Faculty Bibliography

Background. The morbidity and mortality associated with malaria are heightened because of the spread of drug-resistant parasites and the lack of an effective vaccine. Plasmodium liver stages are the targets of new chemotherapeutics and vaccines, but there are limited tools available to study this stage in vivo. Methods. To overcome this obstacle, we developed a method with which to study Plasmodium liver stages by means of bioluminescent imaging (BLI) of the rodent malaria parasite Plasmodium yoelii. We created a P. yoelii YM strain (PyLuc) that stably expresses firefly luciferase driven by a constitutive promoter. Results. Using BLI, we performed imaging of the Plasmodium liver stages of mice infected with PyLuc sporozoites and monitored parasite dissemination during blood-stage infection. Because PyLuc luciferase activity is proportional to the number of parasites, BLI can be used to quantify the effect of drugs on liver-stage development. Moreover, using BLI, we demonstrated that immunization with blood-stage parasites confers partial protective immunity against the development of liver stages. Conclusions. BLI is a noninvasive technique that is useful for screening potential drugs and candidate vaccines with which to combat malaria. The prospect of cross-stage protective immunity increases the number of avenues to be explored in the development of an effective vaccine against malaria

HIV and malaria have similar global distributions. Annually, 500 million are infected and 1 million die because of malaria. 33 million have HIV and 2 million die from it each year. Minor effects of one infection on the disease course or outcome for the other would significantly impact public health because of the sheer number of people at risk for coinfection. While early population-based studies showed no difference in outcomes between HIV-positive and HIV-negative individuals with malaria, more recent work suggests that those with HIV have more frequent episodes of symptomatic malaria and that malaria increases HIV plasma viral load and decreases CD4+ T cells. HIV and malaria each interact with the host's immune system, resulting in a complex activation of immune cells, and subsequent dysregulated production of cytokines and antibodies. Further investigation of these interactions is needed to better define effects of coinfection.

BACKGROUND: Hormonally active environmental exposures are suspected to alter onset of puberty in girls, but research on this question has been very limited. OBJECTIVE: We investigated pubertal status in relation to hormonally active environmental exposures among a multiethnic group of 192 healthy 9-year-old girls residing in New York City. METHODS: Information was collected on breast and pubic hair stages, weight and height. Phytoestrogen intake was estimated from a food-frequency questionnaire. Three phytoestrogens and bis-phenolA (BPA) were measured in urine. In a subset, 1,1'-dichloro-2,2'-bis(4-chlorophenyl)ethylene (DDE), polychlorinated biphenyls (PCBs) were measured in blood plasma and lead (Pb) in blood. Associations of exposures with pubertal stages (present=stage 2+ vs absent=stage 1) were examined using t-tests and Poisson multivariate regression to derive prevalence ratios (PR, 95%-confidence limits [CI]). RESULTS: Breast development was present in 53% of girls. DDE, Pb, and dietary intakes of phytoestrogens were not significantly associated with breast stage. Urinary phytoestrogen biomarker concentrations were lower among girls with breast development compared with no development. In multivariate models, main effects were strongest for two urinary isoflavones, daidzein (PR 0.89 [0.83-0.96] per ln microg/g creatinine) and genistein (0.94 [0.88-1.01]). Body mass index (BMI) is a hormonally relevant, strong risk factor for breast development. Therefore, BMI-modification of exposure effects was examined, and associations became stronger. Delayed breast development was observed among girls with below-median BMI and third tertile (high exposure) of urinary daidzein (PR 0.46 [0.26-0.78]); a similar effect was seen with genistein, comparing to girls >or= median BMI and lowest two tertiles (combined) of these isoflavones. With urinary enterolactone a phytoestrogen effect was seen only among girls with high BMI, where breast development was delayed among those with high urinary enterolactone (PR 0.55 [0.32-0.96] for the upper tertile vs lower two combined). There was no main effect of PCBs on breast stage, but girls with below-median BMI and >or= median PCB levels had reduced risk for breast development (any vs none) compared with other BMI-PCB groups. No biomarkers were associated with hair development, which was present in 31% of girls. CONCLUSIONS: Phytoestrogens and PCBs are environmental exposures that may delay breast development, especially in conjunction with BMI, which governs the endogenous hormonal milieu. Further research to confirm these findings may improve our understanding of the role of early life development in breast cancer risk and other chronic diseases related to obesity.

PURPOSE: Early age at menarche increases future disease risk. Secular decline in age at menarche has been attributed to body size characteristics, diet, and energy expenditure. Risk factors for puberty have been less frequently explored. METHODS: A cross-sectional study of 186 New York Metropolitan Area, 9-year-old girls (54 African-American, 70 Hispanic, 62 Caucasians) used interviewer-administered questionnaires to assess exposures. Height and weight were measured. Pediatricians assessed pubertal development according to Tanner stages. RESULTS: African-Americans were more likely than Caucasians to have achieved puberty as determined by breast or hair development (stage 2 or higher) [age-adjusted odds ratios and 95% confidence intervals = 4.91 (2.15-11.19) and 4.25 (1.85-9.77), respectively]. Pubertal development was similar among Hispanics and Caucasians. Adiposity and height were significantly positively associated with breast or hair development. More sedentary activity hours non-significantly increased the likelihood of hair development. Lower energy, but higher polyunsaturated fat, consumption were suggestive of an association with breast development. Vitamin C and hair development were inversely related. No other nutrients or physical activity measures were related to pubertal development. CONCLUSIONS: Results are consistent with height and adiposity being associated with pubertal development. Sedentary activity or diet might possibly influence maturation.