphagia played a role in the development of NAFLD in this case. This is the first report of patient with NAFLD and an insulinoma.

  20. Toward Understanding Ambulatory Activity Decline in Parkinson Disease.

    Science.gov (United States)

    Cavanaugh, James T; Ellis, Terry D; Earhart, Gammon M; Ford, Matthew P; Foreman, K Bo; Dibble, Leland E

    2015-08-01

    Declining ambulatory activity represents an important facet of disablement in Parkinson disease (PD). The primary study aim was to compare the 2-year trajectory of ambulatory activity decline with concurrently evolving facets of disability in a small cohort of people with PD. The secondary aim was to identify baseline variables associated with ambulatory activity at 1- and 2-year follow-up assessments. This was a prospective, longitudinal cohort study. Seventeen people with PD (Hoehn and Yahr stages 1-3) were recruited from 2 outpatient settings. Ambulatory activity data were collected at baseline and at 1- and 2-year annual assessments. Motor, mood, balance, gait, upper extremity function, quality of life, self-efficacy, and levodopa equivalent daily dose data and data on activities of daily living also were collected. Participants displayed significant 1- and 2-year declines in the amount and intensity of ambulatory activity concurrently with increasing levodopa equivalent daily dose. Worsening motor symptoms and slowing of gait were apparent only after 2 years. Concurrent changes in the remaining clinical variables were not observed. Baseline ambulatory activity and physical performance variables had the strongest relationships with 1- and 2-year mean daily steps. The sample was small and homogeneous. Future research that combines ambulatory activity monitoring with a broader and more balanced array of measures would further illuminate the dynamic interactions among evolving facets of disablement and help determine the extent to which sustained patterns of recommended daily physical activity might slow the rate of disablement in PD. © 2015 American Physical Therapy Association.

  1. METHODS OF ESTIMATION AND THE ROLE OF RESPIRATORY BURST IN THE PATHOGENESIS OF INFECTIOUS AND INFLAMMATORY DISEASES

    Directory of Open Access Journals (Sweden)

    A. A. Savchenko

    2017-01-01

    Full Text Available According to the modern concepts the respiratory burst directly related to the processes of phagocytosis characterizes the functional activity of phagocytic cells. This review presents modern methods for assessing the respiratory burst state of phagocytes based on cytofluorometric and chemiluminescent analysis. The sequence and mechanisms of the reactions of reactive oxygen species (ROS synthesis in the process of respiratory cell burst are presented in detail. The sequence of synthesis from ROS with low bactericidal activity to ROS with high bactericidal activity is characterized. The review describes in detail the most popular dyes for cytofluorometric analysis to assess the levels of ROS synthesis. Characteristics and examples of the use of such dyes as dihydroethidine, dichlorodihydrofluorescein and dihydrorhodamine 123 are given. The main stages and mechanisms of the chemiluminescence reaction are presented. The features of the use of the main indicators (luminol and lucigenin of the chemiluminescence reaction are described. A mechanism for estimating the parameters of the chemiluminescence reaction characterizing the features of the state and kinetics of the respiratory burst of phagocytic cells is given. The separate section of the review is devoted to the role of a respiratory burst in phagocytic cells in various immunopathological states. Data on the pathogenetic significance of changes in the intensity and kinetics of respiratory burst of phagocytes in infectious, inflammatory and oncological diseases were presented. Examples of new methods for diagnosing and predicting the course of the immunopathological states characters are presented on the basis of an assessment of the respiratory burst of phagocytic cells. The literature data show that at present, in the diagnosis and evaluation of the nature of the diseases characters the state of a respiratory burst is evaluated in various types of cells of innate immunity: neutrophils

  2. Cellular and molecular mechanisms of chikungunya pathogenesis.

    Science.gov (United States)

    Lum, Fok-Moon; Ng, Lisa F P

    2015-08-01

    Chikungunya virus (CHIKV) is an arthropod-borne virus that causes chikungunya fever, a disease characterized by the onset of fever and rashes, with arthralgia as its hallmark symptom. CHIKV has re-emerged over the past decade, causing numerous outbreaks around the world. Since late 2013, CHIKV has reached the shores of the Americas, causing more than a million cases of infection. Despite concentrated efforts to understand the pathogenesis of the disease, further outbreaks remain a threat. This review highlights important findings regarding CHIKV-associated immunopathogenesis and offers important insights into future directions. This article forms part of a symposium in Antiviral Research on "Chikungunya discovers the New World." Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Extra-intestinal malignancies in inflammatory bowel disease: results of the 3rd ECCO Pathogenesis Scientific Workshop (III).

    Science.gov (United States)

    Magro, Fernando; Peyrin-Biroulet, Laurent; Sokol, Harry; Aldeger, Xavier; Costa, Antonia; Higgins, Peter D; Joyce, Joel C; Katsanos, Konstantinos H; Lopez, Anthony; de Xaxars, Teresa Mas; Toader, Elena; Beaugerie, Laurent

    2014-01-01

    The incidence of lymphoproliferative disorders (LD) is increasing in developed countries. Patients with inflammatory bowel disease (IBD) exposed to thiopurines are at additional risk of three specific forms of LD: Epstein-Barr-Virus-related post-transplant like LD, hepato-splenic T-cell lymphoma and post-mononucleosis lymphoproliferation. The risk of the two latter forms of LD can be reduced when considering specific immunosuppressive strategies in young males. It is still unclear whether the risk of uterine cervix abnormalities is increased in IBD women, irrespective of the use of immunosuppressants. Given the excess risk demonstrated in various other contexts of immunosuppression, it is currently recommended that all women with IBD, particularly those receiving immunosuppressants, strictly adhere to a screening program of cervical surveillance and undergo vaccination against HPV, when appropriate. Patients with IBD receiving immunosuppressants are at increased risk of skin cancers. The risk of non-melanoma skin cancer is notably increased in patients receiving thiopurines. Recent data suggest that the risk of melanoma is mildly increased in patients exposed to anti-TNF therapy. All IBD patients should adhere to a program of sun protection and dermatological surveillance, whose details should take into account the other non-IBD-related risk factors. Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.

