Germline variation in RASAL2 may predict survival in patients with RAS-activated colorectal cancer.

BACKGROUND: Therapeutic agents that specifically target patients with RAS mutant colorectal cancer (CRC) are needed. We sought potential drug targets by relating genome-wide association study and survival data in patients with advanced CRC profiled for mitogen-activated protein kinase (MAPK) pathway mutations. METHODS: In total, 694 patients from the clinical trials COIN and COIN-B had MAPK-activated CRCs (assigned as KRAS, NRAS, or BRAF mutant). Genome-wide single nucleotide polymorphism (SNP), gene, and gene-set analyses were performed to identify determinants of survival. For rs12028023 in RAS protein activator-like 2 (RASAL2), we studied its effect by MAPK pathway activation status (by comparing to 760 patients without MAPK-activated CRCs), MAPK gene mutation status, surface area of the primary tumor (as a marker of proliferation), and expression on RASAL2. RESULTS: In MAGMA genome-wide analyses, RASAL2 was the most significant gene associated with survival (p = 2.0 × 10-5 ). Patients carrying the minor (A) allele in the lead SNP, rs12028023 in intron 1 of RASAL2, had a median increase in survival of 167 days as compared with patients carrying the major allele. rs12028023 was predictive for survival by MAPK-activation status (pZ-test  = 2.1 × 10-3 ). Furthermore, rs12028023 improved survival in patients with RAS mutant (hazard ratio [HR] = 0.62, 95% confidence intervals [CI] = 0.5-0.8, p = 3.4 × 10-5 ) but not BRAF mutant (p = 0.87) CRCs. The rs12028023 A-allele was associated with reduced surface area of the primary tumor (Beta = -0.037, standard error [SE] = 0.017, p = 3.2 × 10-2 ) and reduced RASAL2 expression in cultured fibroblasts (p = 1.6 × 10-11 ). CONCLUSION: Our data demonstrate a prognostic role for RASAL2 in patients with MAPK-activated CRCs, with potential as a therapeutic target.

Relationship between 233 colorectal cancer risk loci and survival in 1926 patients with advanced disease.

Background: Genome, transcriptome and methylome-wide association studies have identified single-nucleotide polymorphisms (SNPs) or genes at 258 loci associated with colorectal cancer (CRC) risk. We studied the relationship between these and patient outcome. Methods: We studied 1926 unrelated patients with advanced CRC from COIN and COIN-B. Of 205 CRC-risk SNPs, 19 were directly genotyped and 162 were imputed, and of 53 risk genes, 52 were tested. An additive Cox model for overall survival was adjusted for known prognostic factors. For nominally significant SNPs or genes, we considered a recessive model with a Bonferroni corrected threshold of P = 2.1 × 10-4. We examined SNPs as expression quantitative trait loci (eQTL) and the relationship between gene expression in colorectal tumours and survival in 597 unrelated patients. Results: Eleven SNPs or genes were nominally associated with survival under an additive model. Only rs117079142 mapping to UTP23 and EIF3H (Hazard Ratio [HR] = 2.79, 95% Confidence Intervals [CI] = 1.70-4.58, P = 4.7 × 10-5) and rs9924886 mapping to CDH1 and CDH3 (HR = 1.24, 95% CI = 1.12-1.38, P = 5.2 × 10-5) passed the multiple testing threshold under a recessive model. rs117079142 was an eQTL for UTP23 and rs9924886 for CDH1, CDH3 and ZFP90. Decreased CDH1 expression in CRCs was associated with worse survival (HR = 2.18, 95% CI = 1.3-3.5, P = 1.8 × 10-3). Conclusion: rs117079142 and rs9924886 may represent potential prognostic biomarkers for CRC.

Genetic variation in ST6GAL1 is a determinant of capecitabine and oxaliplatin induced hand-foot syndrome.

