Maternal mood disorders and lithium exposure in utero were not associated with poor cognitive development during childhood.

AIM: This study evaluated whether maternal mood disorders (MMD), particularly bipolar disorder, and lithium treatment during pregnancy influenced the neonatal health and cognition of children born from 2006 to 2010. METHODS: Our study at Karolinska University Hospital, Stockholm, Sweden, focused on women with and without mood disorders and their children. Information on pharmacotherapy, mental health, delivery and neonatal complications was retrospectively collected from electronic patient records. Children were tested in a blinded manner at four to five years of age with the Wechsler Preschool and Primary Scale of Intelligence, 3rd edition. Maternal health, child health and social situations were evaluated. RESULTS: Of the 39 children, 20 were exposed to lithium and MMD during pregnancy, eight were exposed to MMD but not lithium and 11 were not exposed to MMD or lithium. The children's full scale intelligence quotient (IQ), performance IQ and verbal IQ results did not differ significantly between the groups. The processing speed quotient was significantly lower in children exposed to mood disorders, but there was a high level of missing data for this subtest. CONCLUSION: This small, clinical cohort showed no significant association between mothers' prenatal exposure to lithium or mood disorders and their offspring's IQ.

The Swedish CArdioPulmonary BioImage Study: objectives and design.

Cardiopulmonary diseases are major causes of death worldwide, but currently recommended strategies for diagnosis and prevention may be outdated because of recent changes in risk factor patterns. The Swedish CArdioPulmonarybioImage Study (SCAPIS) combines the use of new imaging technologies, advances in large-scale 'omics' and epidemiological analyses to extensively characterize a Swedish cohort of 30 000 men and women aged between 50 and 64 years. The information obtained will be used to improve risk prediction of cardiopulmonary diseases and optimize the ability to study disease mechanisms. A comprehensive pilot study in 1111 individuals, which was completed in 2012, demonstrated the feasibility and financial and ethical consequences of SCAPIS. Recruitment to the national, multicentre study has recently started.

Weak associations between human leucocyte antigen genotype and acute myocardial infarction.

OBJECTIVES: Human leucocyte antigens (HLAs) are polymorphic molecules involved in antigen presentation. Associations between HLA type and autoimmune diseases, such as type 1 diabetes and rheumatoid arthritis, are well established but the potential association of genetic variation affecting antigen presentation with cardiovascular disease has not been systematically investigated in large cohorts. The importance of such studies is stressed by recent experimental findings of an involvement of autoimmunity in the atherosclerotic disease process. RESULTS: An SSP-PCR method was used for HLA genotyping to determine associations of HLA-DRB1, -DQA1 and -DQB1 with cardiovascular disease in a population-based cohort of 1188 acute myocardial infarction (AMI) patients and 1191 matched healthy controls. The HLA-DRB1*0101 allele, as well as the HLA-DRB1*0101-DQA1*01-DQB1*05 haplotype, was found to be associated with increased risk for AMI (OR 1.24; 95% CI 1.00-1.54 for both). In contrast, the DRB1*07 and DQA*02 alleles (OR 0.78; 95% CI 0.65-0.95 for both), as well as the DRB1*07-DQA*02-DQB*02 haplotype, conferred protection (OR 0.79; 95% CI 0.63-0.98). An HLA risk score taking each individual's both haplotypes into account was higher amongst cases (2.43 +/- 0.92 vs. 2.29 +/- 0.95, P = 0.001). The association between HLA risk score and AMI was independent of other cardiovascular risk factors assessed. CONCLUSIONS: This study demonstrates that the associations between HLA-DRB1 and DQA1 loci and cardiovascular disease exists but that they are considerably weaker than those previously reported for other diseases with an established autoimmune aetiology such as type 1 diabetes, systemic lupus erythematosus and rheumatoid arthritis.

Linoleic acid, a dietary n-6 polyunsaturated fatty acid, and the aetiology of ulcerative colitis: a nested case-control study within a European prospective cohort study.

