Carboxymethyl lysine, an advanced glycation end product, and incident diabetes: a case-cohort analysis of the ARIC Study.

AIMS: To verify whether elevated fasting levels of circulating carboxymethyl lysine (CML), an advanced glycation end product, predict the development of diabetes in middle-age adults. METHODS: Using a stratified case-cohort design, we followed 543 middle-aged individuals who developed diabetes and 514 who did not over a median 9 years in the Atherosclerosis Risk in Communities Study. Weighted Cox proportional hazards analyses were used to account for the design. RESULTS: In weighted analyses, correlation between CML levels and anthropometric, inflammatory or metabolic variables was minimal (Pearson correlations usually < 0.10). CML, when modelled as a continuous variable and after adjustment for age, sex, race, centre, parental history of diabetes, BMI, waist-to-hip ratio, non-esterified fatty acids, oxidized LDL-cholesterol, GFR, smoking, an inflammation score, adiponectin, leptin, insulin and glucose levels, was associated with an increased risk of diabetes [Hazard ratio (HR) = 1.35; 95% confidence interval (CI) 1.09-1.67, for each 100 ng/ml CML increment]. Baseline glucose level and race each modified the association (P < 0.05 for interaction), which was present only among those with impaired fasting glucose (≥ 5.6 mmol/l, HR = 1.61, 95% CI 1.26-2.05) and among white participants (HR = 1.50, 95% CI 1.13-1.99). CONCLUSIONS: Elevated fasting CML, after adjustment for multiple risk factors for diabetes, predicts the development of incident diabetes, the association being present among those with impaired fasting glucose and in white participants. These prospective findings suggest that advanced glycation end products might play a role in the development of diabetes.

Development and validation of an ankle brachial index risk model for the prediction of cardiovascular events.

BACKGROUND: The ankle brachial index (ABI) is related to risk of cardiovascular events independent of the Framingham risk score (FRS). The aim of this study was to develop and evaluate a risk model for cardiovascular events incorporating the ABI and FRS. DESIGN: An analysis of participant data from 18 cohorts in which 24,375 men and 20,377 women free of coronary heart disease had ABI measured and were followed up for events. METHODS: Subjects were divided into a development and internal validation dataset and an external validation dataset. Two models, comprising FRS and FRS + ABI, were fitted for the primary outcome of major coronary events. RESULTS: In predicting events in the external validation dataset, C-index for the FRS was 0.672 (95% CI 0.599 to 0.737) in men and 0.578 (95% CI 0.492 to 0.661) in women. The FRS + ABI led to a small increase in C-index in men to 0.685 (95% CI 0.612 to 0.749) and large increase in women to 0.690 (95% CI 0.605 to 0.764) with net reclassification improvement (NRI) of 4.3% (95% CI 0.0 to 7.6%, p = 0.050) and 9.6% (95% CI 6.1 to 16.4%, p < 0.001), respectively. Restricting the FRS + ABI model to those with FRS intermediate 10-year risk of 10 to 19% resulted in higher NRI of 15.9% (95% CI 6.1 to 20.6%, p < 0.001) in men and 23.3% (95% CI 13.8 to 62.5%, p = 0.002) in women. However, incorporating ABI in an improved newly fitted risk factor model had a nonsignificant effect: NRI 2.0% (95% CI 2.3 to 4.2%, p = 0.567) in men and 1.1% (95% CI 1.9 to 4.0%, p = 0.483) in women. CONCLUSIONS: An ABI risk model may improve prediction especially in individuals at intermediate risk and when performance of the base risk factor model is modest.

Cyclooxygenase polymorphisms and risk of cardiovascular events: the Atherosclerosis Risk in Communities (ARIC) study.

Cyclooxygenase-derived prostaglandins modulate cardiovascular disease risk. We genotyped 2212 Atherosclerosis Risk in Communities study participants (1,023 incident coronary heart disease (CHD) cases; 270 incident ischemic stroke cases; 919 non-cases) with available DNA for polymorphisms in PTGS1 and PTGS2. Using a case-cohort design, associations between genotype and CHD or stroke risk were evaluated using proportional hazards regression. In Caucasians, the reduced function PTGS1 -1006A variant allele was significantly more common among stroke cases compared to non-cases (18.2 versus 10.6%, P=0.027). In African Americans, the reduced function PTGS2 -765C variant allele was significantly more common in stroke cases (61.4 versus 49.4%, P=0.032). No significant relationships with CHD risk were observed. However, aspirin utilization appeared to modify the relationship between the PTGS2 G-765C polymorphism and CHD risk (interaction P=0.072). These findings suggest that genetic variation in PTGS1 and PTGS2 may be important risk factors for the development of cardiovascular disease events. Confirmation in independent populations is necessary.

Migraine and retinal microvascular abnormalities: the Atherosclerosis Risk in Communities Study.

OBJECTIVE: This study examined the association between vascular headaches and retinal microvascular disease. METHODS: We investigated the cross-sectional association between headaches (migraine/other headaches with aura, migraine without aura, other headaches without aura, no headaches) and retinal microvascular signs (retinopathy, focal arteriolar narrowing, arteriovenous nicking; arteriolar and venular calibers) among middle-aged African American and white men and women from the third examination of the Atherosclerosis Risk in Communities Study (1993 through 1995). RESULTS: After controlling for age, gender, race, study center, and cardiovascular risk factors, we determined that persons with headaches were more likely to have retinopathy than those without a history of headaches (odds ratio [OR] = 1.38, 95% CI = 0.96 to 1.99 for migraine/other headaches with aura; OR = 1.49, 95% CI = 1.05 to 2.12 for migraine without aura; and OR = 1.28, 95% CI = 0.99 to 1.65 for other headaches). Associations with migraine were stronger among the subset of participants without a history of diabetes or hypertension (OR = 1.79, 95% CI = 1.09 to 2.95 for migraine/other headaches with aura; and OR = 1.74, 95% CI = 1.11 to 2.71 for migraine without aura). Headaches were not associated with focal arteriolar narrowing or arteriovenous nicking. Persons with headaches tended to have smaller mean arteriolar and venular calibers; however, these associations did not tend to persist among those without hypertension or diabetes. CONCLUSION: Middle-aged persons with migraine and other headaches were more likely to have retinopathy signs, supporting the hypothesis that neurovascular dysfunction may underlie vascular headaches.

Do retinopathy signs in non-diabetic individuals predict the subsequent risk of diabetes?

BACKGROUND/AIMS: Isolated retinopathy signs are common in non-diabetic individuals and have been shown to be associated with impaired glucose metabolism. In a cohort of people without diabetes, the association of these retinopathy signs and subsequent development of diabetes were examined. METHODS: A population based cohort study of 7992 people aged 49-73 years without diabetes was conducted. Retinal photographs of these participants were evaluated for the presence of retinopathy signs according to a standardised protocol. Incident cases of diabetes were identified prospectively. RESULTS: After a follow up of 3 years, 291 (3.6%) people developed incident diabetes. In the total cohort, retinopathy was not significantly associated with incident diabetes (4.7% v 3.6%, multivariable adjusted odds ratio (OR) 1.1, 95% confidence intervals (CI), 0.7 to 1.9). However, among participants with a positive family history of diabetes, retinopathy was associated with incident diabetes (10.4% v 4.8%, multivariable adjusted OR 2.3, 95% CI, 1.0 to 5.3). Among participants without a family history of diabetes, retinopathy was not associated with incident diabetes CONCLUSIONS: In individuals with a family history of diabetes, retinopathy signs predict subsequent risk of clinical diabetes.

Mathematical estimation of the potential effect of vascular remodelling/dilatation on B-mode ultrasound intima-medial thickness.

BACKGROUND: Arterial diameter changes are known to impact wall thickness, but the clinical relevance of the changes is unclear. AIM: To use known mathematical relationships to estimate anticipated changes in arterial wall thicknesses occurring with enlargement of atherosclerotic regions. DESIGN: Mathematical relationships between a cylinder's diameter and its wall thickness were used to calculate the theoretical effect of diameter enlargement on the thickness of an atherosclerotic wall. METHODS: Equating the wall areas of two cylinders, one of smaller diameter than the other, allowed estimation of the degree of thickening that would be needed to maintain intima-medial thickness (IMT) after arterial remodelling. The difference in cylinder diameters was based on arterial diameter enlargement reported with atherosclerosis progression. Thus, the calculated wall changes estimate arterial changes which could go undetected if only IMT is measured by ultrasound. RESULTS: The expected IMT change for diameter enlargement is not a linear function of the diameter change, but varies depending upon initial size (diameter and IMT). Thus a 0.6 mm arterial diameter enlargement would be expected to cause a 0.039-0.235 mm change in IMT, depending on artery size. The estimated IMT change is similar to that associated with major atherosclerotic risk factors. DISCUSSION: The level of vascular remodelling reported with atherosclerosis could have a measurable impact on IMT, suggesting that indicators incorporating both diameter and IMT may be better disease indicators than IMT alone. Arterial diameters, as well as IMT, should be obtained in ultrasound studies of atherosclerosis.