Cancer patients treated with capecitabine and oxaliplatin (XELOX) often develop hand-foot syndrome (HFS) or palmar-plantar erythrodysesthesia. Genetic variation in ST6GAL1 is a risk factor for type-2 diabetes (T2D), a disease also associated with HFS. We analysed genome-wide association data for 10 toxicities in advanced colorectal cancer (CRC) patients from the COIN and COIN-B trials. One thousand and fifty-five patients were treated with XELOX ± cetuximab and 745 with folinic acid, fluorouracil and oxaliplatin ± cetuximab. We also analysed rs6783836 in ST6GAL1 with HFS in CRC patients from QUASAR2. Using UK Biobank data, we sought to confirm an association between ST6GAL1 and T2D (17 384 cases, 317 887 controls) and analysed rs6783836 against markers of diabetes, inflammation and psoriasis. We found that 68% of patients from COIN and COIN-B with grade 2-3 HFS responded to treatment as compared to 58% with grade 0-1 HFS (odds ratio [OR] = 1.1, 95% confidence interval [CI] = 1.02-1.2, P = 2.0 × 10-4 ). HFS was also associated with improved overall survival (hazard ratio = 0.92, 95% CI = 0.84-0.99, P = 4.6 × 10-2 ). rs6783836 at ST6GAL1 was associated with HFS in patients treated with XELOX (OR = 3.1, 95% CI = 2.1-4.6, P = 4.3 × 10-8 ) and was borderline significant in patients receiving capecitabine from QUASAR2, but with an opposite allele effect (OR = 0.66, 95% CI = 0.42-1.03, P = .05). ST6GAL1 was associated with T2D (lead SNP rs3887925, OR = 0.94, 95% CI = 0.92-0.96, P = 1.2 × 10-8 ) and the rs6783836-T allele was associated with lowered HbA1c levels (P = 5.9 × 10-3 ) and lymphocyte count (P = 2.7 × 10-3 ), and psoriasis (P = 7.5 × 10-3 ) beyond thresholds for multiple testing. In conclusion, HFS is a biomarker of treatment outcome and rs6783836 in ST6GAL1 is a potential biomarker for HFS with links to T2D and inflammation.

A genome-wide search for determinants of survival in 1926 patients with advanced colorectal cancer with follow-up in over 22,000 patients.

BACKGROUND: While genome-wide association studies (GWAS) have identified germline variants influencing the risk of developing colorectal cancer (CRC), there has been limited examination of the possible role of inherited variation as a determinant of patient outcome. PATIENTS AND METHODS: We performed a GWAS for overall survival (OS) in 1926 patients with advanced CRC from the COIN and COIN-B clinical trials. For single nucleotide polymorphisms (SNPs) showing an association with OS (P < 1.0 × 10-5), we conducted sensitivity analyses based on the time from diagnosis to death and sought independent replications in 5675 patients from the Study of Colorectal Cancer in Scotland (SOCCS) and 16,964 patients from the International Survival Analysis in Colorectal cancer Consortium (ISACC). We analysed the Human Protein Atlas to determine if ERBB4 expression was associated with survival in 438 patients with colon adenocarcinomas. RESULTS: The most significant SNP associated with OS was rs79612564 in ERBB4 (hazard ratio [HR] = 1.24, 95% confidence interval [CI] = 1.16-1.32, P = 1.9 × 10-7). SNPs at 17 loci had suggestive associations for OS and all had similar effects on the time from diagnosis to death. No lead SNPs were independently replicated in the meta-analysis of all patients from SOCCS and ISACC. However, rs79612564 was significant in stage-IV patients from SOCCS (P = 2.1 × 10-2) but not ISACC (P = 0.89) and SOCCS combined with COIN and COIN-B attained genome-wide significance (P = 1.7 × 10-8). Patients with high ERBB4 expression in their colon adenocarcinomas had worse survival (HR = 1.50, 95% CI = 1.1-1.9, P = 4.6 × 10-2). CONCLUSIONS: Genetic and expression data support a potential role for rs79612564 in the receptor tyrosine kinase ERBB4 as a predictive biomarker of survival.

Genome-wide association studies of toxicity to oxaliplatin and fluoropyrimidine chemotherapy with or without cetuximab in 1800 patients with advanced colorectal cancer.

