BACKGROUND & AIMS: :We examined the effect of exercise on postprandial lipemia (PPL) and insulin resistance in individuals with metabolic syndrome. Subjects were 10 hypertriglyceridemia (HTG) males with insulin resistance [age = 40.1 +/- 2.2 years, body weight = 96.3 +/- 3.3 kg, fasting triglyceride (TG) = 263 +/- 25 mg/dl, VO(2)max = 37 +/- 1.1 ml/kg/min, and Homeostatic Model Assessment (HOMA-IR, an index of insulin resistance) = 3.05 +/- 0.40]. Each subject performed a control trial (Ctr, no exercise), and three exercise trials at 40% (40%T), 60% (60%T), and 70% (70%T) of their VO(2)max. The order of trials was randomized and there were 1-2 weeks wash-out period between the trials. All subjects had a fat-meal in each trial. In the exercise trials, subjects jogged on a treadmill for 1 h at a designated intensity 12 h prior to a fat-meal ingestion. Blood samples were taken at 0 h (before the meal), and 2, 4, 6, and 8 h after the meal. The plasma TG, area score under TG concentration curve for over an 8 h-period (TG AUC) after the meal, and HOMA-IR were analyzed. The TG AUC score in 40%T was 30% lower (P = 0.003), 60%T was 31% lower (P = 0.02), and 70%T was 39% lower (P = 0.02) than Ctr. There were no significant differences in the TG AUC scores among the exercise trials (P > 0.05). The insulin concentrations in both 60 and 70%T were lower than Ctr (P < 0.01) which did not differ from 40%T. HOMA-IR in both 60%T (P = 0.041) and 70%T (P = 0.002) were lower than Ctr, but not different from 40%T (HOMA-IR: Ctr = 3.05 +/- 0.40, 40%T = 2.67 +/- 0.35, 60%T = 2.49 +/- 0.31, 70%T = 2.21 +/- 0.27). The results suggest that for physically inactive individuals with metabolic syndrome, exercising at low to moderate intensity may be sufficient to attenuate PPL and increase insulin sensitivity, whereas higher intensity exercise may be needed to normalize blood glucose.

背景与目标： : 我们研究了运动对代谢综合征患者餐后脂血症 (PPL) 和胰岛素抵抗的影响。研究对象为胰岛素抵抗男性高甘油三酯血症 (HTG) 10例 [年龄 = 40.1 +/- 2.2岁，体重 = 96.3 +/-3.3千克，空腹甘油三酯 (TG) = 263 +/- 25 mg/dl，VO(2)max = 37 +/-1.1毫升/kg/min，稳态模型评估 (homa-ir，胰岛素抵抗指数) = 3.05 +/- 0.40]。每个受试者在其VO(2) 最大值的40% (40% T) 、60% (60% T) 和70% (70% T) 下进行对照试验 (Ctr，无运动) 和三个运动试验。试验顺序是随机的，试验之间有1-2周的冲洗期。在每个试验中，所有受试者都吃了一顿脂肪餐。在运动试验中，受试者在摄入脂肪餐之前以指定的强度在跑步机上慢跑1小时。在餐前0小时，餐后2、4、6和8小时采集血样。分析了餐后8小时内的血浆TG，TG浓度曲线下的面积评分 (TG AUC) 和homa-ir。40% T的TG AUC评分30% 低于Ctr (P = 0.003)，60% T 31% 低于Ctr (P = 0.02)，70% T 39% 低于Ctr (P = 0.02)。运动试验之间的TG AUC评分无显着差异 (P> 0.05)。60% 和70% T中的胰岛素浓度均低于Ctr (P <0.01)，这与40% T没有差异。60% T (P = 0.041) 和70% T (P = 0.002) 的homa-ir均低于Ctr，但与40% T (homa-ir: Ctr = 3.05/- 0.40，40% T = 2.67/- 0.35，60% T = 2.49 +/- 0.31，70% T = 2.21 +/- 0.27)。结果表明，对于代谢综合征的身体不活跃的个体，低至中等强度的运动可能足以减弱PPL并增加胰岛素敏感性，而可能需要高强度的运动才能使血糖正常化。

