A common polymorphism in SCN5A is associated with lone atrial fibrillation

The cardiac sodium channel (SCN5A) is a target for the treatment of arrhythmias. We hypothesized that vulnerability to atrial fibrillation (AF) could be caused by genetic variation in SCN5A. We recruited 157 patients with early-onset AF who lacked traditional risk factors, and 314 matched controls. SCN5A was subject to targeted genotyping of a common loss-of-function H558R polymorphism and comprehensive mutation scanning. Genotype frequencies in the AF cohort vs controls were as follows: HH, 50 vs 63%; HR, 40 vs 33%; and RR, 10 vs 4% (P=0.008). Additional coding sequence mutations were ruled out. The R558 allele was more common in patients than in controls (30 vs 21%, P=0.002), conferring an odds ratios for AF of 1.6 (95% confidence interval 1.2-2.2). The SCN5A R558 allele, present in one-third of the population, thus constitutes a risk factor for lone AF and may increase susceptibility to sodium channel blocker-induced proarrhythmia.     

Bacteriuria is associated with urge urinary incontinence in older women

Objective

To investigate the association between bacteriuria and frequency and type of urinary incontinence in elderly people living in the community. Bacteriuria and urinary incontinence are common conditions and often coexisting in this population; the authors have previously reported the prevalence of bacteriuria to be 22.4% in women and 9.4% in men.

Design

Cross-sectional study.

Setting

The catchment area of a primary healthcare centre in a Swedish middle-sized town.

Subjects

Residents, except for those in nursing homes, aged 80 and over. Participation rate: 80.3% (431/537).

Main outcome measures

Urinary cultures and questionnaire data on urinary incontinence.

Results

In women the OR for having bacteriuria increased with increasing frequency of urinary incontinence; the OR was 2.83 (95% CI 1.35–5.94) for women who were incontinent daily as compared with continent women. Reporting urge urinary incontinence increased the risk of having bacteriuria: 3.36 (95% CI 1.49–7.58) in comparison with continent women while there was no significant association between stress urinary incontinence and bacteriuria. The prevalence of bacteriuria among men was too low to make any meaningful calculations about the association between bacteriuria and frequency and type of incontinence.

Conclusion

Bacteriuria is associated with more frequent leakage and predominantly with urge urinary incontinence. The causes of this association and their clinical implications remain unclear. There might be some individuals who would benefit from antibiotic treatment, but further studies are warranted.     

肾素血管紧张素系统激活在环孢霉素A肾病中的作用

目的 :探讨肾素血管紧张素系统 (RAS)的激活在环孢霉素 A (Cs A)肾病中的作用。方法 :低盐饮食大鼠皮下注射 Cs A(1 5 mg· kg- 1· d- 1 ) 2 8d制成 Cs A肾病模型。 Cs A肾病大鼠分别胃内灌入自来水、盐酸维拉帕米、依那普利 ,剂量均为 1 0 m g· kg- 1· d- 1。采用放射免疫法检测各组实验动物血管紧张素 (Ang )水平 ;Northern杂交检测肾组织血管紧张素 1型受体 (AT1 R) m RNA的表达 ,同时对各组实验动物肾间质纤维化程度进行半定量计分。结果 :Cs A处理组血浆和肾组织 Ang 水平为 (4 92± 92 ) ng/L 和 (2 9.8± 6 .0 ) ng/g,均明显高于对照组 (1 90± 36 ) ng/L和 (8.7± 1 .7) ng/g,P均 <0 .0 0 1 ;而依那普利可以明显降低血浆和肾组织 Ang 水平 (P均 <0 .0 5 )。 Cs A处理后出现明显的肾间质纤维化 ,依那普利能明显减轻肾间质纤维化 ,盐酸维拉帕米对肾间质纤维化无显著改善。结论 :RAS的激活在 Cs A肾间质纤维化过程中起重要作用 ,阻断 RAS可以明显减轻 Cs A引起的肾间质纤维化。     