  4. Ex vivo evidence for the contribution of hemodynamic shear stress abnormalities to the early pathogenesis of calcific bicuspid aortic valve disease.

    Directory of Open Access Journals (Sweden)

    Ling Sun

    Full Text Available The bicuspid aortic valve (BAV is the most common congenital cardiac anomaly and is frequently associated with calcific aortic valve disease (CAVD. The most prevalent type-I morphology, which results from left-/right-coronary cusp fusion, generates different hemodynamics than a tricuspid aortic valve (TAV. While valvular calcification has been linked to genetic and atherogenic predispositions, hemodynamic abnormalities are increasingly pointed as potential pathogenic contributors. In particular, the wall shear stress (WSS produced by blood flow on the leaflets regulates homeostasis in the TAV. In contrast, WSS alterations cause valve dysfunction and disease. While such observations support the existence of synergies between valvular hemodynamics and biology, the role played by BAV WSS in valvular calcification remains unknown. The objective of this study was to isolate the acute effects of native BAV WSS abnormalities on CAVD pathogenesis. Porcine aortic valve leaflets were subjected ex vivo to the native WSS experienced by TAV and type-I BAV leaflets for 48 hours. Immunostaining, immunoblotting and zymography were performed to characterize endothelial activation, pro-inflammatory paracrine signaling, extracellular matrix remodeling and markers involved in valvular interstitial cell activation and osteogenesis. While TAV and non-coronary BAV leaflet WSS essentially maintained valvular homeostasis, fused BAV leaflet WSS promoted fibrosa endothelial activation, paracrine signaling (2.4-fold and 3.7-fold increase in BMP-4 and TGF-β1, respectively, relative to fresh controls, catabolic enzyme secretion (6.3-fold, 16.8-fold, 11.7-fold, 16.7-fold and 5.5-fold increase in MMP-2, MMP-9, cathepsin L, cathepsin S and TIMP-2, respectively and activity (1.7-fold and 2.4-fold increase in MMP-2 and MMP-9 activity, respectively, and bone matrix synthesis (5-fold increase in osteocalcin. In contrast, BAV WSS did not significantly affect α-SMA and Runx2

  5. The role of myeloid cell activation and arginine metabolism in the pathogenesis of virus-induced diseases

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    Kristina S. Burrack

    2014-09-01

    Full Text Available When an antiviral immune response is generated, a balance must be reached between two opposing pathways: the production of proinflammatory and cytotoxic effectors that drive a robust antiviral immune response to control the infection and regulators that function to limit or blunt an excessive immune response to minimize immune-mediated pathology and repair tissue damage. Myeloid cells, including monocytes and macrophages, play an important role in this balance, particularly through the activities of the arginine-hydrolyzing enzymes nitric oxide synthase 2 (Nos2; iNOS and arginase 1 (Arg1. Nitric oxide (NO production by iNOS is an important proinflammatory mediator, whereas Arg1-expressing macrophages contribute to the resolution of inflammation and wound repair. In the context of viral infections, expression of these enzymes can result in a variety of outcomes for the host. NO has direct antiviral properties against some viruses, whereas during other virus infections NO can mediate immunopathology and/or inhibit the antiviral immune response to promote chronic infection. Arg1 activity has important wound healing functions but can also inhibit the antiviral immune response during some viral infections. Thus, depending on the specific virus and the tissue(s involved, the activity of both of these arginine-hydrolyzing enzymes can either exacerbate or limit the severity of virus-induced disease. In this review, we will discuss a variety of viral infections, including HIV, SARS-CoV, LCMV, HCV, RSV, and others, where myeloid cells influence the control and clearance of the virus from the host, as well as the severity and resolution of tissue damage, via the activities of iNOS and/or Arg1. Clearly, monocyte/macrophage activation and arginine metabolism will continue to be important areas of investigation in the context of viral infections.

  6. Ebola virus disease and pregnancy - A review of the current knowledge of Ebola virus pathogenesis, maternal and neonatal outcomes

    Science.gov (United States)

    Bebell, Lisa M.; Oduyebo, Titilope; Riley, Laura E.

    2016-01-01

    The 2014-2016 Ebola virus disease (EVD) outbreak in West Africa devastated local health systems and caused thousands of deaths. Historical reports from Zaire ebolavirus outbreaks suggested pregnancy was associated with an increased risk of severe illness and death, with mortality rates from 74-100%. In total, 111 cases of pregnant patients with EVD are reported in the literature, with an aggregate maternal mortality of 86%. Pregnancy-specific data published from the recent outbreak include four small descriptive cohort studies and five case reports. Despite limitations including reporting bias and small sample size, these studies suggest mortality in pregnant women may be lower than previously reported, with five of 13(39%) infected women dying. Optimal treatments for pregnant women, and differences in EVD course between pregnant women and non-pregnant individuals are major scientific gaps that have not yet been systematically addressed. Ebola virus may be transmitted from mother to baby in utero, during delivery, or through contact with maternal body fluids after birth including breast milk. EVD is almost universally fatal to the developing fetus, and limited fetal autopsy data prevent inferences on risk of birth defects. Decisions about delivery mode and other obstetric interventions should be individualized. WHO recommends close monitoring of survivors who later become pregnant, but does not recommend enhanced precautions at subsequent delivery. Though sexual transmission of Ebola virus has been documented, birth outcomes among survivors have not been published and will be important to appropriately counsel women on pregnancy outcomes and inform delivery precautions for healthcare providers. PMID:28398679

  7. New Insights into the Immunobiology of Mononuclear Phagocytic Cells and Their Relevance to the Pathogenesis of Cardiovascular Diseases

    Directory of Open Access Journals (Sweden)

