Evaluation of SMN protein, transcript, and copy number in the biomarkers for spinal muscular atrophy (BforSMA clinical study.

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Thomas O Crawford

Full Text Available The universal presence of a gene (SMN2 nearly identical to the mutated SMN1 gene responsible for Spinal Muscular Atrophy (SMA has proved an enticing incentive to therapeutics development. Early disappointments from putative SMN-enhancing agent clinical trials have increased interest in improving the assessment of SMN expression in blood as an early "biomarker" of treatment effect.A cross-sectional, single visit, multi-center design assessed SMN transcript and protein in 108 SMA and 22 age and gender-matched healthy control subjects, while motor function was assessed by the Modified Hammersmith Functional Motor Scale (MHFMS. Enrollment selectively targeted a broad range of SMA subjects that would permit maximum power to distinguish the relative influence of SMN2 copy number, SMA type, present motor function, and age.SMN2 copy number and levels of full-length SMN2 transcripts correlated with SMA type, and like SMN protein levels, were lower in SMA subjects compared to controls. No measure of SMN expression correlated strongly with MHFMS. A key finding is that SMN2 copy number, levels of transcript and protein showed no correlation with each other.This is a prospective study that uses the most advanced techniques of SMN transcript and protein measurement in a large selectively-recruited cohort of individuals with SMA. There is a relationship between measures of SMN expression in blood and SMA type, but not a strong correlation to motor function as measured by the MHFMS. Low SMN transcript and protein levels in the SMA subjects relative to controls suggest that these measures of SMN in accessible tissues may be amenable to an "early look" for target engagement in clinical trials of putative SMN-enhancing agents. Full length SMN transcript abundance may provide insight into the molecular mechanism of phenotypic variation as a function of SMN2 copy number.Clinicaltrials.gov NCT00756821.

Atrofia muscular espinal en el niño Spinal muscular atrophy present in children

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Nicolás Garófalo Gómez

2009-09-01

Full Text Available INTRODUCCIÓN. Las atrofias musculares espinales en la infancia (AME son trastornos genéticos autosómicos recesivos, caracterizados por degeneración de las motoneuronas espinales y bulbares. El presente estudio tuvo el objetivo principal de describir las principales características clínicas en una serie de niños con AME. MÉTODOS. Se realizó un estudio retrospectivo de los pacientes con AME atendidos en el Instituto de Neurología y Neurocirugía de Cuba, entre enero de 1997 y diciembre de 2001. Se recopilaron los datos de 35 pacientes, 4 de ellos, fetos con confirmación prenatal de AME. Se precisaron las principales características clínicas, electromiográficas, de la biopsia muscular y de los estudios genéticos moleculares realizados en cada caso. RESULTADOS. La AME de tipo II resultó la forma clínica más frecuente (58 %, seguida por la AME de tipo I (42 %. Las principales manifestaciones clínicas resultaron la debilidad muscular generalizada con predominio proximal en extremidades, asociada a hipotonía y arreflexia osteotendinosa. La deleción de los exones 7 y 8 del gen SMN1 se detectó en 20 de 23 casos estudiados (87 %.INTRODUCTION: Spinal muscular atrophies (SMA in childhood are autosomal recessive genetic disorders, characterized by spinal and bulbar motoneurons degenerations. Aim of present paper was to describe the main clinical features in a series of children presenting SMA. METHODS: A retrospective study of patients with SMA seen in the Neurology and Neurosurgery Institute of Cuba from January, 2997 and December, 2001 was made. Data from 35 patients were available; four of them were fetus with prenatal confirmation of SMA. Main clinical, electromyography, muscular biopsy, and of molecular genetic studies performed in each case were determined. RESULTS: Type II SMA was the more frequent clinical presentation (58%, followed by type I SMA (42,%. Main clinical manifestations were a systemic muscular weakness with

Deletion analysis of SMN1 and NAIP genes in southern Chinese children with spinal muscular atrophy

Institute of Scientific and Technical Information of China (English)

Yu-hua LIANG; Xiao-ling CHEN; Zhong-sheng YU; Chun-yue CHEN; Sheng BI; Lian-gen MAO; Bo-lin ZHOU; Xian-ning ZHANG

2009-01-01

Spinal muscular atrophy (SMA) is a disorder characterized by degeneration of lower motor neurons and occasionally bulbar motor neurons leading to progressive limb and trunk paralysis as well as muscular atrophy. Three types of SMA are rec-ognized depending on the age of onset, the maximum muscular activity achieved, and survivorship: SMA1, SMA2, and SMA3. The survival of motor neuron (SMN) gene has been identified as an SMA determining gene, whereas the neuronal apoptosis inhibitory protein (NAIP) gene is considered to be a modifying factor of the severity of SMA. The main objective of this study was to analyze the deletion of SMN1 and NAIP genes in southern Chinese children with SMA. Here, polymerase chain reaction (PCR) combined with restriction fragment length polymorphism (RFLP) was performed to detect the deletion of both exon 7 and exon 8 of SMNI and exon 5 of NAIP in 62 southern Chinese children with strongly suspected clinical symptoms of SMA. All the 32 SMAI patients and 76% (13/17) of SMA2 patients showed homozygous deletions for exon 7 and exon 8, and all the 13 SMA3 patients showed single deletion of SMN1 exon 7 along with 24% (4/17) of SMA2 patients. Eleven out of 32 (34%) SMA1 patients showed NAIP deletion, and none of SMA2 and SMA3 patients was found to have NAIP deletion. The findings of homozygous deletions of exon 7 and/or exon 8 of SMN1 gene confirmed the diagnosis of SMA, and suggested that the deletion of SMN1 exon 7 is a major cause of SMA in southern Chinese children, and that the NA1P gene may be a modifying factor for disease severity of SMA 1. The molecular diagnosis system based on PCR-RFLP analysis can conveniently be applied in the clinical testing, genetic counseling, prenatal diagnosis and preimplantation genetic diagnosis of SMA.

Forced oscillation technique in spinal muscular atrophy.

Science.gov (United States)

Gauld, Leanne M; Keeling, Lucy A; Shackleton, Claire E; Sly, Peter D

2014-09-01

Spinal muscular atrophy (SMA) causes respiratory compromise that is difficult to assess in young children. The forced oscillation technique (FOT) is commercially available for children as young as 2 years of age and is nonvolitional. The aim of this study was to assess the usefulness of FOT in young children with SMA. Children with SMA aged resistance at 8 Hz (Rrs8) (mean z score, +0.66; SD, 1.34; P = .12) were abnormal. Four children performed spirometry. Linear relationships to Xrs8 exist: FVC (R2, 0.54), unassisted PCF (R2, 0.33), assisted PCF (R2, 0.43), and AHI (R2, 0.32). Over 12 months, Xrs8z score worsened (rate of change of +1.08, P change +0.51, P .05) was found between clinical characteristics and FOT values. FOT is feasible in young children with SMA, with abnormal values of reactance and resistance on grouped data, worsening over 12 months. Xrs8 is related to respiratory tests used to monitor progress in SMA (FVC, PCF, AHI). Further research on the value of FOT in managing individuals is warranted.

Therapeutic strategies for spinal muscular atrophy: SMN and beyond

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Melissa Bowerman

2017-08-01

Full Text Available Spinal muscular atrophy (SMA is a devastating neuromuscular disorder characterized by loss of motor neurons and muscle atrophy, generally presenting in childhood. SMA is caused by low levels of the survival motor neuron protein (SMN due to inactivating mutations in the encoding gene SMN1. A second duplicated gene, SMN2, produces very little but sufficient functional protein for survival. Therapeutic strategies to increase SMN are in clinical trials, and the first SMN2-directed antisense oligonucleotide (ASO therapy has recently been licensed. However, several factors suggest that complementary strategies may be needed for the long-term maintenance of neuromuscular and other functions in SMA patients. Pre-clinical SMA models demonstrate that the requirement for SMN protein is highest when the structural connections of the neuromuscular system are being established, from late fetal life throughout infancy. Augmenting SMN may not address the slow neurodegenerative process underlying progressive functional decline beyond childhood in less severe types of SMA. Furthermore, individuals receiving SMN-based treatments may be vulnerable to delayed symptoms if rescue of the neuromuscular system is incomplete. Finally, a large number of older patients living with SMA do not fulfill the present criteria for inclusion in gene therapy and ASO clinical trials, and may not benefit from SMN-inducing treatments. Therefore, a comprehensive whole-lifespan approach to SMA therapy is required that includes both SMN-dependent and SMN-independent strategies that treat the CNS and periphery. Here, we review the range of non-SMN pathways implicated in SMA pathophysiology and discuss how various model systems can serve as valuable tools for SMA drug discovery.

Serum cholinesterase activity in infantile and juvenile spinal muscular atrophy.

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Niebroj-Dobosz, I; Hausmanowa-Petrusewicz, I

1989-09-01

Serum acetylcholinesterase (AChE) and pseudocholinesterase (ChE) activity in infantile and juvenile spinal muscular atrophy (SMA) was determined. The total AChE activity was either normal or decreased in the childhood SMA (Type 1), the other SMA groups and disease controls (ALS, X-linked SMA). In the majority of SMA Type 1 cases (6/7 tested) an absence of the asymmetric A12 form was found. This was accompanied by changes in the other asymmetric and globular forms. The latter was, however, not specific for SMA Type 1 cases. The ChE activity was increased in the majority of SMA cases as well as disease controls. The asymmetric A12 ChE form was increased in all SMA Type 3 cases, the values of this form in SMA Type 1 was variable. A change in the ChE globular forms in SMA Type 1 and SMA Type 2 was a frequent finding. It is suggested that the absence of the asymmetric A12 AChE form in SMA Type 1 arises because of muscle cell immaturity and undeveloped muscle-nerve interactions. The reason of ChE changes is obscure.

Social/economic costs and health-related quality of life in patients with spinal muscular atrophy (SMA) in Spain.

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López-Bastida, Julio; Peña-Longobardo, Luz María; Aranda-Reneo, Isaac; Tizzano, Eduardo; Sefton, Mark; Oliva-Moreno, Juan

2017-08-18

The aim of this study was to determine the economic burden and health-related quality of life (HRQOL) of patients with Spinal Muscular Atrophy (SMA) and their caregivers in Spain. This was a cross-sectional and retrospective study of patients diagnosed with SMA in Spain. We adopted a bottom up, prevalence approach design to study patients with SMA. The patient's caregivers completed an anonymous questionnaire regarding their socio-demographic characteristics, use of healthcare services and non-healthcare services. Costs were estimated from a societal perspective (including healthcare costs and non-healthcare costs), and health-related quality of life (HRQOL) was assessed using the EQ-5D questionnaire. The main caregivers also answered a questionnaire on their characteristics and on their HRQOL. A total of 81 caregivers of patients with different subtypes of SMA completed the questionnaire. Based on the reference unitary prices for 2014, the average annual costs per patient were € 33,721. Direct healthcare costs were € 10,882 (representing around 32.3% of the total cost) and the direct non-healthcare costs were € 22,839 (67.7% of the total cost). The mean EQ-5D social tariff score for patients was 0.16, and the mean score of the EQ-5D visual analogue scale was 54. The mean EQ-5D social tariff score for caregivers was 0.49 and their mean score on the EQ-5D visual analogue scale was 69. The results highlight the burden that SMA has in terms of costs and decreased HRQOL, not only for patients but also for their caregivers. In particular, the substantial social/economic burden is mostly attributable to the high direct non-healthcare costs.

Prenatal diagnosis of spinal muscular atrophy in Chinese by genetic analysis of fetal cells

Institute of Scientific and Technical Information of China (English)

WU Ting; DING Xin-sheng; LI Wen-lei; YAO Juan; DENG Xiao-xuan

2005-01-01

Background Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by degeneration of anterior horn cells of the spinal cord.The survival motor neuron gene is SMA-determining gene deleted in approximately 95% of SMA patients.This study was undertaken to predict prenatal SMA efficiently and rapidly in families with previously affected child.Methods Prenatal diagnosis was made in 8 fetuses with a family history of SMA.Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were used for the detection of the survival motor neuron gene.Results The survival motor neuron gene was not found in 6 fetuses, ruling out the diagnosis of SMA.Two fetuses were detected positive and the pregnancies were terminated.Conclusion Our method is effective and convenient in prenatal diagnosis of SMA.

Novel mutations expand the clinical spectrum of DYNC1H1-associated spinal muscular atrophy

NARCIS (Netherlands)

Scoto, Mariacristina; Rossor, Alexander M.; Harms, Matthew B.; Cirak, Sebahattin; Calissano, Mattia; Robb, Stephanie; Manzur, Adnan Y.; Martínez Arroyo, Amaia; Rodriguez Sanz, Aida; Mansour, Sahar; Fallon, Penny; Hadjikoumi, Irene; Klein, Andrea; Yang, Michele; de Visser, Marianne; Overweg-Plandsoen, W. C. G. Truus; Baas, Frank; Taylor, J. Paul; Benatar, Michael; Connolly, Anne M.; Al-Lozi, Muhammad T.; Nixon, John; de Goede, Christian G. E. L.; Foley, A. Reghan; Mcwilliam, Catherine; Pitt, Matthew; Sewry, Caroline; Phadke, Rahul; Hafezparast, Majid; Chong, W. K. Kling; Mercuri, Eugenio; Baloh, Robert H.; Reilly, Mary M.; Muntoni, Francesco

2015-01-01

To expand the clinical phenotype of autosomal dominant congenital spinal muscular atrophy with lower extremity predominance (SMA-LED) due to mutations in the dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) gene. Patients with a phenotype suggestive of a motor, non-length-dependent neuronopathy

A Perturbed MicroRNA Expression Pattern Characterizes Embryonic Neural Stem Cells Derived from a Severe Mouse Model of Spinal Muscular Atrophy (SMA

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Andrea Luchetti

2015-08-01

Full Text Available Spinal muscular atrophy (SMA is an inherited neuromuscular disorder and the leading genetic cause of death in infants. Despite the disease-causing gene, survival motor neuron (SMN1, encodes a ubiquitous protein, SMN1 deficiency preferentially affects spinal motor neurons (MNs, leaving the basis of this selective cell damage still unexplained. As neural stem cells (NSCs are multipotent self-renewing cells that can differentiate into neurons, they represent an in vitro model for elucidating the pathogenetic mechanism of neurodegenerative diseases such as SMA. Here we characterize for the first time neural stem cells (NSCs derived from embryonic spinal cords of a severe SMNΔ7 SMA mouse model. SMNΔ7 NSCs behave as their wild type (WT counterparts, when we consider neurosphere formation ability and the expression levels of specific regional and self-renewal markers. However, they show a perturbed cell cycle phase distribution and an increased proliferation rate compared to wild type cells. Moreover, SMNΔ7 NSCs are characterized by the differential expression of a limited number of miRNAs, among which miR-335-5p and miR-100-5p, reduced in SMNΔ7 NSCs compared to WT cells. We suggest that such miRNAs may be related to the proliferation differences characterizing SMNΔ7 NSCs, and may be potentially involved in the molecular mechanisms of SMA.

A Perturbed MicroRNA Expression Pattern Characterizes Embryonic Neural Stem Cells Derived from a Severe Mouse Model of Spinal Muscular Atrophy (SMA).

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Luchetti, Andrea; Ciafrè, Silvia Anna; Murdocca, Michela; Malgieri, Arianna; Masotti, Andrea; Sanchez, Massimo; Farace, Maria Giulia; Novelli, Giuseppe; Sangiuolo, Federica

2015-08-06

Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder and the leading genetic cause of death in infants. Despite the disease-causing gene, survival motor neuron (SMN1), encodes a ubiquitous protein, SMN1 deficiency preferentially affects spinal motor neurons (MNs), leaving the basis of this selective cell damage still unexplained. As neural stem cells (NSCs) are multipotent self-renewing cells that can differentiate into neurons, they represent an in vitro model for elucidating the pathogenetic mechanism of neurodegenerative diseases such as SMA. Here we characterize for the first time neural stem cells (NSCs) derived from embryonic spinal cords of a severe SMNΔ7 SMA mouse model. SMNΔ7 NSCs behave as their wild type (WT) counterparts, when we consider neurosphere formation ability and the expression levels of specific regional and self-renewal markers. However, they show a perturbed cell cycle phase distribution and an increased proliferation rate compared to wild type cells. Moreover, SMNΔ7 NSCs are characterized by the differential expression of a limited number of miRNAs, among which miR-335-5p and miR-100-5p, reduced in SMNΔ7 NSCs compared to WT cells. We suggest that such miRNAs may be related to the proliferation differences characterizing SMNΔ7 NSCs, and may be potentially involved in the molecular mechanisms of SMA.

Muscular atrophy in diabetic neuropathy

DEFF Research Database (Denmark)

Andersen, H; Gadeberg, P C; Brock, B

1997-01-01

Diabetic patients with polyneuropathy develop motor dysfunction. To establish whether motor dysfunction is associated with muscular atrophy the ankle dorsal and plantar flexors of the non-dominant leg were evaluated with magnetic resonance imaging in 8 patients with symptomatic neuropathy, in 8 non...... confirmed that the atrophy predominated distally. We conclude that muscular atrophy underlies motor weakness at the ankle in diabetic patients with polyneuropathy and that the atrophy is most pronounced in distal muscles of the lower leg indicating that a length dependent neuropathic process explains...

Defective Ca2+ channel clustering in axon terminals disturbs excitability in motoneurons in spinal muscular atrophy

OpenAIRE

Jablonka, Sibylle; Beck, Marcus; Lechner, Barbara Dorothea; Mayer, Christine; Sendtner, Michael

2007-01-01

Proximal spinal muscular atrophy (SMA) is a motoneuron disease for which there is currently no effective treatment. In animal models of SMA, spinal motoneurons exhibit reduced axon elongation and growth cone size. These defects correlate with reduced β-actin messenger RNA and protein levels in distal axons. We show that survival motoneuron gene (Smn)–deficient motoneurons exhibit severe defects in clustering Cav2.2 channels in axonal growth cones. These defects also correlate with a reduced f...

Machine learning algorithms to classify spinal muscular atrophy subtypes.

Science.gov (United States)

Srivastava, Tuhin; Darras, Basil T; Wu, Jim S; Rutkove, Seward B

2012-07-24

The development of better biomarkers for disease assessment remains an ongoing effort across the spectrum of neurologic illnesses. One approach for refining biomarkers is based on the concept of machine learning, in which individual, unrelated biomarkers are simultaneously evaluated. In this cross-sectional study, we assess the possibility of using machine learning, incorporating both quantitative muscle ultrasound (QMU) and electrical impedance myography (EIM) data, for classification of muscles affected by spinal muscular atrophy (SMA). Twenty-one normal subjects, 15 subjects with SMA type 2, and 10 subjects with SMA type 3 underwent EIM and QMU measurements of unilateral biceps, wrist extensors, quadriceps, and tibialis anterior. EIM and QMU parameters were then applied in combination using a support vector machine (SVM), a type of machine learning, in an attempt to accurately categorize 165 individual muscles. For all 3 classification problems, normal vs SMA, normal vs SMA 3, and SMA 2 vs SMA 3, use of SVM provided the greatest accuracy in discrimination, surpassing both EIM and QMU individually. For example, the accuracy, as measured by the receiver operating characteristic area under the curve (ROC-AUC) for the SVM discriminating SMA 2 muscles from SMA 3 muscles was 0.928; in comparison, the ROC-AUCs for EIM and QMU parameters alone were only 0.877 (p < 0.05) and 0.627 (p < 0.05), respectively. Combining EIM and QMU data categorizes individual SMA-affected muscles with very high accuracy. Further investigation of this approach for classifying and for following the progression of neuromuscular illness is warranted.

Genetics Home Reference: spinal muscular atrophy

Science.gov (United States)

... difficulty breathing. Children with this type often have joint deformities (contractures) that impair movement. In severe cases, ... Proximal spinal muscular atrophy Washington University, St. Louis: Neuromuscular Disease Center: Spinal Muscular Atrophy Patient Support and ...

SMA CARNIVAL TRIAL PART II: a prospective, single-armed trial of L-carnitine and valproic acid in ambulatory children with spinal muscular atrophy.

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John T Kissel

Full Text Available BACKGROUND: Multiple lines of evidence have suggested that valproic acid (VPA might benefit patients with spinal muscular atrophy (SMA. The SMA CARNIVAL TRIAL was a two part prospective trial to evaluate oral VPA and L-carnitine in SMA children. Part 1 targeted non-ambulatory children ages 2-8 in a 12 month cross over design. We report here Part 2, a twelve month prospective, open-label trial of VPA and L-carnitine in ambulatory SMA children. METHODS: This study involved 33 genetically proven type 3 SMA subjects ages 3-17 years. Subjects underwent two baseline assessments over 4-6 weeks and then were placed on VPA and L-carnitine for 12 months. Assessments were performed at baseline, 3, 6 and 12 months. Primary outcomes included safety, adverse events and the change at 6 and 12 months in motor function assessed using the Modified Hammersmith Functional Motor Scale Extend (MHFMS-Extend, timed motor tests and fine motor modules. Secondary outcomes included changes in ulnar compound muscle action potential amplitudes (CMAP, handheld dynamometry, pulmonary function, and Pediatric Quality of Life Inventory scores. RESULTS: Twenty-eight subjects completed the study. VPA and carnitine were generally well tolerated. Although adverse events occurred in 85% of subjects, they were usually mild and transient. Weight gain of 20% above body weight occurred in 17% of subjects. There was no significant change in any primary outcome at six or 12 months. Some pulmonary function measures showed improvement at one year as expected with normal growth. CMAP significantly improved suggesting a modest biologic effect not clinically meaningful. CONCLUSIONS: This study, coupled with the CARNIVAL Part 1 study, indicate that VPA is not effective in improving strength or function in SMA children. The outcomes used in this study are feasible and reliable, and can be employed in future trials in SMA. TRIAL REGSITRATION: Clinicaltrials.gov NCT00227266.

Prenatal molecular diagnosis of inherited neuromuscular diseases: Duchenne/Becker muscular dystrophy, myotonic dystrophy type 1 and spinal muscular atrophy.

Science.gov (United States)

Esposito, Gabriella; Ruggiero, Raffaella; Savarese, Maria; Savarese, Giovanni; Tremolaterra, Maria Roberta; Salvatore, Francesco; Carsana, Antonella

2013-12-01

Neuromuscular disease is a broad term that encompasses many diseases that either directly, via an intrinsic muscle disorder, or indirectly, via a nerve disorder, impairs muscle function. Here we report the experience of our group in the counselling and molecular prenatal diagnosis of three inherited neuromuscular diseases, i.e., Duchenne/Becker muscular dystrophy (DMD/BMD), myotonic dystrophy type 1 (DM1), spinal muscular atrophy (SMA). We performed a total of 83 DMD/BMD, 15 DM1 and 54 SMA prenatal diagnoses using a combination of technologies for either direct or linkage diagnosis. We identified 16, 5 and 10 affected foetuses, respectively. The improvement of analytical procedures in recent years has increased the mutation detection rate and reduced the analytical time. Due to the complexity of the experimental procedures and the high, specific professional expertise required for both laboratory activities and the related counselling, these types of analyses should be preferentially performed in reference molecular diagnostic centres.

Quantification of SMN protein in leucocytes from spinal muscular atrophy patients: effects of treatment with valproic acid

NARCIS (Netherlands)

Piepers, Sanne; Cobben, Jan-Maarten; Sodaar, Peter; Jansen, Marc D.; Wadman, Renske I.; Meester-Delver, Ann; Poll-The, Bwee Tien; Lemmink, Henny H.; Wokke, John H. J.; van der Pol, W.-Ludo; van den Berg, Leonard H.

2011-01-01

Spinal muscular atrophy (SMA) is caused by the homozygous deletion of the survival motor neuron (SMN)1 gene. The nearly identical SMN2 gene produces small amounts of full-length mRNA and functional SMN protein, due to a point mutation in a critical splicing site. Increasing SMN protein production by

Spinal muscular atrophy associated with progressive myoclonus epilepsy.

Science.gov (United States)

Topaloglu, Haluk; Melki, Judith

2016-09-01

A rare syndrome characterized by lower motor neuron disease associated with progressive myoclonic epilepsy, referred to as "spinal muscular atrophy associated with progressive myoclonic epilepsy" (SMA-PME), has been described in childhood and is inherited as an autosomal recessive trait. SMA-PME is caused by mutation in the ASAH1 gene encoding acid ceramidase. Ceramide and the metabolites participate in various cellular events as lipid mediators. The catabolism of ceramide in mammals occurs in lysosomes through the activity of ceramidase. Three different ceramidases (acid, neutral and alkaline) have been identified and appear to play distinct roles in sphingolipid metabolism. The enzymatic activity of acid ceramidase is deficient in two rare inherited disorders; Farber disease and SMA-PME. Farber disease is a very rare and severe autosomal recessive condition with a distinct clinical phenotype. The marked difference in disease manifestations may explain why Farber and SMA-PME diseases were not previously suspected to be allelic conditions. The precise molecular mechanism underlying the phenotypic differences remains to be clarified. Recently, a condition with mutation in CERS1, the gene encoding ceramide synthase 1, has been identified as a novel form of PME. This finding underlies the essential role of enzymes regulating either the synthesis (CERS1) or degradation (ASAH1) of ceramide, and the link between defects in ceramide metabolism and PME.

Inhibition of apoptosis blocks human motor neuron cell death in a stem cell model of spinal muscular atrophy.

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Dhruv Sareen

Full Text Available Spinal muscular atrophy (SMA is a genetic disorder caused by a deletion of the survival motor neuron 1 gene leading to motor neuron loss, muscle atrophy, paralysis, and death. We show here that induced pluripotent stem cell (iPSC lines generated from two Type I SMA subjects-one produced with lentiviral constructs and the second using a virus-free plasmid-based approach-recapitulate the disease phenotype and generate significantly fewer motor neurons at later developmental time periods in culture compared to two separate control subject iPSC lines. During motor neuron development, both SMA lines showed an increase in Fas ligand-mediated apoptosis and increased caspase-8 and-3 activation. Importantly, this could be mitigated by addition of either a Fas blocking antibody or a caspase-3 inhibitor. Together, these data further validate this human stem cell model of SMA, suggesting that specific inhibitors of apoptotic pathways may be beneficial for patients.

Palliative care in children with spinal muscular atrophy type I: What do they need?

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García-Salido, Alberto; de Paso-Mora, María García; Monleón-Luque, Manuel; Martino-Alba, Ricardo

2015-04-01

Our aim was to describe the clinical evolution and needs of children with spinal muscular atrophy type I treated in a domiciliary palliative care program. We undertook a retrospective chart review of nine consecutive patients. Descriptions of the clinical and demographic profile of children with spinal muscular atrophy (SMA) type I were referred to a pediatric palliative care team (PPCT). Six males and three females were admitted to the PPCT, all before six months of age, except for one afflicted with SMA type I with respiratory distress. The median time of attention was 57 days (range 1-150). The domiciliary attention mainly consisted of respiratory care. The patient with SMA type I with respiratory distress required domiciliary mechanical ventilation by tracheotomy. In all cases, a nasogastric tube (NT) was indicated. As end-of-life care, eight required morphine to manage the dyspnea, four received it only by enteral (oral or NT) administration, and four received it first by enteral administration with continuous subcutaneous infusion (CSI) later. Three of the four patients with CSI also received benzodiazepines. While they were attended by the PPCT, none required hospital admission. All the patients died at home except for the one attended to for just one day. Domiciliary care for these patients is possible. The respiratory morbidity and its management are the main issues. Application of an NT is useful to maintain nutritional balance. Morphine administration is necessary to manage the dyspnea. Palliative sedation is not always necessary.

Revised upper limb module for spinal muscular atrophy: Development of a new module.

Science.gov (United States)

Mazzone, Elena S; Mayhew, Anna; Montes, Jacqueline; Ramsey, Danielle; Fanelli, Lavinia; Young, Sally Dunaway; Salazar, Rachel; De Sanctis, Roberto; Pasternak, Amy; Glanzman, Allan; Coratti, Giorgia; Civitello, Matthew; Forcina, Nicola; Gee, Richard; Duong, Tina; Pane, Marika; Scoto, Mariacristina; Pera, Maria Carmela; Messina, Sonia; Tennekoon, Gihan; Day, John W; Darras, Basil T; De Vivo, Darryl C; Finkel, Richard; Muntoni, Francesco; Mercuri, Eugenio

2017-06-01

There is a growing need for a robust clinical measure to assess upper limb motor function in spinal muscular atrophy (SMA), as the available scales lack sensitivity at the extremes of the clinical spectrum. We report the development of the Revised Upper Limb Module (RULM), an assessment specifically designed for upper limb function in SMA patients. An international panel with specific neuromuscular expertise performed a thorough review of scales currently available to assess upper limb function in SMA. This review facilitated a revision of the existing upper limb function scales to make a more robust clinical scale. Multiple revisions of the scale included statistical analysis and captured clinically relevant changes to fulfill requirements by regulators and advocacy groups. The resulting RULM scale shows good reliability and validity, making it a suitable tool to assess upper extremity function in the SMA population for multi-center clinical research. Muscle Nerve 55: 869-874, 2017. © 2016 Wiley Periodicals, Inc.

Dysfunction of the neuromuscular junction in spinal muscular atrophy types 2 and 3.

Science.gov (United States)

Wadman, Renske I; Vrancken, Alexander F J E; van den Berg, Leonard H; van der Pol, W Ludo

2012-11-13

Spinal muscular atrophy (SMA) is pathologically characterized by degeneration of anterior horn cells. Recent observations in animal models of SMA and muscle tissue from patients with SMA suggest additional abnormalities in the development and maturation of the neuromuscular junction. We therefore evaluated neuromuscular junction function in SMA with repetitive nerve stimulation. In this case-control study, repetitive nerve stimulation was performed in 35 patients with SMA types 2, 3, and 4, 20 healthy controls, and 5 controls with motor neuron disease. Pathologic decremental responses (>10%) during 3-Hz repetitive nerve stimulation were observed in 17 of 35 patients (49%) with SMA types 2 and 3, but not in healthy controls or controls with motor neuron disease. None of the patients or controls had an abnormal incremental response of >60%. The presence of an abnormal decremental response was not specific for the type of SMA, nor was it associated with compound muscle action potential amplitude, clinical scores, or disease duration. Two of 4 patients with SMA type 3 who tried pyridostigmine reported increased stamina. These data suggest dysfunction of the neuromuscular junction in patients with SMA types 2 and 3. Therefore, drugs that facilitate neuromuscular transmission are candidate drugs for evaluation in carefully designed, placebo-controlled, clinical trials.

Neuroprotective effect of non-viral gene therapy treatment based on tetanus toxin C-fragment in a severe mouse model of Spinal Muscular Atrophy.

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Sara Olivan Garcia

2016-08-01

Full Text Available Spinal muscular atrophy (SMA is a hereditary childhood disease that causes paralysis and progressive degeneration of skeletal muscles and spinal motor neurons. SMA is associated with reduced levels of full-length Survival of Motor Neuron (SMN protein, due to mutations in the Survival of Motor Neuron 1 gene. Nowadays there are no effective therapies available to treat patients with SMA, so our aim was to test whether the non-toxic carboxy-terminal fragment of tetanus toxin heavy chain (TTC, which exhibits neurotrophic properties, might have a therapeutic role or benefit in SMA. In this manuscript, we have demonstrated that TTC enhance the SMN expression in motor neurons in vitro and evaluated the effect of intramuscular injection of TTC-encoding plasmid in the spinal cord and the skeletal muscle of SMNdelta7 mice. For this purpose, we studied the weight and the survival time, as well as, the survival and cell death pathways and muscular atrophy. Our results showed that TTC treatment reduced the expression of autophagy markers (Becn1, Atg5, Lc3 and p62 and pro-apoptotic genes such as Bax and Casp3 in spinal cord. In skeletal muscle, TTC was able to downregulate the expression of the main marker of autophagy, Lc3, to wild type levels and the expression of the apoptosis effector protein, Casp3. Regarding the genes related to muscular atrophy (Ankrd1, Calm1, Col19a1, Fbox32, Mt2, Myod1, NogoA, Pax7, Rrad, and Sln, TTC suggest a compensatory effect for muscle damage response, diminished oxidative stress and modulated calcium homeostasis. These preliminary findings suggest the need for further experiments to depth study the effect of TTC in SMA disease.

[Upper limb functional assessment scale for children with Duchenne muscular dystrophy and Spinal muscular atrophy].

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Escobar, Raúl G; Lucero, Nayadet; Solares, Carmen; Espinoza, Victoria; Moscoso, Odalie; Olguín, Polín; Muñoz, Karin T; Rosas, Ricardo

2016-08-16

Duchenne muscular dystrophy (DMD) and Spinal muscular atrophy (SMA) causes significant disability and progressive functional impairment. Readily available instruments that assess functionality, especially in advanced stages of the disease, are required to monitor the progress of the disease and the impact of therapeutic interventions. To describe the development of a scale to evaluate upper limb function (UL) in patients with DMD and SMA, and describe its validation process, which includes self-training for evaluators. The development of the scale included a review of published scales, an exploratory application of a pilot scale in healthy children and those with DMD, self-training of evaluators in applying the scale using a handbook and video tutorial, and assessment of a group of children with DMD and SMA using the final scale. Reliability was assessed using Cronbach and Kendall concordance and with intra and inter-rater test-retest, and validity with concordance and factorial analysis. A high level of reliability was observed, with high internal consistency (Cronbach α=0.97), and inter-rater (Kendall W=0.96) and intra-rater concordance (r=0.97 to 0.99). The validity was demonstrated by the absence of significant differences between results by different evaluators with an expert evaluator (F=0.023, P>.5), and by the factor analysis that showed that four factors account for 85.44% of total variance. This scale is a reliable and valid tool for assessing UL functionality in children with DMD and SMA. It is also easily implementable due to the possibility of self-training and the use of simple and inexpensive materials. Copyright © 2016 Sociedad Chilena de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy

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Christian M. Simon

2017-12-01

Full Text Available The hallmark of spinal muscular atrophy (SMA, an inherited disease caused by ubiquitous deficiency in the SMN protein, is the selective degeneration of subsets of spinal motor neurons. Here, we show that cell-autonomous activation of p53 occurs in vulnerable but not resistant motor neurons of SMA mice at pre-symptomatic stages. Moreover, pharmacological or genetic inhibition of p53 prevents motor neuron death, demonstrating that induction of p53 signaling drives neurodegeneration. At late disease stages, however, nuclear accumulation of p53 extends to resistant motor neurons and spinal interneurons but is not associated with cell death. Importantly, we identify phosphorylation of serine 18 as a specific post-translational modification of p53 that exclusively marks vulnerable SMA motor neurons and provide evidence that amino-terminal phosphorylation of p53 is required for the neurodegenerative process. Our findings indicate that distinct events induced by SMN deficiency converge on p53 to trigger selective death of vulnerable SMA motor neurons.

Construction of a yeast artifical chromosome contig spanning the spinal muscular atrophy disease gene region

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Kleyn, P.W.; Wang, C.H.; Vitale, E.; Pan, J.; Ross, B.M.; Grunn, A.; Palmer, D.A.; Warburton, D.; Brzustowicz, L.M.; Gilliam, T.G. (New York State Psychiatric Institute, NY (United States)); Lien, L.L.; Kunkel, L.M. (Howard Hughes Medical Institute, Boston, MA (United States))

1993-07-15

The childhood spinal muscular atrophies (SMAs) are the most common, serious neuromuscular disorders of childhood second to Duchenne muscular dystrophy. A single locus for these disorders has been mapped by recombination events to a region of 0.7 centimorgan (range, 0.1-2.1 centimorgans) between loci D5S435 and MAP1B on chromosome 5q11.2-13.3. By using PCR amplification to screen yeast artificial chromosome (YAC) DNA pools and the PCR-vectorette method to amplify YAC ends, a YAC contig was constructed across the disease gene region. Nine walk steps identified 32 YACs, including a minimum of seven overlapping YAC clones (average size, 460 kb) that span the SMA region. The contig is characterized by a collection of 30 YAC-end sequence tag sites together with seven genetic markers. The entire YAC contig spans a minimum of 3.2 Mb; the SMA locus is confined to roughly half of this region. Microsatellite markers generated along the YAC contig segregate with the SMA locus in all families where the flanking markers (D5S435 and MAP1B) recombine. Construction of a YAC contig across the disease gene region is an essential step in isolation of the SMA-encoding gene. 26 refs., 3 figs., 1 tab.

Interventions Targeting Glucocorticoid-Krüppel-like Factor 15-Branched-Chain Amino Acid Signaling Improve Disease Phenotypes in Spinal Muscular Atrophy Mice

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Lisa M. Walter

2018-05-01

Full Text Available The circadian glucocorticoid-Krüppel-like factor 15-branched-chain amino acid (GC-KLF15-BCAA signaling pathway is a key regulatory axis in muscle, whose imbalance has wide-reaching effects on metabolic homeostasis. Spinal muscular atrophy (SMA is a neuromuscular disorder also characterized by intrinsic muscle pathologies, metabolic abnormalities and disrupted sleep patterns, which can influence or be influenced by circadian regulatory networks that control behavioral and metabolic rhythms. We therefore set out to investigate the contribution of the GC-KLF15-BCAA pathway in SMA pathophysiology of Taiwanese Smn−/−;SMN2 and Smn2B/− mouse models. We thus uncover substantial dysregulation of GC-KLF15-BCAA diurnal rhythmicity in serum, skeletal muscle and metabolic tissues of SMA mice. Importantly, modulating the components of the GC-KLF15-BCAA pathway via pharmacological (prednisolone, genetic (muscle-specific Klf15 overexpression and dietary (BCAA supplementation interventions significantly improves disease phenotypes in SMA mice. Our study highlights the GC-KLF15-BCAA pathway as a contributor to SMA pathogenesis and provides several treatment avenues to alleviate peripheral manifestations of the disease. The therapeutic potential of targeting metabolic perturbations by diet and commercially available drugs could have a broader implementation across other neuromuscular and metabolic disorders characterized by altered GC-KLF15-BCAA signaling. Keywords: Spinal muscular atrophy, KLF15, Glucocorticoids, Branched-chain amino acids, Metabolism, Therapy

Is Spinal Muscular Atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications?

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Simone, Chiara; Ramirez, Agnese; Bucchia, Monica; Rinchetti, Paola; Rideout, Hardy; Papadimitriou, Dimitra; Re, Diane B.; Corti, Stefania

2016-01-01

Spinal Muscular Atrophy (SMA) is a genetic neurological disease that causes infant mortality; no effective therapies are currently available. SMA is due to homozygous mutations and/or deletions in the Survival Motor Neuron 1 (SMN1) gene and subsequent reduction of the SMN protein, leading to the death of motor neurons. However, there is increasing evidence that in addition to motor neurons, other cell types are contributing to SMA pathology. In this review, we will discuss the involvement of non-motor neuronal cells, located both inside and outside the central nervous system, in disease onset and progression. These contribution of non-motor neuronal cells to disease pathogenesis has important therapeutic implications: in fact, even if SMN restoration in motor neurons is needed, it has been shown that optimal phenotypic amelioration in animal models of SMA requires a more widespread SMN correction. It will be crucial to take this evidence into account before clinical translation of the novel therapeutic approaches that are currently under development. PMID:26681261

Early functional impairment of sensory-motor connectivity in a mouse model of spinal muscular atrophy

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Mentis, George Z.; Blivis, Dvir; Liu, Wenfang; Drobac, Estelle; Crowder, Melissa E.; Kong, Lingling; Alvarez, Francisco J.; Sumner, Charlotte J.; O'Donovan, Michael J.

2011-01-01

SUMMARY To define alterations of neuronal connectivity that occur during motor neuron degeneration, we characterized the function and structure of spinal circuitry in spinal muscular atrophy (SMA) model mice. SMA motor neurons show reduced proprioceptive reflexes that correlate with decreased number and function of synapses on motor neuron somata and proximal dendrites. These abnormalities occur at an early stage of disease in motor neurons innervating proximal hindlimb muscles and medial motor neurons innervating axial muscles, but only at end-stage disease in motor neurons innervating distal hindlimb muscles. Motor neuron loss follows afferent synapse loss with the same temporal and topographical pattern. Trichostatin A, which improves motor behavior and survival of SMA mice, partially restores spinal reflexes illustrating the reversibility of these synaptic defects. De-afferentation of motor neurons is an early event in SMA and may be a primary cause of motor dysfunction that is amenable to therapeutic intervention. PMID:21315257

Analysis of the fibroblast growth factor system reveals alterations in a mouse model of spinal muscular atrophy.

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Hensel, Niko; Ratzka, Andreas; Brinkmann, Hella; Klimaschewski, Lars; Grothe, Claudia; Claus, Peter

2012-01-01

The monogenetic disease Spinal Muscular Atrophy (SMA) is characterized by a progressive loss of motoneurons leading to muscle weakness and atrophy due to severe reduction of the Survival of Motoneuron (SMN) protein. Several models of SMA show deficits in neurite outgrowth and maintenance of neuromuscular junction (NMJ) structure. Survival of motoneurons, axonal outgrowth and formation of NMJ is controlled by neurotrophic factors such as the Fibroblast Growth Factor (FGF) system. Besides their classical role as extracellular ligands, some FGFs exert also intracellular functions controlling neuronal differentiation. We have previously shown that intracellular FGF-2 binds to SMN and regulates the number of a subtype of nuclear bodies which are reduced in SMA patients. In the light of these findings, we systematically analyzed the FGF-system comprising five canonical receptors and 22 ligands in a severe mouse model of SMA. In this study, we demonstrate widespread alterations of the FGF-system in both muscle and spinal cord. Importantly, FGF-receptor 1 is upregulated in spinal cord at a pre-symptomatic stage as well as in a mouse motoneuron-like cell-line NSC34 based model of SMA. Consistent with that, phosphorylations of FGFR-downstream targets Akt and ERK are increased. Moreover, ERK hyper-phosphorylation is functionally linked to FGFR-1 as revealed by receptor inhibition experiments. Our study shows that the FGF system is dysregulated at an early stage in SMA and may contribute to the SMA pathogenesis.

Notch Signaling Pathway Is Activated in Motoneurons of Spinal Muscular Atrophy

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Gabriel Olmos

2013-05-01

Full Text Available Spinal muscular atrophy (SMA is a neurodegenerative disease produced by low levels of Survival Motor Neuron (SMN protein that affects alpha motoneurons in the spinal cord. Notch signaling is a cell-cell communication system well known as a master regulator of neural development, but also with important roles in the adult central nervous system. Aberrant Notch function is associated with several developmental neurological disorders; however, the potential implication of the Notch pathway in SMA pathogenesis has not been studied yet. We report here that SMN deficiency, induced in the astroglioma cell line U87MG after lentiviral transduction with a shSMN construct, was associated with an increase in the expression of the main components of Notch signaling pathway, namely its ligands, Jagged1 and Delta1, the Notch receptor and its active intracellular form (NICD. In the SMNΔ7 mouse model of SMA we also found increased astrocyte processes positive for Jagged1 and Delta1 in intimate contact with lumbar spinal cord motoneurons. In these motoneurons an increased Notch signaling was found, as denoted by increased NICD levels and reduced expression of the proneural gene neurogenin 3, whose transcription is negatively regulated by Notch. Together, these findings may be relevant to understand some pathologic attributes of SMA motoneurons.

Edaravone is a candidate agent for spinal muscular atrophy: In vitro analysis using a human induced pluripotent stem cells-derived disease model.

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Ando, Shiori; Funato, Michinori; Ohuchi, Kazuki; Kameyama, Tsubasa; Inagaki, Satoshi; Seki, Junko; Kawase, Chizuru; Tsuruma, Kazuhiro; Shimazawa, Masamitsu; Kaneko, Hideo; Hara, Hideaki

2017-11-05

Spinal muscular atrophy (SMA) is an intractable disease characterized by a progressive loss of spinal motor neurons, which leads to skeletal muscle weakness and atrophy. Currently, there are no curative agents for SMA, although it is understood to be caused by reduced levels of survival motor neuron (SMN) protein. Additionally, why reduced SMN protein level results in selective apoptosis in spinal motor neurons is still not understood. Our purpose in this study was to evaluate the therapeutic potential of edaravone, a free radical scavenger, by using induced pluripotent stem cells from an SMA patient (SMA-iPSCs) and to address oxidative stress-induced apoptosis in spinal motor neurons. We first found that edaravone could improve impaired neural development of SMA-iPSCs-derived spinal motor neurons with limited effect on nuclear SMN protein expression. Furthermore, edaravone inhibited the generation of reactive oxygen species and mitochondrial reactive oxygen species upregulated in SMA-iPSCs-derived spinal motor neurons, and reversed oxidative-stress induced apoptosis. In this study, we suggest that oxidative stress might be partly the reason for selective apoptosis in spinal motor neurons in SMA pathology, and that oxidative stress-induced apoptosis might be the therapeutic target of SMA. Copyright © 2017 Elsevier B.V. All rights reserved.

SMA CARNI-VAL trial part I: double-blind, randomized, placebo-controlled trial of L-carnitine and valproic acid in spinal muscular atrophy.

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Kathryn J Swoboda

2010-08-01

Full Text Available Valproic acid (VPA has demonstrated potential as a therapeutic candidate for spinal muscular atrophy (SMA in vitro and in vivo.Two cohorts of subjects were enrolled in the SMA CARNIVAL TRIAL, a non-ambulatory group of "sitters" (cohort 1 and an ambulatory group of "walkers" (cohort 2. Here, we present results for cohort 1: a multicenter phase II randomized double-blind intention-to-treat protocol in non-ambulatory SMA subjects 2-8 years of age. Sixty-one subjects were randomized 1:1 to placebo or treatment for the first six months; all received active treatment the subsequent six months. The primary outcome was change in the modified Hammersmith Functional Motor Scale (MHFMS score following six months of treatment. Secondary outcomes included safety and adverse event data, and change in MHFMS score for twelve versus six months of active treatment, body composition, quantitative SMN mRNA levels, maximum ulnar CMAP amplitudes, myometry and PFT measures.At 6 months, there was no difference in change from the baseline MHFMS score between treatment and placebo groups (difference = 0.643, 95% CI = -1.22-2.51. Adverse events occurred in >80% of subjects and were more common in the treatment group. Excessive weight gain was the most frequent drug-related adverse event, and increased fat mass was negatively related to change in MHFMS values (p = 0.0409. Post-hoc analysis found that children ages two to three years that received 12 months treatment, when adjusted for baseline weight, had significantly improved MHFMS scores (p = 0.03 compared to those who received placebo the first six months. A linear regression analysis limited to the influence of age demonstrates young age as a significant factor in improved MHFMS scores (p = 0.007.This study demonstrated no benefit from six months treatment with VPA and L-carnitine in a young non-ambulatory cohort of subjects with SMA. Weight gain, age and treatment duration were significant confounding variables that

An Evaluation of a Continuing Education Program for Family Caregivers of Ventilator-Dependent Children with Spinal Muscular Atrophy (SMA

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Deborah S. Boroughs

2017-04-01

Full Text Available Until 25 years ago, there were limited options for long-term mechanical ventilation of children, and the majority of children were cared for in hospitals. However, with improving technology, the pediatric intensive care unit has moved from the hospital to a home setting, as children with increasingly complex healthcare needs are now often cared for by family members. One of the most complex care conditions involves ventilator and tracheostomy support. Advanced respiratory technologies that augment natural respiratory function prolong the lives of children with respiratory compromise; however, this care often comes with serious risks, including respiratory muscle impairment, respiratory failure, and chronic pulmonary disease. Both non-invasive assisted ventilation and assisted ventilation via tracheostomy can prolong survival into adulthood in many cases; however, mechanical ventilation in the home is a high-stakes, high risk intervention. Increasing complexity of care over time requires perpetual skill training of family caregivers that is delivered and supported by professional caregivers; yet, opportunities for additional training outside of the hospital rarely exist. Recent data has confirmed that repetitive caregiver education is essential for retention of memory and skills in adult learners. This study analyzes the use of continued education and training in the community for family caregivers of ventilator-dependent children diagnosed with spinal muscular atrophy (SMA.

Air stacking: effects on pulmonary function in patients with spinal muscular atrophy and in patients with congenital muscular dystrophy,

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Tanyse Bahia Carvalho Marques

2014-10-01

Full Text Available OBJECTIVE: Respiratory complications are the main causes of morbidity and mortality in patients with neuromuscular disease (NMD. The objectives of this study were to determine the effects that routine daily home air-stacking maneuvers have on pulmonary function in patients with spinal muscular atrophy (SMA and in patients with congenital muscular dystrophy (CMD, as well as to identify associations between spinal deformities and the effects of the maneuvers. METHODS: Eighteen NMD patients (ten with CMD and eight with SMA were submitted to routine daily air-stacking maneuvers at home with manual resuscitators for four to six months, undergoing pulmonary function tests before and after that period. The pulmonary function tests included measurements of FVC; PEF; maximum insufflation capacity (MIC; and assisted and unassisted peak cough flow (APCF and UPCF, respectively with insufflations. RESULTS: After the use of home air-stacking maneuvers, there were improvements in the APCF and UPCF. In the patients without scoliosis, there was also a significant increase in FVC. When comparing patients with and without scoliosis, the increases in APCF and UPCF were more pronounced in those without scoliosis. CONCLUSIONS: Routine daily air-stacking maneuvers with a manual resuscitator appear to increase UPCF and APCF in patients with NMD, especially in those without scoliosis.

Established Stem Cell Model of Spinal Muscular Atrophy Is Applicable in the Evaluation of the Efficacy of Thyrotropin-Releasing Hormone Analog.

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Ohuchi, Kazuki; Funato, Michinori; Kato, Zenichiro; Seki, Junko; Kawase, Chizuru; Tamai, Yuya; Ono, Yoko; Nagahara, Yuki; Noda, Yasuhiro; Kameyama, Tsubasa; Ando, Shiori; Tsuruma, Kazuhiro; Shimazawa, Masamitsu; Hara, Hideaki; Kaneko, Hideo

2016-02-01

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by the degeneration of spinal motor neurons. This disease is mainly caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene. Currently, no effective treatment is available, and only symptomatic treatment can be provided. Our purpose in the present study was to establish a human SMA-derived induced pluripotent stem cell (SMA-iPSC) disease model and assay a therapeutic drug in preparation for the development of a novel treatment of SMA. We generated iPSCs from the skin fibroblasts of a patient with SMA and confirmed that they were pluripotent and undifferentiated. The neural differentiation of SMA-iPSCs shortened the dendrite and axon length and increased the apoptosis of the spinal motor neurons. In addition, we found activated astrocytes in differentiated SMA-iPSCs. Using this model, we confirmed that treatment with the thyrotropin-releasing hormone (TRH) analog, 5-oxo-l-prolyl-l-histidyl-l-prolinamide, which had marginal effects in clinical trials, increases the SMN protein level. This increase was mediated through the transcriptional activation of the SMN2 gene and inhibition of glycogen synthase kinase-3β activity. Finally, the TRH analog treatment resulted in dendrite and axon development of spinal motor neurons in differentiated SMA-iPSCs. These results suggest that this human in vitro disease model stimulates SMA pathology and reveal the potential efficacy of TRH analog treatment for SMA. Therefore, we can screen novel therapeutic drugs such as TRH for SMA easily and effectively using the human SMA-iPSC model. Significance: Platelet-derived growth factor (PDGF) has recently been reported to produce the greatest increase in survival motor neuron protein levels by inhibiting glycogen synthase kinase (GSK)-3β; however, motor neurons lack PDGF receptors. A human in vitro spinal muscular atrophy-derived induced pluripotent stem cell model was

Computed tomography of skeletal muscles in childhood spinal progressive muscular atrophies

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Arai, Yumi; Osawa, Makiko; Sumida, Sawako; Shishikura, Keiko; Suzuki, Haruko; Fukuyama, Yukio; Kohno, Atsushi

1992-01-01

Computed tomographic (CT) scanning of skeletal muscles was performed in patients with type 1 and type 2 spinal progressive muscular atrophy (SPMA) and Kugelberg-Welander disease (K-W) to delineate the characteristic CT features of each category. Marked muscular atrophy was observed in type 1 SPMA, and both muscular atrophy and intramuscular low density areas in type 2 SPMA, changes being more pronounced in older patients. In contrast, in K-W, muscular atrophy was slight, and intramuscular low density areas constituted the most prominent findings. These observations indicate that SPMA and K-W are each characterized by distinct CT findings. (author)

Compensatory axon sprouting for very slow axonal die-back in a transgenic model of spinal muscular atrophy type III.

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Udina, Esther; Putman, Charles T; Harris, Luke R; Tyreman, Neil; Cook, Victoria E; Gordon, Tessa

2017-03-01

Smn +/- transgenic mouse is a model of the mildest form of spinal muscular atrophy. Although there is a loss of spinal motoneurons in 11-month-old animals, muscular force is maintained. This maintained muscular force is mediated by reinnervation of the denervated fibres by surviving motoneurons. The spinal motoneurons in these animals do not show an increased susceptibility to death after nerve injury and they retain their regenerative capacity. We conclude that the hypothesized immaturity of the neuromuscular system in this model cannot explain the loss of motoneurons by systematic die-back. Spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans and is the leading genetic cause of infantile death. Patients lack the SMN1 gene with the severity of the disease depending on the number of copies of the highly homologous SMN2 gene. Although motoneuron death in the Smn +/- transgenic mouse model of the mildest form of SMA, SMA type III, has been reported, we have used retrograde tracing of sciatic and femoral motoneurons in the hindlimb with recording of muscle and motor unit isometric forces to count the number of motoneurons with intact neuromuscular connections. Thereby, we investigated whether incomplete maturation of the neuromuscular system induced by survival motoneuron protein (SMN) defects is responsible for die-back of axons relative to survival of motoneurons. First, a reduction of ∼30% of backlabelled motoneurons began relatively late, at 11 months of age, with a significant loss of 19% at 7 months. Motor axon die-back was affirmed by motor unit number estimation. Loss of functional motor units was fully compensated by axonal sprouting to retain normal contractile force in four hindlimb muscles (three fast-twitch and one slow-twitch) innervated by branches of the sciatic nerve. Second, our evaluation of whether axotomy of motoneurons in the adult Smn +/- transgenic mouse increases their susceptibility to cell death demonstrated

Respiratory muscle function in infants with spinal muscular atrophy type I.

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Finkel, Richard S; Weiner, Daniel J; Mayer, Oscar H; McDonough, Joseph M; Panitch, Howard B

2014-12-01

To determine the feasibility and safety of respiratory muscle function testing in weak infants with a progressive neuromuscular disorder. Respiratory insufficiency is the major cause of morbidity and mortality in infants with spinal muscular atrophy type I (SMA-I). Tests of respiratory muscle strength, endurance, and breathing patterns can be performed safely in SMA-I infants. Useful data can be collected which parallels the clinical course of pulmonary function in SMA-I. An exploratory study of respiratory muscle function testing and breathing patterns in seven infants with SMA-I seen in our neuromuscular clinic. Measurements were made at initial study visit and, where possible, longitudinally over time. We measured maximal inspiratory (MIP) and transdiaphragmatic pressures, mean transdiaphragmatic pressure, airway occlusion pressure at 100 msec of inspiration, inspiratory and total respiratory cycle time, and aspects of relative thoracoabdominal motion using respiratory inductive plethysmography (RIP). The tension time index of the diaphragm and of the respiratory muscles, phase angle (Φ), phase relation during the total breath, and labored breathing index were calculated. Age at baseline study was 54-237 (median 131) days. Reliable data were obtained safely for MIP, phase angle, labored breathing index, and the invasive and non-invasive tension time indices, even in very weak infants. Data obtained corresponded to the clinical estimate of severity and predicted the need for respiratory support. The testing employed was both safe and feasible. Measurements of MIP and RIP are easily performed tests that are well tolerated and provide clinically useful information for infants with SMA-I. © 2014 Wiley Periodicals, Inc.

Sensory neurons do not induce motor neuron loss in a human stem cell model of spinal muscular atrophy.

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Schwab, Andrew J; Ebert, Allison D

2014-01-01

Spinal muscular atrophy (SMA) is an autosomal recessive disorder leading to paralysis and early death due to reduced SMN protein. It is unclear why there is such a profound motor neuron loss, but recent evidence from fly and mouse studies indicate that cells comprising the whole sensory-motor circuit may contribute to motor neuron dysfunction and loss. Here, we used induced pluripotent stem cells derived from SMA patients to test whether sensory neurons directly contribute to motor neuron loss. We generated sensory neurons from SMA induced pluripotent stem cells and found no difference in neuron generation or survival, although there was a reduced calcium response to depolarizing stimuli. Using co-culture of SMA induced pluripotent stem cell derived sensory neurons with control induced pluripotent stem cell derived motor neurons, we found no significant reduction in motor neuron number or glutamate transporter boutons on motor neuron cell bodies or neurites. We conclude that SMA sensory neurons do not overtly contribute to motor neuron loss in this human stem cell system.

Protective Effects of Butyrate-based Compounds on a Mouse Model for Spinal Muscular Atrophy

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Butchbach, Matthew E. R.; Lumpkin, Casey J.; Harris, Ashlee W.; Saieva, Luciano; Edwards, Jonathan D.; Workman, Eileen; Simard, Louise R.; Pellizzoni, Livio; Burghes, Arthur H. M.

2016-01-01

Proximal spinal muscular atrophy (SMA) is a childhood-onset degenerative disease resulting from the selective loss of motor neurons in the spinal cord. SMA is caused by the loss of SMN1 (survival motor neuron 1) but retention of SMN2. The number of copies of SMN2 modifies disease severity in SMA patients as well as in mouse models, making SMN2 a target for therapeutics development. Sodium butyrate (BA) and its analogue (4PBA) have been shown to increase SMN2 expression in SMA cultured cells. In this study, we examined the effects of BA, 4PBA as well as two BA prodrugs—glyceryl tributyrate (BA3G) and VX563—on the phenotype of SMNΔ7 SMA mice. Treatment with 4PBA, BA3G and VX563 but not BA beginning at PND04 significantly improved the lifespan and delayed disease end stage, with administration of VX563 also improving the growth rate of these mice. 4PBA and VX563 improved the motor phenotype of SMNΔ7 SMA mice and prevented spinal motor neuron loss. Interestingly, neither 4PBA nor VX563 had an effect on SMN expression in the spinal cords of treated SMNΔ7 SMA mice; however, they inhibited histone deacetylase (HDAC) activity and restored the normal phosphorylation states of Akt and glycogen synthase kinase 3β, both of which are altered by SMN deficiency in vivo. These observations show that BA-based compounds with favourable pharmacokinetics ameliorate SMA pathology possibly by modulating HDAC and Akt signaling. PMID:26892876

Modeling the phenotype of spinal muscular atrophy by the direct conversion of human fibroblasts to motor neurons.

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Zhang, Qi-Jie; Li, Jin-Jing; Lin, Xiang; Lu, Ying-Qian; Guo, Xin-Xin; Dong, En-Lin; Zhao, Miao; He, Jin; Wang, Ning; Chen, Wan-Jin

2017-02-14

Spinal muscular atrophy (SMA) is a lethal autosomal recessive neurological disease characterized by selective degeneration of motor neurons in the spinal cord. In recent years, the development of cellular reprogramming technology has provided an alternative and effective method for obtaining patient-specific neurons in vitro. In the present study, we applied this technology to the field of SMA to acquire patient-specific induced motor neurons that were directly converted from fibroblasts via the forced expression of 8 defined transcription factors. The infected fibroblasts began to grow in a dipolar manner, and the nuclei gradually enlarged. Typical Tuj1-positive neurons were generated at day 23. After day 35, induced neurons with multiple neurites were observed, and these neurons also expressed the hallmarks of Tuj1, HB9, ISL1 and CHAT. The conversion efficiencies were approximately 5.8% and 5.5% in the SMA and control groups, respectively. Additionally, the SMA-induced neurons exhibited a significantly reduced neurite outgrowth rate compared with the control neurons. After day 60, the SMA-induced neurons also exhibited a liability of neuronal degeneration and remarkable fracturing of the neurites was observed. By directly reprogramming fibroblasts, we established a feeder-free conversion system to acquire SMA patient-specific induced motor neurons that partially modeled the phenotype of SMA in vitro.

Clinical applications of MARSALA for preimplantation genetic diagnosis of spinal muscular atrophy.

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Ren, Yixin; Zhi, Xu; Zhu, Xiaohui; Huang, Jin; Lian, Ying; Li, Rong; Jin, Hongyan; Zhang, Yan; Zhang, Wenxin; Nie, Yanli; Wei, Yuan; Liu, Zhaohui; Song, Donghong; Liu, Ping; Qiao, Jie; Yan, Liying

2016-09-20

Conventional PCR methods combined with linkage analysis based on short tandem repeats (STRs) or Karyomapping with single nucleotide polymorphism (SNP) arrays, have been applied to preimplantation genetic diagnosis (PGD) for spinal muscular atrophy (SMA), an autosome recessive disorder. However, it has limitations in SMA diagnosis by Karyomapping, and these methods are unable to distinguish wild-type embryos with carriers effectively. Mutated allele revealed by sequencing with aneuploidy and linkage analyses (MARSALA) is a new method allowing embryo selection by a one-step next-generation sequencing (NGS) procedure, which has been applied in PGD for both autosome dominant and X-linked diseases in our group previously. In this study, we carried out PGD based on MARSALA for two carrier families with SMA affected children. As a result, one of the couples has given birth to a healthy baby free of mutations in SMA-causing gene. It is the first time that MARSALA was applied to PGD for SMA, and we can distinguish the embryos with heterozygous deletion (carriers) from the wild-type (normal) ones accurately through this NGS-based method. In addition, direct mutation detection allows us to identify the affected embryos (homozygous deletion), which can be regarded as probands for linkage analysis, in case that the affected family member is absent. In the future, the NGS-based MARSALA method is expected to be used in PGD for all monogenetic disorders with known pathogenic gene mutation. Copyright © 2016 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Ltd. All rights reserved.

Motor neuronal repletion of the NMJ organizer, Agrin, modulates the severity of the spinal muscular atrophy disease phenotype in model mice.

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Kim, Jeong-Ki; Caine, Charlotte; Awano, Tomoyuki; Herbst, Ruth; Monani, Umrao R

2017-07-01

Spinal muscular atrophy (SMA) is a common and often fatal neuromuscular disorder caused by low levels of the Survival Motor Neuron (SMN) protein. Amongst the earliest detectable consequences of SMN deficiency are profound defects of the neuromuscular junctions (NMJs). In model mice these synapses appear disorganized, fail to mature and are characterized by poorly arborized nerve terminals. Given one role of the SMN protein in orchestrating the assembly of spliceosomal snRNP particles and subsequently regulating the alternative splicing of pre-mRNAs, a plausible link between SMN function and the distal neuromuscular SMA phenotype is an incorrectly spliced transcript or transcripts involved in establishing or maintaining NMJ structure. In this study, we explore the effects of one such transcript-Z+Agrin-known to be a critical organizer of the NMJ. We confirm that low SMN protein reduces motor neuronal levels of Z+Agrin. Repletion of this isoform of Agrin in the motor neurons of SMA model mice increases muscle fiber size, enhances the post-synaptic NMJ area, reduces the abnormal accumulation of intermediate filaments in nerve terminals of the neuromuscular synapse and improves the innervation of muscles. While these effects are independent of changes in SMN levels or increases in motor neuron numbers they nevertheless have a significant effect on the overall disease phenotype, enhancing mean survival in severely affected SMA model mice by ∼40%. We conclude that Agrin is an important target of the SMN protein and that mitigating NMJ defects may be one strategy in treating human spinal muscular atrophy. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Feasibility of Using Microsoft Kinect to Assess Upper Limb Movement in Type III Spinal Muscular Atrophy Patients.

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Xing Chen

Full Text Available Although functional rating scales are being used increasingly as primary outcome measures in spinal muscular atrophy (SMA, sensitive and objective assessment of early-stage disease progression and drug efficacy remains challenging. We have developed a game based on the Microsoft Kinect sensor, specifically designed to measure active upper limb movement. An explorative study was conducted to determine the feasibility of this new tool in 18 ambulant SMA type III patients and 19 age- and gender-matched healthy controls. Upper limb movement was analysed elaborately through derived features such as elbow flexion and extension angles, arm lifting angle, velocity and acceleration. No significant differences were found in the active range of motion between ambulant SMA type III patients and controls. Hand velocity was found to be different but further validation is necessary. This study presents an important step in the process of designing and handling digital biomarkers as complementary outcome measures for clinical trials.

Immune dysregulation may contribute to disease pathogenesis in spinal muscular atrophy mice.

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Deguise, Marc-Olivier; De Repentigny, Yves; McFall, Emily; Auclair, Nicole; Sad, Subash; Kothary, Rashmi

2017-02-15

Spinal muscular atrophy (SMA) has long been solely considered a neurodegenerative disorder. However, recent work has highlighted defects in many other cell types that could contribute to disease aetiology. Interestingly, the immune system has never been extensively studied in SMA. Defects in lymphoid organs could exacerbate disease progression by neuroinflammation or immunodeficiency. Smn depletion led to severe alterations in the thymus and spleen of two different mouse models of SMA. The spleen from Smn depleted mice was dramatically smaller at a very young age and its histological architecture was marked by mislocalization of immune cells in the Smn2B/- model mice. In comparison, the thymus was relatively spared in gross morphology but showed many histological alterations including cortex thinning in both mouse models at symptomatic ages. Thymocyte development was also impaired as evidenced by abnormal population frequencies in the Smn2B/- thymus. Cytokine profiling revealed major changes in different tissues of both mouse models. Consistent with our observations, we found that survival motor neuron (Smn) protein levels were relatively high in lymphoid organs compared to skeletal muscle and spinal cord during postnatal development in wild type mice. Genetic introduction of one copy of the human SMN2 transgene was enough to rescue splenic and thymic defects in Smn2B/- mice. Thus, Smn is required for the normal development of lymphoid organs, and altered immune function may contribute to SMA disease pathogenesis. © The Author 2017. Published by Oxford University Press.

The Smn-independent beneficial effects of trichostatin A on an intermediate mouse model of spinal muscular atrophy.

