Study protocol for a Developmental Epidemiological Study of Children born through Reproductive Technologies (DESCRT).

STUDY QUESTIONS: The primary objective of this study is to determine what parental factors or specific ART may influence the risk for adverse cardiometabolic outcomes among children so conceived and their parents. The secondary objective of this study is to prospectively examine the effects of infertility or ART on the intrauterine environment, obstetric and neonatal outcomes. WHAT IS KNOWN ALREADY: Pregnancies conceived with ART are at an increased risk of being affected by adverse obstetric and neonatal outcomes when compared to spontaneously conceived (SC) pregnancies among fertile women. Small cohort studies have suggested ART-conceived children may have a higher risk of long-term cardiometabolic disturbances as well. Currently, few studies have compared long-term cardiometabolic outcomes among ART-conceived children and non-IVF treated (NIFT) children, to children conceived spontaneously to parents with infertility (subfertile parents). STUDY DESIGN SIZE DURATION: The Developmental Epidemiological Study of Children born through Reproductive Technologies (DESCRT) is a prospective cohort study that aims to: establish a biobank and epidemiological cohort of children born to subfertile or infertile parents who either conceived spontaneously (without assistance) or used reproductive technologies to conceive (all offspring were from couples assessed and/or treated in the same institute); prospectively examine the effects of infertility or ART on the intrauterine environment, obstetric and neonatal outcomes; and determine what parental factors or ART may influence the cardiometabolic risk of children so conceived. Pregnancies and resultant children will be compared by mode of conception, namely offspring that were conceived without medical assistance or SC or following NIFT, IVF with fresh embryo transfer or frozen embryo transfer (FET), and by fertilization method (conventional versus ICSI). DESCRT has a Child group evaluating long-term outcomes of children as well as a Pregnancy group that will compare obstetric and neonatal outcomes of children conceived since the commencement of the study. Recruitment started in May of 2017 and is ongoing. When the study began, we estimated that ∼4000 children would be eligible for enrollment. PARTICIPANTS/MATERIALS SETTING METHODS: Eligible participants are first-trimester pregnancies (Pregnancy group) or children (Child group) born to parents who were evaluated at an infertility center in the University of California, San Francisco, CA, USA who were SC or conceived after reproductive treatments (NIFT, IVF ± ICSI, FET). Children in the Child group were conceived at UCSF and born from 2001 onwards. In the Pregnancy group, enrollment began in November of 2017.The primary outcome is the cardiometabolic health of offspring in the Child group, as measured by blood pressure and laboratory data (homeostatic model assessment for insulin resistance (HOMA-IR), oral glucose disposition). There are several secondary outcome measures, including: outcomes from parental survey response (assessing parent/child medical history since delivery-incidence of cardiometabolic adverse events), anthropomorphic measurements (BMI, waist circumference, skinfold thickness), and laboratory data (liver enzymes, lipid panel, metabolomic profiles). In the Pregnancy group, outcomes include laboratory assessments (bhCG, maternal serum analytes, soluble fms-like tyrosine kinase-1 (sFLT-1), and placental growth factor (PlGF)) and placental assessments (placental volume in the second and third trimester and placental weight at delivery). Importantly, aliquots of blood and urine are stored from parents and offspring as part of a biobank. The DESCRT cohort is unique in two ways. First, there is an extensive amount of clinical and laboratory treatment data: parental medical history and physical examination at the time of treatment, along with ovarian reserve and infertility diagnosis; and treatment specifics: for example, fertilization method, culture O2 status, embryo quality linked to each participant. These reproductive data will aid in identifying explanatory variables that may influence the primary cardiometabolic outcomes of the offspring-and their parents. Second, the DESCRT control group includes pregnancies and children SC from parents with subfertility, which may help to assess when infertility, as opposed to reproductive treatments, may be affecting offspring cardiometabolic health. STUDY FUNDING/COMPETING INTERESTS: This study is funded by the National Institutes of Health NICHD (1R01HD084380-01A1). A.J.A. is a shareholder in Carrot and consultant for Flo Health. The other authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: NCT03799107. TRIAL REGISTRATION DATE: 10 January 2019. DATE OF FIRST PATIENT'S ENROLLMENT: 10 May 2017.

