Publications

OBJECTIVE

Percent fat is often considered the reference for establishing the magnitude of adipose tissue accumulation and the risk of excess adiposity. However, the increasing recognition of a strong link between central adiposity and metabolic disturbances led us to test whether waist circumference (WC) is more highly correlated with metabolic syndrome components than percent fat and other related anthropometric measures such as BMI.

RESEARCH METHODS AND PROCEDURES

BMI, WC, and percent fat, measured by DXA, were evaluated in 1010 healthy white and African-American men and women [age, 48.3 +/- 17.2 (standard deviation) years; BMI, 27.0 +/- 5.3 kg/m(2)]. The associations of BMI, WC, and percent fat with age and laboratory-adjusted health risk indicators (i.e., serum glucose, insulin, triglycerides, high-density lipoprotein cholesterol, blood pressure) in each sex and ethnicity group were examined.

RESULTS

For 18 of 24 comparisons, the age- and laboratory-adjusted correlations were lowest for percent fat and in 16 of 24 comparisons were highest for WC. Fifteen of the between-method differences reached statistical significance. With health risk indicator as the dependent variable and anthropometric measures as the independent variable, the contribution of percent fat to the WC regression model was not statistically significant; in contrast, adding WC to the percent fat regression model did make a significant independent contribution for most health risk indicators.

DISCUSSION

WC had the strongest associations with health risk indicators, followed by BMI. Although percent fat is a useful measure of overall adiposity, health risks are best represented by the simply measured WC.

OBJECTIVE

The objective of this study was to investigate the relationship between sex work and HIV infection among young injection drug-using men who have sex with men (MSM-IDU).

STUDY DESIGN

This study was a cross-sectional analysis of behavioral and serologic data collected from 227 street-recruited MSM-IDU in San Francisco, California, between January 2000 and November 2001.

RESULTS

Sixty-eight percent of participants reported being paid by another man for sex. HIV prevalence was 12% (95% confidence interval, 8-16%); 42% of seropositive participants were unaware of their infection. HIV was independently associated with higher number of paying male partners and history of gonorrhea and inversely associated with number of female partners, education, and syringe-sharing. Consistent condom use overall was 41%, but varied significantly by type of partner.

CONCLUSIONS

Among MSM-IDU in San Francisco, sex work with men is strongly associated with HIV infection and the prevalence of condom use is low. HIV prevention among MSM-IDU must be tailored to address the excess risk associated with sex work.

OBJECTIVES

This study examined the association between genetic polymorphisms and enzyme activity for antioxidant enzymes that share a common detoxification pathway: manganese superoxide dismutase (MnSOD), glutathione peroxidase-1 (GPX1) and catalase.

METHODS

MnSOD, GPX1, and catalase activities were measured in isolated erythrocytes of 231 healthy, non-smoking student volunteers (55% women, ages 17-21, majority Asian or Caucasian). DNA from blood clots was genotyped by Taqman PCR (C47T : MnSOD and C593T : GPX1) and standard PCR (-262C>T : catalase). Associations between genotype and enzyme activity were analyzed by multiple linear regression, adjusted for baseline factors including gender and ethnicity.

RESULTS

Minor allele frequencies ranged from 13% for catalase (T) to 18% for GPX1 (T), and 33% for MnSOD(C) with significant variation between ethnicities. Median GPX1 activity was 13.2 U/g Hb with a six-fold difference between lowest and highest levels. Catalase activity ranged eight-fold (median: 86.3 k/g Hb), while median MnSOD activity was 2.8 U/mg Hb with a 56-fold range of values. MnSOD enzyme activity was 15% higher in females than males (95%CI : -1%, 32%), and 33% higher in CT or TT individuals (C47T) versus CC individuals (95%CI : 7-59%). On average, catalase activity was 18.1 k/g Hb lower for TT subjects (-262C>T) versus CC subjects (95% CI: -32.3, -4.0). All enzyme activities were correlated (r=0.3-0.4, P<0.001).

CONCLUSIONS

Interindividual variability of antioxidant enzyme activity in healthy young adults was partially explained by significant associations with three known genetic polymorphisms, and was further modified by gender and ethnicity. A substantial component of this variability may be attributable to differences in diet, environmental exposures, and additional genetic factors.

The genotype frequencies of MDR1 T-129C, C1236T, G2677A,T and C3435T SNPs were compared in 154 healthy Japanese and 100 healthy Caucasians to provide basic information on the inter-ethnic differences of pharmacotherapeutic outcome. The variants were found at allelic frequencies of 5.5%, 65.6%, 16.6%, 40.6% and 40.6%, for T-129C, C1236T, G2677A, G2677T and C3435T, respectively, in Japanese, and at 5.1%, 45.9%, 3.6%, 46.4% and 56.6%, respectively, in Caucasians, with a statistically significant difference for C1236T, G2677A,T and C3435T (p<0.001). G2677A was about 5-fold more frequent in Japanese than Caucasians. These genotype frequencies were also investigated in 95 Japanese patients with colorectal cancer (CRC) and esophageal squamous cell carcinoma (ESCC), but no significant difference was detected, when compared with healthy Japanese subjects. The haplotype frequency reached a total of about 85% in Japanese with the following 4 major haplotypes; T(-129)-T1236-T2677-T3435 (36.1%), T(-129)-T1236-G2677-C3435 (22.5%), T(-129)-C1236-G2677-C3435 (14.2%) and T(-129)-C1236-A2677-C3435 (13.3%). The second and fourth haplotypes were hardly inferred in Caucasian, whereas T(-129)-C1236-G2677-T3435 (12.8%) was found to be Caucasian-specific. There was a tendency for higher frequencies of the T(-129)/C-(129)-C1236-A2677-C3435 haplotype in Japanese CRC patients and T(-129)-T1236-T2677-T3435 haplotype in Japanese ESCC patients, compared with that in healthy Japanese subjects.

The number of older prisoners is increasing exponentially. For example, the number of geriatric female prisoners in California has increased 350% in the past decade. Despite an increasing population of geriatric female prisoners, the degree of functional impairment in this population is unknown. Therefore, the goals of this study were to describe the prevalence and nature of functional impairment in geriatric female prisoners in California and to identify aspects of the prison environment that may exacerbate functional impairments. Questionnaires were analyzed from 120 geriatric women in California state prisons. Functional impairment was defined as impairment in activities of daily living (ADLs) or in prison ADLs (PADLs), including dropping to the floor for alarms, standing for count, getting to meals, hearing orders, and climbing onto the top bunk. The mean age of participants was 62; 16% were dependent in one ADL, and 69% reported one PADL impairment. Increasing severity of functional impairment was associated with worse health status and more adverse prison experiences. For example, fall rates ranged from 33% in women without impairment to 57% with PADL impairment to 63% with ADL dependence (P=.02). Several prison environmental stressors were identified that likely exacerbate functional impairment. For example, 29% of geriatric women were assigned to a top bunk. Geriatric female prisoners report high rates of functional impairment. ADL and PADL impairment were associated with worse health status and adverse prison experiences. Therefore, the evaluation of functional impairment in geriatric female prisoners needs to consider the unique demands of the prison environment.

Conducting research in the home setting with homebound older adults presents distinct ethical and practical challenges that require special consideration. This article describes the methodological issues that make studying homebound older adults especially vulnerable to therapeutic misconception and researcher role conflict and offers practical strategies for researchers to deal with these problems when studying this population. In writing this article, we draw on more than a decade of descriptive and intervention research focusing exclusively on the homebound older population in which the authors have collaborated. Therapeutic misconception and researcher role conflict may occur because of methodological issues related to the recruitment of participants, the "homebound" status of participants, and the home setting as the interview site. Particular care is required on the part of the researcher to address these ethical issues. This may be accomplished especially through clear communication during the informed consent process with participants and in scientific communication with colleagues.

Quinacrine (QA), an antimalarial drug used for over seven decades, has been found to have potent antiprion activity in vitro. To determine whether QA can be used to treat prion diseases, we investigated its metabolism and ability to traverse the blood-brain barrier in mice. In vitro and in vivo, we identified by liquid chromatography-tandem mass spectrometry the major metabolic pathway of QA as N-desethylation and compared our results with an authentic reference compound. The major human cytochrome (P450) isoforms involved in QA mono-desethylation were identified as CYP3A4/5 by using specific chemical and antibody inhibition as well as cDNA-expressed P450 studies. QA transport from the basolateral to apical side in multidrug resistance protein 1 gene (MDR1)-transfected Madin-Darby canine kidney (MDCK) cells was markedly greater than in control MDCK cells and was inhibited by the potent P-glycoprotein (P-gp) inhibitor GG918 (N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-iso-1-quinolynyl)-ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamine). In MDR1-knockout (KO) mice, QA brain levels were 6 to 9 times higher after a single i.v. dose of 2 mg/kg QA and 49 times higher after multiple oral doses of 10 mg/kg/day QA for 7 days, compared with those in wild-type (WT) FVB mice. In contrast, the QA levels in plasma, liver, spleen, and kidney were similar after a single 2 mg/kg i.v. dose and <2 times greater after 10 mg/kg oral doses in MDR1-KO mice compared with WT mice. These results indicate that P-gp plays a critical role in transporting QA from the brain.

Poly(ADP-ribose) polymerase-1 (PARP-1), the most abundant member of the PARP family, is a nuclear enzyme that catalyzes ADP-ribose transfer from NAD+ to specific acceptor proteins in response to DNA damage. Excessive PARP-1 activation is an important cause of infarction and contractile dysfunction in heart tissue during interruptions of blood flow. The mechanisms by which PARP-1 inhibition and disruption dramatically improve metabolic recovery and reduce oxidative stress during cardiac reperfusion have not been fully explored. We developed a mouse heart experimental protocol to test the hypothesis that mitochondrial respiratory complex I is a downstream mediator of beneficial effects of PARP-1 inhibition or disruption. Pharmacological inhibition of PARP-1 activity produced no deterioration of hemodynamic function in C57BL/6 mouse hearts. Hearts from PARP-1 knockout mice also exhibited normal baseline contractility. Prolonged ischemia-reperfusion produced a selective defect in complex I function distal to the NADH dehydrogenase component. PARP-1 inhibition and PARP-1 gene disruption conferred equivalent protection against mitochondrial complex I injury and were strongly associated with improvement in myocardial energetics, contractility, and tissue viability. Interestingly, ischemic preconditioning abolished cardioprotection stimulated by PARP-1 gene disruption. Treatment with the antioxidant N-(2-mercaptopropionyl)-glycine or xanthine oxidase inhibitor allopurinol restored the function of preconditioned PARP-1 knockout hearts. This investigation establishes a strong association between PARP-1 hyperactivity and mitochondrial complex I dysfunction in cardiac myocytes. Our findings advance understanding of metabolic regulation in myocardium and identify potential therapeutic targets for prevention and treatment of ischemic heart disease.