WorldWideScience

Sample records for pathophysiology importantly targeting

  1. The Sphenopalatine Ganglion: Anatomy, Pathophysiology, and Therapeutic Targeting in Headache.

    Science.gov (United States)

    Robbins, Matthew S; Robertson, Carrie E; Kaplan, Eugene; Ailani, Jessica; Charleston, Larry; Kuruvilla, Deena; Blumenfeld, Andrew; Berliner, Randall; Rosen, Noah L; Duarte, Robert; Vidwan, Jaskiran; Halker, Rashmi B; Gill, Nicole; Ashkenazi, Avi

    2016-02-01

    The sphenopalatine ganglion (SPG) has attracted the interest of practitioners treating head and face pain for over a century because of its anatomical connections and role in the trigemino-autonomic reflex. In this review, we discuss the anatomy of the SPG, as well as what is known about its role in the pathophysiology of headache disorders, including cluster headache and migraine. We then address various therapies that target the SPG, including intranasal medication delivery, new SPG blocking catheter devices, neurostimulation, chemical neurolysis, and ablation procedures. © 2015 American Headache Society.

  2. Targeting autophagy in obesity: from pathophysiology to management.

    Science.gov (United States)

    Zhang, Yingmei; Sowers, James R; Ren, Jun

    2018-04-23

    Obesity poses a severe threat to human health, including the increased prevalence of hypertension, insulin resistance, diabetes mellitus, cancer, inflammation, sleep apnoea and other chronic diseases. Current therapies focus mainly on suppressing caloric intake, but the efficacy of this approach remains poor. A better understanding of the pathophysiology of obesity will be essential for the management of obesity and its complications. Knowledge gained over the past three decades regarding the aetiological mechanisms underpinning obesity has provided a framework that emphasizes energy imbalance and neurohormonal dysregulation, which are tightly regulated by autophagy. Accordingly, there is an emerging interest in the role of autophagy, a conserved homeostatic process for cellular quality control through the disposal and recycling of cellular components, in the maintenance of cellular homeostasis and organ function by selectively ridding cells of potentially toxic proteins, lipids and organelles. Indeed, defects in autophagy homeostasis are implicated in metabolic disorders, including obesity, insulin resistance, diabetes mellitus and atherosclerosis. In this Review, the alterations in autophagy that occur in response to nutrient stress, and how these changes alter the course of obesogenesis and obesity-related complications, are discussed. The potential of pharmacological modulation of autophagy for the management of obesity is also addressed.

  3. Cognitive dysfunction in depression - pathophysiology and novel targets

    DEFF Research Database (Denmark)

    Carvalho, Andre F; Miskowiak, Kamilla Woznica; Hyphantis, Thomas N

    2014-01-01

    , inflammation (e.g., enhanced production of pro-inflammatory cytokines), mitochondrial dysfunction, increased apoptosis as well as a diminished neurotrophic support. Several promising neurotherapeutic targets were identified such as minocycline, statins, anti-inflammatory compounds, N-acetylcysteine, omega-3...... poliunsaturated fatty acids, erythropoietin, thiazolidinediones, glucagon-like peptide-1 analogues, S-adenosyl-l-methionine (SAMe), cocoa flavonols, creatine monohydrate and lithium. Erythropoietin and SAMe had pro-cognitive effects in randomized controlled trials (RCT) involving MDD patients. Despite having...

  4. Cognitive dysfunction in depression - pathophysiology and novel targets.

    Science.gov (United States)

    Carvalho, Andre F; Miskowiak, Kamilla K; Hyphantis, Thomas N; Kohler, Cristiano A; Alves, Gilberto S; Bortolato, Beatrice; G Sales, Paulo Marcelo; Machado-Vieira, Rodrigo; Berk, Michael; McIntyre, Roger S

    2014-01-01

    Major depressive disorder (MDD) is associated with cognitive dysfunction encompassing several domains, including memory, executive function, processing speed and attention. Cognitive deficits persist in a significant proportion of patients even in remission, compromising psychosocial functioning and workforce performance. While monoaminergic antidepressants may improve cognitive performance in MDD, most antidepressants have limited clinical efficacy. The overarching aims of this review were: (1) to synthesize extant literature on putative biological pathways related to cognitive dysfunction in MDD and (2) to review novel neurotherapeutic targets for cognitive enhancement in MDD. We found that reciprocal and overlapping biological pathways may contribute to cognitive dysfunction in MDD, including an hyperactive hypothalamic-pituitary-adrenal axis, an increase in oxidative and nitrosative stress, inflammation (e.g., enhanced production of pro-inflammatory cytokines), mitochondrial dysfunction, increased apoptosis as well as a diminished neurotrophic support. Several promising neurotherapeutic targets were identified such as minocycline, statins, anti-inflammatory compounds, N-acetylcysteine, omega-3 poliunsaturated fatty acids, erythropoietin, thiazolidinediones, glucagon-like peptide-1 analogues, S-adenosyl-l-methionine (SAMe), cocoa flavonols, creatine monohydrate and lithium. Erythropoietin and SAMe had pro-cognitive effects in randomized controlled trials (RCT) involving MDD patients. Despite having preclinical and/or preliminary evidences from trials suggesting possible efficacy as novel cognitive enhancing agents for MDD, no RCT to date was performed for most of the other therapeutic targets reviewed herein. In conclusion, multiple biological pathways are involved in cognitive dysfunction in MDD. RCTs testing genuinely novel pro-cognitive compounds for MDD are warranted.

  5. The importance of obstructive sleep apnoea and hypopnea pathophysiology for customized therapy.

    Science.gov (United States)

    Bosi, Marcello; De Vito, Andrea; Gobbi, Riccardo; Poletti, Venerino; Vicini, Claudio

    2017-03-01

    The objective of this study is to highlight the importance of anatomical and not-anatomical factors' identification for customized therapy in OSAHS patients. The data sources are: MEDLINE, The Cochrane Library and EMBASE. A systematic review was performed to identify studies that analyze the role of multiple interacting factors involved in the OSAHS pathophysiology. 85 out of 1242 abstracts were selected for full-text review. A variable combinations pathophysiological factors contribute to realize differentiated OSAHS phenotypes: a small pharyngeal airway with a low resistance to collapse (increased critical closing pressure), an inadequate responses of pharyngeal dilator muscles (wakefulness drive to breathe), an unstable ventilator responsiveness to hypercapnia (high loop gain), and an increased propensity to wake related to upper airway obstruction (low arousal threshold). Identifying if the anatomical or not-anatomical factors are predominant in each OSAHS patient represents the current challenge in clinical practice, moreover for the treatment decision-making. In the future, if a reliable and accurate pathophysiological pattern for each OSAHS patient can be identified, a customized therapy will be feasible, with a significant improvement of surgical success in sleep surgery and a better understanding of surgical failure.

  6. Molecular Targets of Antihypertensive Peptides: Understanding the Mechanisms of Action Based on the Pathophysiology of Hypertension

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    Kaustav Majumder

    2014-12-01

    Full Text Available There is growing interest in using functional foods or nutraceuticals for the prevention and treatment of hypertension or high blood pressure. Although numerous preventive and therapeutic pharmacological interventions are available on the market, unfortunately, many patients still suffer from poorly controlled hypertension. Furthermore, most pharmacological drugs, such as inhibitors of angiotensin-I converting enzyme (ACE, are often associated with significant adverse effects. Many bioactive food compounds have been characterized over the past decades that may contribute to the management of hypertension; for example, bioactive peptides derived from various food proteins with antihypertensive properties have gained a great deal of attention. Some of these peptides have exhibited potent in vivo antihypertensive activity in both animal models and human clinical trials. This review provides an overview about the complex pathophysiology of hypertension and demonstrates the potential roles of food derived bioactive peptides as viable interventions targeting specific pathways involved in this disease process. This review offers a comprehensive guide for understanding and utilizing the molecular mechanisms of antihypertensive actions of food protein derived peptides.

  7. B-cell activating factor in the pathophysiology of multiple myeloma: a target for therapy?

    International Nuclear Information System (INIS)

    Hengeveld, P J; Kersten, M J

    2015-01-01

    Multiple myeloma (MM) is a currently incurable malignancy of plasma cells. Malignant myeloma cells (MMCs) are heavily dependent upon the bone marrow (BM) microenvironment for their survival. One component of this tumor microenvironment, B-Cell Activating Factor (BAFF), has been implicated as a key player in this interaction. This review discusses the role of BAFF in the pathophysiology of MM, and the potential of BAFF-inhibitory therapy for the treatment of MM. Multiple studies have shown that BAFF functions as a survival factor for MMCs. Furthermore, MMCs express several BAFF-binding receptors. Of these, only Transmembrane Activator and CAML Interactor (TACI) correlates with the MMC's capability to ligate BAFF. Additionally, the level of expression of TACI correlates with the level of the MMC's BM dependency. Ligation of BAFF receptors on MMCs causes activation of the Nuclear Factor of κ-B (NF-κB) pathway, a crucial pathway for the pathogenesis of many B-cell malignancies. Serum BAFF levels are significantly elevated in MM patients when compared to healthy controls, and correlate inversely with overall survival. BAFF signaling is thus an interesting target for the treatment of MM. Several BAFF-inhibitory drugs are currently under evaluation for the treatment of MM. These include BAFF-monoclonal antibodies (tabalumab) and antibody-drug conjugates (GSK2857916)

  8. Role of anxiety in the pathophysiology of irritable bowel syndrome: importance of the amygdala

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    Brent Myers

    2009-06-01

    Full Text Available A common characteristic of irritable bowel syndrome (IBS is that symptoms, including abdominal pain and abnormal bowel habits, are often triggered or exacerbated during periods of stress and anxiety. However, the impact of anxiety and affective disorders on the gastrointestinal (GI tract is poorly understood and may in part explain the lack of effective therapeutic approaches to treat IBS. The amygdala is an important structure for regulating anxiety with the central nucleus of the amygdala (CeA facilitating the activation of the hypothalamic-pituitary-adrenal (HPA axis and the autonomic nervous system in response to stress. Moreover, chronic stress enhances function of the amygdala and promotes neural plasticity throughout the amygdaloid complex. This review outlines the latest findings obtained from human studies and animal models related to the role of the emotional brain in the regulation of enteric function, specifically how increasing the gain of the amygdala to induce anxiety-like behavior using corticosterone (CORT or chronic stress increases responsiveness to both visceral and somatic stimuli in rodents. A focus of the review is the relative importance of mineralocorticoid receptor (MR and glucocorticoid receptor (GR-mediated mechanisms within the amygdala in the regulation of anxiety and nociceptive behaviors that are characteristic features of IBS. This review also discusses several outstanding questions important for future research on the role of the amygdala in the generation of abnormal GI function that may lead to potential targets for new therapies to treat functional bowel disorders such as IBS.

  9. The Pathophysiology of Insomnia

    Science.gov (United States)

    Levenson, Jessica C.; Kay, Daniel B.

    2015-01-01

    Insomnia disorder is characterized by chronic dissatisfaction with sleep quantity or quality that is associated with difficulty falling asleep, frequent nighttime awakenings with difficulty returning to sleep, and/or awakening earlier in the morning than desired. Although progress has been made in our understanding of the nature, etiology, and pathophysiology of insomnia, there is still no universally accepted model. Greater understanding of the pathophysiology of insomnia may provide important information regarding how, and under what conditions, the disorder develops and is maintained as well as potential targets for prevention and treatment. The aims of this report are (1) to summarize current knowledge on the pathophysiology of insomnia and (2) to present a model of the pathophysiology of insomnia that considers evidence from various domains of research. Working within several models of insomnia, evidence for the pathophysiology of the disorder is presented across levels of analysis, from genetic to molecular and cellular mechanisms, neural circuitry, physiologic mechanisms, sleep behavior, and self-report. We discuss the role of hyperarousal as an overarching theme that guides our conceptualization of insomnia. Finally, we propose a model of the pathophysiology of insomnia that integrates the various types of evidence presented. PMID:25846534

  10. Subcellular neuropharmacology: the importance of intracellular targeting.

    Science.gov (United States)

    Miyashiro, Kevin Y; Bell, Thomas J; Sul, Jai-Yoon; Eberwine, James

    2009-04-01

    Few cell types are more adapted for cell-cell signaling than neurons. Their responsiveness lies in the formation of highly specialized compartments composed of unique repertoires of selectively distributed protein complexes generated, in part, by the local translation of mRNAs and regulated by their RNA-binding proteins. Utilizing the selective distribution of these neuronal proteins and the underlying mechanisms that generate the differential patterns of expression as central facets of drug design promises to enhance the therapeutic ratio of a drug. It is in this context that we discuss the unique arrangement of mRNAs, RNA-binding proteins and the protein macromolecular complexes at the dendrite, which is the postsynaptic site of synaptic transmission. Recent advances in identifying the function of dendritic components of the mechanisms of protein and RNA transport, non-nuclear RNA splicing and localized translation underscore their importance as targets of neuropharmacology.

  11. The KATP channel in migraine pathophysiology: a novel therapeutic target for migraine.

    Science.gov (United States)

    Al-Karagholi, Mohammad Al-Mahdi; Hansen, Jakob Møller; Severinsen, Johanne; Jansen-Olesen, Inger; Ashina, Messoud

    2017-08-23

    To review the distribution and function of K ATP channels, describe the use of K ATP channels openers in clinical trials and make the case that these channels may play a role in headache and migraine. K ATP channels are widely present in the trigeminovascular system and play an important role in the regulation of tone in cerebral and meningeal arteries. Clinical trials using synthetic K ATP channel openers report headache as a prevalent-side effect in non-migraine sufferers, indicating that K ATP channel opening may cause headache, possibly due to vascular mechanisms. Whether K ATP channel openers can provoke migraine in migraine sufferers is not known. We suggest that K ATP channels may play an important role in migraine pathogenesis and could be a potential novel therapeutic anti-migraine target.

  12. The Fourth Element Targeting hypothesis of Alzheimer’s disease pathogenesis and pathophysiology

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    Rodrigo O Kuljiš

    2010-11-01

    Full Text Available Despite well over a century of research on all forms of the disorder known as Alzheimer’s disease (AD, it is still not known whether the condition targets initially neurons, glial cells, other cellular elements in the brain, or components of cells, such as synapses, or molecules independently of their cellular compartmentalization, or otherwise (e.g. specific neuronal circuits. Multiple lines of highly suggestive but as yet insufficient experimental evidence are discussed here to formulate the hypothesis that AD results from primary (i.e. direct and initial or secondary targeting of what we designate as the Fourth Element Cell (4EC: a relatively recently identified type of brain cell that exhibits features in common with neurons (e.g. synapses, participation in glutamatergic and GABAergic neurotransmission, astrocytes, oligodendrocytes and their precursors, but is in other respects clearly distinct from all of them. The 4EC is proposed to be the main target of both: (1 converging insults (i.e. not true causes that over time cause sporadic forms of AD as postulated by the Danger Signal Hypothesis — which was not formulated with 4EC in mind — as well as (2 the causes of inherited (i.e. familial forms of neurodegeneration that resemble certain aspects of the clinical manifestations of sporadic AD.

  13. Imaging Alzheimer's disease pathophysiology with PET

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    Lucas Porcello Schilling

    Full Text Available ABSTRACT Alzheimer's disease (AD has been reconceptualised as a dynamic pathophysiological process characterized by preclinical, mild cognitive impairment (MCI, and dementia stages. Positron emission tomography (PET associated with various molecular imaging agents reveals numerous aspects of dementia pathophysiology, such as brain amyloidosis, tau accumulation, neuroreceptor changes, metabolism abnormalities and neuroinflammation in dementia patients. In the context of a growing shift toward presymptomatic early diagnosis and disease-modifying interventions, PET molecular imaging agents provide an unprecedented means of quantifying the AD pathophysiological process, monitoring disease progression, ascertaining whether therapies engage their respective brain molecular targets, as well as quantifying pharmacological responses. In the present study, we highlight the most important contributions of PET in describing brain molecular abnormalities in AD.

  14. Importância do camundongo mdx na fisiopatologia da distrofia muscular de Duchenne The importance of mdx mouse in the pathophysiology of Duchenne's muscular distrophy

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    Sandra Lopes Seixas

    1997-09-01

    Full Text Available O camundongo mdx desenvolve distrofia muscular recessiva ligada ao cromossoma X (locus Xp21.1 e não expressa distrofina. Embora não apresente intensa fibrose do tecido muscular e acúmulo de tecido adiposo, é considerado o modelo animal mais adequado da distrofia muscular de Duchenne. As alterações estruturais no tecido muscular associadas à mionecrose e presença do infiltrado inflamatório com predomínio de linfócitos e monócitos/macrófagos sugerem uma participação do sistema imunológico nesta miopatia. Além disso a modulação na expressão dos componentes da matriz extracelular no microambiente muscular nas várias fases da doença (início, mionecrose, regeneração indicam um papel importante do conjuntivo no direcionamento das células inflamatórias para o foco da lesão muscular. O camundongo mdx coloca-se como um excelente modelo para o estudo dos mecanismos patogenéticos da mionecrose e regeneração na distrofia muscular de Duchenne, possibilitando inclusive o desenvolvimento de estratégias terapêuticas mais adequadas.The mdx mouse develop an X-linked recessive muscular dystrophy (locus Xp21.1 and lack dystrophin expression. Despite showing less intense myofibrosis and scarce deposition of fatty tissue, mdx mice are considered an adequate animal model for studies on the pathogenesis of Duchenne-type muscular dystrophy. Marked histological alterations in the muscular tissues associated to myonecrosis and inflammatory mononuclear cell infiltrate (lymphocytes, monocytes/macrophages suggest a participation of the immune system in this myopathy. Modulation of the extracellular matrix (ECM components in the muscular tissue during all phases (onset, myonecrosis and regeneration of disease, indicate an important role for the ECM driving inflammatory cells to the foci of lesion. Therefore mdx mice should be regarded as an important tool for studies on pathogenetic mechanisms of Duchenne-type muscular dystrophy. Such

  15. Factor XII (Hageman factor) is a missing link between stress and hypercoagulability and plays an important role in the pathophysiology of ischemic stroke.

    Science.gov (United States)

    Eggers, Arnold E

    2006-01-01

    A new hypothesis is presented on the function of factor XII, which is postulated to be a "missing link" between acute stress and transient hypercoagulability. The implications of this idea are developed to show how chronic stress, which involves activation of hypertension and migraine as well as hypercoagulability, can cause of cerebrovascular disease. "Acute stress" is defined as "the normal short-term physiological response to the perception of major threats or demands". "Chronic stress" is "the abnormal ongoing physiological response to the continuing perception of unresolvable major threats or demands". The factor XII hypothesis is as follows: Acute stress includes release of epinephrine by the adrenal medulla. Epinephrine activates platelets by binding to alpha-2A adrenergic receptors. Activated platelets convert pre-bound factor XII to its active form, which then initiates the intrinsic coagulation cascade. This can be called the "activated platelet initiation pathway" for coagulation. Neither tissue factor nor pre-formed thrombin is required. Thrombosis proceeds to completion, but only a minute amount of thrombin is formed, and the process normally stops at this point. In people who lapse into a state of chronic stress, essential hypertension, which is also a manifestation of stress, synergizes with hypercoagulability: there is both a baseline rise in blood pressure and systemic platelet activation as well as superimposed labile rises of both. Upregulation of these two stress parameters is atherogenic: epinephrine-activated platelets stimulating thrombin formation interact with endothelial cells activated by angiotensin II to cause, first, smooth muscle cell proliferation, which is a histological hallmark of atherosclerosis, and, lastly, a symptomatic thrombotic occlusion-the stroke. The migraine symptoms which often accompany this process are a marker of chronic stress and ongoing pathophysiologic damage. Therapeutic predictions are made regarding novel

  16. Impact of surgery targeting the caudal intralaminar thalamic nuclei on the pathophysiological functioning of basal ganglia in a rat model of Parkinson's disease.

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    Kerkerian-Le Goff, Lydia; Bacci, Jean-Jacques; Jouve, Loreline; Melon, Christophe; Salin, Pascal

    2009-02-16

    There is accumulating evidence that the centre median-parafascicular (CM/Pf) complex of the thalamus is implicated in basal ganglia-related movement disorders and notably in Parkinson's disease. However, the impact of the changes affecting CM/Pf on the pathophysiological functioning of basal ganglia in parkinsonian state remains poorly understood. To address this issue, we have examined the effects of excitotoxic lesion of CM/Pf and of 6-hydroxydopamine-induced lesion of nigral dopamine neurons, separately or in association, on gene expression of markers of neuronal activity in the rat basal ganglia (striatal neuropeptide precursors, GAD67, cytochrome oxidase subunit I) by quantitative in situ hybridization histochemistry. CM/Pf lesion prevented the changes produced by the dopamine denervation in the components of the indirect pathway connecting the striatum to the output structures (striatopallidal neurons, globus pallidus, subthalamic nucleus), and among the output structures, in the entopeduncular nucleus. Preliminary data on the effects of deep brain stimulation of CM/Pf in rats with nigral dopamine lesion show that this surgical approach produces efficient anti-akinetic effect associated with partial reversal of the dopamine lesion-induced increase in striatal preproenkephalin A mRNA levels, a marker of the striatopallidal neurons. These data, which provide substrates for the potential of CM/Pf surgery in the treatment of movement disorders, are discussed in comparison with the effects of lesion or deep brain stimulation of the subthalamic nucleus, the currently preferred target for the surgical treatment of PD.

  17. Some important questions connected with non-targeted effects

    International Nuclear Information System (INIS)

    Baverstock, Keith; Belyakov, Oleg V.

    2010-01-01

    This paper briefly reviews the highlights of experimental evidence that led to the adoption of the term 'non-targeted' to describe new effects induced by ionising radiation that did not fit the classical radiobiological paradigm, principally genomic instability and bystander effect, identifying the reports that were most influential on the subsequent course of radiobiological research. The issue of appropriate terminology for the new effects is discussed. Particular emphasis is placed on the inheritance of genomic instability, where there are issues concerning which effects should be considered as transgenerational. Finally, in respect of the question as to whether these new effects are likely to have an impact on human health is addressed. It is concluded that there is a need for a clearer terminology to facilitate research progress, that real health effects cannot be ruled out and that therefore there is a need for new paradigms not only for radiobiology but also for risk assessment and radiological protection.

  18. The pathophysiology of bronchiectasis

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    Paul T King

    2009-10-01

    Full Text Available Paul T KingDepartment of Medicine, Department of Respiratory and Sleep Medicine, Monash University, Monash Medical Centre, Melbourne, Victoria, AustraliaAbstract: Bronchiectasis is defined by permanent and abnormal widening of the bronchi. This process occurs in the context of chronic airway infection and inflammation. It is usually diagnosed using computed tomography scanning to visualize the larger bronchi. Bronchiectasis is also characterized by mild to moderate airflow obstruction. This review will describe the pathophysiology of noncystic fibrosis bronchiectasis. Studies have demonstrated that the small airways in bronchiectasis are obstructed from an inflammatory infiltrate in the wall. As most of the bronchial tree is composed of small airways, the net effect is obstruction. The bronchial wall is typically thickened by an inflammatory infiltrate of lymphocytes and macrophages which may form lymphoid follicles. It has recently been demonstrated that patients with bronchiectasis have a progressive decline in lung function. There are a large number of etiologic risk factors associated with bronchiectasis. As there is generally a long-term retrospective history, it may be difficult to determine the exact role of such factors in the pathogenesis. Extremes of age and smoking/chronic obstructive pulmonary disease may be important considerations. There are a variety of different pathogens involved in bronchiectasis, but a common finding despite the presence of purulent sputum is failure to identify any pathogenic microorganisms. The bacterial flora appears to change with progression of disease. Keywords: bronchiectasis, inflammation, obstructive lung disease, pathophysiology, pathology

  19. Pathophysiological mechanisms of insulin resistance

    NARCIS (Netherlands)

    Brands, M.

    2013-01-01

    In this thesis we studied pathophysiological mechanisms of insulin resistance in different conditions in humans, i.e. in obesity, during lipid infusions, after hypercaloric feeding, and glucocorticoid treatment. We focused on 3 important hypotheses that are suggested to be implicated in the

  20. Assessing pathophysiology of cancer anorexia.

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    Laviano, Alessandro; Koverech, Angela; Seelaender, Marilia

    2017-09-01

    Cancer anorexia is a negative prognostic factor and is broadly defined as the loss of the interest in food. However, multiple clinical domains contribute to the phenotype of cancer anorexia. The characterization of the clinical and molecular pathophysiology of cancer anorexia may enhance the efficacy of preventive and therapeutic strategies. Clinical trials showed that cancer anorexia should be considered as an umbrella encompassing different signs and symptoms contributing to appetite disruption in cancer patients. Loss of appetite, early satiety, changes in taste and smell are determinants of cancer anorexia, whose presence should be assessed in cancer patients. Interestingly, neuronal correlates of cancer anorexia-related symptoms have been revealed by brain imaging techniques. The pathophysiology of cancer anorexia is complex and involves different domains influencing eating behavior. Limiting the assessment of cancer anorexia to questions investigating changes in appetite may impede correct identification of the targets to address.

  1. A single peroxisomal targeting signal mediates matrix protein import in diatoms.

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    Nicola H Gonzalez

    Full Text Available Peroxisomes are single membrane bound compartments. They are thought to be present in almost all eukaryotic cells, although the bulk of our knowledge about peroxisomes has been generated from only a handful of model organisms. Peroxisomal matrix proteins are synthesized cytosolically and posttranslationally imported into the peroxisomal matrix. The import is generally thought to be mediated by two different targeting signals. These are respectively recognized by the two import receptor proteins Pex5 and Pex7, which facilitate transport across the peroxisomal membrane. Here, we show the first in vivo localization studies of peroxisomes in a representative organism of the ecologically relevant group of diatoms using fluorescence and transmission electron microscopy. By expression of various homologous and heterologous fusion proteins we demonstrate that targeting of Phaeodactylum tricornutum peroxisomal matrix proteins is mediated only by PTS1 targeting signals, also for proteins that are in other systems imported via a PTS2 mode of action. Additional in silico analyses suggest this surprising finding may also apply to further diatoms. Our data suggest that loss of the PTS2 peroxisomal import signal is not reserved to Caenorhabditis elegans as a single exception, but has also occurred in evolutionary divergent organisms. Obviously, targeting switching from PTS2 to PTS1 across different major eukaryotic groups might have occurred for different reasons. Thus, our findings question the widespread assumption that import of peroxisomal matrix proteins is generally mediated by two different targeting signals. Our results implicate that there apparently must have been an event causing the loss of one targeting signal even in the group of diatoms. Different possibilities are discussed that indicate multiple reasons for the detected targeting switching from PTS2 to PTS1.

  2. Pathophysiological significance and therapeutic applications of snake venom protease inhibitors.

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    Thakur, Rupamoni; Mukherjee, Ashis K

    2017-06-01

    Protease inhibitors are important constituents of snake venom and play important roles in the pathophysiology of snakebite. Recently, research on snake venom protease inhibitors has provided valuable information to decipher the molecular details of various biological processes and offer insight for the development of some therapeutically important molecules from snake venom. The process of blood coagulation and fibrinolysis, in addition to affecting platelet function, are well known as the major targets of several snake venom protease inhibitors. This review summarizes the structure-functional aspects of snake venom protease inhibitors that have been described to date. Because diverse biological functions have been demonstrated by protease inhibitors, a comparative overview of their pharmacological and pathophysiological properties is also highlighted. In addition, since most snake venom protease inhibitors are non-toxic on their own, this review evaluates the different roles of individual protease inhibitors that could lead to the identification of drug candidates and diagnostic molecules. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Pathophysiology of Glucocorticoid Signaling.

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    Vitellius, Géraldine; Trabado, Séverine; Bouligand, Jérôme; Delemer, Brigitte; Lombès, Marc

    2018-06-01

    Glucocorticoids (GC), such as cortisol or dexamethasone, control various physiological functions, notably those involved in development, metabolism, inflammatory processes and stress, and exert most of their effects upon binding to the glucocorticoid receptor (GR, encoded by NR3C1 gene). GC signaling follows several consecutive steps leading to target gene transactivation, including ligand binding, nuclear translocation of ligand-activated GR complexes, DNA binding, coactivator interaction and recruitment of functional transcriptional machinery. Any step may be impaired and may account for altered GC signaling. Partial or generalized glucocorticoid resistance syndrome may result in a reduced level of functional GR, a decreased hormone affinity and binding, a defect in nuclear GR translocation, a decrease or lack of DNA binding and/or post-transcriptional GR modifications. To date, 26 loss-of-function NR3C1 mutations have been reported in the context of hypertension, hirsutism, adrenal hyperplasia or metabolic disorders. These clinical signs are generally associated with biological features including hypercortisolism without negative regulatory feedback loop on the hypothalamic-pituitary-adrenal axis. Patients had often low plasma aldosterone and renin levels despite hypertension. Only one GR gain-of-function mutation has been described associating Cushing's syndrome phenotype with normal urinary-free cortisol. Some GR polymorphisms (ER22/23EK, GR-9β) have been linked to glucocorticoid resistance and a healthier metabolic profile whereas some others seemed to be associated with GC hypersensitivity (N363S, BclI), increasing cardiovascular risk (diabetes type 2, visceral obesity). This review focuses on the earlier findings on the pathophysiology of GR signaling and presents criteria facilitating identification of novel NR3C1 mutations in selected patients. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  4. Membrane-lipid therapy: A historical perspective of membrane-targeted therapies - From lipid bilayer structure to the pathophysiological regulation of cells.

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    Escribá, Pablo V

    2017-09-01

    Our current understanding of membrane lipid composition, structure and functions has led to the investigation of their role in cell signaling, both in healthy and pathological cells. As a consequence, therapies based on the regulation of membrane lipid composition and structure have been recently developed. This novel field, known as Membrane Lipid Therapy, is growing and evolving rapidly, providing treatments that are now in use or that are being studied for their application to oncological disorders, Alzheimer's disease, spinal cord injury, stroke, diabetes, obesity, and neuropathic pain. This field has arisen from relevant discoveries on the behavior of membranes in recent decades, and it paves the way to adopt new approaches in modern pharmacology and nutrition. This innovative area will promote further investigation into membranes and the development of new therapies with molecules that target the cell membrane. Due to the prominent roles of membranes in the cells' physiology and the paucity of therapeutic approaches based on the regulation of the lipids they contain, it is expected that membrane lipid therapy will provide new treatments for numerous pathologies. The first on-purpose rationally designed molecule in this field, minerval, is currently being tested in clinical trials and it is expected to enter the market around 2020. However, it seems feasible that during the next few decades other membrane regulators will also be marketed for the treatment of human pathologies. This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escribá. Copyright © 2017. Published by Elsevier B.V.

  5. Obesity: Pathophysiology and Intervention

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    Yi Zhang

    2014-11-01

    Full Text Available Obesity presents a major health hazard of the 21st century. It promotes co-morbid diseases such as heart disease, type 2 diabetes, obstructive sleep apnea, certain types of cancer, and osteoarthritis. Excessive energy intake, physical inactivity, and genetic susceptibility are main causal factors for obesity, while gene mutations, endocrine disorders, medication, or psychiatric illnesses may be underlying causes in some cases. The development and maintenance of obesity may involve central pathophysiological mechanisms such as impaired brain circuit regulation and neuroendocrine hormone dysfunction. Dieting and physical exercise offer the mainstays of obesity treatment, and anti-obesity drugs may be taken in conjunction to reduce appetite or fat absorption. Bariatric surgeries may be performed in overtly obese patients to lessen stomach volume and nutrient absorption, and induce faster satiety. This review provides a summary of literature on the pathophysiological studies of obesity and discusses relevant therapeutic strategies for managing obesity.

  6. Undertaking and writing research that is important, targeted, and the best you can do.

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    McLeod, Sharynne

    2014-04-01

    Conducting and writing research is a privilege. It is a privilege because researchers can change lives through their findings and can influence public knowledge and debate. It is also a privilege because researchers are reliant on the time and goodwill of participants (and colleagues), and research is often underpinned by funding raised by the public, either through taxes or philanthropic donations. This privilege comes with responsibility. Researchers have a responsibility to undertake research that is important, targeted, and of high quality. This editorial aims to inspire, challenge, and bolster the research efforts of individuals and teams.

  7. Pathophysiology of cervical myelopathy.

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    Baptiste, Darryl C; Fehlings, Michael G

    2006-01-01

    Cervical myelopathy is a group of closely related disorders usually caused by spondylosis or by ossification of the posterior longitudinal ligament and is characterized by compression of the cervical spinal cord or nerve roots by varying degrees and number of levels. The decrease in diameter of the vertebral canal secondary to disc degeneration and osteophytic spurs compresses the spinal cord and nerve roots at one or several levels, producing direct damage and often secondary ischemic changes. Clinicians who treat cervical myelopathy cord injuries should have a basic understanding of the pathophysiology and the processes that are initiated after the spinal cord has been injured. Literature review. Literature review of human cervical myelopathy and clinically relevant animal models to further our understanding of the pathological mechanisms involved. The pathophysiology of cervical myelopathy involves static factors, which result in acquired or developmental stenosis of the cervical canal and dynamic factors, which involve repetitive injury to the cervical cord. These mechanical factors in turn result in direct injury to neurons and glia as well as a secondary cascade of events including ischemia, excitotoxicity, and apoptosis; a pathobiology similar to that occurring in traumatic spinal cord injury. This review summarizes some of the significant pathophysiological processes involved in cervical myelopathy.

  8. Protecting Important Sites for Biodiversity Contributes to Meeting Global Conservation Targets

    Science.gov (United States)

    Butchart, Stuart H. M.; Scharlemann, Jörn P. W.; Evans, Mike I.; Quader, Suhel; Aricò, Salvatore; Arinaitwe, Julius; Balman, Mark; Bennun, Leon A.; Bertzky, Bastian; Besançon, Charles; Boucher, Timothy M.; Brooks, Thomas M.; Burfield, Ian J.; Burgess, Neil D.; Chan, Simba; Clay, Rob P.; Crosby, Mike J.; Davidson, Nicholas C.; De Silva, Naamal; Devenish, Christian; Dutson, Guy C. L.; Fernández, David F. Día z; Fishpool, Lincoln D. C.; Fitzgerald, Claire; Foster, Matt; Heath, Melanie F.; Hockings, Marc; Hoffmann, Michael; Knox, David; Larsen, Frank W.; Lamoreux, John F.; Loucks, Colby; May, Ian; Millett, James; Molloy, Dominic; Morling, Paul; Parr, Mike; Ricketts, Taylor H.; Seddon, Nathalie; Skolnik, Benjamin; Stuart, Simon N.; Upgren, Amy; Woodley, Stephen

    2012-01-01

    Protected areas (PAs) are a cornerstone of conservation efforts and now cover nearly 13% of the world's land surface, with the world's governments committed to expand this to 17%. However, as biodiversity continues to decline, the effectiveness of PAs in reducing the extinction risk of species remains largely untested. We analyzed PA coverage and trends in species' extinction risk at globally significant sites for conserving birds (10,993 Important Bird Areas, IBAs) and highly threatened vertebrates and conifers (588 Alliance for Zero Extinction sites, AZEs) (referred to collectively hereafter as ‘important sites’). Species occurring in important sites with greater PA coverage experienced smaller increases in extinction risk over recent decades: the increase was half as large for bird species with>50% of the IBAs at which they occur completely covered by PAs, and a third lower for birds, mammals and amphibians restricted to protected AZEs (compared with unprotected or partially protected sites). Globally, half of the important sites for biodiversity conservation remain unprotected (49% of IBAs, 51% of AZEs). While PA coverage of important sites has increased over time, the proportion of PA area covering important sites, as opposed to less important land, has declined (by 0.45–1.14% annually since 1950 for IBAs and 0.79–1.49% annually for AZEs). Thus, while appropriately located PAs may slow the rate at which species are driven towards extinction, recent PA network expansion has under-represented important sites. We conclude that better targeted expansion of PA networks would help to improve biodiversity trends. PMID:22457717

  9. Protecting important sites for biodiversity contributes to meeting global conservation targets.

    Directory of Open Access Journals (Sweden)

    Stuart H M Butchart

    Full Text Available Protected areas (PAs are a cornerstone of conservation efforts and now cover nearly 13% of the world's land surface, with the world's governments committed to expand this to 17%. However, as biodiversity continues to decline, the effectiveness of PAs in reducing the extinction risk of species remains largely untested. We analyzed PA coverage and trends in species' extinction risk at globally significant sites for conserving birds (10,993 Important Bird Areas, IBAs and highly threatened vertebrates and conifers (588 Alliance for Zero Extinction sites, AZEs (referred to collectively hereafter as 'important sites'. Species occurring in important sites with greater PA coverage experienced smaller increases in extinction risk over recent decades: the increase was half as large for bird species with>50% of the IBAs at which they occur completely covered by PAs, and a third lower for birds, mammals and amphibians restricted to protected AZEs (compared with unprotected or partially protected sites. Globally, half of the important sites for biodiversity conservation remain unprotected (49% of IBAs, 51% of AZEs. While PA coverage of important sites has increased over time, the proportion of PA area covering important sites, as opposed to less important land, has declined (by 0.45-1.14% annually since 1950 for IBAs and 0.79-1.49% annually for AZEs. Thus, while appropriately located PAs may slow the rate at which species are driven towards extinction, recent PA network expansion has under-represented important sites. We conclude that better targeted expansion of PA networks would help to improve biodiversity trends.

  10. Current concepts in the pathophysiology of glaucoma

    Directory of Open Access Journals (Sweden)

    Agarwal Renu

    2009-01-01

    Full Text Available Glaucoma, the second leading cause of blindness, is characterized by changes in the optic disc and visual field defects. The elevated intraocular pressure was considered the prime factor responsible for the glaucomatous optic neuropathy involving death of retinal ganglion cells and their axons. Extensive investigations into the pathophysiology of glaucoma now reveal the role of multiple factors in the development of retinal ganglion cell death. A better understanding of the pathophysiological mechanisms involved in the onset and progression of glaucomatous optic neuropathy is crucial in the development of better therapeutic options. This review is an effort to summarize the current concepts in the pathophysiology of glaucoma so that newer therapeutic targets can be recognized. The literature available in the National Medical Library and online Pubmed search engine was used for literature review.

  11. [Functional pathophysiology of consciousness].

    Science.gov (United States)

    Jellinger, Kurt A

    2009-01-01

    from important somatic and sensory pathways and acts as a control system of neuronal activities of the cerebral cortex. The principal function of the ARAS is to focus our alertness on specific stimuli or internal processes, which run via complex neuronal cell groups and numerous neurotransmitters that influence various aspects of consciousness and wakefulness. Stimulation of the ARAS produces an arousal reaction as the electric correlate of consciousness; its destruction causes coma and related states. The highest level are cortical (prefrontal and association) networks for recognition, motor activity, longterm memory and attention, the left hemisphere being considered as the dominant one. Different levels of consciousness are distinguished: 1. hyperalertness, 2. alertness (normal state of wakefulness), 3. somnolence or lethargy, 4. obtundation with tendency to fall asleep, 5. stupor, 6. coma and its subtypes, like akinetic mutism, apallic syndrome or persistent vegative state, locked-in syndrome, delirium, and catatonia. They are caused by damages in various functional levels of the brain, by psychogenic factors or experimentally, and are accompanied by characteristic neurological and psychiatric disorders. The relevant morphological lesions can be detected by electrophysiological and imaging studies. The bases of functional anatomy and pathophysiology of consciousness, its cognitive aspects and its major disorders, their causes and functional substrates with reference to sleep and both spontaneous and iatrogenic disorders of consciousness are critically summarized.

  12. Increased importance of methane reduction for a 1.5 degree target

    Science.gov (United States)

    Collins, William J.; Webber, Christopher P.; Cox, Peter M.; Huntingford, Chris; Lowe, Jason; Sitch, Stephen; Chadburn, Sarah E.; Comyn-Platt, Edward; Harper, Anna B.; Hayman, Garry; Powell, Tom

    2018-04-01

    To understand the importance of methane on the levels of carbon emission reductions required to achieve temperature goals, a processed-based approach is necessary rather than reliance on the transient climate response to emissions. We show that plausible levels of methane (CH4) mitigation can make a substantial difference to the feasibility of achieving the Paris climate targets through increasing the allowable carbon emissions. This benefit is enhanced by the indirect effects of CH4 on ozone (O3). Here the differing effects of CH4 and CO2 on land carbon storage, including the effects of surface O3, lead to an additional increase in the allowable carbon emissions with CH4 mitigation. We find a simple robust relationship between the change in the 2100 CH4 concentration and the extra allowable cumulative carbon emissions between now and 2100 (0.27 ± 0.05 GtC per ppb CH4). This relationship is independent of modelled climate sensitivity and precise temperature target, although later mitigation of CH4 reduces its value and thus methane reduction effectiveness. Up to 12% of this increase in allowable emissions is due to the effect of surface ozone. We conclude early mitigation of CH4 emissions would significantly increase the feasibility of stabilising global warming below 1.5 °C, alongside having co-benefits for human and ecosystem health.

  13. [Exposure degree of important non-target arthropods to Cry2Aa in Bt rice fields].

    Science.gov (United States)

    Zhang, Qing-Ling; Li, Yun-He; Hua, Hong-Xia; Yang, Chang-Ju; Wu, Hong-Jin; Peng, Yu-Fa

    2013-06-01

    Based on the principle of "risk = hazard x exposure", the selected representative nontarget organisms in the assessment of the potential effects of insect-resistant genetically modified (GM) crops on non-target arthropods in laboratory are generally the arthropod species highly exposed to the insecticidal proteins expressed by the GM crops in farmland ecosystem. In order to understand the exposure degree of the important arthropod species to Cry proteins in Bt rice fields, and to select the appropriate non-target arthropods in the risk assessment of insect-resistant GM crops, the enzyme-linked immunosorbent assay (ELISA) was conducted to measure the Cry2Aa protein concentration in the arthropods collected from the cry2Aa rice fields at different rice growth stages. The results showed that there was a significant difference in the Cry2Aa content protein concentration in different arthropod species. Some species did not contain Cry2Aa protein, while some species contained larger amounts of Cry2Aa protein. Relative to the arthropods colleted after rice anthesis, the arthropods colleted in rice anthesis contained relative higher concentrations of Cry2Aa protein, especially for the predacious arthropods. No Cry proteins were detected in parasitic arthropods. This study provided references for the laboratory assessment of the effects of GM rice on nontarget arthropods.

  14. The adipocyte as an important target cell for Trypanosoma cruzi infection.

    Science.gov (United States)

    Combs, Terry P; Nagajyothi; Mukherjee, Shankar; de Almeida, Cecilia J G; Jelicks, Linda A; Schubert, William; Lin, Ying; Jayabalan, David S; Zhao, Dazhi; Braunstein, Vicki L; Landskroner-Eiger, Shira; Cordero, Aisha; Factor, Stephen M; Weiss, Louis M; Lisanti, Michael P; Tanowitz, Herbert B; Scherer, Philipp E

    2005-06-24

    Adipose tissue plays an active role in normal metabolic homeostasis as well as in the development of human disease. Beyond its obvious role as a depot for triglycerides, adipose tissue controls energy expenditure through secretion of several factors. Little attention has been given to the role of adipocytes in the pathogenesis of Chagas disease and the associated metabolic alterations. Our previous studies have indicated that hyperglycemia significantly increases parasitemia and mortality in mice infected with Trypanosoma cruzi. We determined the consequences of adipocyte infection in vitro and in vivo. Cultured 3T3-L1 adipocytes can be infected with high efficiency. Electron micrographs of infected cells revealed a large number of intracellular parasites that cluster around lipid droplets. Furthermore, infected adipocytes exhibited changes in expression levels of a number of different adipocyte-specific or adipocyte-enriched proteins. The adipocyte is therefore an important target cell during acute Chagas disease. Infection of adipocytes by T. cruzi profoundly influences the pattern of adipokines. During chronic infection, adipocytes may represent an important long-term reservoir for parasites from which relapse of infection can occur. We have demonstrated that acute infection has a unique metabolic profile with a high degree of local inflammation in adipose tissue, hypoadiponectinemia, hypoglycemia, and hypoinsulinemia but with relatively normal glucose disposal during an oral glucose tolerance test.

  15. New strategies for heart failure with preserved ejection fraction: the importance of targeted therapies for heart failure phenotypes

    Science.gov (United States)

    Senni, Michele; Paulus, Walter J.; Gavazzi, Antonello; Fraser, Alan G.; Díez, Javier; Solomon, Scott D.; Smiseth, Otto A.; Guazzi, Marco; Lam, Carolyn S. P.; Maggioni, Aldo P.; Tschöpe, Carsten; Metra, Marco; Hummel, Scott L.; Edelmann, Frank; Ambrosio, Giuseppe; Stewart Coats, Andrew J.; Filippatos, Gerasimos S.; Gheorghiade, Mihai; Anker, Stefan D.; Levy, Daniel; Pfeffer, Marc A.; Stough, Wendy Gattis; Pieske, Burkert M.

    2014-01-01

    The management of heart failure with reduced ejection fraction (HF-REF) has improved significantly over the last two decades. In contrast, little or no progress has been made in identifying evidence-based, effective treatments for heart failure with preserved ejection fraction (HF-PEF). Despite the high prevalence, mortality, and cost of HF-PEF, large phase III international clinical trials investigating interventions to improve outcomes in HF-PEF have yielded disappointing results. Therefore, treatment of HF-PEF remains largely empiric, and almost no acknowledged standards exist. There is no single explanation for the negative results of past HF-PEF trials. Potential contributors include an incomplete understanding of HF-PEF pathophysiology, the heterogeneity of the patient population, inadequate diagnostic criteria, recruitment of patients without true heart failure or at early stages of the syndrome, poor matching of therapeutic mechanisms and primary pathophysiological processes, suboptimal study designs, or inadequate statistical power. Many novel agents are in various stages of research and development for potential use in patients with HF-PEF. To maximize the likelihood of identifying effective therapeutics for HF-PEF, lessons learned from the past decade of research should be applied to the design, conduct, and interpretation of future trials. This paper represents a synthesis of a workshop held in Bergamo, Italy, and it examines new and emerging therapies in the context of specific, targeted HF-PEF phenotypes where positive clinical benefit may be detected in clinical trials. Specific considerations related to patient and endpoint selection for future clinical trials design are also discussed. PMID:25104786

  16. Pathophysiology of glucagon secretion

    International Nuclear Information System (INIS)

    Boettger, J.; Pabst, H.W.

    1980-01-01

    Pathophysiology of glucagon secretion is reviewed in brief separating hyperglucagonemic from hypoclucagonemic states. Many questions concerning the role of glucagon in diabetes mellitus and in other diseases are still unresolved. The clucagon RIA is of clinical significance in a few diseases like glucagonoma, which may present without symptoms of the 'glucagonoma syndrome', the probably very rare hyperglucagonemia and some of the spontaneous hypoglycemias. Glucagon secretion may be evaluated by the determination of fasting immunoreactive glucagon (IRG) and by appropriate function tests as stimulation with i.v. arginine and suppression with oral glucose. However, the glucagon RIA at present is not a routine method, although commercial kits are available. Many pitfalls of radioimmunological glucagon determination still exist. (orig.) [de

  17. Pathophysiology of nocturnal enuresis

    DEFF Research Database (Denmark)

    Rittig, Søren; Kamperis, Konstantinos

    2015-01-01

    The perception of the pathogenesis of enuresis has undergone marked changes over the past 30 years from a psychiatric/psychological background to a more somatic model where nighttime urine production and bladder capacity are main components together with an arousal dysfunction that prevents...... that dysfunction of the intrinsic circadian regulation located in the suprachiasmatic nucleus results in dysfunction of one or more of the brainstem centers involved in AVP secretion, arousal function, bladder control, and blood pressure regulation. Furthermore, nocturnal enuresis has a strong genetic influence...... that in some families present as autosomal dominant inheritance with high degree of penetrance. Linkage to several chromosomal areas have been confirmed in such families although a specific causative enuresis gene has not yet been identified. In conclusion, our understanding of enuresis pathophysiology has...

  18. Proteomic amino-termini profiling reveals targeting information for protein import into complex plastids.

    Directory of Open Access Journals (Sweden)

    Pitter F Huesgen

    Full Text Available In organisms with complex plastids acquired by secondary endosymbiosis from a photosynthetic eukaryote, the majority of plastid proteins are nuclear-encoded, translated on cytoplasmic ribosomes, and guided across four membranes by a bipartite targeting sequence. In-depth understanding of this vital import process has been impeded by a lack of information about the transit peptide part of this sequence, which mediates transport across the inner three membranes. We determined the mature N-termini of hundreds of proteins from the model diatom Thalassiosira pseudonana, revealing extensive N-terminal modification by acetylation and proteolytic processing in both cytosol and plastid. We identified 63 mature N-termini of nucleus-encoded plastid proteins, deduced their complete transit peptide sequences, determined a consensus motif for their cleavage by the stromal processing peptidase, and found evidence for subsequent processing by a plastid methionine aminopeptidase. The cleavage motif differs from that of higher plants, but is shared with other eukaryotes with complex plastids.

  19. Antibodies: From novel repertoires to defining and refining the structure of biologically important targets.

    Science.gov (United States)

    Conroy, Paul J; Law, Ruby H P; Caradoc-Davies, Tom T; Whisstock, James C

    2017-03-01

    Antibodies represent a highly successful class of molecules that bind a wide-range of targets in therapeutic-, diagnostic- and research-based applications. The antibody repertoire is composed of the building blocks required to develop an effective adaptive immune response against foreign insults. A number of species have developed novel genetic and structural mechanisms from which they derive these antibody repertoires, however, traditionally antibodies are isolated from human, and rodent sources. Due to their high-value therapeutic, diagnostic, biotechnological and research applications, much innovation has resulted in techniques and approaches to isolate novel antibodies. These approaches are bolstered by advances in our understanding of species immune repertoires, next generation sequencing capacity, combinatorial antibody discovery and high-throughput screening. Structural determination of antibodies and antibody-antigen complexes has proven to be pivotal to our current understanding of the immune repertoire for a range of species leading to advances in man-made libraries and fine tuning approaches to develop antibodies from immune-repertoires. Furthermore, the isolation of antibodies directed against antigens of importance in health, disease and developmental processes, has yielded a plethora of structural and functional insights. This review highlights the significant contribution of antibody-based crystallography to our understanding of adaptive immunity and its application to providing critical information on a range of human-health related indications. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Adult hippocampal neurogenesis: an important target associated with antidepressant effects of exercise.

    Science.gov (United States)

    Sun, Lina; Sun, Qingshan; Qi, Jinshun

    2017-10-26

    Depression is a prevalent devastating mental disorder that affects the normal life of patients and brings a heavy burden to whole society. Although many efforts have been made to attenuate depressive/anxiety symptoms, the current clinic antidepressants have limited effects. Scientists have long been making attempts to find some new strategies that can be applied as the alternative antidepressant therapy. Exercise, a widely recognized healthy lifestyle, has been suggested as a therapy that can relieve psychiatric stress. However, how exercise improves the brain functions and reaches the antidepressant target needs systematic summarization due to the complexity and heterogeneous feature of depression. Brain plasticity, especially adult neurogenesis in the hippocampus, is an important neurophysiology to facilitate animals for neurogenesis can occur in not only humans. Many studies indicated that an appropriate level of exercise can promote neurogenesis in the adult brains. In this article, we provide information about the antidepressant effects of exercise and its implications in adult neurogenesis. From the neurogenesis perspective, we summarize evidence about the effects of exercise in enhancing neurogenesis in the hippocampus through regulating growth factors, neurotrophins, neurotransmitters and metabolism as well as inflammations. Taken together, a large number of published works indicate the multiple benefits of exercise in the brain functions of animals, particularly brain plasticity like neurogenesis and synaptogenesis. Therefore, a new treatment method for depression therapy can be developed by regulating the exercise activity.

  1. The importance of the genomic landscape in Waldenström's Macroglobulinemia for targeted therapeutical interventions.

    Science.gov (United States)

    Sacco, Antonio; Fenotti, Adriano; Affò, Loredana; Bazzana, Stefano; Russo, Domenico; Presta, Marco; Malagola, Michele; Anastasia, Antonella; Motta, Marina; Patterson, Christopher J; Rossi, Giuseppe; Imberti, Luisa; Treon, Steven P; Ghobrial, Irene M; Roccaro, Aldo M

    2017-05-23

    The Literature has recently reported on the importance of genomics in the field of hematologic malignancies, including B-cell lymphoproliferative disorders such as Waldenström's Macrolgobulinemia (WM). Particularly, whole exome sequencing has led to the identification of the MYD88L265P and CXCR4C1013G somatic variants in WM, occurring in about 90% and 30% of the patients, respectively. Subsequently, functional studies have demonstrated their functional role in supporting WM pathogenesis and disease progression, both in vitro and in vivo, thus providing the pre-clinical evidences for extremely attractive targets for novel therapeutic interventions in WM. Of note, recent evidences have also approached and defined the transcriptome profiling of WM cells, revealing a signature that mirrors the somatic aberrations demonstrated within the tumor clone. A parallel research field has also reported on microRNAs (miRNAs), highlighting the oncogenic role of miRNA-155 in WM. In the present review, we focus on the latest reports on genomics and miRNAs in WM, providing an overview of the clinical relevance of the latest acquired knowledge about genomics and miRNA aberrations in WM.

  2. Fisiopatologia da enxaqueca Migraine pathophysiology

    Directory of Open Access Journals (Sweden)

    MAURICE B. VINCENT

    1998-12-01

    Full Text Available A fisiopatologia da enxaqueca ainda não foi completamente elucidada. As principais estruturas envolvidas parecem ser o sistema nervoso central (córtex e tronco cerebral, o sistema trigeminovascular e os vasos correspondentes, outras fibras autonômicas que inervam estes vasos, e os vários agentes vasoativos locais, como a SP, CGRP, NO, VIP, NPY, ACh, NA, NKA, entre outros. A depressão alastrante é o fenômeno neurológico que provavelmente justifica achados experimenais e clínicos na enxaqueca. Ela tem velocidade de propagação semelhante à aura, ativa o núcleo espinhal do trigêmeo e está relacionada à liberação de CGRP e NO. Alterações circulatórias detectadas por métodos complementares reforçam o papel da depressão alastrante. A identificação de anormalidades em pelo menos três loci (cromossomas 19 e 1 na enxaqueca hemiplégica familiar ocorreu recentemente. Elas estão relacionadas a anormalidades nos canais de cálcio voltagem dependentes tipo P/Q, específicos do sistema nervoso central, que regulam a liberação de vários neurotransmissores, incluindo possivelmente a serotonina. A exemplo de outras anormalidades neurológicas paroxísticas que resultam da hiperexcitabilidade da membrana plasmática, é possível que a enxaqueca ocorra devido a uma desordem de canais iônicos.The pathophysiology of migraine is not yet fully understood. The most important structures involved seem to be the central nervous system (cortex and brain stem, the trigeminovascular system and related cranial arteries, other autonomic fibres innervating such vessels, and various local vasoactive agents, including SP, CGRP, NO, VIP, NPY, ACh, NA, NKA, among others. The spreading depression phenomenon may explain clinical as well experimental findings in migraine. Its propagation velocity mirrors what is found in clinical aura, it may activate the spinal trigeminal nucleus and may induce CGRP and NO release. Circulatory changes detected with

  3. Hemorrhoids: From basic pathophysiology to clinical management

    Science.gov (United States)

    Lohsiriwat, Varut

    2012-01-01

    This review discusses the pathophysiology, epidemiology, risk factors, classification, clinical evaluation, and current non-operative and operative treatment of hemorrhoids. Hemorrhoids are defined as the symptomatic enlargement and distal displacement of the normal anal cushions. The most common symptom of hemorrhoids is rectal bleeding associated with bowel movement. The abnormal dilatation and distortion of the vascular channel, together with destructive changes in the supporting connective tissue within the anal cushion, is a paramount finding of hemorrhoids. It appears that the dysregulation of the vascular tone and vascular hyperplasia might play an important role in hemorrhoidal development, and could be a potential target for medical treatment. In most instances, hemorrhoids are treated conservatively, using many methods such as lifestyle modification, fiber supplement, suppository-delivered anti-inflammatory drugs, and administration of venotonic drugs. Non-operative approaches include sclerotherapy and, preferably, rubber band ligation. An operation is indicated when non-operative approaches have failed or complications have occurred. Several surgical approaches for treating hemorrhoids have been introduced including hemorrhoidectomy and stapled hemorrhoidopexy, but postoperative pain is invariable. Some of the surgical treatments potentially cause appreciable morbidity such as anal stricture and incontinence. The applications and outcomes of each treatment are thoroughly discussed. PMID:22563187

  4. The importance of surrounding tissues and window settings for contouring of moving targets

    Energy Technology Data Exchange (ETDEWEB)

    Borm, Kai Joachim [Technische Universitaet Muenchen, Medical School, Munich (Germany); Klinikum rechts der Isar, Technische Universitaet Muenchen, Department of Radiation Oncology, Munich (Germany); Oechsner, Markus; Berndt, Johannes; Combs, Stephanie Elisabeth; Molls, Michael; Duma, Marciana Nona [Klinikum rechts der Isar, Technische Universitaet Muenchen, Department of Radiation Oncology, Munich (Germany)

    2015-09-15

    The aim of the study was to assess the importance of surrounding tissues for the delineation of moving targets in tissue-specific phantoms and to find optimal settings for lung, soft tissue, and liver tumors. Tumor movement was simulated by a water-filled table tennis ball (target volume, TV). Three phantoms were created: corkboards to simulate lung tissue (lung phantom, LunPh), animal fat as fatty soft tissue (fatty tissue phantom, FatPh), and water enhanced with contrast medium as the liver tissue (liver phantom, LivPh). Slow planning three-dimensional compute tomography images (3D-CTs) were acquired with and without phantom movements. One-dimensional tumor movement (1D), three-dimensional tumor movement (3D), as well as a real patient's tumor trajectories were simulated. The TV was contoured using two lung window settings, two soft-tissue window settings, and one liver window setting. The volumes were compared to mathematical calculated values. TVs were underestimated in all phantoms due to movement. The use of soft-tissue windows in the LivPh led to a significantunderestimation of the TV (70.8 % of calculated TV). When common window settings [LunPh + 200 HU/-1,000 HU (upper window/lower window threshold); FatPh: + 240 HU/-120 HU; LivPh: + 175 HU/+ 50 HU] were used, the contoured TVs were: LivPh, 84.0 %; LunPh, 93.2 %, and FatPh, 92.8 %. The lower window threshold had a significant impact on the size of the delineated TV, whereas changes of the upper threshold led only to small differences. The decisive factor for window settings is the lower window threshold (for adequate TV delineation in the lung and fatty-soft tissue it should be lower than density values of surrounding tissue). The use of a liver window should be considered. (orig.) [German] Das Ziel dieser Arbeit war es, den Einfluss des umgebenden Gewebes auf die Konturierung bewegter Objekte zu untersuchen. Um die optimalen CT-Fensterungen fuer Lungen-, Weichteil- und Lebertumoren zu bestimmen

  5. Changing paradigm from one target one ligand towards multi target directed ligand design for key drug targets of Alzheimer disease: An important role of Insilco methods in multi target directed ligands design.

    Science.gov (United States)

    Kumar, Akhil; Tiwari, Ashish; Sharma, Ashok

    2018-03-15

    discovery and play an important role in optimizing multi-target drug discovery. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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

    Directory of Open Access Journals (Sweden)

    Tong Liu

    2017-04-01

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

  7. The Planck Satellite LFI and the Microwave Background: Importance of the 4 K Reference Targets

    Directory of Open Access Journals (Sweden)

    Robitaille P.-M.

    2010-07-01

    Full Text Available Armed with 4 K reference targets, the Planck satellite low frequency instrument (LFI is intended to map the microwave anisotropies of the sky from the second Lagrange point, L2. Recently, the complete design and pre-flight testing of these 4 K targets has been published (Valenziano L. et al., JINST 4, 2009, T12006. The receiver chain of the LFI is based on a pseudo-correlation architecture. Consequently, the presence of a 3 K microwave background signal at L2 can be established, if the 4 K reference targets function as intended. Conversely, demonstration that the targets are unable to provide the desired emission implies that the 3 K signal cannot exist, at this location. Careful study reveals that only the second scenario can be valid. This analysis thereby provides firm evidence that the monopole of the microwave background, as initially detected by Penzias and Wilson, is being produced by the Earth itself.

  8. The Planck Satellite LFI and the Microwave Background: Importance of the 4K Reference Targets

    Directory of Open Access Journals (Sweden)

    Robitaille P.-M.

    2010-04-01

    Full Text Available Armed with ~4K reference targets, the Planck satellite low frequency instrument (LFI is intended to map the microwave anisotropies of the sky from the second Lagrange point, L2. Recently, the complete design and pre-flight testing of these ~4K targets has been published (Valenziano L. et al., JINST 4, 2009, T12006. The receiver chain of the LFI is based on a pseudo-correlation architecture. Consequently, the presence of a ~3K microwave background signal at L2 can be established, if the ~4K reference targets function as intended. Conversely, demonstration that the targets are unable to provide the desired emission implies that the ~3K signal cannot exist, at this location. Careful study reveals that only the second scenario can be valid. This analysis thereby provides firm evidence that the monopole of the microwave background, as initially detected by Penzias and Wilson, is being produced by the Earth itself.

  9. The importance of reaching lipid targets: statins and the prevention of atherosclerosis.

    Science.gov (United States)

    Schwandt, P

    2003-06-01

    To help prevent the development of coronary heart disease (CHD), the European and NCEP guidelines have recommended target cholesterol levels for all individuals. Lifestyle changes are advocated for individuals not achieving these targets. Intervention with lipid-modifying agents may be required for patients at high risk of a cardiovascular event and statins are generally recognised as first-line therapy. Unfortunately, large numbers of patients at risk of cardiovascular events are not being treated to the guideline targets. Primary care physicians are in a good position to improve lipid management by assessing risk factors, implementing lipid management strategies, monitoring whether targets are being reached and amending treatment appropriately. Furthermore, by educating and motivating patients,primary care physicians may improve compliance with lifestyle changes and medication. These approaches may help more patients to achieve recommended lipid levels and prevent the development of cardiovascular disease.

  10. TFOS DEWS II pathophysiology report.

    Science.gov (United States)

    Bron, Anthony J; de Paiva, Cintia S; Chauhan, Sunil K; Bonini, Stefano; Gabison, Eric E; Jain, Sandeep; Knop, Erich; Markoulli, Maria; Ogawa, Yoko; Perez, Victor; Uchino, Yuichi; Yokoi, Norihiko; Zoukhri, Driss; Sullivan, David A

    2017-07-01

    The TFOS DEWS II Pathophysiology Subcommittee reviewed the mechanisms involved in the initiation and perpetuation of dry eye disease. Its central mechanism is evaporative water loss leading to hyperosmolar tissue damage. Research in human disease and in animal models has shown that this, either directly or by inducing inflammation, causes a loss of both epithelial and goblet cells. The consequent decrease in surface wettability leads to early tear film breakup and amplifies hyperosmolarity via a Vicious Circle. Pain in dry eye is caused by tear hyperosmolarity, loss of lubrication, inflammatory mediators and neurosensory factors, while visual symptoms arise from tear and ocular surface irregularity. Increased friction targets damage to the lids and ocular surface, resulting in characteristic punctate epithelial keratitis, superior limbic keratoconjunctivitis, filamentary keratitis, lid parallel conjunctival folds, and lid wiper epitheliopathy. Hybrid dry eye disease, with features of both aqueous deficiency and increased evaporation, is common and efforts should be made to determine the relative contribution of each form to the total picture. To this end, practical methods are needed to measure tear evaporation in the clinic, and similarly, methods are needed to measure osmolarity at the tissue level across the ocular surface, to better determine the severity of dry eye. Areas for future research include the role of genetic mechanisms in non-Sjögren syndrome dry eye, the targeting of the terminal duct in meibomian gland disease and the influence of gaze dynamics and the closed eye state on tear stability and ocular surface inflammation. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Glutamate abnormalities in obsessive compulsive disorder: neurobiology, pathophysiology, and treatment.

    Science.gov (United States)

    Pittenger, Christopher; Bloch, Michael H; Williams, Kyle

    2011-12-01

    Obsessive compulsive disorder is prevalent, disabling, incompletely understood, and often resistant to current therapies. Established treatments consist of specialized cognitive-behavioral psychotherapy and pharmacotherapy with medications targeting serotonergic and dopaminergic neurotransmission. However, remission is rare, and more than a quarter of OCD sufferers receive little or no benefit from these approaches, even when they are optimally delivered. New insights into the disorder, and new treatment strategies, are urgently needed. Recent evidence suggests that the ubiquitous excitatory neurotransmitter glutamate is dysregulated in OCD, and that this dysregulation may contribute to the pathophysiology of the disorder. Here we review the current state of this evidence, including neuroimaging studies, genetics, neurochemical investigations, and insights from animal models. Finally, we review recent findings from small clinical trials of glutamate-modulating medications in treatment-refractory OCD. The precise role of glutamate dysregulation in OCD remains unclear, and we lack blinded, well-controlled studies demonstrating therapeutic benefit from glutamate-modulating agents. Nevertheless, the evidence supporting some important perturbation of glutamate in the disorder is increasingly strong. This new perspective on the pathophysiology of OCD, which complements the older focus on monoaminergic neurotransmission, constitutes an important focus of current research and a promising area for the ongoing development of new therapeutics. Copyright © 2011 Elsevier Inc. All rights reserved.

  12. Pathophysiology of Cushing's disease.

    Science.gov (United States)

    Fehm, H L; Voigt, K H

    1979-01-01

    The term Cushing's disease is applied to those cases of Cushing's syndrome in which hypercortisolism is secondary to inappropriate secretion of ACTH by the pituitary. Studies on control of ACTH secretion in these patients reveal: (a) that the episodic secretion of ACTH is similar to the normal; however, frequency and amplitude of the secretory episodes lack the normal circadian rhythm; (b) that ACTH release can be stimulated by vasopressin and metyrapone in a normal or above-normal manner; and (c) that it can be suppressed by large doses of corticosteroids. When the dynamic aspects of the ACTH response to corticosteroid administration are studied, it appears that the normally negative differential feedback mechanism is converted into a positive one, whereas the delayed, integral mechanism is undisturbed. Patients with Cushing's disease in the presence of obvious pituitary tumors cannot be distinguished from those without pituitary tumors by studying only the pituitary function. All these and other well-known facts would favor the concept that ACTH secretion in Cushing's disease is under hypothalamic control whether or not a pituitary tumor is present. Moreover, there are observations that suggest that brain centers superior to the hypophysiotropic area of the hypothalamus are involved in the pathophysiology of Cushing's disease. This concept has led to the discovery of neurotropic drugs that are able to induce complete remission of Cushing's syndrome in a cerain percentage of patients. In some patients with severe psychiatric diseases, neuroendocrine abnormalities are present that resemble closely those characteristic for Cushing's disease. With the most refined neuroradiological methods, pituitary microadenomas are demonstrable in approximately 70% of patients with Cushing's disease, and this number compares well with those of earlier autopsy findings (70 to 80%). In a small number of patients (4 to 10%), these tumors are large and can easily be detected by

  13. How much importance do we give to target audiences in article writing?

    Science.gov (United States)

    Nedjat, Sima; Nedjat, Saharnaz; Gholami, Jaleh; Ashoorkhani, Mahnaz; Maleki, Katayoun; Hejrie, Soroush Mortaz; Majdzadeh, Reza

    2010-01-01

    Writing papers can be used as a means to convey a message. Knowledge transfer is also about conveying the right message to the right target audience. The aim of this study was to determine the proportion of articles that had mentioned a clear message and the target audience in the abstract and the article as a whole, and also to examine their association with different determinant factors. Articles published from 2001 to 2006 that were based on clinical and health system research conducted on Iranian populations and on maternal care, diabetes and tuberculosis were searched systematically in domestic and international databases. Eventually checklists (Additional file 1) were completed for 795 articles. Overall, 98.5% of articles had a clear message, whereas 12.5% had addressed the direct target audience. Presence of a clear message in formatted abstracts were seen 3.6 times more (CI95%: 1.5-8.7) than in articles without formatted abstracts (p = 0.005). Addressing of the direct target audience was seen twice as much in health system research articles as compared to clinical studies, odds ratio was 2.3 (CI95%: 1.47-3.48, p<0.001). Creating a format for journal abstracts seems to be an effective intervention for presenting the message in articles.

  14. The Importance and Use of Targeted Content Knowledge with Scaffolding Aid in Educational Simulation Games

    Science.gov (United States)

    Tsai, Fu-Hsing; Kinzer, Charles; Hung, Kuo-Hsun; Chen, Cheng-Ling Alice; Hsu, I-Ying

    2013-01-01

    While most current educational simulation games provide learners with gameplay experience to motivate learning, there is often a lack of focus on ensuring that the desired content knowledge is actually learned. Students may focus on completing game activities without learning the targeted content knowledge, thus negating the desired learning…

  15. Importance of Lorentz structure in the parton model: Target mass corrections, transverse momentum dependence, positivity bounds

    International Nuclear Information System (INIS)

    D'Alesio, U.; Leader, E.; Murgia, F.

    2010-01-01

    We show that respecting the underlying Lorentz structure in the parton model has very strong consequences. Failure to insist on the correct Lorentz covariance is responsible for the existence of contradictory results in the literature for the polarized structure function g 2 (x), whereas with the correct imposition we are able to derive the Wandzura-Wilczek relation for g 2 (x) and the target-mass corrections for polarized deep inelastic scattering without recourse to the operator product expansion. We comment briefly on the problem of threshold behavior in the presence of target-mass corrections. Careful attention to the Lorentz structure has also profound implications for the structure of the transverse momentum dependent parton densities often used in parton model treatments of hadron production, allowing the k T dependence to be derived explicitly. It also leads to stronger positivity and Soffer-type bounds than usually utilized for the collinear densities.

  16. Targeting imported malaria through social networks: a potential strategy for malaria elimination in Swaziland.

    Science.gov (United States)

    Koita, Kadiatou; Novotny, Joseph; Kunene, Simon; Zulu, Zulizile; Ntshalintshali, Nyasatu; Gandhi, Monica; Gosling, Roland

    2013-06-27

    Swaziland has made great progress towards its goal of malaria elimination by 2015. However, malaria importation from neighbouring high-endemic Mozambique through Swaziland's eastern border remains a major factor that could prevent elimination from being achieved. In order to reach elimination, Swaziland must rapidly identify and treat imported malaria cases before onward transmission occurs. A nationwide formative assessment was conducted over eight weeks to determine if the imported cases of malaria identified by the Swaziland National Malaria Control Programme could be linked to broader social networks and to explore methods to access these networks. Using a structured format, interviews were carried out with malaria surveillance agents (6), health providers (10), previously identified imported malaria cases (19) and people belonging to the networks identified through these interviews (25). Most imported malaria cases were Mozambicans (63%, 12/19) making a living in Swaziland and sustaining their families in Mozambique. The majority of imported cases (73%, 14/19) were labourers and self-employed contractors who travelled frequently to Mozambique to visit their families and conduct business. Social networks of imported cases with similar travel patterns were identified through these interviews. Nearly all imported cases (89%, 17/19) were willing to share contact information to enable network members to be interviewed. Interviews of network members and key informants revealed common congregation points, such as the urban market places in Manzini and Malkerns, as well as certain bus stations, where people with similar travel patterns and malaria risk behaviours could be located and tested for malaria. This study demonstrated that imported cases of malaria belonged to networks of people with similar travel patterns. This study may provide novel methods for screening high-risk groups of travellers using both snowball sampling and time-location sampling of networks to

  17. Otosclerosis update (1). Pathophysiology and diagnosis

    International Nuclear Information System (INIS)

    Ogawa, Kaoru; Inoue, Yasuhiro; Saito, Hideyuki; Kanzaki, Sho; Okamoto, Yasuhide; Mizutari, Kunio; Suzuki, Takashi; Oishi, Naoki

    2009-01-01

    Otosclerosis is an otological disease that typicaly causes conductive hearing loss. This disease is an important clinical entity since hearing impairment in these case can be dramatically improved by surgery. In this review paper, we review recent research into the pathophysiology of otosclerosis and summarize clinical features, audiometry and diagnostic imaging examinations in 160 ears with otosclerosis that we treated surgically in our department. (author)

  18. Priority of domestic biomass resources for energy: Importance of national environmental targets in a climate perspective

    DEFF Research Database (Denmark)

    Tonini, Davide; Vadenbo, Carl; Astrup, Thomas Fruergaard

    2017-01-01

    ) for electricity/heat is generally preferred, as long as coal/oil is still used within the energy system. Yet, to fulfill environmental targets for renewable energy in the transport sector, the diversion of a significant share of biogas (and/or other biofuels) from these more beneficial uses is necessary...... that utilizing the energy potential of manure and straw represents the primary opportunity for further global warming mitigation. For this purpose, co-digestion (for manure) and combustion with heat-and-power production (for straw) appear as the most promising technologies. The utilization of biomass (or biogas...

  19. Hypophosphatasia - pathophysiology and treatment.

    Science.gov (United States)

    Millán, José Luis; Plotkin, Horacio

    2012-09-01

    Hypophosphatasia (HPP) is the inborn-error-of-metabolism caused by loss-of-function mutation(s) in the gene that encodes the tissue-nonspecific isozyme of alkaline phosphatase (TNAP). The disease has been classified according to patient age when the first signs and symptoms manifest; i.e., perinatal, infantile, childhood, adult HPP. Other types include odonto HPP and perinatal benign. Babies with the perinatal/infantile forms of HPP often die with severe rickets and respiratory insufficiency and sometimes hypercalcemia and vitamin B 6 -responsive seizures. The primary biochemical defect in HPP is a deficiency of TNAP activity that leads to elevated circulating levels of substrates, in particular inorganic pyrophosphate (PP i ), a potent calcification inhibitor. To-date, the management of HPP has been essentially symptomatic or orthopedic. However, enzyme replacement therapy with mineral-targeting TNAP (sALP-FcD 10 , also known as ENB-0040 or asfotase alfa) has shown promising results in a mouse model of HPP ( Alpl -/- mice). Administration of mineral-targeting TNAP from birth increased survival and prevented the seizures, rickets, as well as all the tooth abnormalities, including dentin, acellular cementum, and enamel defects in this model of severe HPP. Clinical trials using mineral-targeting TNAP in children 3 years of age or younger with life-threatening HPP was associated with healing of the skeletal manifestations of HPP as well as improved respiratory and motor function. Improvement is still being observed in the patients receiving continued asfotase alfa therapy, with more than 3 years of treatment in some children. Enzyme replacement therapy with asfotase alfa has to-date been successful in patients with life-threatening HPP.

  20. On the importance of targeting parasite stem cells in anti-echinococcosis drug development

    Directory of Open Access Journals (Sweden)

    Brehm Klaus

    2014-01-01

    Full Text Available The life-threatening diseases alveolar and cystic echinococcoses are caused by larvae of the tapeworms Echinococcus multilocularis and E. granulosus, respectively. In both cases, intermediate hosts, such as humans, are infected by oral uptake of oncosphere larvae, followed by asexual multiplication and almost unrestricted growth of the metacestode within host organs. Besides surgery, echinococcosis treatment relies on benzimidazole-based chemotherapy, directed against parasite beta-tubulin. However, since beta-tubulins are highly similar between cestodes and humans, benzimidazoles can only be applied at parasitostatic doses and are associated with adverse side effects. Mostly aiming at identifying alternative drug targets, the nuclear genome sequences of E. multilocularis and E. granulosus have recently been characterized, revealing a large number of druggable targets that are expressed by the metacestode. Furthermore, recent cell biological investigations have demonstrated that E. multilocularis employs pluripotent stem cells, called germinative cells, which are the only parasite cells capable of proliferation and which give rise to all differentiated cells. Hence, the germinative cells are the crucial cell type mediating proliferation of E. multilocularis, and most likely also E. granulosus, within host organs and should also be responsible for parasite recurrence upon discontinuation of chemotherapy. Interestingly, recent investigations have also indicated that germinative cells might be less sensitive to chemotherapy because they express a beta-tubulin isoform with limited affinity to benzimidazoles. In this article, we briefly review the recent findings concerning Echinococcus genomics and stem cell research and propose that future research into anti-echinococcosis drugs should also focus on the parasite’s stem cell population.

  1. Pathophysiology of osteoporosis: new mechanistic insights.

    Science.gov (United States)

    Armas, Laura A G; Recker, Robert R

    2012-09-01

    Understanding of the pathophysiology of osteoporosis has evolved to include compromised bone strength and skeletal fragility caused by several factors: (1) defects in microarchitecture of trabeculae, (2) defective intrinsic material properties of bone tissue, (3) defective repair of microdamage from normal daily activities, and (4) excessive bone remodeling rates. These factors occur in the context of age-related bone loss. Clinical studies of estrogen deprivation, antiresorptives, mechanical loading, and disuse have helped further knowledge of the factors affecting bone quality and the mechanisms that underlie them. This progress has led to several new drug targets in the treatment of osteoporosis. Copyright © 2012 Elsevier Inc. All rights reserved.

  2. Sepsis: Current Definition, Pathophysiology, Diagnosis, and Management.

    Science.gov (United States)

    Taeb, Abdalsamih M; Hooper, Michael H; Marik, Paul E

    2017-06-01

    Sepsis is a clinical syndrome that results from the dysregulated inflammatory response to infection that leads to organ dysfunction. The resulting losses to society in terms of financial burden, morbidity, and mortality are enormous. We provide a review of sepsis, its underlying pathophysiology, and guidance for diagnosis and management of this common disease. Current established treatments include appropriate antimicrobial agents to target the underlying infection, optimization of intravascular volume to improve stroke volume, vasopressors to counteract vasoplegic shock, and high-quality supportive care. Appropriate implementation of established treatments combined with novel therapeutic approaches promises to continue to decrease the impact of this disease.

  3. The metabolic syndrome in long-term cancer survivors, an important target for secondary preventive measures

    NARCIS (Netherlands)

    Nuver, J; Smit, AJ; Postma, A; Sleijfer, DT; Gietema, JA

    With increasing numbers of cancer survivors, attention has been drawn to long-term complications of curative cancer treatment, including a range of metabolic disorders. These metabolic disorders often resemble the components of the so-called metabolic syndrome, or syndrome X, which is an important

  4. Foreign Language Learners' Views on the Importance of Learning the Target Language Pronunciation

    Science.gov (United States)

    Çakir, Ismail; Baytar, Birtan

    2014-01-01

    Pronunciation is one of the controversial topics in the field of English language teaching as a second or foreign language. The aim of this study is to understand the attitudes of prep class students at Kastamonu University (state university) in Turkey towards the importance of pronunciation in language learning. Therefore, a pronunciation…

  5. The pathophysiology of migraine: implications for clinical management.

    Science.gov (United States)

    Charles, Andrew

    2018-02-01

    The understanding of migraine pathophysiology is advancing rapidly. Improved characterisation and diagnosis of its clinical features have led to the view of migraine as a complex, variable disorder of nervous system function rather than simply a vascular headache. Recent studies have provided important new insights into its genetic causes, anatomical and physiological features, and pharmacological mechanisms. The identification of new migraine-associated genes, the visualisation of brain regions that are activated at the earliest stages of a migraine attack, a greater appreciation of the potential role of the cervical nerves, and the recognition of the crucial role for neuropeptides are among the advances that have led to novel targets for migraine therapy. Future management of migraine will have the capacity to tailor treatments based on the distinct mechanisms of migraine that affect individual patients. Copyright © 2018 Elsevier Ltd. All rights reserved.

  6. [Pathophysiology of prolonged hypokinesia].

    Science.gov (United States)

    Kovalenko, E A

    1976-01-01

    Hypokinesia is an important problem in modern medicine. In the pathogenetic effect of prolonged hypokinesia the main etiological factor is diminished motor activity; of major importance are disorders in the energy and plastic metabolism which affect the muscle system; the contributing factors are cardiovascular deconditioning and orthostatic intolerance. This is attributed to a decreased oxygen supply and eliminated hydrostatic influences during a prolonged recumbency. Blood redistribution in the vascular bed is related to the Gauer-Henry reflex and subsequent changes in the fluid-electrolyte balance. Decreased load on the bone system induces changes in the protein-phosphate-calcium metabolism, diminished bone density and increased calcium content in the blood and urine. Changes in the calcium metabolism are systemic. The activity of the higher nervous system and reflex functions is lowered. Changes in the function of the autonomic nervous system which include a noticeable decline of its adaptive-trophic role as a result of the decrease of afferent and efferent impulsation are of great importance. Changes in the hormonal function involve a peculiar stress-reaction which develops at an early stage of hypokinesia as a response to an unusual situation. Prolonged hypokinesia may result in a disturbed function of the pituitary-adrenal system. It is assumed that prolonged hypokinesia may induce a specific disease of hypokinesia during which man cannot lead a normal mode of life and work.

  7. Targeting and Assembly of Components of the TOC Protein Import Complex at the Chloroplast Outer Envelope Membrane

    Directory of Open Access Journals (Sweden)

    Lynn G.L. Richardson

    2014-06-01

    Full Text Available The translocon at the outer envelope membrane of chloroplasts (TOC initiates the import of thousands of nuclear encoded preproteins required for chloroplast biogenesis and function. The multimeric TOC complex contains two GTP-regulated receptors, Toc34 and Toc159, which recognize the transit peptides of preproteins and initiate protein import through a β–barrel membrane channel, Toc75. Different isoforms of Toc34 and Toc159 assemble with Toc75 to form structurally and functionally diverse translocons, and the composition and levels of TOC translocons is required for the import of specific subsets of coordinately expressed proteins during plant growth and development. Consequently, the proper assembly of the TOC complexes is key to ensuring organelle homeostasis. This review will focus on our current knowledge of the targeting and assembly of TOC components to form functional translocons at the outer membrane. Our analyses reveal that the targeting of TOC components involves elements common to the targeting of other outer membrane proteins, but also include unique features that appear to have evolved to specifically facilitate assembly of the import apparatus.

  8. Targeting and assembly of components of the TOC protein import complex at the chloroplast outer envelope membrane.

    Science.gov (United States)

    Richardson, Lynn G L; Paila, Yamuna D; Siman, Steven R; Chen, Yi; Smith, Matthew D; Schnell, Danny J

    2014-01-01

    The translocon at the outer envelope membrane of chloroplasts (TOC) initiates the import of thousands of nuclear encoded preproteins required for chloroplast biogenesis and function. The multimeric TOC complex contains two GTP-regulated receptors, Toc34 and Toc159, which recognize the transit peptides of preproteins and initiate protein import through a β-barrel membrane channel, Toc75. Different isoforms of Toc34 and Toc159 assemble with Toc75 to form structurally and functionally diverse translocons, and the composition and levels of TOC translocons is required for the import of specific subsets of coordinately expressed proteins during plant growth and development. Consequently, the proper assembly of the TOC complexes is key to ensuring organelle homeostasis. This review will focus on our current knowledge of the targeting and assembly of TOC components to form functional translocons at the outer membrane. Our analyses reveal that the targeting of TOC components involves elements common to the targeting of other outer membrane proteins, but also include unique features that appear to have evolved to specifically facilitate assembly of the import apparatus.

  9. Pathophysiology of the anorexia of aging.

    Science.gov (United States)

    Morley, John E

    2013-01-01

    Anorexia represents a major problem for older persons leading to weight loss, sarcopenia, functional decline, and mortality. There is increasing information on the pathophysiological mechanisms that lead to anorexia. Increasing evidence has shown the importance of gastrointestinal hormones (ghrelin, cholecystokinin, and glucagon-like peptide) and adipokines in producing the anorexia of aging. Numerous neurotransmitters have been shown to be involved in this aging anorexia, but evidence in humans is lacking. The early recognition of anorexia of aging is important to allow intervention and prevent functional deterioration in older persons. Screening tests for anorexia have been developed. New approaches to managing anorexia are being tested.

  10. Appealing to an important customer. Physicians should be the target of marketing.

    Science.gov (United States)

    Weiss, R

    1989-05-01

    Although many healthcare professionals are turning to the general public to increase market share and referrals, they should be directing their attention to physicians instead. One of the major challenges facing hospitals is determining physician needs. A survey may be necessary to identify physicians' perceptions, attitudes, values, expectations, market, and hospital loyalty. Another important research document is the physician profile, which includes each doctor by age, specialty, office location, admitting and outpatient referral activity, financial contribution, and referral and other affiliations. Surveying should not end with the physician. One of the best means of evaluating patient and physician satisfaction is by questioning physicians' office staff. To centralize physician services, a number of hospitals have established physician liaison programs, which bridge the gap between the hospital and the physician's office, heighten physician satisfaction, and increase referrals. Physician orientation is a key element of most outreach programs, providing an opportunity to develop relationships with new physicians. Other means of directly aiding physicians are physician referral services and practice enhancement and assistance.

  11. HIV-Infected Adolescent, Young Adult and Pregnant Smokers: Important Targets for Effective Tobacco Control Programs

    Directory of Open Access Journals (Sweden)

    Gerome Escota

    2013-06-01

    Full Text Available Tobacco use is inextricably linked to a number of health risks both in the general and HIV-infected populations. There is, however, a dearth of research on effective tobacco control programs among people living with HIV, and especially among adolescents, young adults and pregnant women, groups with heightened or increased vulnerability secondary to tobacco use. Adolescents and young adults constitute a growing population of persons living with HIV infection. Early and continued tobacco use in this population living with a disease characterized by premature onset multimorbidity and chronic inflammation is of concern. Additionally, there is an increased acuity for tobacco control among HIV-infected pregnant women to reduce pregnancy morbidity and improve fetal outcome. This review will provide an important summary of current knowledge of tobacco use among HIV-infected adolescents, young adults and pregnant women. The effects of tobacco use in these specific populations will be presented and the current state of tobacco control within these populations, assessed.

  12. NMDA receptors are important regulators of pancreatic cancer and are potential targets for treatment

    Directory of Open Access Journals (Sweden)

    North WG

    2017-07-01

    Full Text Available William G North,1,2 Fuli Liu,1 Liz Z Lin,1 Ruiyang Tian,2 Bonnie Akerman1 1Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth College, 2Woomera Therapeutics Inc, Lebanon, NH, USA Abstract: Pancreatic cancer, particularly adenocarcinoma of the pancreas, is a common disease with a poor prognosis. In this study, the importance of N-methyl-D-aspartate (NMDA receptors for the growth and survival of pancreatic cancer was investigated. Immunohistochemistry performed with antibodies against GluN1 and GluN2B revealed that all invasive adenocarcinoma and neuroendocrine pancreatic tumors likely express these two NMDA receptor proteins. These proteins were found to be membrane components of pancreatic cancer cell lines, and both channel-blocker antagonist and GluN2B antagonist significantly reduced cell viability in vitro. Both types of antagonists caused an internalization of the receptors. Dizocilpine maleate (MK-801 and ifenprodil hemitartrate both significantly inhibited the growth of pancreatic tumor xenografts in nu/nu mice. These findings predict that, as for other solid tumors investigated by us, pancreatic cancer could be successfully treated, alone or in combination, with NMDA receptor antagonists or other receptor-inhibiting blocking agents. Keywords: pancreatic cancer, NMDA receptors, inhibitors, potential therapy

  13. Pathophysiology of gastroesophageal reflux disease

    NARCIS (Netherlands)

    Boeckxstaens, Guy E.; Rohof, Wout O.

    2014-01-01

    Gastroesophageal reflux disease (GERD) is one of the most common digestive diseases in the Western world, with typical symptoms, such as heartburn, regurgitation, or retrosternal pain, reported by 15% to 20% of the general population. The pathophysiology of GERD is multifactorial. Our understanding

  14. Gas embolism: pathophysiology and treatment

    NARCIS (Netherlands)

    van Hulst, Robert A.; Klein, Jan; Lachmann, Burkhard

    2003-01-01

    Based on a literature search, an overview is presented of the pathophysiology of venous and arterial gas embolism in the experimental and clinical environment, as well as the relevance and aims of diagnostics and treatment of gas embolism. The review starts with a few historical observations and

  15. A review on Alzheimer's disease pathophysiology and its management: an update.

    Science.gov (United States)

    Kumar, Anil; Singh, Arti; Ekavali

    2015-04-01

    Alzheimer's disease acknowledged as progressive multifarious neurodegenerative disorder, is the leading cause of dementia in late adult life. Pathologically it is characterized by intracellular neurofibrillary tangles and extracellular amyloidal protein deposits contributing to senile plaques. Over the last two decades, advances in the field of pathogenesis have inspired the researchers for the investigation of novel pharmacological therapeutics centered more towards the pathophysiological events of the disease. Currently available treatments i.e. acetylcholinesterase inhibitors (rivastigmine, galantamine, donepezil) and N-methyl d-aspartate receptor antagonist (memantine) contribute minimal impact on the disease and target late aspects of the disease. These drugs decelerate the progression of the disease, provide symptomatic relief but fail to achieve a definite cure. While the neuropathological features of Alzheimer's disease are recognized but the intricacies of the mechanism have not been clearly defined. This lack of understanding regarding the pathogenic process may be the likely reason for the non-availability of effective treatment which can prevent onset and progression of the disease. Owing to the important progress in the field of pathophysiology in the last couple of years, new therapeutic targets are available that should render the underlying disease process to be tackled directly. In this review, authors will discusses the different aspects of pathophysiological mechanisms behind Alzheimer's disease and its management through conventional drug therapy, including modern investigational therapeutic strategies, recently completed and ongoing. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  16. Pathogenesis and Pathophysiology of Pneumococcal Meningitis

    Science.gov (United States)

    Mook-Kanamori, Barry B.; Geldhoff, Madelijn; van der Poll, Tom; van de Beek, Diederik

    2011-01-01

    Summary: Pneumococcal meningitis continues to be associated with high rates of mortality and long-term neurological sequelae. The most common route of infection starts by nasopharyngeal colonization by Streptococcus pneumoniae, which must avoid mucosal entrapment and evade the host immune system after local activation. During invasive disease, pneumococcal epithelial adhesion is followed by bloodstream invasion and activation of the complement and coagulation systems. The release of inflammatory mediators facilitates pneumococcal crossing of the blood-brain barrier into the brain, where the bacteria multiply freely and trigger activation of circulating antigen-presenting cells and resident microglial cells. The resulting massive inflammation leads to further neutrophil recruitment and inflammation, resulting in the well-known features of bacterial meningitis, including cerebrospinal fluid pleocytosis, cochlear damage, cerebral edema, hydrocephalus, and cerebrovascular complications. Experimental animal models continue to further our understanding of the pathophysiology of pneumococcal meningitis and provide the platform for the development of new adjuvant treatments and antimicrobial therapy. This review discusses the most recent views on the pathophysiology of pneumococcal meningitis, as well as potential targets for (adjunctive) therapy. PMID:21734248

  17. The pathophysiology of Peyronie's disease.

    Science.gov (United States)

    El-Sakka, Ahmed I; Salabas, Emre; Dinçer, Murat; Kadioglu, Ates

    2013-09-01

    To review the contemporary knowledge of the pathophysiology of Peyronie's disease (PD). Medline was searched for papers published in English from 2000 to March 2013, using the keywords 'Peyronie's disease' and 'pathophysiology'. More than 300 relevant articles were identified for the purpose of this review. Unfortunately only a few studies had a high level of evidence, and the remaining studies were not controlled in their design. Many theories have been proposed to explain the cause of PD, but the true pathogenesis of PD remains an enigma. Identifying particular growth factors and the specific genes responsible for the induction of PD have been the ultimate goal of research over the past several decades. This would provide the means to devise a possible gene therapy for this devastating condition. We discuss present controversies and new discoveries related to the pathophysiology of this condition. PD is one of the most puzzling diseases in urology. The pathogenesis remains uncertain and there is still controversy about the best management. The pathogenesis of PD has been explored in animal models, cell cultures and clinical trials, but the results have led to further questions. New research on the aetiology and pathogenesis of PD is needed, and which will hopefully improve the understanding and management for patients with this frustrating disease.

  18. Multi-disciplinary management of athletes with post-concussion syndrome: an evolving pathophysiological approach

    Directory of Open Access Journals (Sweden)

    Michael John Ellis

    2016-08-01

    Full Text Available Historically, patients with sports-related concussion (SRC have been managed in a uniform fashion consisting mostly of prescribed physical and cognitive rest with the expectation that all symptoms will spontaneously resolve with time. Although this approach will result in successful return to school and sports activities in the majority of athletes, an important proportion will develop persistent concussion symptoms characteristic of post-concussion syndrome (PCS. Recent advances in exercise science, neuroimaging, and clinical research suggest that the clinical manifestations of PCS are mediated by unique pathophysiological processes that can be identified by features of the clinical history and physical examination as well as the use of graded aerobic treadmill testing. Athletes who develop PCS represent a unique population whose care must be individualized and must incorporate a rehabilitative strategy that promotes enhanced recovery of concussion-related symptoms while preventing physical deconditioning. In this review we present our evolving evidence-based approach to evaluation and management of athletes with PCS that aims to identify the pathophysiological mechanisms mediating persistent concussion symptoms and guides the initiation of individually-tailored rehabilitation programs that target these processes. In addition, we outline the important qualified roles that multi-disciplinary healthcare professionals can play in the management of this patient population, and discuss where future research efforts must be focused to further validate this evolving pathophysiological approach.

  19. Multi-Disciplinary Management of Athletes with Post-Concussion Syndrome: An Evolving Pathophysiological Approach.

    Science.gov (United States)

    Ellis, Michael J; Leddy, John; Willer, Barry

    2016-01-01

    Historically, patients with sports-related concussion (SRC) have been managed in a uniform fashion consisting mostly of prescribed physical and cognitive rest with the expectation that all symptoms will spontaneously resolve with time. Although this approach will result in successful return to school and sports activities in the majority of athletes, an important proportion will develop persistent concussion symptoms characteristic of post-concussion syndrome (PCS). Recent advances in exercise science, neuroimaging, and clinical research suggest that the clinical manifestations of PCS are mediated by unique pathophysiological processes that can be identified by features of the clinical history and physical examination as well as the use of graded aerobic treadmill testing. Athletes who develop PCS represent a unique population whose care must be individualized and must incorporate a rehabilitative strategy that promotes enhanced recovery of concussion-related symptoms while preventing physical deconditioning. In this review, we present our evolving evidence-based approach to evaluation and management of athletes with PCS that aims to identify the pathophysiological mechanisms mediating persistent concussion symptoms and guides the initiation of individually tailored rehabilitation programs that target these processes. In addition, we outline the important qualified roles that multi-disciplinary healthcare professionals can play in the management of this patient population, and discuss where future research efforts must be focused to further evaluate this evolving pathophysiological approach.

  20. Tinnitus: Network pathophysiology-network pharmacology

    Directory of Open Access Journals (Sweden)

    Ana Belen eElgoyhen

    2012-01-01

    Full Text Available Tinnitus, the phantom perception of sound, is a prevalent disorder. One in 10 adults has clinically significant subjective tinnitus, and for 1 in 100, tinnitus severely affects their quality of life. Despite the significant unmet clinical need for a safe and effective drug targeting tinnitus relief, there is currently not a single FDA-approved drug on the market. The search for drugs that target tinnitus is hampered by the lack of a deep knowledge of the underlying neural substrates of this pathology. Recent studies are increasingly demonstrating that, as described for other central nervous system disorders, tinnitus is a pathology of brain networks. The application of graph theoretical analysis to brain networks has recently provided new information concerning their topology, their robustness and their vulnerability to attacks. Moreover, the philosophy behind drug design and pharmacotherapy in central nervous system pathologies is changing from that of magic bullets that target individual chemoreceptors or disease-causing genes into that of magic shotguns, promiscuous or dirty drugs that target disease-causing networks, also known as network pharmacology. In the present work we provide some insight into how this knowledge could be applied to tinnitus pathophysiology and pharmacotherapy.

  1. Tinnitus: network pathophysiology-network pharmacology.

    Science.gov (United States)

    Elgoyhen, Ana B; Langguth, Berthold; Vanneste, Sven; De Ridder, Dirk

    2012-01-01

    Tinnitus, the phantom perception of sound, is a prevalent disorder. One in 10 adults has clinically significant subjective tinnitus, and for one in 100, tinnitus severely affects their quality of life. Despite the significant unmet clinical need for a safe and effective drug targeting tinnitus relief, there is currently not a single Food and Drug Administration (FDA)-approved drug on the market. The search for drugs that target tinnitus is hampered by the lack of a deep knowledge of the underlying neural substrates of this pathology. Recent studies are increasingly demonstrating that, as described for other central nervous system (CNS) disorders, tinnitus is a pathology of brain networks. The application of graph theoretical analysis to brain networks has recently provided new information concerning their topology, their robustness and their vulnerability to attacks. Moreover, the philosophy behind drug design and pharmacotherapy in CNS pathologies is changing from that of "magic bullets" that target individual chemoreceptors or "disease-causing genes" into that of "magic shotguns," "promiscuous" or "dirty drugs" that target "disease-causing networks," also known as network pharmacology. In the present work we provide some insight into how this knowledge could be applied to tinnitus pathophysiology and pharmacotherapy.

  2. Oxidative stress in sickle cell disease; pathophysiology and potential implications for disease management.

    Science.gov (United States)

    Nur, Erfan; Biemond, Bart J; Otten, Hans-Martin; Brandjes, Dees P; Schnog, John-John B

    2011-06-01

    Sickle cell disease (SCD) is a hemoglobinopathy characterized by hemolytic anemia, increased susceptibility to infections and vaso-occlusion leading to a reduced quality of life and life expectancy. Oxidative stress is an important feature of SCD and plays a significant role in the pathophysiology of hemolysis, vaso-occlusion and ensuing organ damage in sickle cell patients. Reactive oxygen species (ROS) and the (end-)products of their oxidative reactions are potential markers of disease severity and could be targets for antioxidant therapies. This review will summarize the role of ROS in SCD and their potential implication for SCD management. Copyright © 2011 Wiley-Liss, Inc.

  3. Role of leukotrienes in asthma pathophysiology

    DEFF Research Database (Denmark)

    Bisgaard, H

    2000-01-01

    Inflammation is an essential component of asthma pathophysiology. While beta(2)-agonists are often used for short-term relief of acute bronchospasm, anti-inflammatory agents are required for the long-term management of chronic inflammation in this disease. Corticosteroids have emerged as the first......-line anti-inflammatory therapy for asthma management. However, in some patients, especially children, the high doses of corticosteroids that may be required to control features of hyperresponsiveness, including exercise-induced asthma, raise safety concerns. Thus, there is a need for complementary anti......-inflammatory, steroid-sparing agents in asthma therapy. Several inflammatory mediators have been targeted in an attempt to thwart this inflammatory process, but so far with little success. The cysteinyl leukotrienes (CysLT), LTC(4), LTD(4), and LTE(4), have been shown to be essential mediators in asthma, making them...

  4. Molecular pathophysiology of cerebral edema

    Science.gov (United States)

    Gerzanich, Volodymyr; Simard, J Marc

    2015-01-01

    Advancements in molecular biology have led to a greater understanding of the individual proteins responsible for generating cerebral edema. In large part, the study of cerebral edema is the study of maladaptive ion transport. Following acute CNS injury, cells of the neurovascular unit, particularly brain endothelial cells and astrocytes, undergo a program of pre- and post-transcriptional changes in the activity of ion channels and transporters. These changes can result in maladaptive ion transport and the generation of abnormal osmotic forces that, ultimately, manifest as cerebral edema. This review discusses past models and current knowledge regarding the molecular and cellular pathophysiology of cerebral edema. PMID:26661240

  5. Narcolepsy: Pathophysiology and Neuropsychological Changes

    Directory of Open Access Journals (Sweden)

    Angela Naumann

    2003-01-01

    Full Text Available Narcolepsy is now recognized as a distinctive disorder with specific pathophysiology and neurochemical abnormalities. Findings on the role of the neuropeptide hypocretin are opening new avenues of research and new strategies for therapy. Recently, neuropsychological and electrophysiological studies have provided evidence for reduced memory performance on standard memory tests in addition to subjective complaints of forgetfulness which may be related to changes in attentional processing. Further studies are, however, necessary to clarify the neuropsychological profile in narcolepsy. This review focuses on the recent advances in understanding narcolepsy.

  6. Identification of functionally important amino acid residues in the mitochondria targeting sequence of Hepatitis B virus X protein

    International Nuclear Information System (INIS)

    Li, Sai Kam; Ho, Sai Fan; Tsui, Kwok Wing; Fung, Kwok Pui; Waye, M.Y. Mary

    2008-01-01

    Chronic hepatitis B virus (HBV) infection has been strongly associated with hepatocellular carcinoma (HCC) and the X protein (HBx) is thought to mediate the cellular changes associated with carcinogenesis. Recently, isolation of the hepatitis B virus integrants from HCC tissue by others have established the fact that the X gene is often truncated at its C-terminus. Expression of the GFP fusion proteins of HBx and its truncation mutants with a GFP tag in human liver cell-lines in this study revealed that the C-terminus of HBx is indispensable for its specific localization in the mitochondria. A crucial region of seven amino acids at the C-terminus has been mapped out in which the cysteine residue at position 115 serves as the most important residue for the subcellular localization. When cysteine 115 of HBx is mutated to alanine the mitochondria targeting property of HBx is abrogated

  7. Short overview on metabolomics approach to study pathophysiology of oxidative stress in cancer

    Directory of Open Access Journals (Sweden)

    Luka Andrisic

    2018-04-01

    Full Text Available Association of oxidative stress with carcinogenesis is well known, but not understood well, as is pathophysiology of oxidative stress generated during different types of anti-cancer treatments. Moreover, recent findings indicate that cancer associated lipid peroxidation might eventually help defending adjacent nonmalignant cells from cancer invasion. Therefore, untargeted metabolomics studies designed for advanced translational and clinical studies are needed to understand the existing paradoxes in oncology, including those related to controversial usage of antioxidants aiming to prevent or treat cancer. In this short review we have tried to put emphasis on the importance of pathophysiology of oxidative stress and lipid peroxidation in cancer development in relation to metabolic adaptation of particular types of cancer allowing us to conclude that adaptation to oxidative stress is one of the main driving forces of cancer pathophysiology. With the help of metabolomics many novel findings are being achieved thus encouraging further scientific breakthroughs. Combined with targeted qualitative and quantitative methods, especially immunochemistry, further research might reveal bio-signatures of individual patients and respective malignant diseases, leading to individualized treatment approach, according to the concepts of modern integrative medicine. Keywords: Carcinogenesis, Cancer, Oxidative stress, Lipid peroxidation, 4-hydroxynonenal, Glutathione, Metabolomics, Immunochemistry, Biomarkers, Omics science

  8. [Current concepts in pathophysiology of CRPS I].

    Science.gov (United States)

    Nickel, F T; Maihöfner, C

    2010-02-01

    Knowledge about the pathophysiology underlying the complex regional pain syndrome (CRPS) has increased over the last years. Classically, CRPS has been considered to be mainly driven by sympathetic dysfunction with sympathetically maintained pain being its major pathogenetic mechanism. Currently, the disease is understood as result of a complex interplay between altered somatosensory, motor, autonomic and inflammatory systems. Peripheral and central sensitization is a common feature in CRPS as in other neuropathic pain syndromes. One important mechanism is the sensitization of spinal dorsal horn cells via activation of postsynaptic NMDA-receptors by chronic C-fiber input. Differential activity of endogenous pain modulating systems may play a pivotal role in the development of CRPS, too. Neuronal plasticity of the somatosensory cortex accounts for central sensory signs. Also the motor system is subject to central adaptive changes in patients with CRPS. Calcitonin-gene related peptide (CGRP) and substance P mediate neurogenic inflammation. Additionally other proinflammatory cytokines involved in the inflammatory response in CRPS have been identified. In terms of the sympathetic nervous system, recent evidence rather points to a sensitization of adrenergic receptors than to increased efferent sympathetic activity. Particularly the expression of alpha (1)-adrenoceptors on nociceptive C-fibers may play a major role. These pathophysiological ideas do not exclude each other. In fact they complement one another. The variety of the involved systems may explain the versatile clinical picture of CRPS. Georg Thieme Verlag KG Stuttgart, New York.

  9. The Pathophysiology of Eosinophilic Esophagitis

    Directory of Open Access Journals (Sweden)

    Daniel Avi Lemberg

    2014-05-01

    Full Text Available Eosinophilic Esophagitis (EoE is an emerging disease characterised by esophageal eosinophilia (>15eos/hpf, lack of responsiveness to acid-suppressive medication and is managed by allergen elimination and anti-allergy therapy. Although the pathophysiology of EoE is currently unsubstantiated, evidence implicates food and aeroallergen hypersensitivity in genetically predisposed individuals as contributory factors. Genome-wide expression analyses have isolated a remarkably conserved gene-expression profile irrespective of age and gender, suggesting a genetic contribution. EoE has characteristics of mainly TH2 type immune responses but also some TH1 cytokines, which appear to strongly contribute to tissue fibrosis, with esophageal epithelial cells providing a hospitable environment for this inflammatory process. Eosinophil-degranulation products appear to play a central role in tissue remodeling in EoE. This remodeling and dysregulation predisposes to fibrosis. Mast cell-derived molecules such as histamine may have an effect on enteric nerves and may also act in concert with TGF-β to interfere with esophageal musculature. Additionally, the esophageal epithelium may facilitate the inflammatory process under pathogenic contexts such as in EoE. This article aims to discuss the contributory factors in the pathophysiology of EoE.

  10. 95th Anniversary of Pathophysiology in Croatia.

    Science.gov (United States)

    Kovač, Zdenko

    2017-12-01

    lasting legacy on generations to come. Professor Stjepan Gamulin made molecular medicine the working reality at Rebro. Both in clinical research, and in health system as diagnostic service and tool for all centers in Croatia, molecular measurement in tissue samples came into usage in daily physicians reasoning and therapy prescriptions. Macromolecular aspects of disease have come of age and became clinimetric signs of patients' condition. Professor Gamulin with his group and associated authors wrote the textbook of pathophysiology, which in upcoming 30 years had 7 editions, has become the bestseller in medicine. The textbook was translated and published in English and Albanian. In the most recent book professor Gamulin turned the focus of medical community to clinical epidemiology and a need for retrospective insights into medical efficiency. Medical performance can be improved with the improvement of understanding of underlying etiopathogenetic relations as the foundation of therapy-is the main message. Following the academic legacy and spirit of three charismatic authorities we established two methods of teaching/learning in medicine. The two methods opened up a new avenue, so important for the era of postgenomic plethora of information and demands of precision/personalized medicine. Methodology has been introduced timely. It is student-friendly and usable for advanced types of education. Problem based algorhytmic matrices stimulate analysis and resynthesis of etiopathogenetic pathways. Graphic presentation of the solution integrates horizontal, vertical and longitudinal aspects of the problem. The companion textbook in the form of problem solver has been published in 3 editions, and contains 128 study solved cases. It was published in English, as well. Out of algorhythmic analysis the etiopathogenetic clusters (EPCs) are composed of etiopathogenetic pathway analysis. EPCs are natural units of disease development, the crossing points of processes. They are integrative

  11. Quantitative Phase Imaging Techniques for the Study of Cell Pathophysiology: From Principles to Applications

    Directory of Open Access Journals (Sweden)

    Hyunjoo Park

    2013-03-01

    Full Text Available A cellular-level study of the pathophysiology is crucial for understanding the mechanisms behind human diseases. Recent advances in quantitative phase imaging (QPI techniques show promises for the cellular-level understanding of the pathophysiology of diseases. To provide important insight on how the QPI techniques potentially improve the study of cell pathophysiology, here we present the principles of QPI and highlight some of the recent applications of QPI ranging from cell homeostasis to infectious diseases and cancer.

  12. Understanding changes in cardiovascular pathophysiology.

    Science.gov (United States)

    Chummun, Harry

    Cardiovascular pathophysiological changes, such as hypertension and enlarged ventricles, reflect the altered functions of the heart and its circulation during ill-health. This article examines the normal and altered anatomy of the cardiac valves, the contractile elements and enzymes of the myocardium, the significance of the different factors associated with cardiac output, and the role of the autonomic nervous system in the heart beat. It also explores how certain diseases alter these functions and result in cardiac symptoms. Nurses can benefit from knowledge of these specific changes, for example, by being able to ask relevant questions in order to ascertain the nature of a patients condition, by being able to take an effective patient history and by being able to read diagnostic results, such as electrocardiograms and cardiac enzyme results. All this will help nurses to promote sound cardiac care based on a physiological rationale.

  13. Pathophysiology of MDS: genomic aberrations.

    Science.gov (United States)

    Ichikawa, Motoshi

    2016-01-01

    Myelodysplastic syndromes (MDS) are characterized by clonal proliferation of hematopoietic stem/progenitor cells and their apoptosis, and show a propensity to progress to acute myelogenous leukemia (AML). Although MDS are recognized as neoplastic diseases caused by genomic aberrations of hematopoietic cells, the details of the genetic abnormalities underlying disease development have not as yet been fully elucidated due to difficulties in analyzing chromosomal abnormalities. Recent advances in comprehensive analyses of disease genomes including whole-genome sequencing technologies have revealed the genomic abnormalities in MDS. Surprisingly, gene mutations were found in approximately 80-90% of cases with MDS, and the novel mutations discovered with these technologies included previously unknown, MDS-specific, mutations such as those of the genes in the RNA-splicing machinery. It is anticipated that these recent studies will shed new light on the pathophysiology of MDS due to genomic aberrations.

  14. Preeclampsia: from Pathophysiology to Treatment

    Directory of Open Access Journals (Sweden)

    Kaculini Enton

    2016-12-01

    Full Text Available Preeclampsia is a multisystem disorder unique to human pregnancy and is its most common glomerular complication. It occurs in 2% to 8% of pregnancies and is a major contributor to maternal mortality worldwide. Although the pathophysiology of this syndrome is not fully understood, many pathogenetic mechanisms are involved in this disorder. The role of the placenta is crucial in the development of this disorder. Some pathogenetic mechanisms involved in this disease comprise defective deep placentation, autoantibodies to type-1 angiotensin II receptor, endothelial dysfunction, oxidative stress, platelet and thrombin activation, intravascular inflammation, and the imbalance between angiogenic and antiangiogenic factors which is thought to be one of the most crucial mechanisms. Further understanding of the full picture could enhance our current knowledge of the pathogenesis of preeclampsia and improve its treatment. Thus, based on specific biomarkers the diagnosis and subclassification of preeclampsia might be more accurate in identifying patients at risk, monitoring disease progression and providing effective interventions

  15. Contrast medium-induced nephropathy: the pathophysiology

    DEFF Research Database (Denmark)

    Persson, P B; Tepel, Martin

    2006-01-01

    A widespread, rather general, definition of contrast-induced nephropathy (CIN) is an impairment in renal function occurring within 3 days following the intravascular administration of contrast media (CM) and the absence of an alternative aetiology. In spite of the vast clinical importance of CIN...... haemodynamics, regional hypoxia, auto-, and paracrine factors (adenosine, endothelin, reactive oxygen species) to direct cytotoxic effects. Although these potential mediators of CIN will be discussed separately, several factors may act in concert to perturb kidney function after exposure to contrast media. From...... the current knowledge of the mechanisms causing CIN, it is not possible to recommend a certain class of contrast media, except to avoid large doses of CM of the first generation. From a pathophysiological perspective, volume expansion is effective in avoiding CIN, since water permeability of the collecting...

  16. 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

  17. Nuclear import inhibitor N-(4-hydroxyphenyl) retinamide targets Zika virus (ZIKV) nonstructural protein 5 to inhibit ZIKV infection.

    Science.gov (United States)

    Wang, Chunxiao; Yang, Sundy N Y; Smith, Kate; Forwood, Jade K; Jans, David A

    2017-12-02

    In the absence of approved therapeutics, Zika virus (ZIKV)'s recent prolific outbreaks in the Americas, together with impacts on unborn fetuses of infected mothers, make it a pressing human health concern worldwide. Although a key player in viral replication in the infected host cell cytoplasm, ZIKV non-structural protein 5 (NS5) appears to contribute integrally to pathogenesis by localising in the host cell nucleus, in similar fashion to NS5 from Dengue virus (DENV). We show here for the first time that ZIKV NS5 is recognized with high nanomolar affinity by the host cell importin α/β1 heterodimer, and that this interaction can be blocked by the novel DENV NS5 targeting inhibitor N-(4-hydroxyphenyl) retinamide (4-HPR). Importantly, we show that 4-HPR has potent anti-ZIKV activity at low μM concentrations. With an established safety profile for human use, 4-HPR represents an exciting possibility as an anti-ZIKV agent. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. The Importance of Target Market Selection for More Profitable Olive Oil Exports by Turkey: A Case Study

    Directory of Open Access Journals (Sweden)

    Mustafa METE

    2015-12-01

    Full Text Available In this study, the quotas and taxes implemented by EU to Turkey were examined and it was observed that these policies have negative effects on Turkey’s olive oil exports. Due to the restrictive policies and low profitability in the entry to the EU market, it was determined that Turkey should be directed to the markets that have higher profitability compared with the exports to EU countries. These detections were carried out in accordance with the information obtained from International Trade Center (ITC and Market Access Database (MAD. As a result of the detections it has been found that exports to the EU countries are more profitable and the entry to the market is easier than to the US. As a result of the researches in ITC and MAD databases, actual companies in oil imports in the US market have been determined and it has shown by examining a bill of loading sample that the firms that make olive oils exports in Turkey easily enter new target markets if they know the usage of the databases

  19. An update on oxidative stress-mediated organ pathophysiology.

    Science.gov (United States)

    Rashid, Kahkashan; Sinha, Krishnendu; Sil, Parames C

    2013-12-01

    Exposure to environmental pollutants and drugs can result in pathophysiological situations in the body. Research in this area is essential as the knowledge on cellular survival and death would help in designing effective therapeutic strategies that are needed for the maintenance of the normal physiological functions of the body. In this regard, naturally occurring bio-molecules can be considered as potential therapeutic targets as they are normally available in commonly consumed foodstuffs and are thought to have minimum side effects. This review article describes the detailed mechanisms of oxidative stress-mediated organ pathophysiology and the ultimate fate of the cells either to survive or to undergo necrotic or apoptotic death. The mechanisms underlying the beneficial role of a number of naturally occurring bioactive molecules in oxidative stress-mediated organ pathophysiology have also been included in the review. The review provides useful information about the recent progress in understanding the mechanism(s) of various types of organ pathophysiology, the complex cross-talk between these pathways, as well as their modulation in stressed conditions. Additionally, it suggests possible therapeutic applications of a number of naturally occurring bioactive molecules in conditions involving oxidative stress. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. Capillary leak syndrome: etiologies, pathophysiology, and management.

    Science.gov (United States)

    Siddall, Eric; Khatri, Minesh; Radhakrishnan, Jai

    2017-07-01

    In various human diseases, an increase in capillary permeability to proteins leads to the loss of protein-rich fluid from the intravascular to the interstitial space. Although sepsis is the disease most commonly associated with this phenomenon, many other diseases can lead to a "sepsis-like" syndrome with manifestations of diffuse pitting edema, exudative serous cavity effusions, noncardiogenic pulmonary edema, hypotension, and, in some cases, hypovolemic shock with multiple-organ failure. The term capillary leak syndrome has been used to describe this constellation of disease manifestations associated with an increased capillary permeability to proteins. Diseases other than sepsis that can result in capillary leak syndrome include the idiopathic systemic capillary leak syndrome or Clarkson's disease, engraftment syndrome, differentiation syndrome, the ovarian hyperstimulation syndrome, hemophagocytic lymphohistiocytosis, viral hemorrhagic fevers, autoimmune diseases, snakebite envenomation, and ricin poisoning. Drugs including some interleukins, some monoclonal antibodies, and gemcitabine can also cause capillary leak syndrome. Acute kidney injury is commonly seen in all of these diseases. In addition to hypotension, cytokines are likely to be important in the pathophysiology of acute kidney injury in capillary leak syndrome. Fluid management is a critical part of the treatment of capillary leak syndrome; hypovolemia and hypotension can cause organ injury, whereas capillary leakage of administered fluid can worsen organ edema leading to progressive organ injury. The purpose of this article is to discuss the diseases other than sepsis that produce capillary leak and review their collective pathophysiology and treatment. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  1. The steroid catabolic pathway of the intracellular pathogen Rhodococcus equi is important for pathogenesis and a target for vaccine development.

    Directory of Open Access Journals (Sweden)

    R van der Geize

    2011-08-01

    Full Text Available Rhodococcus equi causes fatal pyogranulomatous pneumonia in foals and immunocompromised animals and humans. Despite its importance, there is currently no effective vaccine against the disease. The actinobacteria R. equi and the human pathogen Mycobacterium tuberculosis are related, and both cause pulmonary diseases. Recently, we have shown that essential steps in the cholesterol catabolic pathway are involved in the pathogenicity of M. tuberculosis. Bioinformatic analysis revealed the presence of a similar cholesterol catabolic gene cluster in R. equi. Orthologs of predicted M. tuberculosis virulence genes located within this cluster, i.e. ipdA (rv3551, ipdB (rv3552, fadA6 and fadE30, were identified in R. equi RE1 and inactivated. The ipdA and ipdB genes of R. equi RE1 appear to constitute the α-subunit and β-subunit, respectively, of a heterodimeric coenzyme A transferase. Mutant strains RE1ΔipdAB and RE1ΔfadE30, but not RE1ΔfadA6, were impaired in growth on the steroid catabolic pathway intermediates 4-androstene-3,17-dione (AD and 3aα-H-4α(3'-propionic acid-5α-hydroxy-7aβ-methylhexahydro-1-indanone (5α-hydroxy-methylhexahydro-1-indanone propionate; 5OH-HIP. Interestingly, RE1ΔipdAB and RE1ΔfadE30, but not RE1ΔfadA6, also displayed an attenuated phenotype in a macrophage infection assay. Gene products important for growth on 5OH-HIP, as part of the steroid catabolic pathway, thus appear to act as factors involved in the pathogenicity of R. equi. Challenge experiments showed that RE1ΔipdAB could be safely administered intratracheally to 2 to 5 week-old foals and oral immunization of foals even elicited a substantial protective immunity against a virulent R. equi strain. Our data show that genes involved in steroid catabolism are promising targets for the development of a live-attenuated vaccine against R. equi infections.

  2. Tuberculosis 2: Pathophysiology and microbiology of pulmonary ...

    African Journals Online (AJOL)

    2005-08-01

    Aug 1, 2005 ... February 2013 Downloaded from www.southsudanmedicaljournal.com. MaIN arTIClES. 10. Tuberculosis 2: Pathophysiology and microbiology of pulmonary tuberculosis. Robert L. Serafino Wania MBBS, MrCP, MSc (Trop Med). Pathophysiology. Inhalation of Mycobacterium tuberculosis leads to one of.

  3. Pathophysiologic mechanisms of biomedical nanomaterials

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Liming, E-mail: wangliming@ihep.ac.cn; Chen, Chunying, E-mail: chenchy@nanoctr.cn

    2016-05-15

    Nanomaterials (NMs) have been widespread used in biomedical fields, daily consuming, and even food industry. It is crucial to understand the safety and biomedical efficacy of NMs. In this review, we summarized the recent progress about the physiological and pathological effects of NMs from several levels: protein-nano interface, NM-subcellular structures, and cell–cell interaction. We focused on the detailed information of nano-bio interaction, especially about protein adsorption, intracellular trafficking, biological barriers, and signaling pathways as well as the associated mechanism mediated by nanomaterials. We also introduced related analytical methods that are meaningful and helpful for biomedical effect studies in the future. We believe that knowledge about pathophysiologic effects of NMs is not only significant for rational design of medical NMs but also helps predict their safety and further improve their applications in the future. - Highlights: • Rapid protein adsorption onto nanomaterials that affects biomedical effects • Nanomaterials and their interaction with biological membrane, intracellular trafficking and specific cellular effects • Nanomaterials and their interaction with biological barriers • The signaling pathways mediated by nanomaterials and related biomedical effects • Novel techniques for studying translocation and biomedical effects of NMs.

  4. Pathophysiologic mechanisms of biomedical nanomaterials

    International Nuclear Information System (INIS)

    Wang, Liming; Chen, Chunying

    2016-01-01

    Nanomaterials (NMs) have been widespread used in biomedical fields, daily consuming, and even food industry. It is crucial to understand the safety and biomedical efficacy of NMs. In this review, we summarized the recent progress about the physiological and pathological effects of NMs from several levels: protein-nano interface, NM-subcellular structures, and cell–cell interaction. We focused on the detailed information of nano-bio interaction, especially about protein adsorption, intracellular trafficking, biological barriers, and signaling pathways as well as the associated mechanism mediated by nanomaterials. We also introduced related analytical methods that are meaningful and helpful for biomedical effect studies in the future. We believe that knowledge about pathophysiologic effects of NMs is not only significant for rational design of medical NMs but also helps predict their safety and further improve their applications in the future. - Highlights: • Rapid protein adsorption onto nanomaterials that affects biomedical effects • Nanomaterials and their interaction with biological membrane, intracellular trafficking and specific cellular effects • Nanomaterials and their interaction with biological barriers • The signaling pathways mediated by nanomaterials and related biomedical effects • Novel techniques for studying translocation and biomedical effects of NMs

  5. Pathophysiology of AAA: heredity vs environment.

    Science.gov (United States)

    Björck, Martin; Wanhainen, Anders

    2013-01-01

    Abdominal aortic aneurysm (AAA) has a complex pathophysiology, in which both environmental and genetic factors play important roles, the most important being smoking. The recently reported falling prevalence rates of AAA in northern Europe and Australia/New Zeeland are largely explained by healthier smoking habits. Dietary factors and obesity, in particular abdominal obesity, are also of importance. A family history of AAA among first-degree relatives is present in approximately 13% of incident cases. The probability that a monozygotic twin of a person with an AAA has the disease is 24%, 71 times higher than that for a monozygotic twin of a person without AAA. Approximately 1000 SNPs in 100 candidate genes have been studied, and three genome-wide association studies were published, identifying different diverse weak associations. An example of interaction between environmental and genetic factors is the effect of cholesterol, where genetic and dietary factors affect levels of both HDL and LDL. True epigenetic studies have not yet been published. Copyright © 2013 Elsevier Inc. All rights reserved.

  6. SU-E-J-75: Importance of 4DCT for Target Volume Definition in Stereotactic Lung Radiotherapy

    International Nuclear Information System (INIS)

    Goksel, E; Cone, D; Kucucuk, H; Senkesen, O; Yilmaz, M; Aslay, I; Tezcanli, E; Garipagaoglu, M; Sengoz, M

    2014-01-01

    Purpose: We aimed to investigate the importance of 4DCT for lung tumors treated with SBRT and whether maximum intensity projection (MIP) and free breathing (FB) images can compansate for tumor movement. Methods: Six patients with primary lung cancer and 2 patients with lung metastasis with a median age of 69.5 (42–86) were included. Patients were positioned supine on a vacuum bag. In addition to FB planning CT images, 4DCT images were obtained at 3 mm intervals using Varian RPM system with (Siemens Somatom Sensetion 64). MIP series were reconstructed using 4DCT images. PTV-FB and PTV-MIP (GTV+5mm) volumes were contoured using FB and MIP series, respectively. GTVs were defined on each of eight different breathing phase images and were merged to create the ITV. PTV-4D was generated with a 5 mm margin to ITV. PTV-MIP and PTV-4D contours were copied to FB CT series and treatment plans for PTV-MIP and PTV-FB were generated using RapidArc (2 partial arc) technique in Eclipse (version 11, AAA algorithm). The prescription dose was 5600cGy in 7 fractions. ITV volumes receiving prescription dose (%) and V95 for ITV were calculated for each treatment plan. Results: The mean PTV-4B, PTV-MIP and PTV-FB volumes were 23.2 cc, 15.4cc ve 11cc respectively. Median volume of ITV receiving the prescription dose was 34.6% (16.4–70 %) and median V95 dose for ITV was 1699cGy (232cGy-5117cGy) in the plan optimized for PTV-FB as the reference. When the plan was optimized for PTV-MIP, median ITV volume receiving the prescription dose was 67.15% (26–86%) and median V95 dose for ITV was 4231cGy (1735cGy-5290cGy). Conclusion: Images used in lung SBRT are critical for treatment quality; FB and MIP images did not compensate target movement, therefore 4DCT images should be obtained for all patients undergoing lung SBRT or the safety margins should be adjusted

  7. The pathophysiology of heart failure.

    Science.gov (United States)

    Kemp, Clinton D; Conte, John V

    2012-01-01

    Heart failure is a clinical syndrome that results when the heart is unable to provide sufficient blood flow to meet metabolic requirements or accommodate systemic venous return. This common condition affects over 5 million people in the United States at a cost of $10-38 billion per year. Heart failure results from injury to the myocardium from a variety of causes including ischemic heart disease, hypertension, and diabetes. Less common etiologies include cardiomyopathies, valvular disease, myocarditis, infections, systemic toxins, and cardiotoxic drugs. As the heart fails, patients develop symptoms which include dyspnea from pulmonary congestion, and peripheral edema and ascites from impaired venous return. Constitutional symptoms such as nausea, lack of appetite, and fatigue are also common. There are several compensatory mechanisms that occur as the failing heart attempts to maintain adequate function. These include increasing cardiac output via the Frank-Starling mechanism, increasing ventricular volume and wall thickness through ventricular remodeling, and maintaining tissue perfusion with augmented mean arterial pressure through activation of neurohormonal systems. Although initially beneficial in the early stages of heart failure, all of these compensatory mechanisms eventually lead to a vicious cycle of worsening heart failure. Treatment strategies have been developed based upon the understanding of these compensatory mechanisms. Medical therapy includes diuresis, suppression of the overactive neurohormonal systems, and augmentation of contractility. Surgical options include ventricular resynchronization therapy, surgical ventricular remodeling, ventricular assist device implantation, and heart transplantation. Despite significant understanding of the underlying pathophysiological mechanisms in heart failure, this disease causes significant morbidity and carries a 50% 5-year mortality. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. Stroke MRI: pathophysiology, potential and perspectives

    International Nuclear Information System (INIS)

    Fiehler, J.; Kucinski, T.; Zeumer, H.

    2004-01-01

    Magnetic resonance imaging (MRT) is increasingly utilized as the primary imaging modality in major stroke centers. The ability to depict several aspects of individual pathophysiology makes the use of MRI in stroke both attractive and complex. Profound knowledge of the pathophysiology of the imaging findings is crucial for a rational diagnostic workup. The pathophysiology of MRI in stroke will be reviewed considering recent experiences in clinical application, and the potential of stroke MRI will be assessed. Further perspectives like application of 'blood oxygen level dependent' (BOLD) and the use of multiparametric prediction maps will be discussed. (orig.) [de

  9. Synaptic Loss and the Pathophysiology of PTSD: Implications for Ketamine as a Prototype Novel Therapeutic

    Science.gov (United States)

    Krystal, John H.; Abdallah, Chadi G.; Averill, Lynette A.; Kelmendi, Benjamin; Harpaz-Rotem, Ilan; Sanacora, Gerard; Southwick, Steven M.; Duman, Ronald S.

    2018-01-01

    Purpose of Review Studies of the neurobiology and treatment of PTSD have highlighted many aspects of the pathophysiology of this disorder that might be relevant to treatment. The purpose of this review is to highlight the potential clinical importance of an often-neglected consequence of stress models in animals that may be relevant to PTSD: the stress-related loss of synaptic connectivity. Recent Findings Here, we will briefly review evidence that PTSD might be a “synaptic disconnection syndrome” and highlight the importance of this perspective for the emerging therapeutic application of ketamine as a potential rapid-acting treatment for this disorder that may work, in part, by restoring synaptic connectivity. Summary Synaptic disconnection may contribute to the profile of PTSD symptoms that may be targeted by novel pharmacotherapeutics. PMID:28844076

  10. Chemical sensitivity: pathophysiology or pathopsychology?

    Science.gov (United States)

    Genuis, Stephen J

    2013-05-01

    symptoms in some cases. Sustained resolution of the CS state occurs after successful elimination of the accrued body burden of toxicants through natural mechanisms of toxicant bioelimination and/or interventions of clinical detoxification. Despite extensive clinical evidence to support the veracity of this clinical state, many members of the medical community are reluctant to accept this condition as a pathophysiologic disorder. The emerging problem of ubiquitous adverse toxicant exposures in modern society has resulted in escalating numbers of individuals developing a CS disorder. As usual in medical history, iconoclastic ideas and emerging evidence regarding novel disease mechanisms, such as the pathogenesis of CS, have been met with controversy, resistance, and sluggish knowledge translation. Copyright © 2013 Elsevier HS Journals, Inc. All rights reserved.

  11. Setting ART initiation targets in response to changing guidelines: The importance of addressing both steady-state and backlog.

    Science.gov (United States)

    Martin, Catherine; Naidoo, Nicolette P; Venter, W D Francois; Jaffer, Ambereen; Barker, Pierre M

    2014-05-12

    Target setting is useful in planning, assessing and improving antiretroviral treatment (ART) programmes. In the past 4 years, the ART initiation environment has been transformed due to the change in eligibility criteria (starting ART at a CD4+ count ART. To describe and illustrate the use of a target-setting model for estimating district-based targets in the era of an expanding ART programme and changing CD4+ count thresholds for ART initiation. Using previously described models and data for annual new HIV infections, we estimated both steady-state need for ART initiation and backlog in a North West Province district, accounting for the shift in eligibility. Comparison of actual v. targeted ART initiations was undertaken. The change in CD4+ count threshold adds a once-off group of newly eligible patients to the pool requiring ART - the backlog. The steady-state remains unchanged as it is determined by the annual rate of new HIV infections in previous years. The steady-state need for the district was 639 initiations/month, and the backlog was ~15,388 patients. After the shift in eligibility in September 2011, the steady-state target was exceeded over several months with some backlog addressed. Of the total backlog for this district, 72% remains to be cleared. South Africa has two pools of patients who need ART: the steady-state of HIV-infected patients entering the programme each year, determined by historical infection rates; and the backlog created by the shift in eligibility. The healthcare system needs to build long- term capacity to meet the steady-state need for ART and additional capacity to address the backlog.

  12. Thalassemia: Pathophysiology and management. Part A

    International Nuclear Information System (INIS)

    Fucharoen, S.; Rowley, P.T.; Paul, N.W.

    1988-01-01

    This book contains papers divided among the following sections: molecular biology and pathogenesis; pathophysiology - molecular and cellular; clinical manifestations and hematologic changes; cardiopulmonary defects and platelet function; hormones and minerals; and infection and immunology

  13. A vicious circle in chronic lymphoedema pathophysiology?

    DEFF Research Database (Denmark)

    Cucchi, F; Rossmeislova, L; Simonsen, L

    2017-01-01

    Chronic lymphoedema is a disease caused by a congenital or acquired damage to the lymphatic system and characterized by complex chains of pathophysiologic events such as lymphatic fluid stasis, chronic inflammation, lymphatic vessels impairment, adipose tissue deposition and fibrosis. These event....... Together, these observations indicate strong reciprocal relationship between lymphatics and adipose tissue and suggest a possible key role of the adipocyte in the pathophysiology of chronic lymphoedema's vicious circle....

  14. Identifying diabetes-related important protein targets with few interacting partners with the PageRank algorithm.

    Science.gov (United States)

    Grolmusz, Vince I

    2015-04-01

    Diabetes is a growing concern for the developed nations worldwide. New genomic, metagenomic and gene-technologic approaches may yield considerable results in the next several years in its early diagnosis, or in advances in therapy and management. In this work, we highlight some human proteins that may serve as new targets in the early diagnosis and therapy. With the help of a very successful mathematical tool for network analysis that formed the basis of the early successes of Google(TM), Inc., we analyse the human protein-protein interaction network gained from the IntAct database with a mathematical algorithm. The novelty of our approach is that the new protein targets suggested do not have many interacting partners (so, they are not hubs or super-hubs), so their inhibition or promotion probably will not have serious side effects. We have identified numerous possible protein targets for diabetes therapy and/or management; some of these have been well known for a long time (these validate our method), some of them appeared in the literature in the last 12 months (these show the cutting edge of the algorithm), and the remainder are still unknown to be connected with diabetes, witnessing completely new hits of the method.

  15. The space-math link in preschool boys and girls: Importance of mental transformation, targeting accuracy, and spatial anxiety.

    Science.gov (United States)

    Wong, Wang I

    2017-06-01

    Spatial abilities are pertinent to mathematical competence, but evidence of the space-math link has largely been confined to older samples and intrinsic spatial abilities (e.g., mental transformation). The roles of gender and affective factors are also unclear. This study examined the correlations between counting ability, mental transformation, and targeting accuracy in 182 Hong Kong preschoolers, and whether these relationships were weaker at higher spatial anxiety levels. Both spatial abilities related with counting similarly for boys and girls. Targeting accuracy also mediated the male advantage in counting. Interestingly, spatial anxiety moderated the space-math links, but differently for boys and girls. For boys, spatial abilities were irrelevant to counting at high anxiety levels; for girls, the role of anxiety on the space-math link is less clear. Results extend the evidence base of the space-math link to include an extrinsic spatial ability (targeting accuracy) and have implications for intervention programmes. Statement of contribution What is already known on this subject? Much evidence of a space-math link in adolescent and adult samples and for intrinsic spatial abilities. What does this study add? Extended the space-math link to include both intrinsic and extrinsic spatial abilities in a preschool sample. Showed how spatial anxiety moderated the space-math link differently for boys and girls. © 2016 The British Psychological Society.

  16. Pathophysiological mechanisms in antiphospholipid syndrome

    Science.gov (United States)

    Harper, Brock E; Wills, Rohan; Pierangeli, Silvia S

    2013-01-01

    Antiphospholipid syndrome is a systemic autoimmune disease associated with thrombosis and recurrent fetal loss in the setting of detectable antiphospholipid (aPL) antibodies. The major antigenic target has been identifed as β2-glycoprotein I (β2GPI), which mediates binding of aPL antibodies to target cells including endothelial cells, monocytes, platelets and trophoblasts, leading to prothrombotic and proinfammatory changes that ultimately result in thrombosis and fetal loss. This article summarizes recent insights into the role of β2GPI in normal hemostasis, interactions between aPL antibodies, β2GPI and cell-surface molecules, molecular prothrombotic and proinfammatory changes induced by aPL antibodies and pathogenic changes leading to fetal loss in antiphospholipid syndrome. New directions in therapy using these insights are examined. PMID:23487578

  17. Orexinergic system and pathophysiology of epilepsy.

    Science.gov (United States)

    Doreulee, N; Alania, M; Vashalomidze, G; Skhirtladze, E; Kapanadze, Ts

    2010-11-01

    Neuropeptids orexins, also known as the hypocretins, are expressed in the lateral hypothalamus. Orexin-containing cells project widely throughout the brains, are crucial for the regulation of wakefulness and dysfunction of this system is associated with pathophysiology of narcolepsy-cataplexy. Orexin neurons play an important role in motivation, feeding and adaptive behaviors. Distribution of orexinergic receptors in the hippocampus tended to the ideas that orexins might be involved in the functions relating to the hippocampus. Effects of neuropeptide orexin-A on epileptiform activity in hippocampal slices were investigated. 500 µm thick hippocampal slices from 8-10 week-old rodents were used. Field excitatory postsynaptic potential (pop-fEPSP) and population spike in CA1 of hippocamopus were registered using standard protocol of in vitro electrophysiological experiments. Initial slope of the fEPSP and amplitude of II pop-spike were measured. Bursting neurons in CA3 were recorded in modified saline. We have found that orexin-A decreases duration/amplitude of multiple discharges of pop-spikes and inhibits spontaneous epileptiform afterdischarges induced by bicuculline methiodide in CA1. Orexin-A also modulates the frequency of discharges of bursting neurons in CA3. Our results suggest possible involvement of orexinergic system in antiepileptic action. Supported by ISTC Grant G-1318.

  18. Metabolic syndrome pathophysiology and clinical presentation.

    Science.gov (United States)

    Handelsman, Yehuda

    2009-01-01

    Metabolic syndrome is a relatively new definition, designed to help the health care practitioner to easily identify people at risk for the development of cardiovascular disease and diabetes. With the obesity epidemic, we are witnessing an epidemic of multiple-risk patients. Insulin resistance is the perceived pathophysiology of metabolic syndrome and defines its clinical presentation. Hypertension, dyslipedemia, polycystic ovarian syndrome, fatty liver disease, pre-diabetes, sleep and breathing disorder, certain cancers, and cognitive impairment are many of the presentations of the syndrome; patients with any of these conditions are at a high risk of developing cardiovascular disease and diabetes. The metabolic syndrome helps identify people at risk to allow early intervention for prevention. Lifestyle modification is the most important part of the management of people with the syndrome. Lately medications--though none approved by the U.S. Food and Drug Administration (FDA)--have been recommended by major medical societies when lifestyle modification is not enough or when it fails.

  19. The scaffold protein RACK1 is a target of endocrine disrupting chemicals (EDCs) with important implication in immunity

    Energy Technology Data Exchange (ETDEWEB)

    Buoso, Erica; Galasso, Marilisa; Ronfani, Melania [Dipartimento di Scienze del Farmaco, Università degli Studi di Pavia, Viale Taramelli 12/14, 27100 Pavia (Italy); Papale, Angela; Galbiati, Valentina [Laboratory of Toxicology, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano (Italy); Eberini, Ivano [Laboratorio di Biochimica e Biofisica Computazionale, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan (Italy); Marinovich, Marina [Laboratory of Toxicology, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano (Italy); Racchi, Marco [Dipartimento di Scienze del Farmaco, Università degli Studi di Pavia, Viale Taramelli 12/14, 27100 Pavia (Italy); Corsini, Emanuela, E-mail: emanuela.corsini@unimi.it [Laboratory of Toxicology, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano (Italy)

    2017-06-15

    We recently demonstrated the existence of a complex hormonal balance between steroid hormones in the control of RACK1 (Receptor for Activated C Kinase 1) expression and immune activation, suggesting that this scaffold protein may also be targeted by endocrine disrupting chemicals (EDCs). As a proof of concept, we investigated the effect of the doping agent nandrolone, an androgen receptor (AR) agonist, and of p,p′DDT (dichlorodiphenyltrichloroethane) and its main metabolite p,p′DDE (dichlorodiphenyldichloroethylene), a weak and strong AR antagonist, respectively, on RACK1 expression and innate immune response. In analogy to endogenous androgens, nandrolone induced a dose-related increase in RACK1 transcriptional activity and protein expression, resulting in increased LPS-induced IL-8 and TNF-α production and proliferation in THP-1 cells. Conversely, p,p′DDT and p,p′DDE significantly decrease RACK1 expression, LPS-induced cytokine production and CD86 expression; with p,p′DDE exerting a stronger repressor effect than p,p′DDT, consistent with its stronger AR antagonistic effect. These results indicate that RACK1 could be a relevant target of EDCs, responding in opposite ways to agonist or antagonist of AR, representing a bridge between the endocrine system and the innate immune system. - Highlights: • RACK1 expression can be induced by AR agonists with a consequent enhancement of the response to LPS. • RACK1 can be negatively modulated by the AR antagonists DDT and its main metabolite p,p′DDE. • RACK1 can be a relevant target of EDCs, representing a bridge between the endocrine system and the immune system.

  20. Central voice production and pathophysiology of spasmodic dysphonia.

    Science.gov (United States)

    Mor, Niv; Simonyan, Kristina; Blitzer, Andrew

    2018-01-01

    Our ability to speak is complex, and the role of the central nervous system in controlling speech production is often overlooked in the field of otolaryngology. In this brief review, we present an integrated overview of speech production with a focus on the role of central nervous system. The role of central control of voice production is then further discussed in relation to the potential pathophysiology of spasmodic dysphonia (SD). Peer-review articles on central laryngeal control and SD were identified from PUBMED search. Selected articles were augmented with designated relevant publications. Publications that discussed central and peripheral nervous system control of voice production and the central pathophysiology of laryngeal dystonia were chosen. Our ability to speak is regulated by specialized complex mechanisms coordinated by high-level cortical signaling, brainstem reflexes, peripheral nerves, muscles, and mucosal actions. Recent studies suggest that SD results from a primary central disturbance associated with dysfunction at our highest levels of central voice control. The efficacy of botulinum toxin in treating SD may not be limited solely to its local effect on laryngeal muscles and also may modulate the disorder at the level of the central nervous system. Future therapeutic options that target the central nervous system may help modulate the underlying disorder in SD and allow clinicians to better understand the principal pathophysiology. NA.Laryngoscope, 128:177-183, 2018. © 2017 The American Laryngological, Rhinological and Otological Society, Inc.

  1. Intravenous delivery of HIV-based lentiviral vectors preferentially transduces F4/80+ and Ly-6C+ cells in spleen, important target cells in autoimmune arthritis

    NARCIS (Netherlands)

    Brand, B.T. van den; Vermeij, E.A.; Waterborg, C.E.J.; Arntz, O.J.; Kracht, M.; Bennink, M.B.; Berg, W.B. van den; Loo, F.A. van de

    2013-01-01

    Antigen presenting cells (APCs) play an important role in arthritis and APC specific gene therapeutic targeting will enable intracellular modulation of cell activity. Viral mediated overexpression is a potent approach to achieve adequate transgene expression levels and lentivirus (LV) is useful for

  2. Effects of ongoing task context and target typicality on prospective memory performance: the importance of associative cueing

    Science.gov (United States)

    Nowinski, Jessica Lang; Dismukes, Key R.

    2005-01-01

    Two experiments examined whether prospective memory performance is influenced by contextual cues. In our automatic activation model, any information available at encoding and retrieval should aid recall of the prospective task. The first experiment demonstrated an effect of the ongoing task context; performance was better when information about the ongoing task present at retrieval was available at encoding. Performance was also improved by a strong association between the prospective memory target as it was presented at retrieval and the intention as it was encoded. Experiment 2 demonstrated boundary conditions of the ongoing task context effect, which implicate the association between the ongoing and prospective tasks formed at encoding as the source of the context effect. The results of this study are consistent with predictions based on automatic activation of intentions.

  3. CEBPA exerts a specific and biologically important proapoptotic role in pancreatic β cells through its downstream network targets

    Science.gov (United States)

    Barbagallo, Davide; Condorelli, Angelo Giuseppe; Piro, Salvatore; Parrinello, Nunziatina; Fløyel, Tina; Ragusa, Marco; Rabuazzo, Agata Maria; Størling, Joachim; Purrello, Francesco; Di Pietro, Cinzia; Purrello, Michele

    2014-01-01

    Transcription factor CEBPA has been widely studied for its involvement in hematopoietic cell differentiation and causal role in hematological malignancies. We demonstrate here that it also performs a causal role in cytokine-induced apoptosis of pancreas β cells. Treatment of two mouse pancreatic α and β cell lines (αTC1-6 and βTC1) with proinflammatory cytokines IL-1β, IFN-γ, and TNF-α at doses that specifically induce apoptosis of βTC1 significantly increased the amount of mRNA and protein encoded by Cebpa and its proapoptotic targets, Arl6ip5 and Tnfrsf10b, in βTC1 but not in αTC1-6. Cebpa knockdown in βTC1 significantly decreased cytokine-induced apoptosis, together with the amount of Arl6ip5 and Tnfrsf10b. Analysis of the network comprising CEBPA, its targets, their first interactants, and proteins encoded by genes known to regulate cytokine-induced apoptosis in pancreatic β cells (genes from the apoptotic machinery and from MAPK and NFkB pathways) revealed that CEBPA, ARL6IP5, TNFRSF10B, TRAF2, and UBC are the top five central nodes. In silico analysis further suggests TRAF2 as trait d'union node between CEBPA and the NFkB pathway. Our results strongly suggest that Cebpa is a key regulator within the apoptotic network activated in pancreatic β cells during insulitis, and Arl6ip5, Tnfrsf10b, Traf2, and Ubc are key executioners of this program. PMID:24943845

  4. Pathophysiology of Portal Hypertension and Its Clinical Links

    Science.gov (United States)

    Seo, Yeon Seok; Shah, Vijay H

    2011-01-01

    Portal hypertension is a major cause of morbidity and mortality in patients with liver cirrhosis. Intrahepatic vascular resistance due to architectural distortion and intrahepatic vasoconstriction, increased portal blood flow due to splanchnic vasodilatation, and development of collateral circulation have been considered as major factors for the development of portal hypertension. Recently, sinusoidal remodeling and angiogenesis have been focused as potential etiologic factors and various researchers have tried to improve portal hypertension by modulating these new targets. This article reviews potential new treatments in the context of portal hypertension pathophysiology concepts. PMID:25755320

  5. Modern iron replacement therapy: clinical and pathophysiological insights.

    Science.gov (United States)

    Girelli, Domenico; Ugolini, Sara; Busti, Fabiana; Marchi, Giacomo; Castagna, Annalisa

    2018-01-01

    Iron deficiency, with or without anemia, is extremely frequent worldwide, representing a major public health problem. Iron replacement therapy dates back to the seventeenth century, and has progressed relatively slowly until recently. Both oral and intravenous traditional iron formulations are known to be far from ideal, mainly because of tolerability and safety issues, respectively. At the beginning of this century, the discovery of hepcidin/ferroportin axis has represented a turning point in the knowledge of the pathophysiology of iron metabolism disorders, ushering a new era. In the meantime, advances in the pharmaceutical technologies are producing newer iron formulations aimed at minimizing the problems inherent with traditional approaches. The pharmacokinetic of oral and parenteral iron is substantially different, and diversities have become even clearer in light of the hepcidin master role in regulating systemic iron homeostasis. Here we review how iron therapy is changing because of such important advances in both pathophysiology and pharmacology.

  6. Hypertension in women--pathophysiological and clinical aspects.

    Science.gov (United States)

    Erdine, Serap; Arslan, Eren; Olszanecka, Agnieszka

    2012-01-01

    Hypertension is the most important risk factor, responsible for cardiovascular morbidity and mortality worldwide, both in men and women. Cardiovascular disorders in women are still underestimated, due to lower absolute risk calculations and the underdetection of classical risk factors. In recent years the differences in pathophysiology and the clinical presentation and treatment of cardiac diseases in women have become fields of interest and research. Several studies have examined gender-related differences in the pathophysiology of hypertension, its prevalence and control. The influence of menopause, obesity and salt-sensitivity on the pathogenesis of hypertension in women has been widely investigated. This article presents current data on differences in prevalence, control and mechanisms of hypertension in women.

  7. Pathophysiology of obstructive sleep apnea-hypopnea syndrome (OSAHS

    Directory of Open Access Journals (Sweden)

    Marco Venegas-Mariño

    2017-08-01

    Full Text Available Obstructive sleep apnea-hypopnea syndrome (OSAHS is a disease characterized by recurrent upper airway obstruction (UAO, with decreased airflow, intermittent hypoxemia, and awakening during sleep. Two essential factors are related to the pathophysiology of OSAHS: anatomical alterations and reduction or absence of neural control. While studying OSAHS, the site or sites of obstruction of the UA should be identified; they may extend from the nasal wings to the hypopharynx. Another important factor in this syndrome is the nervous influence on muscle tone of the hypopharynx, as well as the changes in blood pH, which are secondary to micro-arousals. Body position and sleep stage determine the severity. The pathophysiology of OSAHS should be understood to properly study a patient and provide the best treatment option.

  8. Restless Legs Syndrome: From Pathophysiology to Clinical Diagnosis and Management

    Directory of Open Access Journals (Sweden)

    Shiyi Guo

    2017-06-01

    Full Text Available Restless legs syndrome (RLS, a common neurological sensorimotor disorder in western countries, has gained more and more attention in Asian countries. The prevalence of RLS is higher in older people and females. RLS is most commonly related to iron deficiency, pregnancy and uremia. The RLS symptoms show a significant circadian rhythm and a close relationship to periodic limb movements (PLMs in clinical observations, while the pathophysiological pathways are still unknown. The diagnostic criteria have been revised in 2012 to improve the validity of RLS diagnosis. Recent studies have suggested an important role of iron decrease of brain in RLS pathophysiology. Dopaminergic (DA system dysfunction in A11 cell groups has been recognized long ago from clinical treatment and autopsy. Nowadays, it is believed that iron dysfunction can affect DA system from different pathways and opioids have a protective effect on DA system. Several susceptible single nucleotide polymorphisms such as BTBD9 and MEIS1, which are thought to be involved in embryonic neuronal development, have been reported to be associated with RLS. Several pharmacological and non-pharmacological treatment are discussed in this review. First-line treatments of RLS include DA agents and α2δ agonists. Augmentation is very common in long-term treatment of RLS which makes prevention and management of augmentation very important for RLS patients. A combination of different types of medication is effective in preventing and treating augmentation. The knowledge on RLS is still limited, the pathophysiology and better management of RLS remain to be discovered.

  9. The importance of being urgent: The impact of surveillance target and scale on mosquito-borne disease control

    Directory of Open Access Journals (Sweden)

    Samantha R. Schwab

    2018-06-01

    Full Text Available With the emergence or re-emergence of numerous mosquito-borne diseases in recent years, effective methods for emergency vector control responses are necessary to reduce human infections. Current vector control practices often vary significantly between different jurisdictions, and are executed independently and at different spatial scales. Various types of surveillance information (e.g. number of human infections or adult mosquitoes trigger the implementation of control measures, though the target and scale of surveillance vary locally. This patchy implementation of control measures likely alters the efficacy of control.We modeled six different scenarios, with larval mosquito control occurring in response to surveillance data of different types and at different scales (e.g. across the landscape or in each patch. Our results indicate that: earlier application of larvicide after an escalation of disease risk achieves much greater reductions in human infections than later control implementation; uniform control across the landscape provides better outbreak mitigation than patchy control application; and different types of surveillance data require different levels of sensitivity in their collection to effectively inform control measures. Our simulations also demonstrate a potential logical fallacy of reactive, surveillance-driven vector control: measures stop being implemented as soon as they are deemed effective. This false sense of security leads to patchier control efforts that will do little to curb the size of future vector-borne disease outbreaks. More investment should be placed in collecting high quality information that can trigger early and uniform implementation, while researchers work to discover more informative metrics of human risk to trigger more effective control. Keywords: Zika control, Epidemiological surveillance, Disease surveillance, Mosquito control, Vector-borne disease control, Epidemiological modeling

  10. Keys to Achieving Target First Medical Contact to Balloon Times and Bypassing Emergency Department More Important Than Distance

    Directory of Open Access Journals (Sweden)

    Saad Ezad

    2018-01-01

    Full Text Available Background. Australian guidelines advocate primary percutaneous coronary intervention (PPCI as the reperfusion strategy of choice for ST elevation myocardial infarction (STEMI in patients in whom it can be performed within 90 minutes of first medical contact; otherwise, fibrinolytic therapy is preferred. In a large health district, the reperfusion strategy is often chosen in the prehospital setting. We sought to identify a distance from a PCI centre, which made it unlikely first medical contact to balloon time (FMCTB of less than 90 minutes could be achieved in the Hunter New England health district and to identify causes of delay in patients who were triaged to a PPCI strategy. Methods and Results. We studied 116 patients presenting via the ambulance service with STEMI from January 2016 to December 2016. In patients who were taken directly to the cardiac catheterisation lab, a maximum distance of 50 km from hospital resulted in 75% of patients receiving PCI within 90 minutes and approximately 95% of patients receiving PCI within 120 minutes. Patients who bypassed the emergency department (ED were significantly more likely to have FMCTB of less than 90 minutes (p<0.001 despite having a longer travel distance (28.5 km versus 17.4 km, p<0.001. Patients transiting via the ED were significantly more likely to present out of hours (60 versus 24.2% p<0.001. Conclusions. Patients who do not bypass the ED have a longer FMCTB across all spectrum of distances from the PCI centre; therefore, bypassing the ED is key to achieving target FMCTB times. Using a cutoff distance of 50 km may reduce human error in estimating travel time to our PCI centre and thereby identifying patients who should receive prehospital thrombolysis.

  11. The pathophysiology of restless legs syndrome

    International Nuclear Information System (INIS)

    Miyamoto, Masayuki; Miyamoto, Tomoyuki; Iwanami, Masaoki; Suzuki, Keisuke; Hirata, Koichi

    2009-01-01

    Restless legs syndrome (RLS) is a sensorimotor disorder that is frequently associated with periodic leg movements (PLMS). RLS is generally considered to be a central nervous system (CNS)-related disorder although no specific lesion has been found to be associated with the syndrome. Reduced intracortical inhibition has been demonstrated in RLS by transcranial magnetic stimulation. Some MRI studies have revealed the presence of morphologic changes in the somatosensory cortex, motor cortex and thalamic gray matter. The results of single photon emission computed tomography (SPECT) and positron emission tomography (PET) studies showed that the limbic and opioid systems also play important roles in the pathophysiology of RLS. A functional MRI study revealed abnormal bilateral cerebellar and thalamic activation during the manifestation of sensory symptoms, with additional red nucleus and reticular formation activity during PLMS. PLMS is likely to occur in patients with spinal cord lesions, and some patients with sensory polyneuropathy may exhibit RLS symptoms. RLS symptoms seem to depend on abnormal spinal sensorimotor integration at the spinal cord level and abnormal central somatosensory processing. PLMS appears to depend on increased excitability of the spinal cord and a decreased supraspinal inhibitory mechanism from the A11 diencephalic dopaminergic system. RLS symptoms respond very dramatically to dopaminergic therapy. The results of analysis by PET and SPECT studies of striatal D2 receptor binding in humans are inconclusive. However, studies in animal models suggest that the participation of the A11 dopaminergic system and the D3 receptor in RLS symptoms. The symptoms of RLS are aggravated in those with iron deficiency, and iron treatment ameliorates the symptoms in some patients. Neuroimaging studies, analysis of the cerebrospinal fluid, and studies on postmortem tissue and use of animal models have indicated that low brain iron concentrations and dysfunction of

  12. Dry eye disease: pathophysiology, classification, and diagnosis.

    Science.gov (United States)

    Perry, Henry D

    2008-04-01

    Dry eye disease (DED) is a multifactorial disorder of the tear film and ocular surface that results in eye discomfort, visual disturbance, and often ocular surface damage. Although recent research has made progress in elucidating DED pathophysiology, currently there are no uniform diagnostic criteria. This article discusses the normal anatomy and physiology of the lacrimal functional unit and the tear film; the pathophysiology of DED; DED etiology, classification, and risk factors; and DED diagnosis, including symptom assessment and the roles of selected diagnostic tests.

  13. Pathophysiology, Evaluation, and Treatment of Bloating

    Science.gov (United States)

    Gabbard, Scott L.; Crowell, Michael D.

    2011-01-01

    Abdominal bloating is commonly reported by men and women of all ages. Bloating occurs in nearly all patients with irritable bowel syndrome, and it also occurs in patients with other functional and organic disorders. Bloating is frequently disturbing to patients and frustrating to clinicians, as effective treatments are limited and are not universally successful. Although the terms bloating and abdominal distention are often used interchangeably, these symptoms likely involve different pathophysiologic processes, both of which are still not completely understood. The goal of this paper is to review the pathophysiology, evaluation, and treatment of bloating and abdominal distention. PMID:22298969

  14. Faecal soiling: pathophysiology of postdefaecatory incontinence.

    Science.gov (United States)

    Pucciani, F

    2013-08-01

    Passive postdefaecatory incontinence is poorly understood and yet is an important clinical problem. The aim of this study was to characterize the pathophysiology of postdefaecatory incontinence in patients affected by faecal soiling. Seventy-two patients (30 women, age range 49-79 years; 42 men, age range, 53-75 years) affected by faecal passive incontinence with faecal soiling were included in the study. Two patient groups were identified: Group 1 comprised 42 patients with postdefaecatory incontinence and Group 2 had 30 patients without incontinence after bowel movements. After a preliminary clinical evaluation, including the Faecal Incontinence Severity Index (FISI) score and the obstructed defaecation syndrome (ODS) score, all patients of Groups 1 and 2 were studied by means of endoanal ultrasound and anorectal manometry. The results were compared with those from 20 healthy control subjects. A significantly higher ODS score was found in Group 1 (P IAS) in Group 2 (P IAS atrophy and the FISI score (ρs 0.78; P < 0.03). Anal resting pressure (Pmax and Pm ) was significantly lower in Group 2 (P < 0.04). The straining test was considered positive in 30 (71.4%) patients in Group 1, significantly greater than in Group 2 (P < 0.01). A significantly higher conscious rectal sensitivity threshold (CRST) was found in Group 1 patients (P < 0.01). The ODS score, a positive straining test and high CRST values suggest that postdefaecatory incontinence is secondary to impaired defaecation. Colorectal Disease © 2013 The Association of Coloproctology of Great Britain and Ireland.

  15. Experimental validation of plant peroxisomal targeting prediction algorithms by systematic comparison of in vivo import efficiency and in vitro PTS1 binding affinity.

    Science.gov (United States)

    Skoulding, Nicola S; Chowdhary, Gopal; Deus, Mara J; Baker, Alison; Reumann, Sigrun; Warriner, Stuart L

    2015-03-13

    Most peroxisomal matrix proteins possess a C-terminal targeting signal type 1 (PTS1). Accurate prediction of functional PTS1 sequences and their relative strength by computational methods is essential for determination of peroxisomal proteomes in silico but has proved challenging due to high levels of sequence variability of non-canonical targeting signals, particularly in higher plants, and low levels of availability of experimentally validated non-canonical examples. In this study, in silico predictions were compared with in vivo targeting analyses and in vitro thermodynamic binding of mutated variants within the context of one model targeting sequence. There was broad agreement between the methods for entire PTS1 domains and position-specific single amino acid residues, including residues upstream of the PTS1 tripeptide. The hierarchy Leu>Met>Ile>Val at the C-terminal position was determined for all methods but both experimental approaches suggest that Tyr is underweighted in the prediction algorithm due to the absence of this residue in the positive training dataset. A combination of methods better defines the score range that discriminates a functional PTS1. In vitro binding to the PEX5 receptor could discriminate among strong targeting signals while in vivo targeting assays were more sensitive, allowing detection of weak functional import signals that were below the limit of detection in the binding assay. Together, the data provide a comprehensive assessment of the factors driving PTS1 efficacy and provide a framework for the more quantitative assessment of the protein import pathway in higher plants. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Pathophysiology of overuse tendon injury

    International Nuclear Information System (INIS)

    Kannus, P.; Paavola, M.; Paakkala, T.; Parkkari, J.; Jaervinen, T.; Jaervinen, M.

    2002-01-01

    Overuse tendon injury is one of the most common injuries in sports.The etiology as well as the pathophysilogical mechanisms leading to tendinopathy are of crucial medical importance.At the moment intrinsic and extrinsic factors are assumed as mechanisms of overuse tendon injury. Except for the acute, extrinsic trauma, the chronic overuse tendon injury is a multifactorial process. There are many other factors, such as local hypoxia, less of nutrition, impaired metabolism and local inflammatory that may also contribute to the development of tissue damage.The exact interaction of these factors cannot be explained entirely at the moment.Further studies will be necessary in order to get more information. (orig.) [de

  17. [Neural pathophysiology of cancer anorexia].

    Science.gov (United States)

    Sánchez-Lara, K; Sosa-Sánchez, R; Green-Renner, D; Méndez-Sánchez, N

    2011-01-01

    Approximately two thirds of cancer patients at advanced stages of the disease suffer from anorexia. Defined as the loss of the desire to eat, anorexia lower the energy intake which further exacerbates a progressive deterioration of the patient nutritional status. Malnutrition has a large impact on morbidity and mortality affecting the quality of life. Cancer anorexia etiology is multifactorial including complex interactions among the tumor, host metabolism and antineoplastic treatment. New related theories include peripheral and brain mechanisms affecting hypothalamic pathways; inducing behavioral and metabolic failure of responses to energy balance. The aim of this review is to describe actual concepts involved in the pathogenesis of cancer anorexia with special interest in brain mechanisms. Anorexia and reduced food intake are important issues in the management of cancer patients, more knowledge about pathogenic mechanism is needed to improve therapeutic options, prognosis and quality of life in cancer patients.

  18. Acute Kidney Injury: Definition, Pathophysiology and Clinical Phenotypes.

    Science.gov (United States)

    Makris, Konstantinos; Spanou, Loukia

    2016-05-01

    Acute kidney injury (AKI) is a clinical syndrome that complicates the course and worsens the outcome in a significant number of hospitalised patients. Recent advances in clinical and basic research will help with a more accurate definition of this syndrome and in the elucidation of its pathogenesis. With this knowledge we will be able to conduct more accurate epidemiologic studies in an effort to gain a better understanding of the impact of this syndrome. AKI is a syndrome that rarely has a sole and distinct pathophysiology. Recent evidence, in both basic science and clinical research, is beginning to change our view for AKI from a single organ failure syndrome to a syndrome where the kidney plays an active role in the progress of multi-organ dysfunction. Accurate and prompt recognition of AKI and better understanding of the pathophysiologic mechanisms underlying the various clinical phenotypes are of great importance to research for effective therapeutic interventions. In this review we provide the most recent updates in the definition, epidemiology and pathophysiology of AKI.

  19. Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells

    DEFF Research Database (Denmark)

    Frankel, Lisa; Christoffersen, Nanna R; Jacobsen, Anders

    2008-01-01

    growth. Using array expression analysis of MCF-7 cells depleted of miR-21, we have identified mRNA targets of mir-21 and have shown a link between miR-21 and the p53 tumor suppressor protein. We furthermore found that the tumor suppressor protein Programmed Cell Death 4 (PDCD4) is regulated by miR-21......MicroRNAs are emerging as important regulators of cancer-related processes. The miR-21 microRNA is overexpressed in a wide variety of cancers and has been causally linked to cellular proliferation, apoptosis, and migration. Inhibition of mir-21 in MCF-7 breast cancer cells causes reduced cell...... and demonstrated that PDCD4 is a functionally important target for miR-21 in breast cancer cells....

  20. Midlatitude Ice-Rich Ground on Mars: An Important Target for Science and In Situ Resource Utilization on Human Missions

    Science.gov (United States)

    Stoker, Carol; Heldmann, Jennifer

    2015-01-01

    The region of ROI is characterized by proven presence of near surface ground ice and numerous periglacial features. Midlatitude ground ice on Mars is of significant scientific interest for understanding the history and evolution of ice stability on Mars, the impact that changes in insolation produced by variations in Mars’ orbital parameters has on the regions climate, and could provide human exploration with a reliable and plentiful in situ resource. For both science and exploration, assessing the astrobiological potential of the ice is important in terms of (1) understanding the potential for life on Mars and (2) evaluating the presence of possible biohazards in advance of human exploration. Heldmann et al. (2014) studied locations on Mars in the Amazonis Planitia region where near surface ground ice was exposed by new impact craters (Byrne et al. 2009). The study examined whether sites in this region were suitable for human exploration including reviewing the evidence for midlatitude ground ice, discussing the possible explanations for its occurrence, assessing its potential habitability for modern life, and evaluating the resource potential. They systematically analyzed remote-sensing data sets to identify a viable landing site. Five sites where ground ice was exposed were examined with HiRise imaging and were classified according to (1) presence of polygons as a proxy for subsurface ice, (2) presence and abundance of rough topographic obstacles (e.g., large cracks, cliffs, uneven topography), (3) rock density, (4) presence and abundance of large boulders, and (5) presence of craters. A suitable landing site was found having ground ice at only 0.15m depth, and no landing site hazards within a 25 km landing ellipse. This paper presents results of that study and examines the relevance of this ROI to the workshop goals.

  1. Pathophysiology of valvular heart disease.

    Science.gov (United States)

    Zeng, Y I; Sun, Rongrong; Li, Xianchi; Liu, Min; Chen, Shuang; Zhang, Peiying

    2016-04-01

    Valvular heart disease (VHD) is caused by either damage or defect in one of the four heart valves, aortic, mitral, tricuspid or pulmonary. Defects in these valves can be congenital or acquired. Age, gender, tobacco use, hypercholesterolemia, hypertension, and type II diabetes contribute to the risk of disease. VHD is an escalating health issue with a prevalence of 2.5% in the United States alone. Considering the likely increase of the aging population worldwide, the incidence of acquired VHD is expected to increase. Technological advances are instrumental in identifying congenital heart defects in infants, thereby adding to the growing VHD population. Almost one-third of elderly individuals have echocardiographic or radiological evidence of calcific aortic valve (CAV) sclerosis, an early and subclinical form of CAV disease (CAVD). Of individuals ages >60, ~2% suffer from disease progression to its most severe form, calcific aortic stenosis. Surgical intervention is therefore required in these patients as no effective pharmacotherapies exist. Valvular calcium load and valve biomineralization are orchestrated by the concerted action of diverse cell-dependent mechanisms. Signaling pathways important in skeletal morphogenesis are also involved in the regulation of cardiac valve morphogenesis, CAVD and the pathobiology of cardiovascular calcification. CAVD usually occurs without any obvious symptoms in early stages over a long period of time and symptoms are identified at advanced stages of the disease, leading to a high rate of mortality. Aortic valve replacement is the only primary treatment of choice. Biomarkers such as asymmetric dimethylarginine, fetuin-A, calcium phosphate product, natriuretic peptides and osteopontin have been useful in improving outcomes among various disease states. This review, highlights the current understanding of the biology of VHD, with particular reference to molecular and cellular aspects of its regulation. Current clinical questions

  2. Retinal vein occlusion: pathophysiology and treatment options

    OpenAIRE

    Karia, Niral

    2010-01-01

    Niral KariaDepartment of Ophthalmology, Southend Hospital, Prittlewell Chase, Westcliff on Sea, Essex, United KingdomAbstract: This paper reviews the current thinking about retinal vein occlusion. It gives an overview of its pathophysiology and discusses the evidence behind the various established and emerging treatment paradigms.Keywords: central, hemispheric, branch, retinal vein occlusion, visual loss

  3. Pathophysiology of diurnal drooling in Parkinson's disease

    NARCIS (Netherlands)

    Kalf, J.G.; Munneke, M.; Engel-Hoek, L. van den; Swart, B.J.M. de; Borm, G.F.; Bloem, B.R.; Zwarts, M.J.

    2011-01-01

    Drooling is an incapacitating feature of Parkinson's disease. Better pathophysiological insights are needed to improve treatment. In this study, we tested the hypothesis that the cause of drooling is multifactorial. We examined 15 patients with Parkinson's disease with distinct diurnal saliva loss

  4. The central importance of the EU emission trading scheme for achievement of the German climate protection target of 40% until 2020

    International Nuclear Information System (INIS)

    Hermann, Hauke; Cludius, Johanna

    2014-02-01

    ETS has faced structurally low allowance prices from 2012 on-wards because of a massive supply of EU emission allowances (EUA) and external emission reduction credits, which exceeds the demand significantly. The surplus amounted to 1.8 billion EUAs at the end of the second trading period (2008-2012), will reach approx. 2 billion EUAs in 2013 and remain at up to 2 billion EUAs until the end of the third trading period (2013-2020). This structural surplus has significant implications for the fulfilment of European and national targets. The present research project concludes that the current design of the ETS is not ambitious enough to meet the national 40% target. Germany will also not be able to reach this target if the structural reform of the ETS is not improved considerably. Without this revision, there is a gap of 10.7 % to meeting the target based on 1990 levels, meaning that Germany would achieve an emissions reduction target of 29.3% instead of 40% in 2020. A combination of three factors is responsible for this gap: - surplus allowances being carried over from the second trading period (6.2 % compared to 1990); - a relatively unambitious reduction factor throughout the third trading phase compared to what should be achieved in the ETS sectors under the 40% national target (3 % compared to 1990); - a lack of ambition in the sectors not covered by the EU ETS compared to what should be achieved in the non-ETS sectors under the 40% national target (1.5 % compared to 1990). To meet the 40 % target in Germany, structural measures for reforming the EU ETS are necessary before 2020. Between 1.8 and 2.3 billion EU emission allowances (EUAs) have to be taken off the market in the long term (long-term set-aside) to remove current surpluses (1.8 billion EUAs) and to compensate for the expected imports of external emission reduction credits (0.5 billion CERs and ERUs) allowed to enter the market before 2020. Furthermore, the linear reduction factor needs to be tightened from

  5. Intravenous delivery of HIV-based lentiviral vectors preferentially transduces F4/80+ and Ly-6C+ cells in spleen, important target cells in autoimmune arthritis.

    Directory of Open Access Journals (Sweden)

    Ben T van den Brand

    Full Text Available Antigen presenting cells (APCs play an important role in arthritis and APC specific gene therapeutic targeting will enable intracellular modulation of cell activity. Viral mediated overexpression is a potent approach to achieve adequate transgene expression levels and lentivirus (LV is useful for sustained expression in target cells. Therefore, we studied the feasibility of lentiviral mediated targeting of APCs in experimental arthritis. Third generation VSV-G pseudotyped self-inactivating (SIN-LV were injected intravenously and spleen cells were analyzed with flow cytometry for green fluorescent protein (GFP transgene expression and cell surface markers. Collagen-induced arthritis (CIA was induced by immunization with bovine collagen type II in complete Freund's adjuvant. Effect on inflammation was monitored macroscopically and T-cell subsets in spleen were analyzed by flow cytometry. Synovium from arthritic knee joints were analyzed for proinflammatory cytokine expression. Lentiviruses injected via the tail vein preferentially infected the spleen and transduction peaks at day 10. A dose escalating study showed that 8% of all spleen cells were targeted and further analysis showed that predominantly Ly6C+ and F4/80+ cells in spleen were targeted by the LV. To study the feasibility of blocking TAK1-dependent pathways by this approach, a catalytically inactive mutant of TAK1 (TAK1-K63W was overexpressed during CIA. LV-TAK1-K63W significantly reduced incidence and arthritis severity macroscopically. Further histological analysis showed a significant decrease in bone erosion in LV-TAK1-K63W treated animals. Moreover, systemic Th17 levels were decreased by LV-TAK1-K63W treatment in addition to diminished IL-6 and KC production in inflamed synovium. In conclusion, systemically delivered LV efficiently targets monocytes and macrophages in spleen that are involved in autoimmune arthritis. Moreover, this study confirms efficacy of TAK1 targeting in

  6. Pathophysiological aspects of ureterorenoscopic management of upper urinary tract calculi

    DEFF Research Database (Denmark)

    Osther, Palle J S; Pedersen, Katja V; Lildal, Søren K

    2016-01-01

    PURPOSE OF REVIEW: Indications for ureterorenoscopy are expanding without hard scientific evidence to support its efficacy. Therefore, it is extremely important to focus on potential harmful effects of the procedure itself. This review explores how physiology of the upper urinary tract reacts...... of the β-receptor agonist isoproterenol in the irrigation fluid has shown a potential for reducing both intrarenal pressure and ureteral tone during ureterorenoscopy. SUMMARY: Upper urinary tract physiology has unique features that may be pushed into pathophysiological processes by the unique elements...

  7. Role of renal vascular potassium channels in physiology and pathophysiology

    DEFF Research Database (Denmark)

    Salomonsson, Max; Brasen, Jens Christian; Sorensen, Charlotte Mehlin

    2017-01-01

    The control of renal vascular tone is important for the regulation of salt and water balance, blood pressure and the protection against damaging elevated glomerular pressure. The K+ conductance is a major factor in the regulation of the membrane potential (Vm ) in vascular smooth muscle (VSMC...... the ambiguous in vitro and in vivo results. We discuss the role of single types of K+ channels and the integrated function of several classes. We also deal with the possible role of renal vascular K+ channels in the pathophysiology of hypertension, diabetes mellitus and sepsis. This article is protected...

  8. Pathophysiology of spontaneous venous gas embolism

    Science.gov (United States)

    Lambertsen, C. J.; Albertine, K. H.; Pisarello, J. B.; Flores, N. D.

    1991-01-01

    The use of controllable degrees and durations of continuous isobaric counterdiffusion venous gas embolism to investigate effects of venous gas embolism upon blood, cardiovascular, and respiratory gas exchange function, as well as pathological effects upon the lung and its microcirculation is discussed. Use of N2O/He counterdiffusion permitted performance of the pathophysiologic and pulmonary microstructural effects at one ATA without hyperbaric or hypobaric exposures.

  9. Studies on the Pathophysiology and Genetic Basis of Migraine

    Science.gov (United States)

    Gasparini, Claudia F; Sutherland, Heidi G.; Griffiths, Lyn R

    2013-01-01

    Migraine is a neurological disorder that affects the central nervous system causing painful attacks of headache. A genetic vulnerability and exposure to environmental triggers can influence the migraine phenotype. Migraine interferes in many facets of people’s daily life including employment commitments and their ability to look after their families resulting in a reduced quality of life. Identification of the biological processes that underlie this relatively common affliction has been difficult because migraine does not have any clearly identifiable pathology or structural lesion detectable by current medical technology. Theories to explain the symptoms of migraine have focused on the physiological mechanisms involved in the various phases of headache and include the vascular and neurogenic theories. In relation to migraine pathophysiology the trigeminovascular system and cortical spreading depression have also been implicated with supporting evidence from imaging studies and animal models. The objective of current research is to better understand the pathways and mechanisms involved in causing pain and headache to be able to target interventions. The genetic component of migraine has been teased apart using linkage studies and both candidate gene and genome-wide association studies, in family and case-control cohorts. Genomic regions that increase individual risk to migraine have been identified in neurological, vascular and hormonal pathways. This review discusses knowledge of the pathophysiology and genetic basis of migraine with the latest scientific evidence from genetic studies. PMID:24403849

  10. Evidence-Based Revised View of the Pathophysiology of Preeclampsia.

    Science.gov (United States)

    Ahmed, Asif; Rezai, Homira; Broadway-Stringer, Sophie

    2017-01-01

    Preeclampsia is a life-threatening vascular disorder of pregnancy due to a failing stressed placenta. Millions of women risk death to give birth each year and globally each year, almost 300,000 lose their life in this process and over 500,000 babies die as a consequence of preeclampsia. Despite decades of research, we lack pharmacological agents to treat it. Maternal endothelial oxidative stress is a central phenomenon responsible for the preeclampsia phenotype of high maternal blood pressure and proteinuria. In 1997, it was proposed that preeclampsia arises due to the loss of VEGF activity, possibly due to elevation in anti-angiogenic factor, soluble Flt-1 (sFlt-1). Researchers showed that high sFlt-1 and soluble endoglin (sEng) elicit the severe preeclampsia phenotype in pregnant rodents. We demonstrated that heme oxygenase-1 (HO-1)/carbon monoxide (CO) pathway prevents placental stress and suppresses sFlt-1 and sEng release. Likewise, hydrogen sulphide (H 2 S)/cystathionine-γ-lyase (Cth) systems limit sFlt-1 and sEng and protect against the preeclampsia phenotype in mice. Importantly, H 2 S restores placental vasculature, and in doing so improves lagging fetal growth. These molecules act as the inhibitor systems in pregnancy and when they fail, preeclampsia is triggered. In this review, we discuss what are the hypotheses and models for the pathophysiology of preeclampsia on the basis of Bradford Hill causation criteria for disease causation and how further in vivo experimentation is needed to establish 'proof of principle'. Hypotheses that fail to meet the Bradford Hill causation criteria include abnormal spiral artery remodelling and inflammation and should be considered associated or consequential to the disorder. In contrast, the protection against cellular stress hypothesis that states that the protective pathways mitigate cellular stress by limiting elevation of anti-angiogenic factors or oxidative stress and the subsequent clinical signs of preeclampsia

  11. The role of nitric oxide in the physiology and pathophysiology of the exocrine pancreas.

    Science.gov (United States)

    Hegyi, Péter; Rakonczay, Zoltán

    2011-11-15

    Nitric oxide (NO), a ubiquitous gaseous signaling molecule, contributes to both pancreatic physiology and pathophysiology. The present review provides a general overview of NO synthesis, signaling, and function. Further, it specifically discusses NO metabolism and its effects in the exocrine pancreas and focuses on the role of NO in the pathogenesis of acute pancreatitis and pancreatic ischemia/reperfusion injury. Unfortunately, the role of NO in pancreatic physiology and pathophysiology remains controversial in numerous areas. Many questions regarding the messenger molecule still remain unanswered. Probably the least is known about the downstream targets of NO, which need to be identified, especially at the molecular level.

  12. Pathogenesis and treatment of psoriasis: exploiting pathophysiological pathways for precision medicine.

    Science.gov (United States)

    Alwan, Wisam; Nestle, Frank O

    2015-01-01

    Psoriasis is a common, chronic inflammatory skin disease associated with multi-system manifestations including arthritis and obesity. Our knowledge of the aetiology of the condition, including the key genomic, immune and environmental factors, has led to the development of targeted, precision therapies that alleviate patient morbidity. This article reviews the key pathophysiological pathways and therapeutic targets and highlights future areas of interest in psoriasis research.

  13. The KATP channel in migraine pathophysiology

    DEFF Research Database (Denmark)

    Al-Karagholi, Mohammad Al-Mahdi; Hansen, Jakob Møller; Severinsen, Johanne

    2017-01-01

    BACKGROUND: To review the distribution and function of KATP channels, describe the use of KATP channels openers in clinical trials and make the case that these channels may play a role in headache and migraine. DISCUSSION: KATP channels are widely present in the trigeminovascular system and play...... an important role in the regulation of tone in cerebral and meningeal arteries. Clinical trials using synthetic KATP channel openers report headache as a prevalent-side effect in non-migraine sufferers, indicating that KATP channel opening may cause headache, possibly due to vascular mechanisms. Whether KATP...... channel openers can provoke migraine in migraine sufferers is not known. CONCLUSION: We suggest that KATP channels may play an important role in migraine pathogenesis and could be a potential novel therapeutic anti-migraine target....

  14. Importance of Neutralizing Monoclonal Antibodies Targeting Multiple Antigenic Sites on the Middle East Respiratory Syndrome Coronavirus Spike Glycoprotein To Avoid Neutralization Escape

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Lingshu; Shi, Wei; Chappell, James D.; Joyce, M. Gordon; Zhang, Yi; Kanekiyo, Masaru; Becker, Michelle M.; van Doremalen, Neeltje; Fischer, Robert; Wang, Nianshuang; Corbett, Kizzmekia S.; Choe, Misook; Mason, Rosemarie D.; Van Galen, Joseph G.; Zhou, Tongqing; Saunders, Kevin O.; Tatti, Kathleen M.; Haynes, Lia M.; Kwong, Peter D.; Modjarrad, Kayvon; Kong, Wing-Pui; McLellan, Jason S.; Denison, Mark R.; Munster, Vincent J.; Mascola, John R.; Graham, Barney S.; Gallagher, Tom

    2018-03-07

    ABSTRACT

    Middle East respiratory syndrome coronavirus (MERS-CoV) causes a highly lethal pulmonary infection with ~35% mortality. The potential for a future pandemic originating from animal reservoirs or health care-associated events is a major public health concern. There are no vaccines or therapeutic agents currently available for MERS-CoV. Using a probe-based single B cell cloning strategy, we have identified and characterized multiple neutralizing monoclonal antibodies (MAbs) specifically binding to the receptor-binding domain (RBD) or S1 (non-RBD) regions from a convalescent MERS-CoV-infected patient and from immunized rhesus macaques. RBD-specific MAbs tended to have greater neutralizing potency than non-RBD S1-specific MAbs. Six RBD-specific and five S1-specific MAbs could be sorted into four RBD and three non-RBD distinct binding patterns, based on competition assays, mapping neutralization escape variants, and structural analysis. We determined cocrystal structures for two MAbs targeting the RBD from different angles and show they can bind the RBD only in the “out” position. We then showed that selected RBD-specific, non-RBD S1-specific, and S2-specific MAbs given prophylactically prevented MERS-CoV replication in lungs and protected mice from lethal challenge. Importantly, combining RBD- and non-RBD MAbs delayed the emergence of escape mutations in a cell-based virus escape assay. These studies identify MAbs targeting different antigenic sites on S that will be useful for defining mechanisms of MERS-CoV neutralization and for developing more effective interventions to prevent or treat MERS-CoV infections.

    IMPORTANCEMERS-CoV causes a highly lethal respiratory infection for which no vaccines or antiviral therapeutic options are currently available. Based on continuing exposure from established reservoirs in dromedary camels and bats, transmission of MERS-CoV into humans and future outbreaks are expected. Using

  15. Importance of protocol target definition on the ability to spare normal tissue: An IMRT and 3D-CRT planning comparison for intraorbital tumors

    International Nuclear Information System (INIS)

    Hein, Patrick A.; Gladstone, David J.; Bellerive, Marc R.; Hug, Eugen B.

    2005-01-01

    were fulfilled in all cases (5/5) with 3D-CRT and IMRT. Using the protocol criteria, lens sparing was achieved only for two tumor sites (retrobulbar and lateral position) with either planning technique. Mean lens doses were 8.5 and 10.4 Gy for 3D-CRT and 7.5 and 13.2 Gy for IMRT, respectively. The mean lens doses for the other three tumor locations averaged 26.8 Gy. IMRT plans reduced the lens dose in four of five cases by an average of 2.6 Gy compared with 3D-CRT. Modified target protocol prescription markedly reduced mean lens doses by 23-50% and by as much as 18 Gy. Recorded mean lens doses after protocol modification were 26% lower using IMRT plans compared with 3D-CRT. The cold spot as a result of the relaxed volume coverage requirements was within 2% of the original protocol criteria and located at the edge of the PTV, outside the CTV. Compared with 3D-CRT, IMRT resulted in an increase of brain volume receiving 10% (V10) and 20% (V20) of the prescribed dose. Conclusion: Strict adherence to IRS-V protocol criteria prohibits at present lens sparing within compliance criteria for the majority of intraorbital tumor locations because of protocol-specific CTV and PTV target definitions. Changing protocol definitions by prescribing to the volume rather than to a dose constraint, IMRT planning significantly reduced lens doses. This was not accomplished to the same degree with 3D-CRT. Our study underlines the importance of appropriate selection of planning objectives to maximize the specific capabilities and advantages of IMRT in terms of sufficient target coverage and simultaneous sparing of critical structures. Our results can add to the ongoing discussion in the design of future 3D-CRT/IMRT protocols

  16. SREBP-regulated lipid metabolism: convergent physiology - divergent pathophysiology.

    Science.gov (United States)

    Shimano, Hitoshi; Sato, Ryuichiro

    2017-12-01

    Cellular lipid metabolism and homeostasis are controlled by sterol regulatory-element binding proteins (SREBPs). In addition to performing canonical functions in the transcriptional regulation of genes involved in the biosynthesis and uptake of lipids, genome-wide system analyses have revealed that these versatile transcription factors act as important nodes of convergence and divergence within biological signalling networks. Thus, they are involved in myriad physiological and pathophysiological processes, highlighting the importance of lipid metabolism in biology. Changes in cell metabolism and growth are reciprocally linked through SREBPs. Anabolic and growth signalling pathways branch off and connect to multiple steps of SREBP activation and form complex regulatory networks. In addition, SREBPs are implicated in numerous pathogenic processes such as endoplasmic reticulum stress, inflammation, autophagy and apoptosis, and in this way, they contribute to obesity, dyslipidaemia, diabetes mellitus, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, chronic kidney disease, neurodegenerative diseases and cancers. This Review aims to provide a comprehensive understanding of the role of SREBPs in physiology and pathophysiology at the cell, organ and organism levels.

  17. Pathophysiology of Resistant Hypertension: The Role of Sympathetic Nervous System

    Directory of Open Access Journals (Sweden)

    Costas Tsioufis

    2011-01-01

    Full Text Available Resistant hypertension (RH is a powerful risk factor for cardiovascular morbidity and mortality. Among the characteristics of patients with RH, obesity, obstructive sleep apnea, and aldosterone excess are covering a great area of the mosaic of RH phenotype. Increased sympathetic nervous system (SNS activity is present in all these underlying conditions, supporting its crucial role in the pathophysiology of antihypertensive treatment resistance. Current clinical and experimental knowledge points towards an impact of several factors on SNS activation, namely, insulin resistance, adipokines, endothelial dysfunction, cyclic intermittent hypoxaemia, aldosterone effects on central nervous system, chemoreceptors, and baroreceptors dysregulation. The further investigation and understanding of the mechanisms leading to SNS activation could reveal novel therapeutic targets and expand our treatment options in the challenging management of RH.

  18. Renal Denervation for Chronic Heart Failure: Background and Pathophysiological Rationale.

    Science.gov (United States)

    Böhm, Michael; Ewen, Sebastian; Mahfoud, Felix

    2017-01-01

    The activation of the sympathetic nervous system is associated with cardiovascular hospitalizations and death in heart failure. Renal denervation has been shown to effectively reduce sympathetic overdrive in certain patients with uncontrolled hypertension. Pilot trials investigating renal denervation as a potential treatment approach for heart failure were initiated. Heart failure comorbidities like obstructive sleep apnea, metabolic syndrome and arrhythmias could also be targets for renal denervation, because these occurrences are also mediated by the activation of the sympathetic nervous system. Therefore, renal denervation in heart failure is worthy of further investigation, although its effectiveness still has to be proven. Herein, we describe the pathophysiological rationale and the effect of renal denervation on surrogates of the heart failure syndrome.

  19. Renal Denervation for Chronic Heart Failure: Background and Pathophysiological Rationale

    Science.gov (United States)

    Ewen, Sebastian; Mahfoud, Felix

    2017-01-01

    The activation of the sympathetic nervous system is associated with cardiovascular hospitalizations and death in heart failure. Renal denervation has been shown to effectively reduce sympathetic overdrive in certain patients with uncontrolled hypertension. Pilot trials investigating renal denervation as a potential treatment approach for heart failure were initiated. Heart failure comorbidities like obstructive sleep apnea, metabolic syndrome and arrhythmias could also be targets for renal denervation, because these occurrences are also mediated by the activation of the sympathetic nervous system. Therefore, renal denervation in heart failure is worthy of further investigation, although its effectiveness still has to be proven. Herein, we describe the pathophysiological rationale and the effect of renal denervation on surrogates of the heart failure syndrome. PMID:28154583

  20. The Physiological/Pathophysiological Significance of Vitamin D in Cancer, Cardiovascular Disorders and Beyond.

    Science.gov (United States)

    AlMatar, Manaf; AlMandeal, Husam; Makky, Essam A; Kayar, Begum; Yarar, Emel; Var, Isıl; Koksal, Fatih

    2017-01-01

    Vitamin D, a molecular precursor of the potent steroid hormone calcitriol, has crucial functions and roles in physiology and pathophysiology. Tellingly, calcitriol has been shown to regulate various cellular signalling networks and cascades that have crucial role in cancer biology and diagnostics. Mounting lines of evidences from previous clinical and preclinical investigations indicate that the deficiency of vitamin D may contribute to the carcinogenesis risk. Concomitantly, recent reports suggested that significant reduction in the cancer occurrence and progression is more likely to appear after vitamin D supplementation. Furthermore, a pivotal role functioned by vitamin D in cardiovascular physiology indicates that the deficiency of vitamin D is significantly correlated with enhanced prevalence of stroke, hypertension and myocardial infarction. Notably, vitamin D status is more likely to be used as a lifestyle biomarker, since poor and unhealthy lifestyles are correlated with the deficiency of vitamin D, a feature which may result in cardiovascular complications. Moreover, recent reports revealed that the effect of vitamin D is to cover not only cardiovascular system but also skeletal system. Herein, we are highlighting the recent knowledge of vitamin D roles and functions with respect to pathophysiological disorders such as cancer, cardiovascular diseases, rheumatoid arthritis (RA) and debate the potential avails of vitamin D on slowing cancer, cardiovascular disease and RA progression. The findings of this review confirm that the importance of vitamin D metabolites or analogues which can provide a helpful platform to target some kinds of cancer, particularly when used in combination with existing therapies. Moreover, the correlation between vitamin D deficiencies with cardiovascular diseases and rheumatoid arthritis (RA) progression might suggest a pivotal role of vitamin D in either initiation or progression of these diseases. Copyright© Bentham Science

  1. The PACAP receptor: a novel target for migraine treatment

    DEFF Research Database (Denmark)

    Schytz, Henrik W; Olesen, Jes; Ashina, Messoud

    2010-01-01

    The origin of migraine pain has not yet been clarified, but accumulating data point to neuropeptides present in the perivascular space of cranial vessels as important mediators of nociceptive input during migraine attacks. Pituitary adenylate cyclase-activating polypeptide (PACAP) is present in s......) receptor, which suggests a possible signaling pathway implicated in migraine pain. This review summarizes the current evidence supporting the involvement of PACAP in migraine pathophysiology and the PAC(1) receptor as a possible novel target for migraine treatment....

  2. Quantifying the importance of MSP1-19 as a target of growth-inhibitory and protective antibodies against Plasmodium falciparum in humans.

    Directory of Open Access Journals (Sweden)

    Danny W Wilson

    Full Text Available BACKGROUND: Antibodies targeting blood stage antigens are important in protection against malaria, but the key targets and mechanisms of immunity are not well understood. Merozoite surface protein 1 (MSP1 is an abundant and essential protein. The C-terminal 19 kDa region (MSP1-19 is regarded as a promising vaccine candidate and may also be an important target of immunity. METHODOLOGY/FINDINGS: Growth inhibitory antibodies against asexual-stage parasites and IgG to recombinant MSP1-19 were measured in plasma samples from a longitudinal cohort of 206 children in Papua New Guinea. Differential inhibition by samples of mutant P. falciparum lines that expressed either the P. falciparum or P. chabaudi form of MSP1-19 were used to quantify MSP1-19 specific growth-inhibitory antibodies. The great majority of children had detectable IgG to MSP1-19, and high levels of IgG were significantly associated with a reduced risk of symptomatic P. falciparum malaria during the 6-month follow-up period. However, there was little evidence of PfMSP1-19 specific growth inhibition by plasma samples from children. Similar results were found when testing non-dialysed or dialysed plasma, or purified antibodies, or when measuring growth inhibition in flow cytometry or microscopy-based assays. Rabbit antisera generated by immunization with recombinant MSP1-19 demonstrated strong MSP1-19 specific growth-inhibitory activity, which appeared to be due to much higher antibody levels than human samples; antibody avidity was similar between rabbit antisera and human plasma. CONCLUSIONS/SIGNIFICANCE: These data suggest that MSP1-19 is not a major target of growth inhibitory antibodies and that the protective effects of antibodies to MSP1-19 are not due to growth inhibitory activity, but may instead be mediated by other mechanisms. Alternatively, antibodies to MSP1-19 may act as a marker of protective immunity.

  3. Chronic Pruritus in the Absence of Skin Disease: Pathophysiology, Diagnosis and Treatment.

    Science.gov (United States)

    Pereira, Manuel P; Kremer, Andreas E; Mettang, Thomas; Ständer, Sonja

    2016-08-01

    Chronic pruritus arises not only from dermatoses, but also, in up to half of cases, from extracutaneous origins. A multitude of systemic, neurological, psychiatric, and somatoform conditions are associated with pruritus in the absence of skin disease. Moreover, pruritus is a frequently observed side effect of many drugs. It is therefore difficult for physicians to make a correct diagnosis. Chronic pruritus patients frequently present to the dermatologist with skin lesions secondary to a long-lasting scratching behavior, such as lichenification and prurigo nodularis. A structured clinical history and physical examination are essential in order to evaluate the pruritus, along with systematic, medical history-adapted laboratory and radiological tests carried out according to the differential diagnosis. For therapeutic reasons, a symptomatic therapy should be promptly initiated parallel to the diagnostic procedures. Once the underlying factor(s) leading to the pruritus are identified, a targeted therapy should be implemented. Importantly, the treatment of accompanying disorders such as sleep disturbances or mental symptoms should be taken into consideration. Even after successful treatment of the underlying cause, pruritus may persist, likely due to chronicity processes including peripheral and central sensitization or impaired inhibition at spinal level. A vast arsenal of topical and systemic agents targeting these pathophysiological mechanisms has been used to deter further chronicity. The therapeutic options currently available are, however, still insufficient for many patients. Thus, future studies aiming to unveil the complex mechanisms underlying chronic pruritus and develop new therapeutic agents are urgently needed.

  4. The pathophysiology of lifelong premature ejaculation

    Science.gov (United States)

    2016-01-01

    For many decades it has been thought that lifelong premature ejaculation (PE) is only characterized by persistent early ejaculations. Despite enormous progress of in vivo animal research, and neurobiological, genetic and pharmacological research in men with lifelong PE, our current understanding of the mechanisms behind early ejaculations is far from complete. The new classification of PE into four PE subtypes has shown that the symptomatology of lifelong PE strongly differs from acquired PE, subjective PE and variable PE. The phenotype of lifelong PE and therefore also the pathophysiology of lifelong PE is much more complex. A substantial number of men with lifelong PE not only have PE, but also premature erection and premature penile detumescence as part of an acute hypertonic or hypererotic state when engaged in an erotic situation or when making love. As both erectio praecox, ejaculatio praecox, detumescentia praecox, and the hypererotic state are part of the phenotype lifelong PE, it is argued that lifelong PE is not only a disturbance of the timing of ejaculation but also a disturbance of the timing of erection, detumescence and arousal. Since 1998, the pathophysiology of lifelong PE was thought to be mainly mediated by the central serotonergic system in line with genetic polymorphisms of specific serotonergic genes. However, by accepting that lifelong PE is characterized by the reversible hypertonic state the hypothesis of mainly serotonergic dysfunction is no longer tenable. Instead, it has been postulated that the pathophysiology of lifelong PE is mediated by a very complex interplay of central and peripheral serotonergic, dopaminergic, oxytocinergic, endocrinological, genetic and probably also epigenetic factors. Progress in research of lifelong PE can only be accomplished when a stopwatch is used to measure the IELT and the cut-off point of 1 minute for the definition of lifelong PE is maintained. Current use of validated questionnaires, neglect of

  5. Diagnosing the pathophysiologic mechanisms of nocturnal polyuria.

    Science.gov (United States)

    Goessaert, An-Sofie; Krott, Louise; Hoebeke, Piet; Vande Walle, Johan; Everaert, Karel

    2015-02-01

    Diagnosis of nocturnal polyuria (NP) is based on a bladder diary. Addition of a renal function profile (RFP) for analysis of concentrating and solute-conserving capacity allows differentiation of NP pathophysiology and could facilitate individualized treatment. To map circadian rhythms of water and solute diuresis by comparing participants with and without NP. This prospective observational study was carried out in Ghent University Hospital between 2011 and 2013. Participants with and without NP completed a 72-h bladder dairy. RFP, free water clearance (FWC), and creatinine, solute, sodium, and urea clearance were measured for all participants. The study participants were divided into those with (n=77) and those without (n=35) NP. The mean age was 57 yr (SD 16 yr) and 41% of the participants were female. Compared to participants without NP, the NP group exhibited a higher diuresis rate throughout the night (p=0.015); higher FWC (p=0.013) and lower osmolality (p=0.030) at the start of the night; and persistently higher sodium clearance during the night (p<0.001). The pathophysiologic mechanism of NP was identified as water diuresis alone in 22%, sodium diuresis alone in 19%, and a combination of water and sodium diuresis in 47% of the NP group. RFP measurement in first-line NP screening to discriminate between water and solute diuresis as pathophysiologic mechanisms complements the bladder diary and could facilitate optimal individualized treatment of patients with NP. We evaluated eight urine samples collected over 24h to detect the underlying problem in NP. We found that NP can be attributed to water or sodium diuresis or a combination of both. This urinalysis can be used to adapt treatment according to the underlying mechanism in patients with bothersome consequences of NP, such as nocturia and urinary incontinence. Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.

  6. The control of independent students’ work effectiveness during pathophysiology study

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    О. V. Melnikova

    2013-06-01

    Full Text Available The course of Pathophysiology study includes both auditoria hours (lectures and practical classes and independent work of students. The latter makes up 38% of total hours given for Pathophysiology study. Independent work of students includes the following items: preparation for practical classes, writing reviews on different topics, preparation for current and final computer testing, study of the topics which are not discussed during lectures and practical classes. In order to assimilate the course of Pathophysiology completely students should effectively use their hours given for independent work. Unfortunately, the level of students’ independent individual work is low; it includes only learning of single facts, that is not enough for higher medical education. THE AIM OF STUDY: To propose the method of control of the effectiveness of students’ independent work. The most important part of student’s individual work is preparation for study in auditoria, because it determines the qualitative level of study during practical classes. The student should enter the class not only with the knowledge of basic sciences (Anatomy, Histology, Biochemistry, Normal Physiology etc. but also with the understanding of key items of the topic of the practical class. The problem consists in the following: the teacher can’t check the level of basic knowledge in each student – there is not enough time during practical class for this procedure. In order to increase the effectiveness of individual students’ work a special workbook for the practical classes was developed at the Pathophysiology department. While preparing for practical classes students write down basic items of the topic, refresh some questions from Normal Physiology, Biochemistry and other subjects. In the beginning of the practical class the teacher controls the level of student’s preparation to the topic by checking the fulfillment of tasks in the workbook. It takes a little time, but it

  7. Lafora disease: epidemiology, pathophysiology and management.

    LENUS (Irish Health Repository)

    Monaghan, Thomas S

    2010-07-01

    Lafora disease is a rare, fatal, autosomal recessive, progressive myoclonic epilepsy. It may also be considered as a disorder of carbohydrate metabolism because of the formation of polyglucosan inclusion bodies in neural and other tissues due to abnormalities of the proteins laforin or malin. The condition is characterized by epilepsy, myoclonus and dementia. Diagnostic findings on MRI and neurophysiological testing are not definitive and biopsy or genetic studies may be required. Therapy in Lafora disease is currently limited to symptomatic management of the epilepsy, myoclonus and intercurrent complications. With a greater understanding of the pathophysiological processes involved, there is justified hope for future therapies.

  8. Pathophysiology of muscle contractures in cerebral palsy.

    Science.gov (United States)

    Mathewson, Margie A; Lieber, Richard L

    2015-02-01

    Patients with cerebral palsy present with a variety of adaptations to muscle structure and function. These pathophysiologic symptoms include functional deficits such as decreased force production and range of motion, in addition to changes in muscle structure such as decreased muscle belly size, increased sarcomere length, and altered extracellular matrix structure and composition. On a cellular level, patients with cerebral palsy have fewer muscle stem cells, termed satellite cells, and altered gene expression. Understanding the nature of these changes may present opportunities for the development of new muscle treatment therapies. Published by Elsevier Inc.

  9. Discrete Pathophysiology is Uncommon in Patients with Nonspecific Arm Pain.

    Science.gov (United States)

    Kortlever, Joost T P; Janssen, Stein J; Molleman, Jeroen; Hageman, Michiel G J S; Ring, David

    2016-06-01

    Nonspecific symptoms are common in all areas of medicine. Patients and caregivers can be frustrated when an illness cannot be reduced to a discrete pathophysiological process that corresponds with the symptoms. We therefore asked the following questions: 1) Which demographic factors and psychological comorbidities are associated with change from an initial diagnosis of nonspecific arm pain to eventual identification of discrete pathophysiology that corresponds with symptoms? 2) What is the percentage of patients eventually diagnosed with discrete pathophysiology, what are those pathologies, and do they account for the symptoms? We evaluated 634 patients with an isolated diagnosis of nonspecific upper extremity pain to see if discrete pathophysiology was diagnosed on subsequent visits to the same hand surgeon, a different hand surgeon, or any physician within our health system for the same pain. There were too few patients with discrete pathophysiology at follow-up to address the primary study question. Definite discrete pathophysiology that corresponded with the symptoms was identified in subsequent evaluations by the index surgeon in one patient (0.16% of all patients) and cured with surgery (nodular fasciitis). Subsequent doctors identified possible discrete pathophysiology in one patient and speculative pathophysiology in four patients and the index surgeon identified possible discrete pathophysiology in four patients, but the five discrete diagnoses accounted for only a fraction of the symptoms. Nonspecific diagnoses are not harmful. Prospective randomized research is merited to determine if nonspecific, descriptive diagnoses are better for patients than specific diagnoses that imply pathophysiology in the absence of discrete verifiable pathophysiology.

  10. Pathophysiology and biology of peritoneal carcinomatosis.

    Science.gov (United States)

    Kusamura, Shigeki; Baratti, Dario; Zaffaroni, Nadia; Villa, Raffaella; Laterza, Barbara; Balestra, Maria Rosaria; Deraco, Marcello

    2010-01-15

    Peritoneal carcinomatosis represents a devastating form of cancer progression with a very poor prognosis. Its complex pathogenesis is represented by a dynamic process comprising several steps. To the best of our knowledge pathogenesis can be partly explained by 3 major molecular pathways: (1) dissemination from the primary tumor; (2) primary tumor of peritoneum; and (3) independent origins of the primary tumor and peritoneal implants. These are not mutually exclusive and combinations of different mechanisms could occur inside a single case. There are still several aspects which need explanation by future studies. A comprehensive understanding of molecular events involved in peritoneal carcinomatosis is of paramount importance and should be systematically pursued not only to identify novel strategies for the prevention of the condition, but also to obtain therapeutic advances, through the identification of surrogate markers of prognosis and development of future molecular targeted therapies.

  11. Epidemiology, genetics, pathophysiology, and prognostic classifications of cerebral arteriovenous malformations.

    Science.gov (United States)

    Ozpinar, Alp; Mendez, Gustavo; Abla, Adib A

    2017-01-01

    Arteriovenous malformations (AVMs) are vascular deformities involving fistula formation of arterial to venous structures without an intervening capillary bed. Such anomalies can prove fatal as the high arterial flow can disrupt the integrity of venous walls, thus leading to dangerous sequelae such as hemorrhage. Diagnosis of these lesions in the central nervous system can often prove challenging as intracranial AVMs represent a heterogeneous vascular pathology with various presentations and symptomatology. The literature suggests that most brain AVMs (bAVMs) are identified following evaluation of the etiology of acute cerebral hemorrhage, or incidentally on imaging associated with seizure or headache workup. Given the low incidence of this disease, most of the data accrued on this pathology comes from single-center experiences. This chapter aims to distill the most important information from these studies as well as examine meta-analyses on bAVMs in order to provide a comprehensive introduction into the natural history, classification, genetic underpinnings of disease, and proposed pathophysiology. While there is yet much to be elucidated about AVMs of the central nervous system, we aim to provide an overview of bAVM etiology, classification, genetics, and pathophysiology inherent to the disease process. © 2017 Elsevier B.V. All rights reserved.

  12. Concussion: the history of clinical and pathophysiological concepts and misconceptions.

    Science.gov (United States)

    McCrory, P R; Berkovic, S F

    2001-12-26

    Concussion is a well-recognized clinical entity; however, its pathophysiologic basis remains a mystery. One unresolved issue is whether concussion is associated with lesser degrees of diffuse structural change seen in severe traumatic brain injury, or is the mechanism entirely caused by reversible functional changes. This issue is clouded not only by the lack of critical data, but also by confusion in terminology, even in contemporary literature. This confusion began in ancient times when no distinction was made between the transient effects of concussion and severe traumatic brain injury. The first clear separate recognition of concussion was made by the Persian physician, Rhazes, in the 10th century. Lanfrancus subsequently expanded this concept as brain "commotion" in the 13th century, although other Renaissance physicians continued to obscure this concept. By the 18th century, a variety of hypotheses for concussion had emerged. The 19th century discovery of petechial hemorrhagic lesions in severe traumatic brain injury led to these being posited as the basis of concussion, and a similar logic was used later to suggest diffuse axonal injury was responsible. The neuropathology and pathophysiology of concussion has important implications in neurology, sports medicine, medicolegal medicine, and in the understanding of consciousness. Fresh approaches to these questions are needed and modern research tools, including functional imaging and experimental studies of ion-channel function, could help elucidate this puzzle that has evolved over the past 3,000 years.

  13. Pathophysiology, diagnosis, and treatment of canine hip dysplasia

    International Nuclear Information System (INIS)

    Cook, J.L.; Tomlinson, J.L.; Constantinescu, G.M.

    1996-01-01

    Dogs with hip dysplasia are commonly presented to veterinarians for evaluation. Although many causes of the condition have been proposed, a definitive cause has not been established. The multifactorial nature of canine hip dysplasia can confuse client education and management ofthe disease. The basic concept involved is the biomechanical imbalance between the forces on the coxofemoral joint and the associated muscle mass; the result is joint laxity in young, growing dogs. This laxity leads to incongruity; the eventual result is degenerative joint disease. Canine hip dysplasia can affect any breed but is most often reported in large and giant breeds. Understanding the pathophysiology and biomechanics involved with this developmental disease is important in providing clients with diagnostic, therapeutic, and prognostic information. The selection of treatment is influenced by the following factors:the age, health, and intended use of the patient; clinical signs; diagnostic findings; the availability of treatment; and the financial constraints of the owner. This article discusses the current concepts concerning the pathophysiology and biomechanics of canine hip dysplasia and outlines diagnostic and therapeutic options. The objective of the article is to provide practitioners with a reference for decision making and client education

  14. Genetic Variants Associated with Hyperandrogenemia in PCOS Pathophysiology

    Science.gov (United States)

    2018-01-01

    Polycystic ovary syndrome is a multifactorial endocrine disorder whose pathophysiology baffles many researchers till today. This syndrome is typically characterized by anovulatory cycles and infertility, altered gonadotropin levels, obesity, and bulky multifollicular ovaries on ultrasound. Hyperandrogenism and insulin resistance are hallmark features of its complex pathophysiology. Hyperandrogenemia is a salient feature of PCOS and a major contributor to cosmetic anomalies including hirsutism, acne, and male pattern alopecia in affected women. Increased androgen levels may be intrinsic or aggravated by preexisting insulin resistance in women with PCOS. Studies have reported augmented ovarian steroidogenesis patterns attributed mainly to theca cell hypertrophy and altered expression of key enzymes in the steroidogenic pathway. Candidate gene studies have been performed in order to delineate the association of polymorphisms in genes, which encode enzymes in the intricate cascade of steroidogenesis or modulate the levels and action of circulating androgens, with risk of PCOS development and its related traits. However, inconsistent findings have impacted the emergence of a unanimously accepted genetic marker for PCOS susceptibility. In the current review, we have summarized the influence of polymorphisms in important androgen related genes in governing genetic predisposition to PCOS and its related metabolic and reproductive traits. PMID:29670770

  15. Extra-osseous uterine pathophysiology demonstrated on skeletal scintigraphy

    International Nuclear Information System (INIS)

    Mansberg, R.; Lewis, G.

    1999-01-01

    Full text: Skeletal scintigraphy is a sensitive procedure for evaluating disease and trauma involving the skeleton. Extra-skeletal pathophysiology is also often demonstrated. This may include uptake by tumours, soft tissue calcification and infection as well as renal pathology. Skeletal scintigraphy is often performed to evaluate hip and back pain and extra-osseous uterine pathophysiology can be demonstrated in both the early and late phases of the study as in the following cases. Three women underwent skeletal scintigraphy for the investigation of low back pain in two patients and post-partum hip pain in one. A large vascular uterus with deviation of the bladder was demonstrated in the post-partum patient. Increased pelvic vascularity and bladder deviation in the second patient was shown by ultrasound to correspond to a left-sided fibroid with associated adenomyosis. In the third case, right-sided pelvic vascularity and left bladder deviation were shown on ultrasound to be due to an anteverted, anteflexed uterus tilted to the right. These cases illustrate the importance of documenting extra-osseous findings on skeletal scintigraphy and the benefits of correlation with anatomical imaging

  16. Genetic Variants Associated with Hyperandrogenemia in PCOS Pathophysiology

    Directory of Open Access Journals (Sweden)

    Roshan Dadachanji

    2018-01-01

    Full Text Available Polycystic ovary syndrome is a multifactorial endocrine disorder whose pathophysiology baffles many researchers till today. This syndrome is typically characterized by anovulatory cycles and infertility, altered gonadotropin levels, obesity, and bulky multifollicular ovaries on ultrasound. Hyperandrogenism and insulin resistance are hallmark features of its complex pathophysiology. Hyperandrogenemia is a salient feature of PCOS and a major contributor to cosmetic anomalies including hirsutism, acne, and male pattern alopecia in affected women. Increased androgen levels may be intrinsic or aggravated by preexisting insulin resistance in women with PCOS. Studies have reported augmented ovarian steroidogenesis patterns attributed mainly to theca cell hypertrophy and altered expression of key enzymes in the steroidogenic pathway. Candidate gene studies have been performed in order to delineate the association of polymorphisms in genes, which encode enzymes in the intricate cascade of steroidogenesis or modulate the levels and action of circulating androgens, with risk of PCOS development and its related traits. However, inconsistent findings have impacted the emergence of a unanimously accepted genetic marker for PCOS susceptibility. In the current review, we have summarized the influence of polymorphisms in important androgen related genes in governing genetic predisposition to PCOS and its related metabolic and reproductive traits.

  17. Human Pathophysiological Adaptations to the Space Environment

    Directory of Open Access Journals (Sweden)

    Gian C. Demontis

    2017-08-01

    Full Text Available Space is an extreme environment for the human body, where during long-term missions microgravity and high radiation levels represent major threats to crew health. Intriguingly, space flight (SF imposes on the body of highly selected, well-trained, and healthy individuals (astronauts and cosmonauts pathophysiological adaptive changes akin to an accelerated aging process and to some diseases. Such effects, becoming manifest over a time span of weeks (i.e., cardiovascular deconditioning to months (i.e., loss of bone density and muscle atrophy of exposure to weightlessness, can be reduced through proper countermeasures during SF and in due time are mostly reversible after landing. Based on these considerations, it is increasingly accepted that SF might provide a mechanistic insight into certain pathophysiological processes, a concept of interest to pre-nosological medicine. In this article, we will review the main stress factors encountered in space and their impact on the human body and will also discuss the possible lessons learned with space exploration in reference to human health on Earth. In fact, this is a productive, cross-fertilized, endeavor in which studies performed on Earth yield countermeasures for protection of space crew health, and space research is translated into health measures for Earth-bound population.

  18. Pathophysiology and management of pediatric ascites.

    Science.gov (United States)

    Sabri, Mahmoud; Saps, Miguel; Peters, John M

    2003-06-01

    Ascites accumulation is the product of a complex process involving hepatic, renal, systemic, hemodynamic, and neurohormonal factors. The main pathophysiologic theories of ascites formation include the "underfill," "overflow," and peripheral arterial vasodilation hypotheses. These theories are not necessarily mutually exclusive and are linked at some level by a common pathophysiologic thread: The body senses a decreased effective arterial blood volume, leading to stimulation of the sympathetic nervous system, arginine-vasopressin feedback loops, and the renin-angiotensin-aldosterone system. Cornerstones of ascites management include dietary sodium restriction and diuretics. Spironolactone is generally tried initially, with furosemide added if clinical response is suboptimal. More refractory patients require large-volume paracentesis (LVP) accompanied by volume expansion with albumin. Placement of a transjugular intrahepatic portosystemic shunt is reserved for individuals with compensated liver function who require very frequent sessions of LVP. Peritoneovenous shunts are not used in contemporary ascites management. Liver transplantation remains the definitive therapy for refractory ascites. Although treatment of ascites fails to improve survival, it benefits quality of life and limits the development of such complications as spontaneous bacterial peritonitis.

  19. Adropin – physiological and pathophysiological role

    Directory of Open Access Journals (Sweden)

    Natalia Marczuk

    2016-09-01

    Full Text Available Adropin is a peptide hormone that was discovered in 2008 by Kumar et al. This protein consists of 76 amino acids, and it was originally described as a secreted peptide, with residues 1-33 encoding a secretory signal peptide sequence. The amino acid sequence of this protein in humans, mice and rats is identical. While our knowledge of the exact physiological roles of this poorly understood peptide continues to evolve, recent data suggest a role in energy homeostasis and the control of glucose and fatty acid metabolism. This protein is encoded by the Enho gene, which is expressed primarily in the liver and the central nervous system. The regulation of adropin secretion is controversial. Adropin immunoreactivity has been reported by several laboratories in the circulation of humans, non-human primates and rodents. However, more recently it has been suggested that adropin is a membrane-bound protein that modulates cell-cell communication. Moreover, adropin has been detected in various tissues and body fluids, such as brain, cerebellum, liver, kidney, heart, pancreas, small intestine, endothelial cells, colostrum, cheese whey and milk. The protein level, as shown by previous research, changes in various physiological and pathophysiological conditions. Adropin is involved in carbohydrate-lipid metabolism, metabolic diseases, central nervous system function, endothelial function and cardiovascular disease. The knowledge of this interesting protein, its exact role and mechanism of action is insufficient. This article provides an overview of the existing literature about the role of adropin, both in physiological and pathophysiological conditions.

  20. Pathophysiology and Treatment of Alien Hand Syndrome

    Directory of Open Access Journals (Sweden)

    Harini Sarva

    2014-12-01

    Full Text Available Background: Alien hand syndrome (AHS is a disorder of involuntary, yet purposeful, hand movements that may be accompanied by agnosia, aphasia, weakness, or sensory loss. We herein review the most reported cases, current understanding of the pathophysiology, and treatments.Methods: We performed a PubMed search in July of 2014 using the phrases “alien hand syndrome,” “alien hand syndrome pathophysiology,” “alien hand syndrome treatment,” and “anarchic hand syndrome.” The search yielded 141 papers (reviews, case reports, case series, and clinical studies, of which we reviewed 109. Non‐English reports without English abstracts were excluded.Results: Accumulating evidence indicates that there are three AHS variants: frontal, callosal, and posterior. Patients may demonstrate symptoms of multiple types; there is a lack of correlation between phenomenology and neuroimaging findings. Most pathologic and functional imaging studies suggest network disruption causing loss of inhibition as the likely cause. Successful interventions include botulinum toxin injections, clonazepam, visuospatial coaching techniques, distracting the affected hand, and cognitive behavioral therapy.Discussion: The available literature suggests that overlap between AHS subtypes is common. The evidence for effective treatments remains anecdotal, and, given the rarity of AHS, the possibility of performing randomized, placebo‐controlled trials seems unlikely. As with many other interventions for movement disorders, identifying the specific functional impairments caused by AHS may provide the best guidance towards individualized supportive care.

  1. Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy

    Directory of Open Access Journals (Sweden)

    Hana Starobova

    2017-05-01

    Full Text Available Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of several antineoplastics. It can lead to detrimental dose reductions and discontinuation of treatment, and severely affects the quality of life of cancer survivors. Clinically, chemotherapy-induced peripheral neuropathy presents as deficits in sensory, motor, and autonomic function which develop in a glove and stocking distribution due to preferential effects on longer axons. The pathophysiological processes are multi-factorial and involve oxidative stress, apoptotic mechanisms, altered calcium homeostasis, axon degeneration and membrane remodeling as well as immune processes and neuroinflammation. This review focusses on the commonly used antineoplastic substances oxaliplatin, cisplatin, vincristine, docetaxel, and paclitaxel which interfere with the cancer cell cycle—leading to cell death and tumor degradation—and cause severe acute and chronic peripheral neuropathies. We discuss drug mechanism of action and pharmacokinetic disposition relevant to the development of peripheral neuropathy, the epidemiology and clinical presentation of chemotherapy-induced neuropathy, emerging insight into genetic susceptibilities as well as current understanding of the pathophysiology and treatment approaches.

  2. Anemia of Chronic Disease and Iron Deficiency Anemia in Inflammatory Bowel Diseases: Pathophysiology, Diagnosis, and Treatment.

    Science.gov (United States)

    Murawska, Natalia; Fabisiak, Adam; Fichna, Jakub

    2016-05-01

    Anemia coexists with inflammatory bowel disease (IBD) in up to two-thirds of patients, significantly impairing quality of life. The most common types of anemia in patients with IBD are iron deficiency anemia and anemia of chronic disease, which often overlap. In most cases, available laboratory tests allow successful diagnosis of iron deficiency, where difficulties appear, recently established indices such as soluble transferrin-ferritin ratio or percentage of hypochromic red cells are used. In this review, we discuss the management of the most common types of anemia in respect of the latest available data. Thus, we provide the mechanisms underlying pathophysiology of these entities; furthermore, we discuss the role of hepcidin in developing anemia in IBD. Next, we present the treatment options for each type of anemia and highlight the importance of individual choice of action. We also focus on newly developed intravenous iron preparations and novel, promising drug candidates targeting hepcidin. Concurrently, we talk about difficulties in differentiating between the true and functional iron deficiency, and discuss tools facilitating the process. Finally, we emphasize the importance of proper diagnosis and treatment of anemia in IBD. We conclude that management of anemia in patients with IBD is tricky, and appropriate screening of patients regarding anemia is substantial.

  3. Pathophysiology of Manganese-Associated Neurotoxicity

    Science.gov (United States)

    Racette, Brad A.; Aschner, Michael; Guilarte, Tomas R.; Dydak, Ulrike; Criswell, Susan R.; Zheng, Wei

    2012-01-01

    Conference Summary Manganese (Mn) is a well established neurotoxin associated with specific damage to the basal ganglia in humans. The phenotype associated with Mn neurotoxicity was first described in two workers with occupational exposure to Mn oxide.(Couper, 1837) Although the description did not use modern clinical terminology, a parkinsonian illness characterized by slowness of movement (bradykinesia), masked facies, and gait impairment (postural instability) appears to have predominated. Nearly 100 years later an outbreak of an atypical parkinsonian illness in a Chilean Mn mine provided a phenotypic description of a fulminant neurologic disorder with parkinsonism, dystonia, and neuropsychiatric symptoms.(Rodier J, 1955) Exposures associated with this syndrome were massive and an order of magnitude greater than modern exposures.(Rodier J, 1955; Hobson et al., 2011) The clinical syndrome associated with Mn neurotoxicity has been called manganism. Modern exposures to Mn occur primarily through occupations in the steel industry and welding. These exposures are often chronic and varied, occurring over decades in the healthy workforce. Although the severe neurologic disorder described by Rodier and Couper are no longer seen, several reports have suggested a possible increased risk of neurotoxicity in these workers.(Racette et al., 2005b; Bowler et al., 2007; Harris et al., 2011) Based upon limited prior imaging and pathologic investigations into the pathophysiology of neurotoxicity in Mn exposed workers,(Huang et al., 2003) many investigators have concluded that the syndrome spares the dopamine system distinguishing manganism from Parkinson disease (PD), the most common cause of parkinsonism in the general population, and a disease with characteristic degenerative changes in the dopaminergic system.(Jankovic, 2005) The purpose of this symposium was to highlight recent advances in the understanding of the pathophysiology of Mn associated neurotoxicity from C. elegans

  4. Retinopathy of Prematurity: Therapeutic Strategies Based on Pathophysiology.

    Science.gov (United States)

    Cayabyab, Rowena; Ramanathan, Rangasamy

    2016-01-01

    Retinopathy of prematurity (ROP) continues to be a major preventable cause of blindness and visual handicaps globally. With improved perinatal care, improved survival of moderately preterm infants, and limited resources for oxygen delivery and monitoring, more mature preterm infants are developing severe ROP in developing countries. The pathophysiology of ROP is characterized by two phases. Phase I ROP is due to vaso-obliteration beginning immediately after birth secondary to a marked decrease in vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1). Phase II begins around 33 weeks' postmenstrual age (PMA). During this phase, VEGF levels increase, especially if there is retinal hypoxia with increasing retinal metabolism and demand for oxygen leading to abnormal vasoproliferation. Since the original description of ROP in 1942 by Terry et al. [Am J Ophthalmol 1942;25:203-204], four epidemics of ROP have been observed. Prevention or early treatment of ROP involves careful titration of oxygen saturation by pulse oximeter (SpO2). Optimal SpO2 target remains elusive. Most of the large trials have focused on either a low SpO2 (85-89%) or a high SpO2 (91-95%) from the first day of birth to 36 weeks' PMA. Although the incidence of severe ROP and bronchopulmonary dysplasia decreased significantly, predischarge mortality was higher in these studies. Use of graded SpO2 during the 2 different phases of ROP (early, low SpO2 during phase I vs. late, high SpO2 during phase II) may be the best approach to prevent this disabling condition. Further trials should focus on this strategy. Other biological agents that are currently being studied include IGF-1 with IGF-binding protein-3 (rhIGF-1 + rhIGFBP-3) and propranolol. For advanced stages of ROP, laser ablation of avascular retina, early treatment of ROP (ETROP) protocol, intravitreal injection of anti-VEGF antibodies (e.g. bevacizumab) and vitrectomy are used to protect central vision and prevent

  5. [Pathophysiology and treatment of orofacial pain.

    Science.gov (United States)

    Shinoda, Masamichi; Noma, Noboru

    "Pain" is one of body defense mechanisms and crucial for the life support. However, orofacial pain such as myofascial pain syndrome, burning mouth syndrome and trigeminal neuralgia plays no part in body defense mechanisms and requires therapeutic intervention. Recent studies have indicated that plastic changes in the activities of trigeminal neurons, satellite glial cells in trigeminal ganglion, secondary neurons, microglia and astrocytes in trigeminal spinal subnucleus following orofacial inflammation and trigeminal nerve injury are responsible for orofacial pain mechanisms. Clinically, it is well known that the etiologic differential diagnosis which consists of careful history-taking and physical examination is essential for therapeutic decision in patients with orofacial pain. This report outlines the current knowledge on the pathophysiology, diagnosis, treatment of orofacial pain.

  6. Pathophysiology, Clinical, and Therapeutic Aspects of Narcolepsy

    Directory of Open Access Journals (Sweden)

    Pinar Guzel Ozdemir

    2014-09-01

    Full Text Available Narcolepsy is a lifelong sleep disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucination, and sleep paralysis. The exact cause remains unknown, but there is significant evidence that hypocretin deficiency plays an integral role. There have been advances in the understanding of the pathogenesis of narcolepsy. It has a negative effect on the quality of life and can restrict the patients from certain careers and activities. Diagnosis relies on patient history and objective data gathered from polysomnography and multiple sleep latency testing. Treatment focuses on symptom relief through medication, education, and behavioral modification. Both classic pharmacological treatments as well as newer options have significant problems, especially because of side effects and abuse potential. Some novel modalities are being examined to expand options for treatment. In this review, the pathophysiological, clinical, and pharmacotherapeutic aspects of narcolepsy are discussed. [Psikiyatride Guncel Yaklasimlar - Current Approaches in Psychiatry 2014; 6(3.000: 271-283

  7. The role of ADAMs in disease pathophysiology.

    LENUS (Irish Health Repository)

    Duffy, Michael J

    2012-02-01

    The ADAMs are a family of multidomain transmembrane and secreted proteins involved in both proteolysis and cell adhesion. Altered expression of specific ADAMs is implicated in the pathophysiology of several diseases including rheumatoid arthritis, Alzheimer\\'s disease, cardiac hypertrophy, asthma and cancer. Of these different diseases, it is in cancer where most research has been carried out. Multiple ADAMs, including ADAM-9, ADAM-10, ADAM-12, ADAM-15 and ADAM-17, have been shown to play a role in either cancer formation or progression. Consistent with these findings, increased expression of specific ADAMs in several cancer types was found to correlate with features of aggressive disease and poor prognosis. Currently, selective ADAM inhibitors against ADAM-10 and ADAM-17 are undergoing clinical trials for the treatment of cancer. Further work is required in order to establish a causative role for ADAMs in rheumatoid arthritis, Alzheimer\\'s disease, cardiac hypertrophy and asthma.

  8. New insights into pathophysiology of vestibular migraine

    Directory of Open Access Journals (Sweden)

    Juan Manuel Espinosa-Sanchez

    2015-02-01

    Full Text Available Vestibular migraine (VM is a common disorder in which genetic, epigenetic and environmental factors probably contribute to its development. The pathophysiology of VM is unknown; nevertheless in the last few years, several studies are contributing to understand the neurophysiological pathways involved in VM. The current hypotheses are mostly based on the knowledge of migraine itself. The evidence of trigeminal innervation of the labyrinth vessels and the localization of vasoactive neuropeptides in the perivascular afferent terminals of these trigeminal fibers support the involvement of the trigemino-vascular system. The neurogenic inflammation triggered by activation of the trigeminal-vestibulocochlear reflex, with the subsequent inner ear plasma protein extravasation and the release of inflammatory mediators, can contribute to a sustained activation and sensitization of the trigeminal primary afferent neurons explaining VM symptoms. The reciprocal connections between brainstem vestibular nuclei and the structures that modulate trigeminal nociceptive inputs (rostral ventromedial medulla, ventrolateral periaqueductal grey, locus coeruleus and nucleus raphe magnus are critical to understand the pathophysiology of VM. Although cortical spreading depression can affect cortical areas involved in processing vestibular information, functional neuroimaging techniques suggest a dysmodulation in the multimodal sensory integration and processing of vestibular and nociceptive information, resulting from a vestibulo-thalamo-cortical dysfunction, as the pathogenic mechanism underlying VM. The elevated prevalence of VM suggests that multiple functional variants may confer a genetic susceptibility leading to a dysregulation of excitatory-inhibitory balance in brain structures involved in the processing of sensory information, vestibular inputs and pain. The interactions among several functional and structural neural networks could explain the pathogenic

  9. Vitiligo: An Update on Pathophysiology and Treatment Options.

    Science.gov (United States)

    Speeckaert, Reinhart; van Geel, Nanja

    2017-12-01

    The pathophysiology of vitiligo is becoming increasingly clarified. In non-segmental vitiligo, early factors include activation of innate immunity, inflammasome activation, oxidative stress, and loss of melanocyte adhesion. Nonetheless, the main mechanism leading to non-segmental vitiligo involves an immune-mediated destruction of melanocytes. Anti-melanocyte-specific cytotoxic T cells exert a central role in the final effector stage. Genetic research revealed a multi-genetic inheritance displaying an overlap with other autoimmune disorders. However, some melanocyte-specific genes were also affected. Segmental vitiligo carries a different pathogenesis with most evidence indicating a mosaic skin disorder. Current management includes topical corticosteroids and immunomodulators. Narrow-band ultraviolet B can be used in patients not responding to topical treatment or in patients with extensive disease. Pigment cell transplantation offers an alternative for the treatment of segmental vitiligo or stable non-segmental lesions. Recent findings have revealed new targets for treatment that could lead to more efficient therapies. Targeted immunotherapy may halt the active immune pathways, although combination therapy may still be required to induce satisfying repigmentation. A recently established core set of outcome measures, new measurement instruments, and biomarker research pave the way for future standardized clinical trials.

  10. Astroglial role in the pathophysiology of status epilepticus: an overview.

    Science.gov (United States)

    Vargas-Sánchez, Karina; Mogilevskaya, Maria; Rodríguez-Pérez, John; Rubiano, María G; Javela, José J; González-Reyes, Rodrigo E

    2018-06-01

    Status epilepticus is a medical emergency with elevated morbidity and mortality rates, and represents a leading cause of epilepsy-related deaths. Though status epilepticus can occur at any age, it manifests more likely in children and elderly people. Despite the common prevalence of epileptic disorders, a complete explanation for the mechanisms leading to development of self-limited or long lasting seizures (as in status epilepticus) are still lacking. Apart from neurons, research evidence suggests the involvement of immune and glial cells in epileptogenesis. Among glial cells, astrocytes represent an ideal target for the study of the pathophysiology of status epilepticus, due to their key role in homeostatic balance of the central nervous system. During status epilepticus, astroglial cells are activated by the presence of cytokines, damage associated molecular patterns and reactive oxygen species. The persistent activation of astrocytes leads to a decrease in glutamate clearance with a corresponding accumulation in the synaptic extracellular space, increasing the chance of neuronal excitotoxicity. Moreover, major alterations in astrocytic gap junction coupling, inflammation and receptor expression, facilitate the generation of seizures. Astrocytes are also involved in dysregulation of inhibitory transmission in the central nervous system and directly participate in ionic homeostatic alterations during status epilepticus. In the present review, we focus on the functional and structural changes in astrocytic activity that participate in the development and maintenance of status epilepticus, with special attention on concurrent inflammatory alterations. We also include potential astrocytic treatment targets for status epilepticus.

