Urinary MicroRNA Profiling in the Nephropathy of Type 1 Diabetes

Background: Patients with Type 1 Diabetes (T1D) are particularly vulnerable to development of Diabetic nephropathy (DN) leading to End Stage Renal Disease. Hence a better understanding of the factors affecting kidney disease progression in T1D is urgently needed. In recent years microRNAs have emerged as important post-transcriptional regulators of gene expression in many different health conditions. We hypothesized that urinary microRNA profile of patients will differ in the different stages of diabetic renal disease. Methods and Findings: We studied urine microRNA profiles with qPCR in 40 T1D with >20 year follow up 10 who never developed renal disease (N) matched against 10 patients who went on to develop overt nephropathy (DN), 10 patients with intermittent microalbuminuria (IMA) matched against 10 patients with persistent (PMA) microalbuminuria. A Bayesian procedure was used to normalize and convert raw signals to expression ratios. We applied formal statistical techniques to translate fold changes to profiles of microRNA targets which were then used to make inferences about biological pathways in the Gene Ontology and REACTOME structured vocabularies. A total of 27 microRNAs were found to be present at significantly different levels in different stages of untreated nephropathy. These microRNAs mapped to overlapping pathways pertaining to growth factor signaling and renal fibrosis known to be targeted in diabetic kidney disease. Conclusions: Urinary microRNA profiles differ across the different stages of diabetic nephropathy. Previous work using experimental, clinical chemistry or biopsy samples has demonstrated differential expression of many of these microRNAs in a variety of chronic renal conditions and diabetes. Combining expression ratios of microRNAs with formal inferences about their predicted mRNA targets and associated biological pathways may yield useful markers for early diagnosis and risk stratification of DN in T1D by inferring the alteration of renal molecular processes. © 2013 Argyropoulos et al

Modeling global transfusion medicine education

This document provides an analysis and oversight of the necessary educational infrastructure at national level needed for successful and sustainable education programs undergraduate and post-graduate and is focused on desired outcomes needed to secure general Transfusion Medicine (TM) competence and basic skills when appointed in a professional TM position. It provides a global model framework for TM education allowing individual countries to tailor the context and contents of the institutional curriculum. Education in transfusion medicine is a complex set of intimately interrelated and interconnected components that allow student and fellow exposure to knowledge and skills, the ultimate curriculum. The extent to which knowledge and skills, professionalism and leadership principles are offered depends on the expected outcomes needed for the desired roles, tasks and functions. A model for the development and implementation of an education (teaching and training) curriculum in Transfusion Medicine aimed at medical students and doctors, nurses and midwives, and laboratory professionals should ideally include an outcomes-based component, with clear recommendations on the required roles, skills, attitudes, and knowledge of a trainee completing such a curriculum. This should correspond to the environment and scope of practice required from such a vocational or academic professional and should address deficiencies in knowledge, skills and attitudes present before the curriculum is completed, while taking into account fundamental international standards of knowledge and the needs of their working climate and environment. Therefore, it is considered more practical to provide a set of outcomes that would be useful in most contexts and settings, while equipping students, as adult learners, with the tools for advancing their educational, professional and leadership development suited to their availability and socio-economic environment. The framework or model recognizes that no one set of education or training initiatives will be appropriate in all countries or settings and should be tailored to specific settings based on the assessment of local needs and available environments

Proactive and politically skilled professionals: What is the relationship with affective occupational commitment?

The aim of this study is to extend research on employee affective commitment in three ways: (1) instead of organizational commitment the focus is on occupational commitment; (2) the role of proactive personality on affective occupational commitment is examined; and (3) occupational satisfaction is examined as a mediator and political skills as moderator in the relationship between proactive personality and affective occupational commitment. Two connected studies, one in a hospital located in the private sector and one in a university located in the public sector, are carried out in Pakistan, drawing on a total sample of over 400 employees. The results show that proactive personality is positively related to affective occupational commitment, and that occupational satisfaction partly mediates the relationship between proactive personality and affective occupational commitment. No effect is found for a moderator effect of political skills in the relationship between proactive personality and affective occupational commitment. Political skills however moderate the relationship between proactive personality and affective organizational commitment

JWST Reveals Star Formation Across a Spiral Arm in M33

Young stellar objects (YSOs) are the gold standard for tracing star formation in galaxies but have been unobservable beyond the Milky Way and Magellanic Clouds. But that all changed when the James Webb Space Telescope was launched, which we use to identify YSOs in the Local Group galaxy M33, marking the first time that individual YSOs have been identified at these large distances. We present MIRI imaging mosaics at 5.6 and 21 microns that cover a significant portion of one of M33's spiral arms that has existing panchromatic imaging from the Hubble Space Telescope and deep ALMA CO measurements. Using these MIRI and Hubble Space Telescope images, we identify point sources using the new DOLPHOT MIRI module. We identify 793 candidate YSOs from cuts based on colour, proximity to giant molecular clouds (GMCs), and visual inspection. Similar to Milky Way GMCs, we find that higher mass GMCs contain more YSOs and YSO emission, which further shows YSOs identify star formation better than most tracers that cannot capture this relationship at cloud scales. We find evidence of enhanced star formation efficiency in the southern spiral arm by comparing the YSOs to the molecular gas mass.Comment: 12 pages, 10 figures, 1 tables, accepted for publication at MNRA

GWAS and transcriptional analysis prioritize ITPR1 and CNTN4 for a serum uric acid 3p26 QTL in Mexican Americans

Background: The variation in serum uric acid concentrations is under significant genetic influence. Elevated SUA concentrations have been linked to increased risk for gout, kidney stones, chronic kidney disease, and cardiovascular disease whereas reduced serum uric acid concentrations have been linked to multiple sclerosis, Parkinson’s disease and Alzheimer’s disease. Previously, we identified a novel locus on chromosome 3p26 affecting serum uric acid concentrations in Mexican Americans from San Antonio Family Heart Study. As a follow up, we examined genome-wide single nucleotide polymorphism data in an extended cohort of 1281 Mexican Americans from multigenerational families of the San Antonio Family Heart Study and the San Antonio Family Diabetes/ Gallbladder Study. We used a linear regression-based joint linkage/association test under an additive model of allelic effect, while accounting for non-independence among family members via a kinship variance component. Results:Univariate genetic analysis indicated serum uric acid concentrations to be significant heritable (h2 = 0.50 ± 0.05, p Conclusion: Our results confirm the importance of the chromosome 3p26 locus and genetic variants in this region in the regulation of serum uric acid concentrations

Elderly persons in the risk zone. Design of a multidimensional, health-promoting, randomised three-armed controlled trial for "prefrail" people of 80+ years living at home

Background The very old (80+) are often described as a "frail" group that is particularly exposed to diseases and functional disability. They are at great risk of losing the ability to manage their activities of daily living independently. A health-promoting intervention programme might prevent or delay dependence in activities of daily life and the development of functional decline. Studies have shown that those who benefit most from a health-promoting and disease-preventive programme are persons with no, or discrete, activity restrictions. The three-armed study "Elderly in the risk zone" is designed to evaluate if multi-dimensional and multi-professional educational senior meetings are more effective than preventive home visits, and if it is possible to prevent or delay deterioration if an intervention is made when the persons are not so frail. In this paper the study design, the intervention and the outcome measures as well as the baseline characteristics of the study participants are presented. Methods/Design The study is a randomised three-armed single-blind controlled trial with follow-ups 3 months, 1 and 2 years. The study group should comprise a representative sample of pre-frail 80-year old persons still living at home in two municipalities of Gothenburg. To allow for drop-outs, it was estimated that a total of about 450 persons would need to be included in the study. The participants should live in their ordinary housing and not be dependent on the municipal home help service or care. Further, they should be independent of help from another person in activities of daily living and be cognitively intact, having a score of 25 or higher as assessed with the Mini Mental State Examination (MMSE). Discussion We believe that the design of the study, the randomisation procedure, outcome measurements and the study protocol meetings should ensure the quality of the study. Furthermore, the multi-dimensionality of the intervention, the involvement of both the professionals and the senior citizens in the planning of the intervention should have the potential to effectively target the heterogeneous needs of the elderly. Trial registration ClinicalTrials.gov, NCT0087705

Assessment of a carbon dioxide laser for the measurement of thermal nociceptive thresholds following intramuscular administration of analgesic drugs in pain-free female cats

Objective: To assess the potential for using a thermal carbon dioxide (CO2) laser to 8 assess anti-nociception in pain-free cats. Animals: Sixty healthy adult female cats with a mean weight (± SD) of 3.3 k g (± 0. 6 11 kg). Methods: This is a prospective, blinded and randomised study. Cats were systematically allocated to one of six treatments 1) saline 0.2 ml/cat; 2) morphine 0.5 mg/kg; 3) buprenorphine 20 μg/kg; 4) medetomidine 2 μg/kg; 5) tramadol 2mg/kg; 6) ketoprofen 2 mg/kg. Latency to respond to thermal stimulation was assessed prior to intramuscular injection and at 6 time periods following injection (15-30; 30-45; 45- 18 60; 60-75; 90-105; 120-135 min). Thermal thresholds were assessed using time to respond behaviourally to stimulation with a 500 mW CO2 laser with maximum latency to respond set at 60 seconds. Differences in response latency for each treatment across the duration of the experiment were assessed using a Friedman's test. Differences between treatments at any given time were assessed using an independent Kruskal-Wallis test. Where significant effects were identified, pair-wise comparisons were conducted at 30-45, 60-75 and 120-135 min to further explain the direction of the effect. Results: Cats treated with morphine (χ2 = 12.90; df = 6; P = 0.045) and tramadol (χ2 = 20.28; df = 6; P = 0.002) showed significant increases in latency to respond over the duration of the test period. However, subsequent pairwise comparisons indicated that latencies at specific time points were only significantly different (P < 0.05) for tramadol at 60-75 and 90-105 min after administration. No significant pairwise comparisons were found within the morphine treatment group. Injection of saline, ketoprofen, medetomidine or buprenorphine showed no significant effect on latency to respond. Conclusions: This project further validates the CO 2 laser technique for use in cats. It can be used for assessment of thermal nociceptive thresholds in pain-free cats after analgesic administration and shows some promise in differentiating amongst analgesic treatments. It may provide a simpler alternative to existing systems although further exploration is required both in terms of its sensitivity and comparative utility (i.e. relative to other thermal threshold systems). Future experiments should seek to quantify the effects of skin temperature and sedation on latency to respond. Given that this technique was found to cause minor skin blistering in individuals that reached the 60 s exposure limit, a cut off time of <45 s is recommended

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A&gt;T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations