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Objective— To explore to what extent homocysteine, S-adenosylmethionine (SAM), S-adenosylhomocysteine, total folate, 5-methyltetrahydrofolate (5-MTHF), vitamin B12, and vitamin B6 are associated with endothelium-dependent, flow-mediated vasodilation (FMD), and whether these associations are stronger in individuals with diabetes or other cardiovascular risk factors. Methods and Results— In this population-based study of 608 elderly people, FMD and endothelium-independent nitroglycerin-mediated dilation (NMD) were ultrasonically estimated from the brachial artery (absolute change in diameter [μm]). High SAM and low 5-MTHF were significantly associated with high and low FMD, respectively (linear regression coefficient, [95% confidence interval]): 48.57 μm (21.16; 75.98) and −32.15 μm (−59.09; −5.20), but high homocysteine was not (−15.11 μm (−42.99; 12.78). High SAM and low 5-MTHF were also significantly associated with high and low NMD, respectively. NMD explained the association of 5-MTHF with FMD but not of SAM. No interactions were observed for diabetes or cardiovascular risk factors. Conclusions— In this elderly population, both SAM and 5-MTHF are associated with endothelial and smooth muscle cell function. The effect of homocysteine on endothelial function is relatively small compared with SAM and 5-MTHF. The relative impact of SAM, 5-MTHF, and homocysteine, and the mechanisms through which these moieties may affect endothelial and smooth muscle cell function need clarification.

Aims/hypothesis. There is accumulating evidence that depression is common in people with Type 2 diabetes. However, most prevalence-studies are uncontrolled and could also be inaccurate from selection-bias, as they are conducted in specialized treatment settings. We studied the prevalence and risk factors of co-morbid depression in a community-based sample of older adults, comparing Type 2 diabetic patients with healthy control subjects. Methods. A large (n=3107) community-based study in Dutch adults (55-85 years of age) was conducted. Pervasive depression was defined as a CES-D score greater than 15. Diagnosis of Type 2 diabetes was obtained from self-reports and data from general practitioners. Results. A number of 216 patients (7%) were identified as having Type 2 diabetes. The prevalence of pervasive depression was increased in people with Type 2 diabetes and co-morbid chronic disease (20%) but not in patients with Type 2 diabetes only (8%), compared with the healthy control subjects (9%). Regression analyses in diabetic patients yielded that being single, being female, having functional limitations, receiving instrumental support and having an external locus of control were associated with higher levels of depression. Conclusions/interpretation. The Results suggest that the prevalence of pervasive depression is increased in patients with Type 2 diabetes and co-morbid disease(s), but not in patients with Type 2 diabetes only. Functional limitations that often accompany co-morbid chronic disease could play an essential role in the development of depression in Type 2 diabetes. These findings can enable clinicians and researchers to identify high-risk groups and set up prevention and treatment programs.

Objective: Hyperhomocysteinemia is a risk factor for atherothrombosis. Through unknown mechanisms, individuals with type 2 diabetes appear particularly susceptible. We determined whether components of homocysteine metabolism are associated with intima-media thickness in individuals with and without type 2 diabetes. Methods and results: In a cross-sectional design, we studied 231 Caucasian individuals, 60.6% having type 2 diabetes. We measured fasting homocysteine, vitamin B6 and vitamin B12 in plasma, and folate, S-adenosylmethionine and S-adenosylhomocysteine in plasma and erythrocytes. A homocysteine concentration >12 μmol/l was associated with a greater intima-media thickness of +0.07 mm (95% CI, +0.01 to +0.13; P = 0.03) among diabetic individuals and of -0.004 mm (95%CI, -0.08 to +0.07; P = 0.92) among non-diabetic individuals. An erythrocyte S-adenosylmethionine concentration above >4000 nmol/l was associated with a smaller intima-media thickness of -0.04 mm (95%CI, -0.10 to +0.02; P = 0.17) for diabetic individuals versus -0.12 mm (95%CI, -0.20 to -0.36; P = 0.005) for non-diabetic individuals. Conclusions: With regard to carotid intima-media thickness, individuals with diabetes appear more susceptible to the detrimental effects of homocysteine than non-diabetic individuals. In addition, diabetic individuals may lack the protective effect on the vascular wall conferred by high concentrations of S-adenosylmethionine. These findings may help explain why hyperhomocysteinemia is an especially strong risk factor for atherothrombosis among individuals with type 2 diabetes. © 2003 Elsevier Ireland Ltd. All rights reserved.