BACKGROUND & AIMS: :In vitro experiments and expression patterns have long suggested important roles for the genetically related cytosolic fatty acid binding proteins (FABPs) in lipid metabolism. However, evidence for such roles in vivo has become available only recently from genetic manipulation of FABP expression in mice. Here, we summarize the fuel-metabolic phenotypes of mice lacking the genes encoding heart-type FABP (H-/- mice) or liver-type FABP (L-/- mice). Cytosolic extracts from H-/- heart and skeletal muscle and from L-/- liver showed massively reduced binding of long chain fatty acids (LCFA) and, in case of L-/- liver, also of LCFA-CoA. Uptake, oxidation, and esterification LCFA, when measured in vivo and/or ex vivo, were markedly reduced in H-/- heart and muscle and in L-/- liver. The reduced LCFA oxidation in H-/- heart and L-/- liver was not due to reduced activity of PPARa, a fatty acid-sensitive transcription factor that determines the lipid-oxidative capacity in these organs. In H-/- mice, mechanisms of compensation were partially studied and included a redistribution of muscle mitochondria as well as increases of cardiac and skeletal muscle glucose uptakes and of hepatic ketogenesis. In skeletal muscle, the altered glucose uptake included decreased basal but increased insulin-dependent components. Metabolic compensation was only partial, however, since the H-/- mice showed decreased exercise tolerance. In conclusion, the recent studies established H- and L-FABP as major determinants of regional LCFA utilization; therefore the H-/- and L-/- mice are attractive models for studying principles of fuel selection and metabolic homeostasis.

背景与目标： : 体外实验和表达模式长期以来一直表明遗传相关的胞质脂肪酸结合蛋白 (fabp) 在脂质代谢中起重要作用。然而，仅在最近才从小鼠中FABP表达的基因操纵中获得体内这种作用的证据。在这里，我们总结了缺乏编码心脏型FABP (H-/-小鼠) 或肝型FABP (L-/-小鼠) 基因的小鼠的燃料代谢表型。来自H-/-心脏和骨骼肌以及L-/-肝脏的胞质提取物显示长链脂肪酸 (LCFA) 的结合大大降低，对于L-/-肝脏，lcfa-coa的结合也大大降低。在体内和/或离体测量时，LCFA的摄取，氧化和酯化作用在H-/-心脏和肌肉以及L-/-肝脏中显着降低。H-/-心脏和L-/-肝脏中LCFA氧化的降低不是由于PPARa的活性降低，PPARa是一种脂肪酸敏感的转录因子，决定了这些器官中的脂质氧化能力。在H-/-小鼠中，部分研究了补偿机制，包括肌肉线粒体的重新分布以及心脏和骨骼肌葡萄糖摄取的增加以及肝酮发生。在骨骼肌中，葡萄糖摄取的改变包括基础减少但胰岛素依赖性成分增加。代谢补偿只是部分的，因为H-/-小鼠表现出运动耐受性降低。总之，最近的研究确定H-和L-FABP是区域LCFA利用的主要决定因素; 因此，H-/-和L-/-小鼠是研究燃料选择和代谢稳态原理的有吸引力的模型。

BACKGROUND & AIMS: PURPOSE OF REVIEW:Postthrombotic syndrome (PTS) is the most common complication of deep venous thrombosis (DVT). Identifying which patients are at high risk of developing PTS would help improve the management of patients with DVT and allow physicians to provide patients with individualized information on their expected prognosis. This review discusses the knowledge gained from key studies over the last decade on the incidence and determinants of PTS, with special emphasis on published studies from the last 2 years. RECENT FINDINGS:About a third to half of DVT patients will develop PTS, in most cases within 1-2 years of acute DVT. Important risk factors for PTS appear to be ipsilateral recurrence of DVT, poor quality of initial anticoagulation for the treatment of DVT and increased body mass index. SUMMARY:Preventing DVT recurrence by providing adequate intensity and duration of anticoagulation for the initial DVT and using effective thromboprophylaxis in high-risk settings is likely to reduce the frequency of PTS. Despite some advances in identifying risk factors for PTS, however, it is still not possible to reliably predict an individual patient's risk of developing PTS after an episode of DVT. Further studies of clinical determinants and biological markers of increased risk of PTS are needed to ultimately improve long-term prognosis after DVT.

