Trends in cancer diagnoses and survival among persons with AIDS in a high HIV prevalence urban area.

Washington, DC (DC), has among the highest AIDS prevalence and cancer incidence in the USA. This study compared cancer diagnoses and survival among AIDS cases with AIDS-defining cancers (ADCs) to those with non-AIDS-defining cancers (NADCs) in DC from 1996 to 2006. Survival by cancer type and time period was also examined for 300 individuals diagnosed with AIDS who developed cancer; 49% of AIDS cases developed an ADC. ADC cases were younger at both AIDS and cancer diagnosis and had significantly lower median CD4 counts at AIDS diagnosis than NADC cases. The most frequent cancers were non-Hodgkin lymphoma (NHL; 44% of ADC), Kaposi's sarcoma (40% of ADC), and lung cancer (20% of NADC). There was no significant difference in distribution of cancers when comparing ADCs to NADCs, or over time (1996-2001 vs. 2002-2006). Survival among NHL, oral cavity, and lung cancer cases was 0.4, 0.8, and 0.3 years, respectively; the risk of death was approximately two times higher for each of these cancers when compared to other cancers. Given the high burden of cancer and HIV in DC, early highly active antiretroviral therapy initiation, routine cancer screening, and risk reduction through behavioral modification should be emphasized to prevent cancer among HIV-infected persons.

HIV testing among heterosexuals at elevated risk for HIV in the District of Columbia: has anything changed over time?

The District of Columbia launched a routine HIV testing initiative in 2006. We examined HIV testing behaviors among heterosexuals at risk for HIV over time using CDC National HIV Behavioral Surveillance data from Washington, DC for the heterosexual cycles from 2006 to 2007 (Cycle 1) and 2010 (Cycle 2). Past year and past 2-year HIV testing across study cycles were compared using Chi square tests. Weighted multivariable logistic regression identified correlates of past year testing. The majority of participants across both cycles were black and female. Cycle 1 participants were significantly more likely to have ≥4 partners in the past year, casual sex partners, and have anal sex at last sexual encounter (p < 0.05). Lifetime testing was high, and individuals from Cycle 2 versus Cycle 1 were more likely to have been tested in the past 2 years. There were no significant differences in past year testing or being offered the HIV test at last health care visit by cycle. Independent correlates of past year testing were seeing a health care provider in the past year and using condoms at last vaginal sex. In conclusion, although past year testing did not differ between the two data collection years, the proportion of heterosexuals testing in the past 2 years was higher in Cycle 2 versus Cycle 1, suggesting successful expansion of HIV testing between the two time periods.

Site migration in seeking care services from multiple providers is associated with worse clinical outcomes among HIV-infected individuals in Washington, DC.

Washington, DC, is a metropolitan city with a severe HIV epidemic and faces challenges in retaining people living with HIV (PLWH) in quality care. This study assessed site migration in seeking care services and its correlates among PLWH in DC. PLWH diagnosed before 2008 and living through the end of 2010 were analyzed. Six scenarios of site migration were examined as patients visited =2, =3, and =4 different providers for their CD4 cell count and/or viral load (VL) tests in the past 3 years from 2008 to 2010 and 2 years from 2009 to 2010, respectively. Of 6480 patients analyzed from 2008 to 2010, 18.4% had CD4 < 200 cells/mm(3), 30.5% had VL > 400 copies/mL, and 76.6% were retained in same care sites; 23.4%, 5.0%, and 0.9% visited =2, =3, and =4 sites in the past 3 years from 2008 to 2010, respectively. Of 5954 patients analyzed from 2009 to 2010, 16.8% had CD4 < 200 cells/mm(3), 29.4% had VL > 400 copies/mL, and 81.9% were retained in same care sites; 18.1%, 3.1%, and 0.6% visited =2, =3, and =4 sites in the past 2 years from 2009 to 2010, respectively. Multivariable logistic regression analyses revealed that migration across six scenarios are consistently associated with CD4 < 200 cells/mm(3) and VL > 400 copies/mL. Site migration was common and associated with lower CD4 and higher VL among PLWH in DC. Frequent migration might be a factor in achieving optimal health outcomes for a subset of patients. Site migration might potentially limit effective delivery of high quality care and treatment services. The preliminary findings underscore the need for further research to assess the predictors of migration and its impact on stage of care.

