Jeffrey M. Roseman

γ-Glutamyltransferase Is a Predictor of Incident Diabetes and Hypertension: The Coronary Artery Risk Development in Young Adults (CARDIA) Study

Background: γ-Glutamyltransferase (GGT), which maintains cellular concentrations of glutathione, may be a marker of oxidative stress, and GGT itself may produce oxidative stress. We performed a prospective study to examine whether serum GGT predicts diabetes and hypertension. Methods: Study participants were 4844 black and white men and women 18–30 years of age in 1985–1986; they were reexamined 2, 5, 7, 10, and 15 years later. Year 0 GGT cutpoints were 12, 17, 25, and 36 U/L (overall 25th, 50th, 75th, and 90th percentiles; the laboratory cutpoints for abnormal are 40 U/L in women and 50 U/L in men). We deleted 32 participants with prevalent diabetes and 140 participants with prevalent hypertension from the respective incidence analyses. Results: After adjustment for study center, race, sex, and age in proportional hazards regression, the hazard ratios across year 0 GGT categories were 1.0, 1.6, 1.7, 4.0 (95% confidence interval, 2.0–8.1), and 5.5 (2.7–11.1) for 15-year incident diabetes and 1.0, 1.2, 1.7 (1.2–2.2), 2.3 (1.7–3.2), and 2.3 (1.7–3.2) for hypertension. Additional adjustment for year 0 alcohol consumption, body mass index, cigarette smoking, and physical activity attenuated this relationship, but GGT remained a significant predictor. Conclusions: Serum GGT within a range regarded as physiologically normal is associated with incident diabetes and hypertension. Considering known functionality of GGT, these associations are consistent with a role for oxidative stress in risk for diabetes and hypertension.

Longitudinal study of elbow and shoulder pain in youth baseball pitchers.

PURPOSE Previous studies among young pitchers have focused on the frequency and description of elbow injuries. The purpose of this study was to evaluate the frequency of elbow and shoulder complaints in young pitchers and to identify the associations between pitch types, pitch volume, and other risk factors for these conditions. METHODS A prospective cohort study of 298 youth pitchers was conducted over two seasons. Each participant was contacted via telephone after each game pitched to identify arm complaints. Generalized estimating equations were used to assess associations between arm complaints and independent variables. RESULTS The frequency of elbow pain was 26%; that of shoulder pain, 32%. Risk factors for elbow pain were increased age, increased weight, decreased height, lifting weights during the season, playing baseball outside the league, decreased self-satisfaction, arm fatigue during the game pitched, and throwing fewer than 300 or more than 600 pitches during the season. Risk factors for shoulder pain included decreased satisfaction, arm fatigue during the game pitched, throwing more than 75 pitches in a game, and throwing fewer than 300 pitches during the season. CONCLUSION Arm complaints are common, with nearly half of the subjects reporting pain. The factors associated with elbow and shoulder pain were different, suggesting differing etiologies. Developmental factors may be important in both. To lower the risk of pain at both locations, young pitchers probably should not throw more than 75 pitches in a game. Other recommendations are to remove pitchers from a game if they demonstrate arm fatigue and limit pitching in nonleague games.

Systemic lupus erythematosus in three ethnic groups. VIII. Predictors of early mortality in the LUMINA cohort

Objective To determine the features associated with mortality in a multiethnic US cohort of patients with systemic lupus erythematosus (SLE) within 5 years of study onset. Methods Socioeconomic and demographic features (age, gender, ethnicity, marital status, education, occupation, poverty, and health-related behaviors [drinking, smoking, exercising]), clinical and immunologic features (disease duration, disease onset type, disease activity according to the Systemic Lupus Activity Measure [SLAM], disease damage according to the Systemic Lupus International Collaborating Clinics [SLICC] Damage Index [SDI], number of American College of Rheumatology criteria at diagnosis, organ system manifestations, fatigue and pain ratings, and medication usage and autoantibodies), immunogenetic features (HLA class II genotypes), and behavioral and psychosocial features (social support, illness-related behaviors, and helplessness), as obtained at enrollment into the study, were compared between survivors and deceased patients. Logistic regression analysis was used to determine significant independent risk factors for mortality. Results Within 5 years of study onset, 34 of 288 patients have died. Fourteen deaths could be directly attributed to SLE and 11 to infections. In 1 patient the cause of death could not be determined. In the remaining 8 patients the cause of death was neither infectious nor disease-related. There were 10 deaths among Hispanics, 18 among African Americans, and 6 among Caucasians (P< 0.05). Variables associated with mortality in the univariable analyses included poverty, less than full-time employment, difficulty in accessing health care, shorter disease duration, cardiovascular and renal involvement, higher serum creatinine levels and lower hematocrit values, higher SLAM and SDI scores, lower use of antimalarial drugs, and higher use of (some) immunosuppressants. Specific autoantibodies and class II HLA genotypes were not associated with mortality. Poverty and higher baseline SLAM and SDI scores were independently associated with mortality in the multivariable analyses. Conclusions Disease activity, disease damage, and poverty appear to be the most important determinants of mortality in this multiethnic US cohort of SLE patients. These results have applicability to the management of patients with SLE, a disease that more severely affects disadvantaged minority population groups.