背景与目标：

BACKGROUND & AIMS: :Japanese people in both Japan and in Hawaii have a lower incidence of hip fractures than white people in Hawaii or on the mainland of the United States. Hip fractures usually occur after a fall, and differing incidence rates of falls might contribute to the observed differences in hip fracture rates. To investigate this possibility we undertook a prospective study of falls among elderly Japanese men and women living in Hawaii using intensive surveillance methods similar to those used in studies of predominantly white populations. For our Japanese participants, the incidence rates of total falls were 139 per 1000 person years for men and 276 per 1000 person years for women. Age adjusted rate ratios of falls for predominantly white populations compared with our Japanese participants ranged from 1.8 to 2.3 for women and from 2.6 to 4.7 for men. The risk of injuries when they did fall, however, was not lower for our Japanese participants than reported for white participants. For our Japanese population, past falls, female gender, and daytime hours were associated with an increased incidence of falls.

背景与目标： : 日本和夏威夷的日本人髋部骨折的发生率都比夏威夷或美国本土的白人低。髋部骨折通常发生在跌倒后，不同的跌倒发生率可能会导致观察到的髋部骨折发生率差异。为了调查这种可能性，我们使用了类似于以白人为主的研究中使用的强化监测方法，对居住在夏威夷的日本老年男性和女性的跌倒进行了前瞻性研究。对于我们的日本参与者，男性的总跌倒发生率为139/1000人年，女性为276/1000人年。与我们的日本参与者相比，以白人为主的年龄调整后的跌倒率比率为女性的1.8至2.3，男性的2.6至4.7。但是，我们的日本参与者跌倒时受伤的风险并不比白人参与者低。对于我们的日本人口，过去的跌倒，女性性别和白天的时间与跌倒的发生率增加有关。

BACKGROUND & AIMS: :Immunocompromise after a major injury is presumed to be a predisposing factor for sepsis. Mice subjected to sublethal cecal ligation and puncture (CLP) and challenged 5 days later with Pseudomonas aeruginosa had more bacterial growth in lung tissue, lower serum interferon gamma (IFN-gamma) and interleukin (IL) 12,and higher serum IL-10 when compared with sham CLP mice challenged with Pseudomonas. To test the functional significance of these alterations in cytokine production in the immune response to bacteria, we administered IFN-gamma and anti-IL-10 to post-CLP mice before the Pseudomonas challenge. Administration of IFN-gamma and anti-IL-10 did not improve bacterial clearance or mortality in post-CLP mice. In further studies, we administered IFN-gamma to IL-10 knockout mice before a challenge with P. aeruginosa. Our results showed no significant differences in bacterial clearance or mortality in IL-10 knockout mice with or without IFN-gamma treatment compared with wild-type controls. Finally, because most mortality occurred within 2 to 3 days of the Pseudomonas challenge in the aforementioned studies and was likely associated with a marked proinflammatory response, we investigated the effect of IFN-gamma and anti-IL-10 on clearance of Pseudomonas in C3H/HeJ mice, which do not mount an exaggerated proinflammatory response to endotoxin or Gram-negative bacteria. Neither clearance of the Pseudomonas bacteria nor mortality was improved in C3H/HeJ mice receiving anti-IL-10 and IFN-gamma. These results suggest that the suppressed IFN-gamma and IL-12 responses, in combination with an exaggerated IL-10 response to P. aeruginosa challenge after injury, do not correlate with bacterial clearance or survival.

背景与目标： : 重大损伤后的免疫损害被认为是败血症的诱发因素。与假单胞菌相比，接受亚致死性盲肠结扎和穿刺 (CLP) 并在5天后用铜绿假单胞菌攻击的小鼠肺组织中细菌生长更多，血清干扰素 γ (IFN-γ) 和白介素 (IL) 12降低，血清IL-10更高。为了测试这些细胞因子产生变化在对细菌的免疫反应中的功能意义，我们在假单胞菌攻击之前对CLP后小鼠施用IFN-γ 和anti-IL-10。施用IFN-γ 和anti-IL-10不会改善CLP后小鼠的细菌清除率或死亡率。在进一步的研究中，我们在用铜绿假单胞菌攻击之前对IL-10基因敲除小鼠施用IFN-γ。我们的结果表明，与野生型对照相比，有或没有IFN-γ 处理的IL-10基因敲除小鼠的细菌清除率或死亡率没有显着差异。最后，由于大多数死亡率发生在上述研究中假单胞菌攻击的2至3天内，并且可能与明显的促炎反应有关，因此我们研究了IFN-γ 和anti-IL-10对C3H/HeJ小鼠中假单胞菌清除的影响，它们不会对内毒素或革兰氏阴性细菌产生夸张的促炎反应。在接受anti-IL-10和IFN-γ 的C3H/HeJ小鼠中，假单胞菌的清除率和死亡率均未改善。这些结果表明，受抑制的IFN-γ 和IL-12反应，再加上损伤后对铜绿假单胞菌攻击的过度IL-10反应，与细菌清除或存活无关。