Chemotherapies administered at normal therapeutic dosages can cause significant side-effects and may result in early treatment discontinuation. Inter-individual variation in toxicity highlights the need for biomarkers to personalise treatment. We sought to identify such biomarkers by conducting 40 genome-wide association studies, together with gene and gene set analyses, for any toxicity and 10 individual toxicities in 1800 patients with advanced colorectal cancer treated with oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab from the MRC COIN and COIN-B trials (385 patients received FOLFOX, 360 FOLFOX + cetuximab, 707 XELOX and 348 XELOX + cetuximab). Single nucleotide polymorphisms (SNPs), genes and gene sets that reached genome-wide or suggestive significance were validated in independent patient groups. We found that MROH5 was significantly associated with neutropenia in MAGMA gene analyses in patients treated with XELOX (P = 6.6 × 10-7 ) and was independently validated in those receiving XELOX + cetuximab; pooled P = 3.7 × 10-7 . rs13260246 at 8q21.13 was significantly associated with vomiting in patients treated with XELOX (odds ratio = 5.0, 95% confidence interval = 3.0-8.3, P = 9.8 × 10-10 ) but was not independently replicated. SNPs at 139 loci had suggestive associations for toxicities and lead SNPs at five of these were independently validated (rs6030266 with diarrhoea, rs1546161 with hand-foot syndrome, rs9601722 with neutropenia, rs13413764 with lethargy and rs4600090 with nausea; all with pooled P's < 5.0 × 10-6 ). In conclusion, the association of MROH5 with neutropenia and five other putative biomarkers warrant further investigation for their potential clinical utility. Despite our comprehensive genome-wide analyses of large, well-characterised, clinical trials, we found a lack of common variants with modest effect sizes associated with toxicities.

Correction to: Persistent physical symptoms reduction intervention: a system change and evaluation in secondary care (PRINCE secondary) - a CBT-based transdiagnostic approach: study protocol for a randomised controlled trial.

An amendment to this paper has been published and can be accessed via the original article.

Persistent physical symptoms reduction intervention: a system change and evaluation in secondary care (PRINCE secondary) - a CBT-based transdiagnostic approach: study protocol for a randomised controlled trial.

BACKGROUND: Persistent physical symptoms (PPS), also known as medically unexplained symptoms (MUS), affect approximately 50% of patients in secondary care and are often associated with disability, psychological distress and increased health care costs. Cognitive behavioural therapy (CBT) has demonstrated both short- and long-term efficacy with small to medium effect sizes for PPS, with larger treatment effects for specific PPS syndromes, including non-cardiac chest pain, irritable bowel syndrome (IBS) and chronic fatigue syndrome (CFS). Research indicates that PPS conditions share similar cognitive and behavioural responses to symptoms, such as avoidance and unhelpful beliefs. This suggests that a transdiagnostic approach may be beneficial for patients with PPS. METHODS: A randomised controlled trial (RCT) will be conducted to evaluate the efficacy and cost-effectiveness of a transdiagnostic CBT-based intervention for PPS. 322 participants with PPS will be recruited from secondary care clinics. Participants stratified by clinic and disability level will be randomised to CBT plus standard medical care (SMC) versus SMC alone. The intervention consists of 8 CBT sessions delivered by a qualified therapist over a period of 20 weeks. Outcomes will be assessed at 9, 20, 40- and 52-weeks post randomisation. Efficacy will be assessed by examining the difference between arms in the primary outcome Work and Social Adjustment Scale (WSAS) at 52 weeks after randomisation. Secondary outcomes will include mood, symptom severity and clinical global impression at 9, 20, 40 and 52 weeks. Cost-effectiveness will be evaluated by combining measures of health service use, informal care, loss of working hours and financial benefits at 52 weeks. DISCUSSION: This trial will provide a powered evaluation of the efficacy and cost-effectiveness of a transdiagnostic CBT approach versus SMC for patients with PPS. It will also provide valuable information about potential healthcare pathways for patients with PPS within the National Health Service (NHS). TRIAL REGISTRATION: ClinicalTrials.gov NCT02426788. Registered 27 April 2015. Overall trial status: Ongoing; Recruitment status: No longer recruiting.