  11. [Refeeding syndrome : Pathophysiology, risk factors, prevention, and treatment].

    Science.gov (United States)

    Wirth, R; Diekmann, R; Janssen, G; Fleiter, O; Fricke, L; Kreilkamp, A; Modreker, M K; Marburger, C; Nels, S; Pourhassan, M; Schaefer, R; Willschrei, H-P; Volkert, D

    2018-04-01

    Refeeding syndrome is a life-threatening complication that may occur after initiation of nutritional therapy in malnourished patients, as well as after periods of fasting and hunger. Refeeding syndrome can be effectively prevented and treated if its risk factors and pathophysiology are known. The initial measurement of thiamine level and serum electrolytes, including phosphate and magnesium, their supplementation if necessary, and a slow increase in nutritional intake along with close monitoring of serum electrolytes play an important role. Since refeeding syndrome is not well known and the symptoms can be extremely heterogeneous, this complication is poorly recognized, especially against the background of severe disease and multimorbidity. This overview aims to summarize the current knowledge and increase awareness about refeeding syndrome.

  12. Update on Mastocytosis (Part 1): Pathophysiology, Clinical Features, and Diagnosis.

    Science.gov (United States)

    Azaña, J M; Torrelo, A; Matito, A

    2016-01-01

    Mastocytosis is a term used to describe a heterogeneous group of disorders characterized by clonal proliferation of mast cells in various organs. The organ most often affected is the skin. Mastocytosis is a relatively rare disorder that affects both sexes equally. It can occur at any age, although it tends to appear in the first decade of life, or later, between the second and fifth decades. Our understanding of the pathophysiology of mastocytosis has improved greatly in recent years, with the discovery that somatic c-kit mutations and aberrant immunophenotypic features have an important role. The clinical manifestations of mastocytosis are diverse, and skin lesions are the key to diagnosis in most patients. Copyright © 2015 Elsevier España, S.L.U. and AEDV. All rights reserved.

  13. Transforming pathophysiology instruction through narrative pedagogy and Socratic questioning.

    Science.gov (United States)

    Rogge, M M

    2001-01-01

    Pathophysiology, heavily content driven, has typically been taught through the use of traditional behavioral pedagogy and a reliance on the formal lecture. The author describes the limitations of this approach to teaching pathophysiology and describes the use of narrative pedagogy and Socratic questioning as alternative methods of instruction to augment lecture methods. Specific strategies for transforming traditional classroom teaching by using Socratic questions in a pathophysiology course for nurse practitioners are described. Student and faculty reactions to the initial efforts to transform pathophysiology instruction are also described.

  14. Pathophysiological implications of the chemical messengers

    International Nuclear Information System (INIS)

    Blazquez Fernandez, E.

    2009-01-01

    To maintain a physical organization and a different composition of its surroundings environment, living beings use a great part of the energy that they produce. Vital processes require an elevated number of reactions which are regulated and integrated by chemical messengers. They use autocrine, paracrine, endocrine and synaptic signals through receptors of cell surface, nuclear or associated with ionic channels, enzymes, trim eric G proteins and to intracellular kinases. Through these mechanisms pheromones play an important role in the relationships between different individuals, and hormones are able to regulate the integrative functions of our organism. In the nervous system, neurotransmitters, neuromodulators, sensors and receptors between other messengers, play functions of great relevance, while growth factors stimulate cell proliferation and cytokines have many effects but the most important is the ones related with the control of the immflamatory process. Alterations of these messengers permit us a better understanding of the diseases and possibly of its treatments in a near future. Modifications of the expression of genes from the nuclear and mitochondrial genomes are responsible of monogenic, polygenic and mitochondrial diseases, while alterations in the activities of dopamine and serotonin neurotransmitters are related with schizophrenia, Parkinson disease and depression, respectively. Other example is the hyperthyroidism of the Graves-Bassedow disease due to the competitive interference of the LATS immunoglobulin with TSH at the level of the follicular cells producing thyroid hormones Twenty five years ago in the reviews on the mechanisms of insulin action, there was presentations in which the insulin receptor was located in the plasma membrane of the target cells while in the cytoplasm only a big interrogative was observed, that at present is replaced by chemical mediators cascades responsible of the multiple effects of insulin. This finding is similar

  15. An update on pancreatic pathophysiology (do we have to rewrite pancreatic pathophysiology?).

    Science.gov (United States)

    Hammer, Heinz F

    2014-02-01

    This review focuses on seven aspects of physiology and pathophysiology of the exocrine pancreas that have been intensively discussed and studied within the past few years: (1) the role of neurohormonal mechanisms like melatonin, leptin, or ghrelin in the stimulation of pancreatic enzyme secretion; (2) the initiation processes of acute pancreatitis, like fusion of zymogen granules with lysosomes leading to intracellular activation of trypsinogen by the lysosomal enzyme cathepsin B, or autoactivation of trypsinogen; (3) the role of genes in the pathogenesis of acute pancreatitis; (4) the role of alcohol and constituents of alcoholic beverages in the pathogenesis of acute pancreatitis; (5) the role of pancreatic hypertension, neuropathy, and central mechanisms for the pathogenesis of pain in chronic pancreatitis; (6) the relation between exocrine pancreatic function and diabetes mellitus; and (7) pathophysiology, diagnosis and treatment of pancreatic steatorrhea.

  16. Deep Brain Stimulation in Huntington’s Disease—Preliminary Evidence on Pathophysiology, Efficacy and Safety

    Directory of Open Access Journals (Sweden)

    Lars Wojtecki

    2016-08-01

    Full Text Available Huntington’s disease (HD is one of the most disabling degenerative movement disorders, as it not only affects the motor system but also leads to cognitive disabilities and psychiatric symptoms. Deep brain stimulation (DBS of the pallidum is a promising symptomatic treatment targeting the core motor symptom: chorea. This article gives an overview of preliminary evidence on pathophysiology, safety and efficacy of DBS in HD.

  17. Sirtuin 3, a new target of PGC-1alpha, plays an important role in the suppression of ROS and mitochondrial biogenesis.

    Directory of Open Access Journals (Sweden)

    Xingxing Kong

    2010-07-01

    Full Text Available Sirtuin 3 (SIRT3 is one of the seven mammalian sirtuins, which are homologs of the yeast Sir2 gene. SIRT3 is the only sirtuin with a reported association with the human life span. Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha plays important roles in adaptive thermogenesis, gluconeogenesis, mitochondrial biogenesis and respiration. PGC-1alpha induces several key reactive oxygen species (ROS-detoxifying enzymes, but the molecular mechanism underlying this is not well understood.Here we show that PGC-1alpha strongly stimulated mouse Sirt3 gene expression in muscle cells and hepatocytes. Knockdown of PGC-1alpha led to decreased Sirt3 gene expression. PGC-1alpha activated the mouse SIRT3 promoter, which was mediated by an estrogen-related receptor (ERR binding element (ERRE (-407/-399 mapped to the promoter region. Chromatin immunoprecipitation and electrophoretic mobility shift assays confirmed that ERRalpha bound to the identified ERRE and PGC-1alpha co-localized with ERRalpha in the mSirt3 promoter. Knockdown of ERRalpha reduced the induction of Sirt3 by PGC-1alpha in C(2C(12 myotubes. Furthermore, Sirt3 was essential for PGC-1alpha-dependent induction of ROS-detoxifying enzymes and several components of the respiratory chain, including glutathione peroxidase-1, superoxide dismutase 2, ATP synthase 5c, and cytochrome c. Overexpression of SIRT3 or PGC-1alpha in C(2C(12 myotubes decreased basal ROS level. In contrast, knockdown of mSIRT3 increased basal ROS level and blocked the inhibitory effect of PGC-1alpha on cellular ROS production. Finally, SIRT3 stimulated mitochondrial biogenesis, and SIRT3 knockdown decreased the stimulatory effect of PGC-1alpha on mitochondrial biogenesis in C(2C(12 myotubes.Our results indicate that Sirt3 functions as a downstream target gene of PGC-1alpha and mediates the PGC-1alpha effects on cellular ROS production and mitochondrial biogenesis. Thus, SIRT3 integrates cellular energy

  18. Retinovascular physiology and pathophysiology: new experimental approach/new insights

    Science.gov (United States)

    Puro, Donald G.

    2012-01-01

    An important challenge in visual neuroscience is understand the physiology and pathophysiology of the intra-retinal vasculature, whose function is required for ophthalmoception by humans and most other mammals. In the quest to learn more about this highly specialized portion of the circulatory system, a newly developed method for isolating vast microvascular complexes from the rodent retina has opened the way for using techniques such as patch-clamping, fluorescence imaging and time-lapse photography to elucidate the functional organization of a capillary network and its pre-capillary arteriole. For example, the ability to obtain dual perforated-patch recordings from well-defined sites within an isolated microvascular complex permitted the first characterization of the electrotonic architecture of a capillary/arteriole unit. This analysis revealed that this operational unit is not simply a homogenous synctium, but has a complex functional organization that is dynamically modulated by extracellular signals such as angiotensin II. Another recent discovery is that a capillary and its pre-capillary arteriole have distinct physiological differences; capillaries have an abundance of ATP-sensitive potassium (KATP) channels and a dearth of voltage-dependent calcium channels (VDCCs) while the converse is true for arterioles. In addition, voltage transmission between abluminal cells and the endothelium is more efficient in the capillaries. Thus, the capillary network is well-equipped to generate and transmit voltages, and the pre-capillary arteriole is well-adapted to transduce a capillary-generated voltage into a change in abluminal cell calcium and thereby, a vasomotor response. Use of microvessels isolated from the diabetic retina has led to new insights concerning retinal vascular pathophysiology. For example, soon after the onset of diabetes, the efficacy of voltage transmission through the endothelium is diminished; arteriolar VDCCs is inhibited, and there is increased

  19. Neonatal posthemorrhagic hydrocephalus from prematurity: pathophysiology and current treatment concepts

    Science.gov (United States)

    Robinson, Shenandoah

    2013-01-01

    Object Preterm infants are at risk for perinatal complications, including germinal matrix–intraventricular hemorrhage (IVH) and subsequent posthemorrhagic hydrocephalus (PHH). This review summarizes the current understanding of the epidemiology, pathophysiology, management, and outcomes of IVH and PHH in preterm infants. Methods The MEDLINE database was systematically searched using terms related to IVH, PHH, and relevant neurosurgical procedures to identify publications in the English medical literature. To complement information from the systematic search, pertinent articles were selected from the references of articles identifed in the initial search. Results This review summarizes the current knowledge regarding the epidemiology and pathophysiology of IVH and PHH, primarily using evidence-based studies. Advances in obstetrics and neonatology over the past few decades have contributed to a marked improvement in the survival of preterm infants, and neurological morbidity is also starting to decrease. The incidence of IVH is declining, and the incidence of PHH will likely follow. Currently, approximately 15% of preterm infants who suffer severe IVH will require permanent CSF diversion. The clinical presentation and surgical management of symptomatic PHH with temporary ventricular reservoirs (ventricular access devices) and ventriculosubgaleal shunts and permanent ventriculoperitoneal shunts are discussed. Preterm infants who develop PHH that requires surgical treatment remain at high risk for other related neurological problems, including cerebral palsy, epilepsy, and cognitive and behavioral delay. This review highlights numerous opportunities for further study to improve the care of these children. Conclusions A better grasp of the pathophysiology of IVH is beginning to impact the incidence of IVH and PHH. Neonatologists conduct rigorous Class I and II studies to advance the outcomes of preterm infants. The need for well-designed multicenter trials is

  20. [Circadian blood pressure variation under several pathophysiological conditions including secondary hypertension].

    Science.gov (United States)

    Imai, Yutaka; Hosaka, Miki; Satoh, Michihiro

    2014-08-01

    Abnormality of circadian blood pressure (BP) variation, i.e. non-dipper, riser, nocturnal hypertension etc, is brought by several pathophysiological conditions especially by secondary hypertension. These pathophysiological conditions are classified into several categories, i.e. disturbance of autonomic nervous system, metabolic disorder, endocrine disorder, disorder of Na and water excretion (e.g. sodium sensitivity), severe target organ damage and ischemia, cardiovascular complications and drug induced hypertension. Each pathophysiological condition which brings disturbance of circadian BP variation is included in several categories, e.g. diabetes mellitus is included in metabolic disorder, autonomic imbalance, sodium sensitivity and endocrine disorder. However, it seems that unified principle of the genesis of disturbance of circadian BP variation in many pathophysiological conditions is autonomic imbalance. Thus, it is concluded that disturbance of circadian BP variation is not purposive biological behavior but the result of autonomic imbalance which looks as if compensatory reaction such as exaggerated Na-water excretion during night in patient with Na-water retention who reveals disturbed circadian BP variation.

  1. Hypoxia-Inducible Factor-1 in Physiological and Pathophysiological Angiogenesis: Applications and Therapies

    Science.gov (United States)

    Zimna, Agnieszka; Kurpisz, Maciej

    2015-01-01

    The cardiovascular system ensures the delivery of oxygen and nutrients to all cells, tissues, and organs. Under extended exposure to reduced oxygen levels, cells are able to survive through the transcriptional activation of a series of genes that participate in angiogenesis, glucose metabolism, and cell proliferation. The oxygen-sensitive transcriptional activator HIF-1 (hypoxia-inducible factor-1) is a key transcriptional mediator of the response to hypoxic conditions. The HIF-1 pathway was found to be a master regulator of angiogenesis. Whether the process is physiological or pathological, HIF-1 seems to participate in vasculature formation by synergistic correlations with other proangiogenic factors such as VEGF (vascular endothelial growth factor), PlGF (placental growth factor), or angiopoietins. Considering the important contributions of HIF-1 in angiogenesis and vasculogenesis, it should be considered a promising target for treating ischaemic diseases or cancer. In this review, we discuss the roles of HIF-1 in both physiological/pathophysiological angiogenesis and potential strategies for clinical therapy. PMID:26146622

  2. Identification of Forensically Important Calliphoridae and Sarcophagidae Species Collected in Korea Using SNaPshot Multiplex System Targeting the Cytochrome c Oxidase Subunit I Gene

    Directory of Open Access Journals (Sweden)

    Ji Hye Park

    2018-01-01

    Full Text Available Estimation of postmortem interval (PMI is paramount in modern forensic investigation. After the disappearance of the early postmortem phenomena conventionally used to estimate PMI, entomologic evidence provides important indicators for PMI estimation. The age of the oldest fly larvae or pupae can be estimated to pinpoint the time of oviposition, which is considered the minimum PMI (PMImin. The development rate of insects is usually temperature dependent and species specific. Therefore, species identification is mandatory for PMImin estimation using entomological evidence. The classical morphological identification method cannot be applied when specimens are damaged or have not yet matured. To overcome this limitation, some investigators employ molecular identification using mitochondrial cytochrome c oxidase subunit I (COI nucleotide sequences. The molecular identification method commonly uses Sanger’s nucleotide sequencing and molecular phylogeny, which are complex and time consuming and constitute another obstacle for forensic investigators. In this study, instead of using conventional Sanger’s nucleotide sequencing, single-nucleotide polymorphisms (SNPs in the COI gene region, which are unique between fly species, were selected and targeted for single-base extension (SBE technology. These SNPs were genotyped using a SNaPshot® kit. Eleven Calliphoridae and seven Sarcophagidae species were covered. To validate this genotyping, fly DNA samples (103 adults, 84 larvae, and 4 pupae previously confirmed by DNA barcoding were used. This method worked quickly with minimal DNA, providing a potential alternative to conventional DNA barcoding. Consisting of only a few simple electropherogram peaks, the results were more straightforward compared with those of the conventional DNA barcoding produced by Sanger’s nucleotide sequencing.

  3. Missing cells: pathophysiology, diagnosis and management of (pancytopenia in childhood

    Directory of Open Access Journals (Sweden)

    Miriam eErlacher

    2015-07-01

    Full Text Available Peripheral blood cytopenia in children can be due to a variety of acquired or inherited diseases. Genetic disorders affecting a single hematopoietic lineage are frequently characterized by typical bone marrow findings such as lack of progenitors or maturation arrest in congenital neutropenia or a lack of megakaryocytes in congenital amegakaryocytic thrombocytopenia whereas antibody mediated diseases such as autoimmune neutropenia are associated with a rather unremarkable bone marrow morphology. In contrast, pancytopenia is frequently associated with a hypocellular bone marrow and the differential diagnosis includes acquired aplastic anemia, myelodysplastic syndrome, inherited bone marrow failure syndromes such as Fanconi anemia and dyskeratosis congenita and a variety of immunological disorders including hemophagocytic lymphohistiocytosis. Thorough bone marrow analysis is of special importance for the diagnostic work-up of most patients. Cellularity, cellular composition and dysplastic signs are the cornerstones of the differential diagnosis. Pancytopenia in the presence of a normo- or hypercellular marrow with dysplastic changes may indicate myelodysplastic syndrome. More challenging for the hematologist is the evaluation of the hypocellular bone marrow. Although aplastic anemia and hypocellular refractory cytopenia of childhood (RCC can reliably be differentiated on a morphological level the overlapping pathophysiology remains a significant challenge for the choice of the therapeutic strategy. Furthermore, inherited bone marrow failure syndromes are usually associated with the morphological picture of RCC and the recognition of these entities is essential as they often present a multisystem disease requiring different diagnostic and therapeutic approaches. This paper gives an overview over the different disease entities presenting with (pancytopenia, their pathophysiology, characteristic bone marrow findings and therapeutic approaches.

  4. Study of pathophysiology of pulmonary circulation in polycythemia using scintigraphy

    Energy Technology Data Exchange (ETDEWEB)

    Fujii, Tadashige; Tanaka, Masao; Takeda, Tadashi; Kawashima, Akira; Kubo, Keiji; Kobayashi, Toshio; Handa, Kenjiro; Yoshimura, Kazuhiko (Shinshu Univ., Matsumoto, Nagano (Japan). Faculty of Medicine)

    1993-09-01

    In order to evaluate the pathophysiology of pulmonary circulation in polycythemia, Tl-201 myocardial scintigraphy and perfusion lung scintigraphy with 99m-Tc-MAA were performed in 19 cases of polycythemia including polycythemia rubra vera and in 11 cases of secondary polycythemia due to pulmonary diseases. Tl-201 lung uptake, right ventricular visualization and pulmonary perfusion impairment were studied. In the 19 cases, Tl-201 lung uptake was observed in all cases and 54.5% of them showed moderate lung uptake. The grade of right ventricular visualization was moderate in one case and slight in 16 cases; right ventricular hypertrophy was shown in 89.5% of all cases by Tl-201 scintigraphy, only one of which showed right ventricular hypertrophy on electrocardiography. Abnormalities of lung perfusion consisted of scattered small areas of hypoperfusion in 36.8%, peripheral hypoperfusion in 78.9% and uneven distribution of pulmonary perfusion in 94.7%. The degree of hypoperfusion was slightly related to decrease in FEV 1.0%, V25 and PaO[sub 2] and increase in circulating blood volume and peripheral red blood cell counts. Abnormalities of pulmonary function consisted of increased RV/TLC in 50.0%, increased CV/VC in 35.7% and decreased V25 in 36.8%. Arterial blood gases showed hypoxemia in 57.1%, the degree of which was slightly related to increase in RV/TLC and CV/VC and decrease in V25. Cases of secondary polycythemia due to pulmonary diseases showed more marked right ventricular visualization, pulmonary perfusion impairment and abnormalities of various kinds of pulmonary function than polycythemia rubra vera cases. It seems to be important to evaluate the pathophysiology of pulmonary circulation in polycythemia rubra vera as well as secondary polycythemia due to cardio-pulmonary diseases, because pulmonary perfusion impairment and moderate right ventricular visualization are observed frequently in polycythemia rubra vera. (author).

  5. Study of pathophysiology of pulmonary circulation in polycythemia using scintigraphy

    International Nuclear Information System (INIS)

    Fujii, Tadashige; Tanaka, Masao; Takeda, Tadashi; Kawashima, Akira; Kubo, Keiji; Kobayashi, Toshio; Handa, Kenjiro; Yoshimura, Kazuhiko

    1993-01-01

    In order to evaluate the pathophysiology of pulmonary circulation in polycythemia, Tl-201 myocardial scintigraphy and perfusion lung scintigraphy with 99m-Tc-MAA were performed in 19 cases of polycythemia including polycythemia rubra vera and in 11 cases of secondary polycythemia due to pulmonary diseases. Tl-201 lung uptake, right ventricular visualization and pulmonary perfusion impairment were studied. In the 19 cases, Tl-201 lung uptake was observed in all cases and 54.5% of them showed moderate lung uptake. The grade of right ventricular visualization was moderate in one case and slight in 16 cases; right ventricular hypertrophy was shown in 89.5% of all cases by Tl-201 scintigraphy, only one of which showed right ventricular hypertrophy on electrocardiography. Abnormalities of lung perfusion consisted of scattered small areas of hypoperfusion in 36.8%, peripheral hypoperfusion in 78.9% and uneven distribution of pulmonary perfusion in 94.7%. The degree of hypoperfusion was slightly related to decrease in FEV 1.0%, V25 and PaO 2 and increase in circulating blood volume and peripheral red blood cell counts. Abnormalities of pulmonary function consisted of increased RV/TLC in 50.0%, increased CV/VC in 35.7% and decreased V25 in 36.8%. Arterial blood gases showed hypoxemia in 57.1%, the degree of which was slightly related to increase in RV/TLC and CV/VC and decrease in V25. Cases of secondary polycythemia due to pulmonary diseases showed more marked right ventricular visualization, pulmonary perfusion impairment and abnormalities of various kinds of pulmonary function than polycythemia rubra vera cases. It seems to be important to evaluate the pathophysiology of pulmonary circulation in polycythemia rubra vera as well as secondary polycythemia due to cardio-pulmonary diseases, because pulmonary perfusion impairment and moderate right ventricular visualization are observed frequently in polycythemia rubra vera. (author)

  6. Pathophysiology and Biomarkers in Acute Ischemic Stroke – A Review

    African Journals Online (AJOL)

    The pathophysiology of ischemic stroke is complex, and majorly involves excitotoxicity, oxidative stress, inflammation, blood-brain barrier dysfunction, apoptosis, etc. Several of the biomarkers are related to these pathophysiologic mechanisms and they may have applications in stroke prediction, diagnosis, assessment, ...

  7. Orthostatic intolerance: potential pathophysiology and therapy.

    Science.gov (United States)

    Lu, Chih-Cherng; Tseng, Ching-Jiunn; Tang, Hung-Shang; Tung, Che-Se

    2004-09-30

    Orthostatic intolerance affects an estimated 1 in 500 persons and causes a wide range of disabilities. After essential hypertension, it is the most frequently encountered dysautonomia, accounting for the majority of patients referred to centers specializing in autonomic disorders. Patients are typically young females with symptoms such as dizziness, visual changes, head and neck discomfort, poor concentration, fatigue, palpitations, tremulousness, anxiety, and, in some cases, syncope. Syncope is the most hazardous symptom of orthostatic intolerance, presumably occurring because of impaired cerebral perfusion and in part to compensatory autonomic mechanisms. The etiology of this syndrome is still unclear but is heterogeneous. Orthostatic intolerance used to be characterized by an overall enhancement of noradrenergic tone at rest in some patients and by a patchy dysautonomia of postganglionic sympathetic fibers with a compensatory cardiac sympathetic activation in others. However, recent advances in molecular genetics are improving our understanding of orthostatic intolerance, such as several genetic diseases (such as Ehler-Danlos syndrome and norepinephrine transporter deficiency) presenting with symptoms typical of orthostatic intolerance. Future work will include investigation of genetic functional mutations underlying interindividual differences in autonomic cardiovascular control, body fluid regulation, and vascular regulation in orthostatic intolerance patients. The goal of this review article is to describe recent advances in understanding the pathophysiological mechanisms of orthostatic intolerance and their clinical significance.

  8. [Pathophysiology and new treatment of uveitis].

    Science.gov (United States)

    Yanai, Ryoji; Takeda, Atsunobu; Yoshimura, Takeru; Sonoda, Koh-Hei

    2014-01-01

    Uveitis is narrow-defined inflammation of the uvea, also clinically include all inflammatory conditions in the eye. Uveitis may occur as a consequence of various causes and background, such as autoimmune diseases, infections, and hematopoietic malignancy. We have to treat uveitis not only controlling the inflammation but also maintaining up the visual function of the eye because the most uveitis is chronic and relapsing inflammatory disorder. Behçét's disease is a systemic disease and results in loss of vision without adequate treatment. Behçét's disease was a representative of vision loss uveitis because Behçét's patient usually had treatment resistance of conventional treatment, such as colchicine and cyclosporine. However, biological therapy with TNF-α, which started from 2007, has revolutionized the treatment strategy of Behçét's disease. It is not too much to say that Behçét's patient is free from fear of vision loss by the dramatic decrease of ocular attach. Biological therapy is not approved as a treatment of uveitis except Behçét's disease. Some protracted cases of Sarcoidosis and Vogt-Koyanagi-Harada disease are resistant to corticosteroid therapy and require new treatment. In this review, we discuss the pathophysiology of uveitis and report new treatment of Behçét's disease by biological therapy.

  9. The pathophysiology of trauma-induced coagulopathy.

    Science.gov (United States)

    Frith, Daniel; Brohi, Karim

    2012-12-01

    Transfusion paradigms and protocols have evolved at a rapid pace in the last few years to ameliorate the adverse effects of trauma-induced coagulopathy (TIC). This has occurred despite fragmented and inadequate knowledge of the underlying pathophysiology that they are supposed to treat. This review will collate and assimilate the most recent data about TIC in order to present our state-of-the-art understanding of this condition. TIC was conventionally construed simply as depletion, dysfunction or dilution of procoagulant factors. However, contemporary understanding recognizes it as an imbalance of the dynamic equilibrium between procoagulant factors, anticoagulant factors, platelets, endothelium and fibrinolysis. The endogenous component of TIC (acute traumatic coagulopathy) is not merely a consumptive coagulopathy, but is characterized by isolated factor V inhibition, dysfibrinogenaemia, systemic anticoagulation, impaired platelet function and hyperfibrinolysis. Acute traumatic coagulopathy then becomes exacerbated by hypothermia, acidosis and resuscitation with hypocoagulable fluids. Further improvement in the outcome from trauma-haemorrhage is possible with more refined and tailored haemostatic resuscitation. Achieving this will depend upon a better understanding of the haemostatic defects that develop after injury.

  10. The pathophysiology of amenorrhea in the adolescent.

    Science.gov (United States)

    Golden, Neville H; Carlson, Jennifer L

    2008-01-01

    Menstrual irregularity is a common occurrence during adolescence, especially within the first 2-3 years after menarche. Prolonged amenorrhea, however, is not normal and can be associated with significant medical morbidity, which differs depending on whether the adolescent is estrogen-deficient or estrogen-replete. Estrogen-deficient amenorrhea is associated with reduced bone mineral density and increased fracture risk, while estrogen-replete amenorrhea can lead to dysfunctional uterine bleeding in the short term and predispose to endometrial carcinoma in the long term. In both situations, appropriate intervention can reduce morbidity. Old paradigms of whom to evaluate for amenorrhea have been challenged by recent research that provides a better understanding of the normal menstrual cycle and its variability. Hypothalamic amenorrhea is the most prevalent cause of amenorrhea in the adolescent age group, followed by polycystic ovary syndrome. In anorexia nervosa, exercise-induced amenorrhea, and amenorrhea associated with chronic illness, an energy deficit results in suppression of hypothalamic secretion of GnRH, mediated in part by leptin. Administration of recombinant leptin to women with hypothalamic amenorrhea has been shown to restore LH pulsatility and ovulatory menstrual cycles. The use of recombinant leptin may improve our understanding of the pathophysiology of hypothalamic amenorrhea in adolescents and may also have therapeutic possibilities.

  11. Clinical manifestations and pathophysiology of lissencephaly

    International Nuclear Information System (INIS)

    Oi, Shizuo; Sasaki, Koji; Yamada, Hiroshi; Ando, Shoko; Tamura, Yasunori; Fukuda, Kuniaki; Furukawa, Seikyo; Matsumoto, Satoshi.

    1985-01-01

    Four cases of lissencephaly were analyzed in light of clinical manifestations, CT findings and the state of hydrocephalus. Lissencephaly had been diagnosed mainly by autopsy until CT scan was introduced in the early 1970's. Since then, diagnosis of lissencephaly early in life is possible. Presently the major interest in this congenital CNS anomaly, which is caused by a neuronal migration disorder in the relatively late stages of fetal development, is to learn the dynamic pathophysiological state and management. The purpose of this paper is to analyze those points of lissencephaly in diagnosis during life and possible treatment in the hydrocephalic state. The common findings in CT in all four cases are as follows: No. 1. smooth cortical surface (agyria--pachygyria), No. 2. wide sylvian fissure (complete or incomplete lack of opercularization, No. 3. ventricular dilatation (remarkable bilateral enlargement of lateral ventricle and third ventricle--colpocephaly), No. 4. wide subdural or subarachnoid space in supratentorial region, No. 5. periventricular low density, No. 6. midline cavum, No. 7. normal CT findings in posterior fossa structure. Three out of four patients demonstrated full or bulged and tense anterior fontanella. Because of this suggestion of increased intracranial pressure and enlarged ventricles with periventricular lucency in CT findings, one patient underwent CT cisternography for dynamic analysis of the CSF circulation and continuous ICP monitoring for dynamic evaluation of the ICP pattern. The results revealed very much delayed CSF circulation and intermittently increased. ICP, with pressure waves appearing in 35.7 % of all recordings. (J.P.N.)

  12. Pathophysiology and Immune Dysfunction in Endometriosis

    Science.gov (United States)

    Ahn, Soo Hyun; Monsanto, Stephany P.; Miller, Caragh; Singh, Sukhbir S.; Thomas, Richard; Tayade, Chandrakant

    2015-01-01

    Endometriosis is an estrogen-dependent, chronic, proinflammatory disease prevalent in 10% of women of reproductive age worldwide. Characterized by the growth of endometrium-like tissue in aberrant locations outside of the uterus, it is responsible for symptoms including chronic pelvic pain, dysmenorrhea, and subfertility that degrade quality of life of women significantly. In Canada, direct and indirect economic cost of endometriosis amounts to 1.8 billion dollars, and this is elevated to 20 billion dollars in the United States. Despite decades of research, the etiology and pathophysiology of endometriosis still remain to be elucidated. This review aims to bring together the current understanding regarding the pathogenesis of endometriosis with specific focus on mechanisms behind vascularization of the lesions and the contribution of immune factors in facilitating lesion establishment and development. The role of hormones, immune cells, and cytokine signaling is highlighted, in addition to discussing the current pharmaceutical options available for management of pain symptoms in women with endometriosis. PMID:26247027

  13. Pathophysiology and Immune Dysfunction in Endometriosis

    Directory of Open Access Journals (Sweden)

    Soo Hyun Ahn

    2015-01-01

    Full Text Available Endometriosis is an estrogen-dependent, chronic, proinflammatory disease prevalent in 10% of women of reproductive age worldwide. Characterized by the growth of endometrium-like tissue in aberrant locations outside of the uterus, it is responsible for symptoms including chronic pelvic pain, dysmenorrhea, and subfertility that degrade quality of life of women significantly. In Canada, direct and indirect economic cost of endometriosis amounts to 1.8 billion dollars, and this is elevated to 20 billion dollars in the United States. Despite decades of research, the etiology and pathophysiology of endometriosis still remain to be elucidated. This review aims to bring together the current understanding regarding the pathogenesis of endometriosis with specific focus on mechanisms behind vascularization of the lesions and the contribution of immune factors in facilitating lesion establishment and development. The role of hormones, immune cells, and cytokine signaling is highlighted, in addition to discussing the current pharmaceutical options available for management of pain symptoms in women with endometriosis.

  14. IQGAP1 is important for activation of caspase-1 in macrophages and is targeted by Yersinia pestis type III effector YopM.

    Science.gov (United States)

    Chung, Lawton K; Philip, Naomi H; Schmidt, Valentina A; Koller, Antonius; Strowig, Till; Flavell, Richard A; Brodsky, Igor E; Bliska, James B

    2014-07-01

    YopM is a leucine-rich repeat (LRR)-containing effector in several Yersinia species, including Yersinia pestis and Y. pseudotuberculosis. Different Yersinia strains encode distinct YopM isoforms with variable numbers of LRRs but conserved C-terminal tails. A 15-LRR isoform in Y. pseudotuberculosis YPIII was recently shown to bind and inhibit caspase-1 via a YLTD motif in LRR 10, and attenuation of YopM(-) YPIII was reversed in mice lacking caspase-1, indicating that caspase-1 inhibition is a major virulence function of YopM(YPIII). To determine if other YopM proteins inhibit caspase-1, we utilized Y. pseudotuberculosis strains natively expressing a 21-LRR isoform lacking the YLTD motif (YopM(32777)) or ectopically expressing a Y. pestis 15-LRR version with a functional (YopM(KIM)) or inactivated (YopM(KIM) D271A) YLTD motif. Results of mouse and macrophage infections with these strains showed that YopM(32777), YopM(KIM), and YopM(KIM) D271A inhibit caspase-1 activation, indicating that the YLTD motif is dispensable for this activity. Analysis of YopM(KIM) deletion variants revealed that LRRs 6 to 15 and the C-terminal tail are required to inhibit caspase-1 activation. YopM(32777), YopM(KIM), and YopM(KIM) deletion variants were purified, and binding partners in macrophage lysates were identified. Caspase-1 bound to YopM(KIM) but not YopM(32777). Additionally, YopM(KIM) bound IQGAP1 and the use of Iqgap1(-/-) macrophages revealed that this scaffolding protein is important for caspase-1 activation upon infection with YopM(-) Y. pseudotuberculosis. Thus, while multiple YopM isoforms inhibit caspase-1 activation, their variable LRR domains bind different host proteins to perform this function and the LRRs of YopM(KIM) target IQGAP1, a novel regulator of caspase-1, in macrophages. Importance: Activation of caspase-1, mediated by macromolecular complexes termed inflammasomes, is important for innate immune defense against pathogens. Pathogens can, in turn, subvert

  15. Molecular Pathophysiology of Epithelial Barrier Dysfunction in Inflammatory Bowel Diseases

    Directory of Open Access Journals (Sweden)

    Jessica Y. Lee

    2018-03-01

    Full Text Available Over the years, the scientific community has explored myriads of theories in search of the etiology and a cure for inflammatory bowel disease (IBD. The cumulative evidence has pointed to the key role of the intestinal barrier and the breakdown of these mechanisms in IBD. More and more scientists and clinicians are embracing the concept of the impaired intestinal epithelial barrier and its role in the pathogenesis and natural history of IBD. However, we are missing a key tool that bridges these scientific insights to clinical practice. Our goal is to overcome the limitations in understanding the molecular physiology of intestinal barrier function and develop a clinical tool to assess and quantify it. This review article explores the proteins in the intestinal tissue that are pivotal in regulating intestinal permeability. Understanding the molecular pathophysiology of impaired intestinal barrier function in IBD may lead to the development of a biochemical method of assessing intestinal tissue integrity which will have a significant impact on the development of novel therapies targeting the intestinal mucosa.

  16. Dissecting carboxypeptidase E: properties, functions and pathophysiological roles in disease

    Directory of Open Access Journals (Sweden)

    Lin Ji

    2017-04-01

    Full Text Available Since discovery in 1982, carboxypeptidase E (CPE has been shown to be involved in the biosynthesis of a wide range of neuropeptides and peptide hormones in endocrine tissues, and in the nervous system. This protein is produced from pro-CPE and exists in soluble and membrane forms. Membrane CPE mediates the targeting of prohormones to the regulated secretory pathway, while soluble CPE acts as an exopeptidase and cleaves C-terminal basic residues from peptide intermediates to generate bioactive peptides. CPE also participates in protein internalization, vesicle transport and regulation of signaling pathways. Therefore, in two types of CPE mutant mice, Cpefat/Cpefat and Cpe knockout, loss of normal CPE leads to a lot of disorders, including diabetes, hyperproinsulinemia, low bone mineral density and deficits in learning and memory. In addition, the potential roles of CPE and ΔN-CPE, an N-terminal truncated form, in tumorigenesis and diagnosis were also addressed. Herein, we focus on dissecting the pathophysiological roles of CPE in the endocrine and nervous systems, and related diseases.

  17. Mitochondrial dynamics in type 2 diabetes: Pathophysiological implications

    Directory of Open Access Journals (Sweden)

    Susana Rovira-Llopis

    2017-04-01

    Full Text Available Mitochondria play a key role in maintaining cellular metabolic homeostasis. These organelles have a high plasticity and are involved in dynamic processes such as mitochondrial fusion and fission, mitophagy and mitochondrial biogenesis. Type 2 diabetes is characterised by mitochondrial dysfunction, high production of reactive oxygen species (ROS and low levels of ATP. Mitochondrial fusion is modulated by different proteins, including mitofusin-1 (MFN1, mitofusin-2 (MFN2 and optic atrophy (OPA-1, while fission is controlled by mitochondrial fission 1 (FIS1, dynamin-related protein 1 (DRP1 and mitochondrial fission factor (MFF. PARKIN and (PTEN-induced putative kinase 1 (PINK1 participate in the process of mitophagy, for which mitochondrial fission is necessary. In this review, we discuss the molecular pathways of mitochondrial dynamics, their impairment under type 2 diabetes, and pharmaceutical approaches for targeting mitochondrial dynamics, such as mitochondrial division inhibitor-1 (mdivi-1, dynasore, P110 and 15-oxospiramilactone. Furthermore, we discuss the pathophysiological implications of impaired mitochondrial dynamics, especially in type 2 diabetes.

  18. Estrogens and Androgens in Skeletal Physiology and Pathophysiology.

    Science.gov (United States)

    Almeida, Maria; Laurent, Michaël R; Dubois, Vanessa; Claessens, Frank; O'Brien, Charles A; Bouillon, Roger; Vanderschueren, Dirk; Manolagas, Stavros C

    2017-01-01

    Estrogens and androgens influence the growth and maintenance of the mammalian skeleton and are responsible for its sexual dimorphism. Estrogen deficiency at menopause or loss of both estrogens and androgens in elderly men contribute to the development of osteoporosis, one of the most common and impactful metabolic diseases of old age. In the last 20 years, basic and clinical research advances, genetic insights from humans and rodents, and newer imaging technologies have changed considerably the landscape of our understanding of bone biology as well as the relationship between sex steroids and the physiology and pathophysiology of bone metabolism. Together with the appreciation of the side effects of estrogen-related therapies on breast cancer and cardiovascular diseases, these advances have also drastically altered the treatment of osteoporosis. In this article, we provide a comprehensive review of the molecular and cellular mechanisms of action of estrogens and androgens on bone, their influences on skeletal homeostasis during growth and adulthood, the pathogenetic mechanisms of the adverse effects of their deficiency on the female and male skeleton, as well as the role of natural and synthetic estrogenic or androgenic compounds in the pharmacotherapy of osteoporosis. We highlight latest advances on the crosstalk between hormonal and mechanical signals, the relevance of the antioxidant properties of estrogens and androgens, the difference of their cellular targets in different bone envelopes, the role of estrogen deficiency in male osteoporosis, and the contribution of estrogen or androgen deficiency to the monomorphic effects of aging on skeletal involution. Copyright © 2017 the American Physiological Society.

  19. Altered Mitochondrial Dynamics and TBI Pathophysiology

    Directory of Open Access Journals (Sweden)

    Tara Diane Fischer

    2016-03-01

    Full Text Available Mitochondrial function is intimately linked to cellular survival, growth, and death. Mitochondria not only generate ATP from oxidative phosphorylation, but also mediate intracellular calcium buffering, generation of reactive oxygen species (ROS, and apoptosis. Electron leakage from the electron transport chain, especially from damaged or depolarized mitochondria, can generate excess free radicals that damage cellular proteins, DNA, and lipids. Furthermore, mitochondrial damage releases pro-apoptotic factors to initiate cell death. Previous studies have reported that traumatic brain injury (TBI reduces mitochondrial respiration, enhances production of ROS, and triggers apoptotic cell death, suggesting a prominent role of mitochondria in TBI pathophysiology. Mitochondria maintain cellular energy homeostasis and health via balanced processes of fusion and fission, continuously dividing and fusing to form an interconnected network throughout the cell. An imbalance of these processes, particularly an excess of fission, can be detrimental to mitochondrial function, causing decreased respiration, ROS production, and apoptosis. Mitochondrial fission is regulated by the cytosolic GTPase, dynamin-related protein 1 (Drp1, which translocates to the mitochondrial outer membrane to initiate fission. Aberrant Drp1 activity has been linked to excessive mitochondrial fission and neurodegeneration. Measurement of Drp1 levels in purified hippocampal mitochondria showed an increase in TBI animals as compared to sham controls. Analysis of cryo-electron micrographs of these mitochondria also showed that TBI caused an initial increase in the length of hippocampal mitochondria at 24 hours post-injury, followed by a significant decrease in length at 72 hours. Post-TBI administration of Mdivi-1, a pharmacological inhibitor of Drp1, prevented this decrease in mitochondria length. Mdivi-1 treatment also reduced the loss of newborn neurons in the hippocampus and improved

  20. Pathophysiological characterization of asthma transitions across adolescence.

    Science.gov (United States)

    Arshad, Syed Hasan; Raza, Abid; Lau, Laurie; Bawakid, Khalid; Karmaus, Wilfried; Zhang, Hongmei; Ewart, Susan; Patil, Veersh; Roberts, Graham; Kurukulaaratchy, Ramesh

    2014-11-29

    Adolescence is a period of change, which coincides with disease remission in a significant proportion of subjects with childhood asthma. There is incomplete understanding of the changing characteristics underlying different adolescent asthma transitions. We undertook pathophysiological characterization of transitional adolescent asthma phenotypes in a longitudinal birth cohort. The Isle of Wight Birth Cohort (N = 1456) was reviewed at 1, 2, 4, 10 and 18-years. Characterization included questionnaires, skin tests, spirometry, exhaled nitric oxide, bronchial challenge and (in a subset of 100 at 18-years) induced sputum. Asthma groups were "never asthma" (no asthma since birth), "persistent asthma" (asthma at age 10 and 18), "remission asthma" (asthma at age 10 but not at 18) and "adolescent-onset asthma" (asthma at age 18 but not at age 10). Participants whose asthma remitted during adolescence had lower bronchial reactivity (odds ratio (OR) 0.30; CI 0.10 -0.90; p = 0.03) at age 10 plus greater improvement in lung function (forced expiratory flow 25-75% gain: 1.7 L; 1.0-2.9; p = 0.04) compared to persistent asthma by age 18. Male sex (0.3; 0.1-0.7; p adolescent-onset asthma showed eosinophilic airway inflammation (3.0%, 0.7-6.6), not seen in persistent asthma (1.0%, 0-3.9), while remission group had the lowest sputum eosinophil count (0.3%, 0-1.4) and lowest eosinophils/neutrophils ratio of 0.0 (Interquartile range: 0.1). Asthma remission during adolescence is associated with lower initial BHR and greater gain in small airways function, while adolescent-onset asthma is primarily eosinophilic.

  1. Chagas disease. A new pathophysiological assessment

    International Nuclear Information System (INIS)

    Redruello, M.; Masoli, O.; Hasson, I.; Cragnolino, D.; Traverso, S.; Perez Balino, N.; Sarmiento, R.; Lazzari, J.; Luluaga, E.

    2002-01-01

    Background: There is scarce information on myocardial perfusion abnormalities and on the coronary vasomotor condition in Chagas disease patients. Aims: To assess regional perfusion abnormalities and the coronary vasomotor response of patients in the chronic phase of Chagas disease. Methods: With the use of 99mTc-sestamibi SPECT imaging and cold pressor test and intracoronary acetylcoline (ACH) perfusion, we studied 9 patients aged 42,6±12 years, 4 males, in the chronic stage of Chagas disease (5 with the indeterminate form and 4 with heart lesion) with normal coronary arteries. Vasomotor responses to intracoronary increasing doses of ACH and to a single dose of nitroglycerine (NTG) were assessed with digital quantitative angiography. Regional myocardial perfusion was evaluated at rest and after cold pressor test by a semi quantitative score analysis in an 18-segment model with 99mTc-sestamibi SPECT images. Results were expressed as mean ± 2SD. Differences between continuous variables were measured by two tails Student's t test for paired variables and the significance level was set at 5 %. Results: All patients had regional perfusion defects and abnormal vasomotor response. The diameter of the left anterior descending artery decreased 34% from a basal diameter of 3.66∫0.95 mm down to 2.42±0.74 mm after maximal response to ACH (p<0.002). NTG infusion augmented its diameter to 3.86±0.77 mm (p<0.0002) that is a 60% increase from post ACH diameter. Myocardial perfusion score was 1∫2.66 at rest and 6.22±3.6 after cold pressor test (p<0.0001). Conclusions: This group of patients in the chronic phase of Chagas disease showed an abnormal vasoconstrictive response to intracoronary ACH and cold-induced perfusion defects suggesting that endothelial dysfunction plays a role in the pathophysiology of chronic Chagas heart disease

  2. Epilepsy in autism: A pathophysiological consideration.

    Science.gov (United States)

    Nomura, Yoshiko; Nagao, Yuri; Kimura, Kazue; Hachimori, Kei; Segawa, Masaya

    2010-11-01

    Eighty cases of idiopathic autism with epilepsy and 97 cases without epilepsy were studied to evaluate the pathophysiology of epilepsy in autism. The initial visit to this clinic ranged 8months-30years 3months of age, and the current ages are 5years 8months-42years 3months, 60% reaching to over 30years of age. The average follow up duration is 22.2years±9.4years. The ages of onset of epilepsy were from 7months to 30years of age, with the two peaks at 3.2years and 16.7years. EEG central focus appeared earlier than frontal focus. Abnormality of locomotion and atonic NREM were observed more frequently in epileptic group. These suggest the neuronal system related to abnormality of locomotion and atonic NREM, which are the hypofunction of the brainstem monoaminergic system, is the pathomechanism underling the epilepsy in autism. By showing the abnormal sleep-wake rhythm and locomotion being the very initial symptoms in autism, we had shown the hypofunction of the brainstem monoaminergic system is the initial pathomechanism of autism. Thus, epilepsy in autism is not the secondary manifestation, but one of the pathognomonic symptoms of autism. The brainstem monoaminergic system project to the wider cortical area, and the initial monoaminergic hypofunction may lead to the central focus which appears earlier. The failure of the monoaminergic (serotonergic) system causes dysfunction of the pedunculo-pontine nucleus (PPN) and induces dysfunction of the dopamine (DA) system, and with development of the DA receptor supersensitivity consequently disinhibits the thalamo-frontal pathway, which after maturation of this pathway in teens cause the epileptogenesis in the frontal cortex. Copyright © 2010 Elsevier B.V. All rights reserved.

  3. Pathophysiology of heatstroke in dogs - revisited.

    Science.gov (United States)

    Bruchim, Yaron; Horowitz, Michal; Aroch, Itamar

    2017-01-01

    Heatstroke results from a failure to dissipate accumulated heat during exposure to hot environments, or during strenuous physical exercise under heat stress. It is characterized by core body temperatures > 41°C, with central nervous system dysfunction. Functional morphology and thermoregulatory effectors differences between dogs and humans may require special heatstroke protective adaptations in dogs, however, the risk factors for developing heatstroke are similar in both. In dogs, these include hot, especially highly humid environments, excessive physical activity, obesity, large (>15 kg) body weight, being of certain breed (e.g., Labrador retrievers and brachycephalic breeds), upper airway obstruction and prolonged seizures. Lack of acclimation to heat and physical fitness decreases the survival of heat stroked dogs. At the systemic level, blood pooling within the large internal organs (e.g., spleen, liver) is a major contributor to the development of shock and consequent intestinal ischemia, hypoxia and endothelial hyperpermeability, commonly occurring in heatstroke patients. Evoked serious complications include rhabdomyolysis, acute kidney injury, acute respiratory distress syndrome and ultimately, sepsis and disseminated intravascular coagulation. The most common clinical signs in dogs include acute collapse, tachypnea, spontaneous bleeding, shock signs and mental abnormalities, including depression, disorientation or delirium, seizures, stupor and coma. In such dogs, presence of peripheral blood nucleated red blood cells uniquely occurs, and is a highly sensitive diagnostic and prognostic biomarker. Despite early, appropriate body cooling, and intensive supportive treatment, with no available specific treatment to ameliorate the severe inflammatory and hemostatic derangements, the mortality rate is around 50%, similar to that of human heatstroke victims. This review discusses the pathophysiology of canine heatstroke from a veterinarian's point of view

  4. Pathophysiology of Pulmonary Hypertension in Chronic Parenchymal Lung Disease.

    Science.gov (United States)

    Singh, Inderjit; Ma, Kevin Cong; Berlin, David Adam

    2016-04-01

    Pulmonary hypertension commonly complicates chronic obstructive pulmonary disease and interstitial lung disease. The association of chronic lung disease and pulmonary hypertension portends a worse prognosis. The pathophysiology of pulmonary hypertension differs in the presence or absence of lung disease. We describe the physiological determinants of the normal pulmonary circulation to better understand the pathophysiological factors implicated in chronic parenchymal lung disease-associated pulmonary hypertension. This review will focus on the pathophysiology of 3 forms of chronic lung disease-associated pulmonary hypertension: idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and sarcoidosis. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. An in vitro and in vivo study of peptide-functionalized nanoparticles for brain targeting : The importance of selective blood–brain barrier uptake

    NARCIS (Netherlands)

    Bode, Gerard H.; Coué, G.M.J.P.C.; Freese, Christian; Pickl, Karin E.; Sanchez-Purrà, Maria; Albaiges, Berta; Borrós, Salvador; van Winden, Ewoud C.; Tziveleka, Leto Aikaterini; Sideratou, Zili; Engbersen, Johan F.J.; Singh, Smriti; Albrecht, Krystyna; Groll, Jürgen; Möller, Martin; Pötgens, Andy J.G.; Schmitz, Christoph; Fröhlich, Eleonore; Grandfils, Christian; Sinner, Frank M.; Kirkpatrick, C. James; Steinbusch, Harry W.M.; Frank, Hans Georg; Unger, Ronald E.; Martinez-Martinez, Pilar

    2017-01-01

    Targeted delivery of drugs across endothelial barriers remains a formidable challenge, especially in the case of the brain, where the blood–brain barrier severely limits entry of drugs into the central nervous system. Nanoparticle-mediated transport of peptide/protein-based drugs across endothelial

  6. In silico target network analysis of de novo-discovered, tick saliva-specific microRNAs reveals important combinatorial effects in their interference with vertebrate host physiology

    Czech Academy of Sciences Publication Activity Database

    Hackenberg, M.; Langenberger, D.; Schwarz, Alexandra; Erhart, Jan; Kotsyfakis, Michalis

    2017-01-01

    Roč. 23, č. 8 (2017), s. 1259-1269 ISSN 1355-8382 Institutional support: RVO:60077344 Keywords : tick-vertebrate host interaction * deep-sequencing * microRNA * gene target prediction * interactomes/systems biology * disease biology Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Biochemistry and molecular biology Impact factor: 4.605, year: 2016

  7. The methylotrophic yeast Hansenula polymorpha contains an inducible import pathway for peroxisomal matrix proteins with an N-terminal targeting signal (PTS2 proteins)

    NARCIS (Netherlands)

    Faber, Klaas Nico; Haima, Pieter; Gietl, Christine; Harder, Willem; Ab, Geert; Veenhuis, Marten

    1994-01-01

    Two main types of peroxisomal targeting signals have been identified that reside either at the extreme C terminus (PTS1) or the N terminus (PTS2) of the protein. In the methylotrophic yeast Hansenula polymorpha the majority of peroxisomal matrix proteins are of the PTS1 type. Thus far, for H.

  8. Transrectal real-time tissue elastography targeted biopsy coupled with peak strain index improves the detection of clinically important prostate cancer.

    Science.gov (United States)

    Ma, Qi; Yang, Dong-Rong; Xue, Bo-Xin; Wang, Cheng; Chen, Han-Bin; Dong, Yun; Wang, Cai-Shan; Shan, Yu-Xi

    2017-07-01

    The focus of the present study was to evaluate transrectal real-time tissue elastography (RTE)-targeted two-core biopsy coupled with peak strain index for the detection of prostate cancer (PCa) and to compare this method with 10-core systematic biopsy. A total of 141 patients were enrolled for evaluation. The diagnostic value of peak strain index was assessed using a receiver operating characteristic curve. The cancer detection rates of the two approaches and corresponding positive cores and Gleason score were compared. The cancer detection rate per core in the RTE-targeted biopsy (44%) was higher compared with that in systematic biopsy (30%). The peak strain index value of PCa was higher compared with that of the benign lesion. PCa was detected with the highest sensitivity (87.5%) and specificity (85.5%) using the threshold value of a peak strain index of ≥5.97 with an area under the curve value of 0.95. When the Gleason score was ≥7, RTE-targeted biopsy coupled with peak strain index detected 95.6% of PCa cases, but 84.4% were detected using systematic biopsy. Peak strain index as a quantitative parameter may improve the differentiation of PCa from benign lesions in the prostate peripheral zone. Transrectal RTE-targeted biopsy coupled with peak strain index may enhance the detection of clinically significant PCa, particularly when combined with systematic biopsy.

  9. Increasing Importance of Balamuthia mandrillaris

    OpenAIRE

    Matin, Abdul; Siddiqui, Ruqaiyyah; Jayasekera, Samantha; Khan, Naveed Ahmed

    2008-01-01

    Balamuthia mandrillaris is an emerging protozoan parasite, an agent of granulomatous amoebic encephalitis involving the central nervous system, with a case fatality rate of >98%. This review presents our current understanding of Balamuthia infections, their pathogenesis and pathophysiology, and molecular mechanisms associated with the disease, as well as virulence traits of Balamuthia that may be potential targets for therapeutic interventions and/or for the development of preventative measures.

  10. ROCK as a therapeutic target for ischemic stroke.

    Science.gov (United States)

    Sladojevic, Nikola; Yu, Brian; Liao, James K

    2017-12-01

    Stroke is a major cause of disability and the fifth leading cause of death. Currently, the only approved acute medical treatment of ischemic stroke is tissue plasminogen activator (tPA), but its effectiveness is greatly predicated upon early administration of the drug. There is, therefore, an urgent need to find new therapeutic options for acute stroke. Areas covered: In this review, we summarize the role of Rho-associated coiled-coil containing kinase (ROCK) and its potential as a therapeutic target in stroke pathophysiology. ROCK is a major regulator of cell contractility, motility, and proliferation. Many of these ROCK-mediated processes in endothelial cells, vascular smooth muscle cells, pericytes, astrocytes, glia, neurons, leukocytes, and platelets are important in stroke pathophysiology, and the inhibition of such processes could improve stroke outcome. Expert commentary: ROCK is a potential therapeutic target for cardiovascular disease and ROCK inhibitors have already been approved for human use in Japan and China for the treatment of acute stroke. Further studies are needed to determine the role of ROCK isoforms in the pathophysiology of cerebral ischemia and whether there are further therapeutic benefits with selective ROCK inhibitors.

  11. Pathophysiological basis of pharmacotherapy in the hepatorenal syndrome

    DEFF Research Database (Denmark)

    Møller, Søren; Bendtsen, Flemming; Henriksen, Jens H

    2005-01-01

    Hepatorenal syndrome (HRS) is a functional and reversible impairment of renal function in patients with severe cirrhosis. Major pathophysiological elements include liver dysfunction, a circulatory derangement with central hypovolaemia and neurohumoral activation of potent vasoactive systems leading...

  12. Pathophysiology of shunt dysfunction in shunt treated hydrocephalus

    DEFF Research Database (Denmark)

    Blegvad, C.; Skjolding, A D; Broholm, H

    2013-01-01

    We hypothesized that shunt dysfunction in the ventricular catheter and the shunt valve is caused by different cellular responses. We also hypothesized that the cellular responses depend on different pathophysiological mechanisms....

  13. Visceral hypersensitivity in Irritable Bowel Syndrome:pathophysiological mechanisms

    NARCIS (Netherlands)

    Kerckhoffs, A.P.M.

    2009-01-01

    Irritable Bowel Syndrome (IBS) is a functional bowel disease characterized by abdominal pain or discomfort associated with a disordered defecation. No unique pathophysiological mechanism has been identified. It is most likely a multifactorial disease involving alterations in intestinal microbiota

  14. Mitochondrial import of human and yeast fumarase in live mammalian cells: Retrograde translocation of the yeast enzyme is mainly caused by its poor targeting sequence

    International Nuclear Information System (INIS)

    Singh, Bhag; Gupta, Radhey S.

    2006-01-01

    Studies on yeast fumarase provide the main evidence for dual localization of a protein in mitochondria and cytosol by means of retrograde translocation. We have examined the subcellular targeting of yeast and human fumarase in live cells to identify factors responsible for this. The cDNAs for mature yeast or human fumarase were fused to the gene for enhanced green fluorescent protein (eGFP) and they contained, at their N-terminus, a mitochondrial targeting sequence (MTS) derived from either yeast fumarase, human fumarase, or cytochrome c oxidase subunit VIII (COX) protein. Two nuclear localization sequences (2x NLS) were also added to these constructs to facilitate detection of any cytosolic protein by its targeting to nucleus. In Cos-1 cells transfected with these constructs, human fumarase with either the native or COX MTSs was detected exclusively in mitochondria in >98% of the cells, while the remainder 1-2% of the cells showed varying amounts of nuclear labeling. In contrast, when human fumarase was fused to the yeast MTS, >50% of the cells showed nuclear labeling. Similar studies with yeast fumarase showed that with its native MTS, nuclear labeling was seen in 80-85% of the cells, but upon fusion to either human or COX MTS, nuclear labeling was observed in only 10-15% of the cells. These results provide evidence that extramitochondrial presence of yeast fumarase is mainly caused by the poor mitochondrial targeting characteristics of its MTS (but also affected by its primary sequence), and that the retrograde translocation mechanism does not play a significant role in the extramitochondrial presence of mammalian fumarase

  15. Pathophysiology of acute small bowel disease with CT correlation

    International Nuclear Information System (INIS)

    Sarwani, N.; Tappouni, R.; Tice, J.

    2011-01-01

    The objective of this article is to review the pathophysiology of acute small bowel diseases, and to correlate the mechanisms of disease with computed tomography (CT) findings. Disease entities will be classified into the following: immune mediated and infectious causes, vascular causes, mechanical causes, trauma, and others. Having an understanding of acute small bowel pathophysiology is a useful teaching tool, and can lead to imaging clues to the most likely diagnosis of acute small bowel disorders.

  16. Hypertension and obesity after pediatric kidney transplantation: management based on pathophysiology: A mini review

    Directory of Open Access Journals (Sweden)

    Eunice G John

    2014-01-01

    Full Text Available Hypertension after pediatric renal transplant is a common and important risk factor for graft loss and patient survival. The mechanism of post kidney transplant hypertension is complex and multifactorial. Control of blood pressure in renal transplant patients is important but often times blood pressures remain uncontrolled. The management of hypertension and obesity in pediatric kidney transplant patients is based on the pathophysiology. Compared to the general pediatric hypertensive population, special attention needs to be focused on the additional impact of immunosuppressive medications side effects and interactions, recurrent disease, and donor and recipient comorbidities such as obesity on blood pressure control with thoughtful consideration of the risk of graft failure. In general, there is a need for prospective studies in pediatric kidney transplant patients to understand the pathophysiology of hypertension and obesity and the appropriate approach to achieve a balance between the primary need to avoid rejection and the need to lower blood pressure and prevent obesity.

  17. Ankle sprain: pathophysiology, predisposing factors, and management strategies

    Directory of Open Access Journals (Sweden)

    Tricia J Hubbard

    2010-07-01

    Full Text Available Tricia J Hubbard, Erik A WikstromUNC Charlotte, Department of Kinesiology, CharlotteAbstract: With the high percentage (up to 75% of initial lateral ankle sprains (LAS leading to repetitive sprains and chronic symptoms, it is imperative to better understand how best to treat and rehabilitate LAS events. The purpose of this paper is to review LAS pathophysiology, predisposing factors, and the current evidence regarding therapeutic modalities and exercises used in the treatment of LAS. Functional rehabilitation, early mobilization with support, is the current standard of care for LAS. However, the high percentage of reinjury occurrence and development of chronic symptoms (up to 75% after a LAS, suggests the current standard of care may not be effective. Recent evidence has shown the need for more stringent immobilization to facilitate ligament healing and restoration of joint stability and function after a LAS. Additionally, the importance of adding adjunctive therapies, specifically joint mobilizations and balance training have been shown to improve function and decrease the incidence of reinjury after a LAS. Modifying current rehabilitation protocols to include protecting the ankle joint with stringent immobilization, and including joint mobilizations and balance training may be the first step to decreasing the incidence of short and long term ankle joint dysfunction.Keywords: rehabilitation, recurrent sprains, chronic ankle instability (CAI

  18. Physiological and pathophysiological bone turnover - role of the immune system.

    Science.gov (United States)

    Weitzmann, M Neale; Ofotokun, Ighovwerha

    2016-09-01

    Osteoporosis develops when the rate of osteoclastic bone breakdown (resorption) exceeds that of osteoblastic bone formation, which leads to loss of BMD and deterioration of bone structure and strength. Osteoporosis increases the risk of fragility fractures, a cause of substantial morbidity and mortality, especially in elderly patients. This imbalance between bone formation and bone resorption is brought about by natural ageing processes, but is frequently exacerbated by a number of pathological conditions. Of importance to the aetiology of osteoporosis are findings over the past two decades attesting to a deep integration of the skeletal system with the immune system (the immuno-skeletal interface (ISI)). Although protective of the skeleton under physiological conditions, the ISI might contribute to bone destruction in a growing number of pathophysiological states. Although numerous research groups have investigated how the immune system affects basal and pathological osteoclastic bone resorption, recent findings suggest that the reach of the adaptive immune response extends to the regulation of osteoblastic bone formation. This Review examines the evolution of the field of osteoimmunology and how advances in our understanding of the ISI might lead to novel approaches to prevent and treat bone loss, and avert fractures.

  19. Genetics of liver disease: From pathophysiology to clinical practice.

    Science.gov (United States)

    Karlsen, Tom H; Lammert, Frank; Thompson, Richard J

    2015-04-01

    Paralleling the first 30 years of the Journal of Hepatology we have witnessed huge advances in our understanding of liver disease and physiology. Genetic advances have played no small part in that. Initial studies in the 1970s and 1980s identified the strong major histocompatibility complex associations in autoimmune liver diseases. During the 1990 s, developments in genomic technologies drove the identification of genes responsible for Mendelian liver diseases. Over the last decade, genome-wide association studies have allowed for the dissection of the genetic susceptibility to complex liver disorders, in which also environmental co-factors play important roles. Findings have allowed the identification and elaboration of pathophysiological processes, have indicated the need for reclassification of liver diseases and have already pointed to new disease treatments. In the immediate future genetics will allow further stratification of liver diseases and contribute to personalized medicine. Challenges exist with regard to clinical implementation of rapidly developing technologies and interpretation of the wealth of accumulating genetic data. The historical perspective of genetics in liver diseases illustrates the opportunities for future research and clinical care of our patients. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  20. Physiology and pathophysiology of ClC-K/barttin channels.

    Science.gov (United States)

    Fahlke, Christoph; Fischer, Martin

    2010-01-01

    ClC-K channels form a subgroup of anion channels within the ClC family of anion transport proteins. They are expressed predominantly in the kidney and in the inner ear, and are necessary for NaCl resorption in the loop of Henle and for K+ secretion by the stria vascularis. Subcellular distribution as well as the function of these channels are tightly regulated by an accessory subunit, barttin. Barttin improves the stability of ClC-K channel protein, stimulates the exit from the endoplasmic reticulum and insertion into the plasma membrane and changes its function by modifying voltage-dependent gating processes. The importance of ClC-K/barttin channels is highlighted by several genetic diseases. Dysfunctions of ClC-K channels result in Bartter syndrome, an inherited human condition characterized by impaired urinary concentration. Mutations in the gene encoding barttin, BSND, affect the urinary concentration as well as the sensory function of the inner ear. Surprisingly, there is one BSND mutation that causes deafness without affecting renal function, indicating that kidney function tolerates a reduction of anion channel activity that is not sufficient to support normal signal transduction in inner hair cells. This review summarizes recent work on molecular mechanisms, physiology, and pathophysiology of ClC-K/barttin channels.

  1. Neurobehavioral aspects, pathophysiology, and management of Tourette syndrome.

    Science.gov (United States)

    Shprecher, David R; Schrock, Lauren; Himle, Michael

    2014-08-01

    This update summarizes progress in understanding Tourette syndrome clinical characteristics, etiology, and treatment over the past year. Premonitory sensory phenomena were found to have important impacts on Tourette syndrome quality of life. A rare genetic form of Tourette syndrome due to L-histidine-decarboxylase mutation, with similar features in human and rodent, has inspired new research on functional anatomy of Tourette syndrome. In response to new data, treatment guidelines have been revised to include behavioral therapy as first-line treatment. Novel dopamine receptor antagonists aripiprazole and ecopipam have shown potential efficacy - as well as tolerability concerns. Recent work has suggested efficacy and tolerability of topiramate and fluphenazine, but more rigorous studies are needed to further understand their role in Tourette syndrome management. Recent consensus guidelines explain when deep brain stimulation can be considered for severe refractory cases under a multidisciplinary team. More research is needed to identify better tolerated treatments for, to understand pathophysiology or functional anatomy of, and to predict or influence longitudinal outcome of Tourette syndrome.

  2. Nondopaminergic neurotransmission in the pathophysiology of Tourette syndrome.

    Science.gov (United States)

    Udvardi, Patrick T; Nespoli, Ester; Rizzo, Francesca; Hengerer, Bastian; Ludolph, Andrea G

    2013-01-01

    A major pathophysiological role for the dopaminergic system in Tourette's syndrome (TS) has been presumed ever since the discovery that dopamine-receptor antagonists can alleviate tics. Especially recent molecular genetic studies, functional imaging studies, and some rare postmortem studies have given more and more hints that other neurotransmitter systems are involved as well. Dysfunction in the dopamine metabolism-in particular during early development-might lead to counter-regulations in the other systems or vice versa. This chapter will give an overview of the studies that prove the involvement of other neurotransmitter systems such as the major monoaminergic neurotransmitters norepinephrine, serotonin, and histamine; the most important excitatory neurotransmitter, the amino acid glutamate; the major inhibitory neurotransmitter y-aminobutyric acid, as well as acetylcholine, endocannabinoid, corticoid; and others. These studies will hopefully lead to fundamental advances in the psychopharmacological treatment of TS. While tic disorders have been previously treated mainly with dopamine antagonists, some authors already favor alpha-agonists. Clinical trials with glutamate agonists and antagonists and compounds influencing the histaminergic system are currently being conducted. Since the different neurotransmitter systems consist of several receptor subtypes which might mediate different effects on locomotor activity, patients with TS may respond differentially to selective agonists or antagonists. Effects of agonistic or antagonistic compounds on tic symptoms might also be dose dependent. Further studies will lead to a broader spectrum of psychopharmacological treatment options in TS. © 2013 Elsevier Inc. All rights reserved.

  3. Left main coronary artery disease: pathophysiology, diagnosis, and treatment.

    Science.gov (United States)

    Collet, Carlos; Capodanno, Davide; Onuma, Yoshinobu; Banning, Adrian; Stone, Gregg W; Taggart, David P; Sabik, Joseph; Serruys, Patrick W

    2018-06-01

    The advent of coronary angiography in the 1960s allowed for the risk stratification of patients with stable angina. Patients with unprotected left main coronary artery disease have an increased risk of death related to the large amount of myocardium supplied by this vessel. Although coronary angiography remains the preferred imaging modality for the evaluation of left main coronary artery stenosis, this technique has important limitations. Angiograms of the left main coronary artery segment can be difficult to interpret, and almost one-third of patients can be misclassified when fractional flow reserve is used as the reference. In patients with clinically significant unprotected left main coronary artery disease, surgical revascularization was shown to improve survival compared with medical therapy and has been regarded as the treatment of choice for unprotected left main coronary artery disease. Two large-scale clinical trials published in 2016 support the usefulness of catheter-based revascularization in selected patients with unprotected left main coronary artery disease. In this Review, we describe the pathophysiology of unprotected left main coronary artery disease, discuss diagnostic approaches in light of new noninvasive and invasive imaging techniques, and detail risk stratification models to aid the Heart Team in the decision-making process for determining the best revascularization strategy for these patients.

  4. Physiology and pathophysiology of ClC-K/barttin channels

    Directory of Open Access Journals (Sweden)

    Christoph eFahlke

    2010-11-01

    Full Text Available ClC-K channels form a subgroup of anion channels within the ClC family of anion transport proteins. They are expressed predominantly in the kidney and in the inner ear, and are necessary for NaCl resorption in the loop of Henle and for K+ secretion by the stria vascularis. Subcellular distribution as well as the function of these channels are tightly regulated by an accessory subunit, barttin. Barttin improves the stability of ClC-K channel protein, stimulates the exit from the endoplasmic reticulum and insertion into the plasma membrane and changes its function by modifying voltage-dependent gating processes. The importance of ClC-K/barttin channels is highlighted by several genetic diseases. Dysfunctions of ClC-K channels result in Bartter syndrome, an inherited human condition characterized by impaired urinary concentration. Mutations in the gene encoding barttin, BSND, affect the urinary concentration as well as the sensory function of the inner ear. Surprisingly, there is one BSND mutation that causes deafness without affecting renal function, indicating that kidney function tolerates a reduction of anion channel activity that is not sufficient to support normal signal transduction in inner hair cells. This review summarizes recent work on molecular mechanisms, physiology and pathophysiology of ClC-K/barttin channels.

  5. POTENTIAL PATHOPHYSIOLOGICAL MECHANISMS OF ULTRAFINE PARTICLE TOXIC EFFECTS IN HUMANS

    Directory of Open Access Journals (Sweden)

    JASMINA JOVIĆ-STOŠIĆ

    2008-03-01

    Full Text Available Epidemiological and clinical studies suggested the association of the particulate matter ambient air pollution and the increased morbidity and mortality, mainly from respiratory and cardiovascular diseases. The size of particles has great influence on their toxicity, because it determines the site in the respiratory tract where they deposit. The most well established theory explaining the mechanisms behind the increased toxicity of ultrafine particles (UFP, < 0.1 µm is that it has to do with the increased surface area and/or the combination with the increased number of particles. Biological effects of UFP are also determined by their shape and chemical composition, so it is not possible to estimate their toxicity in a general way. General hypothesis suggested that exposure to inhaled particles induces pulmonary alveolar inflammation as a basic pathophysiological event, triggering release of various proinflammatory cytokines. Chronic inflammation is a very important underlying mechanism in the genesis of atherosclerosis and cardiovascular diseases. UFP can freely move through the circulation, but their effects on the secondary organs are not known yet, so more studies on recognizing toxicological endpoints of UFP are needed. Determination of UFP toxicity and the estimation of their internal and biologically active dose are necessary for the evidence based conclusions connecting air pollution by UFP and human diseases.

  6. Gait post-stroke: Pathophysiology and rehabilitation strategies.

    Science.gov (United States)

    Beyaert, C; Vasa, R; Frykberg, G E

    2015-11-01

    We reviewed neural control and biomechanical description of gait in both non-disabled and post-stroke subjects. In addition, we reviewed most of the gait rehabilitation strategies currently in use or in development and observed their principles in relation to recent pathophysiology of post-stroke gait. In both non-disabled and post-stroke subjects, motor control is organized on a task-oriented basis using a common set of a few muscle modules to simultaneously achieve body support, balance control, and forward progression during gait. Hemiparesis following stroke is due to disruption of descending neural pathways, usually with no direct lesion of the brainstem and cerebellar structures involved in motor automatic processes. Post-stroke, improvements of motor activities including standing and locomotion are variable but are typically characterized by a common postural behaviour which involves the unaffected side more for body support and balance control, likely in response to initial muscle weakness of the affected side. Various rehabilitation strategies are regularly used or in development, targeting muscle activity, postural and gait tasks, using more or less high-technology equipment. Reduced walking speed often improves with time and with various rehabilitation strategies, but asymmetric postural behaviour during standing and walking is often reinforced, maintained, or only transitorily decreased. This asymmetric compensatory postural behaviour appears to be robust, driven by support and balance tasks maintaining the predominant use of the unaffected side over the initially impaired affected side. Based on these elements, stroke rehabilitation including affected muscle strengthening and often stretching would first need to correct the postural asymmetric pattern by exploiting postural automatic processes in various particular motor tasks secondarily beneficial to gait. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  7. Pathophysiological mechanisms of severe anaemia in Malawian children.

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    Michaël Boele van Hensbroek

    2010-09-01

    Full Text Available Severe anaemia is a major cause of morbidity and mortality in African children. The aetiology is multi-factorial, but interventions have often targeted only one or a few causal factors, with limited success.We assessed the contribution of different pathophysiological mechanisms (red cell production failure [RCPF], haemolysis and blood loss to severe anaemia in Malawian children in whom etiological factors have been described previously. More complex associations between etiological factors and the mechanisms were explored using structural equation modelling. In 235 children with severe anaemia (haemoglobin<3.2 mMol/L [5.0 g/dl] studied, RCPF, haemolysis and blood loss were found in 48.1%, 21.7% and 6.9%, respectively. The RCPF figure increased to 86% when a less stringent definition of RCPF was applied. RCPF was the most common mechanism in each of the major etiological subgroups (39.7-59.7%. Multiple aetiologies were common in children with severe anaemia. In the final model, nutritional and infectious factors, including malaria, were directly or indirectly associated with RCPF, but not with haemolysis.RCPF was the most common pathway leading to severe anaemia, from a variety of etiological factors, often found in combination. Unlike haemolysis or blood loss, RCPF is a defect that is likely to persist to a significant degree unless all of its contributing aetiologies are corrected. This provides a further explanation for the limited success of the single factor interventions that have commonly been applied to the prevention or treatment of severe anaemia. Our findings underline the need for a package of measures directed against all of the local aetiologies of this often fatal paediatric syndrome.

