Inhibition of Mef2a Enhances Neovascularization via Post-transcriptional Regulation of 14q32 MicroRNAs miR-329 and miR-494

Vascular Surger

Dynamic Contrast-enhanced MR Imaging of Carotid Atherosclerotic Plaque: Model Selection, Reproducibility, and Validation.

Purpose: compare four known pharmacokinetic models for their ability to describe dynamic contrast material-enhanced magnetic resonance (MR) imaging of carotid atherosclerotic plaques, to determine reproducibility, and to validate the results with histologic findings. Materials and Methods: The study was approved by the institutional medical ethics committee. Written informed consent was obtained from all patients. Forty-five patients with 30%-99% carotid stenosis underwent dynamic contrast-enhanced MR imaging. Plaque enhancement was measured at 16 time points at approximately 25-second image intervals by using a gadolinium-based contrast material. Pharmacokinetic parameters (volume transfer constant, Ktrans; extracellular extravascular volume fraction, v e; and blood plasma fraction, v p) were determined by fitting a two-compartment model to plaque and blood gadolinium concentration curves. The relative fit errors and parameter uncertainties were determined to find the most suitable model. Sixteen patients underwent imaging twice to determine reproducibility. Carotid endarterectomy specimens from 16 patients who were scheduled for surgery were collected for histologic validation. Parameter uncertainties were compared with the Wilcoxon signed rank test. Reproducibility was assessed by using the coefficient of variation. Correlation with histologic findings was evaluated with the Pearson correlation coefficient. Results: The mean relative fit uncertainty (+/- standard error) for Ktrans was 10% +/- 1 with the Patlak model, which was significantly lower than that with the Tofts (20% +/- 1), extended Tofts (33% +/- 3), and extended graphical (29% +/- 3) models (P <.001). The relative uncertainty for v p was 20% 6 2 with the Patlak model and was significantly higher with the extended Tofts (46% +/- 9) and extended graphical (35% +/- 5) models (P <.001). The reproducibility (coefficient of variation) for the Patlak model was 16% for Ktrans and 26% for v p. Significant positive correlations were found between Ktrans and the endothelial microvessel content determined on histologic slices (Pearson r = 0.72, P = .005). Conclusion: The Patlak model is most suited for describing carotid plaque enhancement. Correlation with histologic findings validated Ktrans as an indicator of plaque microvasculature, and the reproducibility of Ktrans was good. (C)RSNA, 201

The frequency of osteogenic activities and the pattern of intermittence between periods of physical activity and sedentary behaviour affects bone mineral content: the cross-sectional NHANES study

BACKGROUND: Sedentary behaviours, defined as non exercising seated activities, have been shown to have deleterious effects on health. It has been hypothesised that too much sitting time can have a detrimental effect on bone health in youth. The aim of this study is to test this hypothesis by exploring the association between objectively measured volume and patterns of time spent in sedentary behaviours, time spent in specific screen-based sedentary pursuits and bone mineral content (BMC) accrual in youth. METHODS: NHANES 2005–2006 cycle data includes BMC of the femoral and spinal region via dual-energy X-ray absorptiometry (DEXA), assessment of physical activity and sedentary behaviour patterns through accelerometry, self reported time spent in screen based pursuits (watching TV and using a computer), and frequency of vigorous playtime and strengthening activities. Multiple regression analysis, stratified by gender was performed on N = 671 males and N = 677 females aged from 8 to 22 years. RESULTS: Time spent in screen-based sedentary behaviours is negatively associated with femoral BMC (males and females) and spinal BMC (females only) after correction for time spent in moderate and vigorous activity. Regression coefficients indicate that an additional hour per day of screen-based sitting corresponds to a difference of −0.77 g femoral BMC in females [95% CI: -1.31 to −0.22] and of −0.45 g femoral BMC in males [95% CI: -0.83 to −0.06]. This association is attenuated when self-reported engagement in regular (average 5 times per week) strengthening exercise (for males) and vigorous playing (for both males and females) is taken into account. Total sitting time and non screen-based sitting do not appear to have a negative association with BMC, whereas screen based sedentary time does. Patterns of intermittence between periods of sitting and moderate to vigorous activity appears to be positively associated with bone health when activity is clustered in time and inter-spaced with long continuous bouts of sitting. CONCLUSIONS: Some specific sedentary pursuits (screen-based) are negatively associated with bone health in youth. This association is specific to gender and anatomical area. This relationship between screen-based time and bone health is independent of the total amount of physical activity measured objectively, but not independent of self-reported frequency of strengthening and vigorous play activities. The data clearly suggests that the frequency, rather than the volume, of osteogenic activities is important in counteracting the effect of sedentary behaviour on bone health. The pattern of intermittence between sedentary periods and activity also plays a role in bone accrual, with clustered short bouts of activity interspaced with long periods of sedentary behaviours appearing to be more beneficial than activities more evenly spread in time

The development and implementation of a regional network of physiotherapists for exercise therapy in patients with peripheral arterial disease, a preliminary report