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Hong Liu

Full Text Available Spinal muscular atrophy is an autosomal recessive neuromuscular disease characterized by the progressive loss of alpha motor neurons in the spinal cord. Trichostatin A (TSA is a histone deacetylase inhibitor with beneficial effects in spinal muscular atrophy mouse models that carry the human SMN2 transgene. It is currently unclear whether TSA specifically targets the SMN2 gene or whether other genes respond to TSA and in turn provide neuroprotection in SMA mice. We have taken advantage of the Smn2B/- mouse model that does not harbor the human SMN2 transgene, to test the hypothesis that TSA has its beneficial effects through a non-SMN mediated pathway. TSA increased the median lifespan of Smn2B/- mice from twenty days to eight weeks. As well, there was a significant attenuation of weight loss and improved motor behavior. Pen test and righting reflex both showed significant improvement, and motor neurons in the spinal cord of Smn2B/- mice were protected from degeneration. Both the size and maturity of neuromuscular junctions were significantly improved in TSA treated Smn2B/- mice. Of interest, TSA treatment did not increase the levels of Smn protein in mouse embryonic fibroblasts or myoblasts obtained from the Smn2B/- mice. In addition, no change in the level of Smn transcripts or protein in the brain or spinal cord of TSA-treated SMA model mice was observed. Furthermore, TSA did not increase Smn protein levels in the hind limb muscle, heart, or liver of Smn2B/- mice. We therefore conclude that TSA likely exerts its effects independent of the endogenous mouse Smn gene. As such, identification of the pathways regulated by TSA in the Smn2B/- mice could lead to the development of novel therapeutics for treating SMA.

Synaptic defects in the spinal and neuromuscular circuitry in a mouse model of spinal muscular atrophy.

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Karen K Y Ling

2010-11-01

Full Text Available Spinal muscular atrophy (SMA is a major genetic cause of death in childhood characterized by marked muscle weakness. To investigate mechanisms underlying motor impairment in SMA, we examined the spinal and neuromuscular circuitry governing hindlimb ambulatory behavior in SMA model mice (SMNΔ7. In the neuromuscular circuitry, we found that nearly all neuromuscular junctions (NMJs in hindlimb muscles of SMNΔ7 mice remained fully innervated at the disease end stage and were capable of eliciting muscle contraction, despite a modest reduction in quantal content. In the spinal circuitry, we observed a ∼28% loss of synapses onto spinal motoneurons in the lateral column of lumbar segments 3-5, and a significant reduction in proprioceptive sensory neurons, which may contribute to the 50% reduction in vesicular glutamate transporter 1(VGLUT1-positive synapses onto SMNΔ7 motoneurons. In addition, there was an increase in the association of activated microglia with SMNΔ7 motoneurons. Together, our results present a novel concept that synaptic defects occur at multiple levels of the spinal and neuromuscular circuitry in SMNΔ7 mice, and that proprioceptive spinal synapses could be a potential target for SMA therapy.

Columbia SMA Project: A Randomized, Control Trial of the Effects of Exercise on Motor Function and Strength in Patients with Spinal Muscular Atrophy (SMA)

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2012-06-01

management of the disease. Manual muscle testing (MMT) is performed as part of a routine neurological exam. Manual muscle testing (MMT) was found to be...dynamometry in spinal muscular atrophy. Muscle Nerve. 2002;26(1):64-70. Mostert & Kesselring. Effects of a short-term exercise training program on aerobic...dictated by the diseased motor neuron. The surviving muscles have more viable hypertrophied type 1 motor units possibly resulting in a lower MPF. Our

Dominant inherited distal spinal muscular atrophy with atrophic and hypertrophic calves

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Groen, R J; Sie, O G; van Weerden, T W

The clinical, electrophysiological, radiological and morphological data of 3 members of a family with autosomal dominant distal spinal muscular atrophy (DSMA) are reported. One patient has the clinical picture of peroneal muscular atrophy with atrophic calves. His father and sister suffer from

Prevention of pectus excavatum for children with spinal muscular atrophy type 1.

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Bach, John R; Bianchi, Carlo

2003-10-01

To demonstrate the elimination of pectus excavatum and promotion of more normal lung growth and chest wall development by the use of high-span positive inspiratory pressure plus positive end-expiratory pressure (PIP+PEEP), patients with spinal muscular atrophy type 1 with paradoxical breathing were placed on high-span PIP+PEEP when sleeping from the point of diagnosis of spinal muscular atrophy. Although the appearance of pectus excavatum is ubiquitous in untreated infants with spinal muscular atrophy type 1, after institution of high-span PIP+PEEP, pectus resolves and lungs and chest walls grow more normally. High-span PIP+PEEP is indicated for all infants diagnosed with spinal muscular atrophy who demonstrate paradoxical breathing for the purpose of promoting more normal lung and chest development.

Spinal muscular atrophy pathogenic mutations impair the axonogenic properties of axonal-survival of motor neuron.

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Locatelli, Denise; d'Errico, Paolo; Capra, Silvia; Finardi, Adele; Colciaghi, Francesca; Setola, Veronica; Terao, Mineko; Garattini, Enrico; Battaglia, Giorgio

2012-05-01

The axonal survival of motor neuron (a-SMN) protein is a truncated isoform of SMN1, the spinal muscular atrophy (SMA) disease gene. a-SMN is selectively localized in axons and endowed with remarkable axonogenic properties. At present, the role of a-SMN in SMA is unknown. As a first step to verify a link between a-SMN and SMA, we investigated by means of over-expression experiments in neuroblastoma-spinal cord hybrid cell line (NSC34) whether SMA pathogenic mutations located in the N-terminal part of the protein affected a-SMN function. We demonstrated here that either SMN1 missense mutations or small intragenic re-arrangements located in the Tudor domain consistently altered the a-SMN capability of inducing axonal elongation in vitro. Mutated human a-SMN proteins determined in almost all NSC34 motor neurons the growth of short axons with prominent morphologic abnormalities. Our data indicate that the Tudor domain is critical in dictating a-SMN function possibly because it is an association domain for proteins involved in axon growth. They also indicate that Tudor domain mutations are functionally relevant not only for FL-SMN but also for a-SMN, raising the possibility that also a-SMN loss of function may contribute to the pathogenic steps leading to SMA. © 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.

Identification of a Peptide for Systemic Brain Delivery of a Morpholino Oligonucleotide in Mouse Models of Spinal Muscular Atrophy

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Shabanpoor, Fazel; Hammond, Suzan M; Abendroth, Frank; Hazell, Gareth; Wood, Matthew J.A.

2017-01-01

Splice-switching antisense oligonucleotides are emerging treatments for neuromuscular diseases, with several splice-switching oligonucleotides (SSOs) currently undergoing clinical trials such as for Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA). However, the development of systemically delivered antisense therapeutics has been hampered by poor tissue penetration and cellular uptake, including crossing of the blood–brain barrier (BBB) to reach targets in the central nervous system (CNS). For SMA application, we have investigated the ability of various BBB-crossing peptides for CNS delivery of a splice-switching phosphorodiamidate morpholino oligonucleotide (PMO) targeting survival motor neuron 2 (SMN2) exon 7 inclusion. We identified a branched derivative of the well-known ApoE (141–150) peptide, which as a PMO conjugate was capable of exon inclusion in the CNS following systemic administration, leading to an increase in the level of full-length SMN2 transcript. Treatment of newborn SMA mice with this peptide-PMO (P-PMO) conjugate resulted in a significant increase in the average lifespan and gains in weight, muscle strength, and righting reflexes. Systemic treatment of adult SMA mice with this newly identified P-PMO also resulted in small but significant increases in the levels of SMN2 pre-messenger RNA (mRNA) exon inclusion in the CNS and peripheral tissues. This work provides proof of principle for the ability to select new peptide paradigms to enhance CNS delivery and activity of a PMO SSO through use of a peptide-based delivery platform for the treatment of SMA potentially extending to other neuromuscular and neurodegenerative diseases. PMID:28118087

Spinal muscular atrophy: Selective motor neuron loss and global defect in the assembly of ribonucleoproteins.

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Beattie, Christine E; Kolb, Stephen J

2018-08-15

Spinal muscular atrophy is caused by deletions or mutations in the SMN1 gene that result in reduced expression of the SMN protein. The SMN protein is an essential molecular chaperone that is required for the biogenesis of multiple ribonucleoprotein (RNP) complexes including spliceosomal small nuclear RNPs (snRNPs). Reductions in SMN expression result in a reduced abundance of snRNPs and to downstream RNA splicing alterations. SMN is also present in axons and dendrites and appears to have important roles in the formation of neuronal mRNA-protein complexes during development or neuronal repair. Thus, SMA is an exemplar, selective motor neuron disorder that is caused by defects in fundamental RNA processing events. A detailed molecular understanding of how motor neurons fail, and why other neurons do not, in SMA will yield important principals about motor neuron maintenance and neuronal specificity in neurodegenerative diseases. Copyright © 2018 Elsevier B.V. All rights reserved.

Stem cell-derived neurotrophic support for the neuromuscular junction in spinal muscular atrophy.

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Wyatt, Tanya J; Keirstead, Hans S

2010-11-01

Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by specific degeneration of α-motor neurons in the spinal cord. The use of cell transplantation to restore lost function through cell replacement or prevent further degeneration of motor neurons and synapses through neurotrophic support heralds tremendous hope in the SMA field. Much research has been carried out in the last decade on the use of embryonic stem cells in cell replacement strategies for various neurodegenerative diseases. Cell replacement is contingent on the ability of transplanted cells to integrate and form new functional connections with host cells. In the case of SMA, cell replacement is a tall order in that axons of transplanted cells would be required to grow over long distances from the spinal cord through growth-averse terrain to synapse with muscles in the periphery. The efficacy of neurotrophic support is contingent on the ability of transplanted cells to secrete neurotrophins appropriate for degenerating motor neurons in the spinal cord or development/stability of the neuromuscular junction (NMJ) in the periphery. The reader will gain an understanding of the potential of neurotrophins to promote development of the NMJ in a diseased or injured environment. Neurotrophins play a major role in NMJ development and thus may be a key factor in the pathogenesis of NMJs in SMA. Further research into the signaling mechanisms involved in NMJ maturation may identify additional mechanisms by which transplanted cells may be of therapeutic benefit.

Novel BICD2 mutation in a Japanese family with autosomal dominant lower extremity-predominant spinal muscular atrophy-2.

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Yoshioka, Mieko; Morisada, Naoya; Toyoshima, Daisaku; Yoshimura, Hajime; Nishio, Hisahide; Iijima, Kazumoto; Takeshima, Yasuhiro; Uehara, Tomoko; Kosaki, Kenjiro

2018-04-01

The most common form of spinal muscular atrophy (SMA) is a recessive disorder caused by SMN1 mutations in 5q13, whereas the genetic etiologies of non-5q SMA are very heterogenous and largely remain to be elucidated. We present a father and son with atrophy and weakness of the lower leg muscles since infancy. Genetic studies in this family revealed a novel BICD2 mutation causing autosomal dominant lower extremity-predominant SMA type 2. The proband was the father, aged 30, and the son was aged 3. Both of them were born uneventfully to nonconsanguineous parents. While the father first walked at the age of 19 months, the son was unable to walk at age 3 years. In both, knee and ankle reflexes were absent and sensation was intact. Serum creatine kinase levels were normal. The son showed congenital arthrogryposis and underwent orthopedic corrections for talipes calcaneovalgus. Investigation of the father at the age of 5 years revealed normal results on nerve conduction studies and sural nerve biopsy. Electromyography showed chronic neurogenic change, and muscle biopsy showed features suggestive of denervation. The father was diagnosed clinically with a sporadic distal SMA. Follow-up studies showed very slow progression. Next-generation and Sanger sequencing revealed a deleterious mutation in BICD2: c.1667A>G, p.Tyr556Cys, in this family. BICD2 is a cytoplasmic conserved motor-adaptor protein involved in anterograde and retrograde transport along the microtubules. Next-generation sequencing will further clarify the genetic basis of non-5q SMA. Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Investigation of New Morpholino Oligomers to Increase Survival Motor Neuron Protein Levels in Spinal Muscular Atrophy.

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Ramirez, Agnese; Crisafulli, Sebastiano G; Rizzuti, Mafalda; Bresolin, Nereo; Comi, Giacomo P; Corti, Stefania; Nizzardo, Monica

2018-01-06

Spinal muscular atrophy (SMA) is an autosomal-recessive childhood motor neuron disease and the main genetic cause of infant mortality. SMA is caused by deletions or mutations in the survival motor neuron 1 ( SMN1 ) gene, which results in SMN protein deficiency. Only one approved drug has recently become available and allows for the correction of aberrant splicing of the paralogous SMN2 gene by antisense oligonucleotides (ASOs), leading to production of full-length SMN protein. We have already demonstrated that a sequence of an ASO variant, Morpholino (MO), is particularly suitable because of its safety and efficacy profile and is both able to increase SMN levels and rescue the murine SMA phenotype. Here, we optimized this strategy by testing the efficacy of four new MO sequences targeting SMN2 . Two out of the four new MO sequences showed better efficacy in terms of SMN protein production both in SMA induced pluripotent stem cells (iPSCs) and SMAΔ7 mice. Further, the effect was enhanced when different MO sequences were administered in combination. Our data provide an important insight for MO-based treatment for SMA. Optimization of the target sequence and validation of a treatment based on a combination of different MO sequences could support further pre-clinical studies and the progression toward future clinical trials.

Abnormal mitochondrial transport and morphology as early pathological changes in human models of spinal muscular atrophy

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Chong-Chong Xu

2016-01-01

Full Text Available Spinal muscular atrophy (SMA, characterized by specific degeneration of spinal motor neurons, is caused by mutations in the survival of motor neuron 1, telomeric (SMN1 gene and subsequent decreased levels of functional SMN. How the deficiency of SMN, a ubiquitously expressed protein, leads to spinal motor neuron-specific degeneration in individuals affected by SMA remains unknown. In this study, we examined the role of SMN in mitochondrial axonal transport and morphology in human motor neurons by generating SMA type 1 patient-specific induced pluripotent stem cells (iPSCs and differentiating these cells into spinal motor neurons. The initial specification of spinal motor neurons was not affected, but these SMA spinal motor neurons specifically degenerated following long-term culture. Moreover, at an early stage in SMA spinal motor neurons, but not in SMA forebrain neurons, the number of mitochondria, mitochondrial area and mitochondrial transport were significantly reduced in axons. Knocking down of SMN expression led to similar mitochondrial defects in spinal motor neurons derived from human embryonic stem cells, confirming that SMN deficiency results in impaired mitochondrial dynamics. Finally, the application of N-acetylcysteine (NAC mitigated the impairment in mitochondrial transport and morphology and rescued motor neuron degeneration in SMA long-term cultures. Furthermore, NAC ameliorated the reduction in mitochondrial membrane potential in SMA spinal motor neurons, suggesting that NAC might rescue apoptosis and motor neuron degeneration by improving mitochondrial health. Overall, our data demonstrate that SMN deficiency results in abnormal mitochondrial transport and morphology and a subsequent reduction in mitochondrial health, which are implicated in the specific degeneration of spinal motor neurons in SMA.

Histopathological Defects in Intestine in Severe Spinal Muscular Atrophy Mice Are Improved by Systemic Antisense Oligonucleotide Treatment.

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Palittiya Sintusek

Full Text Available Gastrointestinal (GI defects, including gastroesophageal reflux, constipation and delayed gastric emptying, are common in patients with spinal muscular atrophy (SMA. Similar GI dysmotility has been identified in mouse models with survival of motor neuron (SMN protein deficiency. We previously described vascular defects in skeletal muscle and spinal cord of SMA mice and we hypothesized that similar defects could be involved in the GI pathology observed in these mice. We therefore investigated the gross anatomical structure, enteric vasculature and neurons in the small intestine in a severe mouse model of SMA. We also assessed the therapeutic response of GI histopathology to systemic administration of morpholino antisense oligonucleotide (AON designed to increase SMN protein expression. Significant anatomical and histopathological abnormalities, with striking reduction of vascular density, overabundance of enteric neurons and increased macrophage infiltration, were detected in the small intestine in SMA mice. After systemic AON treatment in neonatal mice, all the abnormalities observed were significantly restored to near-normal levels. We conclude that the observed GI histopathological phenotypes and functional defects observed in these SMA mice are strongly linked to SMN deficiency which can be rescued by systemic administration of AON. This study on the histopathological changes in the gastrointestinal system in severe SMA mice provides further indication of the complex role that SMN plays in multiple tissues and suggests that at least in SMA mice restoration of SMN production in peripheral tissues is essential for optimal outcome.

Histopathological Defects in Intestine in Severe Spinal Muscular Atrophy Mice Are Improved by Systemic Antisense Oligonucleotide Treatment

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Sintusek, Palittiya; Catapano, Francesco; Angkathunkayul, Napat; Marrosu, Elena; Parson, Simon H.; Morgan, Jennifer E.; Muntoni, Francesco; Zhou, Haiyan

2016-01-01

Gastrointestinal (GI) defects, including gastroesophageal reflux, constipation and delayed gastric emptying, are common in patients with spinal muscular atrophy (SMA). Similar GI dysmotility has been identified in mouse models with survival of motor neuron (SMN) protein deficiency. We previously described vascular defects in skeletal muscle and spinal cord of SMA mice and we hypothesized that similar defects could be involved in the GI pathology observed in these mice. We therefore investigated the gross anatomical structure, enteric vasculature and neurons in the small intestine in a severe mouse model of SMA. We also assessed the therapeutic response of GI histopathology to systemic administration of morpholino antisense oligonucleotide (AON) designed to increase SMN protein expression. Significant anatomical and histopathological abnormalities, with striking reduction of vascular density, overabundance of enteric neurons and increased macrophage infiltration, were detected in the small intestine in SMA mice. After systemic AON treatment in neonatal mice, all the abnormalities observed were significantly restored to near-normal levels. We conclude that the observed GI histopathological phenotypes and functional defects observed in these SMA mice are strongly linked to SMN deficiency which can be rescued by systemic administration of AON. This study on the histopathological changes in the gastrointestinal system in severe SMA mice provides further indication of the complex role that SMN plays in multiple tissues and suggests that at least in SMA mice restoration of SMN production in peripheral tissues is essential for optimal outcome. PMID:27163330

Computed tomographic myelography characteristics of spinal cord atrophy in juvenile muscular atrophy of the upper extremity

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Hirabuki, Norio; Mitomo, Masanori; Miura, Takashi; Hashimoto, Tsutomu; Kawai, Ryuji; Kozuka, Takahiro

1991-01-01

Although atrophy of the lower cervical and upper thoracic cord in juvenile muscular atrophy of distal upper extremity has been reported, the atrophic patterns of the cord, especially in the transverse section, have not been studied extensively. The aim of this study is to clarify the atrophic patterns of the cord by CT myelography (CTM) and to discuss the pathogenesis of cord atrophy. Sixteen patients with juvenile muscular atrophy of distal upper extremity were examined by CTM. Atrophy of the lower cervical and upper thoracic cord, consistent with the segmental weakness, was seen in all patients. Flattening of the ventral convexity was a characteristic atrophic pattern of the cord. Bilateral cord atrophy was commonly observed; 8/12 patients with unilateral clinical form and all 4 patients with bilateral form showed bilateral cord atrophy with dominance on the clinical side. There was no correlation between the degree of cord atrophy and duration of symptoms. Flattening of the ventral convexity, associated with purely motor disturbances, reflects selective atrophy of the anterior horns in the cord, which is attributable to chronic ischemia. Cord atrophy proved to precede clinical manifestations. The characteristic atrophy of the cord provides useful information to confirm the diagnosis without long-term observation. (author). 21 refs.; 3 figs.; 2 tabs

Reduced sensory synaptic excitation impairs motor neuron function via Kv2.1 in spinal muscular atrophy.

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Fletcher, Emily V; Simon, Christian M; Pagiazitis, John G; Chalif, Joshua I; Vukojicic, Aleksandra; Drobac, Estelle; Wang, Xiaojian; Mentis, George Z

2017-07-01

Behavioral deficits in neurodegenerative diseases are often attributed to the selective dysfunction of vulnerable neurons via cell-autonomous mechanisms. Although vulnerable neurons are embedded in neuronal circuits, the contributions of their synaptic partners to disease process are largely unknown. Here we show that, in a mouse model of spinal muscular atrophy (SMA), a reduction in proprioceptive synaptic drive leads to motor neuron dysfunction and motor behavior impairments. In SMA mice or after the blockade of proprioceptive synaptic transmission, we observed a decrease in the motor neuron firing that could be explained by the reduction in the expression of the potassium channel Kv2.1 at the surface of motor neurons. Chronically increasing neuronal activity pharmacologically in vivo led to a normalization of Kv2.1 expression and an improvement in motor function. Our results demonstrate a key role of excitatory synaptic drive in shaping the function of motor neurons during development and the contribution of its disruption to a neurodegenerative disease.

ROCK inhibition as a therapy for spinal muscular atrophy: understanding the repercussions on multiple cellular targets

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Emmanuelle eCoque

2014-08-01

Full Text Available Spinal muscular atrophy (SMA is the most common genetic disease causing infant death, due to an extended loss of motoneurons. This neuromuscular disorder results from deletions and/or mutations within the surviving motor neuron 1 (SMN1 gene, leading to a pathological decreased expression of functional full-length SMN protein. Emerging studies suggest that the small GTPase RhoA and its major downstream effector Rho kinase (ROCK, which both play an instrumental role in cytoskeleton organization, contribute to the pathology of motoneuron diseases. Indeed, an enhanced activation of RhoA and ROCK has been reported in the spinal cord of an SMA mouse model. Moreover, the treatment of SMA mice with ROCK inhibitors leads to an increased lifespan as well as improved skeletal muscle and neuromuscular junction pathology, without preventing motoneuron degeneration. Although motoneurons are the primary target in SMA, an increasing number of reports show that other cell types inside and outside the central nervous system contribute to SMA pathogenesis. As administration of ROCK inhibitors to SMA mice was systemic, the improvement in survival and phenotype could therefore be attributed to specific effects on motoneurons and/or on other non-neuronal cell types. In the present review, we will present the various roles of the RhoA/ROCK pathway in several SMA cellular targets including neurons, myocytes, glial cells, cardiomyocytes and pancreatic cells as well as discuss how ROCK inhibition may ameliorate their health and function. It is most likely a concerted influence of ROCK modulation on all these cell types that ultimately lead to the observed benefits of pharmacological ROCK inhibition in SMA mice.

ROCK inhibition as a therapy for spinal muscular atrophy: understanding the repercussions on multiple cellular targets

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Coque, Emmanuelle; Raoul, Cédric; Bowerman, Mélissa

2014-01-01

Spinal muscular atrophy (SMA) is the most common genetic disease causing infant death, due to an extended loss of motoneurons. This neuromuscular disorder results from deletions and/or mutations within the Survival Motor Neuron 1 (SMN1) gene, leading to a pathological decreased expression of functional full-length SMN protein. Emerging studies suggest that the small GTPase RhoA and its major downstream effector Rho kinase (ROCK), which both play an instrumental role in cytoskeleton organization, contribute to the pathology of motoneuron diseases. Indeed, an enhanced activation of RhoA and ROCK has been reported in the spinal cord of an SMA mouse model. Moreover, the treatment of SMA mice with ROCK inhibitors leads to an increased lifespan as well as improved skeletal muscle and neuromuscular junction pathology, without preventing motoneuron degeneration. Although motoneurons are the primary target in SMA, an increasing number of reports show that other cell types inside and outside the central nervous system contribute to SMA pathogenesis. As administration of ROCK inhibitors to SMA mice was systemic, the improvement in survival and phenotype could therefore be attributed to specific effects on motoneurons and/or on other non-neuronal cell types. In the present review, we will present the various roles of the RhoA/ROCK pathway in several SMA cellular targets including neurons, myoblasts, glial cells, cardiomyocytes and pancreatic cells as well as discuss how ROCK inhibition may ameliorate their health and function. It is most likely a concerted influence of ROCK modulation on all these cell types that ultimately lead to the observed benefits of pharmacological ROCK inhibition in SMA mice. PMID:25221469

Survival motor neuron protein in motor neurons determines synaptic integrity in spinal muscular atrophy.

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Martinez, Tara L; Kong, Lingling; Wang, Xueyong; Osborne, Melissa A; Crowder, Melissa E; Van Meerbeke, James P; Xu, Xixi; Davis, Crystal; Wooley, Joe; Goldhamer, David J; Lutz, Cathleen M; Rich, Mark M; Sumner, Charlotte J

2012-06-20

The inherited motor neuron disease spinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein and results in severe muscle weakness. In SMA mice, synaptic dysfunction of both neuromuscular junctions (NMJs) and central sensorimotor synapses precedes motor neuron cell death. To address whether this synaptic dysfunction is due to SMN deficiency in motor neurons, muscle, or both, we generated three lines of conditional SMA mice with tissue-specific increases in SMN expression. All three lines of mice showed increased survival, weights, and improved motor behavior. While increased SMN expression in motor neurons prevented synaptic dysfunction at the NMJ and restored motor neuron somal synapses, increased SMN expression in muscle did not affect synaptic function although it did improve myofiber size. Together these data indicate that both peripheral and central synaptic integrity are dependent on motor neurons in SMA, but SMN may have variable roles in the maintenance of these different synapses. At the NMJ, it functions at the presynaptic terminal in a cell-autonomous fashion, but may be necessary for retrograde trophic signaling to presynaptic inputs onto motor neurons. Importantly, SMN also appears to function in muscle growth and/or maintenance independent of motor neurons. Our data suggest that SMN plays distinct roles in muscle, NMJs, and motor neuron somal synapses and that restored function of SMN at all three sites will be necessary for full recovery of muscle power.

Congenital contractural arachnodactyly with neurogenic muscular atrophy: case report

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Scola Rosana Herminia

2001-01-01

Full Text Available We report the case of a 3-1/2-year-old girl with hypotonia, multiple joint contractures, hip luxation, arachnodactyly, adducted thumbs, dolichostenomelia, and abnormal external ears suggesting the diagnosis of congenital contractural arachnodactyly (CCA. The serum muscle enzimes were normal and the needle electromyography showed active and chronic denervation. The muscle biopsy demonstrated active and chronic denervation compatible with spinal muscular atrophy. Analysis of exons 7 and 8 of survival motor neuron gene through polymerase chain reaction did not show deletions. Neurogenic muscular atrophy is a new abnormality associated with CCA, suggesting that CCA is clinically heterogeneous.

A two-site ELISA can quantify upregulation of SMN protein by drugs for spinal muscular atrophy.

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Nguyen thi Man; Humphrey, E; Lam, L T; Fuller, H R; Lynch, T A; Sewry, C A; Goodwin, P R; Mackenzie, A E; Morris, G E

2008-11-25

Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by loss of lower motor neurons during early or postnatal development. Severity is variable and is inversely related to the levels of survival of motor neurons (SMN) protein. The aim of this study was to produce a two-site ELISA capable of measuring both the low, basal levels of SMN protein in cell cultures from patients with severe SMA and small increases in these levels after treatment of cells with drugs. A monoclonal antibody against recombinant SMN, MANSMA1, was selected for capture of SMN onto microtiter plates. A selected rabbit antiserum against refolded recombinant SMN was used for detection of the captured SMN. The ratio of SMN levels in control fibroblasts to levels in SMA fibroblasts was greater than 3.0, consistent with Western blot data. The limit of detection was 0.13 ng/mL and SMN could be measured in human NT-2 neuronal precursor cells grown in 96-well culture plates (3 x 10(4) cells per well). Increases in SMN levels of 50% were demonstrable by ELISA after 24 hours treatment of 10(5) SMA fibroblasts with valproate or phenylbutyrate. A rapid and specific two-site, 96-well ELISA assay, available in kit format, can now quantify the effects of drugs on survival of motor neurons protein levels in cell cultures.

Tissue-specific models of spinal muscular atrophy confirm a critical role of SMN in motor neurons from embryonic to adult stages.

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Laird, Angela S; Mackovski, Nikolce; Rinkwitz, Silke; Becker, Thomas S; Giacomotto, Jean

2016-05-01

Spinal muscular atrophy (SMA) is an autosomal recessive disease linked to survival motor neuron (SMN) protein deficiency. While SMN protein is expressed ubiquitously, its deficiency triggers tissue-specific hallmarks, including motor neuron death and muscle atrophy, leading to impaired motor functions and premature death. Here, using stable miR-mediated knockdown technology in zebrafish, we developed the first vertebrate system allowing transgenic spatio-temporal control of the smn1 gene. Using this new model it is now possible to investigate normal and pathogenic SMN function(s) in specific cell types, independently or in synergy with other cell populations. We took advantage of this new system to first test the effect of motor neuron or muscle-specific smn1 silencing. Anti-smn1 miRNA expression in motor neurons, but not in muscles, reproduced SMA hallmarks, including abnormal motor neuron development, poor motor function and premature death. Interestingly, smn1 knockdown in motor neurons also induced severe late-onset phenotypes including scoliosis-like body deformities, weight loss, muscle atrophy and, seen for the first time in zebrafish, reduction in the number of motor neurons, indicating motor neuron degeneration. Taken together, we have developed a new transgenic system allowing spatio-temporal control of smn1 expression in zebrafish, and using this model, we have demonstrated that smn1 silencing in motor neurons alone is sufficient to reproduce SMA hallmarks in zebrafish. It is noteworthy that this research is going beyond SMA as this versatile gene-silencing transgenic system can be used to knockdown any genes of interest, filling the gap in the zebrafish genetic toolbox and opening new avenues to study gene functions in this organism. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy.

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Mercuri, Eugenio; Darras, Basil T; Chiriboga, Claudia A; Day, John W; Campbell, Craig; Connolly, Anne M; Iannaccone, Susan T; Kirschner, Janbernd; Kuntz, Nancy L; Saito, Kayoko; Shieh, Perry B; Tulinius, Már; Mazzone, Elena S; Montes, Jacqueline; Bishop, Kathie M; Yang, Qingqing; Foster, Richard; Gheuens, Sarah; Bennett, C Frank; Farwell, Wildon; Schneider, Eugene; De Vivo, Darryl C; Finkel, Richard S

2018-02-15

Nusinersen is an antisense oligonucleotide drug that modulates pre-messenger RNA splicing of the survival motor neuron 2 ( SMN2) gene. It has been developed for the treatment of spinal muscular atrophy (SMA). We conducted a multicenter, double-blind, sham-controlled, phase 3 trial of nusinersen in 126 children with SMA who had symptom onset after 6 months of age. The children were randomly assigned, in a 2:1 ratio, to undergo intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) or a sham procedure (control group) on days 1, 29, 85, and 274. The primary end point was the least-squares mean change from baseline in the Hammersmith Functional Motor Scale-Expanded (HFMSE) score at 15 months of treatment; HFMSE scores range from 0 to 66, with higher scores indicating better motor function. Secondary end points included the percentage of children with a clinically meaningful increase from baseline in the HFMSE score (≥3 points), an outcome that indicates improvement in at least two motor skills. In the prespecified interim analysis, there was a least-squares mean increase from baseline to month 15 in the HFMSE score in the nusinersen group (by 4.0 points) and a least-squares mean decrease in the control group (by -1.9 points), with a significant between-group difference favoring nusinersen (least-squares mean difference in change, 5.9 points; 95% confidence interval, 3.7 to 8.1; PCHERISH ClinicalTrials.gov number, NCT02292537 .).

Spinal Muscular Atrophy: From Defective Chaperoning of snRNP Assembly to Neuromuscular Dysfunction

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Maia Lanfranco

2017-06-01

Full Text Available Spinal Muscular Atrophy (SMA is a neuromuscular disorder that results from decreased levels of the survival motor neuron (SMN protein. SMN is part of a multiprotein complex that also includes Gemins 2–8 and Unrip. The SMN-Gemins complex cooperates with the protein arginine methyltransferase 5 (PRMT5 complex, whose constituents include WD45, PRMT5 and pICln. Both complexes function as molecular chaperones, interacting with and assisting in the assembly of an Sm protein core onto small nuclear RNAs (snRNAs to generate small nuclear ribonucleoproteins (snRNPs, which are the operating components of the spliceosome. Molecular and structural studies have refined our knowledge of the key events taking place within the crowded environment of cells and the numerous precautions undertaken to ensure the faithful assembly of snRNPs. Nonetheless, it remains unclear whether a loss of chaperoning in snRNP assembly, considered as a “housekeeping” activity, is responsible for the selective neuromuscular phenotype in SMA. This review thus shines light on in vivo studies that point toward disturbances in snRNP assembly and the consequential transcriptome abnormalities as the primary drivers of the progressive neuromuscular degeneration underpinning the disease. Disruption of U1 snRNP or snRNP assembly factors other than SMN induces phenotypes that mirror aspects of SMN deficiency, and splicing defects, described in numerous SMA models, can lead to a DNA damage and stress response that compromises the survival of the motor system. Restoring the correct chaperoning of snRNP assembly is therefore predicted to enhance the benefit of SMA therapeutic modalities based on augmenting SMN expression.

Phase II open label study of valproic acid in spinal muscular atrophy.

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Kathryn J Swoboda

Full Text Available Preliminary in vitro and in vivo studies with valproic acid (VPA in cell lines and patients with spinal muscular atrophy (SMA demonstrate increased expression of SMN, supporting the possibility of therapeutic benefit. We performed an open label trial of VPA in 42 subjects with SMA to assess safety and explore potential outcome measures to help guide design of future controlled clinical trials. Subjects included 2 SMA type I ages 2-3 years, 29 SMA type II ages 2-14 years and 11 type III ages 2-31 years, recruited from a natural history study. VPA was well-tolerated and without evident hepatotoxicity. Carnitine depletion was frequent and temporally associated with increased weakness in two subjects. Exploratory outcome measures included assessment of gross motor function via the modified Hammersmith Functional Motor Scale (MHFMS, electrophysiologic measures of innervation including maximum ulnar compound muscle action potential (CMAP amplitudes and motor unit number estimation (MUNE, body composition and bone density via dual-energy X-ray absorptiometry (DEXA, and quantitative blood SMN mRNA levels. Clear decline in motor function occurred in several subjects in association with weight gain; mean fat mass increased without a corresponding increase in lean mass. We observed an increased mean score on the MHFMS scale in 27 subjects with SMA type II (p

Pain in adolescents with spinal muscular atrophy and Duchenne and Becker muscular dystrophy.

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Lager, Christina; Kroksmark, Anna-Karin

2015-09-01

The purpose of this study was to explore the prevalence, nature and scope of pain in adolescents with spinal muscular atrophy and Duchenne and Becker muscular dystrophy and whether the pain differs between diagnostic groups or between adolescents with different ambulation status. Furthermore to study the consequences of pain and to identify pain-exacerbating and pain-relieving factors. In a national survey, fifty-five adolescents with spinal muscular atrophy and dystrophinopathy completed a questionnaire assessing pain frequency, duration, location using a body map, intensity and discomfort using visual analogue scales, pain interference using a modified version of Brief Pain Inventory and factors exacerbating and relieving pain. Sixty-nine per cent of the adolescents reported pain during the past three months and 50% reported chronic pain. The pain prevalence did not differ significantly between diagnostic groups or between ambulators and non-ambulators. The average pain intensity was graded as mild and the worst pain as moderate. The pain typically occurred weekly, most frequently in the neck/back or legs. General activity and mood were the areas that were most affected by pain. Common pain-exacerbating factors were sitting, too much movement/activity and being lifted or transferred. Pain is a frequent problem in adolescents with spinal muscular atrophy and dystrophinopathy. The assessments used enable an understanding both of the nature and scope of pain and of the impact of pain in everyday life. The study highlights the importance of assessing pain in a systematic manner and offering an individual approach to interventions designed to reduce pain in this population. Copyright © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Rapidly worsening bulbar symptoms in a patient with spinobulbar muscular atrophy

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Montserrat Diaz-Abad

2013-12-01

Full Text Available X-linked spinobulbar muscular atrophy (Kennedy’s disease affects muscles and motor neurons, manifesting as weakness and wasting of bulbar, facial, and proximal limb muscles due to loss of anterior horn cells in the brain and spinal cord. We present the case of a patient with X-linked spinobulbar muscular atrophy with rapidly worsening bulbar symptoms caused by laryngopharyngeal irritation associated with a viral upper respiratory tract infection, seasonal allergies and laryngopharyngeal reflux, who dramatically improved with multimodality therapy.

Living with illness and self-transcendence: the lived experience of patients with spinal muscular atrophy.

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Ho, Hsin-Mei; Tseng, Ying-Hua; Hsin, Yu-Mei; Chou, Fan-Hao; Lin, Wei-Ting

2016-11-01

The aim of this study was to explore the lived experiences of patients afflicted with spinal muscular atrophy. Existing research studies on spinal muscular atrophy address the physical and psychological effects and complications of the disease; they also provide suggestions for how to improve the current management of this disease. However, information is limited on the disease process and the lived experience of spinal muscular atrophy patients. A phenomenological approach was conducted. Through 18 in-depth interviews recorded by a pen voice recorder, this study collected data obtained from a purposive sample of nine patients from the, 'Taiwan spinal muscular atrophy Families,' between November 2010-August 2011. The audio recordings were transcribed verbatim and data were analysed using Colaizzi's steps. Four themes and eight subthemes were identified: a loss of control (loss of muscular strength and independence), breaking limitations (assistive device use and mobility design), transcending limitations (independence/autonomy and social development) and living with hope (cherishing life and self-control). The results showed that the lived experiences of the spinal muscular atrophy patients involved living with illness, transcending the self and pursuing the meaning of life. Facing a life-threatening illness, these patients made self-adjustments in their lifestyles and exerted themselves to positively cope with hardships and maintain dignity and self-control. These findings could serve as evidence-based practice resources for healthcare professionals in helping individuals and their family members gain an in-depth understanding of spinal muscular atrophy's progression and life course and assist individuals in improving self-integrity to with hope. © 2016 John Wiley & Sons Ltd.

How do SMA-linked mutations of SMN1 lead to structural/functional deficiency of the SMA protein?

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Wei Li

Full Text Available Spinal muscular atrophy (SMA is an autosomal recessive neuromuscular disease with dysfunctional α-motor neurons in the anterior horn of the spinal cord. SMA is caused by loss (∼95% of SMA cases or mutation (∼5% of SMA cases of the survival motor neuron 1 gene SMN1. As the product of SMN1, SMN is a component of the SMN complex, and is also involved in the biosynthesis of the small nuclear ribonucleoproteins (snRNPs, which play critical roles in pre-mRNA splicing in the pathogenesis of SMA. To investigate how SMA-linked mutations of SMN1 lead to structural/functional deficiency of SMN, a set of computational analysis of SMN-related structures were conducted and are described in this article. Of extraordinary interest, the structural analysis highlights three SMN residues (Asp44, Glu134 and Gln136 with SMA-linked missense mutations, which cause disruptions of electrostatic interactions for Asp44, Glu134 and Gln136, and result in three functionally deficient SMA-linked SMN mutants, Asp44Val, Glu134Lys and Gln136Glu. From the computational analysis, it is also possible that SMN's Lys45 and Asp36 act as two electrostatic clips at the SMN-Gemin2 complex structure interface.

Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy

Institute of Scientific and Technical Information of China (English)

Zhi-Bo Wang; Xiaoqing Zhang; Xue-Jun Li

2013-01-01

Establishing human cell models of spinal muscular atrophy (SMA) to mimic motor neuron-specific phenotypes holds the key to understanding the pathogenesis of this devastating disease.Here,we developed a closely representative cell model of SMA by knocking down the disease-determining gene,survival motor neuron (SMN),in human embryonic stem cells (hESCs).Our study with this cell model demonstrated that knocking down of SMN does not interfere with neural induction or the initial specification of spinal motor neurons.Notably,the axonal outgrowth of spinal motor neurons was significantly impaired and these disease-mimicking neurons subsequently degenerated.Furthermore,these disease phenotypes were caused by SMN-full length (SMN-FL) but not SMN-A7 (lacking exon 7)knockdown,and were specific to spinal motor neurons.Restoring the expression of SMN-FL completely ameliorated all of the disease phenotypes,including specific axonal defects and motor neuron loss.Finally,knockdown of SMNFL led to excessive mitochondrial oxidative stress in human motor neuron progenitors.The involvement of oxidative stress in the degeneration of spinal motor neurons in the SMA cell model was further confirmed by the administration of N-acetylcysteine,a potent antioxidant,which prevented disease-related apoptosis and subsequent motor neuron death.Thus,we report here the successful establishment of an hESC-based SMA model,which exhibits disease gene isoform specificity,cell type specificity,and phenotype reversibility.Our model provides a unique paradigm for studying how motor neurons specifically degenerate and highlights the potential importance of antioxidants for the treatment of SMA.

Genetic and expression studies of SMN2 gene in Russian patients with spinal muscular atrophy type II and III

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Schiöth Helgi B

2011-07-01

Full Text Available Abstract Background Spinal muscular atrophy (SMA type I, II and III is an autosomal recessive neuromuscular disorder caused by mutations in the survival motor neuron gene (SMN1. SMN2 is a centromeric copy gene that has been characterized as a major modifier of SMA severity. SMA type I patients have one or two SMN2 copies while most SMA type II patients carry three SMN2 copies and SMA III patients have three or four SMN2 copies. The SMN1 gene produces a full-length transcript (FL-SMN while SMN2 is only able to produce a small portion of the FL-SMN because of a splice mutation which results in the production of abnormal SMNΔ7 mRNA. Methods In this study we performed quantification of the SMN2 gene copy number in Russian patients affected by SMA type II and III (42 and 19 patients, respectively by means of real-time PCR. Moreover, we present two families consisting of asymptomatic carriers of a homozygous absence of the SMN1 gene. We also developed a novel RT-qPCR-based assay to determine the FL-SMN/SMNΔ7 mRNA ratio as SMA biomarker. Results Comparison of the SMN2 copy number and clinical features revealed a significant correlation between mild clinical phenotype (SMA type III and presence of four copies of the SMN2 gene. In both asymptomatic cases we found an increased number of SMN2 copies in the healthy carriers and a biallelic SMN1 absence. Furthermore, the novel assay revealed a difference between SMA patients and healthy controls. Conclusions We suggest that the SMN2 gene copy quantification in SMA patients could be used as a prognostic tool for discrimination between the SMA type II and SMA type III diagnoses, whereas the FL-SMN/SMNΔ7 mRNA ratio could be a useful biomarker for detecting changes during SMA pharmacotherapy.

[Ethical attitudes of intensive care paediatricians as regards patients with spinal muscular atrophy type 1].

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Agra Tuñas, María Carmen; Hernández Rastrollo, Ramón; Hernández González, Arturo; Ramil Fraga, Carmen; Cambra Lasaosa, Francisco José; Quintero Otero, Sebastián; Ruiz Extremera, Angela; Rodríguez Núñez, Antonio

2017-03-01

Spinal muscular atrophy type 1 (SMA-1) is a progressive and fatal disease that leads to ethical problems for Paediatric professionals. Our objective was to determine the ethical options of Paediatric Intensive Care Unit (PICU) paediatricians as regards a child with SMA-1 and respiratory failure. A cross-sectional descriptive study was conducted using an anonymous questionnaire sent to PICUs in Spain (which can be accessed through the Spanish Society of Paediatric Critical Care web page). Of the 124 responses analysed, 70% were from women, 51% younger than 40 years, 54% from a PICU with more than 10 beds, 69% with prior experience in such cases, and 53% with religious beliefs. In the last patient cared for, most paediatricians opted for non-invasive mechanical ventilation (NIV) and limitation of therapeutic effort (LET) in case of NIV failure. Confronted with a future hypothetical case, half of paediatricians would opt for the same plan (NIV+LET), and 74% would support the family's decision, even in case of disagreement. Age, prior experience and sex were not related to the preferred options. Paediatricians with religious beliefs were less in favour of initial LET. Less than two-thirds (63%) scored the quality of life of a child with SMA-1 and invasive mechanical ventilation as very poor. Faced with child with SMA-1 and respiratory failure, most paediatricians are in favour of initiating NIV and LET when such support is insufficient, but they would accept the family's decision, even in case of disagreement. Copyright © 2015 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

Association between the SMN2 gene copy number and clinical characteristics of patients with spinal muscular atrophy with homozygous deletion of exon 7 of the SMN1 gene

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Žarkov Marija

2015-01-01

Full Text Available Background/Aim. Spinal muscular atrophy (SMA is an autosomal recessive disease characterized by degeneration of alpha motor neurons in the spinal cord and the medulla oblongata, causing progressive muscle weakness and atrophy. The aim of this study was to determine association between the SMN2 gene copy number and disease phenotype in Serbian patients with SMA with homozygous deletion of exon 7 of the SMN1 gene. Methods. The patients were identified using regional Serbian hospital databases. Investigated clinical characteristics of the disease were: patients’ gender, age at disease onset, achieved and current developmental milestones, disease duration, current age, and the presence of the spinal deformities and joint contractures. The number of SMN1 and SMN2 gene copies was determined using real-time polymerase chain reaction (PCR. Results. Among 43 identified patients, 37 (86.0% showed homozygous deletion of SMN1 exon 7. One (2.7% of 37 patients had SMA type I with 3 SMN2 copies, 11 (29.7% patients had SMA type II with 3.1 ± 0.7 copies, 17 (45.9% patients had SMA type III with 3.7 ± 0.9 copies, while 8 (21.6% patients had SMA type IV with 4.2 ± 0.9 copies. There was a progressive increase in the SMN2 gene copy number from type II towards type IV (p < 0.05. A higher SMN2 gene copy number was associated with better current motor performance (p < 0.05. Conclusion. In the Serbian patients with SMA, a higher SMN2 gene copy number correlated with less severe disease phenotype. A possible effect of other phenotype modifiers should not be neglected.

Physical complaints in ageing persons with spinal muscular atrophy.

NARCIS (Netherlands)

Groot, I.J.M. de; Witte, L.P de

2005-01-01

OBJECTIVE: While life expectancy is improving for persons with spinal muscular atrophy, new physical complaints may arise. To investigate this, we studied persons with a long duration and severe course (high functional limitations) of the disease. DESIGN: Cross-sectional descriptive study.

Recent developments in the treatment of Duchenne muscular dystrophy and spinal muscular atrophy

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Liew, Wendy K. M.

2013-01-01

Pediatric neuromuscular disorders comprise a large variety of disorders that can be classified based on their neuroanatomical localization, patterns of weakness, and laboratory test results. Over the last decade, the field of translational research has been active with many ongoing clinical trials. This is particularly so in two common pediatric neuromuscular disorders: Duchenne muscular dystrophy and spinal muscular atrophy. Although no definitive therapy has yet been found, numerous active areas of research raise the potential for novel therapies in these two disorders, offering hope for improved quality of life and life expectancy for affected individuals. PMID:23634188

Functional characterizations of rare UBA1 variants in X-linked Spinal Muscular Atrophy [version 1; referees: 2 approved

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Chris D. Balak

2017-09-01

Full Text Available Background: X-linked spinal muscular atrophy (XL-SMA results from mutations in the Ubiquitin-Like Modifier Activating Enzyme 1 (UBA1. Previously, four novel closely clustered mutations have been shown to cause this fatal infantile disorder affecting only males. These mutations, three missense and one synonymous, all lie within Exon15 of the UBA1 gene, which contains the active adenylation domain (AAD. Methods: In this study, our group characterized the three known missense variants in vitro. Using a novel Uba1 assay and other methods, we investigated Uba1 adenylation, thioester, and transthioesterification reactions in vitro to determine possible biochemical effects of the missense variants. Results: Our data revealed that only one of the three XL-SMA missense variants impairs the Ubiquitin-adenylating ability of Uba1. Additionally, these missense variants retained Ubiquitin thioester bond formation and transthioesterification rates equal to that found in the wild type. Conclusions: Our results demonstrate a surprising shift from the likelihood of these XL-SMA mutations playing a damaging role in Uba1’s enzymatic activity with Ubiquitin, to other roles such as altering UBA1 mRNA splicing via the disruption of splicing factor binding sites, similar to a mechanism in traditional SMA, or disrupting binding to other important in vivo binding partners.  These findings help to narrow the search for the areas of possible dysfunction in the Ubiquitin-proteasome pathway that ultimately result in XL-SMA. Moreover, this investigation provides additional critical understanding of the mutations’ biochemical mechanisms, vital for the development of future effective diagnostic assays and therapeutics.

The experiences of families living with the anticipatory loss of a school-age child with spinal muscular atrophy - the parents' perspectives.

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Yang, Bao-Huan; Mu, Pei-Fan; Wang, Wen-Sheng

2016-09-01

To probe into parents' anticipatory loss of school-age children with Type I or II spinal muscular atrophy. Spinal muscular atrophy is a rare disorder that causes death. Children die early due to either gradual atrophy or an infection of the lungs. Therefore, family members experience anticipatory loss, which causes grief before the actual loss. Family members feel physically and mentally exhausted, which results in a family crisis. Therefore, it is important to explore their experiences related to anticipatory loss to assist with the adjustment of the families to their circumstances. This study applied a phenomenology method and purposive sampling. The 19 parents who participated in this study were referred to us by two medical centers in Taiwan. Their average age was 32-49 years. Using in-depth interviews, this study explored parents' anticipatory loss. The interviews were recorded and transcribed. Meanings were extracted using Giorgi analysis, and precision was assessed according to Guba and Lincoln, which was treated as the evaluation standard. Four themes were identified from the parents' interviews. The themes included enduring the helplessness and pressure of care, suffering due to the child's rare and unknown condition, loss of hope and a reinforcement of the parent-child attachment, and avoiding the pressure of death and enriching the child's life. The research findings help nurses identify anticipatory loss among parents of school-age children with type I or II spinal muscular atrophy. They enhance health professionals' understanding of the panic that occurs in the society surrounding the families, family members' dynamic relationships, and the families' demands for care. In an attempt to providing intersubjective empathy and support with family having a child with type I and II SMA, nurses may recognize relevant family reactions and enhancing their hope and parent-child attachment. Encourage family members and child go beyond the pressure of death and

Muscles in a mouse model of spinal muscular atrophy show profound defects in neuromuscular development even in the absence of failure in neuromuscular transmission or loss of motor neurons

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Lee, Young il; Mikesh, Michelle; Smith, Ian; Rimer, Mendell; Thompson, Wesley

2011-01-01

A mouse model of the devastating human disease "spinal muscular atrophy" (SMA) was used to investigate the severe muscle weakness and spasticity that precedes the death of these animals near the end of the 2nd postnatal week. Counts of motor units to the soleus muscle as well as of axons in the soleus muscle nerve showed no loss of motor neurons. Similarly, neither immunostaining of neuromuscular junctions nor the measurement of the tension generated by nerve stimulation gave evidence of any ...

Spinal muscular atrophy type II (intermediary and III (Kugelberg-Welander: evolution of 50 patients with physiotherapy and hydrotherapy in a swimming pool Atrofia muscular espinhal tipo II (intermediária e III (Kugelberg-Welander: evolução de 50 pacientes com fisioterapia e hidroterapia em piscina

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Márcia C. B. Cunha

1996-09-01

Full Text Available We added hydrotherapy to 50 patients with spinal muscular atrophy (SMA who were being treated with individual conventional physiotherapy. Hydrotherapy was performed at an approximate temperature of 30 degrees Celsius, twice a week, for thirty minutes in children and for forty-five minutes in adults during a 2-year period. The outcome derived from this combined modality of treatment was rated according to physiotherapeutic evaluations, the MMT (Manual Muscular Test, and the Barthel Ladder. Patients were reevaluated at 2-month intervals. After two years of ongoing treatment, we were able to observe that the deformities in hip, knee and foot were progressive in all SMA Type II patients, and in some Type III. Muscle strength stabilized in most SMA Type III patients, and improved in some. MMT was not done in SMA Type II. In all patients we were able to detect an improvement in the Barthel Ladder scale. This study suggests that a measurable improvement in the quality of daily living may be obtained in patients with SMA Types II and III subjected to conventional physiotherapy when associated with hydrotherapy.A hidroterapia foi realizada em SO pacientes com atrofia muscular espinhal, os quais foram também tratados com fisioterapia individual convencional. O tratamento hidroterápico foi realizado em piscina aquecida numa temperatura de aproximadamente 30° Celsius, duas vezes por semana, durante 30 minutos em crianças e 45 minutos em adultos num período de dois anos. Os benefícios deste tipo de tratamento foram avaliados de acordo com a evolução clínica, o MMT(Teste de Força Muscular e a Escala de Barthel. Os pacientes foram reavaliados a cada dois meses. Após dois anos de tratamento nós observamos que as deformidades nos quadris, joelhos e pés foram progressivas em todos os pacientes do Tipo II e em alguns do Tipo III. Houve estabilização da força muscular na maioria dos pacientes com SMA Tipo III, e melhora da força em alguns; nos

[Spinal muscular atrophy and respiratory failure. How do primary care pediatricians act in a simulated scenario?].

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Agra Tuñas, M C; Sánchez Santos, L; Busto Cuiñas, M; Rodríguez Núñez, A

2015-11-01

Spinal muscular atrophy type 1 (SMA-1) tends to be fatal in the first year of life if there is no ventilatory support. The decision whether to start such support is an ethical conflict for healthcare professionals. A scenario of acute respiratory failure in an infant with SMA-1 has been included in a training program using advanced simulation for Primary Care pediatricians (PCP). The performances of 34 groups of 4 pediatricians, who participated in 17 courses, were systematically analyzed. Clinical, ethical and communication aspects with parents were evaluated. The initial technical assistance (Administration of oxygen and immediate ventilatory support) was correctly performed by 94% of the teams. However, the PCP had problems in dealing with the ethical aspects of the case. Of the 85% of the teams that raised the ethical conflict with parents, 29% did so on their own initiative, 23% actively excluded them, and only 6% involved them and took their opinion into account in making decisions. Only 11.7% asked about the quality of life of children and 12% for their knowledge of the prognosis of the disease. None explained treatment alternatives, nor tried to contact the pediatrician responsible for the child. When faced with a simulated SMA-1 infant with respiratory failure, PCP have difficulties in interacting with the family, and to involve it in the decision making process. Practical training of all pediatricians should include case scenarios with an ethical clinical problem. Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.

[Infantile spinal atrophy: our experience in the last 25 years].

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Madrid Rodríguez, A; Martínez Martínez, P L; Ramos Fernández, J M; Urda Cardona, A; Martínez Antón, J

2015-03-01

To determine the incidence of spinal muscular atrophy (SMA) in our study population and genetic distribution and epidemiological and clinical characteristics and to analyze the level of care and development. Retrospective descriptive study of patients treated in our hospital in the past 25 years (from 1987 to early 2013), with a clinical and neurophysiological diagnosis of SMA. A total of 37 patients were found, representing an incidence for our reference population and year of 1 case per 10,000 live births. Males predominated (male/female ratio: 1.6/1). The type of SMA diagnosed more frequently was, type i (26 cases), followed by type ii (9 cases), one case with SMA type iii, and one case of spinal muscular atrophy with respiratory distress type 1 (SMARD1). The most frequent genetic alteration was homozygous deletion of exons 7 and 8 of SMN1 gene in 31 cases, while five patients had atypical genetics. The median survival for type i was 8.0 months and 15.8 years for type ii. The incidence in our population remains stable at around 1/10.000. Most cases presented with, predominantly male, typical genetics. In approximately 1/10 patients the genetic alteration was different from the classical one to the SMN gene. The prevalence of AME unrelated SMN gene was 1/37. The level of care has increased in line with social and welfare demands in recent years. Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.

Prefrontal involvement related to cognitive impairment in progressive muscular atrophy

NARCIS (Netherlands)

Raaphorst, J.; Tol, M.J. van; Groot, P.F.M.; Altena, E.; Werf, Y.D. van der; Majoie, C.B.; Kooi, A.J. van der; Berg, L.H. van den; Schmand, B.A.; Visser, M de; Veltman, D.J.

2014-01-01

OBJECTIVE: To examine brain activation patterns during verbal fluency performance in patients with progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS). METHODS: fMRI was used to examine the blood oxygen level-dependent response during letter and category fluency performance in

Prefrontal involvement related to cognitive impairment in progressive muscular atrophy

NARCIS (Netherlands)

Raaphorst, Joost; van Tol, Marie-Jose; Groot, Paul F. C.; Altena, Ellemarije; van der Werf, Ysbrand D.; Majoie, Charles B.; van der Kooi, Anneke J.; van den Berg, Leonard H.; Schmand, Ben; de Visser, Marianne; Veltman, Dick J.

2014-01-01

Objective: To examine brain activation patterns during verbal fluency performance in patients with progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS). Methods: fMRI was used to examine the blood oxygen level-dependent response during letter and category fluency performance in

Prefrontal involvement related to cognitive impairment in progressive muscular atrophy

NARCIS (Netherlands)

Raaphorst, Joost; van Tol, Marie-José; Groot, Paul F. C.; Altena, Ellemarije; van der Werf, Ysbrand D.; Majoie, Charles B.; van der Kooi, Anneke J.; van den Berg, Leonard H.; Schmand, Ben; de Visser, Marianne; Veltman, Dick J.

2014-01-01

To examine brain activation patterns during verbal fluency performance in patients with progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS). fMRI was used to examine the blood oxygen level-dependent response during letter and category fluency performance in 18 patients with

Spinal and bulbar muscular atrophy.

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Lieberman, Andrew P

2018-01-01

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset degenerative disorder of the neuromuscular system resulting in slowly progressive weakness and atrophy of the proximal limb and bulbar muscles. The disease is caused by the expansion of a CAG/glutamine tract in the amino-terminus of the androgen receptor. That SBMA exclusively affects males reflects the fact that critical pathogenic events are hormone-dependent. These include translocation of the polyglutamine androgen receptor from the cytoplasm to the nucleus and unfolding of the mutant protein. Studies of the pathology of SBMA subjects have revealed nuclear aggregates of the mutant androgen receptor, loss of lower motor neurons in the brainstem and spinal cord, and both neurogenic and myopathic changes in skeletal muscle. Mechanisms underlying disease pathogenesis include toxicity in both lower motor neurons and skeletal muscle, where effects on transcription, intracellular transport, and mitochondrial function have been documented. Therapies to treat SBMA patients remain largely supportive, although experimental approaches targeting androgen action or promoting degradation of the mutant androgen receptor protein or the encoding RNA are under active study. Copyright © 2018 Elsevier B.V. All rights reserved.

Cross‐disease comparison of amyotrophic lateral sclerosis and spinal muscular atrophy reveals conservation of selective vulnerability but differential neuromuscular junction pathology

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Nijssen, Jik; Frost‐Nylen, Johanna

2015-01-01

Neuromuscular junctions are primary pathological targets in the lethal motor neuron diseases spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). Synaptic pathology and denervation of target muscle fibers has been reported prior to the appearance of clinical symptoms in mouse models of both diseases, suggesting that neuromuscular junctions are highly vulnerable from the very early stages, and are a key target for therapeutic intervention. Here we examined neuromuscular pathology longitudinally in three clinically relevant muscle groups in mouse models of ALS and SMA in order to assess their relative vulnerabilities. We show for the first time that neuromuscular junctions of the extraocular muscles (responsible for the control of eye movement) were resistant to degeneration in endstage SMA mice, as well as in late symptomatic ALS mice. Tongue muscle neuromuscular junctions were also spared in both animal models. Conversely, neuromuscular junctions of the lumbrical muscles of the hind‐paw were vulnerable in both SMA and ALS, with a loss of neuronal innervation and shrinkage of motor endplates in both diseases. Thus, the pattern of selective vulnerability was conserved across these two models of motor neuron disease. However, the first evidence of neuromuscular pathology occurred at different timepoints of disease progression, with much earlier evidence of presynaptic involvement in ALS, progressing to changes on the postsynaptic side. Conversely, in SMA changes appeared concomitantly at the neuromuscular junction, suggesting that mechanisms of neuromuscular disruption are distinct in these diseases. J. Comp. Neurol. 524:1424–1442, 2016. © 2015 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc. PMID:26502195

Spinal Muscular Atrophy

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... most often affected. Complications include scoliosis and joint contractures—chronic shortening of muscles or tendons around joints, ... of SMA include: Congenital SMA with arthrogryposis (persistent contracture of joints with fixed abnormal posture of the ...

Seamless Genetic Conversion of SMN2 to SMN1 via CRISPR/Cpf1 and Single-Stranded Oligodeoxynucleotides in Spinal Muscular Atrophy Patient-Specific Induced Pluripotent Stem Cells.

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Zhou, Miaojin; Hu, Zhiqing; Qiu, Liyan; Zhou, Tao; Feng, Mai; Hu, Qian; Zeng, Baitao; Li, Zhuo; Sun, Qianru; Wu, Yong; Liu, Xionghao; Wu, Lingqian; Liang, Desheng

2018-05-09

Spinal muscular atrophy (SMA) is a kind of neuromuscular disease characterized by progressive motor neuron loss in the spinal cord. It is caused by mutations in the survival motor neuron 1 (SMN1) gene. SMN1 has a paralogous gene, survival motor neuron 2 (SMN2), in humans that is present in almost all SMA patients. The generation and genetic correction of SMA patient-specific induced pluripotent stem cells (iPSCs) is a viable, autologous therapeutic strategy for the disease. Here, c-Myc-free and non-integrating iPSCs were generated from the urine cells of an SMA patient using an episomal iPSC reprogramming vector, and a unique crRNA was designed that does not have similar sequences (≤3 mismatches) anywhere in the human reference genome. In situ gene conversion of the SMN2 gene to an SMN1-like gene in SMA-iPSCs was achieved using CRISPR/Cpf1 and single-stranded oligodeoxynucleotide with a high efficiency of 4/36. Seamlessly gene-converted iPSC lines contained no exogenous sequences and retained a normal karyotype. Significantly, the SMN expression and gems localization were rescued in the gene-converted iPSCs and their derived motor neurons. This is the first report of an efficient gene conversion mediated by Cpf1 homology-directed repair in human cells and may provide a universal gene therapeutic approach for most SMA patients.

Genetic screening of spinal muscular atrophy using a real-time modified COP-PCR technique with dried blood-spot DNA.

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Ar Rochmah, Mawaddah; Harahap, Nur Imma Fatimah; Niba, Emma Tabe Eko; Nakanishi, Kenta; Awano, Hiroyuki; Morioka, Ichiro; Iijima, Kazumoto; Saito, Toshio; Saito, Kayoko; Lai, Poh San; Takeshima, Yasuhiro; Takeuchi, Atsuko; Bouike, Yoshihiro; Okamoto, Maya; Nishio, Hisahide; Shinohara, Masakazu

2017-10-01

Spinal muscular atrophy (SMA) is a common neuromuscular disorder caused by mutations in SMN1. More than 95% of SMA patients carry homozygous SMN1 deletion. SMA is the leading genetic cause of infant death, and has been considered an incurable disease. However, a recent clinical trial with an antisense oligonucleotide drug has shown encouraging clinical efficacy. Thus, early and accurate detection of SMN1 deletion may improve prognosis of many infantile SMA patients. A total of 88 DNA samples (37 SMA patients, 12 carriers and 39 controls) from dried blood spots (DBS) on filter paper were analyzed. All participants had previously been screened for SMN genes by PCR restriction fragment length polymorphism (PCR-RFLP) using DNA extracted from freshly collected blood. DNA was extracted from DBS that had been stored at room temperature (20-25°C) for 1week to 5years. To ensure sufficient quality and quantity of DNA samples, target sequences were pre-amplified by conventional PCR. Real-time modified competitive oligonucleotide priming-PCR (mCOP-PCR) with the pre-amplified PCR products was performed for the gene-specific amplification of SMN1 and SMN2 exon 7. Compared with PCR-RFLP using DNA from freshly collected blood, results from real-time mCOP-PCR using DBS-DNA for detection of SMN1 exon 7 deletion showed a sensitivity of 1.00 (CI [0.87, 1.00])] and specificity of 1.00 (CI [0.90, 1.00]), respectively. We combined DNA extraction from DBS on filter paper, pre-amplification of target DNA, and real-time mCOP-PCR to specifically detect SMN1 and SMN2 genes, thereby establishing a rapid, accurate, and high-throughput system for detecting SMN1-deletion with practical applications for newborn screening. Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Head and Arm Tremor in X-linked Spinal and Bulbar Muscular Atrophy

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Irene Aicua

2014-10-01

Full Text Available Background: X‐linked spinal and bulbar muscular atrophy (SBMA is a rare adult‐onset neuronopathy. Although tremor is known to occur in this disease, the number of reported cases of SBMA with tremor is rare, and the number with videotaped documentation is exceedingly rare. Our aim was to describe/document the characteristic signs of tremor in spinal and bulbar muscular atrophy.Case Report: We report a case of a 58‐year‐old male with a positive family history of tremor. On examination, the patient had jaw and hand tremors but he also exhibited gynecomastia, progressive bulbar paresis, and wasting and weakness primarily in the proximal limb muscles. The laboratory tests revealed an elevated creatine phosphokinase. Genetic testing was positive for X‐SBMA, with 42 CAG repeats.Discussion: Essential tremor is one of the most common movement disorders, yet it is important for clinicians to be aware of the presence of other distinguishing features that point to alternative diagnoses. The presence of action tremor associated with muscle atrophy and gynecomastia should lead to a suspicion of SBMA.

Imaging Flow Cytometry Analysis to Identify Differences of Survival Motor Neuron Protein Expression in Patients With Spinal Muscular Atrophy.

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Arakawa, Reiko; Arakawa, Masayuki; Kaneko, Kaori; Otsuki, Noriko; Aoki, Ryoko; Saito, Kayoko

2016-08-01

Spinal muscular atrophy is a neurodegenerative disorder caused by the deficient expression of survival motor neuron protein in motor neurons. A major goal of disease-modifying therapy is to increase survival motor neuron expression. Changes in survival motor neuron protein expression can be monitored via peripheral blood cells in patients; therefore we tested the sensitivity and utility of imaging flow cytometry for this purpose. After the immortalization of peripheral blood lymphocytes from a human healthy control subject and two patients with spinal muscular atrophy type 1 with two and three copies of SMN2 gene, respectively, we used imaging flow cytometry analysis to identify significant differences in survival motor neuron expression. A bright detail intensity analysis was used to investigate differences in the cellular localization of survival motor neuron protein. Survival motor neuron expression was significantly decreased in cells derived from patients with spinal muscular atrophy relative to those derived from a healthy control subject. Moreover, survival motor neuron expression correlated with the clinical severity of spinal muscular atrophy according to SMN2 copy number. The cellular accumulation of survival motor neuron protein was also significantly decreased in cells derived from patients with spinal muscular atrophy relative to those derived from a healthy control subject. The benefits of imaging flow cytometry for peripheral blood analysis include its capacities for analyzing heterogeneous cell populations; visualizing cell morphology; and evaluating the accumulation, localization, and expression of a target protein. Imaging flow cytometry analysis should be implemented in future studies to optimize its application as a tool for spinal muscular atrophy clinical trials. Copyright © 2016 Elsevier Inc. All rights reserved.

