Pharmacology and therapeutic potential of pattern recognition receptors.

Pharmacologists have used pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS) for decades as a stimulus for studying mediators involved in inflammation and for the screening of anti-inflammatory compounds. However, in the view of immunologists, LPS was too non-specific for studying the mechanisms of immune signalling in infection and inflammation, as no receptors had been identified. This changed in the late 1990s with the discovery of the Toll-like receptors. These 'pattern recognition receptors' (PRRs) were able to recognise highly conserved sequences, the so called pathogen associated molecular patterns (PAMPs) present in or on pathogens. This specificity of particular PAMPs and their newly defined receptors provided a common ground between pharmacologists and immunologists for the study of inflammation. PRRs also recognise endogenous agonists, the so called danger-associated molecular patterns (DAMPs), which can result in sterile inflammation. The signalling pathways and ligands of many PRRs have now been characterised and there is no doubt that this rich vein of research will aid the discovery of new therapeutics for infectious conditions and chronic inflammatory disease.

Factors of caregiver isolation in a rural midwest area.

The authors, working with a Veterans Affairs Home Based Primary Care Team in rural areas of Illinois and Indiana, noted the relative social isolation of many family caregivers of patients. They explored several factors that could contribute to this isolation: values held by the caregiver, transportation restraints, limited caregiver resources and caregiver health. Caregiver values, such as obligation and responsibility, stood out, contributing to generally excellent care for the elderly veteran patients, but also to the observed isolation. A solution would be increased funding for in-home respite, to help the family caregivers get needed rest and outings, thus responding to an expressed need, and enhancing their ability to provide "low-tech" in-home care to their loved ones.

Predictors of healthy aging in men with high life expectancies.

OBJECTIVE: The purpose of this study was to identify risk factors that consistently predict staying healthy in contrast to developing clinical illness and/or physical and mental impairments. METHODS: More than 8000 men of Japanese ancestry were followed for 28 years with repeat examinations and surveillance for deaths and incident clinical illness. Physical and cognitive functions were measured in 1993. Measures of healthy aging included surviving and remaining free of major chronic illnesses and physical and cognitive impairments. RESULTS: Of 6505 healthy men at baseline, 2524 (39%) died prior to the final exam. Of the 3263 available survivors, 41% remained free of major clinical illnesses, 40% remained free of both physical and cognitive impairment, and 19% remained free of both illness and impairment. The most consistent predictors of healthy aging were low blood pressure, low serum glucose, not smoking cigarettes, and not being obese. CONCLUSIONS: Beyond the biological effects of aging, much of the illness and disability in the elderly is related to risk factors present at midlife.

Can money buy happiness? Depressive symptoms in an affluent older population.

OBJECTIVES: To determine if the inverse association between depressive symptoms and income reported in predominantly low- and middle-income older populations is present in a more affluent population of older adults and to determine if this pattern is independent of other known correlates of depressive symptoms such as medical problems, physical disability, and social support. DESIGN: Cross-sectional analysis within a prospective cohort study. SETTING: An ongoing, community-based cohort study conducted by an independent research institution in an affluent Northern California county. PARTICIPANTS: A total of 1948 randomly selected, noninstitutionalized county residents 55 years of age and older who completed the baseline questionnaire and physical performance tests. MEASUREMENTS: The outcome measure was high level of depressive symptoms (score > or = 16) using the Center for Epidemiologic Studies-Depression scale (CES-D). RESULTS: The prevalence of high levels of depressive symptoms (CES-D score > or = 16) was lower than in most other population-based samples using an identical CES-D scale. In age-adjusted, sex-specific analyses, increasing income level was associated significantly with lower levels of depressive symptoms, but the nature of the relationship appeared quadratic rather than linear (Men: odds ratio (OR) income .80, 95% confidence interval (CI) .68-.94; income2 OR 1.006, 95% CI 1.001-1.011. Women: OR income .80, 95% CI .69-.91; income2 OR 1.007, 95% CI 1.002-1.011). In multivariate regression analyses including potential confounding risk factors, the magnitude of the association between depressive symptoms and income decreased and was not statistically significant when measures of health conditions, physical disability, and social support were included in the model (Men: OR income .90, 95% CI .75-1.06; income2 OR 1.003, 95% CI .998-1.009. Women: OR income .90, 95% CI .78-1.05; income2 OR 1.003, 95% CI .998-1.008). CONCLUSION: These findings suggest that poor health, physical disability, and social isolation are the major factors responsible for the observed inverse relationship between income and symptoms of depression in affluent, as well as economically disadvantaged, older populations.

Expanding handgun bullets.

BACKGROUND: Many new types of expanding or fragmenting handgun ammunition have been developed. Knowledge of these unusual bullets may aid in the management of patients and their wounds. METHODS: Eleven different expanding or fragmenting .45 caliber bullets and a nondeforming, full metal jacketed bullet for comparison were fired multiple times from the same handgun into both a water reservoir and ordnance gelatin. Performance was observed and recorded. Muzzle velocities were measured using a chronograph. Bullets were disassembled and cross-sectioned to facilitate inspection. RESULTS: The distinguishing surface and internal features of each bullet are described. When fired into water and ordnance gelatin, the bullets reliably expanded to 1.49 to 1.89 times their prefired diameters. Rates of kinetic energy loss of bullets of equal mass fired into ordnance gelatin were plotted. Full metal jacketed bullets penetrated twice as deeply as deforming bullets. Jackets of some of the expanding bullets separated when fired into water. CONCLUSION: Expanding/fragmenting bullets produce larger, shallower wounds than do full metal jacketed bullets. Recognition of the wound and roentgenographic appearances of these unusual bullets will help the trauma surgeon to properly treat gunshot victims. Because of the occurrence of jacket separation in water, ordnance gelatin should be used for optimal evaluation of bullet performance.

Variability in systolic blood pressure--a risk factor for coronary heart disease?

Among 1,433 men of Japanese ancestry living in Hawaii with blood pressure measured at four different physical examinations over a 10-year period, 110 events of definite coronary heart disease (CHD) occurred during 11.6 years of subsequent follow-up. Each subject's mean blood pressure, the slope of the regression of his blood pressure on age, and the variance of blood pressure about this regression line were tested for association with subsequent incident definite CHD. Adjusted for mean systolic blood pressure (SBP), the variance of SBP was significantly associated with CHD (p < 0.001); however, the slope was not significantly associated with CHD. Variation in body weight was an independent risk factor for CHD. The effect of variation in SBP was significantly higher among men not taking antihypertensive medication; among men taking antihypertension medication, the standardized relative risk was 1.00. Comparing men in the highest quintile of SBP variation with those in the lowest quintile, the relative risk of CHD was 2.0 among all subjects and 5.3 among the 1,007 men not taking antihypertensive medication (95% confidence interval 1.8-15.4). Some of the beneficial effect of taking antihypertensive medication may have been due to reducing the effect of SBP variance rather than simply lowering the average SBP.

Visualization of compression neuropathies through volume deformation.

This paper describes an interdisciplinary effort to simulate and visualize the mechanisms involved in compression neuropathies, specifically tissue deformation occurring during vaginal delivery. These neuropathies often evolve into chronic pelvic pain. We present our methodologies of using high resolution magnetic resonance acquisitions from submillimeter pulse sequences to develop interactive computer simulations based on physically plausible volume models to drive 3D simulations of childbirth. This effort will elucidate tissue movements and mechanics involved in pain disorders and better explain the etiology of these disorders.

Predictors of myocardial lesions in men with minimal coronary atherosclerosis at autopsy. The Honolulu heart program.

Some cardiovascular risk factors are associated with clinical coronary heart disease but not with autopsy evidence of coronary atherosclerosis. To determine whether these risk factors might operate through mechanisms other than atherosclerosis, we examined associations between cardiovascular risk factors and subsequent intramural myocardial lesions assessed by protocol autopsy between 1965 and 1984 in 120 Japanese-American men from the Honolulu Heart Program who had minimal coronary atherosclerosis (American Heart Association (AHA) panel score < 3 on scale of 1 to 7). Age-adjusted prevalence of myocardial lesions was related to smoking status (P < 0.01), as well as amount, duration, and pack-years of smoking (P < 0.03). In a multiple logistic model, smoking (20 pack-years) was directly associated and fish intake (> or = 2 times/wk) was inversely associated with myocardial lesions independently of age, cholesterol, systolic blood pressure, body mass index, alcohol, diabetes, total calories, and animal protein intake (odds ratio (OR) = 1.5, 95% confidence intervals (CI) = 1.1 to 2.0 and OR = 0.35, 95% CI = 0.2 to 0.9, respectively). The protective effect of fish intake was most evident among men who did not have hypertension at baseline. Indices of obesity, body fat distribution, and physical activity and levels of triglyceride and alcohol intake were not associated with myocardial lesions. Thus, the adverse effects of smoking and the protective effects of fish consumption may extend to individuals relatively free of coronary atherosclerosis, possibly through hemostatic mechanisms or effects on small intramural arteries.

