Instruct: Given a scientific claim, retrieve documents that support or refute the claim.
Query: The DESMOND program caused substantial weight loss in most participants.
OBJECTIVE To measure whether the benefits of a single education and self management structured programme for people with newly diagnosed type 2 diabetes mellitus are sustained at three years. DESIGN Three year follow-up of a multicentre cluster randomised controlled trial in primary care, with randomisation at practice level. SETTING 207 general practices in 13 primary care sites in the United Kingdom. PARTICIPANTS 731 of the 824 participants included in the original trial were eligible for follow-up. Biomedical data were collected on 604 (82.6%) and questionnaire data on 513 (70.1%) participants. INTERVENTION A structured group education programme for six hours delivered in the community by two trained healthcare professional educators compared with usual care. MAIN OUTCOME MEASURES The primary outcome was glycated haemoglobin (HbA(1c)) levels. The secondary outcomes were blood pressure, weight, blood lipid levels, smoking status, physical activity, quality of life, beliefs about illness, depression, emotional impact of diabetes, and drug use at three years. RESULTS HbA(1c) levels at three years had decreased in both groups. After adjusting for baseline and cluster the difference was not significant (difference -0.02, 95% confidence interval -0.22 to 0.17). The groups did not differ for the other biomedical and lifestyle outcomes and drug use. The significant benefits in the intervention group across four out of five health beliefs seen at 12 months were sustained at three years (P<0.01). Depression scores and quality of life did not differ at three years. CONCLUSION A single programme for people with newly diagnosed type 2 diabetes mellitus showed no difference in biomedical or lifestyle outcomes at three years although there were sustained improvements in some illness beliefs. TRIAL REGISTRATION Current Controlled Trials ISRCTN17844016.
CONTEXT Dexamethasone is widely used to prevent postoperative nausea and vomiting (PONV) in pediatric tonsillectomy. OBJECTIVE To assess whether dexamethasone dose-dependently reduces the risk of PONV at 24 hours after tonsillectomy. DESIGN, SETTING, AND PATIENTS Randomized placebo-controlled trial conducted among 215 children undergoing elective tonsillectomy at a major public teaching hospital in Switzerland from February 2005 to December 2007. INTERVENTIONS Children were randomly assigned to receive dexamethasone (0.05, 0.15, or 0.5 mg/kg) or placebo intravenously after induction of anesthesia. Acetaminophen-codeine and ibuprofen were given as postoperative analgesia. Follow-up continued until the 10th postoperative day. MAIN OUTCOME MEASURES The primary end point was prevention of PONV at 24 hours; secondary end points were decrease in the need for ibuprofen at 24 hours and evaluation of adverse effects. RESULTS At 24 hours, 24 of 54 participants who received placebo (44%; 95% confidence interval [CI], 31%-59%) had experienced PONV compared with 20 of 53 (38%; 95% CI, 25%-52%), 13 of 54 (24%; 95% CI, 13%-38%), and 6 of 52 (12%; 95% CI, 4%-23%) who received dexamethasone at 0.05, 0.15, and 0.5 mg/kg, respectively (P<.001 for linear trend). Children who received dexamethasone received significantly less ibuprofen. There were 26 postoperative bleeding episodes in 22 children. Two of 53 (4%; 95% CI, 0.5%-13%) children who received placebo had bleeding compared with 6 of 53 (11%; 95% CI, 4%-23%), 2 of 51 (4%; 95% CI, 0.5%-13%), and 12 of 50 (24%; 95% CI, 13%-38%) who received dexamethasone at 0.05, 0.15, and 0.5 mg/kg, respectively (P = .003). Dexamethasone, 0.5 mg/kg, was associated with the highest bleeding risk (adjusted relative risk, 6.80; 95% CI, 1.77-16.5). Eight children had to undergo emergency reoperation because of bleeding, all of whom had received dexamethasone. The trial was stopped early for safety reasons. CONCLUSION In this study of children undergoing tonsillectomy, dexamethasone decreased the risk of PONV dose dependently but was associated with an increased risk of postoperative bleeding. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00403806.
The weight lowering potential of glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) is inter-individually different and clinically unpredictable. The potential role of genetic variability of GLP-1R on body weight response to GLP-1 RAs in obese women with polycystic ovary syndrome (PCOS) has not yet been evaluated. Fifty-seven obese women with PCOS (aged 30.7 ± 7.0, BMI 38.6 ± 5.3 kg/m2) were assigned to liraglutide 1.2 mg QD s.c. for 12 weeks and classified as strong responders regarding weight loss if they lost 5 % or more of their initial body weight. They were genotyped for common GLP-1R single nucleotide polymorphisms (SNPs) rs6923761 and rs10305420. Changes of measures of obesity were measured before and at the end of the treatment. Twenty out of 57 subjects were strong responders and lost 7.38 ± 1.74 compared to 2.11 ± 2.17 kg lost in poor responders. Carriers of at least one polymorphic rs10305420 allele had poor treatment response compared to carriers of two wild type alleles (OR = 0.27, 95 % CI = 0.09–0.85, P = 0.025). Carriers of at least one polymorphic rs6923761 allele tended to have stronger treatment response compared to carriers of two wild type alleles (OR = 3.06, 95 % CI = 0.96–9.74, P = 0.058). Fasting glucose and glucose after oral glucose tolerance test (OGTT) comparably decreased in both groups when compared to baseline, whereas no within treatment differences were found in androgen profile. Gastrointestinal adverse events were transit and balanced between strong and poor responders. GLP-1R rs10305420 polymorphism explained some of the inter-individual differences in response to liraglutide regarding weight loss in obese PCOS women.
