Bed-rest and exercise remobilization: Concurrent adaptations in muscle glucose and protein metabolism.

BACKGROUND: Bed-rest (BR) of only a few days duration reduces muscle protein synthesis and induces skeletal muscle atrophy and insulin resistance, but the scale and juxtaposition of these events have not been investigated concurrently in the same individuals. Moreover, the impact of short-term exercise-supplemented remobilization (ESR) on muscle volume, protein turnover and leg glucose uptake (LGU) in humans is unknown. METHODS: Ten healthy males (24 ± 1 years, body mass index 22.7 ± 0.6 kg/m2) underwent 3 days of BR, followed immediately by 3 days of ESR consisting of 5 × 30 maximal voluntary single-leg isokinetic knee extensions at 90°/s each day. An isoenergetic diet was maintained throughout the study (30% fat, 15% protein and 55% carbohydrate). Resting LGU was calculated from arterialized-venous versus venous difference across the leg and leg blood flow during the steady-state of a 3-h hyperinsulinaemic-euglycaemic clamp (60 mU/m2/min) measured before BR, after BR and after remobilization. Glycogen content was measured in vastus lateralis muscle biopsy samples obtained before and after each clamp. Leg muscle volume (LMV) was measured using magnetic resonance imaging before BR, after BR and after remobilization. Cumulative myofibrillar protein fractional synthetic rate (FSR) and whole-body muscle protein breakdown (MPB) were measured over the course of BR and remobilization using deuterium oxide and 3-methylhistidine stable isotope tracers that were administered orally. RESULTS: Compared with before BR, there was a 45% decline in insulin-stimulated LGU (P < 0.05) after BR, which was paralleled by a reduction in insulin-stimulated leg blood flow (P < 0.01) and removal of insulin-stimulated muscle glycogen storage. These events were accompanied by a 43% reduction in myofibrillar protein FSR (P < 0.05) and a 2.5% decrease in LMV (P < 0.01) during BR, along with a 30% decline in whole-body MPB after 2 days of BR (P < 0.05). Myofibrillar protein FSR and LMV were restored by 3 days of ESR (P < 0.01 and P < 0.01, respectively) but not by ambulation alone. However, insulin-stimulated LGU and muscle glycogen storage were not restored by ESR. CONCLUSIONS: Three days of BR caused concurrent reductions in LMV, myofibrillar protein FSR, myofibrillar protein breakdown and insulin-stimulated LGU, leg blood flow and muscle glycogen storage in healthy, young volunteers. Resistance ESR restored LMV and myofibrillar protein FSR, but LGU and muscle glycogen storage remained depressed, highlighting divergences in muscle fuel and protein metabolism. Furthermore, ambulation alone did not restore LMV and myofibrillar protein FSR in the non-exercised contralateral limb, emphasizing the importance of exercise rehabilitation following even short-term BR.

A comparative, randomised MRI study of the physiological and appetitive responses to gelling (alginate) and non-gelling nasogastric tube feeds in healthy men.

Inclusion in nasogastric tube feeds (NGTF) of acid-sensitive, seaweed-derived alginate, expected to form a reversible gel in the stomach, may create a more normal intragastric state and modified gastrointestinal responses. This may ameliorate NGTF-associated risk of diarrhoea, upper gastrointestinal symptoms and appetite suppression. In a randomised, crossover, comparison study, undertaken in twelve healthy males, an alginate-containing feed (F + ALG) or one that was alginate-free (F-ALG) (300 ml) was given over 1 h with a 7-14-d washout period between treatments. Baseline and for 4-h post-feed initiation, MRI measurements were made to establish small bowel water content (SBWC), gastric contents volume (GCV) and appearance, and superior mesenteric artery blood flux. Blood glucose and gut peptides were measured. Subjective appetite and upper gastrointestinal symptoms scores were obtained. Ad libitum pasta consumption 3-h post-feeding was measured. F + ALG exhibited a gastric appearance consistent with gelling surrounded by a freely mobile water halo. Significant main effects of feed were seen for SBWC (P = 0·03) and peptide YY (PYY) (P = 0·004) which were attributed to generally higher values for SBWC with F + ALG (max difference between adjusted means 72 ml at 210 min) and generally lower values for PYY with F + ALG. GCV showed a faster reduction with F + ALG, less between-participant variation and a feed-by-time interaction (P = 0·04). Feed-by-time interactions were also seen with glucagon-like-peptide 1 (GLP-1) (P = 0·02) and glucose-dependent insulinotropic polypeptide (GIP) (P = 0·002), both showing a blunted response with F + ALG. Apparent intragastric gelling with F + ALG and subsequent differences in gastrointestinal and endocrine responses have been demonstrated between an alginate-containing and alginate-free feed.

