Hippocampal Gene Expression Analysis Highlights Ly6a/Sca-1 as Candidate Gene for Previously Mapped Novelty Induced Behaviors in Mice

In this study, we show that the covariance between behavior and gene expression in the brain can help further unravel the determinants of neurobehavioral traits. Previously, a QTL for novelty induced motor activity levels was identified on murine chromosome 15 using consomic strains. With the goal of narrowing down the linked region and possibly identifying the gene underlying the quantitative trait, gene expression data from this F2-population was collected and used for expression QTL analysis. While genetic variation in these mice was limited to chromosome 15, eQTL analysis of gene expression showed strong cis-effects as well as trans-effects elsewhere in the genome. Using weighted gene co-expression network analysis, we were able to identify modules of co-expressed genes related to novelty induced motor activity levels. In eQTL analyses, the expression of Ly6a (a.k.a. Sca-1) was found to be cis-regulated by chromosome 15. Ly6a also surfaced in a group of genes resulting from the network analysis that was correlated with behavior. Behavioral analysis of Ly6a knock-out mice revealed reduced novelty induced motor activity levels when compared to wild type controls, confirming functional importance of Ly6a in this behavior, possibly through regulating other genes in a pathway. This study shows that gene expression profiling can be used to narrow down a previously identified behavioral QTL in mice, providing support for Ly6a as a candidate gene for functional involvement in novelty responsiveness

Intra-observer and interobserver variability of biventricular function, volumes and mass in patients with congenital heart disease measured by CMR imaging

Cardiovascular magnetic resonance (CMR) imaging provides highly accurate measurements of biventricular volumes and mass and is frequently used in the follow-up of patients with acquired and congenital heart disease (CHD). Data on reproducibility are limited in patients with CHD, while measurements should be reproducible, since CMR imaging has a main contribution to decision making and timing of (re)interventions. The aim of this study was to assess intra-observer and interobserver variability of biventricular function, volumes and mass in a heterogeneous group of patients with CHD using CMR imaging. Thirty-five patients with CHD (7–62 years) were included in this study. A short axis set was acquired using a steady-state free precession pulse sequence. Intra-observer and interobserver variability was assessed for left ventricular (LV) and right ventricular (RV) volumes, function and mass by calculating the coefficient of variability. Intra-observer variability was between 2.9 and 6.8% and interobserver variability was between 3.9 and 10.2%. Overall, variations were smallest for biventricular end-diastolic volume and highest for biventricular end-systolic volume. Intra-observer and interobserver variability of biventricular parameters assessed by CMR imaging is good for a heterogeneous group of patients with CHD. CMR imaging is an accurate and reproducible method and should allow adequate assessment of changes in ventricular size and global ventricular function

Disparities and risks of sexually transmissible infections among men who have sex with men in China: a meta-analysis and data synthesis.

BACKGROUND: Sexually transmitted infections (STIs), including Hepatitis B and C virus, are emerging public health risks in China, especially among men who have sex with men (MSM). This study aims to assess the magnitude and risks of STIs among Chinese MSM. METHODS: Chinese and English peer-reviewed articles were searched in five electronic databases from January 2000 to February 2013. Pooled prevalence estimates for each STI infection were calculated using meta-analysis. Infection risks of STIs in MSM, HIV-positive MSM and male sex workers (MSW) were obtained. This review followed the PRISMA guidelines and was registered in PROSPERO. RESULTS: Eighty-eight articles (11 in English and 77 in Chinese) investigating 35,203 MSM in 28 provinces were included in this review. The prevalence levels of STIs among MSM were 6.3% (95% CI: 3.5-11.0%) for chlamydia, 1.5% (0.7-2.9%) for genital wart, 1.9% (1.3-2.7%) for gonorrhoea, 8.9% (7.8-10.2%) for hepatitis B (HBV), 1.2% (1.0-1.6%) for hepatitis C (HCV), 66.3% (57.4-74.1%) for human papillomavirus (HPV), 10.6% (6.2-17.6%) for herpes simplex virus (HSV-2) and 4.3% (3.2-5.8%) for Ureaplasma urealyticum. HIV-positive MSM have consistently higher odds of all these infections than the broader MSM population. As a subgroup of MSM, MSW were 2.5 (1.4-4.7), 5.7 (2.7-12.3), and 2.2 (1.4-3.7) times more likely to be infected with chlamydia, gonorrhoea and HCV than the broader MSM population, respectively. CONCLUSION: Prevalence levels of STIs among MSW were significantly higher than the broader MSM population. Co-infection of HIV and STIs were prevalent among Chinese MSM. Integration of HIV and STIs healthcare and surveillance systems is essential in providing effective HIV/STIs preventive measures and treatments. TRIAL REGISTRATION: PROSPERO NO: CRD42013003721

