Journal articles on the topic 'Achille Duchêne'
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1
Hyde, Sylvia A., Ida Fløytrup, Sara Glent, Anna-Karin Kroksmark, Betty Salling, Birgit F. Steffensen, Ulla Werlauff, and Mogens Erlandsen. "A randomized comparative study of two methods for controlling Tendo Achilles contracture in Duchenne muscular dystrophy." Neuromuscular Disorders 10, no. 4-5 (June 2000): 257–63. http://dx.doi.org/10.1016/s0960-8966(99)00135-2.
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Śliwińska, Martyna, Anna Rakuś-Kwiatosz, and Katarzyna Wojciechowska. "Duchenne muscular dystrophy diagnosed in infancy – a case report." Pediatria i Medycyna Rodzinna 18, no. 3 (December 30, 2022): 285–89. http://dx.doi.org/10.15557/pimr.2022.0044.
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Duchenne muscular dystrophy is the most common inherited neuromuscular disorder. The onset of myopathic symptoms is observed at an average age of 2.5 years. However, the definitive diagnosis is not reached until between 3 and 5 years of age, indicating a delay in relation to the onset of first symptoms. The diagnosis is confirmed with genetic testing. This paper presents a case of a 6.5-month-old boy with reduced motor activity already in the foetal period, hypertransaminasaemia, constipation and reduced muscle tone. Extensive differential diagnosis of these abnormalities, including genetic testing, confirmed Duchenne muscular dystrophy. Detection of this disease at an early, poorly symptomatic stage offers a chance to achieve better treatment outcomes and improve the patient’s quality of life. Modern gene therapies implemented before irreversible changes are induced by the disease may in the future give the patient a chance to be completely cured. In the presented case, the symptoms of myopathy were present already in foetal life, and the diagnosis was reached at a younger age than the typical age reported in most of the available literature data.
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Ohtsuka, Yoshikazu, Keiko Udaka, Yuichiro Yamashiro, Hideo Yagita, and Ko Okumura. "Dystrophin Acts as a Transplantation Rejection Antigen in Dystrophin-Deficient Mice: Implication for Gene Therapy." Journal of Immunology 160, no. 9 (May 1, 1998): 4635–40. http://dx.doi.org/10.4049/jimmunol.160.9.4635.
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Abstract Duchenne muscular dystrophy is a lethal and common X-linked recessive disease caused by a defect in dystrophin. Normal myoblast transplantation and dystrophin gene transfer have been expected to correct the deficiency in the muscles, but their clinical application has been hampered by the limited preservation of dystrophin-positive myofibers. In this study we investigated the mechanism for immunologic rejection of normal C57BL/10 (B10) myoblasts transplanted into dystrophin-deficient mdx mice, an animal model of Duchenne muscular dystrophy. We found that mdx mice develop CTL specific for dystrophin itself, which were CD8 dominant and restricted by H-2Kb. We identified several antigenic peptides derived from dystrophin that bind to H-2Kb and are recognized by the mdx anti-B10 CTL. Immunologic tolerance against dystrophin was successfully induced by i.v. injection of these peptides before B10 myoblast transplantation, which resulted in sustained preservation of dystrophin-expressing myofibers in mdx mice. These results demonstrate that dystrophin is antigenic in dystrophin-deficient mice and that immunologic regimen would be necessary to achieve the persistent expression of introduced dystrophin in the muscles of dystrophin-deficient individuals.
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Ho, Peggy P., Lauren J. Lahey, Foteini Mourkioti, Peggy E. Kraft, Antonio Filareto, Moritz Brandt, Klas E. G. Magnusson, et al. "Engineered DNA plasmid reduces immunity to dystrophin while improving muscle force in a model of gene therapy of Duchenne dystrophy." Proceedings of the National Academy of Sciences 115, no. 39 (September 4, 2018): E9182—E9191. http://dx.doi.org/10.1073/pnas.1808648115.
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In gene therapy for Duchenne muscular dystrophy there are two potential immunological obstacles. An individual with Duchenne muscular dystrophy has a genetic mutation in dystrophin, and therefore the wild-type protein is “foreign,” and thus potentially immunogenic. The adeno-associated virus serotype-6 (AAV6) vector for delivery of dystrophin is a viral-derived vector with its own inherent immunogenicity. We have developed a technology where an engineered plasmid DNA is delivered to reduce autoimmunity. We have taken this approach into humans, tolerizing to myelin proteins in multiple sclerosis and to proinsulin in type 1 diabetes. Here, we extend this technology to a model of gene therapy to reduce the immunogenicity of the AAV vector and of the wild-type protein product that is missing in the genetic disease. Following gene therapy with systemic administration of recombinant AAV6-microdystrophin to mdx/mTRG2 mice, we demonstrated the development of antibodies targeting dystrophin and AAV6 capsid in control mice. Treatment with the engineered DNA construct encoding microdystrophin markedly reduced antibody responses to dystrophin and to AAV6. Muscle force in the treated mice was also improved compared with control mice. These data highlight the potential benefits of administration of an engineered DNA plasmid encoding the delivered protein to overcome critical barriers in gene therapy to achieve optimal functional gene expression.
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Naidoo, Michael, and Karen Anthony. "Dystrophin Dp71 and the Neuropathophysiology of Duchenne Muscular Dystrophy." Molecular Neurobiology 57, no. 3 (December 13, 2019): 1748–67. http://dx.doi.org/10.1007/s12035-019-01845-w.
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AbstractDuchenne muscular dystrophy (DMD) is caused by frameshift mutations in the DMD gene that prevent the body-wide translation of its protein product, dystrophin. Besides a severe muscle phenotype, cognitive impairment and neuropsychiatric symptoms are prevalent. Dystrophin protein 71 (Dp71) is the major DMD gene product expressed in the brain and mutations affecting its expression are associated with the DMD neuropsychiatric syndrome. As with dystrophin in muscle, Dp71 localises to dystrophin-associated protein complexes in the brain. However, unlike in skeletal muscle; in the brain, Dp71 is alternatively spliced to produce many isoforms with differential subcellular localisations and diverse cellular functions. These include neuronal differentiation, adhesion, cell division and excitatory synapse organisation as well as nuclear functions such as nuclear scaffolding and DNA repair. In this review, we first describe brain involvement in DMD and the abnormalities observed in the DMD brain. We then review the gene expression, RNA processing and functions of Dp71. We review genotype-phenotype correlations and discuss emerging cellular/tissue evidence for the involvement of Dp71 in the neuropathophysiology of DMD. The literature suggests changes observed in the DMD brain are neurodevelopmental in origin and that their risk and severity is associated with a cumulative loss of distal DMD gene products such as Dp71. The high risk of neuropsychiatric syndromes in Duchenne patients warrants early intervention to achieve the best possible quality of life. Unravelling the function and pathophysiological significance of dystrophin in the brain has become a high research priority to inform the development of brain-targeting treatments for Duchenne.
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Starosta, Alicja, and Patryk Konieczny. "Therapeutic aspects of cell signaling and communication in Duchenne muscular dystrophy." Cellular and Molecular Life Sciences 78, no. 11 (April 7, 2021): 4867–91. http://dx.doi.org/10.1007/s00018-021-03821-x.
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AbstractDuchenne muscular dystrophy (DMD) is a devastating chromosome X-linked disease that manifests predominantly in progressive skeletal muscle wasting and dysfunctions in the heart and diaphragm. Approximately 1/5000 boys and 1/50,000,000 girls suffer from DMD, and to date, the disease is incurable and leads to premature death. This phenotypic severity is due to mutations in the DMD gene, which result in the absence of functional dystrophin protein. Initially, dystrophin was thought to be a force transducer; however, it is now considered an essential component of the dystrophin-associated protein complex (DAPC), viewed as a multicomponent mechanical scaffold and a signal transduction hub. Modulating signal pathway activation or gene expression through epigenetic modifications has emerged at the forefront of therapeutic approaches as either an adjunct or stand-alone strategy. In this review, we propose a broader perspective by considering DMD to be a disease that affects myofibers and muscle stem (satellite) cells, as well as a disorder in which abrogated communication between different cell types occurs. We believe that by taking this systemic view, we can achieve safe and holistic treatments that can restore correct signal transmission and gene expression in diseased DMD tissues.
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Marchenko, L. A. "Productivity of garden strawberry and breeding possibilities to improve it." Siberian Herald of Agricultural Science 51, no. 3 (July 29, 2021): 65–74. http://dx.doi.org/10.26898/0370-8799-2021-3-7.
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The information on the productivity trait of garden strawberry Fragaria × ananassa (Duchesne ex Weston) Duchesne ex Rozier has been summarized on the basis of literary sources. The productivity trait has a complex polygenic character. Independent inheritance of individual productivity components allows modeling their optimal combination in a new variety. The creation of highly productive varieties of strawberries is based on intraspecific hybridization. The established positive correlation between the size of berries and the yield indicates the possibility of increasing the productivity of varieties by using large-fruited forms in breeding. At present, in various zones of horticulture, researchers distinguish large-fruited varieties of domestic breeding: ‘Atlas', ‘Bereginya', ‘Vityaz', ‘Grenada', ‘Zabelinskaya', ‘Kemiya', ‘Nashe Podmoscovie', ‘Nelly', ‘Pervoklassnitsa', ‘Rusich', ‘Solnechnaya Polyanka', ‘Solovushka', ‘Festivalnaya Romashka', ‘Fruktovaya', ‘Tsaritsa', ‘Yaponka', and foreign breeding: ‘Alba', ‘Asia', ‘Elsanta', ‘Finesse', ‘Florense', ‘Vivaldi', ‘Galia', ‘Jive', ‘Joly', ‘M. Champion', ‘Merced', ‘Murano', ‘Onda', ‘Roxana', ‘Rumba', ‘Tarda Vicoda', ‘Vima Kimberly', ‘Vima Tarda', ‘Vima Rina', ‘Vima Xima'. It was noted that when using the inbreeding method, it is possible to achieve a heterotic effect on the basis of the productivity trait. The method of genetic modifications of plants is of great importance for breeding of complex quantitative traits of productivity, including yield. Expansion of the genetic base of garden strawberry by means of octoploid and polyploid forms of wild species will ensure an increase in the productivity of new varieties due to the inclusion of traits of adaptability to biotic and abiotic factors in the genotype. The use of modern research methods (screening of the metabolomic and biochemical profile, DNA certification, molecular labeling) increases the objectivity of research and the efficiency of the breeding process.