Risk of brainstem necrosis in pediatric patients with central nervous system malignancies after pencil beam scanning proton therapy.

Background: Radiation therapy (RT) plays an important role in management of pediatric central nervous system (CNS) malignancies. Centers are increasingly utilizing pencil beam scanning proton therapy (PBS-PT). However, the risk of brainstem necrosis has not yet been reported. In this study, we evaluate the rate of brainstem necrosis in pediatric patients with CNS malignancies treated with PBS-PT.Material and methods: Pediatric patients with non-hematologic CNS malignancies treated with PBS-PT who received dose to the brainstem were included. All procedures were approved by the institutional review board. Brainstem necrosis was defined as symptomatic toxicity. The actuarial rate was analyzed by the Kaplan Meier method.Results: One hundred and sixty-six consecutive patients were reviewed. Median age was 10 years (range 0.5-21 years). Four patients (2.4%) had prior radiation. Median maximum brainstem dose in the treated course was 55.4 Gy[RBE] (range 0.15-61.4 Gy[RBE]). In patients with prior RT, cumulative median maximum brainstem dose was 98.0 Gy [RBE] (range 17.0-111.0 Gy [RBE]). Median follow up was 19.6 months (range, 2.0-63.0). One patient who had previously been treated with twice-daily radiation therapy and intrathecal (IT) methotrexate experienced brainstem necrosis. The actuarial incidence of brainstem necrosis was 0.7% at 24 months (95% CI 0.1-5.1%).Conclusion: The rate of symptomatic brainstem necrosis was extremely low after treatment with PBS-PT in this study. Further work to clarify clinical and dosimetric parameters associated with risk of brainstem necrosis after PBS-PT is needed.

Effects of a Mindfulness-Based Intervention on Distress, Weight Gain, and Glucose Control for Pregnant Low-Income Women: A Quasi-Experimental Trial Using the ORBIT Model.

BACKGROUND: Stress can lead to excessive weight gain. Mindfulness-based stress reduction that incorporates mindful eating shows promise for reducing stress, overeating, and improving glucose control. No interventions have tested mindfulness training with a focus on healthy eating and weight gain during pregnancy, a period of common excessive weight gain. Here, we test the effectiveness of such an intervention, the Mindful Moms Training (MMT), on perceived stress, eating behaviors, and gestational weight gain in a high-risk sample of low income women with overweight/obesity. METHOD: We conducted a quasi-experimental study assigning 115 pregnant women to MMT for 8 weeks and comparing them to 105 sociodemographically and weight equivalent pregnant women receiving treatment as usual. Our main outcomes included weight gain (primary outcome), perceived stress, and depression. RESULTS: Women in MMT showed significant reductions in perceived stress (ß = - 0.16) and depressive symptoms (ß = - 0.21) compared to the treatment as usual (TAU) control group. Consistent with national norms, the majority of women (68%) gained excessive weight according to Institute of Medicine weight-gain categories, regardless of group. Slightly more women in the MMT group gained below the recommendation. Among secondary outcomes, women in MMT reported increased physical activity (ß = 0.26) and had lower glucose post-oral glucose tolerance test (ß = - 0.23), being 66% less likely to have impaired glucose tolerance, compared to the TAU group. CONCLUSION: A short-term intervention led to significant improvements in stress, and showed promise for preventing glucose intolerance. However, the majority of women gained excessive weight. A longer more intensive intervention may be needed for this high-risk population. Clinical Trials.gov #NCT01307683.

Novel Interventions to Reduce Stress and Overeating in Overweight Pregnant Women: A Feasibility Study.

Background High stress and depression during pregnancy are risk factors for worsened health trajectories for both mother and offspring. This is also true for pre-pregnancy obesity and excessive gestational weight gain. Reducing stress and depression may be one path to prevent excessive caloric intake and gestational weight gain. Study Purpose We tested the feasibility of two novel interventions aimed at reducing stress and overeating during pregnancy. Reflecting different theoretical underpinnings, the interventions target different mechanisms. Mindful Moms Training (MMT) uses mindfulness to improve awareness and acceptance of experiences and promote conscious rather than automatic behavior choices. Emotional Brain Training (EBT) uses active coping to change perceptions of negative experience and promote positive affective states. Methods Forty-six overweight/obese low-income women were assigned to either MMT (n = 24) or EBT (n = 22) for an 8-week feasibility study. Pre-post changes in perceived stress, eating and presumed mechanisms were assessed. Results Women reported high levels of stress at baseline. Both interventions were well attended and demonstrated clinically significant pre-post reductions in stress, depressive symptoms, and improved eating behaviors. MMT significantly decreased experiential avoidance, whereas EBT significantly increased positive reappraisal; these changes were marginally significantly different by group. Conclusions This feasibility study found that both interventions promoted meaningful reductions in stress and depressive symptoms and improved reported eating behaviors in a high-risk group of pregnant women. Each intervention has a potentially different pathway-acceptance for MMT and reappraisal for EBT. Larger studies are needed to test efficacy on longer term reductions in stress and overeating.