Objectives. Amongst nondiabetic individuals, a high serum homocysteine concentration is an independent but relatively weak risk factor for coronary events. However, it is not known whether homocysteine increases risk of coronary events in type 2 diabetes. Therefore, we examined the combined effect of homocysteine and type 2 diabetes on risk of fatal and nonfatal coronary events. Subjects. We assessed the 10-year risk of coronary events associated with homocysteine amongst diabetic (n = 140) and nondiabetic (n = 361) individuals. Design. We did this in the Hoorn Study, a population-based study of glucose tolerance and related complications in Caucasian men and women aged 50-75 years. Results. The incidence rate for coronary events was 2.63 (29 of 140) per 100 person-years amongst diabetic and 1.29 (42 of 361) amongst nondiabetic individuals. Amongst diabetic individuals, risk of coronary events increased 28% for each 5-μmol L-1 increment of homocysteine (hazard ratio, 1.28:95% CI, 1.02-1.58). This risk was independent of age, sex, hypertension, total cholesterol, HDL-cholesterol, cigarette smoking, body mass index and glomerular filtration rate. In nondiabetic participants, homocysteine was not associated with an increased risk of coronary events (hazard ratio for each 5-μmol L-1 increment of homocysteine, 0.86; 0.52-1.41). Conclusions. These data suggest that homocysteine is significantly associated with coronary events in individuals with type 2 diabetes, independent of traditional cardiovascular risk factors. Investigation of the effect of treatment with vitamin B on prognosis of individuals with type 2 diabetes is warranted.

Objective: Type 2 diabetic patients have an increased arterial stiffness and a very high risk of cardiovascular death. The present study investigated the relationship between pulse pressure, an indicator of vascular stiffness, and risk of cardiovascular mortality among type 2 diabetic and non-diabetic individuals. Second, we determined the relationship between pulse pressure and its main determinant (i.e. age), and the influence of diabetes and mean arterial pressure on this relationship. Design and methods: We studied a cohort of 2484 individuals including 208 type 2 diabetic patients. Mean age and median follow-up for non-diabetic and diabetic individuals, respectively, were 61 and 66 years, and 8.8 and 8.6 years. One-hundred and sixteen non-diabetic and 34 diabetic individuals died of cardiovascular causes. Relative risks of cardiovascular mortality were estimated by Cox proportional hazards regression adjusted for age, gender and mean arterial pressure. Results: Pulse pressure was associated with cardiovascular mortality among the diabetic, but not among the non-diabetic individuals [adjusted relative risk (95% confidence interval) per 10 mmHg increase, 1.27 (1.00-1.61) and 0.98 (0.85-1.13), P interaction = 0.07]. Further adjustment for other risk factors gave similar results. The association, at baseline, between age and pulse pressure was dependent on the presence of diabetes (P interaction = 0.03) and on the mean arterial pressure (P interaction < 0.001) (i.e. there was a stronger association when diabetes was present and when mean arterial pressure was higher). Conclusions: We conclude that, in type 2 diabetes, pulse pressure is positively associated with cardiovascular mortality. The association between age and pulse pressure is influenced by the presence of type 2 diabetes and by the height of the mean arterial pressure. These findings support the concept of accelerated vascular aging in type 2 diabetes. © 2002 Lippincott Williams & Wilkins.

Background —A high serum total homocysteine (tHcy) concentration is a risk factor for death, but the strength of the relation in patients with type 2 (non–insulin-dependent) diabetes mellitus compared with nondiabetic subjects is not known. A cross-sectional study suggested that the association between tHcy and cardiovascular disease is stronger in diabetic than in nondiabetic subjects. We therefore prospectively investigated the combined effect of hyperhomocysteinemia and type 2 diabetes on mortality. Methods and Results —Between October 1, 1989, and December 31, 1991, serum was saved from 2484 men and women, 50 to 75 years of age, who were randomly selected from the town of Hoorn, The Netherlands. Fasting serum tHcy concentration was measured in 171 subjects who died (cases; 76 of cardiovascular disease) and in a stratified random sample of 640 survivors (control subjects). Mortality risks were calculated over 5 years of follow-up by means of logistic regression. The prevalence of hyperhomocysteinemia (tHcy >14 μmol/L) was 25.8%. After adjustment for major cardiovascular risk factors, serum albumin, and HbA 1c , the odds ratio (95% CI) for 5-year mortality was 1.56 (1.07 to 2.30) for hyperhomocysteinemia and 1.26 (1.02 to 1.55) per 5-μmol/L increment of tHcy. The odds ratio for 5-year mortality for hyperhomocysteinemia was 1.34 (0.87 to 2.06) in nondiabetic subjects and 2.51 (1.07 to 5.91) in diabetic subjects ( P =0.08 for interaction). Conclusions —Hyperhomocysteinemia is related to 5-year mortality independent of other major risk factors and appears to be a stronger (1.9-fold) risk factor for mortality in type 2 diabetic patients than in nondiabetic subjects.

OBJECTIVE A randomized trial with 1-year follow-up was conducted in 23 general practices to study the relationship between target values for glycemic control and well-being in type 2 diabetes RESEARCH DESIGN AND METHODS A total of 176 patients with type 2 diabetes, aged 40–75 years, were included. General practitioners were encouraged to make decisions according to a standardized step-up regimen until the target levelof glycemic control was reached. The random allocation to a strict or a less strict target level of glycemic control (fasting capillary glucose RESULTS Positive affect (an odds ratio [OR] [95% CI] of 0.39 [0.19–0.83]) and perceived treatment burden (OR 0.48[0.23–0.98]) were unfavorably altered in the group randomly allocated to stricter target levels (fasting capillary glucose CONCLUSIONS Perceived treatment burden and positive effect are unfavorably affected by random allocation to a strict target level for glycemic control. Improved glycemic control is associated with favorable mood and possibly general well-being in type 2 diabetes.

Microalbuminuria is a strong predictor of cardiovascular disease. The aim of this study was to investigate whether microalbuminuria is part of a cluster of risk factors, the insulin resistance syndrome (IRS), or whether it is only associated with, and presumably a complication of, hypertension and non-insulin-dependent diabetes mellitus (NIDDM). An age-, sex- and glucose tolerance-stratified random sample from a 50–75 year old general population (n = 622) was investigated. The urinary albumin-to-creatinine ratio was measured in an early morning spot urine sample. Microalbuminuria was defined as an albumin-to-creatinine ratio greater than 2.0 mg/mmol. We considered, as IRS-related variables, fasting hyperinsulinaemia, insulin resistance (IR; calculated from the formula of the homeostasis model assessment), dyslipidaemia, glucose intolerance, hypertension and waist-to-hip ratio (WHR). Dyslipidaemia was defined as levels of HDL-cholesterol in the lowest and / or levels of triglyceride in the highest tertile. Fasting insulin levels, IR and WHR were divided into tertiles; the highest tertiles were compared to the lowest tertiles. Age-, sex- and glucose tolerance-adjusted analyses showed microalbuminuria to be significantly associated with hypertension, NIDDM and WHR. In multiple logistic regression analyses, microalbuminuria showed independent associations with hypertension, NIDDM and WHR, with odds ratios (ORs [95 % confidence interval]) of 3.33 (1.86–5.96), 2.26 (1.14–4.48) and 2.49 (1.09–5.70), respectively. No associations were found with impaired glucose tolerance, hyperinsulinaemia, IR or dyslipidaemia. Multiple logistic regression analyses in diabetic and non-diabetic subjects separately showed that microalbuminuria was independently associated only with hypertension (ORs 4.31 and 2.69). In this Caucasian population, microalbuminuria was associated with hypertension, NIDDM and WHR and not with other variables of the IRS. It is therefore likely that microalbuminuria is a complication of hypertension and NIDDM, and not an integral part of the IRS. [Diabetologia (1998) 41: 694–700]