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Makkar, Raj R., Dean J. Kereiakes, Frank Aguirre, Glenn Kowalchuk, Tarun Chakravarty, Konstantinos Malliaras, Gary S. Francis, et al. "Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR): a randomized, placebo-controlled, double-blinded trial." European Heart Journal 41, no. 36 (August 4, 2020): 3451–58. http://dx.doi.org/10.1093/eurheartj/ehaa541.
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Abstract Aims Cardiosphere-derived cells (CDCs) are cardiac progenitor cells that exhibit disease-modifying bioactivity in various models of cardiomyopathy and in previous clinical studies of acute myocardial infarction (MI), dilated cardiomyopathy, and Duchenne muscular dystrophy. The aim of the study was to assess the safety and efficacy of intracoronary administration of allogeneic CDCs in the multicentre, randomized, double-blinded, placebo-controlled, intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR) trial. Methods and results We enrolled patients 4 weeks to 12 months after MI, with left ventricular ejection fraction (LVEF) ≤45% and LV scar size ≥15% of LV mass by magnetic resonance imaging (MRI). A pre-specified interim analysis was performed when 6-month MRI data were available. The trial was subsequently stopped due to the low probability of detecting a significant treatment effect of CDCs based on the primary endpoint. Patients were randomly allocated in a 2:1 ratio to receive CDCs or placebo in the infarct-related artery by stop-flow technique. The primary safety endpoint was the occurrence, during 1-month post-intracoronary infusion, of acute myocarditis attributable to allogeneic CDCs, ventricular tachycardia- or ventricular fibrillation-related death, sudden unexpected death, or a major adverse cardiac event (death or hospitalization for heart failure or non-fatal MI or need for left ventricular assist device or heart transplant). The primary efficacy endpoint was the relative percentage change in infarct size at 12 months post-infusion as assessed by contrast-enhanced cardiac MRI. We randomly allocated 142 eligible patients of whom 134 were treated (90 to the CDC group and 44 to the placebo group). The mean baseline LVEF was 40% and the mean scar size was 22% of LV mass. No primary safety endpoint events occurred. There was no difference in the percentage change from baseline in scar size (P = 0.51) between CDCs and placebo groups at 6 months. Compared with placebo, there were significant reductions in LV end-diastolic volume (P = 0.02), LV end-systolic volume (P = 0.02), and N-terminal pro b-type natriuretic peptide (NT-proBNP) (P = 0.02) at 6 months in CDC-treated patients. Conclusion Intracoronary infusion of allogeneic CDCs in patients with post-MI LV dysfunction was safe but did not reduce scar size relative to placebo at 6 months. Nevertheless, the reductions in LV volumes and NT-proBNP reveal disease-modifying bioactivity of CDCs. Trial registration Clinicaltrials.gov identifier: NCT01458405.
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Nesmith, Alexander P., Matthew A. Wagner, Francesco S. Pasqualini, Blakely B. O’Connor, Mark J. Pincus, Paul R. August, and Kevin Kit Parker. "A human in vitro model of Duchenne muscular dystrophy muscle formation and contractility." Journal of Cell Biology 215, no. 1 (October 3, 2016): 47–56. http://dx.doi.org/10.1083/jcb.201603111.
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Tongue weakness, like all weakness in Duchenne muscular dystrophy (DMD), occurs as a result of contraction-induced muscle damage and deficient muscular repair. Although membrane fragility is known to potentiate injury in DMD, whether muscle stem cells are implicated in deficient muscular repair remains unclear. We hypothesized that DMD myoblasts are less sensitive to cues in the extracellular matrix designed to potentiate structure–function relationships of healthy muscle. To test this hypothesis, we drew inspiration from the tongue and engineered contractile human muscle tissues on thin films. On this platform, DMD myoblasts formed fewer and smaller myotubes and exhibited impaired polarization of the cell nucleus and contractile cytoskeleton when compared with healthy cells. These structural aberrations were reflected in their functional behavior, as engineered tongues from DMD myoblasts failed to achieve the same contractile strength as healthy tongue structures. These data suggest that dystrophic muscle may fail to organize with respect to extracellular cues necessary to potentiate adaptive growth and remodeling.
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Guiraud, Simon, Benjamin Edwards, Arran Babbs, Sarah E. Squire, Adam Berg, Lee Moir, Matthew J. Wood, and Kay E. Davies. "The potential of utrophin and dystrophin combination therapies for Duchenne muscular dystrophy." Human Molecular Genetics 28, no. 13 (March 5, 2019): 2189–200. http://dx.doi.org/10.1093/hmg/ddz049.
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Abstract Duchenne muscular dystrophy (DMD) is a lethal neuromuscular disorder caused by loss of dystrophin. Several therapeutic modalities are currently in clinical trials but none will achieve maximum functional rescue and full disease correction. Therefore, we explored the potential of combining the benefits of dystrophin with increases of utrophin, an autosomal paralogue of dystrophin. Utrophin and dystrophin can be co-expressed and co-localized at the same muscle membrane. Wild-type (wt) levels of dystrophin are not significantly affected by a moderate increase of utrophin whereas higher levels of utrophin reduce wt dystrophin, suggesting a finite number of actin binding sites at the sarcolemma. Thus, utrophin upregulation strategies may be applied to the more mildly affected Becker patients with lower dystrophin levels. Whereas increased dystrophin in wt animals does not offer functional improvement, overexpression of utrophin in wt mice results in a significant supra-functional benefit over wt. These findings highlight an additive benefit of the combined therapy and potential new unique roles of utrophin. Finally, we show a 30% restoration of wt dystrophin levels, using exon-skipping, together with increased utrophin levels restores dystrophic muscle function to wt levels offering greater therapeutic benefit than either single approach alone. Thus, this combination therapy results in additive functional benefit and paves the way for potential future combinations of dystrophin- and utrophin-based strategies.
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Yu, Guoyong, Jing Zhao, Yunlu Wei, Linlin Huang, Fei Li, Yu Zhang, and Quanhong Li. "Physicochemical Properties and Antioxidant Activity of Pumpkin Polysaccharide (Cucurbita moschata Duchesne ex Poiret) Modified by Subcritical Water." Foods 10, no. 1 (January 19, 2021): 197. http://dx.doi.org/10.3390/foods10010197.
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In this paper, subcritical water (SCW) was applied to modify pumpkin (Cucurbita moschata Duchesne ex Poiret) polysaccharides, and the properties and antioxidant activity of pumpkin polysaccharides were investigated. SCW treatments at varying temperature led to changes in the rheological and emulsifying properties of pumpkin polysaccharides. SCW treatments efficiently degraded pumpkin polysaccharides and changed the molecular weight distribution. Decreases in intrinsic viscosity, viscosity-average molecular weight, and apparent viscosity were also observed, while the activation energy and flow behavior indices increased. The temperature of SCW treatment has a great influence on the linear viscoelastic properties and antioxidant activity of pumpkin polysaccharides. Pumpkin polysaccharides solution treated by SCW at 150 °C exhibited the highest emulsifying activity and antioxidant activity, which was probably due to a broader molecular mass distribution and more reducing ends exposed after treatment. Scanning electron microscopy showed that SCW treatment changed the microstructure of pumpkin polysaccharides, resulting in the exposure of bigger surface area. Our results suggest that SCW treatment is an effective approach to modify pumpkin polysaccharides to achieve improved solution properties and antioxidant activity.
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Bian, Qian, Laura McAdam, Marc Grynpas, Jane Mitchell, and Jennifer Harrington. "Increased Rates of Vitamin D Insufficiency in Boys With Duchenne Muscular Dystrophy Despite Higher Vitamin D3 Supplementation." Global Pediatric Health 6 (January 2019): 2333794X1983566. http://dx.doi.org/10.1177/2333794x19835661.
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Vitamin D supplementation is important for many chronic pediatric conditions to help maintain bone health; however, there is little evidence about how disease-related factors affect vitamin D status. The objective was to compare 25-hydroxyvitamin D (25(OH)D) concentrations in 3 pediatric cohorts (Duchenne muscular dystrophy [DMD], systemic lupus erythematosus [SLE], and osteogenesis imperfecta [OI]). In a retrospective study of 367 subjects, children with DMD had increased prevalence of vitamin D insufficiency (25% vs 14% [SLE] and 10% [OI], P = .002), despite higher vitamin D3 supplementation doses. Boys with DMD also had higher weight, fat mass, and lower lean mass percentage Z scores. DMD was associated with having higher rates of vitamin D insufficiency than other comparable pediatric chronic disease cohorts, the effect of which may be modulated by clinical factors such as increased adiposity. While corroboration of these results is needed given baseline differences between the patient groups, greater vitamin D supplementation doses may be required to achieve optimal serum 25(OH)D concentrations in boys with DMD.