Metabolic Syndrome Components After Pediatric Liver Transplantation: Prevalence and the Impact of Obesity and Immunosuppression.

Metabolic syndrome is associated with long-term morbidity and mortality after adult liver transplantation (LT). Whether pediatric LT recipients have a higher prevalence of metabolic syndrome remains controversial. In a cross-sectional study, we evaluated pediatric LT recipients aged 8-30 years using National Health and Nutrition Examination Survey (NHANES) protocols. LT recipients were matched by gender, race/ethnicity, and age with controls from NHANES. Pediatric LT recipients (n = 83), after adjusting for overweight/obesity and glucocorticoid use, had increased prevalence of prehypertension and hypertension, impaired glucose tolerance (IGT; 2-h glucose after oral glucose tolerance test ≥140 mg/dL), and low high-density lipoprotein compared to matched NHANES controls (n = 235) despite a lower prevalence of overweight/obesity. Among LT recipients, the adjusted odds of IGT doubled for every 7.5 years taking calcineurin inhibitors (odds ratio = 2.10, 95% confidence interval 1.06-4.17 per 7.5 years taking calcineurin inhibitors, p = 0.03). Among all subjects with IGT, LT recipients had a lower prevalence of overweight/obesity and less insulin resistance (homeostatic model assessment of insulin resistance) than did controls with IGT. Among normal weight subjects, LT recipients were significantly more likely than controls to have prehypertension/hypertension, IGT, low high-density lipoprotein, and metabolic syndrome. Pediatric LT recipients have unique metabolic syndrome profiles and risk factors and will require tailored screening and management protocols.

Influenza-attributable burden in United Kingdom primary care.

Influenza is rarely laboratory-confirmed and the outpatient influenza burden is rarely studied due to a lack of suitable data. We used the Clinical Practice Research Datalink (CPRD) and surveillance data from Public Health England in a linear regression model to assess the number of persons consulting UK general practitioners (GP episodes) for respiratory illness, otitis media and antibiotic prescriptions attributable to influenza during 14 seasons, 1995-2009. In CPRD we ascertained influenza vaccination status in each season and risk status (conditions associated with severe influenza outcomes). Seasonal mean estimates of influenza-attributable GP episodes in the UK were 857 996 for respiratory disease including 68 777 for otitis media, with wide inter-seasonal variability. In an average season, 2·4%/0·5% of children aged <5 years and 1·3%/0·1% of seniors aged ⩾75 years had a GP episode for respiratory illness attributed to influenza A/B. Two-thirds of influenza-attributable GP episodes were estimated to result in prescription of antibiotics. These estimates are substantially greater than those derived from clinically reported influenza-like illness in surveillance programmes. Because health service costs of influenza are largely borne in general practice, these are important findings for cost-benefit assessment of influenza vaccination programmes.

Differentiating Tumor Progression from Pseudoprogression in Patients with Glioblastomas Using Diffusion Tensor Imaging and Dynamic Susceptibility Contrast MRI.