Cocoa Flavanol Supplementation and the Effect on Insulin Resistance in Females Who Are Overweight or Obese: A Randomized, Placebo-Controlled Trial.

There is interest in the impact that dietary interventions can have on preventing the transition from insulin resistance to type 2 diabetes, including a suggestion that the bioactive components of cocoa may enhance fasting insulin sensitivity. However, a role for cocoa flavanols (CF) in reducing insulin resistance in the insulin-stimulated state, an important risk factor for cardiovascular disease, is unresolved. This study investigated whether CF consumption improved whole-body insulin-mediated glucose uptake ('M') in females with overweight/obesity, using a randomized, double-blinded, placebo-controlled, parallel-group design. Thirty-two premenopausal females (19-49 years; 27-35 kg·m-2) with elevated HOMA-IR (HOMA-IR >1.5) supplemented their habitual diet with two servings/day of a high-flavanol cocoa drink (HFC; 609 mg CF/serving; n = 16) or low-flavanol cocoa drink (LFC; 13 mg CF/serving; n = 16) for 4 weeks. Assessment of HOMA-IR and 'M' during a 3-h, 60 mIU insulin·m-2·min-1 euglycemic clamp was performed before and after the intervention. Data are the mean (SD). Changes to HOMA-IR (HFC -0.003 (0.57); LFC -0.0402 (0.86)) and 'M' (HFC 0.99 (7.62); LFC -1.32 (4.88) µmol·kg-1·min-1) after the intervention were not different between groups. Four weeks' consumption of ~1.2 g CF/day did not improve indices of fasting insulin sensitivity or insulin-mediated glucose uptake. A recommendation for dietary supplementation with cocoa flavanols to improve glycemic control is therefore not established.

Characterization of Hepatoma-Derived Growth Factor-Related Protein 2 Interactions with Heterochromatin.

The expression of genetic information is tightly controlled by chromatin regulatory proteins, including those in the heterochromatin gene repression family. Many of these regulatory proteins work together on the chromatin substrate to precisely regulate gene expression during mammalian development, giving rise to many different tissues in higher organisms from a fixed genomic template. Here we identify and characterize the interactions of two related heterochromatin regulatory proteins, heterochromatin protein 1 alpha (HP1α) and M-phase phosphoprotein 8 (MPP8), with hepatoma-derived growth factor-related protein 2 (HRP2). We find in biochemical experiments that HRP2 copurifies and co-sediments with heterochromatin-associated proteins, including HP1α and MPP8. Using the Chromatin in vivo Assay in multiple cell types, we demonstrate that HP1α-mediated gene repression dynamics are altered by the presence of HRP2. Furthermore, the knockout of HRP2 in MDA-MB-231 cells results in significant changes to chromatin structure and stability, which alter gene expression patterns. Here, we detail a mechanism by which HRP2 contributes to epigenetic transcriptional regulation through engagement with heterochromatin-associated proteins to stabilize the chromatin landscape and influence gene expression.

Human adaptation to immobilization: Novel insights of impacts on glucose disposal and fuel utilization.