Systemic lupus erythematosus in three ethnic groups: III A comparison of characteristics early in the natural history of the LUMINA cohort

Aim: To determine and contrast the socioeconomic-demographic and clinical features of patients with recent onset (5 y) systemic lupus erythematosus (SLE) from three ethnic groups, Hispanic, African-American and Caucasian (H, AA, C). Subjects and methods: SLE cases (American College of Rheumatology criteria) (incident (n ‘ 56), prevalent (n ‘ 173)), were enrolled in a longitudinal study at The University of Alabama at Birmingham, The University of Texas-Houston Health Science Center and The University of Texas Medical Branch at Galveston. Socioeconomic-demographic, clinical, immunological, behavioral and psychological data were obtained using validated instruments and standard laboratory techniques, and compared. Results: 70 H, 88 AA and 71 C SLE patients constitutethis cohort. H and AA patients were younger and of lower socioeconomic-demographic status. They also had evidence of more frequent organ system involvement (renal, cardiovascular), more auto-antibodies, more active disease (after adjusting for discrepant socioeconomic-demographic features), lower levels of social support and more abnormal illness-related behaviors (more in H than in AA). H also were more likely to have an abrupt disease onset; C were more likely to be on antimalarials but less likely to be on corticosteroids. H, AA, and C used health care resources comparably. They had similar levels of pain and physical and mental functioning after adjusting for age, disease duration, income, education, social support, illness-related behaviors, and Systemic Lupus Activity Measure or SLAM scores. Conclusions: H and AA patients have more active SLE, at an earlier age of onset, and a less favorable socioeconomic-demographic structure (worse among the H than AA) which predispose them to a less favorable natural history.

Systemic lupus erythematosus in three ethnic groups. XII. Risk factors for lupus nephritis after diagnosis

The purpose of this study was to determine the cumulative incidence of lupus nephritis (LN) and the factors predictive of its occurrencein a multiethnic systemic lupus erythematosus (SLE) cohort. We studied 353 SLE patients as de” ned by the American College of Rheumatology (ACR) criteria (65 Hispanics, 93 African-Americans and 91 Caucasians). First, we determined the cumulative incidence of LN in all patients. Next, we determined the predictors for LN in those with nephritis occurring after diagnosis. The dependent variable, LN, was de” ned by: (1) A renal biopsy demonstrating World Health Organization (WHO), class II–V histopathology; and/or (2) proteinuria≥ 0.5 g=24 h or 3 + proteinuria attributable to SLE; and/or (3) one of the following features also attributable to SLE and present on two or more visits, which were performed at least 6 months apart— proteinuria≥ 2 +, serum creatinine≥ 1.4 mg/dl, creatinine clearance ≤ 79 ml/min, 10 RBCs or WBCs per high power ” eld (hpf), oŗ 3 granular or cellular casts per hpf. Independent variables assessed at diagnosis, and if absent, at baseline, were from four domains: sociodemographic, clinical, immunologic and immunogenetic (including the complete antibody pro” le and MHC class II alleles), and health habits. Variables with P < 0.05 by chi square analyses were entered into domain-speci”c stepwise logistic regression analyses controlling for disease duration, with LN as the dependent variable. Signi” cant domain-speci”c regression variables (P ≤ 0.1) were then entered into an overall model. The cumulative incidence of LN was 54.3% in all patients, and 35.3% for those developing LN after diagnosis. LN after diagnosis occurred in 43.1% of 65 Hispanics, 50.5% of 93 African-Americans, and 14.3% of 91 Caucasians, P < 0.0001. The duration of follow-up for those with LN after diagnosis was 5.5§ 2.4 vs 4.0§ 2.9 years for those without LN. Hispanic (odds ratio (OR) = 2.71, 95% con” dence limits (CL) = 1.07–6.87, P < 0.04) and African-American ethnicities (OR = 3.13, 95% CL = 1.21–8.09, P < 0.02), not married or living together (OR = 3.45, 95% CL = 1.69–7.69, P < 0.0003), higher SLAM score (OR = 1.11, 95% CL = 1.02–1.19, P < 0.007), anti-dsDNA (OR = 3.14, 95% CL = 1.50–6.57, P < 0.0001) and anti-RNP (OR = 4.24, CL = 1.98–9.07, P < 0.0001) antibodies were shown to be signi” cant predictors of the occurrence of LN. Repeated analyses excluding the patients with missing HLA data showed that absence of HLA-DQB1*0201 was also a signi” cant predictor for the occurrence of LN (OR = 2.34, CL = 1.13–5.26, P < 0.04). In conclusion, LN occurred signi” cantly more often in Hispanics and African-Americans with SLE. Sociodemographic,clinical and immunologic/immunogenetic factors seem to be predictive of LN occurring after the diagnosis of SLE has been made.

