Dietary glycemic index and glycemic load in relation to changes in body composition measures during adolescence: Northern Ireland Young Hearts Study.

BACKGROUND: Epidemiologic evidence on the influence of dietary glycemic index (GI) and glycemic load (GL) on the development of obesity is limited. OBJECTIVE: This prospective study examined the associations between dietary GI and GL and changes in body composition measures during adolescence. DESIGN: In a representative sample of Northern Irish adolescents aged 12 years at baseline and 15 years at follow-up (n=426), dietary intake was assessed by a diet history interview. Body composition measures included body mass index (BMI; kg m(-2)), BMI z-score, sum of four skinfold thicknesses, percentage body fat, fat mass index (FMI; kg m(-2)) and fat-free mass index (kg m(-2)). RESULTS: After adjustment for potential confounding factors, baseline GI was associated with increased change in FMI. Mean (95% confidence interval) values of changes in FMI according to tertiles of baseline GI were 0.41 (0.25, 0.57), 0.42 (0.26, 0.58) and 0.67 (0.51, 0.83) kg m(-2), respectively (P for trend=0.03). There was no significant association of baseline GI with changes in other body composition measures (P for trend≥0.054). Conversely, baseline GL showed no association with changes in any of the measures (P for trend≥0.41). Furthermore, changes in GI or GL were not associated with changes in any of the measures (P for trend≥0.16). CONCLUSION: Dietary GI at age 12 years was independently associated with increased change in FMI between ages 12 and 15 years in a representative sample from Northern Ireland, whereas dietary GL showed no association with changes in any of the body composition measures examined.

Glucose-lowering agents and the patterns of risk for cancer: a study with the General Practice Research Database and secondary care data.

INTRODUCTION: Recent studies suggesting an increased cancer risk with glucose-lowering agents have received widespread publicity. The objectives of this study were to evaluate the comparability in underlying cancer risk and patterns of cancer risk over time with different glucose-lowering agents. METHODS: The General Practice Research Database (GPRD) was used to identify cohorts of new users. Cancer outcomes were obtained from the GPRD, Hospital Episode Statistics and cancer registries. Relative rates of cancer comparing different glucose-lowering agents were estimated using Poisson regression. RESULTS: A total of 206,940 patients was identified. There was no difference in cancer risk and quartile for HbA(1c) value. There were differences in cancer incidence in the first 6 months after starting treatment (adjusted relative rate of 0.83 [95% CI 0.70, 0.99] with thiazolidinediones, 1.34 [95% CI 1.19, 1.51] with sulfonylureas and 1.79 [95% CI 1.53, 2.10] with insulin, compared with metformin). Insulin users had decreasing cancer incidence over time (adjusted relative rate of 0.58 [95% CI 0.50, 0.68] during months 6-24, relative rate of 0.50 [95% CI 0.42, 0.59] during months 25-60 and relative rate of 0.48 [95% CI 0.40, 0.59] during months 60+) compared with months 0-6 after starting insulin. Similar patterns were found with sulfonylureas and metformin. There were no increases over time with insulin glargine (A21Gly, B31Arg, B32Arg human insulin; relative rate of 0.70 [95% CI 0.52, 0.95], 0.77 [95% CI 0.56, 1.07] and 0.60 [95% CI 0.36, 1.02], respectively, for 6-24, 25-60 and >60 months). CONCLUSIONS: These findings do not provide evidence of either beneficial or adverse effects of glucose-lowering agents on cancer risk and are consistent with changes in diabetes treatment in the few months prior to the diagnosis of cancer.

Risk markers for both chronic fatigue and irritable bowel syndromes: a prospective case-control study in primary care.