BACKGROUND: Bed rest (BR) reduces whole-body insulin-stimulated glucose disposal (GD) and alters muscle fuel metabolism, but little is known about metabolic adaptation from acute to chronic BR nor the mechanisms involved, particularly when volunteers are maintained in energy balance. METHODS: Healthy males (n = 10, 24.0 ± 1.3 years), maintained in energy balance, underwent 3-day BR (acute BR). A second cohort matched for sex and body mass index (n = 20, 34.2 ± 1.8 years) underwent 56-day BR (chronic BR). A hyperinsulinaemic euglycaemic clamp (60 mU/m2 /min) was performed to determine rates of whole-body insulin-stimulated GD before and after BR (normalized to lean body mass). Indirect calorimetry was performed before and during steady state of each clamp to calculate rates of whole-body fuel oxidation. Muscle biopsies were taken to determine muscle glycogen, metabolite and intramyocellular lipid (IMCL) contents, and the expression of 191 mRNA targets before and after BR. Two-way repeated measures analysis of variance was used to detect differences in endpoint measures. RESULTS: Acute BR reduced insulin-mediated GD (Pre 11.5 ± 0.7 vs. Post 9.3 ± 0.6 mg/kg/min, P < 0.001), which was unchanged in magnitude following chronic BR (Pre 10.2 ± 0.4 vs. Post 7.9 ± 0.3 mg/kg/min, P < 0.05). This reduction in GD was paralleled by the elimination of the 35% increase in insulin-stimulated muscle glycogen storage following both acute and chronic BR. Acute BR had no impact on insulin-stimulated carbohydrate (CHO; Pre 3.69 ± 0.39 vs. Post 4.34 ± 0.22 mg/kg/min) and lipid (Pre 1.13 ± 0.14 vs. Post 0.59 ± 0.11 mg/kg/min) oxidation, but chronic BR reduced CHO oxidation (Pre 3.34 ± 0.18 vs. Post 2.72 ± 0.13 mg/kg/min, P < 0.05) and blunted the magnitude of insulin-mediated inhibition of lipid oxidation (Pre 0.60 ± 0.07 vs. Post 0.85 ± 0.06 mg/kg/min, P < 0.05). Neither acute nor chronic BR increased muscle IMCL content. Plentiful mRNA abundance changes were detected following acute BR, which waned following chronic BR and reflected changes in fuel oxidation and muscle glycogen storage at this time point. CONCLUSIONS: Acute BR suppressed insulin-stimulated GD and storage, but the extent of this suppression increased no further in chronic BR. However, insulin-mediated inhibition of fat oxidation after chronic BR was less than acute BR and was accompanied by blunted CHO oxidation. The juxtaposition of these responses shows that the regulation of GD and storage can be dissociated from substrate oxidation. Additionally, the shift in substrate oxidation after chronic BR was not explained by IMCL accumulation but reflected by muscle mRNA and pyruvate dehydrogenase kinase 4 protein abundance changes, pointing to lack of muscle contraction per se as the primary signal for muscle adaptation.

The PREVIEW intervention study: Results from a 3-year randomized 2 x 2 factorial multinational trial investigating the role of protein, glycaemic index and physical activity for prevention of type 2 diabetes.

AIM: To compare the impact of two long-term weight-maintenance diets, a high protein (HP) and low glycaemic index (GI) diet versus a moderate protein (MP) and moderate GI diet, combined with either high intensity (HI) or moderate intensity physical activity (PA), on the incidence of type 2 diabetes (T2D) after rapid weight loss. MATERIALS AND METHODS: A 3-year multicentre randomized trial in eight countries using a 2 x 2 diet-by-PA factorial design was conducted. Eight-week weight reduction was followed by a 3-year randomized weight-maintenance phase. In total, 2326 adults (age 25-70 years, body mass index ≥ 25 kg/m2 ) with prediabetes were enrolled. The primary endpoint was 3-year incidence of T2D analysed by diet treatment. Secondary outcomes included glucose, insulin, HbA1c and body weight. RESULTS: The total number of T2D cases was 62 and the cumulative incidence rate was 3.1%, with no significant differences between the two diets, PA or their combination. T2D incidence was similar across intervention centres, irrespective of attrition. Significantly fewer participants achieved normoglycaemia in the HP compared with the MP group (P < .0001). At 3 years, normoglycaemia was lowest in HP-HI (11.9%) compared with the other three groups (20.0%-21.0%, P < .05). There were no group differences in body weight change (-11% after 8-week weight reduction; -5% after 3-year weight maintenance) or in other secondary outcomes. CONCLUSIONS: Three-year incidence of T2D was much lower than predicted and did not differ between diets, PA or their combination. Maintaining the target intakes of protein and GI over 3 years was difficult, but the overall protocol combining weight loss, healthy eating and PA was successful in markedly reducing the risk of T2D. This is an important clinically relevant outcome.

Glycaemic, gastrointestinal, hormonal and appetitive responses to pearl millet or oats porridge breakfasts: a randomised, crossover trial in healthy humans.