OBJECTIVE: Dietary linoleic acid, an n-6 polyunsaturated fatty acid, is metabolised to arachidonic acid, a component of colonocyte membranes. Metabolites of arachidonic acid have pro-inflammatory properties and are increased in the mucosa of patients with ulcerative colitis. The aim of this investigation was to conduct the first prospective cohort study investigating if a high dietary intake of linoleic acid increases the risk of developing incident ulcerative colitis. DESIGN AND SETTING: Dietary data from food frequency questionnaires were available for 203 193 men and women aged 30-74 years, resident in the UK, Sweden, Denmark, Germany or Italy and participating in a prospective cohort study, the European Prospective Investigation into Cancer and Nutrition (EPIC). These participants were followed up for the diagnosis of ulcerative colitis. Each case was matched with four controls and the risk of disease calculated by quartile of intake of linoleic acid adjusted for gender, age, smoking, total energy intake and centre. RESULTS: A total of 126 participants developed ulcerative colitis (47% women) after a median follow-up of 4.0 years (range, 1.7-11.3 years). The highest quartile of intake of linoleic acid was associated with an increased risk of ulcerative colitis (odds ratio (OR) = 2.49, 95% confidence interval (CI) = 1.23 to 5.07, p = 0.01) with a significant trend across quartiles (OR = 1.32 per quartile increase, 95% CI = 1.04 to 1.66, p = 0.02 for trend). CONCLUSIONS: The data support a role for dietary linoleic acid in the aetiology of ulcerative colitis. An estimated 30% of cases could be attributed to having dietary intakes higher than the lowest quartile of linoleic acid intake.

Assessing the effect of interaction between an FTO variant (rs9939609) and physical activity on obesity in 15,925 Swedish and 2,511 Finnish adults.

AIMS/HYPOTHESIS: Recent reports have suggested that genotypes at the FTO locus interact with physical activity to modify levels of obesity-related traits. We tested this hypothesis in two non-diabetic population-based cohorts, the first from southern Sweden and the second from the Botnia region of western Finland. METHODS: In total 2,511 Finnish and 15,925 Swedish non-diabetic middle-aged adults were genotyped for the FTO rs9939609 variant. Physical activity was assessed by questionnaires and standard clinical procedures were conducted, including measures of height and weight and glucose regulation. Tests of gene x physical activity interaction were performed using linear interaction effects to determine whether the effect of this variant on BMI is modified by physical activity. RESULTS: The minor A allele at rs9939609 was associated with higher BMI in both cohorts, with the per allele difference in BMI being about 0.13 and 0.43 kg/m(2) in the Swedish and Finnish cohorts, respectively (p < 0.0001). The test of interaction between physical activity and the rs9939609 variant on BMI was not statistically significant after controlling for age and sex in either cohort (Sweden: p = 0.71, Finland: p = 0.18). CONCLUSIONS/INTERPRETATION: The present report does not support the notion that physical activity modifies the effects of the FTO rs9939609 variant on obesity risk in the non-diabetic Swedish or Finnish adults studied here.

Immune responses against fibronectin modified by lipoprotein oxidation and their association with cardiovascular disease.

OBJECTIVES: Accumulation and subsequent oxidation of LDL in the arterial wall are considered as key events in the development of atherosclerosis. We have investigated the possibility that LDL oxidation results in release of aldehydes that modify surrounding matrix proteins and that this may target immune responses against the plaque extracellular matrix and modulate the disease progression. RESULTS: Using custom-made ELISAs we demonstrate that human plasma contains autoantibodies against aldehyde-modified fibronectin (FN) and to a lesser extent also other extracellular matrix proteins including collagen type I, type III, and tenascin-C. Immunohistochemistry and western blot analysis showed that aldehyde-modified FN is present in human atherosclerotic plaques and that aldehydes generated by oxidation of LDL formed adducts with FN in vitro. We also demonstrate that aldehyde-modification of FN results in a loss of its ability to promote basal secretion of cytokines and growth factors from cultured macrophages without affecting the ability of the cells to respond to stimulation with LPS. A prospective clinical study demonstrated that subjects that subsequently developed acute myocardial infarction or sudden cardiac death had lower baseline levels of autoantibodies against aldehyde-modified FN than matched controls. CONCLUSIONS: These observations demonstrate that oxidation of LDL in the arterial wall may lead to aldehyde-modification of surrounding extracellular matrix proteins and that these modifications may affect macrophage function and activate autoimmune responses of pathophysiological importance for the development of atherosclerosis.