Extreme obesity is associated with severe psychiatric and somatic comorbidity and impairment of psychosocial functioning. Bariatric surgery is the most effective treatment not only with regard to weight loss but also with obesity-associated illnesses. Health-related psychological and psychosocial variables have been increasingly considered as important outcome variables of bariatric surgery. However, the long-term impact of bariatric surgery on psychological and psychosocial functioning is largely unclear. The aim of this study was to evaluate the relationship between the course of weight and psychological variables including depression, anxiety, health-related quality of life (HRQOL), and self-esteem up to 4 years after obesity surgery. By standardized questionnaires prior to (T1) and 1 year (T2), 2 years (T3), and 4 years (T4) after surgery, 148 patients (47 males (31.8 %), 101 females (68.2 %), mean age 38.8 ± 10.2 years) were assessed. On average, participants lost 24.6 % of their initial weight 1 year after surgery, 25.1 % after 2 years, and 22.3 % after 4 years. Statistical analysis revealed significant improvements in depressive symptoms, physical dimension of quality of life, and self-esteem with peak improvements 1 year after surgery. These improvements were largely maintained. Significant correlations between weight loss and improvements in depression, physical aspects of HRQOL (T2, T3, and T4), and self-esteem (T3) were observed. Corresponding to the considerable weight loss after bariatric surgery, important aspects of mental health improved significantly during the 4-year follow-up period. However, parallel to weight regain, psychological improvements showed a slow but not significant decline over time.
Obesity affects 32% of adults in the USA. Surgery generates substantial weight loss, but 20–30% fails to achieve successful weight loss. Our objective was to identify preoperative psychosocial factors associated with weight loss following bariatric surgery. We performed a literature search of PubMed® and the Cochrane Database of Reviews of Effectiveness between 1988 and April 2010. Articles were screened for bariatric surgery and weight loss if they included a preoperative predictor of weight loss: body mass index (BMI), preoperative weight loss, eating disorders, or psychiatric disorder/substance abuse. One thousand seven titles were reviewed, 534 articles screened, and 115 included in the review. Factors that may be positively associated with weight loss after surgery include mandatory preoperative weight loss (7 of 14 studies with positive association). Factors that may be negatively associated with weight loss include preoperative BMI (37 out of 62 studies with negative association), super-obesity (24 out of 33 studies), and personality disorders (7 out of 14 studies). Meta-analysis revealed a decrease of 10.1% excess weight loss (EWL) for super-obese patients (95% confidence interval (CI) [3.7–16.5%]), though there was significant heterogeneity in the meta-analysis, and an increase of 5.9% EWL for patients with binge eating at 12 months after surgery (95% CI [1.9–9.8%]). Further studies are necessary to investigate whether preoperative factors can predict a clinically meaningful difference in weight loss after bariatric surgery. The identification of predictive factors may improve patient selection and help develop interventions targeting specific needs of patients.
OBJECTIVE To evaluate the effectiveness of integrated care for chronic physical diseases and depression in reducing disability and improving quality of life. DESIGN A randomised controlled trial of multi-condition collaborative care for depression and poorly controlled diabetes and/or risk factors for coronary heart disease compared with usual care among middle aged and elderly people   SETTING Fourteen primary care clinics in Seattle, Washington.   PARTICIPANTS Patients with diabetes or coronary heart disease, or both, and blood pressure above 140/90 mm Hg, low density lipoprotein concentration >3.37 mmol/L, or glycated haemoglobin 8.5% or higher, and PHQ-9 depression scores of ≥ 10. INTERVENTION A 12 month intervention to improve depression, glycaemic control, blood pressure, and lipid control by integrating a "treat to target" programme for diabetes and risk factors for coronary heart disease with collaborative care for depression. The intervention combined self management support, monitoring of disease control, and pharmacotherapy to control depression, hyperglycaemia, hypertension, and hyperlipidaemia. MAIN OUTCOME MEASURES Social role disability (Sheehan disability scale), global quality of life rating, and World Health Organization disability assessment schedule (WHODAS-2) scales to measure disabilities in activities of daily living (mobility, self care, household maintenance). RESULTS Of 214 patients enrolled (106 intervention and 108 usual care), disability and quality of life measures were obtained for 97 intervention patients at six months (92%) and 92 at 12 months (87%), and for 96 usual care patients at six months (89%) and 92 at 12 months (85%). Improvements from baseline on the Sheehan disability scale (-0.9, 95% confidence interval -1.5 to -0.2; P = 0.006) and global quality of life rating (0.7, 0.2 to 1.2; P = 0.005) were significantly greater at six and 12 months in patients in the intervention group. There was a trend toward greater improvement in disabilities in activities of daily living (-1.5, -3.3 to 0.4; P = 0.10). CONCLUSIONS Integrated care that covers chronic physical disease and comorbid depression can reduce social role disability and enhance global quality of life. Trial registration Clinical Trials NCT00468676.