Klinefelter′s syndrome associated with progressive muscular atrophy simulating Kennedy′s disease

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Pedro Enrique Jiménez Caballero

2012-01-01

Kennedy's disease, an X-linked spinal and bulbar muscular atrophy, is characterized by loss of lower motor neurons. Mild sensory deficits, gynecomastia and infertility may be observed. Klinefelter's syndrome is a variation of sex chromosome disorder characterized by hypogonadism, gynecomastia and azoospermia, and the most frequent karyotype is XXY. A 55-year-old man who presented with slowly progressive and diffuse neurogenic muscle atrophy without bulbar or sensory symptoms. He also had Klin...

The spinal muscular atrophy with pontocerebellar hypoplasia gene VRK1 regulates neuronal migration through an amyloid-β precursor protein-dependent mechanism.

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Vinograd-Byk, Hadar; Sapir, Tamar; Cantarero, Lara; Lazo, Pedro A; Zeligson, Sharon; Lev, Dorit; Lerman-Sagie, Tally; Renbaum, Paul; Reiner, Orly; Levy-Lahad, Ephrat

2015-01-21

Spinal muscular atrophy with pontocerebellar hypoplasia (SMA-PCH) is an infantile SMA variant with additional manifestations, particularly severe microcephaly. We previously identified a nonsense mutation in Vaccinia-related kinase 1 (VRK1), R358X, as a cause of SMA-PCH. VRK1-R358X is a rare founder mutation in Ashkenazi Jews, and additional mutations in patients of different origins have recently been identified. VRK1 is a nuclear serine/threonine protein kinase known to play multiple roles in cellular proliferation, cell cycle regulation, and carcinogenesis. However, VRK1 was not known to have neuronal functions before its identification as a gene mutated in SMA-PCH. Here we show that VRK1-R358X homozygosity results in lack of VRK1 protein, and demonstrate a role for VRK1 in neuronal migration and neuronal stem cell proliferation. Using shRNA in utero electroporation in mice, we show that Vrk1 knockdown significantly impairs cortical neuronal migration, and affects the cell cycle of neuronal progenitors. Expression of wild-type human VRK1 rescues both proliferation and migration phenotypes. However, kinase-dead human VRK1 rescues only the migration impairment, suggesting the role of VRK1 in neuronal migration is partly noncatalytic. Furthermore, we found that VRK1 deficiency in human and mouse leads to downregulation of amyloid-β precursor protein (APP), a known neuronal migration gene. APP overexpression rescues the phenotype caused by Vrk1 knockdown, suggesting that VRK1 affects neuronal migration through an APP-dependent mechanism. Copyright © 2015 the authors 0270-6474/15/350936-08$15.00/0.

Improvement of neuromuscular synaptic phenotypes without enhanced survival and motor function in severe spinal muscular atrophy mice selectively rescued in motor neurons.

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Ximena Paez-Colasante

Full Text Available In the inherited childhood neuromuscular disease spinal muscular atrophy (SMA, lower motor neuron death and severe muscle weakness result from the reduction of the ubiquitously expressed protein survival of motor neuron (SMN. Although SMA mice recapitulate many features of the human disease, it has remained unclear if their short lifespan and motor weakness are primarily due to cell-autonomous defects in motor neurons. Using Hb9(Cre as a driver, we selectively raised SMN expression in motor neurons in conditional SMAΔ7 mice. Unlike a previous study that used choline acetyltransferase (ChAT(Cre+ as a driver on the same mice, and another report that used Hb9(Cre as a driver on a different line of conditional SMA mice, we found no improvement in survival, weight, motor behavior and presynaptic neurofilament accumulation. However, like in ChAT(Cre+ mice, we detected rescue of endplate size and mitigation of neuromuscular junction (NMJ denervation status. The rescue of endplate size occurred in the absence of an increase in myofiber size, suggesting endplate size is determined by the motor neuron in these animals. Real time-PCR showed that the expression of spinal cord SMN transcript was sharply reduced in Hb9(Cre+ SMA mice relative to ChAT(Cre+ SMA mice. This suggests that our lack of overall phenotypic improvement is most likely due to an unexpectedly poor recombination efficiency driven by Hb9(Cre . Nonetheless, the low levels of SMN were sufficient to rescue two NMJ structural parameters indicating that these motor neuron cell autonomous phenotypes are very sensitive to changes in motoneuronal SMN levels. Our results directly suggest that even those therapeutic interventions with very modest effects in raising SMN in motor neurons may provide mitigation of neuromuscular phenotypes in SMA patients.

Spinal Muscular Atrophy (SMA)

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... age 3 or so, depending on the child’s maturity and general outlook. Many professionals have observed that ... mak- ing it hard to smile or convey emotion through facial expressions. SBMA is like other forms ...

New, Improved Version of the mCOP-PCR Screening System for Detection of Spinal Muscular Atrophy Gene (SMN1) Deletion.

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Shinohara, Masakazu; Ar Rochmah, Mawaddah; Nakanishi, Kenta; Harahap, Nur Imma Fatimah; Niba, Emma Tabe Eko; Saito, Toshio; Saito, Kayoko; Takeuchi, Atsuko; Bouike, Yoshihiro; Nishio, Hisahide

2017-09-07

Spinal muscular atrophy (SMA) is a frequent autosomal recessive disorder, characterized by lower motor neuron loss in the spinal cord. More than 95% of SMA patients show homozygous survival motor neuron 1 (SMN1) deletion. We previously developed a screening system for SMN1 deletion based on a modified competitive oligonucleotide priming-PCR (mCOP-PCR) technique. However, non-specific amplification products were observed with mCOP-PCR, which might lead to erroneous interpretation of the screening results. To establish an improved version of the mCOP-PCR screening system without non-specific amplification. DNA samples were assayed using a new version of the mCOP-PCR screening system. DNA samples had already been genotyped by PCR-restriction fragment length polymorphism (PCR-RFLP), showing the presence or absence of SMN1 exon 7. The new mCOP-PCR method contained a targeted pre-amplification step of the region, including an SMN1-specific nucleotide, prior to the mCOP-PCR step. mCOP-PCR products were electrophoresed on agarose gels. No non-specific amplification products were detected in electrophoresis gels with the new mCOP-PCR screening system. An additional targeted pre-amplification step eliminated non-specific amplification from mCOP-PCR screening.

Spinal muscular atrophy type I and the dual role of viruses: An interview with Professor Basil T. Darras, Professor of Neurology (Pediatrics) at Harvard Medical School.

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Mammas, Ioannis N; Spandidos, Demetrios A

2018-04-01

According to Professor Basil T. Darras, Professor of Neurology (Pediatrics) at Harvard Medical School and Director of the Spinal Muscular Atrophy (SMA) Program at Boston Children's Hospital in Boston (MA, USA), the diagnosis of SMA type I is clinical and is based on detailed general physical and neurological examinations. SMA type I remains the most common genetic disease resulting in death in infancy and is really devastating for the child, the parents, as well as the medical professionals with the privilege of caring for patients with SMA and their parents. The proposed management options include: i) no respiratory support; ii) non-invasive ventilation; and iii) tracheotomy with mechanical ventilation. Deciding, which option is the best, is indeed a very personal decision. The optimal clinical care should be extremely mindful of parents' wishes and management goals with regard to the quality of life. Since the end of 2016 in the USA, and recently in Europe, there exists the possibility of accessing a novel treatment drug for SMA, namely Nusinersen. This antisense oligonucleotide is administered intrathecally and increases the production of the fully functional SMN protein, thus improving motor function, the quality of life and survival. Among the ongoing clinical trials, oral treatment with RG7916, a small molecule SMN2 splicing modifier, appears to be really promising. Gene therapy using viral vectors is expected to offer an 'one and done' therapy and possibly a cure, if administered early in life, before any symptoms appear. It is really interesting that viruses, which at the moment are the cause of death of children with SMA, if genetically modified, may be used for their treatment.

High-resolution melting (HRM) analysis as a feasible method for detecting spinal muscular atrophy via dried blood spots.

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Er, Tze-Kiong; Kan, Tzu-Min; Su, Yu-Fa; Liu, Ta-Chih; Chang, Jan-Gowth; Hung, Shih-Ya; Jong, Yuh-Jyh

2012-11-12

Spinal muscular atrophy (SMA) is a neurodegenerative disease with the leading genetic cause of infant mortality. More than 95% of patients with SMA have a homozygous disruption in the survival motor neuron1 (SMN1) gene, caused by mutation, deletion, or rearrangement. Recently, treatment in humans in the immediate postnatal period, prior to the development of weakness or very early in the course of the disease, may be effective. Therefore, our objective was to establish a feasible method for SMA screening. High-resolution melting (HRM) analysis is rapidly becoming the most important mutation-scanning methodology that allows mutation scanning and genotyping without the need for costly labeled oligonucleotides. In the current study, we aim to develop a method for identifying the substitution of single nucleotide in SMN1 exon 7 (c.840C>T) by HRM analysis. Genomic DNA was extracted from peripheral blood samples and dried blood spots obtained from 30 patients with SMA and 30 normal individuals. All results were previously confirmed by denaturing high-performance liquid chromatography (DHPLC). In order to identify the substitution of single nucleotide in SMN1 exon 7 (c.840C>T) by HRM analysis, a primer set was used in HRM analysis. At first, we failed to identify the substitution of single nucleotide in SMN1 exon 7 (c.840C>T) by HRM analysis because the homozygous CC and homozygous TT cannot be distinguished by HRM analysis. Therefore, all samples were mixed with a known SMN1/SMN2 copy number (SMN1/SMN2=0:3), which we may call driver. This strategy is used to differentiate between homozygous CC and homozygous TT. After mixing with driver, the melting profile of homozygous CC becomes heteroduplex; however, the homozygous TT remains the same in the normalized and temperature-shifted difference plots. HRM analysis can be successfully applied to screen SMA via DNA obtained from whole blood and dried blood spots. We strongly believe that HRM analysis, a high-throughput method

Gene therapy for spinomuscular atrophy: a biomedical advance, a missed opportunity for more equitable drug pricing.

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Friedmann, T

2017-09-01

An experimental approach for gene therapy of spinomuscular atrophy has been reported to prevent development of the neuromuscular features of this lethal and previously untreatable disorder. The approach involves treatment of patients suffering from SMN1-associated infantile form of the disease with a splice-switching antisense oligonucleotide (ASO) that corrects aberrant splicing of the nearly identical SMN2 gene to allow the generation of functional SMN protein, thereby mitigating the development of the disease. This technique represents the first apparently effective therapy for spinal muscular atrophy (SMA) and an important documentation for ASO technology for therapy of neurodegenerative disease. These results with one form of SMA are likely to be relevant for similar applications to other SMA types and are likely to inspire application to a number of other intractable neurodegenerative diseases such as Huntington's disease, amyotrophic lateral sclerosis and possibly even the extremely common Parkinson's and Alzheimer's diseases and others. Nevertheless, the scientific and medical importance of this advance is marred by a pricing policy by the corporate sponsors that may complicate accessibility of the drug for some desperate patients.

Automated analysis of whole skeletal muscle for muscular atrophy detection of ALS in whole-body CT images: preliminary study

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Kamiya, Naoki; Ieda, Kosuke; Zhou, Xiangrong; Yamada, Megumi; Kato, Hiroki; Muramatsu, Chisako; Hara, Takeshi; Miyoshi, Toshiharu; Inuzuka, Takashi; Matsuo, Masayuki; Fujita, Hiroshi

2017-03-01

Amyotrophic lateral sclerosis (ALS) causes functional disorders such as difficulty in breathing and swallowing through the atrophy of voluntary muscles. ALS in its early stages is difficult to diagnose because of the difficulty in differentiating it from other muscular diseases. In addition, image inspection methods for aggressive diagnosis for ALS have not yet been established. The purpose of this study is to develop an automatic analysis system of the whole skeletal muscle to support the early differential diagnosis of ALS using whole-body CT images. In this study, the muscular atrophy parts including ALS patients are automatically identified by recognizing and segmenting whole skeletal muscle in the preliminary steps. First, the skeleton is identified by its gray value information. Second, the initial area of the body cavity is recognized by the deformation of the thoracic cavity based on the anatomical segmented skeleton. Third, the abdominal cavity boundary is recognized using ABM for precisely recognizing the body cavity. The body cavity is precisely recognized by non-rigid registration method based on the reference points of the abdominal cavity boundary. Fourth, the whole skeletal muscle is recognized by excluding the skeleton, the body cavity, and the subcutaneous fat. Additionally, the areas of muscular atrophy including ALS patients are automatically identified by comparison of the muscle mass. The experiments were carried out for ten cases with abnormality in the skeletal muscle. Global recognition and segmentation of the whole skeletal muscle were well realized in eight cases. Moreover, the areas of muscular atrophy including ALS patients were well identified in the lower limbs. As a result, this study indicated the basic technology to detect the muscle atrophy including ALS. In the future, it will be necessary to consider methods to differentiate other kinds of muscular atrophy as well as the clinical application of this detection method for early ALS

Electromyographic and computed tomographic findings in five patients with monomelic spinal muscular atrophy

NARCIS (Netherlands)

de Visser, M.; Ongerboer de Visser, B. W.; Verbeeten, B.

1988-01-01

Five patients with monomelic spinal muscular atrophy are described. Clinical features included insidious onset of wasting and weakness of one limb, lack of involvement of the cranial nerves, brain stem, pyramidal tracts and sensory system, and a stable condition over a period of 4-20 years. Clinical

Effect of aerobic training in patients with spinal and bulbar muscular atrophy (Kennedy disease)

DEFF Research Database (Denmark)

Preisler, N; Andersen, G; Thøgersen, F

2009-01-01

) or any of the other variables examined before and after training, and the patients with SBMA did not feel improvements in ADL. CONCLUSIONS: Frequent, moderate-intensity aerobic conditioning is of little beneficial effect in patients with spinal and bulbar muscular atrophy (SBMA). High levels of plasma......OBJECTIVE: We examined the effect of aerobic exercise in patients with spinal and bulbar muscular atrophy (SBMA). SBMA is caused by a defect androgen receptor. This defect causes motor neuron death, but considering the important function of androgens in muscle, it is possible that muscle damage...... measurements, lung function, plasma proteins, and hormones were evaluated before and after training. Evaluation of improvements in activities of daily living (ADL) was conducted after training. RESULTS: W(max) increased by 18%, and CS activity increased by 35%. There was no significant change in Vo(2max...

Spliceosome integrity is defective in the motor neuron diseases ALS and SMA

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Tsuiji, Hitomi; Iguchi, Yohei; Furuya, Asako; Kataoka, Ayane; Hatsuta, Hiroyuki; Atsuta, Naoki; Tanaka, Fumiaki; Hashizume, Yoshio; Akatsu, Hiroyasu; Murayama, Shigeo; Sobue, Gen; Yamanaka, Koji

2013-01-01

Two motor neuron diseases, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are caused by distinct genes involved in RNA metabolism, TDP-43 and FUS/TLS, and SMN, respectively. However, whether there is a shared defective mechanism in RNA metabolism common to these two diseases remains unclear. Here, we show that TDP-43 and FUS/TLS localize in nuclear Gems through an association with SMN, and that all three proteins function in spliceosome maintenance. We also show that in ALS, Gems are lost, U snRNA levels are up-regulated and spliceosomal U snRNPs abnormally and extensively accumulate in motor neuron nuclei, but not in the temporal lobe of FTLD with TDP-43 pathology. This aberrant accumulation of U snRNAs in ALS motor neurons is in direct contrast to SMA motor neurons, which show reduced amounts of U snRNAs, while both have defects in the spliceosome. These findings indicate that a profound loss of spliceosome integrity is a critical mechanism common to neurodegeneration in ALS and SMA, and may explain cell-type specific vulnerability of motor neurons. PMID:23255347

Exercise Therapy in Spinobulbar Muscular Atrophy and Other Neuromuscular Disorders

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Dahlqvist, Julia Rebecka; Vissing, John

2016-01-01

There is no curative treatment for most neuromuscular disorders. Exercise, as a treatment for these diseases, has therefore received growing attention. When executed properly, exercise can maintain and improve health and reduce the risk of cardiovascular disease, obesity, and diabetes. In persons...... in patients with neuromuscular diseases associated with weakness and wasting. We review studies that have investigated different types of exercise in both myopathies and motor neuron diseases, with particular emphasis on training of persons affected by spinobulbar muscular atrophy (SBMA). Finally, we provide...

Management of neuromuscular diseases and spinal muscular atrophy in Latin America.

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Monges, S; Rosa, A L

2017-09-01

Latin America (LA) has a population of ~645 million people distributed over 33 countries with marked political, cultural and economic differences. In LA, patients with inherited neuromuscular diseases (NMDs) often do not have access to specialized medical centers and many of them go undiagnosed. General management and care of spinal muscular dystrophy (SMA) patients in the region varies due to heterogeneous health care. An active generation of young clinical neurologists is being trained for the specialized care of SMA and other neuromuscular (NM) patients, both in the private and public sectors. The Euro-Latin-American Summer School of Myology (EVELAM) as well as efforts of professionals at large public centers in the major cities of LA have a leading role in this development. Different regional academic-scientific organizations as well as the expanding number of telethon centers and the creation of parent organizations, mostly concerning SMA, all together are contributing to the increased quality of the management of NMD patients. Over the past years, academic and clinical research, as well as the establishment of qualified centers for the molecular testing of NMD are pushing forward the creation of patient registries and the development of specific clinical trials, with Argentina and Brazil having a major role in this field. Nevertheless, increased awareness and further training of specialized health professionals are necessary to reach patients that are currently lacking care throughout the region.

Klinefelter′s syndrome associated with progressive muscular atrophy simulating Kennedy′s disease

Directory of Open Access Journals (Sweden)

Pedro Enrique Jiménez Caballero

2012-01-01

Full Text Available Kennedy′s disease, an X-linked spinal and bulbar muscular atrophy, is characterized by loss of lower motor neurons. Mild sensory deficits, gynecomastia and infertility may be observed. Klinefelter′s syndrome is a variation of sex chromosome disorder characterized by hypogonadism, gynecomastia and azoospermia, and the most frequent karyotype is XXY. A 55-year-old man who presented with slowly progressive and diffuse neurogenic muscle atrophy without bulbar or sensory symptoms. He also had Klinefelter′s syndrome. Genetic study of Kennedy′s disease was normal. Our patient differs from those with Kennedy′s disease in the absence of bulbar and sensory symptoms. It is suggested that the X chromosome plays an important role in the biology of motor neurons.

Phenotypic and genotypic studies of ALS cases in ALS-SMA families.

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Corcia, Philippe; Vourc'h, Patrick; Blasco, Helene; Couratier, Philippe; Dangoumau, Audrey; Bellance, Remi; Desnuelle, Claude; Viader, Fausto; Pautot, Vivien; Millecamps, Stephanie; Bakkouche, Salah; Salachas, FranÇois; Andres, Christian R; Meininger, Vincent; Camu, William

2018-03-01

Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are the most frequent motor neuron disorders in adulthood and infancy, respectively. There is a growing literature supporting common pathophysiological patterns between those disorders. One important clinical issue for that is the co-occurrence of both diseases within a family. To collect families in which ALS and SMA patients co-exist and describe the phenotype and the genotype of ALS patients. Nine families with co-occurrence of SMA and ALS have been gathered over the last 15 years. Epidemiological, phenotype and genetic status were collected. Out of the nine families, six corresponded to the criteria of familial ALS (FALS). Clinical data were available for 11 patients out of the 15 ALS cases. Mean age of onset was 58.5 years, site of onset was lower limbs in nine cases (81.8%), median duration was 22 months. Four ALS patients carried a mutation: three mutations in SOD1 gene (G147N in two cases and one with E121G) and one repeat expansion in the C9ORF72 gene. Three patients had abnormal SMN1 copy numbers. While the high proportion of familial history of ALS cases in these ALS-SMA pedigrees could have suggested that these familial clusters of the two most frequent MND rely on a genetic background, we failed to exclude that this occurred by chance.

Mitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy-like disease.

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Boczonadi, Veronika; King, Martin S; Smith, Anthony C; Olahova, Monika; Bansagi, Boglarka; Roos, Andreas; Eyassu, Filmon; Borchers, Christoph; Ramesh, Venkateswaran; Lochmüller, Hanns; Polvikoski, Tuomo; Whittaker, Roger G; Pyle, Angela; Griffin, Helen; Taylor, Robert W; Chinnery, Patrick F; Robinson, Alan J; Kunji, Edmund R S; Horvath, Rita

2018-03-08

PurposeTo understand the role of the mitochondrial oxodicarboxylate carrier (SLC25A21) in the development of spinal muscular atrophy-like disease.MethodsWe identified a novel pathogenic variant in a patient by whole-exome sequencing. The pathogenicity of the mutation was studied by transport assays, computer modeling, followed by targeted metabolic testing and in vitro studies in human fibroblasts and neurons.ResultsThe patient carries a homozygous pathogenic variant c.695A>G; p.(Lys232Arg) in the SLC25A21 gene, encoding the mitochondrial oxodicarboxylate carrier, and developed spinal muscular atrophy and mitochondrial myopathy. Transport assays show that the mutation renders SLC25A21 dysfunctional and 2-oxoadipate cannot be imported into the mitochondrial matrix. Computer models of central metabolism predicted that impaired transport of oxodicarboxylate disrupts the pathways of lysine and tryptophan degradation, and causes accumulation of 2-oxoadipate, pipecolic acid, and quinolinic acid, which was confirmed in the patient's urine by targeted metabolomics. Exposure to 2-oxoadipate and quinolinic acid decreased the level of mitochondrial complexes in neuronal cells (SH-SY5Y) and induced apoptosis.ConclusionMitochondrial oxodicarboxylate carrier deficiency leads to mitochondrial dysfunction and the accumulation of oxoadipate and quinolinic acid, which in turn cause toxicity in spinal motor neurons leading to spinal muscular atrophy-like disease.GENETICS in MEDICINE advance online publication, 8 March 2018; doi:10.1038/gim.2017.251.

Neuropathology and Therapeutic Intervention in Spinal and Bulbar Muscular Atrophy

Directory of Open Access Journals (Sweden)

Haruhiko Banno

2009-03-01

Full Text Available Spinal and bulbar muscular atrophy (SBMA is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR. The histopathological finding in SBMA is loss of lower motor neurons in the anterior horn of the spinal cord as well as in the brainstem motor nuclei. Animal studies have revealed that the pathogenesis of SBMA depends on the level of serum testosterone, and that androgen deprivation mitigates neurodegeneration through inhibition of nuclear accumulation of the pathogenic AR. Heat shock proteins, ubiquitin-proteasome system and transcriptional regulation are also potential targets of therapy development for SBMA.

Prefrontal involvement related to cognitive impairment in progressive muscular atrophy.

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Raaphorst, Joost; van Tol, Marie-José; Groot, Paul F C; Altena, Ellemarije; van der Werf, Ysbrand D; Majoie, Charles B; van der Kooi, Anneke J; van den Berg, Leonard H; Schmand, Ben; de Visser, Marianne; Veltman, Dick J

2014-08-26

To examine brain activation patterns during verbal fluency performance in patients with progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS). fMRI was used to examine the blood oxygen level-dependent response during letter and category fluency performance in 18 patients with PMA, 21 patients with ALS, and 17 healthy control subjects, matched for age and education. fMRI results are reported at pfrontal gyrus (IFG, Brodmann area 45) during letter fluency, which was unaffected by performance, ARWMC, and IFG volume: patients with PMA showed lower activation than controls but higher than that of patients with ALS (ALSupper motor neuron signs. © 2014 American Academy of Neurology.

Pathogenesis-targeting therapeutics for spinal and bulbar muscular atrophy (SBMA).

Science.gov (United States)

Suzuki, Keisuke; Kastuno, Masahisa; Banno, Haruhiko; Sobue, Gen

2009-08-01

Spinal and bulbar muscular atrophy (SBMA) is an hereditary, adult-onset, lower motor neuron disease caused by an aberrant elongation of a trinucleotide CAG repeat, which encodes the polyglutamine tract, in the first exon of the androgen receptor (AR) gene. The main symptoms are slowly progressive muscle weakness and atrophy of bulbar, facial and limb muscles. The cardinal histopathological findings of SBMA are an extensive loss of lower motor neurons in the anterior horn of the spinal cord as well as in brainstem motor nuclei and intranuclear accumulations of mutant AR protein in the residual motor neurons. Androgen deprivation therapy rescues neuronal dysfunction in animal models of SBMA, suggesting that the molecular basis for motor neuron degeneration in this disorder is testosterone-dependent nuclear accumulation of the mutant AR. Suppression of disease progression by leuprorelin acetate has also been demonstrated in a phase 2 clinical trial. In addition, the clarification of pathophysiology leads to appearance of candidate drugs to treat this devastating disease: heat shock protein (HSP) inducer, Hsp90 inhibitor, and histone deacetylase inhibitor. Advances in basic and clinical research on SBMA are now paving the way for clinical application of pathogenesis-targeting therapeutics.

Spinal Muscular Atrophy, types I and II: What are the differences in body composition and resting energy expenditure?

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Bertoli, Simona; De Amicis, Ramona; Mastella, Chiara; Pieri, Giulia; Giaquinto, Ester; Battezzati, Alberto; Leone, Alessandro; Baranello, Giovanni

2017-12-01

Different neuromuscular functional domains in types I and II Spinal Muscular Atrophy (SMAI and SMAII) could lead to differences in body composition (BC) and resting energy expenditure (REE). Their identification could provide the key to defining appropriate strategies in clinical dietary management, but data comparing SMAI and SMAII in terms of BC and REE are not yet available. We measured total and regional fat (FM), lean (LBM), mineral (BMC) masses, body water (total, intra- and extra-cellular, TBW, ICW, ECW) and REE in a sample of SMAI and II children, matched for age and sex, and also adjusting for body size to compare these features of the two SMA phenotypes. 15 SMAI and 15 SMAII children, (M/F = 9/6 vs 9/6, age 3.6 ± 1.9 vs 3.5 ± 1.8 years, p = 0.99), confirmed genetically, were measured as follows: Anthropometric measurements [Body Weight (BW), Supine Length (SL), Arm Length (AL), Femur Length (FL), Tibia Length (TL)], Dual x-ray Energy Absorptiometry (DEXA) [total and segmental FM, LBM, FFM, and BMC], Bioelectrical impedance (BIA) [TBW, ICW, ECW] and Indirect Calorimetry (REE, respiratory quotients) were collected by the same trained dietician. BW, SL and Body Mass Index (BMI) Z-scores were calculated according to CDC Growth Charts (2000). SMA children had high percentages of FM and a lower percentage of TBW and ECW compared to the respective reference values for sex and age, whereas the BMC percentages did not differ, even splitting the two phenotypes. SMA I children had a lower BW and BMI-Z score compared to children with SMA II, but similar total and segmental FM. On the contrary, total FFM and LBM were significantly lower in SMAI (7290.0 ± 1729.1 g vs 8410.1 ± 1508.4 g; 6971.8 ± 1637.1 g vs 8041.7 ± 1427.7 g, p = 0.039, p = 0.037, respectively), particularly at the trunk level. Arm BMC also resulted significantly lower in SMAI. The measured REE values were similar (684 ± 143 kcal/day vs 703 ± 122 Kcal/day p = 0

Anti‐Ma2 associated paraneoplastic neurological syndrome presenting as encephalitis and progressive muscular atrophy

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Waragai, M; Chiba, A; Uchibori, A; Fukushima, T; Anno, M; Tanaka, K

2006-01-01

A 36 year old man with a history of testicular germ cell tumour presented six months after bilateral orchidectomy with progressive amnesia, irritability, vertical gaze palsy, and generalised seizures. Eight months after initial onset of symptoms, he demonstrated a head drop with muscular atrophy of the upper limbs, shoulder girdle, and posterior neck. He reported no sensory disturbances and his sensory examination was normal. The overall clinical presentation was consistent with motor neurone disease. Cerebrospinal fluid analysis revealed mild pleocytosis and increased protein concentration. Serum and cerebrospinal fluid were positive for the anti‐Ma2 antibody by western blot analysis and immunostaining. Abnormal high signal in the grey matter was noted in the cervical spinal cord and brain by T2 weighted magnetic resonance imaging (MRI). The patient was treated with corticosteroids, intravenous immunoglobulin, and antiepileptic medication. The patient improved clinically and symptom progression ceased after initiation of treatment. There was complete resolution of the abnormal brain MRI lesions; however, the cervical spinal cord MRI lesion and muscular atrophy remained unchanged. It is suggested that the anti‐Ma2 antibody is involved not only in encephalitis, but may also play a role in the cervical spinal cord lesions resulting in a motor neurone disease‐like presentation. PMID:16361608

Anti-Ma2 associated paraneoplastic neurological syndrome presenting as encephalitis and progressive muscular atrophy.

Science.gov (United States)

Waragai, M; Chiba, A; Uchibori, A; Fukushima, T; Anno, M; Tanaka, K

2006-01-01

A 36 year old man with a history of testicular germ cell tumour presented six months after bilateral orchidectomy with progressive amnesia, irritability, vertical gaze palsy, and generalised seizures. Eight months after initial onset of symptoms, he demonstrated a head drop with muscular atrophy of the upper limbs, shoulder girdle, and posterior neck. He reported no sensory disturbances and his sensory examination was normal. The overall clinical presentation was consistent with motor neurone disease. Cerebrospinal fluid analysis revealed mild pleocytosis and increased protein concentration. Serum and cerebrospinal fluid were positive for the anti-Ma2 antibody by western blot analysis and immunostaining. Abnormal high signal in the grey matter was noted in the cervical spinal cord and brain by T2 weighted magnetic resonance imaging (MRI). The patient was treated with corticosteroids, intravenous immunoglobulin, and antiepileptic medication. The patient improved clinically and symptom progression ceased after initiation of treatment. There was complete resolution of the abnormal brain MRI lesions; however, the cervical spinal cord MRI lesion and muscular atrophy remained unchanged. It is suggested that the anti-Ma2 antibody is involved not only in encephalitis, but may also play a role in the cervical spinal cord lesions resulting in a motor neurone disease-like presentation.

Cure SMA

Science.gov (United States)

... 2, 2017 New Clinical Trial Data Published in New England Journal of Medicine Two new papers of clinical trial data for spinal muscular atrophy were published today in the November issue of the New England Journal of... READ MORE October 25, 2017 Fall 2017 ...

Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics.

Science.gov (United States)

Finkel, Richard S; Mercuri, Eugenio; Meyer, Oscar H; Simonds, Anita K; Schroth, Mary K; Graham, Robert J; Kirschner, Janbernd; Iannaccone, Susan T; Crawford, Thomas O; Woods, Simon; Muntoni, Francesco; Wirth, Brunhilde; Montes, Jacqueline; Main, Marion; Mazzone, Elena S; Vitale, Michael; Snyder, Brian; Quijano-Roy, Susana; Bertini, Enrico; Davis, Rebecca Hurst; Qian, Ying; Sejersen, Thomas

2018-03-01

This is the second half of a two-part document updating the standard of care recommendations for spinal muscular atrophy published in 2007. This part includes updated recommendations on pulmonary management and acute care issues, and topics that have emerged in the last few years such as other organ involvement in the severe forms of spinal muscular atrophy and the role of medications. Ethical issues and the choice of palliative versus supportive care are also addressed. These recommendations are becoming increasingly relevant given recent clinical trials and the prospect that commercially available therapies will likely change the survival and natural history of this disease. Copyright © 2017. Published by Elsevier B.V.

The diagnosis of a fully flexed neck position MRI diagnosis in juvenile muscular atrophy of the distal upper extremity

International Nuclear Information System (INIS)

Liu Huaijun; Li Caiying; He Dan; Chi Chen; Cui Caixia; Huang Boyuan; Wang Guoshi; Zhu Qingfeng

2006-01-01

Objective: To investigate the value of the diagnosis of MRI during neck flexion in juvenile muscular atrophy of the distal upper extremity. Methods: Five young male patients (mean age 21 years old) with clinical and electrophysiological alterations were performed MR examination with routine neck position and a fully flexed neck position. Eight age-match young men were examined as control subjects. SE T 1 WI, T 2 WI, Fluid-attenuated inversion recovery (FLAIR) sequences were scanned. Results: A distinctive finding in the disorder was forward displacement of the cervical dural sac, compressive flattening of the lower cervical cord during neck flexion and flow void in the posterior epidural space. The forward displacement was significantly greater in patients than in age-matched control subjects. Conclusion: Flexed neck position MRI is helpful to find radiological abnormalities of the lower cervical dural sac and spinal cord, which were combined with clinical disorder to diagnose juvenile muscular atrophy of the distal upper extremity. (authors)

Synergic prodegradative activity of Bicalutamide and trehalose on the mutant androgen receptor responsible for spinal and bulbar muscular atrophy

NARCIS (Netherlands)

Giorgetti, Elise; Rusmini, Paola; Crippa, Valeria; Cristofani, Riccardo; Boncoraglio, Alessandra; Cicardi, Maria E.; Galbiati, Mariarita; Poletti, Angelo

2015-01-01

Spinal and bulbar muscular atrophy (SBMA) is an X-linked motoneuron disease due to a CAG triplet-repeat expansion in the androgen receptor (AR) gene, which is translated into an elongated polyglutamine (polyQ) tract in AR protein (ARpolyQ). ARpolyQ toxicity is activated by the AR ligand testosterone

X-linked lethal infantile spinal muscular atrophy: From clinical description to molecular mapping

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Baumbach, L.; Schiavi, A. [Univ. of Miami, FL (United States)] [and others

1994-09-01

The proximal spinal muscular atrophies (PSMA), one of the most common forms of lower motor neuron disease in children, are characterized by progressive muscle weakness due to loss of anterior horn cells. All three autosomal recessive forms have been mapped to chromosome 5q11.2-11.3, implying an allelic association between these disorders. Recent evidence from our laboratories, as well as others, suggests that a distinct form of lethal neonatal spinal muscular atrophy, associated with early onset contractures, is determined by a gene on the X chromosome. We report our efforts in mapping this disease locus. Our original studies have focused on two unrelated multigenerational families with similar clinical presentations of severe hypotonia, muscle weakness, and a disease course similar to Werdnig Hoffman except for the additional finding of congenital or early onset contractures. Muscle biopsy and/or autopsy were indicative of anterior horn cell loss in affected males. Disease occurrence in each of the families was consistent with an X-linked recessive mode of inheritance. Subsequently, two additional families have been identified, as well as several sporadic male cases. Linkage analysis has been completed in one of these families using highly polymorphic repeats dispersed 10 cM on the X chromosome. Interpretation of results was achieved using an automated data acquisition program. Analysis of over 300 haplotypes generated using PCR-based DNA markers have identified two 16 cM regions on Xp with complete concordance to the disease phenotype. Our currents efforts are focused on the region surrounding the Kallman gene, in attempts to better define a candidate region, as well as analyze possible candidate genes within this region.

Combined application of neutrophin-3 gene and neural stem cells is ameliorative to delay of denervated skeletal muscular atrophy after tibial nerve transection in rats.

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Lin, Sen; Xu, Jianguang; Hu, Shaonan; Xu, Lei; Zhang, Changqing; Wang, Yang; Gu, Yudong

2011-01-01

Examination of the therapeutic efficacy of neural stem cells (NSCs) has recently become the focus of much investigation. In this study we present an insight of the effects of combined application with neurotrophin-3 (NT-3) and NSCs that derived from rat embryo spinal cord on delaying denervated skeletal muscular atrophy after tibial nerve was severed. NT-3 gene was amplified by PCR and subcloned into lentiviral vector pWPXL-MOD to construct a lentiviral expression vector pWPXL-MOD-NT-3. A positive clone expressing NT-3 (named NSCs-NT-3) was obtained and used for differentiation in vitro and transplantation. Sixty adult rats, whose tibial nerves were sectioned, were divided into two groups: one grafted with NSCs-NT-3 (experimental group, n = 30) and the other with NSCs transfected by pWPXL-MOD (control group, n = 30). The cell survival and differentiation, NT-3 gene expression, and effect of delaying denervated skeletal muscular atrophy were examined through immunohistostaining, RT-PCR, Western blot, electrophysiological analysis, and mean cross-sectional area (CSA) of gastrocnemius, respectively. The results show that the NT-3 gene, which is comprised of 777 bp, was cloned and significantly different expression were detected between NSCs and NSCs-NT-3 in vitro. Quantitative analysis of the choline acetyltransferase (ChAT) immunopositive cells revealed a significant increase in experimental group compared to the control group 4 weeks after implantation (p ChAT immunopositive cells were detected near the engrafted region only in experimental group. Furthermore, the effect in delaying denervated skeletal muscular atrophy is indicated in the EMG examination and mean CSA of gastrocnemius. These findings suggest that the neural stem cells expressing NT-3 endogenously would be a better graft candidate for the delay of denervated skeletal muscular atrophy.

Molecular chaperones enhance the degradation of expanded polyglutamine repeat androgen receptor in a cellular model of spinal and bulbar muscular atrophy

NARCIS (Netherlands)

Bailey, CK; Andriola, IFM; Kampinga, HH; Merry, DE

2002-01-01

Spinal and bulbar muscular atrophy (SBMA) is one of a growing number of neurodegenerative diseases caused by a polyglutamine-encoding CAG trinucleotide repeat expansion, and is caused by an expansion within exon 1 of the androgen receptor (AR) gene. The family of polyglutamine diseases is

Silencing neuronal mutant androgen receptor in a mouse model of spinal and bulbar muscular atrophy.

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Sahashi, Kentaro; Katsuno, Masahisa; Hung, Gene; Adachi, Hiroaki; Kondo, Naohide; Nakatsuji, Hideaki; Tohnai, Genki; Iida, Madoka; Bennett, C Frank; Sobue, Gen

2015-11-01

Spinal and bulbar muscular atrophy (SBMA), an adult-onset neurodegenerative disease that affects males, results from a CAG triplet repeat/polyglutamine expansions in the androgen receptor (AR) gene. Patients develop progressive muscular weakness and atrophy, and no effective therapy is currently available. The tissue-specific pathogenesis, especially relative pathological contributions between degenerative motor neurons and muscles, remains inconclusive. Though peripheral pathology in skeletal muscle caused by toxic AR protein has been recently reported to play a pivotal role in the pathogenesis of SBMA using mouse models, the role of motor neuron degeneration in SBMA has not been rigorously investigated. Here, we exploited synthetic antisense oligonucleotides to inhibit the RNA levels of mutant AR in the central nervous system (CNS) and explore its therapeutic effects in our SBMA mouse model that harbors a mutant AR gene with 97 CAG expansions and characteristic SBMA-like neurogenic phenotypes. A single intracerebroventricular administration of the antisense oligonucleotides in the presymptomatic phase efficiently suppressed the mutant gene expression in the CNS, and delayed the onset and progression of motor dysfunction, improved body weight gain and survival with the amelioration of neuronal histopathology in motor units such as spinal motor neurons, neuromuscular junctions and skeletal muscle. These findings highlight the importance of the neurotoxicity of mutant AR protein in motor neurons as a therapeutic target. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Muscles in a mouse model of spinal muscular atrophy show profound defects in neuromuscular development even in the absence of failure in neuromuscular transmission or loss of motor neurons.

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Lee, Young Il; Mikesh, Michelle; Smith, Ian; Rimer, Mendell; Thompson, Wesley

2011-08-15

A mouse model of the devastating human disease "spinal muscular atrophy" (SMA) was used to investigate the severe muscle weakness and spasticity that precede the death of these animals near the end of the 2nd postnatal week. Counts of motor units to the soleus muscle as well as of axons in the soleus muscle nerve showed no loss of motor neurons. Similarly, neither immunostaining of neuromuscular junctions nor the measurement of the tension generated by nerve stimulation gave evidence of any significant impairment in neuromuscular transmission, even when animals were maintained up to 5days longer via a supplementary diet. However, the muscles were clearly weaker, generating less than half their normal tension. Weakness in 3 muscles examined in the study appears due to a severe but uniform reduction in muscle fiber size. The size reduction results from a failure of muscle fibers to grow during early postnatal development and, in soleus, to a reduction in number of fibers generated. Neuromuscular development is severely delayed in these mutant animals: expression of myosin heavy chain isoforms, the elimination of polyneuronal innervation, the maturation in the shape of the AChR plaque, the arrival of SCs at the junctions and their coverage of the nerve terminal, the development of junctional folds. Thus, if SMA in this particular mouse is a disease of motor neurons, it can act in a manner that does not result in their death or disconnection from their targets but nonetheless alters many aspects of neuromuscular development. Copyright © 2011 Elsevier Inc. All rights reserved.

Atrophy of sacrospinal muscle groups in patients with chronic, diffusely radiating lumbar back pain

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Laasonen, E.M.

1984-01-01

After surgery necessitated by lumbar back pain syndromes, radiolucency verified by CT may appear in the sacrospinal muscle group on the operate side. This radiolucency represents muscular atrophy and is in its most severe form a result of the replacement of muscle tissue with adipose tissue. Such muscular atrophy appeared in the present series in 31 out of all 156 patients (19.9%) and in 29 out of 94 patients operated on because of radiating lumbar back pain (30.9%). The radiological appearance, extent, and HU values of this muscular atrophy are presented in detail. Only weak correlations with the multitude of clinical symptoms and signs were found in this retrospective study. The effects of irreversible muscular atrophy on the indications for surgery and physiotherapy are discussed.

Transcriptional activator TAp63 is upregulated in muscular atrophy during ALS and induces the pro-atrophic ubiquitin ligase Trim63

Science.gov (United States)

von Grabowiecki, Yannick; Abreu, Paula; Blanchard, Orphee; Palamiuc, Lavinia; Benosman, Samir; Mériaux, Sophie; Devignot, Véronique; Gross, Isabelle; Mellitzer, Georg; Gonzalez de Aguilar, José L; Gaiddon, Christian

2016-01-01

Mechanisms of muscle atrophy are complex and their understanding might help finding therapeutic solutions for pathologies such as amyotrophic lateral sclerosis (ALS). We meta-analyzed transcriptomic experiments of muscles of ALS patients and mouse models, uncovering a p53 deregulation as common denominator. We then characterized the induction of several p53 family members (p53, p63, p73) and a correlation between the levels of p53 family target genes and the severity of muscle atrophy in ALS patients and mice. In particular, we observed increased p63 protein levels in the fibers of atrophic muscles via denervation-dependent and -independent mechanisms. At a functional level, we demonstrated that TAp63 and p53 transactivate the promoter and increased the expression of Trim63 (MuRF1), an effector of muscle atrophy. Altogether, these results suggest a novel function for p63 as a contributor to muscular atrophic processes via the regulation of multiple genes, including the muscle atrophy gene Trim63. DOI: http://dx.doi.org/10.7554/eLife.10528.001 PMID:26919175

Peripheral Androgen Receptor Gene Suppression Rescues Disease in Mouse Models of Spinal and Bulbar Muscular Atrophy

Directory of Open Access Journals (Sweden)

Andrew P. Lieberman

2014-05-01

Full Text Available Spinal and bulbar muscular atrophy (SBMA is caused by the polyglutamine androgen receptor (polyQ-AR, a protein expressed by both lower motor neurons and skeletal muscle. Although viewed as a motor neuronopathy, data from patients and mouse models suggest that muscle contributes to disease pathogenesis. Here, we tested this hypothesis using AR113Q knockin and human bacterial artificial chromosome/clone (BAC transgenic mice that express the full-length polyQ-AR and display androgen-dependent weakness, muscle atrophy, and early death. We developed antisense oligonucleotides that suppressed AR gene expression in the periphery but not the CNS after subcutaneous administration. Suppression of polyQ-AR in the periphery rescued deficits in muscle weight, fiber size, and grip strength, reversed changes in muscle gene expression, and extended the lifespan of mutant males. We conclude that polyQ-AR expression in the periphery is an important contributor to pathology in SBMA mice and that peripheral administration of therapeutics should be explored for SBMA patients.

Atrophy of sacrospinal muscle groups in patients with chronic, diffusely radiating lumbar back pain

International Nuclear Information System (INIS)

Laasonen, E.M.

1984-01-01

After surgery necessitated by lumbar back pain syndromes, radiolucency verified by CT may appear in the sacrospinal muscle group on the operate side. This radiolucency represents muscular atrophy and is in its most severe form a result of the replacement of muscle tissue with adipose tissue. Such muscular atrophy appeared in the present series in 31 out of all 156 patients (19.9%) and in 29 out of 94 patients operated on because of radiating lumbar back pain (30.9%). The radiological appearance, extent, and HU values of this muscular atrophy are presented in detail. Only weak correlations with the multitude of clinical symptoms and signs were found in this retrospective study. The effects of irreversible muscular atrophy on the indications for surgery and physiotherapy are discussed. (orig.)

Protective effects of long-term lithium administration in a slowly progressive SMA mouse model.

Science.gov (United States)

Biagioni, Francesca; Ferrucci, Michela; Ryskalin, Larisa; Fulceri, Federica; Lazzeri, Gloria; Calierno, Maria Teresa; Busceti, Carla L; Ruffoli, Riccardo; Fornai, Francesco

2017-12-01

In the present study we evaluated the long-term effects of lithium administration to a knock-out double transgenic mouse model (Smn-/-; SMN1A2G+/-; SMN2+/+) of Spinal Muscle Atrophy type III (SMA-III). This model is characterized by very low levels of the survival motor neuron protein, slow disease progression and motor neuron loss, which enables to detect disease-modifying effects at delayed time intervals. Lithium administration attenuates the decrease in motor activity and provides full protection from motor neuron loss occurring in SMA-III mice, throughout the disease course. In addition, lithium prevents motor neuron enlargement and motor neuron heterotopy and suppresses the occurrence of radial-like glial fibrillary acidic protein immunostaining in the ventral white matter of SMA-III mice. In SMA-III mice long-term lithium administration determines a dramatic increase of survival motor neuron protein levels in the spinal cord. These data demonstrate that long-term lithium administration during a long-lasting motor neuron disorder attenuates behavioural deficit and neuropathology. Since low level of survival motor neuron protein is bound to disease severity in SMA, the robust increase in protein level produced by lithium provides solid evidence which calls for further investigations considering lithium in the long-term treatment of spinal muscle atrophy.

More than a bystander: the contributions of intrinsic skeletal muscle defects in motor neuron diseases.

Science.gov (United States)

Boyer, Justin G; Ferrier, Andrew; Kothary, Rashmi

2013-12-18

Spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), and spinal-bulbar muscular atrophy (SBMA) are devastating diseases characterized by the degeneration of motor neurons. Although the molecular causes underlying these diseases differ, recent findings have highlighted the contribution of intrinsic skeletal muscle defects in motor neuron diseases. The use of cell culture and animal models has led to the important finding that muscle defects occur prior to and independently of motor neuron degeneration in motor neuron diseases. In SMA for instance, the muscle specific requirements of the SMA disease-causing gene have been demonstrated by a series of genetic rescue experiments in SMA models. Conditional ALS mouse models expressing a muscle specific mutant SOD1 gene develop atrophy and muscle degeneration in the absence of motor neuron pathology. Treating SBMA mice by over-expressing IGF-1 in a skeletal muscle-specific manner attenuates disease severity and improves motor neuron pathology. In the present review, we provide an in depth description of muscle intrinsic defects, and discuss how they impact muscle function in these diseases. Furthermore, we discuss muscle-specific therapeutic strategies used to treat animal models of SMA, ALS, and SBMA. The study of intrinsic skeletal muscle defects is crucial for the understanding of the pathophysiology of these diseases and will open new therapeutic options for the treatment of motor neuron diseases.

Estudio clínico, genético y molecular en un paciente con atrofia muscular espinal

Directory of Open Access Journals (Sweden)

Ibis Menéndez Alejo

1998-03-01

Full Text Available Las atrofias musculares espinales (AME infantiles son enfermedades neuromusculares hereditarias caracterizadas por la degeneración de las motoneuronas alfa del asta anterior de la médula espinal. La enfermedad de Werdnig-Hoffmann, AME tipo I, es la forma más grave, se transmite como un carácter autosómico recesivo y los afectados suelen fallecer durante el primer año de vida por fallo respiratorio. En este trabajo se presenta una familia cubana con 2 hijos con AME tipo I, en la cual el estudio molecular en uno de ellos permitió identificar los 2 cromosomas parentales asociados con ésta. Se encontró además en el paciente una deleción de ambas copias del gen SMN (exón 8 y del gen NAIP (exón 5. Los hallazgos ilustran la utilidad de estos estudios, con vistas a posibilitar el diagnóstico prenatal de la enfermedad.The infantile spinal muscular atrophies (SMA are hereditary neuromuscular diseases characterized by degenerated Alfa-motoneurons of the anterior spinal marrow horn. Werdning-Hoffman disease, Type 1 SMA, is the most serious affection being transmitted as an autosomal recessive character, so those affected may die from respiratory failures in the first year of life. This paper presents a Cuban family with two kids who suffer from Type-1 SMA; the molecular analysis carried out in one of them identified two parental chromosomes responsible for the disease. Also, a deletion of both copies of SMN gene (exon 8 and NAIP gene (exon 5 were discovered in this patient. These findings showed the usefulness of this kind of studies with a view to making a prenatal diagnosis of Werdning-Hoffman disease.

Short (16-mer locked nucleic acid splice-switching oligonucleotides restore dystrophin production in Duchenne Muscular Dystrophy myotubes.

Directory of Open Access Journals (Sweden)

Vanessa Borges Pires

Full Text Available Splice-switching antisense oligonucleotides (SSOs offer great potential for RNA-targeting therapies, and two SSO drugs have been recently approved for treating Duchenne Muscular Dystrophy (DMD and Spinal Muscular Atrophy (SMA. Despite promising results, new developments are still needed for more efficient chemistries and delivery systems. Locked nucleic acid (LNA is a chemically modified nucleic acid that presents several attractive properties, such as high melting temperature when bound to RNA, potent biological activity, high stability and low toxicity in vivo. Here, we designed a series of LNA-based SSOs complementary to two sequences of the human dystrophin exon 51 that are most evolutionary conserved and evaluated their ability to induce exon skipping upon transfection into myoblasts derived from a DMD patient. We show that 16-mers with 60% of LNA modification efficiently induce exon skipping and restore synthesis of a truncated dystrophin isoform that localizes to the plasma membrane of patient-derived myotubes differentiated in culture. In sum, this study underscores the value of short LNA-modified SSOs for therapeutic applications.

Low levels of Survival Motor Neuron protein are sufficient for normal muscle function in the SMNΔ7 mouse model of SMA.

Science.gov (United States)

Iyer, Chitra C; McGovern, Vicki L; Murray, Jason D; Gombash, Sara E; Zaworski, Phillip G; Foust, Kevin D; Janssen, Paul M L; Burghes, Arthur H M

2015-11-01

Spinal Muscular Atrophy (SMA) is an autosomal recessive disorder characterized by loss of lower motor neurons. SMA is caused by deletion or mutation of the Survival Motor Neuron 1 (SMN1) gene and retention of the SMN2 gene. The loss of SMN1 results in reduced levels of the SMN protein. SMN levels appear to be particularly important in motor neurons; however SMN levels above that produced by two copies of SMN2 have been suggested to be important in muscle. Studying the spatial requirement of SMN is important in both understanding how SMN deficiency causes SMA and in the development of effective therapies. Using Myf5-Cre, a muscle-specific Cre driver, and the Cre-loxP recombination system, we deleted mouse Smn in the muscle of mice with SMN2 and SMNΔ7 transgenes in the background, thus providing low level of SMN in the muscle. As a reciprocal experiment, we restored normal levels of SMN in the muscle with low SMN levels in all other tissues. We observed that decreasing SMN in the muscle has no phenotypic effect. This was corroborated by muscle physiology studies with twitch force, tetanic and eccentric contraction all being normal. In addition, electrocardiogram and muscle fiber size distribution were also normal. Replacement of Smn in muscle did not rescue SMA mice. Thus the muscle does not appear to require high levels of SMN above what is produced by two copies of SMN2 (and SMNΔ7). © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Neuroelectrophysiological indexes and clinical characteristics of patients with peroneal muscular atrophy: Retrospective analysis of 24 cases

Institute of Scientific and Technical Information of China (English)

Changchun Su; Qinbao Qin

2006-01-01

BACKGROUND: Peroneal muscular atrophy (PMA) is characterized by insidious onset, gradually progressive course of disease, very mild disability degree and easily subjecting to missed diagnosis and misdiagnosis.Nerve conductive velocity is helpful in the diagnosis of atypical cases.OBJECTIVE: To retrospectively analyze the characteristics of clinical manifestation, electromyogram (EMG),motor and sensory nerve conduction velocity of patients with PMA.DESIGN: Retrospective case analysis.SETTING: Department of Neurology, Guangzhou First People's Hospital.PARTICIPANTS: Twenty-four patients with PMA, including 16 males and 8 females, aged 5-68 years old,admitted to Guangzhou First People's Hospital between March 1996 and January 2006 were recruited.Informed consents were obtained from all the patients.METHODS: All the patients subjected to EMG and detection of nerve conduction velocity at distal end of four extremities with a Keypoint evoked potential/ EMG instrument (Denmark). Sensory and motor conduction velocity, EMG changes of upper and lower extremities were observed, and relationship of neuroelectrophysiological characteristics and clinical symptoms was analyzed.MAIN OUTCOME MEASURES: Changes in sensory and motor conduction velocity, EMG and clinical manifestations of 24 patients.RESULTS: ① All the patients suffered from insidious onset and gradually progressive course of PMA.Muscular atrophy of lower extremity was found in 14 patients, and that of upper extremity in 5 patients. ② Routine nerve conduction study showed that sensory and motor conduction velocity were stepped down,especially in 16 patients with type Ⅰ PMA (demyelinating pattern, nerve conduction velocity below normal level 50%). Motor nerve conduction velocity of median nerve, ulnar nerve, common peroneal nerve and tibial nerve averaged 34.8 m/s, 37.2 m/s, 16.5 m/s and 17.4 m/s, respectively; Sensory nerve conduction velocity of median nerve, ulnar nerve and sural nerve averaged 27.9%, 24.6 m

The SMN1 common variant c.22 dupA in Chinese patients causes spinal muscular atrophy by nonsense-mediated mRNA decay in humans.

Science.gov (United States)

Bai, JinLi; Qu, YuJin; Cao, YanYan; Yang, Lan; Ge, Lin; Jin, YuWei; Wang, Hong; Song, Fang

2018-02-20

Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder that is mostly caused by homozygous deletion of the SMN1 gene. Approximately 5%-10% of SMA patients are believed to have SMN1 variants. c.22 dupA (p.Ser8lysfs*23) has been identified as the most frequent variant in the Chinese SMA population and to be associated with a severe phenotype. However, the exact molecular mechanism of the variant on the pathogenesis of SMA is unclear. We observed that SMN1 mRNA and the SMN protein in the peripheral blood cells of a patient with c.22 dupA were lower than those of controls. The aim of this study is to investigate whether nonsense-mediated mRNA decay (NMD) plays a role in the mechanism of the c.22 dupA variant of the SMN1 gene as it causes SMA. Two lymphoblasts cell lines from two patients (patient 1 and 2) with the c.22 dupA, and one dermal fibroblasts cell line from patient 2 were included in our study. Two-stage validation of the NMD mechanism was supplied. We first measured the changes in the transcript levels of the SMN1 gene by real-time quantitative PCR after immortalized B-lymphoblasts and dermal fibroblasts cells of the SMA patients were treated with inhibitors of the NMD pathway, including puromycin and cyclohemide. Next, lentivirus-mediated knockdown of the key NMD factor-Up-frameshift protein 1 (UPF1)-was performed in the fibroblasts cell line to further clarify whether the variant led to NMD, as UPF1 recognizes abnormally terminated transcripts as NMD substrates during translation. SC35 1.7-kb transcripts, a physiological NMD substrate was determined to be a NMD positive gene in our experiments. The two inhibitors resulted in a dramatic escalation of the levels of the full-length SMN1 (fl-SMN1) transcripts. Additionally, the SC35 1.7-kb mRNA levels were also increased, suggesting that NMD pathway is suppressed by the two inhibitors. For the 3 cell lines, the fold increase of the SMN1 transcript levels of cycloheximide ranged

Muscular hypertrophy and atrophy in normal rats provoked by the administration of normal and denervated muscle extracts.

Science.gov (United States)

Agüera, Eduardo; Castilla, Salvador; Luque, Evelio; Jimena, Ignacio; Leiva-Cepas, Fernando; Ruz-Caracuel, Ignacio; Peña, José

2016-12-01

This study was conducted to determine the effects of extracts obtained from both normal and denervated muscles on different muscle types. Wistar rats were used and were divided into a control group and four experimental groups. Each experimental group was treated intraperitoneally during 10 consecutive days with a different extract. These extracts were obtained from normal soleus muscle, denervated soleus, normal extensor digitorum longus, and denervated extensor digitorum longus. Following treatment, the soleus and extensor digitorum longus muscles were obtained for study under optic and transmission electron microscope; morphometric parameters and myogenic responses were also analyzed. The results demonstrated that the treatment with normal soleus muscle and denervated soleus muscle extracts provoked hypertrophy and increased myogenic activity. In contrast, treatment with extracts from the normal and denervated EDL had a different effect depending on the muscle analyzed. In the soleus muscle it provoked hypertrophy of type I fibers and increased myogenic activity, while in the extensor digitorum longus atrophy of the type II fibers was observed without changes in myogenic activity. This suggests that the muscular responses of atrophy and hypertrophy may depend on different factors related to the muscle type which could be related to innervation.

Influência da adequação postural em cadeira de rodas na função respiratória de pacientes com amiotrofia espinhal tipo II Influence of wheelchair positioning aids on the respiratory function of patients with type II spinal muscular atrophy

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Luanda André Collange

2009-09-01

Full Text Available Este estudo visou determinar a influência da adequação postural em cadeira de rodas na função respiratória de pacientes com amiotrofia espinhal tipo II (AME. Doze pacientes (idades entre 7 e 24 anos com diagnóstico de AME II, confirmado por achados clínicos e análise genética, participaram do estudo. Os parâmetros respiratórios - volume minuto (VM, volume corrente (VC, capacidade vital forçada (CVF, pressões inspiratória (PImáx e expiratória (PEmáx máximas e pico de fluxo expiratório (PFE - na cadeira de rodas individual, com adaptações, e em uma cadeira de rodas padrão, isto é, sem reclinação ou inclinação. Os resultados mostram valores melhores estatisticamente significativos de todos os parâmetros respiratórios (VM, p=0,002; VC, p=0,003; CVF, p=0,017; PImáx, p=0,002; PEmáx, p=0,006; e PFE, p=0,007 nas medidas tomadas na cadeira adaptada para a postura adequada. Os resultados permitem concluir que a adequação postural em cadeira de rodas influencia positivamente a função respiratória de pacientes com AME tipo II.This study aimed at determining the influence of adequate wheelchair positioning aids on the respiratory function in spinal muscular atrophy (SMA type II patients. Twelve patients (aged 7 to 24 with SMA diagnosed by clinical findings and confirmed by genetic analysis, who owned wheelchairs with positioning aids, underwent spirometric assessment - as to minute volume (MV, tidal volume (TV, forced vital capacity (FVC, maximum inspiratory (IPmax and expiratory (EPmax pressures, and peak expiratory flow (PEF - both on their own wheelchair and on a standard wheelchair with no recline or tilt. Results show significantly better values in all assessed parameters (MV, p=0.002; TV, p=0.003; FVC, p=0.017; IPmax, p=0.002, EPmax, p=0.006; and PEF, p=0.007 of measures taken at the patient's own chair, with positioning aids. These results allow for concluding that wheelchair positioning aids may positively

Mutations in Subunits of the Activating Signal Cointegrator 1 Complex Are Associated with Prenatal Spinal Muscular Atrophy and Congenital Bone Fractures

Science.gov (United States)

Knierim, Ellen; Hirata, Hiromi; Wolf, Nicole I.; Morales-Gonzalez, Susanne; Schottmann, Gudrun; Tanaka, Yu; Rudnik-Schöneborn, Sabine; Orgeur, Mickael; Zerres, Klaus; Vogt, Stefanie; van Riesen, Anne; Gill, Esther; Seifert, Franziska; Zwirner, Angelika; Kirschner, Janbernd; Goebel, Hans Hilmar; Hübner, Christoph; Stricker, Sigmar; Meierhofer, David; Stenzel, Werner; Schuelke, Markus

2016-01-01

Transcriptional signal cointegrators associate with transcription factors or nuclear receptors and coregulate tissue-specific gene transcription. We report on recessive loss-of-function mutations in two genes (TRIP4 and ASCC1) that encode subunits of the nuclear activating signal cointegrator 1 (ASC-1) complex. We used autozygosity mapping and whole-exome sequencing to search for pathogenic mutations in four families. Affected individuals presented with prenatal-onset spinal muscular atrophy (SMA), multiple congenital contractures (arthrogryposis multiplex congenita), respiratory distress, and congenital bone fractures. We identified homozygous and compound-heterozygous nonsense and frameshift TRIP4 and ASCC1 mutations that led to a truncation or the entire absence of the respective proteins and cosegregated with the disease phenotype. Trip4 and Ascc1 have identical expression patterns in 17.5-day-old mouse embryos with high expression levels in the spinal cord, brain, paraspinal ganglia, thyroid, and submandibular glands. Antisense morpholino-mediated knockdown of either trip4 or ascc1 in zebrafish disrupted the highly patterned and coordinated process of α-motoneuron outgrowth and formation of myotomes and neuromuscular junctions and led to a swimming defect in the larvae. Immunoprecipitation of the ASC-1 complex consistently copurified cysteine and glycine rich protein 1 (CSRP1), a transcriptional cofactor, which is known to be involved in spinal cord regeneration upon injury in adult zebrafish. ASCC1 mutant fibroblasts downregulated genes associated with neurogenesis, neuronal migration, and pathfinding (SERPINF1, DAB1, SEMA3D, SEMA3A), as well as with bone development (TNFRSF11B, RASSF2, STC1). Our findings indicate that the dysfunction of a transcriptional coactivator complex can result in a clinical syndrome affecting the neuromuscular system. PMID:26924529

Modeling motor neuron disease: the matter of time

NARCIS (Netherlands)

Arbab, Manda; Baars, S.E.; geijsen, n

2014-01-01

Stem cell technologies have created new opportunities to generate unlimited numbers of human neurons in the lab and study neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Although some disease hallmarks have been reported in patient-derived

Modeling motor neuron disease : the matter of time

NARCIS (Netherlands)

Arbab, Mandana; Baars, Susanne; Geijsen, Niels

2014-01-01

Stem cell technologies have created new opportunities to generate unlimited numbers of human neurons in the lab and study neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Although some disease hallmarks have been reported in patient-derived

Sonographic Visualization of the Rotator Cable in Patients With Symptomatic Full-Thickness Rotator Cuff Tears: Correlation With Tear Size, Muscular Fatty Infiltration and Atrophy, and Functional Outcome.

Science.gov (United States)

Bureau, Nathalie J; Blain-Paré, Etienne; Tétreault, Patrice; Rouleau, Dominique M; Hagemeister, Nicola

2016-09-01

To assess the prevalence of sonographic visualization of the rotator cable in patients with symptomatic full-thickness rotator cuff tears and asymptomatic controls and to correlate rotator cable visualization with tear size, muscular fatty infiltration and atrophy, and the functional outcome in the patients with rotator cuff tears. Fifty-seven patients with rotator cuff tears and 30 asymptomatic volunteers underwent shoulder sonography for prospective assessment of the rotator cable and rotator cuff tear and responded to 2 functional outcome questionnaires (shortened Disabilities of the Arm, Shoulder, and Hand [QuickDASH] and Constant). In the patients with rotator cuff tears, appropriate tests were used to correlate rotator cable visualization with the tear size, functional outcome, muscular fatty infiltration, and atrophy. The patients with rotator cuff tears included 25 women and 32 men (mean age,57 years; range, 39-67 years), and the volunteers included 13 women and 17 men (mean age, 56 years; range, 35-64 years). The rotator cable was identified in 77% (23 of 30) of controls and 23% (13 of 57) of patients with rotator cuff tears. In the patients, nonvisualization of the rotator cable correlated with larger tears (P tears than asymptomatic controls and was associated with a larger tear size and greater supraspinatus fatty infiltration and atrophy. Diligent assessment of the supraspinatus muscle should be done in patients with rotator cuff tears without a visible rotator cable, as the integrity of these anatomic structures may be interdependent.

SMN genotypes producing less SMN protein increase susceptibility to and severity of sporadic ALS.

NARCIS (Netherlands)

Veldink, J.H.; Kalmijn, S.; Hout, A.H. van der; Lemmink, H.H.; Groeneveld, G.J.; Lummen, C.; Scheffer, H.; Wokke, J.H.J.; Berg, L.H. van den

2005-01-01

BACKGROUND: ALS is believed to be multifactorial in origin with modifying genes affecting its clinical expression. Childhood-onset spinal muscular atrophy (SMA) is an autosomal recessive disorder of motor neurons, caused by mutations of the survival motor neuron (SMN) gene. The SMN gene exists in

Use of sugammadex in a patient with progressive muscular atrophy and in a patient with amyotrophic lateral sclerosis

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Yoo, Jae Hwa; Kim, Soon Im; Park, Sun Young; Jun, Mi Roung; Kim, Yong Eun; Kim, Hyoung June

2017-01-01

Abstract Introduction: We herein present 2 cases involving the combination of rocuronium and sugammadex in patients with motor neuron disease. The patients were a 54-year-old man with progressive muscular atrophy who underwent removal of internal fixators in the arm and leg, and a 66-year-old woman with amyotrophic lateral sclerosis who underwent skin grafting in the left lower leg. General anesthesia was induced with propofol, rocuronium, and remifentanil and maintained with desflurane and remifentanil. At the end of the surgical procedure, we administered sugammadex. Three or 4 minutes after administration of sugammadex, the patients began to breathe spontaneously and were extubated without complications. Conclusion: Sugammadex can be used successfully to reverse neuromuscular blockade in patients with motor neuron disease. PMID:28591053

Estimulação elétrica neuromuscular de média freqüência (russa em cães com atrofia muscular induzida Medium frequency neuromuscular electrical stimulation (russian in dogs with induced muscle atrophy

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Charles Pelizzari

2008-06-01

Full Text Available A estimulação elétrica neuromuscular (EENM de média freqüência (Russa ou de Kotz pode ser empregada para a recuperação de massa muscular em animais apresentando atrofia muscular por desuso. Assim, o objetivo deste trabalho foi empregar a EENM de média freqüência no quadríceps femoral de cães com atrofia muscular induzida, avaliando-se a ocorrência de ganho de massa. Foram utilizados oito cães em dois grupos denominados de GI ou controle e de GII ou tratado. Para a indução da atrofia muscular, a articulação fêmoro-tíbio-patelar esquerda foi imobilizada por 30 dias. Após 48 horas da remoção, foi realizada a EENM nos cães do grupo II, três vezes por semana, com intervalo de 48 horas cada sessão, pelo período de 60 dias. Foram avaliadas a mensuração da perimetria da coxa, da goniometria do joelho, as enzimas creatina-quinase (CK e morfometria das fibras musculares em cortes transversais do músculo vasto lateral, colhido mediante a biópsia muscular. A EENM foi empregada no músculo quadríceps femoral numa freqüência de 2.500Hz, largura de pulso de 50% e relação de tempo on/off de 1:2. Não houve diferença significativa quanto aos valores de perimetria da coxa e a atividade da enzima CK entre os grupos I e II. Na goniometria, houve diminuição significativa (PThe medium frequency neuromuscular electrical stimulation (NMES (Russa or Kotz is designed for recuperation of muscle mass in dogs with muscular atrophy in disuse. This study aims to utilize medium frequency NMES on the femoral quadriceps of dogs with induced muscular atrophy and evaluate the occurrence of gain in mass. Eight dogs in two groups denominated GI, or control, and GII, or treated were used. For the induction of muscular atrophy, the left femoral-tibial-patellar joint was immobilized for 30 days. NMES treatment began 48 hours after the removal of the immobilization device on dogs from group II and was carried out three times per week, with an

Familial adult spinal muscular atrophy associated with the VAPB gene: report of 42 cases in Brazil

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Victor Kosac

2013-10-01

Full Text Available Familial spinal muscular atrophy (FSMA associated with the vesicle-associated membrane protein-associated protein B (VAPB gene is a rare autosomal dominant disease with late onset and slow progression. We studied 10 of 42 patients from 5 families by taking clinical histories and performing physical exams, electrophysiological studies, and genetic tests. All patients presented late onset disease with slow progression characterized by fasciculations, proximal weakness, amyotrophy, and hypoactive deep tendon reflex, except two who exhibited brisk reflex. Two patients showed tongue fasciculations and respiratory insufficiency. Electrophysiological studies revealed patterns of lower motor neuron disease, and genetic testing identified a P56S mutation of the VAPB gene. Although it is a rare motor neuron disease, FSMA with this mutation might be much more prevalent in Brazil than expected, and many cases may be undiagnosed. Genetic exams should be performed whenever it is suspected in Brazil.