Breast feeding, but not use of oral contraceptives, is associated with a reduced risk of rheumatoid arthritis.

OBJECTIVE: To determine whether breast feeding or the use of oral contraceptives (OCs) affects the future risk of rheumatoid arthritis (RA) in a community-based prospective cohort. METHODS: A community-based health survey (18 326 women) was linked to regional and national registers, and incident cases of RA were identified. All women with a diagnosis of RA after inclusion in the health survey (n = 136) and four female controls for every case, who were alive and free from RA when the index person was given a diagnosis of RA, were included in a case-control study. Data on lifestyle factors at baseline were derived from a self-administered questionnaire. Potential predictors were examined in logistic regression models. RESULTS: 136 women with incident RA were compared with 544 age-matched controls. A longer history of breast feeding was associated with a reduced risk of RA (OR 0.46 (95% CI 0.24 to 0.91) for women who had breast fed for >/=13 months and OR 0.74 (95% CI 0.45 to 1.20) for those who had breast fed for 1-12 months, compared with those who had never breast fed). The protective effect of longer breast feeding remained significant after adjustment for smoking and level of education in multivariate models, and point estimates were protective also when the analyses were restricted to parous women. Neither parity nor OC use had any significant effect on the risk of RA. CONCLUSION: In this study, long-term breast feeding, but not OC use, was associated with a significant reduction in the risk of RA.

The search for putative unifying genetic factors for components of the metabolic syndrome.

AIMS/HYPOTHESIS: The metabolic syndrome is a cluster of factors contributing to increased risk of cardiovascular disease and type 2 diabetes but unifying mechanisms have not been identified. Our aim was to study whether common variations in 17 genes previously associated with type 2 diabetes or components of the metabolic syndrome and variants in nine genes with inconsistent association with at least two components of the metabolic syndrome would also predict future development of components of the metabolic syndrome, individually or in combination. METHODS: Genetic variants were studied in a large prospective study of 16,143 non-diabetic individuals (mean follow-up time 23 years) from the Malmö Preventive Project. In this study, development of at least three of obesity (BMI >or= 30 kg/m(2)), dyslipidaemia (triacylglycerol >or= 1.7 mmol/l and/or lipid-lowering treatment), hypertension (blood pressure >or= 140/90 mmHg and/or antihypertensive medication) and hyperglycaemia (fasting plasma glucose >or= 5.6 mmol/l and/or known diabetes) was defined as development of the metabolic syndrome. The risk of developing at least three components of the metabolic syndrome or the individual components was calculated by logistic regression adjusted for age at baseline, follow-up time and sex. RESULTS: Polymorphisms in TCF7L2 (rs7903146, OR 1.10, 95% CI 1.04-1.17, p = 0.00097), FTO (rs9939609, OR 1.08, 95% CI 1.02-1.14, p = 0.0065), WFS1 (rs10010131, OR 1.07, 95% CI 1.02-1.13, p = 0.0078) and IGF2BP2 (rs4402960, OR 1.07, 95% CI 1.01-1.13, p = 0.021) predicted the development of at least three components of the metabolic syndrome in both univariate and multivariate analysis; in the case of TCF7L2, WFS1 and IGF2BP this was due to their association with hyperglycaemia (p < 0.00001, p = 0.0033 and p = 0.027, respectively) and for FTO it was due to its association with obesity (p = 0.004). A polymorphism in the GCKR gene predicted dyslipidaemia (rs1260326, OR 1.15, 95% CI 1.09-1.22, p < 0.00001) but not the metabolic syndrome. None of the studied polymorphisms was associated with more than two components of the metabolic syndrome. A composite genotype score of the 17 polymorphisms associated with type 2 diabetes predicted the development of at least three components of the metabolic syndrome (OR 1.04, p < 0.00001) and the development of hyperglycaemia (OR 1.06, p < 0.00001). Carriers of >or=19 risk alleles had 51 and 72% increased risk of developing at least three components of the metabolic syndrome and hyperglycaemia, respectively, compared with carriers of

Health-related quality of life and distress in cancer patients: results from a large randomised study.