Whole-grain cereal breakfast consumption has been associated with beneficial effects on glucose and insulin metabolism as well as satiety. Pearl millet is a popular ancient grain variety that can be grown in hot, dry regions. However, little is known about its health effects. The present study investigated the effect of a pearl millet porridge (PMP) compared with a well-known Scottish oats porridge (SOP) on glycaemic, gastrointestinal, hormonal and appetitive responses. In a randomised, two-way crossover trial, twenty-six healthy participants consumed two isoenergetic/isovolumetric PMP or SOP breakfast meals, served with a drink of water. Blood samples for glucose, insulin, glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide (GIP), peptide YY, gastric volumes and appetite ratings were collected 2 h postprandially, followed by an ad libitum meal and food intake records for the remainder of the day. The incremental AUC (iAUC2h) for blood glucose was not significantly different between the porridges (P > 0·05). The iAUC2h for gastric volume was larger for PMP compared with SOP (P = 0·045). The iAUC2h for GIP concentration was significantly lower for PMP compared with SOP (P = 0·001). Other hormones and appetite responses were similar between meals. In conclusion, the present study reports, for the first time, data on glycaemic and physiological responses to a pearl millet breakfast, showing that this ancient grain could represent a sustainable alternative with health-promoting characteristics comparable with oats. GIP is an incretin hormone linked to TAG absorption in adipose tissue; therefore, the lower GIP response for PMP may be an added health benefit.

Interaction of nutrition and genetics via DNMT3L-mediated DNA methylation determines cognitive decline.

Low homocysteine levels and B vitamin treatment are reported to protect against declining cognitive health. Both B vitamins and homocysteine are involved in the production of S-adenosylmethionine, a universal methyl donor essential for the process of DNA methylation. We investigated the effect of a damaging coding variant within the DNA methyltransferase gene DNMT3L (R278G, A/G) by examining B vitamin intake, homocysteine levels, cognitive performance, and brain atrophy in individuals in the VITACOG study of mild cognitive impairment and the TwinsUK cohort. In the VITACOG study, individuals who received a 2-year treatment of B vitamins and carried the G allele showed better "visuospatial associative memory" and slower rates of brain atrophy. In the TwinsUK study, improved "visuospatial associative memory" was evident in individuals who reported regular vitamin intake and were A/A homozygotes. In silico modeling indicated that R278G disrupts protein interaction between DNMT3L and DNMT3A, affecting the DNMT3A-3L-H3 complex required for DNA methylation. These findings show that vitamin intake and genetic variation within DNMT3L interact to influence cognitive decline.

Deferiprone: Pan-selective Histone Lysine Demethylase Inhibition Activity and Structure Activity Relationship Study.

Deferiprone (DFP) is a hydroxypyridinone-derived iron chelator currently in clinical use for iron chelation therapy. DFP has also been known to elicit antiproliferative activities, yet the mechanism of this effect has remained elusive. We herein report that DFP chelates the Fe2+ ion at the active sites of selected iron-dependent histone lysine demethylases (KDMs), resulting in pan inhibition of a subfamily of KDMs. Specifically, DFP inhibits the demethylase activities of six KDMs - 2A, 2B, 5C, 6A, 7A and 7B - with low micromolar IC50s while considerably less active or inactive against eleven KDMs - 1A, 3A, 3B, 4A-E, 5A, 5B and 6B. The KDM that is most sensitive to DFP, KDM6A, has an IC50 that is between 7- and 70-fold lower than the iron binding equivalence concentrations at which DFP inhibits ribonucleotide reductase (RNR) activities and/or reduces the labile intracellular zinc ion pool. In breast cancer cell lines, DFP potently inhibits the demethylation of H3K4me3 and H3K27me3, two chromatin posttranslational marks that are subject to removal by several KDM subfamilies which are inhibited by DFP in cell-free assay. These data strongly suggest that DFP derives its anti-proliferative activity largely from the inhibition of a sub-set of KDMs. The docked poses adopted by DFP at the KDM active sites enabled identification of new DFP-based KDM inhibitors which are more cytotoxic to cancer cell lines. We also found that a cohort of these agents inhibited HP1-mediated gene silencing and one lead compound potently inhibited breast tumor growth in murine xenograft models. Overall, this study identified a new chemical scaffold capable of inhibiting KDM enzymes, globally changing histone modification profiles, and with specific anti-tumor activities.

Postoperative inflammation and insulin resistance in relation to body composition, adiposity and carbohydrate treatment: A randomised controlled study.

BACKGROUND & AIMS: The aims of this study were to identify whether differences in distribution of adipose tissue and skeletal muscle in obese and non-obese individuals contribute to the magnitude of the postoperative inflammatory response and insulin resistance, with and without preoperative treatment with carbohydrate drinks. METHODS: Thirty-two adults (16 obese/16 non-obese) undergoing elective major open abdominal surgery participated in this 2 × 2 factorial, randomised, double-blind, placebo-controlled study. Participants received Nutricia preOp® or placebo (800 ml on the night before surgery/400 ml 2-3 h preoperatively) after stratifying for obesity. Insulin sensitivity was measured using the hyperinsulinaemic-euglycaemic clamp preoperatively and on the 1st postoperative day. Vastus lateralis, omental and subcutaneous fat biopsies were taken pre- and postoperatively and analysed after RNA extraction. The primary endpoint was within subject differences in insulin sensitivity. RESULTS: Major abdominal surgery was associated with a 42% reduction in insulin sensitivity from mean(SD) M value of 37.3(11.8) µmol kg-1 fat free mass (FFM) to 21.7(7.4) µmol kg-1 FFM, but this was not influenced by obesity or preoperative carbohydrate treatment. Activation of the triggering receptor expressed on myeloid cells (TREM1) pathway was seen in response to surgery in omental fat samples. In postoperative muscle samples, gene expression differences indicated activation of the peroxisome proliferator-activated receptor (PPAR-α)/retinoid X-receptor (RXR-α) pathway in obese but not in non-obese participants. There were no significant changes in gene expression pathways associated with carbohydrate treatment. CONCLUSION: The reduction in insulin sensitivity associated with major abdominal surgery was confirmed but there were no differences associated with preoperative carbohydrates or obesity.

A comparison of three methods to assess body composition.

OBJECTIVE: The aim of this study was to compare the accuracy of measurements of body composition made using dual x-ray absorptiometry (DXA), analysis of computed tomography (CT) scans at the L3 vertebral level, and bioelectrical impedance analysis (BIA). METHODS: DXA, CT, and BIA were performed in 47 patients recruited from two clinical trials investigating metabolic changes associated with major abdominal surgery or neoadjuvant chemotherapy for esophagogastric cancer. DXA was performed the week before surgery and before and after commencement of neoadjuvant chemotherapy. BIA was performed at the same time points and used with standard equations to calculate fat-free mass (FFM). Analysis of CT scans performed within 3 mo of the study was used to estimate FFM and fat mass (FM). RESULTS: There was good correlation between FM on DXA and CT (r2 = 0.6632; P < 0.0001) and FFM on DXA and CT (r2 = 0.7634; P < 0.0001), as well as FFM on DXA and BIA (r2 = 0.6275; P < 0.0001). Correlation between FFM on CT and BIA also was significant (r2 = 0.2742; P < 0.0001). On Bland-Altman analysis, average bias for FM on DXA and CT was 0.2564 with 95% limits of agreement (LOA) of -9.451 to 9.964. For FFM on DXA and CT, average bias was -0.1477, with LOA of -8.621 to 8.325. For FFM on DXA and BIA, average bias was -3.792, with LOA of -15.52 to 7.936. For FFM on CT and BIA, average bias was -2.661, with LOA of -22.71 to 17.39. CONCLUSION: Although a systematic error underestimating FFM was demonstrated with BIA, it may be a useful modality to quantify body composition in the clinical situation.

Report and Application of a Tool Compound Data Set.

Small molecule tool compounds have enabled profound advances in life science research. These chemicals are potent, cell active, and selective, and, thus, are suitable for interrogating biological processes. For these chemicals to be useful they must be correctly characterized and researchers must be aware of them. We mined the ChEMBL bioactivity database to identify high quality tool compounds in an unbiased way. We identified 407 best-in-class compounds for 278 protein targets, and these are reported in an annotated data set. Additionally, we developed informatics functions and a web application for data visualization and automated pharmacological hypothesis generation. These functions were used to predict inhibitors of the Chromobox Protein Homologue 5 (CBX5) mediated gene repression pathway that currently lacks appropriate inhibitors. The predictions were subsequently validated by a highly specific cell based assay, revealing new chemical modulators of CBX5-mediated heterochromatin formation. This data set and associated functions will help researchers make the best use of these valuable compounds.