  8. Involvement of the kynurenine pathway in human glioma pathophysiology.

    Directory of Open Access Journals (Sweden)

    Seray Adams

    Full Text Available The kynurenine pathway (KP is the principal route of L-tryptophan (TRP catabolism leading to the production of kynurenine (KYN, the neuroprotectants, kynurenic acid (KYNA and picolinic acid (PIC, the excitotoxin, quinolinic acid (QUIN and the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD(+. The enzymes indoleamine 2,3-dioxygenase-1 (IDO-1, indoleamine 2,3-dioxygenase-2 (IDO-2 and tryptophan 2,3-dioxygenase (TDO-2 initiate the first step of the KP. IDO-1 and TDO-2 induction in tumors are crucial mechanisms implicated to play pivotal roles in suppressing anti-tumor immunity. Here, we report the first comprehensive characterisation of the KP in 1 cultured human glioma cells and 2 plasma from patients with glioblastoma (GBM. Our data revealed that interferon-gamma (IFN-γ stimulation significantly potentiated the expression of the KP enzymes, IDO-1 IDO-2, kynureninase (KYNU, kynurenine hydroxylase (KMO and significantly down-regulated 2-amino-3-carboxymuconate semialdehyde decarboxylase (ACMSD and kynurenine aminotransferase-I (KAT-I expression in cultured human glioma cells. This significantly increased KP activity but significantly lowered the KYNA/KYN neuroprotective ratio in human cultured glioma cells. KP activation (KYN/TRP was significantly higher, whereas the concentrations of the neuroreactive KP metabolites TRP, KYNA, QUIN and PIC and the KYNA/KYN ratio were significantly lower in GBM patient plasma (n = 18 compared to controls. These results provide further evidence for the involvement of the KP in glioma pathophysiology and highlight a potential role of KP products as novel and highly attractive therapeutic targets to evaluate for the treatment of brain tumors, aimed at restoring anti-tumor immunity and reducing the capacity for malignant cells to produce NAD(+, which is necessary for energy production and DNA repair.

  9. Caveolins and caveolae in ocular physiology and pathophysiology.

    Science.gov (United States)

    Gu, Xiaowu; Reagan, Alaina M; McClellan, Mark E; Elliott, Michael H

    2017-01-01

    Caveolae are specialized, invaginated plasma membrane domains that are defined morphologically and by the expression of signature proteins called, caveolins. Caveolae and caveolins are abundant in a variety of cell types including vascular endothelium, glia, and fibroblasts where they play critical roles in transcellular transport, endocytosis, mechanotransduction, cell proliferation, membrane lipid homeostasis, and signal transduction. Given these critical cellular functions, it is surprising that ablation of the caveolae organelle does not result in lethality suggesting instead that caveolae and caveolins play modulatory roles in cellular homeostasis. Caveolar components are also expressed in ocular cell types including retinal vascular cells, Müller glia, retinal pigment epithelium (RPE), conventional aqueous humor outflow cells, the corneal epithelium and endothelium, and the lens epithelium. In the eye, studies of caveolae and other membrane microdomains (i.e., "lipid rafts") have lagged behind what is a substantial body of literature outside vision science. However, interest in caveolae and their molecular components has increased with accumulating evidence of important roles in vision-related functions such as blood-retinal barrier homeostasis, ocular inflammatory signaling, pathogen entry at the ocular surface, and aqueous humor drainage. The recent association of CAV1/2 gene loci with primary open angle glaucoma and intraocular pressure has further enhanced the need to better understand caveolar functions in the context of ocular physiology and disease. Herein, we provide the first comprehensive review of literature on caveolae, caveolins, and other membrane domains in the context of visual system function. This review highlights the importance of caveolae domains and their components in ocular physiology and pathophysiology and emphasizes the need to better understand these important modulators of cellular function. Copyright © 2016 Elsevier Ltd. All

  10. First applications of a targeted exome sequencing approach in fetuses with ultrasound abnormalities reveals an important fraction of cases with associated gene defects

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    Constantinos Pangalos

    2016-04-01

    Full Text Available Background. Fetal malformations and other structural abnormalities are relatively frequent findings in the course of routine prenatal ultrasonographic examination. Due to their considerable genetic and clinical heterogeneity, the underlying genetic cause is often elusive and the resulting inability to provide a precise diagnosis precludes proper reproductive and fetal risk assessment. We report the development and first applications of an expanded exome sequencing-based test, coupled to a bioinformatics-driven prioritization algorithm, targeting gene disorders presenting with abnormal prenatal ultrasound findings. Methods. We applied the testing strategy to14 euploid fetuses, from 11 on-going pregnancies and three products of abortion, all with various abnormalities or malformations detected through prenatal ultrasound examination. Whole exome sequencing (WES was followed by variant prioritization, utilizing a custom analysis pipeline (Fetalis algorithm, targeting 758 genes associated with genetic disorders which may present with abnormal fetal ultrasound findings. Results. A definitive or highly-likely diagnosis was made in 6 of 14 cases (43%, of which 3 were abortuses (Ellis-van Creveld syndrome, Ehlers-Danlos syndrome and Nemaline myopathy 2 and 3 involved on-going pregnancies (Citrullinemia, Noonan syndrome, PROKR2-related Kallmann syndrome. In the remaining eight on-going pregnancy cases (57%, a ZIC1 variant of unknown clinical significance was detected in one case, while in seven cases testing did not reveal any pathogenic variant(s. Pregnancies were followed-up to birth, resulting in one neonate harboring the PROKR2 mutation, presenting with isolated minor structural cardiac abnormalities, and in seven apparently healthy neonates. Discussion. The expanded targeted exome sequencing-based approach described herein (Fetalis, provides strong evidence suggesting a definite and beneficial increase in our diagnostic capabilities in prenatal

  11. IDO chronic immune activation and tryptophan metabolic pathway: A potential pathophysiological link between depression and obesity.

    Science.gov (United States)

    Chaves Filho, Adriano José Maia; Lima, Camila Nayane Carvalho; Vasconcelos, Silvânia Maria Mendes; de Lucena, David Freitas; Maes, Michael; Macedo, Danielle

    2018-01-03

    Obesity and depression are among the most pressing health problems in the contemporary world. Obesity and depression share a bidirectional relationship, whereby each condition increases the risk of the other. By inference, shared pathways may underpin the comorbidity between obesity and depression. Activation of cell-mediated immunity (CMI) is a key factor in the pathophysiology of depression. CMI cytokines, including IFN-γ, TNFα and IL-1β, induce the catabolism of tryptophan (TRY) by stimulating indoleamine 2,3-dioxygenase (IDO) resulting in the synthesis of kynurenine (KYN) and other tryptophan catabolites (TRYCATs). In the CNS, TRYCATs have been related to oxidative damage, inflammation, mitochondrial dysfunction, cytotoxicity, excitotoxicity, neurotoxicity and lowered neuroplasticity. The pathophysiology of obesity is also associated with a state of aberrant inflammation that activates aryl hydrocarbon receptor (AHR), a pathway involved in the detection of intracellular or environmental changes as well as with increases in the production of TRYCATs, being KYN an agonists of AHR. Both AHR and TRYCATS are involved in obesity and related metabolic disorders. These changes in the TRYCAT pathway may contribute to the onset of neuropsychiatric symptoms in obesity. This paper reviews the role of immune activation, IDO stimulation and increased TRYCAT production in the pathophysiology of depression and obesity. Here we suggest that increased synthesis of detrimental TRYCATs is implicated in comorbid obesity and depression and is a new drug target to treat both diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Pathophysiology and clinical characteristics of hypothalamic obesity in children and adolescents

    Directory of Open Access Journals (Sweden)

    Ja Hye Kim

    2013-12-01

    Full Text Available The hypothalamus plays a key role in the regulation of body weight by balancing the intake of food, energy expenditure, and body fat stores, as evidenced by the fact that most monogenic syndromes of morbid obesity result from mutations in genes expressed in the hypothalamus. Hypothalamic obesity is a result of impairment in the hypothalamic regulatory centers of body weight and energy expenditure, and is caused by structural damage to the hypothalamus, radiotherapy, Prader-Willi syndrome, and mutations in the LEP, LEPR, POMC, MC4R and CART genes. The pathophysiology includes loss of sensitivity to afferent peripheral humoral signals, such as leptin, dysregulated insulin secretion, and impaired activity of the sympathetic nervous system. Dysregulation of 11β-hydroxysteroid dehydrogenase 1 activity and melatonin may also have a role in the development of hypothalamic obesity. Intervention of this complex entity requires simultaneous targeting of several mechanisms that are deranged in patients with hypothalamic obesity. Despite a great deal of theoretical understanding, effective treatment for hypothalamic obesity has not yet been developed. Therefore, understanding the mechanisms that control food intake and energy homeostasis and pathophysiology of hypothalamic obesity can be the cornerstone of the development of new treatments options. Early identification of patients at-risk can relieve the severity of weight gain by the provision of dietary and behavioral modification, and antiobesity medication. This review summarizes recent advances of the pathophysiology, endocrine characteristics, and treatment strategies of hypothalamic obesity.

  13. PRMT1 methylates the single Argonaute of Toxoplasma gondii and is important for the recruitment of Tudor nuclease for target RNA cleavage by antisense guide RNA

    Science.gov (United States)

    Musiyenko, Alla; Majumdar, Tanmay; Andrews, Joel; Adams, Brian; Barik, Sailen

    2013-01-01

    Summary Argonaute (Ago) plays a central role in RNA interference in metazoans, but its status in lower organisms remains ill-defined. We report on the Ago complex of the unicellular protozoan, Toxoplasma gondii (Tg), an obligatory pathogen of mammalian hosts. The PIWI-like domain of TgAgo lacked the canonical DDE/H catalytic triad, explaining its weak target RNA cleavage activity. However, TgAgo associated with a stronger RNA slicer, a Tudor staphylococcal nuclease (TSN), and with a protein Arg methyl transferase, PRMT1. Mutational analysis suggested that the N-terminal RGG-repeat domain of TgAgo was methylated by PRMT1, correlating with the recruitment of TSN. The slicer activity of TgAgo was Mg2+-dependent and required perfect complementarity between the guide RNA and the target. In contrast, the TSN activity was Ca2+-dependent and required an imperfectly paired guide RNA. Ago knockout parasites showed essentially normal growth, but in contrast, the PRMT1 knockouts grew abnormally. Chemical inhibition of Arg-methylation also had an anti-parasitic effect. These results suggest that the parasitic PRMT1 plays multiple roles, and its loss affects the recruitment of a more potent second slicer to the parasitic RNA silencing complex, the exact mechanism of which remains to be determined. PMID:22309152

  14. Effects of ADMA upon gene expression: an insight into the pathophysiological significance of raised plasma ADMA.

    Directory of Open Access Journals (Sweden)

    Caroline L Smith

    2005-10-01

    Full Text Available Asymmetric dimethylarginine (ADMA is a naturally occurring inhibitor of nitric oxide synthesis that accumulates in a wide range of diseases associated with endothelial dysfunction and enhanced atherosclerosis. Clinical studies implicate plasma ADMA as a major novel cardiovascular risk factor, but the mechanisms by which low concentrations of ADMA produce adverse effects on the cardiovascular system are unclear.We treated human coronary artery endothelial cells with pathophysiological concentrations of ADMA and assessed the effects on gene expression using U133A GeneChips (Affymetrix. Changes in several genes, including bone morphogenetic protein 2 inducible kinase (BMP2K, SMA-related protein 5 (Smad5, bone morphogenetic protein receptor 1A, and protein arginine methyltransferase 3 (PRMT3; also known as HRMT1L3, were confirmed by Northern blotting, quantitative PCR, and in some instances Western blotting analysis to detect changes in protein expression. To determine whether these changes also occurred in vivo, tissue from gene deletion mice with raised ADMA levels was examined. More than 50 genes were significantly altered in endothelial cells after treatment with pathophysiological concentrations of ADMA (2 microM. We detected specific patterns of changes that identify pathways involved in processes relevant to cardiovascular risk and pulmonary hypertension. Changes in BMP2K and PRMT3 were confirmed at mRNA and protein levels, in vitro and in vivo.Pathophysiological concentrations of ADMA are sufficient to elicit significant changes in coronary artery endothelial cell gene expression. Changes in bone morphogenetic protein signalling, and in enzymes involved in arginine methylation, may be particularly relevant to understanding the pathophysiological significance of raised ADMA levels. This study identifies the mechanisms by which increased ADMA may contribute to common cardiovascular diseases and thereby indicates possible targets for therapies.

  15. Melatonin plays a protective role in postburn rodent gut pathophysiology.

    Science.gov (United States)

    Al-Ghoul, Walid M; Abu-Shaqra, Steven; Park, Byeong Gyu; Fazal, Nadeem

    2010-05-17

    Melatonin is a possible protective agent in postburn gut pathophysiological dynamics. We investigated the role of endogenously-produced versus exogenously-administered melatonin in a major thermal injury rat model with well-characterized gut inflammatory complications. Our rationale is that understanding in vivo melatonin mechanisms in control and inflamed tissues will improve our understanding of its potential as a safe anti-inflammatory/antioxidant therapeutic alternative. Towards this end, we tested the hypothesis that the gut is both a source and a target for melatonin and that mesenteric melatonin plays an anti-inflammatory role following major thermal injury in rats with 3rd degree hot water scald over 30% TBSA. Our methods for assessing the gut as a source of melatonin included plasma melatonin ELISA measurements in systemic and mesenteric circulation as well as rtPCR measurement of jejunum and terminal ileum expression of the melatonin synthesizing enzymes arylalkylamine N-acetyltransferase (AA-NAT) and 5-hydroxyindole-O-methyltransferase (HIOMT) in sham versus day-3 postburn rats. Our melatonin ELISA results revealed that mesenteric circulation has much higher melatonin than systemic circulation and that both mesenteric and systemic melatonin levels are increased three days following major thermal injury. Our rtPCR results complemented the ELISA data in showing that the melatonin synthesizing enzymes AA-NAT and HIOMT are expressed in the ileum and jejunum and that this expression is increased three days following major thermal injury. Interestingly, the rtPCR data also revealed negative feedback by melatonin as exogenous melatonin supplementation at a dose of 7.43 mg (32 micromole/kg), but not 1.86 mg/kg (8 micromole/kg) drastically suppressed AA-NAT mRNA expression. Our methods also included an assessment of the gut as a target for melatonin utilizing computerized immunohistochemical measurements to quantify the effects of exogenous melatonin

  16. The role of the IGF-1 Ec in myoskeletal system and osteosarcoma pathophysiology.

    Science.gov (United States)

    Armakolas, Nikolaos; Armakolas, Athanasios; Antonopoulos, Athanasios; Dimakakos, Andreas; Stathaki, Martha; Koutsilieris, Michael

    2016-12-01

    Growth hormone (GH) regulated mainly liver-produced insulin-like growth factor 1 (IGF-1) is a key molecule in embryonic & post embryonic development that is also involved in cancer biology. Herein we review new insights of the role of igf-1 gene products and of the IGF-1Ec isoform in muscle and bone development/repair and its role in osteosarcoma pathophysiology, underlying the possible role of the Ec peptide as a future therapeutic target. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  17. The pathophysiology of the migraine attack

    NARCIS (Netherlands)

    E.L.H. Spierings

    1980-01-01

    textabstractMigraine, a word of French origin, is a mediaeval corruption of the Greek hemicrania". Its etymological meaning, half-headache, indicates two important features of the disorder, the headache and its onesidedness. In classical migraine, the headache is preceded by an 'aura' of

  18. MicroRNA-orchestrated pathophysiologic control in gut homeostasis and inflammation.

    Science.gov (United States)

    Lee, Juneyoung; Park, Eun Jeong; Kiyono, Hiroshi

    2016-05-01

    The intestine represents the largest and most elaborate immune system organ, in which dynamic and reciprocal interplay among numerous immune and epithelial cells, commensal microbiota, and external antigens contributes to establishing both homeostatic and pathologic conditions. The mechanisms that sustain gut homeostasis are pivotal in maintaining gut health in the harsh environment of the gut lumen. Intestinal epithelial cells are critical players in creating the mucosal platform for interplay between host immune cells and luminal stress inducers. Thus, knowledge of the epithelial interface between immune cells and the luminal environment is a prerequisite for a better understanding of gut homeostasis and pathophysiologies such as inflammation. In this review, we explore the importance of the epithelium in limiting or promoting gut inflammation (e.g., inflammatory bowel disease). We also introduce recent findings on how small RNAs such as microRNAs orchestrate pathophysiologic gene regulation. [BMB Reports 2016; 49(5): 263-269].

  19. The Emerging Role of Chronic Low-Grade Inflammation in the Pathophysiology of Polycystic Ovary Syndrome.

    Science.gov (United States)

    Shorakae, Soulmaz; Teede, Helena; de Courten, Barbora; Lambert, Gavin; Boyle, Jacqueline; Moran, Lisa J

    2015-07-01

    Polycystic ovary syndrome (PCOS) has become increasingly common over recent years and is associated with reproductive features as well as cardiometabolic risk factors, including visceral obesity, dyslipidemia and impaired glucose homeostasis, and potentially cardiovascular disease. Emerging evidence suggests that these long-term metabolic effects are linked to a low-grade chronic inflammatory state with the triad of hyperinsulinemia, hyperandrogenism, and low-grade inflammation acting together in a vicious cycle in the pathophysiology of PCOS. Dysregulation of the sympathetic nervous system may also act as an important component, potentially creating a tetrad in the pathophysiology of PCOS. The aim of this review is to examine the role of chronic inflammation and the sympathetic nervous system in the development of obesity and PCOS and review potential therapeutic options to alleviate low-grade inflammation in this setting. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  20. A targeted genotyping approach enhances identification of variants in taste receptor and appetite/reward genes of potential functional importance for obesity-related porcine traits.

    Science.gov (United States)

    Cirera, S; Clop, A; Jacobsen, M J; Guerin, M; Lesnik, P; Jørgensen, C B; Fredholm, M; Karlskov-Mortensen, P

    2018-04-01

    Taste receptors (TASRs) and appetite and reward (AR) mechanisms influence eating behaviour, which in turn affects food intake and risk of obesity. In a previous study, we used next generation sequencing to identify potentially functional mutations in TASR and AR genes and found indications for genetic associations between identified variants and growth and fat deposition in a subgroup of animals (n = 38) from the UNIK resource pig population. This population was created for studying obesity and obesity-related diseases. In the present study we validated results from our previous study by investigating genetic associations between 24 selected single nucleotide variants in TASR and AR gene variants and 35 phenotypes describing obesity and metabolism in the entire UNIK population (n = 564). Fifteen variants showed significant association with specific obesity-related phenotypes after Bonferroni correction. Six of the 15 genes, namely SIM1, FOS, TAS2R4, TAS2R9, MCHR2 and LEPR, showed good correlation between known biological function and associated phenotype. We verified a genetic association between potentially functional variants in TASR/AR genes and growth/obesity and conclude that the combination of identification of potentially functional variants by next generation sequencing followed by targeted genotyping and association studies is a powerful and cost-effective approach for increasing the power of genetic association studies. © 2018 Stichting International Foundation for Animal Genetics.

  1. Favorable Response of Metastatic Merkel Cell Carcinoma to Targeted 177Lu-DOTATATE Therapy: Will PRRT Evolve to Become an Important Approach in Receptor-Positive Cases?

    Science.gov (United States)

    Basu, Sandip; Ranade, Rohit

    2016-06-01

    This report illustrates an excellent partial response of Merkel cell carcinoma with multiple bilobar hepatic metastases to a single cycle of peptide receptor radionuclide therapy (PRRT) with (177)Lu-DOTATATE. This response, coupled with minimal side effects, warrants consideration of this therapy early in the disease course (rather than at an advanced stage after failure of other therapies) if the metastatic lesions exhibit adequate tracer avidity on somatostatin receptor-based imaging. Our patient showed progression of systemic disease after having undergone a second surgery and adjuvant radiotherapy to the head and neck, as well as chemotherapy, and hence was considered a candidate for PRRT. In a pretreatment study, the metastatic lesions demonstrated avidity to both somatostatin receptors and (18)F-FDG. Three months after the first cycle of treatment, when the patient was being evaluated for a second cycle, both imaging parameters showed evidence of a partial response that included nearly complete resolution of the two previously seen lesions. In view of the relatively good tolerability, minimal side effects, and targeted nature of the treatment, PRRT may evolve to become the first-line therapy for metastatic Merkel cell carcinoma and should be examined further in a larger number of patients. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  2. Falls: epidemiology, pathophysiology, and relationship to fracture.

    Science.gov (United States)

    Berry, Sarah D; Miller, Ram R

    2008-12-01

    Falls are common in the elderly, and frequently result in injury and disability. Most falls result from an interaction between individual characteristics that increase an individual's propensity to fall and acute mediating risk factors that provide the opportunity to fall. Predisposing risk factors include age-associated changes in strength and balance, comorbidities such as osteoarthritis, visual impairment and dementia, psychotropic medications, and certain types of footwear. Fewer studies have focused on acute precipitating factors, but environmental and situational factors are clearly important to fall risk. Approximately 30% of falls result in an injury that requires medical attention, with fractures occurring in approximately 10%. In addition to the risk factors for falls, the fall descent, fall impact, and bone strength are all important determinants of whether a fall will result in a fracture. In recent years, numerous studies have been directed toward the development of effective fall and fall-related fracture prevention interventions.

  3. Bioactive lipids in kidney physiology and pathophysiology

    Directory of Open Access Journals (Sweden)

    Daria Sałata

    2014-01-01

    Full Text Available Lipids not only have structural functions, but also play an important role as signaling and regulatory molecules and participate in many cellular processes such as proliferation, differentiation, migration, and apoptosis. Bioactive lipids act both as extracellular mediators, which are associated with receptors on the surface of cells, and intracellular mediators triggering different signal pathways. They are present and active in physiological conditions, and are also involved in the pathogenesis of inflammation, asthma, cancer, diabetes, and hypertension. Bioactive lipids such as derivatives of arachidonic acid and sphingolipids have an important role in renal development, physiology and in many renal diseases. Some of them are potential indicators of kidney damage degree and/or function of the transplanted kidneys.

  4. Diagnosis, pathophysiology, and management of cluster headache.

    Science.gov (United States)

    Hoffmann, Jan; May, Arne

    2018-01-01

    Cluster headache is a trigeminal autonomic cephalalgia characterised by extremely painful, strictly unilateral, short-lasting headache attacks accompanied by ipsilateral autonomic symptoms or the sense of restlessness and agitation, or both. The severity of the disorder has major effects on the patient's quality of life and, in some cases, might lead to suicidal ideation. Cluster headache is now thought to involve a synchronised abnormal activity in the hypothalamus, the trigeminovascular system, and the autonomic nervous system. The hypothalamus appears to play a fundamental role in the generation of a permissive state that allows the initiation of an episode, whereas the attacks are likely to require the involvement of the peripheral nervous system. Triptans are the most effective drugs to treat an acute cluster headache attack. Monoclonal antibodies against calcitonin gene-related peptide, a crucial neurotransmitter of the trigeminal system, are under investigation for the preventive treatment of cluster headache. These studies will increase our understanding of the disorder and perhaps reveal other therapeutic targets. Copyright © 2018 Elsevier Ltd. All rights reserved.

  5. Velopharyngeal sphincter pathophysiologic aspects in the in cleft palat

    Directory of Open Access Journals (Sweden)

    Collares, Marcus Vinicius Martins

    2008-09-01

    Full Text Available Introduction: Cleft lip and palate are common congenital abnormalities with typical functional disorders on speech, deglutition and middle ear function. Objective: This article reviews functional labiopalatine disorders through a pathophysiological view. Method: We performed a literature search on line, as well as books and periodicals related to velopharyngeal sphincter. Our sources were LILACS, MEDLINE and SciELO databases, and we applied to the research Keywords of interest on the velopharyngeal pathophysiology, for articles published between 1965 and 2007. Conclusion: Velopharyngeal sphincter plays a central role in speech, swallowing and middle ear physiology in patients with labiopalatine cleft. At the end of our bibliographic review, pursuant to the velopharyngeal physiology in individuals with this disorder in the functional speech, deglutition and otologic function, we observed that although there is a great number of published data discussing this issue, further studies are necessary to completely understand the pathophysiology, due to the fact they have been exploited superficially.

  6. A Unified Pathophysiological Construct of Diabetes and its Complications.

    Science.gov (United States)

    Schwartz, Stanley S; Epstein, Solomon; Corkey, Barbara E; Grant, Struan F A; Gavin Iii, James R; Aguilar, Richard B; Herman, Mary E

    2017-09-01

    Advances in understanding diabetes mellitus (DM) through basic and clinical research have helped clarify and reunify a disease state fragmented into numerous etiologies and subtypes. It is now understood that a common pathophysiology drives the diabetic state throughout its natural history and across its varied clinical presentations, a pathophysiology involving metabolic insults, oxidative damage, and vicious cycles that aggravate and intensify organ dysfunction and damage. This new understanding of the disease requires that we revisit existing diagnostics and treatment approaches, which were built upon outmoded assumptions. 'The Common Pathophysiologic Origins of Diabetes Mellitus and its Complications Construct' is presented as a more accurate, foundational, and translatable construct of DM that helps make sense of the hitherto ambiguous findings of long-term outcome studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. The syndemic of HIV, HIV-related risk and multiple co-morbidities among women who use drugs in Malaysia: Important targets for intervention.

    Science.gov (United States)

    Loeliger, Kelsey B; Marcus, Ruthanne; Wickersham, Jeffrey A; Pillai, Veena; Kamarulzaman, Adeeba; Altice, Frederick L

    2016-02-01

    Substance use and HIV are syndemic public health problems in Malaysia. Harm reduction efforts to reduce HIV transmission have primarily focused on men with substance use disorders. To explore HIV risk behaviors, substance use, and social factors associated with poor health outcomes among women who use drugs in Malaysia. A cross-sectional survey of 103 drug-using women in Kuala Lumpur, Malaysia were recruited to assess their medical, psychiatric and social comorbidity as well as their engagement in nationally recommended HIV testing and monitoring activities. One-third reported having ever injected drugs, with most (68.2%) having recently shared injection paraphernalia. Sex work (44.7%) and infrequent condom use (42.4%) were common as was underlying psychiatric illness and physical and sexual violence during childhood and adulthood. Most women (62.1%) had unstable living situations and suffered from an unmet need for social support and health services. HIV prevalence was high (20%) with only two thirds of women eligible for antiretroviral therapy having received it. Suboptimal HIV testing and/or monitoring was positively associated with interpersonal violence (AOR 2.73; 95% CI 1.04-7.14) and negatively associated with drug injection (AOR 0.28; 95% CI 0.10-0.77). Women who use drugs in Malaysia demonstrate considerable medical, psychiatric and social co-morbidity, which negatively contributes to optimal and crucial engagement in HIV treatment-as-prevention strategies. Mental health and social support may be key targets for future public health interventions aimed at drug-using women in Malaysia. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Physiology and pathophysiology of cell organelles

    Directory of Open Access Journals (Sweden)

    J. J. Theron

    1998-07-01

    Full Text Available Mitochondria are found in all eucaryotic cells except mature red blood cells. The structural components of these organelles are briefly described. The primary function of mitochondria, i.e. transduction of energy with formation of ATP through a process of oxidative phosphorylation (OXPHOS occurs in six protein complexes arranged in sequence on the mitochondrial cristae formed by infoldings of the internal membrane. Mitochondrial DNA and ribosomes are found in mitochondria and protein synthesis can therefore occur in these organelles. However, most mitochondrial proteins and practically all lipids are imported from the cytoplasm.

  9. Mycotoxins in pathophysiology of cattle diet

    Directory of Open Access Journals (Sweden)

    Mašić Zoran

    2003-01-01

    Full Text Available Depending on the age and production category, cattle show different sensitivity towards certain mycotoxins. Microflora of the rumen degrades to a different degree and inactivates mycotoxins. In the work are presented the most important mycotoxicoses of cattle caused by fungal metabolites from the genera Fusarium, Aspergillus and Penicillium. Poisoning of cattle in our area is most often caused by Zearalenone, Dioxinivalenol, T-2 toxin, Ochratoxin A and Aflatoxin, but in the work are also presented Fumonisin B1 and B2. The work also describes preventive possibilities and protection of animal health from the effects of mycotoxins.

  10. Targeted inactivation of integrin-linked kinase in hair follicle stem cells reveals an important modulatory role in skin repair after injury.

    Science.gov (United States)

    Nakrieko, Kerry-Ann; Rudkouskaya, Alena; Irvine, Timothy S; D'Souza, Sudhir J A; Dagnino, Lina

    2011-07-15

    Integrin-linked kinase (ILK) is key for normal epidermal morphogenesis, but little is known about its role in hair follicle stem cells and epidermal regeneration. Hair follicle stem cells are important contributors to newly formed epidermis following injury. We inactivated the Ilk gene in the keratin 15--expressing stem cell population of the mouse hair follicle bulge. Loss of ILK expression in these cells resulted in impaired cutaneous wound healing, with substantially decreased wound closure rates. ILK-deficient stem cells produced very few descendants that moved toward the epidermal surface and into the advancing epithelium that covers the wound. Furthermore, those few mutant cells that homed in the regenerated epidermis exhibited a reduced residence time. Paradoxically, ILK-deficient bulge stem cells responded to anagen growth signals and contributed to newly regenerated hair follicles during this phase of hair follicle growth. Thus ILK plays an important modulatory role in the normal contribution of hair follicle stem cell progeny to the regenerating epidermis following injury.

  11. PATHOPHYSIOLOGY STROKE NON-HEMORRHAGIC ET CAUSA THROMBUS

    Directory of Open Access Journals (Sweden)

    Aji Kristianto Wijaya

    2013-10-01

    Full Text Available Normal 0 false false false EN-US X-NONE X-NONE Stroke is one of the most common cause of death worldwide and the third leading cause of death in the United States. Stroke composed 90,000 deaths of women and 60,000 men each year. In Indonesia, 8 of 1000 people suffered a stroke. Stroke is divided into two, non-hemorrhagic stroke and hemorrhagic stroke. Most of them (80% is non-hemorrhagic stroke. Non-hemorrhagic stroke can be caused by thrombi or emboli. Understanding the pathophysiology of non-hemorrhagic stroke caused by a thrombus is very important in regard with providing appropriate patient management. /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin-top:0in; mso-para-margin-right:0in; mso-para-margin-bottom:10.0pt; mso-para-margin-left:0in; line-height:115%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;}

  12. Pathophysiological consequences of hemolysis. Role of cell-free hemoglobin

    Directory of Open Access Journals (Sweden)

    Tomasz Misztal

    2011-09-01

    Full Text Available Abundant hemolysis is associated with a number of inherent and acquired diseases including sickle-cell disease (SCD, polycythemia, paroxysmal nocturnal hemoglobinuria (PNH and drug-induced hemolytic anemia. Despite different etiopathology of hemolytic diseases, many concomitant symptoms are comparable and include e.g. hypertension, hemoglobinuria and hypercoagulation state. Studies in the last years have shown a growing list of mechanisms lying at the basis of those symptoms, in particular irreversible reaction between cell-free hemoglobin (Hb and nitric oxide (NO – endogenous vasorelaxant and anti-thrombotic agent. Saturation of protective physiological cell-free Hb-scavenging mechanisms results in accumulation of Hb in plasma and hemoglobinemia. Extensive hemoglobinemia subsequently leads to hemoglobinuria, which may cause kidney damage and development of Fanconi syndrome. A severe problem in patients with SCD and PNH is pulmonary and systemic hypertension. It may lead to circulation failure, including stroke, and it is related to abolition of NO bioavailability for vascular smooth muscle cells. Thrombotic events are the major cause of death in SCD and PNH. It ensues from lack of platelet inhibition evoked by Hb-mediated NO scavenging. A serious complication that affects patients with excessive hemolysis is erectile dysfunction. Also direct cytotoxic, prooxidant and proinflammatory effects of cell-free hemoglobin and heme compose the clinical picture of hemolytic diseases. The pathophysiological role of plasma Hb, mechanisms of its elimination, and direct and indirect (via NO scavenging deleterious effects of cell-free Hb are presented in detail in this review. Understanding the critical role of hemolysis and cell-free Hb is important in the perspective of treating patients with hemolytic diseases and to design new effective therapies in future.

  13. The Importance of Health Surveys in Workplaces, with Emphasis on the Field of Public Health, in the Target Group of Employees Who Work in Shifts

    Directory of Open Access Journals (Sweden)

    Vámosiné-Rovó Gyöngyvér

    2016-08-01

    Full Text Available In today’s world the economic uncertainty, the huge overload of work, the expectations related to the work performance – which are not said –, the monotone work and the risk of violence contribute to the increase of psychosocial risks, which can lead to serious consequences in a company. If we succeed in preventing the negative impact of stress originating from the workplace, then the employer can keep the productivity of the company and besides that, the company gets rid of large expenses. The occupational health and safety is an important component of the social responsibility taking. One of the most efficient tools of prevention is the psychosocial risk assessment and the changes based on this in the company’s operation and regulation.

  14. [Lung protective ventilation - pathophysiology and diagnostics].

    Science.gov (United States)

    Uhlig, Stefan; Frerichs, Inéz

    2008-06-01

    Mechanical ventilation may lead to lung injury depending on the ventilatory settings (e.g. pressure amplitudes, endexpiratory pressures, frequency) and the length of mechanical ventilation. Particularly in the inhomogeneously injured lungs of ARDS patients, alveolar overextension results in volutrauma, cyclic opening and closure of alveolar units in atelectrauma. Particularly important appears to be the fact that these processes may also cause biotrauma, i.e. the ventilator-induced hyperactivation of inflammatory responses in the lung. These side effects are reduced, but not eliminated with the currently recommended ventilation strategy with a tidal volume of 6 ml/kg idealized body weight. It is our hope that in the future optimization of ventilator settings will be facilated by bedside monitoring of novel indices of respiratory mechanics such as the stress index or the Slice technique, and by innovative real-time imaging technologies such as electrical impedance tomography.

  15. Rethinking mercury: the role of selenium in the pathophysiology of mercury toxicity.

    Science.gov (United States)

    Spiller, Henry A

    2018-05-01

    There is increasing evidence that the pathophysiological target of mercury is in fact selenium, rather than the covalent binding of mercury to sulfur in the body's ubiquitous sulfhydryl groups. The role of selenium in mercury poisoning is multifaceted, bidirectional, and central to understanding the target organ toxicity of mercury. An initial search was performed using Medline/PubMed, Toxline, Google Scholar, and Google for published work on mercury and selenium. These searches yielded 2018 citations. Publications that did not evaluate selenium status or evaluated environmental status (e.g., lake or ocean sediment) were excluded, leaving approximately 500 citations. This initial selection was scrutinized carefully and 117 of the most relevant and representative references were selected for use in this review. Binding of mercury to thiol/sulfhydryl groups: Mercury has a lower affinity for thiol groups and higher affinity for selenium containing groups by several orders of magnitude, allowing for binding in a multifaceted way. The established binding of mercury to thiol moieties appears to primarily involve the transport across membranes, tissue distribution, and enhanced excretion, but does not explain the oxidative stress, calcium dyshomeostasis, or specific organ injury seen with mercury. Effects of mercury on selenium and the role this plays in the pathophysiology of mercury toxicity: Mercury impairs control of intracellular redox homeostasis with subsequent increased intracellular oxidative stress. Recent work has provided convincing evidence that the primary cellular targets are the selenoproteins of the thioredoxin system (thioredoxin reductase 1 and thioredoxin reductase 2) and the glutathione-glutaredoxin system (glutathione peroxidase). Mercury binds to the selenium site on these proteins and permanently inhibits their function, disrupting the intracellular redox environment. A number of other important possible target selenoproteins have been identified

  16. Oxidative Stress as an Important Factor in the Pathophysiology of alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Tanise Gemelli,

    2013-06-01

    Full Text Available Oxidative stress has been associated to play a crucial role in the pathogenesis of many diseases, including neurodegenerative diseases. Alzheimer's disease is an age-related neurodegenerative disorder, which is recognized as the most common form of dementia. In this article, the aim was to review the involvement of oxidative stress on Alzheimer's disease. Alzheimer's disease is histopathologically characterized by the presence of extracellular amyloid plaques, intracellular neurofibrillary tangles, the presence of oligomers of amyloid-? peptide and loss of synapses. Moreover, the brain and the nervous system are more prone to oxidative stress and oxidative damage influences the neurodegenerative diseases. However, increased oxidative damage, mitochondrial dysfunction, accumulation of oxidized aggregated proteins, inflammation, and defects in proteins constitute complex intertwined pathologies that lead to neuronal cell death. Mitochondrial mutations on deoxyribonucleic acid and oxidative stress contribute to aging, affecting different cell signaling systems, as well as the connectivity and neuronal cell death may lead to the largest risk factor for neurodegenerative diseases such as Alzheimer's Disease.

  17. The importance of mdx mouse in the pathophysiology of Duchenne's muscular distrophy

    OpenAIRE

    Seixas, Sandra Lopes; Lagrota-Cândido, Jussara; Savino, Wilson; Quirico-Santos, Thereza

    1997-01-01

    O camundongo mdx desenvolve distrofia muscular recessiva ligada ao cromossoma X (locus Xp21.1) e não expressa distrofina. Embora não apresente intensa fibrose do tecido muscular e acúmulo de tecido adiposo, é considerado o modelo animal mais adequado da distrofia muscular de Duchenne. As alterações estruturais no tecido muscular associadas à mionecrose e presença do infiltrado inflamatório com predomínio de linfócitos e monócitos/macrófagos sugerem uma participação do sistema imunológico nest...

  18. The pathology and pathophysiology of vascular dementia.

    Science.gov (United States)

    Kalaria, Raj N

    2017-12-19

    Vascular dementia (VaD) is widely recognised as the second most common type of dementia. Consensus and accurate diagnosis of clinically suspected VaD relies on wide-ranging clinical, neuropsychological and neuroimaging measures in life but more importantly pathological confirmation. Factors defining subtypes of VaD include the nature and extent of vascular pathologies, degree of involvement of extra and intracranial vessels and the anatomical location of tissue changes as well as time after the initial vascular event. Atherosclerotic and cardioembolic diseases combined appear the most common subtypes of vascular brain injury. In recent years, cerebral small vessel disease (SVD) has gained prominence worldwide as an important substrate of cognitive impairment. SVD is characterised by arteriolosclerosis, lacunar infarcts and cortical and subcortical microinfarcts and diffuse white matter changes, which involve myelin loss and axonal abnormalities. Global brain atrophy and focal degeneration of the cerebrum including medial temporal lobe atrophy are also features of VaD similar to Alzheimer's disease. Hereditary arteriopathies have provided insights into the mechanisms of dementia particularly how arteriolosclerosis, a major contributor of SVD promotes cognitive impairment. Recently developed and validated neuropathology guidelines indicated that the best predictors of vascular cognitive impairment were small or lacunar infarcts, microinfarcts, perivascular space dilation, myelin loss, arteriolosclerosis and leptomeningeal cerebral amyloid angiopathy. While these substrates do not suggest high specificity, VaD is likely defined by key neuronal and dendro-synaptic changes resulting in executive dysfunction and related cognitive deficits. Greater understanding of the molecular pathology is needed to clearly define microvascular disease and vascular substrates of dementia. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Pathophysiology of GPCR Homo- and Heterodimerization: Special Emphasis on Somatostatin Receptors

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    Rishi K. Somvanshi

    2012-04-01

    Full Text Available G-protein coupled receptors (GPCRs are cell surface proteins responsible for translating >80% of extracellular reception to intracellular signals. The extracellular information in the form of neurotransmitters, peptides, ions, odorants etc is converted to intracellular signals via a wide variety of effector molecules activating distinct downstream signaling pathways. All GPCRs share common structural features including an extracellular N-terminal, seven-transmembrane domains (TMs linked by extracellular/intracellular loops and the C-terminal tail. Recent studies have shown that most GPCRs function as dimers (homo- and/or heterodimers or even higher order of oligomers. Protein-protein interaction among GPCRs and other receptor proteins play a critical role in the modulation of receptor pharmacology and functions. Although ~50% of the current drugs available in the market target GPCRs, still many GPCRs remain unexplored as potential therapeutic targets, opening immense possibility to discover the role of GPCRs in pathophysiological conditions. This review explores the existing information and future possibilities of GPCRs as tools in clinical pharmacology and is specifically focused for the role of somatostatin receptors (SSTRs in pathophysiology of diseases and as the potential candidate for drug discovery.

  20. Classification and pathophysiology of radiocontrast media hypersensitivity.

    Science.gov (United States)

    Brockow, Knut; Ring, Johannes

    2010-01-01

    Hypersensitivity reactions to radiocontrast media (RCM) are unpredictable and are a concern for radiologists and cardiologists. Immediate hypersensitivity reactions manifest as anaphylaxis, and an allergic IgE-mediated mechanism has been continuously discussed for decades. Non-immediate reactions clinically are exanthemas resembling other drug-induced non-immediate hypersensitivities. During the past years, evidence is increasing that some of these reactions may be immunological. Repeated reactions after re-exposure, positive skin tests, and presence of specific IgE antibodies as well as positive basophil activation tests in some cases, and positive lymphocyte transformation or lymphocyte activation tests in others, indicate that a subgroup of both immediate and non-immediate reactions are of an allergic origin, although many questions remain unanswered. Recently reported cases highlight that pharmacological premedication is not safe to prevent RCM hypersensitivity in patients with previous severe reactions. These insights may have important consequences. A large multicenter study on the value of skin tests in RCM hypersensitivity concluded that skin testing is a useful tool for diagnosis of RCM allergy. It may have a role for the selection of a safe product in previous reactors, although confirmatory validation data is still scarce. In vitro tests to search for RCM-specific cell activation still are in development. In conclusion, recent data indicate that RCM hypersensitivity may have an allergic mechanism and that allergological testing is useful and may indicate tolerability. Copyright 2010 S. Karger AG, Basel.

  1. Uromodulin biology and pathophysiology--an update.

    Science.gov (United States)

    Vyletal, Petr; Bleyer, Anthony J; Kmoch, Stanislav

    2010-01-01

    Uromodulin (UMOD) is a glycoprotein expressed on the luminal surface of the apical membrane of renal tubular epithelial cells forming the thick ascending limb of Henle. Here, UMOD forms filamentous structures probably ensuring water impermeability and the countercurrent gradient. The multidomain structure, cellular topology of UMOD and clinical consequences associated with UMOD dysfunction, however, suggest that it may be involved in other biological processes such as receptor-mediated endocytosis, mechanosensation of urinary flow, Wnt-signaling, cell cycle regulation and planar cell polarity. A specific, but as yet unidentified, protease(s) releases UMOD into the urine, where it probably contributes to colloid osmotic pressure, retards passage of positively charged electrolytes, prevents urinary tract infection and modulates formation of supersaturated salts and their crystals. UMOD expression, biosynthesis and excretion are regulated in a complex manner, and dysregulation is found in a wide range of pathological conditions. It is strongly reduced or absent in cases with mutations in UMOD, renin, HNF1B and other genetic disorders causing autosomal dominant hyperuricemic nephropathy. In contrast, elevated UMOD excretion may be associated with, and thus predictive of, chronic kidney disease. UMOD analysis is therefore of importance in all conditions with renal involvement and may be useful in the proper classification of renal diseases. 2010 S. Karger AG, Basel.

  2. [Gut microbiota: Description, role and pathophysiologic implications].

    Science.gov (United States)

    Landman, C; Quévrain, E

    2016-06-01

    The human gut contains 10(14) bacteria and many other micro-organisms such as Archaea, viruses and fungi. Studying the gut microbiota showed how this entity participates to gut physiology and beyond this to human health, as a real "hidden organ". In this review, we aimed to bring information about gut microbiota, its structure, its roles and its implication in human pathology. After bacterial colonization in infant, intestinal microbial composition is unique for each individual although more than 95% can be assigned to four major phyla. The use of culture independent methods and more recently the development of high throughput sequencing allowed to depict precisely gut microbiota structure and diversity as well as its alteration in diseases. Gut microbiota is implicated in the maturation of the host immune system and in many fundamental metabolic pathways including sugars and proteins fermentation and metabolism of bile acids and xenobiotics. Imbalance of gut microbial populations or dysbiosis has important functional consequences and is implicated in many digestive diseases (inflammatory bowel diseases, colorectal cancer, etc.) but also in obesity and autism. These observations have led to a surge of studies exploring therapeutics which aims to restore gut microbiota equilibrium such as probiotics or fecal microbiota transplantation. But recent research also investigates biological activity of microbial products which could lead to interesting therapeutics leads. Copyright © 2015 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  3. Diabetic Macular Edema Pathophysiology: Vasogenic versus Inflammatory

    Directory of Open Access Journals (Sweden)

    Pedro Romero-Aroca

    2016-01-01

    Full Text Available Diabetic macular edema (DME can cause blindness in diabetic patients suffering from diabetic retinopathy (DR. DM parameters controls (glycemia, arterial tension, and lipids are the gold standard for preventing DR and DME. Although the vascular endothelial growth factor (VEGF is known to play a role in the development of DME, the pathological processes leading to the onset of this disease are highly complex and the exact sequence in which they occur is still not completely understood. Angiogenesis and inflammation have been shown to be involved in the pathogenesis of this disease. However, it still remains to be clarified whether angiogenesis following VEGF overexpression is a cause or a consequence of inflammation. This paper provides a review of the data currently available, focusing on VEGF, angiogenesis, and inflammation. Our analysis suggests that angiogenesis and inflammation act interdependently during the development of DME. Knowledge of DME etiology seems to be important in treatments with anti-VEGF or anti-inflammatory drugs. Current diagnostic techniques do not permit us to differentiate between both etiologies. In the future, diagnosing the physiopathology of each patient with DME will help us to select the most effective drug.

  4. Islet Amyloid Polypeptide: Structure, Function, and Pathophysiology

    Directory of Open Access Journals (Sweden)

    Rehana Akter

    2016-01-01

    Full Text Available The hormone islet amyloid polypeptide (IAPP, or amylin plays a role in glucose homeostasis but aggregates to form islet amyloid in type-2 diabetes. Islet amyloid formation contributes to β-cell dysfunction and death in the disease and to the failure of islet transplants. Recent work suggests a role for IAPP aggregation in cardiovascular complications of type-2 diabetes and hints at a possible role in type-1 diabetes. The mechanisms of IAPP amyloid formation in vivo or in vitro are not understood and the mechanisms of IAPP induced β-cell death are not fully defined. Activation of the inflammasome, defects in autophagy, ER stress, generation of reactive oxygen species, membrane disruption, and receptor mediated mechanisms have all been proposed to play a role. Open questions in the field include the relative importance of the various mechanisms of β-cell death, the relevance of reductionist biophysical studies to the situation in vivo, the molecular mechanism of amyloid formation in vitro and in vivo, the factors which trigger amyloid formation in type-2 diabetes, the potential role of IAPP in type-1 diabetes, the development of clinically relevant inhibitors of islet amyloidosis toxicity, and the design of soluble, bioactive variants of IAPP for use as adjuncts to insulin therapy.

  5. Therapy of rheumatic polymyalgia: the pathophysiologic management

    Directory of Open Access Journals (Sweden)

    M.A. Cimino

    2011-09-01

    Full Text Available Polymyalgia rheumatica (PMR is an inflammatory syndrome affecting older people whose prevalence has increased in recent years. The suppression of the hypothalamic-pituitary-adrenal axis (HPA and ageing may contribute to the pathogenesis of PMR. Chronic stress (i.e. interpersonal, chronic infections etc. in elderly people may represent a risk factor for the development of PMR. In fact, elderly represent per se a condition of endocrine senescence including adrenal hypofunction, in addition chronic stress represents a further harmful stimulus to seriously compromise endogenous glucocorticoid production. Synovitis and vasculitis characterize the majority of the patients. Serum cytokine and steroidal hormone patterns suggest that patients with PMR have an intensive inflammatory reaction. As a matter of fact, glucocorticoids represent the most useful temporary “replacement” treatment during the active phase of PMR. The use of modified-release glucocorticoids that might induce higher levels during the night (circadian rhythms as in physiological conditions, will represent another important approach to optimize PMR treatment and reduce the side effects. Combination therapy between glucocorticoids and inhibitors of pro-inflammatory cytokines should be tested in large studies and early cases of PMR.

  6. Pathophysiology and treatment of psychosis in Parkinson's disease: a review.

    Science.gov (United States)

    Zahodne, Laura B; Fernandez, Hubert H

    2008-01-01

    Psychotic symptoms in Parkinson's disease (PD) are relatively common and, in addition to creating a disturbance in patients' daily lives, have consistently been shown to be associated with poor outcome. Our understanding of the pathophysiology of psychosis in PD has expanded dramatically over the past 15 years, from an initial interpretation of symptoms as dopaminergic drug adverse effects to the current view of a complex interplay of extrinsic and disease-related factors.PD psychosis has unique clinical features, namely that it arises within a context of a clear sensorium and retained insight, there is relative prominence of visual hallucinations and progression occurs over time. PD psychosis tends to emerge later in the disease course, and disease duration represents one risk factor for its development. The use of anti-PD medications (particularly dopamine receptor agonists) has been the most widely identified risk factor for PD psychosis. Other risk factors discussed in the literature include older age, disease severity, sleep disturbance, cognitive impairment, dementia and/or depression.Recent efforts have aimed to explore the complex pathophysiology of PD psychosis, which is now known to involve an interaction between extrinsic, drug-related and intrinsic, disease-related components. The most important extrinsic factor is use of dopaminergic medication, which plays a prominent role in PD psychosis. Intrinsic factors include visual processing deficits (e.g. lower visual acuity, colour and contrast recognition deficits, ocular pathology and functional brain abnormalities identified amongst hallucinating PD patients); sleep dysregulation (e.g. sleep fragmentation and altered dream phenomena); neurochemical (dopamine, serotonin, acetylcholine, etc.) and structural abnormalities involving site-specific Lewy body deposition; and genetics (e.g. apolipoprotein E epsilon4 allele and tau H1H1 genotype). Preliminary reports have also shown a potential relationship

  7. Fucosylated chondroitin sulfate oligosaccharides exert anticoagulant activity by targeting at intrinsic tenase complex with low FXII activation: Importance of sulfation pattern and molecular size.

    Science.gov (United States)

    Li, Junhui; Li, Shan; Yan, Lufeng; Ding, Tian; Linhardt, Robert J; Yu, Yanlei; Liu, Xinyue; Liu, Donghong; Ye, Xingqian; Chen, Shiguo

    2017-10-20

    Fucosylated chondroitin sulfates (fCSs) are structurally unusual glycosaminoglycans isolated from sea cucumbers that exhibit potent anticoagulant activity. These fCSs were isolated from sea cucumber, Isostichopus badionotus and Pearsonothuria graeffei. Fenton reaction followed by gel filtration chromatography afforded fCS oligosaccharides, with different sulfation patterns identified by mass and NMR spectroscopy, and these were used to clarify the relationship between the structures and the anticoagulant activities of fCSs. In vitro activities were measured by activated partial thromboplastin time (APTT), thrombin time (TT), thrombin and factor Xa inhibition, and activation of FXII. The results showed that free radicals preferentially acted on GlcA residues affording oligosaccharides that were purified from both fCSs. The inhibition of thrombin and factor X activities, mediated through antithrombin III and heparin cofactor II of fCSs oligosaccharides were affected by their molecular weight and fucose branches. Oligosaccharides with different sulfation patterns of the fucose branching had a similar ability to inhibit the FXa by the intrinsic factor Xase (factor IXa-VIIIa complex). Oligosaccharides with 2,4-O-sulfo fucose branches from fCS-Ib showed higher activities than ones with 3,4-O-disulfo branches obtained from fCS-Pg. Furthermore, a heptasaccharide is the minimum size oligosaccharide required for anticoagulation and FXII activation. This activity was absent for fCS oligosaccharides smaller than nonasaccharides. Molecular size and fucose branch sulfation are important for anticoagulant activity and reduction of size can reverse the activation of FXII caused by native fCSs. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  8. Mitochondria and Energetic Depression in Cell Pathophysiology

    Directory of Open Access Journals (Sweden)

    Stephan Zierz

    2009-05-01

    Full Text Available Mitochondrial dysfunction is a hallmark of almost all diseases. Acquired or inherited mutations of the mitochondrial genome DNA may give rise to mitochondrial diseases. Another class of disorders, in which mitochondrial impairments are initiated by extramitochondrial factors, includes neurodegenerative diseases and syndromes resulting from typical pathological processes, such as hypoxia/ischemia, inflammation, intoxications, and carcinogenesis. Both classes of diseases lead to cellular energetic depression (CED, which is characterized by decreased cytosolic phosphorylation potential that suppresses the cell’s ability to do work and control the intracellular Ca2+ homeostasis and its redox state. If progressing, CED leads to cell death, whose type is linked to the functional status of the mitochondria. In the case of limited deterioration, when some amounts of ATP can still be generated due to oxidative phosphorylation (OXPHOS, mitochondria launch the apoptotic cell death program by release of cytochrome c. Following pronounced CED, cytoplasmic ATP levels fall below the thresholds required for processing the ATP-dependent apoptotic cascade and the cell dies from necrosis. Both types of death can be grouped together as a mitochondrial cell death (MCD. However, there exist multiple adaptive reactions aimed at protecting cells against CED. In this context, a metabolic shift characterized by suppression of OXPHOS combined with activation of aerobic glycolysis as the main pathway for ATP synthesis (Warburg effect is of central importance. Whereas this type of adaptation is sufficiently effective to avoid CED and to control the cellular redox state, thereby ensuring the cell survival, it also favors the avoidance of apoptotic cell death. This scenario may underlie uncontrolled cellular proliferation and growth, eventually resulting in carcinogenesis.

  9. Pathophysiological mechanisms linking obesity and esophageal adenocarcinoma

    Science.gov (United States)

    Alexandre, Leo; Long, Elizabeth; Beales, Ian LP

    2014-01-01

    In recent decades there has been a dramatic rise in the incidence of esophageal adenocarcinoma (EAC) in the developed world. Over approximately the same period there has also been an increase in the prevalence of obesity. Obesity, especially visceral obesity, is an important independent risk factor for the development of gastro-esophageal reflux disease, Barrett’s esophagus and EAC. Although the simplest explanation is that this mediated by the mechanical effects of abdominal obesity promoting gastro-esophageal reflux, the epidemiological data suggest that the EAC-promoting effects are independent of reflux. Several, not mutually exclusive, mechanisms have been implicated, which may have different effects at various points along the reflux-Barrett’s-cancer pathway. These mechanisms include a reduction in the prevalence of Helicobacter pylori infection enhancing gastric acidity and possibly appetite by increasing gastric ghrelin secretion, induction of both low-grade systemic inflammation by factors secreted by adipose tissue and the metabolic syndrome with insulin-resistance. Obesity is associated with enhanced secretion of leptin and decreased secretion of adiponectin from adipose tissue and both increased leptin and decreased adiponectin have been shown to be independent risk factors for progression to EAC. Leptin and adiponectin have a set of mutually antagonistic actions on Barrett’s cells which appear to influence the progression of malignant behaviour. At present no drugs are of proven benefit to prevent obesity associated EAC. Roux-en-Y reconstruction is the preferred bariatric surgical option for weight loss in patients with reflux. Statins and aspirin may have chemopreventative effects and are indicated for their circulatory benefits. PMID:25400997

  10. Idiopathic Intracranial Hypertension – Pathophysiology Based on Case Series

    Directory of Open Access Journals (Sweden)

    Ljubisavljević Srdjan

    2016-09-01

    Full Text Available According to the definition, idiopathic intracranial hypertension (IIH is a pathological state characterized by an increase in intracranial pressure; however, there are no obvious intracranial pathological processes. The pathophysiology of this disorder is not clear, although there are many reports related to it.

  11. Pathophysiology of diurnal drooling in Parkinson’s disease

    NARCIS (Netherlands)

    Lenie van den Engel-Hoek; Johanna Kalf; Bastiaan Bloem; George Borm; Machiel Zwarts; Bert de Swart; Marten Munneke

    2011-01-01

    Drooling is an incapacitating feature of Parkinson's disease. Better pathophysiological insights are needed to improve treatment. In this study, we tested the hypothesis that the cause of drooling is multifactorial. We examined 15 patients with Parkinson's disease with distinct diurnal saliva loss

  12. New insights into the pathophysiology of postoperative cognitive dysfunction

    DEFF Research Database (Denmark)

    Krenk, Lene; Rasmussen, Lars Simon; Kehlet, H

    2010-01-01

    There is evidence that postoperative cognitive dysfunction (POCD) is a significant problem after major surgery, but the pathophysiology has not been fully elucidated. The interpretation of available studies is difficult due to differences in neuropsychological test batteries as well as the lack...

  13. Pathophysiology and Contributing Factors in Postprostatectomy Incontinence: A Review

    NARCIS (Netherlands)

    Heesakkers, J.P.F.A.; Farag, F.; Bauer, R.M.M.J.; Sandhu, J.; Ridder, D. de; Stenzl, A.

    2017-01-01

    CONTEXT: The incidence and awareness of postprostatectomy incontinence (PPI) has increased during the past few years, probably because of an increase in prostate cancer surgery. Many theories have been postulated to explain the pathophysiology of PPI. OBJECTIVE: The current review scrutinizes

  14. Pathophysiology of acute mountain sickness and high altitude pulmonary oedema

    DEFF Research Database (Denmark)

    Sutton, J R; Lassen, N

    1979-01-01

    We review the evidence that acute mountain sickness (AMS) and high altitude pulmonary oedema (HAPO) occur together more often than is realized. We hypothesize that AMS and HAPO have a common pathophysiological basis: both are due to increased pressure and flow in the microcirculation, causing...

  15. Elucidation of pathophysiology and treatment of neuropathic pain

    NARCIS (Netherlands)

    Vranken, Jan H.

    2012-01-01

    Neuropathic pain, pain arising as a direct consequence of a lesion or disease affecting the somatosensory system, is relatively common, occurring in about 1% of the population. Studies in animal models describe a number of peripheral and central pathophysiological processes after nerve injury that

  16. Pathophysiological and pharmacotherapeutic aspects of serotonin and serotonergic drugs

    NARCIS (Netherlands)

    van Zwieten, P. A.; Blauw, G. J.; van Brummelen, P.

    1990-01-01

    A survey shall be given on the physiological, pathophysiological and pharmacotherapeutic backgrounds of the biogenic amine 5-hydroxytryptamine (serotonin; 5HT), to be preceded by a few historical remarks. 5HT is biosynthesized from L-tryptophan via hydroxylation and subsequent decarboxylation. 5HT

  17. Unravelling narcolepsy : from pathophysiology to measuring treatment effects

    NARCIS (Netherlands)

    Heide, van der A.

    2017-01-01

    Narcolepsy is a disorder of the regulation of sleep and wakefulness, with as its major features excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, sleep paralysis and disturbed nocturnal sleep. The first part of this thesis concernes an overview of the pathophysiology,

  18. Effects of Triphasic Exercise on Blood Rheology and Pathophysiology

    African Journals Online (AJOL)

    The aim of this work is to study the relevance of physiology and pathophysiology in blood rheology as effects of triphasic exercise. Regular exercise which has been established as life prolonging has led to decrease in both peripheral vascular and coronary morbidity that has been associated with certain improvements in ...

  19. Pathophysiology of mitochondrial lipid oxidation: Role of 4-hydroxynonenal (4-HNE) and other bioactive lipids in mitochondria.

    Science.gov (United States)

    Xiao, Mengqing; Zhong, Huiqin; Xia, Lin; Tao, Yongzhen; Yin, Huiyong

    2017-10-01

    Mitochondrial lipids are essential for maintaining the integrity of mitochondrial membranes and the proper functions of mitochondria. As the "powerhouse" of a cell, mitochondria are also the major cellular source of reactive oxygen species (ROS). Oxidative stress occurs when the antioxidant system is overwhelmed by overproduction of ROS. Polyunsaturated fatty acids in mitochondrial membranes are primary targets for ROS attack, which may lead to lipid peroxidation (LPO) and generation of reactive lipids, such as 4-hydroxynonenal. When mitochondrial lipids are oxidized, the integrity and function of mitochondria may be compromised and this may eventually lead to mitochondrial dysfunction, which has been associated with many human diseases including cancer, cardiovascular diseases, diabetes, and neurodegenerative diseases. How mitochondrial lipids are oxidized and the underlying molecular mechanisms and pathophysiological consequences associated with mitochondrial LPO remain poorly defined. Oxidation of the mitochondria-specific phospholipid cardiolipin and generation of bioactive lipids through mitochondrial LPO has been increasingly recognized as an important event orchestrating apoptosis, metabolic reprogramming of energy production, mitophagy, and immune responses. In this review, we focus on the current understanding of how mitochondrial LPO and generation of bioactive lipid mediators in mitochondria are involved in the modulation of mitochondrial functions in the context of relevant human diseases associated with oxidative stress. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. The central importance of the EU emission trading scheme for achievement of the German climate protection target of 40% until 2020; Die zentrale Bedeutung des EU-Emissionshandels zur Erreichung des deutschen Klimaziels in Hoehe von 40 % bis 2020

    Energy Technology Data Exchange (ETDEWEB)

    Hermann, Hauke; Cludius, Johanna

    2014-02-15

    time, the ETS has faced structurally low allowance prices from 2012 on-wards because of a massive supply of EU emission allowances (EUA) and external emission reduction credits, which exceeds the demand significantly. The surplus amounted to 1.8 billion EUAs at the end of the second trading period (2008-2012), will reach approx. 2 billion EUAs in 2013 and remain at up to 2 billion EUAs until the end of the third trading period (2013-2020). This structural surplus has significant implications for the fulfilment of European and national targets. The present research project concludes that the current design of the ETS is not ambitious enough to meet the national 40% target. Germany will also not be able to reach this target if the structural reform of the ETS is not improved considerably. Without this revision, there is a gap of 10.7 % to meeting the target based on 1990 levels, meaning that Germany would achieve an emissions reduction target of 29.3% instead of 40% in 2020. A combination of three factors is responsible for this gap: - surplus allowances being carried over from the second trading period (6.2 % compared to 1990); - a relatively unambitious reduction factor throughout the third trading phase compared to what should be achieved in the ETS sectors under the 40% national target (3 % compared to 1990); - a lack of ambition in the sectors not covered by the EU ETS compared to what should be achieved in the non-ETS sectors under the 40% national target (1.5 % compared to 1990). To meet the 40 % target in Germany, structural measures for reforming the EU ETS are necessary before 2020. Between 1.8 and 2.3 billion EU emission allowances (EUAs) have to be taken off the market in the long term (long-term set-aside) to remove current surpluses (1.8 billion EUAs) and to compensate for the expected imports of external emission reduction credits (0.5 billion CERs and ERUs) allowed to enter the market before 2020. Furthermore, the linear reduction factor needs to be

  1. Hypocretin (orexin) biology and the pathophysiology of narcolepsy with cataplexy.

    Science.gov (United States)

    Liblau, Roland S; Vassalli, Anne; Seifinejad, Ali; Tafti, Mehdi

    2015-03-01

    The discovery of hypocretins (orexins) and their causal implication in narcolepsy is the most important advance in sleep research and sleep medicine since the discovery of rapid eye movement sleep. Narcolepsy with cataplexy is caused by hypocretin deficiency owing to destruction of most of the hypocretin-producing neurons in the hypothalamus. Ablation of hypocretin or hypocretin receptors also leads to narcolepsy phenotypes in animal models. Although the exact mechanism of hypocretin deficiency is unknown, evidence from the past 20 years strongly favours an immune-mediated or autoimmune attack, targeting specifically hypocretin neurons in genetically predisposed individuals. These neurons form an extensive network of projections throughout the brain and show activity linked to motivational behaviours. The hypothesis that a targeted immune-mediated or autoimmune attack causes the specific degeneration of hypocretin neurons arose mainly through the discovery of genetic associations, first with the HLA-DQB1*06:02 allele and then with the T-cell receptor α locus. Guided by these genetic findings and now awaiting experimental testing are models of the possible immune mechanisms by which a specific and localised brain cell population could become targeted by T-cell subsets. Great hopes for the identification of new targets for therapeutic intervention in narcolepsy also reside in the development of patient-derived induced pluripotent stem cell systems. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Pathophysiology of major depressive disorder: mechanisms involved in etiology are not associated with clinical progression.

    Science.gov (United States)

    Verduijn, J; Milaneschi, Y; Schoevers, R A; van Hemert, A M; Beekman, A T F; Penninx, B W J H

    2015-09-29

    Meta-analyses support the involvement of different pathophysiological mechanisms (inflammation, hypothalamic-pituitary (HPA)-axis, neurotrophic growth and vitamin D) in major depressive disorder (MDD). However, it remains unknown whether dysregulations in these mechanisms are more pronounced when MDD progresses toward multiple episodes and/or chronicity. We hypothesized that four central pathophysiological mechanisms of MDD are not only involved in etiology, but also associated with clinical disease progression. Therefore, we expected to find increasingly more dysregulation across consecutive stages of MDD progression. The sample from the Netherlands Study of Depression and Anxiety (18-65 years) consisted of 230 controls and 2333 participants assigned to a clinical staging model categorizing MDD in eight stages (0, 1A, 1B, 2, 3A, 3B, 3C and 4), from familial risk at MDD (stage 0) to chronic MDD (stage 4). Analyses of covariance examined whether pathophysiological mechanism markers (interleukin (IL)-6, C-reactive protein (CRP), cortisol, brain-derived neurotrophic factor and vitamin D) showed a linear trend across controls, those at risk for MDD (stages 0, 1A and 1B), and those with full-threshold MDD (stages 2, 3A, 3B, 3C and 4). Subsequently, pathophysiological differences across separate stages within those at risk and with full-threshold MDD were examined. A linear increase of inflammatory markers (CRP P=0.026; IL-6 P=0.090), cortisol (P=0.025) and decrease of vitamin D (P<0.001) was found across the entire sample (for example, from controls to those at risk and those with full-threshold MDD). Significant trends of dysregulations across stages were present in analyses focusing on at-risk individuals (IL-6 P=0.050; cortisol P=0.008; vitamin D P<0.001); however, no linear trends were found in dysregulations for any of the mechanisms across more progressive stages of full-threshold MDD. Our results support that the examined pathophysiological mechanisms are

  3. Importance measures

    International Nuclear Information System (INIS)

    Gomez Cobo, A.

    1997-01-01

    The presentation discusses the following: general concepts of importance measures; example fault tree, used to illustrate importance measures; Birnbaum's structural importance; criticality importance; Fussel-Vesely importance; upgrading function; risk achievement worth; risk reduction worth

  4. Pathophysiology of esophageal impairment due to button battery ingestion.

    Science.gov (United States)

    Völker, Johannes; Völker, Christine; Schendzielorz, Philipp; Schraven, Sebastian P; Radeloff, Andreas; Mlynski, Robert; Hagen, Rudolf; Rak, Kristen

    2017-09-01

    The increased use of button batteries with high energy densities in devices of daily life presents a high risk of injury, especially for toddlers and young children. If an accidental ingestion of a button battery occurs, this foreign body can become caught in the constrictions of the esophagus and cause serious damage to the adjacent tissue layers. The consequences can be ulcerations, perforations with fistula formation and damage to the surrounding anatomical structures. In order to gain a better understanding of the pathophysiology after ingestion, we carried out systematic studies on fresh preparations of porcine esophagi. The lithium button battery type CR2032, used most frequently in daily life, was exposed in preparations of porcine esophagi and incubated under the addition of artificial saliva at 37 °C. A total of eight esophagi were analysed by different methods. Measurements of the pH value around the battery electrodes and histological studies of the tissue damage were carried out after 0.5-24 h exposure time. In addition, macroscopic time-lapse images were recorded. Measurements of the battery voltage and the course of the electric current supplemented the experiments. The investigations showed that the batteries caused an electrolysis reaction in the moist environment. The positive electrode formed an acidic and the negative electrode a basic medium. Consequently, a coagulation necrosis at the positive pole, and a deep colliquation necrosis at the minus pole occurred. After an exposure time of 12 h, tissue damage caused by the lye corrosion was observed on the side of the negative electrode up to the lamina muscularis. The corrosion progressed up to the final exposure time of 24 h, but the batteries still had sufficient residual voltage, such that further advancing damage would be expected. Button battery ingestion in humans poses an acute life-threatening danger and immediate endoscopic removal of the foreign body is essential. After only 2

  5. Deaths during apprehensions of agitated persons. A review of proposed pathophysiological theories

    Directory of Open Access Journals (Sweden)

    Tamsen Fredrik

    2014-06-01

    Full Text Available The pathophysiology of sudden death during apprehension remains largely unclear. The most frequently discussed mechanisms are excited delirium, positional asphyxia, metabolic acidosis, acute and chronic drug abuse, and autonomic instability. As in most areas of forensic medicine, much of the knowledge comes from case reports, which are of little use in understanding causality. Experimental studies of some aspects have been performed, and they show somewhat divergent results and interpretations. The aim of this review is to summarize the different proposed theories, and to point out important issues for further research.

  6. A review of the pathophysiology, diagnosis, and management of allergic reactions in the dental office.

    Science.gov (United States)

    Rochford, Christopher; Milles, Maano

    2011-02-01

    Since more than 50 million people in the United States have allergies, knowledge of the management of allergic reactions in the dental office is extremely important. Appropriate care may range from a simple referral to a primary care physician to lifesaving measures implemented during acute anaphylactic reactions. The authors present a basic review of the pathophysiology of allergic reactions and provide information detailing the diagnosis and management of allergic reactions that may be encountered in the dental office. Utilizing this information, the dental practitioner and ancillary staff will have a thorough understanding of allergic reactions and be prepared to successfully identify and treat these reactions.

  7. Pathophysiological relationships between heart failure and depression and anxiety.

    Science.gov (United States)

    Chapa, Deborah W; Akintade, Bimbola; Son, Heesook; Woltz, Patricia; Hunt, Dennis; Friedmann, Erika; Hartung, Mary Kay; Thomas, Sue Ann

    2014-04-01

    Depression and anxiety are common comorbid conditions in patients with heart failure. Patients with heart failure and depression have increased mortality. The association of anxiety with increased mortality in patients with heart failure is not established. The purpose of this article is to illustrate the similarities of the underlying pathophysiology of heart failure, depression, and anxiety by using the Biopsychosocial Holistic Model of Cardiovascular Health. Depression and anxiety affect biological processes of cardiovascular function in patients with heart failure by altering neurohormonal function via activation of the hypothalamic-pituitary-adrenal axis, autonomic dysregulation, and activation of cytokine cascades and platelets. Patients with heart failure and depression or anxiety may exhibit a continued cycle of heart failure progression, increased depression, and increased anxiety. Understanding the underlying pathophysiological relationships in patients with heart failure who experience comorbid depression and/or anxiety is critical in order to implement appropriate treatments, educate patients and caregivers, and educate other health professionals.

  8. Different Pathophysiological Phenotypes among Newly Diagnosed Type 2 Diabetes Patients

    DEFF Research Database (Denmark)

    Stidsen, Jacob

    2013-01-01

    Type 2 diabetes (T2D) can be considered a syndrome with several different pathophysiological mechanisms leading to hyperglycemia. Nonetheless, T2D is treated according to algorithms as if it was one disease entity. Methods: We investigated the prevalence of different pathophysiological phenotypes...... or secondary diabetes), classic obesity-associated insulin resistant diabetes ( f-P-C-peptide >= 568 pmol/l) and a normoinsulinopenic group (333 age of our new T2D patients was 61 years (range 21-95 years), 57% were men. We found that 3.0% newly diagnosed T2D patients...... suffered from LADA, 3.9% from secondary diabetes, 6.0% from steroid induced diabetes 5.9% had insulinopenic diabetes, whereas 56.7% presented the classic obesity-associated insulin-resistant phenotype. 24.6% was classified as normoinsulinopenic patients. Conclusion: We conclude that newly diagnosed T2D...

  9. Pathophysiological analyses of leptomeningeal heterotopia using gyrencephalic mammals.

    Science.gov (United States)

    Matsumoto, Naoyuki; Kobayashi, Naoki; Uda, Natsu; Hirota, Miwako; Kawasaki, Hiroshi

    2018-03-15

    Leptomeningeal glioneuronal heterotopia (LGH) is a focal malformation of the cerebral cortex and frequently found in patients with thanatophoric dysplasia (TD). The pathophysiological mechanisms underlying LGH formation are still largely unclear because of difficulties in obtaining brain samples from human TD patients. Recently, we established a new animal model for analysing cortical malformations of human TD by utilizing our genetic manipulation technique for gyrencephalic carnivore ferrets. Here we investigated the pathophysiological mechanisms underlying the formation of LGH using our TD ferrets. We found that LGH was formed during corticogenesis in TD ferrets. Interestingly, we rarely found Ki-67-positive and phospho-histone H3-positive cells in LGH, suggesting that LGH formation does not involve cell proliferation. We uncovered that vimentin-positive radial glial fibers and doublecortin-positive migrating neurons were accumulated in LGH. This result may indicate that preferential cell migration into LGH underlies LGH formation. Our findings provide novel mechanistic insights into the pathogenesis of LGH in TD.

  10. The pathophysiology of arterial vasodilatation and hyperdynamic circulation in cirrhosis

    DEFF Research Database (Denmark)

    Møller, Søren; Bendtsen, Flemming

    2018-01-01

    transplantation and point to the pathophysiological significance of portal hypertension. In this paper we aimed to review current knowledge on the pathophysiology of arterial vasodilatation and the hyperdynamic circulation in cirrhosis. This article is protected by copyright. All rights reserved.......Patients with cirrhosis and portal hypertension often develop complications from a variety of organ systems leading to a multiple organ failure. The combination of liver failure and portal hypertension result in a hyperdynamic circulatory state partly owing to simultaneous splanchnic and peripheral...... arterial vasodilatation. Increases in circulatory vasodilators are believed to be due to portosystemic shunting and bacterial translocation leading to redistribution of the blood volume with central hypovolemia. Portal hypertension per se and increased splanchnic blood flow are mainly responsible...

  11. Gender Differences in Epidemiology, Pathophysiology, and Treatment of Hypertension.

    Science.gov (United States)

    Di Giosia, Paolo; Giorgini, Paolo; Stamerra, Cosimo Andrea; Petrarca, Marco; Ferri, Claudio; Sahebkar, Amirhossein

    2018-02-14

    This review aims to examine gender differences in both the epidemiology and pathophysiology of hypertension and to explore gender peculiarities on the effects of antihypertensive agents in decreasing BP and CV events. Men and women differ in prevalence, awareness, and control rate of hypertension in an age-dependent manner. Studies suggest that sex hormones changes play a pivotal role in the pathophysiology of hypertension in postmenopausal women. Estrogens influence the vascular system inducing vasodilatation, inhibiting vascular remodeling processes, and modulating the renin-angiotensin aldosterone system and the sympathetic system. This leads to a protective effect on arterial stiffness during reproductive age that is dramatically reversed after menopause. Data on the efficacy of antihypertensive therapy between genders are conflicting, and the underrepresentation of aged women in large clinical trials could influence the results. Therefore, further clinical research is needed to uncover potential gender differences in hypertension to promote the development of a gender-oriented approach to antihypertensive treatment.

  12. Abnormal function of monoamine oxidase-A in comorbid major depressive disorder and cardiovascular disease: pathophysiological and therapeutic implications (review).

    Science.gov (United States)

    Machado-Vieira, Rodrigo; Mallinger, Alan G

    2012-11-01

    The association between major depressive disorder (MDD) and cardiovascular disease (CVD) is among the best described medical comorbidities. The presence of MDD increases the risk of cardiac admissions and mortality and increases healthcare costs in patients with CVD, and similarly, CVD affects the course and outcome of MDD. The potential shared biological mechanisms involved in these comorbid conditions are not well known. However, the enzyme monoamine oxidase-A (MAO-A), which has a key role in the degradation of catecholamines, has been associated with the pathophysiology and therapeutics of both MDD and CVD. Increased MAO-A activity results in the dysregulation of downstream targets of this enzyme and thus affects the pathophysiology of the two diseases. These deleterious effects include altered noradrenaline turnover, with a direct elevation in oxidative stress parameters, as well as increased platelet activity and cytokine levels. These effects were shown to be reversed by MAO inhibitors. Here, a model describing a key role for the MAO-A in comorbid MDD and CVD is proposed, with focus on the shared pathophysiological mechanisms and the potential therapeutic relevance of agents targeting this enzyme.

