Identification of the REST regulon reveals extensive transposable element-mediated binding site duplication

The genome-wide mapping of gene-regulatory motifs remains a major goal that will facilitate the modelling of gene-regulatory networks and their evolution. The repressor element 1 is a long, conserved transcription factor-binding site which recruits the transcriptional repressor REST to numerous neuron-specific target genes. REST plays important roles in multiple biological processes and disease states. To map RE1 sites and target genes, we created a position specific scoring matrix representing the RE1 and used it to search the human and mouse genomes. We identified 1301 and 997 RE1s inhuman and mouse genomes, respectively, of which >40% are novel. By employing an ontological analysis we show that REST target genes are significantly enriched in a number of functional classes. Taking the novel REST target gene CACNA1A as an experimental model, we show that it can be regulated by multiple RE1s of different binding affinities, which are only partially conserved between human and mouse. A novel BLAST methodology indicated that many RE1s belong to closely related families. Most of these sequences are associated with transposable elements, leading us to propose that transposon-mediated duplication and insertion of RE1s has led to the acquisition of novel target genes by REST during evolution

Body composition and body fat distribution are related to cardiac autonomic control in non-alcoholic fatty liver disease patients

BACKGROUND/OBJECTIVES: Heart rate recovery (HRR), a cardiac autonomic control marker, was shown to be related to body composition (BC), yet this was not tested in non-alcoholic fatty liver disease (NAFLD) patients. The aim of this study was to determine if, and to what extent, markers of BC and body fat (BF) distribution are related to cardiac autonomic control in NAFLD patients. SUBJECTS/METHODS: BC was assessed with dual-energy X-ray absorptiometry in 28 NAFLD patients (19 men, 51±13 years, and 9 women, 47±13 years). BF depots ratios were calculated to assess BF distribution. Subjects’ HRR was recorded 1 (HRR1) and 2 min (HRR2) immediately after a maximum graded exercise test. RESULTS: BC and BF distribution were related to HRR; particularly weight, trunk BF and trunk BF-to-appendicular BF ratio showed a negative relation with HRR1 (r 1⁄4 0.613, r 1⁄4 0.597 and r 1⁄4 0.547, respectively, Po0.01) and HRR2 (r 1⁄4 0.484, r 1⁄4 0.446, Po0.05, and r 1⁄4 0.590, Po0.01, respectively). Age seems to be related to both HRR1 and HRR2 except when controlled for BF distribution. The preferred model in multiple regression should include trunk BF-to-appendicular BF ratio and BF to predict HRR1 (r2 1⁄4 0.549; Po0.05), and trunk BF-to-appendicular BF ratio alone to predict HRR2 (r2 1⁄4 0.430; Po0.001). CONCLUSIONS: BC and BF distribution were related to HRR in NAFLD patients. Trunk BF-to-appendicular BF ratio was the best independent predictor of HRR and therefore may be best related to cardiovascular increased risk, and possibly act as a mediator in age-related cardiac autonomic control variation.info:eu-repo/semantics/publishedVersio

Cardiovascular risk factors and cognitive decline in older people with type 2 diabetes