Immunogenic Profiling in Mice of a HIV/AIDS Vaccine Candidate (MVA-B) Expressing Four HIV-1 Antigens and Potentiation by Specific Gene Deletions

BACKGROUND: The immune parameters of HIV/AIDS vaccine candidates that might be relevant in protection against HIV-1 infection are still undefined. The highly attenuated poxvirus strain MVA is one of the most promising vectors to be use as HIV-1 vaccine. We have previously described a recombinant MVA expressing HIV-1 Env, Gag, Pol and Nef antigens from clade B (referred as MVA-B), that induced HIV-1-specific immune responses in different animal models and gene signatures in human dendritic cells (DCs) with immunoregulatory function. METHODOLOGY/PRINCIPAL FINDINGS: In an effort to characterize in more detail the immunogenic profile of MVA-B and to improve its immunogenicity we have generated a new vector lacking two genes (A41L and B16R), known to counteract host immune responses by blocking the action of CC-chemokines and of interleukin 1beta, respectively (referred as MVA-B DeltaA41L/DeltaB16R). A DNA prime/MVA boost immunization protocol was used to compare the adaptive and memory HIV-1 specific immune responses induced in mice by the parental MVA-B and by the double deletion mutant MVA-B DeltaA41L/DeltaB16R. Flow cytometry analysis revealed that both vectors triggered HIV-1-specific CD4(+) and CD8(+) T cells, with the CD8(+) T-cell compartment responsible for >91.9% of the total HIV-1 responses in both immunization groups. However, MVA-B DeltaA41L/DeltaB16R enhanced the magnitude and polyfunctionality of the HIV-1-specific CD4(+) and CD8(+) T-cell immune responses. HIV-1-specific CD4(+) T-cell responses were polyfunctional and preferentially Env-specific in both immunization groups. Significantly, while MVA-B induced preferentially Env-specific CD8(+) T-cell responses, MVA-B DeltaA41L/DeltaB16R induced more GPN-specific CD8(+) T-cell responses, with an enhanced polyfunctional pattern. Both vectors were capable of producing similar levels of antibodies against Env. CONCLUSIONS/SIGNIFICANCE: These findings revealed that MVA-B and MVA-B DeltaA41L/DeltaB16R induced in mice robust, polyfunctional and durable T-cell responses to HIV-1 antigens, but the double deletion mutant showed enhanced magnitude and quality of HIV-1 adaptive and memory responses. Our observations are relevant in the immune evaluation of MVA-B and on improvements of MVA vectors as HIV-1 vaccines

Effect of sulodexide on endothelial glycocalyx and vascular permeability in patients with type 2 diabetes mellitus

Endothelial glycocalyx perturbation contributes to increased vascular permeability. In the present study we set out to evaluate whether: (1) glycocalyx is perturbed in individuals with type 2 diabetes mellitus, and (2) oral glycocalyx precursor treatment improves glycocalyx properties. Male participants with type 2 diabetes (n = 10) and controls (n = 10) were evaluated before and after 2 months of sulodexide administration (200 mg/day). The glycocalyx dimension was estimated in two different vascular beds using sidestream dark field imaging and combined fluorescein/indocyanine green angiography for sublingual and retinal vessels, respectively. Transcapillary escape rate of albumin (TER(alb)) and hyaluronan catabolism were assessed as measures of vascular permeability. Both sublingual dimensions (0.64 [0.57-0.75] μm vs 0.78 [0.71-0.85] μm, p <0.05, medians [interquartile range]) and retinal glycocalyx dimensions (5.38 [4.88-6.59] μm vs 8.89 [4.74-11.84] μm, p <0.05) were reduced in the type 2 diabetes group compared with the controls whereas TER(alb) was increased (5.6 ± 2.3% vs 3.7 ± 1.7% in the controls, p <0.05). In line with these findings, markers of hyaluronan catabolism were increased with diabetes (hyaluronan 137 ± 29 vs 81 ± 8 ng/ml and hyaluronidase 78 ± 4 vs 67 ± 2 U/ml, both p <0.05). Sulodexide increased both the sublingual and retinal glycocalyx dimensions in participants with diabetes (to 0.93 [0.83-0.99] μm and to 5.88 [5.33-6.26] μm, respectively, p <0.05). In line, a trend towards TER(alb) normalisation (to 4.0 ± 2.3%) and decreases in plasma hyaluronidase (to 72 ± 2 U/ml, p <0.05) were observed in the diabetes group. Type 2 diabetes is associated with glycocalyx perturbation and increased vascular permeability, which are partially restored following sulodexide administration. Further studies are warranted to determine whether long-term treatment with sulodexide has a beneficial effect on cardiovascular risk. www.trialregister.nl NTR780/ http://isrctn.org ISRCTN82695186 An unrestricted Novartis Foundation for Cardiovascular Excellence grant (2006) to M. Nieuwdorp/E. S. G. Stroes, Dutch Heart Foundation (grant number 2005T037

Dendritic Cells Exposed to MVA-Based HIV-1 Vaccine Induce Highly Functional HIV-1-Specific CD8+ T Cell Responses in HIV-1-Infected Individuals

Currently, MVA virus vectors carrying HIV-1 genes are being developed as HIV-1/AIDS prophylactic/therapeutic vaccines. Nevertheless, little is known about the impact of these vectors on human dendritic cells (DC) and their capacity to present HIV-1 antigens to human HIV-specific T cells. This study aimed to characterize the interaction of MVA and MVA expressing the HIV-1 genes Env-Gag-Pol-Nef of clade B (referred to as MVA-B) in human monocyte-derived dendritic cells (MDDC) and the subsequent processes of HIV-1 antigen presentation and activation of memory HIV-1-specific T lymphocytes. For these purposes, we performed ex vivo assays with MDDC and autologous lymphocytes from asymptomatic HIV-infected patients. Infection of MDDC with MVA-B or MVA, at the optimal dose of 0.3 PFU/MDDC, induced by itself a moderate degree of maturation of MDDC, involving secretion of cytokines and chemokines (IL1-ra, IL-7, TNF-α, IL-6, IL-12, IL-15, IL-8, MCP-1, MIP-1α, MIP-1β, RANTES, IP-10, MIG, and IFN-α). MDDC infected with MVA or MVA-B and following a period of 48 h or 72 h of maturation were able to migrate toward CCL19 or CCL21 chemokine gradients. MVA-B infection induced apoptosis of the infected cells and the resulting apoptotic bodies were engulfed by the uninfected MDDC, which cross-presented HIV-1 antigens to autologous CD8+ T lymphocytes. MVA-B-infected MDDC co-cultured with autologous T lymphocytes induced a highly functional HIV-specific CD8+ T cell response including proliferation, secretion of IFN-γ, IL-2, TNF-α, MIP-1β, MIP-1α, RANTES and IL-6, and strong cytotoxic activity against autologous HIV-1-infected CD4+ T lymphocytes. These results evidence the adjuvant role of the vector itself (MVA) and support the clinical development of prophylactic and therapeutic anti-HIV vaccines based on MVA-B

Association of genomic domains in BRCA1 and BRCA2 with prostate cancer risk and aggressiveness

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. Weevaluated whether PSVs inBRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 30 region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.Peer reviewe

Assessment of age-related changes in pediatric gastrointestinal solubility

PurposeCompound solubility serves as a surrogate indicator of oral biopharmaceutical performance. Between infancy and adulthood, marked compositional changes in gastrointestinal (GI) fluids occur. This study serves to assess how developmental changes in GI fluid composition affects compound solubility.MethodsSolubility assessments were conducted in vitro using biorelevant media reflective of age-specific pediatric cohorts (i.e., neonates and infants). Previously published adult media (i.e., FaSSGF, FeSSGF, FaSSIF.v2, and FeSSIF.v2) were employed as references for pediatric media development. Investigations assessing age-specific changes in GI fluid parameters (i.e., pepsin, bile acids, pH, osmolality, etc.) were collected from the literature and served to define the composition of neonatal and infant media. Solubility assessments at 37°C were conducted for seven BCS Class II compounds within the developed pediatric and reference adult media.ResultsFor six of the seven compounds investigated, solubility fell outside an 80–125% range from adult values in at least one of the developed pediatric media. This result indicates a potential for age-related alterations in oral drug performance, especially for compounds whose absorption is delimited by solubility (i.e., BCS Class II).ConclusionDevelopmental changes in GI fluid composition can result in relevant discrepancies in luminal compound solubility between children and adults.<br/