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Herbelet, Sandrine, Arthur Rodenbach, Boel De Paepe, and Jan L. De Bleecker. "Anti-Inflammatory and General Glucocorticoid Physiology in Skeletal Muscles Affected by Duchenne Muscular Dystrophy: Exploration of Steroid-Sparing Agents." International Journal of Molecular Sciences 21, no. 13 (June 28, 2020): 4596. http://dx.doi.org/10.3390/ijms21134596.
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In Duchenne muscular dystrophy (DMD), the activation of proinflammatory and metabolic cellular pathways in skeletal muscle cells is an inherent characteristic. Synthetic glucocorticoid intake counteracts the majority of these mechanisms. However, glucocorticoids induce burdensome secondary effects, including hypertension, arrhythmias, hyperglycemia, osteoporosis, weight gain, growth delay, skin thinning, cushingoid appearance, and tissue-specific glucocorticoid resistance. Hence, lowering the glucocorticoid dosage could be beneficial for DMD patients. A more profound insight into the major cellular pathways that are stabilized after synthetic glucocorticoid administration in DMD is needed when searching for the molecules able to achieve similar pathway stabilization. This review provides a concise overview of the major anti-inflammatory pathways, as well as the metabolic effects of glucocorticoids in the skeletal muscle affected in DMD. The known drugs able to stabilize these pathways, and which could potentially be combined with glucocorticoid therapy as steroid-sparing agents, are described. This could create new opportunities for testing in DMD animal models and/or clinical trials, possibly leading to smaller glucocorticoids dosage regimens for DMD patients.
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Onori, Annalisa, Agata Desantis, Serena Buontempo, Maria Grazia Di Certo, Maurizio Fanciulli, Luisa Salvatori, Claudio Passananti, and Nicoletta Corbi. "The artificial 4-zinc-finger protein Bagly binds human utrophin promoter A at the endogenous chromosomal site and activates transcription." Biochemistry and Cell Biology 85, no. 3 (June 2007): 358–65. http://dx.doi.org/10.1139/o07-015.
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Our aim is to upregulate the expression of the dystrophin-related gene utrophin in Duchenne muscular dystrophy, in this way complementing the lack of dystrophin function. To achieve utrophin upregulation, we designed and engineered synthetic zinc-inger based transcription factors. We have previously shown that the artificial 3-zinc-finger protein Jazz, fused with the appropriate effector domain, is able to drive the transcription of a test gene from utrophin promoter A. Here we report a novel artificial 4-zinc-finger protein, Bagly, which binds with optimized affinity–specificity to a 12 bp DNA target sequence that is internal to human utrophin promoter A. Bagly was generated adding to Jazz protein an extra-fourth zinc finger, derived from transcription factor YY1. Importantly, the Bagly DNA target sequence is statistically present in the human genome only 210 times, about 60 fewer times than the 9 bp Jazz DNA target sequence. Thanks to its additional zinc-finger domain, Bagly protein shows enhanced transcriptional activity. Moreover, we demonstrated Bagly's effective access and binding to active chromatin in the chromosomal context and its ability to upregulate endogenous utrophin.
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Lovering, Richard M., and Susan V. Brooks. "Eccentric exercise in aging and diseased skeletal muscle: good or bad?" Journal of Applied Physiology 116, no. 11 (June 1, 2014): 1439–45. http://dx.doi.org/10.1152/japplphysiol.00174.2013.
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Evidence is accumulating regarding the benefits of exercise in people who are more susceptible to injury, such as the elderly, or those with a neuromuscular disease, for example Duchenne muscular dystrophy (DMD). There appears to be a consensus that exercise can be safely performed in aging and diseased muscles, but the role of eccentric exercise is not as clear. Eccentric (lengthening) contractions have risks and benefits. Eccentric contractions are commonly performed on a daily basis, and high-force voluntary eccentric contractions are often employed in strength training paradigms with excellent results; however, high-force eccentric contractions are also linked to muscle damage. This minireview examines the benefits and safety issues of using eccentric exercise in at-risk populations. A common recommendation for all individuals is difficult to achieve, and guidelines are still being established. Some form of exercise is generally recommended with aging and even with diseased muscles, but the prescription (frequency, intensity, and duration) and type (resistance vs. aerobic) of exercise requires personal attention, as there is great diversity in the functional level and comorbidities in the elderly and those with neuromuscular disease.
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Maktite, Abderrahim, and Ali Faleh. "Cartographie Des Zones À Risque D’incendies De Forêts À L'aide Du SIG Et La Télédétection Dans L'arrière-Pays Du Port Tanger Med." European Scientific Journal, ESJ 13, no. 32 (November 30, 2017): 205. http://dx.doi.org/10.19044/esj.2017.v13n32p205.
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Moroccan natural environments, in recent decades, have undergone considerable degradation which is related primarily to the development of populations and the pressure they have exerted on natural resources. One aspect of this degradation is forest fire that has accelerated alarmingly. The study area belongs to the forest area of Tangier which covers an area of 42.000ha. The latter is known for its sensitivity to heat, especially because of the nature of the vegetation cover, weather conditions (frequent and strong wind), and high population density. The present work aims to prioritize the plot study area according to the degree of fire risk of forests using the model established by Dagorne Y. Duche in 1994. To achieve this goal, the application of GIS and Remote Sensing is required to develop a fire risk map in the hinterland of Tangier Mediterranean port.
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Li, Na, and Yafeng Song. "Strategies for Bottlenecks of rAAV-Mediated Expression in Skeletal and Cardiac Muscle of Duchenne Muscular Dystrophy." Genes 13, no. 11 (November 3, 2022): 2021. http://dx.doi.org/10.3390/genes13112021.
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Gene therapy using the adeno-associated virus (rAAV) to deliver mini/micro- dystrophin is the current promising strategy for Duchenne Muscular Dystrophy (DMD). However, the further transformation of this strategy still faces many “bottlenecks”. Most gene therapies are only suitable for infants with strong muscle cell regeneration and immature immune system, and the treatment depends heavily on the high dose of rAAV. However, high-dose rAAV inevitably causes side effects such as immune response and acute liver toxicity. Therefore, how to reduce the degree of fibrosis and excessive immune response in older patients and uncouple the dependence association between therapeutic effect and high dose rAAV are crucial steps for the transformation of rAAV-based gene therapy. The article analyzes the latest research and finds that the application of utrophin, the homologous protein of dystrophin, could avoid the immune response associated with dystrophin, and the exploration of methods to improve the expression level of mini/micro-utrophin in striated muscle, combined with the novel MyoAAV with high efficiency and specific infection of striated muscle, is expected to achieve the same therapeutic efficacy under the condition of reducing the dose of rAAV. Furthermore, the delivery of allogeneic cardio sphere-derived cells (CDCs) with anti-inflammatory and anti-fibrotic characteristics combined with immune suppression can provide a continuous and appropriate “window period” for gene therapy. This strategy can expand the number of patients who could benefit from gene therapy.
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Schabron, Bridget, Jaydip Desai, and Yimesker Yihun. "Wheelchair-Mounted Upper Limb Robotic Exoskeleton with Adaptive Controller for Activities of Daily Living." Sensors 21, no. 17 (August 26, 2021): 5738. http://dx.doi.org/10.3390/s21175738.
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Neuro-muscular disorders and diseases such as cerebral palsy and Duchenne Muscular Dystrophy can severely limit a person’s ability to perform activities of daily living (ADL). Exoskeletons can provide an active or passive support solution to assist these groups of people to perform ADL. This study presents an artificial neural network-trained adaptive controller mechanism that uses surface electromyography (sEMG) signals from the human forearm to detect hand gestures and navigate an in-house-built wheelchair-mounted upper limb robotic exoskeleton based on the user’s intent while ensuring safety. To achieve the desired position of the exoskeleton based on human intent, 10 hand gestures were recorded from 8 participants without upper limb movement disabilities. Participants were tasked to perform water bottle pick and place activities while using the exoskeleton, and sEMG signals were collected from the forearm and processed through root mean square, median filter, and mean feature extractors prior to training a scaled conjugate gradient backpropagation artificial neural network. The trained network achieved an average of more than 93% accuracy, while all 8 participants who did not have any prior experience of using an exoskeleton were successfully able to perform the task in less than 20 s using the proposed artificial neural network-trained adaptive controller mechanism. These results are significant and promising thus could be tested on people with muscular dystrophy and neuro-degenerative diseases.
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Bremer, William, Katherine Campbell, Louise Rodino-Klapac, Laurie Goodchild, Danielle Griffin, Chrystal Montgomery, and Christopher Walker. "CD4+ helper T cells and immunity to therapeutic proteins in gene therapy (P4431)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 126.2. http://dx.doi.org/10.4049/jimmunol.190.supp.126.2.
