Faculty Bibliography

OBJECTIVE:Currently, there is no effective medical treatment for patients with pituitary-dependent Cushing's disease. A novel somatostatin (SS) analogue, named SOM230, with high binding affinity to SS receptor subtypes sst(1), sst(2), sst(3) and sst(5) was recently introduced. We compared the in vitro effects of the sst(2)-preferring SS analogue octreotide (OCT) and the multi-ligand SOM230 on ACTH release by human and mouse corticotroph tumour cells. METHODS:By quantitative RT-PCR the sst subtype expression level was determined in human corticotroph adenomas. In vitro, the inhibitory effect of OCT and SOM230 on ACTH release by dispersed human corticotroph adenoma cells and mouse AtT20 corticotroph adenoma cells was determined. In addition, the influence of dexamethasone on the responsiveness to OCT and SOM230 was studied. RESULTS:Corticotroph adenomas expressed predominantly sst(5) mRNA (six out of six adenomas), whereas sst(2) mRNA expression was detected at significantly lower levels. In a 72 h incubation with 10 nmol/l SOM230, ACTH release was inhibited in three out of five cultures (range -30 to -40%). Ten nmol/l OCT slightly inhibited ACTH release in only one of five cultures (- 28%). In AtT20 cells, expressing sst(2), sst(3) and sst(5), SOM230 inhibited ACTH secretion with high potency (IC(50) 0.2 nmol/l). Dexamethasone (10 nmol/l) pre-treatment did not influence the sensitivity of the cells to the inhibitory effect of SOM230, suggesting that sst(5) is relatively resistant to negative control by glucocorticoids. CONCLUSIONS:The selective expression of sst(5) receptors in corticotroph adenomas and the preferential inhibition of ACTH release by human corticotroph adenoma cells by SOM230 in vitro, suggest that SOM230 may have potential in the treatment of patients with pituitary-dependent Cushing's disease.

The production of melanin pigments is associated with virulence for many microbes. Melanin is believed to contribute to microbial virulence by protecting microbial cells from oxidative attack during infection. However, there is also evidence from various systems that melanins have immunomodulatory properties, which conceivably could contribute to virulence by altering immune responses. To investigate the effect of melanin on the immune response, we compared the murine pulmonary responses to infection with melanized and nonmelanized Cryptococcus neoformans cells. Infection with melanized cells resulted in a greater fungal burden during the early stages of infection and was associated with higher levels of interleukin-4 and MCP-1 and greater numbers of infiltrating leukocytes. Infection with laccase-positive (melanotic) C. neoformans cells also elicited higher MCP-1 levels and more infiltrating leukocytes than did infection with laccase-negative cells. Melanization interfered with phagocytosis in vivo for encapsulated C. neoformans but not for nonencapsulated cells. The results provide strong evidence that cryptococcal melanization can influence the immune response to infection and suggest that immunomodulation is an additional mechanism by which the pigment contributes to virulence.

Skin color, a predictor of social interactions and risk factor for several types of cancer, is due to two contrasting forms of melanin, the darker eumelanin and lighter phaeomelanin. The lighter pigment phaeomelanin is the product of the antagonistic function of the agouti signaling protein (ASIP) on the alpha-melanocyte stimulating hormone receptor (MC1R). Studies have shown that a single-nucleotide polymorphism (SNP) in the 3'UTR of the ASIP gene is associated with dark hair and eyes; however, little is known about its role in inter-individual variation in skin color. Here we examine the relationship between the ASIP g.8818A>G SNP and skin color (M index) as assessed by reflectometry in 234 African Americans. Analyses of variance (ANOVA) were performed to evaluate the effects of ASIP genotypes, age, individual ancestry, and sex on skin color variation. Significant effects on M index variation were observed for ASIP genotypes (F(2,236)=4.37, P=0.01), ancestry (F(1,243)=37.2, P<0.001), and sex (F(1,244)=4.08, P=0.05). Subsequent analyses revealed a strong effect on M index from ASIP genotypes in African American females (P<0.001). Our study suggests that the ASIP G>A polymorphism exhibits a dominant effect leading to lighter skin color and that variation in the ASIP gene may have been one of several factors contributing to reductions in pigmentation in some populations. Further study is needed to reveal how interactions between ASIP and several other genes, such as MC1R and P, predict human pigmentation.

Smokeless tobacco and areca nut usage are integral cultural traditions in South Asia. Paan and gutka are two commonly used products which contain these ingredients. They are immensely popular in South Asia and with South Asian immigrants. Regular paan and gutka use is associated with several deleterious health consequences, most significantly oral cancer. Of particular concern is the markedly increased risk of oral cancer in South Asian immigrants when compared with the natives in new areas of settlement. The South Asian community in the United States is large and rapidly growing. Paan and gutka are legal in the United States, and readily available in ethnic enclaves. Smokeless tobacco prevention and cessation research and interventions have not yet addressed the unique sociocultural circumstances of this growing, at-risk community. The medical, dental, and public health communities need to join forces to combat this emerging threat

Cigarette ads in popular magazines play a role in smoking and in brand preferences among women and men, but few studies have analyzed ads directed at women vs men, and no study has examined ads directed at women of different ethnic groups. Hence, we examined cigarette ads in popular magazines for White women, Latinas, and men 1998 through 2002 for the first time. Significant differences in the number of cigarette ads by magazine audience were found, along with significant differences in the type and brands of cigarettes advertised to each group. These preliminary findings suggest that the tobacco industry may target women in a manner that differs from its targeting of men, and may target Latinas in a manner that it does not target White women. Results are discussed in terms of the need for further research on tobacco ads directed at women

PURPOSE/OBJECTIVE:Extending the scheduled return visit interval has been suggested as one means to improve clinic access to the provider. However, prolonging the return visit interval may affect quality of care if prevention measures and chronic disease management receive less attention as clinic visits become less frequent. The purpose of this study was to determine whether a comprehensive education program could encourage providers to lengthen their return visit interval without compromising performance on key quality indicators. SUBJECTS AND METHODS/METHODS:This was a prospective cohort study monitoring scheduling and performance data of primary care providers at the Milwaukee Veterans Affairs Medical Center. Following collection of baseline data (January through June 1999), providers were encouraged to lengthen the return visit interval while increasing reliance on nurses and other clinic staff for interim management of chronic disease. Provider-specific feedback of return visit interval and performance data was utilized to motivate behavioral change. Scheduling and clinical data were abstracted from random medical record audits performed at baseline and from July through December in the years 2000 and 2001. RESULTS:Compared with the baseline period, the percent of patients scheduled > or =6 months was significantly increased among staff providers and medicine residents at 2 years (Staff providers: 31% vs. 62%, P <0.001; Medicine residents: 22 vs. 44%, P <0.001). Colorectal screening, pneumonia immunizations, and achievement of therapeutic goals for diabetes, hypertension, and lipid disorders significantly improved at 2 years compared with baseline measurements. CONCLUSIONS:Educational interventions can successfully retrain providers to extend the return visit interval and reduce the scheduling of routine and perhaps unnecessary appointments. This can be accomplished without compromising important performance monitors for diabetes, lipid disorders, hypertension, and prevention.