X-ray diagnostic sign for the differentiation of neurogenic and primary muscular diseases

International Nuclear Information System (INIS)

Palvoelgyi, R.; Gallai, M.

1981-01-01

The authors give an account of X-ray examinations of the limb musculature of 70 patients suffering from neurogenic muscular diseases, 42 suffering from primary muscular diseases and 45 suffering from senile degeneration of the muscles. Different degree of damage to different parts of the same muscle could only been observed in one case of neurogenic atrophy (in the postpoliomyelitic states) and in two cases of senile degeneration, while it was found in 11 cases (20%) for the other muscular diseases. In the latter cases the more severe muscle damage, which could be demonstrated radiographically, was always found in the part of the muscle adjacent to a tendon. On the above reasons the authors consider that radiographically demonstrable partial or uneven damage to any particular muscle can be used as a new diagnostical information in distinguishing muscular diseases from neurogenic muscular atrophy. (orig.) [de

Spinal muscular atrophy present in children

OpenAIRE

Garófalo Gómez, Nicolás; Zaldívar Vaillant, Tatiana; Vargas Díaz, José; Rojas Massipe, Edelsia; Novoa López, Lucía

2009-01-01

INTRODUCCIÓN. Las atrofias musculares espinales en la infancia (AME) son trastornos genéticos autosómicos recesivos, caracterizados por degeneración de las motoneuronas espinales y bulbares. El presente estudio tuvo el objetivo principal de describir las principales características clínicas en una serie de niños con AME. MÉTODOS. Se realizó un estudio retrospectivo de los pacientes con AME atendidos en el Instituto de Neurología y Neurocirugía de Cuba, entre enero de 1997 y diciembre de 2001....

Dysregulation of RNA Mediated Gene Expression in Motor Neuron Diseases.

Science.gov (United States)

Gonçalves, Inês do Carmo G; Rehorst, Wiebke A; Kye, Min Jeong

2016-01-01

Recent findings indicate an important role for RNA-mediated gene expression in motor neuron diseases, including ALS (amyotrophic lateral sclerosis) and SMA (spinal muscular atrophy). ALS, also known as Lou Gehrig's disease, is an adult-onset progressive neurodegenerative disorder, whereby SMA or "children's Lou Gehrig's disease" is considered a pediatric neurodevelopmental disorder. Despite the difference in genetic causes, both ALS and SMA share common phenotypes; dysfunction/loss of motor neurons that eventually leads to muscle weakness and atrophy. With advanced techniques in molecular genetics and cell biology, current data suggest that these two distinct motor neuron diseases share more than phenotypes; ALS and SMA have similar cellular pathological mechanisms including mitochondrial dysfunction, oxidative stress and dysregulation in RNA-mediated gene expression. Here, we will discuss the current findings on these two diseases with specific focus on RNA-mediated gene regulation including miRNA expression, pre-mRNA processing and RNA binding proteins.

Gestational Age-Dependent Increase of Survival Motor Neuron Protein in Umbilical Cord-Derived Mesenchymal Stem Cells

OpenAIRE

Iwatani, Sota; Harahap, Nur Imma Fatimah; Nurputra, Dian Kesumapramudya; Tairaku, Shinya; Shono, Akemi; Kurokawa, Daisuke; Yamana, Keiji; Thwin, Khin Kyae Mon; Yoshida, Makiko; Mizobuchi, Masami; Koda, Tsubasa; Fujioka, Kazumichi; Taniguchi-Ikeda, Mariko; Yamada, Hideto; Morioka, Ichiro

2017-01-01

Background: Spinal muscular atrophy (SMA) is the most common genetic neurological disease leading to infant death. It is caused by loss of survival motor neuron (SMN) 1 gene and subsequent reduction of SMN protein in motor neurons. Because SMN is ubiquitously expressed and functionally linked to general RNA metabolism pathway, fibroblasts (FBs) are most widely used for the assessment of SMN expression in SMA patients but usually isolated from skin biopsy samples after the onset of overt sympt...

17-AAG increases autophagic removal of mutant androgen receptor in spinal and bulbar muscular atrophy.

Science.gov (United States)

Rusmini, Paola; Simonini, Francesca; Crippa, Valeria; Bolzoni, Elena; Onesto, Elisa; Cagnin, Monica; Sau, Daniela; Ferri, Nicola; Poletti, Angelo

2011-01-01

Several types of motorneuron diseases are linked to neurotoxic mutant proteins. These acquire aberrant conformations (misfolding) that trigger deleterious downstream events responsible for neuronal dysfunction and degeneration. The pharmacological removal of misfolded proteins might thus be useful in these diseases. We utilized a peculiar motorneuronal disease model, spinobulbar muscular atrophy (SBMA), in which the neurotoxicity of the protein involved, the mutant androgen receptor (ARpolyQ), can be modulated by its ligand testosterone (T). 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) has already been proven to exert beneficial action in SBMA. Here we demonstrated that 17-AAG exerts its pro-degradative activity on mutant ARpolyQ without impacting on proteasome functions. 17-AAG removes ARpolyQ misfolded species and aggregates by activating the autophagic system. We next analyzed the 17-AAG effects on two proteins (SOD1 and TDP-43) involved in related motorneuronal diseases, such as amyotrophic lateral sclerosis (ALS). In these models 17-AAG was unable to counteract protein aggregation. Copyright © 2010 Elsevier Inc. All rights reserved.

[Human myopathy and animal muscular dystrophy].

Science.gov (United States)

Schapira, G; Dreyfus, J C; Schapira, F

1977-08-01

Two hereditary muscular dystrophies similar to human progressive muscular dystrophy (P.M.D. Duchenne type) have been isolated in animals, one in mouse, the other in chicken. The decrease in the activity of glycogenolytic enzymes is similar to that observed in denervated muscle. Isozymic fetal types for several muscular enzymes have been observed as well in chicken as in man, but this fetal type may also be found in neurogenic atrophy. The release in circulation of muscle enzymes seems more specific. But the origin of the genetic lesion is still unknown. We describe here the three different theories about this problem: i.e. neurogenic, vascular, or myogenic. This last theory implies a trouble of membrane permeability.

Evaluation of muscle strength and motor abilities in children with type II and III spinal muscle atrophy treated with valproic acid

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Zanoteli Edmar

2011-03-01

Full Text Available Abstract Background Spinal muscular atrophy (SMA is an autosomal recessive disorder that affects the motoneurons of the spinal anterior horn, resulting in hypotonia and muscle weakness. The disease is caused by deletion or mutation in the telomeric copy of SMN gene (SMN1 and clinical severity is in part determined by the copy number of the centromeric copy of the SMN gene (SMN2. The SMN2 mRNA lacks exon 7, resulting in a production of lower amounts of the full-length SMN protein. Knowledge of the molecular mechanism of diseases has led to the discovery of drugs capable of increasing SMN protein level through activation of SMN2 gene. One of these drugs is the valproic acid (VPA, a histone deacetylase inhibitor. Methods Twenty-two patients with type II and III SMA, aged between 2 and 18 years, were treated with VPA and were evaluated five times during a one-year period using the Manual Muscle Test (Medical Research Council scale-MRC, the Hammersmith Functional Motor Scale (HFMS, and the Barthel Index. Results After 12 months of therapy, the patients did not gain muscle strength. The group of children with SMA type II presented a significant gain in HFMS scores during the treatment. This improvement was not observed in the group of type III patients. The analysis of the HFMS scores during the treatment period in the groups of patients younger and older than 6 years of age did not show any significant result. There was an improvement of the daily activities at the end of the VPA treatment period. Conclusion Treatment of SMA patients with VPA may be a potential alternative to alleviate the progression of the disease. Trial Registration ClinicalTrials.gov: NCT01033331

Effect of Electroacupuncture on the Expression of Glycyl-tRNA Synthetase and Ultrastructure Changes in Atrophied Rat Peroneus Longus Muscle Induced by Sciatic Nerve Injection Injury

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Meng Wang

2016-01-01

Full Text Available Glycyl-tRNA synthetase (GlyRS is one of the key enzymes involved in protein synthesis. Its mutations have been reported to cause Charcot-Marie-Tooth disease which demonstrates muscular atrophy in distal extremities, particularly manifested in peroneus muscles. In this situation, the dysfunctions of mitochondria and sarcoplasmic reticulum (SR affect energy supply and excitation-contraction coupling of muscle fibers, therefore resulting in muscular atrophy. Although the treatment of muscular atrophy is a global urgent problem, it can be improved by electroacupuncture (EA treatment. To investigate the mechanism underlying EA treatment improving muscular atrophy, we focused on the perspective of protein synthesis by establishing a penicillin injection-induced sciatic nerve injury model. In our model, injured rats without treatment showed decreased sciatic functional index (SFI, decreased peroneus longus muscle weight and muscle fiber cross-sectional area, aggregated mitochondria with vacuoles appearing, swollen SR, and downregulated mRNA and protein expression levels of GlyRS and myosin heavy chain IIb (MHC-IIb. The injured rats with EA treatment showed significant recovery. These results indicated that EA stimulation can alleviate peroneus longus muscular atrophy induced by iatrogenic sciatic nerve injury through promoting the recovery of GlyRS and muscle ultrastructure and increasing muscle protein synthesis.

Histopathological findings in Becker-type muscular dystrophy

NARCIS (Netherlands)

ten Houten, R.; de Visser, M.

1984-01-01

Muscle biopsy specimens from 14 patients with Becker-type muscular dystrophy were analyzed to investigate possible neurogenic factors underlying the histopathological changes. Group atrophy, pyknotic nuclear clumps, and angular small fibers were seen respectively in 71%, 85%, and 100% of the cases.

SMA Diagnosis: Detection of SMN1 Deletion with Real-Time mCOP-PCR System Using Fresh Blood DNA.

Science.gov (United States)

Niba, Emma Tabe Eko; Ar Rochmah, Mawaddah; Harahap, Nur Imma Fatimah; Awano, Hiroyuki; Morioka, Ichiro; Iijima, Kazumoto; Saito, Toshio; Saito, Kayoko; Takeuchi, Atsuko; Lai, Poh San; Bouike, Yoshihiro; Nishio, Hisahide; Shinohara, Masakazu

2017-12-18

Spinal muscular atrophy (SMA) is one of the most common autosomal recessive disorders. The symptoms are caused by defects of lower motor neurons in the spinal cord. More than 95% of SMA patients are homozygous for survival motor neuron 1 (SMN1) deletion. We previously developed a screening system for SMN1 deletion based on a modified competitive oligonucleotide priming-PCR (mCOP-PCR) technique using dried blood spot (DBS) on filter paper. This system is convenient for mass screening in the large population and/or first-tier diagnostic method of the patients in the remote areas. However, this system was still time-consuming and effort-taking, because it required pre-amplification procedure to avoid non-specific amplification and gel-electrophoresis to detect the presence or absence of SMN1 deletion. When the fresh blood samples are used instead of DBS, or when the gel-electrophoresis is replaced by real-time PCR, we may have a simpler and more rapid diagnostic method for SMA. To establish a simpler and more rapid diagnostic method of SMN1 deletion using fresh blood DNA. DNA samples extracted from fresh blood and stored at 4 ℃ for 1 month. The samples were assayed using a real-time mCOP-PCR system without pre-amplification procedures. DNA samples had already been genotyped by PCR-restriction fragment length polymorphism (PCR-RFLP), showing the presence or absence of SMN1 exon 7. The DNA samples were directly subjected to the mCOP-PCR step. The amplification of mCOP-PCR was monitored in a real-time PCR apparatus. The genotyping results of the real-time mCOP-PCR system using fresh blood DNA were completely matched with those of PCR-RFLP. In this real-time mCOP-PCR system using fresh blood-DNA, it took only four hours from extraction of DNA to detection of the presence or absence of SMN1 deletion, while it took more than 12 hours in PCR-RFLP. Our real-time mCOP-PCR system using fresh blood DNA was rapid and accurate, suggesting it may be useful for the first

Minority Undergraduate Research in Prostate Cancer: Bridging Opportunities for Post-Baccalaureate Education

Science.gov (United States)

2010-04-01

Rubrics for the ASBMB Undergraduate Poster Competition 2007 Dr. David Usher (Dept. of Biological Sciences), Tyler Larsen and Laura Sloofman. A good site...did his research on a genetic disease called Spinal Muscular Atrophy, also known as SMA. "I did research up at the Children’s Hospital because this is a

A designated centre for people with disabilities operated by RehabCare, Tipperary

LENUS (Irish Health Repository)

Power, CL

2018-03-01

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder, with a current estimated incidence of 1 in 11,000 live births. Although there is a variable phenotype, 60% of patients with SMA have type 1 disease. Typically diagnosed by the age of six months, this severe form of the condition is characterised by progressive weakness and the failure to meet motor milestones. There is an early need for permanent assisted ventilation, without which the median life expectancy is less than two years.\\r\

Distrofia muscular progressiva: alguns aspectos do diagnõstico diferencial

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Sylvio Saraiva

1960-09-01

Full Text Available The authors call attention to some clinical entities which are less known and more difficult to recognize and with which differential diagnosis of progressive muscular dystrophy should be made (infantile spinal muscular atrophy, amyotonia congenita, congenital acute anterior poliomyelitis, anthro-griposis multiplex, von Gierke's disease, central core disease, chronical polymyositis and dermatomyositis, thyrotoxic myopathy and menopausal dys- trophy. The importance of muscle biopsy in the differential diagnosis is emphasized.

Training improves oxidative capacity, but not function, in spinal muscular atrophy type III

DEFF Research Database (Denmark)

Madsen, Karen Lindhardt; Hansen, Regitze Sølling; Preisler, Nicolai

2015-01-01

max (17 ± 2 to 21 ± 2 ml/kg/min, P sleep in 3 patients, and led to training modifications in 2 patients. CONCLUSIONS: Cycle exercise improves VO2max in SMA III without causing muscle...... a 12-week training program, performing 42 30-minute sessions exercising at 65-70% of maximal oxygen uptake (VO2max ). VO2max , muscle strength, functional tests, and self-reported activities of daily living were assessed before and after the training. RESULTS: Training induced a 27 ± 3% increase in VO2...... damage, but it also induces significant fatigue. This warrants study into alternative training methods to improve exercise capacity in SMA III patients....

Effect of Oenothera odorata Root Extract on Microgravity and Disuse-Induced Muscle Atrophy.

Science.gov (United States)

Lee, Yong-Hyeon; Seo, Dong-Hyun; Park, Ji-Hyung; Kabayama, Kazuya; Opitz, Joerg; Lee, Kwang Ho; Kim, Han-Sung; Kim, Tack-Joong

2015-01-01

Muscle atrophy, a reduction of muscle mass, strength, and volume, results from reduced muscle use and plays a key role in various muscular diseases. In the microgravity environment of space especially, muscle atrophy is induced by muscle inactivity. Exposure to microgravity induces muscle atrophy through several biological effects, including associations with reactive oxygen species (ROS). This study used 3D-clinostat to investigate muscle atrophy caused by oxidative stress in vitro, and sciatic denervation was used to investigate muscle atrophy in vivo. We assessed the effect of Oenothera odorata root extract (EVP) on muscle atrophy. EVP helped recover cell viability in C2C12 myoblasts exposed to microgravity for 24 h and delayed muscle atrophy in sciatic denervated mice. However, the expressions of HSP70, SOD1, and ceramide in microgravity-exposed C2C12 myoblasts and in sciatic denervated mice were either decreased or completely inhibited. These results suggested that EVP can be expected to have a positive effect on muscle atrophy by disuse and microgravity. In addition, EVP helped characterize the antioxidant function in muscle atrophy.

Microarray analysis of gene expression by skeletal muscle of three mouse models of Kennedy disease/spinal bulbar muscular atrophy.

Directory of Open Access Journals (Sweden)

Kaiguo Mo

2010-09-01

Full Text Available Emerging evidence implicates altered gene expression within skeletal muscle in the pathogenesis of Kennedy disease/spinal bulbar muscular atrophy (KD/SBMA. We therefore broadly characterized gene expression in skeletal muscle of three independently generated mouse models of this disease. The mouse models included a polyglutamine expanded (polyQ AR knock-in model (AR113Q, a polyQ AR transgenic model (AR97Q, and a transgenic mouse that overexpresses wild type AR solely in skeletal muscle (HSA-AR. HSA-AR mice were included because they substantially reproduce the KD/SBMA phenotype despite the absence of polyQ AR.We performed microarray analysis of lower hindlimb muscles taken from these three models relative to wild type controls using high density oligonucleotide arrays. All microarray comparisons were made with at least 3 animals in each condition, and only those genes having at least 2-fold difference and whose coefficient of variance was less than 100% were considered to be differentially expressed. When considered globally, there was a similar overlap in gene changes between the 3 models: 19% between HSA-AR and AR97Q, 21% between AR97Q and AR113Q, and 17% between HSA-AR and AR113Q, with 8% shared by all models. Several patterns of gene expression relevant to the disease process were observed. Notably, patterns of gene expression typical of loss of AR function were observed in all three models, as were alterations in genes involved in cell adhesion, energy balance, muscle atrophy and myogenesis. We additionally measured changes similar to those observed in skeletal muscle of a mouse model of Huntington's Disease, and to those common to muscle atrophy from diverse causes.By comparing patterns of gene expression in three independent models of KD/SBMA, we have been able to identify candidate genes that might mediate the core myogenic features of KD/SBMA.

Research highlights of partial neuromuscular disorders

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Cheng ZHANG

2014-05-01

Full Text Available In order to understand the latest progression on neuromuscular disorders for clinicians, this review screened and systemized the papers on neuromuscular disorders which were collected by PubMed from January 2013 to February 2014. This review also introduced the clinical diagnosis and treatment hightlights on glycogen storage disease type Ⅱ (GSD Ⅱ, Duchenne muscular dystrophy (DMD, amyotrophic lateral sclerosis (ALS and spinal muscular atrophy (SMA. The important references will be useful for clinicians. doi: 10.3969/j.issn.1672-6731.2014.05.004

Cellular and molecular mechanisms of muscle atrophy

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Paolo Bonaldo

2013-01-01

Full Text Available Skeletal muscle is a plastic organ that is maintained by multiple pathways regulating cell and protein turnover. During muscle atrophy, proteolytic systems are activated, and contractile proteins and organelles are removed, resulting in the shrinkage of muscle fibers. Excessive loss of muscle mass is associated with poor prognosis in several diseases, including myopathies and muscular dystrophies, as well as in systemic disorders such as cancer, diabetes, sepsis and heart failure. Muscle loss also occurs during aging. In this paper, we review the key mechanisms that regulate the turnover of contractile proteins and organelles in muscle tissue, and discuss how impairments in these mechanisms can contribute to muscle atrophy. We also discuss how protein synthesis and degradation are coordinately regulated by signaling pathways that are influenced by mechanical stress, physical activity, and the availability of nutrients and growth factors. Understanding how these pathways regulate muscle mass will provide new therapeutic targets for the prevention and treatment of muscle atrophy in metabolic and neuromuscular diseases.

Non-neural phenotype of spinal and bulbar muscular atrophy: results from a large cohort of Italian patients.

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Querin, Giorgia; Bertolin, Cinzia; Da Re, Elisa; Volpe, Marco; Zara, Gabriella; Pegoraro, Elena; Caretta, Nicola; Foresta, Carlo; Silvano, Maria; Corrado, Domenico; Iafrate, Massimo; Angelini, Lorenzo; Sartori, Leonardo; Pennuto, Maria; Gaiani, Alessandra; Bello, Luca; Semplicini, Claudio; Pareyson, Davide; Silani, Vincenzo; Ermani, Mario; Ferlin, Alberto; Sorarù, Gianni

2016-08-01

To carry out a deep characterisation of the main androgen-responsive tissues involved in spinal and bulbar muscular atrophy (SBMA). 73 consecutive Italian patients underwent a full clinical protocol including biochemical and hormonal analyses, genitourinary examination, bone metabolism and densitometry, cardiological evaluation and muscle pathology. Creatine kinase levels were slightly to markedly elevated in almost all cases (68 of the 73; 94%). 30 (41%) patients had fasting glucose above the reference limit, and many patients had total cholesterol (40; 54.7%), low-density lipoproteins cholesterol (29; 39.7%) and triglyceride (35; 48%) levels above the recommended values. Although testosterone, luteinising hormone and follicle-stimulating hormone values were generally normal, in one-third of cases we calculated an increased Androgen Sensitivity Index reflecting the presence of androgen resistance in these patients. According to the International Prostate Symptom Score (IPSS), 7/70 (10%) patients reported severe lower urinal tract symptoms (IPSS score >19), and 21/73 (30%) patients were moderately symptomatic (IPSS score from 8 to 19). In addition, 3 patients were carriers of an indwelling bladder catheter. Videourodynamic evaluation indicated that 4 of the 7 patients reporting severe urinary symptoms had an overt prostate-unrelated bladder outlet obstruction. Dual-energy X-ray absorptiometry scan data were consistent with low bone mass in 25/61 (41%) patients. Low bone mass was more frequent at the femoral than at the lumbar level. Skeletal muscle biopsy was carried out in 20 patients and myogenic changes in addition to the neurogenic atrophy were mostly observed. Our study provides evidence of a wide non-neural clinical phenotype in SBMA, suggesting the need for comprehensive multidisciplinary protocols for these patients. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Nutcracker and SMA syndromes: What is the normal SMA angle in children?

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Arthurs, O.J., E-mail: oja20@owenarthurs.co.uk [Department of Radiology, Box 219, Addenbrooke' s Hospital, Cambridge University Teaching Hospitals NHS Foundation Trust, Hills Road, Cambridge, CB2 0QQ (United Kingdom); Mehta, U. [Department of Radiology, Box 219, Addenbrooke' s Hospital, Cambridge University Teaching Hospitals NHS Foundation Trust, Hills Road, Cambridge, CB2 0QQ (United Kingdom); Set, P.A.K., E-mail: p.set@addenbrookes.nhs.uk [Department of Radiology, Box 219, Addenbrooke' s Hospital, Cambridge University Teaching Hospitals NHS Foundation Trust, Hills Road, Cambridge, CB2 0QQ (United Kingdom)

2012-08-15

Objective: The nutcracker and superior mesenteric artery (SMA) syndromes are rare conditions where the left renal vein or duodenum may be compressed by an unusually acute angle between the SMA and aorta, although the normal angle in children is unknown. We measured the SMA angle to define the normal range in children. Methods: We retrospectively measured SMA angles, left renal vein (LRV) distance, and duodenal distance (DD) in 205 consecutive pediatric abdominal CT. Total and visceral intra-abdominal fat at the level of the umbilicus were also assessed. Results: Mean SMA angle was 45.6 {+-} 19.6 Degree-Sign (range 10.6-112.9 Degree-Sign ), mean LRV distance was 8.6 {+-} 3.9 mm (range 2.0-28.6 mm) and mean DD was 11.3 {+-} 4.8 mm (range 3.6-35.3 mm). There was a significant but weak correlation between %visceral fat volume (%VF) and SMA angle (R = 0.30; p < 0.001), LRV distance (R = 0.37, p < 0.001) and DD (R = 0.32; p < 0.001). Conclusion: There is a wide range of SMA angle, LRV and DD in normal children, which correlated weakly with visceral fat volume. Using a definition of SMA angle <25 Degree-Sign would diagnose 9.3% of asymptomatic children with nutcracker syndrome, and using a DD definition of <8 mm would diagnose 20% with SMA compression. Our findings suggest exercising caution when attributing these rare syndromes to an absolute SMA angle.

Nutcracker and SMA syndromes: What is the normal SMA angle in children?

International Nuclear Information System (INIS)

Arthurs, O.J.; Mehta, U.; Set, P.A.K.

2012-01-01

Objective: The nutcracker and superior mesenteric artery (SMA) syndromes are rare conditions where the left renal vein or duodenum may be compressed by an unusually acute angle between the SMA and aorta, although the normal angle in children is unknown. We measured the SMA angle to define the normal range in children. Methods: We retrospectively measured SMA angles, left renal vein (LRV) distance, and duodenal distance (DD) in 205 consecutive pediatric abdominal CT. Total and visceral intra-abdominal fat at the level of the umbilicus were also assessed. Results: Mean SMA angle was 45.6 ± 19.6° (range 10.6–112.9°), mean LRV distance was 8.6 ± 3.9 mm (range 2.0–28.6 mm) and mean DD was 11.3 ± 4.8 mm (range 3.6–35.3 mm). There was a significant but weak correlation between %visceral fat volume (%VF) and SMA angle (R = 0.30; p < 0.001), LRV distance (R = 0.37, p < 0.001) and DD (R = 0.32; p < 0.001). Conclusion: There is a wide range of SMA angle, LRV and DD in normal children, which correlated weakly with visceral fat volume. Using a definition of SMA angle <25° would diagnose 9.3% of asymptomatic children with nutcracker syndrome, and using a DD definition of <8 mm would diagnose 20% with SMA compression. Our findings suggest exercising caution when attributing these rare syndromes to an absolute SMA angle.

Muscle atrophy reversed by growth factor activation of satellite cells in a mouse muscle atrophy model.

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Simon Hauerslev

Full Text Available Muscular dystrophies comprise a large group of inherited disorders that lead to progressive muscle wasting. We wanted to investigate if targeting satellite cells can enhance muscle regeneration and thus increase muscle mass. We treated mice with hepatocyte growth factor and leukemia inhibitory factor under three conditions: normoxia, hypoxia and during myostatin deficiency. We found that hepatocyte growth factor treatment led to activation of the Akt/mTOR/p70S6K protein synthesis pathway, up-regulation of the myognic transcription factors MyoD and myogenin, and subsequently the negative growth control factor, myostatin and atrophy markers MAFbx and MuRF1. Hypoxia-induced atrophy was partially restored by hepatocyte growth factor combined with leukemia inhibitory factor treatment. Dividing satellite cells were three-fold increased in the treatment group compared to control. Finally, we demonstrated that myostatin regulates satellite cell activation and myogenesis in vivo following treatment, consistent with previous findings in vitro. Our results suggest, not only a novel in vivo pharmacological treatment directed specifically at activating the satellite cells, but also a myostatin dependent mechanism that may contribute to the progressive muscle wasting seen in severely affected patients with muscular dystrophy and significant on-going regeneration. This treatment could potentially be applied to many conditions that feature muscle wasting to increase muscle bulk and strength.

Estimulação elétrica neuromuscular em cães com atrofia muscular induzida Neuromuscular electric stimulation in dogs with induced muscle atrophy

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C. Pelizzari

2008-02-01

Full Text Available Empregou-se a estimulação elétrica neuromuscular (EENM de baixa freqüência no músculo quadríceps femoral de cães com atrofia induzida e avaliou-se a ocorrência de ganho de massa nessa musculatura. Foram utilizados oito cães com pesos entre 15 e 30kg, distribuídos aleatoriamente em dois grupos denominados de I ou controle e II ou tratado. A articulação femorotibiopatelar esquerda foi imobilizada por 30 dias pelo método de transfixação percutânea tipo II, com retirada de aparelho de imobilização após esse período. Decorridas 48 horas da remoção, foi realizada a EENM nos cães do grupo II, cinco vezes por semana, com intervalo de 24 horas cada sessão, pelo período de 60 dias. Foram avaliadas a circunferência da coxa, a goniometria do joelho, a análise clínica da marcha, as enzimas creatina-quinase (CK e aspartato-amino-transferase (AST e a morfometria das fibras musculares em cortes transversais do músculo vasto lateral colhido mediante biópsia muscular. A EENM foi empregada no músculo quadríceps femoral na freqüência de 50Hz, duração de pulso de 300 milisegundos e relação de tempo on/off de 1:2. Quanto à morfometria das fibras do músculo vasto lateral, no grupo tratado houve aumento significativo (PLow frequency neuromuscular electrical stimulation (NMES was used on the femoral quadriceps of dogs with induced muscular atrophy and the occurrence of gain in mass in these muscles was evaluated. Eight dogs from 15 to 30kg were randomly distributed in two groups named I, or control; and II, or treated. For the induction of muscular atrophy, the left femoral-tibial-patellar joint was immobilized for 30 days by percutaneous transfixation type II. After 30 days, the immobilization device was removed. The NMES treatment began 48 hours after the removal of the immobilization device of the dogs of group II, and it was carried out five times per week with an interval of 24 hours between each session, for 60 days. The

Advantage of CT scan in muscular pathology. Personal cases and review of the literature

International Nuclear Information System (INIS)

Laroche, M.; Rousseau, H.; Mazieres, B.; Bonafe, A.; Joffre, F.; Arlet, J.

1989-01-01

The advantage of CT scans in muscular pathology is studied. The scan, in addition to the diagnosis of tumors and muscular abscesses, permits to differentiate primary myopathies from neurogenic atrophies: in the course of myopathies, the muscle volume is preserved and they appear as a hypodensity; in neurogenic atrophies, the muscle volume is reduced with preserved density. The CT scan permits to determine the extension of these lesions. In the course of polymyositis, certain forms of rheumatid arthritis, the scan discloses a trabecular and 'worm-eaten' aspect of the muscles. This is also observed after long-term steroid therapy and other endocrine diseases (hyperthyroidism, osteomalacia) indicating an infra-clinical myopathy. In vertebral osteoporosis with fractures and patients with chronic lumbalgia, very ofter, an atrophy of the spinal muscle is observed. Finally, in the course of acquired kyphosis of the adult patient (camptocormia), the CT scan suggest an isolated myopathy, with late manifestations, of the paravertebral muscles [fr

Advantage of CT scan in muscular pathology. Personal cases and review of the literature

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Laroche, M.; Rousseau, H.; Mazieres, B.; Bonafe, A.; Joffre, F.; Arlet, J.

1989-05-01

The advantage of CT scans in muscular pathology is studied. The scan, in addition to the diagnosis of tumors and muscular abscesses, permits to differentiate primary myopathies from neurogenic atrophies: in the course of myopathies, the muscle volume is preserved and they appear as a hypodensity; in neurogenic atrophies, the muscle volume is reduced with preserved density. The CT scan permits to determine the extension of these lesions. In the course of polymyositis, certain forms of rheumatid arthritis, the scan discloses a trabecular and 'worm-eaten' aspect of the muscles. This is also observed after long-term steroid therapy and other endocrine diseases (hyperthyroidism, osteomalacia) indicating an infra-clinical myopathy. In vertebral osteoporosis with fractures and patients with chronic lumbalgia, very ofter, an atrophy of the spinal muscle is observed. Finally, in the course of acquired kyphosis of the adult patient (camptocormia), the CT scan suggest an isolated myopathy, with late manifestations, of the paravertebral muscles.

Positive radionuclide imaging of miRNA expression using RILES and the human sodium iodide symporter as reporter gene is feasible and supports a protective role of miRNA-23a in response to muscular atrophy.

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Viorel Simion

Full Text Available MicroRNAs (miRNAs are key players in many biological processes and are considered as an emerging class of pharmacology drugs for diagnosis and therapy. However to fully exploit the therapeutic potential of miRNAs, it is becoming crucial to monitor their expression pattern using medical imaging modalities. Recently, we developed a method called RILES, for RNAi-Inducible Luciferase Expression System that relies on an engineered regulatable expression system to switch-ON the expression of the luciferase gene when a miRNA of interest is expressed in cells. Here we investigated whether replacing the luciferase reporter gene with the human sodium iodide symporter (hNIS reporter gene will be also suited to monitor the expression of miRNAs in a clinical setting context. We provide evidence that radionuclide imaging of miRNA expression using hNIS is feasible although it is not as robust as when the luciferase reporter gene is used. However, under appropriate conditions, we monitored the expression of several miRNAs in cells, in the liver and in the tibialis anterior muscle of mice undergoing muscular atrophy. We demonstrated that radiotracer accumulation in transfected cells correlated with the induction of hNIS and with the expression of miRNAs detected by real time PCR. We established the kinetic of miRNA-23a expression in mice and demonstrated that this miRNA follows a biphasic expression pattern characterized by a loss of expression at a late time point of muscular atrophy. At autopsy, we found an opposite expression pattern between miRNA-23a and one of the main transcriptional target of this miRNA, APAF-1, and as downstream target, Caspase 9. Our results report the first positive monitoring of endogenously expressed miRNAs in a nuclear medicine imaging context and support the development of additional work to establish the potential therapeutic value of miRNA-23 to prevent the damaging effects of muscular atrophy.

Positive radionuclide imaging of miRNA expression using RILES and the human sodium iodide symporter as reporter gene is feasible and supports a protective role of miRNA-23a in response to muscular atrophy.

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Simion, Viorel; Sobilo, Julien; Clemoncon, Rudy; Natkunarajah, Sharuja; Ezzine, Safia; Abdallah, Florence; Lerondel, Stephanie; Pichon, Chantal; Baril, Patrick

2017-01-01

MicroRNAs (miRNAs) are key players in many biological processes and are considered as an emerging class of pharmacology drugs for diagnosis and therapy. However to fully exploit the therapeutic potential of miRNAs, it is becoming crucial to monitor their expression pattern using medical imaging modalities. Recently, we developed a method called RILES, for RNAi-Inducible Luciferase Expression System that relies on an engineered regulatable expression system to switch-ON the expression of the luciferase gene when a miRNA of interest is expressed in cells. Here we investigated whether replacing the luciferase reporter gene with the human sodium iodide symporter (hNIS) reporter gene will be also suited to monitor the expression of miRNAs in a clinical setting context. We provide evidence that radionuclide imaging of miRNA expression using hNIS is feasible although it is not as robust as when the luciferase reporter gene is used. However, under appropriate conditions, we monitored the expression of several miRNAs in cells, in the liver and in the tibialis anterior muscle of mice undergoing muscular atrophy. We demonstrated that radiotracer accumulation in transfected cells correlated with the induction of hNIS and with the expression of miRNAs detected by real time PCR. We established the kinetic of miRNA-23a expression in mice and demonstrated that this miRNA follows a biphasic expression pattern characterized by a loss of expression at a late time point of muscular atrophy. At autopsy, we found an opposite expression pattern between miRNA-23a and one of the main transcriptional target of this miRNA, APAF-1, and as downstream target, Caspase 9. Our results report the first positive monitoring of endogenously expressed miRNAs in a nuclear medicine imaging context and support the development of additional work to establish the potential therapeutic value of miRNA-23 to prevent the damaging effects of muscular atrophy.

Juvenile muscular atrophy of the distal upper extremities associated with x-linked periventricular heterotopia with features of Ehlers-Danlos syndrome.

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Hommel, Alyson L; Jewett, Tamison; Mortenson, Megan; Caress, James B

2016-10-01

Juvenile muscular atrophy of the distal upper extremities (JMADUE) is a rare, sporadic disorder that affects adolescent males and is characterized by progressive but self-limited weakness of the distal upper extremities. The etiology is unknown, but cervical hyperflexion has been hypothesized. We report a case of an adolescent male who presented with typical JMADUE but also had joint hypermobility and multiple congenital anomalies, including periventricular heterotopias, suggesting a multisystem syndrome. Subsequent diagnostic testing confirmed a diagnosis of JMADUE, and sequencing of the filamin-A gene showed a novel, pathogenic mutation that confirmed an additional diagnosis of X-linked periventricular heterotopias with features of Ehlers-Danlos syndrome (XLPH-EDS). The concurrent diagnosis of these 2 rare conditions suggests a pathogenic connection. It is likely that the joint hypermobility from XLPH-EDS predisposed this patient to developing JMADUE. This supports the cervical hyperflexion theory of pathogenesis. This case also expands the phenotype associated with FLNA mutations. Muscle Nerve 54: 794-797, 2016. © 2016 Wiley Periodicals, Inc.

Effect of Oenothera odorata Root Extract on Microgravity and Disuse-Induced Muscle Atrophy

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Yong-Hyeon Lee

2015-01-01

Full Text Available Muscle atrophy, a reduction of muscle mass, strength, and volume, results from reduced muscle use and plays a key role in various muscular diseases. In the microgravity environment of space especially, muscle atrophy is induced by muscle inactivity. Exposure to microgravity induces muscle atrophy through several biological effects, including associations with reactive oxygen species (ROS. This study used 3D-clinostat to investigate muscle atrophy caused by oxidative stress in vitro, and sciatic denervation was used to investigate muscle atrophy in vivo. We assessed the effect of Oenothera odorata root extract (EVP on muscle atrophy. EVP helped recover cell viability in C2C12 myoblasts exposed to microgravity for 24 h and delayed muscle atrophy in sciatic denervated mice. However, the expressions of HSP70, SOD1, and ceramide in microgravity-exposed C2C12 myoblasts and in sciatic denervated mice were either decreased or completely inhibited. These results suggested that EVP can be expected to have a positive effect on muscle atrophy by disuse and microgravity. In addition, EVP helped characterize the antioxidant function in muscle atrophy.

Muscle MRI findings in facioscapulohumeral muscular dystrophy

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Gerevini, Simonetta; Caliendo, Giandomenico; Falini, Andrea [IRCCS San Raffaele Scientific Institute, Neuroradiology Unit, Head and Neck Department, Milan (Italy); Scarlato, Marina; Previtali, Stefano Carlo [IRCCS San Raffaele Scientific Institute, Department of Neurology, INSPE and Division of Neuroscience, Milan (Italy); Maggi, Lorenzo; Pasanisi, Barbara; Morandi, Lucia [Fondazione IRCCS Istituto Neurologico ' ' Carlo Besta' ' , Neuromuscular Diseases and Neuroimmunology Unit, Milan (Italy); Cava, Mariangela [IRCCS San Raffaele Scientific Institute, Department of Radiology and Center for Experimental Imaging, Milan (Italy)

2016-03-15

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by extremely variable degrees of facial, scapular and lower limb muscle involvement. Clinical and genetic determination can be difficult, as molecular analysis is not always definitive, and other similar muscle disorders may have overlapping clinical manifestations. Whole-body muscle MRI examination for fat infiltration, atrophy and oedema was performed to identify specific patterns of muscle involvement in FSHD patients (30 subjects), and compared to a group of control patients (23) affected by other myopathies (NFSHD). In FSHD patients, we detected a specific pattern of muscle fatty replacement and atrophy, particularly in upper girdle muscles. The most frequently affected muscles, including paucisymptomatic and severely affected FSHD patients, were trapezius, teres major and serratus anterior. Moreover, asymmetric muscle involvement was significantly higher in FSHD as compared to NFSHD patients. In conclusion, muscle MRI is very sensitive for identifying a specific pattern of involvement in FSHD patients and in detecting selective muscle involvement of non-clinically testable muscles. Muscle MRI constitutes a reliable tool for differentiating FSHD from other muscular dystrophies to direct diagnostic molecular analysis, as well as to investigate FSHD natural history and follow-up of the disease. (orig.)

Deficiency of the Survival of Motor Neuron Protein Impairs mRNA Localization and Local Translation in the Growth Cone of Motor Neurons.

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Fallini, Claudia; Donlin-Asp, Paul G; Rouanet, Jeremy P; Bassell, Gary J; Rossoll, Wilfried

2016-03-30

Spinal muscular atrophy (SMA) is a neurodegenerative disease primarily affecting spinal motor neurons. It is caused by reduced levels of the survival of motor neuron (SMN) protein, which plays an essential role in the biogenesis of spliceosomal small nuclear ribonucleoproteins in all tissues. The etiology of the specific defects in the motor circuitry in SMA is still unclear, but SMN has also been implicated in mediating the axonal localization of mRNA-protein complexes, which may contribute to the axonal degeneration observed in SMA. Here, we report that SMN deficiency severely disrupts local protein synthesis within neuronal growth cones. We also identify the cytoskeleton-associated growth-associated protein 43 (GAP43) mRNA as a new target of SMN and show that motor neurons from SMA mouse models have reduced levels ofGAP43mRNA and protein in axons and growth cones. Importantly, overexpression of two mRNA-binding proteins, HuD and IMP1, restoresGAP43mRNA and protein levels in growth cones and rescues axon outgrowth defects in SMA neurons. These findings demonstrate that SMN plays an important role in the localization and local translation of mRNAs with important axonal functions and suggest that disruption of this function may contribute to the axonal defects observed in SMA. The motor neuron disease spinal muscular atrophy (SMA) is caused by reduced levels of the survival of motor neuron (SMN) protein, which plays a key role in assembling RNA/protein complexes that are essential for mRNA splicing. It remains unclear whether defects in this well characterized housekeeping function cause the specific degeneration of spinal motor neurons observed in SMA. Here, we describe an additional role of SMN in regulating the axonal localization and local translation of the mRNA encoding growth-associated protein 43 (GAP43). This study supports a model whereby SMN deficiency impedes transport and local translation of mRNAs important for neurite outgrowth and stabilization

Translation and validation of the Life Satisfaction Index for Adolescents scale with neuromuscular disorders: LSI-A Brazil

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Valdecir Antonio Simon

Full Text Available ABSTRACT Objective To validate the Life Satisfaction Index for Adolescents (LSI-A scale, parent version and patient version, for Duchenne muscular dystrophy (DMD, spinal muscular atrophy (SMA and limb-girdle muscular dystrophy (LGMD. Methods The parent version of the instrument was divided into Groups A, B, C and D; and the patient version, divided into B, C and D. For the statistical calculation, the following tests were used: Cronbach’s α, ICC, Pearson and the ROC Curve. Results The parent and patient versions of the instrument are presented, with the following results in the overall score, respectively: Cronbach’s α, 0.87 and 0.89; reliability, r 0.98 and 0.97; reproducibility, ICC 0.69 and 0.80; sensitivity, 0.78 and 0.72; specificity, 0.5 and 0.69; and accuracy, 64% and 70.4%. Conclusion According to the validity and reproducibility values, the LSI-A Brazil parent and patient versions, are clinically useful to assess quality of life in DMD, SMA or LGMD and may also be useful for other neuromuscular disorders.

Translation and validation of the Life Satisfaction Index for Adolescents scale with neuromuscular disorders: LSI-A Brazil.

Science.gov (United States)

Simon, Valdecir Antonio; Zanoteli, Edmar; Simon, Margarete Andreozzi Vaz Pereira; Resende, Maria Bernadete Dutra de; Reed, Umbertina Conti

2017-08-01

To validate the Life Satisfaction Index for Adolescents (LSI-A) scale, parent version and patient version, for Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA) and limb-girdle muscular dystrophy (LGMD). The parent version of the instrument was divided into Groups A, B, C and D; and the patient version, divided into B, C and D. For the statistical calculation, the following tests were used: Cronbach's α, ICC, Pearson and the ROC Curve. The parent and patient versions of the instrument are presented, with the following results in the overall score, respectively: Cronbach's α, 0.87 and 0.89; reliability, r 0.98 and 0.97; reproducibility, ICC 0.69 and 0.80; sensitivity, 0.78 and 0.72; specificity, 0.5 and 0.69; and accuracy, 64% and 70.4%. According to the validity and reproducibility values, the LSI-A Brazil parent and patient versions, are clinically useful to assess quality of life in DMD, SMA or LGMD and may also be useful for other neuromuscular disorders.

Treatment with Creatine Monohydrate in Spinal and Bulbar Muscular Atrophy: Protocol for a Randomized, Double-Blind, Placebo-Controlled Trial.

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Hijikata, Yasuhiro; Katsuno, Masahisa; Suzuki, Keisuke; Hashizume, Atsushi; Araki, Amane; Yamada, Shinichiro; Inagaki, Tomonori; Ito, Daisuke; Hirakawa, Akihiro; Kinoshita, Fumie; Gosho, Masahiko; Sobue, Gen

2018-03-05

Although spinal and bulbar muscular atrophy (SBMA) has been classified as a motor neuron disease, several reports have indicated the primary involvement of skeletal muscle in the pathogenesis of this devastating disease. Recent studies reported decreased intramuscular creatine levels in skeletal muscles in both patients with SBMA and transgenic mouse models of SBMA, which appears to contribute to muscle weakness. The present study aimed to examine the efficacy and safety of oral creatine supplementation to improve motor function in patients with SBMA. A randomized, double-blind, placebo-controlled, three-armed clinical trial was conducted to assess the safety and efficacy of creatine therapy in patients with SBMA. Patients with SBMA eligible for this study were assigned randomly in a 1:1:1 ratio to each group of placebo, 10 g, or 15 g daily dose of creatine monohydrate in a double-blind fashion. Participants took creatine or placebo orally 3 times a day for 8 weeks. Outcome measurements were results of neurological assessments, examinations, and questionnaires collected at baseline and at weeks 4, 8, and 16 after a washout period. The primary endpoint was the change in handgrip strength values from baseline to week 8. The secondary endpoints included the following: results of maximum voluntary isometric contraction tests of extremities; tongue pressure; results of the 15-foot timed walk test and the rise from bed test; modified quantitative myasthenia gravis score; respiratory function test results; activities of daily living assessed with the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale and the Spinal and Bulbar Muscular Atrophy Functional Rating Scale; skeletal muscle mass measured with dual-energy X-ray absorptiometry; urinary 8-hydroxydeoxyguanosine levels; and questionnaires examining the quality of life, swallowing function, and fatigue. Participant enrollment in the trial started from June 2014 and follow-up was completed in July 2015. The

Prenatal diagnosis of Werdnig-Hoffmann disease in China

Institute of Scientific and Technical Information of China (English)

无

2003-01-01

Objective To establish a means for prenatal prediction of spinal muscular atrophy (SMA) through survival motor neuron (SMN) gene deletion analysis and genetic counseling in families with a child affected with SMA. Methods Genetic analysis for prenatal prediction of Werdnig-Hoffmann disease was performed in a at risk Chinese family by polymerase chain reaction (PCR)-single-strand conformation polymorphism (SSCP) in SMN gene exons 7 and 8.Results The pregnancy was positive for the homozygous deletion of the SMN gene, thus the fetus was diagnosed as being affected and the pregnancy was terminated.Conclusion This approach is fast and reliable for DNA-based prenatal diagnosis of Werdnig-Hoffmann disease.

Hypoxic ischemia encephalopathy leading to external hydrocephalus and the cerebral atrophy: mechanism and differential diagnosis

International Nuclear Information System (INIS)

Huang Zhenglin; Mo Xiaorong

2002-01-01

Objective: It is a study of the mechanism and differential diagnosis of the infant external hydrocephalus and cerebral atrophy. Methods: In total 84 cases of neonatal hypoxic ischemia encephalopathy followed by infant external hydrocephalus were investigated, among which 26 patients gradually were found having developed cerebral atrophy in follow up. Results: Characteristic dilation of the frontal-parietal subarachnoid space and the adjacent cistern was noted on the CT images of the external hydrocephalus. CT revealed the enlarged ventricle besides the dilated subarachnoid space in the cases of cerebral atrophy, while these two entities were indistinguishable on CT in the early stage. Conclusion: Clinical manifestations make a major differential diagnosis of the external hydrocephalus and cerebral atrophy: tic and mild delayed development of locomotion over major presentation of external hydrocephalus, while cerebral atrophy is featured by remarkable dysnoesia and severe delayed development of locomotion. In addition, hemiplegia and increased muscular tension are presented in a few cases of cerebral atrophy

Hereditary motor and autonomic neuronopathy 1 maps to chromosome 20q13.2-13.3

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W. Marques Jr.

2004-11-01

Full Text Available The spinal muscular atrophies (SMA or hereditary motor neuronopathies result from the continuous degeneration and death of spinal cord lower motor neurons, leading to progressive muscular weakness and atrophy. We describe a large Brazilian family exhibiting an extremely rare, late-onset, dominant, proximal, and progressive SMA accompanied by very unusual manifestations, such as an abnormal sweating pattern, and gastrointestinal and sexual dysfunctions, suggesting concomitant involvement of the autonomic nervous system. We propose a new disease category for this disorder, `hereditary motor and autonomic neuronopathy', and attribute the term, `survival of motor and autonomic neurons 1' (SMAN1 to the respective locus that was mapped to a 14.5 cM region on chromosome 20q13.2-13.3 by genetic linkage analysis and haplotype studies using microsatellite polymorphic markers. This locus lies between markers D20S120 and D20S173 showing a maximum LOD score of 4.6 at D20S171, defining a region with 33 known genes, including several potential candidates. Identifying the SMAN1 gene should not only improve our understanding of the molecular mechanisms underlying lower motor neuron diseases but also help to clarify the relationship between motor and autonomic neurons.

Hereditary motor neuropathies and motor neuron diseases: which is which.

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Hanemann, Clemens O; Ludolph, Albert C

2002-12-01

When Charcot first defined amyotrophic lateral sclerosis (ALS) he used the clinical and neuropathological pattern of vulnerability as a guideline. Similarly other motor neuron diseases such as the spinal muscular atrophies (SMA) and the motor neuropathies (MN) were grouped following clinical criteria. However, ever since the etiology of these diseases has started to be disclosed by genetics, we have learnt that the limits of the syndromes are not as well defined as our forefathers thought. A mutation leading to ALS can also be associated with the clinical picture of spinal muscular atrophy; even more unexpected is the overlap of the so-called motor neuropathies with the clinical syndrome of slowly progressive ALS or that primary lateral sclerosis (PLS) can be caused by the same gene as that responsible for some cases of ALS. In this review we summarise recent work showing that there is a considerable overlap between CMT, MN, SMA, ALS and PLS. Insights into these phenotypes should lead to study of the variants of motor neuron disease and possibly to a reclassification. This comprehensive review should help to improve understanding of the pathogenesis of motor neuron degeneration and finally may aid the research for urgently needed new treatment strategies, perhaps with validity for the entire group of motor neuron diseases.

iPSC-Based Models to Unravel Key Pathogenetic Processes Underlying Motor Neuron Disease Development

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Irene Faravelli

2014-10-01

Full Text Available Motor neuron diseases (MNDs are neuromuscular disorders affecting rather exclusively upper motor neurons (UMNs and/or lower motor neurons (LMNs. The clinical phenotype is characterized by muscular weakness and atrophy leading to paralysis and almost invariably death due to respiratory failure. Adult MNDs include sporadic and familial amyotrophic lateral sclerosis (sALS-fALS, while the most common infantile MND is represented by spinal muscular atrophy (SMA. No effective treatment is ccurrently available for MNDs, as for the vast majority of neurodegenerative disorders, and cures are limited to supportive care and symptom relief. The lack of a deep understanding of MND pathogenesis accounts for the difficulties in finding a cure, together with the scarcity of reliable in vitro models. Recent progresses in stem cell field, in particular in the generation of induced Pluripotent Stem Cells (iPSCs has made possible for the first time obtaining substantial amounts of human cells to recapitulate in vitro some of the key pathogenetic processes underlying MNDs. In the present review, recently published studies involving the use of iPSCs to unravel aspects of ALS and SMA pathogenesis are discussed with an overview of their implications in the process of finding a cure for these still orphan disorders.

The molecular responses of skeletal muscle satellite cells to continuous expression of IGF-1: implications for the rescue of induced muscular atrophy in aged rats

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Chakravarthy, M. V.; Booth, F. W.; Spangenburg, E. E.

2001-01-01

Approximately 50% of humans older than 85 years have physical frailty due to weak skeletal muscles. This indicates a need for determining mechanisms to combat this problem. A critical cellular factor for postnatal muscle growth is a population of myogenic precursor cells called satellite cells. Given the complex process of sarcopenia, it has been postulated that, at some point in this process, a limited satellite cell proliferation potential could become rate-limiting to the regrowth of old muscles. It is conceivable that if satellite cell proliferative capacity can be maintained or enhanced with advanced age, sarcopenia could potentially be delayed or prevented. Therefore, the purposes of this paper are to describe whether IGF-I can prevent muscular atrophy induced by repeated cycles of hindlimb immobilization, increase the in vitro proliferation in satellite cells from these muscles and, if so, the molecular mechanisms by which IGF-I mediates this increased proliferation. Our results provide evidence that IGF-I can enhance aged muscle regrowth possibly through increased satellite cell proliferation. The results also suggest that IGF-I enhances satellite cell proliferation by decreasing the cell cycle inhibitor, p27Kip1, through the PI3'-K/Akt pathway. These data provide molecular evidence for IGF-I's rescue effect upon aging-associated skeletal muscle atrophy.

[DIAGNOSTIC VARIATIONS OF X-LINKED MUSCULAR DYSTROPHY WITH CONTRACTURES].

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Kvirkvelia, N; Shakarishvili, R; Gugutsidze, D; Khizanishvili, N

2015-01-01

Case report with review describes X-linked muscular dystrophy with contractures in 28 years old man and his cousin. The disease revealed itself in an early stage (age 5-10), the process was progressing with apparent tendons retraction and contraction, limited movement in the areas of the neck and back of spine, atrophy of shoulder and pelvic yard and back muscles. Intellect was intact. Cardyomyopathy was exhibited. CK was normal. EMG showed classic myopathic features. Muscle biopsy showed different caliber groups of muscle fibers, growth of endo-perimesial connective tissue. Clinical manifestations together with electrophysiological and histological data suggest consistency with Rotthauwe-Mortier-Bayer X-linked muscular dystrophy.

CABLES MUSCULARES

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Alejandro Gómez

Full Text Available Los cables musculares o fibras de nitinol presentan una excelente alternativa a los actuadores convencionales, con una fuerza de actuación muy alta, equivalente a la de los actuadores hidráulicos, proporcionalmente a su peso, además de su acción silenciosa. Este material, inventado en 1963, aún no es muy conocido y de ahí que se haya realizado una recopilación de sus propiedades. Entre ellas, la temperatura de transición es la más importante, por ser la que activa la aleación. Muchos sistemas se han creado para alcanzar adecuadamente la temperatura de transición, y también se continúa en la investigación de métodos que ayuden a lograr un control preciso del movimiento de la aleación con memoria de forma (SMA.

Atrofia muscular proximal neurogenica hereditaria (doença de Wohlfart-Kugelberg-Welander: estudo clinico, eletromiografico e anatomo-patologico de 3 irmãos Hereditary proximal neurogenic muscular atrophy (Wohlfart-Kugelberg-Welander disease: report of three cases

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Marcos R. G. de Freitas

1976-03-01

Full Text Available Os autores relatam os casos de três irmãos com fraqueza e amiotrofia proximal dos membros de início na infância. Os estudos eletromiográficos e de biópsias musculares revelaram alterações do tipo neurogênico de permeio com alterações miogênicas. Fazem consideração sobre esta singular associação, considerando as alterações do tipo miopático como secundárias à denervação de longa duração. O estudo histopatológico medular, em um dos pacientes, revelou degeneração das células motoras das pontas anteriores, constituindo, assim, o 4.° estudo de autópsia da doença de Wohlfart-Kugelberg-Welander, na literatura.The cases of three brothers with proximal weakness and muscles atrophies beginning in childhood are reported. Muscles biopsies and electromyographic studies have shown neurogenic pattern of atrophy and a dystrophy-like picture. It is concluded that this histological and eletromyographic picture can occur in pure partial denervation of long standing. The histopathologic study of the spinal cord of one patient revealed degenerative changes and loss of anterior horn ganglion cells. This is the fourth case of Wohlfar -Kugelberg-Welander disease with postmortem examination.

Prevalence of muscular dystrophy in patients with muscular disorders in Tehran, Iran

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Khadijeh Hajinaghi Tehrani

2018-05-01

Full Text Available Muscular dystrophy is a group of diseases that is characterized by progressive muscle wasting and the weakness of variable distribution and severity. On the basis of the distribution of predominant muscle weakness, there are many different kinds of muscular dystrophy. Some dystrophies are especially frequent in certain populations. There are no studies on the prevalence of muscular dystrophy in Iran. This study was aimed to survey the prevalence of muscular dystrophy among Iranian patients with muscular disorders. This analytical cross-sectional study was conducted on 1000 patients with musculoskeletal disorders who visited the dystrophy association of Bou-Ali Hospital (Tehran from June 2014 to June 2016. Patients’ data were extracted using a checklist that included age, gender, age of onset, family history, findings from clinical diagnostic tests and types of muscular dystrophy. The clinical findings were the results of genetic tests; EMG-NCV; para-clinical findings, including LDH and CPK; and pathological findings. All data were analyzed by SPSS V.22 (IBM Inc., NY with Chi Square and One way ANOVA tests. All analyses were performed with P = 0.05 considered as the threshold of statistical significant. Out of the 337 patients studied, 262 (77.7% were male and 75 (22.3% were female. Subjects had a mean (± SD age of 26.08 (± 11.86 years with an age range of 3 to 59 years. The most common types of muscular dystrophy were found to be Duchenne dystrophy (131 cases, 38.9%, limb-girdle dystrophy (91 cases, 27%, Becker dystrophy (58 cases, 17.2%, FSHD dystrophy (31 cases, 9.2%, and SMA (26 cases, 7.7%, respectively. The results showed that a statistically significant relationship between dystrophy types and gender, age, family history, age of diagnosis, CPK and LDH levels (P < 0.001. There were no statistical relationship between dystrophy types and pathological findings (P = 0.57, EMG-NCV test results (P = 0.062, and genetic findings (P = 0

Becker muscular dystrophy-like myopathy regarded as so-called "fatty muscular dystrophy" in a pig: a case report and its diagnostic method.

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Horiuchi, Noriyuki; Aihara, Naoyuki; Mizutani, Hiroshi; Kousaka, Shinichi; Nagafuchi, Tsuneyuki; Ochiai, Mariko; Ochiai, Kazuhiko; Kobayashi, Yoshiyasu; Furuoka, Hidefumi; Asai, Tetsuo; Oishi, Koji

2014-03-01

We describe a case of human Becker muscular dystrophy (BMD)-like myopathy that was characterized by the declined stainability of dystrophin at sarcolemma in a pig and the immunostaining for dystrophin on the formalin-fixed, paraffin-embedded (FFPE) tissue. The present case was found in a meat inspection center. The pig looked appeared healthy at the ante-mortem inspection. Muscular abnormalities were detected after carcass dressing as pale, discolored skeletal muscles with prominent fat infiltrations and considered so-called "fatty muscular dystrophy". Microscopic examination revealed following characteristics: diffused fat infiltration into the skeletal muscle and degeneration and regeneration of the remaining skeletal muscle fibers. Any lesions that were suspected of neurogenic atrophy, traumatic muscular degeneration, glycogen storage disease or other porcine muscular disorders were not observed. The immunostaining for dystrophin was conducted and confirmed to be applicable on FFPE porcine muscular tissues and revealed diminished stainability of dystrophin at the sarcolemma in the present case. Based on the histological observations and immunostaining results, the present case was diagnosed with BMD-like myopathy associated with dystrophin abnormality in a pig. Although the genetic properties were not clear, the present BMD-like myopathy implied the occurrence of dystrophinopathy in pigs. To the best of our knowledge, this is the first report of a natural case of myopathy associated with dystrophin abnormalities in a pig.

Theory of mind, empathy and neuropsychological functioning in X-linked spinal and bulbar muscular atrophy: a controlled study of 20 patients.

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Di Rosa, Elisa; Sorarù, Gianni; Kleinbub, Johann Roland; Calvo, Vincenzo; Vallesi, Antonino; Querin, Giorgia; Marcato, Sonia; Grasso, Irene; Palmieri, Arianna

2015-02-01

Recent studies have described brain involvement, mainly at frontal level, in patients with spinal and bulbar muscular atrophy (SBMA), a rare adult-onset motor neuron disease caused by a CAG repeat in the androgen receptor (AR) gene. The aim of our research was to investigate the poorly characterized neuropsychological and psychological profile of these patients, on the basis of previous literature. We administered a neuropsychological screening and tests relating to cognitive and affective empathy, attributed to the theory of mind (ToM) framework, to 20 males with SBMA, and to age- and education-matched controls. Although patients' neuropsychological performance was unimpaired, a clear dissociation emerged between their cognitive and affective empathy. Patients had distinctive deficits in mentalizing, as assessed with the Faux Pas Test, whilst affective empathy (i.e., sharing experience), assessed with the Reading the Mind in the Eyes test, appeared to be preserved. The likely implications of subtle frontal lobe impairments on the one hand, and a protective influence of androgen insensitivity in these patients on the other, are discussed in the light of our results.

Satellite cell senescence underlies myopathy in a mouse model of limb-girdle muscular dystrophy 2H

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Kudryashova, Elena; Kramerova, Irina; Spencer, Melissa J.

2012-01-01

Mutations in the E3 ubiquitin ligase tripartite motif-containing 32 (TRIM32) are responsible for the disease limb-girdle muscular dystrophy 2H (LGMD2H). Previously, we generated Trim32 knockout mice (Trim32–/– mice) and showed that they display a myopathic phenotype accompanied by neurogenic features. Here, we used these mice to investigate the muscle-specific defects arising from the absence of TRIM32, which underlie the myopathic phenotype. Using 2 models of induced atrophy, we showed that TRIM32 is dispensable for muscle atrophy. Conversely, TRIM32 was necessary for muscle regrowth after atrophy. Furthermore, TRIM32-deficient primary myoblasts underwent premature senescence and impaired myogenesis due to accumulation of PIAS4, an E3 SUMO ligase and TRIM32 substrate that was previously shown to be associated with senescence. Premature senescence of myoblasts was also observed in vivo in an atrophy/regrowth model. Trim32–/– muscles had substantially fewer activated satellite cells, increased PIAS4 levels, and growth failure compared with wild-type muscles. Moreover, Trim32–/– muscles exhibited features of premature sarcopenia, such as selective type II fast fiber atrophy. These results imply that premature senescence of muscle satellite cells is an underlying pathogenic feature of LGMD2H and reveal what we believe to be a new mechanism of muscular dystrophy associated with reductions in available satellite cells and premature sarcopenia. PMID:22505452

Bases celulares y moleculares de la atrofia muscular espinal : papel del factor de supervivencia de las motoneuronas (SMN)

OpenAIRE

Castillo Iglesias, María Soledad

2016-01-01

La atrofia muscular espinal (SMA) es una enfermedad infantil hereditaria caracterizada por la muerte de las motoneuronas con denervación y atrofia muscular que puede ocasionar la muerte de los pacientes por insuficiencias respiratoria. Su herencia es autosómica recesiva por deleción o mutaciones en el gen “Survival Motor Neuron 1” (SMN1), que codifica la proteína SMN. En el hombre existe un gen homólogo, SMN2, que produce niveles muy bajos de SMN completa y no evita la aparición de la enferme...

Single-Cell Analysis of SMN Reveals Its Broader Role in Neuromuscular Disease

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Natalia Rodriguez-Muela

2017-02-01

Full Text Available The mechanism underlying selective motor neuron (MN death remains an essential question in the MN disease field. The MN disease spinal muscular atrophy (SMA is attributable to reduced levels of the ubiquitous protein SMN. Here, we report that SMN levels are widely variable in MNs within a single genetic background and that this heterogeneity is seen not only in SMA MNs but also in MNs derived from controls and amyotrophic lateral sclerosis (ALS patients. Furthermore, cells with low SMN are more susceptible to cell death. These findings raise the important clinical implication that some SMN-elevating therapeutics might be effective in MN diseases besides SMA. Supporting this, we found that increasing SMN across all MN populations using an Nedd8-activating enzyme inhibitor promotes survival in both SMA and ALS-derived MNs. Altogether, our work demonstrates that examination of human neurons at the single-cell level can reveal alternative strategies to be explored in the treatment of degenerative diseases.

Description and physical localization of the bovine survival of motor neuron gene (SMN).

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Pietrowski, D; Goldammer, T; Meinert, S; Schwerin, M; Förster, M

1998-01-01

Proximal spinal muscular atrophy (SMA) is an autosomal recessive disease in humans and other mammals, characterized by degeneration of anterior horn cells of the spinal cord. In humans, the survival of motor neuron gene (SMN) has been recognized as the SMA-determining gene and has been mapped to 5q13. In cattle, SMA is a recurrent, inherited disease that plays an important economic role in breeding programs of Brown Swiss stock. Now we have identified the full- length cDNA sequence of the bovine SMN gene. Molecular analysis and characterization of the sequence documents 85% identity to its human counterpart and three evolutionarily conserved domains in different species. Physical mapping data reveals that bovine SMN is localized to chromosome region 20q12-->q13, supporting the conserved synteny of this chromosomal region between humans and cattle.

Congenital muscular dystrophy and severe central nervous system atrophy in two siblings

NARCIS (Netherlands)

Leyten, Q. H.; Barth, P. G.; Gabreëls, F. J.; Renkawek, K.; Renier, W. O.; Gabreëls-Festen, A. A.; ter Laak, H. J.; Smits, M. G.

