Changes to insulin sensitivity in glucose clearance systems and redox following dietary supplementation with a novel cysteine-rich protein: A pilot randomized controlled trial in humans with type-2 diabetes.

We recently developed a novel keratin-derived protein (KDP) rich in cysteine, glycine, and arginine, with the potential to alter tissue redox status and insulin sensitivity. The KDP was tested in 35 human adults with type-2 diabetes mellitus (T2DM) in a 14-wk randomised controlled pilot trial comprising three 2×20 g supplemental protein/day arms: KDP-whey (KDPWHE), whey (WHEY), non-protein isocaloric control (CON), with standardised exercise. Outcomes were measured morning fasted and following insulin-stimulation (80 mU/m2/min hyperinsulinaemic-isoglycaemic clamp). With KDPWHE supplementation there was good and very-good evidence for moderate-sized increases in insulin-stimulated glucose clearance rate (GCR; 26%; 90% confidence limits, CL 2%, 49%) and skeletal-muscle microvascular blood flow (46%; 16%, 83%), respectively, and good evidence for increased insulin-stimulated sarcoplasmic GLUT4 translocation (18%; 0%, 39%) vs CON. In contrast, WHEY did not effect GCR (-2%; -25%, 21%) and attenuated HbA1c lowering (14%; 5%, 24%) vs CON. KDPWHE effects on basal glutathione in erythrocytes and skeletal muscle were unclear, but in muscle there was very-good evidence for large increases in oxidised peroxiredoxin isoform 2 (oxiPRX2) (19%; 2.2%, 35%) and good evidence for lower GPx1 concentrations (-40%; -4.3%, -63%) vs CON; insulin stimulation, however, attenuated the basal oxiPRX2 response (4%; -16%, 24%), and increased GPx1 (39%; -5%, 101%) and SOD1 (26%; -3%, 60%) protein expression. Effects of KDPWHE on oxiPRX3 and NRF2 content, phosphorylation of capillary eNOS and insulin-signalling proteins upstream of GLUT4 translocation AktSer437 and AS160Thr642 were inconclusive, but there was good evidence for increased IRSSer312 (41%; 3%, 95%), insulin-stimulated NFκB-DNA binding (46%; 3.4%, 105%), and basal PAK-1Thr423/2Thr402 phosphorylation (143%; 66%, 257%) vs WHEY. Our findings provide good evidence to suggest that dietary supplementation with a novel edible keratin protein in humans with T2DM may increase glucose clearance and modify skeletal-muscle tissue redox and insulin sensitivity within systems involving peroxiredoxins, antioxidant expression, and glucose uptake.

A Clinical Program for Transgender and Gender-Diverse Neurodiverse/Autistic Adolescents Developed through Community-Based Participatory Design.

Objective: A series of studies report elevated rates of autism and autistic characteristics among gender-diverse youth seeking gender services. Although youth with the co-occurrence present with complex care needs, existing studies have focused on co-occurrence rates. Further, clinical commentaries have emphasized provider-centered interpretations of clinical needs rather than key stakeholder-driven clinical approaches. This study aimed to employ community-based participatory research methodologies to develop a key stakeholder-driven clinical group program.Method: Autistic/neurodiverse gender-diverse (A/ND-GD) youth (N = 31), parents of A/ND-GD youth (N = 46), A/ND-GD self-advocates (N = 10), and expert clinical providers (N = 10) participated in a multi-stage community-based participatory procedure. Needs assessment data were collected repeatedly over time from A/ND-GD youth and their parents as the youth interacted with one another through ongoing clinical groups, the curriculum of which was developed progressively through the iterative needs assessments.Results: Separate adolescent and parent needs assessments revealed key priorities for youth (e.g., the importance of connecting with other A/ND-GD youth and the benefit of experiencing a range of gender-diverse role models to make gender exploration and/or gender affirmation more concrete) and parents (e.g., the need for A/ND-related supports for their children as well as provision of an A/ND-friendly environment that fosters exploration of a range of gender expressions/options). Integration and translation of youth and parent priorities resulted in 11 novel clinical techniques for this population.Conclusions: With generally high acceptability ratings for each component of the group program, this study presents a community-driven clinical model to support broad care needs and preferences of A/ND-GD adolescents.