BACKGROUND: Exercise therapy (ET) is the main conservative and proven effective treatment of patients with intermittent claudication. Currently, the most frequent exercise prescription is a single 'go home and walk' advise, without supervision or follow-up. There is no evidence to support the efficacy of this advise and compliance is known to be low. Therefore, a systematic approach was used to guarantee quality and standardisation of treatment, optimal guideline adherence and improved of inter-professional communication between vascular surgeons and physiotherapists. In this preliminary report we would like to outline the steps taken for the development and implementation of the Network Exercise Therapy Parkstad METHODS: In October 2003 all 59 regional physiotherapy practices were invited to attend a symposium regarding ET in a physiotherapeutic setting. Attending physiotherapists interested in providing ET and willing to follow a certified course on ET, were asked to register. Three tastkgroups were formed to accomplish the set targets: Exercise therapy education, Exercise therapy implementation and continuity, and Inter-professional communication in the Parkstad region. RESULTS: In total 27 physiotherapists, from 22 different practices followed the educational program and are now trained and accredited to provide ET according to the guideline of the Royal Dutch Society for Physiotherapy. A web-based database wasdesigned to contain information on disease specific items provided by the vascular surgery department, and aspects with respect to ET registered by the physiotherapist. The information is regularly updated and available online. Access tothe database is restricted to vascular surgeons and physiotherapists in the network. The secondary purpose of the database is to register essential benchmark data for future analysis of ET in a physiotherapeutic setting in the Netherlands and to enable physiotherapists continuous feedback on patient performance. A triage system was developed to detect patients with a compromised cardiac history. This group receives ET at the in-hospital department of revalidation with the possibility of immediate consultation of a cardiologist in case of cardiac complications or even CPR. CONCLUSION: The Network Exercise Therapy Parkstad of supervised ET is the first initiative in the Netherlands to provide ET close to the patient's home environment. With the implementation of supervised ET in an outpatient physiotherapeutic setting for all eligible patients with symptomatic PAD, the access to care has been improved. A web-based communication system provides physiotherapists and vascular surgeons with all the necessary and continues updated patient information. Future research, currently in progress, will investigate the therapeutic benefits and cost-effectiveness of exercise therapy in a physiotherapeutic setting

Gestational age at birth and body size from infancy through adolescence: An individual participant data meta-analysis on 253,810 singletons in 16 birth cohort studies

Background Preterm birth is the leading cause of perinatal morbidity and mortality and is associated with adverse developmental and long-term health outcomes, including several cardiometabolic risk factors and outcomes. However, evidence about the association of preterm birth with later body size derives mainly from studies using birth weight as a proxy of prematurity rather than an actual length of gestation. We investigated the association of gestational age (GA) at birth with body size from infancy through adolescence. Methods and findings We conducted a two-stage individual participant data (IPD) meta-analysis using data from 253,810 mother-child dyads from 16 general population-based cohort studies in Europe (Denmark, Finland, France, Italy, Norway, Portugal, Spain, the Netherlands, United Kingdom), North America (Canada), and Australasia (Australia) to estimate the association of GA with body mass index (BMI) and overweight (including obesity) adjusted for the following maternal characteristics as potential confounders: education, height, prepregnancy BMI, ethnic background, parity, smoking during pregnancy, age at child's birth, gestational diabetes and hypertension, and preeclampsia. Pregnancy and birth cohort studies from the LifeCycle and the EUCAN-Connect projects were invited and were eligible for inclusion if they had information on GA and minimum one measurement of BMI between infancy and adolescence. Using a federated analytical tool (DataSHIELD), we fitted linear and logistic regression models in each cohort separately with a complete-case approach and combined the regression estimates and standard errors through random-effects study-level meta-analysis providing an overall effect estimate at early infancy (>0.0 to 0.5 years), late infancy (>0.5 to 2.0 years), early childhood (>2.0 to 5.0 years), mid-childhood (>5.0 to 9.0 years), late childhood (>9.0 to 14.0 years), and adolescence (>14.0 to 19.0 years). GA was positively associated with BMI in the first decade of life, with the greatest increase in mean BMI z-score during early infancy (0.02, 95% confidence interval (CI): 0.00; 0.05, p < 0.05) per week of increase in GA, while in adolescence, preterm individuals reached similar levels of BMI (0.00, 95% CI: -0.01; 0.01, p 0.9) as term counterparts. The association between GA and overweight revealed a similar pattern of association with an increase in odds ratio (OR) of overweight from late infancy through mid-childhood (OR 1.01 to 1.02) per week increase in GA. By adolescence, however, GA was slightly negatively associated with the risk of overweight (OR 0.98 [95% CI: 0.97; 1.00], p 0.1) per week of increase in GA. Although based on only four cohorts (n = 32,089) that reached the age of adolescence, data suggest that individuals born very preterm may be at increased odds of overweight (OR 1.46 [95% CI: 1.03; 2.08], p < 0.05) compared with term counterparts. Findings were consistent across cohorts and sensitivity analyses despite considerable heterogeneity in cohort characteristics. However, residual confounding may be a limitation in this study, while findings may be less generalisable to settings in low- and middle-income countries. Conclusions This study based on data from infancy through adolescence from 16 cohort studies found that GA may be important for body size in infancy, but the strength of association attenuates consistently with age. By adolescence, preterm individuals have on average a similar mean BMI to peers born at term.This collaborative project received funding from the European Union's Horizon 2020 research and innovation programme (Grant Agreement No. 733206 LifeCycle, Grand Recipient VWVJ; Grant Agreement No. 824989 EUCAN-Connect, Grand Recipient AMNA). Please, see S1 Appendix for list of cohort-specific funding/support. DAL is supported by the UK Medical Research Council (MC_UU_00011/6) and British Heart Foundation (CH/F/20/90003 and AA/18/7/34219). RCW is supported by UKRI Innovation Fellowship with Health Data Research UK [MR/S003959/1]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Novel internal regulators and candidate miRNAs within miR-379/miR-656 miRNA cluster can alter cellular phenotype of human glioblastoma

