Experimental Search for Neutron to Mirror Neutron Oscillations as an Explanation of the Neutron Lifetime Anomaly.

An unexplained >4σ discrepancy persists between "beam" and "bottle" measurements of the neutron lifetime. A new model proposed that conversions of neutrons n into mirror neutrons n^{'}, part of a dark mirror sector, can increase the apparent neutron lifetime by 1% via a small mass splitting Δm between n and n^{'} inside the 4.6 T magnetic field of the National Institute of Standards and Technology Beam Lifetime experiment. A search for neutron conversions in a 6.6 T magnetic field was performed at the Spallation Neutron Source which excludes this explanation for the neutron lifetime discrepancy.

Obesity is associated with activated and insulin resistant immune cells.

BACKGROUND: Obesity and type 2 diabetes mellitus are characterized by insulin resistance and 'low-grade inflammation'; however, the pathophysiological link is poorly understood. To determine the relative contribution of obesity and insulin resistance to systemic 'inflammation', this study comprehensively characterized circulating immune cells in different grades of obesity. METHODS: Immune cell phenotypes and activation status were analysed by flow cytometry cross-sectionally in morbidly obese (n = 16, body mass index (BMI) 42.2 ± 5.4 kg/m2), overweight (n = 13, BMI 27.4 ± 1.6 kg/m2) and normal weight (n = 12, BMI 22.5 ± 1.9 kg/m2) subjects. RESULTS: Obese, but not overweight subjects, had increased activation marker expression on neutrophils, monocytes, T-lymphocytes and polarization of T helper cells towards a pro-inflammatory type 1-phenotype (Th1). Th1 numbers correlated positively with the degree of insulin resistance (homeostasis model assessment, p < 0.05). Lymphocytes from obese subjects showed reduced insulin-stimulated AKT-phosphorylation in vitro. Supra-physiological insulin concentrations did not affect T-cell differentiation, which under normal circumstances would promote an anti-inflammatory T helper type 2-phenotype. CONCLUSIONS: These results show that morbid obesity is characterized by circulating immune cells that are activated and insulin resistant, with the T-cell balance polarized towards a pro-inflammatory Th1 phenotype. The loss of insulin-induced suppression of inflammatory phenotypes in circulating immune cells could contribute to the systemic and adipose tissue inflammation found in morbid obesity.

Hyperbaric oxygen therapy improves peripheral insulin sensitivity in humans.

AIM: Hyperbaric oxygen therapy is known to reduce fasting blood glucose in individuals with Type 2 diabetes. However, the mechanisms of this effect are not clear. The aim of this study was to determine whether peripheral insulin sensitivity by hyperinsulinaemic euglycaemic clamp is increased in patients presenting for hyperbaric oxygen therapy. METHODS: Participants were non-obese individuals without Type 2 diabetes (n=5) or obese patients with Type 2 diabetes (n=5). Patients were given 100% oxygen at 2.0 absolute atmospheres for 2 h, six sessions per week for 5 weeks. RESULTS: Peripheral insulin sensitivity was increased in the whole cohort (P=0.04). Subsequent analysis revealed that this was significant at both treatment 3 (+37.3 ± 12.7%, P=0.02) and treatment 30 (+40.6 ± 12.6%, P=0.009). HbA(1c) was significantly reduced in subjects without diabetes only (P<0.05). CONCLUSION: Insulin sensitivity increased within 3 days of hyperbaric oxygen treatment and this was maintained for 30 sessions. This increase in insulin sensitivity is equivalent to that observed following moderate weight loss. The mechanisms underlying the insulin-sensitizing effect of hyperbaric oxygen require further elucidation.

Transport model predictions of 225Ac production cross sections via energetic p, d and α irradiation of 232Th targets.

Monte Carlo transport codes PHITS and MCNP6 were used to calculate the production cross sections of 225,227Ac, 227,229Th, 223,225Ra, and 229,230,231Pa via the bombardment of a232Th target with energetic protons, deuterons, and α-particles. The incident projectile energies ranged between 10 and 800 MeV/nucleon. When possible, the predicted production cross sections were compared with the available experimental data and other predictions. The degree of the codes' abilities to match the measured data provides a qualitative assessment of the codes' abilities to predict data from similar, but unmeasured, projectile/target systems. In addition, a comparison between calculated cross sections and data may provide insight into possible improvements in the physics models employed by those transport codes.

