Human immunodeficiency virus (HIV) persistence in latently infected resting memory CD4+ T-cells is the major barrier to HIV cure. Cellular histone deacetylases (HDACs) are important in maintaining HIV latency and histone deacetylase inhibitors (HDACi) may reverse latency by activating HIV transcription from latently infected CD4+ T-cells. We performed a single arm, open label, proof-of-concept study in which vorinostat, a pan-HDACi, was administered 400 mg orally once daily for 14 days to 20 HIV-infected individuals on suppressive antiretroviral therapy (ART). The primary endpoint was change in cell associated unspliced (CA-US) HIV RNA in total CD4+ T-cells from blood at day 14. The study is registered at ClinicalTrials.gov (NCT01365065). Vorinostat was safe and well tolerated and there were no dose modifications or study drug discontinuations. CA-US HIV RNA in blood increased significantly in 18/20 patients (90%) with a median fold change from baseline to peak value of 7.4 (IQR 3.4, 9.1). CA-US RNA was significantly elevated 8 hours post drug and remained elevated 70 days after last dose. Significant early changes in expression of genes associated with chromatin remodeling and activation of HIV transcription correlated with the magnitude of increased CA-US HIV RNA. There were no statistically significant changes in plasma HIV RNA, concentration of HIV DNA, integrated DNA, inducible virus in CD4+ T-cells or markers of T-cell activation. Vorinostat induced a significant and sustained increase in HIV transcription from latency in the majority of HIV-infected patients. However, additional interventions will be needed to efficiently induce virus production and ultimately eliminate latently infected cells.
Combining quantum-mechanical simulations and synthesis tools allows the design of highly efficient CuCo/MoO(x) catalysts for the selective conversion of synthesis gas (CO+H2) into ethanol and higher alcohols, which are of eminent interest for the production of platform chemicals from non-petroleum feedstocks. Density functional theory calculations coupled to microkinetic models identify mixed Cu-Co alloy sites, at Co-enriched surfaces, as ideal for the selective production of long-chain alcohols. Accordingly, a versatile synthesis route is developed based on metal nanoparticle exsolution from a molybdate precursor compound whose crystalline structure isomorphically accommodates Cu(2+) and Co(2+) cations in a wide range of compositions. As revealed by energy-dispersive X-ray nanospectroscopy and temperature-resolved X-ray diffraction, superior mixing of Cu and Co species promotes formation of CuCo alloy nanocrystals after activation, leading to two orders of magnitude higher yield to high alcohols than a benchmark CuCoCr catalyst. Substantiating simulations, the yield to high alcohols is maximized in parallel to the CuCo alloy contribution, for Co-rich surface compositions, for which Cu phase segregation is prevented.
Adults older than 65 years of age with vision impairment are more likely to have difficulty managing medications compared with people having normal vision. This patient population has difficulty reading medication information and may take the wrong medication or incorrect doses of medication, resulting in serious consequences, including overdose or inadequate treatment of health problems. Visually impaired patients report increased anxiety related to medication management and must rely on others to obtain necessary drug information. Pharmacists have a unique opportunity to pursue accurate medication adherence in this special population. This article reviews literature illustrating how severe medication mismanagement can occur in the visually impaired elderly and presents resources and solutions for pharmacists to take a larger role in adherence management in this population.
Hyperactivation of T cells, particularly of CD8(+) T cells, is a hallmark of chronic HIV 1 (HIV-1) infection. Little is known about the antigenic specificities and the mechanisms by which HIV-1 causes activation of CD8(+) T cells during chronic infection. We report that CD8(+) T cells were activated during in vivo HIV-1 replication irrespective of their Ag specificity. Cytokines present during untreated HIV-1 infection, most prominently IL-15, triggered proliferation and expression of activation markers in CD8(+) T cells, but not CD4(+) T cells, in the absence of TCR stimulation. Moreover, LPS or HIV-1-activated dendritic cells (DCs) stimulated CD8(+) T cells in an IL-15-dependent but Ag-independent manner, and IL-15 expression was highly increased in DCs isolated from viremic HIV-1 patients, suggesting that CD8(+) T cells are activated by inflammatory cytokines in untreated HIV-1 patients independent of Ag specificity. This finding contrasts with CD4(+) T cells whose in vivo activation seems biased toward specificities for persistent Ags. These observations explain the higher abundance of activated CD8(+) T cells compared with CD4(+) T cells in untreated HIV-1 infection.
Comorbidities are frequent in chronic obstructive pulmonary disease (COPD) and significantly impact on patients' quality of life, exacerbation frequency, and survival. There is increasing evidence that certain diseases occur in greater frequency amongst patients with COPD than in the general population, and that these comorbidities significantly impact on patient outcomes. Although the mechanisms are yet to be defined, many comorbidities likely result from the chronic inflammatory state that is present in COPD. Common problems in the clinical management of COPD include recognizing new comorbidities, determining the impact of comorbidities on patient symptoms, the concurrent treatment of COPD and comorbidities, and accurate prognostication. The majority of comorbidities in COPD should be treated according to usual practice, and specific COPD management is infrequently altered by the presence of comorbidities. Unfortunately, comorbidities are often under-recognized and under-treated. This review focuses on the epidemiology of ten major comorbidities in patients with COPD. Further, we emphasize the clinical impact upon prognosis and management considerations. This review will highlight the importance of comorbidity identification and management in the practice of caring for patients with COPD.
HIV infection induces chronic immune activation which is associated with accelerated disease progression; the causes of this activation, however, are incompletely understood. We investigated the activation status of CD4+ T cells specific for chronic herpes viruses and the non-persistent antigen tetanus toxoid (TT) in HIV positive and HIV negative donors to assess whether persistent infections contribute to chronic CD4+ T cell activation.
Tracing cell dynamics in the embryo becomes tremendously difficult when cell trajectories cross in space and time and tissue density obscure individual cell borders. Here, we used the chick neural crest (NC) as a model to test multicolor cell labeling and multispectral confocal imaging strategies to overcome these roadblocks.
Sebaldella termitidis (Sebald 1962) Collins and Shah 1986, is the only species in the genus Sebaldella within the fusobacterial family Leptotrichiaceae. The sole and type strain of the species was first isolated about 50 years ago from intestinal content of Mediterranean termites. The species is of interest for its very isolated phylogenetic position within the phylum Fusobacteria in the tree of life, with no other species sharing more than 90% 16S rRNA sequence similarity. The 4,486,650 bp long genome with its 4,210 protein-coding and 54 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project.
Dendritic cells (DCs) are important in allergic diseases such as asthma, although little is known regarding the mechanisms by which DCs induce T(H)2-polarized responses in atopic individuals. It has been suggested that intrinsic properties of allergens can directly stimulate T(H)2 polarizing functions of DCs, but little is known of the underlying mechanisms.
Combination antiretroviral therapy (cART) has led to a reduction in morbidity and mortality in HIV-infected patients but therapy is lifelong and there is no cure for HIV. The major barriers to cure include HIV latency, which has been identified in different T-cell subsets, as well as persistence of HIV in anatomical reservoirs. We review recent developments in our understanding of the major reservoirs of HIV in patients on cART as well as how latency is established and maintained in T cells. Finally, we review the scientific rationale of and clinical experience with pharmacotherapeutic strategies aimed at eliminating latently infected cells.
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