Publications

We assessed risk of transmission among 4,016 HIV-infected patients in primary care, including men who have sex with men (MSM, n = 2,109), women (n = 1,104) and men who had sex with women (MSW, n = 803) in clinics in 15 cities across the U.S. A transmission risk act, assessed by computer assisted interviews, was defined as unprotected vaginal or anal sex with a partner who was HIV-uninfected or of unknown HIV status. MSM were more than twice as likely to report transmission risk acts than MSW (Odds Ratio [OR] = 2.35; 95% Confidence Interval [CI] = 1.84, 3.00; P < or = .001). Women were also more likely to report transmission risk acts than MSW (OR = 1.56; 95% CI = 1.19, 2.05; P < or = .001). Stimulant use was associated with transmission risk in all three groups (P < or = .05). MSM were more likely to use methamphetamines (8% versus 2% and 3% respectively), while MSW (17%) and women (12%, compared to 11% for MSM) were more likely to use cocaine. Clinical settings offer opportunities for preventing HIV transmission, particularly if interventions are tailored to sub-populations of HIV-infected patients.

OBJECTIVES

The objective of this study was to investigate the antimicrobial activity and specificity of globomycin, an inhibitor of lipoprotein signal peptidase II (LspA), against Mycobacterium tuberculosis.

METHODS

The mycobactericidal and mycobacteriostatic activity of globomycin was determined by optical density and cfu plating. The specificity of globomycin was determined by western immunoblotting using anti-MPT83 antibody.

RESULTS

Globomycin is mycobactericidal at concentrations>or=40 mg/L. However, at 80 mg/L, the processing of the lipoprotein MPT-83 is unaffected and growth-inhibitory effect of globomycin is unchanged in an lspA null mutant (DeltalspA::lspAmut) lacking the putative drug target.

CONCLUSIONS

Globomycin kills M. tuberculosis through a mechanism that is independent of LspA.

Estimating the prevalence of asthma is an epidemiologic challenge, particularly in rural areas of lesser-developed countries characterized by low literacy and poor access to health care. To avoid under or over reporting of symptoms, questionnaires must use terminology familiar to participants and that accurately describes the triad of cough, wheeze and breathlessness characteristic of asthma. In preparation for a large longitudinal cohort study entitled Chronic Respiratory Effects of Early Childhood Exposure to Respirable Particulate Matter (CRECER) that will examine the effects of variable early lifetime woodsmoke exposure on the respiratory health of Mam-speaking children residing in communities in the western highlands of Guatemala, we conducted individual interviews (n=18) and five focus groups (n=46) with indigenous women from 17 of these communities to elicit and define local Mam and Spanish terms for common respiratory symptoms used to describe their own and their children's respiratory symptoms. Focus group participants were also shown an International Study of Asthma and Allergies in Childhood (ISAAC) video of wheezing children and adults. We developed a conceptual framework that can be used as an efficient model for future studies investigating health and/or disease terminology in isolated communities, an integral step in the development of standardized questionnaires. Among this Mam-speaking population, wheeze was best described as nxwisen or ntzarrin, "breathing sounds that are heard in the neck but come from the chest." The variation in understanding of terms between women with and without children with a history of wheeze (such that for those without wheezing children some terms were virtually unrecognized), has important implications for large-scale population surveys within countries and comparative surveys such as ISAAC. It is important to use linguistically and culturally appropriate terminology to describe wheeze in prevalence studies of asthmatic symptoms among relatively isolated communities in lesser-developed countries.

Guiding multipotent cells into distinct lineages and controlling their expansion remain fundamental challenges in developmental and stem cell biology. Members of the Wnt pathway control many pivotal embryonic events, often promoting self-renewal or expansion of progenitor cells. In contrast, canonical Wnt ligands are thought to negatively regulate cardiomyogenesis in several species. However, the cell-autonomous role of canonical Wnt signaling within precardiac mesoderm, through its obligatory transcriptional mediator, beta-catenin, is unknown. Using tissue-specific in vivo genetic manipulation, we found that beta-catenin is required for development of cardiac progenitors and is a positive regulator of proliferative expansion of such progenitor cells. At discrete windows of development in embryonic stem cells, activation of canonical Wnt signaling promoted expansion of cardiac progenitors after initial commitment and was required for cardiac differentiation. Together, these data provide in vivo and in vitro evidence that canonical Wnt signaling promotes the expansion of cardiac progenitors and differentiation of cardiomyocytes.

Vacuolar proton-translocating ATPases (V-ATPases) are a family of highly conserved proton pumps that couple hydrolysis of cytosolic ATP to proton transport out of the cytosol. Although V-ATPases are involved in a number of cellular processes, how the proton pumps are regulated under physiological conditions is not well understood. We have reported that the glycolytic enzyme aldolase mediates V-ATPase assembly and activity by physical association with the proton pump (Lu, M., Holliday, L. S., Zhang, L., Dunn, W. A., and Gluck, S. L. (2001) J. Biol. Chem. 276, 30407-30413 and Lu, M., Sautin, Y., Holliday, L. S., and Gluck, S. L. (2004) J. Biol. Chem. 279, 8732-8739). In this study, we generate aldolase mutants that lack binding to the B subunit of V-ATPase but retain normal catalytic activities. Functional analysis of the aldolase mutants shows that disruption of binding between aldolase and the B subunit of V-ATPase results in disassembly and malfunction of V-ATPase. In contrast, aldolase enzymatic activity is not required for V-ATPase assembly. Taken together, these findings strongly suggest an important role for physical association between aldolase and V-ATPase in the regulation of the proton pump.

Hepatic tissue engineering using primary hepatocytes has been considered a valuable new therapeutic modality for several classes of liver diseases. Recent progress in the development of clinically feasible liver tissue engineering approaches, however, has been hampered mainly by insufficient cell-to-cell contact of the engrafted hepatocytes. We developed a method to engineer a uniformly continuous sheet of hepatic tissue using isolated primary hepatocytes cultured on temperature-responsive surfaces. Sheets of hepatic tissue transplanted into the subcutaneous space resulted in efficient engraftment to the surrounding cells, with the formation of two-dimensional hepatic tissues that stably persisted for longer than 200 d. The engineered hepatic tissues also showed several characteristics of liver-specific functionality. Additionally, when the hepatic tissue sheets were layered in vivo, three-dimensional miniature liver systems having persistent survivability could be also engineered. This technology for liver tissue engineering is simple, minimally invasive and free of potentially immunogenic biodegradable scaffolds.

Ciguatoxins (CTX) are a suite of cyclic polyether toxins produced by the marine dinoflagellate Gambierdiscus sp., are potent activators of voltage-gated sodium channels and a leading cause of human poisoning from food fish. This report characterizes the genomic and proteomic response in whole blood of adult male mice exposed i.p. to 264 ng/kg of the Pacific congener of CTX (P-CTX-1) at 1, 4 and 24h. Whole genome microarray expression data were filtered by tightness of fit between replicates, fold change (1.8) and p-value (10(-5)), resulting in 183 annotated genes used for trending analysis, K-means clustering and ontology classification. Genes involved with cytokine signaling, proteasome complex and ribosomal function were dominant. qPCR performed on 19 genes of interest had a correlation of 0.95 to array results by Pearson's correlation coefficient. Serum protein analysis showed small but significant changes in 6 of 60 proteins assayed: Ccl2, Ccl12, CD40, IL-10, leptin and M-CSF. In large part, the gene expression was consistent with a Th2 immune response with interesting similarities to expression seen in asthmatic models.