Overexpression of the orphan receptor Nur77 alters glucose metabolism in rat muscle cells and rat muscle in vivo.

AIMS/HYPOTHESIS: A hallmark feature of the metabolic syndrome is abnormal glucose metabolism which can be improved by exercise. Recently the orphan nuclear receptor subfamily 4, group A, member 1 (NUR77) was found to be induced by exercise in muscle and was linked to transcriptional control of genes involved in lipid and glucose metabolism. Here we investigated if overexpression of Nur77 (also known as Nr4a1) in skeletal muscle has functional consequences for lipid and/or glucose metabolism. METHODS: L6 rat skeletal muscle myotubes were infected with a Nur77-coding adenovirus and lipid and glucose oxidation was measured. Nur77 was also overexpressed in skeletal muscle of chow- and fat-fed rats and the effects on glucose and lipid metabolism evaluated. RESULTS: Nur77 overexpression had no effect on lipid oxidation in L6 cells or rat muscle, but did increase glucose oxidation and glycogen synthesis in L6 cells. In chow- and high-fat-fed rats, Nur77 overexpression by electrotransfer significantly increased basal glucose uptake and glycogen synthesis, but no increase in insulin-stimulated glucose metabolism was observed. Nur77 electrotransfer was associated with increased production of GLUT4 and glycogenin and increased hexokinase and phosphofructokinase activity. Interestingly, Nur77 expression in muscle biopsies from obese men was significantly lower than in those from lean men and was closely correlated with body-fat content and insulin sensitivity. CONCLUSIONS/INTERPRETATION: Our data provide compelling evidence that NUR77 is a functional regulator of glucose metabolism in skeletal muscle in vivo. Importantly, the diminished content in muscle of obese insulin-resistant men suggests that it might be a potential therapeutic target for the treatment of dysregulated glucose metabolism.

A family history of type 2 diabetes increases risk factors associated with overfeeding.

AIMS/HYPOTHESIS: The purpose of the study was to test prospectively whether healthy individuals with a family history of type 2 diabetes are more susceptible to adverse metabolic effects during experimental overfeeding. METHODS: We studied the effects of 3 and 28 days of overfeeding by 5,200 kJ/day in 41 sedentary individuals with and without a family history of type 2 diabetes (FH+ and FH- respectively). Measures included body weight, fat distribution (computed tomography) and insulin sensitivity (hyperinsulinaemic-euglycaemic clamp). RESULTS: Body weight was increased compared with baseline at 3 and 28 days in both groups (p < 0.001), FH+ individuals having gained significantly more weight than FH- individuals at 28 days (3.4 +/- 1.6 vs 2.2 +/- 1.4 kg, p < 0.05). Fasting serum insulin and C-peptide were increased at 3 and 28 days compared with baseline in both groups, with greater increases in FH+ than in FH- for insulin at +3 and +28 days (p < 0.01) and C-peptide at +28 days (p < 0.05). Fasting glucose also increased at both time points, but without a significant group effect (p = 0.1). Peripheral insulin sensitivity decreased in the whole cohort at +28 days (54.8 +/- 17.7 to 50.3 +/- 15.6 micromol min(-1) [kg fat-free mass](-1), p = 0.03), and insulin sensitivity by HOMA-IR decreased at both time points (p < 0.001) and to a greater extent in FH+ than in FH- (p = 0.008). Liver fat, subcutaneous and visceral fat increased similarly in the two groups (p < 0.001). CONCLUSIONS: Overfeeding induced weight and fat gain, insulin resistance and hepatic fat deposition in healthy individuals. However, individuals with a family history of type 2 diabetes gained more weight and greater insulin resistance by HOMA-IR. The results of this study suggest that healthy individuals with a family history of type 2 diabetes are predisposed to adverse effects of overfeeding. TRIAL REGISTRATION: ClinicalTrials.gov NCT00562393 FUNDING: The study was funded by the National Health and Medical Research Council (NHMRC), Australia (no. #427639).