Menopause is associated with the stiffness of the common carotid artery in 50-year-old women

To determine if menopause has an effect on the elasticity of the arteries, the stiffness index of the common carotid artery was studied in 84 premenopausal and 139 post-menopausal women. The study group was age-homogeneous, all women being 50 years of age. There were no significant differences between pre- and post-menopausal women regarding atherosclerosis, when measured as the number of subjects with plaques or intimal-medial thickness. The diameter of the common carotid artery was significantly larger in post-menopausal women. The diameter was correlated to measurements of body size which did not, however, differ between the two groups. The mean stiffness indexes were 4·99 ± 1·02 and 5·38 ± 1·21 in the pre- and post-menopausal groups respectively (P<0·05). In a multivariate analysis, menopause (P<0·05), and also serum insulin levels (P<0·01) and smoking (P<0·05) were found to have independent significant associations to the stiffness index. In conclusion, menopause is associated with reduced elasticity of the carotid arteries in 50-year-old women.     

A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires' disease

Although Toll-like receptors (TLRs) are critical mediators of the immune response to pathogens, the influence of polymorphisms in this gene family on human susceptibility to infection is poorly understood. We demonstrated recently that TLR5 recognizes flagellin, a potent inflammatory stimulus present in the flagellar structure of many bacteria. Here, we show that a common stop codon polymorphism in the ligand-binding domain of TLR5 (TLR5392STOP) is unable to mediate flagellin signaling, acts in a dominant fashion, and is associated with susceptibility to pneumonia caused by Legionella pneumophila, a flagellated bacterium. We also show that flagellin is a principal stimulant of proinflammatory cytokine production in lung epithelial cells. Together, these observations suggest that TLR5392STOP increases human susceptibility to infection through an unusual dominant mechanism that compromises TLR5's essential role as a regulator of the lung epithelial innate immune response.     

Factors associated with successful aging in Brazilian community-dwelling older adults: When physical health is not enough

ObjectivesTo determine the main factors (physical, psychological, social and spiritual) associated with successful aging in community-dwelling older adults.MethodsA cross-sectional study of older adults was conducted evaluating successful aging (Successful Aging Scale-SAS) and its associated factors (sociodemographics, resilience, religiosity/spirituality, meaning in life, quality of life, social support, self-reported diseases, mental health, medications used, among others) using regression models.ResultsA total of 534 older adults were assessed. Linear regression models showed an association of higher SAS score with greater resilience (Beta = 0.371, p < 0.001), spiritual well-being - meaning (Beta = 0.174, p < 0.001) and quality of life - physical (Beta=0.203, p < 0.001), fewer diseases (Beta=-0.128, p < 0.001), greater meaning in life (Beta=0.116, p = 0.001), less loneliness (Beta=-0.133, p = 0.001), lower tobacco use (Beta=0.080, p = 0.013), greater quality of life – environment (Beta=-0.092, p = 0.013) and more frequent religious attendance (Beta=0.068, p = 0.035).ConclusionThe study results suggested that physical factors, although relevant, were not the main factors associated with successful aging.     

Reduced body mass index is associated with increased angiotensin II in young women with postural tachycardia syndrome

