168 research outputs found
Experimental Models of Duchenne Muscular Dystrophy: Relationship with Cardiovascular Disease
Almost every boy that has Duchenne Muscular Dystrophy (DMD) will develop cardiac problems. Whereas, it used to be respiratory problems that was the main cause of death in these DMD boys; with the advent of better respiratory care it is now the cardiac involvement that is becoming the most common cause of their death. Once the heart is affected, there is progressive deterioration in the function of the heart over time. The main problem is the death of the cardiomyocytes. The cause of the cardiomyocyte death is due to the loss of dystrophin, this makes the sarcolemma more susceptible to damage, and leads to a cascade of calcium influx, calcium activated proteases and ultimately the death of the cardiomyocyte. The dead cardiomyocytes are replaced by fibrotic tissue, which results in a dilated cardiomyopathy (DCM) developing, which begins in the base of the left ventricle and progresses to involve the entire left ventricle. The treatments used for the DMD cardiomyopathy are based on ones designed for other forms of cardiac weakness and include ACE-inhibitors and β-blockers. New therapies based around the pathophysiology in DMD are now being introduced. This review will look at the pathophysiology of the cardiac problems in DMD and how the various animal models that are available can be used to design new treatment options for DMD boys
Bmi1 Is Expressed in Postnatal Myogenic Satellite Cells, Controls Their Maintenance and Plays an Essential Role in Repeated Muscle Regeneration
PMCID: PMC3212532This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Deciphering c-MYC-regulated genes in two distinct tissues.
BACKGROUND: The transcription factor MYC is a critical regulator of diverse cellular processes, including both replication and apoptosis. Differences in MYC-regulated gene expression responsible for such opposing outcomes in vivo remain obscure. To address this we have examined time-dependent changes in global gene expression in two transgenic mouse models in which MYC activation, in either skin suprabasal keratinocytes or pancreatic islet β-cells, promotes tissue expansion or involution, respectively. RESULTS: Consistent with observed phenotypes, expression of cell cycle genes is increased in both models (albeit enriched in β-cells), as are those involved in cell growth and metabolism, while expression of genes involved in cell differentiation is down-regulated. However, in β-cells, which unlike suprabasal keratinocytes undergo prominent apoptosis from 24 hours, there is up-regulation of genes associated with DNA-damage response and intrinsic apoptotic pathways, including Atr, Arf, Bax and Cycs. In striking contrast, this is not the case for suprabasal keratinocytes, where pro-apoptotic genes such as Noxa are down-regulated and key anti-apoptotic pathways (such as Igf1-Akt) and those promoting angiogenesis are up-regulated. Moreover, dramatic up-regulation of steroid hormone-regulated Kallikrein serine protease family members in suprabasal keratinocytes alone could further enhance local Igf1 actions, such as through proteolysis of Igf1 binding proteins. CONCLUSIONS: Activation of MYC causes cell growth, loss of differentiation and cell cycle entry in both β-cells and suprabasal keratinocytes in vivo. Apoptosis, which is confined to β-cells, may involve a combination of a DNA-damage response and downstream activation of pro-apoptotic signalling pathways, including Cdc2a and p19(Arf)/p53, and downstream targets. Conversely, avoidance of apoptosis in suprabasal keratinocytes may result primarily from the activation of key anti-apoptotic signalling pathways, particularly Igf1-Akt, and induction of an angiogenic response, though intrinsic resistance to induction of p19(Arf) by MYC in suprabasal keratinocytes may contribute.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are
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Interactions between the stratospheric polar vortex and Atlantic circulation on seasonal to multi-decadal timescales
Variations in the strength of the Northern Hemisphere winter polar stratospheric vortex can influence surface variability in the Atlantic sector. Disruptions of the vortex, known as sudden stratospheric warmings (SSWs), are associated with an equatorward shift and deceleration of the North Atlantic jet stream, negative phases of the North Atlantic Oscillation, and cold snaps over Eurasia and North America. Despite clear influences at the surface on sub-seasonal timescales, how stratospheric vortex variability interacts with ocean circulation on decadal to multi-decadal timescales is less well understood. In this study, we use a 1000 year preindustrial control simulation of the UK Earth System Model to study such interactions, using a wavelet analysis technique to examine non-stationary periodic signals in the vortex and ocean. We find that intervals which exhibit persistent anomalous vortex behaviour lead to oscillatory responses in the Atlantic Meridional Overturning Circulation (AMOC). The origin of these responses appears to be highly non-stationary, with spectral power in vortex variability at periods of 30 and 50 years. In contrast, AMOC variations on longer timescales (near 90-year periods) are found to lead to a vortex response through a pathway involving the equatorial Pacific and quasi-biennial oscillation. Using the relationship between persistent vortex behaviour and the AMOC response established in the model, we use regression analysis to estimate the potential contribution of the 8-year SSW hiatus interval in the 1990s to the recent negative trend in AMOC observations. The result suggests that approximately 30 % of the trend may have been caused by the SSW hiatus
Wnt/Lef1 signaling acts via Pitx2 to regulate somite myogenesis
AbstractWnt signaling has been implicated in somite, limb, and branchial arch myogenesis but the mechanisms and roles are not clear. We now show that Wnt signaling via Lef1 acts to regulate the number of premyogenic cells in somites but does not regulate myogenic initiation in the limb bud or maintenance in the first or second branchial arch. We have also analysed the function and regulation of a putative downstream transcriptional target of canonical Wnt signaling, Pitx2. We show that loss-of-function of Pitx2 decreases the number of myogenic cells in the somite, whereas overexpression increases myocyte number particularly in the epaxial region of the myotome. Increased numbers of mitotic cells were observed following overexpression of Pitx2 or an activated form of Lef1, suggesting an effect on cell proliferation. In addition, we show that Pitx2 expression is regulated by canonical Wnt signaling in the epaxial somite and second branchial arch, but not in the limb or the first branchial arch. These results suggest that Wnt/Lef1 signaling regulates epaxial myogenesis via Pitx2 but that this link is uncoupled in other regions of the body, emphasizing the unique molecular networks that control the development of various muscles in vertebrates
A prospective evaluation of thiamine and magnesium status in relation to clinicopathological characteristics and 1-year mortality in patients with Alcohol Withdrawal Syndrome
Background:
Alcohol withdrawal syndrome (AWS) is routinely treated with B-vitamins. However, the relationship between thiamine status and outcome is rarely examined. The aim of the present study was to examine the relationship between thiamine and magnesium status in patients with AWS.
Methods:
Patients (n = 127) presenting to the Emergency Department with AWS were recruited to a prospective observational study. Blood samples were drawn to measure whole blood thiamine diphosphate (TDP) and serum magnesium concentrations. Routine biochemistry and haematology assays were also conducted. The Glasgow Modified Alcohol Withdrawal Score (GMAWS) measured severity of AWS. Seizure history and current medications were also recorded.
Results:
The majority of patients (99%) had whole blood TDP concentration within/above the reference interval (275–675 ng/gHb) and had been prescribed thiamine (70%). In contrast, the majority of patients (60%) had low serum magnesium concentrations (< 0.75 mmol/L) and had not been prescribed magnesium (93%). The majority of patients (66%) had plasma lactate concentrations above 2.0 mmol/L. At 1 year, 13 patients with AWS had died giving a mortality rate of 11%. Male gender (p < 0.05), BMI < 20 kg/m2 (p < 0.01), GMAWS max ≥ 4 (p < 0.05), elevated plasma lactate (p < 0.01), low albumin (p < 0.05) and elevated serum CRP (p < 0.05) were associated with greater 1-year mortality. Also, low serum magnesium at time of recruitment to study and low serum magnesium at next admission were associated with higher 1-year mortality rates, (84% and 100% respectively; both p < 0.05).
Conclusion:
The prevalence of low circulating thiamine concentrations were rare and it was regularly prescribed in patients with AWS. In contrast, low serum magnesium concentrations were common and not prescribed. Low serum magnesium was associated more severe AWS and increased 1-year mortality
Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers
Peer reviewedPublisher PD
Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers
Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes or . The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates.
We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through populationbased GWAS: for BC (overall, estrogen receptor [ER]–positive, and ER-negative) and for OC. Using data from 15 252 female and 8211 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS.
The PRS for ER-negative BC displayed the strongest association with BC risk in carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, = 8.2 10). In carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, = 7.2 10). The OC PRS was strongly associated with OC risk for both and carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom AR deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS.
BC and OC PRS are predictive of cancer risk in and carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.Cancer Research U
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Historical simulations with HadGEM3-GC3.1 for CMIP6
We describe and evaluate historical simulations which use the third Hadley Centre Global Environment Model in the Global Coupled configuration 3.1 (HadGEM3-GC3.1) model and which form part of the UK's contribution to the sixth Coupled Model Intercomparison Project, CMIP6. These simulations, run at two resolutions, respond to historically evolving forcings such as greenhouse gases, aerosols, solar irradiance, volcanic aerosols, land use, and ozone concentrations. We assess the response of the simulations to these historical forcings and compare against the observational record. This includes the evolution of global mean surface temperature, ocean heat content, sea ice extent, ice sheet mass balance, permafrost extent, snow cover, North Atlantic sea surface temperature and circulation, and decadal precipitation. We find that the simulated time evolution of global mean surface temperature broadly follows the observed record but with important quantitative differences which we find are most likely attributable to strong effective radiative forcing from anthropogenic aerosols and a weak pattern of sea surface temperature response in the low to middle latitudes to volcanic eruptions. We also find evidence that anthropogenic aerosol forcings play a role in driving the Atlantic Multidecadal Variability and the Atlantic Meridional Overturning Circulation, which are key features of the North Atlantic ocean. Overall, the model historical simulations show many features in common with the observed record over the period 1850–2014 and so provide a basis for future in-depth study of recent climate change
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Preindustrial control simulations with HadGEM3-GC3.1 for CMIP6
Pre‐industrial control simulations with the HadGEM3‐GC3.1 climate model are presented at two resolutions. These are N216ORCA025, which has a horizontal resolution of 60km in the atmosphere and 0.25° in the ocean, and N96ORCA1, which has a horizontal resolution of 130km in the atmosphere and 1° in the ocean. The aim of this study is to document the climate variability in these simulations, make comparisons against present‐day observations (albeit under different forcing), and discuss differences arising due to resolution. In terms of interannual variability in the leading modes of climate variability the two resolutions behave generally very similarly. Notable differences are in the westward extent of El‐Niño and the pattern of Atlantic multidecadal variability, in which N216ORCA025 compares more favourably to observations, and in the Antarctic Circumpolar Current, which is far too weak in N216ORCA025. In the North Atlantic region, N216ORCA025 has a stronger and deeper AMOC, which compares well against observations, and reduced biases in temperature and salinity in the North Atlantic subpolar gyre (NA SPG). These simulations are being provided to the sixth Coupled Model Intercomparison Project (CMIP6) and provide a baseline against which further forced experiments may be assessed
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