Abnormal postprandial PYY response in insulin sensitive nondiabetic subjects with a strong family history of type 2 diabetes.

OBJECTIVE: Gut-derived hormone peptide YY (PYY) is low in subjects with obesity and type 2 diabetes (T2D). However, it is unknown whether this is a primary defect or a consequence of metabolic disturbances. In this study, we aimed to assess whether low fasting and postprandial PYY secretion is an early defect, potentially promoting the development of obesity and T2D, and whether it is modified by macronutrient content. DESIGN: Prospective cross-sectional cohort study. SUBJECTS: Nine individuals with a strong family history of T2D (REL) and seven age and adiposity matched individuals with no family history of T2D (CON). INTERVENTIONS: Metabolic studies including hyperinsulinemic-euglycemic clamp, dual X-ray absorptiometry and two meal tests containing 1000 kcal with an either high fat (76%) or high carbohydrate (76%) content. MAIN OUTCOME MEASURES: Fasting and postprandial PYY levels were measured and analyzed for potential correlations with markers for adiposity and insulin resistance. RESULTS: Insulin sensitivity was not different between REL and CON. Fasting glucose, insulin, triglycerides and PYY were also not different between groups. However, the postprandial incremental area under curve (AUC) of PYY was significantly lower in REL after the high carbohydrate (HCHO) meal (+27.3 vs +60.6% increase from baseline, P=0.038). The AUC of insulin during HCHO meal correlated negatively with both AUC and fasting level of PYY (r=-0.58 and -0.60, respectively, P<0.05). CONCLUSIONS: A blunted postprandial PYY secretion is observed in a very early stage in the development of T2D in genetically susceptible individuals. This defect precedes the presence of insulin resistance and adiposity, and could therefore predispose to the development of T2D.

Decorin is a secreted protein associated with obesity and type 2 diabetes.

OBJECTIVE: To characterize the expression of the small leucine-rich glycoprotein decorin in adipose tissue. DESIGN: Real-time PCR was used to measure decorin gene expression in adipose tissue from normal glucose tolerant (NGT), impaired glucose tolerant and type 2 diabetic (T2D) Psammomys obesus. Adipose tissue was fractionated to determine which cells were responsible for decorin expression. The location of decorin protein expression in adipose tissue was determined using immunohistochemistry. Real-time PCR was used to measure decorin mRNA levels in human adipose tissue from 16 insulin-sensitive, 16 insulin-resistant and 6 T2D human subjects. Circulating plasma decorin concentrations were measured by enzyme-linked immunosorbent assay in 145 NGT and 141 T2D human individuals from a large-scale epidemiological study in Mauritius. RESULTS: Decorin mRNA was found to be highly expressed in adipose tissue, and decorin gene expression was significantly higher in visceral than that in subcutaneous adipose tissue depots in both P. obesus and human subjects (P=0.002 and P=0.001, respectively). Decorin mRNA was predominantly expressed by stromal/vascular cells of adipose tissue, and decorin protein in adipose tissue was primarily detected adjacent to blood vessels. Circulating plasma decorin levels in humans were elevated by 12% in T2D (P=0.049) compared to NGT subjects. There was a significant independent correlation between plasma decorin levels and waist-to-hip ratio (WHR, P=0.024). In male subjects, plasma decorin levels were significantly correlated with WHR (P=0.006), and fasting and 2-h glucose levels in an oral glucose tolerance test (P=0.027 and P=0.001, respectively). CONCLUSIONS: Decorin expression in adipose tissue was markedly upregulated in the obese state and may therefore play a role in adipose tissue homeostasis or in pathophysiology associated with obesity.

Psychosocial and behavioral pre-treatment predictors of weight loss outcomes.

