Positive Association Between Plasma Aldosterone Concentration and White Matter Lesions in Patients With Hypertension.

Background and Objective: White matter lesions (WMLs) are imaging changes in MRI of cerebral small vessel disease associated with vascular risk factors, increasing the risk of dementia, depression, and stroke. Aldosterone (ALD) or activation of mineralocorticoid receptor (MR) causes cerebrovascular injury in a mouse model. We aimed to analyze the relationship between ALD and WMLs in a population with hypertension. Methods: We conducted a retrospective review of all patients screened for causes of secondary hypertension. We enrolled 547 patients with WMLs and matched these to controls without WMLs at a 1:1 ratio. White matter lesion load was assessed by using a modified Scheltens' scale. Results: Among the analytic sample (N = 1,094) with ages ranging from 30 to 64 years, 62.2% were male. We divided plasma ALD concentration (PAC), plasma renin activity (PRA), and ALD-renin ratio (ARR) into the third tertile (Q3), second tertile (Q2), and first tertile (Q1). We also analyzed them simultaneously as continuous variables. Multivariate logistic regression analysis showed that participants in Q3 (>17.26 ng/dl) of PAC (OR 1.59, 95% CI 1.15, 2.19), Q3 (<0.80 ng/dl) of PRA (OR 2.50, 95% CI 1.81, 3.44), and Q3 (>18.59 ng/dl per ng/ml*h) of ARR (OR 2.90, 95% CI 2.10, 4.01) had a significantly higher risk of WMLs than those in Q1 (<12.48) of PAC, Q1 (>2.19) of PRA, and Q1 (<6.96) of ARR. In linear regression analysis, we separately analyzed the correlation between the modified Scheltens' scale score and log(PAC) (ß = 2.36; 95% CI 1.30, 3.41; p < 0.001), log(PRA) (ß = -1.76; 95% CI -2.09, -1.43; p < 0.001), and log(ARR) (ß = 1.86; 95% CI 1.55, 2.17; p < 0.001), which were all significantly correlated with white matter lesion load, after adjusting for confounding factors. Simple mediation analyses showed that systolic blood pressure (SBP) or diastolic blood pressure (DBP) mediated -3.83% or -2.66% of the association between PAC and white matter lesion load, respectively. In stratified analyses, there was no evidence of subgroup heterogeneity concerning the change in the risk of WMLs (p > 0.05 for interaction for all). Conclusion: Higher PAC, especially in PAC >17.26 ng/dl, increased the risk of WMLs. PAC was positively associated with white matter lesion load independent of SBP or DBP.

Effects of Simplified Antihypertensive Treatment Algorithm on Hypertension Management and Hypertension-Related Death in Resource-Constricted Primary Care Setting between 1997 and 2017.

Hypertension management is poor in primary care settings of developing countries, where 75% of hypertensives are living. Exploring better ways to improve hypertension management and to decrease stroke and CVD death is needed such as introducing treatment algorithm. Therefore, we selected intervention counties from Xinjiang, an underdeveloped region in China, and introduced antihypertensive treatment algorithm, comprising locally available and affordable agents, to primary health providers since 1998. Program effects were evaluated using the data collected in various ways including cross-sectional screenings to population ≥30 years between 1998 and 2015 by comparing treatment and control rates of hypertension, changes in blood pressure (BP) levels and distribution, and proportion of case/total and NCD death for CVD and stroke. Compared to 1998-2000, treatment rate was improved by 2.78 fold (11.2% vs. 32.1%, P < 0.001), and the overall and treated control rate were improved by 53.5 fold (0.2% vs. 10.7%, P < 0.001) and by 16.8 fold (2.0% vs. 33.5%, P < 0.001), respectively, in 2015. Mean SBP and DBP showed a net reduction by 33.7 mmHg (181.3 vs. 147.6 mmHg) and 21.3 mmHg (106.3 vs. 85.0 mmHg), respectively, in 2015, compared to 1998-2000 (P < 0.001), and stage III hypertension was reduced by 75.2% (33.5 vs. 8.3%, P < 0.001). Compared to 1997-1999, stroke/NCD death was reduced by 34.1% in 2015-2017 (31.7 vs. 20.9%, P = 0.006) in the intervention counties whereas by 7.5% in control county. Introduction of treatment algorithm helps improve hypertension management and reduce stroke death in resource-constricted primary settings.

Minor Change of Plasma Renin Activity during the Saline Infusion Test Provide an Auxiliary Diagnostic Value for Primary Aldosteronism.

OBJECTIVE: To clarify whether it has some hidden diagnostic values for PA, especially in the case of an inconclusive SIT result, we investigated the difference in changes of plasma renin activity (PRA) during SIT between patients with PA and non-PA. METHODS: We measured and compared the SIT parameters of 159 PA patients, 368 non-PA patients, and 43 inconclusive patients who were included in this study. RESULTS: The PA group showed a minor change of PRA during the SIT (ΔPRA, defined as (pre-SIT PRA-post-SIT PRA)) compared with the non-PA group (0.17 ng/ml/h vs. 1.07 ng/ml/h, P < 0.001). According to ROC analysis, ΔPRA showed a greater AUC than post-SIT PRA (0.897 vs. 0.855, P < 0.001). The cutoff value was 0.5 ng/ml/h, with 90.3% sensitivity and 78.6% specificity. When combined with ARR post-SIT, it showed 81.6% sensitivity and 97.0% specificity for PA diagnosis. Further analysis of 43 patients with an inconclusive SIT result who completed AVS found that ΔPRA was smaller in the confirmed PA group compared with the unconfirmed PA group (0.19 ng/ml/h vs. 0.29 ng/ml/h, P < 0.05); there was no significant difference in PAC post-SIT between two groups. ΔPRA ≤ 0.21 ng/ml/h provides 71.4% sensitivity, 80.0% specificity, and 87.0% PPV for their PA diagnosis. CONCLUSIONS: PA patients show minor PRA change during SIT; the change of PRA during SIT provides an auxiliary diagnostic value for PA, especially in patients with an inconclusive SIT result.

Higher prevalence of metabolic disorders in patients with bilateral primary aldosteronism than unilateral primary aldosteronism.

OBJECTIVE: Metabolic syndrome (MetS) is a frequent clinical condition in hypertension patients and is more frequently reported in primary aldosteronism (PA). This study is aimed at investigating the prevalence of MetS and its components in the two major types of patients with adrenal venous sampling (AVS)-confirmed unilateral PA and bilateral PA. DESIGN AND PATIENTS: This was a retrospective cross-section study. We analysed metabolic parameters from 169 PA patients subtyped by AVS, including 85 unilateral PA patients and 84 bilateral PA patients, and we also included 169 non-PA patients matched for age and sex. RESULTS: Patients with unilateral PA had higher concentrations of aldosterone and lower serum potassium than patients with bilateral PA. However, patients with bilateral PA had higher prevalence of MetS (79.8% vs 64.7%, P = .029), obesity (40.5% vs 24.7%, P = .029), dyslipidemia (72.6% vs 55.3%, P = .019) and hyperglycaemia (29.8% vs 16.5%, P = .040) than those with unilateral PA. Meanwhile, bilateral PA had higher BMI (27.55 ± 4.58 vs 25.57 ± 3.28 kg/m2 , P = .001), waist circumference (98.54 ± 11.44 vs 93.32 ± 10.64 cm, P = .003) and fasting plasma glucose (4.98 ± 1.16 vs 4.64 ± 0.93 mmol/L, P = .034). The logistic regression analysis also showed that bilateral PA was associated with the presence of MetS after adjustment for age, sex and duration of hypertension. CONCLUSIONS: Patients with bilateral PA have a higher prevalence of MetS than those with unilateral PA, despite unilateral PA patients exhibiting higher concentrations of aldosterone and lower serum potassium, suggesting that unilateral PA and bilateral PA may have differing mechanisms of MetS.

