Rectal Transmission of Transmitted/Founder HIV-1 Is Efficiently Prevented by Topical 1% Tenofovir in BLT Humanized Mice

Rectal microbicides are being developed to prevent new HIV infections in both men and women. We focused our in vivo preclinical efficacy study on rectally-applied tenofovir. BLT humanized mice (n = 43) were rectally inoculated with either the primary isolate HIV-1(JRCSF) or the MSM-derived transmitted/founder (T/F) virus HIV-1(THRO) within 30 minutes following treatment with topical 1% tenofovir or vehicle. Under our experimental conditions, in the absence of drug treatment we observed 50% and 60% rectal transmission by HIV-1(JRCSF) and HIV-1(THRO), respectively. Topical tenofovir reduced rectal transmission to 8% (1/12; log rank p = 0.03) for HIV-1(JRCSF) and 0% (0/6; log rank p = 0.02) for HIV-1(THRO). This is the first demonstration that any human T/F HIV-1 rectally infects humanized mice and that transmission of the T/F virus can be efficiently blocked by rectally applied 1% tenofovir. These results obtained in BLT mice, along with recent ex vivo, Phase 1 trial and non-human primate reports, provide a critically important step forward in the development of tenofovir-based rectal microbicides

Associations between cardiorespiratory fitness, physical activity and clustered cardiometabolic risk in children and adolescents: the HAPPY study

Clustering of cardiometabolic risk factors can occur during childhood and predisposes individuals to cardiometabolic disease. This study calculated clustered cardiometabolic risk in 100 children and adolescents aged 10-14 years (59 girls) and explored differences according to cardiorespiratory fitness (CRF) levels and time spent at different physical activity (PA) intensities. CRF was determined using a maximal cycle ergometer test, and PA was assessed using accelerometry. A cardiometabolic risk score was computed as the sum of the standardised scores for waist circumference, blood pressure, total cholesterol/high-density lipoprotein ratio, triglycerides and glucose. Differences in clustered cardiometabolic risk between fit and unfit participants, according to previously proposed health-related threshold values, and between tertiles for PA subcomponents were assessed using ANCOVA. Clustered risk was significantly lower (p < 0.001) in the fit group (mean 1.21 ± 3.42) compared to the unfit group (mean -0.74 ± 2.22), while no differences existed between tertiles for any subcomponent of PA. Conclusion These findings suggest that CRF may have an important cardioprotective role in children and adolescents and highlights the importance of promoting CRF in youth

Missed, not missing: Phylogenomic evidence for the existence of Avian FoxP3

The Forkhead box transcription factor FoxP3 is pivotal to the development and function of regulatory T cells (Tregs), which make a major contribution to peripheral tolerance. FoxP3 is believed to perform a regulatory role in all the vertebrate species in which it has been detected. The prevailing view is that FoxP3 is absent in birds and that avian Tregs rely on alternative developmental and suppressive pathways. Prompted by the automated annotation of foxp3 in the ground tit (Parus humilis) genome, we have questioned this assumption. Our analysis of all available avian genomes has revealed that the foxp3 locus is missing, incomplete or of poor quality in the relevant genomic assemblies for nearly all avian species. Nevertheless, in two species, the peregrine falcon (Falco peregrinus) and the saker falcon (F. cherrug), there is compelling evidence for the existence of exons showing synteny with foxp3 in the ground tit. A broader phylogenomic analysis has shown that FoxP3 sequences from these three species are similar to crocodilian sequences, the closest living relatives of birds. In both birds and crocodilians, we have also identified a highly proline-enriched region at the N terminus of FoxP3, a region previously identified only in mammals

Risk of chronic kidney disease after cancer nephrectomy.

The incidence of early stage renal cell carcinoma (RCC) is increasing and observational studies have shown equivalent oncological outcomes of partial versus radical nephrectomy for stage I tumours. Population studies suggest that compared with radical nephrectomy, partial nephrectomy is associated with decreased mortality and a lower rate of postoperative decline in kidney function. However, rates of chronic kidney disease (CKD) in patients who have undergone nephrectomy might be higher than in the general population. The risks of new-onset or accelerated CKD and worsened survival after nephrectomy might be linked, as kidney insufficiency is a risk factor for cardiovascular disease and mortality. Nephron-sparing approaches have, therefore, been proposed as the standard of care for patients with type 1a tumours and as a viable option for those with type 1b tumours. However, prospective data on the incidence of de novo and accelerated CKD after cancer nephrectomy is lacking, and the only randomized trial to date was closed prematurely. Intrinsic abnormalities in non-neoplastic kidney parenchyma and comorbid conditions (including diabetes mellitus and hypertension) might increase the risks of CKD and RCC. More research is needed to better understand the risk of CKD post-nephrectomy, to develop and validate predictive scores for risk-stratification, and to optimize patient management

Ecologic Niche Modeling of Blastomyces dermatitidis in Wisconsin

Background: Blastomycosis is a potentially fatal mycosis that is acquired by inhaling infectious spores of Blastomyces dermatitidis present in the environment. The ecology of this pathogen is poorly understood, in part because it has been extremely difficult to identify the niche(s) it occupies based on culture isolation of the organism from environmental samples. Methodology/Principal Findings: We investigated the ecology of blastomycosis by performing maximum entropy modeling of exposure sites from 156 cases of human and canine blastomycosis to provide a regional-scale perspective of the geographic and ecologic distribution of B. dermatitidis in Wisconsin. Based on analysis with climatic, topographic, surface reflectance and other environmental variables, we predicted that ecologic conditions favorable for maintaining the fungus in nature occur predominantly within northern counties and counties along the western shoreline of Lake Michigan. Areas of highest predicted occurrence were often in proximity to waterways, especially in northcentral Wisconsin, where incidence of infection is highest. Ecologic conditions suitable for B. dermatitidis are present in urban and rural environments, and may differ at the extremes of distribution of the species in the state. Conclusions/Significance: Our results provide a framework for a more informed search for specific environmental factors modulating B. dermatitidis occurrence and transmission and will be useful for improving public health awareness of relativ

