Murine and human myogenic cells identified by elevated aldehyde dehydrogenase activity: Implications for muscle regeneration and repair

Background: Despite the initial promise of myoblast transfer therapy to restore dystrophin in Duchenne muscular dystrophy patients, clinical efficacy has been limited, primarily by poor cell survival post-transplantation. Murine muscle derived stem cells (MDSCs) isolated from slowly adhering cells (SACs) via the preplate technique, induce greater muscle regeneration than murine myoblasts, primarily due to improved post-transplantation survival, which is conferred by their increased stress resistance capacity. Aldehyde dehydrogenase (ALDH) represents a family of enzymes with important morphogenic as well as oxidative damage mitigating roles and has been found to be a marker of stem cells in both normal and malignant tissue. In this study, we hypothesized that elevated ALDH levels could identify murine and human muscle derived cell (hMDC) progenitors, endowed with enhanced stress resistance and muscle regeneration capacity. Methodology/Principal Findings: Skeletal muscle progenitors were isolated from murine and human skeletal muscle by a modified preplate technique and unfractionated enzymatic digestion, respectively. ALDHhisubpopulations isolated by fluorescence activate cell sorting demonstrated increased proliferation and myogenic differentiation capacities compared to their ALDHlocounterparts when cultivated in oxidative and inflammatory stress media conditions. This behavior correlated with increased intracellular levels of reduced glutathione and superoxide dismutase. ALDHhimurine myoblasts were observed to exhibit an increased muscle regenerative potential compared to ALDHlomyoblasts, undergo multipotent differentiation (osteogenic and chondrogenic), and were found predominately in the SAC fraction, characteristics that are also observed in murine MDSCs. Likewise, human ALDHhihMDCs demonstrated superior muscle regenerative capacity compared to ALDHlohMDCs. Conclusions: The methodology of isolating myogenic cells on the basis of elevated ALDH activity yielded cells with increased stress resistance, a behavior that conferred increased regenerative capacity of dystrophic murine skeletal muscle. This result demonstrates the critical role of stress resistance in myogenic cell therapy as well as confirms the role of ALDH as a marker for rapid isolation of murine and human myogenic progenitors for cell therapy. © 2011 Vella et al

Insulin resistance in type 1 diabetes: what is ‘double diabetes’ and what are the risks?

In this review, we explore the concept of ‘double diabetes’, a combination of type 1 diabetes with features of insulin resistance and type 2 diabetes. After considering whether double diabetes is a useful concept, we discuss potential mechanisms of increased insulin resistance in type 1 diabetes before examining the extent to which double diabetes might increase the risk of cardiovascular disease (CVD). We then go on to consider the proposal that weight gain from intensive insulin regimens may be associated with increased CV risk factors in some patients with type 1 diabetes, and explore the complex relationships between weight gain, insulin resistance, glycaemic control and CV outcome. Important comparisons and contrasts between type 1 diabetes and type 2 diabetes are highlighted in terms of hepatic fat, fat partitioning and lipid profile, and how these may differ between type 1 diabetic patients with and without double diabetes. In so doing, we hope this work will stimulate much-needed research in this area and an improvement in clinical practice

SGLT inhibitor adjunct therapy in type 1 diabetes

Non-insulin adjunct therapies in type 1 diabetes have been proposed as a means of improving glycaemic control and reducing risk of hypoglycaemia. Evidence to support this approach is, however, scant and few pharmacological agents have proved effective enough to become part of routine clinical care. Recent short-term Phase II trials and 24 week Phase III trials provide initial support for the use of sodium–glucose cotransporter (SGLT) inhibitors in type 1 diabetes. Two international, multicentre, randomised, controlled clinical trials, Dapagliflozin Evaluation in Patients with Inadequately Controlled Type 1 Diabetes (DEPICT-1) and inTandem3, have reported that SGLT inhibition with dapagliflozin and sotagliflozin, respectively, confer additional benefits in terms of a 5–6 mmol/mol (0.4–0.5%) reduction in HbA1c accompanied by weight loss and reductions in total daily insulin doses. The reduction in HbA1c does not come with a significantly increased risk of hypoglycaemia but does carry an increased risk of diabetic ketoacidosis and mycotic infections. These results suggest that SGLT inhibition will have a place in the management of type 1 diabetes. Longer-term clinical trials (≥52 weeks) and observational cohort studies are needed to determine any additional benefits or adverse effects of this adjunct therapy and to determine which group of patients may benefit most from this approach. In addition, use of SGLT inhibitors in routine type 1 diabetes care will require specific patient and healthcare professional educational packages to ensure patient safety and to minimise risk

