Conscious surgery: influence of the environment on patient anxiety

Aims: i) To investigate anxiety arising from the experience of the clinical environment during surgery under local/ regional anaesthesia and, ii) to uncover the specific aspects patients find anxiety provoking and possibly dissuade them from opting for such anaesthesia. Background: Operating theatres have historical been designed for safe, efficient surgery on the unconscious patient and not primarily designed for the care of the ‘awake’ patient. However, with the rise in day surgery, the quantity of surgery performed under local/ regional anaesthesia is increasing. Method: As part of a larger study investigating anxiety within modern elective day surgery, adult patients undergoing surgery and local/ regional anaesthesia (n=214) were provided with a questionnaire on the day of surgery for return by mail 24 - 48 hours following surgery. Findings: The experience of being awake, possibly feeling surgeon, seeing body cut open or surgery being more painful were anxiety provoking aspects. Utilising factor analysis ‘intra-operative apprehension’, ‘anaesthetic information provision and ‘health control’ were identified as central features. Moreover, when employing multiple regression, apprehension associated with the intra-operative experience and anaesthetic information provision were significantly associated with an increase in the overall level of anxiety. Conclusions: Although the surrounding clinical environment has previously been a cause of apprehension, the sensations associated with the physical act of surgery on the conscious self appear also to have a considerable influence. Focusing care upon managing patient intra-operative experience and providing anaesthetic information in advance may help limit anxiety and expel the apparent misapprehensions associated with conscious surgery

Maternal corticotropin-releasing hormone is associated with LEP DNA methylation at birth and in childhood: an epigenome-wide study in Project Viva

BackgroundCorticotropin-releasing hormone (CRH) plays a central role in regulating the secretion of cortisol which controls a wide range of biological processes. Fetuses overexposed to cortisol have increased risks of disease in later life. DNA methylation may be the underlying association between prenatal cortisol exposure and health effects. We investigated associations between maternal CRH levels and epigenome-wide DNA methylation of cord blood in offsprings and evaluated whether these associations persisted into mid-childhood.MethodsWe investigated mother-child pairs enrolled in the prospective Project Viva pre-birth cohort. We measured DNA methylation in 257 umbilical cord blood samples using the HumanMethylation450 Bead Chip. We tested associations of maternal CRH concentration with cord blood cells DNA methylation, adjusting the model for maternal age at enrollment, education, maternal race/ethnicity, maternal smoking status, pre-pregnancy body mass index, parity, gestational age at delivery, child sex, and cell-type composition in cord blood. We further examined the persistence of associations between maternal CRH levels and DNA methylation in children's blood cells collected at mid-childhood (n = 239, age: 6.7-10.3 years) additionally adjusting for the children's age at blood drawn.ResultsMaternal CRH levels are associated with DNA methylation variability in cord blood cells at 96 individual CpG sites (False Discovery Rate <0.05). Among the 96 CpG sites, we identified 3 CpGs located near the LEP gene. Regional analyses confirmed the association between maternal CRH and DNA methylation near LEP. Moreover, higher maternal CRH levels were associated with higher blood-cell DNA methylation of the promoter region of LEP in mid-childhood (P < 0.05, β = 0.64, SE = 0.30).ConclusionIn our cohort, maternal CRH was associated with DNA methylation levels in newborns at multiple loci, notably in the LEP gene promoter. The association between maternal CRH and LEP DNA methylation levels persisted into mid-childhood

SREBP-2/PNPLA8 axis improves non-alcoholic fatty liver disease through activation of autophagy

Dysregulated autophagy is associated with steatosis and non-alcoholic fatty liver disease (NAFLD), however the mechanisms connecting them remain poorly understand. Here, we show that co-administration of lovastatin and ezetimibe (L/E) significantly reverses hepatic triglyceride accumulation concomitant with an increase in SREBP-2 driven autophagy in mice fed a high-fat diet (HFD). We further show that the statin mediated increase in SREBP-2 directly activates expression of patatin-like phospholipase domain-containing enzyme 8 (PNPLA8) gene, and PNPLA8 associates with autophagosomes and is associated with a decrease in cellular triglyceride. Moreover, we show that over-expression of PNPLA8 dramatically decreases hepatic steatosis through increased autophagy in hepatocytes of HFD-fed mice. Live-cell imaging analyses also reveal that PNPLA8 dynamically interacts with LC3 and we suggest that the SREBP-2/PNPLA8 axis represents a novel regulatory mechanism for lipid homeostasis. These data provide a possible mechanism for the reported beneficial effects of statins for decreasing hepatic triglyceride levels in NAFLD patients.ope

Regulators of genetic risk of breast cancer identified by integrative network analysis.