Production and characterisation of a recombinant scFv reactive with human gastrointestinal carcinomas

SC142-reactive antigen are highly glycosylated glycoproteins expressed on tissues of gastric and colon cancers but not on normal tissues. Murine SC142 antibody specific for the SC142-reactive antigen has been produced by immunisation with SNU16 stomach cancer cells. However, SC142 antibody has several potential problems such as high immunogenicity and poor tumour penetration owing to their large size. To improve tumour penetration potential in vivo, recombinant single-chain fragments have been produced using the original hybridoma cells as a source of variable heavy- and variable light-chain-encoding antibody genes. The use of the polymerase chain reaction, expression cloning technology and gene expression systems in E. coli has led to the production of SC142 single-chain fragments, which was similar in activity to the SC142 parent antibody confirmed by immunohistochemistry. Analysis by DNA sequencing, SDS–PAGE and Western blotting has demonstrated the integrity of the single-chain fragments. Competitive ELISA showed that SC142 single-chain fragments originated from parent SC142 antibody. BIAcore biosensor binding experiments showed that the SC142 single-chain fragments had an ideal dissociation rate constant as a tumour imaging reagent. These results illustrate the potential application of these novel products as an immunodiagnostic and further immunotherapeutic reagent

Induction of Glucose Metabolism in Stimulated T Lymphocytes Is Regulated by Mitogen-Activated Protein Kinase Signaling

T lymphocytes play a critical role in cell-mediated immune responses. During activation, extracellular and intracellular signals alter T cell metabolism in order to meet the energetic and biosynthetic needs of a proliferating, active cell, but control of these phenomena is not well defined. Previous studies have demonstrated that signaling from the costimulatory receptor CD28 enhances glucose utilization via the phosphatidylinositol-3-kinase (PI3K) pathway. However, since CD28 ligation alone does not induce glucose metabolism in resting T cells, contributions from T cell receptor-initiated signaling pathways must also be important. We therefore investigated the role of mitogen-activated protein kinase (MAPK) signaling in the regulation of mouse T cell glucose metabolism. T cell stimulation strongly induces glucose uptake and glycolysis, both of which are severely impaired by inhibition of extracellular signal-regulated kinase (ERK), whereas p38 inhibition had a much smaller effect. Activation also induced hexokinase activity and expression in T cells, and both were similarly dependent on ERK signaling. Thus, the ERK signaling pathway cooperates with PI3K to induce glucose utilization in activated T cells, with hexokinase serving as a potential point for coordinated regulation

Remote maintenance cardiac rehabilitation (MAINTAIN): A protocol for a randomised feasibility study.

Background: Long-term adherence to exercise is often poor for people with coronary heart disease (CHD) who have completed supervised, centre-based cardiac rehabilitation. The aim of this study is to assess the feasibility of a remotely prescribed, delivered and monitored cardiac rehabilitation intervention using a wearable device to support long-term adherence to exercise and physical activity during maintenance of cardiac rehabilitation. Methods: After completing cardiac rehabilitation, 30 participants with CHD, will be randomised (1:1) to an intervention (n = 15) or a usual care group (n = 15) in a 12-month feasibility randomised controlled trial (RCT). The intervention will comprise of an exercise consultation, personalised exercise prescription delivered via a wearable activity monitor using biometric feedback, regular monitoring via check-ins, and feedback text-messages for 6-months. Participants will be assessed at baseline (following completion of cardiac rehabilitation) and at three-, six-, and 12-months post-randomisation. The primary outcome will be feasibility, including assessment of eligibility, recruitment, adherence, and acceptability. Secondary outcomes will include exercise capacity, physical activity behaviours, cardiovascular disease risk and quality of life. Semi-structured interviews will be conducted at three-, six-, and 12-months post-randomisation (and with those who drop-out) to explore the acceptability of the study intervention and procedures. A questionnaire will be offered to those who decline participation. Discussion: The MAINTAIN study will evaluate the feasibility of conducting a future definitive multi-centre RCT testing a remotely prescribed and monitored long-term mHealth maintenance exercise programme, versus usual care, for people with CHD who have completed cardiac rehabilitation

Seek Help from Teachers or Fight Back? Student Perceptions of Teachers’ Actions during Conflicts and Responses to Peer Victimization

Previous research has shown that teachers’ actions when addressing conflict on school grounds can shape adolescent perceptions regarding how well the school manages victimization. Our objective in this study was to determine how these perceptions influenced the likelihood that adolescent students would react to victimization scenarios by either seeking help from school authority or physically fighting back. Vignettes describing two events of victimization were administered to 148 ethnic minority adolescents (Latino, African American, and Asian backgrounds; 49% female) attending an urban high school with high rates of conflict. Positive perceptions of teachers’ actions during conflicts—assessed via a questionnaire tapping how teachers manage student conflicts both generally and in a specific instance of strife—predicted a greater willingness to seek help from school authority, which in turn negatively predicted self-reported aggressive responses to the victimization scenarios. Path analysis established the viability of this indirect effect model, even when we controlled for sex, beliefs about the acceptability of aggression, and previous levels of reactive aggression. Adolescents’ perceptions of teachers’ actions during conflicts are discussed in relation to social information processing models, improving student–teacher relations, and decreasing aggression at schools