Increased Intramuscular Adipose Tissue Is Related to Increased Capillarization in Older Adults.

BACKGROUND: High levels of intramuscular adipose tissue and low levels of capillarization are both predicative of low muscle and mobility function in older adults, however little is known about their relationship. OBJECTIVES: The purpose of this study was to examine the relationship of intramuscular adipose tissue and capillarization in older adults. SETTING: An outpatient medical center. PARTICIPANTS: Forty-seven sedentary adults (age 59.9 ± 1.0 years, BMI 32.0 ± 0.7 kg/m2, VO2max 22.4 ± 0.7 ml/kg/min); Measurements: All participants underwent CT scans to determine intramuscular adipose tissue and muscle biopsies to determine capillarization in the mid-thigh. A step-wise hierarchical linear regression analysis was used to examine the contributions of age, sex, race, body mass index, 2-hour postprandial glucose, VO2max, and muscle capillarization, to the variability in intramuscular adipose tissue. RESULTS: The predictors as a group accounted for 38.1% of the variance in intramuscular adipose tissue, with body mass index and capillarization each significantly contributing to the final model (P<0.001). The part correlation of body mass index with intramuscular adipose tissue was r = 0.47, and the part correlation of capillarization with intramuscular adipose tissue was r = 0.39, indicating that body mass index and capillarization explained 22.1%, and 15.2% of the variance in intramuscular adipose tissue. CONCLUSIONS: While increased muscle capillarization is typically thought of as a positive development, in some clinical conditions, such as tendinopathies, an increase in capillarization is part of the pathological process related to expansion of the extracellular matrix and fibrosis. This may also be an explanation for the surprising finding that high capillarization is related to high levels of intramuscular adipose tissue. Future studies are necessary to determine the relationship of changes in both capillarization and intramuscular adipose tissue after interventions, such as exercise.

Temporal Effects of Sleeve Gastrectomy on Glucose-Insulin Homeostasis and Incretin Hormone Response at 1 and 6 Months.

BACKGROUND: Bariatric surgery is an effective treatment for morbid obesity and glycaemic dysfunction. OBJECTIVES: The aim of the work was to examine both the static and dynamic changes of glucose-insulin homeostasis and incretin hormone response following sleeve gastrectomy (SG) in a sample of 55 participants preoperatively and 1 month and 6 months postoperatively. The focus was on a sample of patients with impaired glucose tolerance and type 2 diabetes (T2D). SETTING: Morriston Hospital, UK. METHODS: Prospective study comprising of 55 participants with impaired glucose homeostasis and T2D undergoing SG (mean body mass index [BMI] 50.4 kg/m2, mean glycated haemoglobin [A1C] 7.4%). Serial measurements of glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic hormone (GIP) were performed during oral glucose tolerance testing preoperatively and 1 and 6 months postoperatively. Areas under the curve (AUC) were examined at 30, 60, and 120 min. RESULTS: We observed significant improvements in measures of obesity, as well as static and dynamic measures of glucose, insulin, C-peptide and HOMA. Furthermore, significant increases in GLP-1 response as early as 6 months postoperatively were also seen. CONCLUSIONS: To our knowledge, no study has examined the detailed dynamic changes in glucose and insulin homeostasis in this number of participants undergoing SG in relation to incretin hormones GIP and GLP-1. This current study supports the role of SG for the treatment of obesity-related glucose dysregulation.

Acyl-ghrelin mediated lipid retention and inflammation in obesity-related Type 2 diabetes.

Acyl-ghrelin has various peripheral effects including the potential role in mediating cellular lipid removal and macrophage polarization. Previous reports are contradictory as to how glycaemia and acyl-ghrelin mediates lipid retention and inflammation within individuals with Type 2 diabetes (T2D). Our aim was to explore acyl-ghrelin levels and ghrelin expression in relation to lipid and inflammatory markers within an ex vivo human model, biopsied visceral adipose tissue. Results indicated that acyl-ghrelin was associated with a decline in key lipid homeostasis genes ABCG1 and LXRß expression. Within T2D there was also a down regulation of these genes which was independent of acyl-ghrelin levels. Circulatory pro-inflammatory markers (IL-6 and TNFα) had no association with ghrelin expression nor circulating acyl-ghrelin levels. Anti-inflammatory marker (IL-10) and total antioxidant status (TAOS%) were positively associated with ghrelin expression across samples from all groups combined (total sample cohort) and specifically within the obesity sample cohorts. Data supported the hypothesis that hyperglycaemia and acyl-ghrelin have a regulatory role in lipid retention. Furthermore, that both acyl- and desacyl-ghrelin is responsible for a protective inflammatory response; however this response is diminished in T2D.