Heterogeneous mass distribution of the rubble-pile asteroid (101955) Bennu.

The gravity field of a small body provides insight into its internal mass distribution. We used two approaches to measure the gravity field of the rubble-pile asteroid (101955) Bennu: (i) tracking and modeling the spacecraft in orbit about the asteroid and (ii) tracking and modeling pebble-sized particles naturally ejected from Bennu's surface into sustained orbits. These approaches yield statistically consistent results up to degree and order 3, with the particle-based field being statistically significant up to degree and order 9. Comparisons with a constant-density shape model show that Bennu has a heterogeneous mass distribution. These deviations can be modeled with lower densities at Bennu's equatorial bulge and center. The lower-density equator is consistent with recent migration and redistribution of material. The lower-density center is consistent with a past period of rapid rotation, either from a previous Yarkovsky-O'Keefe-Radzievskii-Paddack cycle or arising during Bennu's accretion following the disruption of its parent body.

The dynamic geophysical environment of (101955) Bennu based on OSIRIS-REx measurements.

The top-shape morphology of asteroid (101955) Bennu is commonly found among fast-spinning asteroids and binary asteroid primaries, and might have contributed significantly to binary asteroid formation. Yet a detailed geophysical analysis of this morphology for a fast-spinning asteroid has not been possible prior to the Origins, Spectral Interpretation, Resource Identification, and Security-Regolith Explorer (OSIRIS-REx) mission. Combining the measured Bennu mass and shape obtained during the Preliminary Survey phase of OSIRIS-REx, we find a significant transition in Bennu's surface slopes within its rotational Roche lobe, defined as the region where material is energetically trapped to the surface. As the intersection of the rotational Roche lobe with Bennu's surface has been most recently migrating towards its equator (given Bennu's increasing spin rate), we infer that Bennu's surface slopes have been changing across its surface within the last million years. We also find evidence for substantial density heterogeneity within this body, suggesting that its interior has a distribution of voids and boulders. The presence of such heterogeneity and Bennu's top-shape is consistent with spin-induced failure at some point in its past, although the manner of its failure cannot be determined yet. Future measurements by the OSIRIS-REx spacecraft will give additional insights and may resolve questions regarding the formation and evolution of Bennu's top-shape morphology and its link to the formation of binary asteroids.

Dynamical nonlocal coherent-potential approximation for itinerant electron magnetism.

A dynamical generalisation of the nonlocal coherent-potential approximation is derived based upon the functional integral approach to the interacting electron problem. The free energy is proven to be variational with respect to the self-energy provided a self-consistency condition on a cluster of sites is satisfied. In the present work, calculations are performed within the static approximation and the effect of the nonlocal physics on the formation of the local moment state in a simple model is investigated. The results reveal the importance of the dynamical correlations.

Inclusion of intersite spatial correlations in the alloy analogy approach to the half-filled ionic Hubbard model.

Using the nonlocal coherent-potential approximation we study the effect of intersite spatial correlations on the transition from band insulator to metal as well as from metal to Mott insulator in the 'alloy analogy' approach to the paramagnetic solution of the half-filled ionic Hubbard model. We find that intersite spatial correlations enhance the metallic phase.

Reducing co-administration of clopidogrel and proton pump inhibitors in acute coronary syndromes.

BACKGROUND: Recent concerns about clopidogrel and proton pump inhibitor (PPI) co-administration in patients following an acute coronary syndrome (ACS) led us to investigate our practice. Guidance recommends that omeprazole and esomeprazole should not be co-administered with clopidogrel as they can decrease its efficacy. Pantoprazole and lansoprazole are safer for use in these cases. METHODS: Patients discharged between August 2008 and July 2009 with a diagnosis of ACS, on both clopidogrel and any PPI, were identified using the pharmacy database. Their notes were retrospectively reviewed, the indication for a PPI was checked and whether an appropriate one had been prescribed was assessed. As a result of our findings a simple algorithm was introduced to set out guidance on appropriate use and junior doctors were informed of the new procedure. We then performed another audit of patients discharged between August 2009 and February 2010 to ensure that the guidelines were being followed. RESULTS: During the first phase of the audit 43 out of 91 patients (47.5%) received a PPI with clopidogrel. Following our intervention, re-auditing confirmed that clopidogrel and PPI co-administration had decreased significantly to 27 out of 101 patients (26.7%) (p = 0.018). CONCLUSIONS: Through a simple intervention with an algorithm and education of junior doctors we have shown that significant improvement and adherence to guidance can be achieved.

Automated ECG diagnostic P-wave analysis using wavelets.

P-wave characteristics in the human ECG are an important source of information in the diagnosis of atrial conduction pathology. However, diagnosis by visual inspection is a difficult task since the P-wave is relatively small and noise masking is often present. This paper introduces novel wavelet characteristics derived from the continuous wavelet transform (CWT) which are shown to be potentially effective discriminators in an automated diagnostic process. Characteristics of the 12-lead ECG P-wave were derived using CWT and statistical methods. A normal control group and an abnormal (atrial conduction pathology) group were compared. The wavelet characteristics captured frequency, magnitude and variance components of the P-wave. The best individual characteristics (i.e. ones that significantly discriminated the groups) were entered into a linear discriminant analysis (LDA) for four different models: two-lead ECG, three-lead ECG, a derived three-lead ECG and a factor analysis solution consisting of wavelet characteristic loadings on the factors. A comparison was also made between wavelet characteristics derived form individual P-waves verses wavelet characteristics derived from a signal-averaged P-wave for each participant. These wavelet models were also compared to standard cardiological measures of duration, terminal force and duration divided by the PR segment. Results for the individual P-wave approach generally outperformed the standard cardiological measures and the signal-averaged P-wave approach. The best wavelet model on the basis of both classification performance and simplicity was the two-lead model that uses leads II and V1. It was concluded that the wavelet approach of automating classification is worth pursuing with larger samples to validate and extend the present study.

Vibration therapy reduces plasma IL6 and muscle soreness after downhill running.

OBJECTIVE: In this study, the effects of vibration therapy (VT) on delayed-onset muscle soreness (DOMS) and associated inflammatory markers after downhill running were determined. METHODS: 29 male recreational runners (33 (8) years; V(O2)peak 57 (6) ml kg(-1) min(-1)) completed a 40-min downhill run and were randomly allocated to a VT group or Control group. For 5 days post-run, the VT group underwent once-daily sessions of VT on the upper and lower legs. DOMS was assessed pre-run and for 5 days post-run by visual analogue scale. Immune cell subsets and plasma inflammatory markers were assessed pre-run, post-run, 24 and 120 h post-run by full differential cell count, and by ELISA and enzyme immunoassay, respectively. Data were analysed as per cent change from pre-run (ANOVA) and the magnitude of the treatment effect (Cohen's effect size statistics). RESULTS: VT significantly reduced calf pain 96 h post-run (-50% (40%), 90% confidence limits) and gluteal pain 96 h (-50% (40%)) and 120 h post-run (-30% (30%)); decreased interleukin 6 (IL6) 24 h (-46% (31%)) and 120 h post-run (-65% (30%)); substantially decreased histamine 24 h (-40% (50%)) and 120 h post-run (-37% (48%)); substantially increased neutrophils (8.6% (8.1%)) and significantly decreased lymphocytes (-17% (12%)) 24 h post-run. There were no clear substantial effects of VT on other leukocyte subsets and inflammatory markers. CONCLUSION: VT reduces muscle soreness and IL6. It may stimulate lymphocyte and neutrophil responses and may be a useful modality in treating muscle inflammation.