    Liliana Maria Sanmarco

    2018-01-01

    Full Text Available Macrophages are the primary immune cells that reside within the myocardium, suggesting that these mononuclear phagocytes are essential in the orchestration of cardiac immunity and homeostasis. Independent of the nature of the injury, the heart triggers leukocyte activation and recruitment. However, inflammation is harmful to this vital terminally differentiated organ with extremely poor regenerative capacity. As such, cardiac tissue has evolved particular strategies to increase the stress tolerance and minimize the impact of inflammation. In this sense, growing evidences show that mononuclear phagocytic cells are particularly dynamic during cardiac inflammation or infection and would actively participate in tissue repair and functional recovery. They respond to soluble mediators such as metabolites or cytokines, which play central roles in the timing of the intrinsic cardiac stress response. During myocardial infarction two distinct phases of monocyte influx have been identified. Upon infarction, the heart modulates its chemokine expression profile that sequentially and actively recruits inflammatory monocytes, first, and healing monocytes, later. In the same way, a sudden switch from inflammatory macrophages (with microbicidal effectors toward anti-inflammatory macrophages occurs within the myocardium very shortly after infection with Trypanosoma cruzi, the causal agent of Chagas cardiomyopathy. While in sterile injury, healing response is necessary to stop tissue damage; during an intracellular infection, the anti-inflammatory milieu in infected hearts would promote microbial persistence. The balance of mononuclear phagocytic cells seems to be also dynamic in atherosclerosis influencing plaque initiation and fate. This review summarizes the participation of mononuclear phagocyte system in cardiovascular diseases, keeping in mind that the immune system evolved to promote the reestablishment of tissue homeostasis following infection/injury, and

  8. Are stomatal responses the key to understanding the cost of fungal disease resistance in plants?

    Science.gov (United States)

    Withers, Catherine M; Gay, Alan P; Mur, Luis A J

    2011-07-01

    Preventing disease in cereal crops is important for maintaining productivity and as the availability and efficacy of chemical control becomes reduced the emphasis on breeding for disease resistance increases. However, there is evidence that disease resistance may be physiologically costly to the plant and we ask if understanding stomatal responses to fungal attack is the key to minimising reductions in growth associated with disease resistance. Copyright © 2011 Society of Chemical Industry.

  9. The expanding role of fish models in understanding non-alcoholic fatty liver disease

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    Yoichi Asaoka

    2013-07-01

    Full Text Available Non-alcoholic fatty liver disease (NAFLD is a condition in which excessive fat accumulates in the liver of an individual who has not consumed excessive alcohol. Non-alcoholic steatohepatitis (NASH, a severe form of NAFLD, can progress to hepatic cirrhosis and/or hepatocellular carcinoma (HCC. NAFLD is considered to be a hepatic manifestation of metabolic syndrome, and its incidence has risen worldwide in lockstep with the increased global prevalence of obesity. Over the last decade, rodent studies have yielded an impressive list of molecules associated with NAFLD and NASH pathogenesis. However, the identification of currently unknown metabolic factors using mammalian model organisms is inefficient and expensive compared with studies using fish models such as zebrafish (Danio rerio and medaka (Oryzias latipes. Substantial advances in unraveling the molecular pathogenesis of NAFLD have recently been achieved through unbiased forward genetic screens using small fish models. Furthermore, these easily manipulated organisms have been used to great advantage to evaluate the therapeutic effectiveness of various chemical compounds for the treatment of NAFLD. In this Review, we summarize aspects of NAFLD (specifically focusing on NASH pathogenesis that have been previously revealed by rodent models, and discuss how small fish are increasingly being used to uncover factors that contribute to normal hepatic lipid metabolism. We describe the various types of fish models in use for this purpose, including those generated by mutation, transgenesis, or dietary or chemical treatment, and contrast them with rodent models. The use of small fish in identifying novel potential therapeutic agents for the treatment of NAFLD and NASH is also addressed.

  10. Contribution of β-phenethylamine, a component of chocolate and wine, to dopaminergic neurodegeneration: implications for the pathogenesis of Parkinson's disease.

    Science.gov (United States)

    Borah, Anupom; Paul, Rajib; Mazumder, Muhammed Khairujjaman; Bhattacharjee, Nivedita

    2013-10-01

    While the cause of dopaminergic neuronal cell death in Parkinson's disease (PD) is not yet understood, many endogenous molecules have been implicated in its pathogenesis. β-phenethylamine (β-PEA), a component of various food items including chocolate and wine, is an endogenous molecule produced from phenylalanine in the brain. It has been reported recently that long-term administration of β-PEA in rodents causes neurochemical and behavioral alterations similar to that produced by parkinsonian neurotoxins. The toxicity of β-PEA has been linked to the production of hydroxyl radical ((·)OH) and the generation of oxidative stress in dopaminergic areas of the brain, and this may be mediated by inhibition of mitochondrial complex-I. Another significant observation is that administration of β-PEA to rodents reduces striatal dopamine content and induces movement disorders similar to those of parkinsonian rodents. However, no reports are available on the extent of dopaminergic neuronal cell death after administration of β-PEA. Based on the literature, we set out to establish β-PEA as an endogenous molecule that potentially contributes to the progressive development of PD. The sequence of molecular events that could be responsible for dopaminergic neuronal cell death in PD by consumption of β-PEA-containing foods is proposed here. Thus, long-term over-consumption of food items containing β-PEA could be a neurological risk factor having significant pathological consequences.

  11. Alzheimer's Disease-like Early-phase Brain Pathogenesis: Self-curing Amelioration of Neurodegeneration from Pro-inflammatory 'Wounding' to Anti-inflammatory 'Healing'.