Effect of rosuvastatin on risk markers for venous thromboembolism in cancer.

Essentials Statins lower venous thromboembolism risk in general but have not been studied in cancer patients. We completed a randomized trial of rosuvastatin vs. placebo among cancer patients on chemotherapy. Rosuvastatin did not significantly lower prothrombotic biomarkers including D-dimer. The role of statins in venous thrombosis prevention in cancer patients remains unknown. SUMMARY: Background Statin therapy is associated with lower risk of venous thromboembolism (VTE) but has not been prospectively evaluated in patients with advanced cancer. Objectives We determined if statin administration in this high-risk population reduces the risk of VTE, based on established and emerging biomarkers. Patients/Methods This double-blind, crossover, randomized controlled trial among patients with advanced cancer receiving systemic therapy allocated participants to rosuvastatin 20 mg daily or placebo for 3-4 weeks prior to crossover to the alternative therapy, with a 3-5-week washout. D-dimer, C-reactive protein (CRP), soluble (s)P-selectin, factor VIII (FVIII), thrombin generation and exploratory biomarkers focusing on endogenous thrombin potential, including tissue factor (TF), activated factor IX (FIXa) and activated factor XI (FXIa), were measured at the start and end of both treatment periods. The primary outcome was change in D-dimer with rosuvastatin compared with placebo. Results Of 38 enrolled participants, 24 (63%) completed the study. Rosuvastatin did not cause statistically significant changes in D-dimer levels or any other biomarker. CRP levels decreased by 40%; 4.3 mg L-1 (95% confidence interval, -11.0 to +2.5 mg L-1 ) compared with placebo. In post-hoc analysis, participants who received rosuvastatin initially during their first line of treatment had a 13% decrease in D-dimer. Circulating TF, FIXa and FXIa were detected in 26%, 68% and 71% of cancer patients despite not being found in healthy individuals. Conclusions Rosuvastatin did not cause favorable changes in biomarkers of VTE risk in advanced cancer patients receiving chemotherapy. The role of statin therapy as thromboprophylaxis in the cancer population remains uncertain.

Ghrelin function in human obesity and type 2 diabetes: a concise review.

The 28 amino acid hormone, ghrelin, has been found to have various effects on metabolism. This review will focus on the pathways integrated into ghrelin's effect within the hypothalamus, pancreas and adipocytes. The identification of molecules and pathways that regulate ghrelin-mediated lipid retention could establish new mechanisms underlying cellular energy homeostasis. The impact of acyl-ghrelin on glucose metabolism and lipid homeostasis may allow for novel preventative or early intervention therapeutic strategies to treat obesity related type 2 diabetes and associated metabolic dysfunction.

Continuous versus pulse neutron induced gamma spectroscopy for soil carbon analysis.

Neutron induced gamma spectra analysis (NGA) provides a means of measuring carbon in large soil volumes without destructive sampling. Calibration of the NGA system must account for system background and the interference of other nuclei on the carbon peak at 4.43 MeV. Accounting for these factors produced measurements in agreement with theoretical considerations. The continuous NGA mode was twice as fast and just as accurate as the pulse mode, thus this mode was preferable for routine soil carbon analysis.

Changes in markers of oxidative stress and DNA damage in human visceral adipose tissue from subjects with obesity and type 2 diabetes.

AIMS: In the past 30 years, prevalence of obesity has almost trebled resulting in an increased incidence of type 2 diabetes mellitus and other co-morbidities. Visceral adipose tissue is believed to play a vital role, but underlying mechanisms remain unclear. Our aim was to investigate changes in markers of oxidative damage in human visceral adipose tissue to determine levels of oxidative burden that may be attributed to obesity and/or diabetes. METHODS: Visceral adipose tissue samples from 61 subjects undergoing abdominal surgery grouped as lean, obese and obese with type 2 diabetes mellitus, were examined using 3 different markers of oxidative stress. Malondialdehyde (MDA) concentration was measured as a marker of lipid peroxidation, telomere length and Comet assay as markers of oxidative DNA damage. RESULTS: No significant difference in MDA concentration, telomere length and DNA damage was observed between groups, although longer telomere lengths were seen in the obese with diabetes group compared to the obese group (P<0.05). Lower MDA concentration and longer telomere length were seen in subjects with diabetes compared to those without (P<0.05). DNA damage, analysed via Comet assay, was significantly lower in subjects with diabetes compared to those without (P<0.05). CONCLUSION: A paradoxical decrease in oxidative stress and DNA damage was observed in samples from subjects with type 2 diabetes mellitus. Further work is required to investigate this further, however this phenomenon may be due to an up regulation of antioxidant defences in adipose tissue.

