Viability of developing CETP inhibitors

The recent failure of a major inhibitor of the cholesterol ester transfer protein (CETP), in trials on high-risk coronary patients, indicated that potentially this therapeutic target might not be a viable one. This conclusion is, however, not surprising since evaluating prior knowledge, the rationale of this therapeutic approach appears to be extremely weak. Although raising high-density lipoprotein (HDL) by a variety of pharmaceutical approaches may still provide a desirable target, CETP inhibitory treatment has very little to offer. Analysis of the literature pertaining to the CETP approach, epidemiological data on individuals with CETP mutations, and finally and in-depth analyses of pharmacological interventions, all appear to indicate that CETP inhibitory treatment should not be pursued as a viable approach. In addition, some of the findings from the clinical studies, for example, in particular a dramatic rise of infectious complications, cast significant perplexity on the possibility of convincing health authorities on the clinical safety of CETP inhibitors. Potentially CETP stimulation, for example by probucol or derivatives may provide instead a more satisfactory approach to cardiovascular prevention.     

老年前列腺癌去势治疗对血清脂联素及颈动脉内膜-中层厚度的影响

目的探讨老年前列腺癌去势治疗对血清脂联素及颈动脉内膜中层厚度（IMT）的影响。方法 32例老年前列腺癌去势患者（CAS组）,32例单纯前列腺切除患者（PH组）,30例年龄匹配的对照组（CON组）,分别检测IMT、腰臀比（EHR）、总睾酮（TT）、游离睾酮（FT）、一氧化氮（NO）、内皮素（ET-1）及脂联素。结果去势组与对照组比较,TT、FT、脂联素水平降低,WHR显著增高,IMT增厚;IMT与FT负相关（r=-0.382,P=0.04）、脂联素与FT正相关（r=0.535,P=0.033）。结论内源性睾酮缺失是动脉粥样硬化的危险因素之一。     

Subclinical atherosclerosis in diabetic children: results of a longitudinal study

Dalla Pozza R, Netz H, Schwarz HP, Bechtold S. Subclinical atherosclerosis in diabetic children: results of a longitudinal study. Context: Cardiovascular disease caused by atherosclerosis is a major cause of morbidity and mortality in adult diabetic patients. In children, we detected signs of subclinical atherosclerosis in a large patient cohort. This study reports the results of a longitudinal observation in this patient group. Patients and methods: Of the 37/150 diabetic children in whom an increased intima‐media thickness (IMT) of the carotid artery had been found, 27 (mean age 14.6 ± 2.6 yrs) could be reevaluated 2 yrs after the initial study. Of the 27, 5 patients were on medication with angiotensin‐converting enzyme (ACE) inhibitors, and all patients underwent detailed counselling of their lifestyle, sports activity, and nutritional habits. Results: Mean IMT increased significantly (0.49 ± 0.02 mm vs. 0.51 ± 0.026 mm, p < 0.05) However, there was no significant change compared to normal values (mean IMT z‐score 2.4 ± 0.3 vs. 2.6 ± 0.5). Of the 27, 13 patients (48%) showed a progression of the IMT whereas in 14/27 patients the IMT values remained stable. In these subgroups, patients with IMT progression showed a higher hemoglobin A1c (HbA1c) (7.5 ± 0.8 vs. 7.1 ± 0.7, p < 0.05) and a slightly higher systolic blood pressure (120 ± 14.4 vs. 113.9 ± 12.1, p = 0.08). Conclusions: In a well‐selected group of diabetic children, mean IMT progression during a 2‐yr period did not exceed the physiological increase. Children with a higher HbA1c and a higher systolic blood pressure showed a progression of the IMT. Control of atherogenic risk factors in diabetic children may help to avoid subclinical atherosclerosis progression.     

