蛋白酶活化受体(PARs)在肝纤维化中的调节作用

肝星状细胞(hepatic stellate cell,HSC)激活并转化为肌纤维母细胞并分泌细胞外基质 (ECM)成分是肝纤维化发生、发展的核心环节,肝损伤是引发肝纤维化的始动环节．蛋白酶激活受体(protease activated receptors, PARS)属于G蛋白偶联受体家族成员,他可通过介导细胞外信号调节激酶(extracellar signal- regulated kinase,ERK1／2)信号转导通路,引起细胞核反应,激活多种细胞转录因子,参与调节肝纤维化过程中HSC细胞增殖、分化和分泌大量细胞外基质,促使肝纤维化的发生和发展的方法,寻找通过抑制蛋白酶激活受体以期发现能阻断肝纤维化的形成和发展,逆转已形成的肝纤维化,将为肝纤维化的治疗提供新的理论基础．     

Obesity and mortality in elderly nursing home residents

BACKGROUND: The increasing prevalence of obese Americans over the last several decades has been well documented. A number of studies have analyzed the relationship of obesity and mortality in community-dwelling elderly persons, but little work has analyzed this issue within the institutionalized elderly population. METHODS: In an analysis of the 1996 Medical Expenditures Panel Study, we used logistic regression methods to examine the excess mortality associated with obesity, as defined by body mass index (BMI), over calendar year 1996 for existing and new nursing home residents. RESULTS: Across the total sample of existing and new residents, there was not a statistically significant difference in mortality for "obese" (BMI > 28 kg/m2) nursing home residents (odds ratio [OR] 0.89; 95% confidence interval [CI], 0.67-1.17) compared to the "normal" group, but obesity was associated with significantly less mortality among existing residents (OR 0.75; 95% CI, 0.57-0.98). For "thin" (BMI < 19 kg/m2) nursing home residents, there was significantly higher mortality among both current residents (OR 1.40; 95% CI, 1.11-1.77) and new admissions (OR 1.63; 95% CI, 1.17-2.28). For "very obese" (BMI > 35 kg/m2) individuals, there was a significantly higher mortality among new admissions (OR 1.75; 95% CI, 1.10-2.80), but not existing residents (OR 0.67; 95% CI, 0.38-1.15). These effects persisted for "very obese" individuals (BMI > 40 kg/m2). CONCLUSIONS: Very obese nursing home residents experience higher mortality early in their stay, but this association diminishes over time with some evidence suggesting that a higher BMI may be protective among long-stay residents.     

Fabry disease,an under-recognized multisystemic disorder: expert recommendations for diagnosis,management, and enzyme replacement therapy

Fabry disease (alpha-galactosidase A deficiency) is an X-linked recessive lysosomal storage disorder. Although the disease presents in childhood and culminates in cardiac, cerebrovascular, and end-stage renal disease, diagnosis is often delayed or missed. This paper reviews the key signs and symptoms of Fabry disease and provides expert recommendations for diagnosis, follow-up, medical management, and the use of enzyme replacement therapy. Recommendations are based on reviews of the literature on Fabry disease, results of recent clinical trials, and expertise of the authors, all of whom have extensive clinical experience with Fabry disease and lysosomal storage disorders and represent subspecialties involved in treatment. All males and female carriers affected with Fabry disease should be followed closely, regardless of symptoms or treatment status. Clinical trials have shown that recombinant human alpha-galactosidase A replacement therapy--the only disease-specific therapy currently available for Fabry disease--is safe and can reverse substrate storage in the lysosome, the pathophysiologic basis of the disease. Enzyme replacement therapy in all males with Fabry disease (including those with end-stage renal disease) and female carriers with substantial disease manifestations should be initiated as early as possible. Additional experience is needed before more specific recommendations can be made on optimal dosing regimens for reversal; maintenance; and prevention of disease manifestations in affected males, symptomatic carrier females, children, and patients with compromised renal function.     

