Increasing access to medical education for students from medically underserved communities: one program's success.

The Premedical Honors College (PHC) is an eight-year, BS-MD program created in 1994 by Baylor College of Medicine (BCM) and The University of Texas-Pan American (UT-PA) to increase the number of physicians addressing the health care needs of underserved populations in Texas. The PHC targets South Texas, a 13-county, medically underserved area with a population that is 82% Hispanic. To date, the PHC has had 159 matriculants and 71 graduates, of whom 60 (84.5%) have matriculated into medical school. These results are significant considering that in 1996, only four students from all five South Texas colleges (combined enrollment of 30000 students) were accepted to medical school. An outcomes study comparing PHC matriculants with students of similar academic ability, ethnicity, and interest in medicine revealed that the odds of medical school matriculation were seven times higher for PHC students than for non-PHC students. The PHC's initial success has been acknowledged by the Texas legislature, which recently passed a bill to promote the PHC's replication. In addition, the number of PHC students-of whom 95% are Mexican American-who matriculate into medical school annually is significant nationally. In 2001, only 386 U.S. medical school matriculants (2.3% of all matriculants) were Mexican American; 17 of these students (4.4%) were PHC graduates. If current trends continue, the PHC could significantly expand the number of physicians serving minority and medically underserved populations in Texas and the nation. Also, the PHC provides an opportunity for research on programs designed to create pathways from high school to medical school.     

Global gene expression and the role of sigma factors in Neisseria gonorrhoeae in interactions with epithelial cells

Like many bacterial pathogens, Neisseria gonorrhoeae must adapt to environmental changes in order to successfully colonize and proliferate in a new host. Modulation of gene expression in response to environmental signals is an efficient mechanism used by bacteria to achieve this goal. Using DNA microarrays and a tissue culture model for gonococcal infection, we examined global changes in gene expression in N. gonorrhoeae in response to adherence to host cells. Among those genes induced upon adherence to human epithelial cells in culture was rpoH, which encodes a homolog of the heat shock sigma factor, sigma(32) (RpoH), as well as genes of the RpoH regulon, groEL and groES. Attempts to construct an rpoH null mutant in N. gonorrhoeae were unsuccessful, suggesting that RpoH is essential for viability of N. gonorrhoeae. The extracytoplasmic sigma factor, RpoE (sigma(E)), while known to regulate rpoH in other bacteria, was found not to be necessary for the up-regulation of rpoH in gonococci upon adherence to host cells. To examine the role of RpoH in host cell interactions, an N. gonorrhoeae strain conditionally expressing rpoH was constructed. The results of our experiments showed that while induction of rpoH expression is not necessary for adherence of gonococci to epithelial cells, it is important for the subsequent invasion step, as gonococci depleted for rpoH invade cells two- to threefold less efficiently than a wild-type strain. Taken together, these results indicate that sigma(32), but not sigma(E), is important for the response of gonococci in the initial steps of an infection.     

Genomic screen for loci associated with alcohol dependence in Mission Indians.

Alcohol dependence is a leading cause of morbidity and mortality in Native Americans, yet biological factors underlying the disorder in this ethnic group remain elusive. This study's aims were to map susceptibility loci for DSM-III-R alcohol dependence and two narrower alcohol-related phenotypes in Mission Indian families. Each participant gave a blood sample and completed an interview using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) that was used to make alcohol dependence diagnoses and the narrower phenotypes of withdrawal, and drinking severity. Genotypes were determined for a panel 791 microsatellite polymorphisms. Analyses of multipoint variance component LOD scores for the dichotomous DSM-III-R phenotype revealed no peak LOD scores that exceeded 2.0 at any chromosome location. Two chromosomes, 4 and 12, had peak LOD scores that exceeded 2 for the alcohol use severity phenotype and three chromosomes 6, 15, 16 were found to have peaks with LOD scores that exceeded 2 for the withdrawal phenotype. Evidence for linkage to chromosomes 4 and 15, and 16 have been reported previously for alcohol related phenotypes whereas no evidence has as yet been reported for chromosomes 6 and 12. Combined linkage and association analysis suggest that alcohol dehydrogenase 1B gene polymorphisms are partially responsible for the linkage result on chromosome 4 in this population. These results corroborate the importance of several chromosomal regions highlighted in prior segregation studies in alcoholism and further identify new regions of the genome that may be unique to either the restricted phenotypes evaluated or this population of Mission Indians.     