Altered peripheral haemodynamics, decreased cardiac output, decreased blood volume and increased AngII (angiotensin II) have been reported in POTS (postural tachycardia syndrome). Recent findings indicate that BMI (body mass index) may be reduced. In the present study, we investigated the hypothesis that reduced BMI is associated with haemodynamic abnormalities in POTS and that this is related to AngII. We studied 52 patients with POTS, aged 14-29 years, compared with 36 control subjects, aged 14-27 years. BMI was not significantly reduced on average in the POTS patients, but was reduced in patients with decreased peripheral blood flow. POTS patients were then subdivided on the basis of BMI, and supine haemodynamics were measured. There was no difference in blood volume or cardiac output once BMI or body mass were accounted for. When POTS patients with BMI <50th percentile were compared with controls, calf blood flow [1.63+/-0.31 compared with 3.58+/-0.67 ml(-1).min(-1).(100 ml of tissue)(-1)] and maximum venous capacity (3.87+/-0.32 compared with 4.98+/-0.36 ml/100 ml of tissue) were decreased, whereas arterial resistance [56+/-0.5 compared with 30+/-4 mmHg.ml(-1).min(-1).(100 ml of tissue)(-1)] and venous resistance [1.23+/-0.17 compared with 0.79+/-0.11 mmHg.ml(-1).min(-1).(100 ml of tissue)(-1)] were increased. Similar findings were also observed when POTS patients with BMI <50th percentile were compared with POTS patients with BMI >50th percentile. There was no relationship between blood flow, resistance or maximum venous capacity with BMI in control subjects. BMI was inversely related to plasma AngII concentrations in those POTS patients with decreased peripheral blood flow, consistent with cachectic properties of the octapeptide. Patients with low-flow POTS had decreased body mass, but decreased body mass alone cannot account for findings of peripheral vasoconstriction. In conclusion, the findings suggest that reduced body mass relates to increased plasma AngII.     

Leptin increase is associated with markers of the hemostatic system in obese healthy women

Summary.  Background : Leptin, a hormone secreted by the adipose tissue, might be a link between obesity and increased morbidity for cardiovascular disease. Leptin exerts proinflammatory, pro-angiogenic actions by activating a specific receptor (Ob-Rb) which is expressed in human endothelial cells. Thus, a link may exist between leptin expression and endothelial dysfunction. Objectives : We sought to determine whether in obese women there is a correlation between leptin levels, endothelial perturbation and coagulative activation. Methods : Circulating levels of leptin, von Willebrand Factor (VWF), factor (F)VIIa, prothrombin fragment 1 + 2 (F1+2), were measured in 51 non-diabetic, obese women and in 51 normal-weight subjects, using immunoenzymatic assays. Results : Obese women had significantly higher levels of leptin, VWF, FVIIa, F 1+2 compared with healthy women. Simple correlation coefficients showed significant correlation between leptin and either VWF, FVIIa, or F 1+2 concentrations. A multiple linear regression analysis, performed to quantify further the relationship between leptin levels and the above-mentioned variables as well as the inflammatory marker C-reactive protein (CRP) and including age, body mass index (BMI), waist–hip ratio (WHR) and lipid parameters as potential confounders, revealed that only FVIIa and VWF were independently related to leptin levels. Reduction in adipose tissue after weight loss resulted in a decrease in both circulating leptin and endothelial and coagulative activation markers. Conclusions : We suggest that leptin might have pro-atherogenic effects in vivo , with a mechanism involving endothelial cell activation.     

The D allele of angiotensin I-converting enzyme gene insertion/deletion polymorphism is associated with the severity of atherosclerosis

BACKGROUND: Angiotensin II is produced primarily by angiotensin I-converting enzyme (ACE) within atherosclerotic lesions and ACE level in plaques correlates with the severity of vessel wall damage. Therefore, we investigated the possible association of ACE gene insertion/deletion (I/D) polymorphism and the severity of atherosclerosis, estimated on the basis of the number of coronary stenoses and critical arterial occlusions observed during coronary angiography. METHODS: The study cohort included 172 patients with angiographically confirmed premature coronary artery disease. The ACE gene I/D polymorphism was genotyped using a PCR method. RESULTS: The frequencies of DD genotype, D allele carrier-state (DD+ID genotypes) and the D allele increased with the number of stenoses in coronary vessels. D allele carriers (DD+ID genotypes) were more frequent in the subgroup of patients with stenoses in at least four coronary vessels than in other patients including subjects with one-, two- and three-vessel disease (97.4% vs. 74.4%, OR=13.05, 95% CI: 1.81-100.00, chi2=9.84, p=0.0017). Furthermore, the D allele was significantly more frequent in patients with critical arterial occlusions (>90%) than in subjects without critical stenoses (61.1% vs. 49.3%, chi2=9.84, p=0.023). CONCLUSIONS: The ACE I/D polymorphism influences individual differences in severity of coronary artery disease and the D allele promotes generation of numerous and critical atherosclerotic lesions.     

A polymorphism in TIM1 is associated with susceptibility to severe hepatitis A virus infection in humans

During infection with the hepatitis A virus (HAV), most patients develop mild or asymptomatic disease. However, a small number of patients develop serious, life-threatening hepatitis. We investigated this variability in disease severity by examining 30 Argentinean patients with HAV-induced acute liver failure in a case-control, cross-sectional, observational study. We found that HAV-induced severe liver disease was associated with a 6-amino-acid insertion in TIM1/HAVCR1 (157insMTTTVP), the gene encoding the HAV receptor. This polymorphism was previously shown to be associated with protection against asthma and allergic diseases and with HIV progression. In binding assays, the TIM-1 protein containing the 157insMTTTVP insertion polymorphism bound HAV more efficiently. When expressed by human natural killer T (NKT) cells, this long form resulted in greater NKT cell cytolytic activity against HAV-infected liver cells, compared with the shorter TIM-1 protein without the polymorphism. To our knowledge, the 157insMTTTVP polymorphism in TIM1 is the first genetic susceptibility factor shown to predispose to HAV-induced acute liver failure. Furthermore, these results suggest that HAV infection has driven the natural selection of shorter forms of the TIM-1 protein, which binds HAV less efficiently, thereby protecting against severe HAV-induced disease, but which may predispose toward inflammation associated with asthma and allergy.     

A common polymorphism in the ABCB11 gene is associated with advanced fibrosis in hepatitis C but not in non-alcoholic fatty liver disease

Chronic HCV (hepatitis C virus)-associated cirrhosis represents a major indication for liver transplantation. Bile acids contribute to hepatic stellate cell activation as a key event in fibrogenesis. The aim of the present study was to investigate the role of bile acids and polymorphisms in bile acid level-regulating genes on fibrosis progression. A total of 206 subjects with chronic HCV infection were included for ABCB11 (ATP-binding cassette, subfamily B, member II) 1331T>C and NR1H4 (nuclear receptor) -1G>T genotyping, 178 of which were analysed for fibrosis stage. Exclusion criteria were HBV (hepatitis B virus) or HIV coinfection, alcohol >40 g/day and morbid obesity. A total of 358 patients with NAFLD (non-alcoholic fatty liver disease) were genotyped for comparison with a non-viral liver disease. Caucasian individuals (n = 110), undergoing liver resection for focal hepatic metastasis, served as controls. The ABCB11 1331C allele was significantly overrepresented in HCV patients compared with controls {allelic frequency 62.9%; OR (odds ratio), 1.41 [95% CI (confidence interval), 1.012-1.965]}. Median plasma bile acid levels were not significantly increased in the CC compared with TT genotype [7.2 (1-110) μmol/l compared with 3.5 (1-61) μmol/l; values are medians (range). A significant association between the presence of cirrhosis and ABCB11 genotype (CC compared with CT or TT, P=0.047) was observed in the χ2 test and independent of other risk factors of age, gender, body mass index and disease duration in multivariate analysis (P = 0.010). No such association could be observed in fatty liver patients with regard to advanced fibrosis (F ≥ 2). The common ABCB11 1331CC genotype, which is present in 40% of HCV patients and renders the carrier susceptible to increased bile acid levels, is associated with cirrhosis.     