Preliminary evaluation of a multimodal early intervention program for behaviorally inhibited preschoolers.

OBJECTIVE: Approximately 15%-20% of young children can be classified as having a behaviorally inhibited (BI) temperament. Stable BI predicts the development of later anxiety disorders (particularly social anxiety), but not all inhibited children develop anxiety. Parenting characterized by inappropriate warmth/sensitivity and/or intrusive control predicts the stability of BI and moderates risk for anxiety among high-BI children. For these reasons, we developed and examined the preliminary efficacy of the Turtle Program: a multimodal early intervention for inhibited preschool-age children. METHOD: Forty inhibited children between the ages of 42-60 months and their parent(s) were randomized to either the Turtle Program (n = 18) or a waitlist control (WLC; n = 22) condition. Participants randomized to the Turtle Program condition received 8 weeks of concurrent parent and child group treatment. Participants were assessed at baseline and posttreatment with multisource assessments, including parent and teacher report measures of child anxiety, diagnostic interviews, and observations of parenting behavior. RESULTS: The Turtle Program resulted in significant beneficial effects relative to the WLC condition on maternal-reported anxiety symptoms of medium to large magnitude; large effects on parent-reported BI; medium to large effects on teacher-rated school anxiety symptoms; and medium effects on observed maternal positive affect/sensitivity. CONCLUSIONS: This study provides encouraging preliminary support for the Turtle Program for young behaviorally inhibited children. Effects of the Turtle Program generalized to the school setting. Future studies should examine whether this early intervention program improves long-term developmental outcomes for this at-risk group.

Waist circumference predicts cardiovascular risk in young Australian children.

AIM: It has been shown that compared with healthyweight children, overweight and obese primary school-aged children have a higher incidence of hyperinsulinism, dyslipidaemia and hypertension. It is therefore important to investigate clinically relevant markers of cardiovascular risk in children. Waist circumference is a simple, non-invasive anthropometric measure, but its association with cardiovascular risk profile in young Australian children is not clear. METHODS: This study presents cross-sectional data from the Growth and Development Study. The sample included 70 healthy weight children, 50 overweight children and 28 obese children (n = 148, 9.6 +/- 1.9 years). All children had a medical assessment which included a physical examination (waist circumference, blood pressure), and investigations including glycated haemoglobin, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, insulin, glucose and total homocysteine levels. An oral glucose tolerance test was performed in a subgroup of children (n = 119). Body mass index (BMI) was determined and BMI Z-scores calculated. RESULTS: In a multilevel model, waist circumference was the only significant anthropometric predictor of lipid profile (high-density lipoprotein beta = -0.01, P < 0.05; triglycerides beta = 0.01, P < 0.005), systolic blood pressure (beta = 0.29, P < 0.05), fasting insulin (beta = 0.16, P < 0.005), insulin concentrations throughout the oral glucose tolerance (60 min beta = 1.07, P < 0.005; 120 min beta = 1.42, P < 0.001) and insulin resistance (homeostasis model assessment (HOMA-IR): beta = 0.03, P < 0.05), with increasing waist circumference associated with increasing cardiovascular risk. In contrast, BMI Z-score was only predictive of 120-min glucose concentrations during the OGTT (beta = 0.34, P < 0.05). CONCLUSIONS: Waist circumference is a better anthropometric indicator than BMI Z-score of cardiovascular risk in Australian primary school-aged children. Even in young children, measurement of waist circumference represents a simple, non-invasive screening tool to identify children with an increased cardiovascular risk profile.

Resistance training and diastolic myocardial tissue velocities in obese children.

PURPOSE: The primary purpose of this study was to determine the effects of resistance exercise training on early diastolic myocardial velocities (E') in an obese pediatric population. METHODS: Twenty-three obese adolescents were selected to participate in either a resistance-based training program (RT; n = 13, 12.2 +/- 0.4 yr, body mass index [BMI] = 32.5 +/- 1.9 kg m(-2)) or a nonexercise control intervention (n = 10, 13.6 +/- 0.7 yr, BMI = 30.2 +/- 2.6 kg m(-2)) for 8 wk. All subjects had repeated echocardiographic assessments to determine left ventricular (LV) geometry, early transmitral flow velocity (E), and E'. RESULTS: LV mass and wall thicknesses did not significantly change with training or in controls. RT improved E' (11.9 +/- 0.5 to 13.3 +/- 0.5 cm s(-1), P< 0.01) in the presence of a decrease in E/E' (8.17 +/- 0.39 to 7.06 +/- 0.30 cm s(-1), P < 0.01), a marker of left atrial pressure. No changes were evident in the inactive control subjects. CONCLUSIONS: A supervised 8-wk RT exercise program improved early diastolic tissue velocity in obese children, independent of changes in LV morphology.

Exercise alone reduces insulin resistance in obese children independently of changes in body composition.

CONTEXT: The number of obese children with insulin resistance and type 2 diabetes is increasing, but the best management strategy is not clear. OBJECTIVE: The objective of this study was to assess the effect of a structured 8-wk exercise training program on insulin resistance and changes in body composition in obese children. DESIGN: The study was 8 wk of structured supervised exercise intervention with outcome measures before and after the exercise period. SUBJECTS: Fourteen obese children (12.70 +/- 2.32 yr; eight male, six female) with high fasting insulin levels were enrolled into the study. INTERVENTION: INTERVENTION consisted of 8 wk of supervised circuit-based exercise training, composed of three fully supervised 1-h sessions per week. OUTCOME MEASURES: Outcome measures were assessed pretraining program and posttraining program and included insulin sensitivity (euglycemic-hyperinsulinemic clamp studies), fasting insulin and glucose levels, body composition using dual energy x-ray absorptiometry scan, lipid profile, and liver function tests. RESULTS: Insulin sensitivity improved significantly after 8 wk of training (M(lbm) 8.20 +/- 3.44 to 10.03 +/- 4.33 mg/kg.min, P < 0.05). Submaximal exercise heart rate responses were significantly lower following the training (P < 0.05), indicating an improvement in cardiorespiratory fitness. Dual energy x-ray absorptiometry scans revealed no differences in lean body mass or abdominal fat mass. CONCLUSION: An 8-wk exercise training program increases insulin sensitivity in obese children, and this improvement occurred in the presence of increased cardiorespiratory fitness but is independent of measurable changes in body composition.

Do skinfolds accurately assess changes in body fat in obese children and adolescents?

PURPOSE: Obesity is epidemic in Western societies, with rapid rates of increase in the young. Various methods exist for the assessment of body composition, but these have not been compared in obese children and adolescents. This study compared methods of body composition assessment in obese young people to determine whether changes in various measures of body composition as a result of exercise training were correlated. METHODS: Multiple anthropometric measures (weight, height, body mass index (BMI), skinfolds, waist and hip girths) and dual-energy x-ray absorptiometry (DEXA) were undertaken in 38 obese children and adolescents (12.7 +/- 2.1 yr) at baseline and following 8 wk of exercise training. RESULTS: At baseline, there were strong relationships (all P < 0.01) between DEXA total fat and weight (r = 0.83), BMI (r = 0.86), waist girth (r = 0.81), hip girth (r = 0.88), sum of six skinfolds (sum6, r = 0.79), and percent body fat (percent body fat) calculated using a four-skinfold equation (EQ4; r = 0.69). Similar relationships (all P < 0.001) existed between DEXA abdominal fat and weight (r = 0.79), waist girth (r = 0.83), hip girth (r = 0.69), and height (r = 0.71). Neither skinfold sums, nor percent body fat calculated from skinfold equations, were selected as independent predictors of DEXA total or abdominal fat by stepwise hierarchical linear regression. The reductions in DEXA total and abdominal fat following exercise were not predicted by changes in skinfolds or percent body fat calculated from skinfolds. CONCLUSION: These data suggest that body fat derived from skinfold measures is poorly predictive of abdominal and total fat derived from DEXA in obese children and adolescents. This finding highlights the limitations of skinfolds in obese subjects and questions the validity of their use to assess changes in body composition with interventions such as exercise training.

Exercise training in obese children and adolescents: current concepts.