  13. Migraine aura pathophysiology: the role of blood vessels and microembolisation

    OpenAIRE

    Dalkara, Turgay; Nozari, Ala; Moskowitz, Michael A

    2010-01-01

    Migraine attacks with auras are sometimes associated with underlying hereditary or acquired cerebrovascular disorders. A unifying pathophysiological explanation linking migraine to these conditions has been diffcult to identify. On the basis of genetic and epidemiological evidence, we suggest that changes in blood vessels, hypoperfusion disorders, and microembolisation can cause neurovascular dysfunction and evoke cortical spreading depression, an event that is widely thought to underlie aura...

  14. Pathophysiology of pelvic organ prolapse and stress urinary incontinence

    Directory of Open Access Journals (Sweden)

    Payal D Patel

    2006-01-01

    Full Text Available Although they may present with significant morbidity, pelvic organ prolapse and stress urinary incontinence are mainly afflicitions that affect quality of life. To appropiately treat these entities, comprehension of the various theories of pathophysiology is paramount. Utilizing a Medline search, this article reviews recent data concerning intrinsic (i.e., genetics, postmenopausal status and extrinsic factors (i.e., previous hysterectomy, childbirth leading to organ prolapse or stress incontinence

  15. Pathophysiology of Headaches with a Prominent Vascular Component

    Directory of Open Access Journals (Sweden)

    Juan A Pareja

    1996-01-01

    Full Text Available Vascular changes, whether preliminary or secondary, seem to accompany most headaches. The literature concerning pathophysiological mechanisms in headaches where vascular phenomena are a major, integral part, ie, migraine and cluster headache syndrome, is reviewed and the most common forms of headache associated with cerebrovascular disease are discussed. Emphasis is placed on the vascular phenomena and on the abundant hypotheses and theories regarding headache mechanisms. This review also presents alternative explanatory models, and compares the available anatomical, physiological and biochemical results.

  16. Pancreatitis in dogs and cats – definitions and pathophysiology

    OpenAIRE

    Watson, Penelope Jayne

    2014-01-01

    Pancreatitis, or inflammation of the pancreas, is commonly seen in dogs and cats and presents a spectrum of disease severities from acute to chronic and mild to severe. It is usually sterile, but the causes and pathophysiology remain poorly understood. The acute end of the disease spectrum is associated with a high mortality but the potential for complete recovery of organ structure and function if the animal survives. At the other end of the spectrum, chronic pancreatitis in either species c...

  17. Role of altered coagulation-fibrinolytic system in the pathophysiology of diabetic retinopathy.

    Science.gov (United States)

    Behl, Tapan; Velpandian, Thirumurthy; Kotwani, Anita

    2017-05-01

    The implications of altered coagulation-fibrinolytic system in the pathophysiology of several vascular disorders, such as stroke and myocardial infarction, have been well researched upon and established. However, its role in the progression of diabetic retinopathy has not been explored much. Since a decade, it is known that hyperglycemia is associated with a hypercoagulated state and the various impairments it causes are well acknowledged as independent risk factors for the development of cardiovascular diseases. But recent studies suggest that the hypercoagulative state and diminished fibrinolytic responses might also alter retinal homeostasis and induce several deleterious molecular changes in retinal cells which aggravate the already existing hyperglycemia-induced pathological conditions and thereby lead to the progression of diabetic retinopathy. The major mediators of coagulation-fibrinolytic system whose concentration or activity get altered during hyperglycemia include fibrinogen, antithrombin-III (AT-III), plasminogen activator inhibitor-1 (PAI-1) and von Willebrand factor (vWF). Inhibiting the pathways by which these altered mediators get involved in the pathophysiology of diabetic retinopathy can serve as potential targets for the development of an adjuvant novel alternative therapy for diabetic retinopathy. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Blended Learning Versus Traditional Lecture in Introductory Nursing Pathophysiology Courses.

    Science.gov (United States)

    Blissitt, Andrea Marie

    2016-04-01

    Currently, many undergraduate nursing courses use blended-learning course formats with success; however, little evidence exists that supports the use of blended formats in introductory pathophysiology courses. The purpose of this study was to compare the scores on pre- and posttests and course satisfaction between traditional and blended course formats in an introductory nursing pathophysiology course. This study used a quantitative, quasi-experimental, nonrandomized control group, pretest-posttest design. Analysis of covariance compared pre- and posttest scores, and a t test for independent samples compared students' reported course satisfaction of the traditional and blended course formats. Results indicated that the differences in posttest scores were not statistically significant between groups. Students in the traditional group reported statistically significantly higher satisfaction ratings than students in the blended group. The results of this study support the need for further research of using blended learning in introductory pathophysiology courses in undergraduate baccalaureate nursing programs. Further investigation into how satisfaction is affected by course formats is needed. Copyright 2016, SLACK Incorporated.

  19. Pathophysiological analyses of periventricular nodular heterotopia using gyrencephalic mammals.

    Science.gov (United States)

    Matsumoto, Naoyuki; Hoshiba, Yoshio; Morita, Kazuya; Uda, Natsu; Hirota, Miwako; Minamikawa, Maki; Ebisu, Haruka; Shinmyo, Yohei; Kawasaki, Hiroshi

    2017-03-15

    Although periventricular nodular heterotopia (PNH) is often found in the cerebral cortex of people with thanatophoric dysplasia (TD), the pathophysiology of PNH in TD is largely unknown. This is mainly because of difficulties in obtaining brain samples of TD patients and a lack of appropriate animal models for analyzing the pathophysiology of PNH in TD. Here we investigate the pathophysiological mechanisms of PNH in the cerebral cortex of TD by utilizing a ferret TD model which we recently developed. To make TD ferrets, we electroporated fibroblast growth factor 8 (FGF8) into the cerebral cortex of ferrets. Our immunohistochemical analyses showed that PNH nodules in the cerebral cortex of TD ferrets were mostly composed of cortical neurons, including upper layer neurons and GABAergic neurons. We also found disorganizations of radial glial fibers and of the ventricular lining in the TD ferret cortex, indicating that PNH may result from defects in radial migration of cortical neurons along radial glial fibers during development. Our findings provide novel mechanistic insights into the pathogenesis of PNH in TD. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  20. Tics and Tourette's: update on pathophysiology and tic control.

    Science.gov (United States)

    Ganos, Christos

    2016-08-01

    To describe recent advances in the pathophysiology of tics and Tourette syndrome, and novel insights on tic control. The cortico-basal ganglia-thalamo-cortical loops are implicated in generation of tics. Disruption of GABAergic inhibition lies at the core of tic pathophysiology, but novel animal models also implicate cholinergic and histaminergic neurotransmission. Tourette syndrome patients have altered awareness of volition and enhanced formation of habits. Premonitory urges are not the driving force behind all tics. The intensity of premonitory urges depends on patients' capacity to perceive interoceptive signals. The insular cortex is a key structure in this process. The trait intensity of premonitory urges is not a prerequisite of voluntary tic inhibition, a distinct form of motor control. Voluntary tic inhibition is most efficient in the body parts that tic the least. The prefrontal cortex is associated with the capacity to inhibit tics. The management of tics includes behavioral, pharmacological and surgical interventions. Treatment recommendations differ based on patients' age. The study of Tourette syndrome pathophysiology involves different neural disciplines and provides novel, exciting insights of brain function in health and disease. These in turn provide the basis for innovative treatment approaches of tics and their associations.

  1. Spasmodic Dysphonia: A Review. Part 2: Characterization of Pathophysiology.

    Science.gov (United States)

    Hintze, Justin M; Ludlow, Christy L; Bansberg, Stephen F; Adler, Charles H; Lott, David G

    2017-10-01

    Objective The purpose of this review is to describe the recent advances in characterizing spasmodic dysphonia. Spasmodic dysphonia is a task-specific focal laryngeal dystonia characterized by irregular and uncontrolled voice breaks. The pathophysiology is poorly understood, and there are diagnostic difficulties. Data Sources PubMed, Google Scholar, and Cochrane Library. Review Methods The data sources were searched using the following search terms: ( spasmodic dysphonia or laryngeal dystonia) and ( etiology, aetiology, diagnosis, pathogenesis, or pathophysiology). Conclusion The diagnosis of spasmodic dysphonia can be difficult due to the lack of a scientific consensus on diagnostic criteria and the fact that other voice disorders may present similarly. Confusion can arise between spasmodic dysphonia and muscle tension dysphonia. Spasmodic dysphonia symptoms are tied to particular speech sounds, whereas muscle tension dysphonia is not. With the advent of more widespread use of high-speed laryngoscopy and videokymography, measures of the disruptions in phonation and delays in the onset of vocal fold vibration after vocal fold closure can be quantified. Recent technological developments have expanded our understanding of the pathophysiology of spasmodic dysphonia. Implications for Practice A 3-tiered approach, involving a questionnaire, followed by speech assessment and nasolaryngoscopy is the most widely accepted method for making the diagnosis in most cases. More experimental and invasive techniques such as electromyography and neuroimaging have been explored to further characterize spasmodic dysphonia and aid in diagnosing difficult cases.

  2. Pancreatitis in dogs and cats: definitions and pathophysiology.

    Science.gov (United States)

    Watson, P

    2015-01-01

    Pancreatitis, or inflammation of the pancreas, is commonly seen in dogs and cats and presents a spectrum of disease severities from acute to chronic and mild to severe. It is usually sterile, but the causes and pathophysiology remain poorly understood. The acute end of the disease spectrum is associated with a high mortality but the potential for complete recovery of organ structure and function if the animal survives. At the other end of the spectrum, chronic pancreatitis in either species can cause refractory pain and reduce quality of life. It may also result in progressive exocrine and endocrine functional impairment. There is confusion in the veterinary literature about definitions of acute and chronic pancreatitis and there are very few studies on the pathophysiology of naturally occurring pancreatitis in dogs and cats. This article reviews histological and clinical definitions and current understanding of the pathophysiology and causes in small animals by comparison with the much more extensive literature in humans, and suggests many areas that need further study in dogs and cats. © 2015 British Small Animal Veterinary Association.

  3. The role of TGF-β in the pathophysiology of peritoneal endometriosis.

    Science.gov (United States)

    Young, Vicky J; Ahmad, S F; Duncan, W Colin; Horne, Andrew W

    2017-09-01

    Endometriosis is estimated to affect 6-10% of women of reproductive age and it is associated with chronic pelvic pain, dysmenorrhoea and subfertility. It is currently managed surgically or medically but symptoms recur in up to 75% of cases and available medical treatments have undesirable side effects. Endometriosis is defined as the presence of endometrial tissue outside the uterus with lesions typically found on the peritoneum. The aetiology of endometriosis is uncertain but there is increasing evidence that transforming growth factor (TGF)-β plays a major role. A descriptive review was undertaken of the published literature on the expression pattern of TGF-β ligands and signalling molecules in women with and without endometriosis, and on the potential roles of TGF-β signalling in the development and progression of peritoneal endometriosis. The current understanding of the TGF-β signalling pathway is summarized. We searched the Pubmed database using the terms 'transforming growth factor beta' and 'endometriosis' for studies published between 1995 and 2016. The initial search identified 99 studies and these were used as the basic material for this review. We also extended our remit for important older publications. In addition, we searched the reference lists of studies used in this review for additional studies we judged as relevant. Studies which were included in the review focused on peritoneal endometriosis only as increasing evidence suggests that ovarian and deep endometriosis may have a differing pathophysiology. Thus, a final 95 studies were included in the review. TGF-β1 is reported to be increased in the peritoneal fluid, serum, ectopic endometrium and peritoneum of women with endometriosis compared to women without endometriosis, and TGF-β1-null mice have reduced endometriosis lesion growth when compared to their wild-type controls. Studies in mice and women have indicated that increasing levels of TGF-β ligands are associated with decreased

  4. Role of hepcidin-ferroportin axis in the pathophysiology, diagnosis, and treatment of anemia of chronic inflammation.

    Science.gov (United States)

    Langer, Arielle L; Ginzburg, Yelena Z

    2017-06-01

    Anemia of chronic inflammation (ACI) is a frequently diagnosed anemia and portends an independently increased morbidity and poor outcome associated with multiple underlying diseases. The pathophysiology of ACI is multifactorial, resulting from the effects of inflammatory cytokines which both directly and indirectly suppress erythropoiesis. Recent advances in molecular understanding of iron metabolism provide strong evidence that immune mediators, such as IL-6, lead to hepcidin-induced hypoferremia, iron sequestration, and decreased iron availability for erythropoiesis. The role of hepcidin-ferroportin axis in the pathophysiology of ACI is stimulating the development of new diagnostics and targeted therapies. In this review, we present an overview of and rationale for inflammation-, iron-, and erythropoiesis-related strategies currently in development. © 2017 International Society for Hemodialysis.

  5. DMPD: Pathophysiological roles of interleukin-18 in inflammatory liver diseases. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 10807517 Pathophysiological roles of interleukin-18 in inflammatory liver diseases....l) Show Pathophysiological roles of interleukin-18 in inflammatory liver diseases. PubmedID 10807517 Title P...athophysiological roles of interleukin-18 in inflammatory liver diseases. Authors

  6. A mixed methods evaluation of team-based learning for applied pathophysiology in undergraduate nursing education.

    Science.gov (United States)

    Branney, Jonathan; Priego-Hernández, Jacqueline

    2018-02-01

    It is important for nurses to have a thorough understanding of the biosciences such as pathophysiology that underpin nursing care. These courses include content that can be difficult to learn. Team-based learning is emerging as a strategy for enhancing learning in nurse education due to the promotion of individual learning as well as learning in teams. In this study we sought to evaluate the use of team-based learning in the teaching of applied pathophysiology to undergraduate student nurses. A mixed methods observational study. In a year two, undergraduate nursing applied pathophysiology module circulatory shock was taught using Team-based Learning while all remaining topics were taught using traditional lectures. After the Team-based Learning intervention the students were invited to complete the Team-based Learning Student Assessment Instrument, which measures accountability, preference and satisfaction with Team-based Learning. Students were also invited to focus group discussions to gain a more thorough understanding of their experience with Team-based Learning. Exam scores for answers to questions based on Team-based Learning-taught material were compared with those from lecture-taught material. Of the 197 students enrolled on the module, 167 (85% response rate) returned the instrument, the results from which indicated a favourable experience with Team-based Learning. Most students reported higher accountability (93%) and satisfaction (92%) with Team-based Learning. Lectures that promoted active learning were viewed as an important feature of the university experience which may explain the 76% exhibiting a preference for Team-based Learning. Most students wanted to make a meaningful contribution so as not to let down their team and they saw a clear relevance between the Team-based Learning activities and their own experiences of teamwork in clinical practice. Exam scores on the question related to Team-based Learning-taught material were comparable to those

  7. Medical Management of Endometriosis: Emerging Evidence Linking Inflammation to Disease Pathophysiology

    Science.gov (United States)

    Bruner-Tran, Kaylon L.; Herington, Jennifer L.; Duleba, Antoni J.; Taylor, Hugh S.; Osteen, Kevin G.

    2013-01-01

    Progesterone action normally mediates the balance between anti-inflammatory and pro-inflammatory processes throughout the female reproductive tract. However, in women with endometriosis, endometrial progesterone resistance, characterized by alterations in progesterone responsive gene and protein expression, is now considered a central element in disease pathophysiology. Recent studies additionally suggest that the peritoneal microenvironment of endometriosis patients exhibits altered physiological characteristics that may further promote inflammation-driven disease development and progression. Within this review, we summarize our current understanding of the pathogenesis of endometriosis with an emphasis on the role that inflammation plays in generating not only the progesterone-resistant eutopic endometrium but also a peritoneal microenvironment that may contribute significantly to disease establishment. Viewing endometriosis from the emerging perspective that a progesterone resistant endometrium and an immunologically compromised peritoneal microenvironment are biologically linked risk factors for disease development provides a novel mechanistic framework to identify new therapeutic targets for appropriate medical management. PMID:23598784

  8. Scientific Statement on the Diagnostic Criteria, Epidemiology, Pathophysiology, and Molecular Genetics of Polycystic Ovary Syndrome

    Science.gov (United States)

    Dumesic, Daniel A.; Oberfield, Sharon E.; Stener-Victorin, Elisabet; Marshall, John C.; Laven, Joop S.

    2015-01-01

    Polycystic ovary syndrome (PCOS) is a heterogeneous and complex disorder that has both adverse reproductive and metabolic implications for affected women. However, there is generally poor understanding of its etiology. Varying expert-based diagnostic criteria utilize some combination of oligo-ovulation, hyperandrogenism, and the presence of polycystic ovaries. Criteria that require hyperandrogenism tend to identify a more severe reproductive and metabolic phenotype. The phenotype can vary by race and ethnicity, is difficult to define in the perimenarchal and perimenopausal period, and is exacerbated by obesity. The pathophysiology involves abnormal gonadotropin secretion from a reduced hypothalamic feedback response to circulating sex steroids, altered ovarian morphology and functional changes, and disordered insulin action in a variety of target tissues. PCOS clusters in families and both female and male relatives can show stigmata of the syndrome, including metabolic abnormalities. Genome-wide association studies have identified a number of candidate regions, although their role in contributing to PCOS is still largely unknown. PMID:26426951

  9. Changes in blood monocyte Toll-like receptor and serum surfactant protein A reveal a pathophysiological mechanism for community-acquired pneumonia in patients with type 2 diabetes.

    Science.gov (United States)

    Que, Y; Shen, X

    2016-02-01

    The lung is one of the target organs of microangiopathy in diabetes mellitus (DM); patients with type 2 diabetes mellitus (T2DM) are vulnerable to pneumonia, and a variety of pathophysiological mechanisms has been described. This study aimed to determine the pathophysiological mechanism of community-acquired pneumonia (CAP) in T2DM patients. A total of 90 individuals was included in this study comprised of three groups (n = 30): healthy control, T2DM and T2DM+ CAP groups. Toll-like receptor (TLR)2 and 4 protein and messenger RNA expression in peripheral blood monocytes(PBMC) was assessed by western blot and reverse transcription-polymerase chain reaction, respectively, and surfactant protein A (SP-A) levels were examined in serum samples by enzyme-linked immunosorbent assay. In T2DM and T2DM+CAP groups, levels of both TLR2/4 protein and mRNA in PBMC were decreased compared with controls (P <0.05), with lower levels observed in the T2DM+CAP group in comparison with T2DM patients (P <0.05). The serum SP-A levels in T2DM+CAP individuals were significantly higher than the values obtained for T2DM patients (P <0.05). It also showed apparent increases when compared with that in controls although no statistical significance was detected. In T2DM patients with pneumonia, TLR2/4 levels in PBMC and serum SP-A were altered, maybe playing an important role in the susceptibility to pneumonia in T2DM patients. © 2016 Royal Australasian College of Physicians.

  10. Polymeric particulate technologies for oral drug delivery and targeting: A pathophysiological perspective

    DEFF Research Database (Denmark)

    Hunter, A. Christy; Elsom, Jacqueline; Wibroe, Peter Popp

    2012-01-01

    Publication year: 2012 Source:Maturitas, Volume 73, Issue 1 A. Christy Hunter, Jacqueline Elsom, Peter P. Wibroe, S. Moein Moghimi The oral route for delivery of pharmaceuticals is the most widely used and accepted. Nanoparticles and microparticles are increasingly being applied within this arena....... It is the purpose of this review to describe these cutting edge technologies and specifically focus on the interaction and fate of these polymers within the gastrointestinal system....

  11. Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets.

    Science.gov (United States)

    Tham, Yow Keat; Bernardo, Bianca C; Ooi, Jenny Y Y; Weeks, Kate L; McMullen, Julie R

    2015-09-01

    The onset of heart failure is typically preceded by cardiac hypertrophy, a response of the heart to increased workload, a cardiac insult such as a heart attack or genetic mutation. Cardiac hypertrophy is usually characterized by an increase in cardiomyocyte size and thickening of ventricular walls. Initially, such growth is an adaptive response to maintain cardiac function; however, in settings of sustained stress and as time progresses, these changes become maladaptive and the heart ultimately fails. In this review, we discuss the key features of pathological cardiac hypertrophy and the numerous mediators that have been found to be involved in the pathogenesis of cardiac hypertrophy affecting gene transcription, calcium handling, protein synthesis, metabolism, autophagy, oxidative stress and inflammation. We also discuss new mediators including signaling proteins, microRNAs, long noncoding RNAs and new findings related to the role of calcineurin and calcium-/calmodulin-dependent protein kinases. We also highlight mediators and processes which contribute to the transition from adaptive cardiac remodeling to maladaptive remodeling and heart failure. Treatment strategies for heart failure commonly include diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers and β-blockers; however, mortality rates remain high. Here, we discuss new therapeutic approaches (e.g., RNA-based therapies, dietary supplementation, small molecules) either entering clinical trials or in preclinical development. Finally, we address the challenges that remain in translating these discoveries to new and approved therapies for heart failure.

  12. Stable coronary syndromes: pathophysiology, diagnostic advances and therapeutic need

    Science.gov (United States)

    Corcoran, David

    2018-01-01

    The diagnostic management of patients with angina pectoris typically centres on the detection of obstructive epicardial CAD, which aligns with evidence-based treatment options that include medical therapy and myocardial revascularisation. This clinical paradigm fails to account for the considerable proportion (approximately one-third) of patients with angina in whom obstructive CAD is excluded. This common scenario presents a diagnostic conundrum whereby angina occurs but there is no obstructive CAD (ischaemia and no obstructive coronary artery disease—INOCA). We review new insights into the pathophysiology of angina whereby myocardial ischaemia results from a deficient supply of oxygenated blood to the myocardium, due to various combinations of focal or diffuse epicardial disease (macrovascular), microvascular dysfunction or both. Macrovascular disease may be due to the presence of obstructive CAD secondary to atherosclerosis, or may be dynamic due to a functional disorder (eg, coronary artery spasm, myocardial bridging). Pathophysiology of coronary microvascular disease may involve anatomical abnormalities resulting in increased coronary resistance, or functional abnormalities resulting in abnormal vasomotor tone. We consider novel clinical diagnostic techniques enabling new insights into the causes of angina and appraise the need for improved therapeutic options for patients with INOCA. We conclude that the taxonomy of stable CAD could improve to better reflect the heterogeneous pathophysiology of the coronary circulation. We propose the term ‘stable coronary syndromes’ (SCS), which aligns with the well-established terminology for ‘acute coronary syndromes’. SCS subtends a clinically relevant classification that more fully encompasses the different diseases of the epicardial and microvascular coronary circulation. PMID:29030424

  13. Physiology and Pathophysiology in Ultra-Marathon Running

    Directory of Open Access Journals (Sweden)

    Beat Knechtle

    2018-06-01

    Full Text Available In this overview, we summarize the findings of the literature with regards to physiology and pathophysiology of ultra-marathon running. The number of ultra-marathon races and the number of official finishers considerably increased in the last decades especially due to the increased number of female and age-group runners. A typical ultra-marathoner is male, married, well-educated, and ~45 years old. Female ultra-marathoners account for ~20% of the total number of finishers. Ultra-marathoners are older and have a larger weekly training volume, but run more slowly during training compared to marathoners. Previous experience (e.g., number of finishes in ultra-marathon races and personal best marathon time is the most important predictor variable for a successful ultra-marathon performance followed by specific anthropometric (e.g., low body mass index, BMI, and low body fat and training (e.g., high volume and running speed during training characteristics. Women are slower than men, but the sex difference in performance decreased in recent years to ~10–20% depending upon the length of the ultra-marathon. The fastest ultra-marathon race times are generally achieved at the age of 35–45 years or older for both women and men, and the age of peak performance increases with increasing race distance or duration. An ultra-marathon leads to an energy deficit resulting in a reduction of both body fat and skeletal muscle mass. An ultra-marathon in combination with other risk factors, such as extreme weather conditions (either heat or cold or the country where the race is held, can lead to exercise-associated hyponatremia. An ultra-marathon can also lead to changes in biomarkers indicating a pathological process in specific organs or organ systems such as skeletal muscles, heart, liver, kidney, immune and endocrine system. These changes are usually temporary, depending on intensity and duration of the performance, and usually normalize after the race. In

  14. The odontoid process invagination in normal subjects, Chiari malformation and Basilar invagination patients: Pathophysiologic correlations with angular craniometry

    OpenAIRE

    Ferreira, J?nio A.; Botelho, Ricardo V.

    2015-01-01

    Background: Craniometric studies have shown that both Chiari malformation (CM) and basilar invagination (BI) belong to a spectrum of malformations. A more precise method to differentiate between these types of CVJM is desirable. The Chamberlain′s line violation (CLV) is the most common method to identify BI. The authors sought to clarify the real importance of CLV in the spectrum of craniovertebral junction malformations (CVJM) and to identify possible pathophysiological relationships. Me...

  15. Bone pain induced by metastatic cancer: pathophysiology and treatment

    International Nuclear Information System (INIS)

    Salas-Herrera, Isaias; Huertas-Gabert, Luis Carlos

    2004-01-01

    Cancer patients who develop bone metastases are an estimated 60 to 84% . Of these 79% experienced pain syndromes are difficult to manage, of which 50% die without adequate pain relief and with a poor quality of life. Therefore, it is necessary to have accessible and effective medications for the management of this condition. The pathophysiology of pain in bone is reviewed and the drugs used most frequently in the management of this type of cancer pain are described. Furthermore an algorithm of 6 steps is presented and can guide the physician when making a therapeutic decision. (author) [es

  16. The pathophysiology of the nodular and micronodular small bowel fold

    International Nuclear Information System (INIS)

    Olmsted, W.W.; Ros, P.R.; Moser, R.P.; Shekita, K.M.; Lichtenstein, J.E.

    1986-01-01

    The normal small bowel fold is easily seen on conventional studies of the small intestine, but visualization of the small bowel villus is at the limit of resolution of current roentgenographic technique. When the villi are enlarged, they appear radiographically as an irregularity or micronodularity of the small bowel fold. The anatomy of the fold and the pathophysiology of diseases producing fold nodularity (tumor,inflammatory disease, NLH, mastocytosis) and micronodularity (lymphangiectasia, Waldenstrom macroglobulinemia, Whipple disease) are presented, with an emphasis on radiologic-pathologic correlation. The radiologist should suggest certain diseases or conditions based on the roentgenographic characteristics of the closely analyzed small bowel fold

  17. Pathophysiology of the nodular and micronodular small bowel fold

    International Nuclear Information System (INIS)

    Olmstead, W.W.; Ros, P.R.; Moser, R.P.; Shekitka, K.M.; Lichtenstein, J.E.; Buck, J.L.

    1987-01-01

    The normal small bowel fold is easily seen on conventional studies of the small intestine, but visualization of the small bowel villus is just at the resolution of current roentgenographic technique. When the villi are enlarged, they can be seen radiographically as an irregularity or micronodularity of the small bowel fold. The anatomy of the fold and the pathophysiology of diseases producing fold nodularity (tumor, inflammatory disease, NLH, mastocytosis) and micronodularity (lymphangiectasia, Waldenstrom macroglobulinemia, Whipple disease) are presented, with an emphasis on radiologic-pathologic correlation. The radiologist should suggest certain diseases or conditions based on the roentgenographic characteristics of the closely analyzed small bowel fold

  18. Obesity and Pulmonary Hypertension: A Review of Pathophysiologic Mechanisms

    Directory of Open Access Journals (Sweden)

    Scott E. Friedman

    2012-01-01

    Full Text Available Pulmonary hypertension (PH is a potentially life-threatening condition arising from a wide variety of pathophysiologic mechanisms. Effective treatment requires a systematic diagnostic approach to identify all reversible mechanisms. Many of these mechanisms are relevant to those afflicted with obesity. The unique mechanisms of PH in the obese include obstructive sleep apnea, obesity hypoventilation syndrome, anorexigen use, cardiomyopathy of obesity, and pulmonary thromboembolic disease. Novel mechanisms of PH in the obese include endothelial dysfunction and hyperuricemia. A wide range of effective therapies exist to mitigate the disability of PH in the obese.

  19. Oral submucous fibrosis: An update on pathophysiology of malignant transformation.

    Science.gov (United States)

    Arakeri, Gururaj; Patil, Shekar Gowda; Aljabab, Abdulsalam S; Lin, Kuan-Chou; Merkx, M A W; Gao, Shan; Brennan, Peter A

    2017-07-01

    Oral submucous fibrosis (OSMF) is a potentially malignant condition associated with areca nut chewing. Formerly confined to the Indian subcontinent, it is now often seen in Asian populations of the United Kingdom, USA and other developed countries, and is therefore a serious problem for global health. What makes it more sinister is the malignant transformation rate, which has been reported to be around 7.6% over a 17-year period. In this concise article, we review the current trends in the pathophysiology of malignant transformation of OSMF. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. The pathophysiology of the trigeminal autonomic cephalalgias, with clinical implications

    DEFF Research Database (Denmark)

    Barloese, Mads C J

    2018-01-01

    , it is obvious that this brainstem reflex is regulated by higher centers that seemingly play a pivotal role in the attacks and the wide range of other symptoms indicating a homeostatic disturbance. These symptoms, as well as a number of well-validated findings, implicate the hypothalamus in the pathophysiology....... over the course of the past 2-3 decades, novel therapies and technological advances have helped increase our knowledge of these clinical syndromes, and will likely continue to do so in the coming years as we witness the arrival of new drugs and neurostimulation options. In this review, the clinical...

  1. Pathophysiological Mechanisms of Laser Correction in Critical Conditions

    Directory of Open Access Journals (Sweden)

    V. L. Kozhura

    2006-01-01

    Full Text Available The paper provides the generalized results of studies dealing with the use of low-intensive laser irradiation in blood loss-induced critical conditions in an experiment and in patients with severe mechanical injury. In the light of recent data and the data available in the literature, the authors consider some pathophysiological mechanisms of action of laser radiation at all living matter organization levels: molecular, cellular, organ, and systemic. The feasibilities of laser correction of hemostastic disorders are defined in relation to the volume of blood loss and the functional state of compensatory systems. 

  2. Macrophages and Their Role in Atherosclerosis: Pathophysiology and Transcriptome Analysis

    Directory of Open Access Journals (Sweden)

    Yuri V. Bobryshev

    2016-01-01

    Full Text Available Atherosclerosis can be regarded as a chronic inflammatory state, in which macrophages play different and important roles. Phagocytic proinflammatory cells populate growing atherosclerotic lesions, where they actively participate in cholesterol accumulation. Moreover, macrophages promote formation of complicated and unstable plaques by maintaining proinflammatory microenvironment. At the same time, anti-inflammatory macrophages contribute to tissue repair and remodelling and plaque stabilization. Macrophages therefore represent attractive targets for development of antiatherosclerotic therapy, which can aim to reduce monocyte recruitment to the lesion site, inhibit proinflammatory macrophages, or stimulate anti-inflammatory responses and cholesterol efflux. More studies are needed, however, to create a comprehensive classification of different macrophage phenotypes and to define their roles in the pathogenesis of atherosclerosis. In this review, we provide an overview of the current knowledge on macrophage diversity, activation, and plasticity in atherosclerosis and describe macrophage-based cellular tests for evaluation of potential antiatherosclerotic substances.

  3. Translational systems biology: introduction of an engineering approach to the pathophysiology of the burn patient.

    Science.gov (United States)

    An, Gary; Faeder, James; Vodovotz, Yoram

    2008-01-01

    The pathophysiology of the burn patient manifests the full spectrum of the complexity of the inflammatory response. In the acute phase, inflammation may have negative effects via capillary leak, the propagation of inhalation injury, and development of multiple organ failure. Attempts to mediate these processes remain a central subject of burn care research. Conversely, inflammation is a necessary prologue and component in the later stage processes of wound healing. Despite the volume of information concerning the cellular and molecular processes involved in inflammation, there exists a significant gap between the knowledge of mechanistic pathophysiology and the development of effective clinical therapeutic regimens. Translational systems biology (TSB) is the application of dynamic mathematical modeling and certain engineering principles to biological systems to integrate mechanism with phenomenon and, importantly, to revise clinical practice. This study will review the existing applications of TSB in the areas of inflammation and wound healing, relate them to specific areas of interest to the burn community, and present an integrated framework that links TSB with traditional burn research.

  4. Potential Role of Extracellular Vesicles in the Pathophysiology of Drug Addiction.

    Science.gov (United States)

    Rao, P S S; O'Connell, Kelly; Finnerty, Thomas Kyle

    2018-01-23

    Extracellular vesicles (EVs) are small vesicles secreted by cells and are known to carry sub-cellular components including microRNA, proteins, and lipids. Due to their ability to transport cargo between cells, EVs have been identified as important regulators of various pathophysiological conditions and can therefore influence treatment outcomes. In particular, the significance of microRNAs in EV-mediated cell-cell communication is well-documented. While the influence of EVs and the cargo delivered by EVs has been extensively reviewed in other neurological disorders, the available literature on the potential role of EVs in the pathophysiology of drug addiction has not been reviewed. Hence, in this article, the known effects of commonly abused drugs (ethanol, nicotine, opiates, cocaine, and cannabinoids) on EV secretion have been reviewed. In addition, the potential role of drugs of abuse in affecting the delivery of EV-packaged microRNAs, and the subsequent impact on neuronal health and continued drug dependence, has been discussed.

  5. Reevaluation of the Thyroid Scan for the Assessment of Pathophysiologic Status of Thyroid Disease

    International Nuclear Information System (INIS)

    Woo, In Sook; Nah, Jung Il; Kim, Deog Yoon

    1991-01-01

    To diagnosis and understand the pathophysiologic status of thyroid disease, not only hormonal measurements but also thyroid scan is believed to have a unique role. Especially in the cases of the change of the thyroid function by thyroiditis, it is emphasized that thyroid scan can be helpful in differential diagnosis, Discordant results of thyroid hormone levels and thyroid scan are found in transient hyperthyroidism, or in transient hypothyroidism. We analysed and reevaluated thyroid scan to look at the importance of thyroid scan. The results are summarised as follows: 1) 80%. of hyperthyroid patients had hyperthyroidism increased RAIU with even density, they are compatible with Graves' disease. 2) 2.1% of hyperthyroid patients had normal or decreased RAIU, which are classified as high iodine turn over genuine hyperthyroidism. 3) 8.5% of hyperthyroid patients had markedly decreased RAIU at both 2 hour and 24 hour, whose pathologic processes are suggested to be heterogenous namely subacute thyroiditis, postpartum thyroiditis, Hashimoto's thyroiditis, and pamless thyroiditis. 4) 45% of hypothyroid patients had increased 24 hr RAIU, 30% of hypothyroid patients were normal, 25%, decreased. In conclusion, thyroid scan should be reevaluated its useful role to asses the pathophysiologic status of thyroid disease. Especially in cases of transient thyrotoxicosis, thyroid scan is essential to diagnose and follow up the disease process.

  6. Digestive system-related pathophysiological symptoms of Sasang typology: Systematic review.

    Science.gov (United States)

    Lee, Mi Suk; Sohn, Kyungwoo; Kim, Yun Hee; Hwang, Min-Woo; Kwon, Young Kyu; Bae, Na Young; Chae, Han

    2013-06-01

    The purpose of this study was to review clinical studies on digestive system-related pathophysiological symptoms of each Sasang type to obtain the generalizable typespecific clinical features, which are important for the diagnosis of the Sasang type and subsequent disease treatment. Sasang typology and digestive system symptom-related keywords were used to search through eight domestic and foreign databases up to March 2012. The results were organized and analyzed based on four categories [digestive function, appetite, eating pattern, and body mass index (BMI)] to elucidate type-specific symptoms. Sasang type-specific digestive system-related symptoms were identified by reviewing 30 related articles that were gathered by searching through the databases. The Tae-Eum (TE) type had the highest digestive functions and the So-Eum (SE) type had the lowest. The TE type appeared to have larger volume with fast eating speed compared with the SE type and individuals in the TE category preferred fatty or salty food, which is responsible for the high occurrence rates of organic digestive diseases such as gastritis. Moreover, BMI was higher in the TE type and lower in the SE type. We systematically reviewed previously published clinical reports on digestive functions, which can be used to meet the objective of Sasang-type differentiation and pathophysiological pattern identification.

  7. Digestive system-related pathophysiological symptoms of Sasang typology: Systematic review

    Directory of Open Access Journals (Sweden)

    Mi Suk Lee

    2013-06-01

    Full Text Available The purpose of this study was to review clinical studies on digestive system-related pathophysiological symptoms of each Sasang type to obtain the generalizable typespecific clinical features, which are important for the diagnosis of the Sasang type and subsequent disease treatment. Sasang typology and digestive system symptom-related keywords were used to search through eight domestic and foreign databases up to March 2012. The results were organized and analyzed based on four categories [digestive function, appetite, eating pattern, and body mass index (BMI] to elucidate type-specific symptoms. Sasang type-specific digestive system-related symptoms were identified by reviewing 30 related articles that were gathered by searching through the databases. The Tae-Eum (TE type had the highest digestive functions and the So-Eum (SE type had the lowest. The TE type appeared to have larger volume with fast eating speed compared with the SE type and individuals in the TE category preferred fatty or salty food, which is responsible for the high occurrence rates of organic digestive diseases such as gastritis. Moreover, BMI was higher in the TE type and lower in the SE type. We systematically reviewed previously published clinical reports on digestive functions, which can be used to meet the objective of Sasang-type differentiation and pathophysiological pattern identification.

  8. Reevaluation of the Thyroid Scan for the Assessment of Pathophysiologic Status of Thyroid Disease

    Energy Technology Data Exchange (ETDEWEB)

    Woo, In Sook; Nah, Jung Il; Kim, Deog Yoon [Kyunghee University College of Medicine, Seoul (Korea, Republic of)

    1991-03-15

    To diagnosis and understand the pathophysiologic status of thyroid disease, not only hormonal measurements but also thyroid scan is believed to have a unique role. Especially in the cases of the change of the thyroid function by thyroiditis, it is emphasized that thyroid scan can be helpful in differential diagnosis, Discordant results of thyroid hormone levels and thyroid scan are found in transient hyperthyroidism, or in transient hypothyroidism. We analysed and reevaluated thyroid scan to look at the importance of thyroid scan. The results are summarised as follows: 1) 80%. of hyperthyroid patients had hyperthyroidism increased RAIU with even density, they are compatible with Graves' disease. 2) 2.1% of hyperthyroid patients had normal or decreased RAIU, which are classified as high iodine turn over genuine hyperthyroidism. 3) 8.5% of hyperthyroid patients had markedly decreased RAIU at both 2 hour and 24 hour, whose pathologic processes are suggested to be heterogenous namely subacute thyroiditis, postpartum thyroiditis, Hashimoto's thyroiditis, and pamless thyroiditis. 4) 45% of hypothyroid patients had increased 24 hr RAIU, 30% of hypothyroid patients were normal, 25%, decreased. In conclusion, thyroid scan should be reevaluated its useful role to asses the pathophysiologic status of thyroid disease. Especially in cases of transient thyrotoxicosis, thyroid scan is essential to diagnose and follow up the disease process.

  9. The hypertension of Cushing's syndrome: controversies in the pathophysiology and focus on cardiovascular complications

    Science.gov (United States)

    Isidori, Andrea M.; Graziadio, Chiara; Paragliola, Rosa Maria; Cozzolino, Alessia; Ambrogio, Alberto G.; Colao, Annamaria; Corsello, Salvatore M.; Pivonello, Rosario

    2015-01-01

    Cushing's syndrome is associated with increased mortality, mainly due to cardiovascular complications, which are sustained by the common development of systemic arterial hypertension and metabolic syndrome, which partially persist after the disease remission. Cardiovascular diseases and hypertension associated with endogenous hypercortisolism reveal underexplored peculiarities. The use of exogenous corticosteroids also impacts on hypertension and cardiovascular system, especially after prolonged treatment. The mechanisms involved in the development of hypertension differ, whether glucocorticoid excess is acute or chronic, and the source endogenous or exogenous, introducing inconsistencies among published studies. The pleiotropic effects of glucocorticoids and the overlap of the several regulatory mechanisms controlling blood pressure suggest that a rigorous comparison of in-vivo and in-vitro studies is necessary to draw reliable conclusions. This review, developed during the first ‘Altogether to Beat Cushing's syndrome’ workshop held in Capri in 2012, evaluates the most important peculiarities of hypertension associated with CS, with a particular focus on its pathophysiology. A critical appraisal of most significant animal and human studies is compared with a systematic review of the few available clinical trials. A special attention is dedicated to the description of the clinical features and cardiovascular damage secondary to glucocorticoid excess. On the basis of the consensus reached during the workshop, a pathophysiology-oriented therapeutic algorithm has been developed and it could serve as a first attempt to rationalize the treatment of hypertension in Cushing's syndrome. PMID:25415766

  10. Pathophysiology of visual disorders induced by phosphodiesterase inhibitors in the treatment of erectile dysfunction

    Directory of Open Access Journals (Sweden)

    Moschos MM

    2016-10-01

    Full Text Available Marilita M Moschos, Eirini Nitoda 1st Department of Ophthalmology, Medical School, National & Kapodistrian University of Athens, Athens, Greece Aim: The aim of this review was to summarize the ocular action of the most common phosphodiesterase (PDE inhibitors used for the treatment of erectile dysfunction and the subsequent visual disorders.Method: This is a literature review of several important articles focusing on the pathophysiology of visual disorders induced by PDE inhibitors.Results: PDE inhibitors have been associated with ocular side effects, including changes in color vision and light perception, blurred vision, transient alterations in electroretinogram (ERG, conjunctival hyperemia, ocular pain, and photophobia. Sildenafil and tadalafil may induce reversible increase in intraocular pressure and be involved in the development of nonarteritic ischemic optic neuropathy. Reversible idiopathic serous macular detachment, central serous chorioretinopathy, and ERG disturbances have been related to the significant impact of sildenafil and tadalafil on retinal perfusion.Discussion: So far, PDE inhibitors do not seem to cause permanent toxic effects on chorioretinal tissue and photoreceptors. However, physicians should write down any visual symptom observed during PDE treatment and refer the patients to ophthalmologists. Keywords: erectile dysfunction, pathophysiological mechanisms, phosphodiesterase inhibitors, PDE5, visual disorders

  11. Basophils activated via TLR signaling may contribute to pathophysiology of type 1 autoimmune pancreatitis.

    Science.gov (United States)

    Yanagawa, Masato; Uchida, Kazushige; Ando, Yugo; Tomiyama, Takashi; Yamaguchi, Takashi; Ikeura, Tsukasa; Fukui, Toshiro; Nishio, Akiyoshi; Uemura, Yoshiko; Miyara, Takayuki; Okamoto, Hiroyuki; Satoi, Souhei; Okazaki, Kazuichi

    2018-03-01

    Pathophysiology of type 1 autoimmune pancreatitis (AIP) is still unclear. We previously reported that M2 macrophages might play an important role in type 1 AIP. Recently, it has been reported that basophils regulate differentiation to M2 macrophages. In this study, we investigated basophils from the pancreatic tissue and peripheral blood of individuals with type 1 AIP. By using immunohistochemistry, we investigated basophils in pancreatic tissue from 13 patients with type 1 AIP and examined expression of toll-like receptors (TLRs) by these cells. Additionally, we obtained peripheral blood samples from 27 healthy subjects, 40 patients with type 1 AIP, 8 patients with alcoholic chronic pancreatitis, 10 patients with bronchial asthma, and 10 patients with atopic dermatitis, and analyzed activation of basophils by stimulating them with ligands of TLR1-9. We also compared TLR expression in basophils from the tissue and blood samples. Basophils were detected in pancreatic tissues from 10 of 13 patients with type 1 AIP. Flow cytometric analysis revealed that the ratios of basophils activated by TLR4 stimulation in type 1 AIP (9.875 ± 1.148%) and atopic dermatitis (11.768 ± 1.899%) were significantly higher than those in healthy subjects (5.051 ± 0.730%; P pathophysiology of type 1 AIP.

  12. Ophthalmologic Disease in HIV Infection: Recent Changes in Pathophysiology and Treatment.

    Science.gov (United States)

    Stewart, Michael W

    2017-10-19

    Ophthalmologic conditions were among the earliest described findings in patients with the acquired immunodeficiency syndrome (AIDS). The purpose of this review is to highlight recent changes in the pathophysiology and management of ophthalmologic conditions in patients infected with the human immunodeficiency virus (HIV). The introduction of highly active antiretroviral therapy (HAART) in 1996 changed ophthalmologic findings from predominantly acute infectious diseases to chronic, slowly progressive, debilitating conditions. HIV-associated neuroretinal disorder infrequently leads to blindness, but it causes visual disability in a large percentage of patients. Cytomegalovirus retinitis is now seen less commonly in the USA, but it remains an important cause of blindness in HIV-infected patients from developing countries. Immune recovery uveitis has emerged as a major cause of visual disability in the USA. As HIV has become a chronic disease, visual disability due to chronic noninfectious diseases have become increasingly important.

  13. Jaundice associated pruritis: a review of pathophysiology and treatment.

    Science.gov (United States)

    Bassari, Ramez; Koea, Jonathan B

    2015-02-07

    To review the underlying pathophysiology and currently available treatments for pruritis associated with jaundice. English language literature was reviewed using MEDLINE, PubMed, EMBASE and clinicaltrials.gov for papers and trails addressing the pathophysiology and potential treatments for pruritis associated with jaundice. Recent advances in the understanding of the peripheral anatomy of itch transmission have defined a histamine stimulated pathway and a cowhage stimulated pathway with sensation conveyed centrally via the contralateral spinothalamic tract. Centrally, cowhage and histamine stimulated neurons terminate widely within the thalamus and sensorimotor cortex. The causative factors for itch in jaundice have not been clarified although endogenous opioids, serotonin, steroid and lysophosphatidic acid all play a role. Current guidelines for the treatment of itching in jaundice recommend initial management with biliary drainage where possible and medical management with ursodeoxycholic acid, followed by cholestyramine, rifampicin, naltrexone and sertraline. Other than biliary drainage no single treatment has proved universally effective. Pruritis associated with jaundice is a common but poorly understood condition for which biliary drainage is the most effective therapy. Pharmacological therapy has advanced but remains variably effective.

  14. Pathophysiology of increased intestinal permeability in obstructive jaundice

    Science.gov (United States)

    Assimakopoulos, Stelios F; Scopa, Chrisoula D; Vagianos, Constantine E

    2007-01-01

    Despite advances in preoperative evaluation and postoperative care, intervention, especially surgery, for relief of obstructive jaundice still carries high morbidity and mortality rates, mainly due to sepsis and renal dysfunction. The key event in the pathophysiology of obstructive jaundice-associated complications is endotoxemia of gut origin because of intestinal barrier failure. This breakage of the gut barrier in obstructive jaundice is multi-factorial, involving disruption of the immunologic, biological and mechanical barrier. Experimental and clinical studies have shown that obstructive jaundice results in increased intestinal permeability. The mechanisms implicated in this phenomenon remain unresolved, but growing research interest during the last decade has shed light in our knowledge in the field. This review summarizes the current concepts in the pathophysiology of obstructive jaundice-induced gut barrier dysfunction, analyzing pivotal factors, such as altered intestinal tight junctions expression, oxidative stress and imbalance of enterocyte proliferation and apoptosis. Clinicians handling patients with obstructive jaundice should not neglect protecting the intestinal barrier function before, during and after intervention for the relief of this condition, which may improve their patients’ outcome. PMID:18161914

  15. Transcranial magnetic stimulation and sleep disorders: pathophysiologic insights.

    Science.gov (United States)

    Nardone, Raffaele; Höller, Yvonne; Brigo, Francesco; Tezzon, Frediano; Golaszewski, Stefan; Trinka, Eugen

    2013-11-01

    The neural mechanisms underlying the development of the most common intrinsic sleep disorders are not completely known. Therefore, there is a great need for noninvasive tools which can be used to better understand the pathophysiology of these diseases. Transcranial magnetic stimulation (TMS) offers a method to noninvasively investigate the functional integrity of the motor cortex and its corticospinal projections in neurologic and psychiatric diseases. To date, TMS studies have revealed cortical and corticospinal dysfunction in several sleep disorders, with cortical hyperexcitability being a characteristic feature in some disorders (i.e., the restless legs syndrome) and cortical hypoexcitability being a well-established finding in others (i.e., obstructive sleep apnea syndrome narcolepsy). Several research groups also have applied TMS to evaluate the effects of pharmacologic agents, such as dopaminergic agent or wake-promoting substances. Our review will focus on the mechanisms underlying the generation of abnormal TMS measures in the different types of sleep disorders, the contribution of TMS in enhancing the understanding of their pathophysiology, and the potential diagnostic utility of TMS techniques. We also briefly discussed the possible future implications for improving therapeutic approaches. Copyright © 2013 Elsevier B.V. All rights reserved.

  16. Postoperative ileus: Recent developments in pathophysiology and management.

    Science.gov (United States)

    Bragg, Damian; El-Sharkawy, Ahmed M; Psaltis, Emmanouil; Maxwell-Armstrong, Charles A; Lobo, Dileep N

    2015-06-01

    Postoperative ileus (POI) is a frequent occurrence after abdominal and other types of surgery, and is associated with significant morbidity and costs to health care providers. The aims of this narrative review were to provide an update of classification systems, preventive techniques, pathophysiological mechanisms, and treatment options for established POI. The Web of Science, MEDLINE, PubMed and Google Scholar databases were searched using the key phrases 'ileus', 'postoperative ileus' and 'definition', for relevant studies published in English from January 1997 to August 2014. POI is still a problematic and frequent complication of surgery. Fluid overload, exogenous opioids, neurohormonal dysfunction, and gastrointestinal stretch and inflammation are key mechanisms in the pathophysiology of POI. Evidence is supportive of thoracic epidural analgesia, avoidance of salt and water overload, alvimopan and gum chewing as measures for the prevention of POI, and should be incorporated into perioperative care protocols. Minimal access surgery and avoidance of nasogastric tubes may also help. Novel strategies are emerging, but further studies are required for the treatment of prolonged POI, where evidence is still lacking. Although POI is often inevitable, methods to reduce its duration and facilitate recovery of postoperative gastrointestinal function are evolving rapidly. Utilisation of standardised diagnostic classification systems will help improve applicability of future studies. Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  17. Air leak after lung resection: pathophysiology and patients' implications.

    Science.gov (United States)

    Pompili, Cecilia; Miserocchi, Giuseppe

    2016-02-01

    Protocols for the management of air leaks are critical aspects in the postoperative course of patients following lung resections. Many investigations in the last decade are focusing on the chest tube modalities or preventative measures, however, little is known about the pathophysiology of air leak and the patient perception of this common complication. This review concentrates on understanding the reasons why a pulmonary parenchyma may start to leak or an air leak may be longer than others. Experimental works support the notion that lung overdistension may favor air leak. These studies may represent the basis of future investigations. Furthermore, the standardization of nomenclature in the field of pleural space management and the creation of novel air leak scoring systems have contributed to improve the knowledge among thoracic surgeons and facilitate the organization of trials on this matter. We tried to summarize available evidences about the patient perception of a prolonged air leak and about what would be useful for them in order to prevent worsening of their quality of life. Future investigations are warranted to better understand the pathophysiologic mechanisms responsible of prolonged air leak in order to define tailored treatments and protocols. Improving the care at home with web-based telemonitoring or real time connected chest drainage may in a future improve the quality of life of the patients experience this complication and also enhance hospital finances.

  18. Does vasoactive intestinal polypeptide mediate the pathophysiology of bowel obstruction?

    Science.gov (United States)

    Basson, M D; Fielding, L P; Bilchik, A J; Zucker, K A; Ballantyne, G H; Sussman, J; Adrian, T E; Modlin, I M

    1989-01-01

    We hypothesized that bioactive peptides might be released into the portal circulation and mediate pathophysiologic alterations accompanying small bowel obstruction. We studied this question in a subacute canine small bowel obstruction model using 50 percent diameter occlusion. Control animals underwent sham laparotomy. Vasoactive intestinal peptide (VIP), peptide YY, and gastrin were measured in portal and systemic plasma by specific radioimmunoassays at 24-hour intervals as the obstruction progressed to completion over 5 days. All peptides in both groups demonstrated portal and peripheral gradients. In control dogs, peptide concentrations did not change postoperatively but VIP increased markedly in obstructed dogs, demonstrating a median portal level of 95 pmol/liter at 96 hours compared with 31.5 pmol/liter in control animals. These portal VIP levels are known to cause hypersecretion and splanchnic vasodilation in experimental models. The release of vasoactive compounds such as VIP may mediate local pathophysiology in human small bowel obstruction. A similar explanation of the systemic effects is consistent with the known cardiopulmonary bioactivity of VIP.

  19. Recent developments in the pathophysiology of irritable bowel syndrome.

    Science.gov (United States)

    El-Salhy, Magdy

    2015-07-07

    Irritable bowel syndrome (IBS) is a common gastrointestinal disorder, the pathophysiology of which is not completely known, although it has been shown that genetic/social learning factors, diet, intestinal microbiota, intestinal low-grade inflammation, and abnormal gastrointestinal endocrine cells play a major role. Studies of familial aggregation and on twins have confirmed the heritability of IBS. However, the proposed IBS risk genes are thus far nonvalidated hits rather than true predisposing factors. There is no convincing evidence that IBS patients suffer from food allergy/intolerance, with the effect exerted by diet seemingly caused by intake of poorly absorbed carbohydrates and fiber. Obesity is a possible comorbidity of IBS. Differences in the microbiota between IBS patients and healthy controls have been reported, but the association between IBS symptoms and specific bacterial species is uncertain. Low-grade inflammation appears to play a role in the pathophysiology of a major subset of IBS, namely postinfectious IBS. The density of intestinal endocrine cells is reduced in patients with IBS, possibly as a result of genetic factors, diet, intestinal microbiota, and low-grade inflammation interfering with the regulatory signals controlling the intestinal stem-cell clonogenic and differentiation activities. Furthermore, there is speculation that this decreased number of endocrine cells is responsible for the visceral hypersensitivity, disturbed gastrointestinal motility, and abnormal gut secretion seen in IBS patients.

  20. CERN: Fixed target targets

    Energy Technology Data Exchange (ETDEWEB)

    Anon.

    1993-03-15

    time, and help explain the continuing dilemma of the dearth of solar neutrinos (December 1992, page 12). For the longer term future, a larger detector could provide an increased yield, boosting the neutrino capture rate by up to a factor of ten. Other, more spectacular, option is to shine the CERN neutrino beam towards a detector a long way off. Such a beam is practically unimpeded by matter and could pass right through the earth. Possible contenders for underground target stations equipped with big detectors are the Italian Gran Sasso laboratory, 730 kilometres south, or Superkamiokande, 8750 kilometres away in Japan. Other major ongoing 'flagship' SPS projects include the NA48 experiment to continue precision measurements on the still unexplained phenomenon of CP violation (March 1992, page 7) and the 'Spin Muon Collaboration' looking to probe the spin structure of the proton and the neutron using high energy muon beams (April 1992, page 21). Both these experiments address important physics issues. While SMC is already taking data, NA48 will not become operational until 1995, but should run then for more than three years. Elsewhere at the SPS, ongoing studies include a programme using hyperon beams, and a study of beauty particles (WA92) which would be hampered once the new neutrino programme starts. The spectroscopy of particles containing light quarks, although far from having solved all outstanding questions, is slowly coming to the end of its SPS career. The WA91 glueball search at the big Omega detector will continue taking data in 1994. The GAMS experiment took its final CERN data last year. One of the long-standing examples of CERN-Russian collaboration, GAMS earned its acronym from the Russian abbreviation for its characteristic large lead-glass arrays. GAMS experiments have run both at CERN and at Serpukhov's Institute for High Energy Physics near Moscow.

  1. Hypothesis review: are clathrin-mediated endocytosis and clathrin-dependent membrane and protein trafficking core pathophysiological processes in schizophrenia and bipolar disorder?

    LENUS (Irish Health Repository)

    2012-02-01

    Clathrin-mediated endocytosis (CME) is the best-characterized mechanism governing cellular membrane and protein trafficking. In this hypothesis review, we integrate recent evidence implicating CME and related cellular trafficking mechanisms in the pathophysiology of psychotic disorders such as schizophrenia and bipolar disorder. The evidence includes proteomic and genomic findings implicating proteins and genes of the clathrin interactome. Additionally, several important candidate genes for schizophrenia, such as dysbindin, are involved in processes closely linked to CME and membrane trafficking. We discuss that key aspects of psychosis neuropathology such as synaptic dysfunction, white matter changes and aberrant neurodevelopment are all influenced by clathrin-dependent processes, and that other cellular trafficking mechanisms previously linked to psychoses interact with the clathrin interactome in important ways. Furthermore, many antipsychotic drugs have been shown to affect clathrin-interacting proteins. We propose that the targeted pharmacological manipulation of the clathrin interactome may offer fruitful opportunities for novel treatments of schizophrenia.Molecular Psychiatry advance online publication, 11 October 2011; doi:10.1038\\/mp.2011.123.

  2. MicroRNAs take part in pathophysiology and pathogenesis of Male Pattern Baldness.

    Science.gov (United States)

    Goodarzi, Hamed R; Abbasi, Ali; Saffari, Mojtaba; Tabei, Mohammad B; Noori Daloii, Mohammad R

    2010-07-01

    Male Pattern Baldness (MPB) or androgenetic alopecia is a common form of hair loss with androgens and genetics having etiological significance. Androgens are thought to pathophysiologically power on cascades of chronically dramatic alterations in genetically susceptible scalp dermal papillas, specialized cells in hair follicles in which androgens react, and finally resulting in a patterned alopecia. However, the exact mechanisms through which androgens, positive regulators of growth and anabolism in most body sites, paradoxically exert their effects on balding hair follicles, are not yet known. The role of microRNAs, a recently discovered class of non-coding RNAs, with a wide range of regulatory functions, has been documented in hair follicle formation and their deregulation in cancer of prostate, a target organ of androgens has also been delineated. Yet, there is a lack of knowledge in agreement with microRNAs' contribution in pathophysiology of MPB. To investigate the role of microRNAs in pathogenesis of MPB, we selected seven microRNAs, predicted bioinformatically on a reverse engineering basis, from previously published microarray gene expression data and analyzed their expression in balding relative to non-balding dermal papillas. We found for the first time upregulation of four microRNAs (miR-221, miR-125b, miR-106b and miR-410) that could participate in pathogenesis of MPB. Regarding microRNAs' therapeutic potential and accessibility of hair follicles for gene therapy, these microRNAs can be considered as good candidates for a new revolutionized generation of treatments.

  3. Unfolding the mechanism of cisplatin induced pathophysiology in spleen and its amelioration by carnosine.

    Science.gov (United States)

    Banerjee, Sharmistha; Sinha, Krishnendu; Chowdhury, Sayantani; Sil, Parames C

    2018-01-05

    cis-Diamminedichloroplatinum (cisplatin) is an effective chemotherapeutic and is widely used for the treatment of various types of solid tumors. Bio-distribution of cisplatin to other organs due to poor targeting towards only cancer cells constitutes the backbone of cisplatin-induced toxicity. The adverse effect of this drug on spleen is not well characterized so far. Therefore, we have set our goal to explore the mechanism of the cisplatin-induced pathophysiology of the spleen and would also like to evaluate whether carnosine, an endogenous neurotransmitter and antioxidant, can ameliorate this pathophysiological response. We found a dose and time-dependent increase of the pro-inflammatory cytokine, TNF-α, in the spleen tissue of the experimental mice exposed to 10 and 20 mg/kg body weight of cisplatin. The increase in inflammatory cytokine can be attributed to the activation of the transcription factor, NF-ĸB. This also aids in the transcription of other pro-inflammatory cytokines and cellular adhesion molecules. Exposure of animals to cisplatin at both the doses resulted in ROS and NO production leading to oxidative stress. The MAP Kinase pathway, especially JNK activation, was also triggered by cisplatin. Eventually, the persistence of inflammatory response and oxidative stress lead to apoptosis through extrinsic pathway. Carnosine has been found to restore the expression of inflammatory molecules and catalase to normal levels through inhibition of pro-inflammatory cytokines, oxidative stress, NF-ĸB and JNK. Carnosine also protected the splenic cells from apoptosis. Our study elucidated the detailed mechanism of cisplatin-induced spleen toxicity and use of carnosine as a protective agent against this cytotoxic response. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Red Bell Pepper Chromoplasts Exhibit in Vitro Import Competency and Membrane Targeting of Passenger Proteins from the Thylakoidal Sec and ΔpH Pathways but Not the Chloroplast Signal Recognition Particle Pathway1

    Science.gov (United States)

    Summer, Elizabeth J.; Cline, Kenneth

    1999-01-01

    Chloroplast to chromoplast development involves new synthesis and plastid localization of nuclear-encoded proteins, as well as changes in the organization of internal plastid membrane compartments. We have demonstrated that isolated red bell pepper (Capsicum annuum) chromoplasts contain the 75-kD component of the chloroplast outer envelope translocon (Toc75) and are capable of importing chloroplast precursors in an ATP-dependent fashion, indicating a functional general import apparatus. The isolated chromoplasts were able to further localize the 33- and 17-kD subunits of the photosystem II O2-evolution complex (OE33 and OE17, respectively), lumen-targeted precursors that utilize the thylakoidal Sec and ΔpH pathways, respectively, to the lumen of an internal membrane compartment. Chromoplasts contained the thylakoid Sec component protein, cpSecA, at levels comparable to chloroplasts. Routing of OE17 to the lumen was abolished by ionophores, suggesting that routing is dependent on a transmembrane ΔpH. The chloroplast signal recognition particle pathway precursor major photosystem II light-harvesting chlorophyll a/b protein failed to associate with chromoplast membranes and instead accumulated in the stroma following import. The Pftf (plastid fusion/translocation factor), a chromoplast protein, integrated into the internal membranes of chromoplasts during in vitro assays, and immunoblot analysis indicated that endogenous plastid fusion/translocation factor was also an integral membrane protein of chromoplasts. These data demonstrate that the internal membranes of chromoplasts are functional with respect to protein translocation on the thylakoid Sec and ΔpH pathways. PMID:9952453

  5. Pathophysiology, Evaluation, and Management of Chronic Watery Diarrhea

    Science.gov (United States)

    Camilleri, Michael; Sellin, Joseph H.; Barrett, Kim E.

    2016-01-01

    Chronic watery diarrhea poses a diagnostic and therapeutic challenge and is often a disabling condition for patients. Although acute diarrhea is likely to be caused by infection, the causes of chronic diarrhea (more than 4 weeks in duration) are more elusive. We review on the pathophysiology, diagnosis, and treatment of chronic diarrhea. Drawing on recent insights into the molecular mechanisms of intestinal epithelial transport and barrier function, we discuss how diarrhea can result from a decrease in luminal solute absorption, an increase in secretion, or both, as well as derangements in barrier properties. We also describe the various extra-epithelial factors that activate diarrheal mechanisms. Finally, clinical evaluation and tests used in assessment of patients presenting with chronic diarrhea are reviewed, and an algorithm guiding therapeutic decisions and pharmacotherapy is presented. PMID:27773805

  6. Hyperferritinemia and iron metabolism in Gaucher disease: Potential pathophysiological implications.

    Science.gov (United States)

    Regenboog, Martine; van Kuilenburg, André B P; Verheij, Joanne; Swinkels, Dorine W; Hollak, Carla E M

    2016-11-01

    Gaucher disease (GD) is characterized by large amounts of lipid-storing macrophages and is associated with accumulation of iron. High levels of ferritin are a hallmark of the disease. The precise mechanism underlying the changes in iron metabolism has not been elucidated. A systematic search was conducted to summarize available evidence from the literature on iron metabolism in GD and its potential pathophysiological implications. We conclude that in GD, a chronic low grade inflammation state can lead to high ferritin levels and increased hepcidin transcription with subsequent trapping of ferritin in macrophages. Extensive GD manifestations with severe anemia or extreme splenomegaly can lead to a situation of iron-overload resembling hemochromatosis. We hypothesize that specifically this latter situation carries a risk for the occurrence of associated conditions such as the increased cancer risk, metabolic syndrome and neurodegeneration. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Gaucher Disease: The Metabolic Defect, Pathophysiology, Phenotypes And Natural History

    Science.gov (United States)

    Baris, Hagit N.; Cohen, Ian J.; Mistry, Pramod K.

    2015-01-01

    Gaucher disease (GD), a prototype lysosomal storage disorder, results from inherited deficiency of lysosomal glucocerebrosidase due to biallelic mutations in GBA. The result is widespread accumulation of macrophages engorged with predominantly lysosomal glucocerebroside. A complex multisystem phenotype arises involving the liver, spleen, bone marrow and occasionally the lungs in type 1 Gaucher disease; in neuronopathic fulminant type 2 and chronic type 3 disease there is in addition progressive neurodegenerative disease. Manifestations of Gaucher disease type 1 (GD1) include hepatosplenomegaly, cytopenia, a complex pattern of bone involvement with avascular osteonecrosis (AVN), osteoporosis, fractures and lytic lesions. Enzyme replacement therapy became the standard of care in 1991, and this has transformed the natural history of GD1. This article reviews the clinical phenotypes of GD, diagnosis, pathophysiology and its natural history. A subsequent chapter discusses the treatment options. PMID:25345088

  8. Sexual and gonadal dysfunction in chronic kidney disease: Pathophysiology

    Directory of Open Access Journals (Sweden)

    Manish Rathi

    2012-01-01

    Full Text Available Sexual and gonadal dysfunction/infertility are quite common in patients with chronic kidney disease. Forty percent of male and 55% of female dialysis patients do not achieve orgasm. The pathophysiology of gonadal dysfunction is multifactorial. It is usually a combination of psychological, physiological, and other comorbid factors. Erectile dysfunction in males is mainly due to arterial factors, venous leakage, psychological factors, neurogenic factors, endocrine factors, and drugs. Sexual dysfunction in females is mainly due to hormonal factors and manifests mainly as menstrual irregularities, amenorrhea, lack of vaginal lubrication, and failure to conceive. Treatment of gonadal dysfunction in chronic kidney disease is multipronged and an exact understanding of underlying pathology is essential in proper management of these patients.

  9. Etiology, pathophysiology and classifications of the diabetic Charcot foot

    Science.gov (United States)

    Papanas, Nikolaos; Maltezos, Efstratios

    2013-01-01

    In people with diabetes mellitus, the Charcot foot is a specific manifestation of peripheral neuropathy that may involve autonomic neuropathy with high blood flow to the foot, leading to increased bone resorption. It may also involve peripheral somatic polyneuropathy with loss of protective sensation and high risk of unrecognized acute or chronic minor trauma. In both cases, there is excess local inflammatory response to foot injury, resulting in local osteoporosis. In the Charcot foot, the acute and chronic phases have been described. The former is characterized by local erythema, edema, and marked temperature elevation, while pain is not a prominent symptom. In the latter, signs of inflammation gradually recede and deformities may develop, increasing the risk of foot ulceration. The most common anatomical classification describes five patterns, according to the localization of bone and joint pathology. This review article aims to provide a brief overview of the diabetic Charcot foot in terms of etiology, pathophysiology, and classification. PMID:23705058

  10. Female Pattern Hair Loss: a clinical and pathophysiological review.

    Science.gov (United States)

    Ramos, Paulo Müller; Miot, Hélio Amante

    2015-01-01

    Female Pattern Hair Loss or female androgenetic alopecia is the main cause of hair loss in adult women and has a major impact on patients' quality of life. It evolves from the progressive miniaturization of follicles that lead to a subsequent decrease of the hair density, leading to a non-scarring diffuse alopecia, with characteristic clinical, dermoscopic and histological patterns. In spite of the high frequency of the disease and the relevance of its psychological impact, its pathogenesis is not yet fully understood, being influenced by genetic, hormonal and environmental factors. In addition, response to treatment is variable. In this article, authors discuss the main clinical, epidemiological and pathophysiological aspects of female pattern hair loss.

  11. Negative pressure pulmonary edema revisited: Pathophysiology and review of management

    Directory of Open Access Journals (Sweden)

    Balu Bhaskar

    2011-01-01

    Full Text Available Negative pressure pulmonary edema (NPPE is a dangerous and potentially fatal condition with a multifactorial pathogenesis. Frequently, NPPE is a manifestation of upper airway obstruction, the large negative intrathoracic pressure generated by forced inspiration against an obstructed airway is thought to be the principal mechanism involved. This negative pressure leads to an increase in pulmonary vascular volume and pulmonary capillary transmural pressure, creating a risk of disruption of the alveolar-capillary membrane. The early detection of the signs of this syndrome is vital to the treatment and to patient outcome. The purpose of this review is to highlight the available literature on NPPE, while probing the pathophysiological mechanisms relevant in both the development of this condition and that involved in its resolution.

  12. Pathology and pathophysiology of pulmonary manifestations in leptospirosis

    Directory of Open Access Journals (Sweden)

    Marisa Dolhnikoff

    Full Text Available Leptospirosis is a re-emerging zoonosis occurring as large outbreaks throughout the world caused by Leptospira interrogans. The incidence of pulmonary involvement in leptospirosis has been reported to be increasing in the last years, affecting up to 70% of the patients. Alveolar hemorrhage presented as dyspnea and hemoptysis is the main pulmonary manifestation. The emergence of massive hemoptysis and acute respiratory distress syndrome has characterized the recent changes reported in the clinical patterns of leptospirosis. The pulmonary involvement has been emerged as a serious life threat, becoming the main cause of death due to leptospirosis in some countries. In this review we present the main clinical and pathological manifestations of pulmonary involvement in leptospirosis, with special focus on recent data concerning the pathophysiological mechanisms underlying lung injury.

  13. Narcolepsy and Psychiatric Disorders: Comorbidities or Shared Pathophysiology?

    Directory of Open Access Journals (Sweden)

    Anne Marie Morse

    2018-02-01

    Full Text Available Narcolepsy and psychiatric disorders have a significant but unrecognized relationship, which is an area of evolving interest, but unfortunately, the association is poorly understood. It is not uncommon for the two to occur co-morbidly. However, narcolepsy is frequently misdiagnosed initially as a psychiatric condition, contributing to the protracted time to accurate diagnosis and treatment. Narcolepsy is a disabling neurodegenerative condition that carries a high risk for development of social and occupational dysfunction. Deterioration in function may lead to the secondary development of psychiatric symptoms. Inversely, the development of psychiatric symptoms can lead to the deterioration in function and quality of life. The overlap in pharmaceutical intervention may further enhance the difficulty to distinguish between diagnoses. Comprehensive care for patients with narcolepsy should include surveillance for psychiatric illness and appropriate treatment when necessary. Further research is necessary to better understand the underlying pathophysiology between psychiatric disease and narcolepsy.

  14. Pathophysiology-based phenotyping in type 2 diabetes

    DEFF Research Database (Denmark)

    Stidsen, Jacob V; Henriksen, Jan E; Olsen, Michael H

    2018-01-01

    clinically diagnosed type 2 diabetes. METHODS: We first identified all patients with rare subtypes of diabetes, latent autoimmune diabetes of adults (LADA), secondary diabetes, or glucocorticoid-associated diabetes. We then used the homeostatic assessment model to subphenotype all remaining patients......BACKGROUND: Type 2 diabetes may be a more heterogeneous disease than previously thought. Better understanding of pathophysiological subphenotypes could lead to more individualized diabetes treatment. We examined the characteristics of different phenotypes among 5813 Danish patients with new...... into insulinopenic (high insulin sensitivity and low beta cell function), classical (low insulin sensitivity and low beta cell function), or hyperinsulinemic (low insulin sensitivity and high beta cell function) type 2 diabetes. RESULTS: Among 5813 patients diagnosed with incident type 2 diabetes in the community...

  15. Pathophysiology of Degenerative Mitral Regurgitation: New 3-Dimensional Imaging Insights.

    Science.gov (United States)

    Antoine, Clemence; Mantovani, Francesca; Benfari, Giovanni; Mankad, Sunil V; Maalouf, Joseph F; Michelena, Hector I; Enriquez-Sarano, Maurice

    2018-01-01

    Despite its high prevalence, little is known about mechanisms of mitral regurgitation in degenerative mitral valve disease apart from the leaflet prolapse itself. Mitral valve is a complex structure, including mitral annulus, mitral leaflets, papillary muscles, chords, and left ventricular walls. All these structures are involved in physiological and pathological functioning of this valvuloventricular complex but up to now were difficult to analyze because of inherent limitations of 2-dimensional imaging. The advent of 3-dimensional echocardiography, computed tomography, and cardiac magnetic resonance imaging overcoming these limitations provides new insights into mechanistic analysis of degenerative mitral regurgitation. This review will detail the contribution of quantitative and qualitative dynamic analysis of mitral annulus and mitral leaflets by new imaging methods in the understanding of degenerative mitral regurgitation pathophysiology. © 2018 American Heart Association, Inc.

  16. BACE inhibition-dependent repair of Alzheimer's pathophysiology.

    Science.gov (United States)

    Keskin, Aylin D; Kekuš, Maja; Adelsberger, Helmuth; Neumann, Ulf; Shimshek, Derya R; Song, Beomjong; Zott, Benedikt; Peng, Tingying; Förstl, Hans; Staufenbiel, Matthias; Nelken, Israel; Sakmann, Bert; Konnerth, Arthur; Busche, Marc Aurel

    2017-08-08

    Amyloid-β (Aβ) is thought to play an essential pathogenic role in Alzheimer´s disease (AD). A key enzyme involved in the generation of Aβ is the β-secretase BACE, for which powerful inhibitors have been developed and are currently in use in human clinical trials. However, although BACE inhibition can reduce cerebral Aβ levels, whether it also can ameliorate neural circuit and memory impairments remains unclear. Using histochemistry, in vivo Ca 2+ imaging, and behavioral analyses in a mouse model of AD, we demonstrate that along with reducing prefibrillary Aβ surrounding plaques, the inhibition of BACE activity can rescue neuronal hyperactivity, impaired long-range circuit function, and memory defects. The functional neuronal impairments reappeared after infusion of soluble Aβ, mechanistically linking Aβ pathology to neuronal and cognitive dysfunction. These data highlight the potential benefits of BACE inhibition for the effective treatment of a wide range of AD-like pathophysiological and cognitive impairments.

  17. Multimodal approach to control postoperative pathophysiology and rehabilitation

    DEFF Research Database (Denmark)

    Kehlet, H

    1997-01-01

    Major surgery is still associated with undesirable sequelae such as pain, cardiopulmonary, infective and thromboembolic complications, cerebral dysfunction, nausea and gastrointestinal paralysis, fatigue and prolonged convalescence. The key pathogenic factor in postoperative morbidity, excluding...... failures of surgical and anaesthetic technique, is the surgical stress response with subsequent increased demands on organ function. These changes in organ function are thought to be mediated by trauma-induced endocrine metabolic changes and activation of several biological cascade systems (cytokines......, complement, arachidonic acid metabolites, nitric oxide, free oxygen radicals, etc). To understand postoperative morbidity it is therefore necessary to understand the pathophysiological role of the various components of the surgical stress response and to determine if modification of such responses may...

  18. Dysmotility in Esophageal Atresia: Pathophysiology, Characterization, and Treatment

    Science.gov (United States)

    Faure, Christophe; Righini Grunder, Franziska

    2017-01-01

    Esophageal dysmotility is almost universal after esophageal atresia (EA) repair and is mainly related to the developmental anomaly of the esophagus. Esophageal dysmotility is involved in the pathophysiology of numerous symptoms and comorbidities associated with EA such as gastroesophageal reflux disease, aspiration and respiratory complications, and symptoms of dysphagia and feeding disorders. High-resolution esophageal manometry (HREM) has facilitated the characterization of the dysmotility, but there is an incomplete correlation between symptoms and manometrical patterns. Impedance coupled to HREM should help to predict the clinical outcome and therefore personalize patient management. Nowadays, the management of esophageal dysmotility in patients with EA is essentially based on treatment of associated inflammation related to peptic or eosinophilic esophagitis. PMID:28620599

  19. Effects of biological sex on the pathophysiology of the heart.

    Science.gov (United States)

    Fazal, Loubina; Azibani, Feriel; Vodovar, Nicolas; Cohen Solal, Alain; Delcayre, Claude; Samuel, Jane-Lise

    2014-02-01

    Cardiovascular diseases are the leading causes of death in men and women in industrialized countries. While the effects of biological sex on cardiovascular pathophysiology have long been known, the sex-specific mechanisms mediating these processes have been further elucidated over recent years. This review aims at analysing the sex-based differences in cardiac structure and function in adult mammals, and the sex-based differences in the main molecular mechanisms involved in the response of the heart to pathological situations. It emerged from this review that the sex-based difference is a variable that should be dealt with, not only in basic science or clinical research, but also with regards to therapeutic approaches. © 2013 The British Pharmacological Society.