Joint hypermobility syndrome: A common clinical disorder associated with migraine in women

Preliminary studies suggested that headache disorders are more common in patients with joint hypermobility syndrome (JHS). The objectives of this study were to determine if the prevalence, frequency, and disability of migraine differ between female patients with JHS and a control population. Twenty-eight patients with JHS and 232 controls participated in the case-cohort study. Participants underwent a structured verbal interview and were assigned a diagnosis of migraine based on criteria of the International Classification of Headache Disorders, 2nd Edition. The primary outcome measures were the prevalence, frequency, and headache-related disability of migraine. Logistic regression was used for the prevalence analysis and Poisson regression for the frequency and disability analyses. Results indicated that the prevalence of migraine was 75% in JHS patients and 43% in controls. The adjusted odds ratio for the prevalence of migraine was 3.19 (95% CI 1.24, 8.21] in JHS patients. The rate ratios for migraine frequency and headache-related disability were 1.67 (95% CI 1.01, 2.76) and 2.99 (95% CI 1.66, 5.38), respectively, for JHS patients. Our study suggests that JHS is a clinical disorder strongly associated with an increased prevalence, frequency, and disability of migraine in females.     

A single nucleotide polymorphism in LRP2 is associated with susceptibility to Alzheimer's disease in the Chinese population

BackgroundLRP2 (also called megalin) plays a potential key role in the pathogenesis of Alzheimer's disease (AD). Recently, one genome-wide association study has revealed that the rs3755166 (G/A) polymorphism located in the LRP2 promoter is associated with development of AD in Caucasians, while there are no studies on the association LRP2 of with AD risk in Asians.MethodsTo evaluate the relationship between the rs3755166 polymorphism of the LRP2 gene and AD in the ethnic Chinese Han, we conducted a case-control study (n = 361, age > 50) to determine the prevalence of one common single-nucleotide polymorphism (SNP) of LRP2 (rs3755166) in patients with AD in Chinese population of Mainland China, and clarified whether this polymorphism is a risk factor for AD.ResultsThe prevalence of the minor allele (A) in the rs3755166 polymorphism was significantly different in AD patients and control subjects (P < 0.05). The rs3755166 polymorphism was associated with AD in the ethnic Chinese Han (OR = 1.378, 95% CI: 1.017-1.867, P = 0.039), and the results were not influenced by age, gender, or APOE status (P = 0.441, P = 0.94, P = 0.432, respectively).ConclusionOur data revealed the allele (A) of the rs3755166 polymorphism within LRP2 gene may contribute to AD risk in the Chinese Han Population.     

A common polymorphism in CD40 Kozak sequence (-1C/T) is associated with acute coronary syndrome

Objective

Evidence suggests the CD40-CD40L pathway as a key process in the development, progression, and outcome of acute coronary syndrome (ACS). We hypothesized that the -1C/T polymorphism of the CD40 gene would be associated with ACS and influence the CD40 expression.

Methods

The genotype distribution and allele frequency of CD40-1C/T polymorphism in 248 ACS patients and 206 controls were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Monocytes from 90 healthy volunteers were incubated with IFN-γ. CD40 expression was detected by flow cytometry.

Result

Patients with ACS showed a significant increase of CD40 expression compared with controls (P < 0.001). The frequency of the CC genotype in the ACS group was significantly higher than that of the controls (P < 0.001). Frequency of the C allele was higher among ACS patients compared with controls (P < 0.001). Case control association analysis of the CD40 -1C/T SNP showed an association between the C allele and ACS (OR = 1.991, 95%CI: 1.526 ∼ 2.596, P < 0.001). -1C/C carriers presented significantly higher CD40 expression levels than -1C/T and -1T/T subjects, both in ACS group and controls (P < 0.001). When stimulated by IFN-γ, CD40 expression levels on monocytes in individuals with CC, CT and TT genotypes were increased by 9.16, 3.83 and 1.53 fold, respectively, compared with the levels absent with IFN-γ.

Conclusions

These results suggest that the -1C allele of the CD40 (-1C/T) gene polymorphism is a genetic factor that may determine an individual's susceptibility by ACS in Chinese. The CD40 -1C/T polymorphism is a novel regulator of CD40 expression.     