Temporal association between expanded HIV testing and improvements in population-based HIV/AIDS clinical outcomes, District of Columbia.

In 2006, the District of Columbia Department of Health (DC DOH) launched initiatives promoting routine HIV testing and improved linkage to care in support of revised the Centers for Disease Control and Prevention (CDC) HIV-testing guidelines. An ecological analysis was conducted using population-based surveillance data to determine whether these efforts were temporally associated with increased and earlier identification of HIV/AIDS cases and improved linkages to care. Publically funded HIV-testing data and HIV/AIDS surveillance data from 2005 to 2009 were used to measure the number of persons tested, new diagnoses, timing of entry into care, CD4 at diagnosis and rates of progression to AIDS. Tests for trend were used to determine whether statistically significant changes in these indicators were observed over the five-year period. Results indicated that from 2005 to 2009, publically funded testing increased 4.5-fold; the number of newly diagnosed HIV/AIDS cases remained relatively constant. Statistically significant increases in the proportion of cases entering care within three months of diagnosis were observed (p < 0.0001). Median CD4 counts at diagnosis increased over the five-year time period from 346 to 379 cells/µL. The proportion of cases progressing from HIV to AIDS and diagnosed with AIDS initially, decreased significantly (both p < 0.0001). Routine HIV testing and linkage to care efforts in the District of Columbia were temporally associated with earlier diagnoses of cases, more timely entry into HIV-specialized care, and a slowing of HIV disease progression. The continued use of surveillance data to measure the community-level impact of other programmatic initiatives including test and treat strategies will be critical in monitoring the response to the District's HIV epidemic.

Child advocacy center based group treatment for child sexual abuse.

The present study examines initial symptom presentation among participants, outcomes, and social validity for a group treatment for child sexual abuse delivered at a child advocacy center. Participants were 97 children and their nonoffending caregivers who were referred to Project SAFE (Sexual Abuse Family Education), a standardized, 12-week cognitive-behavioral group treatment for families who have experienced child sexual abuse. Sixty-four percent of children presented with clinically significant symptoms on at least one measure with established clinical cutoffs. Caregivers of children who presented with clinically significant symptoms reported more distress about their competence as caregivers. Children who presented as subclinical were more likely to have experienced intrafamilial sexual abuse. Posttreatment results indicated significant improvements in functioning for all children who participated in treatment, with greater improvements reported for children who initially presented with clinically significant symptoms. Overall, the program was rated favorably on the posttreatment evaluation of social validity.

Cost-utility analysis of a female condom promotion program in Washington, DC.

A retrospective economic evaluation of a female condom distribution and education program in Washington, DC. was conducted. Standard methods of cost, threshold and cost-utility analysis were utilized as recommended by the U.S. Panel on cost-effectiveness in health and medicine. The overall cost of the program that distributed 200,000 female condoms and provided educational services was $414,186 (at a total gross cost per condom used during sex of $3.19, including educational services). The number of HIV infections that would have to be averted in order for the program to be cost-saving was 1.13 in the societal perspective and 1.50 in the public sector payor perspective. The cost-effectiveness threshold of HIV infections to be averted was 0.46. Overall, mathematical modeling analyses estimated that the intervention averted approximately 23 HIV infections (even with the uncertainty inherent in this estimate, this value appears to well exceed the necessary thresholds), and the intervention resulted in a substantial net cost savings.

trans-10,cis-12-Conjugated linoleic acid instigates inflammation in human adipocytes compared with preadipocytes.