Effects of short-term energy restriction on liver lipid content and inflammatory status in severely obese adults: Results of a randomized controlled trial using 2 dietary approaches.

Short-term very-low-energy diets (VLEDs) are used in clinical practice prior to bariatric surgery, but regimens vary and outcomes of a short intervention are unclear. We examined the effect of 2 VLEDs, a food-based diet (FD) and a meal-replacement plan (MRP; LighterLife UK Limited, Harlow, UK), over the course of 2 weeks in a randomized controlled trial. We collected clinical and anthropometric data, fasting blood samples, and dietary evaluation questionnaires. Surgeons took liver biopsies and made a visual assessment of the liver. We enrolled 60 participants of whom 54 completed the study (FD, n = 26; MRP, n = 28). Baseline demographic features, reported energy intake, dietary evaluation and liver histology were similar in the 2 groups. Both diets induced significant weight loss. Perceived difficulty of surgery correlated significantly with the degree of steatosis on histology. There were reductions in the circulating inflammatory mediators C-reactive protein, fetuin-A and interleukin-6 between baseline (pre-diet) and post-diet. The diets achieved similar weight loss and reduction in inflammatory biomarkers. There were no significant differences in perceived operative difficulty or between patients' evaluation of diet satisfaction, ease of use or hunger frequency. Non-alcoholic fatty liver disease histology assessments post-diet were also not significantly different between diets. The results of this study show the effectiveness of short-term VLEDs and energy restriction, irrespective of macronutrient composition, although the small sample size precluded detection of subtle differences between interventions.

Effect of weekly physical activity frequency on weight loss in healthy overweight and obese women attending a weight loss program: a randomized controlled trial.

BACKGROUND: The effect of intensity and duration of physical activity (PA) on weight loss has been well described. However, the effect of the frequency of weekly PA on weight loss is still unknown. OBJECTIVE: The purpose of this study was to evaluate the effect of the frequency of weekly PA sessions while maintaining the same total activity time on weight loss during a 24-wk weight loss program. DESIGN: Overweight and obese women [n = 75; body mass index (BMI; in kg/m2): 27-37; age: 18-40 y] who had a normally sedentary lifestyle were randomly allocated to 1 of 2 intervention groups: a high-frequency physical activity (HF) or a low-frequency physical activity (LF) group. The HF group included 50 min/d PA, 6 d/wk (300 min/wk). The LF group included 100 min/d PA, 3 d/wk (300 min/wk). Both groups were advised to follow the same dietary weight loss program. RESULTS: Both groups showed a significant decrease in anthropometric measurements and significant improvements in cardiometabolic disease risk characteristics over the 24 wk of the study. Compared with the HF group, the LF group had a greater decrease in weight (mean ± SD; LF: 9.58 ± 3.77 kg; HF: 7.78 ± 2.68 kg; P = 0.028), BMI (LF: 3.62 ± 1.56; HF: 2.97 ± 1.02; P = 0.029) and waist circumference (LF: 9.36 ± 4.02 cm; HF: 7.86 ± 2.41 cm; P = 0.031). However, there were no significant differences in carbohydrate metabolism characteristics or lipid profile after the 24 wk of intervention. CONCLUSION: Weekly PA undertaken over fewer sessions of longer duration during the week could be more effective for weight loss than when undertaken as more frequent shorter sessions in overweight and obese women on a weight loss program. This may be helpful for those who are neither willing nor able to schedule time for PA almost every day to achieve weight loss. This trial was registered at www.irct.ir as IRCT201402157754N4.

Effects of Bolus and Continuous Nasogastric Feeding on Gastric Emptying, Small Bowel Water Content, Superior Mesenteric Artery Blood Flow, and Plasma Hormone Concentrations in Healthy Adults: A Randomized Crossover Study.

