Benjamin A. Rybicki

Multiple risk factors for Parkinson's disease

OBJECTIVEnTo determine the relative contribution of various risk factors to the development of Parkinsons disease (PD).nnnMETHODSnTen variables that were independently associated with PD in a health system population-based case-control study of epidemiological risk factors for the disease were jointly assessed. Stepwise logistic regression, adjusted for sex, race and age was used to develop a multiple variate model that best predicted the presence of PD. The population attributable risk was estimated for each variable in the final model, as well as for all factors together.nnnRESULTSnThe 10 initial variables included >20 years occupational exposure to manganese or to copper, individually; >20 years joint occupational exposure to either lead and copper, copper and iron, or lead and iron; a positive family history of PD in first- or second-degree relatives; occupational exposure to insecticides or herbicides; occupational exposure to farming; and smoking. Logistic regression resulted in a final model that included >20 years joint occupational exposure to lead and copper (p=0.009; population attributable risk [PAR]=3.9%), occupational exposure to insecticides (p=0.002; PAR=8.1%), a positive family history of PD in first- and second-degree relatives (p=0.001; PAR=12.4%), and smoking </=30 pack-years or not smoking (p=0.005; PAR=41.4%). All four variables combined had a PAR=54.1%.nnnCONCLUSIONSnOur final model of PD risk suggests that occupational, environmental lifestyle and, likely, genetic factors, individually and collectively, play a significant role in the etiology of the disease. Clearly, additional risk factors remain to be determined through future research.

Racial differences in risk of prostate cancer associated with metabolic syndrome.

OBJECTIVESnTo perform a case-control study to test the association between metabolic syndrome features and prostate cancer. The metabolic syndrome refers to a cluster of conditions serving as risk factors for cardiovascular disease. The metabolic syndrome is prevalent in the United States, and the spectrum of specific features has been shown to differ by race and ethnicity. A number of recent reports have linked metabolic syndrome to prostate cancer; however, most studies have not had racially diverse populations to explore differences in risk.nnnMETHODSnA case-control study was conducted to test the association between metabolic syndrome features and prostate cancer among 637 patients and 244 controls, with African-American men constituting 43% of the study population.nnnRESULTSnMetabolic syndrome, defined using a modified version of the Adult Treatment Panel III criteria, was marginally associated with an increased risk of prostate cancer in African-American men (odds ratio [OR] 1.71, 95% confidence interval [CI] 0.97-3.01), but not in white men (OR 1.02, 95% CI 0.64-1.62). After stratifying the patients by stage at diagnosis, African-American men with organ-confined disease were more likely to have a history of metabolic syndrome than were the controls (OR 1.82; 95% CI 1.02-3.23), but no association was observed among those with advanced-stage disease (OR 0.93; 95% CI 0.31-2.77). When evaluating the specific features of the metabolic syndrome, obesity was inversely related to prostate cancer among white men (OR 0.51, 95% CI 0.33-0.80) but unrelated to risk among African-American men (OR 1.15, 95% CI 0.70-1.89).nnnCONCLUSIONSnIn the present investigation, the metabolic syndrome was associated with prostate cancer risk in African-American men, but not in white men. The prevalence of this syndrome, coupled with the racial disparity in prostate cancer incidence and outcomes after diagnosis, warrant additional investigation.

Mutation Analysis of the HFE Gene Associated With Hereditary Hemochromatosis in African Americans

Homozygosity for the mutation Cys282Tyr in the HFE gene has recently been identified as a cause of hereditary hemochromatosis, a disorder resulting in the inappropriate absorption of iron. Approximately 10% of Caucasians are heterozygous for this mutation; however, the gene frequency in African Americans is unknown. A study of a control population of African Americans was performed to determine the frequency of the Cys282Tyr and His63Asp alleles in this ethnic group. The carrier frequency for each mutant allele in our African American population was 3.0%. DNA studies of four African‐American hemochromatosis patients did not identify any individuals with the Cys282Tyr allele. These findings suggest that if the Cys282Tyr mutation confers susceptibility to hemochromatosis in Caucasians (as suggested by recent studies) there is an alternative mechanism for hemochromatosis in the American black population. Am. J. Hematol. 58:213–217, 1998.