We showed previously in cultures of primary human adipocytes and preadipocytes that lipopolysaccharide and trans-10,cis-12-conjugated linoleic acid (10,12-CLA) activate the inflammatory signaling that promotes insulin resistance. Because our published data demonstrated that preadipocytes are the primary instigators of inflammatory signaling in lipopolysaccharide-treated cultures, we hypothesized that they played the same role in 10,12-CLA-mediated inflammation. To test this hypothesis, we employed four distinct models. In model 1, a differentiation model, CLA activation of MAPK and induction of interleukin-8 (IL-8), IL-6, IL-1beta, and cyclo-oxygenase-2 (COX-2) were greatest in differentiated compared with undifferentiated cultures. In model 2, a cell separation model, the mRNA levels of these inflammatory proteins were increased by 10,12-CLA compared with bovine serum albumin vehicle in the adipocyte fraction and the preadipocyte fraction. In model 3, a co-culture insert model, inserts containing approximately 50% adipocytes (AD50) or approximately 100% preadipocytes (AD0) were suspended over wells containing AD50 or AD0 cultures. 10,12-CLA-induced IL-8, IL-6, IL-1beta, and COX-2 mRNA levels were highest in AD50 cultures when co-cultured with AD0 inserts. In model 4, a conditioned medium (CM) model, CM collected from CLA-treated AD50 but not AD0 cultures induced IL-8 and IL-6 mRNA levels and activated phosphorylation of MAPK in naive AD0 and AD50 cultures. Consistent with these data, 10,12-CLA-mediated secretions of IL-8 and IL-6 from AD50 cultures were higher than from AD0 cultures. Notably, blocking adipocytokine secretion prevented the inflammatory capacity of CM from 10,12-CLA-treated cultures. These data suggest that CLA instigates the release of inflammatory signals from adipocytes that subsequently activate adjacent preadipocytes.

Probing platinum-adenine-n3 adduct formation with DNA minor-groove binding agents.

Me-lex(py/py), an adenine-N3-selective alkylating agent, and the reversible minor-groove binder netropsin were used to probe the formation of unusual minor-groove adducts by the cytotoxic hybrid agent PT-ACRAMTU ([PtCl(en)(ACRAMTU)](NO(3))(2); en = ethane-1,2-diamine, ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea). PT-ACRAMTU was found by chemical footprinting to inhibit specific Me-lex-mediated DNA cleavage at several adenine sites but not at nonspecific guanine, which is consistent with the platination of adenine-N3. In a cell proliferation assay, a significant decrease in cytotoxicity was observed for PT-ACRAMTU, when cancer cells were pretreated with netropsin, suggesting that minor-groove adducts in cellular DNA contribute to the biological activity of the hybrid agent.

Xanthones from mangosteen prevent lipopolysaccharide-mediated inflammation and insulin resistance in primary cultures of human adipocytes.

The xanthones, alpha- and gamma-mangostin (MG), are major bioactive compounds found in mangosteen and are reported to have antiinflammatory properties in several murine models. Given the association between obesity, chronic low-grade inflammation, and insulin resistance, we examined the effects of alpha- and gamma-MG on markers of inflammation and insulin resistance in primary cultures of newly differentiated human adipocytes treated with lipopolysaccharide (LPS). alpha- and gamma-MG decreased the induction by LPS of inflammatory genes, including tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, IL-8, monocyte chemoattractant protein-1, and Toll-like receptor-2. Moreover, alpha- and gamma-MG attenuated LPS activation of the mitogen-activated protein kinases (MAPK) c-jun NH(2)-terminal kinase, extracellular signal-related kinase, and p38. alpha- and gamma-MG also attenuated LPS activation of c-Jun and activator protein (AP)-1 activity. gamma-MG was more effective than alpha-MG on an equimolar basis. Furthermore, gamma-MG but not alpha-MG attenuated LPS-mediated IkappaB-alpha degradation and nuclear factor-kappaB (NF-kappaB) activity. In addition, gamma-MG prevented the suppression by LPS of insulin-stimulated glucose uptake and PPAR-gamma and adiponectin gene expression. Taken together, these data demonstrate that MG attenuates LPS-mediated inflammation and insulin resistance in human adipocytes, possibly by inhibiting the activation of MAPK, NF-kappaB, and AP-1.

Autobiographical narratives of deaf and hearing adults: an examination of narrative coherence and the use of internal states.

To examine the impact of early linguistic experiences on later verbal report of autobiographical memory, 13 hearing adults and 13 deaf adults born to hearing parents described events that occurred before and after the age of 10 years. The contextual, temporal, and thematic coherence of the narratives was rated. The use of emotional, perceptual, mental, and physiological states was also recorded. There were differences in the coherence of the narratives and use of internal states according to the age at which the events occurred. There were no group differences in coherence, but hearing adults provided longer narratives than deaf adults. When narrative length was controlled, deaf adults included more emotional states than hearing adults. Results suggest that early unavailability of language does not impact the coherence of adults' narratives, although certain features of linguistic expression specific to ASL may result in greater saturation of emotional states references in autobiographical narratives of deaf adults.

