Victimization and sexual risk behavior in young, HIV positive women: exploration of mediators.

In this study we explore associations between child and adult victimization and sexual risk behavior in 118 young, HIV positive women. Prior research has demonstrated associations between victimization and engagement in sexual risk behavior. Victimization sequelae can include disrupted assertiveness and communication, as well as increased association with risky partners, both of which are also linked with engagement in sexual risk behavior. Thus, we propose a model wherein victimization is linked to sexual risk behavior through two mediating pathways, sexual communication and affiliation with risky partners. We also examine the moderating effects of the presence of an anxiety or depressive disorder on the path from child to adult victimization. Results suggested that adult victimization was associated with unprotected sex with a main partner; however, this association was mediated by less sexual communication and having a risky partner. Trends toward significance were found for depression and anxiety as a moderator of the relationship between child and adult victimization. Child victimization did not have direct effects on unprotected sex. Implications for secondary prevention of HIV and healthy intimate relationships are discussed.

A qualitative study of quality of life after stroke: the importance of social relationships.

BACKGROUND: Stroke is a leading cause of long-term disability in the USA; however, we have an incomplete understanding of how stroke affects long-term quality of life. METHODS: We report here findings from focus groups with 9 long-term stroke survivors and 6 caregivers addressing patients' post-stroke quality of life. RESULTS: Key themes identified by patients were: social support, coping mechanisms, communication, physical functioning and independence. Role changes in patients were important to caregivers. Much of the discussion with patients and caregivers described specific ways in which the stroke altered social relationships. CONCLUSION: These findings are consistent with prior research indicating the importance of social factors to quality of life following stroke. Our findings suggest that measures of stroke-related quality of life should include assessment of social function and social support.

Differences in dendritic cell activation and distribution after intravenous, intraperitoneal, and subcutaneous injection of lymphoma cells in mice.

Dendritic cells (DCs) are key antigen-presenting cells (APCs) for initiating immune responses. However, in recent years, several groups have shown the defective function of DCs in tumor-bearing mice and in cancer patients. Our aim was to study the effects of lymphoma on DC differentiation and maturation and to assess the input of the tumor microenvironment and intravasation of tumor cells on DC precursors. EL-4 lymphoma cells were administrated via different routes (intraperitoneal, subcutaneous, and intravenous) and DC phenotype was investigated. Bone marrow-derived DCs and APCs obtained from the spleen were examined by flow cytometry, and immunohistochemical analysis of lymphoma, lungs, livers, and spleens was also performed. Intravenous administration of lymphoma cells induced suppression of DC differentiation and maturation assessed as a significant decrease of the IAb, CD80, CD86, CD11b, and CD11c expression on DCs and IAb on splenic APCs. Upregulation of APC differentiation was observed in animals after subcutaneous and intraperitoneal administration of lymphoma cells determined as increased expression of CD40 and CD86 in spleen APCs. These data suggest that the development of antitumor immune response might differ in the host receiving tumor vaccines via different injection routes.

Using focus groups to inform the Neuro-QOL measurement tool: exploring patient-centered, health-related quality of life concepts across neurological conditions.

Measurement of health-related quality of life (HRQL) is of particular importance in neurology clinical trials, where differences in clinical measurements or laboratory data may not translate into significant benefit to the patients. A fundamental consideration in the development and use of an HRQL instrument is whether the instrument's conceptual framework accurately reflects the HRQL experience of the population of interest. This study details the findings from formative research that focused on the identification of content area for an HRQL measurement system in neurology. Specifically, 11 focus groups were conducted with caregivers and patients diagnosed with 7 neurological conditions that represented a range of symptomatology and ages. Through an analytic process using techniques derived from grounded theory, several themes emerged that describe the complexity of HRQL issues and the impact of neurological disorders on multiple areas of life functioning and experience. Findings suggest that although HRQL is comparable across neurological disorders, the contribution of specific domains to overall HRQL may differ among disorders.

Increased function and survival of IL-15-transduced human dendritic cells are mediated by up-regulation of IL-15Ralpha and Bcl-2.

It has been recently demonstrated that dendritic cells (DC) coincubated with interleukin (IL)-15 express high levels of the Bcl-2 family of proteins and display an increased resistance to tumor-induced apoptotic death. Here, the phenotype, functions, and survival of human DC transduced with adenoviral vector encoding the human IL-15 gene were studied. The transduction of DC with the IL-15 gene resulted in a significant elevation of expression of CD83, CD86, and CD40 molecules, which was blocked by anti-IL-15 monoclonal antibodies. This effect was also accompanied by an increased production of IL-12 and stimulated ability of DC to induce T cell proliferation. Furthermore, transduction of DC with the IL-15 gene significantly increased their resistance to prostate cancer-induced apoptosis: Overexpression of IL-15 on DC blocked tumor-induced inhibition of Bcl-2 expression and prolonged DC survival after coincubation with tumor cells. Finally, overexpression of IL-15 in DC was associated with a higher level of expression of IL-15 receptor alpha chain mRNA. In summary, these results suggest that transduction of DC with the IL-15 gene markedly stimulates DC function and protects them from tumor-induced apoptosis.