Consensus Paper: Radiological Biomarkers of Cerebellar Diseases

Hereditary and sporadic cerebellar ataxias represent a vast and still growing group of diseases whose diagnosis and differentiation cannot only rely on clinical evaluation. Brain imaging including magnetic resonance (MR) and nuclear medicine techniques allows for characterization of structural and functional abnormalities underlying symptomatic ataxias. These methods thus constitute a potential source of radiological biomarkers, which could be used to identify these diseases and differentiate subgroups of them, and to assess their severity and their evolution. Such biomarkers mainly comprise qualitative and quantitative data obtained from MR including proton spectroscopy, diffusion imaging, tractography, voxel-based morphometry, functional imaging during task execution or in a resting state, and from SPETC and PET with several radiotracers. In the current article, we aim to illustrate briefly some applications of these neuroimaging tools to evaluation of cerebellar disorders such as inherited cerebellar ataxia, fetal developmental malformations, and immune-mediated cerebellar diseases and of neurodegenerative or early-developing diseases, such as dementia and autism in which cerebellar involvement is an emerging feature. Although these radiological biomarkers appear promising and helpful to better understand ataxia-related anatomical and physiological impairments, to date, very few of them have turned out to be specific for a given ataxia with atrophy of the cerebellar system being the main and the most usual alteration being observed. Consequently, much remains to be done to establish sensitivity, specificity, and reproducibility of available MR and nuclear medicine features as diagnostic, progression and surrogate biomarkers in clinical routine

The Safety Attitudes Questionnaire: psychometric properties, benchmarking data, and emerging research

BACKGROUND: There is widespread interest in measuring healthcare provider attitudes about issues relevant to patient safety (often called safety climate or safety culture). Here we report the psychometric properties, establish benchmarking data, and discuss emerging areas of research with the University of Texas Safety Attitudes Questionnaire. METHODS: Six cross-sectional surveys of health care providers (n = 10,843) in 203 clinical areas (including critical care units, operating rooms, inpatient settings, and ambulatory clinics) in three countries (USA, UK, New Zealand). Multilevel factor analyses yielded results at the clinical area level and the respondent nested within clinical area level. We report scale reliability, floor/ceiling effects, item factor loadings, inter-factor correlations, and percentage of respondents who agree with each item and scale. RESULTS: A six factor model of provider attitudes fit to the data at both the clinical area and respondent nested within clinical area levels. The factors were: Teamwork Climate, Safety Climate, Perceptions of Management, Job Satisfaction, Working Conditions, and Stress Recognition. Scale reliability was 0.9. Provider attitudes varied greatly both within and among organizations. Results are presented to allow benchmarking among organizations and emerging research is discussed. CONCLUSION: The Safety Attitudes Questionnaire demonstrated good psychometric properties. Healthcare organizations can use the survey to measure caregiver attitudes about six patient safety-related domains, to compare themselves with other organizations, to prompt interventions to improve safety attitudes and to measure the effectiveness of these interventions

Attainment of Brown Adipocyte Features in White Adipocytes of Hormone-Sensitive Lipase Null Mice