1995-01-01

Severe degenerative features of the nervous system of a hitherto unknown kind, associated with a neuromuscular disorder with histopathological features of congenital muscular dystrophy, are reported in two female siblings. The clinical profile was characterized by generalized hypotonia followed by

Hypomorphic Smn knockdown C2C12 myoblasts reveal intrinsic defects in myoblast fusion and myotube morphology

International Nuclear Information System (INIS)

Shafey, Dina; Cote, Patrice D.; Kothary, Rashmi

2005-01-01

Dosage of the survival motor neuron (SMN) protein has been directly correlated with the severity of disease in patients diagnosed with spinal muscular atrophy (SMA). It is also clear that SMA is a neurodegenerative disorder characterized by the degeneration of the α-motor neurons in the anterior horn of the spinal cord and atrophy of the associated skeletal muscle. What is more controversial is whether it is neuronal and/or muscle-cell-autonomous defects that are responsible for the disease per se. Although motor neuron degeneration is generally accepted as the primary event in SMA, intrinsic muscle defects in this disease have not been ruled out. To gain a better understanding of the influence of SMN protein dosage in muscle, we have generated a hypomorphic series of myoblast (C2C12) stable cell lines with variable Smn knockdown. We show that depletion of Smn in these cells resulted in a decrease in the number of nuclear 'gems' (gemini of coiled bodies), reduced proliferation with no increase in cell death, defects in myoblast fusion, and malformed myotubes. Importantly, the severity of these abnormalities is directly correlated with the decrease in Smn dosage. Taken together, our work supports the view that there is an intrinsic defect in skeletal muscle cells of SMA patients and that this defect contributes to the overall pathogenesis in this devastating disease

BIOLOGY OF SOME NEUROMUSCULAR DISORDERS

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Gerta Vrbova

2004-12-01

Full Text Available In order to understand and possibly interfere/ treat neuromuscular disorders it is important to analyze the biological events that may be causing the disability. We illustrate such attempts on two examples of genetically determined neuromuscular diseases: 1 Duchenne muscular dystrophy (DMD, and 2 Spinal muscular atrophy (SMA.DMD is an x-linked hereditary muscle disease that leads to progressive muscle weakness. The altered gene in DMD affects dystrophin, a muscle membrane associated proteine. Attempts were made to replace the deficient or missing gene/ protein into muscles of Duchenne children. Two main strategies were explored: 1 Myoblast and stem cell transfer and 2 Gene delivery. The possible use of methods other than the introduction of the missing gene for dystrophin into muscle fibres are based on the knowledge about the adaptive potential of muscle to different functional demands and the ability of the muscle to express a new set of genes in response to such stimuli. Stretch or overload is now known to lead to changes of gene expression in normal muscle, and the success of muscle stretch in the management of Duchenne boys is most likely to be due to such adaptive changes. Electrical stimulation of muscles is also a powerful stimulus for inducing the expression of new genes and this method too has produced beneficial effects on the progress of the disease in mice and men.SMA is a heterogeneous group of hereditary neuromuscular disorders where the loss of lower motoneurones leads to progressive weakness and muscle atrophy. The disease subdivides into 3 forms according to the severity of the symptoms and age of onset. All three forms of SMA have been mapped to chromosome 5q11.2-13.2. Clinical features of all these forms of SMA include hypotonia shortly after birth, symmetrical muscle weakness and atrophy, finger tremor, areflexia or hyporeflexia and later contractures. In patients with SMA 1 and 2 the development of all parts of the motor

Lysine-Less Variants of Spinal Muscular Atrophy SMN and SMNΔ7 Proteins Are Degraded by the Proteasome Pathway

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Raúl Sánchez-Lanzas

2017-12-01

Full Text Available Spinal muscular atrophy is due to mutations affecting the SMN1 gene coding for the full-length protein (survival motor neuron; SMN and the SMN2 gene that preferentially generates an exon 7-deleted protein (SMNΔ7 by alternative splicing. To study SMN and SMNΔ7 degradation in the cell, we have used tagged versions at the N- (Flag or C-terminus (V5 of both proteins. Transfection of those constructs into HeLa cells and treatment with cycloheximide showed that those protein constructs were degraded. Proteasomal degradation usually requires prior lysine ubiquitylation. Surprisingly, lysine-less variants of both proteins tagged either at N- (Flag or C-terminus (V5 were also degraded. The degradation of the endogenous SMN protein, and the protein constructs mentioned above, was mediated by the proteasome, as it was blocked by lactacystin, a specific and irreversible proteasomal inhibitor. The results obtained allowed us to conclude that SMN and SMNΔ7 proteasomal degradation did not absolutely require internal ubiquitylation nor N-terminal ubiquitylation (prevented by N-terminal tagging. While the above conclusions are firmly supported by the experimental data presented, we discuss and justify the need of deep proteomic techniques for the study of SMN complex components (orphan and bound turn-over to understand the physiological relevant mechanisms of degradation of SMN and SMNΔ7 in the cell.

Computed tomography in congenital muscular dystrophy (Fukuyama type)

International Nuclear Information System (INIS)

Yoshioka, Mieko; Okuno, Takehiko; Nakano, Yoshihisa; Honda, Yoshihito

1980-01-01

Central-nervous system involvement in 26 patients with congenital muscular dystrophy (CMD) was studied using computed tomography (CT). CT was carried out using the EMI-1000 or 1010. The most characteristic finding in the CT was a low-density area in the white matter, seen in 15 out of the 26 (58%). Ventricular dilatation was also noted in 21 out of the 26 (80%), and cortical atrophy in 16 (65%). In one case, asymmetry of the lateral ventricle was observed. Half of the patients had a low-density area in the white matter in addition to cerebral atrophy, while only three (12%) showed normal CT findings. From the relation between the CT findings and IQ in patients with CMD, those with a low-density area in addition to cerebral atrophy and those with cerebral atrophy alone had extremely low IQs compared with those with a low-density area and with normal CT findings. From the relation between the CT findings and the EEG in patients with CMD, seizure discharges, such as a spike or a sharp wave complex and a spike, were most frequently seen in those with a low-density area in the white matter in addition to cerebral atrophy, and among those patients epileptic seizures occurred in three. From the relation between the CT findings and the stage of disability in patients with CMD, those with a low-density area in addition to cerebral atrophy showed severe motor disability. From the relation between CT findings and age in patients with CMD, severe CT findings were seen in the younger group. On ophthalmological examination, one of the most important findings was the evident bulateral optic nerve atrophy noted in several cases. (J.P.N.)

Emery-Dreifuss muscular dystrophy: the most recognizable laminopathy

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Agnieszka Madej-Pilarczyk

2016-03-01

Full Text Available Emery-Dreifuss muscular dystrophy (EDMD, a rare inherited disease, is characterized clinically by humero-peroneal muscle atrophy and weakness, multijoint contractures, spine rigidity and cardiac insufficiency with conduction defects. There are at least six types of EDMD known so far, of which five have been associated with mutations in genes encoding nuclear proteins. The majority of the EDMD cases described so far are of the emerinopathy (EDMD1 kind, with a recessive X-linked mode of inheritance, or else laminopathy (EDMD2, with an autosomal dominant mode of inheritance. In the work described here, the authors have sought to describe the history by which EDMD came to be distinguished as a separate entity, as well as the clinical and genetic characteristics of the disease, the pathophysiology of lamin-related muscular diseases and, finally, therapeutic issues, prevention and ethical aspects.

Characteristics Analysis and Testing of SMA Spring Actuator

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Jianzuo Ma

2013-01-01

Full Text Available The biasing form two-way shape memory alloy (SMA actuator composed of SMA spring and steel spring is analyzed. Based on the force equilibrium equation, the relationship between load capacity of SMA spring and geometric parameters is established. In order to obtain the characteristics of SMA spring actuator, the output force and output displacement of SMA spring under different temperatures are analyzed by the theoretical model and the experimental method. Based on the shape memory effect of SMA, the relationship of the SMA spring actuator's output displacement with the temperature, the stress and strain, the material parameters, and the size parameters is established. The results indicate that the trend of theoretical results is basically consistent with the experimental data. The output displacement of SMA spring actuator is increased with the increasing temperature.

Noninvasive Respiratory Management of Patients With Neuromuscular Disease.

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Bach, John R

2017-08-01

This review article describes definitive noninvasive respiratory management of respiratory muscle dysfunction to eliminate need to resort to tracheotomy. In 2010 clinicians from 22 centers in 18 countries reported 1,623 spinal muscular atrophy type 1 (SMA1), Duchenne muscular dystrophy (DMD), and amyotrophic lateral sclerosis users of noninvasive ventilatory support (NVS) of whom 760 required it continuously (CNVS). The CNVS sustained their lives by over 3,000 patient-years without resort to indwelling tracheostomy tubes. These centers have now extubated at least 74 consecutive ventilator unweanable patients with DMD, over 95% of CNVS-dependent patients with SMA1, and hundreds of others with advanced neuromuscular disorders (NMDs) without resort to tracheotomy. Two centers reported a 99% success rate at extubating 258 ventilator unweanable patients without resort to tracheotomy. Patients with myopathic or lower motor neuron disorders can be managed noninvasively by up to CNVS, indefinitely, despite having little or no measurable vital capacity, with the use of physical medicine respiratory muscle aids. Ventilator-dependent patients can be decannulated of their tracheostomy tubes.

Onset of small intestinal atrophy is associated with reduced intestinal blood flow in TPN-fed neonatal piglets

DEFF Research Database (Denmark)

Niinikoski, Harri; Stoll, Barbara; Guan, Xinfu

2004-01-01

Our aim was to determine the speed of onset of total parenteral nutrition (TPN)-induced mucosal atrophy, and whether this is associated with changes in intestinal blood flow and tissue metabolism in neonatal piglets. Piglets were implanted with jugular venous and duodenal catheters and either......-phenylalanine to measure crypt cell proliferation and protein synthesis, respectively. After 8 h of TPN, portal and SMA blood flow decreased 30% compared with enteral feeding (P reduced jejunal inducible nitric oxide...

Micromechanical analysis of porous SMA

International Nuclear Information System (INIS)

Sepe, V; Marfia, S; Sacco, E; Auricchio, F

2015-01-01

The present paper deals with computational micromechanical analyses of porous shape memory alloy (SMA). Porous SMAs are considered composite materials made of a dense SMA matrix including voids. A three-dimensional constitutive law is presented for the dense SMA able to reproduce the pseudo-elastic as well as the shape memory effects and, moreover, to account for the different elastic properties of the austenite and martensite phases. Furthermore, a numerical procedure is developed and the overall behavior of the porous SMA is recovered studying a representative volume element. Comparisons between the numerical results, recovered using the proposed modeling, and experimental data available in the literature are presented. The case of closed and open porosity is investigated. Parametric studies have been conducted in order to investigate the influence of the porosity, the shape and orientation of the pores on the overall mechanical response and, mainly, on the energy absorption dissipation capability. (paper)

Yeast Augmented Network Analysis (YANA: a new systems approach to identify therapeutic targets for human genetic diseases [v1; ref status: indexed, http://f1000r.es/3gk

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David J. Wiley

2014-06-01

Full Text Available Genetic interaction networks that underlie most human diseases are highly complex and poorly defined. Better-defined networks will allow identification of a greater number of therapeutic targets. Here we introduce our Yeast Augmented Network Analysis (YANA approach and test it with the X-linked spinal muscular atrophy (SMA disease gene UBA1. First, we express UBA1 and a mutant variant in fission yeast and use high-throughput methods to identify fission yeast genetic modifiers of UBA1. Second, we analyze available protein-protein interaction network databases in both fission yeast and human to construct UBA1 genetic networks. Third, from these networks we identified potential therapeutic targets for SMA. Finally, we validate one of these targets in a vertebrate (zebrafish SMA model. This study demonstrates the power of combining synthetic and chemical genetics with a simple model system to identify human disease gene networks that can be exploited for treating human diseases.

Avaliação dos resultados do tratamento cirúrgico da escoliose na atrofia muscular espinhal tipo 2 Evaluación de los resultados del tratamiento quirúrgico de la escoliosis en la atrofia muscular espinal tipo 2 Results evaluation of surgical treatment of scoliosis in spinal muscular atrophy type 2

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Luiz Eduardo Munhoz da Rocha

2011-01-01

evaluaron el grado y el porcentaje de corrección de la deformidad y la oblicuidad pélvica después de la operación y la pérdida, además de las complicaciones y el impacto del tratamiento sobre la función respiratoria. RESULTADOS: El promedio de seguimiento fue 77,5 meses (6,4 años ± 58,9 meses (4,9 años, el ángulo de Cobb antes de la cirugía en promedio 76,1° ± 31,7° (35° a 144° y el postoperatorio fue 29,5° ± 23,2° (5° a 90°, con un promedio de corrección de 46,6° (61,29%. La oblicuidad pélvica promedio en el preoperatorio fue 15,1 ° ± 13,3° (variación de 0 ° a 37 ° y después de la operación 8,5° ± 9,9° (variación de 0° a 30°, con una corrección promedio de 6,5 ° (43,37%. Cinco pacientes presentaron complicaciones (41,6%. La Capacidad Ventilatoria Forzada (CVF preoperatoria promedio fue 62,9% ± 38,6% (variación de 23,3% a 89%, y 45,9% ± 25,0% (variación de 15% a 86,2% en la última evaluación. La disminución fue de 17% de la capacidad vital, con una reducción de 2,4% por año de seguimiento. CONCLUSIONES: El tratamiento quirúrgico de la escoliosis, en pacientes con AME, permite la corrección de la oblicuidad pélvica y restaurar el equilibrio sagital y coronal, liberando las manos para las actividades de la vida diaria. La función pulmonar se vio afectada positivamente por el tratamiento.OBJECTIVE: To evaluate the outcome of surgical treatment of scoliosis in patients with spinal muscular atrophy (SMA type 2. METHODS: A retrospective study with 12 patients with SMA type 2 who underwent arthrodesis and instrumentation for scoliosis correction with more than two years of follow-up. The degree and rate of correction of deformity and pelvic obliquity postoperatively and loss in the last evaluation were evaluated, in addition to the complications and the impact of treatment on respiratory function. RESULTS: Mean follow-up was 77.5 months (6.4 years ± 58.9 months (4.9 years, Cobb angle before surgery averaged 76.1° ± 31.7�

Human adipose-derived mesenchymal stem cells as a new model of spinal and bulbar muscular atrophy.

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Marta Dossena

Full Text Available Spinal and bulbar muscular atrophy (SBMA or Kennedy's disease is an X-linked CAG/polyglutamine expansion motoneuron disease, in which an elongated polyglutamine tract (polyQ in the N-terminal androgen receptor (ARpolyQ confers toxicity to this protein. Typical markers of SBMA disease are ARpolyQ intranuclear inclusions. These are generated after the ARpolyQ binds to its endogenous ligands, which promotes AR release from chaperones, activation and nuclear translocation, but also cell toxicity. The SBMA mouse models developed so far, and used in preclinical studies, all contain an expanded CAG repeat significantly longer than that of SBMA patients. Here, we propose the use of SBMA patients adipose-derived mesenchymal stem cells (MSCs as a new human in vitro model to study ARpolyQ toxicity. These cells have the advantage to express only ARpolyQ, and not the wild type AR allele. Therefore, we isolated and characterized adipose-derived MSCs from three SBMA patients (ADSC from Kennedy's patients, ADSCK and three control volunteers (ADSCs. We found that both ADSCs and ADSCKs express mesenchymal antigens, even if only ADSCs can differentiate into the three typical cell lineages (adipocytes, chondrocytes and osteocytes, whereas ADSCKs, from SBMA patients, showed a lower growth potential and differentiated only into adipocyte. Moreover, analysing AR expression on our mesenchymal cultures we found lower levels in all ADSCKs than ADSCs, possibly related to negative pressures exerted by toxic ARpolyQ in ADSCKs. In addition, with proteasome inhibition the ARpolyQ levels increased specifically in ADSCKs, inducing the formation of HSP70 and ubiquitin positive nuclear ARpolyQ inclusions. Considering all of this evidence, SBMA patients adipose-derived MSCs cultures should be considered an innovative in vitro human model to understand the molecular mechanisms of ARpolyQ toxicity and to test novel therapeutic approaches in SBMA.

The effectiveness of styrene-maleic acid (SMA) copolymers for solubilisation of integral membrane proteins from SMA-accessible and SMA-resistant membranes.

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Swainsbury, David J K; Scheidelaar, Stefan; Foster, Nicholas; van Grondelle, Rienk; Killian, J Antoinette; Jones, Michael R

2017-10-01

Solubilisation of biological lipid bilayer membranes for analysis of their protein complement has traditionally been carried out using detergents, but there is increasing interest in the use of amphiphilic copolymers such as styrene maleic acid (SMA) for the solubilisation, purification and characterisation of integral membrane proteins in the form of protein/lipid nanodiscs. Here we survey the effectiveness of various commercially-available formulations of the SMA copolymer in solubilising Rhodobacter sphaeroides reaction centres (RCs) from photosynthetic membranes. We find that formulations of SMA with a 2:1 or 3:1 ratio of styrene to maleic acid are almost as effective as detergent in solubilising RCs, with the best solubilisation by short chain variants (membranes was uniformly low, but could be increased through a variety of treatments to increase the lipid:protein ratio. However, proteins isolated from such membranes comprised clusters of complexes in small membrane patches rather than individual proteins. We conclude that short-chain 2:1 and 3:1 formulations of SMA are the most effective in solubilising integral membrane proteins, but that solubilisation efficiencies are strongly influenced by the size of the target protein and the density of packing of proteins in the membrane. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Pregnancy course and outcome in women with hereditary neuromuscular disorders: comparison of obstetric risks in 178 patients.

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Awater, Carina; Zerres, Klaus; Rudnik-Schöneborn, Sabine

2012-06-01

Information about pregnancy and delivery in hereditary neuromuscular disorders (NMD) is limited and largely restricted to small case series and single case reports. Further data of obstetric histories in clinically and genetically defined subgroups are required. We reviewed the obstetric histories of 178 patients with myotonic dystrophy type 1 (DM1) and 2 (DM2), Charcot-Marie-Tooth disease (CMT), spinal muscular atrophy (SMA), limb-girdle muscular dystrophy (LGMD), facioscapulohumeral muscular dystrophy (FSHD), and congenital myopathy (CM) by means of questionnaires and medical reports. Patients were recruited in the period 1992-2010 after they had at least completed one pregnancy. A total of 380 pregnancies resulting in 315 children were documented. Compared to the normal German population, the number of miscarriages and hypertensive diseases in pregnancy was not increased in the cohort. Patients with NMD delivered more frequently by vaginal operations (8.9-18.2%) and by cesarean births with significantly high rates in DM1 (36.7%) and SMA (42.4%). Preterm deliveries were recorded in 30.7% of DM1, 12.6% of DM2, and 29.4% of SMA gestations. Abnormal fetal presentation occurred significantly more frequently in DM1 (34.6%) and LGMD (26.7%) deliveries and was a feature of chairbound patients. Considering a possible influence of pregnancy on the disease course, about half of LGMD, one-third of SMA, and one fifth of CMT patients reported a deterioration of symptoms in pregnancy. Neonatal outcome was favorable in all NMD but DM1, where infantile morbidity and mortality is often but not exclusively related to congenitally affected children. Our data are important for obstetric care and genetic counseling of women with NMD who are contemplating pregnancy. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Pattern Differences of Small Hand Muscle Atrophy in Amyotrophic Lateral Sclerosis and Mimic Disorders.

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Fang, Jia; Liu, Ming-Sheng; Guan, Yu-Zhou; Du, Hua; Li, Ben-Hong; Cui, Bo; Ding, Qing-Yun; Cui, Li-Ying

2016-04-05

Amyotrophic lateral sclerosis (ALS) and some mimic disorders, such as distal-type cervical spondylotic amyotrophy (CSA), Hirayama disease (HD), and spinobulbar muscular atrophy (SBMA) may present with intrinsic hand muscle atrophy. This study aimed to investigate different patterns of small hand muscle involvement in ALS and some mimic disorders. We compared the abductor digiti minimi/abductor pollicis brevis (ADM/APB) compound muscle action potential (CMAP) ratios between 200 ALS patients, 95 patients with distal-type CSA, 88 HD patients, 43 SBMA patients, and 150 normal controls. The ADM/APB CMAP amplitude ratio was significantly higher in the ALS patients (P mimic disorders presumably reflect distinct pathophysiological mechanisms underlying different disorders, and may aid in distinguishing between ALS and mimic disorders.

Modifier genes: Moving from pathogenesis to therapy.

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McCabe, Edward R B

2017-09-01

This commentary will focus on how we can use our knowledge about the complexity of human disease and its pathogenesis to identify novel approaches to therapy. We know that even for single gene Mendelian disorders, patients with identical mutations often have different presentations and outcomes. This lack of genotype-phenotype correlation led us and others to examine the roles of modifier genes in the context of biological networks. These investigations have utilized vertebrate and invertebrate model organisms. Since one of the goals of research on modifier genes and networks is to identify novel therapeutic targets, the challenges to patient access and compliance because of the high costs of medications for rare genetic diseases must be recognized. A recent article explored protective modifiers, including plastin 3 (PLS3) and coronin 1C (CORO1C), in spinal muscular atrophy (SMA). SMA is an autosomal recessive deficit of survival motor neuron protein (SMN) caused by mutations in SMN1. However, the severity of SMA is determined primarily by the number of SMN2 copies, and this results in significant phenotypic variability. PLS3 was upregulated in siblings who were asymptomatic compared with those who had SMA2 or SMA3, but identical homozygous SMN1 deletions and equal numbers of SMN2 copies. CORO1C was identified by interrogation of the PLS3 interactome. Overexpression of these proteins rescued endocytosis in SMA models. In addition, antisense RNA for upregulation of SMN2 protein expression is being developed as another way of modifying the SMA phenotype. These investigations suggest the practical application of protective modifiers to rescue SMA phenotypes. Other examples of the potential therapeutic value of novel protective modifiers will be discussed, including in Duchenne muscular dystrophy and glycerol kinase deficiency. This work shows that while we live in an exciting era of genomic sequencing, a functional understanding of biology, the impact of its

Intracerebroventricular Delivery in Mice for Motor Neuron Diseases.

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Nizzardo, M; Rizzuti, M

2017-01-01

The use of antisense oligonucleotides to target specific mRNA sequences represents a promising therapeutic strategy for neurological disorders. Recent advances in antisense technology enclose the development of phosphorodiamidate morpholino oligomers (MO), which is one of the best candidates for molecular therapies due to MO's excellent pharmacological profile.Nevertheless, the route of administration of antisense compounds represents a critical issue in the neurological field. Particularly, as regards motor neuron diseases, intracerebroventricular (ICV) injection is undoubtedly the most efficient procedure to directly deliver therapeutic molecules in the central nervous system (CNS). Indeed, we recently demonstrated the outstanding efficacy of the MO antisense approach by its direct administration to CNS of the transgenic mouse models of Spinal Muscular Atrophy (SMA) and Amyotrophic Lateral Sclerosis (ALS).Here, we describe methods to perform the ICV delivery of MO in neonatal SMA mice and in adult ALS mice.

SMA DOE Student Fellowship Initiative

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Steel Manufacturers Association

2004-12-24

Steel companies in many areas of the country have found it increasingly difficult to attract talented recent graduates of college and university engineering and applied science programs to the Electric Arc Furnace iron & steel industry. College student involvement in co-operative programs at steel companies can attract needed talent to the industry. Additionally, certain R & D needs identified in the Steel Industry Technology Roadmap are addressed as co-operative program activities. The Steel Manufacturers Association (''SMA'') therefore established a co-operative education program for selected college students who have completed the first or second year of a four or five-year college program, to be recognized as SMA Co-Operative Fellows, in regard to their summer and fall semester projects with SMA's member companies.

Vaginal Atrophy

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... an Endocrinologist Search Featured Resource Menopause Map™ View Vaginal Atrophy October 2017 Download PDFs English Editors Christine ... during this time, including vaginal dryness. What is vaginal atrophy? Vaginal atrophy (also referred to as vulvovaginal ...

A case of Fukuyama type congenital muscular dystrophy with progressive changes of brain CT scanning

International Nuclear Information System (INIS)

Mori, Kenzi; Saijo, Takahiko; Hamaguchi, Hiroshi; Tayama, Masanobu; Kawano, Noboru; Hashimoto, Toshiaki; Miyao, Masuhide

1988-01-01

The Fukuyama type congenital muscular dystrophy (F-CMD) has been generally recognized as a well delineated subgroup of progressive muscular dystrophy with uniform clinical and pathological features. But the pathogenesis is not yet clear. Two theories have been proposed ; autosomal recessive inheritance and intrauterine infection. We experienced a female case of F-CMD, and tried serial brain CT scanning from the birth to one year of age. Low density changes of white matter were not found at the first day of her life. But marked brain atrophy and low density changes of white matter were found after three months. We propose that CT examination should be repeated from early stage to clarify the pathogenesis of F-CMD. (AUTHOR)

Genetics of Pediatric-Onset Motor Neuron and Neuromuscular Diseases

Science.gov (United States)

2015-08-24

Spinal Muscular Atrophy; Charcot-Marie-Tooth Disease; Muscular Dystrophy; Spinal Muscular Atrophy With Respiratory Distress 1; Amyotrophic Lateral Sclerosis; Motor Neuron Disease; Neuromuscular Disease; Peroneal Muscular Atrophy; Fragile X Syndrome

Soft and smart modular structures actuated by shape memory alloy (SMA) wires as tentacles of soft robots

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Jin, Hu; Dong, Erbao; Xu, Min; Liu, Chunshan; Alici, Gursel; Jie, Yang

2016-08-01

This paper introduces the design and fabrication of a multi-layered smart modular structure (SMS) that has been inspired by the muscular organs and modularity in soft animals. The SMS is capable of planar reciprocal motion of bending in heating process and recovering in cooling process when SMA wires carry out phase transformation. An adaptive regulation heating strategy is applied to avoid overheating and achieve bending range control of the SMS based on the resistance feedback of the SMA wires which as actuator of the SMS. The SMS can modular assemble soft robots with multiple morphologies such as lateral robots, bilateral robots and actinomorphic robots. A five-armed actinomorphic soft robot is conducted to crawling in terrestrial ground (max speed: 140 mm s-1, 0.7 body s-1), swimming in underwater environment (max speed: 67 mm s-1, 2.5 height s-1) and griping fragile objects (max object weight: 0.91 kg, 15 times the weight of itself). Those demonstrate that the performance of the SMS is good enough to be modular units to establish soft robots which possess a high speed of response, good adaptability and a safe interaction with their environments.

Computed tomography in Duchenne type muscular dystrophy

International Nuclear Information System (INIS)

Kawai, Mitsuru; Kunimoto, Masanari; Motoyoshi, Yasufumi; Kuwata, Takashi; Nakano, Imaharu

1985-01-01

The computed tomography (CT) scan was performed on 91 Duchenne type muscular dystrophy (DMD) patients on the following four levels; (1) at the level of L3 vertebra, (2) 2-3cm above the symphysis pubica, (3) midposition of the thigh, (4) largest-diameter section of the lower leg. The CT of muscles common to most of the DMD patients were as follows: 1. Muscle atrophy: Muscle atrophy was shown as a reduction in the cross-sectional area of the muscles. Very mild muscle atrophy could be detected either by the clearly identified muscle border or by scattered low-density areas of so-called ''moth-eaten'' appearance within muscles. 2. Fat infiltration: The decrease in radio-density of muscles was interpreted as infiltration of fatty tissue. This type of density change was further classified into diffuse, streaked, cobblestone and salt-and-pepper patterns according to the spacial distribution of low-density areas. 3. Selectivity pattern: As the chronological sequence of DMD muscle degeneration is usually different among individual muscles, it may be seen, in some stages, that some of the synergistic muscles are still only slightly involved, while the others are quite severely atrophied with evident fat infiltration. In certain stages of the disease, most of the patients show relative preservation of particular muscles although they assumed a rounded shape. The most resistent muscle was musculus gracilis, followed by the musculus sartorius, musculus semitendinosus (and/or musculus semimembranosus) in that order. According to the severity of the CT changes, 86 of the 91 patients were classed into five stages from A1 to A5. Morphological stages (A1-A5) were well correlated to the functional disability stages by Ueda with a correlation factor of r=0.88. (J.P.N.)

Differential motor neuron involvement in progressive muscular atrophy: a comparative study with amyotrophic lateral sclerosis.

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Riku, Yuichi; Atsuta, Naoki; Yoshida, Mari; Tatsumi, Shinsui; Iwasaki, Yasushi; Mimuro, Maya; Watanabe, Hirohisa; Ito, Mizuki; Senda, Jo; Nakamura, Ryoichi; Koike, Haruki; Sobue, Gen

2014-05-14

Progressive muscular atrophy (PMA) is a clinical diagnosis characterised by progressive lower motor neuron (LMN) symptoms/signs with sporadic adult onset. It is unclear whether PMA is simply a clinical phenotype of amyotrophic lateral sclerosis (ALS) in which upper motor neuron (UMN) signs are undetectable. To elucidate the clinicopathological features of patients with clinically diagnosed PMA, we studied consecutive autopsied cases. Retrospective, observational. Autopsied patients. We compared clinicopathological profiles of clinically diagnosed PMA and ALS using 107 consecutive autopsied patients. For clinical analysis, 14 and 103 patients were included in clinical PMA and ALS groups, respectively. For neuropathological evaluation, 13 patients with clinical PMA and 29 patients with clinical ALS were included. Clinical features, UMN and LMN degeneration, axonal density in the corticospinal tract (CST) and immunohistochemical profiles. Clinically, no significant difference between the prognosis of clinical PMA and ALS groups was shown. Neuropathologically, 84.6% of patients with clinical PMA displayed UMN and LMN degeneration. In the remaining 15.4% of patients with clinical PMA, neuropathological parameters that we defined as UMN degeneration were all negative or in the normal range. In contrast, all patients with clinical ALS displayed a combination of UMN and LMN system degeneration. CST axon densities were diverse in the clinical PMA group, ranging from low values to the normal range, but consistently lower in the clinical ALS group. Immunohistochemically, 85% of patients with clinical PMA displayed 43-kDa TAR DNA-binding protein (TDP-43) pathology, while 15% displayed fused-in-sarcoma (FUS)-positive basophilic inclusion bodies. All of the patients with clinical ALS displayed TDP-43 pathology. PMA has three neuropathological background patterns. A combination of UMN and LMN degeneration with TDP-43 pathology, consistent with ALS, is the major pathological

Design of shape memory alloy (SMA) actuators

CERN Document Server

Rao, Ashwin; Reddy, J N

2015-01-01

This short monograph presents an analysis and design methodology for shape memory alloy (SMA) components such as wires, beams, and springs for different applications. The solid-solid, diffusionless phase transformations in thermally responsive SMA allows them to demonstrate unique characteristics like superelasticity and shape memory effects. The combined sensing and actuating capabilities of such materials allows them to provide a system level response by combining multiple functions in a single material system. In SMA, the combined mechanical and thermal loading effects influence the functionality of such materials. The aim of this book is to make the analysis of these materials accessible to designers by developing a "strength of materials" approach to the analysis and design of such SMA components inspired from their various applications with a review of various factors influencing the design process for such materials.

Progressive hemifacial atrophy with ciliary body atrophy and ocular hypotony

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T Ashwini Kini

2015-01-01

Full Text Available Progressive hemifacial atrophy (PHA is a disease of unknown etiology affecting one-half of the face. Ocular involvement is uncommon. Atrophy of iris is rare, with only a few cases of partial atrophy being reported in the literature. We report a case of total atrophy of iris and ciliary body with associated ocular hypotony in a 16-year-old girl with PHA. We believe this is the first reported case of complete atrophy of iris and ciliary body in PHA. Ocular hypotony in PHA was thought to be due to intra-ocular inflammation. However in our case it appears to be secondary to severe atrophy of the ciliary body.

Anti-skeletal muscle atrophy effect of Oenothera odorata root extract via reactive oxygen species-dependent signaling pathways in cellular and mouse model.

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Lee, Yong-Hyeon; Kim, Wan-Joong; Lee, Myung-Hun; Kim, Sun-Young; Seo, Dong-Hyun; Kim, Han-Sung; Gelinsky, Michael; Kim, Tack-Joong

2016-01-01

Skeletal muscle atrophy can be defined as a decrease of muscle volume caused by injury or lack of use. This condition is associated with reactive oxygen species (ROS), resulting in various muscular disorders. We acquired 2D and 3D images using micro-computed tomography in gastrocnemius and soleus muscles of sciatic-denervated mice. We confirmed that sciatic denervation-small animal model reduced muscle volume. However, the intraperitoneal injection of Oenothera odorata root extract (EVP) delayed muscle atrophy compared to a control group. We also investigated the mechanism of muscle atrophy's relationship with ROS. EVP suppressed expression of SOD1, and increased expression of HSP70, in both H2O2-treated C2C12 myoblasts and sciatic-denervated mice. Moreover, EVP regulated apoptotic signals, including caspase-3, Bax, Bcl-2, and ceramide. These results indicate that EVP has a positive effect on reducing the effect of ROS on muscle atrophy.

Research progress of motor function assessments and their clinical applications in Duchenne muscular dystrophy

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Wei SHI

2015-07-01

Full Text Available Duchenne muscular dystrophy (DMD, clinically featured as progressive skeletal muscle atrophy with gradual loss of muscle strength and activity abilities, is the most common genetic muscular disease in children throughout the world. The core and continuous characteristic of DMD is motor dysfunction. Motor function assessments of DMD are now focusing on muscle strength, walking ability, range of motion and ability of activities, still without unified standards. Confirming the comprehensive, scientific, reasonable and accurate evaluation tools for DMD assessment is the premise of research in motor developmental rules of DMD, which will help to better understand the motor progress of DMD and to supply evidences for choosing treatment methods, confirming timing of intervention, assessing effect of treatments and designing rehabilitation plans. DOI: 10.3969/j.issn.1672-6731.2015.06.002

A young man with spinal muscular atrophy and impending respiratory arrest.

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Winters, Janine Penfield; Weisleder, Pedro

2011-02-01

From a statutory standpoint, the decision-making capacity of adolescents differs significantly from that of adults because adolescents are considered to lack the experience and judgment necessary to make legally binding decisions. Furthermore, in the case of minors, the principle of protection of life tends to outweigh the principle of autonomy. Here we present the hypothetical case of a 16-year-old boy with spinalmuscular atrophy type II who was admitted to the intensive care unit for severe respiratory distress. We focus on the tension that developed among the patient, his parents, and his physicians when the need for emergency mechanical ventilation became apparent. We review the legal and ethical premises under which adolescents are permitted to make legally binding decisions, ie, the emancipated minor and the mature minor doctrines. Finally, we discuss the concepts of protectionism and liberationism as they apply to adolescents' decision-making capacity.

Investigation on low velocity impact resistance of SMA composite material

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Hu, Dianyin; Zhang, Long; Wang, Rongqiao; Zhang, Xiaoyong

2016-04-01

A method to improve low velocity impact resistance of aeroengine composite casing using shape memory alloy's properties of shape memory(SM) and super-elasticity(SE) is proposed in this study. Firstly, a numerical modeling of SMA reinforced composite laminate under low velocity impact load with impact velocity of 10 m/s is established based on its constitutive model implemented by the VUMAT subroutine of commercial software ABAQUS. Secondly, the responses of SMA composite laminate including stress and deflection distributions were achieved through transient analysis under low velocity impact load. Numerical results show that both peak stress and deflection values of SMA composite laminate are less than that without SMA, which proves that embedding SMA into the composite structure can effectively improve the low velocity impact performance of composite structure. Finally, the influence of SM and SE on low velocity impact resistance is quantitatively investigated. The values of peak stress and deflection of SMA composite based on SM property decrease by 18.28% and 9.43% respectively, compared with those without SMA, instead of 12.87% and 5.19% based on SE. In conclusion, this proposed model described the impact damage of SMA composite structure and turned to be a more beneficial method to enhance the impact resistance by utilizing SM effect.

Carrier detection of duchenne and becker muscular dystrophy using muscle dystrophin immunohistochemistry

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Acary S. Bulle Oliveira

1992-12-01

Full Text Available To ascertain whether dystrophin immunohistochemistry could improve DMD/ BMD carrier detection, we analyzed 14 muscle biopsies from 13 DMD and one BMD probable and possible carriers. All women were also evaluated using conventional methods, including genetic analysis, clinical and neurological evaluation, serum CK levels, KMG, and muscle biopsy. In 6 cases, there was a mosaic of dystrophin-positive and dystrophin-deficient fibers that allowed to make the diagnosis of a carrier state. Comparing dystrophin immunohistochemistry to the traditional methods, it was noted that this method is less sensitive than serum CK measuremens, but is more sensitive than EMG and muscle biopsy. The use of dystrophin immunohistochemistry in addition to CK, EMG and muscle biopsy improved the accuracy of carrier detection. This method is also helpful to distinguish manifesting DMD carriers from patients with other neuromuscular diseases like limb-girdle muscular dystrophy and spinal muscular atrophy.

Skeletal Muscle Metabolism in Duchenne and Becker Muscular Dystrophy—Implications for Therapies

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Ahlke Heydemann

2018-06-01

Full Text Available The interactions between nutrition and metabolism and skeletal muscle have long been known. Muscle is the major metabolic organ—it consumes more calories than other organs—and therefore, there is a clear need to discuss these interactions and provide some direction for future research areas regarding muscle pathologies. In addition, new experiments and manuscripts continually reveal additional highly intricate, reciprocal interactions between metabolism and muscle. These reciprocal interactions include exercise, age, sex, diet, and pathologies including atrophy, hypoxia, obesity, diabetes, and muscle myopathies. Central to this review are the metabolic changes that occur in the skeletal muscle cells of muscular dystrophy patients and mouse models. Many of these metabolic changes are pathogenic (inappropriate body mass changes, mitochondrial dysfunction, reduced adenosine triphosphate (ATP levels, and increased Ca2+ and others are compensatory (increased phosphorylated AMP activated protein kinase (pAMPK, increased slow fiber numbers, and increased utrophin. Therefore, reversing or enhancing these changes with therapies will aid the patients. The multiple therapeutic targets to reverse or enhance the metabolic pathways will be discussed. Among the therapeutic targets are increasing pAMPK, utrophin, mitochondrial number and slow fiber characteristics, and inhibiting reactive oxygen species. Because new data reveals many additional intricate levels of interactions, new questions are rapidly arising. How does muscular dystrophy alter metabolism, and are the changes compensatory or pathogenic? How does metabolism affect muscular dystrophy? Of course, the most profound question is whether clinicians can therapeutically target nutrition and metabolism for muscular dystrophy patient benefit? Obtaining the answers to these questions will greatly aid patients with muscular dystrophy.

Skeletal Muscle Metabolism in Duchenne and Becker Muscular Dystrophy-Implications for Therapies.

Science.gov (United States)

Heydemann, Ahlke

2018-06-20

The interactions between nutrition and metabolism and skeletal muscle have long been known. Muscle is the major metabolic organ—it consumes more calories than other organs—and therefore, there is a clear need to discuss these interactions and provide some direction for future research areas regarding muscle pathologies. In addition, new experiments and manuscripts continually reveal additional highly intricate, reciprocal interactions between metabolism and muscle. These reciprocal interactions include exercise, age, sex, diet, and pathologies including atrophy, hypoxia, obesity, diabetes, and muscle myopathies. Central to this review are the metabolic changes that occur in the skeletal muscle cells of muscular dystrophy patients and mouse models. Many of these metabolic changes are pathogenic (inappropriate body mass changes, mitochondrial dysfunction, reduced adenosine triphosphate (ATP) levels, and increased Ca 2+ ) and others are compensatory (increased phosphorylated AMP activated protein kinase (pAMPK), increased slow fiber numbers, and increased utrophin). Therefore, reversing or enhancing these changes with therapies will aid the patients. The multiple therapeutic targets to reverse or enhance the metabolic pathways will be discussed. Among the therapeutic targets are increasing pAMPK, utrophin, mitochondrial number and slow fiber characteristics, and inhibiting reactive oxygen species. Because new data reveals many additional intricate levels of interactions, new questions are rapidly arising. How does muscular dystrophy alter metabolism, and are the changes compensatory or pathogenic? How does metabolism affect muscular dystrophy? Of course, the most profound question is whether clinicians can therapeutically target nutrition and metabolism for muscular dystrophy patient benefit? Obtaining the answers to these questions will greatly aid patients with muscular dystrophy.

Women’s Attitudes Regarding Prenatal Testing for a Range of Congenital Disorders of Varying Severity

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Mary E. Norton

2014-01-01

Full Text Available Little is known about women’s comparative attitudes towards prenatal testing for different categories of genetic disorders. We interviewed women who delivered healthy infants within the past year and assessed attitudes towards prenatal screening and diagnostic testing, as well as pregnancy termination, for Down syndrome (DS, fragile X (FraX, cystic fibrosis (CF, spinal muscular atrophy (SMA, phenylketonuria (PKU and congenital heart defects (CHD. Ninety-five women aged 21 to 48 years participated, of whom 60% were Caucasian, 23% Asian, 10% Latina and 7% African American; 82% were college graduates. Ninety-five to ninety-eight percent indicated that they would have screening for each condition, and the majority would have amniocentesis (64% for PKU to 72% for SMA. Inclinations regarding pregnancy termination varied by condition: Whereas only 10% reported they would probably or definitely terminate a pregnancy for CHD, 41% indicated they would do so for DS and 62% for SMA. Most women in this cohort reported that they would undergo screening for all six conditions presented, the majority without the intent to terminate an affected pregnancy. These women were least inclined to terminate treatable disorders (PKU, CHD versus those associated with intellectual disability (DS, FraX and were most likely to terminate for SMA, typically lethal in childhood.

Quantitative MRI study of progressive cerebral atrophy in multiple system atrophy

International Nuclear Information System (INIS)

Konagaya, Masaaki; Matsuoka, Yukihiko; Konagaya, Yoko

2002-01-01

We investigated cerebral atrophy in multiple system atrophy (MSA) by quantitative analysis of MRI. The subjects were 28 patients with MSA (14 striato-nigral degeneration; SND, 14 olivo-ponto-cerebellar atrophy; OPCA. 106 MRI examinations were performed totally) and 85 normal persons for control. The ratios of the ventral pons to the infratentorial space in the sagittal section, the putamen, cerebrum, frontal lobe and parietal and occipital lobes to the intracranial space in the horizontal section, and the temporal lobe to the intracranial space in the coronal section were measured. In the early stage of the disease, OPCA showed significant atrophy of the ventral pons compared with SND, and conversely, SND demonstrated significantly smaller putamen than that in OPCA. According to the progression of the disease, the atrophy of these neural tissues progressed, which resulted in so significant differences between SND and OPCA. The cerebral atrophy was observed in 17 MSA patients. The atrophy of the frontal lobe was much frequent and prominent to that in the temporal lobe and parietal and occipital lobes. SND showed higher incidence of the cerebral atrophy than OPCA in the early stage of the disease. In long period follow-up cases, one case showed cerebral atrophy in earlier stage, and another case in late stage. We indicated the involvement of the cerebral hemispheres in MSA, especially the frontal lobe. (author)

Quantitative MRI study of progressive cerebral atrophy in multiple system atrophy

Energy Technology Data Exchange (ETDEWEB)

Konagaya, Masaaki; Matsuoka, Yukihiko [Suzuka National Hospital, Suzuka, Mie (Japan); Konagaya, Yoko [JR Tokai General Hospital, Nagoya (Japan)

2002-02-01

We investigated cerebral atrophy in multiple system atrophy (MSA) by quantitative analysis of MRI. The subjects were 28 patients with MSA (14 striato-nigral degeneration; SND, 14 olivo-ponto-cerebellar atrophy; OPCA. 106 MRI examinations were performed totally) and 85 normal persons for control. The ratios of the ventral pons to the infratentorial space in the sagittal section, the putamen, cerebrum, frontal lobe and parietal and occipital lobes to the intracranial space in the horizontal section, and the temporal lobe to the intracranial space in the coronal section were measured. In the early stage of the disease, OPCA showed significant atrophy of the ventral pons compared with SND, and conversely, SND demonstrated significantly smaller putamen than that in OPCA. According to the progression of the disease, the atrophy of these neural tissues progressed, which resulted in so significant differences between SND and OPCA. The cerebral atrophy was observed in 17 MSA patients. The atrophy of the frontal lobe was much frequent and prominent to that in the temporal lobe and parietal and occipital lobes. SND showed higher incidence of the cerebral atrophy than OPCA in the early stage of the disease. In long period follow-up cases, one case showed cerebral atrophy in earlier stage, and another case in late stage. We indicated the involvement of the cerebral hemispheres in MSA, especially the frontal lobe. (author)

Calpain 3 Expression Pattern during Gastrocnemius Muscle Atrophy and Regeneration Following Sciatic Nerve Injury in Rats

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Ronghua Wu

2015-11-01

Full Text Available Calpain 3 (CAPN3, also known as p94, is a skeletal muscle-specific member of the calpain family that is involved in muscular dystrophy; however, the roles of CAPN3 in muscular atrophy and regeneration are yet to be understood. In the present study, we attempted to explain the effect of CAPN3 in muscle atrophy by evaluating CAPN3 expression in rat gastrocnemius muscle following reversible sciatic nerve injury. After nerve injury, the wet weight ratio and cross sectional area (CSA of gastrocnemius muscle were decreased gradually from 1–14 days and then recovery from 14–28 days. The active form of CAPN3 (~62 kDa protein decreased slightly on day 3 and then increased from day 7 to 14 before a decrease from day 14 to 28. The result of linear correlation analysis showed that expression of the active CAPN3 protein level was negatively correlated with muscle wet weight ratio. CAPN3 knockdown by short interfering RNA (siRNA injection improved muscle recovery on days 7 and 14 after injury as compared to that observed with control siRNA treatment. Depletion of CAPN3 gene expression could promote myoblast differentiation in L6 cells. Based on these findings, we conclude that the expression pattern of the active CAPN3 protein is linked to muscle atrophy and regeneration following denervation: its upregulation during early stages may promote satellite cell renewal by inhibiting differentiation, whereas in later stages, CAPN3 expression may be downregulated to stimulate myogenic differentiation and enhance recovery. These results provide a novel mechanistic insight into the role of CAPN3 protein in muscle regeneration after peripheral nerve injury.

Tensile and fatigue behavior of polymer composites reinforced with superelastic SMA strands

Science.gov (United States)

Daghash, Sherif M.; Ozbulut, Osman E.

2018-06-01

This study explores the use of superelastic shape memory alloy (SMA) strands, which consist of seven individual small-diameter wires, in an epoxy matrix and characterizes the tensile and fatigue responses of the developed SMA/epoxy composites. Using a vacuum assisted hand lay-up technique, twelve SMA fiber reinforced polymer (FRP) specimens were fabricated. The developed SMA-FRP composites had a fiber volume ratio of 50%. Tensile response of SMA-FRP specimens were characterized under both monotonic loading and increasing amplitude loading and unloading cycles. The degradation in superelastic properties of the developed SMA-FRP composites during fatigue loading at different strain amplitudes was investigated. The effect of loading rate on the fatigue response of SMA-FRP composites was also explored. In addition, fractured specimens were examined using the scanning electron microscopy (SEM) technique to study the failure mechanisms of the tested specimens. A good interfacial bonding between the SMA strands and epoxy matrix was observed. The developed SMA-FRP composites exhibited good superelastic behavior at different strain amplitudes up to at least 800 cycle after which significant degradation occurred.

[History of hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P)].

Science.gov (United States)

Takashima, Hiroshi

2013-01-01

We established a new disease autosomal dominant hereditary motor and sensory neuropathy with proximal dominant involvement (HMSNP) in 1997, in Okinawa, Japan. This disease is characterized by proximal dominant neurogenic atrophy with fasciculations, painful muscle cramp, obvious sensory nerve involvement, areflexia, high incidence of elevated creatine kinase levels, hyperlipidemia and hyperglycemia. (MIM %604484). HMSNP is so called or HMSNO (HMSN OKINAWA type),. These clinical features resembled those of Kennedy-Alter-Sung syndrome. Most HMSNP patients have severe muscle atrophy and finally the tracheostomy and artificial ventilation are required. Therefore, we initially thought to classify HMSNP into a subtype of motor neuron disease (MND) like familial amyotrophic lateral sclerosis (FALS) or spinal muscular atrophy (SMA). However, the general consensus for MND was no sensory involvement. Therefore, as the disease showed severe sensory involvement, we categorized HMSNP in subtype of HMSN at that time. We also reported the pathology of HMSNP, showing severely decreased anterior horn cells, decreased posterior horn cells, and loss of posterior funiculus in the spinal cord.

Immunoproteasome in animal models of Duchenne muscular dystrophy.

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Chen, Chiao-Nan Joyce; Graber, Ted G; Bratten, Wendy M; Ferrington, Deborah A; Thompson, LaDora V

2014-04-01

Increased proteasome activity has been implicated in the atrophy and deterioration associated with dystrophic muscles of Duchenne muscular dystrophy (DMD). While proteasome inhibitors show promise in the attenuation of muscle degeneration, proteasome inhibition-induced toxicity was a major drawback of this therapeutic strategy. Inhibitors that selectively target the proteasome subtype that is responsible for the loss in muscle mass and quality would reduce side effects and be less toxic. This study examined proteasome activity and subtype populations, along with muscle function, morphology and damage in wild-type (WT) mice and two murine models of DMD, dystrophin-deficient (MDX) and dystrophin- and utrophin-double-knockout (DKO) mice. We found that immunoproteasome content was increased in dystrophic muscles while the total proteasome content was unchanged among the three genotypes of mice. Proteasome proteolytic activity was elevated in dystrophic muscles, especially in DKO mice. These mice also exhibited more severe muscle atrophy than either WT or MDX mice. Muscle damage and regeneration, characterized by the activity of muscle creatine kinase in the blood and the percentage of central nuclei were equally increased in dystrophic mice. Accordingly, the overall muscle function was similarly reduced in both dystrophic mice compared with WT. These data demonstrated that there was transformation of standard proteasomes to immunoproteasomes in dystrophic muscles. In addition, DKO that showed greatest increase in proteasome activities also demonstrated more severe atrophy compared with MDX and WT. These results suggest a putative role for the immunoproteasome in muscle deterioration associated with DMD and provide a potential target for therapeutic intervention.

Importance of Skin Changes in the Differential Diagnosis of Congenital Muscular Dystrophies

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Uluç Yis

2016-01-01

Full Text Available Megaconial congenital muscular dystrophy (OMIM 602541 is characterized with early-onset hypotonia, muscle wasting, proximal weakness, cardiomyopathy, mildly elevated serum creatine kinase (CK levels, and mild-to-moderate intellectual disability. We report two siblings in a consanguineous family admitted for psychomotor delay. Physical examination revealed proximal muscle weakness, contractures in the knee of elder sibling, diffuse mild generalized muscle atrophy, and dry skin with ichthyosis together with multiple nummular eczema in both siblings. Serum CK values were elevated up to 500 U/L. For genetic work-up, we performed whole exome sequencing (WES after Nimblegen enrichment on the Illumina platform. The WES revealed a novel homozygous missense mutation in the Choline Kinase-Beta (CHKB gene c.1031G>A (p.R344Q in exon 9. Ichthyosis-like skin changes with intense pruritus and nummular eczema may lead to clinical diagnosis in cases with megaconial congenital muscular dystrophy.

A Human Pluripotent Stem Cell Model of Facioscapulohumeral Muscular Dystrophy-Affected Skeletal Muscles.

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Caron, Leslie; Kher, Devaki; Lee, Kian Leong; McKernan, Robert; Dumevska, Biljana; Hidalgo, Alejandro; Li, Jia; Yang, Henry; Main, Heather; Ferri, Giulia; Petek, Lisa M; Poellinger, Lorenz; Miller, Daniel G; Gabellini, Davide; Schmidt, Uli

2016-09-01

: Facioscapulohumeral muscular dystrophy (FSHD) represents a major unmet clinical need arising from the progressive weakness and atrophy of skeletal muscles. The dearth of adequate experimental models has severely hampered our understanding of the disease. To date, no treatment is available for FSHD. Human embryonic stem cells (hESCs) potentially represent a renewable source of skeletal muscle cells (SkMCs) and provide an alternative to invasive patient biopsies. We developed a scalable monolayer system to differentiate hESCs into mature SkMCs within 26 days, without cell sorting or genetic manipulation. Here we show that SkMCs derived from FSHD1-affected hESC lines exclusively express the FSHD pathogenic marker double homeobox 4 and exhibit some of the defects reported in FSHD. FSHD1 myotubes are thinner when compared with unaffected and Becker muscular dystrophy myotubes, and differentially regulate genes involved in cell cycle control, oxidative stress response, and cell adhesion. This cellular model will be a powerful tool for studying FSHD and will ultimately assist in the development of effective treatments for muscular dystrophies. This work describes an efficient and highly scalable monolayer system to differentiate human pluripotent stem cells (hPSCs) into skeletal muscle cells (SkMCs) and demonstrates disease-specific phenotypes in SkMCs derived from both embryonic and induced hPSCs affected with facioscapulohumeral muscular dystrophy. This study represents the first human stem cell-based cellular model for a muscular dystrophy that is suitable for high-throughput screening and drug development. ©AlphaMed Press.

Brain atrophy during aging

International Nuclear Information System (INIS)

Matsuzawa, Taiju; Yamada, Kenji; Yamada, Susumu; Ono, Shuichi; Takeda, Shunpei; Hatazawa, Jun; Ito, Masatoshi; Kubota, Kazuo

1985-01-01

Age-related brain atrophy was investigated in thousands of persons with no neurologic disturbances using X-CT and NMR-CT. Brain atrophy was minimal in 34-35 years old in both sexes, increased exponentially to the increasing age after 34-35 years, and probably resulted in dementia, such as vascular or multi-infarct dementia. Brain atrophy was significantly greater in men than in women at all ages. Brain volumes were maximal in 34-35 years old in both sexes with minimal individual differences which increased proportionally to the increasing age. Remarkable individual differences in the extent of brain atrophy (20 - 30 %) existed among aged subjects. Progression of brain atrophy was closely related to loss of mental activities independently of their ages. Our longitudinal study has revealed that the most important factors promoting brain atrophy during aging was the decrease in the cerebral blood flow. We have classified brain atrophy into sulcal and cisternal enlargement type (type I), ventricular enlargement type (type II) and mixed type (type III) according to the clinical study using NMR-CT. Brain atrophy of type I progresses significantly in almost all of the geriatric disorders. This type of brain atrophy progresses significantly in heavy smokers and drinkers. Therefore this type of brain atrophy might be caused by the decline in the blood flow in anterior and middle cerebral arteries. Brain atrophy of type II was caused by the disturbance of cerebrospinal fluid circulation after cerebral bleeding and subarachnoid bleeding. Brain atrophy of type III was seen in vascular dementia or multi-infarct dementia which was caused by loss of brain matter after multiple infarction, and was seen also in dementia of Alzheimer type in which degeneration of nerve cells results in brain atrophy. NMR-CT can easily detect small infarction (lacunae) and edematous lesions resulting from ischemia and hypertensive encephalopathy. (J.P.N.)

Voxel-based morphometry in the parkinson variant of multiple system atrophy

International Nuclear Information System (INIS)

Zhao Yanping; Wang Han; Li Zhou; Feng Feng

2010-01-01

Objective: To assess patterns of the gray and white matter atrophy in patients with multiple system atrophy-P (MSA-P) variant of whole brain compared with normal controls. Methods: Three dimensional fast spoiled gradient echo (3D-FSPGR) T 1 WI of whole brain were obtained from 13 patients with probable MSA-P and 14 age-matched normal controls. The volume of gray matter (GM) and white matter (WM) of MSA-P patients and normal controls was analyzed with voxel-based morphometry (VBM) using statistical parametric mapping (SPM) 8. Results: Compared with the controls, the MSA-P patients showed decreased gray matter and white matter in broad areas. Gray matter loss mainly symmetrically distributed in bilateral supplementary motor area (SMA), dorsal posterior cingulate cortex (DPCC), medial frontal gyrus, superior temporal gyrus, cerebellum cortex, eta Unilateral involvement of cortices mainly located in right primary motor cortex, somatosensory association cortex (SAC), and left ventral anterior cingulate cortex (VACC). There was white matter loss in bilateral superior frontal gyrus, bilateral precuneus, bilateral sub-gyrus of frontal lobe, left superior temporal gyrus, left cingulate gyrus, right orbitofrontal area, right sub- gyrus of temporal lobe, etc. Conclusion: VBM method is an automatic and comprehensive volumetry method and can objectively detect the difference of the whole brain structure in patients with probable MSA- P comparing with normal controls. (authors)

[Role of growth hormone underproduction and support load deficit in development of muscle atrophy and osteopenia in tail-suspended rats].

Science.gov (United States)

Kaplanskiĭ, A S; Durnova, G N; Ili'ina-Kakueva, E I; Loginov, V I

1999-01-01

In a 20-day experiment with tail-suspended male rats histological and histomorphometric techniques were used to study the effects of growth hormone, thyroxin, and graded support loads on the progress of atrophy in soleus and gastrocnemius m.m., tibial metaphyses spongiosis, and growth of tibiae. Daily injections of growth hormone at a dose of 0.5 mg/kg of the body mass were found to restore the longitudinal growth of tibiae and to suppress osteopenia in the spongiosis of metaphyses; however, they did not have any noteworthy effect on the muscular atrophy in the suspended rats. Support loading of the hind limbs for 2 hours a day in parallel to the treatment with growth hormone and thyroxin (0.02 mg/kg of the body mass per a day) suppressed the atrophy in soleus m. but not in gastrocnemius m. They were not able to oppose to osteoporosis in tibial metaphyses spongiosis; tibial growth was not normalized. Thyroxin did not appear to markedly influence muscle and bone atrophies; moreover, it made hypofunctioning of the thyroid more intense and, when combined with the growth hormone, masked the positive effect of the latter on the rats' bones.

Dynamic changes in the mouse skeletal muscle proteome during denervation-induced atrophy

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Franziska Lang

2017-07-01

Full Text Available Loss of neuronal stimulation enhances protein breakdown and reduces protein synthesis, causing rapid loss of muscle mass. To elucidate the pathophysiological adaptations that occur in atrophying muscles, we used stable isotope labelling and mass spectrometry to quantify protein expression changes accurately during denervation-induced atrophy after sciatic nerve section in the mouse gastrocnemius muscle. Additionally, mice were fed a stable isotope labelling of amino acids in cell culture (SILAC diet containing 13C6-lysine for 4, 7 or 11 days to calculate relative levels of protein synthesis in denervated and control muscles. Ubiquitin remnant peptides (K-ε-GG were profiled by immunoaffinity enrichment to identify potential substrates of the ubiquitin-proteasomal pathway. Of the 4279 skeletal muscle proteins quantified, 850 were differentially expressed significantly within 2 weeks after denervation compared with control muscles. Moreover, pulse labelling identified Lys6 incorporation in 4786 proteins, of which 43 had differential Lys6 incorporation between control and denervated muscle. Enrichment of diglycine remnants identified 2100 endogenous ubiquitination sites and revealed a metabolic and myofibrillar protein diglycine signature, including myosin heavy chains, myomesins and titin, during denervation. Comparative analysis of these proteomic data sets with known atrogenes using a random forest approach identified 92 proteins subject to atrogene-like regulation that have not previously been associated directly with denervation-induced atrophy. Comparison of protein synthesis and proteomic data indicated that upregulation of specific proteins in response to denervation is mainly achieved by protein stabilization. This study provides the first integrated analysis of protein expression, synthesis and ubiquitin signatures during muscular atrophy in a living animal.

National education ideology as the orientation of the school culture development policy at SMA N 1 and SMA N 3 Yogyakarta

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Lusila Andriani Purwastuti

2017-09-01

Full Text Available This study aimed at describing the national education ideology as the orientation of the school culture development policy at SMA N 1 and SMAN 3 Yogyakarta. This research employed the qualitative approach through ethnography method. The subjects of the research were the school community. The object was the implementation of Pancasila on the development of the school culture. The data were collected through interviews, observations, and documentation. The data were analyzed using ethnography analysis as suggested by Spradley and they were validated by data triangulation and member checks. The results show that the national education ideology as the orientation of the school culture development is understood: (1 as an open ideology; (2 implemented on the basis value; instrumental values; the value of practices in the school culture; (3 The school culture in SMA N 1 and SMA N 3 is the implementation and contextualization of the values of Pancasila, along with the uniqueness of SMA N 1 with its “Teladan” icon which represents the religious morality and intellectual, as well as at SMA N 3 with its “Padmanaba” icon representing noble behavior. (4  Both schools have developed the school culture, namely: religious morality, social-culture, intellectual, and environment/management/leadership.

Toxic myopathies: muscle biopsy features Miopatia tóxica: biópsia muscular

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Rosana Herminia Scola

2007-03-01

Full Text Available Several drugs and toxic substances can cause muscular abnormalities and are frequent causes of acquired myopathies. We present a series of 32 patients, predominance of young adult patients, diagnosed with toxic myopathy. The most common substances inducing myopathy were corticosteroids (56.2% followed by the propoxyphene, neuroleptics, zidovudine and drug-induced hypokalemia. The investigation showed normal serum creatine kinase levels in 65.4%, myopathic pattern of the needle electromyography in 40% and the more frequent histological diagnosis of the muscle biopsy was type 2 fiber atrophy (59.3%. Clinical features, etiology, course of the disease, serum levels of muscular enzymes, electromyographic features and, especially, muscle biopsy features are discussed.Diversos medicamentos e substâncias tóxicas podem causar alterações musculares e são causas freqüentes de miopatia adquirida. Apresentamos uma série de 32 pacientes, predomínio de pacientes adulto jovens, com miopatia tóxica. As substâncias mais relacionadas com a miopatia foram os corticosteróides (56,2% seguidos pelo propoxifeno, neurolépticos, zidovudina e drogas indutoras de hipocalemia. A investigação mostrou níveis normais de creatino quinase sérica em 65,4%, eletromiografia de agulha com padrão miopático em 40% e o mais freqüente diagnóstico histológico da biópsia muscular foi atrofia de fibras do tipo 2 (59,3%. As manifestações clínicas, etiologia, tempo de evolução, nível sérico das enzimas musculares, alterações da eletroneuromiografia e, especialmente, da biópsia muscular são discutidos.

Dynamics study of free volume properties of SMA/SMMA blends by PAL method

International Nuclear Information System (INIS)

Jiang, Z.Y.; Jiang, X.Q.; Huang, Y.J.; Lin, J.; Li, S.M.; Li, S.Z.; Hsia, Y.F.

2006-01-01

Miscibility of poly(styrene-co-maleic anhydride) (containing 7 wt% maleic anhydride)/poly(styrene-co-methyl methacrylate) (containing 40 wt% styrene) blends were previously studied. It was obtained that SMA70 (containing 70 wt% of SMA in SMA/SMMA blends) is miscible in molecular level but SMA20 is not. In this paper, the two blends selected were used to investigate the temperature dependence of free volume parameters. It showed there are different deviations of free volume parameters in SMA20 and SMA70, and it was interesting that temperature dependence of ortho-positronium lifetime τ 3 of the SMA20 mixture exhibits two breaks in the range temperature from 90 deg. C to 120 deg. C, which revealed that the mixture has two glass transition ranges. Also, ortho-positronium lifetime τ 3 of the SMA20 mixture is nearly constant in the temperature range from 130 deg. C to 160 deg. C. These indicated that SMA20 blend is phase-separated in room temperature and become miscible above 130 deg. C, which may be due to steric hindrance effect of phenyl rings of SMMA and SMA. From the deviation of o-Ps lifetimes of SMA70, the single glass transition temperature of SMA70 blend was shown. Combining the previous study, it was further concluded that PAL method seems to be a powerful method to detect in situ phase behavior of immiscible polymer blends and glass transition of miscible polymer blends

Adaptive and energy efficient SMA-based handling systems

Science.gov (United States)

Motzki, P.; Kunze, J.; Holz, B.; York, A.; Seelecke, S.

2015-04-01

Shape Memory Alloys (SMA's) are known as actuators with very high energy density. This fact allows for the construction of very light weight and energy-efficient systems. In the field of material handling and automated assembly process, the avoidance of big moments of inertia in robots and kinematic units is essential. High inertial forces require bigger and stronger robot actuators and thus higher energy consumption and costs. For material handling in assembly processes, many different individual grippers for various work piece geometries are used. If one robot has to handle different work pieces, the gripper has to be exchanged and the assembly process is interrupted, which results in higher costs. In this paper, the advantages of using high energy density Shape Memory Alloy actuators in applications of material-handling and gripping-technology are explored. In particular, light-weight SMA actuated prototypes of an adaptive end-effector and a vacuum-gripper are constructed via rapid-prototyping and evaluated. The adaptive end-effector can change its configuration according to the work piece geometry and allows the handling of multiple different shaped objects without exchanging gripper tooling. SMA wires are used to move four independent arms, each arm adds one degree of freedom to the kinematic unit. At the tips of these end-effector arms, SMA-activated suction cups can be installed. The suction cup prototypes are developed separately. The flexible membranes of these suction cups are pulled up by SMA wires and thus a vacuum is created between the membrane and the work piece surface. The self-sensing ability of the SMA wires are used in both prototypes for monitoring their actuation.

Energy-dissipating and self-repairing SMA-ECC composite material system

International Nuclear Information System (INIS)

Li, Xiaopeng; Li, Mo; Song, Gangbing

2015-01-01

Structural component ductility and energy dissipation capacity are crucial factors for achieving reinforced concrete structures more resistant to dynamic loading such as earthquakes. Furthermore, limiting post-event residual damage and deformation allows for immediate re-operation or minimal repairs. These desirable characteristics for structural ‘resilience’, however, present significant challenges due to the brittle nature of concrete, its deformation incompatibility with ductile steel, and the plastic yielding of steel reinforcement. Here, we developed a new composite material system that integrates the unique ductile feature of engineered cementitious composites (ECC) with superelastic shape memory alloy (SMA). In contrast to steel reinforced concrete (RC) and SMA reinforced concrete (SMA-RC), the SMA-ECC beams studied in this research exhibited extraordinary energy dissipation capacity, minimal residual deformation, and full self-recovery of damage under cyclic flexural loading. We found that the tensile strain capacity of ECC, tailored up to 5.5% in this study, allows it to work compatibly with superelastic SMA. Furthermore, the distributed microcracking damage mechanism in ECC is critical for sufficient and reliable recovery of damage upon unloading. This research demonstrates the potential of SMA-ECC for improving resilience of concrete structures under extreme hazard events. (paper)

Numerical tool for SMA material simulation: application to composite structure design

International Nuclear Information System (INIS)

Chemisky, Yves; Tahiri, Vanessa; Duval, Arnaud; Piotrowski, Boris; Ben Zineb, Tarak; Patoor, Etienne

2009-01-01

Composite materials based on shape memory alloys (SMA) have received growing attention over these last few years. In this paper, two particular morphologies of composites are studied. The first one is an SMA/elastomer composite in which a snake-like wire NiTi SMA is embedded into an elastomer ribbon. The second one is a commercial Ni 47 Ti 44 Nb 9 which presents elastic–plastic inclusions in an NiTi SMA matrix. In both cases, the design of such composites required the development of an SMA design tool, based on a macroscopic 3D constitutive law for NiTi alloys. Two different strategies are then applied to compute these composite behaviors. For the SMA/elastomer composite, the macroscopic behavior law is implemented in commercial FEM software, and for the Ni 47 Ti 44 Nb 9 a scale transition approach based on the Mori–Tanaka scheme is developed. In both cases, simulations are compared to experimental data

MODEL EVALUASI INTERNAL KOMPETENSI GURU BAHASA INGGRIS (MODEL_EIKGBI) SMA

OpenAIRE

Sahraini Sahraini; Suwarsih Madya

2015-01-01

Studi ini bertujuan untuk: (1) mengembangkan model evaluasi kompetensi guru bahasa Inggris SMA yang dapat digunakan untuk mengidentifikasi kelebihan dan kekurangan guru dalam proses pemelajaran dan (2) mengetahui efektivitas implementasi evaluasi internal kompetensi guru bahasa Inggris SMA. Studi ini menggunakan metode penelitian dan pengembangan yang dikembangkan oleh Borg & Gall (1983, p.775). Subjek penelitian berjumlah 17 guru yang berasal dari 7 SMA di Sulawesi Selatan. Konstruk instrume...

