7 research outputs found
Skeletal Muscle Homeostasis in Golden Retriever Muscular Dystrophy: The Role of Apoptosis & Autophagy in GRMD Pathogenesis
No full textDuchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder caused by mutations in the DMD gene, which results in loss of the dystrophin protein and cyclic muscle degeneration and regeneration..
Use of digital micromirror devices as dynamic pinhole arrays for adaptive confocal fluorescence microscopy
No full textIn this work, we present a new confocal laser scanning microscope capable to perform sensorless wavefront optimization in real time. The device is a parallelized laser scanning microscope in which the excitation light is structured in a lattice of spots by a spatial light modulator, while a deformable mirror provides aberration correction and scanning. A binary DMD is positioned in an image plane of the detection optical path, acting as a dynamic array of reflective confocal pinholes, images by a high performance CMOS camera. A second camera detects images of the light rejected by the pinholes for sensorless aberration correction.Team Raf Van de Pla
V iskanju inovativnih pristopov pri interdisciplinarnem raziskovanju libretov glasbenogledaliških del
No full textIn order to implement an interdisciplinary theoretical framework for studying libretti in multimodal artistic configurations for music theatre, the author presents an innovative analytical tool: Vokalurlinie. As a reliable metalinguistic notation of the bimodal congruence of literary and musical prosody, the tool provides a pertinent basis for various problem-solving tasks, ranging from translation and libretto adaptation to the optimization of the libretto’s performability and perception.Z namenom implementacije interdisciplinarnega teoretskega aparata za proučevanje libretov v multimodalnih umetniških konfiguracijah v polju glasbenega gledališča avtor članka predstavi lastno inovacijo – analitično orodje Vokalurlinie. Ta nam kot zanesljiv metajezikovni zapis bimodalne kongruence besedne in glasbene prozodije omogoča pertinentno reševanje problemov, povezanih s prevajanjem in adaptacijo libreta, z namenom zagotavljanja karseda optimalnih pogojev pevske izvedbe in percepcije
Adrenal Suppression in Duchenne Muscular Dystrophy: Management Strategies Incorporating Novel Steroid Vamorolone
No full text\ua9 2025 The Author(s). Published by Oxford University Press on behalf of the Endocrine Society.Adrenal suppression is an iatrogenic form of adrenal insufficiency that occurs secondary to exogenous glucocorticoids (GCs) and is a documented cause of premature mortality among individuals with Duchenne muscular dystrophy (DMD). Adrenal suppression in DMD necessitates awareness and careful management, given that GCs are currently the mainstay of therapy for individuals living with DMD. Vamorolone, a novel GC that has recently been approved in some regions worldwide for the treatment of DMD, has also been reported to place individuals at high risk of adrenal suppression in a dose-dependent fashion, requiring health care professional awareness. Vamorolone is a mineralocorticoid receptor antagonist, which differentiates it from classic GCs, and this characteristic impacts the approach to adrenal suppression management. This contemporary perspective provides insights into the mechanisms underlying adrenal suppression due to both classic GCs and novel vamorolone therapy, followed by an overview of adrenal suppression management with a particular focus on the unique aspects of providing care for individuals treated with vamorolone. It also emphasizes the importance of educating the DMD community and health care providers about the recognition and management of adrenal suppression and outlines critical concepts for clinicians managing adrenal suppression risk, tapering GCs, and transitioning from classic GC therapy to vamorolone. The key principles of managing adrenal suppression due to classic GCs and novel vamorolone therapy highlighted in this perspective are expected to enhance clinical practice, mitigate mortality, and optimize health outcomes for individuals with DMD
Delandistrogene moxeparvovec gene therapy in individuals with Duchenne muscular dystrophy: evidence in focus
No full textThis Evidence in Focus reviews the current evidence on the efficacy and adverse effects of delandistrogene moxeparvovec in patients with Duchenne muscular dystrophy (DMD) and presents clinical considerations regarding use. The author panel systematically reviewed available clinical trial data on delandistrogene moxeparvovec in patients with DMD. The risk of bias was evaluated using the American Academy of Neurology's 2017 therapeutic classification of evidence scheme. Safety information, regulatory decisions, and clinical context were also reviewed. Six clinical trials were identified, of which 4 had peer-reviewed data available. From the 4 studies with available data (2 Class I and 2 Class III), exposure data are available on 134 boys, of which 128 are ambulatory and aged ≥4 to <8 years. Both Class I studies failed to meet the primary functional motor outcome as assessed by change in the North Star Ambulatory Assessment score. Several secondary functional motor outcomes demonstrated improvement in the treatment group with small effect sizes, not meeting statistical significance from hierarchical analysis. Corticosteroid dose exposure was higher in the treatment group in the first 12 weeks after infusion, potentially contributing to measured differences between groups. Safety outcomes were similar across studies with multiple treatment-related adverse events, including peri-infusion effects, immune myositis and myocarditis, thrombocytopenia, and liver toxicity. One death has been reported in an individual who was treated with delandistrogene moxeparvovec outside of a trial. Despite not demonstrating efficacy in its primary outcome, delandistrogene moxeparvovec has been approved by the US Food and Drug Administration (FDA) for use in boys with DMD. This decision was supported by the relative safety of the product and secondary outcome measures data in the phase 3 clinical trial. As the drug may now be actively prescribed in the United States and other countries after FDA approval, providers should be aware of the limitations of the treatment and the need to monitor for immune-related side effects including myocarditis, liver injury, and thrombocytopenia, which may require expanded clinical infrastructure. Additional clinical trials and careful collection of real-world evidence from treated patients will be essential to establish short-term and long-term effectiveness and inform understanding of benefits and risks of delandistrogene moxeparvovec across the lifespan
X-chromosome-wide association study for Alzheimer's disease
No full textDue to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on Alzheimer's Disease (AD). To address this and better characterize the genetic landscape of AD, we performed an in-depth X-Chromosome-Wide Association Study (XWAS) in 115,841 AD cases or AD proxy cases, including 52,214 clinically-diagnosed AD cases, and 613,671 controls. We considered three approaches to account for the different X-chromosome inactivation (XCI) states in females, i.e. random XCI, skewed XCI, and escape XCI. We did not detect any genome-wide significant signals (P ≤ 5 × 10 ) but identified seven X-chromosome-wide significant loci (P ≤ 1.6 × 10 ). The index variants were common for the Xp22.32, FRMPD4, DMD and Xq25 loci, and rare for the WNK3, PJA1, and DACH2 loci. Overall, this well-powered XWAS found no genetic risk factors for AD on the non-pseudoautosomal region of the X-chromosome, but it identified suggestive signals warranting further investigations. [Abstract copyright: © 2024. The Author(s).
The long-term effectiveness of efavirenz-based combination antiretroviral therapy, the impact of pharmacogenomics and pharmacokinetic interaction of artemisinin-based antimalarial therapy on efavirenz exposure among Ghanaian HIV-infected patients
No full textDr. Fred Stephen Sarfo, The long-term effectiveness of efavirenz-based combination antiretroviral therapy, the impact of pharmacogenomics and pharmacokinetic interaction of artemisinin-based antimalarial therapy on efavirenz exposure among Ghanaian HIV-infected patients. PhD dissertation, Durham University, January 2013.
Introduction: In sub-Saharan Africa, HIV treatment is initiated with combination of antiretroviral medications comprising of a backbone of either stavudine or zidovudine plus lamivudine with a non-nucleoside reverse transcriptase inhibitor of either efavirenz or nevirapine. Efavirenz is highly efficacious, durable and well tolerated. The risk for toxicity of efavirenz is determined by several factors including single nucleotide polymorphisms in the hepatic enzymes responsible for its metabolism and concurrently administered medications such as antimalarials, which share common metabolic pathways. The aims of this dissertation are to assess the long-term effectiveness of efavirenz-based antiretroviral therapy and the impact of pharmogenomics and pharmacokinetic interactions of artemisinin-based antimalarial therapy on efavirenz exposure among Ghanaian HIV-infected patients.
Methods: The effectiveness of efavirenz- compared with nevirapine-based antiretroviral therapy was assessed retrospectively in nearly 4000 patients starting treatment between 2004 and 2010. The main outcome measure was a composite of toxicity, disease progression and attrition, and CD4 count changes. A prospective pharmacokinetic study of artesunate and efavirenz was conducted among 22 HIV-infected and 21 controls. Plasma efavirenz and artesunate/ dihydroartemisinin concentrations were measured using validated and standardised methods. Genotyping for single nucleotide polymorphisms in CYP2B6 G516T, T983C; CYP2A6*9B, UGT2B7*735 and *802 as well as CAR rs2307424 were performed for 800 patients with real-time polymerase chain reaction with allelic discrimination.
Results: Antiretroviral therapy was associated with robust CD4 increases. Efavirenz was comparable with nevirapine in composite outcomes but better tolerated. Artesunate was well tolerated when administered to HIV-infected patients on efavirenz. Single nucleotide polymorphisms in the CYP2B6 G516T and T983C were associated with increased plasma efavirenz concentrations.
Conclusions/Recommendation: Among this Ghanaian cohort, both efavirenz and nevirapine-based antiretroviral therapy were effective. The better tolerability of efavirenz compared with nevirapine means it can be safely used as the preferred first line non-nucleoside reverse transcriptase inhibitor in sub-Saharan Africa