Guidance on the use of miglustat for treating patients with type 1 Gaucher disease

Type 1 Gaucher disease (GD) is a progressive lysosomal storage disorder due to an autosomal recessive deficiency of glucocerebrosidase. Clinical manifestations include anemia, thrombocytopenia, hepatosplenomegaly, and bone and pulmonary disease. Intravenous enzyme replacement (ERT) with imiglucerase is the accepted standard for treatment of symptomatic patients. More than 3,500 patients worldwide have received ERT with well-documented beneficial effects on the hematological, visceral, skeletal, and pulmonary manifestations, and with resultant improvement in health-related quality of life. Miglustat, an imino sugar that reversibly inhibits glucosylceramide synthase and reduces intracellular substrate burden, is an oral treatment for patients with type 1 GD that was recently approved in the United States for symptomatic patients with mild to moderate clinical manifestations for whom ERT is not an option. Because responses to miglustat are slower and less robust than those observed with ERT, and because miglustat is associated with significant side effects, clinicians who care for patients with GD should become familiar with the limited indications for miglustat use and the circumstances when it may be prescribed appropriately. This review article and position statement represents the current opinion of American physicians with extensive expertise in GD regarding patient management in the context of the availability of standard imiglucerase treatment and the recent introduction of miglustat.     

Usefulness of Diagnostic Indices Comprising Clinical,Sonographic, and Biomarker Data for Discriminating Benign From Malignant Ovarian Masses

The objective of this study was to review the accuracy of indices combining several diagnostic variables, in comparison to other models, sonography alone, and biomarker assays, for predicting benign or malignant ovarian lesions. Different single modalities were reviewed. The most useful complex models were International Ovarian Tumor Analysis (IOTA) sonographic logistic regression model 2 (area under the curve, 0.949), risk of malignancy index–cancer antigen 125–human epididymis protein 4 (0.950), risk of malignancy algorithm (0.953), pelvic mass score (0.960), non‐IOTA logistic regression model (0.970), and histoscanning score logistic regression model (0.970). None of the indices was superior to an expert subjective sonographic assessment (0.968). For women with adnexal tumors, indices with high accuracy are available that are applicable in clinical practice and comparable to an expert subjective sonographic assessment for discriminating benign from malignant masses.     

Scientific Versus Experiential Evidence: Discourse Analysis of the Chronic Cerebrospinal Venous Insufficiency Debate in a Multiple Sclerosis Forum

BackgroundThe vascular hypothesis of multiple sclerosis (MS), called chronic cerebrospinal venous insufficiency (CCSVI), and its treatment (known as liberation therapy) was immediately rejected by experts but enthusiastically gripped by patients who shared their experiences with other patients worldwide by use of social media, such as patient online forums. Contradictions between scientific information and lay experiences may be a source of distress for MS patients, but we do not know how patients perceive and deal with these contradictions.ObjectiveWe aimed to understand whether scientific and experiential knowledge were experienced as contradictory in MS patient online forums and, if so, how these contradictions were resolved and how patients tried to reconcile the CCSVI debate with their own illness history and experience.MethodsBy using critical discourse analysis, we studied CCSVI-related posts in the patient online forum of the German MS Society in a chronological order from the first post mentioning CCSVI to the time point when saturation was reached. For that time period, a total of 117 CCSVI-related threads containing 1907 posts were identified. We analyzed the interaction and communication practices of and between individuals, looked for the relation between concrete subtopics to identify more abstract discourse strands, and tried to reveal discourse positions explaining how users took part in the CCSVI discussion.ResultsThere was an emotionally charged debate about CCSVI which could be generalized to 2 discourse strands: (1) the “downfall of the professional knowledge providers” and (2) the “rise of the nonprofessional treasure trove of experience.” The discourse strands indicated that the discussion moved away from the question whether scientific or experiential knowledge had more evidentiary value. Rather, the question whom to trust (ie, scientists, fellow sufferers, or no one at all) was of fundamental significance. Four discourse positions could be identified by arranging them into the dimensions “trust in evidence-based knowledge,” “trust in experience-based knowledge,” and “subjectivity” (ie, the emotional character of contributions manifested by the use of popular rhetoric that seemed to mask a deep personal involvement).ConclusionsBy critical discourse analysis of the CCSVI discussion in a patient online forum, we reconstruct a lay discourse about the evidentiary value of knowledge. We detected evidence criteria in this lay discourse that are different from those in the expert discourse. But we should be cautious to interpret this dissociation as a sign of an intellectual incapability to understand scientific evidence or a naïve trust in experiential knowledge. Instead, it might be an indication of cognitive dissonance reduction to protect oneself against contradictory information.