Diffusion tensor imaging of deep gray matter in children treated for brain malignancies.

PURPOSE: Previous DTI studies reported microstructural changes in white matter of patients receiving treatment for brain malignancies. The primary aim of this prospective pilot longitudinal study was to examine if DTI can detect microstructural changes in deep gray matter (as evaluated by the apparent diffusion coefficient, ADC) between pediatric patients treated with cranial radiation therapy and typically developing healthy children. The relationship between ADC and neurobehavioral performance was also examined. METHODS: ADC was measured at 1.5 T in the caudate, putamen, globus pallidus, thalamus, and hippocampus in nine patients (mean age 11.8 years) and nine age-matched healthy controls. The study was designed with four visits: baseline, 6-month, 15-month, and 27-month follow-ups. RESULTS: Patients had 24 % higher overall mean ADC in the hippocampus compared with controls (p = 0.003). Post hoc analyses revealed significantly elevated ADC at baseline (p = 0.003) and at the 27-month follow-up (p = 0.006). Nevertheless, patients performed normally on a verbal memory test considered to be a hippocampus-related function. Relative to controls, patients' performance on the tests of the visual-spatial working memory decreased over time (group by visit, p = 0.036). Both patients and controls showed a decline in motor speed with increasing ADC in the globus pallidus and putamen. CONCLUSIONS: Childhood brain malignancies and their treatment may affect gray matter microstructure as measured by water diffusion. Significant findings in the hippocampus but not other regions suggest that differences in tissue sensitivity to disease- and treatment-related injury among gray matter regions may exist. ADC in basal ganglia may be associated with motor performance.

Antibody dynamics and spontaneous viral clearance in patients with acute hepatitis C infection in Rio de Janeiro, Brazil.

BACKGROUND: The anti-HCV antibody response has not been well characterized during the early phase of HCV infection and little is known about its relationship to the clinical course during this period. METHODS: We analyzed serial anti-HCV antibodies longitudinally obtained from a prospective cohort of 65 patients with acute HCV infection by using a microparticle enzyme immunoassay AxSYM HCV 3.0 (Abbott Diagnostics) during the first 12 months from HCV acquisition in Rio de Janeiro, Brazil. Spontaneous viral clearance (SVC) was defined as undetectable HCV RNA in serum, in the absence of treatment, for three consecutive HCV PCR tests within 12-months of follow-up. RESULTS: Baseline antibody values were similar among patient groups with self-limiting HCV evolution (n = 34) and persistent viremia (n = 31) [median (interquartile range) signal/cut-off ratio (s/co) 78.7 (60.7-93.8) vs. 93.9 (67.8-111.9), p = 0.26]. During 12-months follow-up, patients with acute spontaneous resolving HCV infection showed significantly lower serial antibody response in comparison to individuals progressing to chronic infection [median (interquartile range) s/co 62.7 (35.2-85.0) vs. 98.4 (70.4-127.4), p < 0.0001]. In addition, patients with self-limiting HCV evolution exhibited an expeditious, sharp decline of serial antibody values after SVC in comparison to those measured before SVC [median (interquartile range) s/co 56.0 (25.4-79.3) vs. 79.4 (66.3-103.0), p < 0.0001]. CONCLUSION: Our findings indicate a rapid short-term decline of antibody values in patients with acute spontaneous resolving HCV infection.

Longitudinal change in serum gamma-glutamyltransferase and cardiovascular disease mortality: a prospective population-based study in 76,113 Austrian adults.

