HIV Activates the Tyrosine Kinase Hck to Secrete ADAM Protease-Containing Extracellular Vesicles

HIV-Nef activates the myeloid cell-typical tyrosine kinase Hck, but its molecular role in the viral life cycle is not entirely understood. We found that HIV plasma extracellular vesicles (HIV pEV) containing/10 proteases and Nef also harbor Hck, and analyzed its role in the context of HIV pEV secretion. Myeloid cells required Hck for the vesicle-associated release of ADAM17. This could be induced by the introduction of Nef and implied that HIV targeted Hck for vesicle-associated ADAM17 secretion from a myeloid compartment. The other contents of HIV-pEV, however, including miRNA and effector protein profiles, as well as the presence of haptoglobin suggested hepatocytes as a possible cellular source. HIV liver tissue analysis supported this assumption, revealing induction of Hck translation, evidence for ADAMprotease activation and HIV infection. Our findings suggest that HIV targets Hck to induce pro-inflammatory vesicles release and identifies hepatocytes as a possible host cell compartment. (c) 2018 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license.Peer reviewe

Efficacy, safety, tolerability and pharmacokinetics of a novel human immune globulin subcutaneous, 20%: a Phase 2/3 study in Europe in patients with primary immunodeficiencies

A highly concentrated (20%) immunoglobulin (Ig)G preparation for subcutaneous administration (IGSC 20%), would offer a new option for antibody replacement therapy in patients with primary immunodeficiency diseases (PIDD). The efficacy, safety, tolerability and pharmacokinetics of IGSC 20% were evaluated in a prospective trial in Europe in 49 patients with PIDD aged 2-67 years. Over a median of 358 days, patients received 2349 IGSC 20% infusions at monthly doses equivalent to those administered for previous intravenous or subcutaneous IgG treatment. The rate of validated acute bacterial infections (VASBIs) was significantly lower than 1 per year (0.022/patient-year, P /= 8 g/l. There was no serious adverse event (AE) deemed related to IGSC 20% treatment; related non-serious AEs occurred at a rate of 0.101 event/infusion. The incidence of local related AEs was 0.069 event/infusion (0.036 event/infusion, when excluding a 13-year-old patient who reported 79 of 162 total related local AEs). The incidence of related systemic AEs was 0.032 event/infusion. Most related AEs were mild, none were severe. For 64.6% of patients and in 94.8% of IGSC 20% infusions, no local related AE occurred. The median infusion duration was 0.95 (range = 0.3-4.1) h using mainly one to two administration sites [median = 2 sites (range = 1-5)]. Almost all infusions (99.8%) were administered without interruption/stopping or rate reduction. These results demonstrate that IGSC 20% provides an effective and well-tolerated therapy for patients previously on intravenous or subcutaneous treatment, without the need for dose adjustment

Internet interventions for mental health in university students:A systematic review and meta-analysis

OBJECTIVES: Mental health disorders are highly prevalent among university students. Universities could be an optimal setting to provide evidence-based care through the Internet. As part of the World Mental Health International College Student initiative, this systematic review and meta-analysis synthesizes data on the efficacy of Internet-based interventions for university students' mental health. METHOD: A systematic literature search of bibliographical databases (CENTRAL, MEDLINE, and PsycINFO) for randomized trials examining psychological interventions for the mental health (depression, anxiety, stress, sleep problems, and eating disorder symptoms), well-being, and functioning of university students was performed through April 30, 2018. RESULTS: Forty-eight studies were included. Twenty-three studies (48%) were rated to have low risk of bias. Small intervention effects were found on depression (g = 0.18, 95% confidence interval [CI; 0.08, 0.27]), anxiety (g = 0.27, 95% CI [0.13, 0.40]), and stress (g = 0.20, 95% CI [0.02, 0.38]). Moderate effects were found on eating disorder symptoms (g = 0.52, 95% CI [0.22-0.83]) and role functioning (g = 0.41, 95% CI [0.26, 0.56]). Effects on well-being were non-significant (g = 0.15, 95% CI [-0.20, 0.50]). Heterogeneity was moderate to substantial in many analyses. After adjusting for publication bias, effects on anxiety were not significant anymore. DISCUSSION: Internet interventions for university students' mental health can have significant small-to-moderate effects on a range of conditions. However, more research is needed to determine student subsets for which Internet-based interventions are most effective and to explore ways to increase treatment effectiveness. © 2018 John Wiley & Sons, Ltd. KEYWORDS: Internet; college; mental disorders; meta-analysis; psychotherap

Versatile strategy for homogeneous drying patterns of dispersed particles

After spilling coffee, a tell-tale stain is left by the drying droplet. This universal phenomenon, known as the coffee ring effect, is observed independent of the dispersed material. However, for many technological processes such as coating techniques and ink-jet printing a uniform particle deposition is required and the coffee ring effect is a major drawback. Here, we present a simple and versatile strategy to achieve homogeneous drying patterns using surface-modified particle dispersions. High-molecular weight surface-active polymers that physisorb onto the particle surfaces provide enhanced steric stabilization and prevent accumulation and pinning at the droplet edge. In addition, in the absence of free polymer in the dispersion, the surface modification strongly enhances the particle adsorption to the air/liquid interface, where they experience a thermal Marangoni backflow towards the apex of the drop, leading to uniform particle deposition after drying. The method is independent of particle shape and applicable to a variety of commercial pigment particles and different dispersion media, demonstrating the practicality of this work for everyday processes