To compare the effectiveness of individual support, group rehabilitation and a combination of the two in improving health-related quality of life (HRQOL) and psychological well-being in cancer patients during 24 months after diagnosis, as compared with standard care (SC). Furthermore, to compare the study sample and a random sample of the Swedish population with regard to HRQOL. A total of 481 consecutive patients, newly diagnosed with cancer, were randomly assigned to one of the four alternatives. Data on HRQOL and psychological well-being were collected at baseline and after 3, 6, 12 and 24 months. The interventions did not improve HRQOL or psychological well-being, as compared with SC. At 3 months, the study sample reported an HRQOL comparable with the normal population. Many cancer patients are able to manage their cancer-related concerns with the support available from SC. However, it is reasonable to assume that the findings suffer from a lack of data from especially vulnerable patients and a possible Hawthorne effect. It cannot be concluded that cancer patients have no need for additional psychosocial interventions. Future projects should include screening and target interventions for those at risk for significant and prolonged psychological distress.

Animal foods, protein, calcium and prostate cancer risk: the European Prospective Investigation into Cancer and Nutrition.

We examined consumption of animal foods, protein and calcium in relation to risk of prostate cancer among 142 251 men in the European Prospective Investigation into Cancer and Nutrition. Associations were examined using Cox regression, stratified by recruitment centre and adjusted for height, weight, education, marital status and energy intake. After an average of 8.7 years of follow-up, there were 2727 incident cases of prostate cancer, of which 1131 were known to be localised and 541 advanced-stage disease. A high intake of dairy protein was associated with an increased risk, with a hazard ratio for the top versus the bottom fifth of intake of 1.22 (95% confidence interval (CI): 1.07-1.41, P(trend)=0.02). After calibration to allow for measurement error, we estimated that a 35-g day(-1) increase in consumption of dairy protein was associated with an increase in the risk of prostate cancer of 32% (95% CI: 1-72%, P(trend)=0.04). Calcium from dairy products was also positively associated with risk, but not calcium from other foods. The results support the hypothesis that a high intake of protein or calcium from dairy products may increase the risk for prostate cancer.

Cytokine gene polymorphisms and the risk of adenocarcinoma of the stomach in the European prospective investigation into cancer and nutrition (EPIC-EURGAST).

BACKGROUND: The relative contribution to gastric cancer (GC) risk of variants in genes that determine the inflammatory response remains mostly unknown and results from genotyping studies are inconsistent. PATIENTS AND METHODS: A nested case-control study within the prospective European Prospective Investigation into Cancer and Nutrition cohort was carried out, including 248 gastric adenocarcinomas and 770 matched controls. Twenty common polymorphisms at cytokine genes [interleukin (IL)1A, IL1B, IL1RN, IL4, IL4R, IL6, IL8, IL10, IL12A, IL12B, lymphotoxin alpha and tumor necrosis factor (TNF)] were analyzed. Antibodies against Helicobacter pylori (Hp) and CagA were measured. RESULTS: IL1RN 2R/2R genotype [odds ratio (OR) 2.43; 95% confidence interval (CI) 1.19-4.96] and allele IL1RN Ex5-35C were associated with an increased risk of Hp(+) non-cardia GC. IL8 -251AA genotype was associated with a decreased risk of Hp(+) non-cardia GC (OR 0.51; 95% CI 0.32-0.81), mainly of the intestinal type. These associations were not modified by CagA status. Carriers of IL1B -580C and TNF -487A alleles did not associate with an increased risk. A moderately increased risk of Hp(+) non-cardia GC for IL4R -29429T variant was observed (OR 1.74; 95% CI 1.15-2.63). CONCLUSION: This prospective study confirms the association of IL1RN polymorphisms with the risk of non-cardia GC and indicates that IL8 -251T>A may modify the risk for GC.

The Pro12Ala polymorphism of the PPARG gene is not associated with the metabolic syndrome in an urban population of middle-aged Swedish individuals.