Childhood obesity has reached epidemic proportions worldwide and is associated with increased cardiovascular mortality and morbidity in adult life. The increase in fat mass in children and adolescents has occurred concomitantly with a decline in reported time for exercise. Evidence suggests that non-physically active children are more likely to become non-physically active adults and that encouraging the development of physical activity habits in children helps establish patterns that continue into adulthood. Dietary treatment of obesity is relatively ineffective in adults and it has been suggested that prevention of obesity in childhood and adolescence should emphasise increased physical activity rather than diet because of fears relating to the adverse effects of inappropriate eating patterns. Despite this, there are very few randomised controlled studies investigating the efficacy of exercise training in obese children or adolescents and many of the extant studies have been poorly controlled and have not specifically stratified the independent effect of exercise versus dietary modification. This review focuses on the well designed controlled trials that have evaluated the effect of exercise training in obese children and adolescents on body composition, haemodynamic and metabolic variables, cardiovascular fitness, muscular strength and vascular function. These studies indicate that, although exercise training does not consistently decrease bodyweight or body mass index, it is associated with beneficial changes in fat and lean body mass, emphasising the importance of comprehensive assessment of body composition in future exercise-training studies. Exercise training improves cardiovascular fitness and muscular strength; however, it seems to have little effect on blood lipid profile or blood pressure in obese young people. Importantly, recent studies have demonstrated that exercise training improves vascular endothelial function, an important surrogate measure that may predict future atherosclerotic risk in obese children and adolescents. Given that improvement in vascular function in these training studies occurred in the absence of changes in lipid fractions, haemodynamic variables or glucose metabolism, exercise appears to have a direct beneficial effect on the vasculature, in addition to its putative benefits through risk-factor modification.

Effects of exercise training on vascular function in obese children.

OBJECTIVES: Atherosclerosis is a disease that begins in childhood; endothelial dysfunction is its earliest detectable manifestation, and primary prevention strategies are likely to be most effective if instituted early. The aim of this study was to characterize the impact of obesity on vascular function in young children and to determine whether an exercise program improves abnormalities in vascular function. STUDY DESIGN: The influence of 8 weeks of exercise training was examined in 14 obese subjects, 8.9 +/- 0.4 years of age, with the use of a randomized crossover protocol. Conduit vessel endothelial function was assessed by means of high-resolution ultrasound and flow-mediated dilation of the brachial artery (FMD). RESULTS: Exercise training did not change subcutaneous fat mass, body weight, or body mass index. FMD in the obese group was significantly impaired relative to matched control subjects at entry (6.00% +/- 0.69% to 12.32% +/- 3.14%, P <.0001). FMD significantly improved with exercise training (7.35% +/- 0.99%, P <.05) in the obese group. CONCLUSIONS: Conduit vessel FMD, a validated surrogate measure of early atherosclerosis, was impaired in obese children but improved as a result of exercise training. This study supports the value of an exercise program in the treatment of obese children in a primary prevention setting.

Exercise training normalizes vascular dysfunction and improves central adiposity in obese adolescents.

OBJECTIVES: We sought to characterize the impact of obesity on vascular function in adolescents and to determine whether an exercise program reverses abnormalities in endothelial function. BACKGROUND: Obesity, a major modifiable risk factor for cardiovascular disease, is epidemic in Western societies, with rapid rates of increase in the young. Atherosclerosis begins in childhood, and endothelial dysfunction is its earliest detectable manifestation. METHODS: The influence of eight weeks of circuit training (CT) was examined in 19 obese subjects (14.3 +/- 1.5 years), using a randomized, crossover protocol. Functional capacity and muscular strength were assessed by standard techniques. Body composition was examined using anthropometric measures and dual-energy X-ray absorptiometry. Conduit vessel endothelial function was assessed using high-resolution ultrasound and flow-mediated dilation (FMD) of the brachial artery. RESULTS: Circuit training decreased abdominal and trunk fat and significantly improved fitness and muscular strength (p < 0.05). In the obese group, FMD was significantly impaired relative to control subjects (n = 20) at entry (5.3 +/- 0.9% vs. 8.9 +/- 1.5%, p < 0.05) and was normalized after CT (8.8 +/- 0.8%, p < 0.05). CONCLUSIONS: Circuit training improved functional capacity, muscular strength, and body composition in obese adolescents. Furthermore, conduit vessel function was normalized after exercise training. If vascular dysfunction is an integral component of the pathogenesis of vascular disease, this study supports the value of an exercise program in the management of obese adolescents.

Lack of effect of oral glucose loading on conduit vessel endothelial function in healthy subjects.

The aim of the present study was to investigate the impact of an oral glucose load on circulating insulin and glucose levels and arterial function in healthy non-diabetic subjects. Thirty-nine non-obese, healthy subjects (24 female, 15 male), aged 21.0+/-1.8 years of age, were randomly assigned to undergo either an OGTT (oral glucose tolerance test; 75 g of glucose) or administration of a placebo. Analyses of lipids, liver function and HbA(1c) (glycated haemoglobin) at baseline revealed results which were within the standard reference range. Insulin and glucose levels as well as vascular function [FMD (flow-mediated dilation)] were measured at 0, 60 and 120 min. Compared with baseline, the control subjects did not exhibit any significant changes in glucose or insulin levels, whereas, in the OGTT group, blood glucose levels at both 60 (5.4+/-1.7 mmol/l) and 120 (5.0+/-1.1 mmol/l) min increased significantly relative to baseline (4.1+/-0.4 mmol/l; both P<0.001) and, similarly, insulin levels were higher at both 60 (30.1+/-21.3 m-units/l) and 120 (34.9+/-23.6 m-units/l) min compared with baseline (4.7+/-4.3 m-units/l; both P<0.001). Although blood glucose and insulin levels changed, FMD did not significantly differ between time-points or between groups. In summary, despite significantly elevated glucose and insulin concentrations in these subjects, we observed no change in vascular function, suggesting that acute elevations of glucose and insulin within the clinically normal range are not associated with impaired vascular function in vivo.

Effect of lower limb exercise on forearm vascular function: contribution of nitric oxide.

We examined vascular function in an inactive muscle bed, the forearm, during lower limb exercise and determined the contribution of endothelium-derived nitric oxide (NO) to the hyperemic response. Eight young males were randomized to participate in two studies, each consisting of two bouts of lower limb exercise, separated by a 30-min recovery. Peak forearm blood flow (PFBF) and mean blood flow (MFBF) were continuously recorded at baseline and during exercise using continuous high-resolution vascular ultrasound and Doppler flow velocity measurement. During one session, the brachial artery was cannulated to allow continuous infusion of saline or N(G)-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthase. The alternate session was performed to control for possible effects of repeated exercise. At 60, 100, and 160 W, L-NMMA significantly decreased both PFBF and MFBF compared with the saline infusion. These results suggest that systemic production of NO occurs during exercise in resting vessel beds, which do not feed metabolically active tissue. This finding provides a plausible explanation for the antiatherogenic benefits of exercise.

Increased gyrification in Williams syndrome: evidence using 3D MRI methods.

Understanding patterns of gyrification in neurogenetic disorders helps to uncover the neurodevelopmental etiology underlying behavioral phenotypes. This is particularly true in Williams syndrome (WS), a condition caused by de novo deletion of approximately 1 to 2 Mb in the 7q11.23 region. Individuals with WS characteristically possess an unusual dissociation between deficits in visual-spatial ability and relative preservations in language, music, and social drive. A preliminary postmortem study reported anomalous gyri and sulci in individuals with WS. The present study examined gyrification patterns in 17 participants with WS (10 females, 7 males; mean age 28 years 11 months, SD 8 years 6 months) and 17 age- and sex-matched typically developing control participants (mean age 29 years 1 month, SD 8 years 1 month) using new automated techniques in MRI. Significantly increased cortical gyrification was found globally with abnormalities being more marked in the right parietal (p=0.0227), right occipital (p=0.0249), and left frontal (p=0.0086) regions. These results suggest that one or more genes in the 7q11.23 region are involved during the critical period when cortical folding occurs, and may be related to the hypothesized dorsal/ventral dissociation in this condition.