Youths with attention deficit hyperactivity disorder often experience weight loss on stimulants, which may limit optimal dosing and compliance. Cyproheptadine has been shown in medical samples to stimulate weight gain. We conducted a retrospective chart review of 28 consecutive pediatric psychiatry outpatients prescribed cyproheptadine for weight loss or insomnia while on stimulants. Of these, 4 patients never took cyproheptadine consistently, and 3 discontinued it within the first 7 days due to intolerable side effects. Data were analyzed for 21 other patients (age range 4-15 years) who continued with 4-8 mg of cyproheptadine nightly (mean final dose = 4.9 mg/day) for at least 14 days (mean duration = 104.7 days). Most had lost weight on stimulant alone (mean weight loss was 2.1 kg, mean weight velocity was -19.3 g/day). All 21 gained weight taking concomitant cyproheptadine, with a mean gain of 2.2 kg (paired t = 6.87, p < 0.0001) and a mean weight velocity of 32.3 g/day. Eleven of 17 patients who had reported initial insomnia on stimulant alone noted significant improvements in sleep with cyproheptadine added. We conclude that concomitant cyproheptadine may be useful in youths with attention deficit hyperactivity disorder for stimulant-induced weight loss, pending future randomized controlled trials.
When the food intake of organisms such as yeast and rodents is reduced (dietary restriction), they live longer than organisms fed a normal diet. A similar effect is seen when the activity of nutrient-sensing pathways is reduced by mutations or chemical inhibitors. In rodents, both dietary restriction and decreased nutrient-sensing pathway activity can lower the incidence of age-related loss of function and disease, including tumors and neurodegeneration. Dietary restriction also increases life span and protects against diabetes, cancer, and cardiovascular disease in rhesus monkeys, and in humans it causes changes that protect against these age-related pathologies. Tumors and diabetes are also uncommon in humans with mutations in the growth hormone receptor, and natural genetic variants in nutrient-sensing pathways are associated with increased human life span. Dietary restriction and reduced activity of nutrient-sensing pathways may thus slow aging by similar mechanisms, which have been conserved during evolution. We discuss these findings and their potential application to prevention of age-related disease and promotion of healthy aging in humans, and the challenge of possible negative side effects.
IMPORTANCE Bariatric surgery is associated with sustained weight loss and improved physical health status for severely obese individuals. Mental health conditions may be common among patients seeking bariatric surgery; however, the prevalence of these conditions and whether they are associated with postoperative outcomes remains unknown. OBJECTIVE To determine the prevalence of mental health conditions among bariatric surgery candidates and recipients, to evaluate the association between preoperative mental health conditions and health outcomes following bariatric surgery, and to evaluate the association between surgery and the clinical course of mental health conditions. DATA SOURCES We searched PubMed, MEDLINE on OVID, and PsycINFO for studies published between January 1988 and November 2015. Study quality was assessed using an adapted tool for risk of bias; quality of evidence was rated based on GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria. FINDINGS We identified 68 publications meeting inclusion criteria: 59 reporting the prevalence of preoperative mental health conditions (65,363 patients) and 27 reporting associations between preoperative mental health conditions and postoperative outcomes (50,182 patients). Among patients seeking and undergoing bariatric surgery, the most common mental health conditions, based on random-effects estimates of prevalence, were depression (19% [95% CI, 14%-25%]) and binge eating disorder (17% [95% CI, 13%-21%]). There was conflicting evidence regarding the association between preoperative mental health conditions and postoperative weight loss. Neither depression nor binge eating disorder was consistently associated with differences in weight outcomes. Bariatric surgery was, however, consistently associated with postoperative decreases in the prevalence of depression (7 studies; 8%-74% decrease) and the severity of depressive symptoms (6 studies; 40%-70% decrease). CONCLUSIONS AND RELEVANCE Mental health conditions are common among bariatric surgery patients-in particular, depression and binge eating disorder. There is inconsistent evidence regarding the association between preoperative mental health conditions and postoperative weight loss. Moderate-quality evidence supports an association between bariatric surgery and lower rates of depression postoperatively.