The aim of this study was to investigate anthropometric and life-style determinants of insulinaemia. Specific fasting serum insulin (FI) was analysed in a general Caucasian population aged 50-74 years, not known to have diabetes mellitus (n = 2226, sample 1). The analysis was repeated some weeks later in a subgroup of sample 1 in which two individual measurements of FI were available (n = 540, sub-sample 2). Specific serum insulin 2 h after ingestion of 75 g glucose (2hI), also measured on two occasions, was analysed in this same subgroup after excluding 59 subjects with fasting plasma glucose >7 mmol l(-1) (n = 481, sub-sample 3). Multiple regression analyses were performed, stratified for sex, with 10log insulin as the dependent variable. All determinants were adjusted for each other. FI was positively associated with BMI and waist-hip ratio (men and women) and inversely associated with intake of fibre (women), moderate alcohol use (men), and current smoking (women). 2hI was positively associated with BMI and waist-hip ratio (men and women), and intake of fat (women). 2hI was inversely associated with physical activity and moderate alcohol use (men and women), and current smoking (men). Family history of diabetes was not associated with insulinaemia. In conclusion, various life-style factors are related to insulinaemia, independent of obesity.

OBJECTIVE To investigate to what extent a short questionnaire on symptoms and risk factors can be used to identify people at increased risk for undiagnosed NIDDM. RESEARCH DESIGN AND METHODS A general population sample of 2,364 Caucasian subjects, age 50–74 years, not known to have diabetes, completed a questionnaire on diabetes-related symptoms and risk factors. Subsequently, they underwent an oral glucose tolerance test. A backward stepwise multiple logistic regression was carried out with the absence or presence of newly detected diabetes as the dependent variable and the items from the questionnaire as the independent variables. The selected items were included in a new symptom risk questionnaire, which was evaluated in a different population sample of 786 subjects, age 45–74 years, not known to have diabetes and compared with existing questionnaires. RESULTS The newly developed symptom-risk questionnaire contains questions concerning the following items, which were independently and significantly (P < 0.05) associated with the presence of previously undiagnosed diabetes: pain during walking with need to slow down, shortness of breath when walking with people of the same age, frequent thirst, age, sex, obesity, parent or sibling with diabetes, use of antihypertensive drugs, and reluctance to use a bicycle for transportation. The 1993 American Diabetes Association questionnaire, the 1995 Herman et aL (17) questionnaire, and the newly developed symptom-risk questionnaire had sensitivities of 59, 72, and 72%; specificities of 57, 55, and 56%; positive predictive values of 5.6, 6.4, and 6.5%; and negative predictive values of 97, 98, and 98%, respectively. CONCLUSIONS The newly developed symptom-risk questionnaire has good performance characteristics, and the advantage of a variable cutoff makes it a useful screening tool for NIDDM in general practice.

Background: Old people (75+) are underrepresented in studies on the prevalence of and risk factors for depression while the number of elderly people suffering from this mood disorder may be considerably higher than previously assumed. The role - if any - of age and gender in 'Geriatric Depression' is still unclear. Methods: In this community-based study, prevalence of depressive symptomatology and risk indicators were assessed in 2850 participants aged 75 years or more. A clinically relevant level of depressive symptoms was defined as a score of ≥ 16 on the Centre for Epidemiologic Studies Depression scale (CES-D). Demographic data and questions related to physical and psychological health were recorded. Simple and multiple logistic regression techniques were used to determine the risk indicators (Odds Ratios, OR, with 95% confidence intervals, CI) with apparent importance to this population. Results: The prevalence of depressive symptoms was assessed to be 31.1%. This is considerably higher than what has been found in younger elderly samples. The bivariate age effect was OR 1.05 (95% CI = 1.03 to 1.07). Controlling for confounding, the effect of gender and age on depressive symptoms disappeared. Conclusions: Depressive symptoms are highly prevalent in the elderly population and increase with age. This increase seems to be attributable to age-related changes in risk factors rather than to ageing itself. With regard to the risk factors found, attention should perhaps be paid to functional disability, loneliness and apprehensiveness for falling since these risk indicators are amenable for improvement. © 2007 Elsevier B.V. All rights reserved.