Low serum cholesterol and mortality. Which is the cause and which is the effect?

BACKGROUND: Many studies have reported an association between a low or lowered blood total cholesterol (TC) level and subsequent nonatherosclerotic disease incidence or death. The question of whether low TC is a true risk factor or alternatively a consequence of occult disease at the time of TC measurement remains unsettled. To shed new light onto this problem, we analyzed TC change over a 6- year period (from exam 1 in 1965 through 1968 to exam 3 in 1971 through 1974) in relation to subsequent 16-year mortality in a cohort of Japanese American men. METHODS AND RESULTS: The study was based on 5941 men 45 to 68 years of age without prior history of coronary heart disease, stroke, cancer, or gastrointestinal-liver disease at exam 1 who also participated in exam 3 of the Honolulu Heart Program. The association of TC change with mortality end points was investigated with two different approaches (continuous and categorical TC change) with standard survival analysis techniques. Falling TC level was accompanied by a subsequent increased risk of death caused by some cancers (hemopoietic, esophageal, and prostate), noncardiovascular noncancer causes (particularly liver disease), and all causes. The risk-factor-adjusted rate of all-cause mortality was 30% higher (relative risk, 1.30; 95% CI, 1.06 to 1.59) among persons with a decline from middle (180 to 239 mg/dL) to low (< 180 mg/dL) TC than in persons remaining at a stable middle level. By contrast, there was no significant increase in all-cause mortality risk among cohort men with stable low TC levels. Nonillness mortality (deaths caused by trauma and suicide) was not related to either TC change or the average of TC levels in exams 1 and 3. CONCLUSIONS: These results add strength to the reverse-causality proposition that catabolic diseases cause TC to decrease.

Serum total cholesterol and mortality. Confounding factors and risk modification in Japanese-American men.

OBJECTIVE: To further investigate the relationship between serum total cholesterol (TC) level and mortality due to major causes. In particular, is the elevated mortality among persons with low TC levels due to confounding conditions that both lower TC level and increase the risk of mortality, and is the association between low or high TC level and mortality homogeneous in the population or, alternatively, restricted to persons with other risk factors? STUDY DESIGN: Prospective cohort study. SETTING: Free-living population in Oahu, Hawaii. PARTICIPANTS: A total of 7049 middle-aged men of Japanese ancestry. MAIN OUTCOME MEASURES: Age- and risk factor-adjusted mortality due to coronary heart disease, hemorrhagic stroke, cancer, chronic obstructive pulmonary disease, nonmalignant liver disease, trauma, miscellaneous and unknown, and all causes. RESULTS: During 23 years of follow-up, a total of 1954 deaths were documented (38% cancer, 25% cardiovascular, and 37% other). Men with low serum TC levels (< 4.66 mmol/L [< 180 mg/dL]) were found to have several adverse health characteristics, including a higher prevalence of current smoking, heavy drinking, and certain gastrointestinal conditions. In an age-adjusted model, and in relation to the reference group (4.66 to 6.19 mmol/L [180 to 239 mg/dL]), those in the lowest TC group (< 4.66 mmol/L [< 180 mg/dL]) were at significantly higher risk of mortality due to hemorrhagic stroke (relative risk [RR], 2.41; 95% confidence interval [Cl], 1.45 to 4.00), cancer (RR, 1.41; 95% Cl, 1.17 to 1.69), and all causes (RR, 1.23; 95% Cl, 1.09 to 1.38). Adjustment for confounders in multivariate analysis (and exclusion of cases with prevalent disease at baseline and deaths through year 5) did not explain the risk of fatal hemorrhagic stroke but reduced the excess risk of cancer mortality by 51% (to 1.20 from 1.41) and reduced the excess risk of all-cause mortality by 56% (to 1.10 from 1.32) in the low TC group. In addition, there were clear differences in the patterns of risk when comparing men with and without selected risk factors (ie, smoking, alcohol consumption, and untreated hypertension). CONCLUSIONS: We conclude that the excess mortality at low TC levels can be partially explained by confounding with other determinants of death and by preexisting disease at baseline, and TC-mortality associations are not homogeneous in the population. In our study, TC level was not associated with increased cancer or all-cause mortality in the absence of smoking, high alcohol consumption, and hypertension.