Inventory of carbon monoxide emissions in Dutch industry: releasing the objective for reducing emissions?

De koolmonoxide-emissies van de industrie zijn de afgelopen jaren flink afgenomen, maar de doelstelling om de emissies tot 2010 met 90% te verminderen zal de industrie niet halen. Bij de huidige emissies en concentraties koolmonoxide in de lucht verwacht het RIVM geen negatieve gezondheidseffecten voor mensen. Ook de effecten op het milieu zijn naar verwachting gering. In het begin van de jaren '90 heeft de overheid afspraken gemaakt met de industrie om de emissies van koolmonoxide terug te dringen. Een van die afspraken was dat de emissies in 2010 met 90% zouden zijn verminderd ten opzichte van 1985. De Directie Klimaatverandering en Industrie (KvI) van het ministerie van VROM wil deze doelstelling mogelijk herzien. Ze heeft het RIVM gevraagd een inventarisatie te maken van de verschillende aspecten met betrekking tot industriele koolmonoxide emissies. De koolmonoxide-emissies van de industrie zijn door de invoering van betere technieken de afgelopen jaren flink afgenomen. De verwachting is echter dat de emissies niet verder zullen afnemen, tenzij tegen zeer hoge kosten. Bovendien wordt vanuit het milieubeleid meer aandacht gegeven aan het terugdringen van emissies van andere stoffen, zoals stikstofoxiden en het broeikasgas. Omdat grote bedrijven nationaal en internationaal verplicht zijn hun koolmonoxide-emissies te monitoren, blijft er zicht op de ontwikkeling van de totale emissie aan koolmonoxide door de Nederlandse industrie. Wel is door verschillende partijen (Facilitaire Organisatie Industrie, Milieu- en Natuurplanbureau en VROM-Inspectie) de nodige zorg geuit over de kwaliteit van het monitoren. De concentraties koolmonoxide in de buitenlucht zijn de afgelopen jaren flink afgenomen en liggen overal in Nederland ruim beneden de Europese grenswaarde. Hoewel enkele grote bedrijven een relevante bijdrage leveren aan de concentraties koolmonoxide in hun omgeving, liggen ook hier de concentraties onder de Europese grenswaarde.In the early nineteen-nineties, the Dutch government made agreements with the industry to bring down the levels of carbon monoxide emissions. One of the agreements made then was that emissions should be reduced by 90% by the year 2010, compared with 1985. This objective, however, will not be achieved. But no negative health effects are expected to occur due to the current carbon monoxide concentrations in the air. Also the effects on the environment are expected to be negligible. The National Institute for Public Health and the Environment (RIVM) has concluded this. The Climate Change and Industry Directorate operating under the VROM-Directorate was the commissioning body for this study. They have requested the RIVM to make an inventory of the various aspects relating to industrial carbon monoxide emissions. Due to the introduction of improved industrial technology, industrial carbon monoxide emissions have greatly decreased in recent years. It is expected that emissions will not decrease any further unless very high-cost methods are implemented. Moreover, from the perspective of environmental policy, more attention will be given to reducing emissions of other substances, such as nitrogen oxides and greenhouse gases. Because large companies are obliged by national and international legislation to monitor their carbon monoxide emissions, an overview of the development of the carbon monoxide emission is available. Although, various parties such as the Dutch Facility Organization for Industry (FO-Industrie), the Netherlands Environmental Assessment Agency (MNP) and the VROM-Inspectorate express concerns on the quality of the monitoring. The concentrations of carbon monoxide in the Netherlands have decreased sharply in recent years and are well below the European limit value. Whilst a few large industries have an impact on the concentrations of carbon monoxide in their direct environment, even here, the European limit value is not exceeded.VROM-KV