Currently, three categories of cardiovascular autonomic nervous function measures are used: classic Ewing-test measures, measures of heart-rate variability (HRV), and measures of baroreflex sensitivity (BRS). Little is known about the agreement between these measures, and reference and reproducibility values for these measures have not been reported within the same group.As part of the Hoorn Study, 631 subjects aged 50 to 75 participated in a study of autonomic nervous function. Cardiac cycle duration (RR interval) and continuous finger arterial pressure were measured under three conditions: during spontaneous breathing, during six deep breaths over 1 min, and during an active change in position from lying to standing. From these readings, ten measures of autonomic function were assessed (mean heart rate, three Ewing test measures, five HRV measures and one BRS measure).Regression analysis in a healthy subgroup (n=191) showed sex differences for two of the ten measures and seven measures decreased with age. Therefore, appropriate age-specific and sex-specific reference values were calculated. Reproducibility (n=39) of most measures was moderate, with a reliability coefficient of around 50%. Agreement between the measures of autonomic nervous function varied greatly, between 0% and 87%. The HRV-power ratio measure and the blood pressure changes in the lying-to-standing test showed the lowest agreement with all other measures.This study provides age-specific and sex-specific reference values for a wide range of different autonomic function measures in an elderly population. Agreement among the different measures varied widely and reproducibility was only moderate.

The objective of this study was to investigate the extent to which internal risk factors for the development of decubitus ulcers are related to the blood flow response following the relief of a pressure load. There were 122 nursing home patients (43 men, 69 women, mean age: 81 ±8 years; range: 60-97). The following potential, internal risk factors for the development of decubitus ulcers were assessed: chronic disorders (diabetes mellitus, cardiovascular disease [congestive heart failure, history of myocardial infarct or angina pectoris] and cerebrovascular accident), fever, blood pressure, nutritional status, serum hemoglobin concentration, and serum urea and serum creatinine concentrations. Skin temperature response (latency time and total response time) was measured following relief of a 100 kPa test pressure. The presence of cardiovascular disease, cerebrovascular accident, poor nutritional condition, high serum urea and male gender showed a significant relationship with an impaired blood flow response. The delayed latency found showed a similarity to the so-called "no-reflow phenomenon." The association of cardiovascular disease and a cerebrovascular accident with a delay in the blood flow response may result from endothelial damage. A poor nutritional condition may be associated with a deficit of scavengers of oxygen-derived free radicals. The presence of free radicals may damage endothelium during reperfusion, thus influencing the blood flow response. The association of high serum urea with delayed vasodilatation may theo retically be explained by the association of serum urea and impaired kidney functioning, since the kidney is an important organ in the production of vasoactive substances. Serum urea can also be considered a measure for nutritional condition. Gender may function as a substitute for other, unmeasured factors that are related to blood flow response.