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Abstract Adeno-associated (AAV) vectors are being assessed for gene replacement therapy in humans. Proteins encoded by the vector transgene are potentially foreign. Strategies to temper destructive immune responses may be required to achieve a therapeutic effect, particularly in diseases like Duchenne Muscular Dystrophy where the defective gene to be replaced has a large frame-shifting deletion. Here we studied the impact of immunity on expression of enhanced green fluorescent protein (eGFP) in AAV-transduced skeletal muscle of rhesus macaques. Antibodies to eGFP developed rapidly after AAV vector delivery to the tibialis anterior muscle. Cellular immunity was variable. In some animals, strong CD4+ helper and CD8+ cytotoxic T cells were detected in blood 2 weeks after vector administration. In others, low frequency responses were not detected until week 5-6. Regardless of the pace of the response, eGFP was cleared or substantially diminished in muscle after week 6. Antibody-mediated depletion of CD4+ T cells before AAV vector treatment delayed antibody and CD8+ T cell immunity and facilitated robust expression of eGFP persisted through day 42. Some positive muscle fibers were still visible at month 10, an unexpected finding that suggested an inability to sustain destructive cellular immune responses initially primed without CD4+ T cell help. The capacity for recall of eGFP-CD8+ T cell responses upon administration of a serologically distinct AAV vector is now being assessed.
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Alemdaroğlu, İpek, Gozde Gür, Nilgün Bek, Öznur T. Yılmaz, Yavuz Yakut, Fatma Uygur, and Ayşe Karaduman. "Is there any relationship between orthotic usage and functional activities in children with neuromuscular disorders?" Prosthetics and Orthotics International 38, no. 1 (May 17, 2013): 27–33. http://dx.doi.org/10.1177/0309364613486915.
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Background: Contractures of Achilles tendons and gastrocnemius muscle deteriorate the performance in daily living activities of patients with neuromuscular diseases. Ankle–foot orthoses help to prevent the progression of deformities and to obtain optimal position of the joints to support standing and walking. Objective: To investigate the relationship between orthotic usage and functional activities in pediatric patients with different neuromuscular diseases. Study design: Retrospective study. Methods: A total of 127 subjects’ physical assessment forms were analyzed. Functional level, type of orthoses, falling frequencies, ankle joint range of motion, and timed performance tests were examined in two consecutive dates with an interval of 3 months. Results: A total of 91 patients were using orthoses while 36 patients were not within assessment dates. A total of 64 of 91 (70.3%) patients were diagnosed with Duchenne muscular dystrophy. A total of 81 (89.0%) subjects were using plastic ankle–foot orthoses for positioning at nights and 10 (11%) were using different types of the orthoses (knee–ankle–foot orthoses, dynamic ankle–foot orthoses, and so on) for gait in the study group. Conclusions: Night ankle–foot orthoses were not found to be effective directly on functional performance in children with neuromuscular diseases, although they protect ankle from contractures and may help to correct gait and balance. Clinical relevance This retrospective study shows that the positive effects of using an ankle–foot orthosis at night are not reflected in the functional performance of children with neuromuscular diseases. This may be due to the progressive deteriorating nature of the disease.
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Finkel, Richard S., Craig M. McDonald, H. Lee Sweeney, Erika Finanger, Erin Neil Knierbein, Kathryn R. Wagner, Katherine D. Mathews, et al. "A Randomized, Double-Blind, Placebo-Controlled, Global Phase 3 Study of Edasalonexent in Pediatric Patients with Duchenne Muscular Dystrophy: Results of the PolarisDMD Trial." Journal of Neuromuscular Diseases 8, no. 5 (September 14, 2021): 769–84. http://dx.doi.org/10.3233/jnd-210689.
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Background: Edasalonexent (CAT-1004) is an orally-administered novel small molecule drug designed to inhibit NF-κB and potentially reduce inflammation and fibrosis to improve muscle function and thereby slow disease progression and muscle decline in Duchenne muscular dystrophy (DMD). Objective: This international, randomized 2 : 1, placebo-controlled, phase 3 study in patients ≥4 – < 8 years old with DMD due to any dystrophin mutation examined the effect of edasalonexent (100 mg/kg/day) compared to placebo over 52 weeks. Methods: Endpoints were changes in the North Star Ambulatory Assessment (NSAA; primary) and timed function tests (TFTs; secondary). Assessment of health-related function used the Pediatric Outcomes Data Collection tool (PODCI). Results: One hundred thirty one patients received edasalonexent (n = 88) and placebo (n = 43). At week 52, differences between edasalonexent and placebo for NSAA total score and TFTs were not statistically significant, although there were consistently less functional declines in the edasalonexent group. A pre-specified analysis by age demonstrated that younger patients (≤6.0 years) showed more robust and statistically significant differences between edasalonexent and placebo for some assessments. Treatment was well-tolerated and the majority of adverse events were mild, and most commonly involved the gastrointestinal system (primarily diarrhea). Conclusions: Edasalonexent was generally well-tolerated with a manageable safety profile at the dose of 100 mg/kg/day. Although edasalonexent did not achieve statistical significance for improvement in primary and secondary functional endpoints for assessment of DMD, subgroup analysis suggested that edasalonexent may slow disease progression if initiated before 6 years of age. (NCT03703882)
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Matecki, Stefan, Roy W. R. Dudley, Maziar Divangahi, Renald Gilbert, Josephine Nalbantoglu, George Karpati, and Basil J. Petrof. "Therapeutic gene transfer to dystrophic diaphragm by an adenoviral vector deleted of all viral genes." American Journal of Physiology-Lung Cellular and Molecular Physiology 287, no. 3 (September 2004): L569—L576. http://dx.doi.org/10.1152/ajplung.00117.2004.
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Duchenne muscular dystrophy is caused by defects in the dystrophin gene, and the mdx mouse is the most frequently employed genetic model of this disease. It is well known that different muscle groups do not respond in the same way to dystrophin deficiency. In particular, the mdx mouse diaphragm exhibits severe morphological and functional changes not found in other mdx muscles. Use of early generation adenoviral vectors to deliver genes to the diaphragm in immunocompetent mdx mice has been associated with substantial functional toxicity and a rapid loss of transgene expression. Here we determined the response to dystrophin gene replacement in the mdx diaphragm using a “gutted” adenoviral vector that contains the coding sequence of two full-length dystrophin genes and is deleted of most viral DNA sequences. At 1 wk postdelivery of the vector, 23.6 ± 4% of total fibers in the injected diaphragm bundle expressed dystrophin at the sarcolemma, which remained stable over the study duration of 30 days without the need for continuous immunosuppression. Treated diaphragms showed a significantly improved resistance to the abnormal force deficits induced by high-stress muscle contractions, the latter being a functional hallmark of dystrophin-deficient muscle. This functional amelioration was achieved despite the presence of mildly increased inflammation (CD4+ and CD8+ lymphocytes) within the vector-treated diaphragms. To our knowledge, this is the first demonstration that a viral vector can achieve reversal of functional abnormalities in the dystrophic diaphragm via therapeutic dystrophin gene transfer without the need for sustained immunosuppressive therapy.
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Cheng, Jie, Feng Yang, and Yamin Guo. "A Comparative Study of Bulk Parameterization Schemes for Estimating Cloudy-Sky Surface Downward Longwave Radiation." Remote Sensing 11, no. 5 (March 5, 2019): 528. http://dx.doi.org/10.3390/rs11050528.
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Parameterization schemes (bulk formulae) are widely used to estimate all-sky surface downward longwave radiation (SDLR) due to the simple, readily available inputs and acceptable accuracy from local to regional scales. Seven widely used bulk formulae are evaluated using the ground measurements collected from 44 globally distributed flux measurement sites of five networks. The Bayesian model averaging (BMA) method is introduced to integrate multiple bulk formulae to obtain an estimate of cloudy-sky SDLR for the first time. The second multiple linear regression model of Carmona et al. (2014) performs the best, with BIAS, RMSE, and R2 of zero, 20.13 W·m−2 and 0.87, respectively. The BMA method can achieve balanced results that are close to the accuracy of the second multiple linear regression model of Carmona et al. (2014) and better than the average accuracy of seven bulk formulae, with BIAS, RMSE, and R2 of −1.08 W·m−2, 21.99 W·m−2 and 0.87, respectively. In addition, the bulk formula of Crawford and Duchon (1999) is preferred if there is insufficient data to calibrate the bulk formulae because it does not need local calibration and has an acceptable accuracy, with BIAS, RMSE, and R2 of 0.96 W·m−2, 26.58 W·m−2 and 0.82, respectively. The effects of climate type, land cover type, and surface elevation are also investigated to fully assess the applicability of each bulk formula and BMA. In general, there is no cloudy-sky bulk parametrization scheme that can be successfully applied everywhere.
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Guerra-Rebollo, Marta, María Stampa, Miguel Ángel Lázaro, Anna Cascante, Cristina Fornaguera, and Salvador Borrós. "Electrostatic Coating of Viral Particles for Gene Delivery Applications in Muscular Dystrophies: Influence of Size on Stability and Antibody Protection." Journal of Neuromuscular Diseases 8, no. 5 (September 14, 2021): 815–25. http://dx.doi.org/10.3233/jnd-210662.
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Background: Duchenne Muscular Dystrophy (DMD) is one of the most common muscular dystrophies, caused by mutated forms of the dystrophin gene. Currently, the only treatment available is symptoms management. Novel approximations are trying to treat these patients with gene therapy, namely, using viral vectors. However, these vectors can be recognized by the immune system decreasing their therapeutic activity and making impossible a multidose treatment due to the induction of the humoral immunity following the first dose. Objective: Our objective is to demonstrate the feasibility of using a hybrid vector to avoid immune clearance, based on the electrostatic coating of adeno-associated virus (AAVs) vectors with our proprietary polymers. Methods: We coated model adeno-associated virus vectors by electrostatic interaction of our cationic poly (beta aminoester) polymers with the viral anionic capsid and characterized biophysical properties. Once the nanoformulations were designed, we studied their in vivo biodistribution by bioluminescence analysis and we finally studied the capacity of the polymers as potential coatings to avoid antibody neutralization. Results: We tested two polymer combinations and we demonstrated the need for poly(ethylene glycol) addition to avoid vector aggregation after coating. In vivo biodistribution studies demonstrated that viral particles are located in the liver (short times) and also in muscles (long times), the target organ. However, we did not achieve complete antibody neutralization shielding using this electrostatic coating. Conclusions: The null hypothesis stands: although it is feasible to coat viral particles by electrostatic interaction with a proprietary polymer, this strategy is not appropriate for AAVs due to their small size, so other alternatives are required as a novel treatment for DMD patients.