BACKGROUND & AIMS: INTRODUCTION:the potential health impacts due to the decommissioned Nuclear power plants (NPP) located in Borgo Sabotino and Garigliano in Central Italy (active from the early 1960s to the late 1980s) have raised several concerns. Brain, thyroid, breast and lung cancer and leukaemia have been associated with exposure to ionizing radiations, but the health effects of nuclear plants on the resident populations are controversial. OBJECTIVE:to evaluate whether living close to NPPs is associated with an increased risk of cancer incidence and mortality. METHODS:we defined a cohort of residents within 7 km from the NPPs during the period 1996-2002. Individual follow-up for vital status at 01.01.2007 was conducted using municipality data. Gender specific Standardized Incidence and Mortality Ratios, adjusted for age, were calculated (SIR and SMR) using the regional population as reference. Each participant's address was assigned to a distance from the NPP on the basis of a GIS. A relative risk (RR, CI95%), adjusted for age and socioeconomic status, was calculated in 3 bands of increasing radius from the plants: 0-2, 2-4, and 4-7 km (reference group), using a Poisson regression model. RESULTS:the cohort was of 39,775 people, 32%of whom lived near (0-4 km) the NPP. No differences in mortality was found when comparing the cohort with the regional population; among women living within 7 km from the NPP, we found thyroid cancer incidence higher than expected (SIR 1.53 CI95% 1.18-1.95). However, when the analysis was conducted on the basis of the distance from the NPP, we found a statistically significant increase in male mortality only for causes unrelated to radiation exposure (all causes, stomach cancer, and cardiovascular diseases). No mortality excess was observed among women living close to the NPPs. No statistically significant distance-related gradient was observed for cancer incidence both in men and women. CONCLUSIONS:living close to the NPP was not associated with mortality for causes related to radiation exposure. However, the results suggest to continue the epidemiological surveillance of the population.

背景与目标：

BACKGROUND & AIMS: OBJECTIVE:To examine the analytic role of arsenic exposure on cancer mortality among the low-dose (well water arsenic level <150 μg/L) villages in the Blackfoot-disease (BFD) endemic area of southwest Taiwan and with respect to the southwest regional data. METHOD:Poisson analyses of the bladder and lung cancer deaths with respect to arsenic exposure (μg/kg/day) for the low-dose (<150 μg/L) villages with exposure defined by the village median, mean, or maximum and with or without regional data. RESULTS:Use of the village median well water arsenic level as the exposure metric introduced misclassification bias by including villages with levels >500 μg/L, but use of the village mean or the maximum did not. Poisson analyses using mean or maximum arsenic levels showed significant negative cancer slope factors for models of bladder cancers and of bladder and lung cancers combined. Inclusion of the southwest Taiwan regional data did not change the findings when the model contained an explanatory variable for non-arsenic differences. A positive slope could only be generated by including the comparison population as a separate data point with the assumption of zero arsenic exposure from drinking water and eliminating the variable for non-arsenic risk factors. CONCLUSION:The cancer rates are higher among the low-dose (<150 μg/L) villages in the BFD area than in the southwest Taiwan region. However, among the low-dose villages in the BFD area, cancer risks suggest a negative association with well water arsenic levels. Positive differences from regional data seem attributable to non-arsenic ecological factors.