Membrane-bound vascular cell adhesion molecule 1 (VCAM-1) allows the tethering and rolling of monocytes and lymphocytes as well as firm attachment and transendothelial migration of leukocytes. Soluble forms of VCAM (sVCAM-1) may serve as monitors of increased expression of membrane-bound VCAM-1 and thus may reflect progressive formation of atherosclerotic lesions. Levels of sVCAM-1 have been found to be increased among type 2 diabetic as compared with nondiabetic subjects. To study the association of plasma sVCAM-1 concentration and risk of cardiovascular and all-cause mortality among nondiabetic and diabetic subjects, we investigated an age-, sex-, and glucose-tolerance-stratified sample (n = 631) of a population-based cohort aged 50-75 years that was followed prospectively. Plasma levels of sVCAM-1 were determined in frozen -70 degrees C baseline samples. After 7.4 years (mean) of follow-up, 107 (17%) subjects had died (42 of cardiovascular causes). In the entire group, increased sVCAM-1 levels were significantly associated with increased risk of cardiovascular mortality (relative risks [RRs] per 100 ng/ml sVCAM-1 increase, 1.10 [1.05-1.15] after adjustment for age, sex, and glucose tolerance status). This RR was somewhat diminished by further adjustment for the presence of hypertension and cardiovascular disease; levels of total, HDL, and LDL cholesterol and homocysteine; the presence of microalbuminuria (a putative marker of endothelial dysfunction); levels of von Willebrand factor (a marker of endothelial dysfunction) and C-reactive protein (a marker of low-grade inflammation); and estimates of glomerular filtration rate. However, the RR remained statistically significant. The RR among type 2 diabetic subjects was 1.13 (1.07-1.20) per 100 ng/ml sVCAM-1 increase after adjustment for age and sex, which was somewhat higher but not significantly different from the RR in nondiabetic subjects (P value for interaction term, 0.12). Further adjustment for other risk factors gave similar results. In conclusion, levels of sVCAM-1 are independently associated with the risk of cardiovascular mortality in type 2 diabetic subjects and therefore might be useful for identifying subjects at increased cardiovascular risk. Increased plasma sVCAM-1 levels may reflect progressive formation of atherosclerotic lesions, or sVCAM-1 itself may have bioactive properties related to cardiovascular risk. Our data, however, argue against the hypotheses of sVCAM-1 levels simply being a marker of endothelial dysfunction, of low-grade inflammation, or of an impaired renal function.

Hoogeveen EK, Kostense PJ, Jakobs C, Rauwerda JA, Dekker JM, Nijpels G, Bouter LM, Heine RJ, Stehouwer CDA (University Hospital Vrije Universiteit, Amsterdam). Hyperhomocysteinaemia is not associated with isolated crural arterial occlusive disease: the Hoorn Study. J Intern Med 2000; 247: 442–448. Objectives. Hyperhomocysteinaemia is an independent risk factor for peripheral arterial disease (PAD). The localization of peripheral arterial disease is clinically relevant, because proximal (aortoiliac and femoropopliteal) disease is associated with a particularly poor overall prognosis, whereas isolated distal (i.e. crural) disease is associated with a better overall prognosis. The aim of the study was to investigate whether the strength of the association between hyperhomocysteinaemia and peripheral arterial disease differs according to the localization of the anatomical obstruction. Design. Fasting serum total homocysteine (tHcy) was measured in an age-, sex- and glucose-tolerance stratified random sample (n = 631) of a 50- to 75-year-old general Caucasian population. History of a peripheral arterial reconstruction was recorded. Aortoiliac, femoropopliteal and crural arterial obstructions were registered by means of Doppler flow velocity curves. Results. The median serum tHcy level was 12.2 µmol L–1 (interquartile range: 10.0–15.3) in men and 10.7 µmol L–1 (interquartile range: 9.0–13.3) in women. The prevalences of aortoiliac, femoropopliteal and crural obstructions were 2.1%, 2.7% and 11.9%, respectively. After adjustment for age, sex, systolic blood pressure, current smoking, serum cholesterol and diabetes mellitus, the odds ratios (95% confidence interval) per 5 µmol L–1 tHcy increment were 1.41 (1.05–1.89) for aortoiliac, 1.03 (0.70–1.52) for femoropopliteal and 0.82 (0.59–1.15) for crural obstructions. Finally, diabetes mellitus, HbA1c and current smoking were significantly associated with crural and femoropopliteal disease, whereas systolic blood pressure was significantly associated with aortoiliac obstructions. Conclusions. The present study indicates that hyperhomocysteinaemia is associated with aortoiliac but not with isolated crural arterial occlusive disease.