OBJECTIVE: The purpose of this study was to investigate the association of longitudinal change in serum gamma-glutamyltransferase (GGT) with mortality from cardiovascular disease (CVD). METHODS AND RESULTS: A population-based cohort of 76,113 Austrian men and women with 455,331 serial GGT measurements was prospectively followed-up for a median of 10.2 years after assessment of longitudinal GGT change during an average period of 6.9 years. Cox proportional hazards regression with time-varying covariates was used to evaluate GGT change as an independent predictor for CVD death. Independently of baseline GGT and other classical CVD risk factors, a pronounced increase in GGT (7-year change >9.2 U/L) was significantly associated with increased total CVD mortality in men (P=0.005); the adjusted hazard ratio (95% confidence interval) in comparison to stable GGT (7-year change -0.7 to 1.3 U/L) was 1.40 (1.09 to 1.81). Similarly, total CVD risk was elevated for increasing GGT in women, although effects were less pronounced and statistically significant only in subanalyses regarding coronary heart disease. Age of participants significantly modified the relation between GGT change and CVD mortality, with markedly stronger associations to be observable for younger individuals. CONCLUSIONS: Our study is the first to demonstrate that a longitudinal increase in GGT, independently of baseline GGT and even within its normal range, significantly increases risk of fatal CVD.

Age, sex, and race influence single-strand break repair capacity in a human population.

Recently, we developed an improved comet assay protocol for evaluating single-strand break repair capacity (SSB-RC) in unstimulated cryopreserved human peripheral blood mononuclear cells (PBMCs). This methodology facilitates control of interexperimental variability [A.R. Trzeciak, J. Barnes, M.K. Evans, A modified alkaline comet assay for measuring DNA repair capacity in human populations. Radiat. Res. 169 (2008) 110-121]. The fast component of SSB repair (F-SSB-RC) was assessed using a novel parameter, the initial rate of DNA repair, and the widely used half-time of DNA repair. The slow component of SSB repair (S-SSB-RC) was estimated using the residual DNA damage after 60 min. We have examined repair of gamma-radiation-induced DNA damage in PBMCs from four age-matched groups of male and female whites and African-Americans between ages 30 and 64. There is an increase in F-SSB-RC with age in white females (P<0.01) and nonsignificant decrease in F-SSB-RC in African-American females (P=0.061). F-SSB-RC is lower in white females than in white males (P<0.01). There is a decrease in F-SSB-RC with age in African-American females as compared to white females (P<0.002) and African-American males (nonsignificant, P=0.059). Age, sex, and race had a similar effect on intercellular variability of DNA damage in gamma-irradiated and repairing PBMCs. Our findings suggest that age, sex, and race influence SSB-RC as measured by the alkaline comet assay. SSB-RC may be a useful clinical biomarker.

Gamma-glutamyltransferase as a risk factor for cardiovascular disease mortality: an epidemiological investigation in a cohort of 163,944 Austrian adults.

BACKGROUND: There is evidence from recent studies that gamma-glutamyltransferase (GGT) is likely to be associated with cardiovascular disease (CVD). However, few studies to date with sufficient sample size and follow-up investigated the association of GGT with CVD mortality. METHODS AND RESULTS: The relation of GGT to the risk of death from CVD was examined in a cohort of 163,944 Austrian adults that was monitored for up to 17 years. To evaluate GGT as an independent predictor, Cox proportional hazards models were calculated, which adjusted for established risk factors. In both men and women, high GGT was significantly (P<0.001) associated with total mortality from CVD, showing a clear dose-response relationship. Adjusted hazard ratios (95% CI) per log GGT increase were 1.66 (1.40 to 1.98) in men and 1.64 (1.36 to 1.97) in women. In men, subgroup analyses showed that high GGT was positively associated with incident fatal events of chronic forms of coronary heart disease (P=0.009), congestive heart failure (P<0.001), and hemorrhagic (P=0.01) and ischemic stroke (P<0.001). No significant associations were observed for acute myocardial infarction (P=0.16). In women, hazard ratios suggested associations in all subgroups; however, for hemorrhagic and ischemic stroke they were not statistically significant (P=0.09 and P=0.07, respectively). In addition, subgroup analyses stratified by age revealed a stronger relationship of GGT in younger participants. Hazard ratios for total CVD were 2.03 (1.53 to 2.69) in men and 2.60 (1.53 to 4.42) in women younger than 60 years. CONCLUSIONS: This study demonstrates in a large, prospectively observed cohort that GGT is independently associated with cardiovascular mortality.

