Objectives This study evaluated the effects of three class-sparing antiretroviral therapy (ART) regimens on endothelial function in HIV-infected subjects participating in a randomized trial. Background Endothelial dysfunction has been observed in patients receiving ART for human immunodeficiency virus (HIV) infection. Methods This was a prospective, multicenter study of treatment-naïve subjects who were randomly assigned to receive a protease inhibitor-sparing regimen of nucleoside reverse transcriptase inhibitors (NRTIs) + efavirenz, a non-nucleoside reverse transcriptase inhibitor-sparing regimen of NRTIs + lopinavir/ritonavir, or a NRTI-sparing regimen of efavirenz + lopinavir/ritonavir. NRTIs were lamivudine + stavudine, zidovudine, or tenofovir. Brachial artery flow-mediated dilation (FMD) was determined by B-mode ultrasound before starting on ART, then after 4 and 24 weeks. Results There were 82 subjects (median age 35 years, 91% men, 54% white). Baseline CD4 cell counts and plasma HIV RNA values were 245 cells/mm3 and 4.8 log10 copies/ml, respectively. At baseline, FMD was 3.68% (interquartile range 1.98 – 5.51%). After 4 and 24 weeks of ART, plasma HIV RNA decreased by 2.1 and 3.0 log10 copies/mL, respectively. FMD increased by 0.74% (−0.62 – +2.74, p=0.003) and 1.48% (−0.20 – +4.30%, p< 0.001), respectively, with similar changes in each arm (pKW>0.600). The decrease in plasma HIV RNA at 24 weeks was associated with greater FMD (rs=− 0.30, p=0.017). Conclusions Among treatment-naïve individuals with HIV, three different ART regimens rapidly improved endothelial function. Benefits were similar for all ART regimens, appeared quickly, and persisted at 24 weeks. Condensed Abstract Among 82 treatment-naïve HIV-infected subjects participating in a prospective, multicenter study of three class-sparing antiretroviral therapy regimens, flow-mediated dilation of the brachial artery improved after 4 (+0.74%, p=0.003) and 24 weeks (+1.48%, p< 0.001), with similar changes in each arm (pKW>0.600).

These data suggest that ongoing HIV replication and immune depletion significantly contribute to increased prevalence of elevated biomarkers of inflammation, altered coagulation, and monocyte activation. This contribution is independent of and in addition to the substantial contribution from comorbid conditions.

In this cohort of advanced human immunodeficiency virus (HIV)-infected subjects, distal sensory polyneuropathy was common and relatively stable over 48 weeks. Previously established risk factors, including CD4 cell count, plasma HIV RNA, and use of dideoxynucleoside antiretrovirals were not predictive of the progression of distal sensory polyneuropathy (DSP). Distal epidermal denervation was associated with worsening of DSP. As compared with the Total Neuropathy Score, the brief peripheral neuropathy screen had relatively low sensitivity and high specificity for the diagnosis of DSP.

In subjects with advanced HIV-1 infection, epidermal nerve fiber density (ENFD) assessment correlates with the clinical and electrophysiologic severity of distal sensory polyneuropathy (DSP). ENFD did not correlate with previously established risk factors for HIV-DSP, including CD4 cell count, plasma HIV-1 viral load, and neurotoxic antiretroviral therapy exposure.

Recent studies of pregnant women and animal models have raised concerns regarding potentially serious mitochondrial toxicity-related side effects in infants born to mothers who received nucleoside reverse transcriptase inhibitors (NRTIs) during their pregnancy to prevent HIV-1 perinatal transmission. The aim of this study was to assess mitochondrial DNA (mtDNA) content of cord blood and placenta in HIV-infected pregnant women receiving NRTI compared with HIV-negative women, hypothesizing that placenta and cord blood mtDNA copies per cell would be decreased in women on NRTI therapy. Immediately following delivery, placenta and cord blood were obtained from eight HIV-infected pregnant women on NRTIs and five HIV-negative women. Assessment of mtDNA copies per cell was accomplished by quantitative real-time PCR. The mean mtDNA copies per cell from the placenta of the HIV-infected women compared with HIV-negative women was 152 +/- 119 and 880 +/- 136 ( =.0016), respectively. Similarly, the mean mtDNA copies per cell from the cord blood of the HIV-positive women compared with HIV-negative women was 144 +/- 101 and 865 +/- 331 ( =.0026), respectively. There was a statistically significant decrease in mtDNA copies per cell in placenta and cord blood between the HIV-infected women on NRTIs compared with HIV-negative women. Further studies are needed to better understand the morbidity to infants and mothers treated with NRTI to prevent vertical transmission of HIV.