Copy Number Alterations in Prostate Tumors and Disease Aggressiveness

Detecting genomic alterations that result in more aggressive prostate cancer may improve clinical treatment and our understanding of the biology underlying this common but complex disease. To this end, we undertook a genome‐wide copy number alterations (CNAs) study of clinicopathological characteristics of 62 prostate tumors using the Illumina 1M single nucleotide polymorphism array. The highest overall frequencies of CNAs were on chromosomes 8q (gains), 8p (loss and copy‐neutral), and 6q (copy‐loss). Combined loss and copy‐neutral events were associated with increasing disease grade (P = 0.03), stage (P = 0.01), and diagnostic prostate specific antigen (PSA) (P = 0.01). Further evaluation of CNAs using gene ontology identified pathways involved with disease aggressiveness. The “regulation of apoptosis” pathway was associated with stage of disease (P = 0.004), while the “reproductive cellular process” pathway was associated with diagnostic PSA (P = 0.00038). Specific genes within these pathways exhibited strong associations with clinical characteristics; for example, in the apoptosis pathway BNIP3L was associated with increasing prostate tumor stage (P = 0.007). These findings confirm known regions of CNAs in prostate cancer and localize additional regions and possible genes (e.g., BNIP3L, WWOX, and GATM) that may help to clarify the genetic basis of prostate cancer aggressiveness.

A prospective study of socioeconomic status, prostate cancer screening and incidence among men at high risk for prostate cancer

PurposeHigher socioeconomic status (SES) men are at higher risk of prostate cancer (PCa) diagnosis, an association commonly interpreted as a function of higher rates of prostate screening among higher SES men. However, the extent to which screening explains this association has not been well quantified.MethodsWithin a Detroit area cohort of 6,692 men followed up after a benign prostate procedure, a case–control study was conducted of 494 PCa cases and controls matched on age, race, duration of follow-up, and date of initial benign finding; 2000 Census data were used in a principal component analysis to derive a single factor, labeled the neighborhood SES index (NSESI), representing zip code-level SES.ResultsAmong cases, higher SES was associated with a younger age at initial biopsy: −1.48xa0years (95xa0% CI, −2.32, −0.64) per unit NSESI. After adjustment for confounders and duration of follow-up, higher SES was associated with more PSA tests and DRE during follow-up; 9xa0% (95xa0% CI, 2, 16) and 8xa0% (95xa0% CI, 1, 15) more respectively, per unit NSESI. Higher SES was associated with a higher risk of PCa diagnosis during follow-up, multivariable adjusted ORxa0=xa01.26 per unit increase in NSESI (95xa0% CI, 1.04, 1.49). Further adjustment for screening frequency somewhat reduced the association between SES and PCa risk (ORxa0=xa01.19 per unit NSESI, 95xa0% CI, 0.98, 1.44).ConclusionsDifferences in screening frequency only partially explained the association between higher zip code SES and PCa risk; other health care-related factors should also be considered as explanatory factors.

Gastroenterology training and career choices: a prospective longitudinal study of the impact of gender and of managed care.

OBJECTIVE:We aimed to determine if gender differences exist in the selection and training of female and male gastroenterology fellows.METHODS:One hundred seventy-six of 218 training program directors returned an 18-question survey about their programs, including leave policies, training, and prevalence of female faculty. Two cohorts of graduating trainees from 1993 and 1995 (N = 393) returned anonymous surveys regarding their training program experiences, demographics, and business training.RESULTS:Female gastroenterology trainees are more likely to choose programs according to parental leave policies (p < 0.05), female faculty (0.2990 correlation coefficient), and “family reasons” (p < 0.04) than the male trainees. Female trainees were more likely to remain childless (p < 0.001) or have fewer children at the end of training despite marital status not unlike their male colleagues. Female trainees altered their family planning because of training program restrictions (20% vs 7%, p < 0.001). They perceived gender discrimination (39%) and sexual harassment (19%) during gastroenterology training. Trainees of both sexes had mentorship during training (65% vs 71%, ns); female trainees were more likely to have an opposite sex mentor (71% vs 3.4%) despite an almost 50% prevalence of female full-time and clinical faculty. Female trainees were apt to be less trained in advanced endoscopy (p < 0.005). Trainees of both sexes were influenced by the changing health care environment in career choice (49% vs 42%, ns); neither gender felt adequately prepared for the business aspects of gastroenterology.CONCLUSION:Alterations in gastroenterology training are needed to attract qualified female applicants. New graduates of both sexes lack practice management education.