Duchenne and Becker muscular dystrophy: a molecular and immunohistochemical approach Distrofia muscular de Duchenne e Becker: abordagem molecular e imuno-histoquímica

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Aline Andrade Freund

2007-03-01

Full Text Available Duchenne muscular dystrophy (DMD and Becker muscular dystrophy (BMD are caused by mutations in the dystrophin gene. We studied 106 patients with a diagnosis of probable DMD/BMD by analyzing 20 exons of the dystrophin gene in their blood and, in some of the cases, by immunohistochemical assays for dystrophin in muscle biopsies. In 71.7% of the patients, deletions were found in at least one of the exons; 68% of these deletions were in the hot-spot 3' region. Deletions were found in 81.5% of the DMD cases and in all the BMD cases. The cases without deletions, which included the only woman in the study with DMD, had dystrophin deficiency. The symptomatic female carriers had no deletions but had abnormal dystrophin distribution in the sarcolemma (discontinuous immunostains. The following diagnoses were made for the remaining cases without deletions with the aid of a muscle biopsy: spinal muscular atrophy, congenital myopathy; sarcoglycan deficiency and unclassified limb-girdle muscular dystrophy. Dystrophin analysis by immunohistochemistry continues to be the most specific method for diagnosis of DMD/BMD and should be used when no exon deletions are found in the dystrophin gene in the blood.As distrofias musculares de Duchenne (DMD e de Becker (DMB são doenças causadas por mutação no gene da distrofina. Foram estudados 106 casos com a suspeita diagnóstica de DMD/BMD com a analise de 20 exons do gene da distrofina no sangue e biópsia muscular com imuno-histoquímica para distrofina em alguns casos. Em 71,7% dos casos foi encontrada deleção em pelo menos um dos exons, sendo que 68% das deleções localizam-se na região 3' hot spot. Foram encontradas deleções em 81,5% dos DMD e em todos os BMD, sendo que os sem deleção tinham deficiência de distrofina, incluindo a mulher com DMD. As portadoras sintomáticas não tinham deleções mas anormalidades na distribuição da distrofina no sarcolema. Os outros casos sem deleção, com auxilio da

Fabricating Composite-Material Structures Containing SMA Ribbons

Science.gov (United States)

Turner, Travis L.; Cano, Roberto J.; Lach, Cynthia L.

2003-01-01

An improved method of designing and fabricating laminated composite-material (matrix/fiber) structures containing embedded shape-memory-alloy (SMA) actuators has been devised. Structures made by this method have repeatable, predictable properties, and fabrication processes can readily be automated. Such structures, denoted as shape-memory-alloy hybrid composite (SMAHC) structures, have been investigated for their potential to satisfy requirements to control the shapes or thermoelastic responses of themselves or of other structures into which they might be incorporated, or to control noise and vibrations. Much of the prior work on SMAHC structures has involved the use SMA wires embedded within matrices or within sleeves through parent structures. The disadvantages of using SMA wires as the embedded actuators include (1) complexity of fabrication procedures because of the relatively large numbers of actuators usually needed; (2) sensitivity to actuator/ matrix interface flaws because voids can be of significant size, relative to wires; (3) relatively high rates of breakage of actuators during curing of matrix materials because of sensitivity to stress concentrations at mechanical restraints; and (4) difficulty of achieving desirable overall volume fractions of SMA wires when trying to optimize the integration of the wires by placing them in selected layers only.

KESULITAN PEMECAHAN MASALAH FISIKA PADA SISWA SMA

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Rismatul Azizah

2015-12-01

Full Text Available Telah dilakukan penelitian untuk mengidentifikasi kesulitan pemecahan masalah fisika pada siswa SMA. Penelitian ini menggunakan metode survey dengan menyebarkan angket. Responden terdiri dari 120 siswa yang berasal dari 3 sekolah yaitu, SMA Negeri 1 Bangil, SMA Negeri 8 Malang, dan SMA YADIKA Bangil. Dilakukan pula wawancara pada beberapa guru dan siswa. Berdasarkan hasil penyebaran angket, diperoleh 26% siswa mengalami kesulitan pada materi Suhu dan Kalor, 25% Optik, 21% Fluida Statik, 17% Elastisitas dan Hukum Hooke, dan 11% Kinematika. Kesulitan tersebut salah satunya disebabkan pembelajaran bagi siswa yang kurang maksimal dalam bentuk hands on activity. Sebanyak 88% siswa mengatakan bahwa pembelajaran fisika yang sering dialami adalah dengan metode ceramah. Siswa mengalami kesulitan belajar fisika dalam menyelesaikan permasalahan pada soal sebesar 32%, kesulitan memahami konsep dan rumus 26%, kesulitan menggunakan persamaan atau rumus dalam soal 18%, kesulitan menganalisis grafik dan gambar 17%, dan kesulitan menyimpulkan materi yang telah dipelajari 7%. Kesulitan tersebut terlihat ketika siswa memecahkan permasalahan pada soal kinematika serta suhu dan kalor. Diperoleh dari hasil angket, bahwa 76% siswa mengalami kesulitan dalam memecahkan permasalahan pada soal dengan alasan lupa atau tidak paham, sebesar 19% siswa kurang memahami solusi pemecahan masalah pada soal, dan hanya sebesar 5% siswa mampu memecahkan permasalahan pada soal.

Atrofia muscular bulbo espinhal recessiva ligada ao cromossomo X (doença de Kennedy: estudo de uma família X-linked recessive bulbospinal muscular atrophy (Kennedy's disease: study of a family

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DAMACIO RAMÓN KAIMEN-MACIEL

1998-09-01

Full Text Available A doença de Kennedy (DK é forma rara de doença do neurônio motor caracterizada por mutação na região codificadora do gene do receptor androgênico localizado no braço longo do cromossoma X (Xq 11-12. Há expansão das sequências de trinucleotídeos CAG que nos pacientes deve atingir número maior do que 347 repetições de pares de bases. Apresentamos quatro gerações de uma família com dez indivíduos acometidos. Avaliamos três pacientes do sexo masculino com idade variando entre 50 e 60 anos que desenvolveram sintomatologia por volta de 30 anos de idade caracterizada por fraqueza muscular progressiva associada a disfagia e disartria. O exame demonstrou ginecomastia, atrofia testicular, amiotrofia, fasciculações, paresia, abolição de reflexos e tremor postural. A análise do DNA pela técnica do PCR demonstrou número de repetições CAG aumentado no locus Xq 11-12 nos três pacientes e em uma mulher assintomática da família. Demonstramos a primeira família brasileira com diagnóstico de DK através de genética molecular. A DK deve fazer parte do diagnóstico diferencial das doenças do neurônio motor e a identificação destes pacientes é importante para o prognóstico e para o aconselhamento genético.Kennedy's disease is a rare type of motor neuron disease with a sex-linked recessive trait. DNA studies show a mutation at the androgen receptor gene on the long arm of X cromossome (Xq 11-12 with expanded CAG triplets (more than 347 repeats. We present three patients and one carrier among ten patients of a four generation family with clinical phenotype of the disease. The patients' ages ranged from 50 to 60 years with symptomatology usually beginning around 30 years of age. Patients had gynecomastia, testicular atrophy, muscular weakness, fasciculation, amyotrophy, absent deep tendon reflexes and postural tremor. PCR techniques of DNA analysis showed expanded size of CAG repeats on Xq 11-12 in all the three patients and in

HuD and the Survival Motor Neuron Protein Interact in Motoneurons and Are Essential for Motoneuron Development, Function, and mRNA Regulation.

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Hao le, Thi; Duy, Phan Q; An, Min; Talbot, Jared; Iyer, Chitra C; Wolman, Marc; Beattie, Christine E

2017-11-29

Motoneurons establish a critical link between the CNS and muscles. If motoneurons do not develop correctly, they cannot form the required connections, resulting in movement defects or paralysis. Compromised development can also lead to degeneration because the motoneuron is not set up to function properly. Little is known, however, regarding the mechanisms that control vertebrate motoneuron development, particularly the later stages of axon branch and dendrite formation. The motoneuron disease spinal muscular atrophy (SMA) is caused by low levels of the survival motor neuron (SMN) protein leading to defects in vertebrate motoneuron development and synapse formation. Here we show using zebrafish as a model system that SMN interacts with the RNA binding protein (RBP) HuD in motoneurons in vivo during formation of axonal branches and dendrites. To determine the function of HuD in motoneurons, we generated zebrafish HuD mutants and found that they exhibited decreased motor axon branches, dramatically fewer dendrites, and movement defects. These same phenotypes are present in animals expressing low levels of SMN, indicating that both proteins function in motoneuron development. HuD binds and transports mRNAs and one of its target mRNAs, Gap43 , is involved in axonal outgrowth. We found that Gap43 was decreased in both HuD and SMN mutants. Importantly, transgenic expression of HuD in motoneurons of SMN mutants rescued the motoneuron defects, the movement defects, and Gap43 mRNA levels. These data support that the interaction between SMN and HuD is critical for motoneuron development and point to a role for RBPs in SMA. SIGNIFICANCE STATEMENT In zebrafish models of the motoneuron disease spinal muscular atrophy (SMA), motor axons fail to form the normal extent of axonal branches and dendrites leading to decreased motor function. SMA is caused by low levels of the survival motor neuron (SMN) protein. We show in motoneurons in vivo that SMN interacts with the RNA binding

Effects of electrical stimulation and stretching on the adaptation of denervated skeletal muscle: implications for physical therapy Efeitos da eletroestimulação e do alongamento muscular sobre a adaptação do músculo desnervado: implicações para a fisioterapia

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Tania F. Salvini

2012-06-01

Full Text Available BACKGROUND: This review will describe the main cellular mechanisms involved in the reduction and increase of myoproteins synthesis commonly associated with muscle atrophy and hypertrophy, respectively. OBJECTIVE: We analyzed the effects of electrical stimulation (ES and stretching exercise on the molecular pathways involved in muscle atrophy and hypertrophy. We also described the main effects and limits of these resources in the skeletal muscle, particularly on the denervated muscle. DISCUSSION: Recently, our studies showed that the ES applied in a similar manner as performed in clinical practice is able to attenuate the increase of genes expression involved in muscle atrophy. However, ES was not effective to prevent the loss of muscle mass caused by denervation. Regarding to stretching exercises, their mechanisms of action on the denervated muscle are not fully understood and studies on this area are scarce. Studies from our laboratory have found that stretching exercise increased the extracellular matrix remodeling and decreased genes expression related to atrophy in denervated muscle. Nevertheless, it was not enough to prevent muscle atrophy after denervation. CONCLUSIONS: In spite of the use of stretching exercise and ES in clinical practice in order to minimize the atrophy of denervated muscle, there is still lack of scientific evidence to justify the effectiveness of these resources to prevent muscle atrophy in denervated muscle.CONTEXTUALIZAÇÃO: Esta revisão abordará os principais mecanismos celulares envolvidos na redução e aumento da síntese de mioproteínas comumente associadas às situações de atrofia e hipertrofia muscular, respectivamente. OBJETIVO: Analisaremos os efeitos da estimulação elétrica (EE e do exercício de alongamento sobre as vias moleculares envolvidas na atrofia e hipertrofia muscular. Serão descritos os principais efeitos e os limites desses recursos no músculo esquelético, particularmente sobre o m

Feasibility study of an active soft catheter actuated by SMA wires

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Konh, Bardia; Karimi, Saeed; Miller, Scott

2018-03-01

This study aims to assess the feasibility of using a combination of thin elastomer tubes and SMA wires to develop an active catheter. Cardiac catheters have been widely used in investigational and interventional procedures such as angiography, angioplasty, electro- physiology, and endocardial ablation. The commercial models manually steer inside the patient's body via internally installed pull wires. Active catheters, on the other hand, have the potential to revolutionize surgical procedures because of their computer-controlled and enhanced motion. Shape memory alloys have been used for almost a decade as a trustworthy actuator for biomedical applications. In this work, SMA wires were attached to a small pressurized elastomer tube to realize deflection. The tube was pressurized to maintain a constant stress on the SMA wires. The tip motion via actuation of SMA wires was then measured and reported. The results of this study showed that by adopting an appropriate training process for the SMA wires prior to performing the experiments and adopting an appropriate internal pressure for the elastomer tube, less external loads on SMA wires would be needed for a consistent actuation.

Pemanfaatan Informasi Olahraga di Media Massa Cetak oleh Guru Pendidikan Jasmani dan Kesehatan dalam Pembelajaran Pendidikan Jasmani dan Kesehatan di SMA 5, SMA 6, SMA 11 Semarang

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Muhaimin Muhaimin

2011-01-01

Full Text Available Utilization of information in mass media print by master of physical education and health in physical education and health in SMA 5, SMA 6, SMA 11 Semarang. The presence of print media is now a community needs. That's because, the print media presents a variety of information including information of actual politics, culture, economy, crime, entertainment, and sports. Basically, sports information in the print media have educational value and can add insight to a reading of new knowledge. The study produced these findings: (1 third physical education and health teacher at school who becomes the object research have made use of sports information in the print media to support the success of teaching and learning process, (2 the type of information they use to support the success of learning teaching is a form of news, articles about health, (3 form of utilization is appropriate to set clipping and through direct delivery of the material in the field while providing practice in the field. This method is considered more effective because all students can immediately practice, (4 sports information in the print media meets the needs of teachers and physical health education in supporting the learning process.

The complete sequence of human chromosome 5

Energy Technology Data Exchange (ETDEWEB)

Schmutz, Jeremy; Martin, Joel; Terry, Astrid; Couronne, Olivier; Grimwood, Jane; Lowry, State; Gordon, Laurie A.; Scott, Duncan; Xie, Gary; Huang, Wayne; Hellsten, Uffe; Tran-Gyamfi, Mary; She, Xinwei; Prabhakar, Shyam; Aerts, Andrea; Altherr, Michael; Bajorek, Eva; Black, Stacey; Branscomb, Elbert; Caoile, Chenier; Challacombe, Jean F.; Chan, Yee Man; Denys, Mirian; Detter, Chris; Escobar, Julio; Flowers, Dave; Fotopulos, Dea; Glavina, Tijana; Gomez, Maria; Gonzales, Eidelyn; Goodstenin, David; Grigoriev, Igor; Groza, Matthew; Hammon, Nancy; Hawkins, Trevor; Haydu, Lauren; Israni, Sanjay; Jett, Jamie; Kadner, Kristen; Kimbal, Heather; Kobayashi, Arthur; Lopez, Frederick; Lou, Yunian; Martinez, Diego; Medina, Catherine; Morgan, Jenna; Nandkeshwar, Richard; Noonan, James P.; Pitluck, Sam; Pollard, Martin; Predki, Paul; Priest, James; Ramirez, Lucia; Rash, Sam; Retterer, James; Rodriguez, Alex; Rogers, Stephanie; Salamov, Asaf; Salazar, Angelica; Thayer, Nina; Tice, Hope; Tsai, Ming; Ustaszewska, Anna; Vo, Nu; Wheeler, Jeremy; Wu, Kevin; Yang, Joan; Dickson, Mark; Cheng, Jan-Fang; Eichler, Evan E.; Olsen, Anne; Pennacchio, Len A.; Rokhsar, Daniel S.; Richardson, Paul; Lucas, Susan M.; Myers, Richard M.; Rubin, Edward M.

2004-04-15

Chromosome 5 is one of the largest human chromosomes yet has one of the lowest gene densities. This is partially explained by numerous gene-poor regions that display a remarkable degree of noncoding and syntenic conservation with non-mammalian vertebrates, suggesting they are functionally constrained. In total, we compiled 177.7 million base pairs of highly accurate finished sequence containing 923 manually curated protein-encoding genes including the protocadherin and interleukin gene families and the first complete versions of each of the large chromosome 5 specific internal duplications. These duplications are very recent evolutionary events and play a likely mechanistic role, since deletions of these regions are the cause of debilitating disorders including spinal muscular atrophy (SMA).

Faktor Penghambat Operasionalisasi Kunjungan Rumah di SMA Negeri se-Kota Semarang

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Juwita Nasruddin

2015-09-01

Full Text Available Penelitian dilaksanakan berdasarkan fenomena di lapangan pada saat penulis melaksanakan Praktik Pengalaman Lapangan (PPL di SMP Negeri 8 Semarang dan observasi awal di SMA Negeri 8 Semarang. Tujuan dari penelitian ini untuk mengetahui apa faktor penghambat operasionalisasi Home Visit di SMA Negeri se-kota Semarang tahun ajaran 2014/2015. Jenis penelitian yang digunakan oleh penulis dalam penelitian ini yaitu jenis penelitian survei. Untuk populasi pada penelitian ini adalah semua guru BK di SMA se-kota Semarang yaitu sejumlah 59 guru BK. Sampel yang digunakan adalah sejumlah populasi yang ada. Sedangkan instrumen yang digunakan dalam penelitian ini merupakan angket. Analisis data yang digunakan dalam penelitian ini adalah deskriptif persentase. Hasil yang ditemukan bahwa faktor penghambat operasionalisasi Home Visit di SMA Negeri se-kota Semarang mengalami hambatan cukup tinggi dengan presentase sebesar 65,03%. Simpulan yang didapatkan adalah Faktor Penghambat Operasionalisasi Kunjungan Rumah (Home visit di SMA Negeri se-kota Semarang adalah kurangnya pemahaman dari guru BK berkaitan dengan Home Visit. Adapun saran yang diberikan kepada guru BK SMA Negeri se-kota Semarang adalah untuk mempelajari hakikat Home Visit dan melaksanakan prosedur operasionalisasi Home Visit dengan baik dan benar dari perencanaan, pelaksanaan, evaluasi, analisis evaluasi, tindak lanjut hingga laporan. The research was conducted based on the phenomenon on the ground when implementing writer Practice Field Experience (PPL in SMPN 8 Semarang and preliminary observations in SMAN 8 Semarang. The purpose of this study to determine what factors inhibiting the operation of the Home Visit at all SMA Negeri in Semarang throughout the academic year 2014/2015. The type research used by the writer in this study is a survey research. The population in this study were all counselors at SMA in Semarang city. There were 59 counselors. The sample used were as many as the population

Superelastic SMA U-shaped dampers with self-centering functions

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Wang, Bin; Zhu, Songye

2018-05-01

As high-performance metallic materials, shape memory alloys (SMAs) have been investigated increasingly by the earthquake engineering community in recent years, because of their remarkable self-centering (SC) and energy-dissipating capabilities. This paper systematically presents an experimental study on a novel superelastic SMA U-shaped damper (SMA-UD) with SC function under cyclic loading. The mechanical properties, including strength, SC ability, and energy-dissipating capability with varying loading amplitudes and strain rates are evaluated. Test results show that excellent and stable flag-shaped hysteresis loops are exhibited in multiple loading cycles. Strain rate has a negligible effect on the cyclic behavior of the SMA-UD within the dynamic frequency range of typical interest in earthquake engineering. Furthermore, a numerical investigation is performed to understand the mechanical behavior of the SMA-UD. The numerical model is calibrated against the experimental results with reasonable accuracy. Then, the stress–strain states with different phase transformations are also discussed.

Evaluation of skeletal muscular involvement in neuromuscular disorders with thallium-201 whole body scintigraphy

International Nuclear Information System (INIS)

Yamamoto, Shuhei; Sotobata, Iwao; Indo, Toshikatsu; Matsuoka, Yukihiko; Matsushima, Hideo; Suzuki, Akio; Abe, Tetsutaro; Sakuma, Sadayuki

1986-01-01

The extent as well as severity of pathologic changes of skeletal muscles were analyzed with thallium-201 whole body scintigraphy (WBS) in 29 cases of various types of neuromuscular diseases (18 cases of myogenic and 11 cases of neurogenic muscular diseases) and 14 cases of normal controls. After intravenous injection of 2 mCi of thallium-201 chloride, WBS was performed for 15 minutes using a gamma camera with twin-opposed large rectangular detectors. Counts at brachia, forearms, thighs, and calves were assessed after reconstruction of the scintigram of the whole body by taking the geometric mean of the anterior and posterior data. WBS showed uniform tracer activities in the 4 extremities in 12 cases among 14 controls. Laterality in distribution of counts of both legs and arms was noted in the remaining 2 controls. WBS revealed decrease of perfusion in the extremities with muscular atrophy and/or weakness in neuromuscular diseases. The overall diagnostic accuracy of WBS for evaluation of skeletal muscle involvement was 75 to 80 % except for the bilateral brachia for which it decreased to 65 %. All of the three cases of muscular dystrophy with pseudohypertrophy of the calves or thighs showed unequivocal decrease of perfusion of those regions in WBS. In conclusion, thallium-201 WBS was considered to be a useful clinical means in evaluating the extent and severity of muscular involvement of various types of neuromuscular disorders. (author)

Confinement of NORMAL- AND HIGH-STRENGTH CONCRETE by Shape Memory Alloy (SMA) Spirals

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Gholampour, A.; Ozbakkaloglu, T.

2018-01-01

This paper presents the results of an experimental study on the axial compressive behaviour of normal- and high-strength concrete (NSC and HSC) confined by shape memory alloy (SMA) spirals. A spiral pitch space of 36 and 20 mm was used for SMA confinement of NSC and HSC columns, respectively. The confining pressure was applied on the concrete cylinders by SMA spirals that were prestrained at 0, 5.5, and 9.5%. The compression test results on the SMA-confined specimens indicate that the prestrain level of SMA significantly affects the axial compressive behaviour of both NSC and HSC. An increase in the level of prestrain leads to an increase in the peak axial stress and corresponding strain of SMA-confined concrete.

Experimental characterization of self-sensing SMA actuators under controlled convective cooling

International Nuclear Information System (INIS)

Lewis, N; York, A; Seelecke, S

2013-01-01

Shape memory alloy (SMA) wires are attractive for actuation systems due to their high energy density, light weight and silent operation. In addition, they feature self-sensing capabilities by relating electrical resistance measurements to strain changes. In real world applications SMAs typically operate in non-ambient air and it is imperative to understand an actuator’s behavior under varying convective cooling conditions, especially for smaller diameter wires, where convective effects are amplified. This paper shows that the multi-functionality of SMA actuators can be further extended by related heating power to convective air speed. It investigates the relationship between the normalized excess power needed and corresponding airspeed under controlled, laminar airflow patterns in a small-scale wind tunnel. For each experiment, airflow through the wind tunnel, strain in the SMA wire, and power supplied to the SMA wire were controlled, while the stress and resistance of the wire were measured. The ability to understand and predict an SMA wire’s behavior under various external airflows will aid in the design and understanding of future SMA actuated structures, such as micro-air vehicles, and shows that SMAs can function as self-sensing actuators and airspeed sensors. (paper)

Brain atrophy during aging

International Nuclear Information System (INIS)

Matsuzawa, Taiju; Takeda, Shumpei; Hatazawa, Jun

1985-01-01

Age-related brain atrophy was investigated in thousands of persons with no neurologic disturbances using X-CT and NMR-CT and following results were obtained. Brain atrophy was minimal in 34 -- 35 years old in both sexes, increased exponentially to the increasing age after 34 -- 35 years, and probably resulted in dementia, such as vascular or multiinfarct dementia. Brain atrophy was significantly greater in men than in women at all ages. Brain volumes were maximal in 34 -- 35 years old in both sexes with minimal individual differences which increased proportionally to the increasing age. Remarkable individual differences in the extents of brain atrophy (20 -- 30 %) existed among aged subjects. Some aged subjects had little or no atrophy of their brains, as seen in young subjects, and others had markedly shrunken brains associated with senility. From these results there must be pathological factors promoting brain atrophy with a great individual difference. We have studied the relation of intelligence to brain volume, and have ascertained that progression of brain atrophy was closely related to loss of mental activities independently of their ages. Our longitudinal study has revealed that the most important factors promoting brain atrophy during aging was decrease in the cerebral blood flow. MNR-CT can easily detected small infarction (lacunae) and edematous lesions resulting from ischemia and hypertensive encephalopathy, while X-CT can not. Therefore NMR-CT is very useful for detection of subtle changes in the brain. (J.P.N.)

SMA Foils for MEMS: From Material Properties to the Engineering of Microdevices

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Kohl, Manfred; Ossmer, Hinnerk; Gueltig, Marcel; Megnin, Christof

2018-03-01

In the early nineties, microelectromechanical systems (MEMS) technology has been still in its infancy. As silicon (Si) is not a transducer material, it was clear at the very beginning that mechanically active materials had to be introduced to MEMS in order to enable functional microdevices with actuation capability beyond electrostatics. At that time, shape memory alloys (SMAs) have been available in bulk form, mainly as SMA wires and SMA plates. On the macro scale, these materials show highest work densities compared to other actuation principles in the order of 107 J/m3, which stimulated research on the integration of SMA to MEMS. Subsequently, two approaches for producing planar materials have been initiated (1) magnetron sputtering of SMA thin films and (2) the integration of rolled SMA foils, which both turned out to be very successful creating a paradigm change in microactuation technology. The following review covers important milestones of the research and development of SMA foil-based microactuators including materials characterization, design engineering, technology, and demonstrator development as well as first commercial products.

SMA Foils for MEMS: From Material Properties to the Engineering of Microdevices

Science.gov (United States)

Kohl, Manfred; Ossmer, Hinnerk; Gueltig, Marcel; Megnin, Christof

2017-12-01

In the early nineties, microelectromechanical systems (MEMS) technology has been still in its infancy. As silicon (Si) is not a transducer material, it was clear at the very beginning that mechanically active materials had to be introduced to MEMS in order to enable functional microdevices with actuation capability beyond electrostatics. At that time, shape memory alloys (SMAs) have been available in bulk form, mainly as SMA wires and SMA plates. On the macro scale, these materials show highest work densities compared to other actuation principles in the order of 107 J/m3, which stimulated research on the integration of SMA to MEMS. Subsequently, two approaches for producing planar materials have been initiated (1) magnetron sputtering of SMA thin films and (2) the integration of rolled SMA foils, which both turned out to be very successful creating a paradigm change in microactuation technology. The following review covers important milestones of the research and development of SMA foil-based microactuators including materials characterization, design engineering, technology, and demonstrator development as well as first commercial products.

Myotonic Muscular Dystrophy

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... Marie-Tooth Disease (CMT) Congenital Muscular Dystrophy (CMD) Duchenne Muscular Dystrophy (DMD) Emery-Dreifuss Muscular Dystrophy Endocrine Myopathies Metabolic Diseases of Muscle Mitochondrial Myopathies (MM) Myotonic Dystrophy (DM) Spinal-Bulbar ...

Local Overexpression of V1a-Vasopressin Receptor Enhances Regeneration in Tumor Necrosis Factor-Induced Muscle Atrophy

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Alessandra Costa

2014-01-01

Full Text Available Skeletal muscle atrophy occurs during disuse and aging, or as a consequence of chronic diseases such as cancer and diabetes. It is characterized by progressive loss of muscle tissue due to hypotrophic changes, degeneration, and an inability of the regeneration machinery to replace damaged myofibers. Tumor necrosis factor (TNF is a proinflammatory cytokine known to mediate muscle atrophy in many chronic diseases and to inhibit skeletal muscle regeneration. In this study, we investigated the role of Arg-vasopressin-(AVP-dependent pathways in muscles in which atrophy was induced by local overexpression of TNF. AVP is a potent myogenesis-promoting factor and is able to enhance skeletal muscle regeneration by stimulating Ca2+/calmodulin-dependent kinase and calcineurin signaling. We performed morphological and molecular analyses and demonstrated that local over-expression of the AVP receptor V1a enhances regeneration of atrophic muscle. By upregulating the regeneration/differentiation markers, modulating the inflammatory response, and attenuating fibrogenesis, the stimulation of AVP-dependent pathways creates a favourable environment for efficient and sustained muscle regeneration and repair even in the presence of elevated levels of TNF. This study highlights a novel in vivo role for AVP-dependent pathways, which may represent an interesting strategy to counteract muscle decline in aging or in muscular pathologies.

Investigations on Vibration Characteristics of Sma Embedded Horizontal Axis Wind Turbine Blade

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Jagadeesh, V.; Yuvaraja, M.; Chandhru, A.; Viswanathan, P.; Senthil kumar, M.

2018-02-01

Vibration induced in wind turbine blade is a solemn problem as it reduces the life of the blade and also it can create critical vibration onto the tower, which may cause serious damage to the tower. The aim of this paper is to investigate the vibration characteristics of the prototype horizontal axis wind turbine blade. Shape memory alloys (SMA), with its variable physical properties, provides an alternative actuating mechanism. Heating an SMA causes a change in the elastic modulus of the material and hence SMAs are used as a damping material. A prototype blade with S1223 profile has been manufactured and the natural frequency is found. The natural frequency is found by incorporating the single SMA wire of 0.5mm diameter over the surface of the blade for a length of 240 mm. Similarly, number of SMA wires over the blade is increased up to 3 and the natural frequency is found. Frequency responses showed that the embedment of SMA over the blade’s surface will increase the natural frequency and reduce the amplitude of vibration. This is because of super elastic nature of SMA. In this paper, when SMA wire of 0.5 mm diameter and of length of 720 mm is embedded on the blade, an increase in the natural frequency by 6.3% and reducing the amplitude by 64.8%. Results of the experimental modal and harmonic indicates the effectiveness of SMA as a passive vibration absorber and that it has potential as a modest and high-performance method for controlling vibration of the blade.

Spinal Muscular Atrophy

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... and how it led to collaboration with several pharmaceutical and biotechnology companies. Information from the National Library of Medicine’s ... and how it led to collaboration with several pharmaceutical and biotechnology companies. Information from the National Library of Medicine’s ...

SMA bellows as reversible thermal sensors/actuators

International Nuclear Information System (INIS)

Damanpack, A R; Bodaghi, M; Liao, W H

2015-01-01

In this paper, the feasibility of reversible bellows made of shape memory alloys (SMAs) in sensory and actuated applications to transfer pressure and/or temperature into a linear motion is investigated. An analytical three-dimensional model is developed to simulate key features of SMAs including martensitic transformation, reorientation of martensite variants, the shape memory effect, and pseudo-elasticity. Axisymmetric two-dimensional theory of thermo-inelasticity based on the non-linear Green–Lagrange strain tensor is employed to derive the equilibrium equations. A finite element method along with an iterative incremental elastic-predictor–inelastic-corrector procedure is developed to solve the governing equations with both material and geometrical non-linearities. The feasibility of reversible SMA bellows in transferring pressure and/or temperature into a linear motion is numerically demonstrated. In this respect, the effects of geometric parameters, magnitude of thermo-mechanical loadings and end conditions on the performances of SMA bellows are evaluated and discussed in depth. This study provides pertinent results toward an efficient and reliable design of reversible thermally-driven SMA bellows. (paper)

Epidemiological survey of X-linked bulbar and spinal muscular atrophy, or Kennedy disease, in the province of Reggio Emilia, Italy.

Science.gov (United States)

Guidetti, D; Sabadini, R; Ferlini, A; Torrente, I

2001-01-01

Commencing with the work carried out during the epidemiological survey of amyotrophic lateral sclerosis in the period 1980-1992 and the pathology follow-up, we carried out a perspective incidence, prevalence and mortality survey of X-linked bulbar and spinal muscular atrophy (X-BSMA) in the province of Reggio Emilia in Northern Italy. Based on 11 patients (eight familial and three sporadic cases), the mean incidence per year for the period 1980 through 1997, as evaluated at the onset of symptoms, was 0.09 cases/100,000 for the total population and 0.19 cases/100,000 for the male population. On December 31, 1997, the prevalence rate was 1.6/100,000 for the total population and 3.3/100,000 for the male population. In the 18-year period of 1980-1997, the average yearly mortality rate was: 0.03 cases/100,000 per year for the total population and 0.06 cases/ 100,000 for the male population. The average age at onset was 44.8 +/- 10.1, and the average survival period was 27.3 +/- 2.3 years. The average age of the prevalence day was 58.9 +/- 14.9, and the average age at death was 71.3 +/- 4.7 years. Whereas the incidence rate of X-BSMA in the province of Reggio Emilia is 16 times lower that of amyotrophic lateral sclerosis (ALS), the incidence rate of progressive bulbar palsy in the male population is only slightly higher than X-BSMA; and the prevalence rate of ALS for males is two times the prevalence rate for X-BSMA, with overlapping of confidence intervals. X-BSMA is a rare disease, which is probably under-diagnosed, but due to the long survival period of this disease its frequency is not negligible. Because of the presence of sporadic cases or non-evident familial cases, it is appropriate to consider this diagnostic possibility in making a diagnosis of ALS in patients in whom lower motor neuron dysfunction or bulbar onset predominates.

Establishment of Homozygote Mutant Human Embryonic Stem Cells by Parthenogenesis.

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Epsztejn-Litman, Silvina; Cohen-Hadad, Yaara; Aharoni, Shira; Altarescu, Gheona; Renbaum, Paul; Levy-Lahad, Ephrat; Schonberger, Oshrat; Eldar-Geva, Talia; Zeligson, Sharon; Eiges, Rachel

2015-01-01

We report on the derivation of a diploid 46(XX) human embryonic stem cell (HESC) line that is homozygous for the common deletion associated with Spinal muscular atrophy type 1 (SMA) from a pathenogenetic embryo. By characterizing the methylation status of three different imprinted loci (MEST, SNRPN and H19), monitoring the expression of two parentally imprinted genes (SNRPN and H19) and carrying out genome-wide SNP analysis, we provide evidence that this cell line was established from the activation of a mutant oocyte by diploidization of the entire genome. Therefore, our SMA parthenogenetic HESC (pHESC) line provides a proof-of-principle for the establishment of diseased HESC lines without the need for gene manipulation. As mutant oocytes are easily obtained and readily available during preimplantation genetic diagnosis (PGD) cycles, this approach should provide a powerful tool for disease modelling and is especially advantageous since it can be used to induce large or complex mutations in HESCs, including gross DNA alterations and chromosomal rearrangements, which are otherwise hard to achieve.

Establishment of Homozygote Mutant Human Embryonic Stem Cells by Parthenogenesis.

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Silvina Epsztejn-Litman

Full Text Available We report on the derivation of a diploid 46(XX human embryonic stem cell (HESC line that is homozygous for the common deletion associated with Spinal muscular atrophy type 1 (SMA from a pathenogenetic embryo. By characterizing the methylation status of three different imprinted loci (MEST, SNRPN and H19, monitoring the expression of two parentally imprinted genes (SNRPN and H19 and carrying out genome-wide SNP analysis, we provide evidence that this cell line was established from the activation of a mutant oocyte by diploidization of the entire genome. Therefore, our SMA parthenogenetic HESC (pHESC line provides a proof-of-principle for the establishment of diseased HESC lines without the need for gene manipulation. As mutant oocytes are easily obtained and readily available during preimplantation genetic diagnosis (PGD cycles, this approach should provide a powerful tool for disease modelling and is especially advantageous since it can be used to induce large or complex mutations in HESCs, including gross DNA alterations and chromosomal rearrangements, which are otherwise hard to achieve.

Childhood optic atrophy.

Science.gov (United States)

Mudgil, A V; Repka, M X

2000-02-01

To determine the causes, and relative incidence of the common causes, of optic nerve atrophy in children under 10 years old and to compare prevalent aetiologies with those given in previous studies. The Wilmer Information System database was searched to identify all children, diagnosed between 1987 and 1997 with optic atrophy, who were under 10 years old at diagnosis. The medical records of these children were reviewed retrospectively A total of 272 children were identified, Complications from premature birth were the most frequent aetiology of optic atrophy (n = 44, 16%); 68% of these premature infants having a history of intraventricular haemorrhage. Tumour was the second most common aetiology (n = 40, 15%). The most frequent tumour was pilocytic astrocytoma (50%), followed by craniopharyngioma (17%). Hydrocephalus, unrelated to tumour, was the third most common aetiology (n = 26, 10%). In 114 cases (42%), the cause of optic atrophy became manifest in the perinatal period and/or could be attributed to adverse events in utero. A cause was not determined in 4% of cases. In the last decade, prematurity and hydrocephalus appear to have become important causes of optic atrophy in childhood. This trend is probably the result of improved survival of infants with extremely low birth weight.

Persepsi Siswa Terhadap Pembelajaran Guru Pendidikan Jasmani Di SMA Muhammadiyah Kediri

Directory of Open Access Journals (Sweden)

Hendra Mashuri

2017-05-01

Full Text Available Tujuan yang ingin dicapai dalam penelitian ini adalah untuk memperoleh informasi tentang persepsi siswa terhadap pembelajaran guru pendidikan jasmani di SMA Muhammadiyah Kediri. Rumusan masalah dalam penelitian ini adalah bagaimana persepsi siswa terhadap pembelajaran guru pendidikan jasmani di SMA Muhammadiyah Kediri? Jenis penelitian ini adalah penelitian survei. Populasi yang digunakan adalah seluruh siswa SMA Muhammadiyah Kediri, sampel yang diambil berjumlah 60 siswa yang terdiri dari 20 siswa dari masing-masing kelas. Instrumen yang digunakan adalah angket dan dokumentasi. Teknik analisis data menggunakan persentase. Hasil penelitian menunjukkan bahwa persepsi siswa terhadap proses pembelajaran SMA Muhammadiyah Kediri mendapatkan skor 3115 atau rata-rata jawaban siswa 51,917 dengan persentase sebesar 74% dan masuk dalam kategori “Baik”. Dengan demikian dapat dikatakan bahwa persepsi siswa terhadap pembelajaran guru pendidikan jasmani adalah baik.

Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program.

Science.gov (United States)

Morrison-Nozik, Alexander; Anand, Priti; Zhu, Han; Duan, Qiming; Sabeh, Mohamad; Prosdocimo, Domenick A; Lemieux, Madeleine E; Nordsborg, Nikolai; Russell, Aaron P; MacRae, Calum A; Gerber, Anthony N; Jain, Mukesh K; Haldar, Saptarsi M

2015-12-08

Classic physiology studies dating to the 1930s demonstrate that moderate or transient glucocorticoid (GC) exposure improves muscle performance. The ergogenic properties of GCs are further evidenced by their surreptitious use as doping agents by endurance athletes and poorly understood efficacy in Duchenne muscular dystrophy (DMD), a genetic muscle-wasting disease. A defined molecular basis underlying these performance-enhancing properties of GCs in skeletal muscle remains obscure. Here, we demonstrate that ergogenic effects of GCs are mediated by direct induction of the metabolic transcription factor KLF15, defining a downstream pathway distinct from that resulting in GC-related muscle atrophy. Furthermore, we establish that KLF15 deficiency exacerbates dystrophic severity and muscle GC-KLF15 signaling mediates salutary therapeutic effects in the mdx mouse model of DMD. Thus, although glucocorticoid receptor (GR)-mediated transactivation is often associated with muscle atrophy and other adverse effects of pharmacologic GC administration, our data define a distinct GR-induced gene regulatory pathway that contributes to therapeutic effects of GCs in DMD through proergogenic metabolic programming.

Sistem Informasi Akademik pada SMA Swasta Hang Tuah Belawan

OpenAIRE

Syarifuddin, Ruisya

2015-01-01

Perancangan Sistem Informasi Akademik pada SMA Swasta Hang Tuah Belawan ini bertujuan untuk mempermudah proses pencarian atau searching data dan informasi untuk seluruh Siswa SMA Swasta Hang Tuah Belawan yang mengalami kesulitan dalam memperoleh data mengenai masalah Akademik tersebut. Faasilitas yang terdapat dalam aplikasi ini berupa penyediaan data dan informasi mengenai beritaberita terbaru, profil agenda kegiatan, dan data-data yang berguna untuk kelangsungan belajar si...

Manajemen kelas dalam pembelajaran matematika di SMA Negeri Yogyakarta

OpenAIRE

Nisak Ruwah Ibnatur Husnul; Heri Retnawati

2017-01-01

Penelitian ini bertujuan untuk mengetahui manajemen kelas yang berupa perencanaan, pengorganisasian, penggerakan/kepemimpinan dan pengevaluasian dari pembelajaran matematika yang dilakukan oleh guru matematika di SMA Negeri Yogyakarta. Dengan menggunakan penelitian kualitatif jenis studi kasus ini dilakukan di SMA Negeri 5, 8 dan 9 Yogyakarta dengan subjek data adalah kepala sekolah, guru kurikulum, guru matematika dan siswa. Untuk teknik pengumpulan datanya dengan pedoman observasi dan pedom...

[The significance of Ulex europaeus agglutinin I lectin binding fibers in various muscular diseases].

Science.gov (United States)

Yatabe, K; Hiraguri, M; Sueishi, M; Takeuchi, M; Nonaka, I; Kawai, M

1998-05-01

In the present study, we have reported that Ulex europaeus agglutinin I (UEA I) lectin labeled muscle fibers in distal myopathy with rimmed vacuole formation (DMRV). UEA I binding to muscle fibers was also observed in a small number of biopsies with inflammatory myopathy, but not in other diseases, including neurogenic muscular atrophies and muscular dystrophies. In order to elucidate the relationship between this UEA I binding, rimmed vacuole formation and active autophagocytosis, we examined the UEA I binding fibers in other myopathies which frequently showed rimmed vacuoles, including adult onset acid maltase deficiency, oculo-pharyngo-distal type myopathy and oculopharyngeal muscular dystrophy. No UEA I lectin labeling fiber was observed in the diseases examined. We then studied UEA I binding behavior on 70 biopsies of inflammatory myopathy to characterize the clinical features of UEA I binding positive patients. UEA I binding fibers were observed in 3 of 28 patients (11%) with other collagen diseases, 11 of 36 (31%) without these disorders, and 2 of 6 (33%) with inclusion body myositis. There were no common clinical histories, complications or laboratory findings among the UEA I binding positive patients. In conclusion, a common process may exist between the muscle fiber degeneration in DMRV and subgroups of inflammatory myopathy patients, but the basic mechanism remains to be elucidated.

Optimal design of damping layers in SMA/GFRP laminated hybrid composites

Science.gov (United States)

Haghdoust, P.; Cinquemani, S.; Lo Conte, A.; Lecis, N.

2017-10-01

This work describes the optimization of the shape profiles for shape memory alloys (SMA) sheets in hybrid layered composite structures, i.e. slender beams or thinner plates, designed for the passive attenuation of flexural vibrations. The paper starts with the description of the material and architecture of the investigated hybrid layered composite. An analytical method, for evaluating the energy dissipation inside a vibrating cantilever beam is developed. The analytical solution is then followed by a shape profile optimization of the inserts, using a genetic algorithm to minimize the SMA material layer usage, while maintaining target level of structural damping. Delamination problem at SMA/glass fiber reinforced polymer interface is discussed. At the end, the proposed methodology has been applied to study the hybridization of a wind turbine layered structure blade with SMA material, in order to increase its passive damping.

Protein Turnover and Cellular Stress in Mildly and Severely Affected Muscles from Patients with Limb Girdle Muscular Dystrophy Type 2I

DEFF Research Database (Denmark)

Hauerslev, Simon; Sveen, Marie-Louise; Vissing, John

2013-01-01

Patients with Limb girdle muscular dystrophy type 2I (LGMD2I) are characterized by progressive muscle weakness and wasting primarily in the proximal muscles, while distal muscles often are spared. Our aim was to investigate if wasting could be caused by impaired regeneration in the proximal...... by using the developmental markers embryonic myosin heavy chain (eMHC) and neural cell adhesion molecule (NCAM) and also assessing satellite cell activation status by myogenin positivity. Severe muscle histopathology was occasionally observed in the proximal muscles of patients with LGMD2I whereas distal...... highly increased in severely affected muscles compared to mildly affected muscles. Our results indicate that alterations in the protein turnover and myostatin levels could progressively impair the muscle mass maintenance and/or regeneration resulting in gradual muscular atrophy....

Computed tomography in alcoholic cerebellar atrophy

Energy Technology Data Exchange (ETDEWEB)

Haubek, A; Lee, K [Hvidovre Hospital Copenhagen (Denmark). Dept. of Radiology; Municipal Hospital, Copenhagen (Denmark). Dept. of Neurology)

1979-01-01

This is a controlled CT evaluation of the infratentorial region in 41 male alcoholics under age 35. Criteria for the presence of atrophy are outlined. Twelve patients had cerebellar atrophy. Vermian atrophy was present in all. Atrophy of the cerebellar hemispheres was demonstrated in eight patients as well. The results are statistically significant when compared to an age-matched group of 40 non-alcoholic males among whom two cases of vermian atrophy were found. There were clinical signs of alcoholic cerebellar atrophy in one patient only. The disparity between the clinical and the radiological data are discussed with reference to previous pneumoencephalographic findings. (orig.) 891 AJ/orig. 892 MKO.

Behavior of NiTiNb SMA wires under recovery stress or prestressing.

Science.gov (United States)

Choi, Eunsoo; Nam, Tae-Hyun; Chung, Young-Soo; Kim, Yeon-Wook; Lee, Seung-Yong

2012-01-05

The recovery stress of martensitic shape-memory alloy [SMA] wires can be used to confine concrete, and the confining effectiveness of the SMA wires was previously proved through experimental tests. However, the behavior of SMA wires under recovery stress has not been seriously investigated. Thus, this study conducted a series of tests of NiTiNb martensitic SMA wires under recovery stress with varying degrees of prestrain on the wires and compared the behavior under recovery stress with that under prestressing of the wires. The remaining stress was reduced by the procedure of additional strain loading and unloading. More additional strains reduced more remaining stresses. When the SMA wires were heated up to the transformation temperature under prestress, the stress on the wires increased due to the state transformation. Furthermore, the stress decreased with a decreasing temperature of the wires down to room temperature. The stress of the NiTiNb wires was higher than the prestress, and the developed stress seemed to depend on the composition of the SMAs. When an additional strain was subsequently loaded and unloaded on the prestressed SMA wires, the remaining stress decreased. Finally, the remaining stress becomes zero when loading and unloading a specific large strain.

Boosted Regeneration and Reduced Denervated Muscle Atrophy by NeuroHeal in a Pre-clinical Model of Lumbar Root Avulsion with Delayed Reimplantation.

Science.gov (United States)

Romeo-Guitart, David; Forés, Joaquim; Navarro, Xavier; Casas, Caty

2017-09-20

The "gold standard" treatment of patients with spinal root injuries consists of delayed surgical reconnection of nerves. The sooner, the better, but problems such as injury-induced motor neuronal death and muscle atrophy due to long-term denervation mean that normal movement is not restored. Herein we describe a preclinical model of root avulsion with delayed reimplantation of lumbar roots that was used to establish a new adjuvant pharmacological treatment. Chronic treatment (up to 6 months) with NeuroHeal, a new combination drug therapy identified using a systems biology approach, exerted long-lasting neuroprotection, reduced gliosis and matrix proteoglycan content, accelerated nerve regeneration by activating the AKT pathway, promoted the formation of functional neuromuscular junctions, and reduced denervation-induced muscular atrophy. Thus, NeuroHeal is a promising treatment for spinal nerve root injuries and axonal regeneration after trauma.

Consensus Definition for Atrophy Associated with Age-Related Macular Degeneration on OCT: Classification of Atrophy Report 3.

Science.gov (United States)

Sadda, Srinivas R; Guymer, Robyn; Holz, Frank G; Schmitz-Valckenberg, Steffen; Curcio, Christine A; Bird, Alan C; Blodi, Barbara A; Bottoni, Ferdinando; Chakravarthy, Usha; Chew, Emily Y; Csaky, Karl; Danis, Ronald P; Fleckenstein, Monika; Freund, K Bailey; Grunwald, Juan; Hoyng, Carel B; Jaffe, Glenn J; Liakopoulos, Sandra; Monés, Jordi M; Pauleikhoff, Daniel; Rosenfeld, Philip J; Sarraf, David; Spaide, Richard F; Tadayoni, Ramin; Tufail, Adnan; Wolf, Sebastian; Staurenghi, Giovanni

2018-04-01

To develop consensus terminology and criteria for defining atrophy based on OCT findings in the setting of age-related macular degeneration (AMD). Consensus meeting. Panel of retina specialists, image reading center experts, retinal histologists, and optics engineers. As part of the Classification of Atrophy Meetings (CAM) program, an international group of experts surveyed the existing literature, performed a masked analysis of longitudinal multimodal imaging for a series of eyes with AMD, and reviewed the results of this analysis to define areas of agreement and disagreement. Through consensus discussions at 3 meetings over 12 months, a classification system based on OCT was proposed for atrophy secondary to AMD. Specific criteria were defined to establish the presence of atrophy. A consensus classification system for atrophy and OCT-based criteria to identify atrophy. OCT was proposed as the reference standard or base imaging method to diagnose and stage atrophy. Other methods, including fundus autofluorescence, near-infrared reflectance, and color imaging, provided complementary and confirmatory information. Recognizing that photoreceptor atrophy can occur without retinal pigment epithelium (RPE) atrophy and that atrophy can undergo an evolution of different stages, 4 terms and histologic candidates were proposed: complete RPE and outer retinal atrophy (cRORA), incomplete RPE and outer retinal atrophy, complete outer retinal atrophy, and incomplete outer retinal atrophy. Specific OCT criteria to diagnose cRORA were proposed: (1) a region of hypertransmission of at least 250 μm in diameter, (2) a zone of attenuation or disruption of the RPE of at least 250 μm in diameter, (3) evidence of overlying photoreceptor degeneration, and (4) absence of scrolled RPE or other signs of an RPE tear. A classification system and criteria for OCT-defined atrophy in the setting of AMD has been proposed based on an international consensus. This classification is a more complete

PERANGKAT PENGEMBANGAN DIRI UNTUK MENINGKATKAN KOMPETENSI GURU DAN PENGEMBANGAN KEPRIBADIAN SISWA SMA

Directory of Open Access Journals (Sweden)

Wenny Hulukati

2014-06-01

Abstrak: Perangkat Pengembangan Diri untuk Meningkatkan Kompetensi Guru dan Pengembangan Kepribadian Siswa SMA. Penelitian ini bertujuan mengembangkan perangkat pengembangan diri untuk meningkatkan kompetensi guru dan pengembangan kepribadian siswa SMA. Kegiatan penelitian ini diawali dengan studi pendahuluan yang berkaitan dengan kompentensi guru pembimbing dalam melaksanakan pelayanan bimbingan dan konseling dan kecenderungan kepribadian siswa SMA. Langkah berikutnya adalah mendesain dan mengembangkan draf, dan diakhiri dengan kegiatan uji keefektifan produk. Dari kegiatan penelitian pengembangan ini telah dihasilkan produk pengembangan yang valid dan handal yang meliputi panduan guru, panduan siswa, dan panduan penilaian. Berdasarkan hasil uji keefektifan terhadap produk pengembangan diperoleh informasi bahwa perangkat panduan pengembangan diri efektif diguna­kan untuk meningkatkan kompetensi guru pembimbing dalam melaksanakan pelayanan bimbingan dan konseling dan pengembangan kepribadian siswa SMA.

Monotonic and cyclic bond behavior of confined concrete using NiTiNb SMA wires

International Nuclear Information System (INIS)

Choi, Eunsoo; Chung, Young-Soo; Kim, Yeon-Wook; Kim, Joo-Woo

2011-01-01

This study conducts bond tests of reinforced concrete confined by shape memory alloy (SMA) wires which provide active and passive confinement of concrete. This study uses NiTiNb SMA which usually shows wide temperature hysteresis; this is a good advantage for the application of shape memory effects. The aims of this study are to investigate the behavior of SMA wire under residual stress and the performance of SMA wire jackets in improving bond behavior through monotonic-loading tests. This study also conducts cyclic bond tests and analyzes cyclic bond behavior. The use of SMA wire jackets transfers the bond failure from splitting to pull-out mode and satisfactorily increases bond strength and ductile behavior. The active confinement provided by the SMA plays a major role in providing external pressure on the concrete because the developed passive confinement is much smaller than the active confinement. For cyclic behavior, slip and circumferential strain are recovered more with larger bond stress. This recovery of slip and circumferential strain are mainly due to the external pressure of the SMA wires since cracked concrete cannot provide any elastic recovery

Comparison between MRI and 3D-SSP in olivopontocerebellar atrophy and cortical cerebellar atrophy

International Nuclear Information System (INIS)

Hamaguchi, Hirotoshi; Kanda, Fumio; Hosaka, Kayo; Fujii, Masahiko; Chihara, Kazuo

2004-01-01

We compared images of three-dimensional stereotactic surface projections (3D-SSP) of SPECT with MRI images in spinocerebellar degeneration patients (13 olivopontocerebellar atrophy (OPCA) and 7 cortical cerebellar atrophy (CCA)). We analyzed a brain blood flow pattern with an image of statistics by 123 I-IMP SPECT. In OPCA patients, a blood flow reduction was more remarkable in 3D-SSP than a degree of cerebellar atrophy in MRI. In patients with CCA, the cerebellum showed little blood flow reduction in 3D-SSP despite of apparent atrophy in MRI. Simultaneous examination both MRI and 3D-SSP might be useful for differential diagnosis of spinocerebellar degenerations. (author)

Distribution of skeletal muscle involvement in autosomal recessive distal muscular dystrophy

International Nuclear Information System (INIS)

Mizusawa, Hidehiro; Nakanishi, Takao; Kobayashi, Fumie.

1987-01-01

Distribution of skeletal muscle involvement in 5 cases with autosomal recessive distal muscular dystrophy was studied clinically and by computed tomography (CT). Manual muscle test showed muscle involvement with a predilection for flexors in the lower leg and adductors in the thigh. Flexion and extension of the thigh and the lower leg was impaired to similar degree. In progressed cases, neck flexors and trunk muscles were also affected mildly. CT disclosed more clearly the preferential involvement of flexors in the lower leg, and involvement of both hamstrings · adductors group and extensors group of the thigh to similar degree. However, m. popliteus was curiously well preserved. In addition, there was a stage showing high density and hypertrophy of m. sartorius, m. gracilis, m. adductor, m. biceps femoris, m. semimenbranosus, m. semitendinosus or m. rectus femoris, which in thought to be compensatory hypertrophy. M. gluteus minimus in the pelvic girdle and m. dorsi proprii in the trunk were also liable to be affected. The CT findings are regarded as characteristic features noted clearly before muscle weakness and atrophy become apparent clinically. CT is very useful for distinguishing distal muscular dystrophy from rimmed vacuolar distal myopathy in which m. quadriceps femoris and flexors of the lower leg are usually well preserved without compensatory hypertrophy on CT. (author)

Domain general sequence operations contribute to pre-SMA involvement in visuo-spatial processing

Directory of Open Access Journals (Sweden)

E. Charles eLeek

2016-01-01

Full Text Available This study used 3T MRI to elucidate the functional role of supplementary motor area (SMA in relation to visuo-spatial processing. A localizer task contrasting sequential number subtraction and repetitive button pressing was used to functionally delineate non-motor sequence processing in pre-SMA, and activity in SMA-proper associated with motor sequencing. Patterns of BOLD responses in these regions were then contrasted to those from two tasks of visuo-spatial processing. In one task participants performed mental rotation in which recognition memory judgments were made to previously memorized 2D novel patterns across image-plane rotations. The other task involved abstract grid navigation in which observers computed a series of imagined location shifts in response to directional (arrow cues around a mental grid. The results showed overlapping activation in pre-SMA for sequential subtraction and both visuo-spatial tasks. These results suggest that visuo-spatial processing is supported by non-motor sequence operations that involve pre-SMA. More broadly, these data further highlight the functional heterogeneity of pre-SMA, and show that its role extends to processes beyond the planning and online control of movement.

Gestational Age-Dependent Increase of Survival Motor Neuron Protein in Umbilical Cord-Derived Mesenchymal Stem Cells

Directory of Open Access Journals (Sweden)

Sota Iwatani

2017-09-01

Full Text Available BackgroundSpinal muscular atrophy (SMA is the most common genetic neurological disease leading to infant death. It is caused by loss of survival motor neuron (SMN 1 gene and subsequent reduction of SMN protein in motor neurons. Because SMN is ubiquitously expressed and functionally linked to general RNA metabolism pathway, fibroblasts (FBs are most widely used for the assessment of SMN expression in SMA patients but usually isolated from skin biopsy samples after the onset of overt symptoms. Although recent translational studies of SMN-targeted therapies have revealed the very limited time window for effective SMA therapies during perinatal period, the exact time point when SMN shortage became evident is unknown in human samples. In this study, we analyzed SMN mRNA and protein expression during perinatal period by using umbilical cord-derived mesenchymal stem cells (UC-MSCs obtained from preterm and term infants.MethodsUC-MSCs were isolated from 16 control infants delivered at 22–40 weeks of gestation and SMA fetus aborted at 19 weeks of gestation (UC-MSC-Control and UC-MSC-SMA. FBs were isolated from control volunteer and SMA patient (FB-Control and FB-SMA. SMN mRNA and protein expression in UC-MSCs and FBs was determined by RT-qPCR and Western blot.ResultsUC-MSC-Control and UC-MSC-SMA expressed the comparable level of MSC markers on their cell surface and were able to differentiate into adipocytes, osteocytes, and chondrocytes. At steady state, SMN mRNA and protein expression was decreased in UC-MSC-SMA compared to UC-MSC-Control, as observed in FB-SMA and FB-Control. In response to histone deacetylase inhibitor valproic acid, SMN mRNA and protein expression in UC-MSC-SMA and FB-SMA was increased. During perinatal development from 22 to 40 weeks of gestation, SMN mRNA and protein expression in UC-MSC-Control was positively correlated with gestational age.ConclusionUC-MSCs isolated from 17 fetus/infant of 19–40 weeks of gestation

Miskonsepsi Buku Ajar Fisika SMA Kelas X Pada Pokok Bahasan Dinamika Gerak

Directory of Open Access Journals (Sweden)

Fachmi Nurdiansyah

2018-03-01

Full Text Available Penelitian ini bertujuan untuk memaparkan bentuk-bentuk miskonsepsi pada pokok bahasan dinamika gerak dalam buku ajar fisika SMA kelas X. Adapun buku ajar yang digunakan dalam penelitian ini, yaitu: (1 Fisika untuk SMA/MA Kelas X Semester I karangan RA dan SI yang diterbitkan tahun 2012 oleh penerbit IP, (2 Fisika untuk SMA/MA Kelas X Semester I karangan TPM yang diterbitkan tahun 2013 oleh penerbit VP, dan (3 Fisika Peminatan untuk SMA/MA Kelas X karangan SN dan SZ yang diterbitkan tahun 2013 oleh penerbit YW. Penelitian ini merupakan penelitian kualitatif deskriptif. Objek dalam penelitian ini adalah data berupa aspek penjelasan konsep, penulisan rumus, penulisan simbol, penulisan satuan, dan penyajian gambar pada pokok bahasan dinamika gerak dalam buku ajar fisika SMA. Penelitian dilakukan dengan cara menganalisis data dalam buku ajar fisika SMA yang dibandingkan dengan buku teks fisika universitas. Berdasarkan analisis data yang telah dilakukan, dapat disimpulkan bahwa miskonsepsi pada pokok bahasan dinamika gerak terdapat dalam buku ajar fisika SMA. Buku ajar IP mengalami miskonsepsi pada aspek penjelasan konsep dengan persentase 10%, penulisan rumus dengan persentase 57,14%, penulisan simbol dengan persentase 46,15%, dan penyajian gambar dengan persentase 20%. Buku ajar VP mengalami miskonsepsi pada aspek penjelasan konsep dengan persentase 10%, penulisan rumus dengan persentase 85,71%, penulisan simbol dengan persentase 79,62%, dan penyajian gambar dengan persentase 80%. Buku ajar YW mengalami miskonsepsi pada aspek penjelasan konsep dengan persentase 10%, penulisan rumus dengan persentase 85,71%, penulisan simbol dengan persentase 69,23, dan penyajian gambar dengan persentase 20%. Pada aspek penulisan satuan, tidak terdapat miskonsepsi dalam buku ajar IP, VP, dan YW.

Fatigue crack behavior on a Cu-Zn-Al SMA

Directory of Open Access Journals (Sweden)

V. Di Cocco

2014-10-01

Full Text Available In recent years, mechanical property of many SMA has improved in order to introduce these alloys in specific field of industry. Main examples of these alloys are the NiTi, Cu-Zn-Al and Cu-Al-Ni which are used in many fields of engineering such as aerospace or mechanical systems. Cu-Zn-Al alloys are characterized by good shape memory properties due to a bcc disordered structure stable at high temperature called β-phase, which is able to change by means of a reversible transition to a B2 structure after appropriate cooling, and reversible transition from B2 secondary to DO3 order, under other types of cooling. In β-Cu-Zn-Al shape memory alloys, the martensitic transformation is not in equilibrium at room temperature. It is therefore often necessary to obtain the martensitic structure, using a thermal treatment at high temperature followed by quenching. The martensitic phases can be either thermally-induced spontaneous transformation, or stressinduced, or cooling, or stressing the β- phase. Direct quenching from high temperatures to the martensite phase is the most effective because of the non-diffusive character of the transformation. The martensite inherits the atomic order from the β-phase. Precipitation of many kinds of intermetallic phases is the main problem of treatment on cu-based shape memory alloy. For instance, a precipitation of α-phase occurs in many low aluminum copper based SMA alloy and presence of α-phase implies a strong degradation of shape recovery. However, Cu-Zn-Al SMA alloys characterized by aluminum contents less than 5% cover a good cold machining and cost is lower than traditional NiTi SMA alloys. In order to improve the SMA performance, it is always necessary to identify the microstructural changing in mechanical and thermal conditions, using X-Ray analyses. In this work a Cu-Zn-Al SMA alloy obtained in laboratory has been microstructurally and metallographically characterized by means of X-Ray diffraction and Light

Crack-closing of cement mortar beams using NiTi cold-drawn SMA short fibers

Science.gov (United States)

Choi, Eunsoo; Kim, Dong Joo; Chung, Young-Soo; Kim, Hee Sun; Jung, Chungsung

2015-01-01

In this study, crack-closing tests of mortar beams reinforced by shape memory alloy (SMA) short fibers were performed. For this purpose, NiTi SMA fibers with a diameter of 0.965 mm and a length of 30 mm were made from SMA wires of 1.0 mm diameter by cold drawing. Four types of SMA fibers were prepared, namely, straight and dog-bone-shaped fiber and the two types of fibers with paper wrapping in the middle of the fibers. The paper provides an unbonded length of 15 mm. For bending tests, six types of mortar beams with the dimensions of 40 mm × 40 mm × 160 mm (B×H×L) were prepared. The SMA fibers were placed at the bottom center of the beams along with an artificial crack of 10 mm depth and 1 mm thickness. This study investigated the influence of SMA fibers on the flexural strength of the beams from the measured force- deflection curves. After cracking, the beams were heated at the bottom by fire to activate the SMA fibers. Then, the beams recovered the deflection, and the cracks were closed. This study evaluated crack-closing capacity using the degree of crack recovery and deflection-recovery factor. The first factor is estimated from the crack-width before and after crack-closing, and the second one is obtained from the downward deflection due to loading and the upward deflection due to the closing force of the SMA fibers.

Five-Year Follow-Up and Outcomes of Noninvasive Ventilation in Subjects With Neuromuscular Diseases.

Science.gov (United States)

Suh, Mi Ri; Choi, Won Ah; Kim, Dong Hyun; Lee, Jang Woo; Kim, Eun Young; Kang, Seong-Woong

2018-03-01

The purpose of this study was to investigate the 5-year outcomes of noninvasive ventilation (NIV) application in different neuromuscular disease (NMD) groups. We categorized 180 subjects who had initiated NIV between March 2001 and August 2009 into 4 groups and followed them for > 5 y. The NIV maintenance rate and average duration, applying time, and forced vital capacity (FVC) were investigated at the time NIV was initiated and 5 y after NIV initiation in each group. In subjects with amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy (DMD), and spinal muscular atrophy (SMA)-congenital myopathy, the 5-year subjects who continued to use NIV over time were 22.5%, 89.4%, and 91.3%, respectively, and the average NIV maintenance durations were 21.53 ± 19.26 months, 55.22 ± 11.47 months, and 57.48 ± 8.34 months, respectively ( P NIV was tolerated long-term without significant increases in daily application time for most subjects with NMD. However, in individuals with ALS, development of severe bulbar symptoms can risk maintaining NIV. Copyright © 2018 by Daedalus Enterprises.

The water extract of Liuwei dihuang possesses multi-protective properties on neurons and muscle tissue against deficiency of survival motor neuron protein.