BACKGROUND: Fatigue syndromes and irritable bowel syndrome (IBS) often occur together. Explanations include being different manifestations of the same condition and simply sharing some symptoms. METHOD: A matched case-control study in UK primary care, using data collected prospectively in the General Practice Research Database (GPRD). The main outcome measures were: health-care utilization, specific symptoms and diagnoses. Risk markers were divided into distant (from 3 years to 1 year before diagnosis) and recent (1 year before diagnosis). RESULTS: A total of 4388 patients with any fatigue syndrome were matched to two groups of patients: those attending for IBS and those attending for another reason. Infections were specific risk markers for both syndromes, with viral infections being a risk marker for a fatigue syndrome [odds ratios (ORs) 2.3-6.3], with a higher risk closer to onset, and gastroenteritis a risk for IBS (OR 1.47, compared to a fatigue syndrome). Chronic fatigue syndrome (CFS) shared more distant risk markers with IBS than other fatigue syndromes, particularly other symptom-based disorders (OR 3.8) and depressive disorders (OR 2.3), but depressive disorders were a greater risk for CFS than IBS (OR 2.4). Viral infections were more of a recent risk marker for CFS compared to IBS (OR 2.8), with gastroenteritis a greater risk for IBS (OR 2.4). CONCLUSIONS: Both fatigue and irritable bowel syndromes share predisposing risk markers, but triggering risk markers differ. Fatigue syndromes are heterogeneous, with CFS sharing predisposing risks with IBS, suggesting a common predisposing pathophysiology.

Mechanisms underlying the metabolic actions of galegine that contribute to weight loss in mice.

BACKGROUND AND PURPOSE: Galegine and guanidine, originally isolated from Galega officinalis, led to the development of the biguanides. The weight-reducing effects of galegine have not previously been studied and the present investigation was undertaken to determine its mechanism(s) of action. EXPERIMENTAL APPROACH: Body weight and food intake were examined in mice. Glucose uptake and acetyl-CoA carboxylase activity were studied in 3T3-L1 adipocytes and L6 myotubes and AMP activated protein kinase (AMPK) activity was examined in cell lines. The gene expression of some enzymes involved in fat metabolism was examined in 3T3-L1 adipocytes. KEY RESULTS: Galegine administered in the diet reduced body weight in mice. Pair-feeding indicated that at least part of this effect was independent of reduced food intake. In 3T3-L1 adipocytes and L6 myotubes, galegine (50 microM-3 mM) stimulated glucose uptake. Galegine (1-300 microM) also reduced isoprenaline-mediated lipolysis in 3T3-L1 adipocytes and inhibited acetyl-CoA carboxylase activity in 3T3-L1 adipocytes and L6 myotubes. Galegine (500 microM) down-regulated genes concerned with fatty acid synthesis, including fatty acid synthase and its upstream regulator SREBP. Galegine (10 microM and above) produced a concentration-dependent activation of AMP activated protein kinase (AMPK) in H4IIE rat hepatoma, HEK293 human kidney cells, 3T3-L1 adipocytes and L6 myotubes. CONCLUSIONS AND IMPLICATIONS: Activation of AMPK can explain many of the effects of galegine, including enhanced glucose uptake and inhibition of acetyl-CoA carboxylase. Inhibition of acetyl-CoA carboxylase both inhibits fatty acid synthesis and stimulates fatty acid oxidation, and this may to contribute to the in vivo effect of galegine on body weight.

The potential application of a biomarker approach for the investigation of low-calorie sweetener exposure.

Low-calorie sweeteners (LCS) are commonly used as sugar substitutes in the diet to provide a desired sweet taste without increased energy intake. The number of LCS available on the market has increased considerably over the years and despite extensive evaluation of their safety prior to approval, debate continues around the effects of consumption on health. In Europe, Member States are obligated to monitor exposure to LCS and methods currently used tend to rely on self-reported dietary intake data alongside LCS concentrations in products. However, the acquisition of accurate data can be costly in terms of resources and time and are inherently imprecise. Although LCS are intensely sweet, they are chemically diverse and a limitation of many studies investigating the health effects of consumption is that they often fail to discern intakes of individual LCS. An approach which objectively assesses intakes of individual LCS would therefore allow robust investigations of their possible effects on health. Biomarker approaches have been utilised for the objective investigation of intakes of a range of dietary components and the feasibility of any such approach depends upon its validity as well as its applicability within the target population. This review aims to provide an overview of current understanding of LCS intake and explore the possibility of implementing a biomarker approach to enhance such understanding. Several commonly used LCS, once absorbed into the body, are excreted via the kidneys; therefore a urinary biomarker approach may be possible for the investigation of short-term exposure to these compounds.

Is the chronic fatigue syndrome an exercise phobia? A case control study.