The ocular renin–angiotensin system: A therapeutic target for the treatment of ocular disease

The renin–angiotensin system (RAS) is most well-known for its role in regulation and dysregulation of blood pressure as well as fluid and electrolyte homeostasis. Due to its ability to cause cardiovascular disease, the RAS is the target of a multitude of drugs that antagonize its pathophysiological effects. While the “classical” RAS is a systemic hormonal system, there is an increasing awareness of the existence and functional significance of local RASs in a number of organs, e.g., liver, kidney, heart, lungs, reproductive organs, adipose tissue and adrenal. The eye is one of these organs where a compelling body of evidence has demonstrated the presence of a local RAS. Individual components of the RAS have been shown to be present in many structures of the eye and their potential functional significance in ocular disease states is described. Because the eye is one of the most important and complex organs in the body, this review also discusses the implications of dysregulation of the systemic RAS on the pathogenesis of ocular diseases and how pharmacological manipulation of the RAS might lead to novel or adjunctive therapies for ocular disease states.     

The PAI‐1 4G/5G polymorphism is not associated with an increased risk of adverse pregnancy outcome in asymptomatic nulliparous women

Summary. Background: Plasminogen activator inhibitor type 1 (PAI‐1) is an important regulator of fibrinolysis. A common deletion polymorphism that results in a sequence of 4G instead of 5G in the promoter region of the gene is associated with a small increase in the risk of venous thromboembolism. Its potential association with adverse pregnancy events remains controversial. Objective: We aimed to assess the impact of the 4G PAI‐1 polymorphism on pregnancy outcomes in women who had no prior history of adverse pregnancy outcomes or personal or family history of venous thromboembolism. Patients/methods: This study represents a secondary investigation of a prior prospective cohort study investigating the association between inherited thrombophilias and adverse pregnancy events in Australian women. Healthy nulliparous women were recruited to this study prior to 22 weeks gestation. Genotyping for the 4G/5G PAI‐1 gene was performed using Taqman assays in an ABI prism 7700 Sequencer several years after the pregnancy was completed. Pregnancy outcome data were extracted from the medical record. The primary outcome was a composite comprising development of severe pre‐eclampsia, fetal growth restriction, major placental abruption, stillbirth or neonatal death. Results: Pregnancy outcome data were available in 1733 women who were successfully genotyped for this polymorphism. The primary composite outcome was experienced by 139 women (8% of the cohort). Four hundred and fifty‐nine women (26.5%) were homozygous for the 4G deletion polymorphism, while 890 (51.4%) were heterozygous. Neither homozygosity nor heterozygosity for the PAI‐1 4G polymorphism was associated with the primary composite outcome (homozygous OR = 1.30, 95% CI = 0.81–2.09, P = 0.28, heterozygous OR = 0.84, 95% CI = 0.53–1.31, P = 0.44) or with the individual pregnancy complications. Conclusion: The PAI‐1 4G polymorphism is not associated with an increase in the risk of serious adverse pregnancy events in asymptomatic nulliparous women.     

Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin

Renin is an aspartyl protease essential for the control of blood pressure and was long suspected to have cellular receptors. We report the expression cloning of the human renin receptor complementary DNA encoding a 350-amino acid protein with a single transmembrane domain and no homology with any known membrane protein. Transfected cells stably expressing the receptor showed renin- and prorenin-specific binding. The binding of renin induced a fourfold increase of the catalytic efficiency of angiotensinogen conversion to angiotensin I and induced an intracellular signal with phosphorylation of serine and tyrosine residues associated to an activation of MAP kinases ERK1 and ERK2. High levels of the receptor mRNA are detected in the heart, brain, placenta, and lower levels in the kidney and liver. By confocal microscopy the receptor is localized in the mesangium of glomeruli and in the subendothelium of coronary and kidney artery, associated to smooth muscle cells and colocalized with renin. The renin receptor is the first described for an aspartyl protease. This discovery emphasizes the role of the cell surface in angiotensin II generation and opens new perspectives on the tissue renin-angiotensin system and on renin effects independent of angiotensin II.