Science.gov (United States)

Tseng, Yu-Ting; Jong, Yuh-Jyh; Liang, Wei-Fang; Chang, Fang-Rong; Lo, Yi-Ching

2017-10-15

Deficiency of survival motor neuron (SMN) protein, which is encoded by the SMN1 and SMN2 genes, induces widespread splicing defects mainly in spinal motor neurons, and leads to spinal muscular atrophy (SMA). Currently, there is no effective treatment for SMA. Liuwei dihuang (LWDH), a traditional Chinese herbal formula, possesses multiple therapeutic benefits against various diseases via modulation of the nervous, immune and endocrine systems. Previously, we demonstrated water extract of LWDH (LWDH-WE) protects dopaminergic neurons and improves motor activity in models of Parkinson's disease. This study aimed to investigate the potential protection of LWDH-WE on SMN deficiency-induced neurodegeneration and muscle weakness. The effects of LWDH-WE on SMN deficiency-induced neurotoxicity and muscle atrophy were examined by using SMN-deficient NSC34 motor neuron-like cells and SMA-like mice, respectively. Inducible SMN-knockdown NSC34 motor neuron-like cells were used to mimic SMN-deficient condition. Doxycycline (1 µg/ml) was used to induce SMN deficiency in stable NSC34 cell line carrying SMN-specific shRNA. SMAΔ7 mice were used as a severe type of SMA mouse model. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Apoptotic cells and neurite length were observed by inverted microscope. Protein expressions were examined by western blots. Muscle strength of animals was evaluated by hind-limb suspension test. LWDH-WE significantly increased SMN protein level, mitochondrial membrane potential and cell viability of SMN-deficient NSC34 cells. LWDH-WE attenuated SMN deficiency-induced down-regulation of B-cell lymphoma-2 (Bcl-2) and up-regulation of cytosolic cytochrome c and cleaved caspase-3. Moreover, LWDH-WE prevented SMN deficiency-induced inhibition of neurite outgrowth and activation of Ras homolog gene family, member A (RhoA)/ Rho-associated protein kinase (ROCK2)/ phospho

Muscular Dystrophy

Science.gov (United States)

... sets of muscles and cause different degrees of muscle weakness. Duchenne muscular dystrophy is the most common and the most severe ... can walk independently. Prednisone If a child has Duchenne muscular ... to help slow the rate of muscle deterioration. By doing so, the child may be ...

PENGEMBANGAN MODEL PEMBELAJARAN KIMIA UNTUK MENINGKATKAN KETERAMPILAN PROSES DAN KETERAMPILAN BERPIKIR SISWA SMA

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Siti Darsati

2015-01-01

Full Text Available Tujuan penyusunan model pembelajaran kimia ini untuk meningkatkan keterampilan proses dan keterampilan berpikir siswa SMA. Model Pembelajaran Laju Reaksi untuk SMA mengandung 17 konsep, meliputi konsep abstrak, konsep yang berdasarkan prinsip dan konsep yang menyatakan simbol. Keterampilan Berpikir Kritis dan Keterampilan Proses Sains yang dikembangkan lebih banyak pada keterampilan menyimpulkan. Model ini telah di implementasikan pada 2 SMA di Kodya/Kabupaten Bandung. Kata kunci: Model pembelajaran, keterampilan proses, keterampilan berpikir

Cerebellar atrophy in epileptic patients

International Nuclear Information System (INIS)

Taneva, N.

1991-01-01

52 patients with epileptic seizures of different form, frequency and duration who had received long term treatment with anticonvulsive drugs were examined on Siretom 2000, a brain scanner of II generation. 6 standard incisions were made in all patients in the area of cerebellum, side ventricules and high convexity. Additional scanning with an incision width of 5 mm was made when pathological changes were detected. There were found 3 cases of cerebellar atrophy, 3 - cerebral atrophy, 1 - combined atrophy and 4 - with other changes. It was difficult to establish any relation between the rerebellar atrophy and the type of anticonvulsant used because treatment had usually been complex. 1 fig., 1 tab., 4 refs

Fukuyama type congenital muscular dystrophy with unusual features

International Nuclear Information System (INIS)

Mori, Hideo; Oguni, Hirokazu; Osawa, Makiko; Suzuki, Haruko; Fukuyama, Yukio

1980-01-01

The Fukuyama type congenital muscular dystrophy (F-CMD) has been generally recognized as a well delineated subgroup of progressive muscular dystrophy (PMD) with uniform clinical, pathological, and genetic features. However, there are still debate to be solved as to the etiology of the condition, because several neuropathological findings found in F-CMD brain allowed some investigators to hypothesize the intrauterine infection to be a primary causation. The authors reported here two families with two affected siblings in each. In the pedigree A, consanguineous parents produced two sisters, Case 1 (3-year-old) and Case 2 (14-month-old). Two patients in the pedigree B, the products of non-consanguineous parents, Case 3 (4-month-old male) and his elder sister already decreased, were affected with F-CMD and infantile spasms. In all cases, generalized weakness and hypotonia had been remarkable since their early infancy, and muscle atrophy, myopathic facies multiple joint contractures and mental dullness became evident gradually. The above-mentioned clinical features as well as laboratory findings including elevated serum CPK and myogenic EMG were compatible with those of typical F-CMD. However, they were characterized by the following three unusual features. 1. Muscle biopsy: In addition to an overwhelming myogenic change, there was a distinct inflammatory cell infiltration in all cases, and scattered small groups of atrophic fibers were present in Case 2. 2. Brain CT scanning: A symmetrical and extensive low density area was observed in the cerebral white matter in all cases. 3. A favorable response to prednisolone therapy was noted in all cases. (author)

Evaluation of hepatic atrophy after transcatheter arterial embolization

International Nuclear Information System (INIS)

Chung, Hwan Hoon; Lee, Mee Ran; Oh, Min Cheol; Park, Chul Min; Seol, Hae Young; Cha, In Ho

1995-01-01

Hepatic atrophy has been recognized as a complication of hepatic and biliary disease but we have often found it in follow up CT after transcatheter arterial embolization (TACE). The purpose of this study is to evaluate the characteristics of hepatic atrophy after TACE. Of 53 patients who had TACE. We evaluated the relationship between the incidence of hepatic atrophy and the number of TACE, and also evaluated the average number of TACE in patients with hepatic atrophy. Of 20 patients who had received more than average number of TACE for development of hepatic atrophy (2 times with portal vein obstruction, 2.7 times without portal vein obstruction in this study), we evaluated the relationship between the lipiodol uptake pattern of tumor and the incidence of hepatic atrophy. There were 8 cases of hepatic atrophy (3 with portal vein obstruction, 5 without portal vein obstruction), average number for development of hepatic atrophy were 2.5 times. As the number of TACE were increased, the incidence of hepatic atrophy were also increased. Of 20 patients who received more than average number of TACE for development of hepatic atrophy, we noted 6 cases of hepatic atrophy in 11 patients with dense homogenous lipiodol uptake pattern of tumor and noted only 1 case of hepatic atrophy in 9 patient with inhomogenous lipiodol uptake pattern. Hepatic atrophy was one of the CT findings after TACE even without portal vein obstruction. Average number of TACE was 2.5 times and risk factors for development of hepatic atrophy were portal vein obstruction, increased number of TACE, and dense homogenous lipiodol uptake pattern of tumor

Probabilistic fiber tracking of the language and motor white matter pathways of the supplementary motor area (SMA) in patients with brain tumors.

Science.gov (United States)

Jenabi, Mehrnaz; Peck, Kyung K; Young, Robert J; Brennan, Nicole; Holodny, Andrei I

2014-12-01

Accurate localization of anatomically and functionally separate SMA tracts is important to improve planning prior to neurosurgery. Using fMRI and probabilistic DTI techniques, we assessed the connectivity between the frontal language area (Broca's area) and the rostral pre-SMA (language SMA) and caudal SMA proper (motor SMA). Twenty brain tumor patients completed motor and language fMRI paradigms and DTI. Peaks of functional activity in the language SMA, motor SMA and Broca's area were used to define seed regions for probabilistic tractography. fMRI and probabilistic tractography identified separate and unique pathways connecting the SMA to Broca's area - the language SMA pathway and the motor SMA pathway. For all subjects, the language SMA pathway had a larger number of voxels (PProbabilistic tractography can identify unique white matter tracts that connect language SMA and motor SMA to Broca's area. The language SMA is more significantly connected to Broca's area than is the motor subdivision of the SMA proper. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Histopathologic Evolution of Cardiomyopathy in a Canine Model of Duchenne Muscular Dystrophy

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Lygia M.M. Malvestio

2015-07-01

Full Text Available Duchenne muscular dystrophy (DMD is a recessive X-linked disorder characterized for mutation in dystrophin gene and manifested by progressive degeneration and necrosis of skeletal and cardiac muscle with replacement leading to generalized muscular weakness and atrophy. The dog Golden Retriever Muscular Dystrophy (GRMD is the best experimental model for DMD, with genotypic and phenotypic manifestations closely of human disease. Similar to patients with DMD, heart failure is a major cause of death in GRMD animals. The objective of this study was to evaluate the pathological progression of myocardial lesions from GRMD dogs in different ages in order to clarify the pathogenesis of Duchenne´s cardiomyopathy. Fragments of left and right ventricle and interventricular septum, from 18 GRMD dogs between 6 to 51 months were collected, fixed, dehydrated, clarified, and finally embedded in paraffin. Five micrometer thick serial sections were obtained and stained with Hematoxylin-Eosin (HE, Picrosirius red, and Von Kossa. Histological analyses were performed at the light microscopy. Myocardial lesions were observed in all GRMD dogs and the sequence of cardiac lesion classified according to according to the age included: abnormal calcium accumulation, myofibrillar necrosis, proliferation of granulation tissue, endomysial and perimysial fibrosis, and finally myocardial fatty infiltration. Interestingly, several Anitschkow cells, the hallmark of rheumatic carditis, were detected in inflammatory infiltrate present at granulation tissue. Our results demonstrate the sequence of cardiac lesions that determine the cardiomyopathy in Golden Retriever dogs affected by DMD and exhibit, for the first time, the Anitschkow cells in the histological findings of this cardiomyopathy. These results are relevant for to clarify the pathogenesis of cardiomyopathy in dogs and humans affected by DMD.

MRI of rotator cuff muscle atrophy in relation to glenohumeral joint incongruence in brachial plexus birth injury

International Nuclear Information System (INIS)

Poeyhiae, Tiina H.; Nietosvaara, Yrjaenae A.; Peltonen, Jari I.; Remes, Ville M.; Kirjavainen, Mikko O.; Lamminen, Antti E.

2005-01-01

Purpose: To evaluate rotator cuff muscles and the glenohumeral (GH) joint in brachial plexus birth injury (BPBI) using MRI and to determine whether any correlation exists between muscular abnormality and the development of glenoid dysplasia and GH joint incongruity. Thirty-nine consecutive BPBI patients with internal rotation contracture or absent active external rotation of the shoulder joint were examined clinically and imaged with MRI. In the physical examination, passive external rotation was measured to evaluate internal rotation contracture. Both shoulders were imaged and the glenoscapular angle, percentage of humeral head anterior to the middle of the glenoid fossa (PHHA) and the greatest thickness of the subscapular, infraspinous and supraspinous muscles were measured. The muscle ratio between the affected side and the normal side was calculated to exclude age variation in the assessment of muscle atrophy. All muscles of the rotator cuff were atrophic, with the subscapular and infraspinous muscles being most severely affected. A correlation was found between the percentage of humeral head anterior to the middle of the glenoid fossa (PHHA) and the extent of subscapular muscle atrophy (r s =0.45, P=0.01), as well as between its ratio (r s =0.5, P P=0.01). Severity of rotator cuff muscle atrophy correlated with increased glenoid retroversion and the degree of internal rotation contracture. Glenoid retroversion and subluxation of the humeral head are common in patients with BPBI. All rotator cuff muscles are atrophic, especially the subscapular muscle. Muscle atrophy due to neurogenic damage apparently results in an imbalance of the shoulder muscles and progressive retroversion and subluxation of the GH joint, which in turn lead to internal rotation contracture and deformation of the joint. (orig.)

PENGEMBANGAN PERANGKAT PEMBELAJARAN KOMPETENSI SULIT MATEMATIKA SMA DI RIAU

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Ummi Aisyah

2014-05-01

Full Text Available Tujuan penelitian ini adalah untuk menghasilkan perangkat pembelajaran kompetensi sulit matematika SMA di Provinsi Riau yang berkualitas baik/layak yaitu valid, praktis, dan efektif. Penelitian ini merupakan penelitian pengembangan yang mengembangkan perangkat pembelajaran kompetensi sulit matematika SMA dengan menggunakan model pengembangan 4-D yang dikembangkan oleh Thiagarajan, Semmel & Semmel yang telah dimodifikasi sehingga hanya memuat tahap pen-definisian, perancangan, dan pengembangan. Penelitian ini menghasilkan perangkat pembelajaran kompetensi sulit matematika SMA yang meliputi silabus, rencana pelaksanaan pembelajaran (RPP, lembar kegiatan siswa (LKS, dan instrumen tes. Hasil validasi menunjukkan bahwa silabus, RPP, LKS yang dikembangkan memiliki kategori sangat valid untuk masing-masing silabus, RPP, LKS, dan test instrument. Hasil uji coba lapangan menunjukkan bahwa perangkat yang dikembangkan praktis dan efektif. Kepraktisan mencapai hasil sangat baik ditinjau dari penilaian guru dan siswa. Keefektifan ditinjau dari ketuntasan belajar siswa dan hasil observasi keterlaksanaan pembelajaran. Secara klasikal ketuntasan belajar mencapai 84,38%. Secara keseluruhan, hasil penelitian menunjukkan bahwa perangkat pembelajaran yang dikembangkan adalah layak untuk digunakan. Kata Kunci: pengembangan, perangkat pembelajaran, kompetensi sulit matematika

Experience as knowledge: Disability, distillation and (reprogenetic) decision-making.

Science.gov (United States)

Boardman, Felicity K

2017-10-01

'Experiential knowledge' is increasingly recognised as an important influence on reproductive decision-making. 'Experiential knowledge of disability' in particular is a significant resource within prenatal testing/screening contexts, enabling prospective parents to imagine and appraise future lives affected by disability. However, the concept of 'experiential knowledge' has been widely critiqued for its idiosyncrasy, its impermanence and consequently its perceived inferiority to (medical) knowledge. This paper explores some of these key critiques of experiential knowledge through an analysis of its constitution and uses in the context of reproductive decision-making. Seventeen UK-resident women with Spinal Muscular Atrophy (SMA), or with SMA in their family, took part in two in-depth interviews: one in 2007-9 and the other in 2013-4. By comparing and contrasting these women's accounts at two time points, this paper demonstrates the stark contrast between 'lived experience' of SMA (the visceral everyday realities of life with the condition) and the various way(s) this experience was transformed into, and presented as, 'knowledge' through the processes of making, and accounting, for reproductive decisions. The analysis highlights that multiple, distinct and sometimes competing experiential frameworks are used to conceptualise SMA across time and context. However, rather than evidence of its fallibility, this finding highlights that 'knowledge' is an inappropriate vessel with which to capture and transfer 'experiential knowledge'. Rather, we need to consider how to value such insight in ways that harnesses its inherent strength without leaving it vulnerable to the epistemological critiques attracted by labelling it 'knowledge'. Copyright © 2017 The Author. Published by Elsevier Ltd.. All rights reserved.

Limb-Girdle Muscular Dystrophy (LGMD)

Science.gov (United States)

... Marie-Tooth Disease (CMT) Congenital Muscular Dystrophy (CMD) Duchenne Muscular Dystrophy (DMD) Emery-Dreifuss Muscular Dystrophy Endocrine Myopathies Metabolic Diseases of Muscle Mitochondrial Myopathies (MM) Myotonic Dystrophy (DM) Spinal-Bulbar ...

Evaluation of 2’-Deoxy-2’-fluoro Antisense Oligonucleotides for Exon Skipping in Duchenne Muscular Dystrophy

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Silvana M G Jirka

2015-01-01

Full Text Available Duchenne muscular dystrophy (DMD is a severe muscle wasting disorder typically caused by frame-shifting mutations in the DMD gene. Restoration of the reading frame would allow the production of a shorter but partly functional dystrophin protein as seen in Becker muscular dystrophy patients. This can be achieved with antisense oligonucleotides (AONs that induce skipping of specific exons during pre-mRNA splicing. Different chemical modifications have been developed to improve AON properties. The 2’-deoxy-2’-fluoro (2F RNA modification is attractive for exon skipping due to its ability to recruit ILF2/3 proteins to the 2F/pre-mRNA duplex, which resulted in enhanced exon skipping in spinal muscular atrophy models. In this study, we examined the effect of two different 2’-substituted AONs (2’-F phosphorothioate (2FPS and 2’-O-Me phosphorothioate (2OMePS on exon skipping in DMD cell and animal models. In human cell cultures, 2FPS AONs showed higher exon skipping levels than their isosequential 2OMePS counterparts. Interestingly, in the mdx mouse model, 2FPS was less efficient than 2OMePS and suggested safety issues as evidenced by increased spleen size and weight loss. Our results do not support a clinical application for 2FPS AON.

Applications of small surface plasmon resonance sensors for biochemical monitoring

Science.gov (United States)

Masson, Jean-Francois; Battaglia, Tina M.; Beaudoin, Stephen; Booksh, Karl S.

2004-12-01

The development of small surface plasmon resonance (SPR) sensors to detect biological markers for myocardial ischemia (MI), spinal muscular atrophy (SMA), and wound healing was achieved at low ng/mL and in less than 10 minutes. The markers of interest for MIs are myoglobin (MG) and cardiac Troponin I (cTnI). The limits of detection for these markers are respectively 600 pg/mL and 1.4 ng/mL in saline solution. To study SMA, the level of survival motor neuron protein (SMN) was investigated. A limit of detection of 990 pg/mL was achieved for the detection of SMN. The interactions of SMN with MG decreased the signal for both SMN and MG. Interleukin 6 and tumor necrosis factor alpha (TNFa) were investigated to monitor wound healing. The sensor's performance in more complex solutions, e.g.: serum, showed a large non-specific signal. Modifying the support on which the antibodies are attached improved the sensor's stability in serum by a factor of 5. To achieve this non-specific binding (NSB) reduction, different polysaccharides, biocompatible polymers and short chain thiols were investigated.

PEMBELAJARAN THINK-PAIR-SHARE, KETERAMPILAN METAKOGNITIF, DAN HASIL BELAJAR KOGNITIF SISWA SMA

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Sri Amnah S.

2012-05-01

Full Text Available Abstract: Think-Pair-Share Learning, Meta-cognitive Skills and Cognitive Learning Outcomes. The study investigates the effects of meta-cognitive skills based Think-Pair-Share cooperative learning on meta-cognitive skills and cognitive learning outcomes of 11th grade students of Senior High Schools in Pekanbaru. The sample consists of 11th grade students of SMA 9 as an experiment group and 11th grade students SMA 10 as a control group. Based on analyzing the data using ANCOVA, the results show that there is a signifi­cant difference in meta-cognitive skills and cognitive learning outcomes of the students in the experimental and the control groups, and there is no significant difference between students who have high and low academic levels in their meta-cognitive skills and cognitive learning outcomes. Abstrak: Pembelajaran Think-Pair-Share, Keterampilan Metakognitif, dan Hasil Belajar Kognitif Siswa SMA. Penelitian ini bertujuan mengukur pengaruh pembela­jaran koperatif Think-Pair-Share terha­dap keterampilan metakognitif dan hasil belajar kognitif siswa SMA. Sampel dipilih secara acak dari popu­lasi 13 SMA di Pekanbaru. Dengan menggunakan ANAKOVA, hasilnya menunjukkan bahwa terdapat per­bedaan yang nyata keterampilan metakognitif dan hasil belajar kognitif siswa di kelompok eksperimental dan kelompok control, dan tidak ada perbedaan yang nyata antara siswa berkemampuan akademik tinggi dan akademik rendah pada keterampilan metakognitif dan hasil belajar kognitifnya.

Evaluation of Limb-Girdle Muscular Dystrophy

Science.gov (United States)

2014-03-06

Becker Muscular Dystrophy; Limb-Girdle Muscular Dystrophy, Type 2A (Calpain-3 Deficiency); Limb-Girdle Muscular Dystrophy, Type 2B (Miyoshi Myopathy, Dysferlin Deficiency); Limb-Girdle Muscular Dystrophy, Type 2I (FKRP-deficiency)

Correlation of clinical course with MRI findings in olivo-pontocerebellar atrophy and late-cortical cerebellar atrophy

International Nuclear Information System (INIS)

Konagaya, Masaaki; Morishita, Shinji; Konagaya, Yoko; Takayanagi, Tetsuya; Iwasaki, Satoru

1989-01-01

We quantitatively analyzed 1.5 T MRI in 36 cases of sporadic spinocerebellar degeneration (SCD) and 30 control cases without intracranial lesions, using graphic analyzer. SCD consisted of 21 olivo-ponto-cerebellar atrophy (OPCA) and 15 late cortical cerebellar atrophy (LCCA). There was negative correlation between vermian size and the duration of illness both in OPCA (r=0.8960, p<0.001) and LCCA (r=0.7756, p<0.01), but the progression rate in OPCA was three times greater than that in LCCA. LCCA was suggested the preclinical vermian atrophy by the statistical regression study. In OPCA, the duration of illness also revealed significant correlations with atrophy of ventral pons (r=0.8308, p<0.001) and also cerebellar hemisphere (medial hemiphere; r=0.7278, p<0.001. lateral hemisphere; r=0.6039, p<0.01). OPCA showed diffuse atrophy of cerebellar hemisphere, whereas LCCA showed medial dominant atrophy. OPCA demonstrated significant correlation between the fourth ventricle dilatation and the duration of illness (r=0.6005, p<0.01). A discriminant study significantly separated OPCA, LCCA and control each other by sizes of ventral pons and cerebellar vermis (p<0.001). In T2 weighted MRI, 10 cases out of 14 LCCA did not show hypointensity in dentate nucleus in spite of normal appearance in the other portions usually decreased intensity. The dentate nucleus of OPCA showed a significant atrophy. The insidence of putaminal hypointensity in OPCA was significantly greater than that of control group (ki-quare=6.476, p<0.05). There were no atrophies in red nucleus and tegmentum of midbrain, which indicated minimum involvement in cerebellar efferent system both in OPCA and LCCA. We concluded that the quantitative and qualitative analysis of high field MRI is useful in clinical discrimination between OPCA and LCCA. (author)

Full-scale flight tests of aircraft morphing structures using SMA actuators

Science.gov (United States)

Mabe, James H.; Calkins, Frederick T.; Ruggeri, Robert T.

2007-04-01

In August of 2005 The Boeing Company conducted a full-scale flight test utilizing Shape Memory Alloy (SMA) actuators to morph an engine's fan exhaust to correlate exhaust geometry with jet noise reduction. The test was conducted on a 777-300ER with GE-115B engines. The presence of chevrons, serrated aerodynamic surfaces mounted at the trailing edge of the thrust reverser, have been shown to greatly reduce jet noise by encouraging advantageous mixing of the free, and fan streams. The morphing, or Variable Geometry Chevrons (VGC), utilized compact, light weight, and robust SMA actuators to morph the chevron shape to optimize the noise reduction or meet acoustic test objectives. The VGC system was designed for two modes of operation. The entirely autonomous operation utilized changes in the ambient temperature from take-off to cruise to activate the chevron shape change. It required no internal heaters, wiring, control system, or sensing. By design this provided one tip immersion at the warmer take-off temperatures to reduce community noise and another during the cooler cruise state for more efficient engine operation, i.e. reduced specific fuel consumption. For the flight tests a powered mode was added where internal heaters were used to individually control the VGC temperatures. This enabled us to vary the immersions and test a variety of chevron configurations. The flight test demonstrated the value of SMA actuators to solve a real world aerospace problem, validated that the technology could be safely integrated into the airplane's structure and flight system, and represented a large step forward in the realization of SMA actuators for production applications. In this paper the authors describe the development of the actuator system, the steps required to integrate the morphing structure into the thrust reverser, and the analysis and testing that was required to gain approval for flight. Issues related to material strength, thermal environment, vibration

Muscular effects of vitamin D in young athletes and non-athletes and in the elderly.

Science.gov (United States)

Koundourakis, Nikolaos E; Avgoustinaki, Pavlina D; Malliaraki, Niki; Margioris, Andrew N

2016-10-01

Muscles are major targets of vitamin D. Exposure of skeletal muscles to vitamin D induces the expression of multiple myogenic transcription factors enhancing muscle cell proliferation and differentiation. At the same time vitamin D suppresses the expression of myostatin, a negative regulator of muscle mass. Moreover, vitamin D increases the number of type II or fast twitch muscle cells and in particular that of type IIA cells, while its deficiency causes type IIA cell atrophy. Furthermore, vitamin D supplementation in young males with low vitamin D levels increases the percentage of type IIA fibers in muscles, causing an increase in muscular high power output. Vitamin D levels are strongly associated with exercise performance in athletes and physically active individuals. In the elderly and in adults below the age of 65, several studies have established a close association between vitamin D levels and neuromuscular coordination. The aim of this review is to appraise our current understanding of the significance of vitamin D on muscular performance in both older and frail individuals as well as in younger adults, athletes or non-athletes with regard to both ordinary everyday musculoskeletal tasks and peak athletic performance.

Genetics Home Reference: optic atrophy type 1

Science.gov (United States)

... Nerve Atrophy Encyclopedia: Visual Acuity Test Health Topic: Color Blindness Health Topic: Optic Nerve Disorders Genetic and Rare ... Disease InfoSearch: Optic atrophy 1 Kids Health: What's Color Blindness? MalaCards: autosomal dominant optic atrophy, classic form Merck ...

SMA spring-based artificial muscle actuated by hot and cool water using faucet-like valve

Science.gov (United States)

Park, Cheol Hoon; Son, Young Su

2017-04-01

An artificial muscle for a human arm-like manipulator with high strain and high power density are under development, and an SMA(Shape memory alloy) spring is a good actuator for this application. In this study, an artificial muscle composed of a silicon tube and a bundle of SMA(Shape memory alloy) springs is evaluated. A bundle of SMA springs consists of five SMA springs which are fabricated by using SMA wires with a diameter of 0.5 mm, and hot and cool water actuates it by heating and cooling SMA springs. A faucet-like valve was also developed to mix hot water and cool water and control the water temperature. The mass of silicon tube and a bundle of SMA springs is only 3.3 g and 2.25 g, respectively, and the total mass of artificial muscle is 5.55 g. It showed good actuating performance for a load with a mass of 2.3 kg and the power density was more than 800 W/kg for continuous valve switching with a cycle of 0.6 s. The faucet-like valve can switch a water output from hot water to cold water within 0.3s, and the artificial muscle is actuated well in response to the valve position and speed. It is also presented that the temperature of the mixed water can be controlled depending on the valve position, and the displacement of the artificial muscle can be controlled well by the mixed water. Based on these results, SMA spring-based artificial muscle actuated by hot and cool water could be applicable to the human arm-like robot manipulators.

77 FR 8264 - Government-Owned Inventions; Availability for Licensing

Science.gov (United States)

2012-02-14

... Sialylation in Certain Muscular Atrophies, Kidney Disorders, Cancers or Poor Immune Function Description of... as inflammation, immune responses, as well as certain muscular atrophies (including hereditary... enhances successful systemic delivery, including to the central nervous system (crossing the blood-brain...

PENERAPAN TEKNOLOGI WEB SEKOLAH BAGI SMP DAN SMA MUHAMMADIYAH KARTASURA

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Heru Supriyono

2016-03-01

Full Text Available Observation and interview with headmasters, teachers and administrative employees results showed that one of main problems faced by SMP Muhammadiyah 1 Kartasura and SMA Muhammadiyah 4 Kartasura is the do not have a representative school website. Based on this observation, after making discussion with headmasters, the community services team proposed an implementation of school website and train one of chosen teacher to manage implemented website. The outcomes of the community service activities are involving a school website for SMP Muhammadiyah 1 Kartasura and SMA Muhammadiyah 4 Kartasura and scientific publication draft. The contribution of each school is including providing information which will be uploaded to the website, providing fee for domain and hosting cost, and providing facilities for administrator training. The duration of this commuity services is three months. The results of the community services is both SMP Muhammadiyah 1 Kartasura dan SMA Muhammadiyah 4 Kartasura are now have representative website for their promotion and administative activities.

PENGEMBANGAN KINERJA GURU MELALUI PENELITIAN TINDAKAN KELAS PADA SMA NEGERI DI KOTA PALOPO

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Hilal Muhammad

2015-12-01

Tujuan penelitian ini adalah untuk mengungkap: (1 pelaksanaan pengembangan kinerja guru melalui PTK pada SMA Negeri di Kota Palopo; dan (2 hambatan da-lam pelaksanaan pengembangan kinerja guru melalui PTK pada SMA Negeri di Kota Palopo. Jenis penelitian adalah penelitian lapangan yang kajiannya bersifat kualitatif-verifikatif. Pendekatan yang digunakan adalah pendekatan fenomeno-logi. Metode pengumpulan data yang digunakan dalam penelitian ini adalah wawancara, observasi, dan dokumentasi. Hasil penelitian ini menunjukkan dua hal. Pertama, pengembangan kinerja guru melalui PTK pada SMA Negeri di Kota Palopo belum berjalan optimal dan baru sebatas memenuhi kebutuhan persyarat-an kenaikan pangkat. Potensi guru belum dimanfaatkan melalui pemberdayaan, khususnya penelitian tindakan kelas. Kedua, hambatan dalam pelaksanaan pe-ngembangan kinerja guru melalui PTK pada SMA Negeri di Kota Palopo adalah keterbatasan waktu, dana, sumber referensi kurang, lingkungan tidak kondusif, dan motivasi kurang. Selain itu, sebagian guru juga masih mengalami kesulitan dalam melakukan dan menyusun laporan hasil PTK.

Constitutive modeling of SMA SMP multifunctional high performance smart adaptive shape memory composite

International Nuclear Information System (INIS)

Jarali, Chetan S; Raja, S; Upadhya, A R

2010-01-01

Materials design involving the thermomechanical constitutive modeling of shape memory alloy (SMA) and shape memory polymer (SMP) composites is a key topic in the development of smart adaptive shape memory composites (SASMC). In this work, a constitutive model for SASMC is developed. First, a one-dimensional SMA model, which can simulate the pseudoelastic (PE) and shape memory effects (SME) is presented. Subsequently, a one-dimensional SMP model able to reproduce the SME is addressed. Both SMA and SMP models are based on a single internal state variable, namely the martensite fraction and the frozen fraction, which can be expressed as a function of temperature. A consistent form of the analytical solution for the SMP model is obtained using the fourth-order Runge–Kutta method. Finally, the SASMC constitutive model is proposed, following two analytical homogenization approaches. One approach is based on an equivalent inclusion method and the other approach is the rule of mixtures. The SMA and SMP constitutive models are validated independently with experimental results. However, the validation of the composite model is performed using the two homogenization approaches and a close agreement in results is observed. Results regarding the isothermal and thermomechanical stress–strain responses are analyzed as a function of SMA volume fraction. Further, it is concluded that the proposed composite model is able to reproduce consistently the overall composite response by taking into consideration not only the phase transformations, variable modulus and transformation stresses in SMA but also the variable modulus, the evolution of stored strain and thermal strain in the SMP

Fabrication and characterization of a dual-joint smart inhaler nozzle actuated by embedded SMA wires

International Nuclear Information System (INIS)

Furst, Stephen J; Seelecke, Stefan

2014-01-01

Shape memory alloy (SMA) wires offer a novel solution for many embedded actuator and sensor applications. Small SMA wires in particular can be heated with a relatively low electric current, cool rapidly, and serve as a sensor thanks to a measurable resistance change. However, the challenges of fabrication with SMA actuator wires as well as their hysteretic nature have prevented them from finding mainstream application. This work focuses on the process used to control the fabrication of an SMA-actuated adaptive nozzle for the previously presented Smart Inhaler application. The elements of nozzle design that facilitate fabrication are summarized and an assembly setup and procedure is presented for controlling the stress and strain in the SMA wires while they are attached to the nozzle structure via temperature-resistant adhesives. Finally, the performance of the nozzle is characterized by measuring the changes in nozzle deflection and SMA wire strain and resistance in response to a controlled Joule heating power input. Results show controlling pre-stress in the wires during assembly can lead to reproducible behavior, an input heating power serves to control nozzle deflection, and a measured resistance can provide a useful sensor of SMA wire strain and nozzle joint deflection. (paper)

Short-term muscle atrophy caused by botulinum toxin-A local injection impairs fracture healing in the rat femur.

Science.gov (United States)

Hao, Yongqiang; Ma, Yongcheng; Wang, Xuepeng; Jin, Fangchun; Ge, Shengfang

2012-04-01

Damaged bone is sensitive to mechanical stimulation throughout the remodeling phase of bone healing. Muscle damage and muscular atrophy associated with open fractures and subsequent fixation are not beneficial to maintaining optimum conditions for mechanical stability. The aim of this study was to investigate whether local muscle atrophy and dysfunction affect fracture healing in a rat femur fracture model. We combined the rat model of a short period atrophy of the quadriceps with femur fracture. Forty-four-month-old male Wistar rats were adopted for this study. Two units of botulinum toxin-A (BXTA) were administered locally into the right side of the quadriceps of each rat, while the same dose of saline was injected into the contralateral quadriceps. After BXTA had been fully absorbed by the quadriceps, osteotomy was performed in both femurs with intramedullary fixation. Gross observation and weighing of muscle tissue, X-ray analysis, callus histology, and bone biomechanical testing were performed at different time points up to 8 weeks post-surgery. Local injection of BXTA led to a significant decrease in the volume and weight of the quadriceps compared to the control side. At the eighth week, the left side femurs of the saline-injected quadriceps almost reached bony union, and fibrous calluses were completely calcified into woven bone. However, a gap was still visible in the BXTA-treated side on X-ray images. As showed by bone histology, there were no mature osseous calluses or woven bone on the BXTA-treated side, but a resorption pattern was evident. Biomechanical testing indicated that the femurs of the BXTA-treated side exhibited inferior mechanical properties compared with the control side. The inferior outcome following BXTA injection, compared with saline injection, in terms of callus resistance may be the consequence of unexpected load and mechanical unsteadiness caused by muscle atrophy and dysfunction. Copyright © 2011 Orthopaedic Research Society.

Specific methanogenic activity (SMA of industrial sludge from the aerobic and anaerobic biological treatment

Directory of Open Access Journals (Sweden)

Danieli Schneiders

2013-08-01

Full Text Available In this study, specific methanogenic activity (SMA tests were performed on textile sludge and food industry sludge. The textile sludge from an activated sludge was collected at the entrance of the secondary biologic clarifier and the food sludge was collected in a UASB reactor. Once collected, the sludges were characterized and tested for SMA. It was found that the microrganisms present in the food sludge had SMA of 0.17 gCOD-CH4 gSSV.d-1 and 337.05 mL of methane production, while the microrganisms of the textile sludge presented 0.10 gCOD-CH4 gSSV.d-1 of SMA and 3.04 mL of methane production. Therefore, the food sludge was more suitable to be used as a starting inoculum in UASB.

The ubiquitin ligase tripartite-motif-protein 32 is induced in Duchenne muscular dystrophy.

Science.gov (United States)

Assereto, Stefania; Piccirillo, Rosanna; Baratto, Serena; Scudieri, Paolo; Fiorillo, Chiara; Massacesi, Manuela; Traverso, Monica; Galietta, Luis J; Bruno, Claudio; Minetti, Carlo; Zara, Federico; Gazzerro, Elisabetta

2016-08-01

Activation of the proteasome pathway is one of the secondary processes of cell damage, which ultimately lead to muscle degeneration and necrosis in Duchenne muscular dystrophy (DMD). In mdx mice, the proteasome inhibitor bortezomib up-regulates the membrane expression of members of the dystrophin complex and reduces the inflammatory reaction. However, chronic inhibition of the 26S proteasome may be toxic, as indicated by the systemic side-effects caused by this drug. Therefore, we sought to determine the components of the ubiquitin-proteasome pathway that are specifically activated in human dystrophin-deficient muscles. The analysis of a cohort of patients with genetically determined DMD or Becker muscular dystrophy (BMD) unveiled a selective up-regulation of the ubiquitin ligase tripartite motif-containing protein 32 (TRIM32). The induction of TRIM32 was due to a transcriptional effect and it correlated with disease severity in BMD patients. In contrast, atrogin1 and muscle RING-finger protein-1 (MuRF-1), which are strongly increased in distinct types of muscular atrophy, were not affected by the DMD dystrophic process. Knock-out models showed that TRIM32 is involved in ubiquitination of muscle cytoskeletal proteins as well as of protein inhibitor of activated STAT protein gamma (Piasγ) and N-myc downstream-regulated gene, two inhibitors of satellite cell proliferation and differentiation. Accordingly, we showed that in DMD/BMD muscle tissue, TRIM32 induction was more pronounced in regenerating myofibers rather than in necrotic muscle cells, thus pointing out a role of this protein in the regulation of human myoblast cell fate. This finding highlights TRIM32 as a possible therapeutic target to favor skeletal muscle regeneration in DMD patients.

Aspectos clínicos e concentração sérica da creatina-quinase e lactato-desidrogenase em cães submetidos à fisioterapia após atrofia muscular induzida Clinical aspects and serum concentration creatina kinase and lactate dehydrogenase in dogs submitted to physiotherapy after induced muscle atrophy

Directory of Open Access Journals (Sweden)

Soraia Figueiredo de Souza

2011-07-01

Full Text Available Avaliou-se a resposta de diferentes protocolos fisioterapêuticos em cães após a indução de atrofia muscular por meio da imobilização do joelho por 30 dias. Os grupos foram denominados grupo C ou controle, grupo E (massagem, movimentação passiva e eletroterapia, grupo H (massagem, movimentação passiva e hidroterapia em esteira aquática e grupo EH (massagem, movimentação passiva, eletroterapia e hidroterapia em esteira aquática. Foram mensurados os graus de claudicação, arco do movimento, circunferência da coxa e a variação sérica das enzimas creatina-quinase e lactato-desidrogenase. De acordo com os resultados encontrados, foi possível concluir que as modalidades terapêuticas de massagem, movimentação passiva da articulação, estimulação elétrica neuromuscular e hidroterapia por caminhada em esteira aquática aceleram a recuperação clínica em cães com atrofia muscular induzida.The response of different physiotherapeutic treatment protocols was evaluated in dogs after muscle atrophy induced by joint immobilization for 30 days. Groups were named C group or control, E group (massage, passive range of motion and neuromuscular electrical stimulation, H group (massage, passive range of motion and aquatic therapy in underwater treadmill and EH group (massage, passive range of motion, neuromuscular electrical stimulation and aquatic therapy in underwater treadmill. It was measured the degree of lameness, range motion, thigh circumference and range of serum creatine kinase (CK and lactate dehydrogenase (LDH. According to the results, it was possible to conclude that associated therapeutics modalities such as massage, passive range of motion of the joint, neuromuscular electrical stimulation and aquatic therapy by walking on underwater treadmill accelerate clinical recovery in dogs with induced muscle atrophy.

Percutaneous Thrombin Injection to Complete SMA Pseudoaneurysm Exclusion After Failing of Endograft Placement

International Nuclear Information System (INIS)

Szopinski, Piotr; Ciostek, Piotr; Pleban, Eliza; Iwanowski, Jaroslaw; Krol, Malgorzata Serafin-; Marianowska, Agnieszka; Noszczyk, Wojciech

2005-01-01

Visceral aneurysms are potentially life-threatening vascular lesions. Superior mesenteric artery (SMA) pseudoaneurysms are a rare but well-recognized complication of chronic pancreatitis. Open surgical repair of such an aneurysm, especially in patients after previous surgical treatment, might be dangerous and risky. Stent graft implantation makes SMA pseudoaneurysm exclusion possible and therefore avoids a major abdominal operation. Percutaneous direct thrombin injection is also one of the methods of treating aneurysms in this area. We report a first case of percutaneous ultrasound-guided thrombin injection to complete SMA pseudoaneurysm exclusion after an unsuccessful endograft placement. Six-month follow-up did not demonstrate any signs of aneurysm recurrence

The inheritance of peripapillary atrophy

NARCIS (Netherlands)

Healey, Paul R.; Mitchell, Paul; Gilbert, Clare E.; Lee, Anne J.; Ge, Dongliang; Snieder, Harold; Spector, Timothy D.; Hammond, Christopher J.

PURPOSE. To estimate the relative importance of genes and environment in peripapillary atrophy type beta (beta-PPA) in a classic twin study. METHODS. Female twin pairs (n = 506) aged 49 to 79 years were recruited from the St. Thomas' UK Adult Twin Registry. Peripapillary atrophy was identified from

Recovery and residual stress of SMA wires and applications for concrete structures

International Nuclear Information System (INIS)

Choi, Eunsoo; Cho, Sung-Chul; Park, Taehyo; Hu, Jong Wan; Chung, Young-Soo

2010-01-01

In general, NiTi shape memory alloys are used for applications in civil structures. NiTi SMAs show good superelasticity and shape memory effect properties. However, for application of the shape memory effect, it is desirable for SMAs to show a wide temperature hysteresis, especially for civil structures which are exposed to severe environmental conditions. NiTiNb SMAs, in general, show a wider temperature hysteresis than NiTi SMAs and are more applicable for civil structures. This study examines the temperature hysteresis of NiTiNb and NiTi SMAs, and their recovery and residual stress are investigated. In addition, the tensile behaviors of SMA wires under residual stress are evaluated. This study explains the possible applications for concrete structures with the shape memory effect and illustrates two experimental results of concrete cylinders and reinforced concrete columns. For both tests, SMA wires of NiTiNb and NiTi are used to confine concrete using residual stress. The SMA wire jackets on the concrete cylinders increase the peak strength and the ductility compared to the plain concrete cylinders. In addition, the SMA wire jackets on reinforced concrete columns increase the ductility greatly without flexural strength degradation

Submillimeter Array (SMA) Newsletter August 2011

OpenAIRE

Blundell, Raymond

2011-01-01

Submillimeter Array (SMA) Newsletter August 2011 Blundell, Raymond Submillimeter Array Newsletter | Number 12 | August 2011 CONTENTS 1 From the Director SCIENCE HIGHLIGHTS: 2 Faint Submillimeter Sources behind Massive Lensing Clusters 5 Millimeter Imaging of the β Pictoris Debris Disk: Evidence for a Planetesimal Belt 7 Physical Properties of the Circumnuclear Starburst Ring in the Barred Galaxy NGC1097 TECHNICAL HIGHLIGHTS: 9 ...

Identification and characterisation of a nuclear localisation signal in the SMN associated protein, Gemin4

International Nuclear Information System (INIS)

Lorson, Monique A.; Dickson, Alexa M.; Shaw, Debra J.; Todd, Adrian G.; Young, Elizabeth C.; Morse, Robert; Wolstencroft, Catherine; Lorson, Christian L.; Young, Philip J.

2008-01-01

Gemin4 is a ubiquitously expressed multifunctional protein that is involved in U snRNP assembly, apoptosis, nuclear/cytoplasmic transportation, transcription, and RNAi pathways. Gemin4 is one of the core components of the Gemin-complex, which also contains survival motor neuron (SMN), the seven Gemin proteins (Gemin2-8), and Unrip. Mutations in the SMN1 gene cause the autosomal recessive disorder spinal muscular atrophy (SMA). Although the functions assigned to Gemin4 predominantly occur in the nucleus, the mechanisms that mediate the nuclear import of Gemin4 remain unclear. Here, using a novel panel of Gemin4 constructs we identify a canonical nuclear import sequence (NLS) in the N-terminus of Gemin4. The Gemin4 NLS is necessary and independently sufficient to mediate nuclear import of Gemin4. This is the first functional NLS identified within the SMN-Gemin complex

Muscular dystrophy in a dog resembling human becker muscular dystrophy.

Science.gov (United States)

Baroncelli, A B; Abellonio, F; Pagano, T B; Esposito, I; Peirone, B; Papparella, S; Paciello, O

2014-05-01

A 3-year-old, male Labrador retriever dog was presented with clinical signs of progressive exercise intolerance, bilateral elbow extension, rigidity of the forelimbs, hindlimb flexion and kyphosis. Microscopical examination of muscle tissue showed marked variability in myofibre size, replacement of muscle with mature adipose tissue and degeneration/regeneration of muscle fibres, consistent with muscular dystrophy. Immunohistochemical examination for dystrophin showed markedly reduced labelling with monoclonal antibodies specific for the rod domain and the carboxy-terminal of dystrophin, while expression of β-sarcoglycan, γ-sarcoglycan and β-dystroglycan was normal. Immunoblotting revealed a truncated dystrophin protein of approximately 135 kDa. These findings supported a diagnosis of congenital canine muscular dystrophy resembling Becker muscular dystrophy in man. Copyright © 2014 Elsevier Ltd. All rights reserved.

Imagem radiográfica da cavidade torácica de cães Golden Retriever acometidos pela distrofia muscular Radiologic images of the thoracic cavity of Golden Retriever dogs affected by muscular dystrophy

Directory of Open Access Journals (Sweden)

Flávio R. Alves

2009-02-01

Full Text Available A distrofia muscular de Duchenne (DMD é uma doença de origem genética, cuja principal manifestação clínica é enfraquecimento e atrofia progressiva dos músculos. Os cães da raça Golden Retriever podem apresentar distrofia muscular, com características genotípicas e fenotípicas muito próximas à distrofia muscular humana, sendo considerado o modelo animal mais apropriado para o estudo da DMD. Foram realizadas radiografias torácicas látero-laterais e dorsoventrais de 10 cães Golden Retriever afetados pela distrofia muscular, com o objetivo de relatar as alterações radiográficas associadas a essa patologia. O exame radiográfico da cavidade torácica evidenciou: (a padrão pulmonar intersticial e alveolar predominante, (b um quadro de pneumonia e edema pulmonar em fase inicial, (c a cardiomegalia como o principal achado de comprometimento circulatório na cavidade torácica, (d O megaesôfago torácico foi observado deslocando a traquéia e silhueta cardíaca ventralmente e, (e a cúpula diafragmática apresentou modificação morfológica, mostrando protrusão para o interior da cavidade torácica e hérnia hiatal, com deslocamento do estômago para o espaço mediastino caudal. Os achados de necropsia evidenciaram efusão pleural e enfisema pulmonar e lesões compatíveis com processos degenerativos e metaplásicos da musculatura diafragmática e intercostal. A avaliação radiográfica constituiu-se como um meio diagnóstico auxiliar essencial na identificação de doença cardíaca e respiratória em cães Golden Retriever acometidos pela Distrofia Muscular, capaz de identificar processos pneumônicos primários, permitindo o estabelecimento de terapêutica adequada de tratamento, com prognóstico reservado nos estágios mais avançados desta alteração.Duchenne Muscular Dystrophy (DMD is a genetic disorder with clinical signs of muscular weaknesses and progressive atrophy. Golden Retriever dogs show similar genotypic and

Cerebral atrophy in Parkinson's disease - represented in CT

International Nuclear Information System (INIS)

Becker, H.; Schneider, E.; Hacker, H.; Fischer, P.A.; Frankfurt Univ.

1979-01-01

To clarify the importance of brain atrophy in relation to the symptoms of Parkinson's disease, 173 patients were examined by computed tomography (CT). In 51.4% of the CT findings, brain atrophy was considered to be pathological. Statistically significant relations of age and sex were found with regard to the extent and localization of brain atrophy. Cortical atrophy also showed a significant dependence on duration of disease. Linear measurements at the lateral ventricles and the third ventricle lead us to assume that brain atrophy in Parkinson's patients is more prevalent than in normal patients within the scope of age involution. (orig.)

Cerebral atrophy in Parkinson's disease - represented in CT

Energy Technology Data Exchange (ETDEWEB)

Becker, H; Schneider, E; Hacker, H; Fischer, P A [Frankfurt Univ. (Germany, F.R.). Abt. fuer Neuroradiologie; Frankfurt Univ. (Germany, F.R.). Abt. fuer Neurologie)

1979-01-01

To clarify the importance of brain atrophy in relation to the symptoms of Parkinson's disease, 173 patients were examined by computed tomography (CT). In 51.4% of the CT findings, brain atrophy was considered to be pathological. Statistically significant relations of age and sex were found with regard to the extent and localization of brain atrophy. Cortical atrophy also showed a significant dependence on duration of disease. Linear measurements at the lateral ventricles and the third ventricle lead us to assume that brain atrophy in Parkinson's patients is more prevalent than in normal patients within the scope of age involution.

Sistem Informasi Akademik pada SMA Hang Tuah Belawan

OpenAIRE

Tanjung, Dini Syahroni

2015-01-01

Informasi yang disampaikan oleh SMA HANG TUAH BELAWAN selama ini disebarkan melalui brosur dan cara yang seperti itu kurang efektif. Oleh karena itu dibuatlah sistem informasi akademik ini agar penyampaian informasinya lebih efektif dan efisien. 092406181

Rhabdomyolysis featuring muscular dystrophies.

Science.gov (United States)

Lahoria, Rajat; Milone, Margherita

2016-02-15

Rhabdomyolysis is a potentially life threatening condition of various etiology. The association between rhabdomyolysis and muscular dystrophies is under-recognized in clinical practice. To identify muscular dystrophies presenting with rhabdomyolysis at onset or as predominant feature. We retrospectively reviewed clinical and laboratory data of patients with a genetically confirmed muscular dystrophy in whom rhabdomyolysis was the presenting or main clinical manifestation. Thirteen unrelated patients (males=6; females=7) were identified. Median age at time of rhabdomyolysis was 18 years (range, 2-47) and median duration between the first episode of rhabdomyolysis and molecular diagnosis was 2 years. Fukutin-related protein (FKRP) muscular dystrophy (n=6) was the most common diagnosis, followed by anoctaminopathy-5 (n=3), calpainopathy-3 (n=2) and dystrophinopathy (n=2). Four patients experienced recurrent rhabdomyolysis. Eight patients were asymptomatic and 3 reported myalgia and exercise intolerance prior to the rhabdomyolysis. Exercise (n=6) and fever (n=4) were common triggers; rhabdomyolysis was unprovoked in 3 patients. Twelve patients required hospitalization. Baseline CK levels were elevated in all patients (median 1200 IU/L; range, 600-3600). Muscular dystrophies can present with rhabdomyolysis; FKRP mutations are particularly frequent in causing such complication. A persistently elevated CK level in patients with rhabdomyolysis warrants consideration for underlying muscular dystrophy. Copyright © 2015 Elsevier B.V. All rights reserved.

Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program

DEFF Research Database (Denmark)

Morrison-Nozik, Alexander; Anand, Priti; Zhu, Han

2015-01-01

in Duchenne muscular dystrophy (DMD), a genetic muscle-wasting disease. A defined molecular basis underlying these performance-enhancing properties of GCs in skeletal muscle remains obscure. Here, we demonstrate that ergogenic effects of GCs are mediated by direct induction of the metabolic transcription......Classic physiology studies dating to the 1930s demonstrate that moderate or transient glucocorticoid (GC) exposure improves muscle performance. The ergogenic properties of GCs are further evidenced by their surreptitious use as doping agents by endurance athletes and poorly understood efficacy...... factor KLF15, defining a downstream pathway distinct from that resulting in GC-related muscle atrophy. Furthermore, we establish that KLF15 deficiency exacerbates dystrophic severity and muscle GC-KLF15 signaling mediates salutary therapeutic effects in the mdx mouse model of DMD. Thus, although...

PENGEMBANGAN MEDIA PEMBELAJARAN PENDIDIKAN JASMANI OLAHRAGA DAN KESEHATAN BERBASIS KOMPUTER UNTUK SMA

Directory of Open Access Journals (Sweden)

Suci Cahyati

2014-04-01

Full Text Available Penelitian ini bertujuan untuk menghasilkan produk berupa CD pembelajaran pendidikan jasmani olahraga dan kesehatan berbasis komputer untuk SMA yang valid dan efektif. Penelitian ini menggunakan metode Research and Development (R&D. Media yang dikembangkan memuat materi tentang HIV/AIDS. Pengembangan media pembelajaran ini menggunakan software Adobe Flash Cs3 Professional. Media yang telah dikembangkan melalui dua tahap penelitiannya itu validasi ahli dan uji coba lapangan. Berdasarkan validasi ahli dan uji coba lapangan hasil penelitian menunjukkan produk termasuk kriteria “Sangat baik” dengan rerata skor 4,25. Hasil tes siswa mengalami peningkatan dari rerata skor pretest 5,53 dan rerata skor posttest 7,56. Berdasarkan hasil tes tersebut dapat disimpulkan bahwa media pembelajaran pendidikan jasmani olahraga dan kesehatan efektif digunakan dalam pembelajaran di SMA. Kata kunci: Pengembangan media, penjasorkes, SMA

Klasifikasi Kecamatan Berdasarkan Nilai Akhir SMA/MA di Kabupaten Aceh Selatan Menggunakan Analisis Diskriminan

Directory of Open Access Journals (Sweden)

Fitriana A.R.

2015-11-01

Full Text Available Analisis diskriminan merupakan bagian dari analisis peubah ganda. Analisis diskriminan digunakan untuk memodelkan variabel tak bebas yang bersifat kualitatif dengan variabel bebas yang bersifat kuantitatif. Pada penelitian ini, analisis diskriminan lebih dari dua kelompok diterapkan pada data nilai akhir SMA/MA di Kabupaten Aceh Selatan yang bertujuan untuk mendapatkan model untuk pengklasifikasian kecamatan. Pengklasifikasian ini bertujuan untuk melihat perbedaan kualitas siswa SMA/MA yang berada di masing-masing kecamatan Kabupaten Aceh Selatan berdasarkan data nilai akhir. Variabel tak bebas yang digunakan berupa klasifikasi kecamatan berdasarkan rata-rata jumlah nilai akhir SMA/MA yang berada di masing-masing kecamatan yang dibentuk dengan K-Means Cluster. Sedangkan variabel bebas yang digunakan adalah data rata-rata nilai akhir SMA/MA untuk setiap mata pelajaran yang diujiankan pada masing-masing jurusan setiap kecamatan. Model yang didapatkan adalah dua model diskriminan untuk jurusan IPA dan IPS.

Força e arquitetura muscular do gémeo interno na bomba muscular venosa

OpenAIRE

Peixoto, Flávia; Pinto, Ângela; Kozlova, Veronika; Crisóstomo, Rute

2015-01-01

Objetivo: Avaliar e comparar a Força Muscular (FM), Amplitude de Movimento (ADM) e Arquitetura Muscular da bomba muscular venosa em sujeitos com e sem Insuficiência Venosa Crónica (IVC). Relevância: A IVC provoca alterações na função da bomba muscular venosa, no entanto, pouco se conhece acerca das suas repercussões físicas e funcionais. Amostra: Sujeitos com IVC (alterações da tróficas, e úlcera ativa/cicatrizada) e saudáveis. Foram avaliados 33 sujeitos dos quais foram analis...

Semantic memory retrieval circuit: role of pre-SMA, caudate, and thalamus.

Science.gov (United States)

Hart, John; Maguire, Mandy J; Motes, Michael; Mudar, Raksha Anand; Chiang, Hsueh-Sheng; Womack, Kyle B; Kraut, Michael A

2013-07-01

We propose that pre-supplementary motor area (pre-SMA)-thalamic interactions govern processes fundamental to semantic retrieval of an integrated object memory. At the onset of semantic retrieval, pre-SMA initiates electrical interactions between multiple cortical regions associated with semantic memory subsystems encodings as indexed by an increase in theta-band EEG power. This starts between 100-150 ms after stimulus presentation and is sustained throughout the task. We posit that this activity represents initiation of the object memory search, which continues in searching for an object memory. When the correct memory is retrieved, there is a high beta-band EEG power increase, which reflects communication between pre-SMA and thalamus, designates the end of the search process and resultant in object retrieval from multiple semantic memory subsystems. This high beta signal is also detected in cortical regions. This circuit is modulated by the caudate nuclei to facilitate correct and suppress incorrect target memories. Copyright © 2012 Elsevier Inc. All rights reserved.

Development of SMA Actuated Morphing Airfoil for Wind Turbine Load Alleviation

Science.gov (United States)

Karakalas, A.; Machairas, T.; Solomou, A.; Riziotis, V.; Saravanos, D.

Wind turbine rotor upscaling has entered a range of rotor diameters where the blade structure cannot sustain the increased aerodynamic loads without novel load alleviation concepts. Research on load alleviation using morphing blade sections is presented. Antagonistic shape memory alloy (SMA) actuators are implemented to deflect the section trailing edge (TE) to target shapes and target time-series relating TE movement with changes in lift coefficient. Challenges encountered by the complex thermomechanical response of morphing section and the enhancement of SMA transient response to achieve frequencies meaningful for aerodynamic load alleviation are addressed. Using a recently developed finite element for SMA actuators [1], actuator configurations are considered for fast cooling and heating cycles. Numerical results quantify the attained ranges of TE angle movement, the moving time period and the developed stresses. Estimations of the attained variations of lift coefficient vs. time are also presented to assess the performance of the morphing section.

An improved tuned mass damper (SMA-TMD) assisted by a shape memory alloy spring

International Nuclear Information System (INIS)

Mishra, Sudib K; Gur, Sourav; Chakraborty, Subrata

2013-01-01

The tuned mass damper (TMD) is a well acclaimed passive control device for vibration control of structures. However, the requirement of a higher mass ratio restricts its applicability for seismic vibration control of civil engineering structures. Improving the performance of TMDs has been attempted by supplementing them with nonlinear restoring devices. In this regard, the ability of shape memory alloy (SMA) in dissipating energy through a hysteretic phase transformation of its microstructure triggered by cyclic loading is notable. An improved version of TMD assisted by a nonlinear shape memory alloy (SMA) spring, referred as SMA-TMD, is studied here for seismic vibration mitigation. Extensive numerical simulations are conducted based on nonlinear random vibration analysis via stochastic linearization of the nonlinear force–deformation hysteresis of the SMA. A design optimization based on minimizing the root mean square displacement of the main structure is also carried out to postulate the optimal design parameters for the proposed system. The viability of the optimal design is verified with respect to its performance under recorded earthquake motions. Significant improvements of the control efficiency and a reduction of the TMD displacement at a much reduced mass ratio are shown to be achieved in the proposed SMA-TMD over those in the linear TMD. (paper)

Hipoparatireoidismo primário manifestando-se com aumento de enzimas musculares Primary hypoparathyreoidism with raised muscle enzymes

Directory of Open Access Journals (Sweden)

Simone Appenzeller

2005-08-01

Full Text Available Os autores relatam o caso de um jovem de 18 anos de idade com fraqueza muscular generalizada, cãibras e crises convulsivas, tratado com corticosteróides por oito anos em decorrência de um diagnóstico de polimiosite, sem melhora clínica. Ao exame físico apresentava força muscular normal, ausência de atrofias musculares, diminuição de reflexos tendíneos profundos e presença do sinal de Chvostek e Trousseau. A hipótese diagnóstica inicial foi de miopatia metabólica e a investigação laboratorial revelou cálcio sérico e urinário diminuídos e dosagem de paratormônio (PTH indetectável. O diagnóstico final foi de hipoparatireoidismo, tendo sido o paciente tratado com cálcio endovenoso. A tomografia de crânio demonstrou calcificações difusas, características da síndrome de Fahr. O paciente recebeu alta assintomático com carbonato de cálcio e colecalciferol.The authors report a case of an 18-year-old boy using prednisone for eight years for a misdiagnosis of polymyositis. His complains were diffuse weakness, cramps and seizures, with progressive worsening and with no improvement despite treatment with corticosteroid. On admission, the physical examination didn't show muscular weakness or atrophy. Deep tendom reflexes were absent and Chvostek and Trousseau signs were found. The diagnosis of a metabolic myopathy was considered and further laboratory findings revealed a low serum and urinary calcium, undetectable PTH. The diagnosis of hypoparathyreoidism was made and the patient was treated with endovenous calcium. Cranial tomography revealed diffuse calcifications, suggestive of Fahr's syndrome. The patient recovered completely and was discharged with oral calcium carbonate and colecalciferol.

Morphological and ultrastructural evaluation of the golden retriever muscular dystrophy trachea, lungs, and diaphragm muscle.

Science.gov (United States)

Lessa, Thais Borges; de Abreu, Dilayla Kelly; Rodrigues, Márcio Nogueira; Brólio, Marina Pandolphi; Miglino, Maria Angélica; Ambrósio, Carlos Eduardo

2014-11-01

Duchenne muscular dystrophy (DMD) is a genetic disease, characterized by atrophy and muscle weakness. The respiratory failure is a common cause of early death in patients with DMD. Golden retriever muscular dystrophy (GRMD) is a canine model which has been extensively used for many advances in therapeutics applications. As the patients with DMD, the GRMD frequently died from cardiac and respiratory failure. Observing the respiratory failure in DMD is one of the major causes of mortality we aimed to describe the morphological and ultrastructural data of trachea, lungs (conductive and respiratory portion of the system), and diaphragm muscle using histological and ultrastructural analysis. The diaphragm muscle showed discontinuous fibers architecture, with different diameter; a robust perimysium inflammatory infiltrate and some muscle cells displayed central nuclei. GRMD trachea and lungs presented collagen fibers and in addition, the GRMD lungs showed higher of levels collagen fibers that could limit the alveolar ducts and alveoli distension. Therefore, the most features observed were the collagen areas and fibrosis. We suggested in this study that the collagen remodeling in the trachea, lungs, and diaphragm muscle may increase fibrosis and affect the trachea, lungs, and diaphragm muscle function that can be a major cause of respiratory failure that occur in patients with DMD. © 2014 Wiley Periodicals, Inc.

Metal muscles and nerves—a self-sensing SMA-actuated hand concept

Science.gov (United States)

Simone, F.; Rizzello, G.; Seelecke, S.

2017-09-01

Bio-inspired hand-like grippers actuated by Shape Memory Alloy (SMA) wires represent an emerging new technology with potential applications in many different fields, ranging from industrial assembly processes to biomedical systems. The inherently high energy density makes SMAs a natural choice for compact, lightweight, and silent actuator systems capable of producing a high amount of work, such as hand prostheses or robotic systems in industrial human/machine environments. In this work, a concept for a compact and versatile gripping system is developed, in which SMA wires are implemented as antagonistic muscles actuating an artificial hand with three fingers. In order to combine high gripping force with sufficient actuation speed, the muscle implementation pursues a multi-wire concept with several 0.1 mm diameter NiTi wires connected in parallel, in order to increase the surface-to-volume ratio for accelerated cooling. The paper starts with an illustration of the design concept of an individual 3-phalanx-finger, along with kinematic considerations for optimal placement of SMA wires. Three identical fingers are subsequently fabricated via 3D printing and assembled into a hand-like gripper. The maximum displacement of each finger phalanx is measured, and an average phalanxes dynamic responsiveness is evaluated. SMA self-sensing is documented by experiments relating the wires change in resistance to the finger motion. Several finger force measurements are also performed. The versatility of the gripper is finally documented by displaying a variety of achievable grasping configurations.

Optimization of SMA layers in composite structures to enhance damping

Science.gov (United States)

Haghdoust, P.; Cinquemani, S.; Lecis, N.; Bassani, P.

2016-04-01

The performance of lightweight structures can be severely affected by vibration. New design concepts leading to lightweight, slender structural components can increase the vulnerability of the components to failure due to excessive vibration. The intelligent approach to address the problem would be the use of materials which are more capable in dissipating the energy due to their high value of loss factor. Among the different materials available to achieve damping, much attention has been attached to the use of shape memory alloys (SMAs) because of their unique microstructure, leading to good damping capacity. This work describes the design and optimization of a hybrid layered composite structure for the passive suppression of flexural vibrations in slender and light structures. Embedding the SMA layers in composite structure allows to combine different properties: the lightness of the base composite (e.g. fiber glass), the mechanical strength of the insert of metallic material and the relevant damping properties of SMA, in the martensitic phase. In particular, we put our attention on embedding the CuZnAl in the form of thin sheet in a layered composite made by glass fiber reinforced epoxy. By appropriately positioning of the SMA sheets so that they are subjected to the maximum curvature, the damping of the hybrid system can be considerably enhanced. Accordingly analytical method for evaluating the energy dissipation of the thin sheets with different shapes and patterns is developed and is followed by a shape optimization based on genetic algorithm. Eventually different configurations of the hybrid beam structure with different patterns of SMA layer are proposed and compared in the term of damping capacity.

Structural Organization of Muscular Elements of a Skin-Muscular Sac of Trematodes: Literature Survey

OpenAIRE

Kanat Kambarovich Akhmetov; Irina Yurievna Chidunchi

2015-01-01

The issue of structural organization of muscular elements of a trematodes’ skin-muscular sac is considered in the study. Special attention is paid to an analysis of materials of preceding researches, study of foreign authors and also to additional literature reflecting peculiarities of structure of a trematodes’ body muscular system. The stated issue is insufficiently studied and calls for further researches. A comparative analysis of places of trematodes’ localization, taking into considerat...

Pengembangan Program Macromedia Flash 8 untuk Pembelajaran Fisika di SMA

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Wiji Susilowati

2007-12-01

Full Text Available Tujuan penelitian adalah membuat dan mengevaluasi media pembelajaran fisika SMA menggunakan program Macromedia Flash 8. Subjek coba pada penelitian ini berjumlah 40 orang yang terdiri dari 10 siswa untuk uji coba instrumen penelitian, 10 siswa untuk ujicoba kelompok kecdl, dan 20 siswa untuk uji coba lapangan. Pengumpulan data dilakukan dengan mengguna­kan kuesioner dan tes fisika (pre-test dan post-test. Evaluasi terhadap program ditinjau dari aspek pembelajaran dan aspek media. Kritik dan saran digunakan untuk memperbaiki program. Hasil penelitian menunjukkan bahwa program Macromedia Flash 8 untuk pembelajaran fisika di SMA: (1 dirancang sesuai dengan prinsip-prinsip desain pembelajaran, (2 terbukti mampu menaikkan skor rerata tes fisika siswa sebesar 55,42%, (3 memiliki efisiensi waktu yang tinggi, (4 ditinjau dari aspek media Hinilai cukup bagus/menarik (dinilai/dikategorikan sedang oleh siswa, (5 ditinjau dari aspek pembelajaran secara keseluruhan program ini dinilai tinggi/jelas dimengerti oleh siswa, (6 ditinjau dari aspek media dinilai menarik (bagus/kategori tinggi oleh guru fisika, dan (7 ditinjau dari aspek pembelajaran juga dinilai menarik (bagus/kategori tinggi oleh guru fisika. Kata kunci: media pembelajaran fisika diSMA.

Seronegative Intestinal Villous Atrophy: A Diagnostic Challenge

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Cláudio Martins

2016-01-01

Full Text Available Celiac disease is the most important cause of intestinal villous atrophy. Seronegative intestinal villous atrophy, including those that are nonresponsive to a gluten-free diet, is a diagnostic challenge. In these cases, before establishing the diagnosis of seronegative celiac disease, alternative etiologies of atrophic enteropathy should be considered. Recently, a new clinical entity responsible for seronegative villous atrophy was described—olmesartan-induced sprue-like enteropathy. Herein, we report two uncommon cases of atrophic enteropathy in patients with arterial hypertension under olmesartan, who presented with severe chronic diarrhea and significant involuntary weight loss. Further investigation revealed intestinal villous atrophy and intraepithelial lymphocytosis. Celiac disease and other causes of villous atrophy were ruled out. Drug-induced enteropathy was suspected and clinical improvement and histologic recovery were verified after olmesartan withdrawal. These cases highlight the importance for clinicians to maintain a high index of suspicion for olmesartan as a precipitant of sprue-like enteropathy.