Relations of Hyperuricemia with the Various Components of the Insulin Resistance Syndrome in Young Black and White Adults: The CARDIA Study

PURPOSE To assess the association of hyperuricemia with the various components of the Insulin Resistance Syndrome (IRS) in a biracial cohort of young adults. METHODS Cross-sectional study in 4053 young black and white adults aged 18-30 years from the Coronary Artery Risk Development in Young Adults (CARDIA) study. RESULTS Body mass index (BMI), fasting insulin, and triglycerides were significantly higher, and high density lipoprotein (HDL)-cholesterol lower in subjects with hyperuricemia (uric acid > or = 7.0 mg/dl in males; > or = 6.0 mg/dl in females) (all p < 0.001). BMI showed the strongest positive correlation with uric acid among the IRS components. Significant associations of hyperuricemia with these risk factors were observed in all sex-race groups, which persisted after controlling for possible confounders including age, education, physical activity, smoking, alcohol intake, oral contraceptive use, and creatinine. Further adjustment for BMI and/or waist-to-hip ratio caused a large decrease in the strength of the associations. Adjustment for insulin also lead to decreases; however, the influence of fasting insulin appeared weaker than obesity. Even after controlling for obesity, insulin, and the other components of the IRS, male subjects in both races in the upper tertile of triglycerides were still more likely to have hyperuricemia. CONCLUSIONS The association of hyperuricemia with most aspects of the IRS may result predominantly from their covariation with adiposity and secondarily with insulin level. Elevated triglyceride level seems to have an independent relationship with hyperuricemia in males. The relationship between hyperuricemia and cardiovascular disease observed in previous studies may be secondary to its association with the IRS.

Systemic lupus erythematosus in three ethnic groups. IX. Differences in damage accrual.

OBJECTIVE To determine the factors predictive of damage in a multiethnic (Hispanic, African American, and Caucasian) LUMINA (lupus in minority populations, nature versus nurture) cohort of patients with systemic lupus erythematosus (SLE) with disease duration of < or =5 years at enrollment (T0). METHODS Variables (socioeconomic/demographic, clinical, immunologic, immunogenetic, behavioral, and psychological) were measured at T0 and annually thereafter. Disease damage was measured with the Systemic Lupus International Collaborating Clinics Damage Index (SDI), and disease activity was measured with the Systemic Lupus Activity Measure. The relationship between the different variables and the SDI at the last visit (TL) was examined (mean followup from diagnosis to TL 61 months; adjusted for disease duration). Poisson regression was used to identify the independent association between the different variables and SDI scores at TL. RESULTS Seventy-two Hispanics, 104 African Americans, and 82 Caucasians were included. One-half of patients had not accrued any damage. Caucasians had the lowest SDI scores at T0, and Hispanics had the highest scores at TL. Renal damage occurred more frequently among Hispanics and African Americans, while integument damage was more frequent among African Americans. Neuropsychiatric (20%), renal (16%), and ocular (15%) damage occurred most frequently among all patients. Independent predictors of SDI at TL were age, corticosteroid use (maximum dose at T0), number of American College of Rheumatology (ACR) criteria met, disease activity, and abnormal illness-related behaviors. Other variables were less consistently associated with damage accrual (poverty in African Americans, lack of HLA-DRB1*0301 in Hispanics, presence of HLA-DQB1*0201 and acute onset of SLE in Caucasians). CONCLUSION Damage in SLE occurs from the outset in some, but not all, patients; Hispanics accrue damage more rapidly. Disease factors (corticosteroid use, number of ACR criteria met, disease activity, and acute-onset type) are important, but age and abnormal illness-related behaviors also contribute to overall damage in SLE.

