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

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

Environmental Effects of Stratospheric Ozone Depletion, UV Radiation, and interactions with Climate Change: 2022 Assessment Report

The Montreal Protocol on Substances that Deplete the Ozone Layer was established 35 years ago following the 1985 Vienna Convention for protection of the environment and human health against excessive amounts of harmful ultraviolet-B (UV-B, 280-315 nm) radiation reaching the Earth’s surface due to a reduced UV-B-absorbing ozone layer. The Montreal Protocol, ratified globally by all 198 Parties (countries), controls ca 100 ozone-depleting substances (ODS). These substances have been used in many applications, such as in refrigerants, air conditioners, aerosol propellants, fumigants against pests, fire extinguishers, and foam materials. The Montreal Protocol has phased out nearly 99% of ODS, including ODS with high global warming potentials such as chlorofluorocarbons (CFC), thus serving a dual purpose. However, some of the replacements for ODS also have high global warming potentials, for example, the hydrofluorocarbons (HFCs). Several of these replacements have been added to the substances controlled by the Montreal Protocol. The HFCs are now being phased down under the Kigali Amendment. As of December 2022, 145 countries have signed the Kigali Amendment, exemplifying key additional outcomes of the Montreal Protocol, namely, that of also curbing climate warming and stimulating innovations to increase energy efficiency of cooling equipment used industrially as well as domestically. As the concentrations of ODS decline in the upper atmosphere, the stratospheric ozone layer is projected to recover to pre-1980 levels by the middle of the 21st century, assuming full compliance with the control measures of the Montreal Protocol. However, in the coming decades, the ozone layer will be increasingly influenced by emissions of greenhouse gases and ensuing global warming. These trends are highly likely to modify the amount of UV radiation reaching the Earth\u27s surface with implications for the effects on ecosystems and human health. Against this background, four Panels of experts were established in 1988 to support and advise the Parties to the Montreal Protocol with up-to-date information to facilitate decisions for protecting the stratospheric ozone layer. In 1990 the four Panels were consolidated into three, the Scientific Assessment Panel, the Environmental Effects Assessment Panel, and the Technology and Economic Assessment Panel. Every four years, each of the Panels provides their Quadrennial Assessments as well as a Synthesis Report that summarises the key findings of all the Panels. In the in-between years leading up to the quadrennial, the Panels continue to inform the Parties to the Montreal Protocol of new scientific information

Log odds of carrying an Ancestral Mutation in BRCA1 or BRCA2 for a Defined personal and family history in an Ashkenazi Jewish woman (LAMBDA)

INTRODUCTION: Ancestral mutations in BRCA1 and BRCA2 are common in people of Ashkenazi Jewish descent and are associated with a substantially increased risk of breast and ovarian cancer. Women considering mutation testing usually have several personal and family cancer characteristics, so predicting mutation status from one factor alone could be misleading. The aim of this study was to develop a simple algorithm to estimate the probability that an Ashkenazi Jewish woman carries an ancestral mutation, based on multiple predictive factors. METHODS: We studied Ashkenazi Jewish women with a personal or family history of breast or ovarian cancer and living in Melbourne or Sydney, Australia, or with a previous diagnosis of breast or ovarian cancer and living in the UK. DNA samples were tested for the germline mutations 185delAG and 5382insC in BRCA1, and 6174delT in BRCA2. Logistic regression was used to identify, and to estimate the predictive strength of, major determinants. RESULTS: A mutation was detected in 64 of 424 women. An algorithm was developed by combining our findings with those from similar analyses of a large study of unaffected Jewish women in Washington. Starting with a baseline score, a multiple of 0.5 (based on the logistic regression estimates) is added for each predictive feature. The sum is the estimated log odds ratio that a woman is a carrier, and is converted to a probability by using a table. There was good internal consistency. CONCLUSIONS: This simple algorithm might be useful in the clinical and genetic counselling setting. Comparison and validation in other settings should be sought

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

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>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

Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Background: 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 BRCA1 or BRCA2. 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. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 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. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management

Ozone depletion, ultraviolet radiation, climate change and prospects for a sustainable future

Changes in stratospheric ozone and climate over the past 40-plus years have altered the solar ultraviolet (UV) radiation conditions at the Earth's surface. Ozone depletion has also contributed to climate change across the Southern Hemisphere. These changes are interacting in complex ways to affect human health, food and water security, and ecosystem services. Many adverse effects of high UV exposure have been avoided thanks to the Montreal Protocol with its Amendments and Adjustments, which have effectively controlled the production and use of ozone-depleting substances. This international treaty has also played an important role in mitigating climate change. Climate change is modifying UV exposure and affecting how people and ecosystems respond to UV; these effects will become more pronounced in the future. The interactions between stratospheric ozone, climate and UV radiation will therefore shift over time; however, the Montreal Protocol will continue to have far-reaching benefits for human well-being and environmental sustainability.Peer reviewe

Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

Introduction: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. Methods: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. Results: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive as