In vitro and ex vivo testing of tenofovir shows it is effective as an HIV-1 microbicide

Background: Tenofovir gel has entered into clinical trials for use as a topical microbicide to prevent HIV-1 infection but has no published data regarding pre-clinical testing using in vitro and ex vivo models. To validate our findings with on-going clinical trial results, we evaluated topical tenofovir gel for safety and efficacy. We also modeled systemic application of tenofovir for efficacy. Methods and Findings: Formulation assessment of tenofovir gel included osmolality, viscosity, in vitro release, and permeability testing. Safety was evaluated by measuring the effect on the viability of vaginal flora, PBMCs, epithelial cells, and ectocervical and colorectal explant tissues. For efficacy testing, PBMCs were cultured with tenofovir or vehicle control gels and HIV-1 representing subtypes A, B, and C. Additionally, polarized ectocervical and colorectal explant cultures were treated apically with either gel. Tenofovir was added basolaterally to simulate systemic application. All tissues were challenged with HIV-1 applied apically. Infection was assessed by measuring p24 by ELISA on collected supernatants and immunohisto-chemistry for ectocervical explants. Formulation testing showed the tenofovir and vehicle control gels were >10 times isosmolar. Permeability through ectocervical tissue was variable but in all cases the receptor compartment drug concentration reached levels that inhibit HIV-1 infection in vitro. The gels were non-toxic toward vaginal flora, PBMCs, or epithelial cells. A transient reduction in epithelial monolayer integrity and epithelial fracture for ectocervical and colorectal explants was noted and likely due to the hyperosmolar nature of the formulation. Tenofovir gel prevented HIV-1 infection of PBMCs regardless of HIV-1 subtype. Topical and systemic tenofovir were effective at preventing HIV-1 infection of explant cultures. Conclusions: These studies provide a mechanism for pre-clinical prediction of safety and efficacy of formulated microbicides. Tenofovir was effective against HIV-1 infection in our algorithm. These data support the use of tenofovir for pre-exposure prophylaxis. © 2010 Rohan et al

First look at the five-factor model personality facet associations with sensory processing sensitivity

status: publishe

The Regulation of miRNA-211 Expression and Its Role in Melanoma Cell Invasiveness

The immediate molecular mechanisms behind invasive melanoma are poorly understood. Recent studies implicate microRNAs (miRNAs) as important agents in melanoma and other cancers. To investigate the role of miRNAs in melanoma, we subjected human melanoma cell lines to miRNA expression profiling, and report a range of variations in several miRNAs. Specifically, compared with expression levels in melanocytes, levels of miR-211 were consistently reduced in all eight non-pigmented melanoma cell lines we examined; they were also reduced in 21 out of 30 distinct melanoma samples from patients, classified as primary in situ, regional metastatic, distant metastatic, and nodal metastatic. The levels of several predicted target mRNAs of miR-211 were reduced in melanoma cell lines that ectopically expressed miR-211. In vivo target cleavage assays confirmed one such target mRNA encoded by KCNMA1. Mutating the miR-211 binding site seed sequences at the KCNMA1 3′-UTR abolished target cleavage. KCNMA1 mRNA and protein expression levels varied inversely with miR-211 levels. Two different melanoma cell lines ectopically expressing miR-211 exhibited significant growth inhibition and reduced invasiveness compared with the respective parental melanoma cell lines. An shRNA against KCNMA1 mRNA also demonstrated similar effects on melanoma cells. miR-211 is encoded within the sixth intron of TRPM1, a candidate suppressor of melanoma metastasis. The transcription factor MITF, important for melanocyte development and function, is needed for high TRPM1 expression. MITF is also needed for miR-211 expression, suggesting that the tumor-suppressor activities of MITF and/or TRPM1 may at least partially be due to miR-211's negative post transcriptional effects on the KCNMA1 transcript. Given previous reports of high KCNMA1 levels in metastasizing melanoma, prostate cancer and glioma, our findings that miR-211 is a direct posttranscriptional regulator of KCNMA1 expression as well as the dependence of this miRNA's expression on MITF activity, establishes miR-211 as an important regulatory agent in human melanoma

Testing Developmental Pathways to Antisocial Personality Problems

This study examined the development of antisocial personality problems (APP) in young adulthood from disruptive behaviors and internalizing problems in childhood and adolescence. Parent ratings of 507 children’s (aged 6–8 years) symptoms of attention deficit hyperactivity disorder, oppositional defiant disorder, and anxiety, were linked to self-ratings of adolescents’ (aged 14–16 years) symptoms of depression, substance use, conduct problems, and somatic problems, to predict self-ratings of APP in young adulthood (age 20–22 years). The findings suggested a hierarchical development of antisocial behavior problems. Despite being positively associated with conduct problems in adolescence, neither internalizing problems nor substance use added to the prediction of APP in young adulthood from conduct problems in adolescence. The developmental pathways to APP in young adulthood did not differ by gender

Treatment Seeking Problem Gamblers: Characteristics of Individuals who Offend to Finance Gambling