BACKGROUND: Hormone-sensitive lipase (HSL) is expressed predominantly in adipose tissue, where it plays an important role in catecholamine-stimulated hydrolysis of stored tri- and diglycerides, thus mobilizing fatty acids. HSL exhibits broad substrate specificity and besides acylglycerides it hydrolyzes cholesteryl esters, retinyl esters and lipoidal esters. Despite its role in fatty acid mobilization, HSL null mice have been shown to be resistant to diet-induced obesity. METHODOLOGY/PRINCIPAL FINDINGS: Following a high-fat diet (HFD) regimen, energy expenditure, measured using indirect calorimetry, was increased in HSL null mice. White adipose tissue of HSL null mice was characterized by reduced mass and reduced protein expression of PPARgamma, a key transcription factor in adipogenesis, and stearoyl-CoA desaturase 1, the expression of which is known to be positively correlated to the differentiation state of the adipocyte. The protein expression of uncoupling protein-1 (UCP-1), the highly specific marker of brown adipocytes, was increased 7-fold in white adipose tissue of HSL null mice compared to wildtype littermates. Transmission electron microscopy revealed an increase in the size of mitochondria of white adipocytes of HSL null mice. The mRNA expression of pRb and RIP140 was decreased in isolated white adipocytes, while the expression of UCP-1 and CPT1 was increased in HSL null mice compared to wildtype littermates. Basal oxygen consumption was increased almost 3-fold in white adipose tissue of HSL null mice and was accompanied by increased uncoupling activity. CONCLUSIONS: These data suggest that HSL is involved in the determination of white versus brown adipocytes during adipocyte differentiation The exact mechanism(s) underlying this novel role of HSL remains to be elucidated, but it seems clear that HSL is required to sustain normal expression levels of pRb and RIP140, which both promote differentiation into the white, rather than the brown, adipocyte lineage

Variation in CHI3LI in Relation to Type 2 Diabetes and Related Quantitative Traits

CHI3LI encoding the inflammatory glycoprotein YKL-40 is located on chromosome 1q32.1. YKL-40 is involved in inflammatory processes and patients with Type 2 Diabetes (T2D) have elevated circulating YKL-40 levels which correlate with their level of insulin resistance. Interestingly, it has been reported that rs10399931 (-329 G/A) of CHI3LI contributes to the inter-individual plasma YKL-40 levels in patients with sarcoidosis, and that rs4950928 (-131 C/G) is a susceptibility polymorphism for asthma and a decline in lung function. We hypothesized that single nucleotide polymorphisms (SNPs) or haplotypes thereof the CHI3LI locus might influence risk of T2D. The aim of the present study was to investigate the putative association between SNPs and haplotype blocks of CHI3LI and T2D and T2D related quantitative traits.Eleven SNPs of CHI3LI were genotyped in 6514 individuals from the Inter99 cohort and 2924 individuals from the outpatient clinic at Steno Diabetes Center. In cas-control studies a total of 2345 T2D patients and 5302 individuals with a normal glucose tolerance test were examined. We found no association between rs10399931 (OR, 0.98 (CI, 0.88-1.10), p = 0.76), rs4950928 (0.98 (0.87-1.10), p = 0.68) or any of the other SNPs with T2D. Similarly, we found no significant association between any of the 11 tgSNPs and T2D related quantitative traits, all p>0.14. None of the identified haplotype blocks of CHI3LI showed any association with T2D, all p>0.16.None of the examined SNPs or haplotype blocks of CHI3LI showed any association with T2D or T2D related quantitative traits. Estimates of insulin resistance and dysregulated glucose homeostasis in T2D do not seem to be accounted for by the examined variations of CHI3LI

Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes

<p>Abstract</p> <p>Background</p> <p>In a previous pooled analysis of 12 double-blind clinical studies that included data on 6,139 patients with type 2 diabetes, treatment with sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to be generally well tolerated compared with treatment with control agents. As clinical development of sitagliptin continues, additional studies have been completed, and more patients have been exposed to sitagliptin. The purpose of the present analysis is to update the safety and tolerability assessment of sitagliptin by pooling data from 19 double-blind clinical studies.</p> <p>Methods</p> <p>The present analysis included data from 10,246 patients with type 2 diabetes who received either sitagliptin 100 mg/day (N = 5,429; sitagliptin group) or a comparator agent (placebo or an active comparator) (N = 4,817; non-exposed group). The 19 studies from which this pooled population was drawn represent the double-blind, randomized studies that included patients treated with the usual clinical dose of sitagliptin (100 mg/day) for between 12 weeks and 2 years and for which results were available as of July 2009. These 19 studies assessed sitagliptin taken as monotherapy, initial combination therapy with metformin or pioglitazone, or as add-on combination therapy with other antihyperglycemic agents (metformin, pioglitazone, a sulfonylurea ± metformin, insulin ± metformin, or rosiglitazone + metformin). Patients in the non-exposed group were taking placebo, metformin, pioglitazone, a sulfonylurea ± metformin, insulin ± metformin, or rosiglitazone + metformin. The analysis used patient-level data from each study to evaluate between-group differences in the exposure-adjusted incidence rates of adverse events.</p> <p>Results</p> <p>Summary measures of overall adverse events were similar in the sitagliptin and non-exposed groups, except for an increased incidence of drug-related adverse events in the non-exposed group. Incidence rates of specific adverse events were also generally similar between the two groups, except for increased incidence rates of hypoglycemia, related to the greater use of a sulfonylurea, and diarrhea, related to the greater use of metformin, in the non-exposed group and constipation in the sitagliptin group. Treatment with sitagliptin was not associated with an increased risk of major adverse cardiovascular events.</p> <p>Conclusions</p> <p>In this updated pooled safety analysis of data from 10,246 patients with type 2 diabetes, sitagliptin 100 mg/day was generally well tolerated in clinical trials of up to 2 years in duration.</p

Risk factors and a predictive model for under-five mortality in Nigeria: evidence from Nigeria demographic and health survey

<p>Abstract</p> <p>Background</p> <p>Under-5 mortality is a major public health challenge in developing countries. It is essential to identify determinants of under-five mortality (U5M) childhood mortality because these will assist in formulating appropriate health programmes and policies in order to meet the United Nations MDG goal. The objective of this study was to develop a predictive model and identify maternal, child, family and other risk factors associated U5M in Nigeria.</p> <p>Methods</p> <p>Population-based cross-sectional study which explored 2008 demographic and health survey of Nigeria (NDHS) with multivariable logistic regression. Likelihood Ratio Test, Hosmer-Lemeshow Goodness-of-Fit and Variance Inflation Factor were used to check the fit of the model and the predictive power of the model was assessed with Receiver Operating Curve (ROC curve).</p> <p>Results</p> <p>This study yielded an excellent predictive model which revealed that the likelihood of U5M among the children of mothers that had their first marriage at age 20-24 years and ≥ 25 years declined by 20% and 30% respectively compared to children of those that married before the age of 15 years. Also, the following factors reduced odds of U5M: health seeking behaviour, breastfeeding children for > 18 months, use of contraception, small family size, having one wife, low birth order, normal birth weight, child spacing, living in urban areas, and good sanitation.</p> <p>Conclusions</p> <p>This study has revealed that maternal, child, family and other factors were important risk factors of U5M in Nigeria. This study has identified important risk factors that will assist in formulating policies that will improve child survival.</p

Measurement of the Branching Fraction for τ→ρν

This Letter presents a measurement of the decay τ-→ρ-ντ using data obtained with the Mark II detector at SPEAR. In the center-of-mass energy region 4.5&lt;~Ec.m.&lt;~6.0 GeV 85 events are observed in which a charged ρ was found in coincidence with either an electron or a muon. It was determined that B(τ-→ρ-ντ)=(20.5±4.1)% and the ratio B(τ-→ρ-ντ)B(τ-→e-ντν̄e)=1.11± 0.23. © 1979 The American Physical Society