Schizophrenia (SCZ) is a debilitating disorder with a prevalence of approximately 1 % worldwide. SCZ is known to have a high degree of genetic and clinical heterogeneity and is a major health problem worldwide. The integrin-β 3 subunit gene (ITGB3) gene at 17q21.32 has been implicated in psychiatric disorders. We therefore hypothesized that ITGB3 gene polymorphisms might also play a role in SCZ and age at onset (AAO) of SCZ. We investigated the genetic associations of 23 single-nucleotide polymorphisms (SNPs) of the ITGB3 gene with AAO in SCZ in two Caucasian samples (2,166 cases and 2,525 controls) using linear regression analysis and meta-analysis. We observed four ITGB3-SNPs associated with AAO in SCZ in a non-Genetic Association Information Network (GAIN) sample (p < 10-3). Three of these four SNPs were replicated in the GAIN sample. The SNP rs16941771 was most significantly associated with AAO (p = 7.47 × 10-5). Meta-analysis showed that 6 of 23 SNPs were associated with AAO. The haplotype analysis also supports the association of ITGB3 with AAO. Three disease-associated SNPs were located at species-conserved regions, indicating functional importance. This is the first report which shows that ITGB3 variants are associated with AAO in SCZ, providing direct evidence of the use of AAO as an intermediate phenotype to dissect the complex genetics of SCZ.

Schizophrenia (SCZ) is a debilitating disorder with a prevalence of approximately 1 % worldwide. SCZ is known to have a high degree of genetic and clinical heterogeneity and is a major health problem worldwide. The integrin-β 3 subunit gene (ITGB3) gene at 17q21.32 has been implicated in psychiatric disorders. We therefore hypothesized that ITGB3 gene polymorphisms might also play a role in SCZ and age at onset (AAO) of SCZ. We investigated the genetic associations of 23 single-nucleotide polymorphisms (SNPs) of the ITGB3 gene with AAO in SCZ in two Caucasian samples (2,166 cases and 2,525 controls) using linear regression analysis and meta-analysis. We observed four ITGB3-SNPs associated with AAO in SCZ in a non-Genetic Association Information Network (GAIN) sample (p < 10-3). Three of these four SNPs were replicated in the GAIN sample. The SNP rs16941771 was most significantly associated with AAO (p = 7.47 × 10-5). Meta-analysis showed that 6 of 23 SNPs were associated with AAO. The haplotype analysis also supports the association of ITGB3 with AAO. Three disease-associated SNPs were located at species-conserved regions, indicating functional importance. This is the first report which shows that ITGB3 variants are associated with AAO in SCZ, providing direct evidence of the use of AAO as an intermediate phenotype to dissect the complex genetics of SCZ.

Objectives: We meta-Analyzed the effect of meditation on blood pressure (BP), including both transcendental meditation and non-Transcendental meditation interventions. Methods: We identified randomized controlled trials (RCTs) that examined the BP responses to meditation interventions through a systematic literature search of the PubMed, ABI/INFORM, MEDLINE, EMBASE, PsycINFO, and CINAHL databases (from January 1980 to October 2015). We meta-Analyzed the change in SBP and DBP, stratified by type of meditation (transcendental meditation vs. nontranscendental meditation intervention) and by type of BP measurement [ambulatory BP monitoring (ABPM) vs. non-ABPM measurement]. Results: Nineteen studies met the eligibility criteria. Among the studies using the ABPM measurement, the pooled SBP effect estimate was-2.49mmHg [95% confidence interval (CI):-7.51, 2.53] for transcendental meditation intervention (statistically insignificant) and-3.77mmHg (95% CI:-5.33,-2.21) for nontranscendental meditation interventions, whereas the pooled DBP effect estimate was-4.26mmHg (95% CI:-6.21,-2.31) for transcendental meditation interventions and-2.18mmHg (95% CI:-4.28,-0.09) for nontranscendental meditation interventions. Among the studies using the non-ABPM measurement, the pooled SBP effect estimate from transcendental meditation interventions was-5.57mmHg (95% CI:-7.41,-3.73) and was-5.09mmHg with non-Transcendental meditation intervention (95% CI:-6.34,-3.85), whereas the pooled effect size in DBP change for transcendental meditation interventions was-2.86mmHg (95% CI:-4.27,-1.44) and was-2.57mmHg (95% CI:-3.36,-1.79) for nontranscendental meditation interventions. Conclusion: Non-Transcendental meditation may serve as a promising alternative approach for lowering both SBP and DBP. More ABPM-measured transcendental meditation interventions might be needed to examine the benefit of transcendental meditation intervention on SBP reduction.