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Background HIV infection and biomarkers of inflammation (measured by interleukin-6 [IL-6]), monocyte activation (soluble CD14 [sCD14]), and coagulation (D-dimer) are associated with morbidity and mortality. We hypothesized that these immunologic processes mediate (explain) some of the excess risk of mortality among HIV infected (HIV+) versus uninfected people independently of co-morbid diseases. Methods Among 2350 (1521 HIV+) participants from the Veterans Aging Cohort Study Biomarker Cohort (VACS BC) we investigated whether the association between HIV and mortality was altered by adjustment for IL-6, sCD14 and D-dimer, accounting for confounders. Participants were followed from date of blood draw for biomarker assays (baseline) until death or 7/25/2013. Analyses included ordered logistic regression and Cox Proportional Hazards regression. Results During 6·9 years (median), 414 deaths occurred. The proportional odds of being in a higher quartile of IL-6, sCD14 or D-dimer was 2-3 fold higher for viremic HIV+ versus uninfected people. Mortality rates were higher among HIV+ compared to uninfected people (incidence rate ratio (95% CI): 1·31 (1·06-1·62). Mortality risk increased with increasing quartiles of IL-6, sCD14 and D-dimer regardless of HIV status. Adjustment for IL-6, sCD14 and D-dimer partially attenuated mortality risk among HIV+ people with unsuppressed viremia (HIV-1 RNA≥10000 copies/mL) compared to uninfected people – hazard ratio (95% CI) decreased from 2·18 (1·60-2·99) to 2·00 (1·45-2·76). Conclusions HIV infection is associated with elevated IL-6, sCD14 and D-dimer, which are in turn associated with mortality. Baseline measures of these biomarkers partially mediate excess mortality risk among HIV+ versus uninfected people.

This report focuses on the regulation of murine melanoma by the embryonic skin. A surgical technique was developed to allow inijection of B16 melanoma cells into the embryo in utero. A significant decrease in incidence of tumors was noted, which correlated with the time of arrival of normally migrating premelanocytes into the skin. Media were conditioned from skin explanted at the time premelanocytes arrive in it; these media inhibited the growth of melanoma cells in vitro. Under optimal conditions the growth of melanoma cells ceased; the cells had altered morphology and failed to proliferate when placed in fresh growth media.The discovery that cancer cells could differentiate into benign cells and tissues (1, 2) and that the process could be modulated (3) led to the concept that direction of differentiation of malignant to benign cells might serve as an alternative to cytotoxic therapy for cancer (4). In 1974 Brinster produced a chimeric mouse by injecting embryonal carcinoma cells into a blastocyst and putting the injected blastocyst into the uterus of a mouse made pseudopregnant (5). Thus, the blastocyst could regulate embryonal carcinoma cells and their progeny so they behaved as apparently normal embryonic cells. Regulation of tumor (6) and colony (7) formation of embryonal carcinoma by the blastocyst was tissue specific in that it was dependent upon close correspondence of the embryonic field (8) and the malignant cells. Further, contact of the cancer cells with trophectoderm in the presence of blastocele fluid was required (9). The problems occasioned by the paucity of trophectodermal cells made further study of the mechanism of embryonic regulation of embryonal carcinoma extremely difficult.Accordingly, other embryonic fields were examined to see if they could regulate tumor or colony formation of their closely related cancers. The neural-stage mouse embryo regulated neuroblastoma cells (10) MATERIALS AND METHODSIn the surgical approach to mouse embryos in utero, C57BL/6 female mice (The Jackson Laboratory) pregnant for 10 or 14 days (day 1 is the day of observation of the mating plug) were anesthetized with 0.4 ml of Avertin injected intraperitoneally. Avertin is composed of 2.5 g of 2,2,2,-tribromoethanol in 5 ml of 2-methyl-2-butanol and 200 ml of distilled water.A midline abdominal incision was made, a uterine horn was exposed, and the skin and viscera were packed out of the operative field with saline-soaked gauze. The animal was placed under a dissecting microscope using the lowest power objectives and x 10 eyepieces. An assistant observed the operative field through a large magnifying glass. A pursestring suture (6-0 silk) was placed in the uterine muscle, and the muscle inside this suture was divided with fine forceps to expose the fetal membranes. When the yolk sac was reached and before herniation of the embryo could occur, tension was placed on the purse-string suture, and a dam was firmly pressed down over the incision and held in place by the assistant. The dam was a piece of wire b...