Biomarkers of body iron stores and risk of developing type 2 diabetes.

AIM: Iron may contribute to the pathogenesis of type 2 diabetes mellitus (DM) by inducing oxidative stress and interfering with insulin secretion. Elevated ferritin levels are associated with increased DM risk among healthy individuals. However, it is yet unknown if ferritin predicts DM incidence among high-risk individuals with impaired glucose tolerance (IGT). Furthermore, the association between soluble transferrin receptors (sTfR), a novel marker of iron status, and DM risk has not yet been prospectively investigated in these individuals. We conducted this study to evaluate the association between baseline levels of ferritin and sTfR and the risk of developing DM among overweight and obese individuals at high risk of DM. METHODS: This nested case-control study (280 cases and 280 matched controls) was conducted within the placebo arm of the Diabetes Prevention Program, is a clinical trial conducted among overweight/obese individuals with IGT. Ferritin and sTfR levels were measured by immunoturbidimetric assays. Incident DM was ascertained by annual 75-g oral glucose tolerance test and semi-annual fasting glucose. RESULTS: Compared with controls, cases had higher sTfR levels (3.50 +/- 0.07 vs. 3.30 +/- 0.06 mg/l; p = 0.03), but ferritin levels were not statistically different. The multivariable odds ratios (OR) and 95% confidence intervals (95% CI) for DM incidence comparing highest with the lowest quartiles of sTfR was 2.26 (1.37-4.01) (p-trend: 0.008). CONCLUSIONS: Modestly elevated sTfR levels are associated with increased DM risk among overweight and obese individuals with IGT. Future studies should evaluate factors determining sTfR levels and examine if interventions that lower body iron stores reduce DM incidence.

Relationship of current and past smoking to mortality and morbidity in patients with left ventricular dysfunction.

OBJECTIVES: The aim of this study was to evaluate the impact of smoking in patients with left ventricular dysfunction. BACKGROUND: The impact of smoking in patients with left ventricular dysfunction has not been well-studied. METHODS: We compared the incidence of death, hospitalization due to heart failure and myocardial infarction (MI) in current smokers to ex-smokers of < or =2 years and ex-smokers of >2 years duration to never-smokers among participants of the Study Of Left Ventricular Dysfunction (SOLVD) Prevention and Intervention trials. Participants all had left ventricular ejection fraction (LVEF) <35% and follow-up was over a mean of 41 months. RESULTS: Complete smoking status and outcome data were available in 6,704 subjects. There were 1,562 current smokers, 1,317 ex-smokers of < or =2 years, 2,354 ex-smokers of >2 years and 1,471 never-smokers. After adjusting for baseline differences of age, LVEF, race and etiology of heart failure, current smoking was associated with a significantly increased all-cause mortality (relative risk [RR]: 1.41, 95% confidence interval [CI]: 1.25 to 1.58, p < 0.001) compared with ex-smokers and never-smokers. The incidence of death or recurrent congestive heart failure requiring hospitalization or MI was significantly greater (RR: 1.39, 95% CI: 1.26 to 1.52, p < 0.001) in current smokers compared with ex-smokers and never-smokers. There were no significant differences in the number of deaths or hospitalizations due to heart failure between ex-smokers and never-smokers. This effect was consistent across both the SOLVD Prevention and Treatment trials. CONCLUSIONS: Current smoking is a powerful independent predictor of morbidity (recurrent heart failure and MI) and mortality in patients with left ventricular dysfunction. Quitting smoking appears to have a substantial and early effect (within two years) on decreasing morbidity and mortality in patients with left ventricular dysfunction, which is at least as large as proven drug treatments recommended in patients with left ventricular dysfunction.

Enalapril prevents clinical proteinuria in diabetic patients with low ejection fraction.

OBJECTIVE: Clinical proteinuria is a risk factor for both end-stage renal disease and cardiovascular disease. The prevalence of clinical proteinuria, its correlates and predictive value, and the effect of ACE inhibitors in preventing clinical proteinuria in diabetic and nondiabetic patients with left ventricular (LV) dysfunction are unknown. RESEARCH DESIGN AND METHODS: The Studies of Left Ventricular Dysfunction (SOLVD) trials were analyzed to determine the baseline distribution of clinical proteinuria and related cardiovascular risk factors, the effect of baseline proteinuria on the risk of hospitalization for congestive heart failure (CHF) and mortality, and the effect of enalapril in preventing new clinical proteinuria. RESULTS: A total of 5,487 out of 6,797 SOLVD participants (81%) were assessed for proteinuria at baseline. A total of 177 patients (3.2%) had baseline proteinuria. These patients had significantly higher systolic (137 vs. 125 mmHg, P < or = 0.001) and diastolic (83 vs. 77 mmHg, P < or = 0.001) blood pressure levels, a higher prevalence of diabetes (41 vs. 18%, P < or = 0.001), a lower ejection fraction (26.2 vs. 27.3%, P < or = 0.05), and greater degree of CHF (New York Heart Association [NYHA] class III/IV in 22 vs. 10%, P < or = 0.001) than patients without baseline proteinuria. Patients with baseline proteinuria also had higher rates of hospitalization for CHF (relative risk 1.81 [95% CI 1.37-2.41], P = 0.0001) and mortality (1.73 [1.34-2.24], P = 0.0001). Enalapril prevented clinical proteinuria in diabetic patients (0.38 [0.17-0.81], P = 0.0123) but not in nondiabetic patients (1.43 [0.77-2.63], P = 0.2622) without baseline proteinuria. CONCLUSIONS: Clinical proteinuria is an independent predictor of hospitalization for CHF and mortality in diabetic and nondiabetic patients with LV dysfunction. Enalapril significantly reduces the risk of clinical proteinuria in diabetic patients with LV dysfunction.