OBJECTIVE: This study tested whether baseline behavioral and psychological variables predict weight and fat loss among overweight, non-obese individuals participating in a six-month calorie restriction trial. Participants (N=48) were randomly assigned to four groups, three of which included a calorie restriction program and one of which served as a healthy diet weight maintenance control. For the purposes of this study, data were analyzed only for participants assigned to the three calorie restriction groups (n=36). Ten psychological and behavioral measures were investigated through principal components factor analysis to examine whether these measures were assessing similar or distinct psychological and behavioral constructs. Based on the obtained six-factor solution, one measure from each domain was selected for inclusion in hierarchical regression analyses, which was used to test the relative importance of psychosocial and behavioral variables in predicting percent weight and fat loss over six months. After controlling for demographic and treatment variables, the behavioral and psychological measures of negative mood states, poor psychosocial functioning, and somatic symptoms were associated with less weight loss (R2=0.68, p<0.001) and fat loss (R2=0.65, p<0.001) over six months. Among overweight individuals, poor psychological adjustment, somatic symptoms, and negative mood states appear to form a psychosocial profile that is predictive of less weight and fat loss in calorie restriction programs.

The health outcomes of human offspring conceived by assisted reproductive technologies (ART).

Concerns have been raised about the health and development of children conceived by assisted reproductive technologies (ART) since 1978. Controversially, ART has been linked with adverse obstetric and perinatal outcomes, an increased risk of birth defects, cancers, and growth and development disorders. Emerging evidence suggests that ART treatment may also predispose individuals to an increased risk of chronic ageing related diseases such as obesity, type 2 diabetes and cardiovascular disease. This review will summarize the available evidence on the short-term and long-term health outcomes of ART singletons, as multiple pregnancies after multiple embryos transfer, are associated with low birth weight and preterm delivery, which can separately increase risk of adverse postnatal outcomes, and impact long-term health. We will also examine the potential factors that may contribute to these health risks, and discuss underlying mechanisms, including epigenetic changes that may occur during the preimplantation period and reprogram development in utero, and adult health, later in life. Lastly, this review will consider the future directions with the view to optimize the long-term health of ART children.

Serum S-adenosylmethionine, but not methionine, increases in response to overfeeding in humans.

BACKGROUND: Plasma concentration of the methyl donor S-adenosylmethionine (SAM) is linearly associated with body mass index (BMI) and fat mass. As SAM is a high-energy compound and a sensor of cellular nutrient status, we hypothesized that SAM would increase with overfeeding. METHODS: Forty normal to overweight men and women were overfed by 1250 kcal per day for 28 days. RESULTS: Serum SAM increased from 106 to 130 nmol/l (P=0.006). In stratified analysis, only those with weight gain above the median (high-weight gainers; average weight gain 3.9±0.3 kg) had increased SAM (+42%, P=0.001), whereas low-weight gainers (weight gain 1.5±0.2 kg) did not (Pinteraction=0.018). Overfeeding did not alter serum concentrations of the SAM precursor, methionine or the products, S-adenosyl-homocysteine and homocysteine. The SAM/SAH (S-adenosylhomocysteine) ratio was unchanged in the total population, but increased in high-weight gainers (+52%, P=0.006, Pinteraction =0.005). Change in SAM correlated positively with change in weight (r=0.33, P=0.041) and fat mass (r=0.44, P=0.009), but not with change in protein intake or plasma methionine, glucose, insulin or low-density lipoprotein (LDL)-cholesterol. CONCLUSION: Overfeeding raised serum SAM in proportion to the fat mass gained. The increase in SAM may help stabilize methionine levels, and denotes a responsiveness of SAM to nutrient state in humans. The role of SAM in human energy metabolism deserves further attention.

Large scale accelerator production of 225Ac: Effective cross sections for 78-192MeV protons incident on 232Th targets.

Actinium-225 and 213Bi have been used successfully in targeted alpha therapy (TAT) in preclinical and clinical research. This paper is a continuation of research activities aiming to expand the availability of 225Ac. The high-energy proton spallation reaction on natural thorium metal targets has been utilized to produce millicurie quantities of 225Ac. The results of sixteen irradiation experiments of thorium metal at beam energies between 78 and 192MeV are summarized in this work. Irradiations have been conducted at Brookhaven National Laboratory (BNL) and Los Alamos National Laboratory (LANL), while target dissolution and processing was carried out at Oak Ridge National Laboratory (ORNL). Excitation functions for actinium and thorium isotopes, as well as for some of the fission products, are presented. The cross sections for production of 225Ac range from 3.6 to 16.7mb in the incident proton energy range of 78-192MeV. Based on these data, production of curie quantities of 225Ac is possible by irradiating a 5.0gcm-2 232Th target for 10 days in either BNL or LANL proton irradiation facilities.

Energy restriction and weight loss on very-low-fat diets reduce C-reactive protein concentrations in obese, healthy women.

C-reactive protein (CRP) is an inflammatory-response protein that is a strong, independent predictor of cardiovascular mortality. CRP is positively associated with body mass index (BMI). In this study, we investigated the effects of dynamic weight loss on CRP in 83 healthy, obese women (mean BMI, 33.8+/-0.4 kg/m(2); range, 28.2 to 43.8 kg/m(2)). Subjects were placed on very-low-fat, energy-restricted diets (5700 kJ, 15% fat) for 12 weeks. Weight, waist and hip circumferences, plasma lipids, glucose, and CRP were measured at baseline and after 12 weeks. CRP was positively associated with BMI (r=0.281, P=0.01) and waist circumference (r=0.278, P=0.01) but was not related to other atherosclerosis risk factors. BMI was significantly different between groups split above or below the median for CRP (34.8+/-0.6 kg/m(2) vs 33.0+/-0.5 kg/m(2), P=0.02). After 12 weeks, weight loss was 7.9+/-0.3 kg. CRP was significantly decreased by 26% (P<0.001), and a correlation was observed between weight loss and the change in CRP (r=0.309, P=0.005). The variance in the change in CRP was partly explained by initial CRP (13.6%), energy intake (5.4%), and percentage weight loss (4.6%, P=0.001). This study confirms recent observations that BMI is associated with CRP, a marker for low-grade systemic inflammation. Furthermore, we observed that CRP was lowered in proportion to weight loss.

Fragmentation of 1 GeV/nucleon iron ions in thick targets relevant for space exploration.

We have measured charged nuclear fragments produced by 1 GeV/nucleon 56Fe ions interacting with aluminium, polyethylene and lead. These materials are relevant for assessment of radiation risk for manned space flight. The data will be presented in a form suitable for comparison with models of nuclear fragmentation and transport, including linear energy transfer (LET) spectrum, fluence for iron and fragments, event-tack- and event-dose-averaged LET, total dose and iron contribution to dose.

Validation of the HZETRN code for laboratory exposures with 1A GeV iron ions in several targets.

A new version of the HZETRN code capable of validation with HZE ions in either the laboratory or the space environment is under development. The computational model consists of the lowest order asymptotic approximation followed by a Neumann series expansion with non-perturbative corrections. The physical description includes energy loss with straggling, nuclear attenuation, nuclear fragmentation with energy dispersion and downshift. Measurements to test the model were performed at the Alternating Gradient Synchrotron and the NASA Space Radiation Laboratory at Brookhaven National Laboratory with iron ions. Surviving beam particles and produced fragments were measured with solid-state detectors. Beam analysis software has been written to relate the computational results to the measured energy loss spectra of the incident ions for rapid validation of modeled target transmission functions.

Shielding and fragmentation studies.

Radiation dosimetry for manned spaced missions depends on the ability to adequately describe the process of high-energy ion transport through many materials. Since the types of possible nuclear interactions are many and complex, transport models are used which depend upon a reliable source of experimental data. To expand the heavy ion database used in the models we have been measuring charge-changing cross sections and fragment production cross sections from heavy-ion interactions in various elementa targets. These include materials flown on space missions such as carbon and aluminium, as well as those important in radiation dosimetry such as hydrogen, nitrogen and water. Measuring heavy-ion fragmentation through these targets also gives us the ability to determine the effectiveness of new materials proposed for shielding such as graphite composites and polyethylene hybrids. Measurement without a target present gives an indication of the level of contamination of the primary beam, which is also important in radiobiology experiments.

Overview of secondary neutron production relevant to shielding in space.

An overview of experimental secondary neutron measurements relevant to space-related activities is presented. Stopping target yields and cross section measurements conducted at particle accelerators using heavy ions with energies > 100 MeV per nucleon are discussed.