Accelerated longitudinal decline of aerobic capacity in healthy older adults.

BACKGROUND: The ability of older persons to function independently is dependent largely on the maintenance of sufficient aerobic capacity and strength to perform daily activities. Although peak aerobic capacity is widely recognized to decline with age, its rate of decline has been estimated primarily from cross-sectional studies that may provide misleading, overly optimistic estimates of aging changes. METHODS AND RESULTS: To determine longitudinal rate of change in aerobic capacity and the influence of age, gender, and physical activity on these changes, we performed serial measurements of peak treadmill oxygen consumption (peak VO2) in 375 women and 435 men ages 21 to 87 years from the Baltimore Longitudinal Study of Aging, a community-dwelling cohort free of clinical heart disease, over a median follow-up period of 7.9 years. A linear mixed-effects regression model was used to calculate the predicted longitudinal 10-year rate of change in peak VO2, expressed in milliliters per minute, for each age decade from the 20s through the 70s after adjustment for self-reported leisure-time physical activity. A longitudinal decline in peak VO2 was observed in each of the 6 age decades in both sexes; however, the rate of decline accelerated from 3% to 6% per 10 years in the 20s and 30s to >20% per 10 years in the 70s and beyond. The rate of decline for each decade was larger in men than in women from the 40s onward. Similar longitudinal rates of decline prevailed when peak VO2 was indexed per kilogram of body weight or per kilogram of fat-free mass and in all quartiles of self-reported leisure-time physical activity. When the components of peak VO2 were examined, the rate of longitudinal decline of the oxygen pulse (ie, the O2 utilization per heart beat) mirrored that of peak VO2, whereas the longitudinal rate of heart rate decline averaged only 4% to 6% per 10 years, and accelerated only minimally with age. CONCLUSIONS: The longitudinal rate of decline in peak VO2 in healthy adults is not constant across the age span in healthy persons, as assumed by cross-sectional studies, but accelerates markedly with each successive age decade, especially in men, regardless of physical activity habits. The accelerated rate of decline of peak aerobic capacity has substantial implications with regard to functional independence and quality of life, not only in healthy older persons, but particularly when disease-related deficits are superimposed.

Data from a longitudinal study provided measurements of cognition to screen for Alzheimer's disease.

BACKGROUND: This article presents a computerized method to help predict individuals at risk for developing Alzheimer's disease (AD). This would be a valuable tool for clinicians in developing treatment plans for potential AD patients. Using the initial level and rates of change in visual memory performance, such a method could predict potential AD patients in a fast and inexpensive manner. A longitudinal case-control study of 52 female and 145 male participants was performed in a gerontology research center using premorbid tests of visual memory and neurologic examinations to identify individuals with and without dementia and AD. METHODS: The classification method for each individual starts on the second examination and proceeds to compute that person's risk of AD one examination at a time based on all the follow-up information of the remaining individuals. RESULTS: By performing a crossvalidation study, the optimal combination of sensitivity and specificity derived from a receiver operating characteristic (ROC) curve showed 65% of the Alzheimer cases and 75% of the noncases were correctly classified for females, while 65 and 60% of cases and noncases, respectively, were correctly classified for males. CONCLUSION: Longitudinal measurements of cognition can be useful in detecting the presence of AD.

Serum erythropoietin and aging: a longitudinal analysis.