背景与目标：

BACKGROUND & AIMS: BACKGROUND:The complement system is an important mediator of inflammation, which plays a pivotal role in atherosclerosis and acute myocardial infarction (AMI). Animal studies suggest that activation of the complement cascade resulting in the formation of soluble membrane attack complex (sMAC), contributes to both atherosclerosis and plaque rupture and may be the direct cause of tissue damage related to ischemia/reperfusion injury. However clinical data of sMAC during an AMI is sparse. Accordingly the aim was to investigate the prognostic role of sMAC in patients with ST-segment elevation myocardial infarction (STEMI). METHODS:We included 725 STEMI-patients admitted to a single, high-volume invasive heart centre, treated with primary percutaneous coronary intervention (PCI), from September 2006 to December 2008. Blood samples were drawn immediately before PCI. Plasma sMAC was measured using an in-house immunoassay. Endpoints were all-cause mortality (n = 62) and the combined endpoint (n = 122) of major cardiovascular events (MACE) defined as cardiovascular mortality and admission due recurrent AMI or heart failure. Follow-up time was 12 months. RESULTS:During 12 months of follow-up 62 patients died from all causes and 122 patients reached the combined end-point of MACE. Patients with high sMAC (>75th percentile) had increased risk of both all-cause mortality and MACE. Even after adjustment for confounding risk factors by Cox-regression analyses, high levels of sMAC remained an independent predictor of all-cause mortality (hazard ratio 1.81 [95% CI 1.06-3.06; P = .029]) and MACE (hazard ratio 1.70 [95% CI 1.16-2.48; P = .006]). CONCLUSIONS:High plasma sMAC independently predicts all-cause mortality and MACE in STEMI-patients treated with PCI.

背景与目标：

BACKGROUND & AIMS: INTRODUCTION:The aim of this study was to assess population-based changes in incidence, treatment, and in short- and long-term survival of patients with acute respiratory distress syndrome (ARDS) over 23 years. MATERIALS AND METHODS:Analysis of all patients in Iceland who fulfilled the consensus criteria for ARDS in 1988-2010. Demographic variables, Acute Physiology and Chronic Health Evaluation II (APACHE II) scores and ventilation parameters were collected from hospital charts. RESULTS:The age-standardised incidence of ARDS during the study period was 7.2 cases per 100,000 person-years and was increased by 0.2 cases per year (P < 0.001). The most common causes of ARDS were pneumonia (29%) and sepsis (29%). The use of pressure-controlled ventilation became almost dominant from 1993. The peak inspiratory pressure (PIP) has significantly decreased (-0.5 cmH(2) O/year), but the peak end-expiratory pressure (PEEP) has increased (0.1 cmH(2) O/year) during the study period. The hospital mortality decreased by 1% per year (P = 0.03) during the study period, from 50% in 1988-1992 to 33% in 2006-2010. A multivariable logistic regression model revealed that higher age and APACHE II score increased the odds of hospital mortality, while a higher calendar year of diagnosis reduced the odds of mortality. This was unchanged when dominant respiratory treatment, PIP and PEEP were added to the model. The 10-year survival of ARDS survivors was 68% compared with 90% survival of a reference population (P < 0.001). CONCLUSION:The incidence of ARDS has almost doubled, but hospital mortality has decreased during the 23 years of observation. The 10-year survival of ARDS survivors is poor compared with the reference population.

背景与目标：

BACKGROUND & AIMS: :The possible combined effects of caffeine and exercise on blood pressure (BP) regulation were examined in 34 healthy, normotensive (BP less than 135/85 mm Hg) young men (mean age 27 +/- 3 years) in a placebo-controlled, double-blind crossover design. Each subject performed submaximal and symptom-limited maximal supine bicycle exercise 1 hour apart after ingestion of placebo or caffeine (3.3 mg/kg). Heart rate, BP, cardiac output and peripheral vascular resistance were compared for placebo and caffeine days. Postdrug baseline showed that caffeine increased systolic and diastolic BP and peripheral vascular resistance (p less than 0.001 for each) and decreased heart rate (p less than 0.01) but did not change stroke volume or cardiac output. BP and vascular resistance effects of caffeine remained during submaximal exercise resulting in an additive increase in BP while negative chronotropic effects of caffeine disappeared. At maximal exercise substantially more subjects (15 on caffeine vs 7 on placebo, p less than 0.02) had systolic BP greater than or equal to 230 mm Hg and/or greater than or equal to 100 mm Hg for diastolic BP. Plasma norepinephrine levels were not significantly different across days, but epinephrine was higher at maximal exercise and cortisol was increased post-drug and throughout maximal exercise on caffeine days. Data indicate that caffeine increases BP additively during submaximal exercise and may cause excessive BP responses at maximal exercise for some individuals. The pressor effects of caffeine appear to be due to increasing vascular resistance rather than cardiac output.

