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7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK, Purpose There are three classes of HIV‐1 based on diversity of the viral envelope: M (major), O (outlying) and N (new). The M group is subclassified into nine major subtypes [...]

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious healthcare issue that can impair cancer treatment and reduce quality of life for cancer survivors. Currently there is no FDA-approved medication to manage CIPN, emphasizing the urgent need to identify novel mechanism-based interventions for CIPN. Histone deacetylase 6 (HDAC6) is an attractive target, given its pathogenic role in both cancer and neurodegenerative diseases. We show that cisplatin enhances HDAC6 expression and decreases acetylation of the HDAC6 substrate α-tubulin in the dorsal root ganglion (DRG). Pharmacological inhibition of HDAC6 with ACY-1215, an HDAC6 inhibitor that is currently in clinical trials as add-on cancer therapy, prevented cisplatin-induced mechanical allodynia, loss of intraepidermal nerve fibers (IENFs), and mitochondrial dysfunction in the DRG neurons and peripheral nerves in male and female mice. Genetic deletion of HDAC6 also protected against all CIPN signs. Interestingly, cell specific deletion of HDAC6 in Advilin-positive sensory neurons prevented loss of IENFs and mitochondrial deficits in the peripheral nerves, but not mechanical allodynia or DRG neuronal mitochondrial dysfunction. We previously showed that T cells are required for spontaneous resolution of mechanical allodynia in CIPN. Here we assessed the contribution of T cells to the beneficial effects of HDAC6 inhibition. HDAC6 inhibition during chemotherapy in T cell deficient Rag2−/− mice also prevented IENF loss and mitochondrial dysfunction in the peripheral nerves, but not mechanical allodynia or DRG mitochondrial deficits. Reconstitution with T cells normalized the protective effects of ACY-1215. Adoptive transfer of HDAC6 deficient T cells to Rag2−/− mice failed to protect against CIPN, indicating targeting HDAC6 in T cells alone was not sufficient. Taken together, our findings identify cell specific mechanisms for the protective effects of HDAC6 inhibition on cisplatin-induced mechanical allodynia and IENF loss. Our findings also strengthen the rationale for using HDAC6 inhibitors like ACY-1215 for CIPN prevention. [ABSTRACT FROM AUTHOR]

Purpose of the study The proportion of HIV-infected persons diagnosed in an advanced stage of HIV disease (ASH) varies by country from 15 to 30%. Data are lacking on the proportion of new cases diagnosed in this late stage in Russia. The aim of this study was to estimate the proportion of and further characterize patients with ASH among newly diagnosed HIV-1 infected persons in the Russian Federation. Methods This was a cross-sectional, multicenter, epidemiologic study. Adult HIV-1 patients that were newly diagnosed within 90 days and naïve to highly active antiretroviral therapy were included at twelve centers/regions (Moscow Region, St Petersburg, Leningrad Region, Ufa, Kazan, Ulyanovsk, Volgograd, Yekaterinburg, Kemerovo, Krasnoyarsk, Irkutsk and Vladivostok) of the Russian Federation. ASH was defined as a CD4+ cell count ≤200 cells/mm3. Pairwise, two-tailed comparisons were conducted with an unadjusted 5% significance level. For comparison variables between patients with ASH and all other patients, Pearson's chi-square test was used. Summary of results 4540 patients were included. The overall proportion of ASH was 16.3% (95% CI; 15.3%, 17.4%). The median plasma HIV-1 RNA was 4.48 (Q1, Q3; 3.81, 5.07) log10 copies/mL. The proportion of patients with CD4+ cell count by categories is presented in . ASH was associated with male sex (62.3%), 26-40 and >40 years age groups, rural place of residence (18.9%), only primary and/or basic school education (complete or not complete) (39.4%), unemployment (40.5%), intravenous drug user as mode of HIV-1 transmission (39.5%), patient with clinical signs of immunodeficiency or condition related to HIV/AIDS as reason for primary HIV-1 testing (35.2%), HBV (5.4%), HCV (44.0%) as partly shown in . Conclusions The overall prevalence of ASH was 16.3%. At least 9 factors associated with ASH were revealed. Knowledge of these factors is valuable for planning, prevention and post-diagnosis services for HIV-infected patients presenting with advance stage disease. [ABSTRACT FROM AUTHOR]

This study examines current soil contamination in an Australian industrial city, Newcastle. Public (roadside verges and parks) and private (homes) surface soils (n = 170) contained metal(loid)s elevated above their respective Australian Health Investigation Levels (HIL). Lead (Pb), the most common contaminant in the city, exceeds the HIL for residential soils (HIL-A, 300 mg/kg) in 88% of private soils (median: 1140 mg/kg). In-vitro Pb bio-accessibility analysis of selected soils (n = 11) using simulated gastric fluid showed a high affinity for Pb solubilisation (maximum Pb concentration: 5190 mg/kg, equating to 45% Pb bio-accessibility). Highly soluble Pb-laden Fe- and Mn-oxides likely contribute to the bio-accessibility of the Pb. Public and private space surface soils contain substantially less radiogenic Pb (range: 208 Pb/ 207 Pb: 2.345–2.411, 206 Pb/ 207 Pb: 1.068–1.312) than local background soil ( 208 Pb/ 207 Pb: 2.489, 206 Pb/ 207 Pb: 1.198), indicating anthropogenic contamination from the less radiogenic Broken Hill type Pb ores ( 208 Pb/ 207 Pb: 2.319, 206 Pb/ 207 Pb: 1.044). Source apportionment using Pb isotopic ratio quantification and soil mineralogy indicate the city's historic copper and steel industries contributed the majority of the soil contaminants through atmospheric deposition and use of slag waste as fill material. High-temperature silicates and oxides combined with rounded particles in the soil are characteristic of smelter dust emissions. Additionally, a preliminary investigation of polycyclic aromatic hydrocarbons in soils, sometimes associated with ferrous metal smelting, coal processing or burning of fossil fuels, shows that these too pose a health exposure risk (calculated in comparison to benzo( a )pyrene: n = 12, max: 13.5 mg/kg, HIL: 3 mg/kg). [ABSTRACT FROM AUTHOR]