    Science.gov (United States)

    He, Jiang; Liao, Tao; Zhong, Guo-Xin; Zhang, Ji-Da; Chen, Yan-Ping; Wang, Qi; Zeng, Qing-Ping

    2017-01-01

    The etiological initiators of neuroinflammation remain inconclusive, and effective interventions to block neurodegeneration are unavailable. Surprisingly, we found collagen II-combined complete Freund's adjuvant (CC) that usually induces rheumatoid arthritis (RA) also drives Alzheimer's disease (AD)-like neurodegeneration in mice. CC not only upregulates the cerebral pro-inflammatory cytokines including tumor necrosis factor α (TNF-α) and interleukin 8 (IL-8), but also downregulates the cerebral interleukin 10 (IL-10), an anti-inflammatory cytokine, and tyrosine hydroxylase (TH), a ratelimiting enzyme for biosynthesis of the anti-inflammatory neurotransmitter dopamine. In contrast, electroacupuncture (EA) elevates TNF-α/IL-8 and declines IL-10/TH at first, but declines TNF-α/IL-8 and elevates IL-10/TH later. Upon impact on mitochondrial biogenesis, ubiquitination, and autophagy, EA firstly potentates but secondly attenuates CC-triggered signaling cascades leading to oxidation, nitrosylation, hypoxia, and angiogenesis. Eventually, EA compromises neurodegeneration by decreasing amyloid- β peptide (Aβ) and phosphorylated tau protein (p-tau), and also rectifies neuronal dysfunctions by increasing the cholinergic neurotransmitter acetylcholine (Ach) and its rate-limiting biosynthetic enzyme choline acetyltransferase (ChAT). Conclusively, EA initially aggravates and subsequently ameliorates CC-evoked AD-like earlyphase brain pathogenesis via conversion from pro-inflammatory microglia to anti-inflammatory microglia. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  12. Comparative study on the pathogenesis of the generated 9a5b Newcastle disease virus mutant isolate between chickens and waterfowl.

    Science.gov (United States)

    Anis, Z; Morita, T; Azuma, K; Ito, H; Ito, T; Shimada, A

    2013-07-01

    Lentogenic Newcastle disease viruses (NDVs), circulating among waterfowl, have the potential to become highly pathogenic by replication in chickens. The pathological studies that compare NDV infections in chickens and waterfowl are rare. The virulent 9a5b mutant NDV isolate was generated by passaging the lentogenic Goose/Alaska/415/91 NDV isolate in chickens. The pathogenesis of the virulent 9a5b mutant isolate is unknown in both chickens and waterfowl. In this study, the virulent 9a5b mutant NDV isolate was inoculated intranasally in 32-day-old specific pathogen-free white Leghorn chickens and Japanese commercial ducks. Unlike ducks, which remained clinically normal throughout the study, chickens had depression, gasping, oral discharges, and greenish-white soft feces. Gross and histologic lesion patterns as well as viral replication supported the differing clinical outcome. Ducks had slight inflammation mainly in respiratory and digestive tracts, whereas slight nonpurulent encephalitis, necrotizing pancreatitis, tubulointerstitial nephritis, and mild inflammation in respiratory and digestive tracts were detected in chickens. In agreement, interferon-beta (IFN-β)-immunopositive signals were more intense in lung tissue of ducks than that of chickens, and NDV replications were detected intensively in chicken tissues. These results suggest that the 9a5b mutant NDV isolate is more virulent in chickens, and slight histological lesions were induced in ducks even with virulent NDVs.

  13. Pathogenesis and biology.

    Science.gov (United States)

    Winkler, Frank

    2018-01-01

    Metastasis to the brain is an increasing complication of solid cancers. Fortunately, our understanding of its pathogenesis has greatly increased in the last decade, with crucial insights into the molecular and cellular determinants of successful brain colonization; some aspects remain less well understood. The latter include the exact features of brain metastasis-initiating cancer cells, and a potential premetastatic niche. It is clear that a brain-arrested cancer cell has to master a sequence of steps to eventually grow to a clinically relevant brain metastasis. Various brain-specific cell types and molecular niches promote or hinder brain colonization in a dynamic and reciprocal manner. After mandatory extravasation and colonization of a brain-specific perivascular niche, the cancer cell can stay dormant, or further grow by dynamic interactions with cerebral blood vessels. In addition, the activation of certain molecular pathways on site of the cancer cell which are related to growth, motility, survival, and adaptation to the brain environment appears also important, given their characteristic modification in brain metastases of patients. A deeper understanding of the most vulnerable steps of the brain metastatic cascade may foster the development of novel preventive approaches, and that of core biologic mechanisms for macrometastatic growth and persistence will help to develop better therapeutics. Copyright © 2018 Elsevier B.V. All rights reserved.

  14. A new humanized ataxin-3 knock-in mouse model combines the genetic features, pathogenesis of neurons and glia and late disease onset of SCA3/MJD.

    Science.gov (United States)

    Switonski, Pawel M; Szlachcic, Wojciech J; Krzyzosiak, Wlodzimierz J; Figiel, Maciej

    2015-01-01

    Spinocerebellar ataxia type 3 (SCA3/MJD) is a neurodegenerative disease triggered by the expansion of CAG repeats in the ATXN3 gene. Here, we report the generation of the first humanized ataxin-3 knock-in mouse model (Ki91), which provides insights into the neuronal and glial pathology of SCA3/MJD. First, mutant ataxin-3 accumulated in cell nuclei across the Ki91 brain, showing diffused immunostaining and forming intranuclear inclusions. The humanized allele revealed expansion and contraction of CAG repeats in intergenerational transmissions. CAG mutation also exhibited age-dependent tissue-specific expansion, which was most prominent in the cerebellum, pons and testes of Ki91 animals. Moreover, Ki91 mice displayed neuroinflammatory processes, showing astrogliosis in the cerebellar white matter and the substantia nigra that paralleled the transcriptional deregulation of Serpina3n, a molecular sign of neurodegeneration and brain damage. Simultaneously, the cerebellar Purkinje cells in Ki91 mice showed neurodegeneration, a pronounced decrease in Calbindin D-28k immunoreactivity and a mild decrease in cell number, thereby modeling the degeneration of the cerebellum observed in SCA3. Moreover, these molecular and cellular neuropathologies were accompanied by late behavioral deficits in motor coordination observed in rotarod and static rod tests in heterozygous Ki91 animals. In summary, we created an ataxin-3 knock-in mouse model that combines the molecular and behavioral disease phenotypes with the genetic features of SCA3. This model will be very useful for studying the pathogenesis and responses to therapy of SCA3/MJD and other polyQ disorders. Copyright © 2015. Published by Elsevier Inc.

  15. Persistent perineal sinus. Incidence, pathogenesis, risk factors, and management

    International Nuclear Information System (INIS)

    Lohsiriwat, V.