Diagnoses of human immunodeficiency virus (HIV) infection among foreign-born persons living in the District of Columbia.

This study characterizes available surveillance data for HIV infected foreign-born residents in the District of Columbia (DC) to inform local HIV prevention and care efforts. HIV surveillance data were reviewed for adults and adolescents (ages ≥13 years) living with HIV in 2008. Variables analyzed included demographics, region of origin (for persons born outside of the U.S.), insurance coverage, linkage to and continuous HIV care. Of the 16,513 DC residents living with HIV diagnoses, 1,391 (8.4%) were foreign-born. Of foreign-born infected, 71.9% were male; 33.3% were from Africa and 20.8% from Central America; 80.6% were exposed through sex; 36.3% had health coverage at diagnosis. While 100% of foreign-born persons had documented linkage to HIV care, only 18.0% had documentation of continued HIV care. These data suggest that strengthening continuous HIV care support after successful care linkage is warranted for foreign-born persons living with HIV in DC.

Psychosocial stressors and health behaviors: examining sleep, sedentary behaviors, and physical activity in a low-income pediatric sample.

OBJECTIVE: To better understand the relationship between psychosocial stressors and health behaviors in a low-income pediatric sample. METHOD: Participants were 122 children (8-11 years old, 53.3% female) and their parents recruited from a low-income primary care clinic. Measures assessed child stressors and parental financial strain, and child sleep problems, sedentary behaviors, and physical activity. RESULTS: Parental financial strain and child stressors were independently associated with sleep problems and sedentary behaviors, controlling for age and gender. Though stressors in general accounted for significant variance in physical activity, results indicate a complex relationship as parental financial strain predicted more physical activity and child stressors predicted less physical activity. CONCLUSION: Stressors are associated with adverse pediatric health behaviors. Consequently, chronic stressors could negatively affect long-term health, and interventions targeting stressors and health behaviors are indicated. Pediatric health care providers play a key role in promoting health behaviors among youth experiencing significant psychosocial stressors.

Synthesis, aqueous reactivity, and biological evaluation of carboxylic acid ester-functionalized platinum-acridine hybrid anticancer agents.

The synthesis of platinum-acridine hybrid agents containing carboxylic acid ester groups is described. The most active derivatives and the unmodified parent compounds showed up to 6-fold higher activity in ovarian cancer (OVCAR-3) and breast cancer (MCF-7, MDA-MB-231) cell lines than cisplatin. Inhibition of cell proliferation at nanomolar concentrations was observed in pancreatic (PANC-1) and nonsmall cell lung cancer cells (NSCLC, NCI-H460) of 80- and 150-fold, respectively. Introduction of the ester groups did not affect the cytotoxic properties of the hybrids, which form the same monofunctional-intercalative DNA adducts as the parent compounds, as demonstrated in a plasmid unwinding assay. In-line high-performance liquid chromatography and electrospray mass spectrometry (LC-ESMS) shows that the ester moieties undergo platinum-mediated hydrolysis in a chloride concentration-dependent manner to form carboxylate chelates. Potential applications of the chloride-sensitive ester hydrolysis as a self-immolative release mechanism for tumor-selective delivery of platinum-acridines are discussed.

Use of the community viral load as a population-based biomarker of HIV burden.

OBJECTIVES: Recent data suggest that community viral load (CVL) can be used as a population-level biomarker for HIV transmission and its reduction may be associated with a decrease in HIV incidence. Given the magnitude of the HIV epidemic in Washington, District of Columbia, we sought to measure the District of Columbia's CVL. DESIGN: An ecological analysis was conducted. METHODS: Mean and total CVL were calculated using the most recent viral load for prevalent HIV/AIDS cases reported to District of Columbia HIV/AIDS surveillance through 2008. Univariate and multivariable analyses were conducted to assess differences in CVL availability, mean CVL, proportion of undetectable viral loads, and 5-year trends in mean CVL and new HIV/AIDS diagnoses. Geospatial analysis was used to map mean CVL and selected indicators of socioeconomic status by geopolitical designation. RESULTS: Among 15,467 HIV/AIDS cases alive from 2004 to 2008, 48.2% had at least one viral load reported. Viral load data completeness increased significantly over the 5 years (P < 0.001). Mean CVL significantly decreased over time (P < 0.0001). At the end of 2008, the mean CVL was 33,847 copies/ml; 57.4% of cases had undetectable viral loads. Overlaps in the geographic distribution of CVL by census tract were observed with the highest means observed in areas with high poverty rates and low high school diploma rates. CONCLUSION: Mean and total CVL provide markers of access to care and treatment, are indicators of the population's viral burden, and are useful in assessing trends in local HIV/AIDS epidemics. Measurement of CVL is a novel tool for assessing the potential impact of population-level HIV prevention and treatment interventions.