BACKGROUND AND PURPOSE: Early assessment of treatment response is critical in patients with glioblastomas. A combination of DTI and DSC perfusion imaging parameters was evaluated to distinguish glioblastomas with true progression from mixed response and pseudoprogression. MATERIALS AND METHODS: Forty-one patients with glioblastomas exhibiting enhancing lesions within 6 months after completion of chemoradiation therapy were retrospectively studied. All patients underwent surgery after MR imaging and were histologically classified as having true progression (>75% tumor), mixed response (25%-75% tumor), or pseudoprogression (<25% tumor). Mean diffusivity, fractional anisotropy, linear anisotropy coefficient, planar anisotropy coefficient, spheric anisotropy coefficient, and maximum relative cerebral blood volume values were measured from the enhancing tissue. A multivariate logistic regression analysis was used to determine the best model for classification of true progression from mixed response or pseudoprogression. RESULTS: Significantly elevated maximum relative cerebral blood volume, fractional anisotropy, linear anisotropy coefficient, and planar anisotropy coefficient and decreased spheric anisotropy coefficient were observed in true progression compared with pseudoprogression (P < .05). There were also significant differences in maximum relative cerebral blood volume, fractional anisotropy, planar anisotropy coefficient, and spheric anisotropy coefficient measurements between mixed response and true progression groups. The best model to distinguish true progression from non-true progression (pseudoprogression and mixed) consisted of fractional anisotropy, linear anisotropy coefficient, and maximum relative cerebral blood volume, resulting in an area under the curve of 0.905. This model also differentiated true progression from mixed response with an area under the curve of 0.901. A combination of fractional anisotropy and maximum relative cerebral blood volume differentiated pseudoprogression from nonpseudoprogression (true progression and mixed) with an area under the curve of 0.807. CONCLUSIONS: DTI and DSC perfusion imaging can improve accuracy in assessing treatment response and may aid in individualized treatment of patients with glioblastomas.

The effects of titanium mesh on passive-scattering proton dose.

High-density metallic implants can introduce considerable uncertainties in proton therapy treatment planning. These uncertainties eventually translate into proton range errors, which may cause significant underdosing to the target volume or overdosing to normal tissue beyond the target. This study investigated the dosimetric impact of a 0.6 mm titanium (Ti) mesh implant in passive-scattering proton beam therapy through the study of the depth dose and output in water, and the dose profiles in solid water at various depths. The measurements were performed for a beam with a range of 8.5 cm and a modulation of 7.5 cm. The titanium mesh was placed at a depth of 1 cm below the surface of the phantom for all measurements. A range reduction of 0.5 ± 0.1 mm was observed for a beam perpendicular to the mesh, with no further reductions when the incident angle increased to 60°. We conclude that the dosimetric effect of a 0.6 mm titanium mesh implant is small for a passive scattering proton beam. With proper correction applied to metal artifacts, consistent results were observed in the phantom study in the treatment planning system.

Communication: Fundamental equation of state correlation with hybrid data sets.

A strategy is proposed for empirical fundamental equation of state correlations for pure fluids on the basis of hybrid data sets, composed of experimental and molecular simulation data. Argon and hydrogen chloride are used as examples.

Hypothalamic obesity in children.

Hypothalamic obesity is an intractable form of obesity syndrome that was initially described in patients with hypothalamic tumours and surgical damage. However, this definition is now expanded to include obesity developing after a variety of insults, including intracranial infections, infiltrations, trauma, vascular problems and hydrocephalus, in addition to acquired or congenital functional defects in central energy homeostasis in children with the so-called common obesity. The pathogenetic mechanisms underlying hypothalamic obesity are complex and multifactorial. Weight gain results from damage to the ventromedial hypothalamus, which leads, variously, to hyperphagia, a low-resting metabolic rate; autonomic imbalance; growth hormone-, gonadotropins and thyroid-stimulating hormone deficiency; hypomobility; and insomnia. Hypothalamic obesity did not receive enough attention, as evidenced by rarity of studies in this group of patients. A satellite symposium was held during the European Congress of Obesity in May 2011, in Istanbul, Turkey, to discuss recent developments and concepts regarding pathophysiology and management of hypothalamic obesity in children. An international group of leading researchers presented certain aspects of the problem. This paper summarizes the highlights of this symposium. Understanding the central role of the hypothalamus in the regulation of feeding and energy metabolism will help us gain insights into the pathogenesis and management of common obesity.

Bariatric surgery in a patient with complete MC4R deficiency.