OBJECTIVE To evaluate the safety, tolerability, and amyloid beta (Abeta) response to the gamma-secretase inhibitor LY450139 in Alzheimer disease. DESIGN Multicenter, randomized, double-blind, dose-escalation, placebo-controlled trial. SETTING Community-based clinical research centers. Patients Fifty-one individuals with mild to moderate Alzheimer disease were randomized to receive placebo (n=15) or LY450139 (100 mg [n=22] or 140 mg [n=14]), with 43 completing the treatment phase. Intervention The LY450139 groups received 60 mg/d for 2 weeks, then 100 mg/d for 6 weeks, and then either 100 or 140 mg/d for 6 additional weeks. MAIN OUTCOME MEASURES Primary outcome measures were adverse events, plasma and cerebrospinal fluid Abeta levels, vital signs, electrocardiographic data, and laboratory safety test results. Secondary outcome measures included the Alzheimer's Disease Assessment Scale cognitive subscale and the Alzheimer's Disease Cooperative Study Activities of Daily Living Scale. RESULTS Group differences were seen in skin and subcutaneous tissue concerns (P=.05), including 3 possible drug rashes and 3 reports of hair color change in the treatment groups. There were 3 adverse event-related discontinuations, including 1 transient bowel obstruction. The plasma Abeta(40) concentration was reduced by 58.2% for the 100-mg group and 64.6% for the 140-mg group (P<.001). No significant reduction was seen in cerebrospinal fluid Abeta levels. No group differences were seen in cognitive or functional measures. CONCLUSIONS LY450139 was generally well tolerated at doses of up to 140 mg/d for 14 weeks, with several findings indicating the need for close clinical monitoring in future studies. Decreases in plasma Abeta concentrations were consistent with inhibition of gamma-secretase. Trial Registration clinicaltrials.gov Identifier: NCT00244322.
We evaluated the effect of dexamethasone on vomiting after elective tonsillectomy in 133 healthy children aged 2-12 yr in a randomized, stratified, blocked, double-blind, placebo-controlled study. General anesthesia was induced by inhalation of N2O and halothane or intravenously (IV) with propofol. Anesthesia was maintained with N2O and halothane. Dexamethasone 150 micrograms/kg up to a maximum dose of 8 mg, or placebo, was administered IV before surgery. All patients received 1.5 mg/kg codeine intramuscularly (IM) intraoperatively. Perioperative IV fluids, management of emesis, postoperative pain and hospital discharge criteria were all standardized. The groups were similar with respect to number, age, weight, length of surgery, and estimated intraoperative blood loss. Dexamethasone reduced the overall incidence of vomiting from 72% (placebo) to 40% (P < 0.001). Vomiting, both in-hospital and postdischarge, was decreased by the prophylactic administration of dexamethasone. Each episode of in-hospital vomiting prolonged discharge by 13 +/- 2 min, mean +/- SD (P < 0.001). In conclusion, dexamethasone markedly decreased vomiting by healthy children after elective tonsillectomy in an ambulatory hospital setting.
BACKGROUND Type 1 diabetes results from T-cell-mediated destruction of β cells. Findings from preclinical studies and pilot clinical trials suggest that antithymocyte globulin (ATG) might be effective for reducing this autoimmune response. We assessed the safety and efficacy of rabbit ATG in preserving islet function in participants with recent-onset type 1 diabetes, and report here our 12-month results. METHODS For this phase 2, randomised, placebo-controlled, clinical trial, we enrolled patients with recent-onset type 1 diabetes, aged 12-35 years, and with a peak C-peptide of 0.4 nM or greater on mixed meal tolerance test from 11 sites in the USA. We used a computer generated randomisation sequence to randomly assign patients (2:1, with permuted-blocks of size three or six and stratified by study site) to receive either 6.5 mg/kg ATG or placebo over a course of four days. All participants were masked and initially managed by an unmasked drug management team, which managed all aspects of the study until month 3. Thereafter, to maintain masking for diabetes management throughout the remainder of the study, participants received diabetes management from an independent, masked study physician and nurse educator. The primary endpoint was the baseline-adjusted change in 2-h area under the curve C-peptide response to mixed meal tolerance test from baseline to 12 months. Analyses were by intention to treat. This is a planned interim analysis of an on-going trial that will run for 24 months of follow-up. This study is registered with ClinicalTrials.gov, number NCT00515099. FINDINGS Between Sept 10, 2007, and June 1, 2011, we screened 154 individuals, randomly allocating 38 to ATG and 20 to placebo. We recorded no between-group difference in the primary endpoint: participants in the ATG group had a mean change in C-peptide area under the curve of -0.195 pmol/mL (95% CI -0.292 to -0.098) and those in the placebo group had a mean change of -0.239 pmol/mL (-0.361 to -0.118) in the placebo group (p=0.591). All except one participant in the ATG group had both cytokine release syndrome and serum sickness, which was associated with a transient rise in interleukin-6 and acute-phase proteins. Acute T cell depletion occurred in the ATG group, with slow reconstitution over 12 months. However, effector memory T cells were not depleted, and the ratio of regulatory to effector memory T cells declined in the first 6 months and stabilised thereafter. ATG-treated patients had 159 grade 3-4 adverse events, many associated with T-cell depletion, compared with 13 in the placebo group, but we detected no between-group difference in incidence of infectious diseases. INTERPRETATION Our findings suggest that a brief course of ATG does not result in preservation of β-cell function 12 months later in patients with new-onset type 1 diabetes. Generalised T-cell depletion in the absence of specific depletion of effector memory T cells and preservation of regulatory T cells seems to be an ineffective treatment for type 1 diabetes.