Implementing a novel citywide rapid HIV testing campaign in Washington, D.C.: findings and lessons learned.

OBJECTIVES: In June 2006, the District of Columbia (DC) Department of Health launched a citywide rapid HIV screening campaign. Goals included raising HIV awareness, routinizing rapid HIV screening, identifying previously unrecognized infections, and linking positives to care. We describe findings from this seminal campaign and identify lessons learned. METHODS: We applied a mixed-methods approach using quantitative analysis of client data forms (CDFs) and qualitative evaluation of focus groups with DC residents. We measured characteristics and factors associated with client demographics, test results, and community perceptions regarding the campaign. RESULTS: Data were available on 38,586 participants tested from July 2006 to September 2007. Of those, 68% had previously tested for HIV (44% within the last 12 months) and 23% would not have sought testing had it not been offered. Overall, 662 (1.7%) participants screened positive on the OraQuick® Advance™ rapid HIV test, with non-Hispanic black people, transgenders, and first-time testers being significantly more likely to screen positive for HIV than white people, males, and those tested within the last year, respectively. Of those screening positive for HIV, 47% had documented referrals for HIV care and treatment services. Focus groups reported continued stigma regarding HIV and minimal community saturation of the campaign. CONCLUSIONS: This widespread campaign tested thousands of people and identified hundreds of HIV-infected individuals; however, referrals to care were lower than anticipated, and awareness of the campaign was limited. Lessons learned through this scale-up of population-based HIV screening resulted in establishing citywide HIV testing processes that laid the foundation for the implementation of test-and-treat activities in DC.

Unusual Reactivity of a Potent Platinum-Acridine Hybrid Antitumor Agent.

The formation of unusual seven-membered, sterically overloaded chelates [Pt(en)(L/L´)](NO(3))(2) (4a/4b) from the corresponding potent hybrid antitumor agents [PtCl(en)(LH/L´H)](NO(3))(2) (3a/3b) is described, where en is ethane-1,2-diamine and L(H) and L´(H) are (protonated) N-(2-(acridin-9-ylamino)ethyl)-N-methylpropionimidamide and N-(2-(acridin-9-ylamino)ethyl)-N-methylacetimidamide, respectively. Compounds 3a and 3b inhibit H460 lung cancer cell proliferation with IC(50) values of 12 ± 2 nM and 2.8 ± 0.3 nM, respectively. The new derivative 3b proves to be not only the most cytotoxic platinum-acridine hybrid of this kind, but also one of the most potent platinum-based anticancer agents described to date. The chelates 4a and 4b do not undergo ligand substitution reactions with nucleobase nitrogen and cysteine sulfur and do not intercalate into DNA. Despite their inertness, the two chelates appear to maintain micromolar activity in H460 cells. The results are discussed in the context of potential DNA-mediated and DNA-independent cell kill mechanisms and the potential use of the chelates as prodrugs.

Grape powder extract attenuates tumor necrosis factor α-mediated inflammation and insulin resistance in primary cultures of human adipocytes.