The relationship between Crime and gambling is well established, however few studies have examined offending specifically to finance gambling within a UK gambling treatment-seeking population. 1226 treatment-seeking gamblers completed the Problem Gambling Severity Index (PGSI), Patient Health Questionnaire, and the Generalized Anxiety Disorder 7 item scale, and were asked whether they had committed any illegal behaviours to finance gambling. 42.5 % reported offending behaviour. A greater proportion of the offending group were single or married/ cohabiting, had a lower-level qualifications, lower income, had experienced childhood abuse, family mental health problems and gambling related harms compared to the non-offending group. Offenders reported higher anxiety, depression and disordered gambling scores. Disordered gamblers who offend make up a discrete and complex subgroup with distinct vulnerabilities. Findings will be useful to clinicians involved in the assessment and management of problematic gambling. Gamblers who offend to finance gambling may have different treatment needs and treatment providers should administer appropriate clinical interventions to address vulnerabilities

Small mammal responses to Amazonian forest islands are modulated by their forest dependence

Hydroelectric dams have induced widespread loss, fragmentation and degradation of terrestrial habitats in lowland tropical forests. Yet their ecological impacts have been widely neglected, particularly in developing countries, which are currently earmarked for exponential hydropower development. Here we assess small mammal assemblage responses to Amazonian forest habitat insularization induced by the 28-year-old Balbina Hydroelectric Dam. We sampled small mammals on 25 forest islands (0.83–1466 ha) and four continuous forest sites in the mainland to assess the overall community structure and species-specific responses to forest insularization. We classified all species according to their degree of forest-dependency using a multi-scale approach, considering landscape, patch and local habitat characteristics. Based on 65,520 trap-nights, we recorded 884 individuals of at least 22 small mammal species. Species richness was best predicted by island area and isolation, with small islands ( 200 ha; 10.8 ± 1.3 species) and continuous forest sites (∞ ha; 12.5 ± 2.5 species) exhibited similarly high species richness. Forest-dependent species showed higher local extinction rates and were often either absent or persisted at low abundances on small islands, where non-forest-dependent species became hyper-abundant. Species capacity to use non-forest habitat matrices appears to dictate small mammal success in small isolated islands. We suggest that ecosystem functioning may be highly disrupted on small islands, which account for 62.7% of all 3546 islands in the Balbina Reservoir

Study protocol of the iMPaCT project : A longitudinal cohort study assessing psychological determinants, sexual behaviour and chlamydia (re)infections in heterosexual STI clinic visitors

Acknowledgements We are grateful to the staff at the STI clinics of Amsterdam, Kennemerland, Hollands Noorden, Twente, who are involved in the recruitment and data collection of participants, and Marlous Ratten and Klazien Visser from Soapoli-online, who are involved in the coordination of laboratory testing of the home-based sampling kits at six-month follow-up. We also thank the staff at the STI department at the National Institute for Public Health and the Environment, especially Birgit van Benthem. Funding This project is funded by the Strategic Programme (SPR) of the National Institute for Public Health and the Environment (RIVM) (project number S/113004/01/IP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Availability of data and materials The dataset (anonymised) generated during this study will be made available for interested parties on request.Peer reviewedPublisher PD

A Review on the Mechanical Modeling of Composite Manufacturing Processes

© 2016, The Author(s). The increased usage of fiber reinforced polymer composites in load bearing applications requires a detailed understanding of the process induced residual stresses and their effect on the shape distortions. This is utmost necessary in order to have more reliable composite manufacturing since the residual stresses alter the internal stress level of the composite part during the service life and the residual shape distortions may lead to not meeting the desired geometrical tolerances. The occurrence of residual stresses during the manufacturing process inherently contains diverse interactions between the involved physical phenomena mainly related to material flow, heat transfer and polymerization or crystallization. Development of numerical process models is required for virtual design and optimization of the composite manufacturing process which avoids the expensive trial-and-error based approaches. The process models as well as applications focusing on the prediction of residual stresses and shape distortions taking place in composite manufacturing are discussed in this study. The applications on both thermoset and thermoplastic based composites are reviewed in detail

Developmental Considerations for Assessment and Treatment of Impulsivity in Older Adults

Impulsivity is an important factor in many clinical disorders, especially alcohol and substance use disorders. Most of the research on impulsivity in this domain has focused on adolescence and young adulthood, as this developmental period is characterized by onset of and escalation in alcohol and substance use, likely driven in part by brain development patterns. Although many individuals eventually “mature out” of these behaviors in middle adulthood, a critical subset of people do not. The role of impulsivity in middle-to-older adulthood, when certain individuals transition from normative to disordered substance use, has not been carefully examined. The goal of this paper is to review the literature on measuring and modifying impulsivity from adolescence through older adulthood, with a special focus on middle-to-older adulthood. We propose that impulsivity research should include data on middle-to-older adulthood as an important time of transition to disordered use. We consider how impulsivity might have unique meaning at different stages of the adult lifespan and suggest modifications for assessing and treating impulsivity in older adults