Genetic Variants of Angiotensin-Converting Enzyme Are Linked to Autism: A Case-Control Study

BackgroundAutism is a disease of complex nature with a significant genetic component. The importance of renin-angiotensin system (RAS) elements in cognition and behavior besides the interaction of angiotensin II (Ang II), the main product of angiotensin-converting enzyme (ACE), with neurotransmitters in CNS, especially dopamine, proposes the involvement of RAS in autism. Since the genetic architecture of autism has remained elusive, here we postulated that genetic variations in RAS are associated with autism.MethodsConsidering the relation between the three polymorphisms of ACE (I/D, rs4343 and rs4291) with the level of ACE activity, we have investigated this association with autism, in a case-control study. Genotype and allele frequencies of polymorphisms were determined in DNAs extracted from venous blood of 120 autistic patients and their age and sex-matched healthy controls, using polymerase chain reaction (PCR) and PCR–restriction fragment length polymorphism (PCR–RFLP) methods.ResultsThere were strong associations between both DD genotype of ACE I/D and the D allele, with autism (P = 0.006, OR = 2.9, 95% CI = 1.64–5.13 and P = 0.006, OR = 2.18, 95% CI = 1.37–3.48 respectively). Furthermore, a significant association between the G allele of rs4343 and autism was observed (P = 0.006, OR = 1.84, 95%CI = 1.26–2.67). Moreover, haplotype analysis revealed an association between DTG haplotype and autism (P = 0.008).ConclusionOur data suggests the involvement of RAS genetic diversity in increasing the risk of autism.     

Stereotactic Aspiration versus Craniotomy for Primary Intracerebral Hemorrhage: A Meta-Analysis of Randomized Controlled Trials

Background

A wealth of evidence based on the randomized controlled trials (RCTs) has indicated that surgery may be a better choice in the management of primary intracerebral hemorrhage (ICH) compared to conservative treatment. However, there is considerable controversy over selecting appropriate surgical procedures for ICH. Thus, this meta-analysis was performed to assess the effects of stereotactic aspiration compared to craniotomy in patients with ICH.

Methods

According to the study strategy, we searched PUBMED, EMBASE and Cochrane Central Register of Controlled Trials. Other sources such as the internet-based clinical trial registries, relevant journals and the lists of references were also searched. After literature searching, two investigators independently performed literature screening, assessment of quality of the included trials and data extraction. The outcome measures included death or dependence, total risk of complication, and the risk of rebleeding, gastrointestinal hemorrhage and systematic infection.

Results

Four RCTs with 2996 participants were included. The quality of the included trials was acceptable. Stereotactic aspiration significantly decreased the odds of death or dependence at the final follow-up (odds ratio (OR): 0.80, 95% confidence interval (CI): 0.69–0.93; P = 0.004) and the risk of intracerebral rebleeding (OR: 0.44, 95% CI: 0.26–0.74; P = 0.002) compared to craniotomy with no significant heterogeneity among the study results.

Conclusions

The present meta-analysis provides evidence that the stereotactic aspiration may be associated with a reduction in the odds of being dead or dependent in primary ICH, which should be interpreted with caution. Further trials are needed to identify those patients most likely to benefit from the stereotactic aspiration.     

Characterization of Bovine Atrial Angiotensin-Converting Enzyme

Bovine atrial angiotensin-converting enzyme (ACE) was purified to electrophoretic homogeneity. The purification procedure included ion-exchange chromatography on DEAE-Toyopearl 650M, affinity chromatography on lisinopril-agarose and gel filtration on Sephadex G-100. The bovine atrial ACE exhibited similar sensitivities to inhibition by lisinopril and captopril as lung ACE (the K _i values for the atrial and lung enzymes differed insignificantly). However, the kinetic parameters of hydrolysis of some synthetic tripeptide substrates (FA-Phe-Gly-Gly, FA-Phe-Phe-Arg, Cbz-Phe-His-Leu, Hip-His-Leu) catalyzed by bovine atrial and lung ACE varied to a greater extent. The enzymes were also characterized by some differences in activation by chloride, nitrate, and sulfate anions. These data support the hypothesis of tissue specificity of ACEs.     

Meta-analysis of Genome-wide Association Studies Identifies 1q22 as a Susceptibility Locus for Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10⁻⁶ was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10⁻⁸); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10⁻⁸). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10⁻⁴; meta-analysis p = 2.2 × 10⁻¹⁰) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10⁻⁵). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly.     

