A randomized, double-blind, placebo-controlled trial of deprenyl and thioctic acid in human immunodeficiency virus-associated cognitive impairment

Cognitive impairment is a frequent manifestation of advanced human immunodeficiency virus (HIV) infection. The response to antiretroviral medication is often partial and poorly sustained. Recent studies suggest that free radical production within the CNS and neuronal apoptosis may play important roles in the pathogenesis of HIV dementia. We conducted a randomized double-blind, placebo-controlled trial using a parallel group, 2× 2 factorial design evaluating deprenyl, a monoamine oxidase B inhibitor and putative anti-apoptotic agent, and thioctic acid, an antioxidant, in 36 patients with HIV-associated cognitive impairment. Both deprenyl and thioctic acid were well tolerated with few adverse events. Deprenyl recipients showed significant improvement on tests of verbal memory compared with patients not taking deprenyl. Thioctic acid treatment did not improve cognitive function. These results suggest that deprenyl treatment is associated with cognitive improvement in subjects with mild HIV-associated cognitive impairment, whereas thioctic acid has no benefit. A larger efficacy trial is needed to assess the long-term effect of deprenyl on cognitive performance in patients with HIV infection. Human immunodeficiency virus type 1 (HIV-1)-associated dementia complex(HIV dementia) occurs in 15 to 20% of acquired immunodeficiency syndrome(AIDS) patients and is characterized by cognitive impairment, motor dysfunction, and behavioral changes.1-5 The cognitive impairment includes mental slowing, forgetfulness, and poor concentration. Motor symptoms include loss of fine motor control, clumsiness, unsteady gait, and tremor. Behavioral changes include apathy, lethargy, and depression.2,3,6 HIV dementia is usually a rapidly progressive disorder with a mean survival of about 6 months,2 although recently, patients with slower progression or a stable course have been identified.7 HIV-1-associated minor cognitive motor disorder, a milder syndrome, is estimated to occur in 25% of patients with symptomatic HIV infection.8 Few available antiretroviral agents have been studied for the treatment of HIV dementia. Open label studies with zidovudine (ZDV) in demented patients showed improvements in clinical functioning, neuropsychological performance, and neuroimaging studies.9 ZDV, in a placebo-controlled blinded study, also improved neuropsychological function in AIDS or AIDS-related complex patients without dementia.10 The only placebo-controlled trial of ZDV in HIV dementia demonstrated the greatest neurocognitive improvement only with very high dosages (i.e., 2,000 mg/day).11 Unfortunately, the response to ZDV treatment may be short-lived or associated with intolerable side effects and therefore often unsatisfactory. There is very limited information about the therapeutic effects of other antiretroviral medications (e.g., dideoxynucleosides)12 or protease inhibitors. Neurotoxins from HIV-infected activated macrophages or microglia interacting with astrocytes may play a central pathogenetic role in HIV dementia.13,14 Putative neurotoxins include cytokines (tumor necrosis factor alpha [TNF-α]) and oxygen radicals.2,15 Both TNF-α and hydroxyl free radicals may stimulate apoptosis (programmed cell death), and apoptotic neurons have been demonstrated in the cerebral cortex and basal ganglia of both children and adults with HIV encephalitis.16,17 We hypothesized that these indirect mechanisms of neuronal injury could be modified by deprenyl and thioctic acid to improve or even prevent HIV-associated cognitive impairment. Deprenyl, a selective monoamine oxidase type B inhibitor, at very low dosages in in vitro and in vivo systems has a trophic effect on injured neurons.18-21 Thioctic acid is a naturally occurring enzymatic cofactor for pyruvate dehydrogenase and alpha oxoglutarate dehydrogenase and scavenges harmful hydroxyl radicals and other reactive oxygen species.22,23 We conducted a randomized, double-blind, placebo-controlled clinical trial of deprenyl and thioctic acid to assess their safety and tolerability and to assess their impact on HIV-associated cognitive impairment in HIV seropositive (HIV+) patients

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

The relationship between adipokines, body composition, and bone density in men with chronic obstructive pulmonary disease

Sheryl F Vondracek1, Norbert F Voelkel2, Michael T McDermott3, Connie Valdez11Department of Clinical Pharmacy; 3Department of Medicine, University of Colorado Denver, Aurora, CO, USA; 2Department of Internal Medicine and Victoria Johnson Center for Emphysema Research, Virginia Commonwealth University, Richmond, VA, USAAbstract: Osteoporosis is common in patients with chronic obstructive pulmonary disease (COPD). Data regarding the relationship between adipokines and bone mineral density (BMD) in this population is lacking. The purpose of this pilot study was to determine associations between the adipokines tumor necrosis factor-alpha (TNF-&amp;alpha;), leptin, adiponectin and resistin, body composition, and BMD in men with severe COPD. This was a cross-sectional study of men with severe COPD who visited the University of Colorado Hospital COPD Center. Bone density and parameters of body composition were measured by dual-energy X-ray absorptiometry. Twenty-three men were included (mean age = 66 years, mean percent predicted forced expiratory volume in one second = 32%). On bivariate analysis, there was no association between TNF-&amp;alpha; and BMD. Parameters of body composition and serum concentrations of leptin and adiponectin were significantly associated with total hip and spine bone density. However, with partial correlation analysis, total body mass was the only independent predictor of total hip BMD, explaining approximately 50% of the variability. Overall, 18 out of 23 men enrolled (78%) had low bone density by T-score, and nine (39%) were classified as having osteoporosis. The men with osteoporosis had lower parameters of body composition, lower mean serum leptin concentrations, and a greater impairment in measures of lung function compared to the men without osteoporosis. We conclude that the effect of adipokines on BMD does not appear to be independent of body mass. However, larger studies are needed to further evaluate the relationship between adipokines, body weight, and BMD in patients with COPD.Keywords: bone mineral density, osteoporosis, TNF-&amp;alpha;, leptin, adiponectin, chronic obstructive pulmonary disease, adipokine

Why are Indigenous Affairs Policies Framed in ways that Undermine Indigenous Health and Equity? Examining Australia’s Northern Territory Emergency Response

The 2007 Australian Northern Territory Emergency Response policy was harmful to the health of Aboriginal and Torres Strait Islander people. We thematically analysed 72 speech acts and reports from the three prominent perspectives: a Northern Territory government inquiry report, the Federal government, and an Aboriginal civil society coalition to examine how framings during the policy agenda setting phase constrained or supported scope for equitable health outcomes. The report authors and the coalition emphasised colonisation and other social determinants of Indigenous health. The Federal government used a discourse of pathology and white sovereignty. Our findings highlighted the need for Indigenous voice in policy making, and the need to address colonial assumptions underpinning policy framings to achieve Indigenous health equity

Why are Indigenous Affairs Policies Framed in ways that Undermine Indigenous Health and Equity? : Examining Australia’s Northern Territory Emergency Response

The 2007 Australian Northern Territory Emergency Response policy was harmful to the health of Aboriginal and Torres Strait Islander people. We thematically analysed 72 speech acts and reports from the three prominent perspectives: a Northern Territory government inquiry report, the Federal government, and an Aboriginal civil society coalition to examine how framings during the policy agenda setting phase constrained or supported scope for equitable health outcomes. The report authors and the coalition emphasised colonisation and other social determinants of Indigenous health. The Federal government used a discourse of pathology and white sovereignty. Our findings highlighted the need for Indigenous voice in policy making, and the need to address colonial assumptions underpinning policy framings to achieve Indigenous health equity