Lung cancer-derived bombesin-like peptides down-regulate the generation and function of human dendritic cells.

Development of tumors is regulated by tumor-derived neuroendocrine factors, including bombesin-like peptides (BLP). We have evaluated neuroendocrine regulation of dendritic cell (DC) maturation and function by both tumor-derived and purified bombesin (BOM), neuromedin B (NMB), gastrin-releasing peptide (GRP), and a BOM antagonist D-Phe-bombesin (DPB). BOM, NMB and GRP dose-dependently inhibited maturation of DC assessed as down-regulation of CD40, CD80 and CD86 expression on DC. BOM and GRP also inhibited interleukin-12 (IL-12) production by DC and their ability to activate T cells. DPB partly abrogated immunosuppressive effect of tumor cells on DC. These data are a first evidence for the role of BLP in the regulation of DC maturation and function, demonstrating that BLP inhibit DC maturation and longevity in the lung cancer microenvironment. This suggests a new mechanism of tumor escape and provides new targets for the immunopharmacological correction of immune effectors in cancer.

Health related quality of life and psychosocial correlates among HIV-infected adolescent and young adult women in the US.

In this study HIV health-related quality of life (HIV-HRQOL) is examined among 179 behaviorally infected adolescent and young adult women. Modifiable psychosocial variables including depression, stigma, social support, and illness acceptance, and the biological end-points of CD4 cell count and viral load were explored in relation to HIV-HRQOL. The three factors of the HIV-HRQOL measure include current life satisfaction, illness related anxiety and illness burden. Bivariate linear regression analysis demonstrated statistically significant associations for all psychosocial variables and HIV HRQOL factors (p < .01), but not for biological end-points. In multivariate linear regression analysis significant associations remained between: depression (p = .006), illness acceptance (p < .001), social support (p = .001), and current life satisfaction, and depression (p = .012), illness acceptance (p = .015), and illness burden. A trend in association was noted for HIV stigma, with current life satisfaction and illness related anxiety but did not reach statistical significance (p = .097 and p = .109 respectively). Interventions that effectively decrease stigma and depression and increase social support and illness acceptance will likely improve the well-being and quality of life of HIV-infected adolescent women.

Adherence to scheduled appointments among HIV-infected female youth in five U.S. cities.

OBJECTIVE: Identify factors associated with appointment-keeping among HIV-infected adolescents and young adults. METHODS: HIV-infected adolescent and young adult females in five U.S. cities were followed for a period of 18 months to examine adherence to scheduled clinic visits with their HIV care provider. Psychosocial and behavioral factors that have been shown in other populations to influence appointment adherence were measured at baseline and follow-up visits using an audio computer-assisted self-interview questionnaire. These factors included mood disorder, depressive symptoms, social network support, healthcare satisfaction, disease acceptance, HIV stigma, alcohol use, and marijuana use. CD4 count and prescription of antiretroviral therapy medication were also monitored to understand the influence of health status on appointment- keeping. RESULTS: Participants included 178 youth with a mean age of 20.6 years. Forty-two percent had clinically significant depressive symptoms, 10% had a diagnosable mood disorder, 37% reported marijuana use in the last 90 days, and 47% reported alcohol use. Overall, participants attended 67.3% of their scheduled visits. Controlling for age and health status, marijuana use was the only variable that was associated with appointment-keeping behavior. CONCLUSIONS: Considering the importance of appointment-keeping for maintaining personal health and preventing further transmission, screening HIV-infected adolescents for marijuana use could help alert providers of this specific barrier to visit compliance.

CD11b+/Gr-1+ myeloid suppressor cells cause T cell dysfunction after traumatic stress.

T cell dysfunction that occurs after surgery or trauma is associated with a poor clinical outcome. We describe that myeloid suppressor cells expressing CD11b(+)/Gr-1(+) markers invade the spleen after traumatic stress and suppress T cell function through the production of arginase 1. We created a consistent model of traumatic stress in C57BL/6 mice to perform this work. A significant number of CD11b(+)/Gr-1(+) cells expressing arginase 1 accumulated in T cell zones around the germinal centers of the white pulp of the spleen within 6 h of trauma and lasted for at least 72 h. Increased arginase activity and arginase 1 expression, along with increased [(3)H]arginine uptake, l-arginine depletion, and l-ornithine accumulation in the culture medium, were observed exclusively in CD11b(+)/Gr-1(+) cells after traumatic stress. Flow cytometry revealed CD11b(+)/Gr-1(+) as a heterogeneous myeloid suppressor cell also expressing low levels of MHC class I and II, CD80, CD86, CD31, and others. When compared with controls, trauma-induced CD11b(+)/Gr-1(+) cells significantly inhibited CD3/CD28-mediated T cell proliferation, TCR zeta-chain expression, and IL-2 production. The suppressive effects by trauma CD11b(+)/Gr-1(+) cells were overcome with the arginase antagonist N-hydroxy-nor-l-arginine or extrasupplementation of medium with l-arginine. Poor Ag-presenting capacity of control and trauma-induced CD11b(+)/Gr-1(+) cells was detected in allogeneic murine leukocyte reaction. This study demonstrates that CD11b(+)/Gr-1(+) cells invade the spleen following traumatic stress and cause T cell dysfunction by an arginase-mediated mechanism, probably that of arginine depletion. Understanding the mechanism of immune suppression by these cells has important clinical implications in the treatment of immune dysfunction after trauma or surgery.

Loss of new chemokine CXCL14 in tumor tissue is associated with low infiltration by dendritic cells (DC), while restoration of human CXCL14 expression in tumor cells causes attraction of DC both in vitro and in vivo.

Breast and kidney-expressed chemokine (BRAK) CXCL14 is a new CXC chemokine with unknown function and receptor selectivity. The majority of head and neck squamous cell carcinoma (HNSCC) and some cervical squamous cell carcinoma do not express CXCL14 mRNA, as opposed to constitutive expression by normal oral squamous epithelium. In this study, we demonstrate that the loss of CXCL14 in HNSCC cells and at HNSCC primary tumor sites was correlated with low or no attraction of dendritic cell (DC) in vitro, and decreased infiltration of HNSCC mass by DC at the tumor site in vivo. Next, we found that recombinant human CXCL14 and CXCL14-positive HNSCC cell lines induced DC attraction in vitro, whereas CXCL14-negative HNSCC cells did not chemoattract DC. Transduction of CXCL14-negative HNSCC cell lines with the human CXCL14 gene resulted in stimulation of DC attraction in vitro and increased tumor infiltration by DC in vivo in chimeric animal models. Furthermore, evaluating the biologic effect of CXCL14 on DC, we demonstrated that the addition of recombinant human CXCL14 to DC cultures resulted in up-regulation of the expression of DC maturation markers, as well as enhanced proliferation of allogeneic T cells in MLR. Activation of DC with recombinant human CXCL14 was accompanied by up-regulation of NF-kappaB activity. These data suggest that CXCL14 is a potent chemoattractant and activator of DC and might be involved in DC homing in vivo.

Restoration by IL-15 of MHC class I antigen-processing machinery in human dendritic cells inhibited by tumor-derived gangliosides.

We have recently reported that MHC class I Ag-processing machinery (APM) component expression in dendritic cells (DC) might be down-regulated by tumor cells. However, the tumor-derived factors responsible for inhibition of the APM component expression in DC generated in the tumor microenvironment as well as potential protective mechanism have not yet been investigated. In this article, we demonstrate that expression of several MHC class I APM components, including MB1 (beta5), LMP2, LMP7, LMP10, and ERp57, is significantly down-regulated in human DC generated in the presence of primary oral squamous cell carcinoma cell lines or coincubated with purified gangliosides. Suppression of MHC class I APM component expression in DC generated in the presence of tumor cells was significantly attenuated by the inhibition of glucosyl transferase in tumor cells, suggesting that tumor-induced MHC class I APM component down-regulation in DC was mediated in part by oral squamous cell carcinoma-derived gangliosides. Furthermore, rIL-15 restored both tumor cell-induced and ganglioside-induced MHC class I APM component expression in DC, as well as their ability to present Ags to autologous Ag-specific T cells. These results demonstrate that IL-15 restores MHC class I APM component expression in DC down-regulated by tumor-derived gangliosides.

Murine prostate cancer inhibits both in vivo and in vitro generation of dendritic cells from bone marrow precursors.

BACKGROUND: There is increasing evidence to suggest that dendritic cells (DC) are functionally impaired in tumor bearing hosts. However there is little or no data on the effects of murine prostate cancer (CaP) on DC generation from bone marrow precursors. METHODS: Flow cytometry, mixed leukocyte reactions (MLR), and immunohistochemical analyses were used to characterize DC in CaP. RESULTS: DC generated in the presence of CaP cell lines RM1 and the cell line C2 from the transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse in a Transwell system expressed significantly lower levels of DC differentiation markers. This effect was confirmed when TK-neo-transfected RM1 cells were directly added to DC cultures and eliminated 5 days later using gancyclovir (GCV). Furthermore, co-incubation of DC with CaP cells resulted in a decrease in the stimulatory capacity of DC to induce T cell proliferation in the MLR assay. These results were further confirmed in vivo in two different murine models of CaP: i) DC generated from mice intrafemorally injected with TK-neo-transfected RM1 cells; and ii) in DC generated from TRAMP mice. CONCLUSIONS: The generation and function of DC are significantly suppressed in the CaP microenvironment in both in vivo and in vitro murine models.