Factors Associated with Early Deterioration after Spontaneous Intracerebral Hemorrhage: A Systematic Review and Meta-Analysis

Background and Purpose

Spontaneous intracerebral hemorrhage (ICH) is a devastating form of stroke with a poor prognosis overall. We conducted a systematic review and meta-analysis to identify and describe factors associated with early neurologic deterioration (END) after ICH.

Methods

We sought to identify any factor which could be prognostic in the absence of an intervention. The Cochrane Library, EMBASE, the Global Health Library, and PubMed were searched for primary studies from the years 1966 to 2012 with no restrictions on language or study design. Studies of patients who received a surgical intervention or specific experimental therapies were excluded. END was defined as death, or worsening on a reliable outcome scale within seven days after onset.

Results

7,172 abstracts were reviewed, 1,579 full-text papers were obtained and screened. 14 studies were identified; including 2088 patients. Indices of ICH severity such as ICH volume (univariate combined OR per ml:1.37, 95%CI: 1.12–1.68), presence of intraventricular hemorrhage (2.95, 95%CI: 1.57–5.55), glucose concentration (per mmol/l: 2.14, 95%CI: 1.03–4.47), fibrinogen concentration (per g/l: 1.83, 95%CI: 1.03–3.25), and d-dimer concentration at hospital admission (per mg/l: 4.19, 95%CI: 1.88–9.34) were significantly associated with END after random-effects analyses. Whereas commonly described risk factors for ICH progression such as blood pressure, history of hypertension, and ICH growth were not.

Conclusions

This study summarizes the evidence to date on early ICH prognosis and highlights that the amount and distribution of the initial bleed at hospital admission may be the most important factors to consider when predicting early clinical outcomes.     

作为肾素-血管紧张素系统调节器和SARS病毒受体的人血管紧张素转换酶2

人血管紧张素转换酶2(ACE2)是目前已知的惟一的人血管紧张素转换酶(ACE)的同源物,是一种新型的金属羧肽酶,很多特性与ACE截然不同.ACE2在肾素-血管紧张素系统(RAS)中具有独特的作用,调节心脏功能和机体血压.最近ACE2被鉴定为SARS病毒的功能受体.ACE2已经成为目前药物研发的新靶点.对ACE2的认识才刚刚开始,有待进-步深入研究.     

脑出血患者急性期窦性心率震荡结果分析

目的:观察首次脑出血(intracerebral hemorrhage,ICH)患者急性期窦性心率震荡(heart rate turbulence,HRT)的变化特点.方法:从44例脑出血患者选择20例符合HRT分析条件的患者为脑出血组,选择无心脑器质性疾病且符合HRT分析条件的20例患者作为对照组.所有患者发病5天内行24小时动态心电图监测,计算并分析HRT指标震荡初始(turbulence onset,TO)、震荡斜率(turbulence slope,TS),同时收集患者临床资料.结果:与对照组TO、TS比较,脑出血组TO值升高有统计学意义(P＜0.05),TS值降低无显著性意义(P＞0.05).不同部位脑出血患者TO及TS差异无统计学意义(渐进显著性＞0.01).结论:脑出血组患者急性期的HRT减弱,自主神经功能受到损害,推测脑出血患者急性期心脏意外发生可能性大.左右半球、蛛网膜下腔出血时自主神经损害程度是否存在差异仍待探讨.     

MEKK1 Associated with Neuronal Apoptosis Following Intracerebral Hemorrhage

The JNKs have been implicated in a variety of biological functions in mammalian cells, including apoptosis and the responses to stress. However, the physiological role of these pathways in the intracerebral hemorrhage (ICH) has not been fully elucidated. In this study, we identified a MAPK kinase kinase (MAPKKK), MEKK1, may be involved in neuronal apoptosis in the processes of ICH through the activation of JNKs. From the results of western blot, immunohistochemistry and immunofluorescence, we obtained a significant up-regulation of MEKK1 in neurons adjacent to the hematoma following ICH. Increasing MEKK1 level was found to be accompanied with the up-regulation of p-JNK 3, p53, and c-jun. Besides, MEKK1 co-localized well with p-JNK in neurons, indicating its potential role in neuronal apoptosis. What’s more, our in vitro study, using MEKK1 siRNA interference in PC12 cells, further confirmed that MEKK1 might exert its pro-apoptotic function on neuronal apoptosis through extrinsic pathway. Thus, MEKK1 may play a role in promoting the brain damage following ICH.     