Bariatric surgery is often successful for treatment of severe obesity. The mechanisms of weight loss after bariatric surgery and the role of central energy homeostatic pathways in this weight loss process are not well understood. The study of individuals with complete loss of function of genes important in the leptin-melanocortin system may help establish the significance of these pathways for weight loss after bariatric surgery. We describe the outcome of bariatric surgery in an adolescent with compound heterozygosity and complete functional loss of both alleles of the melanocortin 4 receptor (MC4R). The patient underwent laparoscopic adjustable gastric banding and truncal vagotomy at years of age, which resulted in initial, but not long-term weight loss. Our experience with this patient suggests that complete MC4R deficiency impairs response to gastric banding and results in poor weight loss after this surgery.

A Phase II safety and effect on time to tumor progression study of intratumoral light infusion technology using talaporfin sodium in patients with metastatic colorectal cancer.

BACKGROUND AND OBJECTIVES: Twenty-seven patients with refractory liver metastases from colorectal cancer took part in a Phase II study of the light infusion technology (Litx) light-activated drug/device system to assess safety and evaluate time to tumor progression (TTP). METHODS: Litx consists of the light-activated drug, talaporfin sodium (LS11), activated intratumorally by a catheter-like array of light-emitting diodes (LEDs). After placement of the array via ultrasound or computed tomography (CT) guidance, LS11 was administered intravenously, followed 15-60 min later by light infusion for 2.8 hr. Patients were assessed for adverse events and tumor response using physical examination, laboratory values, and CT scan evaluation over a period of 60 days. RESULTS: The observed occurrence of Litx treatment-related adverse events was minimal and cumulative toxicity did not occur when combined with chemotherapy. Assessment of TTP and tumor response rate, although statistically non-robust, suggest potential improvement. CONCLUSIONS: The Litx system was shown to be safe for treating liver metastases from colorectal cancer and there was no cumulative toxicity when combined with standard systemic therapy. Preliminary assessments of TTP and tumor response rate justify further evaluation in a Phase III follow-up study.

A multicenter, randomized, double-blind, placebo-controlled, dose-finding trial of a long-acting formulation of octreotide in promoting weight loss in obese adults with insulin hypersecretion.

OBJECTIVE: To compare changes in weight in obese patients who received long-acting octreotide (octreotide LAR) at one of three dose levels (20, 40, or 60 mg) or placebo over 6 months and to identify the lowest dose of octreotide LAR that safely achieved optimal weight loss. DESIGN: Randomized, double-blind, placebo-controlled trial of octreotide LAR at three dose levels. PATIENTS: A total of 172 adults (28 men and 144 women) with at least moderate obesity (body mass index (BMI) range 30-65 kg/m2) and evidence of insulin hypersecretion were enrolled. Patients were predominantly either Caucasian (50.0%) or African American (45.3%). The mean age (38 +/- 11 year), weight (110.7 +/- 23 kg), and BMI (39.8 +/- 6.5 kg/m2) were similar across the four treatment groups. MEASUREMENTS: Efficacy measures included weight, BMI, fasting serum glucose; triglycerides; percentage of total body fat and abdominal fat as measured by dual-energy X-ray absorptiometry; skin fold thickness; waist-to-hip circumference; leptin; percentage of carbohydrates, fat, and protein ingested; nutritional evaluation (including dietary analysis--3-day food record); quality of life (QoL; using the Impact of Weight on Quality of Life-Lite); Beck Depression Inventory; and Carbohydrate Craving Questionnaire. Safety measures included medical history, vital signs, physical examinations, hematology, blood chemistries, thyroid function tests, hemoglobin A1c, gallbladder ultrasound, electrocardiograms, and adverse events. RESULTS: After 6 months of treatment, patients receiving 40 or 60 mg of octreotide LAR experienced statistically significant weight loss compared to baseline, with mean differences from placebo in percent weight change of -1.98 and -1.87%, respectively. This finding was accompanied by statistically significant mean decreases in BMI compared to baseline, that is, a mean decrease of 0.73 and 0.79 kg/m2 for the 40 and 60 mg treatment arms, respectively. The observed weight loss was progressive during the 6-month treatment in the two higher dose groups. The lowest dose to reach statistical significance in weight loss after 6 months' treatment was 40 mg. Post hoc analysis revealed a 3.5-3.8% weight loss at month 6 in the two higher dose groups among Caucasian patients having insulin secretion greater than the median of the cohort, defined as CIR(gp) (corrected insulin response at the glucose peak) > or = 1.43. There were no statistically significant changes in QoL scores, body fat, leptin concentration, Beck Depression Inventory, or macronutrient intake. Mean changes of blood glucose AUC(0-180 min) during an oral glucose tolerance test in patients taking octreotide LAR were 39-40 mg/dl h higher than those on placebo. A total of 7-21% of the patients taking octreotide LAR reached a 5% or greater decrease in body weight from Baseline, compared to 11% for the placebo group. This was not statistically significant. The most common adverse events included diarrhea, headache, cholelithiasis, nausea, and abdominal pain. CONCLUSION: Octreotide LAR given at 40 or 60 mg resulted in statistically significant weight loss. A post hoc analysis stratifying patients by race and CIR(gp) indicated that Caucasian patients with the greater degree of insulin hypersecretion appeared to derive the most benefit from treatment. The observed safety profile was consistent with the known effects of octreotide from previous studies.