  20. Geographical, environmental and pathophysiological influences on the human blood transcriptome.

    Science.gov (United States)

    Tabassum, Rubina; Nath, Artika; Preininger, Marcela; Gibson, Greg

    2013-12-01

    Gene expression variation provides a read-out of both genetic and environmental influences on gene activity. Geographical, genomic and sociogenomic studies have highlighted how life circumstances of an individual modify the expression of hundreds and in some cases thousands of genes in a co-ordinated manner. This review places such results in the context of a conserved set of 90 transcripts known as Blood Informative Transcripts (BIT) that capture the major conserved components of variation in the peripheral blood transcriptome. Pathophysiological states are also shown to associate with the perturbation of transcript abundance along the major axes. Discussion of false negative rates leads us to argue that simple significance thresholds provide a biased perspective on assessment of differential expression that may cloud the interpretation of studies with small sample sizes.

  1. Acetazolamide in cerebral diagnosis: Physiological and pathophysiological aspects

    International Nuclear Information System (INIS)

    Lerch, H.; Franke, W.G.; Templin, A.

    1990-01-01

    The sensitivity in the diagnosis of cerebrovascular diseases using radiotracers can be enhanced by the use of the acetazolamide test. In this paper we present and discuss some physiological and pathophysiological aspects of its mechanism. The physiological action of the carboanhydrase inhibitor is like the action of enhanced pCO 2 in the tissue, thus acting at the site of metabolic regulation. The reaction of the vascular bed is influenced in part by subcortical structures. Pathologically the reaction can be disturbed at first by an altered regulation with the vessels being mechanically intact, e.g. in hypoxia or transient ischemia. Secondly, the mechanics of the vessels may be not intact e.g., in atherosclerosis or surrounding edema. Lastly, the vessels have already dilated, e.g. poststenotically. All these facts have to be taken into consideration interpreting an acetazolamid test. (orig.) [de

  2. The Postural Tachycardia Syndrome (POTS: Pathophysiology, Diagnosis & Management

    Directory of Open Access Journals (Sweden)

    Satish R Raj

    2006-04-01

    Full Text Available Postural tachycardia syndrome (POTS, characterized by orthostatic tachycardia in the absence of orthostatic hypotension, has been the focus of increasing clinical interest over the last 15 years 1. Patients with POTS complain of symptoms of tachycardia, exercise intolerance, lightheadedness, extreme fatigue, headache and mental clouding. Patients with POTS demonstrate a heart rate increase of ≥30 bpm with prolonged standing (5-30 minutes, often have high levels of upright plasma norepinephrine (reflecting sympathetic nervous system activation, and many patients have a low blood volume. POTS can be associated with a high degree of functional disability. Therapies aimed at correcting the hypovolemia and the autonomic imbalance may help relieve the severity of the symptoms. This review outlines the present understanding of the pathophysiology, diagnosis, and management of POTS.

  3. Epidural haematoma: pathophysiological significance of extravasation and arteriovenous shunting

    International Nuclear Information System (INIS)

    Habash, A.H.; Sortland, O.; Zwetnow, N.N.

    1982-01-01

    35 patients with epidural bleeding operated on at Rikshospitalet, Oslo, during the period 1965 - 1980 had preoperative angiography with visualization of the external carotid artery. Twenty-one patients had extravasation of contrast medium from meningeal arteries. Seventeen of the 21 had also shunting of contrast medium from meningeal arteries to meningeal or diploic veins, while 20 of the 21 also had bled from a ruptured meningeal artery at operation. It was further found that of 20 patients who deteriorated after trauma 18 had an epidural arteriovenous shunt or extravasation. Conversely, of 15 patients who improved after trauma 12 had no evidence of a shunt. The strong correlation between the clinical course and the occurrence of extravasation supports previous experimental and clinical data, indicating the epidural arteriovenous shunt to be a major factor in the pathophysiology and the outcome of epidural bleeding. (author)

  4. Insights into Pathophysiology from Medication-induced Tremor

    Directory of Open Access Journals (Sweden)

    John C. Morgan

    2017-10-01

    Full Text Available Background: Medication-induced tremor (MIT is common in clinical practice and there are many medications/drugs that can cause or exacerbate tremors. MIT typically occurs by enhancement of physiological tremor (EPT, but not all drugs cause tremor in this way. In this manuscript, we review how some common examples of MIT have informed us about the pathophysiology of tremor.Methods: We performed a PubMed literature search for published articles dealing with MIT and attempted to identify articles that especially dealt with the medication’s mechanism of inducing tremor.Results: There is a paucity of literature that deals with the mechanisms of MIT, with most manuscripts only describing the frequency and clinical settings where MIT is observed. That being said, MIT emanates from multiple mechanisms depending on the drug and it often takes an individualized approach to manage MIT in a given patient.Discussion: MIT has provided some insight into the mechanisms of tremors we see in clinical practice. The exact mechanism of MIT is unknown for most medications that cause tremor, but it is assumed that in most cases physiological tremor is influenced by these medications. Some medications (epinephrine that cause EPT likely lead to tremor by peripheral mechanisms in the muscle (β-adrenergic agonists, but others may influence the central component (amitriptyline. Other drugs can cause tremor, presumably by blockade of dopamine receptors in the basal ganglia (dopamine-blocking agents, by secondary effects such as causing hyperthyroidism (amiodarone, or by other mechanisms. We will attempt to discuss what is known and unknown about the pathophysiology of the most common MITs.

  5. The role of beta-endorphin in the pathophysiology of major depression.

    Science.gov (United States)

    Hegadoren, K M; O'Donnell, T; Lanius, R; Coupland, N J; Lacaze-Masmonteil, N

    2009-10-01

    A role for beta-endorphin (beta-END) in the pathophysiology of major depressive disorder (MDD) is suggested by both animal research and studies examining clinical populations. The major etiological theories of depression include brain regions and neural systems that interact with opioid systems and beta-END. Recent preclinical data have demonstrated multiple roles for beta-END in the regulation of complex homeostatic and behavioural processes that are affected during a depressive episode. Additionally, beta-END inputs to regulatory pathways involving feeding behaviours, motivation, and specific types of motor activity have important implications in defining the biological foundations for specific depressive symptoms. Early research linking beta-END to MDD did so in the context of the hypothalamic-pituitary-adrenal (HPA) axis activity, where it was suggested that HPA axis dysregulation may account for depressive symptoms in some individuals. The primary aims of this paper are to use both preclinical and clinical research (a) to critically review data that explores potential roles for beta-END in the pathophysiology of MDD and (b) to highlight gaps in the literature that limit further development of etiological theories of depression and testable hypotheses. In addition to examining methodological and theoretical challenges of past clinical studies, we summarize studies that have investigated basal beta-END levels in MDD and that have used challenge tests to examine beta-END responses to a variety of experimental paradigms. A brief description of the synthesis, location in the CNS and behavioural pharmacology of this neuropeptide is also provided to frame this discussion. Given the lack of clinical improvement observed with currently available antidepressants in a significant proportion of depressed individuals, it is imperative that novel mechanisms be investigated for antidepressant potential. We conclude that the renewed interest in elucidating the role of beta

  6. CERN: Fixed target targets

    International Nuclear Information System (INIS)

    Anon.

    1993-01-01

    visible for the first time, and help explain the continuing dilemma of the dearth of solar neutrinos (December 1992, page 12). For the longer term future, a larger detector could provide an increased yield, boosting the neutrino capture rate by up to a factor of ten. Other, more spectacular, option is to shine the CERN neutrino beam towards a detector a long way off. Such a beam is practically unimpeded by matter and could pass right through the earth. Possible contenders for underground target stations equipped with big detectors are the Italian Gran Sasso laboratory, 730 kilometres south, or Superkamiokande, 8750 kilometres away in Japan. Other major ongoing 'flagship' SPS projects include the NA48 experiment to continue precision measurements on the still unexplained phenomenon of CP violation (March 1992, page 7) and the 'Spin Muon Collaboration' looking to probe the spin structure of the proton and the neutron using high energy muon beams (April 1992, page 21). Both these experiments address important physics issues. While SMC is already taking data, NA48 will not become operational until 1995, but should run then for more than three years. Elsewhere at the SPS, ongoing studies include a programme using hyperon beams, and a study of beauty particles (WA92) which would be hampered once the new neutrino programme starts. The spectroscopy of particles containing light quarks, although far from having solved all outstanding questions, is slowly coming to the end of its SPS career. The WA91 glueball search at the big Omega detector will continue taking data in 1994. The GAMS experiment took its final CERN data last year. One of the long-standing examples of CERN-Russian collaboration, GAMS earned its acronym from the Russian abbreviation for its characteristic large lead-glass arrays. GAMS experiments have run both at CERN and at Serpukhov's Institute for High Energy Physics near Moscow

  7. Chemotherapy-Induced Constipation and Diarrhea: Pathophysiology, Current and Emerging Treatments

    Science.gov (United States)

    McQuade, Rachel M.; Stojanovska, Vanesa; Abalo, Raquel; Bornstein, Joel C.; Nurgali, Kulmira

    2016-01-01

    Gastrointestinal (GI) side-effects of chemotherapy are a debilitating and often overlooked clinical hurdle in cancer management. Chemotherapy-induced constipation (CIC) and Diarrhea (CID) present a constant challenge in the efficient and tolerable treatment of cancer and are amongst the primary contributors to dose reductions, delays and cessation of treatment. Although prevalence of CIC is hard to estimate, it is believed to affect approximately 16% of cancer patients, whilst incidence of CID has been estimated to be as high as 80%. Despite this, the underlying mechanisms of both CID and CIC remain unclear, but are believed to result from a combination of intersecting mechanisms including inflammation, secretory dysfunctions, GI dysmotility and alterations in GI innervation. Current treatments for CIC and CID aim to reduce the severity of symptoms rather than combating the pathophysiological mechanisms of dysfunction, and often result in worsening of already chronic GI symptoms or trigger the onset of a plethora of other side-effects including respiratory depression, uneven heartbeat, seizures, and neurotoxicity. Emerging treatments including those targeting the enteric nervous system present promising avenues to alleviate CID and CIC. Identification of potential targets for novel therapies to alleviate chemotherapy-induced toxicity is essential to improve clinical outcomes and quality of life amongst cancer sufferers. PMID:27857691

  8. An update on the pathophysiology and management of polycystic liver disease.

    Science.gov (United States)

    Wong, May Yw; McCaughan, Geoffrey W; Strasser, Simone I

    2017-06-01

    Polycystic liver disease (PLD) is characterized by the presence of multiple cholangiocyte-derived hepatic cysts that progressively replace liver tissue. They are classified as an inherited ciliopathy /cholangiopathy as pathology exists at the level of the primary cilia of cholangiocytes. Aberrant expression of the proteins in primary cilia can impair their structures and functions, thereby promoting cystogenesis. Areas covered: This review begins by looking at the epidemiology of PLD and its natural history. It then describes the pathophysiology and corresponding potential treatment strategies for PLD. Expert commentary: Traditionally, therapies for symptomatic PLD have been limited to symptomatic management and surgical interventions. Such techniques are not completely effective, do not alter the natural history of the disease, and are linked with high rate of re-accumulation of cysts. As a result, there has been a push for drugs targeted at abnormal cellular signaling cascades to address deregulated proliferation, cell dedifferentiation, apoptosis and fluid secretion. Currently, the only available drug treatments that halt disease progression and improve quality of life in PLD patients are somatostatin analogues. Numerous preclinical studies suggest that targeting components of the signaling pathways that influence cyst development can ameliorate growth of hepatic cysts.

  9. IMPORTANT NOTIFICATION

    CERN Multimedia

    HR Department

    2009-01-01

    Green plates, removals and importation of personal effects Please note that, as from 1 April 2009, formalities relating to K and CD special series French vehicle plates (green plates), removals and importation of personal effects into France and Switzerland will be dealt with by GS Department (Building 73/3-014, tel. 73683/74407). Importation and purchase of tax-free vehicles in Switzerland, as well as diplomatic privileges, will continue to be dealt with by the Installation Service of HR Department (Building 33/1-011, tel. 73962). HR and GS Departments

  10. The physiology of deglutition and the pathophysiology and complications of oropharyngeal dysphagia.

    Science.gov (United States)

    Steele, Catriona M

    2012-01-01

    The opening session of the 2nd International Conference on Oropharyngeal Dysphagia featured a series of invited talks reviewing the definition of dysphagia, its prevalence and its pathophysiology. The discussion arising from these talks focused heavily on the current underrecognition of dysphagia as a significant concern for older adults, particularly those over 75. The burdens associated with dysphagia in this sector of the population were recognized to be substantial, both in social/psychological terms and in terms of economic consequences for the healthcare system. The importance of developing swallow screening protocols as a routine method for the early identification of dysphagia and aspiration was explored. The idea of launching political initiatives aimed at increasing awareness and the utilization of appropriate dysphagia healthcare codes was also discussed. Copyright © 2012 S. Karger AG, Basel.

  11. Association of oxidative stress with the pathophysiology of depresion and bipolar disorder

    Directory of Open Access Journals (Sweden)

    Lačković Maja

    2013-01-01

    Full Text Available The production of free radicals in an organism is under the control of various antioxidant mechanisms. If their production overcomes the capacity of antioxidant protection, oxidative stress occurs which is capable of damaging different cellular structures and biomolecules, leading to various diseases. The importance of oxidative stress was proven in many psychiatric diseases among which are depression and bipolar disorder. Different studies show the significant improvement of clinical presentation when antioxidant substances are administered, suggesting that redox imbalance can influence their symptoms appearance and severity. In addition, oxidative stress is intercrossed with the different comorbidities that appear among depressive and bipolar patients. Beside the clinical presentation, oxidative stress influences the chronicity of depression, which was demonstrated in patients with recurrent depressive disorder. Better understanding of oxidant/antioxidant imbalance and its role in the pathophysiology of depression and bipolar disorder could be useful for the development of a novel therapeutic approach to the management of these diseases.

  12. Current challenges and problems in teaching pathophysiology in Ukraine - another reaction to Churilov's paper.

    Science.gov (United States)

    Ataman, Oleksandr V

    2017-12-01

    Pathophysiology in Ukraine has rich traditions and achievements in the scientific areas, as well as in teaching academic discipline. Its history, the main Ukrainian scientific schools and their famous representatives are briefly described. The content of existing study program, the main approaches to teaching, and some methodological and organizational problems needed to be solved are characterized. The necessity and usefulness of developing and implementing the three separate courses of discipline (Essential, Clinical and Advanced Pathophysiology) are substantiated. The place of Pathophysiology in the training of physicians with different kinds of their future activity is discussed. Relation of teaching Pathophysiology to Translational and Personalized Medicine is tried to be shown.

  13. Advanced MR diagnostic imaging in pediatric glial cell tumors: from morphological to pathophysiological evaluation

    International Nuclear Information System (INIS)

    Balev, B.; Georgiev, R.; Novakova, M.

    2013-01-01

    Full text: Introduction: The conventional MR imaging is important, and in most cases necessary imaging tool for studying the macroscopic structure, for localization and distribution of a glial brain tumor. It is an integral part of the optimal MR protocol, which further comprises a diffusion, perfusion techniques, techniques for the permeability and oxygenation assessment, as well as MR spectroscopy to the metabolism assessment. What you will learn: Glial brain tumors in children - incidence, histology, classification, diagnosis; Nature and principles of MR diffusion, perfusion, techniques for permeability and oxygenation assessment, MR spectroscopy; Contemporary techniques allowing to obtain not only MR morphological information but also to evaluate the tumor the pathophysiology: the cellular atypia, cellularity, tumor neovascularization, oxygen consumption, metabolism, status of the blood-brain barrier. This assessment determines the biological potential of the tumor, treatment options and prognosis. Discussion: The findings from conventional MR examinations, incl. administration of gadolinium contrast agents are associated with the degree of glioma and can be useful for their classification. Taking into account that from 20% to 45 % of the unenhanced supratentorial gliomas are malignant, some low-grade gliomas enhance (ganglioglioma, pilocytic astrocytoma, oligodendroglioma), 9% of malignant gliomas have no contrast enhancement, and in general, the contrast enhancement is not seen as a reliable indicator for the infiltration extent. The contemporary MR techniques improve the assessment of the pathophysiology of the tumor which is relevant to its histology and biological potential. Conclusion: Modern MR techniques besides purely diagnostic advantages (determine the extent and distribution of glioma), enable: differentiation of tumor recurrence from radiation necrosis; identification of optimal locations for biopsy or operative resection; prognosis, planning and

  14. Developments in intervertebral disc disease research: pathophysiology, mechanobiology, and therapeutics.

    Science.gov (United States)

    Weber, Kathryn T; Jacobsen, Timothy D; Maidhof, Robert; Virojanapa, Justin; Overby, Chris; Bloom, Ona; Quraishi, Shaheda; Levine, Mitchell; Chahine, Nadeen O

    2015-03-01

    Low back pain is a leading cause of disability worldwide and the second most common cause of physician visits. There are many causes of back pain, and among them, disc herniation and intervertebral disc degeneration are the most common diagnoses and targets for intervention. Currently, clinical treatment outcomes are not strongly correlated with diagnoses, emphasizing the importance for characterizing more completely the mechanisms of degeneration and their relationships with symptoms. This review covers recent studies elucidating cellular and molecular changes associated with disc mechanobiology, as it relates to degeneration and regeneration. Specifically, we review findings on the biochemical changes in disc diseases, including cytokines, chemokines, and proteases; advancements in disc disease diagnostics using imaging modalities; updates on studies examining the response of the intervertebral disc to injury; and recent developments in repair strategies, including cell-based repair, biomaterials, and tissue engineering. Findings on the effects of the omega-6 fatty acid, linoleic acid, on nucleus pulposus tissue engineering are presented. Studies described in this review provide greater insights into the pathogenesis of disc degeneration and may define new paradigms for early or differential diagnostics of degeneration using new techniques such as systemic biomarkers. In addition, research on the mechanobiology of disease enriches the development of therapeutics for disc repair, with potential to diminish pain and disability associated with disc degeneration.

  15. RNA-Targeted Therapies and Amyotrophic Lateral Sclerosis

    Directory of Open Access Journals (Sweden)

    Stéphane Mathis

    2018-01-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a fatal motor disease in adults. Its pathophysiology remains mysterious, but tremendous advances have been made with the discovery of the most frequent mutations of its more common familial form linked to the C9ORF72 gene. Although most cases are still considered sporadic, these genetic mutations have revealed the role of RNA production, processing and transport in ALS, and may be important players in all ALS forms. There are no disease-modifying treatments for adult human neurodegenerative diseases, including ALS. As in spinal muscular atrophy, RNA-targeted therapies have been proposed as potential strategies for treating this neurodegenerative disorder. Successes achieved in various animal models of ALS have proven that RNA therapies are both safe and effective. With careful consideration of the applicability of such therapies in humans, it is possible to anticipate ongoing in vivo research and clinical trial development of RNA therapies for treating ALS.

  16. RNA-Targeted Therapies and Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Mathis, Stéphane; Le Masson, Gwendal

    2018-01-15

    Amyotrophic lateral sclerosis (ALS) is a fatal motor disease in adults. Its pathophysiology remains mysterious, but tremendous advances have been made with the discovery of the most frequent mutations of its more common familial form linked to the C9ORF72 gene. Although most cases are still considered sporadic, these genetic mutations have revealed the role of RNA production, processing and transport in ALS, and may be important players in all ALS forms. There are no disease-modifying treatments for adult human neurodegenerative diseases, including ALS. As in spinal muscular atrophy, RNA-targeted therapies have been proposed as potential strategies for treating this neurodegenerative disorder. Successes achieved in various animal models of ALS have proven that RNA therapies are both safe and effective. With careful consideration of the applicability of such therapies in humans, it is possible to anticipate ongoing in vivo research and clinical trial development of RNA therapies for treating ALS.

  17. Importance classification

    International Nuclear Information System (INIS)

    Mizumachi, Wataru; Kobayashi, Masahide

    2008-01-01

    Conventionally, the design of a nuclear reactor has been performed from a viewpoint of a safety function and the importance on earthquake-proof on the basis of not giving off the mainly included radioactivity outside. In this Niigataken-Chuetsuoki earthquake, there is almost no damage to the system, components and structure on safe also in the earthquake beyond assumption, and the validity of the design was checked. But, the situation peculiar to a big earthquake was also generated. The emergency plan room which should serve as a connection center with the exterior was not able to open a door and use at the beginning. Fire-extinguishing system piping fractured and self-defense fire fighting was not made. And so on. Discussion from the following three viewpoints was performed. 1st: The importance from a viewpoint which should maintain a function also with the disaster in case of an earthquake like an emergency plan room etc. 2nd: In the earthquake, since the safe system and un-safe system was influenced, the importance from a viewpoint which may have influence safely inquired when the un-safe system broke down. 3rd: Although it was not directly related safely, discussion from a viewpoint which influences fear of insecurity, such as taking out smoke, for example, was performed (author)

  18. Role of brain orexin in the pathophysiology of functional gastrointestinal disorders.

    Science.gov (United States)

    Okumura, Toshikatsu; Nozu, Tsukasa

    2011-04-01

    Orexins are neuropeptides that are localized in neurons within the lateral hypothalamic area and regulate feeding behavior. The lateral hypothalamic area plays an important role in not only feeding but the central regulation of other functions including gut physiology. Accumulating evidence have shown that orexins acts in the brain to regulate a wide variety of body functions including gastrointestinal functions. The purpose of this review is to summarize relevant findings on brain orexins and a digestive system, and discuss the pathophysiological roles of the peptides with special reference to functional gastrointestinal disorders. Exogenously administered orexin or endogenously released orexin in the brain potently stimulates gastric acid secretion in pylorus-ligated conscious rats. The vagal cholinergic pathway is involved in the orexin-induced stimulation of acid secretion, suggesting that orexin-containing neurons in lateral hypothalamic area activates neurons in the dorsal motor nucleus in medulla oblongata, followed by increasing vagal outflow, thereby stimulating gastric acid secretion. In addition, brain orexin stimulates gastric motility, pancreatic secretion and induce gastroprotective action. On the other hand, brain orexin is involved in a number of physiological functions other than gut physiology, such as control of sleep/awake cycle and anti-depressive action in addition to increase in appetite. From these evidence, we would like to make a hypothesis that decreased orexin signaling in the brain may play a role in the pathophysiology in a part of patients with functional gastrointestinal disorders who are frequently accompanied with appetite loss, sleep disturbance, depressive state and the inhibition of gut function. © 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

  19. Epigenetics and obesity cardiomyopathy: From pathophysiology to prevention and management.

    Science.gov (United States)

    Zhang, Yingmei; Ren, Jun

    2016-05-01

    Uncorrected obesity has been associated with cardiac hypertrophy and contractile dysfunction. Several mechanisms for this cardiomyopathy have been identified, including oxidative stress, autophagy, adrenergic and renin-angiotensin aldosterone overflow. Another process that may regulate effects of obesity is epigenetics, which refers to the heritable alterations in gene expression or cellular phenotype that are not encoded on the DNA sequence. Advances in epigenome profiling have greatly improved the understanding of the epigenome in obesity, where environmental exposures during early life result in an increased health risk later on in life. Several mechanisms, including histone modification, DNA methylation and non-coding RNAs, have been reported in obesity and can cause transcriptional suppression or activation, depending on the location within the gene, contributing to obesity-induced complications. Through epigenetic modifications, the fetus may be prone to detrimental insults, leading to cardiac sequelae later in life. Important links between epigenetics and obesity include nutrition, exercise, adiposity, inflammation, insulin sensitivity and hepatic steatosis. Genome-wide studies have identified altered DNA methylation patterns in pancreatic islets, skeletal muscle and adipose tissues from obese subjects compared with non-obese controls. In addition, aging and intrauterine environment are associated with differential DNA methylation. Given the intense research on the molecular mechanisms of the etiology of obesity and its complications, this review will provide insights into the current understanding of epigenetics and pharmacological and non-pharmacological (such as exercise) interventions targeting epigenetics as they relate to treatment of obesity and its complications. Particular focus will be on DNA methylation, histone modification and non-coding RNAs. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Schizophrenia and the immune system: pathophysiology, prevention, and treatment.

    Science.gov (United States)

    Richard, Michelle D; Brahm, Nancy C

    2012-05-01

    Published evidence on established and theoretical connections between immune system dysfunction and schizophrenia is reviewed, with a discussion of developments in the search for immunologically-targeted treatments. A growing body of evidence indicates that immunologic influences may play an important role in the etiology and course of schizophrenia. A literature search identified more than 100 articles pertaining to suspected immunologic influences on schizophrenia published over the past 15 years. Schizophrenia researchers have explored a wide range of potential immune system-related causal or contributory factors, including neurobiological and neuroanatomical disorders, genetic abnormalities, and environmental influences such as maternal perinatal infection. Efforts to establish an immunologic basis for schizophrenia and identify reliable immune markers continue to be hindered by sampling challenges and methodological problems. In aggregate, the available evidence indicates that at least some cases of schizophrenia have an immunologic component, suggesting that immune-focused prevention strategies (e.g., counseling of pregnant women to avoid immune stressors) and close monitoring of at-risk children are appropriate. While antipsychotics remain the standard treatments for schizophrenia, a variety of drugs with immunologic effects have been investigated as adjunctive therapies, with variable and sometimes conflicting results; these include the cyclooxygenase-2 inhibitor celecoxib, immune-modulating agents (e.g., azathioprine and various anticytokine agents such as atlizumab, anakinra, and tumor necrosis factor-α blockers), and an investigational anti-interferon-γ agent. The published evidence indicates that immune system dysfunction related to genetic, environmental, and neurobiological influences may play a role in the etiology of schizophrenia in a subset of patients.

  1. CHRONIC OBSTRUCTIVE PULMONARY DISEASE: DEFINITION, EPIDEMIOLOGY, PATHOPHYSIOLOGY, CLINICAL PICTURE AND TREATMENT (GOLD 2013

    Directory of Open Access Journals (Sweden)

    M. T. Vatutin

    2015-01-01

    Full Text Available Chronic obstructive pulmonary disease: definition, epidemiology, pathophysiology, clinical picture (GOLD 2013. Vatutin M.T., Smyrnova G.S., Taradin G.G. The represented translation of the new international guidelines (GOLD 2013 reflected the epidemiology, pathophysiology, clinical picture and treatment of chronic obstructive pulmonary disease.

  2. The Pathophysiological Effects of Acrylamide in Albino Wister Rats

    Directory of Open Access Journals (Sweden)

    Shler Akram Faqe Mahmood

    2016-07-01

    Full Text Available Studies of the pathophysiological effects of suspected compounds are conducted in rodent species, especially rats and mice, to determine the potential toxic effects of a particular compound. In the assessment of acrylamide (ACR which is available as a dietary compound in daily food stuffs, the potential toxicity was determined following the method described earlier. In this study, Albino Wister rats were used and were observed for clinical abnormalities, changes in food consumption, a n d s y m p t o m s o f toxicity over a period of two months following the oral administration of ACR. Among the parameters used to assess the effect of ACR were include ovarian histopathology, blood sugar, haemogram and lipid profile. The most notable clinical abnormalities observed in a few rats were a rough coat and decreased activity. None of the rats died or howedbehavioural change resulting from treatment with ACR. The concentration of serum biochemical parameters and haemogram showed significant differences between normal and treated rats. Histological examination of the ovaries of the treated rats showed great abnormalities as well. In fact, oral ACR doses are practically toxic with regard to rats after exposure for two months at a dose rate of 30 mg/kg, suggesting the compound is quite non-innocuous.

  3. Cluster Headache: Epidemiology, Pathophysiology, Clinical Features, and Diagnosis.

    Science.gov (United States)

    Wei, Diana Yi-Ting; Yuan Ong, Jonathan Jia; Goadsby, Peter James

    2018-04-01

    Cluster headache is a primary headache disorder affecting up to 0.1% of the population. Patients suffer from cluster headache attacks lasting from 15 to 180 min up to 8 times a day. The attacks are characterized by the severe unilateral pain mainly in the first division of the trigeminal nerve, with associated prominent unilateral cranial autonomic symptoms and a sense of agitation and restlessness during the attacks. The male-to-female ratio is approximately 2.5:1. Experimental, clinical, and neuroimaging studies have advanced our understanding of the pathogenesis of cluster headache. The pathophysiology involves activation of the trigeminovascular complex and the trigeminal-autonomic reflex and accounts for the unilateral severe headache, the prominent ipsilateral cranial autonomic symptoms. In addition, the circadian and circannual rhythmicity unique to this condition is postulated to involve the hypothalamus and suprachiasmatic nucleus. Although the clinical features are distinct, it may be misdiagnosed, with patients often presenting to the otolaryngologist or dentist with symptoms. The prognosis of cluster headache remains difficult to predict. Patients with episodic cluster headache can shift to chronic cluster headache and vice versa. Longitudinally, cluster headache tends to remit with age with less frequent bouts and more prolonged periods of remission in between bouts.

  4. [Bacterial Translocation from Intestine: Microbiological, Immunological and Pathophysiological Aspects].

    Science.gov (United States)

    Podoprigora, G I; Kafarskaya, L I; Bainov, N A; Shkoporov, A N

    2015-01-01

    Bacterial translocation (BT) is both pathology and physiology phenomenon. In healthy newborns it accompanies the process of establishing the autochthonous intestinal microbiota and the host microbiome. In immunodeficiency it can be an aethio-pathogenetic link and a manifestation of infection or septic complications. The host colonization resistance to exogenous microbic colonizers is provided by gastrointestinal microbiota in concert with complex constitutional and adaptive defense mechanisms. BT may be result of barrier dysfunction and self-purification mechanisms involving the host myeloid cell phagocytic system and opsonins. Dynamic cell humoral response to microbial molecular patterns that occurs on the mucous membranes initiates receptorsignalingpathways and cascade ofreactions. Their vector and results are largely determined by cross-reactivity between microbiome and the host genome. Enterocyte barriers interacting with microbiota play leading role in providing adaptive, homeostatic and stress host reactivity. Microcirculatory ischemic tissue alterations and inflammatory reactions increase the intestinal barrier permeability and BT These processes a well as mechanisms for apoptotic cells and bacteria clearance are justified to be of prospective research interest. The inflammatory and related diseases caused by alteration and dysfunction of the intestinal barrier are reasonably considered as diseases of single origin. Maternal microbiota affects theformation of the innate immune system and the microbiota of the newborn, including intestinal commensal translocation during lactation. Deeper understanding of intestinal barrier mechanisms needs complex microbiological, immunological, pathophysiological, etc. investigations using adequate biomodels, including gnotobiotic animals.

  5. Nonmotor fluctuations: phenotypes, pathophysiology, management, and open issues.

    Science.gov (United States)

    Classen, Joseph; Koschel, Jiri; Oehlwein, Christian; Seppi, Klaus; Urban, Peter; Winkler, Christian; Wüllner, Ullrich; Storch, Alexander

    2017-08-01

    Parkinson's disease (PD) is a neurodegenerative multisystem disorder characterized by progressive motor symptoms such as bradykinesia, tremor and muscle rigidity. Over the course of the disease, numerous non-motor symptoms, sometimes preceding the onset of motor symptoms, significantly impair patients' quality of life. The significance of non-motor symptoms may outweigh the burden through progressive motor incapacity, especially in later stages of the disease. The advanced stage of the disease is characterized by motor complications such as fluctuations and dyskinesias induced by the long-term application of levodopa therapy. In recent years, it became evident that various non-motor symptoms such as psychiatric symptoms, fatigue and pain also show fluctuations after chronic levodopa therapy (named non-motor fluctuations or NMFs). Although NMFs have moved into the focus of interest, current national guidelines on the treatment of PD may refer to non-motor symptoms and their management, but do not mention NMF, and do not contain recommendations on their management. The present article summarizes major issues related to NMF including clinical phenomenology and pathophysiology, and outlines a number of open issues and topics for future research.

  6. [Dysphagia in Parkinson's Disease: Pathophysiology, Diagnosis and Therapy].

    Science.gov (United States)

    Suttrup, I; Warnecke, T

    2016-07-01

    Oropharyngeal and esophageal dysphagia are a frequent, but seldom diagnosed symptom of Parkinson's disease (PD). More than 80 % of patients with PD develop dysphagia during the course of their disease leading to a reduced quality of life, complicated medication intake, malnutrition and aspiration pneumonia, which is a major cause of death in PD. The underlying pathophysiology is poorly understood. Impaired dopaminergic and non-dopaminergic mechanisms of the cortical swallowing network as well as peripheral neuromuscular involvement have been suggested to contribute to its multifactorial genesis. Diagnostic screening methods include PD-specific questionnaires and a modified water test. Fiber optic endoscopic evaluation of swallowing (FEES) and videofluoroscopic swallowing study (VFSS), which complement each other, are the gold standard for evaluation of PD-related dysphagia. For evaluation of esophageal dysphagia, the high-resolution manometry (HRM) may be a helpful tool. In addition to dysphagia-specific treatment by speech and language therapists (SLTs), optimized dopaminergic medication is a meaningful therapeutic option. A promising novel method is intensive training of expiratory muscle strength (EMST). Deep brain stimulation does not seem to have a clinically relevant effect on swallowing function in PD. © Georg Thieme Verlag KG Stuttgart · New York.

  7. Pathophysiology, Evaluation, and Management of Edema in Childhood Nephrotic Syndrome

    Science.gov (United States)

    Ellis, Demetrius

    2016-01-01

    Generalized edema is a major presenting clinical feature of children with nephrotic syndrome (NS) exemplified by such primary conditions as minimal change disease (MCD). In these children with classical NS and marked proteinuria and hypoalbuminemia, the ensuing tendency to hypovolemia triggers compensatory physiological mechanisms, which enhance renal sodium (Na+) and water retention; this is known as the “underfill hypothesis.” Edema can also occur in secondary forms of NS and several other glomerulonephritides, in which the degree of proteinuria and hypoalbuminemia, are variable. In contrast to MCD, in these latter conditions, the predominant mechanism of edema formation is “primary” or “pathophysiological,” Na+ and water retention; this is known as the “overfill hypothesis.” A major clinical challenge in children with these disorders is to distinguish the predominant mechanism of edema formation, identify other potential contributing factors, and prevent the deleterious effects of diuretic regimens in those with unsuspected reduced effective circulatory volume (i.e., underfill). This article reviews the Starling forces that become altered in NS so as to tip the balance of fluid movement in favor of edema formation. An understanding of these pathomechanisms then serves to formulate a more rational approach to prevention, evaluation, and management of such edema. PMID:26793696

  8. Insights into pathophysiology of punding reveal possible treatment strategies.

    Science.gov (United States)

    Fasano, A; Petrovic, I

    2010-06-01

    Punding is a stereotyped behavior characterized by an intense fascination with a complex, excessive, nongoal oriented, repetitive activity. Men tend to repetitively tinker with technical equipment such as radio sets, clocks, watches and car engines, the parts of which may be analyzed, arranged, sorted and cataloged but rarely put back together. Women, in contrast, incessantly sort through their handbags, tidy continuously, brush their hair or polish their nails. Punders are normally aware of the inapposite and obtuse nature of the behavior; however, despite the consequent self-injury, they do not stop such behavior. The most common causes of punding are dopaminergic replacement therapy in patients affected by Parkinson's disease (PD) and cocaine and amphetamine use in addicts. The vast majority of information about punding comes from PD cases. A critical review of these cases shows that almost all afflicted patients (90%) were on treatment with drugs acting mainly on dopamine receptors D1 and D2, whereas only three cases were reported in association with selective D2 and D3 agonists. Epidemiological considerations and available data from animal models suggest that punding, drug-induced stereotypies, addiction and dyskinesias all share a common pathophysiological process. Punding may be related to plastic changes in the ventral and dorsal striatal structures, including the nucleus accumbens, and linked to psychomotor stimulation and reward mechanisms. Possible management guidelines are proposed.

  9. Epileptic Seizures Versus Syncope: Pathophysiology and Clinical Approach

    Directory of Open Access Journals (Sweden)

    Marios Charalambous

    2017-02-01

    Full Text Available Generalised epileptic seizures and syncope are two syndromes with similar clinical manifestation and their differentiation can be quite challenging. The aim of this review is to use an evidence-based approach in differentiating these two syndromes through the comprehension of the pathophysiological mechanisms involved and their clinical signs. Both syndromes affect regions of the forebrain and consciousness level, although, different mechanisms are involved. Syncope is a paroxysmal event secondary to a short-term decrease in cerebral perfusion, oxygenation or essential nutrients delivery. Generalised epileptic seizure activity is defined as the clinical manifestation of transient paroxysmal disturbances in brain function secondary to an imbalance between excitatory and inhibitory neurotransmitters. Clinical criteria, including precipitating events, clinical signs preceding, during and following the episodes and event duration, can be used to differentiate the two syndromes. Although these criteria might be useful for the practitioner, definite conclusions should be precluded due to the lack of original research articles and weak evidence on this specific field.Application: The review might be a useful tool for the general practitioner and clinical scientist as it will aid towards the differentiation of two syndromes, i.e. generalised epileptic seizures and syncope, with similar clinical presentation.

  10. Horror Autoinflammaticus: The Molecular Pathophysiology of Autoinflammatory Disease*

    Science.gov (United States)

    Masters, Seth L.; Simon, Anna; Aksentijevich, Ivona; Kastner, Daniel L.

    2010-01-01

    The autoinflammatory diseases are characterized by seemingly unprovoked episodes of inflammation, without high-titer autoantibodies or antigen-specific T cells. The concept was proposed ten years ago with the identification of the genes underlying hereditary periodic fever syndromes. This nosology has taken root because of the dramatic advances in our knowledge of the genetic basis of both mendelian and complex autoinflammatory diseases, and with the recognition that these illnesses derive from genetic variants of the innate immune system. Herein we propose an updated classification scheme based on the molecular insights garnered over the past decade, supplanting a clinical classification that has served well but is opaque to the genetic, immunologic, and therapeutic interrelationships now before us. We define six categories of autoinflammatory disease: IL-1β activation disorders (inflammasomopathies), NF-κB activation syndromes, protein misfolding disorders, complement regulatory diseases, disturbances in cytokine signaling, and macrophage activation syndromes. A system based on molecular pathophysiology will bring greater clarity to our discourse while catalyzing new hypotheses both at the bench and at the bedside. PMID:19302049

  11. Pathophysiology and pathological findings of heatstroke in dogs

    Directory of Open Access Journals (Sweden)

    Romanucci M

    2013-01-01

    Full Text Available Mariarita Romanucci, Leonardo Della SaldaDepartment of Comparative Biomedical Sciences, Faculty of Veterinary Medicine, University of Teramo, Teramo, ItalyAbstract: Canine heatstroke is a life-threatening condition resulting from an imbalance between heat dissipation and production, and characterized by a nonpyrogenic elevation in core body temperature above 41°C (105.8°F. Several exogenous and endogenous factors may predispose dogs to the development of heatstroke; on the other hand, adaptive mechanisms also exists which allow organisms to combat the deleterious effects of heat stress, which are represented by the cellular heat-shock response and heat acclimatization. The pathophysiology and consequences of heatstroke share many similarities to those observable in sepsis and are related to the interaction between the direct cytotoxicity of heat, the acute physiological alterations associated with hyperthermia, such as increased metabolic demand, hypoxia, and circulatory failure, and the inflammatory and coagulation responses of the host to the widespread endothelial and tissue injuries, which may culminate in disseminated intravascular coagulation, systemic inflammatory response syndrome, and multiple organ dysfunction.Keywords: thermoregulation, acclimatization, heat shock proteins, hyperthermia, systemic inflammatory response, multiple organ dysfunction

  12. Retinal Cyclic Nucleotide-Gated Channels: From Pathophysiology to Therapy

    Directory of Open Access Journals (Sweden)

    Stylianos Michalakis

    2018-03-01

    Full Text Available The first step in vision is the absorption of photons by the photopigments in cone and rod photoreceptors. After initial amplification within the phototransduction cascade the signal is translated into an electrical signal by the action of cyclic nucleotide-gated (CNG channels. CNG channels are ligand-gated ion channels that are activated by the binding of cyclic guanosine monophosphate (cGMP or cyclic adenosine monophosphate (cAMP. Retinal CNG channels transduce changes in intracellular concentrations of cGMP into changes of the membrane potential and the Ca2+ concentration. Structurally, the CNG channels belong to the superfamily of pore-loop cation channels and share a common gross structure with hyperpolarization-activated cyclic nucleotide-gated (HCN channels and voltage-gated potassium channels (KCN. In this review, we provide an overview on the molecular properties of CNG channels and describe their physiological role in the phototransduction pathways. We also discuss insights into the pathophysiological role of CNG channel proteins that have emerged from the analysis of CNG channel-deficient animal models and human CNG channelopathies. Finally, we summarize recent gene therapy activities and provide an outlook for future clinical application.

  13. Tics and Tourette: a clinical, pathophysiological and etiological review.

    Science.gov (United States)

    Dale, Russell C

    2017-12-01

    Describe developments in the etiological understanding of Tourette syndrome. Tourette syndrome is a complex heterogenous clinical syndrome, which is not a unitary entity. Pathophysiological models describe gamma-aminobutyric acid-ergic-associated disinhibition of cortico-basal ganglia motor, sensory and limbic loops. MRI studies support basal ganglia volume loss, with additional white matter and cerebellar changes. Tourette syndrome cause likely involves multiple vulnerability genes and environmental factors. Only recently have some vulnerability gene findings been replicated, including histidine decarboxylase and neurexin 1, yet these rare variants only explain a small proportion of patients. Planned large genetic studies will improve genetic understanding. The role of inflammation as a contributor to disease expression is now supported by large epidemiological studies showing an association with maternal autoimmunity and childhood infection. Investigation of blood cytokines, blood mRNA and brain mRNA expression support the role of a persistent immune activation, and there are similarities with the immune literature of autistic spectrum disorder. Current treatment is symptomatic, although there is a better appreciation of factors that influence treatment response. At present, therapeutics is focused on symptom-based treatments, yet with improved etiological understanding, we will move toward disease-modifying therapies in the future.

  14. Mucopolysaccharidosis type I: current knowledge on its pathophysiological mechanisms.

    Science.gov (United States)

    Campos, Derbis; Monaga, Madelyn

    2012-06-01

    Mucopolysaccharidosis type I is one of the most frequent lysosomal storage diseases. It has a high morbidity and mortality, causing in many cases severe neurological and somatic damage in the first years of life. Although the clinical phenotypes have been described for decades, and the enzymatic deficiency and many of the mutations that cause this disease are well known, the underlying pathophysiological mechanisms that lead to its development are not completely understood. In this review we describe and discuss the different pathogenic mechanisms currently proposed for this disease regarding its neurological damage. Deficiency in the lysosomal degradation of heparan sulfate and dermatan sulfate, as well as its primary accumulation, may disrupt a variety of physiological and biochemical processes: the intracellular and extracellular homeostasis of these macromolecules, the pathways related to gangliosides metabolism, mechanisms related to the activation of inflammation, receptor-mediated signaling, oxidative stress and permeability of the lysosomal membrane, as well as alterations in intracellular ionic homeostasis and the endosomal pathway. Many of the pathogenic mechanisms proposed for mucopolysaccharidosis type I are also present in other lysosomal storage diseases with neurological implications. Results from the use of methods that allow the analysis of multiple genes and proteins, in both patients and animal models, will shed light on the role of each of these mechanisms and their combination in the development of different phenotypes due to the same deficiency.

  15. Pathophysiologic insights into motor axonal function in Kennedy disease.

    Science.gov (United States)

    Vucic, Steve; Kiernan, Matthew C

    2007-11-06

    Kennedy disease (KD), or spinobulbomuscular atrophy, is a slowly progressive inherited neurodegenerative disorder, marked by prominent fasciculations that typically precede the development of other symptoms. Although the genetic basis of KD relates to triplet (CAG) repeat expansion in the androgen receptor (AR) gene on the X chromosome, the mechanisms underlying the clinical presentation in KD have yet to be established. Consequently, the present study applied axonal excitability techniques to investigate the pathophysiologic mechanisms associated with KD. Peripheral nerve excitability studies were undertaken in 7 patients with KD with compound muscle action potentials (CMAP) recorded from the right abductor pollicis brevis. Strength-duration time constant (KD 0.54 +/- 0.03 msec; controls, 0.41 +/- 0.02 msec, p TEd [90 to 100 msec], 50.75 +/- 1.98%; controls TEd [90 to 100 msec], 45.67 +/- 0.67%, p < 0.01) and hyperpolarizing (KD TEh [90 to 100 msec], 128.5 +/- 6.9%; controls TEh [90 to 100 msec], 120.5 +/- 2.4%) conditioning pulses. Measurements of refractoriness, superexcitability, and late subexcitability changed appropriately for axonal hyperpolarization, perhaps reflecting the effects of increased ectopic activity. In total, the increase in the strength-duration time constant may be the primary event, occurring early in course of the disease, contributing to the development of axonal hyperexcitability in Kennedy disease, and thereby to the generation of fasciculations, a characteristic hallmark of the disease.

  16. Psychiatric manifestations of Graves' hyperthyroidism: pathophysiology and treatment options.

    Science.gov (United States)

    Bunevicius, Robertas; Prange, Arthur J

    2006-01-01

    Graves' disease is an autoimmune disorder that is the most common cause of hyperthyroidism. Other symptoms associated with the disease are goitre, ophthalmopathy, and psychiatric manifestations such as mood and anxiety disorders and, sometimes, cognitive dysfunction. Graves' hyperthyroidism may result in these latter manifestations via the induction of hyperactivity of the adrenergic nervous system. This review addresses the psychiatric presentations, and their pathophysiology and treatment, in patients with hyperthyroidism, based on literature identified by a PubMed/MEDLINE database search. Although the focus is on mental symptoms associated with Graves' disease, it is not always clear from the literature whether patients had Graves' disease: in some studies, the patients were thought to have Graves' disease based on clinical findings such as diffuse goitre or ophthalmopathy or on measurements of thyroid antibodies in serum; however, in other studies, no distinction was made between Graves' hyperthyroidism and hyperthyroidism from other causes. Antithyroid drugs combined with beta-adrenoceptor antagonists are the treatments of choice for hyperthyroidism, as well as for the psychiatric disorders and mental symptoms caused by hyperthyroidism. A substantial proportion of patients have an altered mental state even after successful treatment of hyperthyroidism, suggesting that mechanisms other than hyperthyroidism, including the Graves' autoimmune process per se and ophthalmopathy, may also be involved. When psychiatric disorders remain after restoration of euthyroidism and after treatment with beta-adrenoceptor antagonists, specific treatment for the psychiatric symptoms, especially psychotropic drugs, may be needed.

  17. Intestinal microbiota in pathophysiology and management of irritable bowel syndrome

    Science.gov (United States)

    Lee, Kang Nyeong; Lee, Oh Young

    2014-01-01

    Irritable bowel syndrome (IBS) is a functional bowel disorder without any structural or metabolic abnormalities that sufficiently explain the symptoms, which include abdominal pain and discomfort, and bowel habit changes such as diarrhea and constipation. Its pathogenesis is multifactorial: visceral hypersensitivity, dysmotility, psychosocial factors, genetic or environmental factors, dysregulation of the brain-gut axis, and altered intestinal microbiota have all been proposed as possible causes. The human intestinal microbiota are composed of more than 1000 different bacterial species and 1014 cells, and are essential for the development, function, and homeostasis of the intestine, and for individual health. The putative mechanisms that explain the role of microbiota in the development of IBS include altered composition or metabolic activity of the microbiota, mucosal immune activation and inflammation, increased intestinal permeability and impaired mucosal barrier function, sensory-motor disturbances provoked by the microbiota, and a disturbed gut-microbiota-brain axis. Therefore, modulation of the intestinal microbiota through dietary changes, and use of antibiotics, probiotics, and anti-inflammatory agents has been suggested as strategies for managing IBS symptoms. This review summarizes and discusses the accumulating evidence that intestinal microbiota play a role in the pathophysiology and management of IBS. PMID:25083061

  18. Intestinal microbiota in pathophysiology and management of irritable bowel syndrome.

    Science.gov (United States)

    Lee, Kang Nyeong; Lee, Oh Young

    2014-07-21

    Irritable bowel syndrome (IBS) is a functional bowel disorder without any structural or metabolic abnormalities that sufficiently explain the symptoms, which include abdominal pain and discomfort, and bowel habit changes such as diarrhea and constipation. Its pathogenesis is multifactorial: visceral hypersensitivity, dysmotility, psychosocial factors, genetic or environmental factors, dysregulation of the brain-gut axis, and altered intestinal microbiota have all been proposed as possible causes. The human intestinal microbiota are composed of more than 1000 different bacterial species and 10(14) cells, and are essential for the development, function, and homeostasis of the intestine, and for individual health. The putative mechanisms that explain the role of microbiota in the development of IBS include altered composition or metabolic activity of the microbiota, mucosal immune activation and inflammation, increased intestinal permeability and impaired mucosal barrier function, sensory-motor disturbances provoked by the microbiota, and a disturbed gut-microbiota-brain axis. Therefore, modulation of the intestinal microbiota through dietary changes, and use of antibiotics, probiotics, and anti-inflammatory agents has been suggested as strategies for managing IBS symptoms. This review summarizes and discusses the accumulating evidence that intestinal microbiota play a role in the pathophysiology and management of IBS.

  19. Pathophysiology of septic shock: From bench to bedside.

    Science.gov (United States)

    McConnell, Kevin W; Coopersmith, Craig M

    2016-04-01

    Our understanding of sepsis and its resultant outcomes remains a paradox. On the one hand, we know more about the pathophysiology of sepsis than ever before. However, this knowledge has not been successfully translated to the bedside, as the vast majority of clinical trials for sepsis have been negative. Yet even in the general absence of positive clinical trials, mortality from sepsis has fallen to its lowest point in history, in large part due to educational campaigns that stress timely antibiotics and hemodynamic support. While additional improvements in outcome will assuredly result from further compliance with evidence based practices, a deeper understanding of the science that underlies the host response in sepsis is critical to the development of novel therapeutics. In this review, we outline immunopathologic abnormalities in sepsis, and then look at potential approaches to therapeutically modulate them. Ultimately, an understanding of the science underlying sepsis should allow the critical care community to utilize precision medicine to combat this devastating disease on an individual basis leading to improved outcomes. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  20. Pathophysiology, Evaluation, and Management of Edema in Childhood Nephrotic Syndrome.

    Science.gov (United States)

    Ellis, Demetrius

    2015-01-01

    Generalized edema is a major presenting clinical feature of children with nephrotic syndrome (NS) exemplified by such primary conditions as minimal change disease (MCD). In these children with classical NS and marked proteinuria and hypoalbuminemia, the ensuing tendency to hypovolemia triggers compensatory physiological mechanisms, which enhance renal sodium (Na(+)) and water retention; this is known as the "underfill hypothesis." Edema can also occur in secondary forms of NS and several other glomerulonephritides, in which the degree of proteinuria and hypoalbuminemia, are variable. In contrast to MCD, in these latter conditions, the predominant mechanism of edema formation is "primary" or "pathophysiological," Na(+) and water retention; this is known as the "overfill hypothesis." A major clinical challenge in children with these disorders is to distinguish the predominant mechanism of edema formation, identify other potential contributing factors, and prevent the deleterious effects of diuretic regimens in those with unsuspected reduced effective circulatory volume (i.e., underfill). This article reviews the Starling forces that become altered in NS so as to tip the balance of fluid movement in favor of edema formation. An understanding of these pathomechanisms then serves to formulate a more rational approach to prevention, evaluation, and management of such edema.

  1. [Irritable bowel syndrome: New pathophysiological hypotheses and practical issues].

    Science.gov (United States)

    Duboc, H; Dior, M; Coffin, B

    2016-08-01

    In 2015, besides the fact that it still fills the gastroenterologists' offices and impairs patient's quality of life, the irritable bowel syndrome has considerably evolved on several points. The pathophysiology is now organized around a consensual hypothesis called the "brain-gut axis", which gather all the influences of peripheral factors as gut microbiota or local serotonin secretion, on the central pain perception, contributing to visceral hypersensitivity and transit modifications. About the diagnosis, the key message is "avoid over-prescription" of additional tests, and reminds that a positive clinical diagnosis based on Rome III criteria is possible after the elimination of simple clinical warning signs. Finally, the food component, a neglected and historical claim of patients, finally finds a strong scientific rational, with a diet low in fermentable sugar and polyols, that gives positive and reproducible results. Copyright © 2016 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  2. Improvised explosive devices: pathophysiology, injury profiles and current medical management.

    Science.gov (United States)

    Ramasamy, A; Hill, A M; Clasper, J C

    2009-12-01

    The improvised explosive device (IED), in all its forms, has become the most significant threat to troops operating in Afghanistan and Iraq. These devices range from rudimentary home made explosives to sophisticated weapon systems containing high-grade explosives. Within this broad definition they may be classified as roadside explosives and blast mines, explosive formed pojectile (EFP) devices and suicide bombings. Each of these groups causeinjury through a number of different mechanisms and can result in vastly different injury profiles. The "Global War on Terror" has meant that incidents which were previously exclusively seen in conflict areas, can occur anywhere, and clinicians who are involved in emergency trauma care may be required to manage casualties from similar terrorist attacks. An understanding of the types of devices and their pathophysiological effects is necessary to allow proper planning of mass casualty events and to allow appropriate management of the complex poly-trauma casualties they invariably cause. The aim of this review article is to firstly describe the physics and injury profile from these different devices and secondly to present the current clinical evidence that underpins their medical management.

  3. Unconventional imports

    International Nuclear Information System (INIS)

    Yamaguchi, N.D.

    2001-01-01

    This article focuses on bitumens and bitumen products from Canadian oil sands and explores how they will affect the Canadian oil industry and the US refining industry. The falling production of crude, the growing demand for it, and the stagnating refining capacity in the US are reported, and Canadian and Mexican exports to the US, the definition of bitumens and bitumen quality, and the position of Canada as world leader in bitumen resources are considered. Bitumen production techniques, sales of bitumens and synthetic crude, the production outlook, and the quality and refining of bitumen and synthetic crude are examined. Plots illustrating North American crude refining capacity, production and demand for 1980-2000; US crude imports from Canada and Mexico (1981-2000), world proven oil reserves (2001), world bitumen resources, and Canadian oil production (1998-2000) are provided. Details of the composition of crudes and bitumens, and recent synthetic crude production are tabulated

  4. New insights into the pathophysiology of achalasia and implications for future treatment.

    Science.gov (United States)

    Furuzawa-Carballeda, Janette; Torres-Landa, Samuel; Valdovinos, Miguel Ángel; Coss-Adame, Enrique; Martín Del Campo, Luis A; Torres-Villalobos, Gonzalo

    2016-09-21

    Idiopathic achalasia is an archetype esophageal motor disorder, causing significant impairment of eating ability and reducing quality of life. The pathophysiological underpinnings of this condition are loss of esophageal peristalsis and insufficient relaxation of the lower esophageal sphincter (LES). The clinical manifestations include dysphagia for both solids and liquids, regurgitation of esophageal contents, retrosternal chest pain, cough, aspiration, weight loss and heartburn. Even though idiopathic achalasia was first described more than 300 years ago, researchers are only now beginning to unravel its complex etiology and molecular pathology. The most recent findings indicate an autoimmune component, as suggested by the presence of circulating anti-myenteric plexus autoantibodies, and a genetic predisposition, as suggested by observed correlations with other well-defined genetic syndromes such as Allgrove syndrome and multiple endocrine neoplasia type 2 B syndrome. Viral agents (herpes, varicella zoster) have also been proposed as causative and promoting factors. Unfortunately, the therapeutic approaches available today do not resolve the causes of the disease, and only target the consequential changes to the involved tissues, such as destruction of the LES, rather than restoring or modifying the underlying pathology. New therapies should aim to stop the disease at early stages, thereby preventing the consequential changes from developing and inhibiting permanent damage. This review focuses on the known characteristics of idiopathic achalasia that will help promote understanding its pathogenesis and improve therapeutic management to positively impact the patient's quality of life.

  5. Bridging from Cells to Cognition in Autism Pathophysiology: Biological Pathways to Defective Brain Function and Plasticity

    Energy Technology Data Exchange (ETDEWEB)

    Anderson, Matthew; Hooker, Brian S.; Herbert, Martha

    2008-01-01

    We review evidence to support the model that autism may begin when a maternal environmental, infectious, or autoantibody insult causes inflammation which increases reactive oxygen species (ROS) production in the fetus, leading to fetal DNA damage (nuclear and mitochondrial), and that these inflammatory and oxidative stressors persist beyond early development (with potential further exacerbations), producing ongoing functional consequences. In organs with a high metabolic demand such as the central nervous system, the continued use of mitochondria with DNA damage may generate additional ROS which will activate the innate immune system leading to more ROS production. Such a mechanism would self-sustain and possibly progressively worsen. The mitochondrial dysfunction and altered redox signal transduction pathways found in autism would conspire to activate both astroglia and microglia. These activated cells can then initiate a broad-spectrum proinflammatory gene response. Neurons may have acquired receptors for these inflammatory signals to inhibit neuronal signaling as a protection from excitotoxic damage during various pathologic insults (e.g., infection). In autism, over-zealous neuroinflammatory responses could not only influence neural developmental processes, but may more significantly impair neural signaling involved in cognition in an ongoing fashion. This model makes specific predictions in patients and experimental animal models and suggests a number of targets sites of intervention. Our model of potentially reversible pathophysiological mechanisms in autism motivates our hope that effective therapies may soon appear on the horizon.

  6. Update on the Pathophysiological Activities of the Cardiac Molecule Cardiotrophin-1 in Obesity

    Directory of Open Access Journals (Sweden)

    Mohamed Asrih

    2013-01-01

    Full Text Available Cardiotrophin-1 (CT-1 is a heart-targeting cytokine that has been reported to exert a variety of activities also in other organs such as the liver, adipose tissue, and atherosclerotic arteries. CT-1 has been shown to induce these effects via binding to a transmembrane receptor, comprising the leukaemia inhibitory factor receptor (LIFRβ subunit and the glycoprotein 130 (gp130, a common signal transducer. Both local and systemic concentrations of CT-1 have been shown to potentially play a critical role in obesity. For instance, CT-1 plasma concentrations have been shown to be increased in metabolic syndrome (a cluster disease including obesity probably due to adipose tissue overexpression. Interestingly, treatment with exogenous CT-1 has been shown to improve lipid and glucose metabolism in animal models of obesity. These benefits might suggest a potential therapeutic role for CT-1. However, beyond its beneficial properties, CT-1 has been also shown to induce some adverse effects, such as cardiac hypertrophy and adipose tissue inflammation. Although scientific evidence is still needed, CT-1 might be considered as a potential example of damage/danger-associated molecular pattern (DAMP in obesity-related cardiovascular diseases. In this narrative review, we aimed at discussing and updating evidence from basic research on the pathophysiological and potential therapeutic roles of CT-1 in obesity.

  7. Update on the pathophysiological activities of the cardiac molecule cardiotrophin-1 in obesity.

    Science.gov (United States)

    Asrih, Mohamed; Mach, François; Quercioli, Alessandra; Dallegri, Franco; Montecucco, Fabrizio

    2013-01-01

    Cardiotrophin-1 (CT-1) is a heart-targeting cytokine that has been reported to exert a variety of activities also in other organs such as the liver, adipose tissue, and atherosclerotic arteries. CT-1 has been shown to induce these effects via binding to a transmembrane receptor, comprising the leukaemia inhibitory factor receptor (LIFR β ) subunit and the glycoprotein 130 (gp130, a common signal transducer). Both local and systemic concentrations of CT-1 have been shown to potentially play a critical role in obesity. For instance, CT-1 plasma concentrations have been shown to be increased in metabolic syndrome (a cluster disease including obesity) probably due to adipose tissue overexpression. Interestingly, treatment with exogenous CT-1 has been shown to improve lipid and glucose metabolism in animal models of obesity. These benefits might suggest a potential therapeutic role for CT-1. However, beyond its beneficial properties, CT-1 has been also shown to induce some adverse effects, such as cardiac hypertrophy and adipose tissue inflammation. Although scientific evidence is still needed, CT-1 might be considered as a potential example of damage/danger-associated molecular pattern (DAMP) in obesity-related cardiovascular diseases. In this narrative review, we aimed at discussing and updating evidence from basic research on the pathophysiological and potential therapeutic roles of CT-1 in obesity.

  8. The Role of the Autonomic Nervous System in the Pathophysiology of Obesity

    Directory of Open Access Journals (Sweden)

    Daniela Guarino

    2017-09-01

    Full Text Available Obesity is reaching epidemic proportions globally and represents a major cause of comorbidities, mostly related to cardiovascular disease. The autonomic nervous system (ANS dysfunction has a two-way relationship with obesity. Indeed, alterations of the ANS might be involved in the pathogenesis of obesity, acting on different pathways. On the other hand, the excess weight induces ANS dysfunction, which may be involved in the haemodynamic and metabolic alterations that increase the cardiovascular risk of obese individuals, i.e., hypertension, insulin resistance and dyslipidemia. This article will review current evidence about the role of the ANS in short-term and long-term regulation of energy homeostasis. Furthermore, an increased sympathetic activity has been demonstrated in obese patients, particularly in the muscle vasculature and in the kidneys, possibily contributing to increased cardiovascular risk. Selective leptin resistance, obstructive sleep apnea syndrome, hyperinsulinemia and low ghrelin levels are possible mechanisms underlying sympathetic activation in obesity. Weight loss is able to reverse metabolic and autonomic alterations associated with obesity. Given the crucial role of autonomic dysfunction in the pathophysiology of obesity and its cardiovascular complications, vagal nerve modulation and sympathetic inhibition may serve as therapeutic targets in this condition.

  9. PKCε promotes human Th17 differentiation: Implications in the pathophysiology of psoriasis.

    Science.gov (United States)

    Martini, Silvia; Pozzi, Giulia; Carubbi, Cecilia; Masselli, Elena; Galli, Daniela; Di Nuzzo, Sergio; Banchini, Antonio; Gobbi, Giuliana; Vitale, Marco; Mirandola, Prisco

    2018-04-01

    PKCε is implicated in T cell activation and proliferation and is overexpressed in CD4 + -T cells from patients with autoimmune Hashimoto's thyroiditis. Although this might induce the suspicion that PKCε takes part in autoimmunity, its role in the molecular pathophysiology of immune-mediated disorders is still largely unknown. We studied PKCε expression in circulating CD4 + -T cells from patients with psoriasis, a skin disorder characterized by an increased amount of Th17 cells, a CD4 + subset that is critical in the development of autoimmunity. Although the mechanisms that underlie Th17 differentiation in humans are still unclear, we here show that: (i) PKCε is overexpressed in CD4 + -T cells from psoriatic patients, and its expression positively correlates with the severity of the disease, being reduced by effective phototherapy; (ii) PKCε interacts with Stat3 during Th17 differentiation and its overexpression results in an enhanced expression of Stat3 and pStat3(Ser727); iii) conversely, when PKCε is forcibly downregulated, CD4 + -T cells show lower levels of pStat3(Ser727) expression and defective in vitro expansion into the Th17-lineage. These data provide a novel insight into the molecular mechanisms of Th17 cell polarization that is known to play a crucial role in autoimmunity, pinpointing PKCε as a potential target in Th17-mediated diseases. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. The redox biology network in cancer pathophysiology and therapeutics

    Directory of Open Access Journals (Sweden)

    Gina Manda

    2015-08-01

    Full Text Available The review pinpoints operational concepts related to the redox biology network applied to the pathophysiology and therapeutics of solid tumors. A sophisticated network of intrinsic and extrinsic cues, integrated in the tumor niche, drives tumorigenesis and tumor progression. Critical mutations and distorted redox signaling pathways orchestrate pathologic events inside cancer cells, resulting in resistance to stress and death signals, aberrant proliferation and efficient repair mechanisms. Additionally, the complex inter-cellular crosstalk within the tumor niche, mediated by cytokines, redox-sensitive danger signals (HMGB1 and exosomes, under the pressure of multiple stresses (oxidative, inflammatory, metabolic, greatly contributes to the malignant phenotype. The tumor-associated inflammatory stress and its suppressive action on the anti-tumor immune response are highlighted. We further emphasize that ROS may act either as supporter or enemy of cancer cells, depending on the context. Oxidative stress-based therapies, such as radiotherapy and photodynamic therapy, take advantage of the cytotoxic face of ROS for killing tumor cells by a non-physiologically sudden, localized and intense oxidative burst. The type of tumor cell death elicited by these therapies is discussed. Therapy outcome depends on the differential sensitivity to oxidative stress of particular tumor cells, such as cancer stem cells, and therefore co-therapies that transiently down-regulate their intrinsic antioxidant system hold great promise. We draw attention on the consequences of the damage signals delivered by oxidative stress-injured cells to neighboring and distant cells, and emphasize the benefits of therapeutically triggered immunologic cell death in metastatic cancer. An integrative approach should be applied when designing therapeutic strategies in cancer, taking into consideration the mutational, metabolic, inflammatory and oxidative status of tumor cells, cellular

  11. Pathophysiological study of experimental hydrocephalus with computed tomography (CT) scan

    International Nuclear Information System (INIS)

    Murata, Takaho

    1980-01-01

    In order to investigate the pathophysiological changes during a development of hydrocephalus, the observations employing computed tomography (CT) scans and monitorings of intracranial epidural pressure (EDP) were performed in a series of kaolin-induced canine hydrocephalus. According to ''volume index'' of ventricles which was calculated from printed-out CT numbers, great individual variations were recognized in the degree of a ventricular enlargement as well as the rate of EDP. They are thought to be due to the difference in types of hydrocephalus, which have been induced by a discrepancy in the site and degree of an obstruction caused by kaolin. Periventricular lucency (PVL) of various degrees were also detected on CT scans of experimental hydrocephalus. It was always marked in the superolateral angle of frontal horn of the lateral ventricles, and differed in degree from severe to mild. PVLs were distinct in the acute stage with high EDP, and gradually became indistinct and had a tendency to disappear thereafter along with decreased EDP. They immediately disappeared after shunting operation. The pathogenesis of PVL was investigated with histological examinations, as well as by using contrast enhancement, Metrizamide ventriculography, the analysis of linear density profiles, and the measurement of regional cerebral blood flow (rCBF). Consequently, PVLs in hydrocephalus are considered to represent an acute edema or a chronic CSF retention in the periventricular white matter caused by increase of water content. In other words, they are regarded as a sign of present or preceding intraventricular hypertension on CT scan, and may become a clinical indication for shunting operation. (author)

  12. Metabolic syndrome, its pathophysiology and the role of melatonin.

    Science.gov (United States)

    Srinivasan, Venkataramanujam; Ohta, Yoshiji; Espino, Javier; Pariente, Jose A; Rodriguez, Ana B; Mohamed, Mahaneem; Zakaria, Rahimah

    2013-01-01

    Metabolic syndrome (MetS) is characterised by symptoms of obesity, insulin resistance, hypertension, dyslipidemia and diabetes mellitus. The pathophysiological mechanisms involved in MetS are complex and involved dysregulation of many biochemical and physiological regulatory mechanisms of the body. Elevated levels of low density lipoproteins like VLDL, and LDL with reduction of HDL seen in patients with MetS contribute to atherogenic dyslipedemia. Melatonin has been suggested to be effective in improving MetS through its anti-hyperlipidemic action. Melatonin reduced both adiposity, and body weight in experimental animal studies and also attenuated weight gain and obesityinduced metabolic alterations and this effect of melatonin is attributed to its anti-oxidative effects. Melatonin administration has been shown to inhibit insulin release by acting through both MT1 and MT2 melatonin receptors present in pancreatic β-cells. Melatonin also increased insulin sensitivity and glucose tolerance in animals fed with either high fat or high sucrose diet. Melatonin exerts most of its beneficial actions by acting through MT1 and MT2 melatonin receptors present in various tissues of the body and some of the metabolic actions of melatonin have been blocked by melatonin antagonist like luzindole. Ramelteon, the newly available melatonin agonist will also have more promising role in the control of MetS. The numbers of patents are available with regard to treatment of MetS. Drug related to antidepressant fluoxetine is used for treatment of MetS (US Patent No. 2008001400450). Anti-oxidants like S-adenosyl-methionine, Vitamin E, and Vitamin C have been found beneficial in treating MetS (US Patent No. 8063024). Melatonin being a powerful Antioxidant will have a promising role in treating patients with metabolic syndrome.

  13. Pompe disease: from pathophysiology to therapy and back again

    Directory of Open Access Journals (Sweden)

    Jeong-A eLim

    2014-07-01

    Full Text Available Pompe disease is a lysosomal storage disorder in which acid alpha-glucosidase is deficient or absent. Deficiency of this lysosomal enzyme results in progressive expansion of glycogen-filled lysosomes in multiple tissues, with cardiac and skeletal muscle being the most severely affected. The clinical spectrum ranges from fatal hypertrophic cardiomyopathy and skeletal muscle myopathy in infants to relatively attenuated forms, which manifest as a progressive myopathy without cardiac involvement. The currently available enzyme replacement therapy proved to be successful in reversing cardiac but not skeletal muscle abnormalities. Although the overall understanding of the disease has progressed, the pathophysiology of muscle damage remains poorly understood. Lysosomal enlargement/rupture has long been considered a mechanism of relentless muscle damage in Pompe disease. In past years, it became clear that this simple view of the pathology is inadequate; the pathological cascade involves dysfunctional autophagy, a major lysosome-dependent intracellular degradative pathway. The autophagic process in Pompe skeletal muscle is affected at the termination stage - impaired autophagosomal-lysosomal fusion. Yet another abnormality in the diseased muscle is the accelerated production of large, unrelated to ageing, lipofuscin deposits - a marker of cellular oxidative damage and a sign of mitochondrial dysfunction. The massive autophagic buildup and lipofuscin inclusions appear to cause a greater effect on muscle architecture than the enlarged lysosomes outside the autophagic regions. Furthermore, the dysfunctional autophagy affects the trafficking of the replacement enzyme and interferes with its delivery to the lysosomes. Several new therapeutic approaches have been tested in Pompe mouse models: substrate reduction therapy, lysosomal exocytosis following the overexpression of transcription factor EB and a closely related but distinct factor E3, and genetic

  14. [Mirror neurons: from anatomy to pathophysiological and therapeutic implications].

    Science.gov (United States)

    Mathon, B

    2013-04-01

    Mirror neurons are a special class of neurons discovered in the 1990s. They respond when we perform an action and also when we see someone else perform that action. They play a role in the pathophysiology of some neuropsychiatric diseases. Mirror neurons have been identified in humans: in Broca's area and the inferior parietal cortex. Their responses are qualitative and selective depending on the observed action. Emotions (including disgust) and empathy seem to operate according to a mirror mechanism. Indeed, the mirror system allows us to encode the sensory experience and to simulate the emotional state of others. This results in our improved identification of the emotions in others. Additionally, mirror neurons can encode an observed action in motor stimuli and allow its reproduction; thus, they are involved in imitation and learning. Current studies are assessing the role of mirror neurons in the pathopysiology of social-behavior disorders, including autism and schizophrenia. Understanding this mirror system will allow us to develop psychotherapy practices based on empathic resonance between the patient and the therapist. Also, some authors report that a passive rehabilitation technique, based on stimulation of the mirror-neuron system, has a beneficial effect in the treatment of patients with post-stroke motor deficits. Mirror neurons are an anatomical entity that enables improved understanding of behavior and emotions, and serves as a base for developing new cognitive therapies. Additional studies are needed to clarify the exact role of this neuronal system in social cognition and its role in the development of some neuropsychiatric diseases. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  15. Inflammatory and Other Biomarkers: Role in Pathophysiology and Prediction of Gestational Diabetes Mellitus

    Science.gov (United States)

    Abell, Sally K.; De Courten, Barbora; Boyle, Jacqueline A.; Teede, Helena J.