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Wasilewska, Eliza, Agnieszka Sobierajska-Rek, Sylwia Małgorzewicz, Mateusz Soliński, and Ewa Jassem. "Benefits of Telemonitoring of Pulmonary Function—3-Month Follow-Up of Home Electronic Spirometry in Patients with Duchenne Muscular Dystrophy." Journal of Clinical Medicine 11, no. 3 (February 6, 2022): 856. http://dx.doi.org/10.3390/jcm11030856.
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Background: In patients with Duchenne Muscular Dystrophy (DMD), the respiratory system determines the quality and length of life; therefore, the search for easy and safe everyday monitoring of the pulmonary function is currently extremely important, particularly in the COVID-19 pandemic. The aim of the study was to evaluate the influence of a three-month home electronic spirometry (e-spirometry) monitoring of the pulmonary function and strength of respiratory muscles as well as the patients’ benefits from this telemetric program. Methods: Twenty-one boys with DMD (aged 7–22; non-ambulatory-11) received a remote electronic spirometer for home use with a special application dedicated for patients and connected with a doctor platform. Control of the hospital spirometry (forced vital capacity-FVC, forced expiratory volume in 1 second-FEV1, peak expiratory flow-PEF) and respiratory muscle strength (maximal inspiratory-MIP and expiratory pressures-MEP) before and after the three-month monitoring were performed as well telemonitoring benefit survey. Results: A total of 1403 measurements were performed; 15 of the participants were able to achieve correct attempts. There were no differences between the hospital and the home spirometry results as well as between respiratory muscle strength during v1 vs. v2 visits for the whole study group (all parameters p > 0.05); the six participants achieved increased value of FVC during the study period. There was a positive correlation between ΔFVC and the number of assessments during the home spirometry (r = 0.7, p < 0.001). Differences between FVC and MIPcmH2O (r = 0.58; p = 0.01), MEPcmH2O (r = 0.75; p < 0.001) was revealed. The mean general satisfaction rating of the telemonitoring was 4.46/5 (SD 0.66) after one month and 4.91/5 (SD 0.28) after three months. The most reported benefit of the home monitoring was the improvement in breathing (38% of participants after one month, 52% after three months of telemonitoring). Forgetting about the procedures was the most common reason for irregular measurements; the participants reported also increased motivation but less time to perform tests. Conclusions: The study indicates high compliance of the home telemonitoring results with the examination in the hospital. Benefits from home spirometry were visible for all participants; the most important benefit was breathing improvement. The remote home spirometry is usable for everyday monitoring of the pulmonary function in DMD patients as well can be also treated as respiratory muscle training.
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Hill, Matthew, Aoife Healy, and Nachiappan Chockalingam. "Defining and grouping children’s therapeutic footwear and criteria for their prescription: an international expert Delphi consensus study." BMJ Open 11, no. 8 (August 2021): e051381. http://dx.doi.org/10.1136/bmjopen-2021-051381.
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ObjectivesThis study aimed to achieve an expert consensus on how to define and group footwear interventions for children, with a further focus on the design characteristics and prescription of off-the-shelf stability footwear for children with mobility impairment.SettingA group of multinational professionals, from clinicians to those involved in the footwear industry, were recruited to ensure a spectrum of opinions.ParticipantsThirty panellists were contacted, of which 24 consented to participate and six withdrew before round 1, a further two withdrew after round 1. Sixteen panellists completed the consensus exercise.Primary and secondary outcome measuresA Delphi consensus method was employed with round 1 split into three sections: (1) terms and definitions, (2) specifics of off-the-shelf stability footwear design and (3) criteria for clinical prescription of off-the-shelf stability footwear. The panel was asked to rate their level of agreement with statements and to provide further insights through open-ended questions. The opinions of the experts were analysed to assess consensus set at 75% agreement or to modify or form new statements presented through the subsequent two rounds.ResultsTherapeutic footwear was the agreed term to represent children’s footwear interventions, with grouping and subgrouping of therapeutic footwear being dependent on their intended clinical outcomes (accommodative, corrective or functional). Both the heel counter and topline as well as the stiffness and width of the sole were identified as potentially influencing mediolateral stability in children’s gait. A consensus was achieved in the prescription criteria and outcome measures for off-the-shelf stability therapeutic footwear for cerebral palsy, mobile symptomatic pes planus, Duchenne muscular dystrophy, spina bifida and Down’s syndrome.ConclusionsThrough a structured synthesis of expert opinion, this study has established a standardisation of terminology and groupings along with prescription criteria for the first time. Reported findings have implications for communication between stakeholders, evidence-based clinical intervention and standardised outcome measures to assess effectiveness.
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EBIHARA, SATORU, GHIABE-HENRI GUIBINGA, RENALD GILBERT, JOSEPHINE NALBANTOGLU, BERNARD MASSIE, GEORGE KARPATI, and BASIL J. PETROF. "Differential effects of dystrophin and utrophin gene transfer in immunocompetent muscular dystrophy (mdx) mice." Physiological Genomics 3, no. 3 (September 8, 2000): 133–44. http://dx.doi.org/10.1152/physiolgenomics.2000.3.3.133.
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Ebihara, Satoru, Ghiabe-Henri Guibinga, Renald Gilbert, Josephine Nalbantoglu, Bernard Massie, George Karpati, and Basil J. Petrof. Differential effects of dystrophin and utrophin gene transfer in immunocompetent muscular dystrophy (mdx) mice. Physiol Genomics 3: 133–144, 2000.—Duchenne muscular dystrophy (DMD) is a fatal disease caused by defects in the gene encoding dystrophin. Dystrophin is a cytoskeletal protein, which together with its associated protein complex, helps to protect the sarcolemma from mechanical stresses associated with muscle contraction. Gene therapy efforts aimed at supplying a normal dystrophin gene to DMD muscles could be hampered by host immune system recognition of dystrophin as a “foreign” protein. In contrast, a closely related protein called utrophin is not foreign to DMD patients and is able to compensate for dystrophin deficiency when overexpressed throughout development in transgenic mice. However, the issue of which of the two candidate molecules is superior for DMD therapy has remained an open question. In this study, dystrophin and utrophin gene transfer effects on dystrophic muscle function were directly compared in the murine (mdx) model of DMD using E1/E3-deleted adenovirus vectors containing either a dystrophin (AdV-Dys) or a utrophin (AdV-Utr) transgene. In immunologically immature neonatal animals, AdV-Dys and AdV-Utr improved tibialis anterior muscle histopathology, force-generating capacity, and the ability to resist injury caused by high-stress contractions to an equivalent degree. By contrast, only AdV-Utr was able to achieve significant improvement in force generation and the ability to resist stress-induced injury in the soleus muscle of immunocompetent mature mdx animals. In addition, in mature mdx mice, there was significantly greater transgene persistence and reduced inflammation with utrophin compared to dystrophin gene transfer. We conclude that dystrophin and utrophin are largely equivalent in their intrinsic abilities to prevent the development of muscle necrosis and weakness when expressed in neonatal mdx animals with an immature immune system. However, because immunity against dystrophin places an important limitation on the efficacy of dystrophin gene replacement in an immunocompetent mature host, the use of utrophin as an alternative to dystrophin gene transfer in this setting appears to offer a significant therapeutic advantage.
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Wallner, K., A. Wuensch, K. Burkhardt, M. Kurome, B. Kessler, P. Fezert, A. Richter, H. Nagashima, N. Klymiuk, and E. Wolf. "338 BACTERIAL ARTIFICIAL CHROMOSOME (BAC) VECTORS FACILITATE EFFICIENT GENE TARGETTING IN KIDNEY CELLS OF PIG." Reproduction, Fertility and Development 23, no. 1 (2011): 264. http://dx.doi.org/10.1071/rdv23n1ab338.
