Respiratory features of centronuclear myopathy in the Netherlands

Centronuclear myopathy (CNM) is a heterogeneous group of muscle disorders primarily characterized by muscle weakness and variable degrees of respiratory dysfunction caused by mutations in MTM1, DNM2, RYR1, TTN and BIN1. X-linked myotubular myopathy has been the focus of recent natural history studies and clinical trials. Data on respiratory function for other genotypes is limited. To better understand the respiratory properties of the CNM spectrum, we performed a retrospective study in a non-selective Dutch CNM cohort. Respiratory dysfunction was defined as an FVC below 70% of predicted and/or a daytime pCO2 higher than 6 kPa. We collected results of other pulmonary function values (FEV1/FVC ratio) and treatment data from the home mechanical ventilation centres. Sixty-one CNM patients were included. Symptoms of respiratory weakness were reported by 15/47 (32%) patients. Thirty-three individuals (54%) with different genotypes except autosomal dominant (AD)-BIN1-related CNM showed respiratory dysfunction. Spirometry showed decreased FVC, FEV1 &amp; PEF values in all but two patients. Sixteen patients were using HMV (26%), thirteen of them only during night-time. In conclusion, this study provides insight into the prevalence of respiratory symptoms in four genetic forms of CNM in the Netherlands and offers the basis for future natural history studies.</p

Identification of kinase modulators as host-directed therapeutics against intracellular methicillin-resistant Staphylococcus aureus

The increasing prevalence of antimicrobial-resistant Staphylococcus aureus strains, especially methicillin-resistant S. aureus (MRSA), poses a threat to successful antibiotic treatment. Unsuccessful attempts to develop a vaccine and rising resistance to last-resort antibiotics urge the need for alternative treatments. Host-directed therapy (HDT) targeting critical intracellular stages of S. aureus emerges as a promising alternative, potentially acting synergistically with antibiotics and reducing the risk of de novo drug resistance. We assessed 201 ATP-competitive kinase inhibitors from Published Kinase Inhibitor Sets (PKIS1 and PKIS2) against intracellular MRSA. Seventeen hit compounds were identified, of which the two most effective and well-tolerated hit compounds (i.e., GW633459A and GW296115X) were selected for further analysis. The compounds did not affect planktonic bacterial cultures, while they were active in a range of human cell lines of cervical, skin, lung, breast and monocyte origin, confirming their host-directed mechanisms. GW633459A, structurally related to lapatinib, exhibited an HDT effect on intracellular MRSA independently of its known human epidermal growth factor receptor (EGFR)/(HER) kinase family targets. GW296115X activated adenosine monophosphate-activated protein kinase (AMPK), thereby enhancing bacterial degradation via autophagy. Finally, GW296115X not only reduced MRSA growth in human cells but also improved the survival rates of MRSA-infected zebrafish embryos, highlighting its potential as HDT

Respiratory features of centronuclear myopathy in the Netherlands

Centronuclear myopathy (CNM) is a heterogeneous group of muscle disorders primarily characterized by muscle weakness and variable degrees of respiratory dysfunction caused by mutations in MTM1, DNM2, RYR1, TTN and BIN1. X-linked myotubular myopathy has been the focus of recent natural history studies and clinical trials. Data on respiratory function for other genotypes is limited. To better understand the respiratory properties of the CNM spectrum, we performed a retrospective study in a non-selective Dutch CNM cohort. Respiratory dysfunction was defined as an FVC below 70% of predicted and/or a daytime pCO2 higher than 6 kPa. We collected results of other pulmonary function values (FEV1/FVC ratio) and treatment data from the home mechanical ventilation centres. Sixty-one CNM patients were included. Symptoms of respiratory weakness were reported by 15/47 (32%) patients. Thirty-three individuals (54%) with different genotypes except autosomal dominant (AD)-BIN1-related CNM showed respiratory dysfunction. Spirometry showed decreased FVC, FEV1 & PEF values in all but two patients. Sixteen patients were using HMV (26%), thirteen of them only during night-time. In conclusion, this study provides insight into the prevalence of respiratory symptoms in four genetic forms of CNM in the Netherlands and offers the basis for future natural history studies

Fatale pneumonitis door oseltamivir-resistente nieuwe influenza A(H1N1) bij een intensive-carepatiënt

A 58-year-old man was submitted to our intensive care ward with respiratory failure due to pneumonitis. He had previously been treated for non-Hodgkin lymphoma by autologous stem cell transplantation, as a result of which bone marrow function was reduced. Further analysis showed infection with new influenza A(H1N1); typing revealed an oseltamivir-resistant subpopulation (H275Y). The patient was treated with oseltamivir and intravenously with zanamivir, but died of respiratory disease progression. This is the first published case of oseltamivir-resistant new influenza A(H1N1) infection in the Netherlands

Fatal pneumonitis due to oseltamivir-resistant new influenza A(H1N1) in the case of an intensive care patient

A 58-year-old man was submitted to our intensive care ward with respiratory failure due to pneumonitis. He had previously been treated for non-Hodgkin lymphoma by autologous stem cell transplantation, as a result of which bone marrow function was reduced. Further analysis showed infection with new influenza A(H1N1); typing revealed an oseltamivir-resistant subpopulation (H275Y). The patient was treated with oseltamivir and intravenously with zanamivir, but died of respiratory disease progression. This is the first published case of oseltamivir-resistant new influenza A(H1N1) infection in the Netherlands.</p