P2X7 receptor deletion suppresses γ-radiation-induced hyposalivation.

Head and neck cancer treatments typically involve a combination of surgery and radiotherapy, often leading to collateral damage to nearby tissues causing unwanted side effects. Radiation damage to salivary glands frequently leads to irreversible dysfunction by poorly understood mechanisms. The P2X7 receptor (P2X7R) is a ligand-gated ion channel activated by extracellular ATP released from damaged cells as "danger signals." P2X7R activation initiates apoptosis and is involved in numerous inflammatory disorders. In this study, we utilized P2X7R knockout (P2X7R-/-) mice to determine the role of the receptor in radiation-induced salivary gland damage. Results indicate a dose-dependent increase in γ-radiation-induced ATP release from primary parotid gland cells of wild-type but not P2X7R-/- mice. Despite these differences, apoptosis levels are similar in parotid glands of wild-type and P2X7R-/- mice 24-72 h after radiation. However, γ-radiation caused elevated prostaglandin E2 (PGE2) release from primary parotid cells of wild-type but not P2X7R-/- mice. To attempt to uncover the mechanism underlying differential PGE2 release, we evaluated the expression and activities of cyclooxygenase and PGE synthase isoforms. There were no consistent trends in these mediators following radiation that could explain the reduction in PGE2 release in P2X7R-/- mice. Irradiated P2X7R-/- mice have stimulated salivary flow rates similar to unirradiated controls, whereas irradiated wild-type mice have significantly decreased salivary flow rates compared with unirradiated controls. Notably, treatment with the P2X7R antagonist A438079 preserves stimulated salivary flow rates in wild-type mice following γ-radiation. These data suggest that P2X7R antagonism is a promising approach for preventing γ-radiation-induced hyposalivation.

Administration of growth factors promotes salisphere formation from irradiated parotid salivary glands.

Worldwide, 500,000 cases of head and neck cancer (HNC) are reported each year and the primary treatment for HNC is radiotherapy. Although the goal of radiotherapy is to target the tumor, secondary exposure occurs in surrounding normal tissues, such as the salivary glands. As a result, despite successful treatment of the cancer, patients are left with long-term side effects due to direct damage to the salivary glands. The effect is chronic and currently there is no treatment. Stem cells are an attractive therapeutic option for treatment of radiation-induced glandular dysfunction because of the potential to regenerate damaged cell populations and restore salivary gland function. However, limited knowledge about the endogenous stem cell population post irradiation hinders the development for stem cell-based therapies. In this study, an ex vivo sphere formation cell culture system was utilized to assess the self-renewal capacity of cells derived from parotid salivary glands at a chronic time point following radiation. Salivary glands from irradiated mice generate significantly fewer salispheres, but can be stimulated with fetal bovine serum (FBS) to generate an equivalent number of salispheres as unirradiated salivary glands. Interestingly, the number and size of salispheres formed is dependent on the concentration of FBS supplemented into the media. Salispheres derived from irradiated glands and cultured in FBS media were found to contain cells that proliferate and express progenitor and acinar cell markers such as Keratin 5, Keratin 14, Aquaporin 5, and NKCC1. Utilization of insulin-like growth factor (IGF1) injections following radiation treatment restores salivary gland function and improves salisphere generation. These findings indicate that stimulation of these cellular populations may provide a promising avenue for the development of cell-based therapies for radiation-induced salivary gland damage.

Sexual violence and associated factors among women in HIV discordant and concordant relationships in Uganda.