Reliability, validity, and responsiveness of the six-minute walk test in patients with heart failure.

BACKGROUND: Our purpose was to evaluate the reliability, validity, and responsiveness of the 6-minute walk test (6MWT) in patients with heart failure (HF) enrolled in the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) pilot study. METHODS: A total of 768 patients was enrolled in a multicenter randomized clinical trial evaluating the effect of candesartan, enalapril, and metoprolol on left ventricular ejection fraction (LVEF), 6MWT distance, neurohormones, and quality of life. The 6MWT was performed once at screening and twice at baseline, 18 weeks, and 43 weeks by a standardized method. RESULTS: Test-retest reliability at baseline (intraclass correlation coefficient [ICC] = 0.90), 18 weeks (ICC = 0.88), and 43 weeks (ICC = 0.91) was very good. Baseline 6MWT distance was weakly inversely correlated to the quality-of-life cumulative score (r = -0.26, P =.0001) and moderately inversely correlated to the New York Heart Association functional classification (NYHA-FC) (r = -0.43, P =.001). In the RESOLVD study, the 6MWT was not responsive to change when effect sizes and standardized response means were used. Disease-specific quality of life was responsive to change in patients treated with candesartan and enalapril and NYHA-FC was responsive to change in the candesartan and enalapril combination and for enalapril alone with small effect sizes. The 6MWT, NYHA-FC, and quality of life were not responsive to change during the metoprolol or placebo phase. CONCLUSIONS: The 6MWT is highly reproducible in patients with symptoms of HF. It is somewhat correlated to NYHA-FC and quality of life. Overall, quality of life was most responsive to change, whereas 6MWT and NYHA-FC were comparable but less responsive to change in the RESOLVD study.

Tree-structured prediction for censored survival data and the Cox model.

Prediction trees for the analysis of survival data are discussed. It is shown that trees are useful not only in summarizing the prognostic information contained in a set of covariates (prognostic classification), but also in detecting and displaying treatment-covariates interactions (subgroup analysis). The RECPAM approach to tree-growing is outlined; prognostic classification and subgroup analysis are then formulated within the RECPAM framework and on the basis of the Cox proportional hazards models with a priori strata. Two examples of data analysis are presented. The issue of cross-validation is discussed in relation to computationally cheaper model selection criteria.

NHPPREG: a computer program for the analysis of nonhomogeneous Poisson process data with covariates.

A program written in C is described which finds maximum likelihood estimates of regression coefficients and other relevant parameters for a point process with covariates. The data are assumed to come from a Poisson point process and may be modelled, at the user's choice, either totally parametrically or semi-parametrically. Furthermore, extra Poisson variation may be introduced, in both the parametric and semi-parametric approach, by the device of random effects. The work closely follows the theory developed by Lawless (1987).

Effect of smoking cessation on cough reflex sensitivity.

Recent studies have shown that cigarette smokers have diminished cough reflex sensitivity compared with nonsmokers. The current authors proposed a mechanism of chronic cigarette smoke-induced desensitisation of airway cough receptors. To investigate this hypothesis, cough sensitivity to inhaled capsaicin (C5) in chronic smokers was measured both while they were actively smoking and 2, 6, 12 and 24 weeks after smoking cessation. In total, 29 subjects underwent baseline capsaicin challenge while smoking and 2 weeks after smoking cessation. Mean+/-sem log C5 fell from 1.86+/-0.12 to 1.60+/-0.12, demonstrating significant enhancement of cough reflex sensitivity. Of the total, 20, 18 and 14 subjects successfully abstained from smoking for 6, 12 and 24 weeks, respectively. Mean log C5 values after 12 and 24 weeks of smoking cessation were significantly diminished from baseline. In a control group of smokers, mean log C5 did not decrease from baseline after 6, 12 and 24 weeks. Overall, the log C5 profile of the smoking cessation group showed a clear, linearly decreasing trend over time compared with the control group. Even after many years of smoking, cough sensitivity is enhanced as early as 2 weeks after smoking cessation. Given the importance of an intact cough reflex, these changes may provide clinical benefit.