Retinal microvascular changes and MRI signs of cerebral atrophy in healthy, middle-aged people.

OBJECTIVE: To examine the relation of retinal microvascular abnormalities and MRI signs of cerebral atrophy in healthy middle-aged people. METHODS: A population-based, cross-sectional study involved 1,684 persons aged 51 to 72 years who had cerebral MRI and retinal photography in 1993 to 1995. Sulcal and ventricular size were quantified from the MRI scans and coded as grades 0 to 9, with sulcal widening (SW) and ventricular enlargement (VE) defined as grades 3 or higher. The presence or absence of retinopathy, microaneurysms, hemorrhages, and other characteristics were defined from retinal photographs using a standardized protocol. Generalized arteriolar narrowing was defined from a computer-assisted measurement of arteriolar diameters from digitized photographs. RESULTS: Persons with retinopathy had higher sulcal (p = 0.001) and ventricular (p = 0.03) grades than persons without retinopathy. After adjusting for age, gender, race, mean arterial blood pressure, diabetes, cigarette smoking, common carotid artery intima-media thickness, and other vascular risk factors, retinopathy was significantly associated with SW (odds ratio [OR], 1.9; 95% CI, 1.2, 3.0) and VE (OR, 1.5; 95% CI, 1.0, 2.3). These associations persisted even in people without diabetes or hypertension (OR 1.9, 95% CI, 0.8, 4.4 for SW; OR 2.7, 95% CI, 1.2, 6.5 for VE). Other retinal arteriolar characteristics (arteriovenous nicking, focal and generalized arteriolar narrowing) were not related to sulcal or ventricular grade. CONCLUSIONS: In healthy, middle-aged people, retinopathy is independently associated with sulcal and ventricular enlargement on MRI. This finding is compatible with the hypothesis that microvascular characteristics may influence the development of cerebral atrophic changes.

Retinal microvascular abnormalities and incident stroke: the Atherosclerosis Risk in Communities Study.

BACKGROUND: Retinal microvascular abnormalities reflect damage from hypertension and other vascular processes. We examined the relation of such abnormalities to incident stroke. METHODS: A cohort of 10358 men and women (aged 51 to 72 years) living in four US communities underwent retinal photography and standard grading for retinal microvascular abnormalities. The calibres of all retinal arterioles and venules were measured after digital conversion of the photographs, and a summary arteriole-to-venule ratio (AVR) was calculated as an index of arteriolar narrowing (smaller AVR indicates greater narrowing). Cases of incident stroke admitted to hospital were identified and validated by case record reviews. FINDINGS: Over an average of 3.5 years, 110 participants had incident strokes. After adjustment for age, sex, race, 6-year mean arterial blood pressure, diabetes, and other stroke risk factors, most retinal microvascular characteristics were predictive of incident stroke, with adjusted relative risks of 2.58 (1.59-4.20) for any retinopathy, 3.11 (1.71-5.65) for microaneurysms, 3.08 (1.42-6.68) for soft exudates, 2.55 (1.27-5.14) for blot haemorrhages, 2.26 (1.00-5.12) for flame-shaped haemorrhages, and 1.60 (1.03-2.47) for arteriovenous nicking. The relative risk of stroke increased with decreasing AVR (p=0.03). The associations were similar for ischaemic strokes specifically, and for strokes in individuals with hypertension, either with or without diabetes. INTERPRETATION: Retinal microvascular abnormalities are related to incident stroke. The findings support a microvascular role in the pathogenesis of stroke. They suggest that retinal photography may be useful for cerebrovascular-risk stratification in appropriate populations.

Orthostatic hypotension as a risk factor for stroke: the atherosclerosis risk in communities (ARIC) study, 1987-1996.

BACKGROUND AND PURPOSE: The association between orthostatic hypotension (OH) and stroke has rarely been investigated in longitudinal studies. The purpose of the present study was to determine whether OH predicts ischemic stroke in a middle-aged, biethnic population after adjustment for known stroke risk factors. Diastolic, systolic, and consensus OH were evaluated for baseline associations and for the ability to predict stroke. METHODS: In 11 707 persons from the Atherosclerosis Risk in Communities (ARIC) cohort who were free of stroke and overt heart disease at baseline, Cox proportional hazards analyses modeled the association between OH at baseline and incident ischemic stroke over 7.9 years of follow-up. OH was defined as a systolic blood pressure drop >/=20 mm Hg (systolic OH), a diastolic blood pressure drop >/=10 mm Hg (diastolic OH), or a drop in either (consensus OH) when a person changed from a supine to standing position. RESULTS: OH was predictive of ischemic stroke, even after adjustment for numerous stroke risk factors (consensus OH: hazard ratio, 2.0; 95% CI, 1.2 to 3.2). While the baseline characteristics associated with OH varied depending on the type of OH, all types of OH had a similar risk of stroke. CONCLUSIONS: OH is an easily obtained measurement that may help to identify middle-aged persons at risk for stroke.