OBJECTIVES: To determine the changes in serum erythropoietin with age in patients with and without anemia and to assess the importance of certain comorbidities on changes in erythropoietin level and the development of anemia. DESIGN: Clinical history, hematological parameters, and serum erythropoietin levels were examined at 1- to 2-year intervals for 8 to 30 years. SETTING: Baltimore Longitudinal Study on Aging (BLSA), National Institute on Aging. PARTICIPANTS: One hundred forty-three BLSA participants. MEASUREMENTS: Complete blood count and serum chemistries were performed at the time of each visit, and archived serum samples were used for erythropoietin level. RESULTS: Although all subjects were healthy and without anemia at the time of initial evaluation, some developed chronic illness-most notably hypertension and diabetes mellitus. Erythropoietin levels rose significantly for the group as a whole, and the slope of the rise was found to be greater for those who did not have associated diabetes mellitus or hypertension. During the subsequent years, subjects who developed anemia but did not have hypertension or diabetes mellitus had the greatest slope in erythropoietin rise over time, whereas those with hypertension or diabetes mellitus and anemia had the lowest erythropoietin slope. CONCLUSION: The increase in serum erythropoietin with aging may be compensation for subclinical blood loss, increased red blood cell turnover, or increased erythropoietin resistance of red cell precursors. It is suspected that, with very advanced age, or in those with compromised renal function (e.g., diabetes mellitus or hypertension), the compensatory mechanism becomes inadequate and anemia results.

Hierarchical linear modeling analyses of the NEO-PI-R scales in the Baltimore Longitudinal Study of Aging.

The authors examined age trends in the 5 factors and 30 facets assessed by the Revised NEO Personality Inventory in Baltimore Longitudinal Study of Aging data (N=1,944; 5,027 assessments) collected between 1989 and 2004. Consistent with cross-sectional results, hierarchical linear modeling analyses showed gradual personality changes in adulthood: a decline in Neuroticism up to age 80, stability and then decline in Extraversion, decline in Openness, increase in Agreeableness, and increase in Conscientiousness up to age 70. Some facets showed different curves from the factor they define. Birth cohort effects were modest, and there were no consistent Gender x Age interactions. Significant nonnormative changes were found for all 5 factors; they were not explained by attrition but might be due to genetic factors, disease, or life experience.

Estimates of future physical functioning by seriously ill hospitalized patients, their families, and their physicians.

OBJECTIVES: To compare prognostic estimates made by seriously ill hospitalized patients, their surrogates, and their physicians about the patients' activities of daily living (ADLs) 2 months after admission; compare the accuracy of their estimates; and identify factors associated with the optimism and accuracy of these estimates. DESIGN: Prospective cohort study. SETTING: Five teaching hospitals. PARTICIPANTS: A subset (n = 716) of patients in the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment. MEASUREMENTS: Prognostic estimates of ADL function. RESULTS: Physicians were less likely than patients or surrogates to give very high or very low estimates for future functioning. Seven of ten (69.3) patients who survived 2 months estimated that they would be functionally independent at Month 2, compared with 58.5 of their surrogates and 49.2 of their physicians. Agreement on prognosis was highest between patients and surrogates (64.2) and lowest between patients and physicians (48.4). Factors significantly associated with an optimistic estimate of independent functioning were better baseline ADL function, male gender, and higher level of education. Patients were significantly more accurate than surrogates and even more so than physicians in predicting independent functioning at Month 2. Worse baseline function and higher income were significantly associated with accurate estimation. CONCLUSION: At hospital admission, seriously ill patients were more optimistic about their prognosis for physical functioning at 2 months, and more accurate in their estimates, than surrogates and physicians. Physicians tended to underestimate the prognosis for future functioning. Physicians should consider patients' and families' estimates before giving advice about treatment options and discharge planning.

Screening for prostate cancer using multivariate mixed-effects models.