AIMS/HYPOTHESIS: The aim of this work was to assess the role of well-established cardiovascular risk factors in the late-life cognitive decline of patients with type 2 diabetes. METHODS: Data from 831 participants (aged 60-75 years) attending the 4 year follow-up of the Edinburgh Type 2 Diabetes Study (ET2DS) were used. Smoking history (pack-years), BP, HbA1c, plasma glucose and cholesterol were determined at baseline clinics (single time measurements) and/or from serial data recorded on a clinical management database from diagnosis until recruitment ('historical' data). Principal component analysis derived a factor, g, of general ability from seven cognitive tests. Linear regression models of follow-up g were adjusted for baseline g to represent 4 year cognitive change. 'Accelerated late-life cognitive decline' was defined as scoring in the lowest tertile of '4 year cognitive change' regression scores. Analyses controlled for age and sex. RESULTS: A baseline history of moderate/heavy smoking (>/= 10 pack-years) and a 1% increased historical HbA1c (equivalent to an increase by 11 mmol/mol) predicted a 64% (OR 1.64; 95% CI 1.14, 2.34; p = 0.007) and 21% (OR 1.21; 95% CI 1.00, 1.45; p = 0.046) increased risk of accelerated cognitive decline, respectively. When treated as continuous measures, higher pack-years, historical HbA1c and historical BP emerged as significant independent predictors of 4 year decline in g (standardised beta range -0.07 to -0.14; all p </= 0.05). CONCLUSIONS/INTERPRETATION: Increased smoking and poorer glycaemic control (with relatively weaker findings for BP) during the life-course were independently associated with accelerated late-life cognitive decline. Where possible, evaluation is warranted of these risk factors as targets for intervention to reduce the burden of cognitive impairment in diabetes

Practice patterns of naturopathic physicians: results from a random survey of licensed practitioners in two US States

BACKGROUND: Despite the growing use of complementary and alternative medicine (CAM) by consumers in the U.S., little is known about the practice of CAM providers. The objective of this study was to describe and compare the practice patterns of naturopathic physicians in Washington State and Connecticut. METHODS: Telephone interviews were conducted with state-wide random samples of licensed naturopathic physicians and data were collected on consecutive patient visits in 1998 and 1999. The main outcome measures were: Sociodemographic, training and practice characteristics of naturopathic physicians; and demographics, reasons for visit, types of treatments, payment source and visit duration for patients. RESULT: One hundred and seventy practitioners were interviewed and 99 recorded data on a total of 1817 patient visits. Naturopathic physicians in Washington and Connecticut had similar demographic and practice characteristics. Both the practitioners and their patients were primarily White and female. Almost 75% of all naturopathic visits were for chronic complaints, most frequently fatigue, headache, and back symptoms. Complete blood counts, serum chemistries, lipids panels and stool analyses were ordered for 4% to 10% of visits. All other diagnostic tests were ordered less frequently. The most commonly prescribed naturopathic therapeutics were: botanical medicines (51% of visits in Connecticut, 43% in Washington), vitamins (41% and 43%), minerals (35% and 39%), homeopathy (29% and 19%) and allergy treatments (11% and 13%). The mean visit length was about 40 minutes. Approximately half the visits were paid directly by the patient. CONCLUSION: This study provides information that will help other health care providers, patients and policy makers better understand the nature of naturopathic care

Competitive endothelial adhesion between Plasmodium falciparum isolates under physiological flow conditions

<p>Abstract</p> <p>Background</p> <p>Sequestration of parasitized red blood cells in the microvasculature of major organs involves a sequence of events that is believed to contribute to the pathogenesis of severe falciparum malaria. <it>Plasmodium falciparum </it>infections are commonly composed of multiple subpopulations of parasites with varied adhesive properties. A key question is: do these subpopulations compete for adhesion to endothelium? This study investigated whether, in a laboratory model of cytoadherence, there is competition in binding to endothelium between pRBC infected with <it>P. falciparum </it>of variant adhesive phenotypes, particularly under flow conditions.</p> <p>Methods</p> <p>Four different <it>P. falciparum </it>isolates, of known adherence phenotypes, were matched in pairs, mixed in different proportions and allowed to bind to cultured human endothelium. Using <it>in vitro </it>competitive static and flow-based adhesion assays, that allow simultaneous testing of the adhesive properties of two different parasite lines, adherence levels of paired <it>P. falciparum </it>isolates were quantified and analysed using either non-parametric Wilcoxon's paired signed rank test or Student paired test.</p> <p>Results</p> <p>Study findings show that <it>P. falciparum </it>parasite lines show marked differences in the efficiency of adhesion to endothelium.</p> <p>Conclusion</p> <p><it>Plasmodium falciparum </it>variants will compete for adhesion to endothelia and variants can be ranked by their efficiency of binding. These findings suggest that variants from a mixed infection will not show uniform cytoadherence and so may vary in their ability to cause disease.</p

