While several clinical studies have shown that HIV-1 infection is associated with increased permeability of the intestinal tract, there is very little understanding of the mechanisms underlying HIV-induced impairment of mucosal barriers. Here we demonstrate that exposure to HIV-1 can directly breach the integrity of mucosal epithelial barrier, allowing translocation of virus and bacteria. Purified primary epithelial cells (EC) isolated from female genital tract and T84 intestinal cell line were grown to form polarized, confluent monolayers and exposed to HIV-1. HIV-1 X4 and R5 tropic laboratory strains and clinical isolates were seen to reduce transepithelial resistance (TER), a measure of monolayer integrity, by 30–60% following exposure for 24 hours, without affecting viability of cells. The decrease in TER correlated with disruption of tight junction proteins (claudin 1, 2, 4, occludin and ZO-1) and increased permeability. Treatment of ECs with HIV envelope protein gp120, but not HIV tat, also resulted in impairment of barrier function. Neutralization of gp120 significantly abrogated the effect of HIV. No changes to the barrier function were observed when ECs were exposed to Env defective mutant of HIV. Significant upregulation of inflammatory cytokines, including TNF-α, were seen in both intestinal and genital epithelial cells following exposure to HIV-1. Neutralization of TNF-α reversed the reduction in TERs. The disruption in barrier functions was associated with viral and bacterial translocation across the epithelial monolayers. Collectively, our data shows that mucosal epithelial cells respond directly to envelope glycoprotein of HIV-1 by upregulating inflammatory cytokines that lead to impairment of barrier functions. The increased permeability could be responsible for small but significant crossing of mucosal epithelium by virus and bacteria present in the lumen of mucosa. This mechanism could be particularly relevant to mucosal transmission of HIV-1 as well as immune activation seen in HIV-1 infected individuals.

Background:The proinflammatory chemokine, CCL5, is a T cell chemoattractant and immunoregulatory molecule. Results: CCL5 induces glucose uptake in an mTOR-dependent manner, activates the nutrient-sensing kinase AMPK, and enhances intracellular ATP. Conclusion: CCL5 regulates glucose uptake and ATP generation in activated T lymphocytes in addition to regulating chemotaxis. Significance: We extend the role of CCL5-mediated signaling beyond lymphocyte chemotaxis.

BackgroundMultiple myeloma is a haematological malignancy characterized by significant morbidity and mortality. This study sought to develop an in-depth understanding of patients’ lived experiences of relapsed or refractory multiple myeloma (RRMM) and its treatment, and to identify which features of treatment were most important to them.MethodsQualitative interviews and focus groups (FGs) were conducted with 32 people living with RRMM across Canada. In Phase 1, interviews focused on participants’ accounts of their experiences with the disease and its treatment and laid the groundwork for the FGs (Phase 2). The FGs developed a deeper understanding of patients’ treatment priorities. Interview and FG transcripts were coded for emergent themes and patterns.ResultsThe interviews identified important side effects that had significant impacts on patients’ lives, including physical, cognitive, and psychological/emotional side effects. Participants also identified specific treatment features (attributes) that were important to them. These were compiled into a list and used in the FGs to understand patients’ priorities. Higher prioritized attributes were: life expectancy, physical and cognitive side effects, and financial impact. Mode of administration, treatment intervals, psychological side effects, and sleep/mood effects were identified as lower priorities.ConclusionsRRMM and its treatments impact importantly on patients’ quality-of-life across a range of domains. Patients prioritized treatment features that could enhance life expectancy, minimize side effects and offset financial burdens.Implications for cancer survivorsA clear articulation of patient priorities can contribute to efforts to design treatment with patients’ concerns in mind, thereby promoting a more patient-centered approach to care.

BackgroundCardiac troponin T (cTnT) is elevated after coronary artery bypass grafting surgery. The aim of this study was to determine the association between cTnT elevations between 6 and 12 hours after coronary artery bypass grafting and in‐hospital outcome.Methods and ResultsWe prospectively studied 1722 patients undergoing isolated coronary artery bypass grafting. We assessed the association between conventional cTnT (749 patients) and high‐sensitivity cTnT (hs‐cTnT; 973 patients) 6 to 12 hours postoperatively with in‐hospital major adverse cardiac or cerebrovascular events (MACCE), a composite of all‐cause death, myocardial infarction, or stroke. The prespecified secondary outcome was a safety composite of MACCE, resuscitation, intensive care unit readmission or admission ≥48 hours, inotrope or vasopressor use ≥24 hours, or new‐onset renal insufficiency. Among patients with a conventional cTnT measurement, 92 experienced a MACCE (12%) and 146 experienced a safety composite event (19%). Likewise, for hs‐cTnT, 114 experienced a MACCE (12%) and 153 experienced a safety composite event (16%). Compared with cTnT ≤200 ng/L, each 200‐ng/L increment in cTnT was associated with a monotonous increase in the odds of MACCE and the safety composite outcome. Conventional and hs‐cTnT demonstrated moderate discrimination for MACCE (areas under the fitted receiver operating characteristics curve, 0.72 and 0.77 for conventional and hs‐cTnT, respectively) and the safety composite outcome (areas under the fitted receiver operating characteristics curve, 0.66 and 0.74 for conventional and hs‐cTnT, respectively) and resulted in improved prognostic performance when added to the EuroSCORE. At a cutoff of 800 ng/L, conventional and hs‐cTnT provided clinically relevant power to rule in MACCE and the safety composite outcome.Conclusions cTnT levels assessed between 6 and 12 hours after coronary artery bypass grafting identify patients at increased risk of MACCE or other complications.