Abstract Objective Our previous 6-month, randomized study demonstrated the beneficial effect of a vegetarian (V) compared to a conventional diet (C) with similar caloric restriction on cardiovascular risk factors for patients with type 2 diabetes (T2D), namely increased insulin sensitivity, reduced body weight, reduced volume of visceral and subcutaneous fat, decreased LDL-cholesterol and improved oxidative stress markers and chosen adipokines. We conducted post-trial monitoring to determine whether the improved outcomes persisted 1 year after the end of the study. Methods 62 subjects with T2D who completed the study were asked to come for a 1-year follow-up to measure weight, waist circumference, HbA1c and blood lipids. No attempts were made to maintain their previously assigned diets. Results 44 patients (71%) attended the post-trial monitoring. Hypoglycemic agents were increased by 14% in V and by 26% in C; insulin therapy was introduced in 5% in V and in 13% in C one year after the end of the intervention. Neither weight nor waist circumference changed significantly in either group. HbA1c increased ( p  ≤ 0.05) similarly in both groups (+0.49 ± 1.04% in V vs. +0.42 ± 0.8% in C). Blood lipids did not change in either group. Conclusion One year after the end of the intervention, the positive effects of a vegetarian diet on cardiovascular risk factors compared to a conventional diet were partially maintained.
We studied 201 consecutive patients who received a relatively fixed dose of radioiodine for the treatment of hyperthyroidism between the years 1981-6. Patients with Graves' disease (170) were initially treated with a mean (SE) dose of 369 (10) MBq 131-I with a remission rate of 94% at 6 months and a cumulative relapse rate of 12% at one year and 21% at 5 years. The cumulative incidence of hypothyroidism was 26% at 3 months, 55% at 6 months, 61% at 1 year and 66% at 5 years. Patients with a uninodular goitre (10) were initially treated with a mean (SE) dose of 438 (85) MBq 131-I with a remission rate of 100% at 6 months, without relapse at 1 year but relapsing in 17% at 5 years. The cumulative incidence of hypothyroidism was 26% at 3 months, 30% at 6 months, 40% at 1 year and 40% at 5 years. Patients with a multinodular goitre (21) were initially treated with a mean (SE) dose of 613 (77) MBq 131-I with a remission rate of 79% at 6 months and a cumulative relapse rate of 26% at 1 year and 39% at 5 years. The cumulative incidence of hypothyroidism was 5% at 3 months, 14% at 6 months, 24% at 1 year and 24% at 5 years.
Type 2 diabetes mellitus (T2DM) affects more than 7% of adults in the US and leads to substantial personal and economic burden. In prediabetic states insulin secretion and action—potential targets of preventive interventions—are impaired. In trials lifestyle modification (i.e. weight loss and exercise) has proven effective in preventing incident T2DM in high-risk groups, although weight loss has the greatest effect. Various medications (e.g. metformin, thiazolidinediones and acarbose) can also prevent or delay T2DM. Whether diabetes-prevention strategies also ultimately prevent the development of diabetic vascular complications is unknown, but cardiovascular risk factors are favorably affected. Preventive strategies that can be implemented in routine clinical settings have been developed and evaluated. Widespread application has, however, been limited by local financial considerations, even though cost-effectiveness might be achieved at the population level.
The ideal anti-obesity drug would produce sustained weight loss with minimal side effects. The mechanisms that regulate energy balance have substantial built-in redundancy, overlap considerably with other physiological functions, and are influenced by social, hedonic and psychological factors that limit the effectiveness of pharmacological interventions. It is therefore unsurprising that anti-obesity drug discovery programmes have been littered with false starts, failures in clinical development, and withdrawals due to adverse effects that were not fully appreciated at the time of launch. Drugs that target pathways in metabolic tissues, such as adipocytes, liver and skeletal muscle, have shown potential in preclinical studies but none has yet reached clinical development. Recent improvements in the understanding of peptidergic signalling of hunger and satiety from the gastrointestinal tract mediated by ghrelin, cholecystokinin (CCK), peptide YY (PYY) and glucagon-like peptide-1 (GLP-1), and of homeostatic mechanisms related to leptin and its upstream pathways in the hypothalamus, have opened up new possibilities. Although some have now reached clinical development, it is uncertain whether they will meet the strict regulatory hurdles required for licensing of an anti-obesity drug. However, GLP-1 receptor agonists have already succeeded in diabetes treatment and, owing to their attractive body-weight-lowering effects in humans, will perhaps also pave the way for other anti-obesity agents. To succeed in developing drugs that control body weight to the extent seen following surgical intervention, it seems obvious that a new paradigm is needed. In other therapeutic arenas, such as diabetes and hypertension, lower doses of multiple agents targeting different pathways often yield better results than strategies that modify one pathway alone. Some combination approaches using peptides and small molecules have now reached clinical trials, although recent regulatory experience suggests that large challenges lie ahead. In future, this polytherapeutic strategy could possibly rival surgery in terms of efficacy, safety and sustainability of weight loss.
Rationale:Atypical antipsychotic drugs (AAD) induce significant weight gain in female C57BL/6J mice. The effect of dietary fat on weight gain and serum lipids in this model is unknown. Objectives: Test the hypothesis that the obesigenic effects of these drugs are greater in the presence of a high-fat diet. Methods:Female C57BL/6J mice were treated with atypical antipsychotics for 3 weeks and fed either a low-fat or high-fat diet (4.6 vs 15.6% fat by wt). Food intake (FI), body weight (BW), body composition, and serum lipids were measured during treatment with optimized doses of olanzapine, quetiapine, and risperidone. Energy intake (EI) and feed efficiency (FE) were calculated. Group differences in change were analyzed via repeated measures analysis of variance (ANOVA). Serum lipid concentrations, EI and FE were compared using two-way ANOVA.Results:AAD-treated mice gained significantly more weight than controls after 3 weeks (P<0.001). Treatment and diet had significant effects on FI and EI over time (P<0.001). AAD-treated mice had significantly higher FE than controls (P<0.05); however, there was no significant drug by diet interaction (P=0.65). Risperidone low-fat mice gained significantly more absolute fat mass than placebo low-fat mice (P<0.05). All treatment groups, except quetiapine low-fat and olanzapine high-fat, gained significantly more absolute lean mass than placebo controls (P<0.05). Cholesterol levels were significantly lower in quetiapine and risperidone than placebo (P<0.05). Risperidone low-fat mice had significantly higher triglyceride levels than placebo and risperidone high-fat mice (P<0.05).Conclusions:A high-fat diet does not increase AAD-induced BW gain in female mice during a 3-week treatment period.
BACKGROUND Being overweight is often cited as a relative contraindication to peritoneal dialysis. Our primary objective was to determine whether actual mortality rates support this opinion. METHODS Retrospective cohort study of United States Medicare patients initiating dialysis between 1995 and 2000 (N = 418,021; 11% peritoneal dialysis). RESULTS Seven percent were underweight [body mass index (BMI) < 18.5 kg/m2], 27% were overweight (BMI 25.0 to 29.9 kg/m2), and 23% were obese (BMI> 29.9 kg/m2) at dialysis initiation. Compared to those with normal BMI, the adjusted odds of initiating peritoneal dialysis were 0.70 (P < 0.05) in underweight, 1.12 (P < 0.05) in overweight, and 0.87 (P < 0.05) in obese subjects. Among peritoneal dialysis patients, adjusted mortality hazard ratios in the first, second, and third year were 1.45 (P < 0.05), 1.28 (P < 0.05), and 1.17 for the underweight, respectively; 0.84 (P < 0.05), 0.89 (P < 0.05), and 0.98 for the overweight, respectively; and 0.89 (P < 0.05), 0.99, and 1.00 for the obese, respectively. Apart from higher third-year mortality in the obese, associations were similar after censoring at a switch to hemodialysis. For transplantation, the corresponding results were 0.76 (P < 0.05), 0.90 (P < 0.05), and 0.88 for the underweight, respectively; 0.95, 1.06, and 0.93 for the overweight, respectively; and 0.62 (P < 0.05), 0.68, and 0.71 for the obese, respectively. For switching to hemodialysis, hazards ratios were 0.92, 0.97, and 0.80 for the underweight, respectively; 1.07, 1.11 (P < 0.05), and 1.03 for the overweight, respectively; and 1.28 (P < 0.05), 1.29 (P < 0.05), and 1.36 (P < 0.05) for the obese, respectively. CONCLUSION Although less likely to initiate peritoneal dialysis, overweight and obese peritoneal dialysis patients have longer survival than those with lower BMI, not adequately explained by lower transplantation and technique survival rates.
OBJECTIVE Oligofructose (OFS) is a prebiotic that reduces energy intake and fat mass via changes in gut satiety hormones and microbiota. The effects of OFS may vary depending on predisposition to obesity. The aim of this study was to examine the effect of OFS in diet-induced obese (DIO) and diet-resistant (DR) rats. METHODS Adult, male DIO, and DR rats were randomized to: high-fat/high-sucrose (HFS) diet or HFS diet + 10% OFS for 6 weeks. Body composition, food intake, gut microbiota, plasma gut hormones, and cannabinoid CB(1) receptor expression in the nodose ganglia were measured. RESULTS OFS reduced body weight, energy intake, and fat mass in both phenotypes (P < 0.05). Select gut microbiota differed in DIO versus DR rats (P < 0.05), the differences being eliminated by OFS. OFS did not modify plasma ghrelin or CB(1) expression in nodose ganglia, but plasma levels of GIP were reduced and PYY were elevated (P < 0.05) by OFS. CONCLUSIONS OFS was able to reduce body weight and adiposity in both prone and resistant obese phenotypes. OFS-induced changes in gut microbiota profiles in DIO and DR rats, along with changes in gut hormone levels, likely contribute to the sustained lower body weights.
We tested here the impact of a long-term inhibition of dipeptidyl peptidase-4 (DPP-4) with sitagliptin on the deposition of amyloid-beta within the brain and deficits in memory-related behavioral paradigms in a model of Alzheimer's disease (AD): double transgenic mice B6*Cg-Tg(APPswe,PSEN1dE9)85Dbo/J. Mice began to receive sitagliptin at 7 months of age. Three different dose of sitagliptin (5, 10 and 20 mg/kg), were administered daily for 12 weeks by gastric gavage. The treatments counteracted: (i) the memory impairment in the contextual fear conditioning test; (ii) increased the brain levels of GLP-1; (iii) produced significant reductions of nitrosative stress and inflammation hallmarks within the brain, as well as (iv) a significant diminution in the ultimate number and total area of betaAPP and Abeta deposits. All these effects much more evident for the dose of 20 mg/kg sitagliptin. The long-term inhibition of the endogenous DPP-4 enzymes with sitagliptin can significantly delay some forms of AD pathology, including amyloid deposition, when administered early in the disease course of a transgenic mouse model of AD.
BACKGROUND The amyloid fibril deposits that cause systemic amyloidosis always contain the nonfibrillar normal plasma protein, serum amyloid P component (SAP). The drug (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC) efficiently depletes SAP from the plasma but leaves some SAP in amyloid deposits that can be specifically targeted by therapeutic IgG anti-SAP antibodies. In murine amyloid A type amyloidosis, the binding of these antibodies to the residual SAP in amyloid deposits activates complement and triggers the rapid clearance of amyloid by macrophage-derived multinucleated giant cells. METHODS We conducted an open-label, single-dose-escalation, phase 1 trial involving 15 patients with systemic amyloidosis. After first using CPHPC to deplete circulating SAP, we infused a fully humanized monoclonal IgG1 anti-SAP antibody. Patients with clinical evidence of cardiac involvement were not included for safety reasons. Organ function, inflammatory markers, and amyloid load were monitored. RESULTS There were no serious adverse events. Infusion reactions occurred in some of the initial recipients of larger doses of antibody; reactions were reduced by slowing the infusion rate for later patients. At 6 weeks, patients who had received a sufficient dose of antibody in relation to their amyloid load had decreased liver stiffness, as measured with the use of transient elastography. These patients also had improvements in liver function in association with a substantial reduction in hepatic amyloid load, as shown by means of SAP scintigraphy and measurement of extracellular volume by magnetic resonance imaging. A reduction in kidney amyloid load and shrinkage of an amyloid-laden lymph node were also observed. CONCLUSIONS Treatment with CPHPC followed by an anti-SAP antibody safely triggered clearance of amyloid deposits from the liver and some other tissues. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01777243.).
The aim of the study was to evaluate whether treatment with recombinant human growth hormone (rhGH) affects the quality of life of young adults who were diagnosed as idiopathic short stature (ISS) during childhood, and whether their quality of life and aspects of the personality are different from normal. Experiences and expectations concerning rhGH treatment of the subjects and their parents were also investigated. Eighty-nine subjects were included into the study: 24 subjects (16M, 8F) were treated with rhGH from childhood, whereas 65 subjects (40M, 25F) were never treated. At the time of the interview all subjects had attained final height [mean (SD) -2.3 (0.9) SDS for Dutch references], and the age of the treated subjects was 20.5 (1.0) y, and 25.7 (3.5) y of the control subjects (p < 0.001). The level of education was similar, but the treated subjects had less often a partner compared to the control subjects (adjusted for age and gender, p < 0.001). The Nottingham Health Profile and Short Form 36 Health Survey showed no difference in general health state between treated and control subjects, and the healthy Dutch age-specific references (norm group). Although 74% of the subjects reported one or more negative events related to their height, and 61% would like to be taller, only 22% and 11% were willing to trade-off at Time Trade-Off and Standard Gamble, respectively. The personality of the subjects, which was measured by the Minnesota Multiphasic Personality Inventory, was not different from the norm group. The satisfaction with the rhGH treatment was high, as it had caused 12 (8) cm and 13 (7) cm gain in final height according to the subjects and parents, respectively. Based on initial predicted adult height (Bayley & Pinneau), this gain was only 3.3 (5.6) cm. We concluded that although the treated subjects had a partner less often when compared to the control subjects, the quality of life of subjects with ISS at adult age is normal and appears not to be affected by rhGH therapy, The treated subjects were very satisfied with the treatment, probably by overestimation of the final height gain.
SETTING Tuberculosis (TB) program, Damien Foundation Projects, Bangladesh. OBJECTIVE To summarize the outcome and its determinants of the first treatment for multidrug-resistant TB using a standardized regimen consisting of a minimum 9 months. DESIGN This was a prospective, observational study of a gatifloxacin (GFX) based directly observed regimen, mainly with initial hospitalization. The 4-month intensive phase was extended until sputum smear conversion. Patients were monitored using culture for up to 2 years after treatment completion. RESULTS Of the 515 patients who met the study inclusion criteria and were successively enrolled from 2005 to 2011, 84.4% had a bacteriologically favorable outcome. Due to extensive disease with delayed sputum conversion, only half of the patients completed treatment within 9 months; however, 95% were able to complete treatment within 12 months. Eleven patients failed or relapsed, and 93.1% of the 435 patients who were successfully treated completed at least 12 months post-treatment follow-up. The strongest risk factor for a bacteriologically unfavorable outcome was high-level fluoroquinolone (FQ) resistance, particularly when compounded by initial pyrazinamide (PZA) resistance. Low-level FQ resistance had no unfavorable effect on treatment outcome. Amplification of drug resistance occurred only once, in a patient strain that was initially only susceptible to kanamycin and clofazimine. CONCLUSION The excellent outcome of the Bangladesh regimen was largely maintained. Bacteriological treatment failures and relapses were rare, except among patients with high-level GFX resistance, notably in the presence of PZA resistance.
BACKGROUND Gastric bypass patients with a range of disturbed eating patterns before surgery may be at risk of returning to old patterns postoperatively. Recent research has shown that binge eating is common among the obese before surgery as well as in the postoperative maintenance phase and appears to be linked to poorer outcome. Although "grazing" behavior has not been specifically studied, it is also a high-risk pattern. This paper is a descriptive investigation summarizing postoperative eating patterns in a group of patients. METHODS Patients completed self-report questionnaires before surgery and were seen for a preoperative mental health evaluation with particular focus on assessing eating patterns. Patients with high-risk eating patterns, both binge eating and "grazing", were identified, invited to attend a post-surgery therapy group, and were given additional follow-up questionnaires regarding postoperative eating patterns. RESULTS Consistent with recent studies, many high-risk patients reported recurrent loss of control over eating and, in some cases, subsequent weight gain. Although no longer able to eat large amounts, "grazing" became a more common pattern, appearing >or=6 months following surgery. CONCLUSION Different forms of overeating need to be assessed in this population, focusing on the subjective loss of control rather than on the quantity consumed. Although many patients do not meet strict criteria for binge eating disorder before surgery, these "grazers" are also high-risk. Former binge eaters often turn into "grazers" following surgery. Interventions are needed for at-risk patients.
OBJECTIVE IL-15 is an inflammatory cytokine secreted by many cell types. IL-15 is also produced during physical exercise by skeletal muscle and has been reported to reduce weight gain in mice. Contrarily, our findings on IL-15 knockout (KO) mice indicate that IL-15 promotes obesity. The aim of this study is to investigate the mechanisms underlying the pro-obesity role of IL-15 in adipose tissues. METHODS Control and IL-15 KO mice were maintained on high fat diet (HFD) or normal control diet. After 16 weeks, body weight, adipose tissue and skeletal mass, serum lipid levels and gene/protein expression in the adipose tissues were evaluated. The effect of IL-15 on thermogenesis and oxygen consumption was also studied in primary cultures of adipocytes differentiated from mouse preadipocyte and human stem cells. RESULTS Our results show that IL-15 deficiency prevents diet-induced weight gain and accumulation of lipids in visceral and subcutaneous white and brown adipose tissues. Gene expression analysis also revealed elevated expression of genes associated with adaptive thermogenesis in the brown and subcutaneous adipose tissues of IL-15 KO mice. Accordingly, oxygen consumption was increased in the brown adipocytes from IL-15 KO mice. In addition, IL-15 KO mice showed decreased expression of pro-inflammatory mediators in their adipose tissues. CONCLUSIONS Absence of IL-15 results in decreased accumulation of fat in the white adipose tissues and increased lipid utilization via adaptive thermogenesis. IL-15 also promotes inflammation in adipose tissues that could sustain chronic inflammation leading to obesity-associated metabolic syndrome.