Effect of energy restriction, weight loss, and diet composition on plasma lipids and glucose in patients with type 2 diabetes.

OBJECTIVE: To determine the optimal diet for improving glucose and lipid profiles in obese patients with type 2 diabetes during moderate energy restriction. RESEARCH DESIGN AND METHODS: A total of 35 free-living obese patients with type 2 diabetes were assigned to one of three 1,600 kcal/day diets for 12 weeks. The diets were high carbohydrate (10% fat, 4% saturated), high monounsaturated fat (MUFA) (32% fat, 7% saturated), or high saturated fat (SFA) (32% fat, 17% saturated). RESULTS: Diet composition did not affect the magnitude of weight loss, with subjects losing an average of 6.6 +/- 0.9 kg. Energy restriction and weight loss resulted in reductions in fasting plasma glucose (-14%), insulin (-27%), GHb (-14%), and systolic (-7%) and diastolic blood pressure (-10%) levels and the glucose response area (-17%) independent of diet composition. Diet composition did affect the lipoprotein profile. LDL was 10% and 17% lower with the high-carbohydrate and high-MUFA diets, respectively, whereas no change was observed with the high-SFA diet (P < 0.001 for effect of diet). HDL was transiently reduced on the high-carbohydrate diet at weeks 1, 4, and 8, whereas higher fat consumption maintained these levels. The total cholesterol:HDL ratio, although significantly reduced on the high-MUFA diet (P < 0.01), was not different from the other two diets after adjustment for baseline differences. CONCLUSIONS: Energy restriction, independent of diet composition, improves glycemic control; however, reducing SFA intake by replacing SFA with carbohydrate or MUFA reduces LDL maximally during weight loss and to a greater degree than has been shown in weight-stable studies.

Relationship between serum resistin concentrations and insulin resistance in nonobese, obese, and obese diabetic subjects.

Early reports suggested that resistin is associated with obesity and insulin resistance in rodents. However, subsequent studies have not supported these findings. To our knowledge, the present study is the first assessment in human subjects of serum resistin and insulin sensitivity by the insulin clamp technique. Thirty-eight nonobese subjects [age, 23 +/- 4 yr; body mass index (BMI), 25.4 +/- 4.3 kg/m(2)], 12 obese subjects (age, 54 +/- 8 yr; BMI, 33.0 +/- 2.5 kg/m(2)), and 22 obese subjects with type 2 diabetes (age, 59 +/- 7 yr; BMI, 34.0 +/- 2.4 kg/m(2)) were studied. Serum resistin concentrations were not different among nonobese (4.1 +/- 1.7 ng/ml), obese (4.2 +/- 1.6 ng/ml), and obese diabetic subjects (3.7 +/- 1.2 ng/ml), and were not significantly correlated to glucose disposal rate during a hyperinsulinemic glucose clamp across groups. Serum resistin was, however, inversely related to insulin sensitivity in nonobese subjects only (r = -0.35; P = 0.05), although this association was lost after adjusting for percent body fat. Serum resistin was not related to percent fat, BMI, or fat cell size. A strong correlation was observed between serum resistin and resistin mRNA expression from abdominal sc adipose tissue in a separate group of obese subjects (r = 0.62; P < 0.01; n = 56). Although the exact function of resistin is unknown, we demonstrated only a weak relationship between resistin and insulin sensitivity in nonobese subjects, indicating that resistin is unlikely to be a major link between obesity and insulin resistance in humans.

The insulin-sensitizing role of the fat derived hormone adiponectin.

Adiponectin is an insulin-sensitizing hormone whose blood concentration is reduced in obesity and type 2 diabetes. Administration of recombinant adiponectin in rodents increases glucose uptake and increases fat oxidation in muscle, reduces fatty acid uptake and hepatic glucose production in liver, and improves whole body insulin resistance. The exact receptor and signaling systems are unknown, however, recent studies suggest adiponectin activates AMPK, a putative master metabolic regulator. Thus, excitement surrounds the potential for adiponectin, or a homologue of adiponectin, as pharamacotherapy agents for patients suffering from the metabolic syndrome and more particularly for individuals with insulin resistance and type 2 diabetes.