Hoogeveen EK, Kostense PJ, Valk GD, Bertelsmann FW, Jakobs C, Dekker JM, Nijpels G, Heine RJ, Bouter LM, Stehouwer CDA (University Hospital Vrije Universiteit, Amsterdam). Hyperhomocysteinaemia is not related to risk of distal somatic polyneuropathy: The Hoorn Study. J Intern Med 1999; 246: 561–566. Objective. Distal somatic polyneuropathy is a major contributing factor in the pathogenesis of chronic foot infections and ulcers, and may lead to lower limb amputations. Both metabolic and vascular abnormalities may contribute to the development of impaired nerve function. We therefore assessed the association between hyperhomocysteinaemia, a risk factor for cardiovascular disease, and polyneuropathy. Design, setting and subjects. We studied an age-, sex- and glucose-tolerance-stratified random sample of a 50- to 75-year-old general Caucasian population in the Hoorn Study (N = 629). Any polyneuropathy (N = 95) was defined as the absence of at least two of the three following sensory modalities or reflexes of either foot: light touch sense, ankle reflex and vibration sensation. Definite polyneuropathy (N = 25) was present if, in addition, the vibration perception threshold of the right big toe was abnormal. Results. The prevalence of any polyneuropathy was 12.4% (33 of 266) in subjects with normal glucose tolerance (NGT), 12.6% (21 of 167) in those with impaired glucose tolerance (IGT), and 25.3% (41 of 162) in those with type 2 diabetes. The prevalence of definite polyneuropathy was 2.6% (7 of 266) in subjects with NGT, 2.4% (4 of 167) in those with IGT and 8.7% (14 of 161) in type 2 diabetic subjects. Polyneuropathy was associated with known risk factors such as diabetes, hyperglycaemia and body height. After adjustment for age, sex, HbA1c and hypertension, the odds ratio (95% CI) for any polyneuropathy per 5 µmol L–1 (about 1 SD) serum total homocysteine increment was 1.00 (0.72–1.39). After adjustment for age and sex, it was 0.62 (0.21–1.89) for definite polyneuropathy. Conclusion. Although a weak relation (as judged from the confidence intervals) cannot be excluded, we conclude that hyperhomocysteinaemia is probably not related to risk of distal somatic polyneuropathy.

Abstract —A high serum total homocysteine (tHcy) level is an independent risk factor for cardiovascular disease. Because it is not known whether the strength of the association between hyperhomocysteinemia and cardiovascular disease is similar for peripheral arterial, coronary artery, and cerebrovascular disease, we compared the three separate risk estimates in an age-, sex-, and glucose tolerance–stratified random sample (n=631) from a 50- to 75-year-old general white population. Furthermore, we investigated the combined effect of hyperhomocysteinemia and diabetes mellitus with regard to cardiovascular disease. The prevalence of fasting hyperhomocysteinemia (>14.0 μmol/L) was 25.8%. After adjustment for age, sex, hypertension, hypercholesterolemia, diabetes, and smoking, the odds ratios (ORs; 95% confidence intervals) per 5 -μmol/L increment in tHcy were 1.44 (1.10 to 1.87) for peripheral arterial, 1.25 (1.03 to 1.51) for coronary artery, 1.24 (0.97 to 1.58) for cerebrovascular, and 1.39 (1.15 to 1.68) for any cardiovascular disease. After stratification by glucose tolerance category and adjustment for the classic risk factors and serum creatinine, the ORs per 5 -μmol/L increment in tHcy for any cardiovascular disease were 1.38 (1.03 to 1.85) in normal glucose tolerance, 1.55 (1.01 to 2.38) in impaired glucose tolerance, and 2.33 (1.11 to 4.90) in non–insulin-dependent diabetes mellitus ( P =.07 for interaction). We conclude that the magnitude of the association between hyperhomocysteinemia and cardiovascular disease is similar for peripheral arterial, coronary artery, and cerebrovascular disease in a 50- to 75-year-old general population. High serum tHcy may be a stronger (1.6-fold) risk factor for cardiovascular disease in subjects with non–insulin-dependent diabetes mellitus than in nondiabetic subjects.

SUMMARY Family and epidemiological studies support a genetic susceptibility to UC and CD. Conflicting reports regarding associations between UC and HLA-DR2 and between CD and various HLA alleles have been published. The aim of this study was to determine whether molecularly defined HLA-DR genes are associated with these diseases in a Dutch group of patients. Fifty-nine unrelated Dutch UC patients and 89 CD patients were typed using DNA-based methods. A total of 2400 healthy local blood donors served as controls. The phenotype frequency of the HLA-DRB1*15 allele was increased in UC patients compared with controls (42% versus 26% in controls; P = 0.006; odds ratio (OR) = 2.1), and was predominantly found in female patients (53% versus 24%; P = 0.001; OR = 3.5). The DRB1*15 allele was increased in UC patients having a positive family history (P = 0.01; OR = 5.8). Among the 16 patients who showed an increase in extent of disease during follow up, 10 were DRB1*15+ (P = 0.002; OR = 4.8). The frequency of the DRB1*13 allele was decreased in patients with UC (15% versus 28% in controls; P = 0.04; OR = 0.5). In CD, no association was observed between disease or particular clinical subgroups and any allele tested. The present study provides additional evidence for the genetic association between UC and HLA-DRB1*15, and supports recent findings that the susceptibility gene(s) for CD is not located in the HLA class II region.

The relationship between first trimester uric acid production and later development of pregnancy induced hypertensive disorders (PIHD) was investigated. An anti-oxidant role for uric acid has been mentioned. Since uric acid and fibronectin (PF) are both markers of preeclampsia, the relationship between these two substances was also studied. Controls (n = 72) and patients with PIHD (n = 120) were selected. Uric acid was measured in serum and 24-hours urine samples (uric acid excretion) and PF in blood plasma in 270 nulliparous women at 13 +/- 2 weeks of gestation. Uric acid excretion was significantly lower in the first trimester in a group of patients who later develop PIHD as compared to patients who remain normotensive (p < 0.05), especially when corrected for body weight (p < 0.01). Patients with elevated PF levels in the first trimester showed a significantly lower uric acid excretion than patients with normal PF levels (p < 0.05). The data show diminished uric acid production in patients who will likely develop preeclampsia suggesting an impaired anti-oxidant production in the first trimester. This observation fits well with the hypothesis that an imbalance between anti-oxidant and oxidants plays an important role in the pathogenesis of preeclampsia.

The aim of the study was to analyze cardiovascular risk factors as predictors for developing non- insulin-dependent diabetes mellitus (NIDDM) in people with impaired glucose tolerance. A cross-sectional sur- vey of glucose tolerance was conducted in people, aged 50-74, w h o were randomly selected from the registry of the middle-sized town Hoorn (The Netherlands). Based on the mean values of two oral glucose tolerance tests, people were classified in glucose tolerance categories according to the WHO criteria. The mean follow- LIP> time was 36 months (range 13-55 months). The cumulative incidence of NIDDM was 34% (95% CI 16.9% 45.1). In multiple logistic regression analysis, cardiovascular risk factors at baseline did not predict the conversion from impaired glucose tolerance to NIDDM, in contrast with the two-hour plasma glucose level (odds ratio 3.56, p < 0.001) and the fasting proinsulin level, as one of the determinants of beta-cell dysfunction (Odds ratio 2.1, p < 0.05). The baseline HDL- h 1 't c o eb ero 1 1 eve , one of the components of the insulin resistance syn- 1 drome, was associated with the conversion from impaired glucose tolerance to normal glucose tolerance (Odds ratio 1.58, p < 0.05). The results of our study seem to support the hypothesis that conversion from impaired glucose tolerance to normal glucose tolerance depends on insulin resistance and the development of NIDDM from impaired glucose tolerance depends on beta-cell dysfunction. J CLIN EPIDEMIOL 50;9:1003-1009, 1997. 0 1997 Elsevier Science Inc.