Background: The organization of risk genes within signaling pathways may provide clues about the converging neurobiological effects of risk genes for alcohol dependence. Aims: Identify risk genes and risk gene pathways for alcohol dependence. Methods: We conducted a pathway-based genome-wide association study (GWAS) of alcohol dependence using a gene-set-rich analytic approach. Approximately one million genetic markers were tested in the discovery sample which included 1409 European-American (EA) alcohol dependent individuals and 1518 EA healthy comparison subjects. An additional 681 African-American (AA) cases and 508 AA healthy subjects served as the replication sample. Results: We identified several genome-wide replicable risk genes and risk pathways that were significantly associated with alcohol dependence. After applying the Bonferroni correction for multiple testing, the 'cellextracellular matrix interactions' pathway (p<2.0E-4 in EAs) and the PXN gene (which encodes paxillin) (p=3.9E-7 in EAs) within this pathway were the most promising risk factors for alcohol dependence. There were also two nominally replicable pathways enriched in alcohol dependence-related genes in both EAs (0.015≤p≤0.035) and AAs (0.025≤p≤0.050): the 'Na+/Cl- dependent neurotransmitter transporters' pathway and the 'other glycan degradation' pathway. Conclusions: These findings provide new evidence highlighting several genes and biological signaling processes that may be related to the risk for alcohol dependence.

This paper aims to determine whether chronic vagus nerve stimulation (VNS) mitigates myocardial infarction (MI)-induced remodeling of the intrinsic cardiac nervous system (ICNS), along with the cardiac tissue it regulates. Guinea pigs underwent VNS implantation on the right cervical vagus. Two weeks later, MI was produced by ligating the ventral descending coronary artery. VNS stimulation started 7 days post-MI (20 Hz, 0.9 ± 0.2 mA, 14 s on, 48 s off; VNS-MI, n = 7) and was compared with time-matched MI animals with sham VNS (MI n = 7) vs. untreated controls (n = 8). Echocardiograms were performed before and at 90 days post-MI. At termination, IC neuronal intracellular voltage recordings were obtained from whole-mount neuronal plexuses. MI increased left ventricular end systolic volume (LVESV) 30% (P = 0.027) and reduced LV ejection fraction (LVEF) 6.5% (P < 0.001) at 90 days post-MI compared with baseline. In the VNS-MI group, LVESV and LVEF did not differ from baseline. IC neurons showed depolarization of resting membrane potentials and increased input resistance in MI compared with VNS-MI and sham controls (P < 0.05). Neuronal excitability and sensitivity to norepinephrine increased in MI and VNS-MI groups compared with controls (P < 0.05). Synaptic efficacy, as determined by evoked responses to stimulating input axons, was reduced in VNS-MI compared with MI or controls (P < 0.05). VNS induced changes in myocytes, consistent with enhanced glycogenolysis, and blunted the MI-induced increase in the proapoptotic Bcl-2-associated X protein (P < 0.05). VNS mitigates MI-induced remodeling of the ICNS, correspondingly preserving ventricular function via both neural and cardiomyocyte-dependent actions.

Background: Annually, over 150,000 cardiovascular events occur among individuals ,65 years old in the United States, including asymptomatic ones. Coronary artery calcium (CAC), a subclinical marker of coronary artery disease (CAD), enhances risk stratification among asymptomatic individuals. This study assessed the prevalence of CAC in a rural population and determined relationships between traditional risk factors for CAD and CAC scores. Methods: During January 2011 to December 2012, asymptomatic individuals from central Appalachia were screened for CAC in the largest tertiary cardiovascular institute. Based on Agatston scale, participants were grouped into 4 CAC scores: zero (CAC 5 0), mild (CAC 5 1-99), moderate (CAC 5 100-399) and severe (CAC $ 400). Multinomial logistic regression was used to examine associations between potential risk factors of CAD and CAC score. Results: Of 1,674 participants, 55.4% had positive CAC score (CAC . 0). Increasing age and being male were positively associated with higher CAC scores. Although there was significant association between mild CAC and hypertension and family history of CAD, moderate CAC was positively associated with smoking status. Except hypercholesterolemia and sedentary lifestyle, severe CAC was significantly associated with major health conditions (obesity, diabetes and hypertension), lifestyle (smoking) and family history of CAD. Conclusions: More than half of participants in the CAC screening had subclinical CAD (CAC score . 0). The association between CAC score and CAD risk factors suggests that education about subclinical atherosclerosis among asymptomatic individuals in this region with high cardiovascular disease prevalence is needed because CAC improves CAD risk stratification, and the knowledge of CAC enhances medication adherence and motivates individuals towards beneficial behavioral/lifestyle modification.