Pancreatic islet beta-cell deficit and glucose intolerance in rats with uninephrectomy.

This study was performed to examine the effect of chronic renal impairment and renin-angiotensin system (RAS) activation induced by unilateral nephrectomy (UNX) on the development of pancreatic islet beta-cell deficit and glucose intolerance. Sprague-Dawley rats were randomized into three groups: untreated UNX (n=10), UNX treated with the angiotensin-converting enzyme inhibitor lisinopril (n=8) and sham operation (n=10). Blood glucose, serum insulin, renal function and histological changes of kidney and pancreas were examined 8 months postoperation. Compared with the sham rats, UNX rats developed renal impairment, insulin deficiency and glucose intolerance. Histological staining revealed an islet beta-cell deficit associated with increased immunoreactivity for angiotensin and angiotensin type 1 receptor in UNX rats. Treatment with lisinopril significantly improved renal dysfunction, hyperglycemia, insulin secretion and islet RAS expression. These data suggest that chronic renal impairment and RAS activation may contribute to islet beta-cell loss and glucose intolerance. RAS blockade may therefore prevent these disorders.

Recent Greenland ice mass loss by drainage system from satellite gravity observations.

Mass changes of the Greenland Ice Sheet resolved by drainage system regions were derived from a local mass concentration analysis of NASA-Deutsches Zentrum für Luftund Raumfahrt Gravity Recovery and Climate Experiment (GRACE mission) observations. From 2003 to 2005, the ice sheet lost 101 +/- 16 gigaton/year, with a gain of 54 gigaton/year above 2000 meters and a loss of 155 gigaton/year at lower elevations. The lower elevations show a large seasonal cycle, with mass losses during summer melting followed by gains from fall through spring. The overall rate of loss reflects a considerable change in trend (-113 +/- 17 gigaton/year) from a near balance during the 1990s but is smaller than some other recent estimates.

Short-term suppression of plasma free fatty acids fails to improve insulin sensitivity when intramyocellular lipid is elevated.

AIMS: Metabolic responses to manipulation of the plasma free fatty acid (FFA) concentration were assessed in six healthy men via cross-over design to determine whether FFAs independently influence insulin sensitivity. METHODS: Intramyocellular lipid (IMCL) was measured by proton magnetic resonance spectroscopy and insulin sensitivity via frequently sampled intravenous glucose tolerance test (IVGTT) after 67 h of two identical low carbohydrate/high fat (LC) diets which were used to elevate IMCL and plasma FFAs. To uncouple the influence of FFAs and IMCL on insulin sensitivity, FFAs were suppressed 30 min prior to and during IVGTT in one treatment [LC + nicotinic acid (NA)] by NA ingestion. RESULTS: Vastus lateralis IMCL was significantly elevated in LC (13.3 +/- 1.1 x 10(-3)) and LC + NA (13.5 +/- 1.1 x 10(-3)) (P < 0.01 for both), but was not different between conditions (P > 0.05). Plasma FFAs were raised in LC (0.79 +/- 0.08 mmol/l) and LC + NA (0.80 +/- 0.11 mmol/l) (P < 0.01 for both) and were significantly reduced by NA ingestion prior to (0.36 +/- 0.05 mmol/l, P < 0.01) and during IVGTT (P < 0.05) in LC + NA. Despite marked differences in plasma FFA availability, insulin sensitivity and glucose tolerance were not different between LC and LC + NA (P > 0.05 for both). CONCLUSIONS: Plasma FFAs appear to exert no immediate effect on insulin sensitivity/glucose tolerance independent of their action on intracellular lipid moieties. Further research is required to elucidate the duration of FFA suppression required to restore insulin sensitivity following lipid-induced insulin resistance.