Clustered miRNAs can affect functioning of downstream pathways due to possible coordinated function. We observed 78-88% of the miR-379/miR-656 cluster (C14MC) miRNAs were downregulated in three sub-types of diffuse gliomas, which was also corroborated with analysis from The Cancer Genome Atlas (TCGA) datasets. The miRNA expression levels decreased with increasing tumor grade, indicating this downregulation as an early event in gliomagenesis. Higher expression of the C14MC miRNAs significantly improved glioblastioma prognosis (Pearson’s r=0.62; p<3.08e-22). ENCODE meta-data analysis, followed by reporter assays validated existence of two novel internal regulators within C14MC. CRISPR activation of the most efficient internal regulator specifically induced members of the downstream miRNA sub-cluster and apoptosis in glioblastoma cells. Luciferase assays validated novel targets for miR-134 and miR-485-5p, two miRNAs from C14MC with the most number of target genes relevant for glioma. Overexpression of miR-134 and miR-485-5p in human glioblastoma cells suppressed invasion and proliferation, respectively. Furthermore, apoptosis was induced by both miRs, individually and in combination. The results emphasize the tumor suppressive role of C14MC in diffuse gliomas, and identifies two specific miRNAs with potential therapeutic value and towards better disease management and therapy

Development and evolution of dentition pattern and tooth order in the Skates and Rays (Batoidea; Chondrichthyes)

Shark and ray (elasmobranch) dentitions are well known for their multiple generations of teeth, with isolated teeth being common in the fossil record. However, how the diverse dentitions characteristic of elasmobranchs form is still poorly understood. Data on the development and maintenance of the dental patterning in this major vertebrate group will allow comparisons to other morphologically diverse taxa, including the bony fishes, in order to identify shared pattern characters for the vertebrate dentition as a whole. Data is especially lacking from the Batoidea (skates and rays), hence our objective is to compile data on embryonic and adult batoid tooth development contributing to ordering of the dentition, from cleared and stained specimens and micro-CT scans, with 3D rendered models. We selected species (adult and embryonic) spanning phylogenetically significant batoid clades, such that our observations may raise questions about relationships within the batoids, particularly with respect to current molecular-based analyses. We include developmental data from embryos of recent model organisms Leucoraja erinacea and Raja clavata to evaluate the earliest establishment of the dentition. Characters of the batoid dentition investigated include alternate addition of teeth as offset successional tooth rows (versus single separate files), presence of a symphyseal initiator region (symphyseal tooth present, or absent, but with two parasymphyseal teeth) and a restriction to tooth addition along each jaw reducing the number of tooth families, relative to addition of successor teeth within each family. Our ultimate aim is to understand the shared characters of the batoids, and whether or not these dental characters are shared more broadly within elasmobranchs, by comparing these to dentitions in shark outgroups. These developmental morphological analyses will provide a solid basis to better understand dental evolution in these important vertebrate groups as well as the general plesiomorphic vertebrate dental condition

Inhibition of 14q32 microRNA miR-495 reduces lesion formation, intimal hyperplasia and plasma cholesterol levels in experimental restenosis

Cardiolog

Annama H chondrite-Mineralogy, physical properties, cosmic ray exposure, and parent body history

The fall of the Annama meteorite occurred early morning (local time) on April 19, 2014 on the Kola Peninsula (Russia). Based on mineralogy and physical properties, Annama is a typical H chondrite. It has a high Ar-Ar age of 4.4 Ga. Its cosmic ray exposure history is atypical as it is not part of the large group of H chondrites with a prominent 7-8 Ma peak in the exposure age histograms. Instead, its exposure age is within uncertainty of a smaller peak at 30 +/- 4 Ma. The results from short-lived radionuclides are compatible with an atmospheric pre-entry radius of 30-40 cm. However, based on noble gas and cosmogenic radionuclide data, Annama must have been part of a larger body (radius >65 cm) for a large part of its cosmic ray exposure history. The Be-10 concentration indicates a recent (3-5 Ma) breakup which may be responsible for the Annama parent body size reduction to 30-35 cm pre-entry radius.Peer reviewe