Background/objectives There are few studies investigating the long-term association between childhood blood pressure (BP) and adult cardiovascular remodeling. We seek to examine the effect of elevated childhood BP on cardiovascular remodeling in early or middle adulthood.Methods We used the "Beijing BP Cohort Study", where 1259 subjects aged 6-18 years old were followed over 24 years from childhood (1987) to early or middle adulthood (2011). Anthropometric measures and BP were obtained at baseline and follow-up examinations. Carotid-femoral pulse wave velocity (cfPWV), carotid intima-media thickness (cIMT), and left ventricular mass index (LVMI) were measured to assess cardiovascular remodeling in early or middle adulthood. Multiple logistic regression models were used to assess the odds ratio (OR) and 95% confidence interval (CI) for cardiovascular remodeling.Results 82 out of 384 children with elevated BP (21.4%) had adult hypertension. Compared to those with normal BP, children with elevated BP were at 2.1 times (95% CI: 1.4-3.1) likely to develop hypertension in early or middle adulthood. Compared to those with normal BP, children with elevated BP were at higher OR of developing high cfPWV (OR = 1.8, 95% CI = 1.3-2.4), high cIMT (1.4, 1.0-1.9), or high LVMI (1.4, 1.0-1.9) in early or middle adulthood. The ORs for remodeling (for any measures) were 1.4 (0.9-2.0) in early adulthood for children age 6-11 years, and 1.6 (1.1-2.4) in middle adulthood for those aged 12-18 years.Conclusions Children with elevated BP from 6 years old have accelerated remodeling on both cardiac and arterial system in early or middle adulthood.

Mechanism underlying nanotoxicity has remained elusive. Hence, efforts to understand whether nanoparticle properties might explain its toxicity are ongoing. Considering three different types of organo-coated silver nanoparticles (AgNPs): citrate-coated AgNP, polyvinylpyrrolidone-coated AgNP, and branched polyethyleneimine-coated AgNP, with different surface charge scenarios and core particle sizes, herein we systematically evaluate the potential role of particle size and surface charge on the toxicity of the three types of AgNPs against two model organisms, Escherichia coli and Daphnia magna. We find particle size, surface charge, and concentration dependent toxicity of all the three types of AgNPs against both the test organisms. Notably, Ag+ (as added AgNO3) toxicity is greater than each type of AgNPs tested and the toxicity follows the trend: AgNO3>BPEI-AgNP>Citrate-AgNP>PVP-AgNP. Modeling particle properties using the general linear model (GLM), a significant interaction effect of primary particle size and surface charge emerges that can explain empirically-derived acute toxicity with great precision. The model explains 99.9% variation of toxicity in E. coli and 99.8% variation of toxicity in D. magna, revealing satisfactory predictability of the regression models developed to predict the toxicity of the three organo-coated AgNPs. We anticipate that the use of GLM to satisfactorily predict the toxicity based on nanoparticle physico-chemical characteristics could contribute to our understanding of nanotoxicology and underscores the need to consider potential interactions among nanoparticle properties to explaining nanotoxicity.

We define and study multivariate and matrix variate skew Pearson type VII and skew t-distributions. We derive the marginal and conditional distributions, the linear transformation, and the stochastic representations of the multivariate and matrix variate skew Pearson type VII distributions and skew t-distributions. Also, we study the limiting distributions.

The tegmentum vasculosum of the duckling consists of a highly folded epithelium which extends over the dorsal and lateral walls of the cochlear duct, separating the scala media from the scala vestibuli. This epithelium consists of two distinct cell types, dark cells and light cells, and is well vascularized. The surface of the epithelium is formed by a mosaic of alternating dark and light cells. The goblet-shaped dark cells have an electron-dense, organelle-rich cytoplasm, and are expanded basally by extensive basolateral plasma membrane infoldings, within which are numerous mitochondria. Dark cells are isolated from each other and from the capillaries within the epithelium by intervening light cells. In contrast, columnar light cells exhibit an electron-lucent, organelle-poor cytoplasm and may extend from the underlying capillaries to the endolymphatic surface. Light cells contain abundant, coated endocytic vesicles on their apical surfaces and are bound, apically, to other light cells or to dark cells by tight junctions and desmosomes. Laterally, light cells are linked to each other either by complex, fluid-filled membrane interdigitations or by extensive gap junctions. Plasma membrane interdigitations and obvious, fluid-filled intercellular spaces characterize the lateral borders between light and dark cells. Vascular corrosion casting reveals the three-dimensional anatomy of the cochlear vasculature. A continuous arteriolar loop fed by anterior and posterior cochlear arterioles encircles the cochlear duct. The rich capillary beds of the tegmentum vasculosum are supplied by arching arterioles arising from this loop. These capillaries are the continuous type and are situated primarily within the core of the epithelium or along its border with the scala vestibuli. The structure and blood supply of the tegmentum vasculosum are characteristic of an epithelium involved in active transport.