Genetic predictors for bacterial vaginosis in women living with and at risk for HIV infection.

PROBLEM: Bacterial vaginosis (BV) disproportionally impacts Black and Hispanic women, placing them at risk for HIV, sexually transmitted infections and preterm birth. It is unknown whether there are differences by genetic ancestry in BV risk or whether polymorphisms associated with BV risk differ by ancestry. METHODS: Women's Interagency HIV Study (WIHS) participants with longitudinal Nugent scores were dichotomized as having (n = 319, Nugent 7-10) or not having BV (n = 367, Nugent 0-3). Genetic ancestry was defined by clustering of principal components from ancestry informative markers and further stratified by BV status. 627 single nucleotide polymorphisms (SNPs) across 41 genes important in mucosal defense were identified in the WIHS GWAS. A logistic regression analysis was adjusted for nongenetic predictors of BV and self-reported race/ethnicity to assess associations between genetic ancestry and genotype. RESULTS: Self-reported race and genetic ancestry were associated with BV risk after adjustment for behavioral factors. Polymorphisms in mucosal defense genes including syndecans, cytokines and toll-like receptors (TLRs) were associated with BV in all ancestral groups. CONCLUSIONS: The common association of syndecan, cytokine and TLR genes and the importance of immune function and inflammatory pathways in BV, suggests these should be targeted for further research on BV pathogenesis and therapeutics.

Decentralizing Maternity Services to Increase Skilled Attendance at Birth and Antenatal Care Utilization in Rural Rwanda: A Prospective Cohort Study.

To evaluate the effectiveness of decentralizing ambulatory reproductive and intrapartum services to increase rates of antenatal care (ANC) utilization and skilled attendance at birth (SAB) in Rwanda. A prospective cohort study was implemented with one control and two intervention sites: decentralized ambulatory reproductive healthcare and decentralized intrapartum care. Multivariate logistic regression analysis was performed with primary outcome of lack of SAB and secondary outcome of ≥3 ANC visits. 536 women were entered in the study. Distance lived from delivery site significantly predicted SAB (p = 0.007), however distance lived to ANC site did not predict ≥3 ANC visits (p = 0.81). Neither decentralization of ambulatory reproductive healthcare (p = 0.10) nor intrapartum care (p = 0.40) was significantly associated with SAB. The control site had the greatest percentage of women receive ≥3 ANC visits (p < 0.001). Receiving <3 ANC visits was associated with a 3.98 times greater odds of not having SAB (p = 0.001). No increase in adverse outcomes was found with decentralization of ambulatory reproductive health care or intrapartum care. The factors that predict utilization of physically accessible services in rural Africa are complex. Decentralization of services may be one strategy to increase rates of SAB and ANC utilization, but selection biases may have precluded accurate analysis. Efforts to increase ANC utilization may be a worthwhile investment to increase SAB.

An increased capacity for adrenal DHEA release is associated with decreased avoidance and negative mood symptoms in women with PTSD.

We recently found increased adrenal cortisol responses to adrenocorticotropic hormone (ACTH)1-24 and increased pituitary ACTH and adrenal cortisol responses to corticotropin-releasing factor in premenopausal women with chronic post-traumatic stress disorder (PTSD) compared to healthy nontraumatized subjects. This pattern of hypothalamic-pituitary-adrenal axis (HPA) hyper-reactivity has been previously seen in healthy individuals treated with the antiglucocorticoid mifepristone. We therefore investigated whether endogenous plasma levels of antiglucocorticoids such as dehydroepiandrosteroine (DHEA) and progesterone were increased in premenopausal women with PTSD at baseline or in response to adrenal activation by ACTH1-24. The study revealed that DHEA responses to 250 microg ACTH1-24 were increased in 13 PTSD subjects compared to 13 healthy nontraumatized subjects, while DHEA levels were generally increased in the PTSD subjects compared to seven healthy traumatized subjects. Cortisol responses to ACTH1-24 were also higher in the women with PTSD, while progesterone levels and responses were not different among the three groups. In addition, among the PTSD subjects, the peak change in DHEA in response to ACTH1-24 was negatively correlated with the total Clinician Administered PTSD Scale score, while the peak DHEA to cortisol ratio was inversely associated with negative mood symptoms measured by the Profile of Mood States scale. This work suggests that an increased capacity for DHEA release in response to extreme adrenal activation may influence the pattern of HPA axis adaptation to extreme stress, as well as mitigate the severity of PTSD and negative mood symptoms in premenopausal women with PTSD.