OBJECTIVE: We aimed to demonstrate the effect of continuous or bolus nasogastric feeding on gastric emptying, small bowel water content, and splanchnic blood flow measured by magnetic resonance imaging (MRI) in the context of changes in plasma gastrointestinal hormone secretion. BACKGROUND: Nasogastric/nasoenteral tube feeding is often complicated by diarrhea but the contribution of feeding strategy to the etiology is unclear. METHODS: Twelve healthy adult male participants who underwent nasogastric intubation before a baseline MRI scan, received 400  mL of Resource Energy (Nestle) as a bolus over 5 minutes or continuously over 4  hours via pump in this randomized crossover study. Changes in gastric volume, small bowel water content, and superior mesenteric artery blood flow and velocity were measured over 4  hours using MRI and blood glucose and plasma concentrations of insulin, peptide YY, and ghrelin were assayed every 30 minutes. RESULTS: Bolus nasogastric feeding led to significant elevations in gastric volume (P < 0.0001), superior mesenteric artery blood flow (P < 0.0001), and velocity (P = 0.0011) compared with continuous feeding. Both types of feeding reduced small bowel water content, although there was an increase in small bowel water content with bolus feeding after 90 minutes (P < 0.0068). Similarly, both types of feeding led to a fall in plasma ghrelin concentration although this fall was greater with bolus feeding (P < 0.0001). Bolus feeding also led to an increase in concentrations of insulin (P = 0.0024) and peptide YY (P < 0.0001), not seen with continuous feeding. CONCLUSION: Continuous nasogastric feeding does not increase small bowel water content, thus fluid flux within the small bowel is not a major contributor to the etiology of tube feeding-related diarrhea.

The impact of sarcopenia and myosteatosis on outcomes of unresectable pancreatic cancer or distal cholangiocarcinoma.

BACKGROUND & AIMS: Patients with pancreatic cancer have a poor prognosis, are often cachectic, and frequently demonstrate features of systemic inflammation, which may contribute to the phenomenon of myosteatosis. Analysis of body composition from CT scans has been used to study sarcopenia and its association with prognosis in a number of types of cancer, particular in combination with obesity. It has also been suggested that myosteatosis, defined as attenuated mean skeletal muscle Hounsfield units (HU), is associated with reduced survival in cancer. This study aimed to assess the association between body composition (sarcopenia and myosteatosis) and outcome in patients with unresectable pancreatic cancer. METHODS: All patients diagnosed with unresectable pancreatic cancer at Nottingham University Hospitals NHS Trust between 2006 and 2013 were considered for the study. A total of 228 patients were included retrospectively. Body composition was assessed using cross-sectional CT analysis to calculate a skeletal muscle index (SMI) for sarcopenia and use mean skeletal muscle HU for myosteatosis. RESULTS: The prevalence of sarcopenia in the whole patient group at baseline was 60.5% (138/228). Overall, patients who were sarcopenic had no significant difference in overall survival versus those who were not (p = 0.779). However, patients who were overweight/obese and sarcopenic had a significantly lower survival (p = 0.013). Of the 58 patients who were overweight or obese and sarcopenic, 32 were also myosteatotic. The prevalence of myosteatosis overall at baseline was 55.3% (126/228) and this was associated with significant reduction in overall survival (p = 0.049). Univariate Cox regression revealed myosteatosis but not sarcopenia to be predictive of reduced survival, however this relationship was lost on multivariate testing. Myosteatosis was associated with significantly greater levels of systemic inflammation (white cell count, neutrophil-lymphocyte ratio and C-reactive protein), anaemia and worsening of baseline blood urea. This relationship was not seen with sarcopenia. CONCLUSIONS: This is the largest study on the association between body composition and survival in patients with unresectable pancreatic cancer and has shown that although sarcopenia alone did not have a bearing on survival, the presence of myosteatosis was associated significantly with the presence of systemic inflammation and reduced survival.

Epigenetic roots of immunologic disease and new methods for examining chromatin regulatory pathways.

The ability to accurately quantitate and experimentally examine epigenetic modifications across the human genome has exploded in the past decade. This has given rise to a wealth of new information concerning the contributions of epigenetic regulatory networks to the pathogenesis of human disease. In particular, immunological disorders have strong developmental roots in chromatin regulatory pathways. In this review, we focus on the epigenetic signatures and new discoveries revealing the epigenetic compositions of specific immunological cancers and autoimmune diseases. We also comment on the conserved epigenetic roots among diverse immunological disorders and suggest inhibition strategies that may be relevant for future treatment. Finally, we highlight emerging experimental tools with the capability to examine the mechanisms of chromatin regulatory enzymes with a high level of temporal control. The knowledge of genetic and epigenetic defects in immunological disease combined with new experimental approaches will elucidate the contribution of individual enzymes in complex epigenetic regulatory networks. This could lead to new diagnostic and therapeutic approaches for some very diverse and difficult to treat human diseases.