Obesity, leptin resistance, and the effects of insulin reduction.

Leptin resistance is a hallmark of obesity, but its etiology is unknown, and its clinical measurement is elusive. Leptin-sensitive subjects have normal resting energy expenditure (REE) at a low leptin concentration, while leptin-resistant subjects have a normal REE at a higher leptin concentration; thus, the ratio of REE:Leptin may provide a surrogate index of leptin sensitivity. We examined changes in REE and leptin in a cohort of 17 obese subjects during experimental weight loss therapy with the insulin-suppressive agent octreotide-LAR, 40 mg i.m. q28d for 6 months. Six subjects lost significant weight (>10%) and BMI (>-3 kg/m(2)) with a 34% decline in leptin and a 46% decrease in insulin area under the curve (IAUC) to oral glucose tolerance testing. These subjects maintained their pretreatment REE, and thus exhibited a rise in REE:Leptin, while the other 11 showed minimal changes in each of these parameters. For the entire cohort, the change in IAUC correlated negatively with the change in REE:Leptin. These results suggest that the REE:Leptin ratio, while derivative, may serve as a useful clinical indicator of changes in leptin sensitivity within obese subjects. They also support the possibilities that hyperinsulinemia may be a proximate cause of leptin resistance, and that reduction of insulinemia may promote weight loss by improving leptin sensitivity.

Race affects insulin and GLP-1 secretion and response to a long-acting somatostatin analogue in obese adults.

OBJECTIVE: This study investigated (1) the effect of octreotide-LAR (Sandostatin-LAR Depot; Novartis) on the enteroinsular axis in a biracial cohort of severely obese adults, (2) whether octreotide suppression of insulin secretion occurs by both a direct beta-cell effect and through mediating a glucagon-like peptide 1 (GLP-1) response, and (3) whether differences in GLP-1 concentrations could explain racial differences in insulin concentrations. DESIGN: Prospective, open-label trial using a pre-post test design. SETTING: Single university, clinical research center. SUBJECTS: In all, 42 healthy, severely obese Caucasian and African-American (AA) adults (93% female, 64% Caucasian, age=37.8+/-1.2 y, weight=123+/-4.2 kg, BMI=44.5+/-1 kg/m(2)), recruited through physician referral and newspaper ads, participated in the study. INTERVENTIONS: Indices of beta-cell activity, insulin and GLP-1 response before and during a 75-gm oral glucose tolerance test were determined before and after 24 weeks of octreotide-LAR. RESULTS: AA exhibited higher beta-cell activity, and insulin and GLP-1 concentrations than Caucasians. Octreotide-LAR suppressed the insulin and GLP-1 levels in both groups.

Racial differences in glucagon-like peptide-1 (GLP-1) concentrations and insulin dynamics during oral glucose tolerance test in obese subjects.