Pharmacogenetic Risk Stratification in Angiotensin-Converting Enzyme Inhibitor-Treated Patients with Congestive Heart Failure: A Retrospective Cohort Study

Background

Evidence for pharmacogenetic risk stratification of angiotensin-converting enzyme inhibitor (ACEI) treatment is limited. Therefore, in a cohort of ACEI-treated patients with congestive heart failure (CHF), we investigated the predictive value of two pharmacogenetic scores that previously were found to predict ACEI efficacy in patients with ischemic heart disease and hypertension, respectively. Score A combined single nucleotide polymorphisms (SNPs) of the angiotensin II receptor type 1 gene (rs275651 and rs5182) and the bradykinin receptor B1 gene (rs12050217). Score B combined SNPs of the angiotensin-converting enzyme gene (rs4343) and ABO blood group genes (rs495828 and rs8176746).

Methods

Danish patients with CHF enrolled in the previously reported Echocardiography and Heart Outcome Study were included. Subjects were genotyped and categorized according to pharmacogenetic scores A and B of ≤1, 2 and ≥3 each, and followed for up to 10 years. Difference in cumulative incidences of cardiovascular death and all-cause death were assessed by the cumulative incidence estimator. Survival was modeled by Cox proportional hazard analyses.

Results

We included 667 patients, of whom 80% were treated with ACEIs. Differences in cumulative incidences of cardiovascular death (P = 0.346 and P = 0.486) and all-cause death (P = 0.515 and P = 0.486) were not significant for score A and B, respectively. There was no difference in risk of cardiovascular death or all-cause death between subjects with score A ≤1 vs. 2 (HR 1.03 [95% CI 0.79–1.34] and HR 1.11 [95% CI 0.88–1.42]), score A ≤1 vs. ≥3 (HR 0.80 [95% CI 0.59–1.08] and HR 0.91 [95% CI 0.70–1.20]), score B ≤1 vs. 2 (HR 1.02 [95% CI 0.78–1.32] and HR 0.98 [95% CI 0.77–1.24]), and score B ≤1 vs. ≥3 (HR 1.03 [95% CI 0.75–1.41] and HR 1.05 [95% CI 0.79–1.40]), respectively.

Conclusions

We found no association between either of the analyzed pharmacogenetic scores and fatal outcomes in ACEI-treated patients with CHF.     

血管紧张素转换酶2的功能和应用

人血管紧张素转换酶2（ACE2）是肾素-血管紧张素系统（RAS）的重要调节分子,它在控制心血管和血压的正常生理活动中具有重要的作用。此外,ACE2作为SARS病毒的受体,对于病毒的入侵起关键作用。目前ACE2已经被用于高血压和心血管相关疾病的药物靶标设计和基因治疗,随着研究的深入,ACE2在临床上的应用将更加广泛。     

Inhibition of Angiotensin-Converting Enzyme Activity by Flavonoids: Structure-Activity Relationship Studies

Previous studies have demonstrated that certain flavonoids can have an inhibitory effect on angiotensin-converting enzyme (ACE) activity, which plays a key role in the regulation of arterial blood pressure. In the present study, 17 flavonoids belonging to five structural subtypes were evaluated in vitro for their ability to inhibit ACE in order to establish the structural basis of their bioactivity. The ACE inhibitory (ACEI) activity of these 17 flavonoids was determined by fluorimetric method at two concentrations (500 µM and 100 µM). Their inhibitory potencies ranged from 17 to 95% at 500 µM and from 0 to 57% at 100 µM. In both cases, the highest ACEI activity was obtained for luteolin. Following the determination of ACEI activity, the flavonoids with higher ACEI activity (i.e., ACEI >60% at 500 µM) were selected for further IC₅₀ determination. The IC₅₀ values for luteolin, quercetin, rutin, kaempferol, rhoifolin and apigenin K were 23, 43, 64, 178, 183 and 196 µM, respectively. Our results suggest that flavonoids are an excellent source of functional antihypertensive products. Furthermore, our structure-activity relationship studies show that the combination of sub-structures on the flavonoid skeleton that increase ACEI activity is made up of the following elements: (a) the catechol group in the B-ring, (b) the double bond between C2 and C3 at the C-ring, and (c) the cetone group in C4 at the C-ring. Protein-ligand docking studies are used to understand the molecular basis for these results.     