Sex differences in the composition of weight gain and loss in overweight and obese adults.

Sex differences in the ratio of fat mass (FM):fat-free mass (FFM) during weight change should differentially affect the extent of weight change during energy imbalance in men and women. In the present study, we determined FM and FFM contents by dual-energy X-ray absorptiometry and calculated the P-ratios (protein energy/total energy) of excess weight and weight loss during a randomised controlled trial of four commercial weight loss regimens. Overweight and obese women (n 210) and men (n 77) were studied at baseline and at 2 and 6 months during weight loss on four dietary regimens: Dr Atkins' New Diet Revolution; The Slim-Fast Plan; Weight-Watchers programme; Rosemary Conley's Diet and Fitness Plan. At baseline, the percentage of FFM (%FFM) and P-ratios of excess weight were 40 % and 0·071 for men and 27 % and 0·039 for women. At 2 months, men had lost twice as much weight as women and three times more FFM than women, indicating higher FFM content and P-ratios of weight loss for men, 0·052, than for women, 0·029, with no dietary effects. Between 2 and 6 months, the rate at which weight was lost decreased and the %FFM of weight loss decreased to similar low levels in men (7 %) and women (5 %): i.e. P-ratios of 0·009 and 0·006, respectively, with no dietary effects. Thus, for men compared with women, there were greater FFM content and P-ratios of weight change, which could partly, but not completely, explain their greater weight loss at 2 months. However, protein-conserving adaptations occur with increasing weight loss and over time, more extensively in men, eventually eliminating any sex difference in the composition of weight loss.

No difference between high-fructose and high-glucose diets on liver triacylglycerol or biochemistry in healthy overweight men.

BACKGROUND & AIMS: Diets high in fructose have been proposed to contribute to nonalcoholic fatty liver disease. We compared the effects of high-fructose and matched glucose intake on hepatic triacylglycerol (TAG) concentration and other liver parameters. DESIGN: In a double-blind study, we randomly assigned 32 healthy but centrally overweight men to groups that received either a high-fructose or high-glucose diet (25% energy). These diets were provided during an initial isocaloric period of 2 weeks, followed by a 6-week washout period, and then again during a hypercaloric 2-week period. The primary outcome measure was hepatic level of TAG, with additional assessments of TAG levels in serum and soleus muscle, hepatic levels of adenosine triphosphate, and systemic and hepatic insulin resistance. RESULTS: During the isocaloric period of the study, both groups had stable body weights and concentrations of TAG in liver, serum, and soleus muscle. The high-fructose diet produced an increase of 22 ± 52 µmol/L in the serum level of uric acid, whereas the high-glucose diet led to a reduction of 23 ± 25 µmol/L (P < .01). The high-fructose diet also produced an increase of 0.8 ± 0.9 in the homeostasis model assessment of insulin resistance, whereas the high-glucose diet produced an increase of only 0.1 ± 0.7 (P = .03). During the hypercaloric period, participants in the high-fructose and high-glucose groups had similar increases in weight (1.0 ± 1.4 vs 0.6 ± 1.0 kg; P = .29) and absolute concentration of TAG in liver (1.70% ± 2.6% vs 2.05% ± 2.9%; P = .73) and serum (0.36 ± 0.75 vs 0.33 ± 0.38 mmol/L; P = .91), and similar results in biochemical assays of liver function. Body weight changes were associated with changes in liver biochemistry and concentration of TAGs. CONCLUSIONS: In the isocaloric period, overweight men who were on a high-fructose or a high-glucose diet did not develop any significant changes in hepatic concentration of TAGs or serum levels of liver enzymes. However, in the hypercaloric period, both high-fructose and high-glucose diets produced significant increases in these parameters without any significant difference between the 2 groups. This indicates an energy-mediated, rather than a specific macronutrient-mediated, effect. Clinical trials.gov no: NCT01050140.