Racial differences in clinical and pathological associations with PhIP-DNA adducts in prostate

African–American men have a higher dietary intake of 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP), which is the most abundant heterocyclic amine in cooked meats and is carcinogenic in rat prostate through the formation of DNA adducts. To determine the clinical and demographic factors associated with PhIP‐DNA adduct levels, the biologically effective dose of PhIP in human prostate, we immunohistochemically measured PhIP‐DNA adducts in a study of 162 Caucasian and 102 African–American men who underwent radical prostatectomy for prostate cancer. A strong correlation between PhIP‐DNA adduct levels in prostate tumor and adjacent non‐tumor cells was observed (ρ = 0.62; p < 0.0001); however, non‐tumor cells had significantly higher adduct levels compared with tumor (0.167 optical density (OD) units ± 0.043 vs. 0.104 OD ± 0.027; p < 0.0001). Race was not associated with PhIP‐DNA adduct levels in either tumor or non‐tumor cells, but race‐specific associations were observed. In prostate tumor and non‐tumor cells, tumor volume had the strongest association with PhIP‐DNA adducts in Caucasians, whereas in African–Americans prostate volume was most strongly associated with adduct levels in tumor cells and advanced Gleason grade had the strongest association in non‐tumor cells. In race interaction models, while the only statistically significant interaction was between African–American race and advanced Gleason grade in non‐tumor cells (β = 0.029; p = 0.02), in tumor cells we observed opposite effects by race (positive for African–Americans, negative for Caucasians) for older age and high PSA levels at diagnosis. In conclusion, while PhIP‐DNA adduct levels in prostate cells do not vary significantly by race, our results suggest that PhIP exposure may have stronger effects on prostate tumor differentiation in African–American men.

Racial Differences in Sarcoidosis Granuloma Density

Study Objectives While sarcoidosis generally inflicts a greater morbidity on African-American compared with Caucasian patients, no studies have examined whether racial differences exist in the intensity of the histologic hallmark of sarcoidosis, noncaseating granulomas. Design and Setting The study was conducted as a retrospective case series in a tertiary referral center. Patients The study included 187 patients with histopathologic confirmation of sarcoidosis by trans- and/or endobronchial biopsy between July 1991 and December 2001. Measurements and Results Granuloma density was the average number of granulomas per biopsy piece on the slide with the most intense granulomatous inflammation at fourfold magnification. Overall, African-American patients had a twofold greater median granuloma density than Caucasians (pxa0=xa00.005). In a negative binomial multivariate model, radiographic pattern had the strongest association with granuloma density, with Scadding stage II and III patients having adjusted granuloma densities of 60% (pxa0=xa00.005) and 105% (pxa0=xa00.0001) higher than stage I patients. In the specific-tissue types, radiographic stage–adjusted granuloma densities in African-American patients were 49% greater in bronchial tissue (pxa0=xa00.03), but only a 27% greater in alveolar tissue (pxa0=xa00.51). Conclusions A greater granuloma density in bronchiolar lung tissue of African-American sarcoidosis patients may explain racial differences in diagnostic yield by lung biopsy and disease severity at diagnosis. This association persists even after controlling for Scadding radiographic stage, a measure of disease severity strongly associated with granuloma density.

Chromosome 6p microsatellite polymorphisms in African-Americans

Allele frequency distributions were determined for seven microsatellite DNA markers spanning the short arm of chromosome 6 in a population of African-Americans. A total of 196 chromosomes were analyzed. African-Americans differed from reported studies on Caucasians in the number of alleles, allele frequency and predominating alleles. These differences resulted in higher heterozygosity and polymorphic information content for these loci in the African-American population than in Caucasians. Each marker appeared to be in Hardy-Weinberg equilibrium within this population. These results demonstrate the need to determine population-specific allele frequency distributions for polymorphic markers when performing genetic linkage studies in racially defined groups. This study provides gene frequency data for this ethnic group in a region of the genome which has attracted attention as contributing genetic susceptibility to a number of diseases.

Case-only gene–environment interaction between ALAD tagSNPs and occupational lead exposure in prostate cancer

Black men have historically had higher blood lead levels than white men in the U.S. and have the highest incidence of prostate cancer in the world. Inorganic lead has been classified as a probable human carcinogen. Lead (Pb) inhibits delta‐aminolevulinic acid dehydratase (ALAD), a gene recently implicated in other genitourinary cancers. The ALAD enzyme is involved in the second step of heme biosynthesis and is an endogenous inhibitor of the 26S proteasome, a master system for protein degradation and a current target of cancer therapy.