Association between the rs1050450 glutathione peroxidase-1 (C > T) gene variant and peripheral neuropathy in two independent samples of subjects with diabetes mellitus.

Glutathione peroxidase-1 (GPx-1) is an endogenous anti-oxidant enzyme. The T allele of the GPx-1 rs1050450 (C > T) gene variant is associated with reduced enzyme activity. Our aim was to examine the association between this gene variant and peripheral neuropathy in two cross-sectional samples of subjects with diabetes: (i) 773 Caucasian subjects were genotyped from the UCL Diabetes and Cardiovascular disease Study (UDACS) and (ii) 382 Caucasian subjects from the Ealing Diabetes Study (EDS). Peripheral neuropathy status (and oxidised-LDL [Ox-LDL:LDL] and plasma Total Ant-ioxidant Status [TAOS] in UDACS), were analysed in relation to genotype. We observed that: (i) In UDACS, the odds ratio (OR) for peripheral neuropathy in the T allele carriers compared to the CC genotype was 1.61 [1.10-2.28], p = 0.01. This remained significant after adjustment for other risk factors. Ox-LDL:LDL ratio was significantly elevated in T allele carriers (CC vs. CT/TT: 16.3 ± 2.4 v 18.0 ± 2.9 U/mmol LDL, p = 0.02). (ii) In EDS, the OR for peripheral neuropathy in the T allele carriers compared to the CC genotype was 1.95 [1.11-3.42], p = 0.02. This remained significant after adjustment for other risk factors. In conclusion, we observed a significant association between the T allele and peripheral neuropathy and LDL oxidation. This is the first paper to examine the rs1050450 variant in two samples of Caucasian subjects with diabetes. Prospective analysis of the gene variant is required in diabetic and healthy cohorts with measured plasma markers of oxidative stress to investigate the described association further.

Effects of short-term therapy with glibenclamide and repaglinide on incretin hormones and oxidative damage associated with postprandial hyperglycaemia in people with type 2 diabetes mellitus.

AIM: To examine the effects of glibenclamide and repaglinide on glucose stimulated insulin release, incretins, oxidative stress and cell adhesion molecules in patients with type 2 diabetes suboptimally treated with metformin. METHODS: A randomized clinical trial was performed recruiting 27 subjects (HbA(1c) between 7.5 and 10.5%) free from cardiovascular and renal disease. Glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), total antioxidant status, F(2)-isoprostane, interleukin-6 and cell adhesion molecules were measured during an oral glucose load at baseline and after eight weeks of treatment. The areas under the curve were analysed at 45, 60 and 120 min (AUC(45), AUC(60), AUC(120)). RESULTS: Significant improvements in glucose were observed with repaglinide (HBA(1c): -1.5%, fasting glucose: -2.8 mmol/L, 2-h glucose: -3.7 mmol/L, AUC(120): -18.9%) and glibenclamide (-1.0%, -2.2 mmol/L, -2.5 mmol/L, -17.5%). Repaglinide was also associated with an increase in the AUC(60) and AUC(120) for insulin (+56%, +61%) and C-peptide (+41%, +36%). GLP-1, GIP, IL-6, ICAM-1 and E-selectin levels did not change in either group. No association was observed between GLP-1, GIP-1 and plasma markers of oxidative stress. CONCLUSION: Repaglinide is associated with improved postprandial glycaemic control via insulin and C-peptide release. We observed no direct effects of glibenclamide or repaglinide on plasma levels of GLP-1 or GIP. We observed no associations of GLP-1 and GIP with plasma markers of oxidative stress.

Association between the rs4880 superoxide dismutase 2 (C>T) gene variant and coronary heart disease in diabetes mellitus.

Mitochondrial superoxide dismutase 2 (SOD2) is an endogenous anti-oxidant enzyme. The rs4880 gene variant results in a C>T substitution, influencing SOD enzymatic activity. This variant has been associated with micro- and macro-vascular complications in diabetes mellitus. Our aim was to examine the association between this variant and coronary heart disease (CHD) risk in a cross-sectional sample of subjects with diabetes. 776 Caucasian subjects with diabetes were genotyped. CHD risk, oxidised-LDL and plasma total anti-oxidant status (TAOS) were analysed in relation to genotype. In females, the TT genotype was associated with CHD (CC/CT/TT: No CHD vs. CHD: 22.4/56.0/21.6% vs. 12.0/50.0/38.0%, p=0.03; for CC/CT vs. TT, p=0.01). The odds ratio for CHD associated with the TT genotype compared to CC/CT was 2.22 [95%CI: 1.17-4.24], p=0.01. The TT genotype was also associated with significantly lower plasma TAOS. In males, no association was observed between genotype and CHD risk, but CHD was significantly associated with age, lower HDL, higher triglycerides, higher BMI and cigarette smoking. The TT genotype of this variant is associated with increased CHD risk and lower plasma anti-oxidant defences in females with diabetes. This modest genotype-effect is not apparent in males where traditional risk factors may play a greater role.