BACKGROUND: To determine if the common Pro12Ala polymorphism (rs1801282) of the peroxisome proliferator-activated receptor (PPARG) gene is associated with the metabolic syndrome (MetS) or with its individual components in middle-aged Swedish individuals. METHODS: MetS was defined according to the National Cholesterol Education Program/Adult Panel III (NCEP/ATP III), the International Diabetes Federation (IDF) and the European Group for the Study of Insulin Resistance (EGIR) criteria in a population-based sample of nearly 5000 subjects participating in the Malmö Diet and Cancer-cardiovascular arm. RESULTS: Of the subjects included in the analysis, 21.8, 29.4 and 20.4% had MetS according to the NCEP/ATP III, IDF and EGIR (only in subjects without diabetes) definitions, respectively. The Pro12Ala was not associated with MetS or with its individual components. These results were similar when patients with diabetes were excluded. Hypertensive and obese ala-carriers had lower fasting glucose and hypertensive ala-carriers also had lower level triglycerides (P < 0.05). CONCLUSIONS: Our data do not support a major role for the Pro12Ala variant of the PPARG gene in MetS and its individual components. The modest difference in triglyceride and glucose levels, restricted to hypertensive and obese subjects in our cohort, suggests that the polymorphism has a minor effect on glucose and lipid metabolism, particularly in individuals at risk for gluco-metabolic disturbances.

Plasma levels of complement C3 is associated with development of hypertension: a longitudinal cohort study.

Hypertension has been associated with raised plasma levels of complement factor 3 and 4 (C3 and C4). The nature of this association is unclear. This population-based longitudinal study explored whether C3 or C4 is associated with development of hypertension. Blood pressure and plasma levels of C3 and C4 were determined in 2178 healthy men, aged 35-50 years, initially without treatment for hypertension. Incidence of hypertension and blood pressure increase over 15.7 (+/-2.2) years follow-up was studied in relation to C3 and C4 at baseline. Among men with initially normal blood pressure (<160/95 mm Hg), incidence of hypertension (>or=160/95 mm Hg or treatment) was 32, 42, 37 and 47%, respectively, for men with C3 in the first, second, third and fourth quartile (trend: P=0.001). This relationship remained significant after adjustment for confounding factors. Among men without blood pressure treatment, systolic BP increase (mean+standard error, adjusted for age, initial blood pressure and follow-up time) was 17.5+0.8, 19.6+0.9, 19.8+0.8 and 20.8+0.8 mm Hg, respectively, in the C3 quartiles (trend: P=0.004). C3 was not associated diastolic blood pressure at follow-up. Although C4 was associated with blood pressure at the baseline examination, there was no relationship between C4 and development of hypertension or future blood pressure increase. It is concluded that C3 in plasma is associated with future blood pressure increase and development of hypertension.

Low-dose metoprolol CR/XL and fluvastatin slow progression of carotid intima-media thickness: Main results from the Beta-Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS).

BACKGROUND: Statins reduce cardiovascular events and progression of carotid intima-media thickness (IMT). beta-Blockers are also known to reduce cardiovascular events, but less is known about their effects on carotid IMT. METHODS AND RESULTS: We conducted a randomized, double-blind, placebo-controlled, single-center trial to compare the effects of low-dose metoprolol CR/XL (25 mg once daily) and fluvastatin (40 mg once daily) on the progression of carotid IMT during 36 months of treatment in 793 subjects who had carotid plaque but no symptoms of carotid artery disease. Changes in mean IMT in the common carotid artery and maximal IMT in the bulb were the main outcome variables. Death and cardiovascular events were monitored. Progression of IMT(max) in the carotid bulb at both 18 and 36 months was reduced by metoprolol CR/XL (-0.058 mm/y; 95% CI, -0.094 to -0.023; P=0.004; and -0.023 mm/y; 95% CI, -0.044 to -0.003; P=0.014, respectively). Incidence of cardiovascular events tended to be lower in metoprolol CR/XL-treated patients (5 versus 13 patients, P=0.055). Rate of IMT(mean) progression in the common carotid at 36 months was reduced by fluvastatin (-0.009 mm/y; 95% CI, -0.015 to -0.003; P=0.002). Women in the fluvastatin group had increased frequency of transiently high liver enzymes. CONCLUSIONS: This is the first randomized trial to show that a beta-blocker can reduce the rate of progression of carotid IMT in clinically healthy, symptom-free subjects with carotid plaque. This suggests that beta-blockers may have a favorable effect on atherosclerosis development.

Effect of endocrine treatment on sexuality in premenopausal breast cancer patients: a prospective randomized study.

PURPOSE: To study the sexual effects of the 2-year adjuvant goserelin (Zoladex [Zeneca AB, Södertälje, Sweden]) alone, tamoxifen alone, and Zoladex and tamoxifen in combination (ZT) versus no adjuvant endocrine therapy among premenopausal breast cancer patients with or without chemotherapy in a controlled clinical trial (a European multicenter trial: Zoladex in Premenopausal Breast Cancer Patients). PATIENTS AND METHODS: This prospective study examined several aspects of sexuality through the use of self-administered questionnaires, which were completed by patients at seven points of assessment for 3 years after randomization. RESULTS: Patients treated with chemotherapy had a higher level of sexual dysfunction than did patients who received no systemic treatment. The addition of endocrine treatment did not alter this result. In contrast, among patients who did not receive chemotherapy, Zoladex and ZT produced a significantly higher level of dysfunction from 1 to 2 years after inclusion, as compared with those who received no endocrine treatment. Tamoxifen alone did not produce side effects. After termination of endocrine treatment, sexual dysfunction began to diminish. Those with chemotherapy had high and frequently increasing levels of dysfunction even after 2 to 3 years of independent of endocrine treatment. Zoladex had a negative effect on sexual fear, which was reduced by the addition of tamoxifen. CONCLUSION: Zoladex increased sexual dysfunction during treatment among patients without chemotherapy, but the disturbances of sexual functioning were reversible. The use of adjuvant chemotherapy was associated with continued sexual problems, even at 3 years after randomization.

Incidence of stroke is related to carotid IMT even in the absence of plaque.

BACKGROUND: The carotid intima-media thickness (IMT) has been associated with incidence of stroke. Whether this association is independent of carotid plaque is controversial. METHODS AND RESULTS: The associations among B-mode ultrasound determined common carotid IMT, carotid plaque (focal IMT>1.2mm) and incident stroke, were investigated in 5163 Swedish middle-aged men and women over a median follow-up of 7 years. Age and sex-adjusted carotid IMT, and carotid plaque were significantly (p<0.05) related to future stroke. Adjustment for cardiovascular risk factors generally reduced the hazard rate ratios, however more prominently so with regard to the carotid measure of plaque than with IMT. The associations between carotid IMT and stroke remained after adjustment for presence of carotid plaque, and graded associations between carotid IMT and stroke was found both among those with and without carotid plaque. CONCLUSIONS: In this population-based study, common carotid IMT was associated with incidence of stroke. This relation was independent of presence of carotid plaque.

Geographic distribution of stroke incidence within an urban population: relations to socioeconomic circumstances and prevalence of cardiovascular risk factors.

BACKGROUND AND PURPOSE: Geographic differences in stroke incidence indicate a potential for prevention. The present study from the city of Malmö, Sweden, sought to investigate whether incidence of stroke in residential areas is related to prevalence of cardiovascular risk factors and socioeconomic circumstances. METHODS: The Stroke Register in Malmö, Sweden, was used for retrieval of the 3540 patients who suffered a first stroke between 1989 and 1998. The Malmö Diet and Cancer cohort (n=28 466) was used to assess area specific prevalence of hypertension, diabetes, smoking, and being overweight and for computation of a cardiovascular risk score. Socioeconomic circumstances for the 17 administrative areas were expressed in terms of a composite score. RESULTS: Standardized stroke incidence ranged among areas from 437 to 743 per 100 000 for men and from 223 to 518 per 100 000 for women. Socioeconomic score correlated significantly with area-specific stroke rates among men (r=-0.62, P=0.008) and women (r=-0.67, P=0.004). Incidence of stroke was significantly associated with cardiovascular risk score for each area (men, r=0.53, P<0.05; women, r=0.76, P<0.001). The cardiovascular score and the socioeconomic score together accounted for 44% of the geographic variance among men and 63% among women. CONCLUSIONS: Marked differences occurred in stroke incidence among residential areas within this urban population. High-rate areas were characterized by a higher prevalence of smoking, hypertension, diabetes, and being overweight and by inferior socioeconomic circumstances. These risk factors accounted for a substantial proportion of the geographic variance in incidence of stroke.