Using several variables known to be related to prostate cancer, a multivariate classification method is developed to predict the onset of clinical prostate cancer. A multivariate mixed-effects model is used to describe longitudinal changes in prostate specific antigen (PSA), a free testosterone index (FTI), and body mass index (BMI) before any clinical evidence of prostate cancer. The patterns of change in these three variables are allowed to vary depending on whether the subject develops prostate cancer or not and the severity of the prostate cancer at diagnosis. An application of Bayes' theorem provides posterior probabilities that we use to predict whether an individual will develop prostate cancer and, if so, whether it is a high-risk or a low-risk cancer. The classification rule is applied sequentially one multivariate observation at a time until the subject is classified as a cancer case or until the last observation has been used. We perform the analyses using each of the three variables individually, combined together in pairs, and all three variables together in one analysis. We compare the classification results among the various analyses and a simulation study demonstrates how the sensitivity of prediction changes with respect to the number and type of variables used in the prediction process.

Examining heterogeneity of functional recovery among older adults with hip fractures.

OBJECTIVE: To examine heterogeneity in 1-year functional recovery following postacute rehabilitation among older adults with hip fracture. METHODS: Two hundred twenty-five community-dwelling older adults with hip fracture who received postacute rehabilitation in 5 rehabilitation facilities in Baltimore, Maryland, were recruited during postacute rehabilitation (baseline) and follow-up at 2, 6, and 12 months following postacute rehabilitation discharge. Functional recovery was measured by the activities of daily living (ADL) and instrumental activities of daily living (IADL) scores. A mixed-effect model was used to examine factors associated with postacute rehabilitation functional recovery; fixed and random effects estimates from the models were used to demonstrate heterogeneity in functional recovery. RESULTS: Results indicated that there was an overall trend in both ADL and IADL functional improvement at 2 months following postacute rehabilitation, with continued improvement to 6 months, after which functional recovery slowed down and remained constant through the year. Individuals whose functional recovery did not conform to these patterns were identified and their functional recovery that deviated substantially from the group mean was demonstrated. CONCLUSIONS: Functional recovery patterns in elderly hip fracture patients are heterogeneous. To foster functional independence, health care professionals should consider individual recovery trajectories using a modeling approach appropriate for longitudinal or repeated measurement data such as a linear mixed-effects model when designing individualized rehabilitation and postacute rehabilitation care plans.

Gender differences in the accuracy of time-dependent blood pressure indices for predicting coronary heart disease: A random-effects modeling approach.

BACKGROUND: Previous studies on blood pressure (BP) indices as a predictor of coronary heart disease (CHD) have provided equivocal results and generally relied on Cox proportional hazards regression methodology, with age and sex accounting for most of the predictive capability of the model. OBJECTIVE: The aim of the present study was to use serially collected BP measurements to examine age-and gender-related differences in BP indices for predicting CHD. METHODS: The predictive accuracy of time-dependent BP indices for CHD was investigated using a method of risk prediction based on posterior probabilities calculated from mixed-effects regression to utilize intraindividual differences in serial BP measurements according to age changes within gender groups. Data were collected prospectively from 2 community-dwelling cohort studies in the United States (Baltimore Longitudinal Study of Aging [BLSA]) and Europe (Vorarlberg Health Monitoring and Promotion Program [VHM&PP]). RESULTS: The study comprised 152,633 participants (aged 30-74 years) and 610,061 BP measurements. During mean follow-up of 7.5 years, 2457 nonfatal and fatal CHD events were observed. In both study populations, pulse pressure (PP) and systolic blood pressure (SBP) performed best as individual predictors of CHD in women (area under the receiver operating characteristic curve [AUC(ROC)] was between 0.83 and 0.85 for PP, and between 0.77 and 0.81 for SBP). Mean arterial pressure (MAP) and diastolic blood pressure (DBP) performed better for men (AUC(ROC) = 0.67 and 0.65 for MAP and DBP, respectively, in the BLSA; AUC(ROC) = 0.77 and 0.75 in the VHM&PP) than for women (AUC(ROC) = 0.60 for both MAP and DBP in the BLSA; AUC(ROC) = 0.75 and 0.52, respectively, in the VHM&PP). The degree of discrimination in both populations was overall greater but more varied for all BP indices for women (AUC(ROC) estimates between 0.85 [PP in the VHM&PP] and 0.52 [DBP in the VHM&PP]) than for men (AUC(ROC) estimates between 0.78 [MAP + PP in the VHM&PP] and 0.63 [PP in the BLSA]). CONCLUSION: Our findings indicate differences in discrimination between women and men in the accuracy of longitudinally collected BP measurements for predicting CHD, implicating the usefulness of gender-specific BP indices to assess individual CHD risk.