Lifestyle and biologic factors associated with atherosclerotic disease in middle-aged men. 20-year findings from the Honolulu Heart Program.

OBJECTIVES: To examine the association between a variety of baseline lifestyle and biologic factors in a middle-aged cohort of Japanese-American men and the 20-year incidence rates of total atherosclerotic end points and each of the initial clinical manifestations of this disease, including fatal and nonfatal coronary heart disease, angina pectoris, thromboembolic strokes, and aortic aneurysms. DESIGN: Prospective epidemiologic study. POPULATION: Japanese-American men (N = 2710) between the ages of 55 and 64 years at the time of the initial clinical examination of the Honolulu Heart Program (1965 through 1968) free from evidence of coronary heart disease, cerebrovascular disease, cancer, or aortic aneurysms. RESULTS: Among the men studied, 602 atherosclerotic events developed during the 23-year period of follow-up (1965 through 1988). After adjustment for each of the baseline characteristics examined, significant positive associations between quartile cutoffs of body mass index, systolic blood pressure, serum levels of cholesterol, triglycerides, glucose, and uric acid, as well as cigarette smoking, and the occurrence of any atherosclerotic end point were seen, while an inverse association with alcohol consumption was observed. Characteristics associated with the development of other fatal and nonfatal clinical events in this cohort, including coronary heart disease, thromboembolic stroke, and aortic aneurysms are presented with accompanying relative and attributable risks. CONCLUSIONS: The results of this prospective epidemiologic study provide insights to the long-term predictive utility of the commonly accepted risk factors for coronary heart disease in relation to the different clinical manifestations of atherosclerosis in a middle-aged male cohort followed up for approximately 20 years. These results provide additional support for risk factor modification in middle-aged men and for the encouragement of positive long-term lifestyle changes.

Serum cholesterol level and mortality due to suicide and trauma in the Honolulu Heart Program.

BACKGROUND: Recent results from cholesterol level-lowering trials and some, but not all, observational studies support an intriguing link between low or lowered serum cholesterol levels and violent death. The reasons behind this relationship are far from clear. METHODS: In this report, we further investigate this issue by assessing the relationship of baseline serum cholesterol levels with long-term risk of mortality due to trauma and suicide in a cohort of 7309 middle-aged Japanese-American men. RESULTS: After 23 years of follow-up, a total of 75 traumatic fatalities and 24 deaths by suicide were documented. Rather than an inverse relation, a positive association between serum cholesterol level and risk of suicide death was observed. After controlling for potential confounders, the relative risk of suicide associated with an increment of 0.98 mmol/L (38 mg/dL) in serum cholesterol level (1 SD) was 1.46 (95% confidence interval, 1.04 to 2.05; P = .02). Multivariate analysis of traumatic mortality failed to detect a relation with serum cholesterol level (relative risk = 0.89; 95% confidence interval, 0.70 to 1.13; P = .44). Heavy alcohol consumption (> 1200 mL of alcohol per month, top quintile) was an independent risk factor for trauma death relative to abstinence (relative risk = 1.86; 95% confidence interval, 1.07 to 3.22; P = .02). CONCLUSIONS: These findings contradict the hypothesis of an inverse relation between serum cholesterol level and suicide, but they support the hypothesis that heavy alcohol consumption is a risk factor for traumatic fatal events.

Trends in stroke incidence and mortality in Hawaiian Japanese men.