Elevated atmospheric carbon dioxide effects on soybean and sorghum gas exchange in conventional and no-tillage systems.

Increasing atmospheric CO(2) concentration has led to concerns about potential effects on production agriculture. In the fall of 1997, a study was initiated to compare the response of two crop management systems (conventional tillage and no-tillage) to elevated CO(2). The study used a split-plot design replicated three times with two management systems as main plots and two atmospheric CO(2) levels (ambient and twice ambient) as split plots using open-top chambers on a Decatur silt loam soil (clayey, kaolinitic, thermic Rhodic Paleudults). The conventional system was a grain sorghum [Sorghum bicolor (L.) Moench.] and soybean [Glycine max (L.) Merr.] rotation with winter fallow and spring tillage practices. In the no-tillage system, sorghum and soybean were rotated, and three cover crops were used [crimson clover (Trifolium incarnatum L.), sunn hemp (Crotalaria juncea L.), and wheat (Triticum aestivum L.)]. Over multiple growing seasons, the effect of management and CO(2) concentration on leaf-level gas exchange during row crop (soybean in 1999, 2001, and 2003; sorghum in 2000, 2002, and 2004) reproductive growth were evaluated. Treatment effects were fairly consistent across years. In general, higher photosynthetic rates were observed under CO(2) enrichment (more so with soybean) regardless of residue management practice. Elevated CO(2) led to decreases in stomatal conductance and transpiration, which resulted in increased water use efficiency. The effects of management system on gas exchange measurements were infrequently significant, as were interactions of CO(2) and management. These results suggest that better soil moisture conservation and high rates of photosynthesis can occur in both tillage systems in CO(2)-enriched environments during reproductive growth.

A study of mitochondrial DNA D-loop mutations and p53 status in nonmelanoma skin cancer.

BACKGROUND: Mitochondrial DNA (mtDNA) displacement-loop (D-loop) mutations have previously demonstrated potential as smoking-induced biomarkers in oral squamous cell carcinoma (SCC). Additionally, they have been observed in SCC and basal cell carcinoma of nonmelanoma skin cancer (NMSC). However, they have not been examined in the SCC precursor lesions, Bowen disease or actinic keratosis. OBJECTIVES: Here, we present a novel study of mtDNA D-loop mutations in these two precursors, a rare keratoacanthoma and NMSC (all tumours not related to smoking). METHODS: We used a polymerase chain reaction and direct sequencing approach. Furthermore, as the tumour suppressor protein p53 has been reported as having a novel role in maintaining mitochondrial genetic stability, we assessed p53 status using immunohistochemistry, evaluating potential association with the presence of mtDNA mutations. RESULTS: Of 36 tumours, nine (25%) exhibited mutations in the D-loop. In total, 13 base substitutions were observed across all patients: seven (53.8%) were A : T to G : C; two (15.4%) were G : C to T : A; two (15.4%) were G : C to A : T and two (15.4%) were G : C to C : G. Four of the 13 (30.8%) base substitutions were observed at nucleotide 146. We observed abnormal p53 accumulation in over half of the samples analysed (55.5%), suggesting it to be a major part of the carcinogenic process of NMSC; however; there was no association between p53 positivity and the presence of mtDNA mutations (P = 0.47). CONCLUSIONS: It is unlikely that alteration in p53 status is a contributing factor to mtDNA mutagenesis.

Use of a patient linked data warehouse to facilitate diabetes trial recruitment from primary care.

Recruitment into clinical trials from primary care may be difficult. Our aim was to use the Secure Anonymised Information Linkage (SAIL) databank to identify potential participants for two factitious trials. We identified 284 and 711 participants for each study (population=250,086). This method appears promising in identifying trial participants.

One hundred questions of importance to the conservation of global biological diversity.