Evaluation of a new carotid intima-media thickness measurement by B-mode ultrasonography using an innovative measurement software, intimascope

Carotid intima-media thickness (IMT), an indicator of atherosclerosis and coronary heart disease (CHD) is usually evaluated by eye measurement under B-scope carotid artery ultrasonography. However, the axial resolution of this system is >/=0.1 mm, which causes difficulties in respect to accuracy and reproducibility. We evaluated a newly developed B-scope carotid artery ultrasonography programmed by an innovative measurement software, Intimascope (Media Cross Co. Ltd., Tokyo, Japan), which measures IMT with 10 times higher axial resolution at an estimated scale of 0.01 mm. Intraobserver or interobserver coefficient of variation (CV) of the computer-based average IMT (aver-IMT) value and 3-point IMT value were much smaller than the corresponding value by conventional eye-measurement method (3-point value). We measured IMT of 427 asymptomatic subjects undergoing medical checkups (243 men and 184 women, 23 to 73 years of age). Although the mean values of aver-IMT and 3-point IMT of 427 subjects were comparable with that of the eye measurement method, the aver-IMT showed the smallest SD (standard deviation) and CV values. In both men and women, multivariate regression analysis revealed significant contributions of age and LDL-C to the aver-IMT value. Univariate regression analysis revealed that the aver-IMT value of total subjects showed the highest correlation coefficient values with most risk factors and risk assessment score, Framingham Risk Assessment, or Prospective Cardiovascular Munster study (PROCAM) Risk Score. These results may suggest superiority of computer-based aver-IMT over 3-point IMT by either computer-based or eye measurement method. Carotid aver-IMT measurement using the new Intimascope software may provide a more precise and reproducible index of atherosclerosis than does conventional IMT measurement.     

老年男性颈动脉粥样硬化与性激素水平的相关性

目的 探讨老年男性颈动脉粥样硬化(AS)与内源性性激素的关系.方法 用彩色多普勒高频超声检测86名老年男性颈动脉中-内膜厚度(IMT)及评估双侧颈动脉有无粥样斑块形成;并用放射免疫法测定血清雌二醇(E_2)、总睾酮(TT)、性激素结合球蛋白(SHBG),计算游离睾酮指数(FTI);以及用比色法测定脂蛋白a(LPa)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL)、总胆固醇(TC)及甘油三酯(TG).根据颈动脉检查结果分为无斑块组及有斑块组两组,比较两组间各因子水平的差异,分析内源性性激素与颈动脉IMT的相关性.结果 排除年龄因素影响后,两组间IMTmean、IMTmax、E_2、TT、FTI有显著性差异,偏相关分析表明IMTmean及IMTmax与TT、FTI有显著相关性(均P＜0.01),而与E2无明显相关(P＞0.05).进一步排除血脂影响后,这种相关性有所减弱,但仍存在显著相关性(均P＜0.05).多元回归分析表明IMTmean的独立危险因子为年龄(B=0.001)、(TC-HDL)/HDL比值(B=0.084)、血清TT(B=-0.007)及FTI(B=-0.012).结论 颈动脉粥样斑块形成的老年男性内源性雄激素(包括血清TT及FTI)水平较无斑块组降低,老年男性中内源性性激素与颈动脉IMT呈显著负相关,提示内源性雄激素具有抗动脉粥样硬化作用,血清TT及FTI可能是老年男性颈动脉IMT的独立危险因素之一.     

Carotid intima media thickness is increased and associated with morning cortisol in subjects with non-functioning adrenal incidentaloma

Data regarding cardiovascular risk in subjects with non-functioning adrenal adenoma are limited. The objectives of this study are to investigate carotid intima media thickness (IMT) as an indicator of atherosclerosis in subjects with non-functioning adrenal incidentaloma (AI) and to evaluate the factors that could be associated with IMT. Forty-nine subjects without findings of hypercortisolism or other adrenal gland disorders, 34 body mass index (BMI)-unmatched controls (C) and 18 BMI-matched controls (BC) were enrolled. Participants underwent hormonal evaluation including morning cortisol, adrenocorticotrophic hormone (ACTH), post dexamethasone suppression test cortisol (DST), dehydroepiandrosterone sulfate (DHEAS), and urinary free cortisol. Anthropometric and metabolic parameters and carotid IMT were measured. AI group had increased BMI, blood pressure, waist circumference, post DST cortisol, uric acid, and homeostasis model assessment (HOMA) levels when compared with C. Blood pressure, uric acid and, post DST cortisol remained significantly elevated in AI versus BC. Average IMT was increased significantly in AI versus C (0.74 mm vs. 0.68 mm, P = 0.029) and insignificantly elevated in AI versus BC (0.74 mm vs. 0.67 mm, P = 0.086). In all participants, IMT was correlated with age, BMI, HOMA, waist circumference, morning cortisol, and uric acid. Morning cortisol was independently associated with HOMA levels in both AI group and all participants. Increased IMT in non-functioning AI was a consequence of insulin resistant state associated with subtle cortisol autonomy rather than a direct effect of cortisol. The correlation between morning cortisol and IMT may be associated with the effect of hypothalamus–pituitary–adrenal axis disturbances on vasculature.     