BACKGROUND AND PURPOSE: Vital statistics show a sharp decline in stroke mortality since the late 1960s. It is not clear whether this has been associated with a decline in stroke incidence. METHODS: Since 1966 the Honolulu Heart Program has monitored the incidence and mortality of coronary heart disease and stroke in a target population of 11,136 men of Japanese ancestry living on Oahu. Trends were analyzed from January 1, 1969, through December 31, 1988. RESULTS: Of 7893 men aged 45 to 68 years and free of stroke at entry examination, 530 developed first episodes of stroke in the period 1969 to 1988 (389 cases of thromboembolic stroke, 124 cases of hemorrhagic stroke, and 17 cases of stroke of unknown type). Age-adjusted annual stroke incidence declined from 5.1 per 1000 person-years in 1969 to 1972 to 2.4 in 1985 to 1988. The incidences of thromboembolic stroke, hemorrhagic stroke, and total stroke decreased 3.5%, 4.2%, and 4.4% per year, respectively. The 1-month case-fatality rates for thromboembolic stroke decreased moderately; those for hemorrhagic stroke fell dramatically. CONCLUSIONS: These findings suggest that the decline in stroke mortality in the past two or three decades results from a decline in both incidence rates and early case-fatality rates in thromboembolic and hemorrhagic stroke and stroke of unknown type. The decreases may be related to changes in risk factors, such as the decline in blood pressure and the decrease in cigarette smoking, as well as improvements in diagnosis and treatment.

A prospective study of the health effects of alcohol consumption in middle-aged and elderly men. The Honolulu Heart Program.

BACKGROUND: The study objective was to determine the association between reported alcohol consumption and total mortality, mortality from selected causes, and incident nonfatal chronic disease events in middle-aged (51 to 64 years old) and elderly (65 to 75 years old) men during an approximate 15-year follow-up period. METHODS AND RESULTS: We conducted a prospective epidemiological study of Japanese-American men who were participating in the Honolulu Heart Program and were free from coronary heart disease, cerebrovascular disease, and cancer at baseline examination and at subsequent reexamination 6 years later. Self-reported alcohol consumption was determined twice: at the baseline examination in 1965 through 1968 and at reexamination approximately 6 years later (1971 through 1974). Four primary alcohol consumption groups who reported similar alcohol intake at the time of these two clinical examinations were considered: abstainers and light (1 to 14 mL of alcohol per day), moderate (15 to 39 mL of alcohol per day), and heavy (> or = 40 mL of alcohol per day) drinkers. Study end points were also determined in very light (1 to 4.9 mL of alcohol per day) drinkers and in men who reported a change in their alcohol intake between examinations. Longitudinal follow-up was carried out through the end of 1988 with determination of selected fatal and nonfatal events according to alcohol intake. After controlling for several potentially confounding factors, total mortality exhibited a J-shaped pattern in relation to alcohol consumption in middle-aged and elderly men. There was a trend for lower rates of occurrence of combined fatal and nonfatal coronary heart disease events with increasing alcohol consumption in both middle-aged and elderly men. Increasing alcohol consumption was related to an increased risk of fatal and nonfatal strokes in middle-aged men, whereas elderly light and moderate drinkers were at increased risk for fatal and nonfatal strokes. Heavy drinkers were at increased risk for fatal and nonfatal malignant neoplasms in the two age groups examined. CONCLUSIONS: The results of this long-term prospective study provide a balanced perspective of the health effects of alcohol consumption in middle-aged and elderly men. High levels of alcohol consumption were shown to be related to an increasing risk of diseases of considerable public health importance. These findings suggest that caution be taken in formulating population-wide recommendations for increases in the population levels of alcohol consumed given the associated significant social and biological problems of high consumption levels.

Determinants of the prognosis after a first myocardial infarction in a migrant Japanese population. The Honolulu Heart Program.

BACKGROUND: Although numerous studies have been published on the prognostic assessment of myocardial infarction, little is known about determinants of the prognosis after a first myocardial infarction, especially regarding the role of standard risk factors for coronary heart disease (CHD) measured before the development of myocardial infarction. METHODS AND RESULTS: In a prospective study of CHD among men of Japanese ancestry living in Hawaii, 457 patients with a first myocardial infarction (age range, 46 to 84 years) were identified during 20 years of follow-up. The relations of clinical variables and CHD risk factors to mortality in early (< 30 days) and two stages of late (30 days to 5 years and 5 to 10 years) periods after myocardial infarction in these patients were investigated. In multivariate analyses using logistic regression models (for early mortality) and Cox regression models (for late mortality), age at myocardial infarction and severe complications (Killip classes 3 and 4) were independent predictors of both early and late mortality (up to 5 years after myocardial infarction). In addition, ventricular arrhythmias predicted only early mortality, whereas anterior myocardial infarction, radiological evidence of cardiomegaly and/or pulmonary congestion, and intraventricular block predicted only late mortality (up to 5 years after myocardial infarction). Only age was an independent predictor of all-cause mortality more than 5 years after myocardial infarction. After adjusting for age at myocardial infarction and these clinical variables, preinfarction-measured risk factors such as 1-hour postload serum glucose (positively) and 1-second forced expiratory volume (inversely) were significantly associated with late mortality up to 5 years, whereas systolic blood pressure was the only independent predictor of late mortality after 5 years. CONCLUSIONS: This study has confirmed the importance of age at myocardial infarction and clinical indicators of complications such as Killip class 3 or 4, radiological evidence of pulmonary congestion, and ventricular arrhythmias or intraventricular block as the prognostic determinants of myocardial infarction. In addition, some of the preinfarction-measured standard risk factors for CHD were found to predict long-term prognosis independent of age and clinical factors.