Health-associated changes in drinking: a period prevalence study of the Atherosclerosis Risk In Communities (ARIC) cohort (1987-1995).

BACKGROUND: Several investigators have suggested that drinking cessation occurs because of poor health which may bias studies on the benefit or risk of alcohol consumption. METHODS: Drinking status, level of alcohol consumption, and two measures of health (perceived health and physician diagnosed chronic disease status) were determined from exams 1 (1987-1989) and 3 (1993-1995) on 12,562 African- and European-American participants, who were aged 45-64 years at exam 1 in the ARIC Study. For those in good health at exam 1, logistic regression analyses were used to model the association between health decline and drinking change at exam 3. RESULTS: Among the total population, drinking cessation was significantly more common among those who reported poor health at exam 3, and nondrinkers were unlikely to begin drinking regardless of exam 3 health. Using different measures of health status resulted in associations whose strength and significance varied with ethnicity and, in some cases, by gender. CONCLUSION: While the current data do not prove that the health decline occurred prior to drinking cessation, our findings support the hypothesis that poor health results in drinking changes which could potentially bias studies of alcohol's benefit and risk even when lifetime abstainers are used as the reference group.

The 1984 Tasmanian insulin treated diabetes mellitus prevalence cohort: an eight and a half year mortality follow-up investigation.

Total mortality and underlying cause of death were examined in a population-based prevalence cohort (n = 1232) of Tasmanians with insulin-treated diabetes mellitus. Eight and a half years after the establishment of the registry, the cause of death based on death certificate information was determined for the overall cohort and for three classification groups of insulin-treated diabetes: Group A--childhood-onset IDDM cases; Group B--adult-onset IDDM cases; and Group C--adult-onset insulin-treated NIDDM cases. A total of 378 deaths occurred, providing an overall SMR of 2.2 (95% CI 2.0-2.4) compared to the Tasmanian population. Diabetic females experienced a higher SMR (2.6, 95% CI 2.3-3.0) than diabetic males (1.9, 95% CI 1.6-2.2). The all-cause SMRs for the diabetic classification groups were 4.6 (95% CI 3.4-6.1) in Group A, 1.8 (95% CI 1.5-2.1) in Group B, and 2.2 (95% CI 1.9-2.6) in Group C. After adjusting for age, gender and duration of diabetes, the mortality in Group C was significantly higher compared to Group B (odds ratio 1.6, 95% CI 1.2-2.3). This study indicates that people with childhood-onset IDDM experience 4.6 times the death rate compared to the Tasmanian population and that the excess mortality is most pronounced in females.

Predictors of carcinomatous invasion of the mandible.

The preoperative assessment of mandibular invasion by oral or oropharyngeal squamous cell carcinoma poses a challenge for the head and neck surgeon. A study of 64 composite resection patients was performed to determine which variables in the patient's history, physical exam, and diagnostic workup had a predictive association with carcinomatous mandibular invasion. Four postoperative variables were included in this analysis. Thirty-nine percent of the mandibular specimens demonstrated cancerous involvement. A multivariate recursive partitioning statistical analysis was performed to create a decision tree. Branching was based on the two statistically predictive variables: computed tomographic (CT) scan results and primary tumor location. The guide provides improved predictive accuracy with a 100% negative predictive value (NPV) and a 46% positive predictive value (PPV). This decision guide should help the surgeon provide accurate patient counseling, anticipate reconstructive needs, and maximize surgical oncologic effectiveness.

The micro- or home computer as a teaching aid in postgraduate medical study.

The home computer 'magic' portrayed by the advertising media, supposed to bring computer science to the fingertips of every man, woman and child, is assessed by a practical medical lecturer. Reviewable data banks from which data can be retrieved almost instantaneously, the elimination of filing cabinets and stockpiles of notes, and the efficient storage of clinical patient data together with the relatively low cost and ease of operation make the computer one of the most exciting additions to modern teaching aids.