    2009-01-01

    This review discusses the incidence, pathogenesis, risk factors, diagnosis, and therapeutic options for persistent perineal sinus (PPS), defined as a perineal wound that remains unhealed more than 6 months after surgery. The incidence of PPS after surgery for inflammatory bowel disease (IBD) ranges from 3% to 70% and after abdominoperineal resection (APR) for Low rectal cancer, it can be up to 30%. These unhealed wounds are frequently related to perioperative pelvic or perineal sepsis. Crohn's disease (CD) and neoadjuvant radiation therapy are also important risk factors. The management of PPS is based on an understanding of pathogenesis and clinical grounds. The advantages and disadvantages of the current therapeutic approaches, including the topical administration of various drugs, vacuum-assisted closure, and perineal reconstruction with a muscle flap or a myocutaneous flap are also discussed. (author)

  16. MicroRNAs in the Cholangiopathies: Pathogenesis, Diagnosis, and Treatment

    Directory of Open Access Journals (Sweden)

    Maria Jose Lorenzo Pisarello

    2015-08-01

    Full Text Available The cholangiopathies are a group of liver diseases resulting from different etiologies but with the cholangiocyte as the primary target. As a group, the cholangiopathies result in significant morbidity and mortality and represent one of the main indications for liver transplant in both children and adults. Contributing to this situation is the absence of a thorough understanding of their pathogenesis and a lack of adequate diagnostic and prognostic biomarkers. MicroRNAs are small non-coding RNAs that modify gene expression post-transcriptionally. They have been implicated in the pathogenesis of many diseases, including the cholangiopathies. Thus, in this review we provide an overview of the literature on miRNAs in the cholangiopathies and discuss future research directions.

  17. A study of various histopathological features and their relevance in pathogenesis of psoriasis

    Directory of Open Access Journals (Sweden)

    Nikhil Moorchung

    2013-01-01

    Full Text Available Background: The pathogenesis of psoriasis is still to be fully unraveled. The immunological theory with T cells at the centre of attraction and peripherally acting cytokines are the present favourites among aetiopathological factors. Histopathology of the skin lesions offers a good study model to understand the pathogenesis of this complex disease. Aims: To study the various histopathological parameters of psoriatic lesions, and to establish their correlation with the pathogenesis of the disorder. Materials and Methods: Eighty eight consecutive histopathologically proven cases of psoriasis were included in the study. Eight common histopathological parameters of psoriasis present in these biopsies were assessed and graded. We then statistically analyzed the relationship of the factors with one another and attempted to establish a better understanding of the pathogenesis of disease. Results: Significant correlations were found between degree of epidermal hyperplasia and inflammatory infiltrate, grade of inflammation and pustules of Kogoj, inflammatory infiltrate and grade of capillary proliferation as also between epidermal hyperplasia and the presence of parakeratosis. Conclusion: The study suggests that the immunopathogenesis of psoriasis is predominantly based on the inflammatory response. This is in consonance with other studies which have suggested that psoriasis is primarily a T lymphocyte based disease. Several treatment modalities are now based on this concept and it is hoped that the future treatment modalities will focus on the central role of inflammatory cells in the pathogenesis of this enigmatic disease.

  18. Vitamin D, Phosphate and Fibroblast Growth Factor 23: A role in the pathogenesis and management of Chronic Kidney Disease and Chronic Kidney Disease Mineral and Bone Disorder

    OpenAIRE

    Damasiewicz, Matthew John

    2017-01-01

    Chronic kidney disease (CKD) is defined by the presence of proteinuria or decreased kidney function, with a prevalence of 10-15% in the adult population. CKD can progress to end-stage kidney disease (ESKD) and is associated with progressive abnormalities of bone and mineral metabolism, defined as CKD mineral and bone disorder (CKD-MBD). The use of vitamin D in CKD, the optimal level for initiating treatment and the use of current and novel biomarkers in the management of ...

  19. Understanding healthful eating from a salutogenic perspective

    NARCIS (Netherlands)

    Swan, E.C.

    2016-01-01

    The biomedical model of health orients towards pathogenesis, the study of disease origins and causes. The starting point is to understand determinants of ill-health, and health is defined in this model as the absence of disease. When applied to nutrition research, the underlying assumption is that

  20. Understanding healthful eating from a salutogenic perspective

    NARCIS (Netherlands)

    Swan, E.C.

    2016-01-01

    The biomedical model of health orients towards pathogenesis, the study of disease origins and causes. The starting point is to understand determinants of ill-health, and health is defined in this model as the absence of disease. When applied to nutrition research, the underlying assumption is

  1. Crohn's disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn's disease.

    Science.gov (United States)

    Brand, S

    2009-08-01

    Traditionally, Crohn's disease has been associated with a Th1 cytokine profile, while Th2 cytokines are modulators of ulcerative colitis. This concept has been challenged by the description of tolerising regulatory T cells (Treg) and by proinflammatory Th17 cells, a novel T cell population characterised by the master transcription factor RORgammat, the surface markers IL23R and CCR6, and by production of the proinflammatory cytokines IL17A, IL17F, IL21, IL22 and IL26, and the chemokine CCL20. Th17 cells differentiate under the influence of IL1beta, IL6, IL21 and IL23. Recent studies indicate that TGFbeta is essential not only for the development of murine Th17 cells but also for differentiation of human Th17 cells. TGFbeta reciprocally regulates the differentiation of inflammatory Th17 cells and suppressive Treg subsets, with the concomitant presence of proinflammatory cytokines favouring Th17 cell differentiation. Several studies demonstrated an important role of Th17 cells in intestinal inflammation, particularly in Crohn's disease. Genome-wide association studies indicate that IL23R and five additional genes involved in Th17 differentiation (IL12B, JAK2, STAT3, CCR6 and TNFSF15) are associated with susceptibility to Crohn's disease and partly also to ulcerative colitis. Taken together, both Th1 and Th17 cells are important mediators of inflammation in Crohn's disease, although activities previously ascribed to IL12 may be mediated by IL23. Anti-IL12/IL23p40 antibody therapy, which targets both Th1 and Th17 cells, is effective in Crohn's disease. However, the complex relationship between Th1 and Th17 cells has not been completely analysed. This will be of great importance to delineate the specific contributions of these cells to Crohn's disease and other autoimmune diseases.