Muscle-specific overexpression of AdipoR1 or AdipoR2 gives rise to common and discrete local effects whilst AdipoR2 promotes additional systemic effects

Hypoadiponectinemia and adiponectin resistance are implicated in the aetiology of obesity-related cardiometabolic disorders, hence represent a potential therapeutic axis. Here we characterised the effects of in vivo electrotransfer-mediated overexpression of the adiponectin receptors, AdipoR1 or AdipoR2, into tibialis anterior muscle (TAM) of lean or obese mice. In lean mice, TAM-specific overexpression of AdipoR1 (TAMR1) or AdipoR2 (TAMR2) increased phosphorylation of AMPK, AKT and ERK and expression of the insulin responsive glucose transporter glut4. In contrast, only TAMR2 increased pparα and a target gene acox1. These effects were decreased in obese mice despite no reduction in circulating adiponectin levels. TAMR2 also increased expression of adipoQ in TAM of lean and obese mice. Furthermore, in obese mice TAMR2 promoted systemic effects including; decreased weight gain; reduced epididymal fat mass and inflammation; increased epididymal adipoQ expression; increased circulating adiponectin. Collectively, these results demonstrate that AdipoR1 and AdipoR2 exhibit overlapping and distinct effects in skeletal muscle consistent with enhanced adiponectin sensitivity but these appear insufficient to ameliorate established obesity-induced adiponectin resistance. We also identify systemic effects upon TAMR2 in obese mice and postulate these are mediated by altered myokine production. Further studies are warranted to investigate this possibility which may reveal novel therapeutic approaches

Emergent Orthotopic Liver Transplantation for Hemorrhage from a Giant Cavernous Hepatic Hemangioma: Case Report and Review

IntroductionCavernous hemangiomas represent the most common benign primary hepatic neoplasm, often being incidentally detected. Although the majority of hepatic hemangiomas remain asymptomatic, symptomatic hepatic hemangiomas can present with abdominal pain, hemorrhage, biliary compression, or a consumptive coagulopathy. The optimal surgical management of symptomatic hepatic hemangiomas remains controversial, with resection, enucleation, and both deceased donor and living donor liver transplantation having been reported.Case reportWe report the case of a patient found to have a unique syndrome of multiorgan cavernous hemangiomatosis involving the liver, lung, omentum, and spleen without cutaneous involvement. Sixteen years following her initial diagnosis, the patient suffered from intra-abdominal hemorrhage due to her giant cavernous hepatic hemangioma. Evidence of continued bleeding, in the setting of Kasabach-Merritt Syndrome and worsening abdominal compartment syndrome, prompted MELD exemption listing. The patient subsequently underwent emergent liver transplantation without complication.ConclusionAlthough cavernous hemangiomas represent the most common benign primary hepatic neoplasm, hepatic hemangioma rupture remains a rare presentation in these patients. Management at a center with expertise in liver transplantation is warranted for those patients presenting with worsening DIC or hemorrhage, given the potential for rapid clinical decompensation

Timing of Favorable Conditions, Competition and Fertility Interact to Govern Recruitment of Invasive Chinese Tallow Tree in Stressful Environments

