Serum-Mediated Inhibition of Enzyme Replacement Therapy in Fabry Disease

Fabry disease (FD) is a progressive multisystemic disorder, treatable with recombinant enzyme replacement therapy (agalsidase). However, recent studies suggest an endogenous inhibition of agalsidase in patients with FD, as reported for other lysosomal storage diseases. To assess the clinical consequences of serum-mediated agalsidase inhibition in affected patients, we determined the agalsidase inhibition status of 168 patients (68 male) with FD and compared outcomes of inhibition-positive patients with those of inhibition-negative patients. The assessment included clinical events during time on agalsidase, determination of renal and cardiac function, and evaluation of FD-related symptoms. The frequency of serum-mediated agalsidase inhibition was 40% in agalsidase-treated males. Inhibition did not depend on the compound initially used (agalsidase-α or -β). Agalsidase inhibition was associated with higher lyso-globotriaosylceramide levels and worse disease severity scores in patients. Compared with agalsidase inhibition-negative men, agalsidase inhibition-positive men showed greater left ventricular mass (P=0.02) and substantially lower renal function (difference in eGFR of about –30 ml/min per 1.73 m²; P=0.04), which was confirmed by a longitudinal 5-year retrospective analysis. Additionally, affected patients presented more often with FD-typical symptoms, such as diarrhea, fatigue, and neuropathic pain, among others. Therefore, patients with poor clinical outcome on agalsidase should be tested for agalsidase inhibition. Future studies are warranted to determine if affected patients with FD benefit from acute reduction of anti-agalsidase antibodies or long-term immune modulation therapies to suppress agalsidase inhibition and to identify mechanisms that minimize antibody generation against agalsidase.     

Cigarettes and health: Historical controversies and constraints‐part II

This paper reports on an experimental study that examines the relative effect of price and personal referral cues on the consumers' perception of dental services. The results of the study show that price and personal referral do effect the perceived competence of the dentist as well as consumer purchase probability.     

Health literacy and public health: A systematic review and integration of definitions and models

Background  

Health literacy concerns the knowledge and competences of persons to meet the complex demands of health in modern society. Although its importance is increasingly recognised, there is no consensus about the definition of health literacy or about its conceptual dimensions, which limits the possibilities for measurement and comparison. The aim of the study is to review definitions and models on health literacy to develop an integrated definition and conceptual model capturing the most comprehensive evidence-based dimensions of health literacy.     

Coronary flow regulation in mouse heart during hypercapnic acidosis: role of NO and its compensation during eNOS impairment

AIMS: This study addressed the hypotheses that the hypercapnic flow response in wild-type (WT) mouse heart is mainly mediated by nitric oxide (NO) and, thus, severely blunted in endothelial nitric oxide synthase knockout (eNOS-KO) mice and in WT mice after continuous pharmacological block (2 weeks) of NOS enzymes (WT-LN). METHODS AND RESULTS: Step changes of arterial pCO(2) were performed in isolated perfused hearts (n = 105). Contributions of NOS (L-NAME, TRIM), cyclooxygenase (indomethacin), epoxyeicosanotrienes (miconazole), adenosine A2A-receptors (SCH 58261), KV-channels (4-AP), KCa-channels (TEA), and K ATP-channels (glibenclamide) were studied in WT and eNOS-KO mouse hearts. Change of arterial pCO(2) increased coronary flow by 31.3 +/- 4% in WT, a response that was significantly decreased to 9.2 +/- 6% after L-NAME. Additional glibenclamide infusion (n = 5) completely abolished the steady-state flow increase during hypercapnic acidosis (-4.2 +/- 2.3%, P = 0.004 vs. control). Hearts from eNOS-KO mice as well as WT-LN showed a fully preserved flow response insensitive towards NOS-blockade. Whereas indomethacin, miconazole, TEA, and SCH 58261 were ineffective to reduce the flow response, glibenclamide blunted it in eNOS-KO hearts. CONCLUSION: NO-production and K ATP-channel activation together may fully account for the steady-state hypercapnic flow response in mouse heart. However, chronic deletion of eNOS does not result in a reduced hypercapnic flow response. Enhanced activation of K ATP-channels and potentially Kv-channels contributes to the compensatory mechanisms involved in the hypercapnic flow response when eNOS activity is absent.     

Recovery of regional myocardial dysfunction after successful coronary angioplasty early after a non-Q wave myocardial infarction

More aggressive therapy has been suggested for patients who have a non-Q wave myocardial infarction (MI) because of the frequency of subsequent unstable angina, recurrent MI, and high mortality rate compared to patients with Q wave MI. The present study was undertaken to investigate the effect of coronary angioplasty on regional myocardial function of the infarct zone in patients with angina early after a non-Q wave MI. The study population consisted of 36 patients undergoing successful coronary angioplasty within 30 days of a non-Q wave MI, in whom sequential left ventricular angiograms of adequate quality were obtained before the initial procedure and at follow-up angiography. The global ejection fraction increased significantly from 60 +/- 9% to 67 +/- 6% (p = 0.0003). This significant increase in the global ejection fraction was primarily due to a significant improvement in the regional myocardial function of the infarct zone. The results of the present study show not only that ischemic attacks early after a non-Q wave MI may lead to prolonged regional myocardial dysfunction but more important that this depressed myocardium has the potential to achieve normal contraction after successful coronary angioplasty.     

004 65岁以上收缩功能正常的心衰者的临床特点

众所周知,充血性心衰(CHF)为老年人较为常见的临床综合征之一.迄今关于左室收缩功能正常的CHF老人的相关临床特点远未清楚,本文特此进行了大样本分析. 对象与方法 4842例老年人,男1922例,女2920例,年龄66～103岁.尔后人均随访1年.旨在分析老年CHF年发病率,以及左室收缩功能正常的CHF老人相关临床特点. 结果随访期内,罹发1次或以上CHF者共425例次(8.8%/年).与未患发CHF老人相比,CHF老人平均年龄更大(79±6岁:77±5岁,P＜0.001),女性居多,尤以高龄女性更多,如85岁以上的高龄女性CHF年发病率约较65～69岁女性高2倍(14%∶6.6%,P＜0.001),AMI史、房颤、高血压、糖尿病、慢性阻塞型肺病、吸烟者均多,血脂及血肌酐亦高.多变量分析表明,罹患CHF与下列因素有关:老年尤其是高龄[年龄每增加5岁的患病奇数率(OR)女性1.2,男性1.1],AMI史(OR7.3),房颤者(OR3.0),糖尿病(OR2.1),肾功能不全(血肌酐≥1.5mg/dl的OR2.0),慢性阻塞肺病(仅老年女性的OR为1.8),以及左房、左室内径增大(内径每递增1cm的OR为2.0),和左室重量增加、左室收缩末期室壁张力增高、早期跨心房血流增多.超声心动图检测结果显示,CHF老人中,左室收缩功能正常者达55%,而仅有左室舒张功能不全,且左室收缩功能正常或轻度减退者高达80%.其中女性左室收缩功能正常者尤较男性多见(67%∶42%,P＜0.001),表现为单纯左室舒张功能不良.而在左室收缩功能正常的CHF老人,常伴有左室内径较小、左室收缩末期室壁张力较低、左室重量较轻、左室收缩末期室壁厚度增加,而左室射血分数正常或仅轻度降低. 讨论以上结果提示,在老年人群中,CHF年发病率相对较高,且随年龄而增加,多数左室收缩功能正常,仅有左室舒张功能障碍,尤其是在高龄女性,亦即高龄女性左室舒张功能不全性CHF更为常见.对此,临床上更应拟出合理的防范措施,来正确诊治老年CHF综合征. (袁志敏摘)