Grapes are rich in phenolic phytochemicals that possess anti-oxidant and anti-inflammatory properties. However, the ability of grape powder extract (GPE) to prevent inflammation and insulin resistance in human adipocytes caused by tumor necrosis factor α (TNFα), a cytokine elevated in plasma and white adipose tissue (WAT) of obese, diabetic individuals, is unknown. Therefore, we examined the effects of GPE on markers of inflammation and insulin resistance in primary cultures of newly differentiated human adipocytes treated with TNFα. We found that GPE attenuated TNFα-induced expression of inflammatory genes including interleukin (IL)-6, IL-1ß, IL-8, monocyte chemoattractant protein (MCP)-1, cyclooxygenase (COX)-2 and Toll-like receptor (TLR)-2. GPE attenuated TNFα-mediated activation of extracellular signal-related kinase (ERK) and c-Jun NH(2)-terminal kinase (JNK) and activator protein-1 (AP-1, i.e., c-Jun). GPE also attenuated TNFα-mediated IκBα degradation and nuclear factor-kappa B (NF-κB) activity. Finally, GPE prevented TNFα-induced expression of protein tyrosine phosphatase (PTP)-1B and phosphorylation of serine residue 307 of insulin receptor substrate-1 (IRS-1), which are negative regulators of insulin sensitivity, and suppression of insulin-stimulated glucose uptake. Taken together, these data demonstrate that GPE attenuates TNFα-mediated inflammation and insulin resistance in human adipocytes, possibly by suppressing the activation of ERK, JNK, c-Jun and NF-κB.

Conjugated linoleic acid-mediated inflammation and insulin resistance in human adipocytes are attenuated by resveratrol.

Inflammation plays a role in trans-10, cis-12 (10,12)-conjugated linoleic acid (CLA)-mediated delipidation and insulin resistance in adipocytes. Given the anti-inflammatory role of resveratrol (RSV), we hypothesized that RSV would attenuate inflammation and insulin resistance caused by 10,12 CLA in human adipocytes. RSV blocked 10,12 CLA induction of the inflammatory response by preventing activation of extracellular signal-related kinase and induction of inflammatory gene expression (i.e., IL-6, IL-8, IL-1beta) within 12 h. Similarly, RSV suppressed 10,12 CLA-mediated activation of the inflammatory prostaglandin pathway involving phospholipase A(2), cyclooxygenase-2, and PGF(2alpha). In addition, RSV attenuated 10,12 CLA increase of intracellular calcium and reactive oxygen species associated with cellular stress, and activation of stress-related proteins (i.e., activating transcription factor 3, JNK) within 12 h. 10,12 CLA-mediated insulin resistance and suppression of fatty acid uptake and triglyceride content were attenuated by RSV. Finally, 10,12 CLA-mediated decrease of peroxisome proliferator-activated receptor gamma (PPARgamma) protein levels and activation of a peroxisome proliferator response element (PPRE) reporter were prevented by RSV. RSV increased the basal activity of PPRE, suggesting that RSV increases PPARgamma activity. Collectively, these data demonstrate for the first time that RSV prevents 10,12 CLA-mediated insulin resistance and delipidation in human adipocytes by attenuating inflammation and cellular stress and increasing PPARgamma activity.

Major allergen measurements: sources of variability, validation, quality assurance, and utility for laboratories, manufacturers, and clinics.

The isolation and characterization of prominent allergenic proteins or glycoproteins is an important step in the development of allergenic extracts exhibiting improved definition, consistency, and clinical utility. Quantitative analyses specific for major allergenic components currently are being performed in numerous corporate and academic laboratories but have not been validated within or across laboratories in a systematic manner. In our laboratory, validation of double-bind (sandwich) ELISA assays for a diverse group of major allergens or extract components revealed a number of critical assay variables and reagent incubation conditions that directly influenced the precision, accuracy, specificity, and robustness of these tests. Data from ELISA methods for six allergens (Dermatophagoides farinae Der f 1, Alternaria Alt a 1, dog albumin, dog Can f 1, fire ant Sol i 3, and yellow jacket venom Ves 5) showed that up to twofold differences in results were observed when analysts or microplates were varied. Analyses of dog allergens using multiple reagents and concentrations indicated that twofold variations in results also can be produced by distinct combinations of materials or incubations from different assay steps. Data from Can f 1 and egg white analyses produced up to fivefold differences in antigen concentrations based on changes in the capture antibody source (mouse monoclonal versus rabbit polyclonal) or storage buffer. These results suggest that differences in major allergen concentrations reported by different testing laboratories may be related to assay differences as well as extract variations and raise questions as to the accuracy of major allergen concentrations and therapeutic dose recommendations reported at regional and national allergy meetings. Validated double-bind ELISA methods may be well suited for consistency monitoring and standardization of extracts provided that reference materials, reagent qualifications, and interlaboratory comparability are defined precisely.