The rate of new exotic recruitment following removal of adult invaders (reinvasion pressure) influences restoration outcomes and costs but is highly variable and poorly understood. We hypothesize that broad variation in average reinvasion pressure of Triadica sebifera (Chinese tallow tree, a major invader) arises from differences among habitats in spatiotemporal availability of realized recruitment windows. These windows are periods of variable duration long enough to permit establishment given local environmental conditions. We tested this hypothesis via a greenhouse mesocosm experiment that quantified how the duration of favorable moisture conditions prior to flood or drought stress (window duration), competition and nutrient availability influenced Triadica success in high stress environments. Window duration influenced pre-stress seedling abundance and size, growth during stress and final abundance; it interacted with other factors to affect final biomass and germination during stress. Stress type and competition impacted final size and biomass, plus germination, mortality and changes in size during stress. Final abundance also depended on competition and the interaction of window duration, stress type and competition. Fertilization interacted with competition and stress to influence biomass and changes in height, respectively, but did not affect Triadica abundance. Overall, longer window durations promoted Triadica establishment, competition and drought (relative to flood) suppressed establishment, and fertilization had weak effects. Interactions among factors frequently produced different effects in specific contexts. Results support our ‘outgrow the stress’ hypothesis and show that temporal availability of abiotic windows and factors that influence growth rates govern Triadica recruitment in stressful environments. These findings suggest that native seed addition can effectively suppress superior competitors in stressful environments. We also describe environmental scenarios where specific management methods may be more or less effective. Our results enable better niche-based estimates of local reinvasion pressure, which can improve restoration efficacy and efficiency by informing site selection and optimal Management

Comparison of diffusion tensor imaging by cardiovascular magnetic resonance and gadolinium enhanced 3D image intensity approaches to investigation of structural anisotropy in explanted rat hearts

Background: Cardiovascular magnetic resonance (CMR) can through the two methods 3D FLASH and diffusion tensor imaging (DTI) give complementary information on the local orientations of cardiomyocytes and their laminar arrays. Methods: Eight explanted rat hearts were perfused with Gd-DTPA contrast agent and fixative and imaged in a 9.4T magnet by two types of acquisition: 3D fast low angle shot (FLASH) imaging, voxels 50 × 50 × 50 μm, and 3D spin echo DTI with monopolar diffusion gradients of 3.6 ms duration at 11.5 ms separation, voxels 200 × 200 × 200 μm. The sensitivity of each approach to imaging parameters was explored. Results:The FLASH data showed laminar alignments of voxels with high signal, in keeping with the presumed predominance of contrast in the interstices between sheetlets. It was analysed, using structure-tensor (ST) analysis, to determine the most (v 1 ST ), intermediate (v 2 ST ) and least (v 3 ST ) extended orthogonal directions of signal continuity. The DTI data was analysed to determine the most (e 1 DTI ), intermediate (e 2 DTI ) and least (e 3 DTI ) orthogonal eigenvectors of extent of diffusion. The correspondence between the FLASH and DTI methods was measured and appraised. The most extended direction of FLASH signal (v 1 ST ) agreed well with that of diffusion (e 1 DTI ) throughout the left ventricle (representative discrepancy in the septum of 13.3 ± 6.7°: median ± absolute deviation) and both were in keeping with the expected local orientations of the long-axis of cardiomyocytes. However, the orientation of the least directions of FLASH signal continuity (v 3 ST ) and diffusion (e 3 ST ) showed greater discrepancies of up to 27.9 ± 17.4°. Both FLASH (v 3 ST ) and DTI (e 3 DTI ) where compared to directly measured laminar arrays in the FLASH images. For FLASH the discrepancy between the structure-tensor calculated v 3 ST and the directly measured FLASH laminar array normal was of 9 ± 7° for the lateral wall and 7 ± 9° for the septum (median ± inter quartile range), and for DTI the discrepancy between the calculated v 3 DTI and the directly measured FLASH laminar array normal was 22 ± 14° and 61 ± 53.4°. DTI was relatively insensitive to the number of diffusion directions and to time up to 72 hours post fixation, but was moderately affected by b-value (which was scaled by modifying diffusion gradient pulse strength with fixed gradient pulse separation). Optimal DTI parameters were b = 1000 mm/s2 and 12 diffusion directions. FLASH acquisitions were relatively insensitive to the image processing parameters explored. Conclusions: We show that ST analysis of FLASH is a useful and accurate tool in the measurement of cardiac microstructure. While both FLASH and the DTI approaches appear promising for mapping of the alignments of myocytes throughout myocardium, marked discrepancies between the cross myocyte anisotropies deduced from each method call for consideration of their respective limitations