We identified 100 scientific questions that, if answered, would have the greatest impact on conservation practice and policy. Representatives from 21 international organizations, regional sections and working groups of the Society for Conservation Biology, and 12 academics, from all continents except Antarctica, compiled 2291 questions of relevance to conservation of biological diversity worldwide. The questions were gathered from 761 individuals through workshops, email requests, and discussions. Voting by email to short-list questions, followed by a 2-day workshop, was used to derive the final list of 100 questions. Most of the final questions were derived through a process of modification and combination as the workshop progressed. The questions are divided into 12 sections: ecosystem functions and services, climate change, technological change, protected areas, ecosystem management and restoration, terrestrial ecosystems, marine ecosystems, freshwater ecosystems, species management, organizational systems and processes, societal context and change, and impacts of conservation interventions. We anticipate that these questions will help identify new directions for researchers and assist funders in directing funds.

Reduced expression of fukutin related protein in mice results in a model for fukutin related protein associated muscular dystrophies.

Mutations in fukutin related protein (FKRP) are responsible for a common group of muscular dystrophies ranging from adult onset limb girdle muscular dystrophies to severe congenital forms with associated structural brain involvement, including Muscle Eye Brain disease. A common feature of these disorders is the variable reduction in the glycosylation of skeletal muscle alpha-dystroglycan. In order to gain insight into the pathogenesis and clinical variability, we have generated two lines of mice, the first containing a missense mutation and a neomycin cassette, FKRP-Neo(Tyr307Asn) and the second containing the FKRP(Tyr307Asn) mutation alone. We have previously associated this missense mutation with a severe muscle-eye-brain phenotype in several families. Homozygote Fkrp-Neo(Tyr307Asn) mice die soon after birth and show a reduction in the laminin-binding epitope of alpha-dystroglycan in muscle, eye and brain, and have reduced levels of FKRP transcript. Homozygous Fkrp(Tyr307Asn) mice showed no discernible phenotype up to 6 months of age, contrary to the severe clinical course observed in patients with the same mutation. These results suggest the generation of a mouse model for FKRP related muscular dystrophy requires a knock-down rather than a knock-in strategy in order to give rise to a disease phenotype.

Free-air CO2 enrichment of sorghum: soil carbon and nitrogen dynamics.

The positive impact of elevated atmospheric CO(2) concentration on crop biomass production suggests more carbon inputs to soil. Further study on the effect of elevated CO(2) on soil carbon and nitrogen dynamics is key to understanding the potential for long-term carbon storage in soil. Soil samples (0- to 5-, 5- to 10-, and 10- to 20-cm depths) were collected after 2 yr of grain sorghum [Sorghum bicolor (L.) Moench.] production under two atmospheric CO(2) levels: (370 [ambient] and 550 muL L(-1) [free-air CO(2) enrichment; FACE]) and two water treatments (ample water and limited water) on a Trix clay loam (fine, loamy, mixed [calcareous], hyperthermic Typic Torrifluvents) at Maricopa, AZ. In addition to assessing treatment effects on soil organic C and total N, potential C and N mineralization and C turnover were determined in a 60-d laboratory incubation study. After 2 yr of FACE, soil C and N were significantly increased at all soil depths. Water regime had no effect on these measures. Increased total N in the soil was associated with reduced N mineralization under FACE. Results indicated that potential C turnover was reduced under water deficit conditions at the top soil depth. Carbon turnover was not affected under FACE, implying that the observed increase in soil C with elevated CO(2) may be stable relative to ambient CO(2) conditions. Results suggest that, over the short-term, a small increase in soil C storage could occur under elevated atmospheric CO(2) conditions in sorghum production systems with differing water regimes.

A randomised controlled trial of a double layer of Allevyn compared to Jellonet and proflavin as a tie-over dressing for small skin grafts.

INTRODUCTION: The tie-over dressing is used to encourage skin graft take by minimising dead space, reducing seroma and haematoma formation and by graft immobilisation. Various materials have been proposed, however we have compared one of the most popular, Jellonet with a bolster of proflavin-soaked cotton wool, to a newer dressing, Allevyn foam. PATIENTS AND METHODS: Sixty patients were recruited and randomised into either group. Any patient requiring surgery involving a split or full thickness graft due to be carried out in the outpatient department on any site was invited to participate. Outcome measures included percentage take, pain on dressing removal (visual analogue scale) and infection. Ethical approval was obtained from the North and Mid Essex Local Research Ethics Committee. RESULTS: There was no statistical difference in graft take between the two groups at day 5 (P=0.963). The Allevyn dressing was statistically more comfortable (P=0.0182). DISCUSSION: We propose that Allevyn foam provides an effective and comfortable method for securing small split and full thickness skin grafts. While offering equal levels of graft take, improved levels of comfort may lend itself to use in sensitive areas such as the nose, ear and around the eye.