Prospective study of the association of serum gamma-glutamyltransferase with cervical intraepithelial neoplasia III and invasive cervical cancer.

Epidemiologic studies indicate that elevated levels of gamma-glutamyltransferase (GGT), a key enzyme of glutathione metabolism, might be associated with increased cancer risk. Furthermore, preclinical studies support a role for GGT in tumor invasion and progression. However, the relationship between GGT and risks of cervical intraepithelial neoplasia III (CIN-III) and invasive cervical cancer (ICC) have not been evaluated. We investigated the association of enzymatically determined GGT in blood serum with subsequent incidence of CIN-III and ICC in a prospective population-based cohort of 92,843 women ages 18 to 95, of whom 79% had at least one gynecologic examination including Pap smear testing during follow-up. Cox regression was used to compute adjusted hazard ratios (HR) with 95% confidence intervals for the association of GGT with CIN-III and ICC. During median follow-up of 13.8 years, 702 CIN-III and 117 ICC diagnoses were observed. Compared with normal low GGT (<17.99 units/L), risk of ICC was significantly elevated for all other baseline GGT categories, with adjusted HRs of 2.31 (1.49-3.59) for normal high GGT (18.00-35.99 units/L), 2.76 (1.52-5.02) for elevated GGT (36.00-71.99 units/L), and 3.38 (1.63-7.00) for highly elevated GGT [>72.00 units/L; P trend < 0.0001, HR log unit increase 3.45 (1.92-6.19)]. In contrast, associations between GGT serum levels and CIN-III risk were not statistically significant in the main analysis. Exclusion of the first 2 or 5 years of follow-up did not change the results. Effects did not differ by age, body mass index, or socioeconomic status. Our findings implicate GGT in the progression of premalignant cervical lesions to invasive cancer.

Model choice can obscure results in longitudinal studies.

BACKGROUND: This article examines how different parameterizations of age and time in modeling observational longitudinal data can affect results. METHODS: When individuals of different ages at study entry are considered, it becomes necessary to distinguish between longitudinal and cross-sectional differences to overcome possible selection biases. RESULTS: Various models were fitted using data from longitudinal studies with participants with different ages and different follow-up lengths. Decomposing age into two components-age at entry into the study (first age) and the longitudinal follow-up (time) compared with considering age alone-leads to different conclusions. CONCLUSIONS: In general, models using both first age and time terms performed better, and these terms are usually necessary to correctly analyze longitudinal data.

Use of penalized splines in extended Cox-type additive hazard regression to flexibly estimate the effect of time-varying serum uric acid on risk of cancer incidence: a prospective, population-based study in 78,850 men.

PURPOSE: We sought to investigate the effect of serum uric acid (SUA) levels on risk of cancer incidence in men and to flexibly determine the shape of this association by using a novel analytical approach. METHODS: A population-based cohort of 78,850 Austrian men who received 264,347 serial SUA measurements was prospectively followed-up for a median of 12.4 years. Data were collected between 1985 and 2003. Penalized splines (P-splines) in extended Cox-type additive hazard regression were used to flexibly model the association between SUA, as a time-dependent covariate, and risk of overall and site-specific cancer incidence and to calculate adjusted hazard ratios with their 95% confidence intervals. RESULTS: During follow-up 5189 incident cancers were observed. Restricted maximum-likelihood optimizing P-spline models revealed a moderately J-shaped effect of SUA on risk of overall cancer incidence, with statistically significantly increased hazard ratios in the upper third of the SUA distribution. Increased SUA (>/=8.00 mg/dL) further significantly increased risk for several site-specific malignancies, with P-spline analyses providing detailed insight about the shape of the association with these outcomes. CONCLUSIONS: Our study is the first to demonstrate a dose-response association between SUA and cancer incidence in men, simultaneously reporting on the usefulness of a novel methodological framework in epidemiologic research.

Serum uric acid and risk of cardiovascular mortality: a prospective long-term study of 83,683 Austrian men.

BACKGROUND: The role of serum uric acid (SUA) as an independent risk factor for cardiovascular disease (CVD) remains controversial, and little is known about its prognostic importance for mortality from congestive heart failure (CHF) and stroke. Few large-scale epidemiologic studies with sufficient follow-up have addressed the association of SUA and CVD mortality in apparently healthy men across a wide age range. METHODS: A cohort of 83 683 Austrian men (mean age, 41.6 years) was prospectively followed for a median of 13.6 years. We used Cox proportional hazards models adjusted for established risk factors to evaluate SUA as an independent predictor for CVD mortality. RESULTS: The highest quintile of SUA concentration (>398.81 mumol/L) was significantly related to mortality from CHF (P = 0.03) and stroke (P <0.0001); adjusted hazard ratios (95% confidence interval) for the highest vs lowest quintiles of SUA were 1.51 (1.03-2.22) and 1.59 (1.23-2.04), respectively. SUA was not associated, however, with mortality from acute, subacute, or chronic forms of coronary heart disease (CHD) after adjustment for potential confounding factors (P = 0.12). Age was a significant effect modifier for the relation of SUA to fatal CHF (P = 0.05), with markedly stronger associations found in younger individuals. CONCLUSIONS: Our study demonstrates for the first time in a large prospective male cohort that SUA is independently related to mortality from CHF and stroke. Although increased SUA is not necessarily a causal risk factor, our results suggest the clinical importance of monitoring and intervention based on the presence of an increased SUA concentration, especially because SUA is routinely measured.

Serum uric acid is an independent predictor for all major forms of cardiovascular death in 28,613 elderly women: a prospective 21-year follow-up study.

BACKGROUND: The role of serum uric acid (SUA) as a risk factor for cardiovascular disease (CVD) remains controversial. Little is known about its predictive value for mortality from congestive heart failure (CHF) and stroke, particularly in elderly, post-menopausal women. METHODS: The relation of SUA to risk of death from total CVD, CHF, stroke and coronary heart disease (CHD) was examined prospectively in a large cohort of 28613 elderly Austrian women (mean age 62.3 years), followed-up for a median of 15.2 years. Adjusted Cox proportional hazards models were calculated to evaluate SUA as an independent predictor for fatal CVD events. RESULTS: SUA in the highest quartile (>or=5.41 mg/dL) was significantly associated with mortality from total CVD (p<0.0001), showing a clear dose-response relationship; the adjusted hazard ratio (95%CI) in comparison to the lowest SUA quartile was 1.35 (1.20-1.52). In subgroup analyses SUA was independently predictive for deaths from acute and subacute (p<0.0001) and chronic forms (p=0.035) of CHD, yielding adjusted hazard ratios for the highest versus lowest SUA quartile of 1.58 (1.19-2.10) and 1.25 (1.01-1.56), respectively. SUA was further significantly related to fatal CHF (p<0.0001) and stroke (p=0.018); the adjusted hazard ratios for the highest versus lowest SUA quartile were 1.50 (1.04-2.17) and 1.37 (1.09-1.74), respectively. CONCLUSIONS: These findings, for the first time, demonstrate that SUA is an independent predictor for all major forms of death from CVD including acute, subacute and chronic forms of CHD, CHF and stroke in elderly, post-menopausal women.