Obese African-American (AA) subjects have higher resting and stimulated insulin concentrations than obese Caucasians (C), which could not be explained by the severity of obesity or the degree of insulin sensitivity. We investigated whether differences in glucagon-like peptide-1 (GLP-1), the most potent incretin that regulates insulin secretion, might explain racial differences in insulin response. Accordingly, we measured fasting and stimulated glucose, insulin, and GLP-1 levels during a 3-h oral glucose tolerance test (OGTT) in 26 obese C (age 38+/-2 y, body mass index 44+/-1 kg/m(2)) and 16 obese AA (age 36+/-2 y, BMI 46+/-2 kg/m(2)) subjects. Corrected insulin response (CIR(30)), a measure of beta-cell activity, whole body insulin sensitivity index (WBISI), and area under the curve (AUC) for insulin, GLP-1, and C-peptide/insulin ratio were computed from the OGTT. Glucose levels, fasting and during the OGTT, were similar between racial groups; 32% of the C and 31% of the AA subjects had impaired glucose tolerance. With a similar WBISI, AAs had significantly higher CIR(30) (2.3+/-0.4 vs 1.01+/-0.1), insulin response (IAUC: 23 974+/-4828 vs 14 478+/-1463), and lower insulin clearance (0.07+/-0.01 vs 0.11+/-0.01) than C (all, P<0.01). Obese AAs also had higher fasting GLP-1 (6.7+/-2.5 vs 4.5+/-1.1) and GLP-1AUC (1174.7+/-412 vs 822.4+/-191) than C (both, P<0.02). Our results indicate that obese AAs had higher concentrations of GLP-1 both at fasting and during the OGTT than obese C. The increased GLP-1 concentration could explain the greater insulin concentration and the increased prevalence of hyperinsulinemia-associated disorders including obesity and type 2 diabetes in AAs.

Suppression of insulin secretion is associated with weight loss and altered macronutrient intake and preference in a subset of obese adults.

PURPOSE: Hyperinsulinemia is a common feature of many obesity syndromes. We investigated whether suppression of insulin secretion, without dietary or exercise intervention, could promote weight loss and alter food intake and preference in obese adults. METHODS: Suppression of insulin secretion was achieved using octreotide-LAR 40 mg IM q28d for 24 weeks in 44 severely obese adults (89% female, 39% minority). Oral glucose tolerance testing was performed before and after treatment, indices of beta-cell activity (CIRgp), insulin sensitivity (CISI), and clearance (CP/I AUC) were computed, and leptin levels, 3-day food records and carbohydrate-craving measurements were obtained. DEXA evaluations were performed pre- and post-therapy in an evaluable subgroup. RESULTS: For the entire cohort, significant insulin suppression was achieved with simultaneous improvements in insulin sensitivity, weight loss, and body mass index (BMI). Leptin, fat mass, total caloric intake, and carbohydrate craving significantly decreased. When grouped by BMI response, high responders (HR; DeltaBMI<-3 kg/m(2)) and low responders (LR; DeltaBMI between -3 and -0.5) exhibited higher suppression of CIRgp and IAUC than nonresponders (NR; DeltaBMI-0.5). CISI improved and significant declines in leptin and fat mass occurred only in HR and LR. Conversely, both leptin and fat mass increased in NR. Carbohydrate intake was markedly suppressed in HR only, while carbohydrate-craving scores decreased in HR and LR. For the entire cohort, DeltaBMI correlated with DeltaCISI, Deltafat mass, and Deltaleptin. DeltaFat mass also correlated with DeltaIAUC and DeltaCISI. CONCLUSIONS: In a subcohort of obese adults, suppression of insulin secretion was associated with loss of body weight and fat mass and with concomitant modulation of caloric intake and macronutrient preference.

Late cognitive and radiographic changes related to radiotherapy: initial prospective findings.

BACKGROUND: Assumptions about the damaging effects of radiotherapy (XRT) are based on studies in which total dose, dose fraction, treatment volume, degree of malignancy, chemotherapy, tumor recurrence, and neurologic comorbidity interact with XRT effects. This is a prospective, long-term study of XRT effects in adults, in which total dose and dose fraction were constrained and data related to tumor recurrence and neurologic comorbidity (e.g., hypertension) were excluded. METHODS: The effects of XRT on the cognitive and radiographic outcomes of 26 patients with low-grade, supratentorial, brain tumors yearly from baseline (6 weeks after surgery and immediately before XRT) and yearly to 6 years were examined. Radiographic findings were examined regionally. RESULTS: Selective cognitive declines (in visual memory) emerged only at 5 years, whereas ratings of clinical MRI (T2 images) showed mild accumulation of hyperintensities with post-treatment onset from 6 months to 3 years, with no further progression. White matter atrophy and total hyperintensities demonstrated this effect, with subcortical and deep white matter, corpus callosum, cerebellar structures, and pons accounting for these changes over time. About half of the patients demonstrated cognitive decline and treatment-related hyperintensities. CONCLUSIONS: There was no evidence of a general cognitive decline or progression of white matter changes after 3 years. Results argue for limited damage from XRT at this frequently used dose and volume in the absence of other clinical risk factors.

