Effect of influenza virus vaccine on the expression of human immunodeficiency virus co-receptor CCR5.

BACKGROUND: Administration of influenza vaccine to human immunodeficiency virus (HIV)-infected children can lead to increased viral load. CCR5 and CXCR4 are known to play an important role in HIV cell entry and viral replication. OBJECTIVE: To determine the effects of influenza vaccine on chemokine receptors and on viral load in HIV-infected children. METHODS: Eight HIV-infected children receiving stable therapy and 11 healthy adults were enrolled. Chemokine expression and immune activation were determined before and 48 hours after influenza vaccination. CCR5 and beta-chemokine gene expression were analyzed using real-time polymerase chain reaction. Viral load was measured at baseline, 48 hours, and 6 to 12 weeks. RESULTS: Forty-eight hours after influenza vaccination, mean CCR5 expression was significantly decreased on the CD3 (21.1% vs 11.3% in HIV-infected children; P = .02; and 18.3% vs 10.7% in controls; P = .008) and CD4 (13.0% vs 3.6% in the HIV group; P = .04; and 13.6% vs 6.5% in controls; P = .02) lymphocytes. This was observed in conjunction with an increase in HLA-DR expression on T lymphocytes in HIV-infected children (P = .046). No significant changes were observed in HIV viral load, CD3 and CD8 lymphocyte counts, expression of interleukin 2 receptor and CXCR4, or gene expression of CCR5 and beta-chemokines 48 hours after vaccination. CONCLUSIONS: Influenza virus vaccine markedly decreased chemokine receptor CCR5 expression on CD4 T lymphocytes. However, this immunomodulatory effect does not seem to affect overall viral replication in HIV-infected children who received highly active antiretroviral therapy.     

Community stressors, mediating conditions and wellbeing in urban neighborhoods.

Individual and community measures of stress are related to the presence of depression/demoralization symptoms (Feeling Bad), to positive Wellbeing (Feeling Good) and to the combination of these two (Wellbeing), in an urban sample of 549 adults. The mediation and moderation of these effects by indicators of social support, evaluation of status, and belief variables intended to measure aspects of individual coping tendencies are examined and tested. The findings suggest the absence of moderating effects of any of the support and coping variables on each stressor or on the effects of stressors on Feeling Bad, Feeling Good, and Wellbeing. A number of the variables do, however, have significant main effects, and thus appear to operate directly on the dependent variables, regardless of the presence or level of stress. Differences between apparent effects on Feeling Good and Feeling Bad and the increase in effects for the combination measure are discussed.     

Behavior genetic investigation of the relationship between spontaneous locomotor activity and the acquisition of morphine self-administration behavior

There is a significant degree of individual variability in response to drugs of abuse. A goal of behavior genetic studies has been to determine the extent to which observed heterogeneity in drug use can be attributed to genetic and environmental factors and to identify the neurobiological factors involved in vulnerability. Recent hypotheses regarding the predictive value of spontaneous locomotor activity in the acquisition of drug-reinforced behavior are amenable to testing using a behavior genetics approach. Genetic differences in locomotor response to a novel environment were determined in naive and catheterized Lewis, F344, NBR and ACI rats. Operant drug-reinforced behavior was examined in a 23h access paradigm in which each lever press by a rat produced a 1mg/kg injection of morphine with a 30s timeout period (FR 1:TO 30"). Acquisition (7 days), extinction (6 days) and reacquisition (7 days) of morphine self-administration behavior was investigated in all four inbred strains. Large genetic differences in the rate of acquisition and extinction of morphine self-administration were found. Lewis rats responded at high rates beginning in the first two days, whereas F344 rats initially responded at low rates and responding increased gradually over seven days. NBR and ACI rats responded at intermediate levels. When vehicle was substituted for drug there was a significant effect of genotype on the rate of extinction; F344 and ACI increased responding to greater than 175% of drug-response levels, whereas the Lewis response rate decreased gradually and NBR response rate decreased immediately during the first several days. When drug was available again, rates of reacquisition did not differ from original acquisition rates. Drug maintained significantly greater amounts of behavior than vehicle in the Lewis, F344 and NBR rats and was thus shown to serve as a positive reinforcer in these three strains under these conditions. There was a significant genetic correlation among strains between drug intake during the first five days of acquisition and spontaneous locomotor response to a novel environment in catheterized rats. Only the ACI rats showed a significant within-strain correlation. The positive relationship between rate of acquisition of self-administration behavior and locomotor activity suggests that these two traits are influenced by common or closely linked genes. To this end, the neurobiological substrates that mediate spontaneous locomotor behavior under these environmental conditions may act, in part, as a template for determining the neurobiological substrates that mediate the relative rate of acquisition of morphine-taking behavior under these conditions.     

Mortality among homeless shelter residents in New York City

OBJECTIVES: This study examined the rates and predictors of mortality among sheltered homeless men and women in New York City. METHODS: Identifying data on a representative sample of shelter residents surveyed in 1987 were matched against national mortality records for 1987 through 1994. Standardized mortality ratios were computed to compare death rates among homeless people with those of the general US and New York City populations. Logistic regression analysis was used to examine predictors of mortality within the homeless sample. RESULTS: Age-adjusted death rates of homeless men and women were 4 times those of the general US population and 2 to 3 times those of the general population of New York City. Among homeless men, prior use of injectable drugs, incarceration, and chronic homelessness increased the likelihood of death. CONCLUSIONS: For homeless shelter users, chronic homelessness itself compounds the high risk of death associated with disease/disability and intravenous drug use. Interventions must address not only the health conditions of the homeless but also the societal conditions that perpetuate homelessness.     

The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin--the Aprepitant Protocol 052 Study Group.

PURPOSE: In early clinical trials with patients receiving highly emetogenic chemotherapy, the neurokinin antagonist aprepitant significantly enhanced the efficacy of a standard antiemetic regimen consisting of a type-three 5-hydroxytryptamine antagonist and a corticosteroid. This multicenter, randomized, double-blind, placebo-controlled phase III study was performed to establish definitively the superiority of the aprepitant regimen versus standard therapy in the prevention of chemotherapy-induced nausea and vomiting (CINV). PATIENTS AND METHODS: Patients receiving cisplatin > or = 70 mg/m2 for the first time were given either standard therapy (ondansetron and dexamethasone on day 1; dexamethasone on days 2 to 4) or an aprepitant regimen (aprepitant plus ondansetron and dexamethasone on day 1; aprepitant and dexamethasone on days 2 to 3; dexamethasone on day 4). Patients recorded nausea and vomiting episodes in a diary. The primary end point was complete response (no emesis and no rescue therapy) on days 1 to 5 postcisplatin, analyzed by a modified intent-to-treat approach. Treatment comparisons were made using logistic regression models. Tolerability was assessed by reported adverse events and physical and laboratory assessments. RESULTS: The percentage of patients with complete response on days 1 to 5 was significantly higher in the aprepitant group (72.7% [n = 260] v 52.3% in the standard therapy group [n = 260]), as were the percentages on day 1, and especially on days 2 to 5 (P <.001 for all three comparisons). CONCLUSION: Compared with standard dual therapy, addition of aprepitant was generally well tolerated and provided consistently superior protection against CINV in patients receiving highly emetogenic cisplatin-based chemotherapy.     

Differential neuroendocrine responsiveness to morphine in Lewis, Fischer 344, and ACI inbred rats

Preclinical evidence suggests there is a link between the responsiveness to stress and the propensity to self-administer drugs of abuse. Our previous findings, for example, have shown a significant positive correlation between the locomotor response to novelty and the acquisition of morphine self-administration in Lewis (LEW), Fischer 344 (F344) and ACI inbred rat strains. As an extension of this work, we now report on the neuroendocrine responses (i.e., corticosterone and prolactin secretion) evoked by morphine administration in these same inbred strains. Male LEW, F344, and ACI rats were surgically prepared with indwelling jugular catheters 7 days prior to the study. Following a habituation period, rats were treated with i.p. saline or morphine (1, 5 or 10 mg/kg). Repeated blood samples were withdrawn via the catheters immediately before and at 20, 40, 60 and 120 min after injection. Plasma samples were assayed for hormone levels by radioimmunoassay. No differences in baseline corticosterone levels were found across strains. There was a significant effect of genotype on the corticosterone response to saline injection (i.e., mild stress), with F344 rats exhibiting sustained elevations in corticosterone compared to LEW and ACI rats. Morphine-induced stimulation of corticosterone release differed significantly across strains, and in this case LEW rats displayed a reduced sensitivity to morphine. Similar to the corticosterone results, LEW rats also had blunted prolactin responses to morphine when compared to F344 rats. Our data demonstrate that genotype is an important factor modulating the neuroendocrine sensitivity to morphine. It is noteworthy that LEW rats acquire self-administration more rapidly than F344 or ACI rats, yet LEW rats display reduced corticosterone responses to stress and morphine. Taking into account the particular conditions of this study (high i.p. doses used here vs. low i.v. doses in self-administration studies), our results do not suggest that corticosterone response to stress and morphine is related to vulnerability to intravenous opiate self-administration. The data, however, are consistent with the idea of that genetic factors might influence the sensitivity to the morphine-induced effects of glucocorticoids across these inbred strains.