  2. Understanding the Effects of Host Evolution and Skin Bacteria Composition on Disease Vector Choices

    Science.gov (United States)

    2016-04-14

    Distribution Unlimited UU UU UU UU 14-04-2016 1-Sep-2014 31-Dec-2015 Final Report: Understanding the effects of host evolution and skin bacteria...reviewed journals: Final Report: Understanding the effects of host evolution and skin bacteria composition on disease vector choices Report Title Here...SECURITY CLASSIFICATION OF: Here we sought to understand how host biology influences the composition of skin microbes, how skin microbes influence

  3. Implications of genetic variability of Trypanosoma cruzi for the pathogenesis of Chagas disease Implicações da variabilidade genética do Trypanosoma cruzi na patogênese da doença de Chagas

    Directory of Open Access Journals (Sweden)

    Fernanda da Silva Manoel-Caetano

    2007-10-01

    Full Text Available Trypanosoma cruzi, the etiological agent of Chagas disease, presents a high degree of intraspecific genetic variability, with possible implications for the clinical forms of the disease, like the development of cardiopathy, megaesophagus, and megacolon, alone or in combination. This tissue tropism involved in the pathogenesis of Chagas disease has still not been totally elucidated. Thus, the current review approaches key aspects of T. cruzi genetic diversity, the clinical forms of Chagas disease, and the infection of the host cell by the parasite and the immune response. Other aspects discussed here include the release of immunosuppressive factors by the parasite, acting in the host's immune response pathways; host cell apoptosis inhibition; the pathogenesis of chagasic megaesophagus, which can be related to host-parasite interaction; and finally the association between megaesophagus and increased risk for the development of squamous-cell esophageal carcinoma. However, despite great advances in the understanding of this disease, it is still not possible to establish the true relationship between the parasite's genetic variability and the clinical form of Chagas disease.O Trypanosoma cruzi, agente etiológico da doença de Chagas, apresenta elevado grau de variabilidade genética intra-específica, com possíveis implicações na forma clínica da doença, como o desenvolvimento de cardiopatia, do megaesôfago e do megacólon de forma isolada ou em associação. Este tropismo tecidual envolvido na patogênese da doença não está totalmente esclarecido. Assim, nesta revisão são abordados alguns aspectos referentes à diversidade genética dos parasitas isolados, às formas clínicas da doença de Chagas, ao processo de infecção do parasita na célula hospedeira e resposta imune. Outros aspectos também são enfocados, como os fatores imunossupressivos liberados pelo parasita que atuam na regulação das respostas imunes, a inibição da

  4. Viral induced oxidative and inflammatory response in Alzheimer's disease pathogenesis with identification of potential drug candidates: A systematic review using systems biology approach.

    Science.gov (United States)

    Talwar, Puneet; Gupta, Renu; Kushwaha, Suman; Agarwal, Rachna; Saso, Luciano; Kukreti, Shrikant; Kukreti, Ritushree

    2018-04-19

    Alzheimer's disease (AD) is genetically complex with multifactorial etiology. Here, we aim to identify the potential viral pathogens leading to aberrant inflammatory and oxidative stress response in AD along with potential drug candidates using systems biology approach. We retrieved protein interactions of amyloid precursor protein (APP) and tau protein (MAPT) from NCBI and genes for oxidative stress from NetAge, for inflammation from NetAge and InnateDB databases. Genes implicated in aging were retrieved from GenAge database and two GEO expression datasets. These genes were individually used to create protein-protein interaction network using STRING database (score≥0.7). The interactions of candidate genes with known viruses were mapped using virhostnet v2.0 database. Drug molecules targeting candidate genes were retrieved using the Drug-Gene Interaction Database (DGIdb). Data mining resulted in 2095 APP, 116 MAPT, 214 oxidative stress, 1269 inflammatory genes. After STRING PPIN analysis, 404 APP, 109 MAPT, 204 oxidative stress and 1014 inflammation related high confidence proteins were identified. The overlap among all datasets yielded eight common markers (AKT1, GSK3B, APP, APOE, EGFR, PIN1, CASP8 and SNCA). These genes showed association with hepatitis C virus (HCV), Epstein-Barr virus (EBV), human herpes virus 8 and Human papillomavirus (HPV). Further, screening of drugs targeting candidate genes, and possessing anti-inflammatory property, antiviral activity along with suggested role in AD pathophysiology yielded 12 potential drug candidates. Our study demonstrated the role of viral etiology in AD pathogenesis by elucidating interaction of oxidative stress and inflammation causing candidate genes with common viruses along with the identification of potential AD drug candidates. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  5. Bony Maturity of the Tibial Tuberosity With Regard to Age and Sex and Its Relationship to Pathogenesis of Osgood-Schlatter Disease: An Ultrasonographic Study.

    Science.gov (United States)

    Kaneuchi, Yoichi; Otoshi, Kenichi; Hakozaki, Michiyuki; Sekiguchi, Miho; Watanabe, Kazuyuki; Igari, Takahiro; Konno, Shinichi

    2018-01-01

    Although tensile force on an immature tibial tuberosity is considered the main cause of Osgood-Schlatter disease (OSD), the relationship between bony maturity and the pathogenesis of OSD remains obscure. To survey the bone maturation process of the tibial tuberosity by age and sex and clarify its relationship to OSD. Cross-sectional study; Level of evidence, 3. A total of 731 Japanese basketball players aged 6 to 14 years were enrolled in this study. Ultrasonographic examination was performed in all participants (1462 knees) to evaluate the bony maturity of the tibial tuberosity by use of the Ehrenborg classification. The age- and sex-specific prevalence of each stage was investigated, and the prevalence of symptomatic OSD and its relationship with bony maturity were also assessed. The process of bone maturation occurred 1 to 2 years earlier in female participants compared with male participants. Among female participants, 59.2% were already at the epiphyseal stage (stage E) by 10 years of age, and 47.4% were skeletally mature by 14 years. Among male participants, conversely, only 8.0% were at stage E by 10 years of age, and only 13.8% were skeletally mature by 14 years. The overall prevalence of symptomatic OSD was 6.8% (males, 6.4%; females, 7.2%), and the onset was 1 year earlier in the female participants. The prevalence of symptomatic OSD tended to increase with age and bony maturity, significantly increasing from the cartilaginous stage (stage C) to the apophyseal stage (stage A) (odds ratio, 9.48) and from stage A to stage E (odds ratio, 2.22). The tibial tuberosity matures earlier in female participants. The risk of OSD is greater in stage A than stage C and in stage E than stage A. The risk of OSD increases with age in males but not in females.

