A naturally occurring variant of endothelial lipase associated with elevated HDL exhibits impaired synthesis

Human endothelial lipase (EL) is a member of a family of lipases and phospholipases that are involved in the metabolism of plasma lipoproteins. EL displays a preference to hydrolyze lipids in HDL. We report here that a naturally occurring low frequency coding variant in the EL gene (LIPG), glycine-26 to serine (G26S), is significantly more common in African-American individuals with elevated HDL cholesterol (HDL-C) levels. To test the hypothesis that this variant results in reduced EL function, we extensively characterized and compared the catalytic and noncatalytic functions of the G26S variant and wild-type (WT) EL. While the catalytic-specific activity of G26S EL is similar to WT EL, its secretion is markedly reduced. Consistent with this observation, we found that carriers of the G26S variant had significantly reduced plasma levels of EL protein. Thus, this N-terminal variant results in reduced secretion of EL protein, plausibly leading to increased HDL-C levels.     

Reconsidering paternalism in clinical research

The ethical standards that regulate clinical research have multiple rationales. Among them is the need to protect potential subjects from making imprudent decisions, which extends beyond the soft paternalistic concern to protect people from making uninformed decisions to participate in trials. This article argues that a plausible risk/benefit restriction on clinical trials is presumptively justified by hard paternalism, which in turn is supported by a deeper fairness‐based rationale. This presumptive case for hard paternalism in research is not defeated by the alleged right to participate in clinical trials, by concerns about insult or status, by the need to conduct early phase trials that promise little to no benefit to participants, or by the recognition that some potential subjects are altruistically motivated.     

The extrapituitary prolactin promoter polymorphism is associated with rheumatoid arthritis and anti-CCP antibodies in Mexican population

Prolactin (PRL) is a hormone–cytokine that has been involved in autoimmunity due to its immunoregulatory and lymphoproliferative effects. It is produced by various extrapituitary sites including immune cells, under control of a superdistal promoter that contains a single nucleotide polymorphism − 1149 G/T previously associated with rheumatoid arthritis (RA) susceptibility in European population. The aim of this study was to investigate the association of the extrapituitary PRL − 1149 G/T promoter polymorphism with clinical parameters, clinical activity and disability indices in RA patients from Western Mexico and to analyze the PRL mRNA expression according to the PRL − 1149 G/T promoter polymorphism in total leucocytes from RA patients and controls. We conducted a case–control study that included 258 RA patients and 333 control subjects (CS). The DNA samples were genotyped using the PCR–RFLP method and the PRL mRNA expression was determined by quantitative real time PCR. PRL serum levels and antibodies to cyclic citrullinated peptides (anti-CCP) were measured with ELISA. We found significant differences in the genotype (p = 0.022) and allelic (p = 0.046) distribution of the polymorphism between RA patients and control subjects. According to the dominant genetic model, there is an association between the T allele (GT + TT genotypes) and decreased RA susceptibility in comparison to the G allele carriers (GG genotype) (OR 0.64, 95% CI 0.45–0.92; p = 0.011). The T allele carriers (GT + TT genotypes) had lower titers of anti-CCP antibodies in comparison to the G allele carriers (GG genotype) (median, 66 U/mL vs. 125 U/mL; p = 0.03). Furthermore, the GG homozygotes had higher PRL mRNA expression in comparison to the GT heterozygotes, and this latter with respect to the TT homozygotes, in both groups (RA: 1 > 0.72 > 0.19; CS: 1 > 0.54 > 0.28). However, PRL serum levels were similar in both groups. Our results suggest that the PRL − 1149 T allele is a genetic marker for decreased RA susceptibility and is associated with lower titers of anti-CCP antibodies in Mexican population. We also suggest influence of genotype upon PRL mRNA expression.     

Prediction of normal values for lactate threshold estimated by gas exchange in men and women

Lactate threshold (LT) is an index of exercise capacity and can be estimated from the gas exchange consequences of a metabolic acidosis (LT_GE). In recent years, it has emerged as a diagnostic tool in the evaluation of subjects with exercise limitation. The purpose of this study was to develop LT_GE prediction equations on a relatively large sample of adults and to cross-validate each equation. A total of 204 healthy, sedentary, nonsmoking subjects (103 men and 101 women), aged 20–70 years, underwent graded exercise testing on a cycle ergometer. The V-slope technique was used to detect LT_GE as the oxygen uptake (V˙O₂) at the breakpoint of the carbon dioxide output versus V˙O₂ relationship. Multiple linear regression was used to develop 12 equations with combinations of the following predictor variables: age, height, body mass, and fat-free mass. Eight of the equations are gender-specific and four are generalized with gender as a dummy variable. The equations were cross-validated using the predicted residual sum of squares (PRESS) method. The results demonstrate that the equations had relatively high multiple correlations (0.577–0.863) and low standard errors of the estimate (0.123–0.228 1 · min⁻¹). The PRESS method demonstrated that the equations are generalizable, i.e., can be used in future studies without a significant loss of accuracy. Since we tested only healthy, sedentary subjects, our equations can be used to predict the lower limit of normal for a given subject. Using individual data for healthy and diseased subjects from the literature, we found that our gender-specific equations rarely miscategorized subjects unless they were obese and mass was a predictor variable. We conclude that our equations provide accurate predictions of normal values for LT_GE and that they are generalizable to other subject populations. Accepted: 13 February 1997     

The Raynaud's Treatment Study: Biofeedback Protocols and Acquisition of Temperature Biofeedback Skills

The Raynaud's Treatment Study (RTS) compared temperature biofeedback training and a behavioral control procedure (frontalis EMG biofeedback) with nifedipine-XL and a medication placebo for treatment of primary Raynaud's phenomenon (RP) in a large (N = 313) multicenter trial. The present study describes the RTS biofeedback protocols and presents data on the acquisition of digital skin temperature and frontalis EMG responses in the RTS. The findings point to substantial problems with acquisition of physiological self-regulation skills in the RTS. Only 34.6% of the Temperature Biofeedback group (N = 81) and 55.4% of the EMG Biofeedback group (N = 74) successfully learned the desired physiological response. In contrast, 67.4% of a Normal Temperature Biofeedback group (N = 46) learned hand warming. Multivariate analysis found that coping strategies, anxiety, gender, and clinic site predicted acquisition of hand-warming skills whereas variables related to RP disease severity did not. Physiological data showed vasoconstriction in response to the onset of biofeedback and also found that performance in the initial sessions was critical for successful acquisition. These findings indicate that attention to the emotional and cognitive aspects of biofeedback training, and a degree of success in the initial biofeedback sessions, are important for acquisition.     

健康体检人群甲状腺结节多普勒超声检查结果及影响因素分析

目的:研究健康体检人群甲状腺结节多普勒超声检查结果及影响因素。方法:将从2018年1月~2019年12月,于医院接受体检的健康体检人员5270例纳入研究,对所有受试者均进行多普勒超声检查,分析超声检查结果和体检人群基线资料的关系,分析甲状腺结节多普勒超声特征。采用单因素以及多因素Logistic回归分析健康体检人群甲状腺结节的影响因素。结果:在5270例健康体检人群中,甲状腺结节检出率为51.86%(2733/5270),女性甲状腺结节检出率为52.83%(2355/4458),高于男性的46.55%(378/812),且随着年龄的不断增长,健康体检人群甲状腺结节检出率呈逐渐升高趋势(均P<0.05)。甲状腺结节患者的多普勒超声检查特征以低回声以及结节直径<2 cm为主(均P<0.05),但是结节数目以及病变部位比较无明显差异(均P>0.05)。经单因素分析发现:吸烟、甲状腺疾病家族史、高血压及糖尿病的健康体检人员甲状腺结节检出率高于不吸烟、无甲状腺疾病家族史、无高血压及无糖尿病的健康体检人员(均P<0.05),而不同民族、受教育年限、体质量指数(BMI)、是否饮酒的健康体检人员甲状腺结节检出率比较无统计学差异(均P>0.05)。经多因素Logistic回归分析发现:女性、年龄、吸烟、甲状腺疾病家族史、高血压及糖尿病均是健康体检人群甲状腺结节发生的独立危险因素(均OR>1,P<0.05)。结论:甲状腺结节多普勒超声检查特征以低回声以及结节直径≤2 cm为主,其影响因素包括年龄、性别、吸烟、甲状腺疾病家族史、高血压及糖尿病,值得临床重点关注。     

高原移居者红细胞滤过指数的变化及其机理

目的：探讨不同海拔和同一海拔高底氧环境不同血色素范围对高原健康人红细胞流变特性的影响及其可能发生的机制。方法：检测不同海拔高度（2260m、3300m、4080m）对320健康人EFI、SOD、和MDA的影响。结果：随海拔高度的升高,高原健康人EFI和MDA含量明显升高,而红细胞SOD活性明显降低;EFI与MDA呈正相关,而与红细胞SOD活性呈负相关。同一海拔低氧环境Hb增高者,EFI和MDA升高,而红细胞SOD活性降低;随海拔升高,EFI和MDA含量明显升高,而红细胞SOD活性明显降低。结论：不同海拔红细胞流变学和氧自由基代谢差异性的形成,低氧环境起核心作用;而随海拔高度升高和同一海拔低氧环境自由基代谢异常加重者是导致高原健康人红细胞流变学异常的中心环节。     

Erosion of informed consent in U.S. research

This paper evaluates four recent randomized clinical trials in which the informed consent of participants was either not sought at all, or else was conducted with critical information missing from the consent documents. As these studies have been taking place, various proposals to conduct randomized clinical trials without consent have been appearing in the medical literature. Some of the explanations offered for why it is appropriate to bypass consent or disclosure requirements appear to represent a fundamental misunderstanding of applicable government regulations and even the research enterprise. Others are the result of conceptual disagreements about the importance and application of traditional research ethics norms to ‘comparative effectiveness research’ and modern research environments. Common among these explanations, however, is a failure to appreciate when a research intervention, rather than merely an observation or review of data, is taking place. Review committees and investigators are failing to see, or choosing to ignore, interventions in the lives of research subjects. When these studies have come to light, government agencies with oversight authority have done little or backed down. Prestigious medical journals have published research results knowing that the required consent was not obtained, or they have stood by the published studies even after the inadequacy of consent is discovered. This article critically examines this erosion of consent in theory and practice and calls for restoring the requirement of informed consent to its proper place as a priority in human subjects research.     

Our flawed approach to undue inducement in medical research

Some worry that offering too much money to participate in medical research can seduce people into participating against their better judgment. These overly attractive offers that impair judgment are often referred to as ‘undue inducements’. The current approach to prevent undue inducement is to limit the size of such offers. The hope is that smaller offers will not be attractive enough to impair judgment. Even if this is true, I argue that we should reject this solution. In Section 1, I go over the problem of undue inducement, and our current approach to preventing it, in more detail. In Section 2, I argue that, like money, therapeutic benefits of medical research may also unduly induce. In Section 3, I argue that the current approach to preventing undue inducement is absurd in the case of therapeutic inducements. In Section 4, I argue that our current approach is analogously problematic in the case of monetary inducements.     

Event related desynchronization: use as a neurophysiologic marker is restricted

The present research aims to show that the occurrence of alpha blocking or event-related desynchronization (ERD) strongly depends on the amplitude and also on the phase angle of alpha activity at the stimulus onset. Simple visual stimulation was presented to 17 healthy subjects during EEG recording. An O₂ electrode was used for analysis with a 32 channel EEG sampling system. We used a segmentation of raw data in order to obtain the evoked potential. Prestimulus and poststimulus activities were filtered in the alpha (8–13 Hz) frequency band. Later, four different events (blocked, time-locked, phase-locked, and eliminated) were separately averaged. Phase-locked sweeps were determined by application of inter-trial coherence analysis. The evaluation of the data shows that “time-locked and phase-locked sweeps” were the dominating pattern and not “the blocked pattern”, which occurred only when the prestimulus alpha was high. In the analyses of EEG-EP sweeps, only 22 % of epochs showed (ERD). The ANOVA revealed significant differences between four different alpha responses (F(3,48) = 11.175; p < 0.001). Furthermore, alpha oscillations in time-locked responses were significantly higher than blocked (p < 0.0001). The analyses clearly demonstrate that important precaution is needed when using the ERD as a cognitive or pathological marker.