Abdominal aortic calcification is more severe in unilateral primary aldosteronism patients and is associated with elevated aldosterone and parathyroid hormone levels.

Primary aldosteronism (PA) is associated with a higher prevalence of abdominal aortic calcification (AAC). Unilateral and bilateral PA are the most common subtypes of PA. However, no studies have addressed the difference in the prevalence of AAC between the two subtypes. In addition to aldosterone, parathyroid hormone (PTH), an important regulator of calcium metabolism, was also reported to be elevated in individuals with unilateral PA. Therefore, we hypothesized that the prevalence of AAC may be higher in individuals with unilateral PA, which may be related to the plasma aldosterone concentration (PAC) and PTH levels. We included 156 PA patients who underwent adrenal venous sampling and 156 with essential hypertension (EH) matched by age and sex. Of the former, 76 were diagnosed with unilateral PA, and 80 were diagnosed with bilateral PA. The aortic calcification index (ACI) presented the severity of AAC and was measured by adrenal computed tomography scan. Our results showed that compared with the EH group, the prevalence and severity of AAC were higher in PA patients (32.7 vs. 19.6%; 4.32 ± 3.61% vs. 2.53 ± 2.42%, respectively). In the PA subgroup analysis, unilateral PA was associated with a higher and more severe AAC than bilateral PA (40.7 vs. 25.0%; 5.12 ± 4.07% vs. 3.08 ± 2.34%, respectively). Moreover, PAC and PTH levels were higher in individuals with unilateral PA than in those with bilateral PA (P < 0.05). After risk adjustment, multivariate regression analysis revealed that PAC and PTH were positively-associated with AAC in patients with PA (P < 0.05). In conclusion, unilateral PA patients exhibited a higher prevalence of AAC and more severe AAC due to elevated PAC and PTH levels.

Mild primary aldosteronism (PA) followed by overt PA are possibly the most common forms of low renin hypertension: a single-center retrospective study.

Low renin hypertension (LRH) is a common condition in hypertensive patients, and mainly includes primary aldosteronism (PA) and low renin essential hypertension. To investigate the distributions and clinical manifestations of the main LRH forms, we reviewed 1267 hypertensive patients who underwent assessment for plasma renin activity (PRA) and plasma aldosterone concentration (PAC) by standardized protocols in our specialized center. LRH was defined as PRA < 1.0 ng/mL/h. A saline infusion test (SIT) was performed when LRH patients showed positive screening results for PA. The main LRH forms were defined as follows: post-SIT PAC > 10 ng/dL as 'overt PA', post-SIT PAC 5-10 ng/dL as 'mild PA', and post-SIT PAC < 5 ng/dL or negative screening results as 'non-PA'. Overall, 760 patients were defined as LRH, with 160 classified as overt PA, 268 as mild PA, and 332 as non-PA. The total proportion of PA amounted to 56.3% with 21.0% overt PA and 35.3% mild PA. Compared with the mild PA, patients with overt PA had higher systolic and diastolic blood pressures, lower serum potassium, higher urine potassium excretion, more frequent incidence of stage 3 hypertension, hypokalemia, diabetes mellitus, and classical unilateral adenoma on computerized tomography (P < 0.05). PA including overt and mild forms is indeed a major form of LRH. Clinical manifestations in mild PA are less severe than those in overt PA. Nevertheless, mild PA is more prevalent than overt PA in LRH and should be recognized.

Prevalence, Awareness, Treatment, and Control and Related Factors of Hypertension in Multiethnic Agriculture, Stock-Raising, and Urban Xinjiang, Northwest China: A Cross-Sectional Screening for 47000 Adults.

BACKGROUND: Hypertension is the leading cause of cardiovascular disease. Distribution of hypertension and related factors among multiethnic population in Northwest China remains scarce. The aim was to determine prevalence, awareness, treatment, control, and risk factors associated with hypertension among multiethnic population in Northwest China. METHODS: We conducted a blood pressure (BP) screening project covering a third of adults in Emin Xinjiang, Northwest China, during 2014-2016. Hypertension was defined as systolic BP ≥ 140 mmHg, diastolic BP ≥ 90 mmHg, and/or taking antihypertension drugs. We compared prevalence, awareness, treatment, and control of hypertension and related factors by different regions (agriculture, stock-raising, or urban) and by ethnic groups. RESULTS: Totally 47,040 adults were screened with 48.5% women. Overall prevalence, awareness, treatment, and control of hypertension were 26.5%, 64.6%, 44.5%, and 15.3%, respectively. Age-gender-adjusted hypertension prevalence was higher in urban (28.2%) than in other regions and in Kazakh (30.3%) than in others. The lowest awareness and treatment rates were observed in the agricultural region and in Kazakh subjects, while the lowest control was in the stock-raising region (13.8%) and in Kazakh subjects (12.6%). After adjusting for age, gender, ethnicity, and regions, compared to normal weight, nonsmokers, and nondrinkers, obesity, smoking, and alcohol intake were significantly related to increased prevalence of hypertension by 94%, 1.5, and 3.9 folds, respectively. CONCLUSIONS: Disparities in hypertension control among regions and ethnic groups suggested inadequate screening and treatment, especially in stock-raising regions and Kazakh populations. Control of alcohol intake, smoking, and obesity should be at high priority of health promotion.

The effect of Glut1 and c-myc on prognosis in esophageal squamous cell carcinoma of Kazakh and Han patients.

AIM: Glucose transporter type 1 (Glut1) plays a crucial role in cancer-specific metabolism. We explored the expression of Glut1 and c-myc, the relationship between them and the effect of Glut1, c-myc on prognosis in esophageal squamous cell carcinoma. MATERIALS & METHODS: Immunohistochemistry was used to examine the expression of Glut1 and c-myc. χ2 test analyzes the relationship between c-myc, Glut1 and pathological parameters. Spearman correlation analyzes the relationship between c-myc and Glut1. Survival analysis was used to investigate the effect of Glut1 and c-myc on prognosis. RESULTS: Glut1 positivity was associated with tumor size (p < 0.01), depth of invasion (p = 0.021), Tumor, Node, Metastasis stage (IA+IB,II+IIB,IIIA+IIIB,IVA+IVB; p = 0.004), lymph node metastasis (p = 0.002) and nerve invasion (p = 0.050). C-myc positivity was associated with tumor location (p = 0.015), depth of invasion (p = 0.022) and lymph node metastasis (p = 0.035). There was a positive correlation between c-myc and Glut1 (r = 0.321). Patients with Glut1 c-myc co-expression had poorer prognosis. CONCLUSION: Inhibiting Glut1 c-myc co-expression may improve the prognosis of esophageal squamous cell carcinoma.

Asynchronous Cholinergic Drive Correlates with Excitation-Inhibition Imbalance via a Neuronal Ca2+ Sensor Protein.

Excitation-inhibition imbalance in neural networks is widely linked to neurological and neuropsychiatric disorders. However, how genetic factors alter neuronal activity, leading to excitation-inhibition imbalance, remains unclear. Here, using the C. elegans locomotor circuit, we examine how altering neuronal activity for varying time periods affects synaptic release pattern and animal behavior. We show that while short-duration activation of excitatory cholinergic neurons elicits a reversible enhancement of presynaptic strength, persistent activation results to asynchronous and reduced cholinergic drive, inducing imbalance between endogenous excitation and inhibition. We find that the neuronal calcium sensor protein NCS-2 is required for asynchronous cholinergic release in an activity-dependent manner and dampens excitability of inhibitory neurons non-cell autonomously. The function of NCS-2 requires its Ca2+ binding and membrane association domains. These results reveal a synaptic mechanism implicating asynchronous release in regulation of excitation-inhibition balance.

Release-dependent feedback inhibition by a presynaptically localized ligand-gated anion channel.

Presynaptic ligand-gated ion channels (LGICs) have long been proposed to affect neurotransmitter release and to tune the neural circuit activity. However, the understanding of their in vivo physiological action remains limited, partly due to the complexity in channel types and scarcity of genetic models. Here we report that C. elegans LGC-46, a member of the Cys-loop acetylcholine (ACh)-gated chloride (ACC) channel family, localizes to presynaptic terminals of cholinergic motor neurons and regulates synaptic vesicle (SV) release kinetics upon evoked release of acetylcholine. Loss of lgc-46 prolongs evoked release, without altering spontaneous activity. Conversely, a gain-of-function mutation of lgc-46 shortens evoked release to reduce synaptic transmission. This inhibition of presynaptic release requires the anion selectivity of LGC-46, and can ameliorate cholinergic over-excitation in a C. elegans model of excitation-inhibition imbalance. These data demonstrate a novel mechanism of presynaptic negative feedback in which an anion-selective LGIC acts as an auto-receptor to inhibit SV release.

Expression of Wnt11 and Rock2 in esophageal squamous cell carcinoma by activation of the WNT/PCP pathway and its clinical significance.

The purpose of this study was to investigate the relation between expression of Wnt11, Rho-associated protein kinase 2 (Rock2), and its clinical characteristics in esophageal squamous cell carcinoma (ESCC). Expression of Wnt11 and Rock2 protein was examined by using immunohistochemistry that contained 260 paraffin-embedded specimens of ESCC and its adjacent normal tissues; expression of Wnt11 and Rock2 protein was verified by Western-blotting that contained 20 specimens of ESCC and its adjacent normal tissues. The positive rates of Wnt11 protein in normal esophageal epithelium tissue was 29.8% and in esophageal carcinomas tissue was 31.9%; there was no significant difference between the two groups(P>0.05); The positive rates of Rock2 protein in normal esophageal epithelium tissue was 12.3% and in esophageal carcinomas tissues was 56.5%, there was a significant difference between the two groups (p<0.05). The expression of Rock2 protein was significantly related with the invasion of vascular and there was no significantly difference between the expression of Rock2 protein and ESCC patients' tumor location, differentiation, T stage, and lymph node metastases. The abnormal expression of Rock2 protein may promote tumor cell invasion.

iTRAQ-based quantitative proteomic analysis of esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers. In this study, our objective was to identify differentially regulated proteins in ESCC using isobaric tag for relative and absolute quantification (iTRAQ) technique and liquid chromatography-tandem mass spectrometry (LC-MS/MS). We compared the protein expression profiles of ESCC tumor tissues with the corresponding adjacent normal tissue from three patients. It was determined that 72 and 57 unique proteins were significantly up-regulated and down-regulated in all three samples. In addition, there were 431 significantly differentially regulated proteins having at least two biological samples. This subject found some of the differential proteins, such as prolyl 4-hydroxylase subunit alpha-1, prolyl 4-hydroxylase subunit alpha-2, and calponin-2, immunoglobulin superfamily containing leucine-rich repeat protein, and prolyl 3-hydroxylase1, which were few studies about them in ESCC. In order to determine the results, we performed another independent experiment. Our results indicated quantitative proteomics, as a robust discovery tool for the identification, differentially regulated proteins in cancers.

Expression of Wnt11 and Rock2 protein with clinical characteristics of esophageal squamous cell carcinoma in Kazakh and Han patients.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most malignancies with a very poor outcome in China. Wnt11 and Rock2, new identified proteins highly associated with metastasis of many cancers, which were never reported in esophageal squamous cell carcinoma (ESCC). Here we measured the expression levels of Wnt11 and Rock2 in tissues from 265 patients with ESCC. Immunohistochemical staining was employed to detect the correlation of Wnt11 and Rock2 expression with clinicopathological features. METHODS: The expression of Wnt11 and Rock2 was detected by immunohistochemistry in esophageal squamous cell carcinomas and normal esophageal tissues. A chi-square test was used to assess the statistical significance of the correlations between Wnt11, Rock2 expression and different clinicopathological parameters, respectively. RESULTS: The high-expression of Wnt11 and Rock2 was observed in ESCCs. Seventy-five cases of ESCC (51.7%) showed a positive expression of Wnt11, which indicated a significant association with the AJCC stage (P=0.007). Ninety-eight cases of ESCC (65.5%) showed a positive expression of Rock2, which indicated a significant association with ethnic background. There were no close correlations between Rock2 expression and gender, tumor location, AJCC stage, lymph node metastasis. Specifically, the expression of Rock2 was significantly different between Hans and Kazaks ethnicities (P=0.000). In Kaplan-Meier curve analysis, no significant correlation was observed between the expression of Wnt11, Rock-2 and the poor prognosis of ESCCs. CONCLUSION: Our finding suggests that the over-expression of Rock2 may play an important role in the carcinogenesis and progression, and may become a new underlying molecular marker in the diagnosis and treatment in ESCC.

Primary pulmonary adenoid cystic carcinoma: clinicopathological analyses of 12 cases.

BACKGROUND AND OBJECTIVES: Adenoid cystic primary pulmonary carcinomas (adenoid cystic carcinomas or ACCs) are rare tumors, so we described the clinical and pathological features of these tumors and related these findings with diagnosis and prognosis of ACC, comparing our data to the existing literature. METHODS: Clinical and pathological features of 12 ACC cases were observed and described. Immunohistochemical EnVision staining, fluorescent PCR detection, and FISH were used to characterize tumor samples and the literature was reviewed. RESULTS: Of the 12 ACC cases (7 male; average 53.1 years-of-age; range 33-78 years), the chief presentation symptom was cough, followed by expectoration, gasping, and bloody sputum. Microscopically, histopathology revealed cribriform, tubular, or solid cords. CD117 was overexpressed in glandular epithelia in 9 cases and calcitonin and thyroid transcription factor-1 (TTF-1) were overexpressed in 4 cases. One case was positive for EML4 ALK gene rearrangement. CONCLUSION: ACC is a low-grade malignant tumor with poor prognosis and high recurrence and metastases. TTF-1 expression indicates a primary tumor and CD117 expression is not significant to prognosis.

Clinicopathological significance of wnt/ß-catenin signaling pathway in esophageal squamous cell carcinoma.

BACKGROUND/AIM: Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors. It has been reported that Wnt signaling pathway plays an important role in Esophageal Cancer progression, metastasis and invasion. However the clinicopathological significance of Wnt2, GSK3ß, and ß-catenin in ESCC has been little reported. In the present study, the aim of this study was to investigate the clinicopathologic and prognosis roles of Wnt2, GSK3ß, and ß-catenin in ESCC tissue. METHODS: 265 ESCC samples were analyzed by immunohistochemistry using Wnt2, GSK3ß, and ß-catenin antibodies. Then, correlation of Wnt2, GSK3ß, and ß-catenin expression with clinicopathological features and prognosis of ESCC patients was statistically analyzed. RESULTS: Cytoplasmic Wnt2 overexpression was detected in 55.5% (147 of 265) ESCCs, which was significantly correlated with the degree of differentiation (P=0.031). Cytoplasmic GSK3ß overexpression was detected in 7.2% (19 of 265) ESCCs, and aberrant ß-catenin expression was identified in 54.3% (144 of 265) of ESCCs. The positive rate of Wnt2 significantly increased with the malignant degree of Kazak ESCC patients. The aberrant ß-catenin expression in GSK3ß-negative ESCC was significantly associated with the ethnic, tumor size, tumor location, degree of differentiation, AJCC stage, lymph node status. Furthermore, the expression of ß-catenin implicated the ethnic difference (P=0.019). In Kaplan-Meier curve analysis, no significant correlation was observed between the expression of Wnt2, GSK3ß, ß-catenin and the poor prognosis of ESCCs. CONCLUSION: The aberrant ß-catenin expression could be an adverse underlying factor in carcinogenesis and progression of ESCC. There was a different statistical signification for ß-catenin in Kazakhs to compare with Hans.

Plasma aldosterone concentration is positively associated with pulse pressure in patients with primary hypertension.

Increasing evidence showed a link between arterial elasticity and stiffness and pulse pressure (PP), in which plasma aldosterone may play a role. The observational study aimed to explore the potential relations between plasma aldosterone concentration (PAC) and PP in patients with hypertension. We evaluated the relation between PP and PAC in supine, seated, and upright positions in 195 patients with primary hypertension who underwent postural stimulation test. They were divided into 3 groups by tertiles of PP: PP ≤ 44 mm Hg (n = 70), 44 mm Hg < PP ≤ 51 mm Hg (n = 63), and PP ≥ 51 mm Hg (n = 62). The PAC in different postures was compared, respectively. The results showed the following. First, segregated by tertiles of PP, serum K⁺, 24-hour systolic blood pressure, 24-hour diastolic blood pressure, sex, upright PAC, and seated PAC showed statistically significant differences in groups. Second, the PAC were significantly different in 3 levels of PP regardless of postures, the individuals with PP ≥ 51 mm Hg had the highest PAC. On contrast, the patients with PAC > 12 ng/dL showed greater PP than those with PAC ≤ 12 ng/dL. Third, weak associations between PP and upright (r = 0.288, P < 0.001), seated (r = 0.265, P < 0.001), and supine postures (r = 0.191, P = 0.008) were detected by simple correlation analysis. After corrected serum K⁺, age, and sex, the partial correlation coefficients did not change greatly. Fourth, the logistic regression model was constructed with PP ≥ 40 mm Hg or PP < 40 mm Hg as the dependent variable; the serum K⁺[OR = 0.043, 95% CI: 1.09(1.00-1.12)] and PAC [OR = 0.025, 95%CI: 0.35(0.13-0.88)] were included as significant contributing factors. The results showed that higher PAC was weakly, but significantly, correlated to greater PP regardless of different postures, suggesting that higher PAC may be a risk factor of reduced arterial elasticity in patients with hypertension.

[Association of KCNJ5 gene rs3740835(C/A) and rs2604204(A/C) polymorphism with unilateral and bilateral primary aldosteronism].

OBJECTIVE: To assess the association between polymorphisms of rs3740835(C/A) and rs2604204(A/C) in KCNJ5 gene with the susceptibility to unilateral and bilateral primary aldosteronism (PA). METHODS: A total of 1043 subjects were studied, which included 83 unilateral PA patients,142 bilateral PA patients and 818 essential hypertensive(EH) patients. The polymorphism of KCNJ5 gene at rs3740835(C/A) and rs2604204(A/C) position were analyzed with a TaqMan genotyping technique. RESULTS: Frequencies of A allele and AA+AC genotype at rs3740835(C/A) in unilateral PA group were significantly higher than EH group (P < 0.05). However, the above frequencies did not show a statistical significance between bilateral PA group and EH group (P > 0.05). No statistical difference was detected in the distribution of alleles or genotypes at rs2604204 (A/C) between unilateral PA and EH group or between bilateral PA and EH group. Haplotypic frequencies of C-A and A-A in unilateral PA group were significantly higher and lower than EH group, respectively. However, there was no statistical difference in the haplotype distribution between bilateral PA and EH groups. CONCLUSION: Rs3740835(C/A) polymorphism may be associated with unilateral PA but not with bilateral PA. rs2604204(A/C) polymorphism is not associated with either unilateral or bilateral PA. Haplotype C-A and A-A may respectively be susceptibility factor and protective factor for unilateral PA. No haplotype has been found to associate with bilateral PA.

Position of UNC-13 in the active zone regulates synaptic vesicle release probability and release kinetics.

The presynaptic active zone proteins UNC-13/Munc13s are essential for synaptic vesicle (SV) exocytosis by directly interacting with SV fusion apparatus. An open question is how their association with active zones, hence their position to Ca(2+) entry sites, regulates SV release. The N-termini of major UNC-13/Munc13 isoforms contain a non-calcium binding C2A domain that mediates protein homo- or hetero-meric interactions. Here, we show that the C2A domain of Caenorhabditis elegans UNC-13 regulates release probability of evoked release and its precise active zone localization. Kinetics analysis of SV release supports that the proximity of UNC-13 to Ca(2+) entry sites, mediated by the C2A-domain containing N-terminus, is critical for accelerating neurotransmitter release. Additionally, the C2A domain is specifically required for spontaneous release. These data reveal multiple roles of UNC-13 C2A domain, and suggest that spontaneous release and the fast phase of evoked release may involve a common pool of SVs at the active zone. DOI: http://dx.doi.org/10.7554/eLife.01180.001.

Optogenetic inhibition of synaptic release with chromophore-assisted light inactivation (CALI).

Optogenetic techniques provide effective ways of manipulating the functions of selected neurons with light. In the current study, we engineered an optogenetic technique that directly inhibits neurotransmitter release. We used a genetically encoded singlet oxygen generator, miniSOG, to conduct chromophore assisted light inactivation (CALI) of synaptic proteins. Fusions of miniSOG to VAMP2 and synaptophysin enabled disruption of presynaptic vesicular release upon illumination with blue light. In cultured neurons and hippocampal organotypic slices, synaptic release was reduced up to 100%. Such inhibition lasted >1 hr and had minimal effects on membrane electrical properties. When miniSOG-VAMP2 was expressed panneuronally in Caenorhabditis elegans, movement of the worms was reduced after illumination, and paralysis was often observed. The movement of the worms recovered overnight. We name this technique Inhibition of Synapses with CALI (InSynC). InSynC is a powerful way to silence genetically specified synapses with light in a spatially and temporally precise manner.

Neuropeptides function in a homeostatic manner to modulate excitation-inhibition imbalance in C. elegans.

Neuropeptides play crucial roles in modulating neuronal networks, including changing intrinsic properties of neurons and synaptic efficacy. We previously reported a Caenorhabditis elegans mutant, acr-2(gf), that displays spontaneous convulsions as the result of a gain-of-function mutation in a neuronal nicotinic acetylcholine receptor subunit. The ACR-2 channel is expressed in the cholinergic motor neurons, and acr-2(gf) causes cholinergic overexcitation accompanied by reduced GABAergic inhibition in the locomotor circuit. Here we show that neuropeptides play a homeostatic role that compensates for this excitation-inhibition imbalance in the locomotor circuit. Loss of function in genes required for neuropeptide processing or release of dense core vesicles specifically modulate the convulsion frequency of acr-2(gf). The proprotein convertase EGL-3 is required in the cholinergic motor neurons to restrain convulsions. Electrophysiological recordings of neuromuscular junctions show that loss of egl-3 in acr-2(gf) causes a further reduction of GABAergic inhibition. We identify two neuropeptide encoding genes, flp-1 and flp-18, that together counteract the excitation-inhibition imbalance in acr-2(gf) mutants. We further find that acr-2(gf) causes an increased expression of flp-18 in the ventral cord cholinergic motor neurons and that overexpression of flp-18 reduces the convulsion of acr-2(gf) mutants. The effects of these peptides are in part mediated by two G-protein coupled receptors, NPR-1 and NPR-5. Our data suggest that the chronic overexcitation of the cholinergic motor neurons imposed by acr-2(gf) leads to an increased production of FMRFamide neuropeptides, which act to decrease the activity level of the locomotor circuit, thereby homeostatically modulating the excitation and inhibition imbalance.