Effects of antihypertensive treatment on prognosis.

Knowledge of the benefit of antihypertensive treatment relies on several large-scale trials, such as the Veterans Administration (VA) Studies, the Hypertension Detection and Follow-up Program (HDFP), the Australian National Blood Pressure Study (ANBP Study), and the Gothenburg Primary Preventive (GPP) study. These studies have shown that antihypertensive drugs decrease the incidence of directly hypertension-related complications like stroke, cardiac decompensation, and accelerating hypertension. It is less clear whether they influence the incidence of coronary events. In the HDFP, the ANBP Study, and the GPP study, the participants were recruited by screening large proportions of the total population. The proportion of the total screened population who met the inclusion criteria and hence were included was 3.3% in the ANBP, 6.9% in the HDFP, and 13.6% in the GPP trial. In most Western countries a substantially larger proportion of the total population is already being treated for hypertension. It is therefore not possible to use the results of these studies to justify treatment of larger segments of the population than we treat today. This is especially important because the milder the hypertension, the less effective the treatment is; hence, more patients will be given treatment without deriving benefit from it.

Glucose modulation of insulin and glucagon secretion is altered in impaired glucose tolerance.

Insulin and glucagon secretion was compared in women with impaired glucose tolerance (IGT; n = 19, age 58.4 +/- 0.3 yr; mean +/- SD) and women with normal glucose tolerance (NGT; n = 40, age 58.4 +/- 0.3 yr). Fasting plasma insulin levels were higher in IGT than in NGT (P = 0.026), whereas fasting glucose and glucagon levels were not different. Arginine was injected intravenously (5 g), which rapidly stimulated insulin and glucagon secretion in all subjects. Raising the blood glucose (BG) to 14 and 28 mmol/L potentiated insulin secretion and inhibited glucagon secretion. The acute insulin response to arginine (AIR = 2-5 min postload increase) at BG 14 mmol/L, but not at fasting BG or BG 28 mmol/L, was lower in IGT than in NGT (P = 0.033), as was the glucose potentiation of AIR (slopeAIR) (P = 0.020). The acute glucagon response (AGR) was higher in IGT than in NGT at BG 14 mmol/L (P = 0.016). SlopeAGR (glucose inhibition of AGR) was reduced in IGT (P = 0.001). In NGT, there was a significant inverse correlation between slopeAIR and slopeAGR (P = 0.002) not seen in IGT. We conclude that in IGT with normal fasting BG, the glucose modulation of islet function is impaired, indicating that islet dysfunction is an early lesion during the development of noninsulin-dependent diabetes mellitus.

Evidence for leptin regulation of food intake in humans.

The adipocyte hormone leptin regulates body weight in mice by decreasing food intake and increasing energy expenditure. Whether leptin is of physiological importance for these processes in humans is, however, not clear. We therefore studied the relation between leptin and habitual food intake in 64 healthy postmenopausal women. Dietary habits were assessed with a modified diet history method. Body fat content was measured using bioelectrical impedance. In the 64 women, aged 58.6+/-0.4 yr (mean+/-SD), serum leptin was 19.3+/-12.7 ng/mL, body mass index was 25.0+/-3.5 kg/m2, body fat content was 31.6+/-4.3%, fasting glucose was 4.6+/-0.5 mmol/L, and fasting insulin was 56+/-21 pmol/L. Leptin levels were negatively correlated to total energy intake (r=-0.34; P=0.006), carbohydrate intake (r=-0.36; P=0.004), and total (r=-0.27; P=0.034) as well as saturated fat intake (r=-0.31; P=0.014). Leptin was correlated to the absolute, but not to the percent, intake of these nutrients. When normalized for body fat content, the correlations remained significant. Our results suggest that plasma leptin is involved in the physiological regulation of food intake in humans, and that leptin is related to the quantity rather than the quality of habitual food intake.