Leg heating and cooling influences running stride parameters but not running economy.

To evaluate the effect of temperature on running economy (RE) and stride parameters in 10 trained male runners (VO2peak 60.8 +/- 6.8 ml . kg (-1) . min (-1)), we used water immersion as a passive temperature manipulation to contrast localised pre-heating, pre-cooling, and thermoneutral interventions prior to running. Runners completed three 10-min treadmill runs at 70 % VO2peak following 40 min of randomised leg immersion in water at 21.0 degrees C (cold), 34.6 degrees C (thermoneutral), or 41.8 degrees C (hot). Treadmill runs were separated by 7 days. External respiratory gas exchange was measured for 30 s before and throughout the exercise and stride parameters were determined from video analysis in the sagittal plane. RE was not affected by prior heating or cooling with no difference in oxygen cost or energy expenditure between the temperature interventions (average VO2 3rd-10th min of exercise: C, 41.6 +/- 3.4 ml . kg (-1) . min (-1); TN, 41.6 +/- 3.0; H, 41.8 +/- 3.5; p = 0.94). Exercise heart rate was affected by temperature (H > TN > C; p < 0.001). During minutes 3 - 5 of running the respiratory-exchange and minute ventilation/oxygen consumption ratios were greater in cold compared with thermoneutral (p < 0.05). Averaged over the full 10 min of exercise, stride length was shorter and stride frequency higher for the C trial compared to TN and H (p < 0.01). Leg temperature manipulation did not influence running economy despite changes in stride parameters that might indicate restricted muscle-tendon elasticity after pre-cooling. Larger changes in stride mechanics than those produced by the current temperature intervention are required to influence running economy.

The structure of foot-and-mouth disease virus.

Structural studies of foot-and-mouth disease virus (FMDV) have largely focused on the mature viral particle, providing atomic resolution images of the spherical protein capsid for a number of sero- and sub-types, structures of the highly immunogenic surface loop, Fab and GAG receptor complexes. Additionally, structures are available for a few non-structural proteins. The chapter reviews our current structural knowledge and its impact on our understanding of the virus life cycle proceeding from the mature virus through immune evasion/inactivation, cell-receptor binding and replication and alludes to future structural targets.

A multi-centre randomised controlled trial of minimally invasive direct coronary bypass grafting versus percutaneous transluminal coronary angioplasty with stenting for proximal stenosis of the left anterior descending coronary artery.