Impact of CYP2B6 983T>C polymorphism on non-nucleoside reverse transcriptase inhibitor plasma concentrations in HIV-infected patients

Objectives The aim of this study was to investigate the frequency of CYP2B6 polymorphisms (according to ethnicity) and the influence of heterozygosity and homozygosity on plasma concentrations of efavirenz and nevirapine. Methods Following written informed consent, 225 Caucasians and 146 Blacks were recruited from the German Competence Network for HIV/AIDS. Plasma concentrations of efavirenz and nevirapine were assessed by HPLC, and genotyping for 516G>T, 983T>C and 1459T>C polymorphisms in CYP2B6 was conducted by real-time PCR-based allelic discrimination. Results The minor allele frequency for 516G>T, 983T>C and 1459T>C was 0.29, 0 and 0.08 in Caucasians and 0.34, 0.07 and 0.02 in Blacks, respectively. Two Black patients with the 983C allele receiving efavirenz were identified and both were withdrawn from therapy within 1 week of sampling due to toxicity. In multivariate analyses, efavirenz and nevirapine plasma concentrations were significantly associated with 983T>C (P T (P T was not associated with plasma concentrations of either drug (P > 0.05 for both drugs). Conclusions This is the first report that the 983T>C genotype (part of the CYP2B6*18 haplotype) impacts on nevirapine plasma concentrations and the first study to assess the impact of 983C homozygosity on efavirenz concentrations. These data have implications for administration of non-nucleoside reverse transcriptase inhibitors to Black patient

The Effects of Meditation, Yoga, and Mindfulness on Depression, Anxiety, and Stress in Tertiary Education Students: A Meta-Analysis

Background: Meditation, yoga, and mindfulness are popular interventions at universities and tertiary education institutes to improve mental health. However, the effects on depression, anxiety, and stress are unclear. This study assessed the effectiveness of meditation, yoga, and mindfulness on symptoms of depression, anxiety, and stress in tertiary education students.Methods: We searched Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, PsycINFO and identified 11,936 articles. After retrieving 181 papers for full-text screening, 24 randomized controlled trials were included in the qualitative analysis. We conducted a random-effects meta-analysis amongst 23 studies with 1,373 participants.Results: At post-test, after exclusion of outliers, effect sizes for depression, g = 0.42 (95% CI: 0.16–0.69), anxiety g = 0.46 (95% CI: 0.34–0.59), stress g = 0.42 (95% CI: 0.27–0.57) were moderate. Heterogeneity was low (I2 = 6%). When compared to active control, the effect decreased to g = 0.13 (95% CI: −0.18–0.43). No RCT reported on safety, only two studies reported on academic achievement, most studies had a high risk of bias.Conclusions: Most studies were of poor quality and results should be interpreted with caution. Overall moderate effects were found which decreased substantially when interventions were compared to active control. It is unclear whether meditation, yoga or mindfulness affect academic achievement or affect have any negative side effects

Cellular Immune Responses and Viral Diversity in Individuals Treated during Acute and Early HIV-1 Infection

Immune responses induced during the early stages of chronic viral infections are thought to influence disease outcome. Using HIV as a model, we examined virus-specific cytotoxic T lymphocytes (CTLs), T helper cells, and viral genetic diversity in relation to duration of infection and subsequent response to antiviral therapy. Individuals with acute HIV-1 infection treated before seroconversion had weaker CTL responses directed at fewer epitopes than persons who were treated after seroconversion. However, treatment-induced control of viremia was associated with the development of strong T helper cell responses in both groups. After 1 yr of antiviral treatment initiated in acute or early infection, all epitope-specific CTL responses persisted despite undetectable viral loads. The breadth and magnitude of CTL responses remained significantly less in treated acute infection than in treated chronic infection, but viral diversity was also significantly less with immediate therapy. We conclude that early treatment of acute HIV infection leads to a more narrowly directed CTL response, stronger T helper cell responses, and a less diverse virus population. Given the need for T helper cells to maintain effective CTL responses and the ability of virus diversification to accommodate immune escape, we hypothesize that early therapy of primary infection may be beneficial despite induction of less robust CTL responses. These data also provide rationale for therapeutic immunization aimed at broadening CTL responses in treated primary HIV infection

Race, colonial history and national identity: Resident Evil 5 as a Japanese game

Resident Evil 5 is a zombie game made by Capcom featuring a White American protagonist and set in Africa. This paper argues that approaching this as a Japanese game reveals aspects of a Japanese racial and colonial social imaginary that are missed if this context of production is ignored. In terms of race, the game presents hybrid racial subjectivities that can be related to Japanese perspectives of Blackness and Whiteness where these terms are two poles of difference and identity through which an essentialised Japanese identity is constructed in what Iwabuchi calls “strategic hybridism” (Iwabuchi, 2002). In terms of colonialism, the game echoes structures of Japanese colonialism through which Japanese colonialism is obliquely memorialised and a “normal” Japanese global subjectivity can be performed