Total lymphocyte count, hemoglobin, and delayed-type hypersensitivity as predictors of death and AIDS illness in HIV-1-infected women receiving highly active antiretroviral therapy.

BACKGROUND: Total lymphocyte count (TLC) and hemoglobin level have been suggested as useful and inexpensive parameters to indicate need for HAART in settings in which CD4 cell counts are unavailable. If delayed-type hypersensitivity (DTH) response predicts clinical response in persons using highly active antiretroviral therapy (HAART), it may also prove useful in resource-poor settings. OBJECTIVE: To examine whether TLC, hemoglobin, and DTH response observed prior to initiation of HAART predict post-HAART clinical response. DESIGN: Prospective cohort study. PARTICIPANTS: 873 women in the Women's Interagency HIV Study. MEASUREMENTS: TLC, hemoglobin, CD4 cell counts, and DTH testing using mumps, candida, and tetanus toxoid antigens, performed within 1 year prior to HAART initiation; death; self-report of initiation of HAART use and AIDS-defining illness (ADI). RESULTS: Three different multivariate analyses were performed: 2 models that excluded CD4 cell count and assessed TLC at either < 850 or < 1250 cells/microL, and 1 model that excluded TLC and included CD4 < 200 cells/microL. TLC < 850, TLC < 1250, CD4 < 200 cells/microL, anergy to DTH testing, hemoglobin < 10.6 g/dL, and a pre-HAART report of ADI were each consistently independently associated both with death and with incident ADI. Log likelihood chi2 values suggested similar power among the 3 models in predicting both death and incident ADI. CONCLUSIONS: Pre-HAART TLC, hemoglobin level, anergy to DTH testing, and clinical disease each independently predicted morbidity and death after HAART initiation. These findings support the use of TLC to guide decision-making for HAART initiation and suggest that further study of TLC, hemoglobin level, and DTH responses as an indication to provide HAART may be useful in resource-limited settings.

Application of gene expression profiling to colon cell maturation, transformation and chemoprevention.

Methods for high-throughput analysis of profiles of gene expression that assay thousands of genes simultaneously are powerful approaches for understanding and classifying cell and tissue phenotype. This includes analysis of normal pathways of cell maturation and their perturbation in transformation, the sensitivity and mechanism of response of normal and tumor cells to physiological and pharmacological agents, and modulation of tumor risk and progression by nutritional factors. However, the complex data generated by such approaches raise difficulties in analysis. We will describe some of the methods we have used in analyzing databases generated in a number of projects in our laboratories. These include: the role of k-ras mutations in colon cell transformation; the role of p21(WAF1/cip1) in intestinal tumor formation and response to sulindac; the development of the absorptive and goblet cell lineages; sensitivity of colonic cells to chemotherapeutic agents; mechanisms that regulate c-myc expression utilizing novel methods of transcriptional imaging; and interaction of nutritional and genetic factors in modulation of intestinal tumor formation.

Basement membrane biomarkers in very low birth weight premature infants. Association with length of NICU stay and bronchopulmonary dysplasia.

Basement membranes, critical for vital organs like the lungs, consist of two interwoven homopolymers, one assembled by type IV collagens and one by laminins. We hypothesized their serum antigens C-IV and P1, respectively, to be global measures for the maturity of these organs. In 39 very low birth weight premature neonates (means: gestational age, 25.8 weeks; birth weight, 779 g) requiring intensive care, we analyzed these biomarkers during the first two months post partum. Median C-IV and P1 exceeded adult levels by one order of magnitude. The individuals with the lowest first week C-IV values (mean: 667 ng/ml) required significantly longer neonatal intensive care unit stays than those with the highest values (mean: 2,467 ng/ml), on average 109 vs. 80 days (p = 0.008) irrespective of gestational age. Patients diagnosed with bronchopulmonary dysplasia (BPD) at 36 weeks postconceptional age, already in their first week of life displayed C-IV levels lower than in controls, suggesting a defect in pulmonary basement membrane remodeling. This is the first identification by a matrix biomarker of a BPD-antecedent state.