Overexpression of CUGBP1 in skeletal muscle from adult classic myotonic dystrophy type 1 but not from myotonic dystrophy type 2

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are progressive multisystemic disorders caused by similar mutations at two different genetic loci. The common key feature of DM pathogenesis is nuclear accumulation of mutant RNA which causes aberrant alternative splicing of specific pre-mRNAs by altering the functions of two RNA binding proteins, MBNL1 and CUGBP1. However, DM1 and DM2 show disease-specific features that make them clearly separate diseases suggesting that other cellular and molecular pathways may be involved. In this study we have analysed the histopathological, and biomolecular features of skeletal muscle biopsies from DM1 and DM2 patients in relation to presenting phenotypes to better define the molecular pathogenesis. Particularly, the expression of CUGBP1 protein has been examined to clarify if this factor may act as modifier of disease-specific manifestations in DM. The results indicate that the splicing and muscle pathological alterations observed are related to the clinical phenotype both in DM1 and in DM2 and that CUGBP1 seems to play a role in classic DM1 but not in DM2. In conclusion, our results indicate that multisystemic disease spectrum of DM pathologies may not be explained only by spliceopathy thus confirming that the molecular pathomechanism of DM is more complex than that actually suggested

A review of methods for assessment of coronary microvascular disease in both clinical and experimental settings

Obstructive disease of the large coronary arteries is the prominent cause for angina pectoris. However, angina may also occur in the absence of significant coronary atherosclerosis or coronary artery spasm, especially in women. Myocardial ischaemia in these patients is often associated with abnormalities of the coronary microcirculation and may thus represent a manifestation of coronary microvascular disease (CMD). Elucidation of the role of the microvasculature in the genesis of myocardial ischaemia and cardiac damage—in the presence or absence of obstructive coronary atherosclerosis—will certainly result in more rational diagnostic and therapeutic interventions for patients with ischaemic heart disease. Specifically targeted research based on improved assessment modalities is needed to improve the diagnosis of CMD and to translate current molecular, cellular, and physiological knowledge into new therapeutic option

Utility of Whole Blood Thiamine Pyrophosphate Evaluation in TPK1-Related Diseases

TPK1 mutations are a rare, but potentially treatable, cause of thiamine deficiency. Diagnosis is challenging given the phenotypic overlap that exists with other metabolic and neurological disorders. We report a case of TPK1-related disease presenting with Leigh-like syndrome and review the diagnostic utility of thiamine pyrophosphate (TPP) blood measurement. The proband, a 35-year-old male, presented at four months of age with recurrent episodes of post-infectious encephalopathy. He subsequently developed epilepsy, learning difficulties, sensorineural hearing loss, spasticity, and dysphagia. There was a positive family history for Leigh syndrome in an older brother. Plasma lactate was elevated (3.51 mmol/L) and brain MRI showed bilateral basal ganglia hyperintensities, indicative of Leigh syndrome. Histochemical and spectrophotometric analysis of mitochondrial respiratory chain complexes I, II+III, and IV was normal. Genetic analysis of muscle mitochondrial DNA was negative. Whole exome sequencing of the proband confirmed compound heterozygous variants in TPK1: c. 426G>C (p. Leu142Phe) and c. 258+1G>A (p.?). Blood TPP levels were reduced, providing functional evidence for the deleterious effects of the variants. We highlight the clinical and bioinformatics challenges to diagnosing rare genetic disorders and the continued utility of biochemical analyses, despite major advances in DNA sequencing technology, when investigating novel, potentially disease-causing, genetic variants. Blood TPP measurement represents a fast and cost-effective diagnostic tool in TPK1-related diseases

The Role of Vasospasm and Microcirculatory Dysfunction in Fluoropyrimidine-Induced Ischemic Heart Disease

Cardiovascular diseases and cancer are the leading cause of morbidity and mortality globally. Cardiotoxicity from chemotherapeutic agents results in substantial morbidity and mortality in cancer survivors and patients with active cancer. Cardiotoxicity induced by 5-fluorouracil (5-FU) has been well established, yet its incidence, mechanisms, and manifestation remain poorly defined. Ischemia secondary to coronary artery vasospasm is thought to be the most frequent cardiotoxic effect of 5-FU. The available evidence of 5-FU-induced epicardial coronary artery spasm and coronary microvascular dysfunction suggests that endothelial dysfunction or primary vascular smooth muscle dysfunction (an endothelial-independent mechanism) are the possible contributing factors to this form of cardiotoxicity. In patients with 5-FU-related coronary artery vasospasm, termination of chemotherapy and administration of nitrates or calcium channel blockers may improve ischemic symptoms. However, there are variable results after administration of nitrates or calcium channel blockers in patients treated with 5-FU presumed to have myocardial ischemia, suggesting mechanisms other than impaired vasodilatory response. Clinicians should investigate whether chest pain and ECG changes can reasonably be attributed to 5-FU-induced cardiotoxicity. More prospective data and clinical randomized trials are required to understand and mitigate potentially adverse outcomes from 5-FU-induced cardiotoxicity

Sex Disparities in Ischemic Heart Disease Mortality in Europe

Background: Ischemic heart disease (IHD) is the leading cause of death in the European Union (EU). Understanding variations by sex, income, and countries can help in tailoring effective public health policies. Objectives: The purpose of the study was to examine trends in sex differences in IHD prevalence and prognosis within the EU. Methods: We conducted a cross-sectional analysis of IHD using the Global Burden of Disease Study Database to examine trends in sex-specific age-standardized mortality rate (ASMR)-to-age-standardized prevalence rate (ASPR) ratio (ASMR-to-ASPR index) per 100,000 inhabitants/year across the EU from 2005 to 2019. Results: Men showed higher ASMR than women. However, the ASMR-to-ASPR index was notably higher in women than in men indicating that women who develop IHD have a higher risk of dying from the disease compared with their male counterparts. Despite a significant decline in ASMR across EU from 2005 to 2019 both among women (from 1.752 to 1.662) and men (from 3.372 to 3.135), sex disparities in ASMR-to-ASPR index (EU average: 4.96% vs 4.34%) persisted (with a women-to-men ratio ranging from 1.05 to 1.44). No significant relationship was found between country-specific ASMR or country income status and ASMR-to-ASPR index. Examples include Romania, which displayed higher ASMR (men: 219.87, women: 143.54) compared with Germany (men: 107.22, women: 60.76), yet with smaller differences in ASMR-to-ASPR index between women and men (Romania: 6.54% vs 5.85%; ratio: 1.12, and Germany: 4.79% vs 3.80%; ratio: 1.26). Conclusions: Mortality from IHD has decreased substantially among EU countries. However, the declines were accompanied by a persistently higher ASMR-to-ASPR index in women, indicating significant potential for further gains in closing the gender gap in IHD mortality

Clinical and genetic characterization of leukoencephalopathies in adults

Leukodystrophies and genetic leukoencephalopathies are a rare group of disorders leading to progressive degeneration of cerebral white matter. They are associated with a spectrum of clinical phenotypes dominated by dementia, psychiatric changes, movement disorders and upper motor neuron signs. Mutations in at least 60 genes can lead to leukoencephalopathy with often overlapping clinical and radiological presentations. For these reasons, patients with genetic leukoencephalopathies often endure a long diagnostic odyssey before receiving a definitive diagnosis or may receive no diagnosis at all. In this study, we used focused and whole exome sequencing to evaluate a cohort of undiagnosed adult patients referred to a specialist leukoencephalopathy service. In total, 100 patients were evaluated using focused exome sequencing of 6100 genes. We detected pathogenic or likely pathogenic variants in 26 cases. The most frequently mutated genes were NOTCH3, EIF2B5, AARS2 and CSF1R. We then carried out whole exome sequencing on the remaining negative cases including four family trios, but could not identify any further potentially disease-causing mutations, confirming the equivalence of focused and whole exome sequencing in the diagnosis of genetic leukoencephalopathies. Here we provide an overview of the clinical and genetic features of these disorders in adults

Coronary revascularisation in stable patients after an acute coronary syndrome: a propensity analysis of early invasive versus conservative management in a register-based cohort study

OBJECTIVES: To compare the effectiveness of in-hospital medical therapy versus coronary revascularisation added to medical therapy in patients who stabilised after an acute coronary syndrome (ACS). DESIGN: Propensity score-matched cohort study from the database of the Tampere ACS registry. SETTING: A single academic hospital in Finland. PARTICIPANTS: 1149 patients with a recent ACS, but no serious coexisting conditions: recurrent ischaemic episodes despite adequate medical therapy, haemodynamic instability, overt congestive heart failure and serious ventricular arrhythmias. PRIMARY AND SECONDARY OUTCOME MEASURES: The composite endpoint of major acute cardiovascular events (MACEs): unstable angina requiring rehospitalisation, stroke, myocardial infarction and all-cause mortality, at 6-month follow-up. RESULTS: Compared with standard medical treatment, revascularisation was associated with a lower rate of MACEs at 6 months in patients of the first quintile (HR 0.81; 95% CI 0.66 to 0.99), but a higher rate of MACEs in the fifth quintile (HR 4.74, CI 1.36 to 16.49; p=0.014). There were no significant differences in the rates of MACEs in the remaining three quintiles. Patients of the first quintile were the oldest (79.7\ub18.3 years) and had a more significant (p<0.001) history of prior myocardial infarction (37%) and poor renal function (creatine, \ub5mol/l: 114.9\ub170.7). They also showed the highest C reactive protein (7.3\ub19.5 mg/l) levels. CONCLUSIONS: Our findings suggest that in-hospital coronary revascularisation did not lead to any advantage with signal of possible harm in the great majority of patients who stabilised after an ACS. An early invasive management strategy may be best reserved for elderly patients having high-risk clinical features and biochemical evidence of a strong inflammatory activity

2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC).

peer reviewe

Multisystem mitochondrial disease caused by a rare m.10038G>A mitochondrial tRNAGly (MT-TG) variant

Most pathogenic mitochondrial DNA (mtDNA) variants occur in the 22 mtDNA-encoded tRNA (mt-tRNA) genes. However, despite more than 270 reported mt-tRNA gene mutations, only 5 reside within mt-tRNAGly (MT-TG). We report a rare MT-TG variant and evaluate this, in addition to all previously reported MT-TG variants, against the published criteria used to help determine the pathogenicity of the mt-tRNA variants