HIV serodiscordance is a sexual partnership in which one partner is infected with HIV while the other is not. Managing emotional and sexual intimacy in HIV serodiscordant unions can be difficult due to concerns about HIV transmission and the challenge of initiating and maintaining safe sex. In situations where couples are jointly aware of their HIV status, women in serodiscordant unions may face increased risk of partner violence. We conducted an investigation to assess risk factors for HIV serodiscordance and determine if HIV serodiscordance is associated with incident sexual violence among a cohort of women attending HIV post-test club services at three AIDS Information Centers (AICs) in Uganda. Using a prospective study of 250 women, we elicited information about sexual violence using structured face-to-face interviews. Sexual violence and risk factors were assessed and compared among HIV positive women in HIV discordant unions, HIV negative women in discordant unions, and HIV negative women in negative concordant unions. Multivariable logistic regression was used to assess the association between participants' serostatus and sexual violence. HIV negative women in serodiscordant relationships (36.1±11.1 years, range: 19-65 years) were significantly older than either HIV positive women in serodiscordant relationships (32.2±9.0 years, range: 18-56 years), or HIV negative women in concordant relationships (32.3±11.0 years, range: 18-62), (p=0.033). Early age at sexual debut was associated with a 2.4-fold increased risk of experiencing sexual violence (OR 2.4, 95% CI 1.27-4.65). Based on unadjusted analysis, HIV positive women in discordant relationship were at highest risk for sexual violence compared to HIV negative women in discordant unions, and HIV negative women in negative concordant unions. HIV negative women in discordant relationships and those in concordant negative relationships showed no increased risk for sexual violence. However, couples' HIV serostatus was not significant related to incident sexual violence after controlling for potential confounding covariates. Nevertheless, the results were able to elucidate the sexual violence risk factor profile of participants based on couples' HIV serostatus. Couple counseling protocols at HIV voluntary counseling and testing centers in Uganda should identify those at risk for sexual violence and develop interventions to reduce its incidence.

Smoking susceptibility among students followed from grade six to eight.

BACKGROUND: Smoking is a leading risk factor for heart disease and cancer. By identifying factors associated with smoking onset, more effective prevention programs can be developed. Research questions are (1) does smoking susceptibility status change from grade six to eight, (2) are indicators of risk (perceived harm, smoking susceptibility status, positive peers, and resilience) measured in sixth grade associated with smoking susceptibility status in eighth grade and, (3) are there differences by gender in either research question? METHODS: The current study is a secondary analysis of data collected during the evaluation of a Safe Schools Healthy Students Project. Students were followed from grade six to grade eight, with survey data collected in each grade from August 2006 to December 2008. Participants (n=577) were in grade six at baseline, 52% were girls and 57% identified as White, non-Hispanic. RESULTS: From grade six to grade eight the number of students in the high smoking susceptibility status doubled (5% to 17%). More boys than girls moved into the high susceptibility group over time. By eighth grade, boys were twice as likely to belong to the high smoking susceptibility group compared to girls (p=0.01). Multiple logistic regression models showed that the positive peers' variable in grade six was protective for girls in their reported smoking susceptibility in grade eight. In contrast, higher resilience scores in grade six were protective for boys' reported smoking susceptibility in grade eight. CONCLUSIONS: Smoking susceptibility rose over time for all adolescents, but boys had notably sharper increases. Positive peers and having resources important to resilience may be beneficial in preventing the attitudes that support smoking initiation. Based on these results, we recommend gender-tailored, school-based smoking prevention programs that begin in grade six.

Adolescent emotional distress: the role of family obligations and school connectedness.

The current study draws upon ecodevelopmental theory to identify protective and risk factors that may influence emotional distress during adolescence. Hierarchical regression analyses were used to examine the relationship among family obligations, school connectedness and emotional distress of 4,198 (51% female) middle and high school students who were primarily (59%) European American. The overall model explained 21.1% of the variance in student emotional distress. A significant interaction effect was found indicating that school connectedness moderated the relationship between family obligations and emotional distress. Specifically, for students with low to moderate levels of family obligations, a stronger sense of school connectedness was associated with lower emotional distress. The buffering effect of school connectedness was weakened as the level of family obligations increased and completely disappeared for students who experienced high levels of family obligations. The creation of a program that takes a holistic approach, in order to curtail the levels of highly emotionally distressed adolescents, must continue to address the ever changing demands that adolescents encounter and prepare youth to deal with functioning within multiple contexts and do so while maintaining emotional well-being.