背景与目标： : 在安慰剂对照中，在34名健康，血压正常 (血压低于135/85mm Hg) 的年轻男性 (平均年龄27/- 3岁) 中检查了咖啡因和运动对血压 (BP) 调节的可能综合作用，双盲交叉设计。每个受试者在摄入安慰剂或咖啡因 (3.3 mg/kg) 后1小时间隔进行次最大和症状受限的最大仰卧自行车运动。比较安慰剂和咖啡因天数的心率，血压，心输出量和外周血管阻力。药物后基线显示，咖啡因增加收缩压和舒张压以及周围血管阻力 (每个p小于0.001) 和降低心率 (p小于0.01)，但不改变中风量或心输出量。在次最大运动期间，咖啡因的BP和血管阻力效应仍然存在，导致BP的累加性增加，而咖啡因的负变时性效应消失了。在最大运动时，明显更多的受试者 (咖啡因组15例，安慰剂组7例，p小于0.02) 的收缩压大于或等于230毫米Hg和/或舒张压大于或等于100毫米Hg。血浆去甲肾上腺素水平在不同的日子没有显着差异，但肾上腺素在最大运动时较高，皮质醇在服药后和咖啡因的整个最大运动中增加。数据表明，咖啡因在次最大运动期间会增加BP，并可能导致某些人在最大运动时产生过多的BP反应。咖啡因的升压作用似乎是由于血管阻力增加而不是心输出量增加所致。

BACKGROUND & AIMS: :Fetal growth, birth weight specific mortality rates and effect of sick leave or hospitalization on the fetal growth were investigated in a material of 476 twin pregnancies managed at University Central Hospital of Turku in years 1970-81. Birth weights of twin babies at any gestational age were slightly but not significantly higher than in earlier materials. When compared to growth curve of singleton fetuses, the growth rate of both twins is equal to singletons up to 30th week of pregnancy, being thereafter slower than in singleton pregnancies. Although duration of sick leave and hospitalization increased considerably during the study period, no change in the duration of pregnancy nor in the weight of twin babies occurred. Instead perinatal mortality decreased from 101/per thousand to 36.2/per thousand. Birth weight specific mortality rates did not differ from those in singleton fetuses.

背景与目标： : 在图尔库大学中央医院1970-81年管理的476例双胎妊娠材料中，研究了胎儿生长，出生体重特定死亡率以及病假或住院对胎儿生长的影响。在任何胎龄的双胞胎婴儿的出生体重均略高于但不显着高于早期材料。与单胎胎儿的生长曲线相比，两个双胞胎的生长速度等于怀孕第30周的单胎，此后比单胎妊娠慢。尽管在研究期间病假和住院时间大大增加，但怀孕时间和双胞胎婴儿的体重没有变化。相反，围产期死亡率从101/每千下降到36.2/每千。出生体重特定死亡率与单胎胎儿没有差异。

BACKGROUND & AIMS: :G protein-coupled receptors (GPCRs) interact with heterotrimeric G proteins and initiate a wide variety of signaling pathways. The molecular nature of GPCR-G protein interactions in the clinically important thromboxane A2 (TxA(2)) receptor (TP) and prostacyclin (PGI(2)) receptor (IP) is poorly understood. The TP activates its cognate G protein (Gαq) in response to the binding of thromboxane, while the IP signals through Gαs in response to the binding of prostacyclin. Here, we utilized a combination of approaches consisting of chimeric receptors, molecular modeling, and site-directed mutagenesis to precisely study the specificity of G protein coupling. Multiple chimeric receptors were constructed by replacing the TP intracellular loops (ICLs) with the ICL regions of the IP. Our results demonstrate that both the sequences and lengths of ICL2 and ICL3 influenced G protein specificity. Importantly, we identified a precise ICL region on the prostanoid receptors TP and IP that can switch G protein specificities. The validities of the chimeric technique and the derived molecular model were confirmed by introducing clinically relevant naturally occurring mutations (R60L in the TP and R212C in the IP). Our findings provide new molecular insights into prostanoid receptor-G protein interactions, which are of general significance for understanding the structural basis of G protein activation by GPCRs in basic health and cardiovascular disease.

背景与目标： : g蛋白偶联受体 (gpcr) 与异三聚体g蛋白相互作用，并启动多种信号通路。临床上重要的血栓烷A2 (TxA(2)) 受体 (TP) 和前列环素 (PGI(2)) 受体 (IP) 中gpcr-g蛋白相互作用的分子性质知之甚少。TP响应血栓烷的结合而激活其同源g蛋白 (G α q)，而IP响应前列环素的结合而通过G α s发出信号。在这里，我们结合了由嵌合受体，分子建模和定点诱变组成的方法来精确研究g蛋白偶联的特异性。通过用IP的ICL区域替换TP细胞内环 (ICL) 来构建多个嵌合受体。我们的结果表明，ICL2和ICL3的序列和长度均影响g蛋白的特异性。重要的是，我们在前列腺素受体TP和IP上确定了一个精确的ICL区域，可以切换g蛋白特异性。通过引入临床相关的自然发生突变 (TP中的R60L和IP中的R212C)，证实了嵌合技术和衍生分子模型的有效性。我们的发现为前列腺素受体-g蛋白相互作用提供了新的分子见解，这对于理解GPCRs在基础健康和心血管疾病中激活g蛋白的结构基础具有普遍意义。

BACKGROUND & AIMS: AIMS:We sought to evaluate bleeding complications and periprocedural outcomes of the radial approach (RA) as compared to the femoral approach (FA) during percutaneous coronary intervention (PCI) in "real-world" patients with ST-segment elevation myocardial infarction (STEMI). METHODS AND RESULTS:The study group consisted of 22,812 consecutive patients with STEMI treated with PCI and stent implantation between January 2014 and June 2015 in 151 tertiary invasive cardiology centres in Poland (the ORPKI Polish National Registry). Patients treated using the RA and FA were compared using a propensity score analysis to avoid possible selection bias. The analysis was carried out in an "as-treated" manner. The FA was used in 9,334 (40.9%) and the RA in 13,478 (59.1%) patients. After propensity score matching, a higher total amount of contrast (191.8±8.0 vs. 174.8±68.8 ml; p=0.001) and lower radiation doses (1,279.5±1,346.3 vs. 1,182.6±887 mGy; p=0.02) were reported in FA. More access-site-related bleeding complications after both angiography (0.17% vs. 0.02%; p=0.004) and PCI (0.23% vs. 0.09%; p=0.049) were reported in the FA group. Periprocedural death (1.94% vs. 0.93%; p=0.001) was more common after PCI performed with the FA. CONCLUSIONS:The radial approach was associated with a lower incidence of periprocedural death in STEMI patients as well as a significant reduction of bleeding complications at the access site.

背景与目标：

BACKGROUND & AIMS: :Obesity affects multiple points along the breast cancer control continuum from prevention to screening and treatment, often in opposing directions. Obesity is also more prevalent in Blacks than Whites at most ages so it might contribute to observed racial disparities in mortality. We use two established simulation models from the Cancer Intervention and Surveillance Modeling Network (CISNET) to evaluate the impact of obesity on race-specific breast cancer outcomes. The models use common national data to inform parameters for the multiple US birth cohorts of Black and White women, including age- and race-specific incidence, competing mortality, mammography characteristics, and treatment effectiveness. Parameters are modified by obesity (BMI of ≥ 30 kg/m(2)) in conjunction with its age-, race-, cohort- and time-period-specific prevalence. We measure age-standardized breast cancer incidence and mortality and cases and deaths attributable to obesity. Obesity is more prevalent among Blacks than Whites until age 74; after age 74 it is more prevalent in Whites. The models estimate that the fraction of the US breast cancer cases attributable to obesity is 3.9-4.5 % (range across models) for Whites and 2.5-3.6 % for Blacks. Given the protective effects of obesity on risk among women <50 years, elimination of obesity in this age group could increase cases for both the races, but decrease cases for women ≥ 50 years. Overall, obesity accounts for 4.4-9.2 % and 3.1-8.4 % of the total number of breast cancer deaths in Whites and Blacks, respectively, across models. However, variations in obesity prevalence have no net effect on race disparities in breast cancer mortality because of the opposing effects of age on risk and patterns of age- and race-specific prevalence. Despite its modest impact on breast cancer control and race disparities, obesity remains one of the few known modifiable risks for cancer and other diseases, underlining its relevance as a public health target.