The neuroendocrinology of obesity.

The regulation of energy balance is enormously complex, with numerous genetic, hormonal, neural/behavioral, and societal influences. Although the current epidemic of obesity has its underpinnings in the changes in culture during the last half century, the role of the neuroendocrine system in the genesis of obesity is physiologically and therapeutically unavoidable. Increased understanding of this system has suggested organic etiologies (and therapies) for some rare and not-so-rare forms of obesity. With so many inputs, it is not implausible that dysfunction of other parts of this feedback system will be found to explain other forms of obesity in the future. Fortunately or unfortunately, diet and exercise remain the mainstays of obesity therapy. Most diet-exercise programs result in an acute 11-kg weight loss in adults; the question is whether it can be sustained without significant long-term behavior modification. In the European Sibutramine Trial of Obesity Reduction and Maintenance (STORM), 42% of treated patients dropped out; of those remaining, 77% of subjects lost more than 5% of initial body weight, but only 43% of these individuals maintained greater than 80% of this loss over 2 years. Could there be an organic component in persons who do not respond? Obesity pharmacotherapies sometimes have beneficial acute effects, but these effects are impermanent; discontinuation tends to result in a rebound weight gain, suggesting that the etiology of the obesity is still present. A useful guiding principle is that patients who do not respond to diet and exercise should undergo an initial medical evaluation, including assessments of birth weight, past medical history, weight history, family history, diet, exercise, and fasting insulin and thyroid levels. As the nosology of obesity improves, diagnostic efficiency and therapeutic success should increase, leading to a decrease in associated morbidity, mortality, and socioeconomic ramifications.

The neuroendocrinology of childhood obesity.

The regulation of energy balance is enormously complex, with numerous genetic, hormonal, neural and behavioral, and societal influences. Although the current epidemic of obesity clearly has its underpinnings in the changes in culture during the past half-century (see other articles in this issue), the role of the neuroendocrine system in the genesis of obesity, as described in this article, is physiologically and therapeutically unavoidable. An understanding of this system has suggested organic causes (and therapies) for some rare and not-so-rare forms of obesity. With so many inputs, it is not far-fetched to assume that dysfunction of other parts of this feedback system will be found to explain other forms of obesity in the future. What does this mean for obese children entering the pediatrician's office? Fortunately or unfortunately, diet and exercise are the mainstays of obesity therapy for children and adults. Most diet-exercise programs result in an acute 11-kg weight loss in adults; the question is whether it can be sustained without significant long-term behavioral modification. For instance, the European Sibutramine Trial of Obesity Reduction and Maintenance trial showed that 42% of treated subjects drop out; of those remaining, 77% of subjects lost more than 5% of initial body weight, but only 43% of those maintained more than 80% of this over 2 years. Could there be an organic component in those who do not respond? Of course, obesity pharmacotherapies sometimes have beneficial acute effects, but these drugs work for only as long as they are consumed; discontinuation tends to result in a "rebound" weight gain, suggesting that the cause of the obesity is still present. Furthermore, in 2001, there are no obesity drugs approved for children. A useful guiding principle is that children deserve at the minimum an initial medical evaluation, including birth weight, medical history, family history, dietary evaluation, and exercise assessment. Perhaps the most important feature that can distinguish "organic" from "behavioral" weight gain in childhood is the age of the "adiposity rebound." The Centers for Disease Control and Prevention now supplies BMI charts for boys and girls at www.cdc.gov/growthcharts. Plotting of the BMI versus age allows pediatricians to determine the age at which the BMI starts to increase (mean, 5.5 years). The earlier the adiposity rebound, the more likely the child will be obese as an adult, and the more likely that an organic cause can be determined. In such patients, thyroid levels and fasting insulin and leptin levels should be measured. An initial attempt at diet and exercise is essential; patients who do not respond with BMI stabilization should be investigated for a more ominous cause of their obesity. As the nosology of obesity improves, pediatricians will be able to increase the diagnostic efficiency and therapeutic success of this unfortunate, debilitating, and expensive epidemic.