Sugarcane workers: morbidity and mortality.

Sugarcane is, after pineapple, the largest agricultural industry in Hawaii. There have been reports that this industry poses certain health hazards. To investigate this possible hazard in Hawaii, the relationship of employment on a sugarcane plantation to total mortality, the development of definite coronary heart disease (CHD), stroke, cancer, lung cancer and certain risk factors were examined in men of Japanese ancestry participating in the Honolulu Heart Program. After 18 years of follow-up, those men who indicated one or more years working on sugarcane plantations had no significant difference in age-adjusted mortality, nor incidence of CHD, stroke, cancer, or lung cancer. There were no differences in risk factors compared to participants who were never employed on sugarcane plantations, nor were there differences in lung function as measured by FEV1. These findings were unchanged after adjusting for several potential confounding variables. No cases of mesothelioma were observed among those with a history of defined exposure. These findings were not due to a "healthy worker bias" and indicate that employment on a sugarcane plantation in Hawaii is not associated with elevated rates of chronic diseases.

Mortality and morbidity among blue and white collar workers in the Honolulu Heart Program cohort.

There has been a controversy regarding occupation, as defined by blue and white collar work, and coronary heart disease (CHD). In a large long-term prospective study of the Honolulu Heart Program cohort, there were no significant differences between these two occupational classifications and the incidence rates of fatal and non-fatal CHD. Nor were there significant differences in total mortality, stroke or total cancer although there were very small but significant differences in some CHD risk factors. Unlike the previous studies, this investigation was free of prevalent cases of CHD at baseline and controlled for the major risk factors of CHD. We question the utility of using this occupational classification to investigate the causes of CHD.

Association of diabetes mellitus with coronary atherosclerosis and myocardial lesions. An autopsy study from the Honolulu Heart Program.

While the excess risk of clinical cardiovascular disease among persons with diabetes mellitus is well established, most autopsy studies have not been able to elucidate reasons for the excess, to assess potential selection bias, or to adjust for other cardiovascular risk factors. The purpose of this study was to examine the predictive relation between diabetes and autopsy evidence of coronary atherosclerosis and myocardial lesions. Among 8,006 Japanese-American men examined at baseline in 1965-1968 as part of the Honolulu Heart Program, 7,591 were free of cardiovascular disease, and 1,515 of these men died over a 17-year follow-up period. Protocol autopsies were performed for 83 diabetic men and 159 nondiabetic men. Diabetes status was defined using self-reported history and treatment at several examinations, as well as physician diagnoses during hospitalization between 1965 and 1984. An excess of coronary artery atherosclerosis, assessed by mean panel score (3.4 vs. 3.0, p = 0.017) and percentage of intimal surface with raised lesions (56.6% vs. 47.4%, p = 0.024), was present among diabetic men but diminished to nonsignificant levels (3.3 vs. 3.0, p = 0.102, and 53.9% vs. 48.8%, p = 0.183, respectively) after adjustment for other cardiovascular risk factors. Myocardial lesions (acute, healing, or fibrotic) occurred significantly more frequently among diabetics than among nondiabetics (77.7% vs. 63.4%, p = 0.035), even after adjustment for other risk factors. Potential autopsy selection bias assessed in several ways appeared minimal. Among men with mild atherosclerosis, diabetics had more small and large myocardial lesions than did nondiabetics, although differences were not statistically significant (p < 0.10). It appears that the more adverse risk factor profile among diabetics accounts for some of the observed excess of coronary atherosclerosis. However, diabetes was independently associated with myocardial lesions, and these findings suggest a role for nonatherosclerotic mechanisms, such as clotting abnormalities or microvascular disease, in accounting for the excess clinical heart disease found in persons with diabetes.