  6. Complement and alcoholic liver disease: role of C1q in the pathogenesis of ethanol-induced liver injury in mice.

    Science.gov (United States)

    Cohen, Jessica I; Roychowdhury, Sanjoy; McMullen, Megan R; Stavitsky, Abram B; Nagy, Laura E

    2010-08-01

    Complement is involved in the development of alcoholic liver disease in mice; however, the mechanisms for complement activation during ethanol exposure have not been identified. C1q, the recognition subunit of the first complement component, binds to apoptotic cells, thereby activating the classical complement pathway. Because ethanol exposure increases hepatocellular apoptosis, we hypothesized that ethanol-induced apoptosis would lead to activation of complement via the classical pathway. Wild-type and C1qa-/- mice were allowed free access to ethanol-containing diets or pair-fed control diets for 4 or 25 days. Ethanol feeding for 4 days increased apoptosis of Kupffer cells in both wild-type and C1qa-/- mice. Ethanol-induced deposition of C1q and C3b/iC3b/C3c was colocalized with apoptotic Kupffer cells in wild-type, but not C1qa-/-, mice. Furthermore, ethanol-induced increases in tumor necrosis factor-alpha and interleukin-6 expression at this early time point were suppressed in C1q-deficient mice. Chronic ethanol feeding (25 days) increased steatosis, hepatocyte apoptosis, and activity of serum alanine and aspartate aminotransferases in wild-type mice. These markers of hepatocyte injury were attenuated in C1qa-/- mice. In contrast, chronic ethanol (25 days)-induced increases in cytochrome P450 2E1 expression and oxidative stress did not differ between wild-type and C1qa-/- mice. For the first time, these data indicate that ethanol activates the classical complement pathway via C1q binding to apoptotic cells in the liver and that C1q contributes to the pathogenesis of ethanol-induced liver injury. Copyright (c) 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

  7. [The perfection of biology and discrepancies of humoral regulation non-surmounted in phylogenesis. The unified algorithm of pathogenesis of metabolic "pandemics" as diseases of civilization].

    Science.gov (United States)

    Titov, V N

    2014-08-01

    The striving to biological perfection became apparent under becoming of each out of seven biological functions at the consequent stages of phylogenesis: at cellular autocrine level; in paracrin regulated functional cenosis of cells, organs; at the organism level. However, regulative interaction simultaneously on all levels in vivo results in functional incoordination. There are no reasons to name them contradictions. They are targeted to development of organism; they are formed on different levels of regulation and sometimes are not comparable in full measure; incoordinations of regulation are never outdone. The striving of biology to perfection resulted in incoordinations becoming less apparent in conditions of physiological level of physical chemical parameters and concentrations of biochemical analytes staying within strict standard limits. The physiological values "are backed up" from below by realization of biological function of homeostasis. The upper level "is limited" by biological function of endoecology--leanliness of intercellular medium. The incoordinations of humoral and nervous regulation are manifested under impact of unfavorable factors of environment on organism. At that, regulatory incoordinations developed at distantly spaced degrees of phylogenesis came out as pathogenic factors of "metabolic pandemics"--civilization diseases. Ifdisease ofn oninfectious etiology is propagated in population with rate of 5 - 7% its pathogenesis is based on disorder ofb iologicalf unctions and biological reactions, meaning those impacts of environment that Homo sapiens didn't learn to match in phylogenesis. The strict normalization of biological functions and biological reactions can be the only pathogenetically and effective prevention and treatment of this pathology. The application ofp harmaceuticals is the foundation ofs ymptomatic therapy only.

  8. Pathogenesis of Mucormycosis

    Science.gov (United States)

    Spellberg, Brad; Walsh, Thomas J.; Kontoyiannis, Dimitrios P.

    2012-01-01

    Mucormycosis is a life-threatening infection that occurs in patients who are immunocompromised because of diabetic ketoacidosis, neutropenia, organ transplantation, and/or increased serum levels of available iron. Because of the increasing prevalence of diabetes mellitus, cancer, and organ transplantation, the number of patients at risk for this deadly infection is increasing. Despite aggressive therapy, which includes disfiguring surgical debridement and frequently adjunctive toxic antifungal therapy, the overall mortality rate is high. New strategies to prevent and treat mucormycosis are urgently needed. Understanding the pathogenesis of mucormycosis and the host response to invading hyphae ultimately will provide targets for novel therapeutic interventions. In this supplement, we review the current knowledge about the virulence traits used by the most common etiologic agent of mucormycosis, Rhizopus oryzae. Because patients with elevated serum levels of available iron are uniquely susceptible to mucormycosis and these infections are highly angioinvasive, emphasis is placed on the ability of the organism to acquire iron from the host and on its interactions with endothelial cells lining blood vessels. Several promising therapeutic strategies in preclinical stages are identified. PMID:22247441

  9. Viral pathogenesis in diagrams

    National Research Council Canada - National Science Library

    Tremblay, Michel; Berthiaume, Laurent; Ackermann, Hans-Wolfgang

    2001-01-01

    .... The 268 diagrams in Viral Pathogenesis in Diagrams were selected from over 800 diagrams of English and French virological literature, including one derived from a famous drawing by Leonardo da Vinci...