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Site-directed mutagenesis provided a powerful tool for studying gene functions in mice, but the lack of embryonic stem cells in other species limited the application of this technology to other species. Various attempts using negative selection, viral vectors, or other auxiliary means promoted specific projects but did not provide methods for routine experiments. Here, we describe a novel approach that enabled the site-directed modification of 3 different porcine genes relevant for biomedical research. Three main technologies were combined to achieve these goals: bacterial artificial chromosome (BAC) vectors, somatic cell transfection, and nuclear transfer (SCNT). BAC vectors contain large genomic regions in bacterial plasmids. They are superior to conventional targeting tools, as they provide extended regions of homology of several kilobases. Novel recombination tools using bacterial enzymes enable the modification of any DNA region of interest and thus allow the introduction of desired mutations into BACs. After verification of the wt-BAC sequence, it was altered by using modification vectors carrying the desired mutation. The modified BAC vectors are linearized and transfected after verification into primary kidney cell lines, and cells are selected for integration of the vectors. Kidney cells provide both good proliferation and high targeting rates, and thus improve the efficiency compared to fetal fibroblasts. Singularized clones are screened for the replacement of wild-type targeting loci by quantitative PCR. Targeted clones are used for SCNT and transfer of the resulting embryos into synchronized gilts. We have evaluated this technology by the modification of the porcine CFTR, GGTA1, and DMD genes. All 3 genes are relevant for biomedical research, as mutations in CFTR are causative for cystic fibrosis, the knockout of GGTA1 is essential for overcoming hyperacute rejection in xenotransplantation, and various deletions in the DMD gene are responsible for Duchenne muscular dystrophy. Gaining 13 targeted clones out of 1152 for CFTR, 9 out of 306 for GGTA1 and 6 out of 203 for DMD, we obtained efficiencies higher than 1% for each of the target genes. The power of our approach is underlined by the fact that CFTR and DMD are loci that are thought to be difficult to manipulate. The viability of targeted kidney cells and their suitability for nuclear transfer is accentuated by the pregnancy rates (2 out of 3) and the delivery of 4 to 10 piglets or fetuses in the case of CFTR and GGTA1. The heterozygous fetuses or piglets are verified by qPCR. In the case of the X-chromosomal DMD gene, we have generated the first full knockout by transfecting male cells. Pregnancies of a successfully targeted clone are under way. Thus, we consider the combination of modified BAC vectors, transfection of kidney cells, and nuclear transfer to be a technology with the potential for routine production of site-directed mutations. Supported by the Mukoviszidose e.V. and the Bayerische Forschungsstiftung.
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Byrne, Patrick J., Leah J. Novinger, and Dane J. Genther. "Tri-Vector Gracilis Microneurovascular Free Tissue Transfer with Periocular Component to Achieve a Duchenne Smile in Patients with Facial Paralysis." Facial Plastic Surgery & Aesthetic Medicine, October 19, 2022. http://dx.doi.org/10.1089/fpsam.2022.0180.
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Davis, Morgan E., and Jacqueline Greene. "Commentary on “Tri-Vector Gracilis Microneurovascular Free Tissue Transfer with Periocular Component to Achieve a Duchenne Smile in Patients with Facial Paralysis” by Byrne et al." Facial Plastic Surgery & Aesthetic Medicine, October 19, 2022. http://dx.doi.org/10.1089/fpsam.2022.0322.
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Ferrer-Mallol, Elisa, Clare Matthews, Madeline Stoodley, Alessandra Gaeta, Elinor George, Emily Reuben, Alex Johnson, and Elin Haf Davies. "Patient-led development of digital endpoints and the use of computer vision analysis in assessment of motor function in rare diseases." Frontiers in Pharmacology 13 (September 12, 2022). http://dx.doi.org/10.3389/fphar.2022.916714.
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Digital health technologies are transforming the way health outcomes are captured and measured. Digital biomarkers may provide more objective measurements than traditional approaches as they encompass continuous and longitudinal data collection and use of automated analysis for data interpretation. In addition, the use of digital health technology allows for home-based disease assessments, which in addition to reducing patient burden from on-site hospital visits, provides a more holistic picture of how the patient feels and functions in the real world. Tools that can robustly capture drug efficacy based on disease-specific outcomes that are meaningful to patients, are going to be key to the successful development of new treatments. This is particularly important for people living with rare and chronic complex conditions, where therapeutic options are limited and need to be developed using a patient-focused approach to achieve the biggest impact. Working in partnership with patient Organisation Duchenne UK, we co-developed a video-based approach, delivered through a new mobile health platform (DMD Home), to assess motor function in patients with Duchenne muscular dystrophy (DMD), a genetic, rare, muscular disease characterized by the progressive loss of muscle function and strength. Motor function tasks were selected to reflect the “transfer stage” of the disease, when patients are no longer able to walk independently but can stand and weight-bear to transfer. This stage is important for patients and families as it represents a significant milestone in the progression of DMD but it is not routinely captured and/or scored by standard DMD clinical and physiotherapy assessments. A total of 62 videos were submitted by eight out of eleven participants who onboarded the app and were analysed with pose estimation software (OpenPose) that led to the extraction of objective, quantitative measures, including time, pattern of movement trajectory, and smoothness and symmetry of movement. Computer vision analysis of video tasks to identify voluntary or compensatory movements within the transfer stage merits further investigation. Longitudinal studies to validate DMD home as a new methodology to predict progression to the non-ambulant stage will be pursued.
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Pini, Veronica, Virginie Mariot, Julie Dumonceaux, John Counsell, Helen C. O’Neill, Sarah Farmer, Francesco Conti, and Francesco Muntoni. "Transiently expressed CRISPR/Cas9 induces wild-type dystrophin in vitro in DMD patient myoblasts carrying duplications." Scientific Reports 12, no. 1 (March 8, 2022). http://dx.doi.org/10.1038/s41598-022-07671-w.
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AbstractAmong the mutations arising in the DMD gene and causing Duchenne Muscular Dystrophy (DMD), 10–15% are multi-exon duplications. There are no current therapeutic approaches with the ability to excise large multi-exon duplications, leaving this patient cohort without mutation-specific treatment. Using CRISPR/Cas9 could provide a valid alternative to achieve targeted excision of genomic duplications of any size. Here we show that the expression of a single CRISPR/Cas9 nuclease targeting a genomic region within a DMD duplication can restore the production of wild-type dystrophin in vitro. We assessed the extent of dystrophin repair following both constitutive and transient nuclease expression by either transducing DMD patient-derived myoblasts with integrating lentiviral vectors or electroporating them with CRISPR/Cas9 expressing plasmids. Comparing genomic, transcript and protein data, we observed that both continuous and transient nuclease expression resulted in approximately 50% dystrophin protein restoration in treated myoblasts. Our data demonstrate that a high transient expression profile of Cas9 circumvents its requirement of continuous expression within the cell for targeting DMD duplications. This proof-of-concept study therefore helps progress towards a clinically relevant gene editing strategy for in vivo dystrophin restoration, by highlighting important considerations for optimizing future therapeutic approaches.
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Bougé, Anne-Laure, Eva Murauer, Emmanuelle Beyne, Julie Miro, Jessica Varilh, Magali Taulan, Michel Koenig, Mireille Claustres, and Sylvie Tuffery-Giraud. "Targeted RNA-Seq profiling of splicing pattern in the DMD gene: exons are mostly constitutively spliced in human skeletal muscle." Scientific Reports 7, no. 1 (January 3, 2017). http://dx.doi.org/10.1038/srep39094.
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Abstract We have analysed the splicing pattern of the human Duchenne Muscular Dystrophy (DMD) transcript in normal skeletal muscle. To achieve depth of coverage required for the analysis of this lowly expressed gene in muscle, we designed a targeted RNA-Seq procedure that combines amplification of the full-length 11.3 kb DMD cDNA sequence and 454 sequencing technology. A high and uniform coverage of the cDNA sequence was obtained that allowed to draw up a reliable inventory of the physiological alternative splicing events in the muscular DMD transcript. In contrast to previous assumptions, we evidenced that most of the 79 DMD exons are constitutively spliced in skeletal muscle. Only a limited number of 12 alternative splicing events were identified, all present at a very low level. These include previously known exon skipping events but also newly described pseudoexon inclusions and alternative 3′ splice sites, of which one is the first functional NAGNAG splice site reported in the DMD gene. This study provides the first RNA-Seq-based reference of DMD splicing pattern in skeletal muscle and reports on an experimental procedure well suited to detect condition-specific differences in this low abundance transcript that may prove useful for diagnostic, research or RNA-based therapeutic applications.
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Benny Klimek, Margaret E., Maria Candida Vila, Katie Edwards, Jessica Boehler, James Novak, Aiping Zhang, Jack H. Van der Mulen, et al. "Effects of Chronic, Maximal Phosphorodiamidate Morpholino Oligomer (PMO) Dosing on Muscle Function and Dystrophin Restoration in a Mouse Model of Duchenne Muscular Dystrophy." Journal of Neuromuscular Diseases, September 18, 2021, 1–13. http://dx.doi.org/10.3233/jnd-210701.
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Background: Phosphorodiamidate morpholino oligomer (PMO)-mediated exon skipping is currently used in clinical development to treat Duchenne muscular dystrophy (DMD), with four exon-skipping drugs achieving regulatory approval. Exon skipping elicits a truncated, but semi-functional dystrophin protein, similar to the truncated dystrophin expressed in patients with Becker Muscular dystrophy (BMD) where the disease phenotype is less severe than DMD. Despite promising results in both dystrophic animal models and DMD boys, restoration of dystrophin by exon skipping is highly variable, leading to contradictory functional outcomes in clinical trials. Objective: To develop optimal PMO dosing protocols that result in increased dystrophin and improved outcome measures in preclinical models of DMD. Methods: Tested effectiveness of multiple chronic, high dose PMO regimens using biochemical, histological, molecular, and imaging techniques in mdx mice. Results: A chronic, monthly regimen of high dose PMO increased dystrophin rescue in mdx mice and improved specific force in the extensor digitorum longus (EDL) muscle. However, monthly high dose PMO administration still results in variable dystrophin expression localized throughout various muscles. Conclusions: High dose monthly PMO administration restores dystrophin expression and increases muscle force; however, the variability of dystrophin expression at both the inter-and intramuscular level remains. Additional strategies to optimize PMO uptake including increased dosing frequencies or combination treatments with other yet-to-be-defined therapies may be necessary to achieve uniform dystrophin restoration and increases in muscle function.
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Schwartz, Carolyn E., Roland B. Stark, David Cella, Katrina Borowiec, Katherine L. Gooch, and Ivana F. Audhya. "Measuring Duchenne muscular dystrophy impact: development of a proxy-reported measure derived from PROMIS item banks." Orphanet Journal of Rare Diseases 16, no. 1 (November 22, 2021). http://dx.doi.org/10.1186/s13023-021-02114-7.
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Abstract Background Person-reported outcomes measurement development for rare diseases has lagged behind that of more common diseases. In studies of caregivers of patients with rare diseases, one relies on proxy report to characterize this disability. It is important to measure the child’s disability accurately and comprehensively because it affects caregiver burden. We aimed to create a condition-specific caregiver proxy-report measure for Duchenne Muscular Dystrophy (DMD) in order to understand the impact of DMD on the caregiver. Drawing on relevant item banks from the Patient-Reported Outcome Measurement Information System (PROMIS), we sought to confirm their reliability and validity in the target sample of DMD caregivers. Methods This web-based study recruited DMD caregivers via Rare Patient Voice, patient-advocacy groups, and word of mouth. Recruitment was stratified by age of the caregiver’s child with DMD, which broadly represents stages of DMD progression: 2–7, 8–12, 13–17, and > 18. Telephone interviews with DMD parent-caregivers pretested possible measures for content validity. The web-based study utilized an algorithm to categorize respondents’ ambulatory status for tailored administration of PROMIS Parent-Proxy items as well as some new items developed based on caregiver interviews. Item response theory analyses were implemented. Results The study sample included 521 DMD caregivers representing equally the four age strata. The proxy-report measure included the following domains: fatigue impact, strength impact, cognitive function, upper extremity function, positive affect, negative affect, sleep-device symptoms, and mobility. The first five domains had strong psychometric characteristics (unidimensionality; acceptable model fit; strong standardized factor loadings; high marginal reliability). Negative Affect, covering anger, anxiety, depressive symptoms, and psychological stress, fit a bifactor model with good model fit, high marginal reliability, and strong factor loadings. The Sleep-device symptoms domain was not unidimensional, and the mobility domain did not have a simple structure due to residual correlations among items at opposite end of the mobility-disability continuum. These two domain scores were retained as clinimetric indices (i.e., uncalibrated scales), to achieve the overall goal of having a content-valid DMD-specific measure across all stages of disease severity. Conclusions The present study derived a DMD-specific proxy-report measure from PROMIS item banks and supplemental items that could potentially be utilized in caregiver research across all stages of the care recipient’s DMD. Future research will focus on assessing the responsiveness and validity of the measure over time and its comparison to DMD patient self-report.
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Schwartz, Carolyn E., Roland B. Stark, Elijah Biletch, and Richard B. B. Stuart. "Comparing human coding to two natural language processing algorithms in aspirations of people affected by Duchenne Muscular Dystrophy." Journal of Methods and Measurement in the Social Sciences 13, no. 1 (October 1, 2022). http://dx.doi.org/10.2458/jmmss.5397.
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Qualitative methods can enhance our understanding of constructs that have not been well portrayed and enable nuanced depiction of experience from study participants who have not been broadly studied. However, qualitative data require time and effort to train raters to achieve validity and reliability. This study compares recent advances in Natural Language Processing (NLP) models with human coding. This web-based study (N=1,253; 3,046 free-text entries, averaging 64 characters per entry) included people with Duchenne Muscular Dystrophy (DMD), their siblings, and a representative comparison group. Human raters (n=6) were trained over multiple sessions in content analysis as per a comprehensive codebook. Three prompts addressed distinct aspects of participants’ aspirations. Unsupervised NLP was implemented using Latent Dirichlet Allocation (LDA), which extracts latent topics across all the free-text entries. Supervised NLP was done using a Bidirectional Encoder Representations from Transformers (BERT) model, which requires training the algorithm to recognize relevant human-coded themes across free-text entries. We compared the human-, LDA-, and BERT-coded themes. Study sample contained 286 people with DMD, 355 DMD siblings, and 997 comparison participants, age 8-69. Human coders generated 95 codes across the three prompts and had an average inter-rater reliability (Fleiss’s kappa) of 0.77, with minimal rater-effect (pseudo R2=4%). Compared to human coders, LDA does not yield easily interpretable themes. BERT correctly classified only 61-70% of the validation set. LDA and BERT required technical expertise to program and took approximately 1.15 minutes per open-text entry, compared to 1.18 minutes for human raters including training time. LDA and BERT provide potentially viable approaches to analyzing large-scale qualitative data, but both have limitations. When text entries are short, LDA yields latent topics that are hard to interpret. BERT accurately identified only about two thirds of new statements. Humans provided reliable and cost-effective coding in the web-based context. The upfront training enables BERT to process enormous quantities of text data in future work, which should examine NLP’s predictive accuracy given different quantities of training data.
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Howard, Zachary M., Chetan K. Gomatam, Arden B. Piepho, and Jill A. Rafael-Fortney. "Mineralocorticoid Receptor Signaling in the Inflammatory Skeletal Muscle Microenvironments of Muscular Dystrophy and Acute Injury." Frontiers in Pharmacology 13 (June 28, 2022). http://dx.doi.org/10.3389/fphar.2022.942660.
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Duchenne muscular dystrophy (DMD) is a striated muscle degenerative disease due to loss of functional dystrophin protein. Loss of dystrophin results in susceptibility of muscle membranes to damage, leading to muscle degeneration and continuous inflammation and fibrosis that further exacerbate pathology. Long-term glucocorticoid receptor (GR) agonist treatment, the current standard-of-care for DMD, modestly improves prognosis but has serious side effects. The mineralocorticoid receptor (MR), a ligand-activated transcription factor present in many cell types, has been implicated as a therapeutic target for DMD. MR antagonists (MRAs) have fewer side effects than GR agonists and are used clinically for heart failure. MRA efficacy has recently been demonstrated for DMD cardiomyopathy and in preclinical studies, MRAs also alleviate dystrophic skeletal muscle pathology. MRAs lead to improvements in muscle force and membrane stability and reductions in degeneration, inflammation, and fibrosis in dystrophic muscles. Myofiber-specific MR knockout leads to most of these improvements, supporting an MR-dependent mechanism of action, but MRAs additionally stabilize myofiber membranes in an MR-independent manner. Immune cell MR signaling in dystrophic and acutely injured normal muscle contributes to wound healing, and myeloid-specific MR knockout is detrimental. More research is needed to fully elucidate MR signaling in striated muscle microenvironments. Direct comparisons of genomic and non-genomic effects of glucocorticoids and MRAs on skeletal muscles and heart will contribute to optimal temporal use of these drugs, since they compete for binding conserved receptors. Despite the advent of genetic medicines, therapies targeting inflammation and fibrosis will be necessary to achieve optimal patient outcomes.
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Yazid, Muhammad Dain, and Chen Hung-Chih. "Perturbation of PI3K/Akt signaling affected autophagy modulation in dystrophin-deficient myoblasts." Cell Communication and Signaling 19, no. 1 (October 27, 2021). http://dx.doi.org/10.1186/s12964-021-00785-0.
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Abstract Background The absence of dystrophin has gave a massive impact on myotube development in Muscular Dystrophy pathogenesis. One of the conserved signaling pathways involved in skeletal muscle differentiation is the PI3K/Akt/mTOR pathway that plays a vital role in autophagy regulation. To further understand and establish targeted therapy in dystrophin-deficient myoblasts, protein expression profiling has been determined which provides information on perturbed autophagy modulation and activation. Methods In this study, a dystrophin-deficient myoblast cell line established from the skeletal muscle of a dystrophic (mdx) mouse was used as a model. The dfd13 (dystrophin-deficient) and C2C12 (non-dystrophic) myoblasts were cultured in low mitogen conditions for 10 days to induce differentiation. The cells were subjected to total protein extraction prior to Western blotting assay technique. Protein sub-fractionation has been conducted to determine protein localization. The live-cell analysis of autophagy assay was done using a flow cytometer. Results In our culture system, the dfd13 myoblasts did not achieve terminal differentiation. PTEN expression was profoundly increased in dfd13 myoblasts throughout the differentiation day subsequently indicates perturbation of PI3K/Akt/mTOR regulation. In addition, rictor-mTORC2 was also found inactivated in this event. This occurrence has caused FoxO3 misregulation leads to higher activation of autophagy-related genes in dfd13 myoblasts. Autophagosome formation was increased as LC3B-I/II showed accumulation upon differentiation. However, the ratio of LC3B lipidation and autophagic flux were shown decreased which exhibited dystrophic features. Conclusion Perturbation of the PTEN-PI3K/Akt pathway triggers excessive autophagosome formation and subsequently reduced autophagic flux within dystrophin-deficient myoblasts where these findings are of importance to understand Duchenne Muscular Dystrophy (DMD) patients. We believe that some manipulation within its regulatory signaling reported in this study could help restore muscle homeostasis and attenuate disease progression.
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Lu, Qi Long. "Revertant Phenomenon in DMD and LGMD2I and Its Therapeutic Implications: A Review of Study Under Mentorship of Terrence Partridge." Journal of Neuromuscular Diseases, June 17, 2021, 1–9. http://dx.doi.org/10.3233/jnd-210692.
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This review recollects my initial research focus on revertant fibers (expressing dystrophin in the background of frame-shifting mutation) in Duchenne muscular dystrophy (DMD) muscles in Professor Terrence Partridge’s Muscle Cell Biology Laboratory in MRC Clinical Research Science Center, Harmmersmith Hospital, London, UK. Our data indicated that revertant fibers are most likely resulted from epigenetic random events which skip exon(s) flanking the mutated exon, leading to the restoration of the reading frame. Some of these events establish themselves as relatively permanent skipping patterns, a mechanism similar to multiple transcript species established in various cell types. With this hypothesis, antisense oligonucleotide-mediated exon skipping is likely to have a great chance to achieve restoration of therapeutic levels of dystrophin in DMD muscles. This leads to our first reports of local and systemic efficacy of antisense oligonucleotide-mediated exon skipping for DMD treatment. The experience under Terry’s mentorship shaped my thinking and led me to explore another revertant feature in the dystroglycanopathy caused by mutations in the Fukutin Related Protein (FKRP) gene which functions as a glycosyltransferase. Mutant FKRPs retain partial function and produce a fraction of normal to no detectable levels of laminin-binding α-dystroglycan (matriglycan) in most of the muscle fibers. Reversion to near normal levels of matriglycan expression in muscles with FKRP mutations depends on muscle regeneration and in muscles of neonate mice, suggesting that changes in metabolism and gene expression could be sufficient to compensate for the reduced function of mutant FKRP genes even those associated with severe congenital muscular dystrophy (CMD). This is now supported by our successful demonstration that supply of FKRP mutant mice with ribitol, a precursor for substrate of FKRP, is sufficient to restore the levels of matriglycan with therapeutic significance. Our data overall suggest that rare events of reversion in muscular dystrophy, and likely other diseases could provide unique insight for mechanisms and therapeutic exploitation.
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Nowak, Joanna. "Specyfika polskiej refleksji romantycznej nad rasą i pojęciami pokrewnymi." Sprawy Narodowościowe, no. 51 (December 23, 2019). http://dx.doi.org/10.11649/sn.1812.
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The specifics of Polish Romantic Reflection on race and cognate notionsThe one and basic characteristic feature of Polish Romantic reflection on race was that it associated race with tribeness. Such a reduction of the notion ‘race’ to ethnicity resulted from the then known definition of nation as a multiethnic and multicultural community which constituted the superior and the superb form of organizing the societal world, as well as from weakness of scholarly reflection in the field of physical anthropology. For Polish Romantics, race was not an objective category that on the basis of exiting physical differences enabled a division of humanity into permanent and clearly delimitated phonotypical populations. Race was identified with tribeness and related to a long gone past when the human kind merely created primitive social ties based on kinship of blood. However, what is really binding people is not biological criteria but spiritual semblance: communion of thought, feelings, and purpose. Color of skin or shape of skull do not determine a given populace’s brain capacities; in fact what counts only is cultural and civilization factors. For Romantics, in their thought a Eurocentric attitude dominated, although it was devoid of clearly racist connotations. Superior and inferior races, if existed at all, appeared only in the context of a level of development of civilization, that is, merely temporarily, because every race was able to achieve the level of the most developed races or even a higher one. Specyfika polskiej refleksji romantycznej nad rasą i pojęciami pokrewnymiSpecyfika polskiej refleksji romantycznej nad rasą miała jedną zasadniczą cechę – utożsamienie jej z plemiennością. Zredukowanie pojęcia rasy do etniczności wynikało z ówczesnej definicji narodu jako wspólnoty wieloetnicznej, wielokulturowej, która stanowiła nadrzędną, najdoskonalszą formę urządzenia świata społecznego, oraz ze słabości naukowej refleksji w zakresie antropologii fizycznej. Rasa nie była dla romantyków polskich kategorią obiektywną, pozwalającą według istniejących różnic fizycznych podzielić ludzkość na trwałe, ograniczone fenotypowo populacje. Utożsamiono ją z plemiennością i łączono z zamierzchłą przeszłością, gdy ludzkość tworzyła jedynie prymitywne związki społeczne oparte na pokrewieństwie krwi. Tymczasem ludzi zespala nie tyle kryterium biologiczne, co podobieństwo duchowe – wspólnota myśli, uczuć i celu. Kolor skóry czy kształt czaszki nie determinowały zdolności umysłowych populacji, a jedynie czynniki natury kulturowo-cywilizacyjnej. Postawa europocentryczna dominowała w ówczesnej myśli, ale bez konotacji stricte rasistowskich. Jeśli istniały rasy niższe i wyższe, to tylko w kontekście stopnia zaawansowania w rozwoju cywilizacyjnym, a zatem czasowo, gdyż każda z nich mogła dojść do poziomu tych najbardziej rozwiniętych, a nawet je przewyższyć.
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Romano, L., F. Fabbrini, P. D’Agostino, and L. Nitsch. "La diagnosi genetica preimpianto: aspetti biomedici con aggiornamenti di letteratura scientifica." Medicina e Morale 55, no. 1 (February 28, 2006). http://dx.doi.org/10.4081/mem.2006.367.
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L’articolo analizza gli aspetti biomedici della diagnosi genetica preimpianto (PGD), in considerazione degli aggiornamenti della letteratura scientifica. La diagnosi genetica preimpianto è definibile, in ambito biomedico, come forma precoce di diagnosi che, mediante diverse tecniche, analizza gli embrioni prodotti con la fecondazione artificiale al fine di poter determinare la presenza di alterazioni genetiche. La PGD viene proposta, poi, anche per massimizzare l’efficacia delle procedure di fecondazione artificiale e viene indicata da alcuni per la selezione di embrioni secondo il sesso e per ragioni non mediche (c.d. bilanciamento familiare o Social Preimplantation Diagnosis). L’articolo analizza i rischi connessi alla tecnica di PGD quali gli errori diagnostici, il danneggiamento e la perdita di embrioni, lo sviluppo della gravidanza. Per poter praticare la PGD si producono embrioni mediante fecondazione artificiale. La diagnosi, attuata con diverse tecniche, è effettuata mediante biopsia e selezione degli embrioni. Una o due cellule sono aspirate attraverso un foro nella zona pellucida dall’embrione allo stato di 6-8 cellule (terzo giorno di sviluppo), mediante una soluzione acidificata di Tyrodes o mediante laser. La rimozione del primo e secondo globulo polare è stata realizzata principalmente per selezionare aneuploidie legate all’età (PGD-AS). L’analisi del globulo polare, però, è limitata alle malattie ereditate per via materna, infatti i cromosomi paterni non possono essere analizzati. La reazione a catena della polimerasi (PCR) è stata usata per la prima volta in PGD per la diagnosi di fibrosi cistica. La PCR è limitata dal rischio di contaminazione e dalla perdita dell’allele (allele droupout). La PGD è stata eseguita per malattie Xlinked (per esempio distrofia muscolare di Duchenne, emofilia, X-fragile), malattie recessive (fibrosi cistica, talassemia, atrofia muscolare spinale) e malattie dominanti (distrofia miotonica, Corea di Huntington, Charcot-Marie- Tooth). L’ibridazione in situ fluorescente (FISH) sui nuclei in interfase è stata usata per analizzare i cromosomi degli embrioni poiché è difficile fare il cariotipo ai singoli bastomeri, La prima applicazione di FISH è stata per determinare il sesso per le malattie X-linked. La PGD viene praticata per i portatori di varie aberrazioni cromosomiche bilanciate, per esempio le traslocazioni, le inversioni, le delezioni, usando sonde specifiche per rilevare l’aberrazione. Nuove tecniche si stanno mettendo a punto: la multiplex PCR, la whole genome amplification la comparative menome hybridisation (CGH) e i DNA “chip”. Le legislazioni che regolano la PGD variano da nazione a nazione: da nessuna alla proibizione. ---------- In this article the authors study biomedical issues of preimplantation genetic diagnosis (PGD), considering the scientific literature. PGD is an early form of diagnosis for patients at risk of transmitting an inherited disease to their offspring. Patients have to go through in vitro fertilization (IVF, ICSI) to produce embryos for PGD. Furthermore, some authors suggest sex selection by PGD for family balancing or social preimplantation diagnosis. The authors analyse the risk of PGD (e.g. diagnostic failure, embryo-survival after biopsy, embryo loss and pregnancy rate). A biopsy of the embryos, removing 1-2 cells, and single cell diagnosis are performed to determine which embryos are free from the genetic disease. 1-2 cells are aspirated through a hole in zona pellucida made by acidified Tyrodes solution or a non-contact laser. Removal of the first and second polar body, either sequentially or simultaneously has also been performed for PGD, mainly for age-related aneuploidy screening (PGD-AS). Polar body analysis is limited to maternally inherited disease as the paternal chromosomes cannot be analyzed. The polymerase chain reaction (PCR) has been used on single cells for PGD since the first report of PGD for cystic fibrosis. PCR is hampered by the risk of contamination and allele dropout. Paternal contamination can be overcome by using intracytoplamatic sperm injection (ICSI) to achieve fertilization. PGD has been performed for X-linked (e.g. Duchenne muscular dystrophy, haemophilia, fragile X syndrome), recessive (e.g. cystic fibrosis, thalassemia, spinal muscular atrophy) and dominant (e.g. myotinic dystrophy, Huntington’s disease, Charcot-Marie-Tooth disorder) diseases. Since it is difficult to karyotype single bastomeres, interphase fluorescent in situ hybridization (FISH) has been used to analyze chromosomes in embryos. FISH for sexing for X-linked disease was the first application, and PGD may be performed for carriers of various balanced chromosome aberrations, e.g. translocations, inversions, deletions, using probes designed to detect the specific aberration. Recent advances in molecular diagnosis technique have included the use of multiplex PC, whole genome amplification, comparative genome hybridisation (CGH) and DNA microarray. The rules and legislation regulating PGD varies from country to country, from no legislation at all to total prohibition.