背景与目标： : 肥胖会影响从预防到筛查和治疗的乳腺癌控制连续体的多个点，通常方向相反。在大多数年龄段，肥胖在黑人中也比白人更普遍，因此可能会导致观察到的种族死亡率差异。我们使用癌症干预和监测建模网络 (CISNET) 建立的两个模拟模型来评估肥胖对种族特异性乳腺癌结局的影响。这些模型使用通用的国家数据来告知美国多个黑人和白人女性出生队列的参数，包括特定于年龄和种族的发病率，竞争性死亡率，乳房x线摄影特征和治疗效果。通过肥胖 (BMI ≥ 30千克/m(2)) 及其年龄，种族，队列和时间段特异性患病率来修改参数。我们测量了年龄标准化的乳腺癌发病率和死亡率以及肥胖导致的病例和死亡。直到74岁，肥胖在黑人中比白人更普遍; 74岁以后，在白人中更普遍。这些模型估计，美国乳腺癌病例中肥胖的比例在白人中是3.9-4.5% (模型范围)，在黑人中是2.5-3.6%。鉴于肥胖对 <50岁女性风险的保护作用，消除该年龄组的肥胖可以增加两个种族的病例，但减少 ≥ 50岁女性的病例。总体而言，肥胖分别占白人和黑人乳腺癌死亡总数的4.4-9.2% 和3.1-8.4%。然而，肥胖患病率的变化对乳腺癌死亡率的种族差异没有净影响，因为年龄对风险以及年龄和种族特定患病率的模式有相反的影响。尽管肥胖对乳腺癌控制和种族差异的影响不大，但它仍然是癌症和其他疾病的少数已知可改变的风险之一，突显了其作为公共卫生目标的相关性。

BACKGROUND & AIMS: :Obesity, diabetes, hypertension, and hyperlipidemia constitute risk factors for morbidity and premature mortality. Based on animal and in vitro studies, resveratrol reverts these risk factors via stimulation of silent mating type information regulation 2 homolog 1 (SIRT1), but data in human subjects are scarce. The objective of this study was to examine the metabolic effects of high-dose resveratrol in obese human subjects. In a randomized, placebo-controlled, double-blinded, and parallel-group design, 24 obese but otherwise healthy men were randomly assigned to 4 weeks of resveratrol or placebo treatment. Extensive metabolic examinations including assessment of glucose turnover and insulin sensitivity (hyperinsulinemic euglycemic clamp) were performed before and after the treatment. Insulin sensitivity, the primary outcome measure, deteriorated insignificantly in both groups. Endogenous glucose production and the turnover and oxidation rates of glucose remained unchanged. Resveratrol supplementation also had no effect on blood pressure; resting energy expenditure; oxidation rates of lipid; ectopic or visceral fat content; or inflammatory and metabolic biomarkers. The lack of effect disagrees with persuasive data obtained from rodent models and raises doubt about the justification of resveratrol as a human nutritional supplement in metabolic disorders.

背景与目标： : 肥胖、糖尿病、高血压和高脂血症是发病和过早死亡的危险因素。基于动物和体外研究，白藜芦醇通过刺激沉默交配型信息调节2同源物1 (SIRT1) 来恢复这些危险因素，但人类受试者的数据很少。这项研究的目的是检查高剂量白藜芦醇在肥胖人类受试者中的代谢作用。在随机，安慰剂对照，双盲和平行组设计中，将24名肥胖但健康的男性随机分配到4周的白藜芦醇或安慰剂治疗中。在治疗前后进行了广泛的代谢检查，包括评估葡萄糖周转和胰岛素敏感性 (高胰岛素性正常血糖钳夹)。主要结局指标胰岛素敏感性在两组中均无明显恶化。内源性葡萄糖的产生以及葡萄糖的周转率和氧化速率保持不变。补充白藜芦醇对血压也没有影响; 静息能量消耗; 脂质的氧化率; 异位或内脏脂肪含量; 或炎症和代谢生物标志物。缺乏效果与从啮齿动物模型获得的有说服力的数据不一致，并且引起了人们对白藜芦醇作为代谢紊乱人体营养补充剂的合理性的怀疑。