阿托伐他汀钙对血脂异常高血压患者血脂及颈动脉内膜-中膜厚度的影响

目的探讨阿托伐他汀钙对血脂异常高血压病患者的调脂作用及对颈动脉内膜-中膜厚度(IMT)的影响。方法将350例血脂异常高血压病患者随机分为对照组170例与观察组180例,对照组常规降压治疗,观察组患者在常规治疗基础上给予阿托伐他汀片口服。比较两组治疗后血压、血脂及IMT的差异。结果治疗后两组血压无显著性差异(P>0.05),观察组甘油三酯(TG)、总胆固醇(TC)和低密度脂蛋白胆固醇(LDL-C)水平均显著低于对照组(P<0.05);与对照组相比,治疗后观察组IMT值显著下降(P<0.05)。结论阿托伐他汀可显著降低血脂异常高血压患者血脂水平,延缓甚至逆转颈动脉粥样硬化斑块。     

辛伐他汀对高脂血症患者颈动脉内膜-中层厚度及凝血系统的影响

目的 :观察辛伐他汀对高脂血症患者颈动脉内膜 中层厚度 (IMT)及凝血系统的变化及其非调脂作用 .方法 :高脂血症患者 4 6例口服辛伐他汀 2 0mg ,Qd ,12wk ,分别于治疗前后观察IMT、血脂总胆固醇 (TC)、三酰甘油 (TG)、低密度脂蛋白胆固醇 (LDL C)、高密度脂蛋白胆固醇 (HDL C)、纤维蛋白原 (FIB)、凝血酶原时间 (TT)、活化部分凝血酶时间(APTT)、凝血酶原时间 (PT)改变 .结果 :血脂紊乱组治疗 12wk后的颈动脉IMT变薄 (P <0 .0 0 1) ;TC ,TG ,LDL C ,FIB均有显著降低 (P <0 .0 0 1) ,HDL C升高 (P <0 .0 0 1) ,TT ,APTT均有显著延长 (P <0 .0 0 1) .PT升高 (P <0 .0 0 1) .结论 :调脂作用的辛伐他汀有效调脂同时可发挥其非调脂作用 ,干预、延迟颈动脉IMT的进程 ,改善凝血系统 ,减低血液黏稠度 .     

Working memory load modulation of parieto-frontal connections: evidence from dynamic causal modeling

Previous neuroimaging studies have shown that working memory load has marked effects on regional neural activation. However, the mechanism through which working memory load modulates brain connectivity is still unclear. In this study, this issue was addressed using dynamic causal modeling (DCM) based on functional magnetic resonance imaging (fMRI) data. Eighteen normal healthy subjects were scanned while they performed a working memory task with variable memory load, as parameterized by two levels of memory delay and three levels of digit load (number of digits presented in each visual stimulus). Eight regions of interest, i.e., bilateral middle frontal gyrus (MFG), anterior cingulate cortex (ACC), inferior frontal cortex (IFC), and posterior parietal cortex (PPC), were chosen for DCM analyses. Analysis of the behavioral data during the fMRI scan revealed that accuracy decreased as digit load increased. Bayesian inference on model structure indicated that a bilinear DCM in which memory delay was the driving input to bilateral PPC and in which digit load modulated several parieto‐frontal connections was the optimal model. Analysis of model parameters showed that higher digit load enhanced connection from L PPC to L IFC, and lower digit load inhibited connection from R PPC to L ACC. These findings suggest that working memory load modulates brain connectivity in a parieto‐frontal network, and may reflect altered neuronal processes, e.g., information processing or error monitoring, with the change in working memory load. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc