Search

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common genetic disease of the cardiac muscle, frequently caused by mutations in MYBPC3. However, little is known about the upstream pathways and key regulators causing the disease. Therefore, we employed a multi-omics approach to study the pathomechanisms underlying HCM comparing patient hearts harboring MYBPC3 mutations to control hearts.RESULTS: Using H3K27ac ChIP-seq and RNA-seq we obtained 9310 differentially acetylated regions and 2033 differentially expressed genes, respectively, between 13 HCM and 10 control hearts. We obtained 441 differentially expressed proteins between 11 HCM and 8 control hearts using proteomics. By integrating multi-omics datasets, we identified a set of DNA regions and genes that differentiate HCM from control hearts and 53 protein-coding genes as the major contributors. This comprehensive analysis consistently points toward altered extracellular matrix formation, muscle contraction, and metabolism. Therefore, we studied enriched transcription factor (TF) binding motifs and identified 9 motif-encoded TFs, including KLF15, ETV4, AR, CLOCK, ETS2, GATA5, MEIS1, RXRA, and ZFX. Selected candidates were examined in stem cell-derived cardiomyocytes with and without mutated MYBPC3. Furthermore, we observed an abundance of acetylation signals and transcripts derived from cardiomyocytes compared to non-myocyte populations.CONCLUSIONS: By integrating histone acetylome, transcriptome, and proteome profiles, we identified major effector genes and protein networks that drive the pathological changes in HCM with mutated MYBPC3. Our work identifies 38 highly affected protein-coding genes as potential plasma HCM biomarkers and 9 TFs as potential upstream regulators of these pathomechanisms that may serve as possible therapeutic targets.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease. While ≈50% of patients with HCM carry a sarcomere gene mutation (sarcomere mutation-positive, HCMSMP), the genetic background is unknown in the other half of the patients (sarcomere mutation-negative, HCMSMN). Genotype-specific differences have been reported in cardiac function. Moreover, HCMSMN patients have later disease onset and a better prognosis than HCMSMP patients. To define if genotype-specific derailments at the protein level may explain the heterogeneity in disease development, we performed a proteomic analysis in cardiac tissue from a clinically well-phenotyped HCM patient group. METHODS: A proteomics screen was performed in cardiac tissue from 39 HCMSMP patients, 11HCMSMN patients, and 8 nonfailing controls. Patients with HCM had obstructive cardiomyopathy with left ventricular outflow tract obstruction and diastolic dysfunction. A novel MYBPC32373insG mouse model was used to confirm functional relevance of our proteomic findings. RESULTS: In all HCM patient samples, we found lower levels of metabolic pathway proteins and higher levels of extracellular matrix proteins. Levels of to

Background: The clinical outcome of hypertrophic cardiomyopathy patients is not only determined by the disease-causing mutation but influenced by a variety of disease modifiers. Here, we defined the role of the mutation location and the mutant protein dose of the troponin T mutations I79N, R94C and R278C. Methods and results: We determined myo

Background: Sex-differences in clinical presentation contribute to the phenotypic heterogeneity of hypertrophic cardiomyopathy (HCM) patients. While disease prevalence is higher in men, women present with more severe diastolic dysfunction and worse survival. Until today, little is known about the cellular differences underlying sex-differences in clinical presentation. Methods: To define sex-differences at the protein level, we performed a proteomic analysis in cardiac tissue obtained during myectomy surgery to relieve left ventricular outflow tract obstruction of age-matched female and male HCM patients harboring a sarcomere mutation (n = 13 in both groups). Furthermore, these samples were compared to 8 non-failing controls. Women presented with more severe diastolic dysfunction. Results: Out of 2099 quantified proteins, direct comparison of male, and female HCM samples revealed only 46 significantly differentially expressed proteins. Increased levels of tubulin and heat shock proteins were observed in female compared to male HCM patients. Western blot analyses confirmed higher levels of tubulin in female HCM samples. In addition, proteins involved in carbohydrate metabolism were significantly lower in female compared to male samples. Furthermore, we found lower levels of translational proteins specifically in male HCM samples. The disease-specificity of these changes were confirmed by a second analysis in which we compared female and male samples separately to non-failing control samples. Transcription factor analysis showed that sex hormone-dependent transcription factors may contribute to differential protein expression, but do not explain the majority of protein changes observed between male and female HCM samples. Conclusion: In conclusion, based on our proteomics analyses we propose that increased levels of tubulin partly underlie more severe diastolic dysfunction in women compared to men. Since heat shock proteins have cardioprotective effects, elevated l

In 2011 the Netherlands Heart Foundation allocated funding (CVON, Cardiovasculair Onderzoek Nederland) to stimulate collaboration between clinical and preclinical researchers on specific areas of research. One of those areas involves genetic heart diseases, which are frequently caused by pathogenic variants in genes that encode sarcomere proteins. In 2014, the DOSIS (Determinants of susceptibility in inherited cardiomyopathy: towards novel therapeutic approaches) consortium was initiated, focusing their research on secondary disease hits involved in the onset and progression of cardiomyopathies. Here we highlight several recent observations from our consortium and collaborators which may ultimately be relevant for clinical practice.

BACKGROUND: In a post-2015 development agenda, achieving Universal Health Coverage (UHC) for women and newborns will require a fit-for-purpose and fit-to-practice sexual, reproductive, maternal, adolescent and newborn health (SRMNAH) workforce. The aim of this paper is to explore barriers, challenges and solutions to the availability, accessibility, acceptability and quality (AAAQ) of SRMNAH services and workforce. METHODS: The State of the World's Midwifery report 2014 used a broad definition of midwifery ("the health services and health workforce needed to support and care for women and newborns") and provided information about a wide range of SRMNAH workers, including doctors, midwives, nurses and auxiliaries. As part of the data collection, 36 out of the 73 participating low- and middle-income countries conducted a one-day workshop, involving a range of different stakeholders. Participants were asked to discuss barriers to the AAAQ of SRMNAH workers, and to suggest strategies for overcoming the identified barriers. The workshop was facilitated using a discussion guide, and a rapporteur took detailed notes. A content analysis was undertaken using N-Vivo software and the AAAQ model as a framework. RESULTS: Across the 36 countries, about 800 participants attended a workshop. The identified barriers to AAAQ of SRMNAH workers included: insufficient size of the workforce and inequity in its distribution, lack of transportation, user fees and out of pocket payments. In some countries, respondents felt that women mistrusted the workforce, and particularly midwives, due to cultural differences, or disrespectful behaviour towards service users. Quality of care was undermined by a lack of supplies/equipment and inadequate regulation. Against these, countries identified a set of solutions including adequate workforce planning supported by a fast and equitable deployment system, aligned with the principles of UHC. Acceptability and quality could be improved with the provisio

© 2018, © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Background: Many countries are responding to the global shortage of midwives by increasing the student intake to their midwifery schools. At the same time, attention must be paid to the quality of education being provided, so that quality of midwifery care can be assured. Methods of assuring quality of education include accreditation schemes, but capacity to implement such schemes is weak in many countries. Objective: This paper describes the process of developing and pilot testing the International Confederation of Midwives’ Midwifery Education Accreditation Programme (ICM MEAP), based on global standards for midwifery education, and discusses the potential contribution it can make to building capacity and improving quality of care for mothers and their newborns. Methods: A review of relevant global, regional and national standards and tools informed the development of a set of assessment criteria (which was validated during an international consultation exercise) and a process for applying these criteria to midwifery schools. The process was pilot tested in two countries: Comoros and Trinidad and Tobago. Results: The assessment criteria and accreditation process were found to be appropriate in both country contexts, but both were refined after the pilot to make them more user-friendly. Conclusion: The ICM MEAP has the potential to contribute to improving health outcomes for women and newborns by building institutional capacity for the provision of high-quality midwifery education and thus improved quality of midwifery care, via improved accountability for the quality of midwifery education.

© 2017 The Author(s). Background: The WHO African region, covering the majority of Sub-Saharan Africa, faces the highest rates of maternal and neonatal mortality in the world. This study uses data from the State of the World's Midwifery 2014 survey to cast a spotlight on the WHO African region, highlight the specific characteristics of its sexual, reproductive, maternal and newborn health (SRMNH) workforce and describe and compare countries' different trajectories in terms of meeting the population need for services. Methods: Using data from 41 African countries, this study used a mathematical model to estimate potential met need for SRMNH services, defined as "the percentage of a universal SRMNH package that could potentially be obtained by women and newborns given the composition, competencies and available working time of the SRMNH workforce." The model defined the 46 key interventions included in this universal SRMNH package and allocated them to the available health worker time and skill set in each country to estimate the potential met need. Results: Based on the current and projected potential met need in the future, the countries were grouped into three categories: (1) 'making or maintaining progress' (expected to meet more, or the same level, of the need in the future than currently): 14 countries including Ghana, Senegal and South Africa, (2) 'at risk' (currently performing relatively well but expected to deteriorate due to the health workforce not keeping pace with population growth): 6 countries including Gabon, Rwanda and Zambia, and (3) 'low performing' (not performing well and not expected to improve): 21 countries including Burkina Faso, Eritrea and Sierra Leone. Conclusion: The three groups face different challenges, and policy solutions to increasing met need should be tailored to the specific context of the country. National health workforce accounts should be strengthened so that workforce planning can be evidence-informed.

In this paper the concept of resilience is discussed on the base of 13 case studies from the German branch of the International Long-Term Ecological Research Program. In the introduction the resilience approach is presented as one possibility to describe ecosystem dynamics. The relations with the concepts of adaptability and ecological integrity are discussed and the research questions are formulated. The focal research objectives are related to the conditions of resilient behaviour of ecosystems, the role of spatio-temporal scales, the differences between short- or long-term dynamics, the basic methodological requirements to exactly define resilience, the role of the reference state and indicators and the suitability of resilience as a management concept. The main part of the paper consists of 13 small case study descriptions, which demonstrate phase transitions and resilient dynamics of several terrestrial and aquatic ecosystems at different time scales. In the discussion, some problems arising from the interpretation of the time series are highlighted and discussed. The topics of discussion are the conceptual challenges of the resilience approach, methodological problems, the role of indicator selection, the complex interactions between different disturbances, the significance of time scales and a comparison of the case studies. The article ends with a conclusion which focuses on the demand to link resilience with adaptability, in order to support the long-term dynamics of ecosystem development.