OBJECTIVE: The aim of this study was to test whether patients with chronic fatigue syndrome (CFS) have an exercise phobia, by measuring anxiety-related physiological and psychological reactions to ordinary activity and exercise. METHODS: Patients and healthy but sedentary controls were assessed over 8 h of an ordinary day, and before, during and after an incremental exercise test on a motorised treadmill. To avoid confounding effects, those with a comorbid psychiatric disorder were excluded. Heart rate, galvanic skin resistance (GSR) and the amount of activity undertaken were measured, along with state and trait measures of anxiety. RESULTS: Patients with CFS were more fatigued and sleep disturbed than were the controls and noted greater effort during the exercise test. No statistically significant differences were found in either heart rate or GSR both during a normal day and before, during and after the exercise test. Patients with CFS were more symptomatically anxious at all times, but this did not increase with exercise. CONCLUSION: The data suggest that CFS patients without a comorbid psychiatric disorder do not have an exercise phobia.

A four-year prospective trial of unmeasured diet in lean diabetic adults.

Fifty-one adult male outpatients at or below ideal body weight (IBW) with no history of weighing more than 15% over IBW in the past 5 yr and no more than 25% in the past 15 yr were randomly assigned to a traditional calorically defined exchange-type diet (EXCH) or an unmeasured diet emphasizing avoidance of refined sugar and balance of food consumption throughout the day. All but 4 patients were insulin treated. With the exception of one patient in each group, all patients were classified as having type II diabetes. Subjects were followed in a single-blind design for 4 yr in the Diabetes Outpatient Clinic every 3 mo. The average mean fasting glycemia (FBS), coefficient of FBS variation, number of reported hypoglycemic reactions, mean fasting serum triglyceride and cholesterol levels, and mean total daily insulin dosage were similar in both groups. Each patient's mean daily caloric intake did vary over time, but there was no difference in mean caloric intake between diet groups. There was a significant correlation between a patient's mean FBS rating and his serum triglyceride level: patients with lower mean FBS had a significantly lower mean triglyceride level than patients with higher FBS. Overall body weights remained stable throughout the study. However, there was a significant difference in the number of patients in the EXCH group whose actual weight was 3% or more above IBW on 50% or more of their visits.(ABSTRACT TRUNCATED AT 250 WORDS)

Attentional bias to food-related visual cues: is there a role in obesity?

The incentive sensitisation model of obesity suggests that modification of the dopaminergic associated reward systems in the brain may result in increased awareness of food-related visual cues present in the current food environment. Having a heightened awareness of these visual food cues may impact on food choices and eating behaviours with those being most aware of or demonstrating greater attention to food-related stimuli potentially being at greater risk of overeating and subsequent weight gain. To date, research related to attentional responses to visual food cues has been both limited and conflicting. Such inconsistent findings may in part be explained by the use of different methodological approaches to measure attentional bias and the impact of other factors such as hunger levels, energy density of visual food cues and individual eating style traits that may influence visual attention to food-related cues outside of weight status alone. This review examines the various methodologies employed to measure attentional bias with a particular focus on the role that attentional processing of food-related visual cues may have in obesity. Based on the findings of this review, it appears that it may be too early to clarify the role visual attention to food-related cues may have in obesity. Results however highlight the importance of considering the most appropriate methodology to use when measuring attentional bias and the characteristics of the study populations targeted while interpreting results to date and in designing future studies.

Bradykinin-induced reductions in collagen gene expression involve prostacyclin.

Cardiac fibrosis after myocardial infarction and in chronic hypertension involves an increase in the synthesis and deposition of collagen within the myocardium. Angiotensin-converting enzyme (ACE) inhibitors limit hypertrophy and fibrosis; their mechanism of action remains controversial, although kinins have been implicated to play a role. Because both bradykinin and prostaglandins (PG) have been shown to reduce collagen gene expression in cardiac fibroblasts, the goal of this study was to determine whether the bradykinin effect was mediated through enhanced prostaglandin formation by cardiac fibroblasts. Bradykinin increased [3H]arachidonic acid metabolite release 2.3-fold over control and stimulated a dose-dependent increase in 6-keto PGF1alpha (the stable metabolite of PGI2) release from these cells, in which 1 nmol/L bradykinin produced a 4-fold increase in 6-keto PGF1alpha release. Beraprost (a PGI2 analogue) reduced steady-state proalpha1(I) and proalpha1(III) collagen mRNA levels by 35.6+/-6.6% and 34.2+/-10.0%, respectively. Bradykinin-induced reductions in collagen type I and III gene expression were reversed by pretreatment with indomethacin. Our results indicate that one mechanism by which bradykinin modulates collagen biosynthesis via the rabbit cardiac fibroblast involves formation of arachidonic acid metabolites, particularly PGI2. The results of the present study argue that stabilization of endogenous kinins (as by ACE inhibitors) would enhance prostacyclin production and result in the attenuation of collagen gene expression, with potential implications for collagen synthesis and deposition within the myocardium.

Prostacyclin release by rat cardiac fibroblasts: inhibition of collagen expression.

Cardiac fibroblasts, as the source of extracellular matrix for the left ventricle, subserve important functions to cardiac remodeling and fibrotic development following myocardial infarction or with pressure-overload cardiac hypertrophy. The fibroblast may be the target cell for angiotensin-converting enzyme inhibitors (ACEI) that are cardioprotective and reverse collagen deposition and remodeling but whose mechanisms of action remain controversial. Because we previously documented phenotypic differences between cardiac fibroblasts from the spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) left ventricle, the present study evaluated whether phenotypic differences also exist in the release of endogenous arachidonic acid metabolites or in the activation of phospholipase D, and the importance of observed differences to the formation of collagen and the mechanism of action of ACEI. The experimental design compared endogenous sources of arachidonic acid with exogenous prelabeling of cells. Angiotensin II stimulated greater arachidonic acid release than bradykinin, and WKY cells were more responsive than SHR. The major prostanoid formed by cardiac fibroblasts was prostaglandin I2 (PGI2), with more prostacyclin production by WKY cells than SHR cells both under nonstimulated conditions and in response to angiotensin II or bradykinin. Beraprost, a PGI2 analogue, was shown to decrease growth rate and DNA synthesis of fibroblasts and to inhibit mRNA expression for collagen types I and III, with SHR cells being less responsive to beraprost than WKY cells. These results potentially implicate eicosanoid metabolism, particularly PGI2, in collagen formation, fibrotic development, and cardiac remodeling, and they imply that the SHR genetic hypertension model may be predisposed to excess cardiac fibrosis.

Relationship between physical activity and bone mineral status in young adults: the Northern Ireland Young Hearts Project.

Physical activity during the first three decades of life may increase peak bone mass and reduce future osteoporosis risk. The aim of this study was to determine the extent to which different components of physical activity may influence bone mineral status within a representative population sample of young men and women. Bone mineral density (BMD) and content (BMC) were determined at the lumbar spine and femoral neck in 242 men and 212 women, aged 20-25 years, by dual-energy X-ray absorptiometry. Physical activity was assessed by a self-report questionnaire designed to measure the frequency and duration of physical activity and its components (i.e., work, non-sports leisure, sports-related activities, and peak strain sports activities). Potential confounding factors such as height, weight, diet, and smoking habits were also assessed. In multivariate linear regression models, sports activity and peak strain sports activity undertaken by men were strongly associated with both lumbar spine BMD (beta = 0.35 [0.21, 0.49] and beta = 0.31 [0.17, 0.44], respectively) and BMC (beta = 0.33 [0.21, 0.45] and beta = 0.26 [0.14, 0.38], respectively) and femoral neck BMD (beta = 0.35 [0.21, 0.48] and beta = 0.27 [0.14, 0.40], respectively) and BMC (beta = 0.32 [0.19, 0.44] and beta = 0.29 [0.17, 0.41], respectively) (all p < 0.01), but work and non-sports leisure activities were not. In women, there were no associations between bone measurements and any component of physical activity. In models involving all subjects the gender/sports activity, but not the gender/peak strain, interaction term was statistically significant. Sports activity explained 10.4% of the observed variance in lumbar spine BMD in men, but <1% in women. These results demonstrate the importance of sports activities, especially those involving high peak strain, in determining peak bone status in young men. Failure to observe this association in women reflects their lower participation in such activities, but they may have the same capacity to benefit from these activities as men. Intervention studies are warranted to determine whether peak bone density in women can be improved by participating, during childhood and adolescence, in sports activities involving high peak strain.

Total homocysteine is not a determinant of arterial pulse wave velocity in young healthy adults.

AIMS: Hyperhomocysteinaemia has been associated with reduced pulse wave velocity (PWV) in patients with end-stage renal disease and in those with hypertension. The aim of this study was to examine the association between total homocysteine (tHcy) concentrations, the biochemical and genetic determinants of tHcy and PWV in healthy young adults. METHODS AND RESULTS: A total of 489 subjects aged 20-25 years participated. A fasting blood sample was taken and PWV measured using a non-invasive optical method. tHcy did not correlate with PWV, whether assessed at the aorto-iliac segment (P = 0.18), the aorto-radial segment (P = 0.39) or the aorto-dorsalis-pedis segment (P = 0.22). When tHcy was classified into normal (<15) and high (> or =15micromol/l), PWV did not differ between the two groups at any segment. PWV did not differ by MTHFR C677T or NOS3 G894T genotype, even when smoking and folate sub-groups were considered. Considering aortic PWV as a dependent variable, stepwise regression analysis showed that the only parameter entering the model for all segments was systolic blood pressure (aorto-iliac, P < 0.001; aorto-radial, P = 0.01; aorto-dorsalis-pedis, P = 0.001). Age, sex, COL1A1 genotype and triglycerides entered the model significantly for two of three segments. CONCLUSION: This study shows that arterial PWV is not associated with tHcy in a healthy young population.

Evidence for differences in cultured left ventricular fibroblast populations isolated from spontaneously hypertensive and Wistar-Kyoto rats.

OBJECTIVE: To compare fibroblast populations derived from spontaneously hypertensive rats (SHRLJ) and normotensive Wistar-Kyoto rats (WKYLJ) for angiotensin II receptor binding, gene expression of the AT1 receptor and angiotensinogen, hormone responsiveness and phenotypic changes. METHODS: Fibroblasts were isolated by either collagenase B or collagenase P and grown to confluency in the presence of 10% fetal bovine serum. Angiotensin II receptor binding was assessed under both serum and serum-free conditions. Hormonal treatment of cells was conducted in a serum-free background. The concentrations of AT1 receptor and angiotensinogen messenger RNA (mRNA) were determined by liquid hybridization. Phenotypic changes in fibroblast populations were analysed by visualization of lipid-containing vacuoles (oil red O stain) or of alpha-smooth muscle actin-containing fibres (immunostain). RESULTS: SHRLJ collagenase-B cells grew more slowly and had nearly twofold fewer angiotensin II receptors than WKYLJ cells as measured by both radioligand binding and AT1 mRNA content (SHRLJ 1.34 +/- 0.05 versus WKYLJ 5.94 +/- 0.41 pg mRNA per microgram total RNA) but contained significantly more angiotensinogen mRNA (SHRLJ 147 +/- 12 versus WKYLJ 98 +/- 8 fg mRNA per microgram total RNA). Collagenase-P cells from the two strains exhibited similar binding and growth properties. Collagenase-B fibroblasts also exhibited greater responses to exogenous steroids, including a greater shift towards an adipocyte phenotype, than collagenase-P cells. Exogenous angiotensin II promoted transformation towards a myofibroblast cell type, especially in collagenase-P SHRLJ cells. CONCLUSION: Our results indicate that subsets of fibroblasts that differ in growth rate, angiotensin II receptor binding, AT1 and angiotensinogen mRNA levels, structure and steroid responsiveness may be isolated from the left ventricle. The potential importance of these altered phenotypes to cardiac remodelling and hypertrophy warrants further examination.

Risks of stroke and mortality associated with suboptimal anticoagulation in atrial fibrillation patients.

Atrial fibrillation (AF) carries an increased risk of ischaemic stroke, and oral anticoagulation with warfarin can reduce this risk. The objective of this study was to evaluate the association between time in therapeutic International Normalised Ratio (INR) range when receiving warfarin and the risk of stroke and mortality. The study cohort included AF patients aged 40 years and older included in the UK General Practice Research Database. For patients treated with warfarin we computed the percentage of follow-up time spent within therapeutic range. Cox regression was used to assess the association between INR and outcomes while controlling for patient demographics, health status and concomitant medication. The study population included 27,458 warfarin-treated (with at least 3 INR measurements) and 10,449 patients not treated with antithrombotic therapy. Overall the warfarin users spent 63% of their time within therapeutic range (TTR). This percentage did not vary substantially by age, sex and CHA2DS2-VASc score. Patients who spent at least 70% of time within therapeutic range had a 79% reduced risk of stroke compared to patients with ≤30% of time in range (adjusted relative rate of 0.21; 95% confidence interval 0.18-0.25). Mortality rates were also significantly lower with at least 70% of time spent within therapeutic range. In conclusion, good anticoagulation control was associated with a reduction in the risk of stroke.

Initiation and persistence of warfarin or aspirin in patients with chronic atrial fibrillation in general practice: do the appropriate patients receive stroke prophylaxis?

BACKGROUND: Practice guidelines recommend long-term stroke prophylaxis in patients with chronic atrial fibrillation (cAF). OBJECTIVES: To examine treatment initiation and persistence and factors that influence the choice of cAF treatment. PATIENTS/METHODS: This study used the General Practice Research Database, including computerized medical records of general practitioners in the UK. Patients aged 40+ years with cAF after 1 January 2000 were included. Cox proportional hazards regression models evaluated initiation and treatment continuation over time of warfarin and aspirin. Treatment discontinuation was defined as no repeat prescription within a three-month period after the expected end of the treatment course. RESULTS: The study population included 41 910 cAF patients. Elderly patients (aged 85+) were less likely to start warfarin [relative rate (RR) = 0.16, 95% confidence interval (CI) 0.15-0.18] and more likely to start aspirin (RR = 1.66, 95% CI 1.47-1.88) than patients aged 40-64 years. A history of dementia (RR = 0.28, 95% CI 0.17-0.44) and falls (RR = 0.76, 95% CI 0.70-0.83) also reduced the likelihood of warfarin initiation. Adjusting for age and gender, higher stroke risk (CHADS2 score) was not found to be associated with initiation of warfarin or aspirin contrary to current guidelines recommendations. One-year persistence was 70% for warfarin and 50% for aspirin. Treatment persistence was higher in elderly patients using warfarin and aspirin. A higher CHADS(2) score was associated with improved persistence only with warfarin. CONCLUSIONS: The low likelihood of patients with cAF in general practice remaining on treatment long-term indicates that not all benefits as observed in clinical trials may be achieved in usual clinical practice.

Socioeconomic differences in risk factors for obesity in adolescents in Northern Ireland.

UNLABELLED: OBJECTIVES. To test for socioeconomic differences in some biological and behavioral risk factors for obesity in a representative and contemporary sample of adolescents. METHODS: Cohort study of 2 016 randomly selected 12- and 15-year-olds representative of Northern Ireland, studied in 2000. We tested for differences in obesity risk factors based on a priori hypotheses between adolescents from affluent (n=487) versus deprived (n=237) families. Potential risk factors were dietary energy and macronutrient intake, habitual physical activity, TV viewing and computer use, and physical fitness. RESULTS: Adolescents of higher socioeconomic status reported significantly lower habitual energy intake (210 kJ/kg/d SD 80 vs. 229 kJ/kg/d SD 91, p < 0.01); significantly higher levels of habitual physical activity (physical activity score 25.9 SD 16.6 vs. 20.9 SD 16.4, p < 0.001), and had significantly higher cardiorespiratory fitness (estimated VO2 max 46.2 ml/kg/min SD 8.4 vs. 43.4 ml/kg/min SD 8.3, p < 0.001). Prevalence of overweight and obesity (BMI >85th percentile) in the cohort was 29.1% and was slightly but not significantly higher in the low (33.8%) versus the high (28.5%) socioeconomic groups. CONCLUSIONS: Differences in some of the biological and behavioral risk factors for obesity exist between adolescents of different socioeconomic status in Northern Ireland. These may help explain the basis of established socioeconomic differences in obesity risk.