    2015-01-01

    Understanding pathophysiology and identifying mothers at risk of major pregnancy complications is vital to effective prevention and optimal management. However, in current antenatal care, understanding of pathophysiology of complications is limited. In gestational diabetes mellitus (GDM), risk prediction is mostly based on maternal history and clinical risk factors and may not optimally identify high risk pregnancies. Hence, universal screening is widely recommended. Here, we will explore the literature on GDM and biomarkers including inflammatory markers, adipokines, endothelial function and lipids to advance understanding of pathophysiology and explore risk prediction, with a goal to guide prevention and treatment of GDM. PMID:26110385

  16. Control of Adipocyte Differentiation in Different Fat Depots; Implications for Pathophysiology or Therapy

    Directory of Open Access Journals (Sweden)

    Xiuquan eMa

    2015-01-01

    Full Text Available Adipocyte differentiation and its impact on restriction or expansion of particular adipose tissue depots has physiological and pathophysiological significance in view of the different functions of these depots. Brown or beige fat [BAT] expansion can enhance thermogenesis, lipid oxidation, insulin sensitivity and glucose tolerance; conversely expanded visceral fat [VAT] is associated with insulin resistance, low grade inflammation, dyslipidaemia and cardiometabolic risk. The largest depot, subcutaneous white fat [WAT], has important beneficial characteristics including storage of lipid out of harms way and secretion of adipokines, especially leptin and adiponectin, with positive metabolic effects including lipid oxidation, energy utilisation, enhanced insulin action and an anti-inflammatory role. The absence of these functions in lipodystrophies leads to major metabolic disturbances. An ability to expand WAT adipocyte differentiation would seem an important defence mechanism against the detrimental effects of energy excess and limit harmful accumulation of lipid in ectopic sites, such as liver and muscle.Adipocyte differentiation involves a transcriptional cascade with PPARg being most important in WAT but less so in VAT, with increased angiogenesis also critical. The transcription factor, Islet1, is fairly specific to VAT and in vitro inhibits adipocyte differentiation. The physiological importance of Islet1 requires further study. Basic control of differentiation is similar in BAT but important differences include the effect of PGC-1a on mitochondrial biosynthesis and upregulation of UCP1; also PRDM16 plays a pivotal role in expression of the BAT phenotype.Modulation of the capacity or function of these different adipose tissue depots, by altering adipocyte differentiation or other means, holds promise for interventions that can be helpful in human disease, particularly cardiometabolic disorders associated with the world wide explosion of

  17. The Role of Hippocampus in the Pathophysiology of Depression

    Directory of Open Access Journals (Sweden)

    Özlem Donat Eker

    2009-06-01

    Full Text Available Hippocampus, as a part of the limbic cortex, has a variety of functions ranging from mating behavior to memory besides its role in the regulation of emotions. The hippocampus has reciprocal interactions of with other brain regions which act in the pathophysiology of major depressive disorder (MDD. Moreover, since the hippocampus is a scene for the neurogenesis, which can be seen as a response to antidepressant treatment, the hippocampus became a focus of attention in neuroimaging studies of MDD. It has been shown that brain derived neurotrophic factor (BDNF, that is responsible from the neurogenesis, is associated with the response to the antidepressants and antidepressant drugs are ineffective if neurogenesis is hindered.Hippocampal atrophy is expected with the decrease of neurogenesis as a result of the lower BDNF levels with the deleterious effects of glucocorticoids in depression. Recurrent and severe depression seems to cause such a volume reduction though first episode MDD subjects do not differ from healthy individuals in respect to their hippocampal volumes (HCVs measured by magnetic resonance imaging methods. One may argue regarding these findings that the atrophy in the hippocampus may be observed in the long term and the decrease in BDNF levels may predispose the volume reduction. Although it has been postulated that smaller HCV as a result of genetic and environmental factors and prior to the illness, may cause a vulnerability to MDD, sufficient evidence has not been accumulated yet and the view that HCV loss develops as depression progresses is widely accepted. Findings that serum BDNF (sBDNF is lower in MDD patients though HCVs of patients do not differ from healthy individuals and the positive correlation of sBDNF with HCV seen only in the patient group support this view. It can be assumed that depressed patients have sensitivity for the fluctuations in BDNF levels. Follow-up studies which consider effects of hipotalamo

  18. Congenital and childhood atrioventricular blocks: pathophysiology and contemporary management.

    Science.gov (United States)

    Baruteau, Alban-Elouen; Pass, Robert H; Thambo, Jean-Benoit; Behaghel, Albin; Le Pennec, Solène; Perdreau, Elodie; Combes, Nicolas; Liberman, Leonardo; McLeod, Christopher J

    2016-09-01

    Atrioventricular block is classified as congenital if diagnosed in utero, at birth, or within the first month of life. The pathophysiological process is believed to be due to immune-mediated injury of the conduction system, which occurs as a result of transplacental passage of maternal anti-SSA/Ro-SSB/La antibodies. Childhood atrioventricular block is therefore diagnosed between the first month and the 18th year of life. Genetic variants in multiple genes have been described to date in the pathogenesis of inherited progressive cardiac conduction disorders. Indications and techniques of cardiac pacing have also evolved to allow safe permanent cardiac pacing in almost all patients, including those with structural heart abnormalities. Early diagnosis and appropriate management are critical in many cases in order to prevent sudden death, and this review critically assesses our current understanding of the pathogenetic mechanisms, clinical course, and optimal management of congenital and childhood AV block. • Prevalence of congenital heart block of 1 per 15,000 to 20,000 live births. AV block is defined as congenital if diagnosed in utero, at birth, or within the first month of life, whereas childhood AV block is diagnosed between the first month and the 18th year of life. As a result of several different etiologies, congenital and childhood atrioventricular block may occur in an entirely structurally normal heart or in association with concomitant congenital heart disease. Cardiac pacing is indicated in symptomatic patients and has several prophylactic indications in asymptomatic patients to prevent sudden death. • Autoimmune, congenital AV block is associated with a high neonatal mortality rate and development of dilated cardiomyopathy in 5 to 30 % cases. What is New: • Several genes including SCN5A have been implicated in autosomal dominant forms of familial progressive cardiac conduction disorders. • Leadless pacemaker technology and gene therapy for

  19. Organelle targeting: third level of drug targeting

    Directory of Open Access Journals (Sweden)

    Sakhrani NM

    2013-07-01

    Full Text Available Niraj M Sakhrani, Harish PadhDepartment of Cell and Molecular Biology, BV Patel Pharmaceutical Education and Research Development (PERD Centre, Gujarat, IndiaAbstract: Drug discovery and drug delivery are two main aspects for treatment of a variety of disorders. However, the real bottleneck associated with systemic drug administration is the lack of target-specific affinity toward a pathological site, resulting in systemic toxicity and innumerable other side effects as well as higher dosage requirement for efficacy. An attractive strategy to increase the therapeutic index of a drug is to specifically deliver the therapeutic molecule in its active form, not only into target tissue, nor even to target cells, but more importantly, into the targeted organelle, ie, to its intracellular therapeutic active site. This would ensure improved efficacy and minimize toxicity. Cancer chemotherapy today faces the major challenge of delivering chemotherapeutic drugs exclusively to tumor cells, while sparing normal proliferating cells. Nanoparticles play a crucial role by acting as a vehicle for delivery of drugs to target sites inside tumor cells. In this review, we spotlight active and passive targeting, followed by discussion of the importance of targeting to specific cell organelles and the potential role of cell-penetrating peptides. Finally, the discussion will address the strategies for drug/DNA targeting to lysosomes, mitochondria, nuclei and Golgi/endoplasmic reticulum.Keywords: intracellular drug delivery, cancer chemotherapy, therapeutic index, cell penetrating peptides

  20. The Pathophysiology of Thyroid Eye Disease (TED): Implications for Immunotherapy

    Science.gov (United States)

    Gupta, Shivani; Douglas, Raymond

    2012-01-01

    Purpose of Review Thyroid eye disease (TED) is a poorly understood autoimmune manifestation most commonly associated with Graves’ disease. Current nonspecific treatment paradigms offer symptomatic improvement but fail to target the underlying pathogenic mechanisms and thus, do not significantly alter the long-term disease outcome. The purpose of this review is to provide an update of the current understanding of the immunopathogenesis of TED and explore these implications for targeted immunotherapy. Recent Findings Orbital fibroblasts are integral to the pathogenesis of TED and may modulate immune responses by production of cytokines and hyaluronan in response to activation of shared autoantigens including thyrotropin receptor (TSHR) and insulin-like growth factor-1 receptor (IGF-R1). Fibrocytes share many of these phenotypic and functional features, suggesting a link between systemic and site-specific disease. Use of targeted immunotherapies in TED is limited, though data from the use Rituximab (RTX), a B cell depleting agent, are encouraging. Sustained clinical response has been seen with RTX in several reports, despite return of peripheral B cell levels to pretreatment levels. Additionally, this response appears to be independent to cytokine and antibody production, suggesting possible modulation of antigen presentation as a mechanism of its effect. Summary Progressive advances in the understanding of the immunopathogenesis of TED continue to spur clinical trials utilizing targeted immune therapies. Continued understanding of the molecular mechanisms of disease will expand potential treatments for TED patients and obviate the need for reconstructive surgical therapies. PMID:21730841

  1. Nicotinic Acetylcholine Receptors in the Pathophysiology of Alzheimer's Disease

    DEFF Research Database (Denmark)

    Thomsen, Morten Skøtt; Andreasen T., Jesper; Arvaniti, Maria

    2016-01-01

    Nicotinic acetylcholine receptors (nAChRs) have been pursued for decades as potential molecular targets to treat cognitive dysfunction in Alzheimer's disease (AD) due to their positioning within regions of the brain critical in learning and memory, such as the prefrontal cortex and hippocampus...

  2. Monoglyceride lipase as a drug target: At the crossroads of arachidonic acid metabolism and endocannabinoid signaling.

    Science.gov (United States)

    Grabner, Gernot F; Zimmermann, Robert; Schicho, Rudolf; Taschler, Ulrike

    2017-07-01

    Monoglyerides (MGs) are short-lived, intermediary lipids deriving from the degradation of phospho- and neutral lipids, and monoglyceride lipase (MGL), also designated as monoacylglycerol lipase (MAGL), is the major enzyme catalyzing the hydrolysis of MGs into glycerol and fatty acids. This distinct function enables MGL to regulate a number of physiological and pathophysiological processes since both MGs and fatty acids can act as signaling lipids or precursors thereof. The most prominent MG species acting as signaling lipid is 2-arachidonoyl glycerol (2-AG) which is the most abundant endogenous agonist of cannabinoid receptors in the body. Importantly, recent observations demonstrate that 2-AG represents a quantitatively important source for arachidonic acid, the precursor of prostaglandins and other inflammatory mediators. Accordingly, MGL-mediated 2-AG degradation affects lipid signaling by cannabinoid receptor-dependent and independent mechanisms. Recent genetic and pharmacological studies gave important insights into MGL's role in (patho-)physiological processes, and the enzyme is now considered as a promising drug target for a number of disorders including cancer, neurodegenerative and inflammatory diseases. This review summarizes the basics of MG (2-AG) metabolism and provides an overview on the therapeutic potential of MGL. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Posttraumatic Headache: Basic Mechanisms and Therapeutic Targets.

    Science.gov (United States)

    Kamins, Joshua; Charles, Andrew

    2018-06-01

    Frequent or continuous headache, often refractory to medical therapy, is a common occurrence after head trauma. In addition to being the most common acute symptom after traumatic brain injury (TBI), headache is also one of the most persistent and disabling symptoms. Different studies indicate that 18-58% of those suffering a TBI will have significant headache at 1 year following the trauma. In addition to being disabling on its own, posttraumatic headache (PTH) is a predictor of overall outcome after concussion. Despite its remarkable prevalence and associated social and economic costs, many fundamental and important questions about PTH remain unanswered. The purpose of this review is to identify key questions regarding the clinical characteristics of posttraumatic headache, its basic mechanisms, and its optimal management. We discuss phenotypic features of PTH, pathophysiological mechanisms of TBI including potential overlaps with those of migraine and other primary headache disorders, and potential novel targets for treatment. We suggest different strategies to finding answers to the questions regarding PTH in order to advance the understanding of the disorder and develop more effective therapies. © 2018 American Headache Society.

  4. Pathophysiology and multifactorial etiology of acquired vasospastic disease (Raynaud syndrome) in vibration-exposed workers.

    Science.gov (United States)

    Gemne, G

    1982-12-01

    The article reviews available pathophysiological evidence for a multifactorial etiology of the Raynaud type of peripheral circulation disorder in persons exposed to vibration from handheld tools and discusses the consequences this viewpoint may have for diagnostics, preventive work, and research.

  5. Symptoms in Inflammatory Bowel Disease: pathophysiologic aspects and their relation with disease activity

    NARCIS (Netherlands)

    Minderhoud, I.M.

    2007-01-01

    Symptoms in Inflammatory Bowel Disease: pathophysiologic aspects and their relation with disease activity Inflammatory bowel disease (IBD) comprises ulcerative colitis (UC) and Crohn's disease (CD). IBD patients frequently complain of fatigue, and a substantial proportion of the patients have

  6. The rise of pathophysiologic research in the United States: the role of two Harvard hospitals.

    Science.gov (United States)

    Tishler, Peter V

    2013-01-01

    Pathophysiologic research, the major approach to understanding and treating disease, was created in the 20th century, and two Harvard-affiliated hospitals, the Peter Bent Brigham Hospital and Boston City Hospital, played a key role in its development. After the Flexner Report of 1910, medical students were assigned clinical clerkships in teaching hospitals. Rockefeller-trained Francis Weld Peabody, who was committed to investigative, pathophysiologic research, was a critical leader in these efforts. At the Brigham, Harvard medical students observed patients closely and asked provocative questions about their diseases. Additionally, physicians returned from World War I with questions concerning the pathophysiology of wartime injuries. At the Boston City Hospital's new Thorndike Memorial Laboratory, Peabody fostered investigative question-based research by physicians. These physicians expanded pathophysiologic investigation from the 1920s. Post-war, Watson and Crick's formulation of the structure of DNA led shortly to modern molecular biology and new research approaches that are being furthered at the Boston Hospitals.

  7. Encapsulating Peritoneal Sclerosis: A study on pathophysiology, clinical aspects and management

    NARCIS (Netherlands)

    S.M. Habib (Meelad)

    2014-01-01

    markdownabstract__Abstract__ This thesis describes the results of studies focusing on the pathophysiology, clinical aspects, and management of encapsulating peritoneal sclerosis (EPS). We have reported on the presence of inflammation in EPS, described several clinical aspects, and focused on

  8. The possible role of gastrointestinal endocrine cells in the pathophysiology of irritable bowel syndrome.

    Science.gov (United States)

    El-Salhy, Magdy; Hausken, Trygve; Gilja, Odd Helge; Hatlebakk, Jan Gunnar

    2017-02-01

    The etiology of irritable bowel syndrome (IBS) is unknown, but several factors appear to play a role in its pathophysiology, including abnormalities of the gastrointestinal endocrine cells. The present review illuminates the possible role of gastrointestinal hormones in the pathophysiology of IBS and the possibility of utilizing the current knowledge in treating the disease. Areas covered: Research into the intestinal endocrine cells and their possible role in the pathophysiology of IBS is discussed. Furthermore, the mechanisms underlying the abnormalities in the gastrointestinal endocrine cells in IBS patients are revealed. Expert commentary: The abnormalities observed in the gastrointestinal endocrine cells in IBS patients explains their visceral hypersensitivity, gastrointestinal dysmotility, and abnormal intestinal secretion, as well as the interchangeability of symptoms over time. Clarifying the role of the intestinal stem cells in the pathophysiology of IBS may lead to new treatment methods for IBS.

  9. Cardiometabolic Risk and Female Sexuality-Part I. Risk Factors and Potential Pathophysiological Underpinnings for Female Vasculogenic Sexual Dysfunction Syndromes.

    Science.gov (United States)

    Maseroli, Elisa; Scavello, Irene; Vignozzi, Linda

    2018-05-02

    Erectile dysfunction is recognized as an opportunity for preventing cardiovascular (CV) events, and assessing the impairment of penile vascular flow by Doppler ultrasound is an important tool to ascertain CV risk. Conversely, the role of genital vascular impairment in the pathophysiology of female sexual dysfunction (FSD) remains contentious. To focus on the current scientific support for an association between CV risk factors and female sexual health in the 1st part of a 2-part review. A thorough literature search of peer-reviewed publications on the associations between CV risk factors and FSD and their underlying mechanisms was performed using the PubMed database. We present a summary of the evidence from clinical studies and discuss the possible mechanisms providing the pathophysiologic bases of vasculogenic FSD syndromes. The peripheral sexual response in women is a vascular-dependent event, and evidence suggests that cardiometabolic-related perturbations in endothelial function can determine vascular insufficiency in female genital tissues. Although epidemiologic and observational studies demonstrate that the prevalence of FSD is higher in women with diabetes mellitus, a cause-effect relation between these clinical conditions cannot be assumed. Evidence on the effect of obesity, metabolic syndrome, and polycystic ovary syndrome on sexual function in women is controversial. Data on the associations of dyslipidemia and hypertension with FSD are limited. Common cardiometabolic alterations could affect vascular function in the female genital tract. Based on limited data, there is an association between CV risk factors and female sexual health in women; however, this association appears milder than in men. Maseroli E, Scavello I, Vignozzi L. Cardiometabolic Risk and Female Sexuality-Part I. Risk Factors and Potential Pathophysiological Underpinnings for Female Vasculogenic Sexual Dysfunction Syndromes. Sex Med Rev 2018;X:XXX-XXX. Copyright © 2018 International

  10. Elucidating the Role of Neurotensin in the Pathophysiology and Management of Major Mental Disorders

    Directory of Open Access Journals (Sweden)

    Mona M Boules

    2014-06-01

    Full Text Available Neurotensin (NT is a neuropeptide that is closely associated with, and is thought to modulate, dopaminergic and other neurotransmitter systems involved in the pathophysiology of various mental disorders. This review outlines data implicating NT in the pathophysiology and management of major mental disorders such as schizophrenia, drug addiction, and autism. The data suggest that NT receptor analogs have the potential to be used as novel therapeutic agents acting through modulation of neurotransmitter systems dys-regulated in these disorders.

  11. Target laboratory

    International Nuclear Information System (INIS)

    Ephraim, D.C.; Pednekar, A.R.

    1993-01-01

    A target laboratory to make stripper foils for the accelerator and various targets for use in the experiments is set up in the pelletron accelerator facility. The facilities available in the laboratory are: (1) D.C. glow discharge setup, (2) carbon arc set up, and (3) vacuum evaporation set up (resistance heating), electron beam source, rolling mill - all for target preparation. They are described. Centrifugal deposition technique is used for target preparation. (author). 3 figs

  12. Ice targets

    International Nuclear Information System (INIS)

    Pacheco, C.; Stark, C.; Tanaka, N.; Hodgkins, D.; Barnhart, J.; Kosty, J.

    1979-12-01

    This report presents a description of ice targets that were constructed for research work at the High Resolution Spectrometer (HRS) and at the Energetic Pion Channel and Spectrometer (EPICS). Reasons for using these ice targets and the instructions for their construction are given. Results of research using ice targets will be published at a later date

  13. Pathophysiology of cerebral circulatory disorders in idiopathic normal pressure hydrocephalus

    International Nuclear Information System (INIS)

    Takeuchi, Totaro; Goto, Hiromi; Izaki, Kenji

    2007-01-01

    -score images, revealed a reduction or disappearance of the hypoperfusion site in 19 of 31 (61.3%) cases, either no-change or a shift of the hypoperfusion site in 12 of 31 (38.7%) cases, and a correlation between the pattern of cortical blood flow reduction on ARG method and the pattern of cerebral cortex hypoperfusion on 3D-SSP Z-score images after surgery. Cerebral circulatory disorders in iNPH manifest as either of two pathophysiological conditions: the ''circulatory disorder of the cerebral cortical region'' and the ''circulatory disorder of the thalamus-basal ganglia region.'' Various patterns develop according to the disease stage. (author)

  14. Pathophysiological Responses in Rat and Mouse Models of Radiation-Induced Brain Injury.

    Science.gov (United States)

    Yang, Lianhong; Yang, Jianhua; Li, Guoqian; Li, Yi; Wu, Rong; Cheng, Jinping; Tang, Yamei

    2017-03-01

    The brain is the major dose-limiting organ in patients undergoing radiotherapy for assorted conditions. Radiation-induced brain injury is common and mainly occurs in patients receiving radiotherapy for malignant head and neck tumors, arteriovenous malformations, or lung cancer-derived brain metastases. Nevertheless, the underlying mechanisms of radiation-induced brain injury are largely unknown. Although many treatment strategies are employed for affected individuals, the effects remain suboptimal. Accordingly, animal models are extremely important for elucidating pathogenic radiation-associated mechanisms and for developing more efficacious therapies. So far, models employing various animal species with different radiation dosages and fractions have been introduced to investigate the prevention, mechanisms, early detection, and management of radiation-induced brain injury. However, these models all have limitations, and none are widely accepted. This review summarizes the animal models currently set forth for studies of radiation-induced brain injury, especially rat and mouse, as well as radiation dosages, dose fractionation, and secondary pathophysiological responses.

  15. Implications of Schwann Cells Biomechanics and Mechanosensitivity for Peripheral Nervous System Physiology and Pathophysiology

    Directory of Open Access Journals (Sweden)

    Gonzalo Rosso

    2017-10-01

    Full Text Available The presence of bones around the central nervous system (CNS provides it with highly effective physiologically crucial mechanical protection. The peripheral nervous system (PNS, in contrast, lacks this barrier. Consequently, the long held belief is that the PNS is mechanically vulnerable. On the other hand, the PNS is exposed to a variety of physiological mechanical stresses during regular daily activities. This fact prompts us to question the dogma of PNS mechanical vulnerability. As a matter of fact, impaired mechanics of PNS nerves is associated with neuropathies with the liability to mechanical stresses paralleled by significant impairment of PNS physiological functions. Our recent biomechanical integrity investigations on nerve fibers from wild-type and neuropathic mice lend strong support in favor of natural mechanical protection of the PNS and demonstrate a key role of Schwann cells (SCs therein. Moreover, recent works point out that SCs can sense mechanical properties of their microenvironment and the evidence is growing that SCs mechanosensitivity is important for PNS development and myelination. Hence, SCs exhibit mechanical strength necessary for PNS mechanoprotection as well as mechanosensitivity necessary for PNS development and myelination. This mini review reflects on the intriguing dual ability of SCs and implications for PNS physiology and pathophysiology.

  16. Convergence of neuro-endocrine-immune pathways in the pathophysiology of irritable bowel syndrome.

    Science.gov (United States)

    Buckley, Maria M; O'Mahony, Siobhain M; O'Malley, Dervla

    2014-07-21

    Disordered signalling between the brain and the gut are generally accepted to underlie the functional bowel disorder, irritable bowel syndrome (IBS). However, partly due to the lack of disease-defining biomarkers, understanding the aetiology of this complex and multifactorial disease remains elusive. This common gastrointestinal disorder is characterised by alterations in bowel habit such as diarrhoea and/or constipation, bloating and abdominal pain, and symptom exacerbation has been linked with periods of stress, both psychosocial and infection-related. Indeed, a high level of comorbidity exists between IBS and stress-related mood disorders such as anxiety and depression. Moreover, studies have observed alterations in autonomic output and neuro-endocrine signalling in IBS patients. Accumulating evidence indicates that a maladaptive stress response, probably mediated by the stress hormone, corticotropin-releasing factor contributes to the initiation, persistence and severity of symptom flares. Other risk factors for developing IBS include a positive family history, childhood trauma, dietary factors and prior gastrointestinal infection. An emerging role has been attributed to the importance of immune factors in the pathophysiology of IBS with evidence of altered cytokine profiles and increased levels of mucosal immune cells. These factors have also been shown to have direct effects on neural signalling. This review discusses how pathological changes in neural, immune and endocrine pathways, and communication between these systems, contribute to symptom flares in IBS.

  17. ACE Inhibitor-Induced Angioedema of the Intestine: Case Report, Incidence, Pathophysiology, Diagnosis and Management

    Directory of Open Access Journals (Sweden)

    Gavin Oudit

    2001-01-01

    Full Text Available A case report of fosinopril-induced angioedema of the intestine with a chronic course accompanied by multiple acute exacerbations is described. Angiotensin-converting enzyme (ACE inhibitor-induced angioedema of the intestine (AIAI occurs in a minority of patients taking an ACE inhibitor. The clinical presentation encompasses acute abdominal symptoms, pronounced bowel edema and ascites with occasional facial and/or oropharyngeal swelling. AIAI is diagnosed based on the temporal relationship between the symptomatic presentation and drug use, absence of alternative diagnoses including other causes of angioedema, and the prompt resolution of symptoms upon discontinuation of the ACE inhibitor. Prompt radiological investigation (abdominal computerized tomography and/or ultrasound is critical in making an early diagnosis and in preventing unnecessary surgical intervention. There is a female predominance of AIAI, which may reflect the interaction of estradiol with the various pathways involved in the pathophysiology of AIAI. Management of AIAI consists mainly of conservative measures and discontinuation of the ACE inhibitor. Angiotensin II receptor antagonists should not be considered as appropriate alternatives. Awareness and knowledge of AIAI are important because of the increasing use of ACE inhibitors, current delays in making the diagnosis, obvious management strategies once the diagnosis is made and the dysutility of alternative diagnoses, which may lead to considerable morbidity. AIAI must be considered in patients taking ACE inhibitors who develop gastrointestinal complaints irrespective of the duration of the therapy.

  18. Pathophysiologic aspects of the development of cognitive disorders in chronic heart failure in elderly patients

    Directory of Open Access Journals (Sweden)

    M A Pokachalova

    2018-04-01

    Full Text Available The present literature review presents current views on pathophysiologic aspects of the formation and progression of cognitive disorders in chronic heart failure in elderly patients. Advanced age itself is an important predictor of the development of cardiovascular, neurodegenerative and other diseases. Involutive changes of cardiovascular system are known to potentiate the development of chronic heart failure. Heart failure in older people usually develops gradually. Formation of the cognitive deficit in heart disease is associated with chronic cerebral ischemia as well as a cascade of neurochemical processes occurring in the brain, eventually forming a vicious circle. Often the symptoms of cerebral ischemia due to reduced stroke volume occur much earlier than congestion signs in other organs and systems. Chronic cerebral ischemia that occurs due to violation of cerebral hemodynamics, is associated with both extracerebral and intracerebral causes, which in turn contributes to the development of chronic brain hypoxia and aggravation of cognitive dysfunction. Thus, the features of the development and course of disease in people of older age groups indicate that in geriatric practice existing diagnostic schemes are not always applicable. When observing patients of elderly and senile age with chronic heart failure, during the assessment of their condition and running diagnostic tests, special attention should be payed to the earliest detection of cognitive dysfunction signs in order to correct the patient's treatment and improve quality of life.

  19. Evaluation of a complementary cyber education program for a pathophysiology class.

    Science.gov (United States)

    Yoo, Ji-Soo; Ryue, Sook-Hee; Lee, Jung Eun; Ahn, Jeong-Ah

    2009-12-01

    The goal of this study was to develop and evaluate a complementary cyber education program for a required pathophysiology class for nursing students. The cyber education program comprised electronic bulletin boards, correspondence material storage, an announcement section, a report submission section, reference sites, and statistics on learning rates. Twelve online lectures complemented five lectures in the classroom. To evaluate the course's educational effectiveness, we performed an online objective questionnaire and an open questionnaire survey anonymously, and compared the complementary cyber education program with traditional classroom education. The complementary cyber education program effected significant improvements in scores for importance with regard to major, clarity of goals and education plans for courses, professor readiness, preciseness and description of lectures, amount and efficiency of assignments, and fairness in appraisal standards compared with the traditional classroom education group. This study indicates that a complementary cyber education program provides nursing students with the flexibility of time and space, the newest information through updated lectures, efficient motivational aids through intimacy between the lecturer and students, and concrete and meaningful tasks. The complementary cyber education course also increased student effort toward studying and student satisfaction with the class.

  20. Type 2 diabetes across generations: from pathophysiology to prevention and management.

    Science.gov (United States)

    Nolan, Christopher J; Damm, Peter; Prentki, Marc

    2011-07-09

    Type 2 diabetes is now a pandemic and shows no signs of abatement. In this Seminar we review the pathophysiology of this disorder, with particular attention to epidemiology, genetics, epigenetics, and molecular cell biology. Evidence is emerging that a substantial part of diabetes susceptibility is acquired early in life, probably owing to fetal or neonatal programming via epigenetic phenomena. Maternal and early childhood health might, therefore, be crucial to the development of effective prevention strategies. Diabetes develops because of inadequate islet β-cell and adipose-tissue responses to chronic fuel excess, which results in so-called nutrient spillover, insulin resistance, and metabolic stress. The latter damages multiple organs. Insulin resistance, while forcing β cells to work harder, might also have an important defensive role against nutrient-related toxic effects in tissues such as the heart. Reversal of overnutrition, healing of the β cells, and lessening of adipose tissue defects should be treatment priorities. Copyright © 2011 Elsevier Ltd. All rights reserved.

  1. Psychomotor Retardation in Depression: A Systematic Review of Diagnostic, Pathophysiologic, and Therapeutic Implications

    Directory of Open Access Journals (Sweden)

    Djamila Bennabi

    2013-01-01

    Full Text Available Psychomotor retardation is a central feature of depression which includes motor and cognitive impairments. Effective management may be useful to improve the classification of depressive subtypes and treatment selection, as well as prediction of outcome in patients with depression. The aim of this paper was to review the current status of knowledge regarding psychomotor retardation in depression, in order to clarify its role in the diagnostic management of mood disorders. Retardation modifies all the actions of the individual, including motility, mental activity, and speech. Objective assessments can highlight the diagnostic importance of psychomotor retardation, especially in melancholic and bipolar depression. Psychomotor retardation is also related to depression severity and therapeutic change and could be considered a good criterion for the prediction of therapeutic effect. The neurobiological process underlying the inhibition of activity includes functional deficits in the prefrontal cortex and abnormalities in dopamine neurotransmission. Future investigations of psychomotor retardation should help improve the understanding of the pathophysiological mechanisms underlying mood disorders and contribute to improving their therapeutic management.

  2. Polycystic Ovary Syndrome, Insulin Resistance, and Obesity: Navigating the Pathophysiologic Labyrinth

    Science.gov (United States)

    Rojas, Joselyn; Chávez, Mervin; Olivar, Luis; Rojas, Milagros; Morillo, Jessenia; Mejías, José; Calvo, María; Bermúdez, Valmore

    2014-01-01

    Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine-metabolic disorder that implies various severe consequences to female health, including alarming rates of infertility. Although its exact etiology remains elusive, it is known to feature several hormonal disturbances, including hyperandrogenemia, insulin resistance (IR), and hyperinsulinemia. Insulin appears to disrupt all components of the hypothalamus-hypophysis-ovary axis, and ovarian tissue insulin resistance results in impaired metabolic signaling but intact mitogenic and steroidogenic activity, favoring hyperandrogenemia, which appears to be the main culprit of the clinical picture in PCOS. In turn, androgens may lead back to IR by increasing levels of free fatty acids and modifying muscle tissue composition and functionality, perpetuating this IR-hyperinsulinemia-hyperandrogenemia cycle. Nonobese women with PCOS showcase several differential features, with unique biochemical and hormonal profiles. Nevertheless, lean and obese patients have chronic inflammation mediating the long term cardiometabolic complications and comorbidities observed in women with PCOS, including dyslipidemia, metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. Given these severe implications, it is important to thoroughly understand the pathophysiologic interconnections underlying PCOS, in order to provide superior therapeutic strategies and warrant improved quality of life to women with this syndrome. PMID:25763405

  3. Polycystic Ovary Syndrome, Insulin Resistance, and Obesity: Navigating the Pathophysiologic Labyrinth

    Directory of Open Access Journals (Sweden)

    Joselyn Rojas

    2014-01-01

    Full Text Available Polycystic ovary syndrome (PCOS is a highly prevalent endocrine-metabolic disorder that implies various severe consequences to female health, including alarming rates of infertility. Although its exact etiology remains elusive, it is known to feature several hormonal disturbances, including hyperandrogenemia, insulin resistance (IR, and hyperinsulinemia. Insulin appears to disrupt all components of the hypothalamus-hypophysis-ovary axis, and ovarian tissue insulin resistance results in impaired metabolic signaling but intact mitogenic and steroidogenic activity, favoring hyperandrogenemia, which appears to be the main culprit of the clinical picture in PCOS. In turn, androgens may lead back to IR by increasing levels of free fatty acids and modifying muscle tissue composition and functionality, perpetuating this IR-hyperinsulinemia-hyperandrogenemia cycle. Nonobese women with PCOS showcase several differential features, with unique biochemical and hormonal profiles. Nevertheless, lean and obese patients have chronic inflammation mediating the long term cardiometabolic complications and comorbidities observed in women with PCOS, including dyslipidemia, metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. Given these severe implications, it is important to thoroughly understand the pathophysiologic interconnections underlying PCOS, in order to provide superior therapeutic strategies and warrant improved quality of life to women with this syndrome.

  4. Polycystic ovary syndrome, insulin resistance, and obesity: navigating the pathophysiologic labyrinth.

    Science.gov (United States)

    Rojas, Joselyn; Chávez, Mervin; Olivar, Luis; Rojas, Milagros; Morillo, Jessenia; Mejías, José; Calvo, María; Bermúdez, Valmore

    2014-01-01

    Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine-metabolic disorder that implies various severe consequences to female health, including alarming rates of infertility. Although its exact etiology remains elusive, it is known to feature several hormonal disturbances, including hyperandrogenemia, insulin resistance (IR), and hyperinsulinemia. Insulin appears to disrupt all components of the hypothalamus-hypophysis-ovary axis, and ovarian tissue insulin resistance results in impaired metabolic signaling but intact mitogenic and steroidogenic activity, favoring hyperandrogenemia, which appears to be the main culprit of the clinical picture in PCOS. In turn, androgens may lead back to IR by increasing levels of free fatty acids and modifying muscle tissue composition and functionality, perpetuating this IR-hyperinsulinemia-hyperandrogenemia cycle. Nonobese women with PCOS showcase several differential features, with unique biochemical and hormonal profiles. Nevertheless, lean and obese patients have chronic inflammation mediating the long term cardiometabolic complications and comorbidities observed in women with PCOS, including dyslipidemia, metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. Given these severe implications, it is important to thoroughly understand the pathophysiologic interconnections underlying PCOS, in order to provide superior therapeutic strategies and warrant improved quality of life to women with this syndrome.

  5. Functional O-GlcNAc modifications: Implications in molecular regulation and pathophysiology

    Science.gov (United States)

    Wells, Lance

    2016-01-01

    O-linked β-N-acetylglucosamine (O-GlcNAc) is a regulatory post-translational modification of intracellular proteins. The dynamic and inducible cycling of the modification is governed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) in response to UDP-GlcNAc levels in the hexosamine biosynthetic pathway (HBP). Due to its reliance on glucose flux and substrate availability, a major focus in the field has been on how O-GlcNAc contributes to metabolic disease. For years this post-translational modification has been known to modify thousands of proteins implicated in various disorders, but direct functional connections have until recently remained elusive. New research is beginning to reveal the specific mechanisms through which O-GlcNAc influences cell dynamics and disease pathology including clear examples of O-GlcNAc modification at a specific site on a given protein altering its biological functions. The following review intends to focus primarily on studies in the last half decade linking O-GlcNAc modification of proteins with chromatin-directed gene regulation, developmental processes, and several metabolically related disorders including Alzheimer’s, heart disease and cancer. These studies illustrate the emerging importance of this post-translational modification in biological processes and multiple pathophysiologies. PMID:24524620

  6. Translational research: precision medicine, personalized medicine, targeted therapies: marketing or science?

    Science.gov (United States)

    Marquet, Pierre; Longeray, Pierre-Henry; Barlesi, Fabrice; Ameye, Véronique; Augé, Pascale; Cazeneuve, Béatrice; Chatelut, Etienne; Diaz, Isabelle; Diviné, Marine; Froguel, Philippe; Goni, Sylvia; Gueyffier, François; Hoog-Labouret, Natalie; Mourah, Samia; Morin-Surroca, Michèle; Perche, Olivier; Perin-Dureau, Florent; Pigeon, Martine; Tisseau, Anne; Verstuyft, Céline

    2015-01-01

    Personalized medicine is based on: 1) improved clinical or non-clinical methods (including biomarkers) for a more discriminating and precise diagnosis of diseases; 2) targeted therapies of the choice or the best drug for each patient among those available; 3) dose adjustment methods to optimize the benefit-risk ratio of the drugs chosen; 4) biomarkers of efficacy, toxicity, treatment discontinuation, relapse, etc. Unfortunately, it is still too often a theoretical concept because of the lack of convenient diagnostic methods or treatments, particularly of drugs corresponding to each subtype of pathology, hence to each patient. Stratified medicine is a component of personalized medicine employing biomarkers and companion diagnostics to target the patients likely to present the best benefit-risk balance for a given active compound. The concept of targeted therapy, mostly used in cancer treatment, relies on the existence of a defined molecular target, involved or not in the pathological process, and/or on the existence of a biomarker able to identify the target population, which should logically be small as compared to the population presenting the disease considered. Targeted therapies and biomarkers represent important stakes for the pharmaceutical industry, in terms of market access, of return on investment and of image among the prescribers. At the same time, they probably represent only the first generation of products resulting from the combination of clinical, pathophysiological and molecular research, i.e. of translational research. © 2015 Société Française de Pharmacologie et de Thérapeutique.

  7. Effects of a chronic lead intoxication on the pathophysiological changes in the digestive system and interactions of lead with trace elements

    Directory of Open Access Journals (Sweden)

    Michał Dobrakowski

    2013-09-01

    Full Text Available Lead compounds are still the most dangerous poisons. The effects of lead intoxication occur mainly as a result of environmental exposure through lead paints, dust, soil, potable water. Pathophysiology of lead poisoning is still poorly understood, especially gastrointestinal and hepatological aspects. In consequence, the aim of the paper is to present the most important data concerning the effects of chronic lead exposure on the digestive system and the interactions between lead and selected trace elements.

  8. Therapeutic targets of renin-angiotensin system in ocular disorders

    Directory of Open Access Journals (Sweden)

    Rajesh Choudhary

    2017-03-01

    Conclusions: The RAS components are present in the extrarenal tissues including ocular tissue and have an imperative role in the ocular pathophysiology. The clinical studies are needed to show the role of therapeutic modalities targeting RAS in the treatment of different ocular disorders.

  9. Causes of CNS inflammation and potential targets for anticonvulsants.

    Science.gov (United States)

    Falip, Mercé; Salas-Puig, Xavier; Cara, Carlos

    2013-08-01

    Inflammation is one of the most important endogenous defence mechanisms in an organism. It has been suggested that inflammation plays an important role in the pathophysiology of a number of human epilepsies and convulsive disorders, and there is clinical and experimental evidence to suggest that inflammatory processes within the CNS may either contribute to or be a consequence of epileptogenesis. This review discusses evidence from human studies on the role of inflammation in epilepsy and highlights potential new targets in the inflammatory cascade for antiepileptic drugs. A number of mechanisms have been shown to be involved in CNS inflammatory reactions. These include an inflammatory response at the level of the blood-brain barrier (BBB), immune-mediated damage to the CNS, stress-induced release of inflammatory mediators and direct neuronal dysfunction or damage as a result of inflammatory reactions. Mediators of inflammation in the CNS include interleukin (IL)-1β, tumour necrosis factor-α, nuclear factor-κB and toll-like receptor-4 (TLR4). IL-1β, BBB and high-mobility group box-1-TLR4 signalling appear to be the most promising targets for anticonvulsant agents directed at inflammation. Such agents may provide effective therapy for drug-resistant epilepsies in the future.

  10. Target support for inertial confinement fusion

    International Nuclear Information System (INIS)

    Schultz, K.R.

    1995-08-01

    General Atomics (GA) plays an important industrial support role for the US Inertial Confinement Fusion (ICF) program in the area of target technology. This includes three major activities: target fabrication support, target handling systems development, and target chamber design. The work includes target fabrication for existing ICF experiments, target and target system development for future experiments, and target research and target chamber design for experiments on future machines, such as the National Ignition Facility (NIF)

  11. Behavioral and pathophysiological outcomes associated with caffeine consumption and repetitive mild traumatic brain injury (RmTBI) in adolescent rats.

    Science.gov (United States)

    Yamakawa, Glenn R; Lengkeek, Connor; Salberg, Sabrina; Spanswick, Simon C; Mychasiuk, Richelle

    2017-01-01

    Given that caffeine consumption is exponentially rising in adolescents and they are at increased risk for repetitive mild traumatic brain injury (RmTBI), we sought to examine the pathophysiological outcomes associated with early life caffeine consumption and RmTBI. Adolescent male and female Sprague Dawley rats received either caffeine in the drinking water or normal water and were then randomly assigned to 3 mild injuries using our lateral impact device or 3 sham procedures. Following injury induction, behavioral outcomes were measured with a test battery designed to examine symptoms consistent with clinical manifestation of PCS (balance and motor coordination, anxiety, short-term working memory, and depressive-like behaviours). In addition, pathophysiological outcomes were examined with histological measures of volume and cellular proliferation in the dentate gyrus, as well as microglia activation in the ventromedial hypothalamus. Finally, modifications to expression of 12 genes (Adora2a, App, Aqp4, Bdnf, Bmal1, Clock, Cry, Gfap, Orx1, Orx2, Per, Tau), in the prefrontal cortex, hippocampus, and/or the hypothalamus were assessed. We found that chronic caffeine consumption in adolescence altered normal developmental trajectories, as well as recovery from RmTBI. Of particular importance, many of the outcomes exhibited sex-dependent responses whereby the sex of the animal modified response to caffeine, RmTBI, and the combination of the two. These results suggest that caffeine consumption in adolescents at high risk for RmTBI should be monitored.

  12. Behavioral and pathophysiological outcomes associated with caffeine consumption and repetitive mild traumatic brain injury (RmTBI in adolescent rats.

    Directory of Open Access Journals (Sweden)

    Glenn R Yamakawa

    Full Text Available Given that caffeine consumption is exponentially rising in adolescents and they are at increased risk for repetitive mild traumatic brain injury (RmTBI, we sought to examine the pathophysiological outcomes associated with early life caffeine consumption and RmTBI. Adolescent male and female Sprague Dawley rats received either caffeine in the drinking water or normal water and were then randomly assigned to 3 mild injuries using our lateral impact device or 3 sham procedures. Following injury induction, behavioral outcomes were measured with a test battery designed to examine symptoms consistent with clinical manifestation of PCS (balance and motor coordination, anxiety, short-term working memory, and depressive-like behaviours. In addition, pathophysiological outcomes were examined with histological measures of volume and cellular proliferation in the dentate gyrus, as well as microglia activation in the ventromedial hypothalamus. Finally, modifications to expression of 12 genes (Adora2a, App, Aqp4, Bdnf, Bmal1, Clock, Cry, Gfap, Orx1, Orx2, Per, Tau, in the prefrontal cortex, hippocampus, and/or the hypothalamus were assessed. We found that chronic caffeine consumption in adolescence altered normal developmental trajectories, as well as recovery from RmTBI. Of particular importance, many of the outcomes exhibited sex-dependent responses whereby the sex of the animal modified response to caffeine, RmTBI, and the combination of the two. These results suggest that caffeine consumption in adolescents at high risk for RmTBI should be monitored.

  13. Atopic Dermatitis in Children: Clinical Features, Pathophysiology and Treatment

    Science.gov (United States)

    Lyons, Jonathan J.; Milner, Joshua D.; Stone, Kelly D.

    2014-01-01

    Atopic dermatitis (AD) is a chronic, relapsing, highly pruritic skin condition resulting from disruption of the epithelial barrier and associated immune dysregulation in the skin of genetically predisposed hosts. AD generally develops in early childhood, has a characteristic age-dependent distribution and is commonly associated with elevated IgE, peripheral eosinophilia and other allergic diseases. Staphylococcus aureus colonization is common and may contribute to disease progression and severity. Targeted therapies to restore both impaired skin barrier and control inflammation are required for optimal outcomes for patients with moderate to severe disease. Pruritus is universal among patients with AD and has a dominant impact on diminishing quality of life. Medications such as anti-histamines have demonstrated poor efficacy in controlling AD-associated itch. Education of patients regarding the primary underlying defects and provision of a comprehensive skin care plan is essential for disease maintenance and management of flares. PMID:25459583

  14. New insights into the pathophysiology of multiple myeloma

    International Nuclear Information System (INIS)

    Tothova, E.; Kafkova, A.

    2013-01-01

    The last decade has seen significant advances in our understanding of the biology of multiple myeloma (MM) and our approaches to its treatment. As a result of these advances, the median survival of patients has increased and we can now achieve a cure in at least some patients. This improved knowledge about MM biology needs to be rapidly translated and transformed into diagnostic and therapeutic applications to finally achieve cure in a larger proportion of patients. Genetic mutations leading to chromosomal translocations and deletions play a key role in the progression to active, malignant MM. As a part of these translation efforts, novel drugs that inhibit oncogenic proteins over expressed in defined molecular subgroups of the disease, are currently being developed. Identification of potential therapeutic targets in the bone marrow microenvironment is leading to the development of therapies that are changing the standard of care for MM patients. (author)

  15. Endocrine Tumors Causing Arterial Hypertension: Pathophysiological Mechanisms and Clinical Implications.

    Science.gov (United States)

    Buonacera, Agata; Stancanelli, Benedetta; Malatino, Lorenzo

    2017-09-01

    Some tumors are a relatively rare and amendable cause of hypertension, often associated with a higher cardiovascular morbidity and mortality, as compared with that of both general population and patients with essential hypertension. This worse prognosis is not entirely related to blood pressure increase, because the release of substances from the tumor can directly influence blood pressure behavior. Diagnostic approach is challenging and needs a deep knowledge of the different neuro-hormonal and genetic mechanisms determining blood pressure increase. Surgical tumor removal can, but not always, cause blood pressure normalization, depending on how early was tumor detection, since a long-standing history of hypertension is often associated with a much weaker effect on blood pressure. Moreover, target organ damage can be affected by the substances themselves released by the tumors as well as by tumor removal. In this review we consider the phenotype and genetic features of patients with tumor-induced hypertension and focus on their diagnostic work-up.

  16. High fructose diet-induced metabolic syndrome: Pathophysiological mechanism and treatment by traditional Chinese medicine.

    Science.gov (United States)

    Pan, Ying; Kong, Ling-Dong

    2018-04-01

    Fructose is a natural monosaccharide broadly used in modern society. Over the past few decades, epidemiological studies have demonstrated that high fructose intake is an etiological factor of metabolic syndrome (MetS). This review highlights research advances on fructose-induced MetS, especially the underlying pathophysiological mechanism as well as pharmacotherapy by traditional Chinese medicine (TCM), using the PubMed, Web of science, China National Knowledge Infrastructure, China Science and Technology Journal and Wanfang Data. This review focuses on de novo lipogenesis (DNL) and uric acid (UA) production, two unique features of fructolysis different from glucose glycolysis. High level of DNL and UA production can result in insulin resistance, the key pathological event in developing MetS, mostly through oxidative stress and inflammation. Some other pathologies like the disturbance in brain and gut microbiota in the development of fructose-induced MetS in the past years, are also discussed. In management of MetS, TCM is an excellent representative in alternative and complementary medicine with a complete theory system and substantial herbal remedies. TCMs against MetS or MetS components, including Chinese patent medicines, TCM compound formulas, single TCM herbs and active compounds of TCM herbs, are reviewed on their effects and molecular mechanisms. TCMs with hypouricemic activity, which specially target fructose-induced MetS, are highlighted. And new technologies and strategies (such as high-throughput assay and systems biology) in this field are further discussed. In summary, fructose-induced MetS is a multifactorial disorder with the underlying complex mechanisms. Current clinical and pre-clinical evidence supports the potential of TCMs in management of MetS. Additionally, TCMs may show some advantages against complex MetS as their holistic feature through multiple target actions. However, further work is needed to confirm the effectivity and safety of TCMs

  17. Colony Collapse Disorder (CCD) and bee age impact honey bee pathophysiology.

    Science.gov (United States)

    vanEngelsdorp, Dennis; Traynor, Kirsten S; Andree, Michael; Lichtenberg, Elinor M; Chen, Yanping; Saegerman, Claude; Cox-Foster, Diana L

    2017-01-01

    Honey bee (Apis mellifera) colonies continue to experience high annual losses that remain poorly explained. Numerous interacting factors have been linked to colony declines. Understanding the pathways linking pathophysiology with symptoms is an important step in understanding the mechanisms of disease. In this study we examined the specific pathologies associated with honey bees collected from colonies suffering from Colony Collapse Disorder (CCD) and compared these with bees collected from apparently healthy colonies. We identified a set of pathological physical characteristics that occurred at different rates in CCD diagnosed colonies prior to their collapse: rectum distension, Malpighian tubule iridescence, fecal matter consistency, rectal enteroliths (hard concretions), and venom sac color. The multiple differences in rectum symptomology in bees from CCD apiaries and colonies suggest effected bees had trouble regulating water. To ensure that pathologies we found associated with CCD were indeed pathologies and not due to normal changes in physical appearances that occur as an adult bee ages (CCD colonies are assumed to be composed mostly of young bees), we documented the changes in bees of different ages taken from healthy colonies. We found that young bees had much greater incidences of white nodules than older cohorts. Prevalent in newly-emerged bees, these white nodules or cellular encapsulations indicate an active immune response. Comparing the two sets of characteristics, we determined a subset of pathologies that reliably predict CCD status rather than bee age (fecal matter consistency, rectal distension size, rectal enteroliths and Malpighian tubule iridescence) and that may serve as biomarkers for colony health. In addition, these pathologies suggest that CCD bees are experiencing disrupted excretory physiology. Our identification of these symptoms is an important first step in understanding the physiological pathways that underlie CCD and factors

  18. Colony Collapse Disorder (CCD and bee age impact honey bee pathophysiology.

    Directory of Open Access Journals (Sweden)

    Dennis vanEngelsdorp

    Full Text Available Honey bee (Apis mellifera colonies continue to experience high annual losses that remain poorly explained. Numerous interacting factors have been linked to colony declines. Understanding the pathways linking pathophysiology with symptoms is an important step in understanding the mechanisms of disease. In this study we examined the specific pathologies associated with honey bees collected from colonies suffering from Colony Collapse Disorder (CCD and compared these with bees collected from apparently healthy colonies. We identified a set of pathological physical characteristics that occurred at different rates in CCD diagnosed colonies prior to their collapse: rectum distension, Malpighian tubule iridescence, fecal matter consistency, rectal enteroliths (hard concretions, and venom sac color. The multiple differences in rectum symptomology in bees from CCD apiaries and colonies suggest effected bees had trouble regulating water. To ensure that pathologies we found associated with CCD were indeed pathologies and not due to normal changes in physical appearances that occur as an adult bee ages (CCD colonies are assumed to be composed mostly of young bees, we documented the changes in bees of different ages taken from healthy colonies. We found that young bees had much greater incidences of white nodules than older cohorts. Prevalent in newly-emerged bees, these white nodules or cellular encapsulations indicate an active immune response. Comparing the two sets of characteristics, we determined a subset of pathologies that reliably predict CCD status rather than bee age (fecal matter consistency, rectal distension size, rectal enteroliths and Malpighian tubule iridescence and that may serve as biomarkers for colony health. In addition, these pathologies suggest that CCD bees are experiencing disrupted excretory physiology. Our identification of these symptoms is an important first step in understanding the physiological pathways that underlie CCD and

  19. Targeted therapies for diarrhea-predominant irritable bowel syndrome

    OpenAIRE

    Olden, Kevin W

    2012-01-01

    Kevin W OldenDepartment of Medicine, St Joseph's Hospital and Medical Center, Phoenix, AZ, USAAbstract: Irritable bowel syndrome (IBS) causes gastrointestinal symptoms such as abdominal pain, bloating, and bowel pattern abnormalities, which compromise patients' daily functioning. Common therapies address one or two IBS symptoms, while others offer wider symptom control, presumably by targeting pathophysiologic mechanisms of IBS. The aim of this targeted literature review was t...

  20. Molecular Targets for Targeted Radionuclide Therapy

    International Nuclear Information System (INIS)

    Mather, S.J.

    2009-01-01

    Molecular targeted radionuclide cancer therapy is becoming of increasing importance, especially for disseminated diseases. Systemic chemotherapies often lack selectivity while targeted radionuclide therapy has important advantages as the radioactive cytotoxic unit of the targeting vector is specifically directed to the cancer, sparing normal tissues. The principle strategy to improve cancer selectivity is to couple therapeutic agents to tumour-targeting vectors. In targeted radionuclide therapy (TRT), the cytotoxic portion of the conjugates normally contains a therapeutic radiometal immobilised by a bifunctional chelator. The aim is therefore to use as ligand-targeted therapeutics vectors coupled to Auger-, alpha- and/or beta-emitting radionuclides. An advantage of using radiation instead of chemotherapeutics as the cytotoxic agent is the so called 'crossfire effect'. This allows sterilisation of tumour cells that are not directly targeted due to heterogeneity in target molecule expression or inhomogeneous vector delivery. However, before the targeting ligands can be selected, the target molecule on the tumour has to be selected. It should be uniquely expressed, or at least highly overexpressed, on or in the target cells relative to normal tissues. The target should be easily accessible for ligand delivery and should not be shed or down- regulated after ligand binding. An important property of a receptor (or antigen) is its potential to be internalized upon binding of the ligand. This provides an active uptake mechanism and allows the therapeutic agent to be trapped within the tumour cells. Molecular targets of current interest include: Receptors: G-protein coupled receptors are overexpressed on many major human tumours. The prototype of these receptors are somatostatin receptors which show very high density in neuroendocrine tumours, but there are many other most interesting receptors to be applied for TRT. The targeting ligands for these receptors are

  1. Adverse cardiovascular effects of anabolic steroids : pathophysiology imaging

    NARCIS (Netherlands)

    Golestani, Reza; Slart, Riemer H. J. A.; Dullaart, Robin P. F.; Glaudemans, Andor W. J. M.; Zeebregts, Clark J.; Boersma, Hendrikus H.; Tio, Rene A.; Dierckx, Rudi A. J. O.

    Eur J Clin Invest 2012; 42 (7): 795803 Abstract Background Anabolic-androgenic steroids (AAS) are widely abused for enhancing muscle mass, strength, growth and improving athletic performance. Materials and methods In recent years, many observational and interventional studies have shown important

  2. Individual variation in the (patho)physiology of energy balance

    NARCIS (Netherlands)

    Boersma, Gretha J.; Benthem, Lambertus; van Dijk, Gertjan; Scheurink, Anton J. W.

    2011-01-01

    There are large individual differences in the susceptibility for metabolic disorders such as obesity, the metabolic syndrome and type 2 diabetes. Unfortunately, most animal studies in this field ignore the importance of individual variation which limits the face validity of these studies for

  3. Neuropeptides in Alzheimer's Disease : From Pathophysiological Mechanisms to Therapeutic Opportunities

    NARCIS (Netherlands)

    Van Dam, Debby; Van Dijck, Annemie; Janssen, Leen; De Deyn, Peter Paul

    Neuropeptides are found throughout the entire nervous system where they can act as neurotransmitter, neuromodulator or neurohormone. In those functions, they play important roles in the regulation of cognition and behavior. In brain disorders like Alzheimer's disease (AD), where abnormal cognition

  4. Epidemiology and pathophysiology of falls in facioscapulohumeral disease

    NARCIS (Netherlands)

    Horlings, C. G. C.; Munneke, M.; Bickerstaffe, A.; Laverman, L.; Allum, J. H. J.; Padberg, G. W. A. M.; Bloem, B. R.; van Engelen, B. G. M.

    2009-01-01

    Muscle weakness is a potentially important, yet poorly studied, risk factor for falls. Detailed studies of patients with specific myopathies may shed new light on the relation between muscle weakness and falls. Here falls in patients with facioscapulohumeral disease (FSHD) who suffered from lower

  5. Epidemiology and pathophysiology of falls in facioscapulohumeral disease.

    NARCIS (Netherlands)

    Horlings, G.C.; Munneke, M.; Bickerstaffe, A.; Laverman, L.; Allum, J.H.J.; Padberg, G.W.A.M.; Bloem, B.R.; Engelen, B.G.M. van

    2009-01-01

    BACKGROUND AND AIMS: Muscle weakness is a potentially important, yet poorly studied, risk factor for falls. Detailed studies of patients with specific myopathies may shed new light on the relation between muscle weakness and falls. Here falls in patients with facioscapulohumeral disease (FSHD) who

  6. Genetic and evolutionary analyses of the human bone morphogenetic protein receptor 2 (BMPR2 in the pathophysiology of obesity.

    Directory of Open Access Journals (Sweden)

    Dorit Schleinitz

    2011-02-01

    Full Text Available Human bone morphogenetic protein receptor 2 (BMPR2 is essential for BMP signalling and may be involved in the regulation of adipogenesis. The BMPR2 locus has been suggested as target of recent selection in human populations. We hypothesized that BMPR2 might have a role in the pathophysiology of obesity.Evolutionary analyses (dN/dS, Fst, iHS were conducted in vertebrates and human populations. BMPR2 mRNA expression was measured in 190 paired samples of visceral and subcutaneous adipose tissue. The gene was sequenced in 48 DNA samples. Nine representative single nucleotide polymorphisms (SNPs were genotyped for subsequent association studies on quantitative traits related to obesity in 1830 German Caucasians. An independent cohort of 925 Sorbs was used for replication. Finally, relation of genotypes to mRNA in fat was examined.The evolutionary analyses indicated signatures of selection on the BMPR2 locus. BMPR2 mRNA expression was significantly increased both in visceral and subcutaneous adipose tissue of 37 overweight (BMI>25 and 30 kg/m² compared with 44 lean subjects (BMI< 25 kg/m² (P<0.001. In a case-control study including lean and obese subjects, two intronic SNPs (rs6717924, rs13426118 were associated with obesity (adjusted P<0.05. Combined analyses including the initial cohort and the Sorbs confirmed a consistent effect for rs6717924 (combined P = 0.01 on obesity. Moreover, rs6717924 was associated with higher BMPR2 mRNA expression in visceral adipose tissue.Combined BMPR2 genotype-phenotype-mRNA expression data as well as evolutionary aspects suggest a role of BMPR2 in the pathophysiology of obesity.

  7. DNA methylation alters transcriptional rates of differentially expressed genes and contributes to pathophysiology in mice fed a high fat diet

    Directory of Open Access Journals (Sweden)

    Pili Zhang

    2017-04-01

    Full Text Available Objective: Overnutrition can alter gene expression patterns through epigenetic mechanisms that may persist through generations. However, it is less clear if overnutrition, for example a high fat diet, modifies epigenetic control of gene expression in adults, or by what molecular mechanisms, or if such mechanisms contribute to the pathology of the metabolic syndrome. Here we test the hypothesis that a high fat diet alters hepatic DNA methylation, transcription and gene expression patterns, and explore the contribution of such changes to the pathophysiology of obesity. Methods: RNA-seq and targeted high-throughput bisulfite DNA sequencing were used to undertake a systematic analysis of the hepatic response to a high fat diet. RT-PCR, chromatin immunoprecipitation and in vivo knockdown of an identified driver gene, Phlda1, were used to validate the results. Results: A high fat diet resulted in the hypermethylation and decreased transcription and expression of Phlda1 and several other genes. A subnetwork of genes associated with Phlda1 was identified from an existing Bayesian gene network that contained numerous hepatic regulatory genes involved in lipid and body weight homeostasis. Hepatic-specific depletion of Phlda1 in mice decreased expression of the genes in the subnetwork, and led to increased oil droplet size in standard chow-fed mice, an early indicator of steatosis, validating the contribution of this gene to the phenotype. Conclusions: We conclude that a high fat diet alters the epigenetics and transcriptional activity of key hepatic genes controlling lipid homeostasis, contributing to the pathophysiology of obesity. Author Video: Author Video Watch what authors say about their articles Keywords: DNA methylation, RNA-seq, Transcription, High fat diet, Liver, Phlda1

  8. Targeting the genital tract mucosa with a lipopeptide/recombinant adenovirus prime/boost vaccine induces potent and long-lasting CD8+ T cell immunity against herpes: importance of MyD88.

    Science.gov (United States)

    Zhang, Xiuli; Dervillez, Xavier; Chentoufi, Aziz Alami; Badakhshan, Tina; Bettahi, Ilham; Benmohamed, Lbachir

    2012-11-01

    Targeting of the mucosal immune system of the genital tract with subunit vaccines has failed to induce potent and durable local CD8(+) T cell immunity, which is crucial for protection against many sexually transmitted viral pathogens, including HSV type 2 (HSV-2), which causes genital herpes. In this study, we aimed to investigate the potential of a novel lipopeptide/adenovirus type 5 (Lipo/rAdv5) prime/boost mucosal vaccine for induction of CD8(+) T cell immunity to protect the female genital tract from herpes. The lipopeptide vaccine and the rAdv5 vaccine express the immunodominant HSV-2 CD8(+) T cell epitope (gB(498-505)), and both were delivered intravaginally in the progesterone-induced B6 mouse model of genital herpes. Compared with mice immunized with the homologous lipopeptide/lipopeptide (Lipo/Lipo) vaccine, the Lipo/rAdv5 prime/boost immunized mice 1) developed potent and sustained HSV-specific CD8(+) T cells, detected in both the genital tract draining nodes and in the vaginal mucosa; 2) had significantly lower virus titers; 3) had decreased overt signs of genital herpes disease; and 4) did not succumb to lethal infection (p herpes infection and disease.

  9. Targeting the Genital Tract Mucosa with a Lipopeptide/Recombinant Adenovirus Prime/Boost Vaccine Induces Potent and Long-Lasting CD8+ T Cell Immunity Against Herpes: Importance of Myeloid Differentiation Factor 881

    Science.gov (United States)

    Zhang, Xiuli; Dervillez, Xavier; Chentoufi, Aziz Alami; Badakhshan, Tina; Bettahi, Ilham; BenMohamed, Lbachir

    2012-01-01

    Targeting the mucosal immune system of the genital tract (GT) with subunit vaccines failed to induce potent and durable local CD8+ T cell immunity, crucial for protection against many sexually transmitted viral (STV) pathogens, including herpes simplex virus type 2 (HSV-2) that causes genital herpes. In this study, we aimed to investigate the potential of a novel lipopeptide/adenovirus type 5 (Lipo/rAdv5) prime/boost mucosal vaccine for induction of CD8+ T cell immunity to protect the female genital tract from herpes. The lipopeptide and the rAdv5 vaccine express the immunodominant HSV-2 CD8+ T cell epitope (gB498-505) and both were delivered intravaginally (IVAG) in the progesterone-induced B6 mouse model of genital herpes. Compared to its homologous lipopeptide/lipopeptide (Lipo/Lipo); the Lipo/rAdv5 prime/boost immunized mice: (i) developed potent and sustained HSV-specific CD8+ T cells, detected in both the GT draining nodes (GT-DLN) and in the vaginal mucosa (VM); (ii) had significantly lower virus titers; (iii) had decreased overt signs of genital herpes disease; and (iv) did not succumb to lethal infection (p herpes infection and disease. PMID:23018456

  10. Inflammation in irritable bowel syndrome: Myth or new treatment target?

    Science.gov (United States)

    Sinagra, Emanuele; Pompei, Giancarlo; Tomasello, Giovanni; Cappello, Francesco; Morreale, Gaetano Cristian; Amvrosiadis, Georgios; Rossi, Francesca; Lo Monte, Attilio Ignazio; Rizzo, Aroldo Gabriele; Raimondo, Dario

    2016-01-01

    Low-grade intestinal inflammation plays a key role in the pathophysiology of irritable bowel syndrome (IBS), and this role is likely to be multifactorial. The aim of this review was to summarize the evidence on the spectrum of mucosal inflammation in IBS, highlighting the relationship of this inflammation to the pathophysiology of IBS and its connection to clinical practice. We carried out a bibliographic search in Medline and the Cochrane Library for the period of January 1966 to December 2014, focusing on publications describing an interaction between inflammation and IBS. Several evidences demonstrate microscopic and molecular abnormalities in IBS patients. Understanding the mechanisms underlying low-grade inflammation in IBS may help to design clinical trials to test the efficacy and safety of drugs that target this pathophysiologic mechanism. PMID:26900287

  11. Pathophysiology of neutrophil-mediated extracellular redox reactions.

    Science.gov (United States)

    Jaganjac, Morana; Cipak, Ana; Schaur, Rudolf Joerg; Zarkovic, Neven

    2016-01-01

    Neutrophil granulocyte leukocytes (neutrophils) play fundamental role in the innate immune response. In the presence of adequate stimuli, neutrophils release excessive amount of reactive oxygen species (ROS) that may induce cell and tissue injury. Oxidative burst of neutrophils acts as a double-edged sword. It may contribute to the pathology of atherosclerosis and brain injury but is also necessary in resolving infections. Moreover, neutrophil-derived ROS may also have both a tumor promoting and tumor suppressing role. ROS have a specific activities and diffusion distance, which is related to their short lifetime. Therefore, the manner in which ROS will act depends on the cells targeted and the intra- and extracellular levels of individual ROS, which can further cause production of reactive aldehydes like 4-hydroxynonenal (HNE) that act as a second messengers of ROS. In this review we discuss the influence of neutrophil mediated extracellular redox reactions in ischemia reperfusion injury, transplant rejection and chronic diseases (atherosclerosis, inflammatory bowel diseases and cancer). At the end a brief overview of cellular mechanisms to maintain ROS homeostasis is given.

  12. Pathophysiological mechanisms of death resistance in colorectal carcinoma.

    Science.gov (United States)

    Huang, Ching-Ying; Yu, Linda Chia-Hui

    2015-11-07

    Colon cancers develop adaptive mechanisms to survive under extreme conditions and display hallmarks of unlimited proliferation and resistance to cell death. The deregulation of cell death is a key factor that contributes to chemoresistance in tumors. In a physiological context, balance between cell proliferation and death, and protection against cell damage are fundamental processes for maintaining gut epithelial homeostasis. The mechanisms underlying anti-death cytoprotection and tumor resistance often bear common pathways, and although distinguishing them would be a challenge, it would also provide an opportunity to develop advanced anti-cancer therapeutics. This review will outline cell death pathways (i.e., apoptosis, necrosis, and necroptosis), and discuss cytoprotective strategies in normal intestinal epithelium and death resistance mechanisms of colon tumor. In colorectal cancers, the intracellular mechanisms of death resistance include the direct alteration of apoptotic and necroptotic machinery and the upstream events modulating death effectors such as tumor suppressor gene inactivation and pro-survival signaling pathways. The autocrine, paracrine and exogenous factors within a tumor microenvironment can also instigate resistance against apoptotic and necroptotic cell death in colon cancers through changes in receptor signaling or transporter uptake. The roles of cyclooxygenase-2/prostaglandin E2, growth factors, glucose, and bacterial lipopolysaccharides in colorectal cancer will be highlighted. Targeting anti-death pathways in the colon cancer tissue might be a promising approach outside of anti-proliferation and anti-angiogenesis strategies for developing novel drugs to treat refractory tumors.

  13. Data Mining FAERS to Analyze Molecular Targets of Drugs Highly Associated with Stevens-Johnson Syndrome.

    Science.gov (United States)

    Burkhart, Keith K; Abernethy, Darrell; Jackson, David

    2015-06-01

    Drug features that are associated with Stevens-Johnson syndrome (SJS) have not been fully characterized. A molecular target analysis of the drugs associated with SJS in the FDA Adverse Event Reporting System (FAERS) may contribute to mechanistic insights into SJS pathophysiology. The publicly available version of FAERS was analyzed to identify disproportionality among the molecular targets, metabolizing enzymes, and transporters for drugs associated with SJS. The FAERS in-house version was also analyzed for an internal comparison of the drugs most highly associated with SJS. Cyclooxygenases 1 and 2, carbonic anhydrase 2, and sodium channel 2 alpha were identified as disproportionately associated with SJS. Cytochrome P450 (CYPs) 3A4 and 2C9 are disproportionately represented as metabolizing enzymes of the drugs associated with SJS adverse event reports. Multidrug resistance protein 1 (MRP-1), organic anion transporter 1 (OAT1), and PEPT2 were also identified and are highly associated with the transport of these drugs. A detailed review of the molecular targets identifies important roles for these targets in immune response. The association with CYP metabolizing enzymes suggests that reactive metabolites and oxidative stress may have a contributory role. Drug transporters may enhance intracellular tissue concentrations and also have vital physiologic roles that impact keratinocyte proliferation and survival. Data mining FAERS may be used to hypothesize mechanisms for adverse drug events by identifying molecular targets that are highly associated with drug-induced adverse events. The information gained may contribute to systems biology disease models.

  14. Physiology and pathophysiology of apoptosis in epithelial cells of the liver, pancreas, and intestine.

    Science.gov (United States)

    Jones, B A; Gores, G J

    1997-12-01

    Cell death of gastrointestinal epithelial cells occurs by a process referred to as apoptosis. In this review, we succinctly define apoptosis and summarize the role of apoptosis in the physiology and pathophysiology of epithelial cells in the liver, pancreas, and small and large intestine. The physiological mediators regulating apoptosis in gastrointestinal epithelial cells, when known, are discussed. Selected pathophysiological consequences of excessive apoptosis and inhibition of apoptosis are used to illustrate the significance of apoptosis in disease processes. These examples demonstrate that excessive apoptosis may result in epithelial cell atrophy, injury, and dysfunction, whereas inhibition of apoptosis results in hyperplasia and promotes malignant transformation. The specific cellular mechanisms responsible for dysregulation of epithelial cell apoptosis during pathophysiological disturbances are emphasized. Potential future areas of physiological research regarding apoptosis in gastrointestinal epithelia are highlighted when appropriate.

  15. Role of negative affects in pathophysiology and clinical expression of irritable bowel syndrome.

    Science.gov (United States)

    Muscatello, Maria Rosaria A; Bruno, Antonio; Scimeca, Giuseppe; Pandolfo, Gianluca; Zoccali, Rocco A

    2014-06-28

    Irritable bowel syndrome (IBS) is regarded as a multifactorial disease in which alterations in the brain-gut axis signaling play a major role. The biopsychosocial model applied to the understanding of IBS pathophysiology assumes that psychosocial factors, interacting with peripheral/central neuroendocrine and immune changes, may induce symptoms of IBS, modulate symptom severity, influence illness experience and quality of life, and affect outcome. The present review focuses on the role of negative affects, including depression, anxiety, and anger, on pathogenesis and clinical expression of IBS. The potential role of the autonomic nervous system, stress-hormone system, and immune system in the pathophysiology of both negative affects and IBS are taken into account. Psychiatric comorbidity and subclinical variations in levels of depression, anxiety, and anger are further discussed in relation to the main pathophysiological and symptomatic correlates of IBS, such as sensorimotor functions, gut microbiota, inflammation/immunity, and symptom reporting.

  16. Antiproton Target

    CERN Multimedia

    1980-01-01

    Antiproton target used for the AA (antiproton accumulator). The first type of antiproton production target used from 1980 to 1982 comprised a rod of copper 3mm diameter and 120mm long embedded in a graphite cylinder that was itself pressed into a finned aluminium container. This assembly was air-cooled and it was used in conjunction with the Van der Meer magnetic horn. In 1983 Fermilab provided us with lithium lenses to replace the horn with a view to increasing the antiproton yield by about 30%. These lenses needed a much shorter target made of heavy metal - iridium was chosen for this purpose. The 50 mm iridium rod was housed in an extension to the original finned target container so that it could be brought very close to the entrance to the lithium lens. Picture 1 shows this target assembly and Picture 2 shows it mounted together with the lithium lens. These target containers had a short lifetime due to a combination of beam heating and radiation damage. This led to the design of the water-cooled target in...

  17. The role of macrophage polarization on bipolar disorder: Identifying new therapeutic targets.

    Science.gov (United States)

    Ascoli, Bruna M; Géa, Luiza P; Colombo, Rafael; Barbé-Tuana, Florência M; Kapczinski, Flávio; Rosa, Adriane Ribeiro

    2016-07-01

    Bipolar disorder is a chronic, severe and disabling disease; however, its pathophysiology remains poorly understood. Recent evidence has suggested that inflammation and immune dysregulation play a significant role in the pathophysiology of bipolar disorder. This review is aimed to highlight the importance of systemic inflammation in modulating the inflammatory response of microglia and hence its potential involvement with bipolar disorder. We also discuss novel therapeutic strategies that emerge from this new research. This article presents a theoretical synthesis of the effects of systemic inflammation on the immune response of the central nervous system in bipolar disorder. The complex relationship between stress, pro-inflammatory cytokines and microglial dysfunction is summarized, emphasizing the role of the kynurenine pathway in this process and, consequently, their effects on neuronal plasticity. Bipolar patients demonstrate increased serum levels of pro-inflammatory cytokines (interleukin-1β, interleukin-6 and tumor necrosis factor-α) and lower hypothalamic-pituitary-adrenal axis sensitivity. This imbalance in the immune system promotes a change in blood-brain barrier permeability, leading to an inflammatory signal spread in the central nervous system from the periphery, through macrophages activation (M1 polarization). Chronic microglial activation can result in neuronal apoptosis, neurogenesis inhibition, hippocampal volume reduction, lower neurotransmitters synthesis and cytotoxicity, by increasing glutamate production and kynurenine metabolism. This review provides an overview of the mechanisms involved in the immune system imbalance and its potential involvement in the pathophysiology of bipolar disorder. Consequently, new strategies that normalize the immune-inflammatory pathways may provide a valuable therapeutic target for the treatment of these disorders. © The Royal Australian and New Zealand College of Psychiatrists 2016.

  18. Hereditary Nephrogenic Diabetes Insipidus: Pathophysiology and Possible Treatment. An Update.

    Science.gov (United States)

    Milano, Serena; Carmosino, Monica; Gerbino, Andrea; Svelto, Maria; Procino, Giuseppe

    2017-11-10

    Under physiological conditions, excessive loss of water through the urine is prevented by the release of the antidiuretic hormone arginine-vasopressin (AVP) from the posterior pituitary. In the kidney, AVP elicits a number of cellular responses, which converge on increasing the osmotic reabsorption of water in the collecting duct. One of the key events triggered by the binding of AVP to its type-2 receptor (AVPR2) is the exocytosis of the water channel aquaporin 2 (AQP2) at the apical membrane the principal cells of the collecting duct. Mutations of either AVPR2 or AQP2 result in a genetic disease known as nephrogenic diabetes insipidus, which is characterized by the lack of responsiveness of the collecting duct to the antidiuretic action of AVP. The affected subject, being incapable of concentrating the urine, presents marked polyuria and compensatory polydipsia and is constantly at risk of severe dehydration. The molecular bases of the disease are fully uncovered, as well as the genetic or clinical tests for a prompt diagnosis of the disease in newborns. A real cure for nephrogenic diabetes insipidus (NDI) is still missing, and the main symptoms of the disease are handled with s continuous supply of water, a restrictive diet, and nonspecific drugs. Unfortunately, the current therapeutic options are limited and only partially beneficial. Further investigation in vitro or using the available animal models of the disease, combined with clinical trials, will eventually lead to the identification of one or more targeted strategies that will improve or replace the current conventional therapy and grant NDI patients a better quality of life. Here we provide an updated overview of the genetic defects causing NDI, the most recent strategies under investigation for rescuing the activity of mutated AVPR2 or AQP2, or for bypassing defective AVPR2 signaling and restoring AQP2 plasma membrane expression.

  19. Hereditary Nephrogenic Diabetes Insipidus: Pathophysiology and Possible Treatment. An Update

    Directory of Open Access Journals (Sweden)

    Serena Milano

    2017-11-01

    Full Text Available Under physiological conditions, excessive loss of water through the urine is prevented by the release of the antidiuretic hormone arginine-vasopressin (AVP from the posterior pituitary. In the kidney, AVP elicits a number of cellular responses, which converge on increasing the osmotic reabsorption of water in the collecting duct. One of the key events triggered by the binding of AVP to its type-2 receptor (AVPR2 is the exocytosis of the water channel aquaporin 2 (AQP2 at the apical membrane the principal cells of the collecting duct. Mutations of either AVPR2 or AQP2 result in a genetic disease known as nephrogenic diabetes insipidus, which is characterized by the lack of responsiveness of the collecting duct to the antidiuretic action of AVP. The affected subject, being incapable of concentrating the urine, presents marked polyuria and compensatory polydipsia and is constantly at risk of severe dehydration. The molecular bases of the disease are fully uncovered, as well as the genetic or clinical tests for a prompt diagnosis of the disease in newborns. A real cure for nephrogenic diabetes insipidus (NDI is still missing, and the main symptoms of the disease are handled with s continuous supply of water, a restrictive diet, and nonspecific drugs. Unfortunately, the current therapeutic options are limited and only partially beneficial. Further investigation in vitro or using the available animal models of the disease, combined with clinical trials, will eventually lead to the identification of one or more targeted strategies that will improve or replace the current conventional therapy and grant NDI patients a better quality of life. Here we provide an updated overview of the genetic defects causing NDI, the most recent strategies under investigation for rescuing the activity of mutated AVPR2 or AQP2, or for bypassing defective AVPR2 signaling and restoring AQP2 plasma membrane expression.

  20. Hereditary Nephrogenic Diabetes Insipidus: Pathophysiology and Possible Treatment. An Update

    Science.gov (United States)

    Milano, Serena; Carmosino, Monica; Gerbino, Andrea; Svelto, Maria

    2017-01-01

    Under physiological conditions, excessive loss of water through the urine is prevented by the release of the antidiuretic hormone arginine-vasopressin (AVP) from the posterior pituitary. In the kidney, AVP elicits a number of cellular responses, which converge on increasing the osmotic reabsorption of water in the collecting duct. One of the key events triggered by the binding of AVP to its type-2 receptor (AVPR2) is the exocytosis of the water channel aquaporin 2 (AQP2) at the apical membrane the principal cells of the collecting duct. Mutations of either AVPR2 or AQP2 result in a genetic disease known as nephrogenic diabetes insipidus, which is characterized by the lack of responsiveness of the collecting duct to the antidiuretic action of AVP. The affected subject, being incapable of concentrating the urine, presents marked polyuria and compensatory polydipsia and is constantly at risk of severe dehydration. The molecular bases of the disease are fully uncovered, as well as the genetic or clinical tests for a prompt diagnosis of the disease in newborns. A real cure for nephrogenic diabetes insipidus (NDI) is still missing, and the main symptoms of the disease are handled with s continuous supply of water, a restrictive diet, and nonspecific drugs. Unfortunately, the current therapeutic options are limited and only partially beneficial. Further investigation in vitro or using the available animal models of the disease, combined with clinical trials, will eventually lead to the identification of one or more targeted strategies that will improve or replace the current conventional therapy and grant NDI patients a better quality of life. Here we provide an updated overview of the genetic defects causing NDI, the most recent strategies under investigation for rescuing the activity of mutated AVPR2 or AQP2, or for bypassing defective AVPR2 signaling and restoring AQP2 plasma membrane expression. PMID:29125546