INTER-HEART: A global study of risk factors for acute myocardial infarction.

BACKGROUND: Although declines in mortality rates have occurred in most developed countries, increases are being seen in developing countries. Our knowledge of risk factors for acute myocardial infarction (AMI) is largely derived from studies in the former. Applicability of these results to other populations is unknown. The objectives of INTER-HEART are to determine the association between risk factors and AMI within populations defined by ethnicity and/or geographic region and to assess the relative importance of risk factors across these populations. METHODS: INTER-HEART is a study of 14,000 cases of AMI and 16,000 matched control patients from 46 countries, which was conducted with a standardized protocol. Questionnaires were translated into 11 languages; physical measurements were obtained, and 20 mL of blood was drawn and shipped frozen to a central laboratory in Canada. The study will evaluate the importance of conventional and emerging risk factors within each geographic region and whether their impact varies by region. RESULTS: INTER-HEART is sponsored by the World Health Organization and the World Heart Federation and has received funding from several peer-reviewed agencies and many different pharmaceutical companies. A vanguard phase (February 1999 to 2000) enrolled 4000 subjects from 41 countries. Full data collection started in April 2000 and is expected to be completed by October 2002. CONCLUSIONS: Several years of targeted work have allowed the development of the concepts that were tested in the pilot studies. This has ensured the feasibility of INTER-HEART. This study has the potential to have a major impact in developing a worldwide strategy for cardiovascular disease prevention, especially in developing countries and nonwhite populations.

GEE analysis of negatively correlated binary responses: a caution.

The method of generalized estimating equations has become almost standard for analysing longitudinal and other correlated response data. However, we have found that if binary responses have less than binomial variation over clusters, and are modelled using exchangeable correlations, prevailing software implementations may give unreliable results. Bounding the negative correlation away from its theoretical minimum may not always be a satisfactory solution. In such instances, using the independence working correlation structure and robust SEs is a more trustworthy alternative.

Interaction between tobacco and alcohol consumption and the risk of cancers of the upper aero-digestive tract in Brazil.

The authors investigated the joint effects of tobacco and alcohol consumption on the risk of squamous cell carcinomas of the upper aero-digestive tract (UADT) using data from a hospital-based case-control study conducted in southern Brazil, 1986-1989. A total of 784 cases of cancers of the mouth, pharynx, and larynx and 1,578 non-cancer controls matched on age, sex, hospital catchment area, and period of admission were interviewed about their smoking and drinking habits and other characteristics. Using logistic regression, evidence was found for interaction between the cumulative exposures for smoking and alcohol on UADT cancer risk. The joint effects for pharyngeal cancers exceeded the levels expected under a multiplicative model for moderate smokers (p = 0.007). There was little statistical evidence, however, for interaction on cancers of the mouth (p = 0.28) or larynx (p = 0.95). Among never smokers, heavy drinkers had 9.2 times (95% confidence interval 1.7, 48.5) greater risk of cancers of mouth, pharynx, and supraglottis than never drinkers, with a dose-response trend (p = 0.013) with cumulative consumption. The authors conclude that the interaction occurring in the pharynx between smoking and alcohol on UADT cancers is not uniform, with varying effects depending on the level of smoking exposure. Alcohol may act as both a promoter for tobacco and as an independent risk factor.

Polymorphism of the insulin gene is associated with increased prostate cancer risk.

High insulin levels are linked with increased cancer risk, including prostate cancer. We examined the associations between prostate cancer with polymorphisms of the insulin gene (INS) and its neighbouring genes, tyrosine-hydroxylase and IGF-II (TH and IGF2). In this study, 126 case-control pairs matched on age, race, and countries of origin were genotyped for +1127 INS-PstI in INS, -4217 TH-PstI in TH, and +3580 IGF2-MspI in IGF2. The homozygous CC genotype of +1127 INS-PstI occurred in over 60% of the population. It was associated with an increased risk of prostate cancer in nondiabetic Blacks and Caucasians (OR=3.14, P=0.008). The CC genotype was also associated with a low Gleason score <7 (OR=2.60, P=0.022) and a late age of diagnosis (OR=2.10, P=0.046). Markers in the neighbouring genes of INS showed only null to modest associations with prostate cancer. The polymorphism of INS may play a role in the aetiology of prostate cancer. Given the high prevalence of the CC genotype and its association with late age of onset of low-grade tumours, this polymorphism may contribute to the unique characteristics of prostate cancer, namely a high prevalence of indolent cancers and the dramatic increase in incidence with age.