Genetic risk for breast cancer is conferred by a combination of multiple variants of small effect. To better understand how risk loci might combine, we examined whether risk-associated genes share regulatory mechanisms. We created a breast cancer gene regulatory network comprising transcription factors and groups of putative target genes (regulons) and asked whether specific regulons are enriched for genes associated with risk loci via expression quantitative trait loci (eQTLs). We identified 36 overlapping regulons that were enriched for risk loci and formed a distinct cluster within the network, suggesting shared biology. The risk transcription factors driving these regulons are frequently mutated in cancer and lie in two opposing subgroups, which relate to estrogen receptor (ER)(+) luminal A or luminal B and ER(-) basal-like cancers and to different luminal epithelial cell populations in the adult mammary gland. Our network approach provides a foundation for determining the regulatory circuits governing breast cancer, to identify targets for intervention, and is transferable to other disease settings.This work was funded by Cancer Research UK and the Breast Cancer Research Foundation. MAAC is funded by the National Research Council (CNPq) of Brazil. TEH held a fellowship from the US DOD Breast Cancer Research Program (W81XWH-11-1-0592) and is currently supported by an RAH Career Development Fellowship (Australia). TEH and WDT are funded by the NHMRC of Australia (NHMRC) (ID: 1008349 WDT; 1084416 WDT, TEH) and Cancer Australia/National Breast Cancer Foundation (ID 627229; WDT, TEH). BAJP is a Gibb Fellow of Cancer Research UK. We would like to acknowledge the support of The University of Cambridge, Cancer Research UK and Hutchison Whampoa Limited.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ng.345

Molecular Basis for Vulnerability to Mitochondrial and Oxidative Stress in a Neuroendocrine CRI-G1 Cell Line

Many age-associated disorders (including diabetes, cancer, and neurodegenerative diseases) are linked to mitochondrial dysfunction, which leads to impaired cellular bioenergetics and increased oxidative stress. However, it is not known what genetic and molecular pathways underlie differential vulnerability to mitochondrial dysfunction observed among different cell types.Starting with an insulinoma cell line as a model for a neuronal/endocrine cell type, we isolated a novel subclonal line (named CRI-G1-RS) that was more susceptible to cell death induced by mitochondrial respiratory chain inhibitors than the parental CRI-G1 line (renamed CRI-G1-RR for clarity). Compared to parental RR cells, RS cells were also more vulnerable to direct oxidative stress, but equally vulnerable to mitochondrial uncoupling and less vulnerable to protein kinase inhibition-induced apoptosis. Thus, differential vulnerability to mitochondrial toxins between these two cell types likely reflects differences in their ability to handle metabolically generated reactive oxygen species rather than differences in ATP production/utilization or in downstream apoptotic machinery. Genome-wide gene expression analysis and follow-up biochemical studies revealed that, in this experimental system, increased vulnerability to mitochondrial and oxidative stress was associated with (1) inhibition of ARE/Nrf2/Keap1 antioxidant pathway; (2) decreased expression of antioxidant and phase I/II conjugation enzymes, most of which are Nrf2 transcriptional targets; (3) increased expression of molecular chaperones, many of which are also considered Nrf2 transcriptional targets; (4) increased expression of β cell-specific genes and transcription factors that specify/maintain β cell fate; and (5) reconstitution of glucose-stimulated insulin secretion.The molecular profile presented here will enable identification of individual genes or gene clusters that shape vulnerability to mitochondrial dysfunction and thus represent potential therapeutic targets for diabetes and neurodegenerative diseases. In addition, the newly identified CRI-G1-RS cell line represents a new experimental model for investigating how endogenous antioxidants affect glucose sensing and insulin release by pancreatic β cells

Gadolinium free cardiovascular magnetic resonance with 2-point Cine balanced steady state free precession

BACKGROUND: Cardiovascular magnetic resonance (CMR) of ventricular structure and function is widely performed using cine balanced steady state free precession (bSSFP) MRI. The bSSFP signal of myocardium is weighted by magnetization transfer (MT) and T1/T2-relaxation times. In edematous and fibrotic tissues, increased T2 and reduced MT lead to increased signal intensity on images acquired with high excitation flip angles. We hypothesized that acquisition of two differentially MT-weighted bSSFP images (termed 2-point bSSFP) can identify tissue that would enhance with gadolinium similar to standard of care late gadolinium enhancement (LGE). METHODS: Cine bSSFP images (flip angles of 5° and 45°) and native-T1 and T2 maps were acquired in one mid-ventricular slice in 47 patients referred for CMR and 10 healthy controls. Afterwards, LGE images and post-contrast T1 maps were acquired and gadolinium partition coefficient (GPC) was calculated. Maps of ΔS/S(o) were calculated as (S(45)-S(5))/S(5)*100 (%), where S(flip_angle) is the voxel signal intensity. RESULTS: Twenty three patients demonstrated areas of myocardial hyper-enhancement with LGE. In enhanced regions, ΔS/S(o), native-T1, T2, and GPC were heightened (p < 0.05 vs. non-enhanced tissues). ΔS/S(o), native-T1, and T2 all demonstrated association with GPC, however the association was strongest for ΔS/S(o). Bland-Altman analysis revealed a slight bias towards larger volume of enhancement with ΔS/S(o) compared to LGE, and similar transmurality. Subjective analysis with 2-blinded expert readers revealed agreement between ΔS/S(o) and LGE of 73.4 %, with false positive detection of 16.7 % and false negative detection of 15.2 %. CONCLUSIONS: Gadolinium free 2-point bSSFP identified tissue that enhances at LGE with strong association to GPC. Our results suggest that with further development, MT-weighted CMR could be used similar to LGE for diagnostic imaging. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12968-015-0194-1) contains supplementary material, which is available to authorized users

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Penilaian Kinerja Keuangan Koperasi di Kabupaten Pelalawan

This paper describe development and financial performance of cooperative in District Pelalawan among 2007 - 2008. Studies on primary and secondary cooperative in 12 sub-districts. Method in this stady use performance measuring of productivity, efficiency, growth, liquidity, and solvability of cooperative. Productivity of cooperative in Pelalawan was highly but efficiency still low. Profit and income were highly, even liquidity of cooperative very high, and solvability was good