Systemic lupus erythematosus in three ethnic groups: I. The effects of HLA class II, C4, and CR1 alleles, socioeconomic factors, and ethnicity at disease onset

Objective To study the relative impact of immunogenetic versus socioeconomic factors on systemic lupus erythematosus (SLE) at disease onset/presentation. Methods Medical records regarding SLE onset/presentation were abstracted on 229 SLE patients who were enrolled in a prospective lupus outcome study. Patients were grouped in equivalent proportions of Caucasians, African Americans, and Hispanics. HLA-DRB1, DQA1, and DQB1 oligotyping, as well as C4 and CR1 allotyping, were carried out by standard methods. In addition to these genetic factors, data on ethnicity, age at SLE onset, monthly income, level of education, and home ownership were entered into stepwise logistic or stepwise multiple linear regression models as independent variables, and each specific clinical feature (neurologic, renal, and cardiovascular disease due to SLE), as well as the total Systemic Lupus Activity Measure (SLAM) score and physicians global assessment of disease activity at disease onset, were entered as dependent variables. Results HLA-DRB1*0301 (DR3), DRB1*1503 (DR2), and DRB1*08 (DR8) alleles were more frequently found in Caucasians, African Americans, and Hispanics, respectively. Hispanics were more likely to have cardiac and renal disease, as well as a higher physicians global assessment of disease activity. African Americans were more likely to have neurologic disease, renal disease, and a higher SLAM score. Those with less education had a higher SLAM score. Patients with HLA-DRB1*01 had less renal disease and a lower SLAM score. Those with C4A*3 alleles had a higher SLAM score and a higher physicians global assessment of disease activity. Conclusion Both genetic and socioeconomic determinants, as well as other factors associated with Hispanic and African-American ethnicity, affect the presentation of SLE.

Association of fasting insulin with blood pressure and lipids in young adults. The CARDIA study.

The association of insulin with cardiovascular disease (CVD) may be mediated in part by the associations of insulin with CVD risk factors, particularly blood pressure and serum lipids. These associations were examined in 4576 black and white young adults in the CARDIA Study. Fasting insulin level was correlated in univariate analysis with systolic blood pressure (r = 0.16), diastolic blood pressure (r = 0.13), triglycerides (r = 0.27), total cholesterol (r = 0.10), high density lipoprotein (HDL) cholesterol (r = -0.25), and low density lipoprotein (LDL) cholesterol (r = 0.14), and with age, sex, race, glucose, body mass index, alcohol intake, cigarette use, physical activity, and treadmill duration (all p less than 0.0001). After adjustment for these covariates, insulin remained positively associated with blood pressure, triglycerides, total and LDL cholesterol, and apolipoprotein B and was negatively associated with HDL, HDL2 and HDL3 cholesterol, and apolipoprotein A-I in all four race-sex groups. Higher levels of fasting insulin are associated with unfavorable levels of CVD risk factors in young adults; these associations, though relatively small, can be expected to increase the risk of atherosclerosis. Demonstration of these relationships in a large, racially diverse, healthy population suggests that insulin may be an important intermediate risk factor for CVD in a broad segment of the U.S. population.

Association between Statin Use and Alzheimer’s Disease

Context: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been associated with a decreased risk for Alzheimer’s disease (AD). Objective: To evaluate the association between statin use and AD adjusted for comorbid medical conditions. Design: A nested case-control study. Patients: Patients at the Veterans Affairs Medical Center in Birmingham, Ala., USA with a new diagnosis of AD (cases) between 1997 and 2001 (n = 309) and age-matched non-AD controls (n = 3,088). Main Outcome Measure: Odds ratio for association between AD and statin use. Results: Statin users had a 39% lower risk of AD relative to nonstatin users (odds ratio 0.61, 95% confidence interval 0.42–0.87). This association appeared to be modified by the presence of certain chronic medical conditions (i.e., hypertension, ischemic heart disease and cerebrovascular disease) in that the reduced risk was observed among those with these diseases, whereas no association was observed among those without any of these conditions. Conclusions: In this study, following adjustment for confounding factors, a statistically significant inverse association between statin use and AD was observed. The results lend support to looking at AD outcomes in trials of statins to further evaluate their possible beneficial effects.