Sensitivity Analysis of Respiratory Parameter Estimates in the Constant-Phase Model

The constant-phase model is increasingly used to fit low-frequency respiratory input impedance (Zrs), highlighting the need for a better understanding of the use of the model. Of particular interest is the extent to which Zrs would be affected by changes in parameters of the model, and conversely, how reliable are parameters estimated from model fits to the measured Zrs. We performed sensitivity analysis on respiratory data from 6 adult mice, at functional residual capacity (FRC), total lung capacity (TLC), and during bronchoconstriction, obtained using a 1-25 Hz oscillatory signal. The partial derivatives of Zrs with respect to each parameter were first examined. The limits of the 95% confidence intervals, 2-dimensional pairwise and p-dimensional joint confidence regions were then calculated. It was found that airway resistance was better estimated at FRC, as determined by the confidence region limits, whereas tissue damping and elastance were better estimated at TLC. Airway inertance was poorly estimated at this frequency range, as expected. During methacholine-evoked pulmonary constriction, there was an increase in the uncertainty of airway resistance and tissue damping, but this can be compensated for by using the relative (weighted residuals) in preference over the absolute (unweighted residuals) fitting criterion. These results are consistent with experimental observation and physiological understanding.     

Pulsed-field gel electrophoresis as an epidemiologic tool for enterococci and streptococci

Enterococci (Enterococcus faecium and Enterococcus faecalis) and streptococci such as Streptococcus pyogenes (Group A streptococcus), Streptococcus agalactiae (Group B streptococcus), and Streptococcus pneumoniae are increasing in importance as both hospital-acquired and community pathogens. Emerging resistance and increasing incidence of these organisms has necessitated the analysis of their epidemiologic mechanisms of spread. Pulsed-field gel electrophoresis (PFGE) has emerged as the one of the most widely applicable, reproducible, and stable methods to examine strain identity in bacterial organisms. The procedure used in our laboratory for PFGE typing of whole cell DNA digested with SmaI for enterococci, S. pneumoniae, S. pyogenes, and S. agalacatiae is presented. Issues regarding interpretation are also reviewed and discussed.     

Notch1 expression on T cells is not required for CD4+ T helper differentiation

Notch1 proteins are involved in binary cell fate decisions. To determine the role of Notch1 in the differentiation of CD4(+) Th1 versus Th2 cells, we have compared T helper polarization in vitro in naive CD4(+) T cells isolated from mice in which the N1 gene is specifically inactivated in all mature T cells. Following activation, Notch1-deficient CD4(+) T cells transcribed and secreted IFN-gamma under Th1 conditions and IL-4 under Th2 conditions at levels similar to that of control CD4(+) T cells. These results show that Notch1 is dispensable for the development of Th1 and Th2 phenotypes in vitro. The requirement for Notch1 in Th1 differentiation in vivo was analyzed following inoculation of Leishmania major in mice with a T cell-specific inactivation of the Notch1 gene. Following infection, these mice controlled parasite growth at the site of infection and healed their lesions. The mice developed a protective Th1 immune response characterized by high levels of IFN-gamma mRNA and protein and low levels of IL-4 mRNA with no IL-4 protein in their lymph node cells. Taken together, these results indicate that Notch1 is not critically involved in CD4(+) T helper 1 differentiation and in resolution of lesions following infection with L. major.     

Orosensory Perception of Fat/Sweet Stimuli and Appetite-Regulating Peptides before and after Sleeve Gastrectomy or Gastric Bypass in Adult Women with Obesity

The aim of this study was to explore the impact of bariatric surgery on fat and sweet taste perceptions and to determine the possible correlations with gut appetite-regulating peptides and subjective food sensations. Women suffering from severe obesity (BMI > 35 kg/m²) were studied 2 weeks before and 6 months after a vertical sleeve gastrectomy (VSG, n = 32) or a Roux-en-Y gastric bypass (RYGB, n = 12). Linoleic acid (LA) and sucrose perception thresholds were determined using the three-alternative forced-choice procedure, gut hormones were assayed before and after a test meal and subjective changes in oral food sensations were self-reported using a standardized questionnaire. Despite a global positive effect of both surgeries on the reported gustatory sensations, a change in the taste sensitivity was only found after RYGB for LA. However, the fat and sweet taste perceptions were not homogenous between patients who underwent the same surgery procedure, suggesting the existence of two subgroups: patients with and without taste improvement. These gustatory changes were not correlated to the surgery-mediated modifications of the main gut appetite-regulating hormones. Collectively these data highlight the complexity of relationships between bariatric surgery and taste sensitivity and suggest that VSG and RYGB might impact the fatty taste perception differently.