  10. The role of radiology in the evolution of the understanding of articular disease.

    Science.gov (United States)

    Huang, Mingqian; Schweitzer, Mark E

    2014-11-01

    Both the clinical practice of radiology and the journal Radiology have had an enormous effect on our understanding of articular disease. Early descriptions of osteoarthritis (OA) appeared in Radiology. More recently, advanced physiologic magnetic resonance (MR) techniques have furthered our understanding of the early prestructural changes in patients with OA. Sodium imaging, delayed gadolinium-enhanced MR imaging of cartilage, and spin-lattice relaxation in the rotating frame (or T1ρ) sequences have advanced understanding of the pathophysiology and pathoanatomy of OA. Many pioneering articles on rheumatoid arthritis (RA) also have been published in Radiology. In the intervening decades, our understanding of the natural history of RA has been altered by these articles. Many of the first descriptions of crystalline arthropathies, including gout, calcium pyrophosphate deposition, and hydroxyapatite deposition disease, appeared in Radiology.

  11. Integrating Survey and Molecular Approaches to Better Understand Wildlife Disease Ecology

    Science.gov (United States)

    Cowled, Brendan D.; Ward, Michael P.; Laffan, Shawn W.; Galea, Francesca; Garner, M. Graeme; MacDonald, Anna J.; Marsh, Ian; Muellner, Petra; Negus, Katherine; Quasim, Sumaiya; Woolnough, Andrew P.; Sarre, Stephen D.

    2012-01-01

    Infectious wildlife diseases have enormous global impacts, leading to human pandemics, global biodiversity declines and socio-economic hardship. Understanding how infection persists and is transmitted in wildlife is critical for managing diseases, but our understanding is limited. Our study aim was to better understand how infectious disease persists in wildlife populations by integrating genetics, ecology and epidemiology approaches. Specifically, we aimed to determine whether environmental or host factors were stronger drivers of Salmonella persistence or transmission within a remote and isolated wild pig (Sus scrofa) population. We determined the Salmonella infection status of wild pigs. Salmonella isolates were genotyped and a range of data was collected on putative risk factors for Salmonella transmission. We a priori identified several plausible biological hypotheses for Salmonella prevalence (cross sectional study design) versus transmission (molecular case series study design) and fit the data to these models. There were 543 wild pig Salmonella observations, sampled at 93 unique locations. Salmonella prevalence was 41% (95% confidence interval [CI]: 37–45%). The median Salmonella DICE coefficient (or Salmonella genetic similarity) was 52% (interquartile range [IQR]: 42–62%). Using the traditional cross sectional prevalence study design, the only supported model was based on the hypothesis that abundance of available ecological resources determines Salmonella prevalence in wild pigs. In the molecular study design, spatial proximity and herd membership as well as some individual risk factors (sex, condition score and relative density) determined transmission between pigs. Traditional cross sectional surveys and molecular epidemiological approaches are complementary and together can enhance understanding of disease ecology: abundance of ecological resources critical for wildlife influences Salmonella prevalence, whereas Salmonella transmission is driven by

  12. Integrating survey and molecular approaches to better understand wildlife disease ecology.

    Directory of Open Access Journals (Sweden)

    Brendan D Cowled

    Full Text Available Infectious wildlife diseases have enormous global impacts, leading to human pandemics, global biodiversity declines and socio-economic hardship. Understanding how infection persists and is transmitted in wildlife is critical for managing diseases, but our understanding is limited. Our study aim was to better understand how infectious disease persists in wildlife populations by integrating genetics, ecology and epidemiology approaches. Specifically, we aimed to determine whether environmental or host factors were stronger drivers of Salmonella persistence or transmission within a remote and isolated wild pig (Sus scrofa population. We determined the Salmonella infection status of wild pigs. Salmonella isolates were genotyped and a range of data was collected on putative risk factors for Salmonella transmission. We a priori identified several plausible biological hypotheses for Salmonella prevalence (cross sectional study design versus transmission (molecular case series study design and fit the data to these models. There were 543 wild pig Salmonella observations, sampled at 93 unique locations. Salmonella prevalence was 41% (95% confidence interval [CI]: 37-45%. The median Salmonella DICE coefficient (or Salmonella genetic similarity was 52% (interquartile range [IQR]: 42-62%. Using the traditional cross sectional prevalence study design, the only supported model was based on the hypothesis that abundance of available ecological resources determines Salmonella prevalence in wild pigs. In the molecular study design, spatial proximity and herd membership as well as some individual risk factors (sex, condition score and relative density determined transmission between pigs. Traditional cross sectional surveys and molecular epidemiological approaches are complementary and together can enhance understanding of disease ecology: abundance of ecological resources critical for wildlife influences Salmonella prevalence, whereas Salmonella transmission is

  13. "Social Crimes": Understandings of HIV/AIDS as a Disease Among Grandparents Raising Grandchildren in Vietnam.

    Science.gov (United States)

    Harris, Lesley M; Boggiano, Victoria; Nguyen, Duy Thang

    2016-10-01

    Grandparent caregivers are vital to the survival of grandchildren who are orphaned and who have been affected by HIV/AIDS. The purpose of this qualitative study was to understand the meaning of HIV as a disease among grandparents raising grandchildren orphaned by HIV/AIDS in northern Vietnam and to gain insight into how this understanding affected grandparents' relationships and health-seeking decisions. Results indicated that grandparents had knowledge deficits about the biomedical aspects of the disease and often hid their grandchildren's HIV status or preferred not to seek testing. Effective interventions must address stigma reduction, family relationships, and access to health care to increase testing and treatment of grandchildren.

  14. How lay people understand and make sense of personalized disease risk information

    OpenAIRE

    Damman, Olga C.; Bogaerts, Nina M. M.; van den Haak, Maaike J.; Timmermans, Danielle R. M.

    2017-01-01

    Abstract Background Disease risk calculators are increasingly web‐based, but previous studies have shown that risk information often poses problems for lay users. Objective To examine how lay people understand the result derived from an online cardiometabolic risk calculator. Design A qualitative study was performed, using the risk calculator in the Du