OBJECTIVES: To compare the clinical- and cost-effectiveness of minimally invasive direct coronary artery bypass grafting (MIDCAB) and percutaneous transluminal coronary angioplasty (PTCA) with or without stenting in patients with single-vessel disease of the left anterior descending coronary artery (LAD). DESIGN: Multi-centre randomised trial without blinding. The computer-generated sequence of randomised assignments was stratified by centre, allocated participants in blocks and was concealed using a centralised telephone facility. SETTING: Four tertiary cardiothoracic surgery centres in England. PARTICIPANTS: Patients with ischaemic heart disease with at least 50% proximal stenosis of the LAD, suitable for either PTCA or MIDCAB, and with no significant disease in another vessel. INTERVENTIONS: Patients randomised to PTCA had local anaesthetic and underwent PTCA according to the method preferred by the operator carrying out the procedure. Patients randomised to MIDCAB had general anaesthetic. The chest was opened through an 8-10-cm left anterior thoracotomy. The ribs were retracted and the left internal thoracic artery (LITA) harvested. The pericardium was opened in the line of the LAD to confirm the feasibility of operation. The distal LITA was anastomosed end-to-side to an arteriotomy in the LAD. All operators were experienced in carrying out MIDCAB. MAIN OUTCOME MEASURES: The primary outcome measure was survival free from cardiac-related events. Relevant events were death, myocardial infarction, repeat coronary revascularisation and recurrence of symptomatic angina or clinical signs of ischaemia during an exercise tolerance test at annual follow-up. Secondary outcome measures were complications, functional outcome, disease-specific and generic quality of life, health and social services resource use and their costs. RESULTS: A total of 12,828 consecutive patients undergoing an angiogram were logged at participating centres from November 1999 to December 2001. Of the 1091 patients with proximal stenosis of the LAD, 127 were eligible and consented to take part; 100 were randomised and the remaining 27 consented to follow-up. All randomised participants were included in an intention-to-treat analysis of survival free from cardiac-related events, which found a non-significant benefit from MIDCAB. Cumulative hazard rates at 12 months were estimated to be 7.1 and 9.2% for MIDCAB and PTCA, respectively. There were no important differences between MIDCAB and PTCA with respect to angina symptoms or disease-specific or generic quality of life. The total NHS procedure costs were 1648 British pounds and 946 British pounds for MIDCAB and PTCA, respectively. The costs of resources used during 1 year of follow-up were 1033 British pounds and 843 British pounds, respectively. CONCLUSIONS: The study found no evidence that MIDCAB was more effective than PTCA. The procedure costs of MIDCAB were observed to be considerably higher than those of PTCA. Given these findings, it is unlikely that MIDCAB represents a cost-effective use of resources in the reference population. Recent advances in cardiac surgery mean that surgeons now tend to carry out off-pump bypass grafting via a sternotomy instead of MIDCAB. At the same time, cardiologists are treating more patients with multi-vessel disease by PTCA. Future primary research should focus on this comparison. Other small trials of PTCA versus MIDCAB have now finished and a more conclusive answer to the original objective could be provided by a systematic review.

Internet based ECG medical information system.

Physiological monitoring of humans for medical applications is well established and ready to be adapted to the Internet. This paper describes the implementation of a Medical Information System (MIS-ECG system) incorporating an Internet based ECG acquisition device. Traditionally clinical monitoring of ECG is largely a labour intensive process with data being typically stored on paper. Until recently, ECG monitoring applications have also been constrained somewhat by the size of the equipment required. Today's technology enables large and fixed hospital monitoring systems to be replaced by small portable devices. With an increasing emphasis on health management a truly integrated information system for the acquisition, analysis, patient particulars and archiving is now a realistic possibility. This paper describes recent Internet and technological advances and presents the design and testing of the MIS-ECG system that utilises those advances.

Distribution and regulation of ENaC subunit and CFTR mRNA expression in murine female reproductive tract.

The present study investigated the regional distribution and cyclic changes in the mRNA expression of epithelial Na+ channel (ENaC) subunit and cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated Cl- channel, in adult female mouse reproductive tract. In situ hybridization revealed that in contrast to the abundant expression of CFTR, ENaC (alpha, beta, gamma) mRNA signal was not detected throughout the estrus cycle in the ovary and oviduct. Messenger RNA for all ENaC subunits was abundantly detected in the cervical and vaginal epithelia throughout the estrus cycle but for CFTR, mRNA was found only at proestrus. In the uterine epithelium, alphaENaC mRNA was detected at diestrus but not found at any other stage, while CFTR mRNA was only detected at early estrus but not other stages. Semi-quantitative RT-PCR detected mRNA for all ENaC subunits in the uterus throughout the cycle with maximal expression at diestrus and CFTR mRNA was only found in the early stages of the cycle. The involvement of ENaC and CFTR in Na+ absorption and Cl- secretion was demonstrated in cultured endometrial epithelia using the short-circuit current technique and found to be influenced by ovarian hormones. Taken together, these data indicate a main secretory role of the ovary and oviduct and a predominantly absorptive role of the cervix and vagina. The present results also suggest an ability of the uterus to secrete and absorb at different stages of the estrus cycle. Variations in the fluid profiles may be dictated by the regional and cyclic variations in expression of ENaC and CFTR and are likely to contribute to various reproductive events in different regions of the female reproductive tract.