脑出血患者脑脊液Abeta水平检测及其临床意义

目的:探讨脑出血患者脑脊液中amylid-beta(Aβ)40和Aβ42水平及其与出血量以及血肿周围低密体积相关性。方法:采集73例脑出血患者及72例健康对照的脑脊液标本,采用酶联免疫吸附法(Elisa)检测脑脊液中的Aβ40和Aβ42的水平,分析其与出血量和血肿周围低密度体积的相关性。结果:(1)脑出血患者脑脊液Aβ40和Aβ42水平显著高于健康对照组(P0.01)。(2)脑出血患者脑脊液Aβ40(r=0.549,P0.01;r=0.791,P0.01)和Aβ42(r=0.450,P0.01;r=0.440,P0.01)水平与出血量及血肿周围低密度体积呈正相关。结论:Aβ40和Aβ42水平为神经元损害的标志物,本研究提示脑脊液Aβ40和Aβ42水平对于判断脑出血严重程度具有临床参考价值。     

老年高血压脑出血的微创治疗分析

目的:探讨微创手术与传统开颅手术治疗高血压脑出血的手术效果。方法:回顾性分析自2005年5月至2009年7月期间开颅手术39例和微创手术治疗44例高血压脑出血的疗效,比较两种方式的优劣。结果:开颅手术组和微创手术组均获得了较好的疗效,两者相比未见有明显的差别。结论:微创手术组和开颅手术比较未见明显的疗效差异,微创手术手术简单,创伤面积小,费用较低,患者耐受性好,值得推广。     

老年高血压脑出血的微创治疗分析

目的：探讨微创手术与传统开颅手术治疗高血压脑出血的手术效果。方法：回顾性分析自2005年5月至2009年7月期间开颅手术39例和微创手术治疗44例高血压脑出血的疗效,比较两种方式的优劣。结果：开颅手术组和微创手术组均获得了较好的疗效,两者相比未见有明显的差剐。结论：微创手术组和开颅手术比较未见明显的疗效差异,微创手术手术简单,创伤面积小,费用较低,患者耐受性好,值得推广。     

Subcellular Localization of Angiotensin-Converting Enzyme in Cultured Neuroblastoma Cells

Angiotensin-converting enzyme (ACE) activity of Neuro-2A mouse neuroblastoma cells was found predominantly in particulate fractions. Density gradient centrifugation of the particulate fractions showed ACE activity in light fractions of the gradient, a result suggesting a plasma membrane localization. This was confirmed using the aqueous two-phase polymer system of plasma membrane isolation. The rapid and energy-independent hydrolysis of exogenous substrate by ACE of intact cells and the sensitivity of the enzyme of intact cells to proteases indicate further that the active site of ACE is oriented extracellularly.     

Polymorphic Markers of the Angiotensin and Angiotensin-Converting Enzyme Genes in Yakuts: A Lack of Association with Blood Pressure

Allele frequency distributions of the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene and the M235T polymorphism of the angiotensinogen gene was studied in a random sample of the indigenous population of the Sakha Republic. The allelic variants of these genes did not showed an association with blood pressure in Yakuts.     

血管紧张素转换酶基因多态性与2型糖尿病发病的相关性研究

目的:探讨血管紧张素转换酶基因(ACE)多态性与其血清水平及2型糖尿病(T2D)发生的相关性.方法:应用聚合酶链反应检测T2D患者287例和正常对照组307例健康人的ACE基因Alu重复序列的插入/缺失(I/D)多态性,采用全自动生化分析仪检测ACE活性及血脂水平,采用SPSS11.0软件包统计分析基因型分布和等位基因频率与其活性、血脂水平及T2D的相关性.结果:ACE I/D多态性在T2D组(DD:13.36%、ID:45.93%、Ⅱ:40.72%)与对照组(DD:13.24%、ID:43.90%、Ⅱ:42.86%)的基因频率无显著性差异(P0.05).T2D组ACE各基因型之间ACE活性有显著性差异(P<0.01).T2D各基因型的血脂水平分析显示Ⅱ型与DD型之间HDL有显著性差异(P<0.05).结论:ACE基因DD型和D等位基因与ACE活性显著相关,但ACE I/D多态性不是T2DM发生的危险因素且无关,DD型与高HDL水平相关.