Shape Memory Alloy (SMA)-Based Launch Lock

Science.gov (United States)

Badescu, Mircea; Bao, Xiaoqi; Bar-Cohen, Yoseph

2014-01-01

Most NASA missions require the use of a launch lock for securing moving components during the launch or securing the payload before release. A launch lock is a device used to prevent unwanted motion and secure the controlled components. The current launch locks are based on pyrotechnic, electro mechanically or NiTi driven pin pullers and they are mostly one time use mechanisms that are usually bulky and involve a relatively high mass. Generally, the use of piezoelectric actuation provides high precession nanometer accuracy but it relies on friction to generate displacement. During launch, the generated vibrations can release the normal force between the actuator components allowing shaft's free motion which could result in damage to the actuated structures or instruments. This problem is common to other linear actuators that consist of a ball screw mechanism. The authors are exploring the development of a novel launch lock mechanism that is activated by a shape memory alloy (SMA) material ring, a rigid element and an SMA ring holding flexure. The proposed design and analytical model will be described and discussed in this paper.

Low power consumption mini rotary actuator with SMA wires

Science.gov (United States)

Manfredi, Luigi; Huan, Yu; Cuschieri, Alfred

2017-11-01

Shape memory alloys (SMAs) are smart materials widely used as actuators for their high power to weight ratio despite their well-known low energy efficiency and limited mechanical bandwidth. For robotic applications, SMAs exhibit limitations due to high power consumption and limited stroke, varying from 4% to 7% of the total length. Hysteresis, during the contraction and extension cycle, requires a complex control algorithm. On the positive side, the small size and low weight are eminently suited for the design of mini actuators for robotic platforms. This paper describes the design and construction of a light weight and low power consuming mini rotary actuator with on-board contact-less position and force sensors. The design is specifically intended to reduce (i) energy consumption, (ii) dimensions of the sensory system, and (iii) provide a simple control without any need for SMA characterisation. The torque produced is controlled by on-board force sensors. Experiments were performed to investigate the energy consumption and performance (step and sinusoidal angle profiles with a frequency varying from 0.5 to 10 Hz and maximal amplitude of {15}\\circ ). We describe a transient capacitor effect related to the SMA wires during the sinusoidal profile when the active SMA wire is powered and the antagonist one switched-off, resulting in a transient current time varying from 300 to 400 ms.

Passive base isolation with superelastic nitinol SMA helical springs

International Nuclear Information System (INIS)

Huang, Bin; Zhang, Haiyang; Wang, Han; Song, Gangbing

2014-01-01

Seismic isolation of structures such as multi-story buildings, nuclear reactors, bridges, and liquid storage tanks should be designed to preserve structural integrity. By implementing seismic isolation technology, the deformation of superstructures can be dramatically reduced, consequently helping to protect their safety as well. In this paper, an innovative type of passive base isolation system, which is mainly composed of superelastic nitinol SMA helical springs, is developed. In order to verify the effectiveness of the proposed system, a two-story experimental steel frame model is constructed, and two superelastic SMA helical springs are thermo-mechanically built in the laboratory. To describe the nonlinear mechanical properties of the superelastic SMA helical springs under reciprocating load, a phenomenological model is presented in terms of a series of tensile tests. Afterwards, a numerical model of the two-story frame with the suggested isolation system is set up to simulate the response of the isolated frame subjected to an earthquake. Both the experimental and the numerical simulation results indicate that the proposed base isolation system can remarkably suppress structural vibrations and has improved isolation effects when compared with a steel spring isolation system. Due to the capabilities of energy dissipation as well as fully re-centering, it is very applicable to utilize the suggested isolation system in base isolated structures to resist earthquakes. (paper)

Design and fabrication of a three-finger prosthetic hand using SMA muscle wires

Science.gov (United States)

Simone, Filomena; York, Alexander; Seelecke, Stefan

2015-03-01

Bio-inspired hand-like gripper systems based on shape memory alloy (SMA) wire actuation have the potential to enable a number of useful applications in, e.g., the biomedical field or industrial assembly systems. The inherent high energy density makes SMA solutions a natural choice for systems with lightweight, low noise and high force requirements, such as hand prostheses or robotic systems in a human/machine environment. The focus of this research is the development, design and realization of a SMA-actuated prosthetic hand prototype with three fingers. The use of thin wires (100 μm diameter) allows for high cooling rates and therefore fast movement of each finger. Grouping several small wires mechanically in parallel allows for high force actuation. To save space and to allow for a direct transmission of the motion to each finger, the SMA wires are attached directly within each finger, across each phalanx. In this way, the contraction of the wires will allow the movement of the fingers without the use of any additional gears. Within each finger, two different bundles of wires are mounted: protagonist ones that create bending movement and the antagonist ones that enable stretching of each phalanx. The resistance change in the SMA wires is measured during actuation, which allows for monitoring of the wire stroke and potentially the gripping force without the use of additional sensors. The hand is built with modern 3D-printing technologies and its performance while grasping objects of different size and shape is experimentally investigated illustrating the usefulness of the actuator concept.

Genetics Home Reference: Fukuyama congenital muscular dystrophy

Science.gov (United States)

... with mental retardation Muscular dystrophy, congenital, Fukuyama type Muscular dystrophy, congenital, with central nervous system involvement Polymicrogyria with muscular dystrophy Related Information How ...

An experimental and analytical study on the feasibility of SMA spring driven actuation of an iris mechanism

International Nuclear Information System (INIS)

Rajan, Aravindh; Abouseada, Mostafa; Manghaipathy, Pavithra; Ozalp, Nesrin; Majid, Feras Abdul; Salem, Ayman; Srinivasa, Arun

2016-01-01

Highlights: • An iris mechanism proposed in response to fluctuations in solar energy. • Iris motion controlled with the use of Nickel–Titanium Shape Memory Alloy springs. • Variation of the force exerted by SMA spring w.r.t. temperature tested experimentally. • An analytical expression that relates the aperture area and crank rotation is given. • SMA springs showed promising actuation mechanism as a replacement to motor. - Abstract: Variation in incoming solar energy adversely affects the temperature inside a solar reactor and lowers its efficiency. Therefore, it is important to develop a mechanism that can maintain semi-constant temperatures inside the reactor from sunrise to sunset. In this paper, we present an iris mechanism that reduces or enlarges its circular opening with the use of Nickel–Titanium Shape Memory Alloy (SMA) springs. SMA springs possess memory of their shapes at certain temperatures. Hence, by controlling the temperature of the spring, it is possible to exert different forces that may then be transferred to the variable aperture mechanism. In this study, variation of the force exerted by an SMA spring with respect to temperature was experimentally tested and the viability of an SMA spring’s use in actuating an iris mechanism aperture was examined. In order to simulate conditions under fluctuating solar radiation, a 7 kW solar simulator was used in experiments at varying power levels. It was observed that SMA springs are promising as a replacement of the actuation mechanism driven by a motor.

Age-related infra-tentorial brain atrophy on CT scan

International Nuclear Information System (INIS)

Kitani, Mitsuhiro; Kobayashi, Shotai; Yamaguchi, Shuhei; Okada, Kazunori; Murata, Akihiro; Tsunematsu, Tokugoro

1985-01-01

We had reported that the brain atrophy progressed significantly with advancing age using the two dimensional CT measurement by digitizer which was connected with personal computer. Using this method, we studied the age-related infra-tentrial brain atrophy in 67 normal subjects (14-90 years), and compared that with age-related supra-tentrial brain atrophy. There was a significant correlation between age and all indices [cranio-ventricular index (CVI), ventricular area index (VAI) and brain atrophy index (BAI)] in supratentrial brain. These indices did not correlated to the age in infra-tentrial brain (brainstem and cerebellum). Significant change of the brain atrophy occured above 60 years old was observed by BAI and VAI in supra-tentrial brain. There was a significant correlation between supra-tentrial brain atrophy index (BAI) and that of infratentrial brain. These results indicate that age-related brain atrophy might progress more slowly in brainstem and cerebellum than in cerebrum. (author)

MODEL PENGEMBANGAN PERANGKAT PEMBELAJARAN SEJARAH BERORIENTASI METAKOGNITIF JENJANG SMA

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Cahyo Budi Utomo

2015-01-01

Full Text Available The importance of metacognitive based history learning in the high school level as requested in the “curriculum 2013” is the main background of this research. The research is focused to find the model of development of metacognitive based learning through research and development (R&D type research. The results showed an essential component in achieving successful management of metacognitive based history learning in high school education which the curriculum as a core competency analysis and basic competencies, lesson plan development, and the development of assessment tools. Development model of metacognitive based learning at high school education have main characteristic of the inclusion of explicit metacognitive learning goals and assignments and devices equipped with a rubric and assessment questionnaire. Metacognitive based history learning instructional tools that are developed in senior high school level has been carried out as optimally as possible by involving history teachers in the process of development and testing through focus group discussions and questionnaire.Keywords: Model, Instructional tool, Metacognitive, senior high school levelPentingnya orientasi metakognitif dalam perangkat pembelajaran sejarah jenjang SMA sebagaimana yang dikehendaki dalam implementasi kurikulum 2013 merupakan latar belakang utama penelitian ini. Penelitian difokuskan untuk menemukan model pengembangan perangkat pembelajaran berorientasi metakognitif melalui penelitian berjenis riset dan pengembangan (R&D. Metode penelitian R&D dilaksanakan melalui tiga tahap utama yaitu: tahap studi pendahuluan, tahap pengembangan, dan tahap uji publik. Hasil penelitian menunjukkan komponen esensial dalam mewujudkan keberhasilan penge-lolaan pembelajaran sejarah berorientasi metakognitif pada jenjang pendidikan SMA adalah kurikulum sebagai bahan analisis kompetensi inti dan kompetensi dasar, pengembangan RPP, dan pengembangan perangkat assesmen. Model

A blended psychosocial support program for partners of patients with amyotrophic lateral sclerosis and progressive muscular atrophy: protocol of a randomized controlled trial.

Science.gov (United States)

de Wit, Jessica; Beelen, Anita; Drossaert, Constance H C; Kolijn, Ruud; van den Berg, Leonard H; Visser-Meily, Johanna M A; Schröder, Carin D

2018-05-02

Informal caregivers of patients with Amyotrophic Lateral Sclerosis (ALS) or Progressive Muscular Atrophy (PMA) face stressful demands due to severe impairments and prospect of early death of the patients they care for. Caregivers often experience feelings of psychological distress and caregiver burden, but supportive interventions are lacking. The objective of this study is to investigate the effectiveness of a psychosocial support program aimed at enhancing feelings of control over caregiving tasks and reducing psychological distress. This support program is based on an existing program for adult partners of people with cancer and is adapted to meet the needs of ALS caregivers. This study is a randomized controlled trial using a wait-list control design. One hundred and forty caregiver-patient dyads, recruited from a nationwide database and through the website of the Dutch ALS Center, will be either randomized to a support program or a wait-list control group. The blended intervention is based on Acceptance and Commitment Therapy and consists of 1 face-to-face contact, 6 online guided modules and 1 telephone contact. The intervention can be worked through in 8 weeks. The effectiveness and the participants' satisfaction with the intervention will be evaluated using a mixed method design. Caregivers and patients will be asked to fill in questionnaires on 4 occasions during the study: baseline, 3 months, 6 months and 9 months. The main study outcome is the psychological distress of the caregiver assessed with the Hospital Anxiety and Depression Scale. Secondary outcomes are caregiver burden, caregiver quality of life, quality of life of the patient and psychological distress of the patient. Group differences in primary and secondary outcomes at 6 months will be compared with linear mixed model analysis. In a subgroup of caregivers we will explore experiences with the support program through semi-structured interviews. Usage of the online modules will be logged

Distrofia muscular de Emery-Dreifuss: relato de caso Emery-Dreifuss muscular dystrophy: case report

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Ana Lucila Moreira Carsten

2006-06-01

Full Text Available A distrofia muscular de Emery-Dreifuss é uma forma de distrofia muscular freqüentemente associada a contraturas articulares e defeitos de condução cardíaca, que pode ser causada pela deficiência da proteína emerina na membrana nuclear interna das fibras musculares. Descrevemos o caso de um homem de 19 anos com diminuição de força muscular, hipotrofia nas cinturas escapular e pélvica, disfagia, contraturas articulares em cotovelos e tornozelos, apresentando história familiar compatível com herança ligada ao cromossomo X. A investigação mostrou creatinaquinase sérica elevada, eletrocardiograma com bloqueio atrioventricular de primeiro grau e bloqueio de ramo direito, eletroneuromiografia normal, biópsia muscular com alterações miopáticas e a análise por imuno-histoquímica mostrou deficiência de emerina. São discutidas as manifestações clínicas e genéticas, alterações laboratoriais e eletroneuromiográficas, bem como, a importância do estudo do padrão de herança no aconselhamento genético destas famílias.The Emery-Dreifuss muscular dystrophy is a form of muscular dystrophy that frequently presents early contractures and cardiac conduction defects, caused by emerin deficiency in the inner nuclear membrane of the muscular fibers. A 19-years-old man it presented muscle weakness and hypotrophy in the proximal upper and lower limbs, dysphagia and early contractures in elbows and ankles, with familiar history compatible with X-linked inheritance form. The investigation showed increased serum creatinekinase levels electrocardiogram had a first degree atrioventricular block and right bundle branch block normal electromyography and nerve conduction study muscle biopsy disclosed myopathic characteristics and nuclear protein immunohystochemical analysis showed deficiency of emerin. The clinical and genetics manifestations, laboratorial and electromyography changes, as well as, the study of the pattern of inheritance for

Relaci??n entre la masa muscular, la densidad mineral ??sea, la fuerza muscular, la aptitud funcional y la calidad muscular en personas mayores

OpenAIRE

Pati??o Villada, Fredy Alonso

2015-01-01

294 p. La tesis pretende determinar la frecuencia de la sarcopenia y osteporosis , problemas que afectan a la salud de las personas mayores, y analizar la relaci??n entre la masa muscular, la densidad mineral ??sea (DMO), la fuerza muscular, la aptitud funcional y la calidad muscular (CM). La muestra estudiada fue la formada por un grupo de 83 hombres y 175 mujeres mayores de Le??n (Espa??a). El estudio transversal eval??a ??ndices de masa grasa y densidad mineral ??sea y niveles d...

Abnormal pain perception in patients with Multiple System Atrophy.

Science.gov (United States)

Ory-Magne, F; Pellaprat, J; Harroch, E; Galitzsky, M; Rousseau, V; Pavy-Le Traon, A; Rascol, O; Gerdelat, A; Brefel-Courbon, C

2018-03-01

Patients with Parkinson's disease or Multiple System Atrophy frequently experience painful sensations. The few studies investigating pain mechanisms in Multiple System Atrophy patients have reported contradictory results. In our study, we compared pain thresholds in Multiple System Atrophy and Parkinson's disease patients and healthy controls and evaluated the effect of l-DOPA on pain thresholds. We assessed subjective and objective pain thresholds (using a thermotest and RIII reflex), and pain tolerance in OFF and ON conditions, clinical pain, motor and psychological evaluation. Pain was reported in 78.6% of Multiple System Atrophy patients and in 37.5% of Parkinson's disease patients. In the OFF condition, subjective and objective pain thresholds were significantly lower in Multiple System Atrophy patients than in healthy controls (43.8 °C ± 1.3 vs 45.7 °C ± 0.8; p = 0.0005 and 7.4 mA ± 3.8 vs 13.7 mA ± 2.8; p = 0.002, respectively). They were also significantly reduced in Multiple System Atrophy compared to Parkinson's disease patients. No significant difference was found in pain tolerance for the 3 groups and in the effect of l-DOPA on pain thresholds in Multiple System Atrophy and Parkinson's disease patients. In the ON condition, pain tolerance tended to be reduced in Multiple System Atrophy versus Parkinson's disease patients (p = 0.05). Multiple System Atrophy patients had an increase in pain perception compared to Parkinson's disease patients and healthy controls. The l-DOPA effect was similar for pain thresholds in Multiple System Atrophy and Parkinson's disease patients, but tended to worsen pain tolerance in Multiple System Atrophy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Para-muscular and trans-muscular approaches to the lumbar inter-vertebral foramen: an anatomical comparison.

Science.gov (United States)

Poetscher, Arthur Werner; Ribas, Guilherme Carvalhal; Yasuda, Alexandre; Nishikuni, Koshiro

2005-03-01

Foraminal and extra-foraminal disc herniations comprise up to 11.7% of all lumbar disc herniations. Facetectomy, which had been the classic approach, is now recognized as cause of pain and instability after surgery. Otherwise, posterior lateral approaches through a trans-muscular or a para-muscular technique offer no significant damage to key structures for spinal stability. The surgical anatomy of these approaches has already been described, but they were not compared. In order to quantify the angle of vision towards the intervertebral foramen offered by each technique, 12 fresh cadavers were dissected and studied regarding these approaches. The angle presented by trans-muscular approach was wider in all studied lumbar levels. Surgery through the trans-muscular approach is performed with a better working angle, requiring a smaller resection of surrounding tissues. Therefore, minor surgical trauma can be expected. Our measurements support previously published data that point the trans-muscular approach as the best surgical option.

Orocaecal transit time in Duchenne muscular dystrophy.

OpenAIRE

Korman, S H; Bar-Oz, B; Granot, E; Meyer, S

1991-01-01

Smooth muscle degeneration may occur in Duchenne muscular dystrophy. We measured fasting orocaecal transit time in patients with advanced Duchenne muscular dystrophy and other muscular dystrophies and in healthy controls. No significant differences were found. In contrast to reports of gastric hypomotility in Duchenne muscular dystrophy, we found no evidence of impaired small intestinal motility.

KREATIVITAS GURU BIOLOGI DALAM MEMETAKAN KOMODITAS HAYATI UNGGULAN LOKAL KE DALAM PEMBELAJARAN BIOLOGI SMA

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Asep Agus Sulaeman

2015-03-01

Full Text Available Tujuan penelitian ini adalah untuk mengetahui kreativitas guru Biologi SMA dalam memetakan topik-topik dari berbagai aspek komoditas hayati unggulan lokal melalui penggunaan metode mind map dan mengetahui kemampuan guru dalam memetakan topik-topik komoditas hayati unggulan lokal ke dalam pembelajaran Biologi di SMA. Analisis data kreativitas guru Biologi SMA dilakukan secara deskriptif kuantitatif terhadap mind map dengan menggunakan kriteria sesuai instrumen yang dikembangkan. Adapun analisis data tentang jumlah topik-topik Biologi dan jenis kegiatan pembelajaran berbasis komoditas hayati unggulan lokal dilakukan secara deskriptif kuantatif dan kualitatif. Hasil kajian ini menunjukkan nilai aspek-aspek kreativitas guru Biologi yang tinggi, yaitu kemampuan berpikir asli (91,67, peka terhadap masalah (91,67, kemampuan berpikir lancar (90, kemampuan berpikir luwes (88,33, dan kemampuan berpikir terperinci (86,67. Berdasarkan hasil pemetaan yang dilakukan guru, dapat diidentifikasi 15 topik Biologi SMA yang berkaitan dengan komoditas hayati unggulan lokal di Kabupaten Majalengka. Adapun kegiatan pembelajaran berbasis komoditas hayati unggulan yang diusulkan oleh guru tersebar di masing-masing tingkatan kelas dan semesternya dengan jumlah yang berbeda-beda.

ANALISIS KESULITAN KOGNITIF DAN MASALAH AFEKTIF SISWA SMA DALAM BELAJAR MATEMATIKA MENGHADAPI UJIAN NASIONAL

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Azis Azis

2015-11-01

Full Text Available Penelitian untuk mendeskripsikan tingkat dan letak kesulitan belajar matematika siswa pada aspek kognitif dan kategorisasi masalah belajar matematika siswa pada aspek afektif dalam menghadapi Ujian Nasional tahun pelajaran 2013/2014 SMA di Kota Baubau. Penelitian ini menggunakan penelitian dengan metode survei. Pengumpulan data yang digunakan adalah teknik pengukuran (tes diagnostik, kuisioner, dan wawancara. Hasil penelitian menunjukkan bahwa tingkat kesulitan belajar matematika yang dialami oleh siswa untuk menyelesaikan soal-soal Ujian Nasional berada pada kategori sedang; letak kesulitan belajar matematika siswa pada aspek kognitif dalam menyelesaikan soal-soal Ujian Nasional dilihat dari segi pengetahuan faktual dengan persentase interval kesulitan sebesar, segi pengetahuan konseptual dengan persentase interval kesulitan sebesar, dan segi pengetahuan prosedural dengan persentase interval kesulitan sebesar; dan kategorisasi masalah belajar matematika siswa pada kategori aspek afektif dalam menghadapi Ujian Nasional tahun pelajaran 2013/2014 SMA di Kota Baubau secara umum berada pada kategori rendah. Kata kunci: kesulitan belajar matematika, kognitif, afektif, ujian nasional SMA   AN ANALYSIS OF DIFFICULTY ON COGNITIVE AND PROBLEM ON AFFECTIVE OF SMA STUDENTS IN MATHEMATICS LEARNING FACING NATIONAL EXAMINATION Abstract This study aims to describe the degree of student’s learning difficulty of mathematics on cognitive and categorization of student’s learning problem on affective aspect in accomplishing mathematic items in facing national final exam of SMA Baubau municipality in 2013/2014 academic year. The research type uses survey method. The technique of data collecting made use of diagnostic test that is National final exam items in 2012/2013 academic year which was modified by the researcher, questionnaires, and interviews. The research result indicates that the degree of students’ learning difficulty of mathematics to accomplish

Group-SMA Algorithm Based Joint Estimation of Train Parameter and State

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Wei Zheng

2015-03-01

Full Text Available The braking rate and train arresting operation is important in the train braking performance. It is difficult to obtain the states of the train on time because of the measurement noise and a long calculation time. A type of Group Stochastic M-algorithm (GSMA based on Rao-Blackwellization Particle Filter (RBPF algorithm and Stochastic M-algorithm (SMA is proposed in this paper. Compared with RBPF, GSMA based estimation precisions for the train braking rate and the control accelerations were improved by 78% and 62%, respectively. The calculation time of the GSMA was decreased by 70% compared with SMA.

SMA-Based System for Environmental Sensors Released from an Unmanned Aerial Vehicle

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Lorenzo Pellone

2017-01-01

Full Text Available In the work at hand, a shape memory alloy (SMA-based system is presented. The system, conceived for releasing environmental sensors from ground or small unmanned aerial vehicles, UAV (often named UAS, unmanned aerial system, is made of a door, integrated into the bottom of the fuselage, a device distributor, operated by a couple of antagonistic SMA springs, and a kinematic chain, to synchronize the deployment operation with the system movement. On the basis of the specifications (weight, available space, energy supply, sensors size, etc., the system design was addressed. After having identified the main system characteristics, a representative mock-up was manufactured, featuring the bottom part of the reference fuselage. Functionality tests were performed to prove the system capability to release the sensors; a detailed characterization was finally carried out, mainly finalized at correlating the kinematic chain displacement with the SMA spring temperature and the supplied electrical power. A comparison between theoretical predictions and experimental outcomes showed good agreement.

Kajian Fisis Energi Terbarukan Panel Surya Melalui Eksperimen Sederhana untuk Siswa SMA

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Sunaryo Sunaryo

2015-12-01

Full Text Available Abstract Has conducted research on the effects of light intensity on the output voltage, current, and power. Research conducted generate data in the form of quantitative and graphs that show a link between the intensity of light, the output voltage, current, and power. The data obtained were used as sources of learning in senior high school (SMA. The implication is capable of enhancing creativity, motivation and learning outcomes of Physics subject of high school students in future studies. Keywords: light intensity, current, voltage, solar panel Abstrak Telah dilakukan penelitian tentang pengaruh intensitas cahaya terhadap tegangan output, arus, dan daya listrik. Penelitian yang dilakukan menghasilkan data dalam bentuk kuantitatif dan grafik yang menunjukkan adanya kaitan antara intensitas cahaya, tegangan output, arus, dan daya listrik. Data yang diperoleh dijadikan sebagai sumber informasi dalam pembelajaran di Sekolah Menengah Atas (SMA. Implikasinya adalah mampu meningkatkan kreativitas, motivasi, dan hasil belajar Fisika siswa SMA pada penelitian selanjutnya. Kata-kata kunci: intensitas cahaya, arus, tegangan, panel surya

Simulación basada en SMA de sistemas originalmente representados con EDO

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Ekaitz Zulueta Guerrero

2011-10-01

Full Text Available Resumen: En el presente trabajo se expone una metodología para modelar mediante un Sistema Multi-Agente (SMA sistemas biológicos y fisiológicos dinámicos con variables cuantificadas discretas, como el crecimiento y decrecimiento de poblaciones o el modelado epidemiológico de enfermedades. Se muestra un procedimiento para transformar un sistema de Ecuaciones Diferenciales Ordinarias (EDO (que modela un entorno de forma correcta en un SMA equivalente mediante un esquema basado en el método de Monte Carlo. Se utiliza un caso práctico fundamentado en un modelo matemático de Leucemia Mieloide Crónica (LMC para comparar la metodología basada en agentes con el modelado tradicional basado en un sistema de EDO. Se realiza una simulación con cada modelo (SMA y EDO y se compara los resultados obtenidos con ambas metodologías. Palabras clave: Ecuaciones diferenciales, modelo basado en agentes, Monte Carlo

PROFIL KESULITAN BELAJAR FISIKA POKOK BAHASAN KELISTRIKAN SISWA SMA DI KOTA SEMARANG

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Ani Rusilowati

2012-01-01

Full Text Available Tujuan penelitian ini adalah menentukan profil kesulitan belajar Fisika, khususnya pokok bahasan Kelistrikan yang dialami oleh siswa SMA di kota Semarang. Sampel penelitian adalah siswa SMA kelas X di kota Semarang, diambil secara cluster, dari SMA negeri dan swasta peringkat I, II, dan III, sebanyak 214 siswa. Kesulitan belajar didiagnosis dengan lima pendekatan, yaitu tujuan pembelajaran, pengetahuan prasyarat, profil materi, miskonsepsi, dan pengetahuan terstruktur. Kesulitan belajar Kelistrikan antara lain disebabkan oleh rendahnya penguasaan konsep, lemahnya kemampuan matematis, dan kekurangmampuan mengkonversi satuan. Penyebab kesulitan belajar dalam pengetahuan terstruktur adalah rendahnya kemampuan: verbal, menggunakan skema, membuat strategi pemecahan masalah, dan membuat algoritma. Hasil penelitian menunjukkan bahwa kesulitan belajar Kelistrikan rata-rata terjadi pada sub pokok bahasan: Kuat Arus Listrik, Hukum Ohm, Hambatan Penghantar, Hukum Kirchof II, Energi & Daya Listrik, dan Transformator. Sebagian siswa masih mengalami miskonsepsi terhadap konsep Hukum Ohm dan Hambatan Penghantar. Bagi siswa  sekolah peringkat III mengalami kesulitan belajar di semua aspek dan materi Kelistrikan Kata kunci : profil, kesulitan belajar, kelistrikan

Major motor atrophic patterns in the face and neck: CT evaluation

International Nuclear Information System (INIS)

Harnsberger, H.R.; Dillon, W.P.

1985-01-01

Cranial nerve deficits from various pathologic processes of the head and neck may result in characteristic patterns of denervation muscular atrophy. Such atrophic patterns may be clues to the location and extent of the lesion, particularly when cranial nerves are involved early in the course of the disease process. Thirty-six patients with computed tomographic (CT) evidence of muscular atrophy secondary to pathologic conditions involving the motor division of cranial nerves were examined. Five characteristic denervation muscular atrophy patterns seen on CT scans were identified. Recognition of these atrophic patterns can prevent misinterpretation of their CT appearance and direct the CT examination to the course of the compromised cranial nerve from the brainstem to its peripheral innervation

Hemifacial atrophy treated with autologous fat transplantation

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Gandhi Vijay

2005-01-01

Full Text Available A 23-year-old male developed right hemifacial atrophy following marphea profunda. Facial asymmetry due to residual atrophy was treated with autologous fat harvested from buttocks with marked cosmetic improvement.

Seismic fragility analysis of lap-spliced reinforced concrete columns retrofitted by SMA wire jackets

International Nuclear Information System (INIS)

Choi, Eunsoo; Park, Sun-Hee; Chung, Young-Soo; Kim, Hee Sun

2013-01-01

The aim of this study is to provide seismic fragility curves of reinforced concrete columns retrofitted by shape memory alloy wire jackets and thus assess the seismic performance of the columns against earthquakes, comparing them with reinforced concrete columns with lap-spliced and continuous reinforcement. For that purpose, this study first developed analytical models of the experimental results of the three types of columns, (1) lap-spliced reinforcement, (2) continuous reinforcement and (3) lap-spliced reinforcement and retrofitted by SMA wire jackets, using the OpenSEES program, which is oriented to nonlinear dynamic analysis. Then, a suite of ten recorded ground motions was used to conduct dynamic analyses of the analytical models with scaling of the peak ground acceleration from 0.1g to 1.0g in steps of 0.1g. From the static experimental tests, the column retrofitted with SMA wire jackets had a larger displacement ductility by a factor of 2.3 times that of the lap-spliced column, which was 6% larger compared with the ductility of the continuous reinforcement column. From the fragility analyses, the SMA wire jacketed column had median values of 0.162g and 0.567g for yield and collapse, respectively. For the yield damage state, the SMA wire jacketed column had a median value similar to the continuous reinforcement column. However, for the complete damage state, the SMA wire jacketed column showed a 1.33 times larger median value than the continuously reinforcement column. (paper)

Dismorfia muscular Muscle dysmorphia

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Sheila Seleri Marques Assunção

2002-12-01

Full Text Available Preocupações mórbidas com a imagem corporal eram tidas até recentemente como problemas eminentemente femininos. Atualmente estas preocupações também têm sido encontradas no sexo masculino. A dismorfia muscular é um subtipo do transtorno dismórfico corporal que ocorre principalmente em homens que, apesar da grande hipertrofia muscular, consideram-se pequenos e fracos. Além de estar associada a prejuízos sociais, ocupacionais, recreativos e em outras áreas do funcionamento do indivíduo, a dismorfia muscular é também um fator de risco para o abuso de esteróides anabolizantes. Este artigo aborda aspectos epidemiológicos, etiológicos e padrões clínicos da dismorfia muscular, além de tecer comentários sobre estratégias de tratamento para este transtorno.Morbid concern over body image was considered, until recently, a female issue. Nowadays, it has been viewed as a common male disorder. Muscle dysmorphia, a subtype of a body dysmorphic disorder, affects men who, despite having clear muscular hypertroph,y see themselves as frail and small. Besides being associated to major social, leisure and occupational dysfunction, muscle dysmorphia is also a risk factor for the abuse of steroids. This article describes epidemiological, etiological and clinical characteristics of muscle dysmorphia and comments on its treatment strategy.

A study of atriphos (ATP) action on muscular circulation in progressive muscular dystrophy by the radioactive xenon clearance technique

International Nuclear Information System (INIS)

Chakyrov, B.; Samardzhiev, A.

1977-01-01

The effect of intramuscularly and intravenously adminostered atriphos on the muscular circulation was studied with radioactive xenon in 12 children with progressive muscular dystrophy. After combined local intramuscular injection of ATP (atriphos) with the radioactive marker a 12-fold increment of muscular circulation ensues, lasting about 15 minutes. No vasodilatating effect on the muscular flow was oberved after intravenous injection of 20-40 mg of atriphos. It is believed that intramuscular administration of atriphos produced dilatation of capillaries and of the venous part of the muscular circulation. (author)

PELAKSANAAN PROGRAM BOARDING SCHOOL DALAM PEMBINAAN MORAL SISWA DI SMA TARUNA INDONESIA PALEMBANG

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Hendriyenti H

2014-12-01

Full Text Available AbstractIndonesia nowadays faces some moral issues in teenagers scope or adult scope such as the use of drugs, violence, rascality, abortion, persecution, gambling, prostitution, and so on. Those problems are very danger for the country. Therefore, moral education is very important in this situation. The study was done at SMA Taruna Indonesia Palembang by the tittle: “the Implementation of boarding School Program for Students Moral education at SMA Taruna Indonesia Palembang”.Based on the result of the stuy, it was found that the implementation of boarding school program to educate students’moral at SMA Taruna Indonesia Palembang was applied throug dicipline implementation program and religion education program. Those two programs were applied by preventive and currative treatment. Moreover, there were some factors which support students’ moral education at SMA Taruna Indonesia Palembang such as students motivation, advisors dedication, 24 hours education and guidance, good coordination between advisors, teachers, securities, and other staff, and far location of boarding school from city center. As long as the teenager is an unstable period, there weremany difficulties in educate them. Finally,it is hoped that school stakeholders could improve the school management so that those difficulties could be solved and moral education could be applied.  Keywords: boarding school, morality building

Cobalt triggers necrotic cell death and atrophy in skeletal C2C12 myotubes

International Nuclear Information System (INIS)

Rovetta, Francesca; Stacchiotti, Alessandra; Faggi, Fiorella; Catalani, Simona; Apostoli, Pietro; Fanzani, Alessandro; Aleo, Maria Francesca

2013-01-01

Severe poisoning has recently been diagnosed in humans having hip implants composed of cobalt–chrome alloys due to the release of particulate wear debris on polyethylene and ceramic implants which stimulates macrophagic infiltration and destroys bone and soft tissue, leading to neurological, sensorial and muscular impairments. Consistent with this premise, in this study, we focused on the mechanisms underlying the toxicity of Co(II) ions on skeletal muscle using mouse skeletal C2C12 myotubes as an in vitro model. As detected using propidium iodide incorporation, increasing CoCl 2 doses (from 5 to 200 μM) affected the viability of C2C12 myotubes, mainly by cell necrosis, which was attenuated by necrostatin-1, an inhibitor of the necroptotic branch of the death domain receptor signaling pathway. On the other hand, apoptosis was hardly detectable as supported by the lack of caspase-3 and -8 activation, the latter resulting in only faint activation after exposure to higher CoCl 2 doses for prolonged time points. Furthermore, CoCl 2 treatment resulted in atrophy of the C2C12 myotubes which was characterized by the increased expression of HSP25 and GRP94 stress proteins and other typical 'pro-atrophic molecular hallmarks, such as early activation of the NF-kB pathway and down-regulation of AKT phosphorylation, followed by the activation of the proteasome and autophagy systems. Overall, these results suggested that cobalt may impact skeletal muscle homeostasis as an inducer of cell necrosis and myofiber atrophy. - Highlights: • The effects of cobalt on muscle myofibers in vitro were investigated. • Cobalt treatment mainly causes cell necrosis in skeletal C2C12 myotubes. • Cobalt impacts the PI3K/AKT and NFkB pathways and induces cell stress markers. • Cobalt induces atrophy of C2C12 myotubes through the activation of proteasome and autophagy systems. • Co treatment triggers NF-kB and PI3K/AKT pathways in C2C12 myotubes

Cobalt triggers necrotic cell death and atrophy in skeletal C2C12 myotubes

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Rovetta, Francesca [Unit of Biotechnologies, Department of Molecular and Translational Medicine, University of Brescia, Brescia I-25123 (Italy); Interuniversity Institute of Myology (IIM) (Italy); Stacchiotti, Alessandra [Institute of Human Anatomy, Department of Clinical and Experimental Sciences, University of Brescia, Brescia I-25123 (Italy); Faggi, Fiorella [Unit of Biotechnologies, Department of Molecular and Translational Medicine, University of Brescia, Brescia I-25123 (Italy); Interuniversity Institute of Myology (IIM) (Italy); Catalani, Simona; Apostoli, Pietro [Unit of Occupational Health and Industrial Hygiene, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia I-25123 (Italy); Fanzani, Alessandro, E-mail: fanzani@med.unibs.it [Unit of Biotechnologies, Department of Molecular and Translational Medicine, University of Brescia, Brescia I-25123 (Italy); Interuniversity Institute of Myology (IIM) (Italy); Aleo, Maria Francesca, E-mail: aleo@med.unibs.it [Unit of Biotechnologies, Department of Molecular and Translational Medicine, University of Brescia, Brescia I-25123 (Italy); Interuniversity Institute of Myology (IIM) (Italy)

2013-09-01

Severe poisoning has recently been diagnosed in humans having hip implants composed of cobalt–chrome alloys due to the release of particulate wear debris on polyethylene and ceramic implants which stimulates macrophagic infiltration and destroys bone and soft tissue, leading to neurological, sensorial and muscular impairments. Consistent with this premise, in this study, we focused on the mechanisms underlying the toxicity of Co(II) ions on skeletal muscle using mouse skeletal C2C12 myotubes as an in vitro model. As detected using propidium iodide incorporation, increasing CoCl{sub 2} doses (from 5 to 200 μM) affected the viability of C2C12 myotubes, mainly by cell necrosis, which was attenuated by necrostatin-1, an inhibitor of the necroptotic branch of the death domain receptor signaling pathway. On the other hand, apoptosis was hardly detectable as supported by the lack of caspase-3 and -8 activation, the latter resulting in only faint activation after exposure to higher CoCl{sub 2} doses for prolonged time points. Furthermore, CoCl{sub 2} treatment resulted in atrophy of the C2C12 myotubes which was characterized by the increased expression of HSP25 and GRP94 stress proteins and other typical 'pro-atrophic molecular hallmarks, such as early activation of the NF-kB pathway and down-regulation of AKT phosphorylation, followed by the activation of the proteasome and autophagy systems. Overall, these results suggested that cobalt may impact skeletal muscle homeostasis as an inducer of cell necrosis and myofiber atrophy. - Highlights: • The effects of cobalt on muscle myofibers in vitro were investigated. • Cobalt treatment mainly causes cell necrosis in skeletal C2C12 myotubes. • Cobalt impacts the PI3K/AKT and NFkB pathways and induces cell stress markers. • Cobalt induces atrophy of C2C12 myotubes through the activation of proteasome and autophagy systems. • Co treatment triggers NF-kB and PI3K/AKT pathways in C2C12 myotubes.

KEEFEKTIFAN TEKNIK RELAKSASI UNTUK MENURUNKAN STRES AKADEMIK SISWA SMA

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Suyono Suyono

2016-08-01

Full Text Available Abstract: This study aims at examining the effectiveness of relaxation techniques to release students’stress and tension regarding academic within Senior High School Assádah in Gresik City. This study employed quasi-experiment design using one group pretest-posttest model. The data of this study were obtained through academic stress inventory to attain a depiction of stress level encountered by the subject. The subjects of this study were seven students of Tenth Graders in SMA Assaadah Bungah Gresik who experienced low to average stress regarding exam preparation. The data were, then, analyzed by using Wilcoxon Statistic Analysis. The result of the study indicated that relaxation technique could lower and release the level of students stress in exam preparation. Key Words: relaxation technique, student academic stress   Abstrak: Penelitian ini bertujuan untuk  menguji keefektifan teknik relaksasi untuk menurunkan stres akademik siswa SMA Ass’adah di Kota Gresik dengan menggunakan rancangan kuasi eksperimen dengan model “one group pretest posttest design. Pengumpulan data dengan menggunakan inventori stres akademik tujuannya untuk memperoleh gambaran tingkat stres akademik pada subjek penelitian. Subjek penelitian adalah siswa yang mengalami stres akademik sedang dan rendah  dalam menghadapi ujian berjumlah 7 orang siswa pada kelas X SMA Assaadah Bungah Gresik. Teknik analisis data dengan menggunakanan analisis statistic Wilcoxon. Hasil penelitian menunjukkan adanya penurunan tingkat stres akademik menjelang ujian sesudah subjek mendapatkan layanan dengan teknik  relaksasi. Kata kunci: Teknik relaksasi, stres akademik siswa

Quantitative evaluation of tongue atrophy on midsagittal magnetic resonance images (MRIs)

International Nuclear Information System (INIS)

Ohnishi, Akio; Oishi, Tomonari; Murai, Yoshiyuki; Tsukamoto, Yoshiki; Ikeda, Masato

1992-01-01

This study was undertaken mainly to establish the quantitative parameter to evaluate the tongue atrophy on midsagittal MRIs and to show the clinical usefulness of such quantitative evaluation. Midsagittal MRIs of the tongue of consecutive 103 patients were analyzed. They were classified into 67 patients showing normal size (group without atrophy), 11 patients showing atrophy (group with atrophy) and 25 patients showing unsatifactory MRIs with artifacts based on the routine evaluation. The patients in the group without atrophy did not show any pathologic processes to produce tongue atrophy on clinical findings. The area and perimeter of tongue and oral cavity, and the ratio of tongue area to oral cavity area and the ratio of tongue perimeter to oral cavity perimeter on midsagittal MRIs were obtained in each patient of groups with and without atrophy by using quantitative image analysis system. In the group without atrophy, regression analysis of the data on age was made and the 95% confidence interval of the data for age was obtained. No evidence that the tongue becomes atrophic with aging was obtained in the group without atrophy. Patients in the group with atrophy were best separated from those in the group without atrophy statistically when the ratio of tongue area to oral cavity area was regressed on age. Among 11 patients in the group with atrophy, 6 patients were not regarded as having tongue atrophy on clinical neurological examinations. Therefore, the evaluation of midsagittal MRIs is clinically useful. (author)

Evaluation of both perfusion and atrophy in multiple system atrophy of the cerebellar type using brain SPECT alone

International Nuclear Information System (INIS)

Matsuda, Hiroshi; Imabayashi, Etsuko; Kuji, Ichiei; Seto, Akira; Ito, Kimiteru; Kikuta, Daisuke; Yamada, Minoru; Shimano, Yasumasa; Sato, Noriko

2010-01-01

Partial volume effects in atrophied areas should be taken into account when interpreting brain perfusion single photon emission computed tomography (SPECT) images of neurodegenerative diseases. To evaluate both perfusion and atrophy using brain SPECT alone, we developed a new technique applying tensor-based morphometry (TBM) to SPECT. After linear spatial normalization of brain perfusion SPECT using 99m Tc-ethyl cysteinate dimer ( 99m Tc-ECD) to a Talairach space, high-dimension-warping was done using an original 99m Tc-ECD template. Contraction map images calculated from Jacobian determinants and spatially normalized SPECT images using this high-dimension-warping were compared using statistical parametric mapping (SPM2) between two groups of 16 multiple system atrophy of the cerebellar type (MSA-C) patients and 73 age-matched normal controls. This comparison was also performed in conventionally warped SPECT images. SPM2 demonstrated statistically significant contraction indicating local atrophy and decreased perfusion in the whole cerebellum and pons of MSA-C patients as compared to normal controls. Higher significance for decreased perfusion in these areas was obtained in high-dimension-warping than in conventional warping, possibly due to sufficient spatial normalization to a 99m Tc-ECD template in high-dimensional warping of severely atrophied cerebellum and pons. In the present high-dimension-warping, modification of tracer activity remained within 3% of the original tracer distribution. The present new technique applying TBM to brain SPECT provides information on both perfusion and atrophy at the same time thereby enhancing the role of brain perfusion SPECT

Evaluation of both perfusion and atrophy in multiple system atrophy of the cerebellar type using brain SPECT alone

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Matsuda Hiroshi

2010-08-01

Full Text Available Abstract Background Partial volume effects in atrophied areas should be taken into account when interpreting brain perfusion single photon emission computed tomography (SPECT images of neurodegenerative diseases. To evaluate both perfusion and atrophy using brain SPECT alone, we developed a new technique applying tensor-based morphometry (TBM to SPECT. Methods After linear spatial normalization of brain perfusion SPECT using 99mTc-ethyl cysteinate dimer (99mTc-ECD to a Talairach space, high-dimension-warping was done using an original 99mTc-ECD template. Contraction map images calculated from Jacobian determinants and spatially normalized SPECT images using this high-dimension-warping were compared using statistical parametric mapping (SPM2 between two groups of 16 multiple system atrophy of the cerebellar type (MSA-C patients and 73 age-matched normal controls. This comparison was also performed in conventionally warped SPECT images. Results SPM2 demonstrated statistically significant contraction indicating local atrophy and decreased perfusion in the whole cerebellum and pons of MSA-C patients as compared to normal controls. Higher significance for decreased perfusion in these areas was obtained in high-dimension-warping than in conventional warping, possibly due to sufficient spatial normalization to a 99mTc-ECD template in high-dimensional warping of severely atrophied cerebellum and pons. In the present high-dimension-warping, modification of tracer activity remained within 3% of the original tracer distribution. Conclusions The present new technique applying TBM to brain SPECT provides information on both perfusion and atrophy at the same time thereby enhancing the role of brain perfusion SPECT

Frontal parenchymal atrophy measures in multiple sclerosis.

Science.gov (United States)

Locatelli, Laura; Zivadinov, Robert; Grop, Attilio; Zorzon, Marino

2004-10-01

The aim of this study was to establish whether, in a cross-sectional study, the normalized measures of whole and regional brain atrophy correlate better with tests assessing the cognitive function than the absolute brain atrophy measures. The neuropsychological performances and disability have been assessed in 39 patients with relapsing-remitting multiple sclerosis (MS). T1- and T2-lesion load (LL) of total brain and frontal lobes (FLs) were measured using a reproducible semiautomated technique. The whole brain volume and the regional brain parenchymal volume (RBPV) of FLs were obtained using a computerized interactive program, which incorporates semiautomated and automated segmentation processes. Normalized measures of brain atrophy, i.e., brain parenchymal fraction (BPF) and regional brain parenchymal fraction (RBPF) of FLs, were calculated. The scan-rescan, inter- and intrarater coefficient of variation (COV) and intraclass correlation coefficient (ICC) have been estimated. The RBPF of FLs showed an acceptable level of reproducibility which ranged from 1.7% for intrarater variability to 3.2% for scan-rescan variability. The mean ICC was 0.88 (CI 0.82-0.93). The RBPF of FLs demonstrated stronger magnitudes of correlation with neuropsychological functioning, disability and quantitative MRI lesion measures than RBPV. These differences were statistically significant: PColor Word Interference test, Pcognitive functions, whereas BPAV did not. The correlation analysis results were supported by the results of multiple regression analysis which showed that only the normalized brain atrophy measures were associated with tests exploring the cognitive functions. These data suggest that RBPF is a reproducible and sensitive method for measuring frontal parenchymal atrophy. The normalized measures of whole and regional brain parenchymal atrophy should be preferred to absolute measures in future studies that correlate neuropsychological performances and brain atrophy measures

MRI study of degenerative process in multiple system atrophy

International Nuclear Information System (INIS)

Yagishita, Toshiyuki; Kojima, Shigeyuki; Hirayama, Keizo

1995-01-01

The characteristic morphological changes of the brainstem and cerebellar regions of multiple system atrophy (MSA) were studied by MRI in varing subtypes, that is olivoponto cerebellar atrophy (OPCA: 23 cases), striatonigral degeneration (SND: 7 cases) and Shy-Drager's syndrome (SDS: 9 cases). OPCA was characterized by atrophy of the entire regions of the brainstem and the cerebellum. SND and SDS tended to show atrophy similar in type but lessin extent to OPCA. The common lesions in MSA were atrophy of the pontine base and cerebellum, and dilation of the fourth ventricle. Atrophy of the pontine base was more dominant in the inferior part than in the superior part, and cerebellar atrophy was more dominant in the superior part than in the inferior part, indicating that degeneration of the pontocerebellar pathway proceeds principally along fibers connecting the inferior part of the pons and the superior part of the cerebellum. Dilation of the fourth ventricle indicated atrophy of the middle cerebellar peduncle. In almost all the cases of OPCA and about a half the cases of SND and SDS, the pontine base and the middle cerebellar peduncle appeared as high signal intensity on T 2 weighted image and as low intensity on T 1 , suggesting degeneration and demyelination. In a few cases of OPCA, the dorsolateral part of the putamen were demonstrated as low signal intensity on T 2 weighted image. (author)

Superior mesenteric artery (SMA) resection during pancreatectomy for malignant disease of the pancreas: a systematic review.

Science.gov (United States)

Jegatheeswaran, Santhalingam; Baltatzis, Minas; Jamdar, Saurabh; Siriwardena, Ajith K

2017-06-01

Resection of the superior mesenteric artery (SMA) during pancreatectomy is performed infrequently and is undertaken with the aim of removing non-metastatic locally advanced pancreatic tumours. SMA resection reports also encompass resection of other visceral vessels. The consequences of resection of these different arteries are not necessarily equivalent. This is a focused systematic review of the outcome of SMA resection during pancreatectomy for cancer. A computerized search of the English language literature was undertaken for the period 1st January 2000 through 30th April 2016. The keywords "Pancreatic surgery" and "Vascular resections" were used. Thirteen studies reported 70 patients undergoing pancreatectomy with SMA resection from 10,726 undergoing pancreatectomy. Individual patient-level outcome data were available for 25. Median (range) accrual period was 132 (48-372) months. Reported peri-operative morbidity ranged from 39% to 91%. There were 5 peri-operative deaths in the 25 patients with individual-outcome data. Median survival was 11 months (95% Confidence interval 9.5-12.5 months; standard error 0.8 months). SMA resection during pancreatectomy is undertaken infrequently incurring high peri-operative morbidity and mortality. Median survival is 11 (95% CI 9.5-12.5) months. In contemporary practice there is no evidence to support SMA resection during pancreatectomy. Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. All rights reserved.

Learning disabilities in neuromuscular disorders: a springboard for adult life.

Science.gov (United States)

Astrea, Guja; Battini, Roberta; Lenzi, Sara; Frosini, Silvia; Bonetti, Silvia; Moretti, Elena; Perazza, Silvia; Santorelli, Filippo M; Pecini, Chiara

2016-10-01

Although the presence of cognitive deficits in Duchenne muscular dystrophy or myotonic dystrophy DM1 is well established in view of brain-specific expression of affected muscle proteins, in other neuromuscular disorders, such as congenital myopathies and limb-girdle muscular dystrophies, cognitive profiles are poorly defined. Also, there are limited characterization of the cognitive profile of children with congenital muscular dystrophies, notwithstanding the presence of cerebral abnormality in some forms, and in spinal muscular atrophies, with the exception of distal spinal muscular atrophy (such as the DYN1CH1- associated form). Starting from the Duchenne muscular dystrophy, which may be considered a kind of paradigm for the co-occurrence of learning disabilities in the contest of a progressive muscular involvement, the findings of neuropsychological (or cognitive) dysfunctions in several forms of neuromuscular diseases will be examined and reviewed.

Analysis of SMA Hybrid Composite Structures in MSC.Nastran and ABAQUS

Science.gov (United States)

Turner, Travis L.; Patel, Hemant D.

2005-01-01

A thermoelastic constitutive model for shape memory alloy (SMA) actuators and SMA hybrid composite (SMAHC) structures was recently implemented in the commercial finite element codes MSC.Nastran and ABAQUS. The model may be easily implemented in any code that has the capability for analysis of laminated composite structures with temperature dependent material properties. The model is also relatively easy to use and requires input of only fundamental engineering properties. A brief description of the model is presented, followed by discussion of implementation and usage in the commercial codes. Results are presented from static and dynamic analysis of SMAHC beams of two types; a beam clamped at each end and a cantilever beam. Nonlinear static (post-buckling) and random response analyses are demonstrated for the first specimen. Static deflection (shape) control is demonstrated for the cantilever beam. Approaches for modeling SMAHC material systems with embedded SMA in ribbon and small round wire product forms are demonstrated and compared. The results from the commercial codes are compared to those from a research code as validation of the commercial implementations; excellent correlation is achieved in all cases.

Distribution of skeletal muscle involvement in autosomal recessive distal muscular dystrophy. A clinical and computed tomographic study

Energy Technology Data Exchange (ETDEWEB)

Mizusawa, Hidehiro; Nakanishi, Takao; Kobayashi, Fumie

1987-02-01

Distribution of skeletal muscle involvement in 5 cases with autosomal recessive distal muscular dystrophy was studied clinically and by computed tomography (CT). Manual muscle test showed muscle involvement with a predilection for flexors in the lower leg and adductors in the thigh. Flexion and extension of the thigh and the lower leg was impaired to similar degree. In progressed cases, neck flexors and trunk muscles were also affected mildly. CT disclosed more clearly the preferential involvement of flexors in the lower leg, and involvement of both hamstrings center dot adductors group and extensors group of the thigh to similar degree. However, m. popliteus was curiously well preserved. In addition, there was a stage showing high density and hypertrophy of m. sartorius, m. gracilis, m. adductor, m. biceps femoris, m. semimenbranosus, m. semitendinosus or m. rectus femoris, which in thought to be compensatory hypertrophy. M. gluteus minimus in the pelvic girdle and m. dorsi proprii in the trunk were also liable to be affected. The CT findings are regarded as characteristic features noted clearly before muscle weakness and atrophy become apparent clinically. CT is very useful for distinguishing distal muscular dystrophy from rimmed vacuolar distal myopathy in which m. quadriceps femoris and flexors of the lower leg are usually well preserved without compensatory hypertrophy on CT.

Force-Deformation Response of a SMA-Based Actuator Considering the Electric Current Intensity as Step-Input

Directory of Open Access Journals (Sweden)

Ion-Cornel Mituletu

2015-06-01

Full Text Available The goal of the paper is to accomplish the response regarding the force-displacement characteristic evolution, of a Shape Memory Alloy (SMA actuator element. This reveals the first research stage in controlling the SMA behavior, providing important information about the heating-cooling time intervals. Step excitation of the SMA is performed by few values of electric current intensity, which produces the heating of SMA element up to 90-95 oC. To meet the testing requirements, an adequate test stand has been set up, consisting of sensors for force, displacement and temperature. The analog values provided by sensors were acquired and afterwards analyzed. The values of temperature, displacement and force were achieved, and their characteristic evolution has been performed. Thus, the time intervals are resulted and some other important aspects have been observed, regarding the delay between parameters and the temperature overshoot

A comparison of swallowing dysfunction in Becker muscular dystrophy and Duchenne muscular dystrophy.

Science.gov (United States)

Yamada, Yuka; Kawakami, Michiyuki; Wada, Ayako; Otsuka, Tomoyoshi; Muraoka, Kaori; Liu, Meigen

2018-06-01

Swallowing dysfunction has been reported in Duchenne muscular dystrophy (DMD), but has not been studied in Becker muscular dystrophy (BMD). The aims of this study were to report the characteristics of swallowing dysfunction in BMD compared with DMD. The study participants were 18 patients with BMD and 18 patients with DMD. All the patients were examined using videofluorography during swallowing of 5 mL of fluid. The penetration-aspiration scale (P-A scale) and the videofluorographic dysphagia scale (VDS) were used to evaluate dysphagia. Swinyard functional ability stage was not significantly different between the BMD and DMD groups. Rate of aspiration, P-A scale score, and total VDS score did not differ across groups, but the VDS item score for laryngeal elevation was lower in the BMD group than in the DMD group (median scores 4.5 and 9, respectively; p Becker muscular dystrophy (BMD) was not well known. Eighteen patients with BMD and 18 patients with Duchenne muscular dystrophy were examined with videofluorography. Patients with BMD have swallowing problems similar to those observed in patients with DMD.

Numerical and Experimental Investigation on Aerodynamic Characteristics of SMA Actuated Smart Wing Model

OpenAIRE

Iyyappan Balaguru; Sathiavelu Sendhilkumar

2013-01-01

Due to the advancements in smart actuators, morphing (changing) of aircraft wings has been investigated by increasing number of researchers in recent years. In this research article, the concept of morphing is introduced to the conventional aircraft wing model with the utilization of Shape memory alloys (SMAs). An actuating mechanism is developed and built inside the aircraft wing model along with the SMA actuators which is used to morph its shape. The aircraft wing model with the SMA actuati...

Morphologic imaging in muscular dystrophies and inflammatory myopathies

International Nuclear Information System (INIS)

Degardin, Adrian; Lacour, Arnaud; Vermersch, Patrick; Morillon, David; Cotten, Anne; Stojkovic, Tanya

2010-01-01

To determine if magnetic resonance imaging (MR imaging) is useful in the diagnostic workup of muscular dystrophies and idiopathic inflammatory myopathies for describing the topography of muscle involvement. MR imaging was performed in 31 patients: 8 with dystrophic myotony types 1 (n = 4) or 2 (n = 4); 11 with limb-girdle muscular dystrophy, including dysferlinopathy, calpainopathy, sarcoglycanopathy, and dystrophy associated with fukutin-related protein mutation; 3 with Becker muscular dystrophy; and 9 with idiopathic inflammatory myopathies, including polymyositis, dermatomyositis, and sporadic inclusion body myositis. Analysis of T1 images enabled us to describe the most affected muscles and the muscles usually spared for each muscular disease. In particular, examination of pelvis, thigh, and leg muscles demonstrated significant differences between the muscular diseases. On STIR images, hyperintensities were present in 62% of our patients with muscular dystrophies. A specific pattern of muscular involvement was established for each muscular disease. Hyperintensities observed on STIR images precede fatty degeneration and are not specific for inflammatory myopathies. (orig.)

Morphologic imaging in muscular dystrophies and inflammatory myopathies

Energy Technology Data Exchange (ETDEWEB)

Degardin, Adrian; Lacour, Arnaud; Vermersch, Patrick [CHU de Lille, Clinique neurologique, Lille (France); Morillon, David; Cotten, Anne [CHRU de Lille, Service de Radiologie Osteoarticulaire, Hopital Roger Salengro, Lille (France); Stojkovic, Tanya [G-H Pitie-Salpetriere, Institut de Myologie, Paris (France)

2010-12-15

To determine if magnetic resonance imaging (MR imaging) is useful in the diagnostic workup of muscular dystrophies and idiopathic inflammatory myopathies for describing the topography of muscle involvement. MR imaging was performed in 31 patients: 8 with dystrophic myotony types 1 (n = 4) or 2 (n = 4); 11 with limb-girdle muscular dystrophy, including dysferlinopathy, calpainopathy, sarcoglycanopathy, and dystrophy associated with fukutin-related protein mutation; 3 with Becker muscular dystrophy; and 9 with idiopathic inflammatory myopathies, including polymyositis, dermatomyositis, and sporadic inclusion body myositis. Analysis of T1 images enabled us to describe the most affected muscles and the muscles usually spared for each muscular disease. In particular, examination of pelvis, thigh, and leg muscles demonstrated significant differences between the muscular diseases. On STIR images, hyperintensities were present in 62% of our patients with muscular dystrophies. A specific pattern of muscular involvement was established for each muscular disease. Hyperintensities observed on STIR images precede fatty degeneration and are not specific for inflammatory myopathies. (orig.)

Learning about Duchenne Muscular Dystrophy

Science.gov (United States)

... protein. Often these boys are classified as having Becker muscular dystrophy. Genetic testing (looking at the body's genetic instructions) ... National Library of Medicine Web site Duchenne and Becker muscular dystrophy [ghr.nlm.nih.gov] From Genetics Home Reference ...

Note: A component-level frequency tunable isolator for vibration-sensitive chips using SMA beams

Energy Technology Data Exchange (ETDEWEB)

Zhang, Xiaoyong, E-mail: zhangxy@buaa.edu.cn, E-mail: yanxiaojun@buaa.edu.cn; Yan, Xiaojun, E-mail: zhangxy@buaa.edu.cn, E-mail: yanxiaojun@buaa.edu.cn [School of Energy and Power Engineering, Beihang University, Beijing 100191 (China); Collaborative Innovation Center of Advanced Aero-Engine, Beijing 100191 (China); National Key Laboratory of Science and Technology on Aero-Engine Aero-Thermodynamics, Beijing 100191 (China); Beijing Key Laboratory of Aero-Engine Structure and Strength, Beijing 100191 (China); Ding, Xin; Wu, Di; Qi, Junlei; Wang, Ruixin; Lu, Siwei [School of Energy and Power Engineering, Beihang University, Beijing 100191 (China)

2016-06-15

This note presents a component-level frequency tunable isolator for vibration-sensitive chips. The isolator employed 8 U-shaped shape memory alloy (SMA) beams to support an isolation island (used for mounting chips). Due to the temperature-induced Young’s modulus variation of SMA, the system stiffness of the isolator can be controlled through heating the SMA beams. In such a way, the natural frequency of the isolator can be tuned. A prototype was fabricated to evaluate the concept. The test results show that the natural frequency of the isolator can be tuned in the range of 64 Hz–97 Hz by applying different heating strategies. Moreover, resonant vibration can be suppressed significantly (the transmissibility decreases about 65% near the resonant frequency) using a real-time tuning method.

Note: A component-level frequency tunable isolator for vibration-sensitive chips using SMA beams

International Nuclear Information System (INIS)

Zhang, Xiaoyong; Yan, Xiaojun; Ding, Xin; Wu, Di; Qi, Junlei; Wang, Ruixin; Lu, Siwei

2016-01-01

This note presents a component-level frequency tunable isolator for vibration-sensitive chips. The isolator employed 8 U-shaped shape memory alloy (SMA) beams to support an isolation island (used for mounting chips). Due to the temperature-induced Young’s modulus variation of SMA, the system stiffness of the isolator can be controlled through heating the SMA beams. In such a way, the natural frequency of the isolator can be tuned. A prototype was fabricated to evaluate the concept. The test results show that the natural frequency of the isolator can be tuned in the range of 64 Hz–97 Hz by applying different heating strategies. Moreover, resonant vibration can be suppressed significantly (the transmissibility decreases about 65% near the resonant frequency) using a real-time tuning method.

MRI study of degenerative process in multiple system atrophy

Energy Technology Data Exchange (ETDEWEB)

Yagishita, Toshiyuki; Kojima, Shigeyuki; Hirayama, Keizo [Chiba Univ. (Japan). School of Medicine

1995-02-01

The characteristic morphological changes of the brainstem and cerebellar regions of multiple system atrophy (MSA) were studied by MRI in varing subtypes, that is olivoponto cerebellar atrophy (OPCA: 23 cases), striatonigral degeneration (SND: 7 cases) and Shy-Drager`s syndrome (SDS: 9 cases). OPCA was characterized by atrophy of the entire regions of the brainstem and the cerebellum. SND and SDS tended to show atrophy similar in type but lessin extent to OPCA. The common lesions in MSA were atrophy of the pontine base and cerebellum, and dilation of the fourth ventricle. Atrophy of the pontine base was more dominant in the inferior part than in the superior part, and cerebellar atrophy was more dominant in the superior part than in the inferior part, indicating that degeneration of the pontocerebellar pathway proceeds principally along fibers connecting the inferior part of the pons and the superior part of the cerebellum. Dilation of the fourth ventricle indicated atrophy of the middle cerebellar peduncle. In almost all the cases of OPCA and about a half the cases of SND and SDS, the pontine base and the middle cerebellar peduncle appeared as high signal intensity on T{sub 2} weighted image and as low intensity on T{sub 1}, suggesting degeneration and demyelination. In a few cases of OPCA, the dorsolateral part of the putamen were demonstrated as low signal intensity on T{sub 2} weighted image. (author).

A lesão muscular na miastenia grave: estudo de 17 casos com histoquimica muscular

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Lineu Cesar Werneck

1982-03-01

Full Text Available Estudo de 17 biópsias musculares de pacientes com miastenia grave, utilizando técnicas de coloração a fresco e histoquímica muscular. Foram encontradas 15 biópsias musculares anormais, sendo que as principais alterações foram fibras musculares angulares escuras atróficas, excesso de gotículas de gordura na membrana externa das fibras, variação no diâmetro das fibras e atrofia de fibras do tipo II. Os achados foram interpretados como denervação em 11 biópsias, atrofia de fibras do tipo II em 7, infiltrado linfocitário em 4, necrose de fibras musculares com fagocitose em 1 e em 2 biópsias não foi encontrada qualquer anormalidade. Quanto maior o tempo de doença, mais severa foi a anormalidade encontrada. Dois pacientes apresentavam timoma, um miastenia grave congênita, um artrite reumatoide, um neurite hipertrófica intersticial, um tireoidite de Hashimoto e um com síndrome miastênica concomitante. São discutidos os achados anatomopatológicos e sua possível explicação.

Learning about Spinal Muscular Atrophy

Science.gov (United States)

... Care Genomic Medicine Working Group New Horizons and Research Patient Management Policy and Ethics Issues Quick Links for Patient Care Education All About the Human Genome Project Fact Sheets Genetic Education Resources for ...

Novel in vitro platform to investigate myotube atrophy

OpenAIRE

Oelkrug, Christopher; Horn, Katharina; Makert, Gustavo R.; Schubert, Andreas

2015-01-01

The electrical current exclusion (ECE) principle provides an alternative to common methods of cell diameter measurement and especially in atrophy and cancer associated cachexia research. C2C12 myoblasts were differentiated into myotubes and treated with 100 μM dexamethasone to induce atrophy in vitro. Subsequently, they were incubated for 24 h with media containing different concentrations of curcumin and/or branched-chain amino acids (BCAAs) in order to counteract atrophy. After treatment wi...

REKAYASA PERANGKAT LUNAK MEDIA INFORMASI SMA QURANIAH PALEMBANG

Directory of Open Access Journals (Sweden)

Herlinda Kusmiati

2017-08-01

Full Text Available Seiring dengan semakin berkembangnya teknologi informasi dan meningkatnya penggunaan internet sebagai media informasi dikalangan masyarakat Indonesia. Hal ini mendorong SMA Quraniah Palembang untuk membenahi media informasi yang ada saat ini untuk meningkatkan jumlah siswa.  Media informasi yang dibuat berbasis website menggantikan Media  informasi saat ini yang masih menggunakan media brosur dan banner, dimana informasi yang diberikan masih sebatas informasi mengenai visi misi, profile, dan syarat pendaftaran siswa baru yang tidak dapat diakses dengan mudah oleh masyarakat. Dengan media informasi berbasis website dapat memberikan kemudahan kepada masyarakat dalam mendapatkan informasi mengenai profil sekolah, persyaratan pendafataran siswa baru. Selain itu, media informasi ini menyediakan informasi mengenai kegiatan-kegiatan yang ada di sekolah, ektrakulikuler siswa, serta fasilitas yang ada di sekolah. Media informasi ini dikelola oleh admin tata usaha, sehingga kesalahan-kesalahan dalam penyampaian informasi akan lebih mudah diperbaiki. Informasi-informasi mengenai SMA Quraniah Palembang dapat diakses kapanpun dan dimanapu, tidak terbatas pada salah satu wilayah saja. Media informasi ini dibuat dengan menggunakan Php & Mysql dan Waterfall sebagai metode pengembangan sistem.

Bilateral optical nerve atrophy secondary to lateral occipital lobe infarction.

Science.gov (United States)

Mao, Junfeng; Wei, Shihui

2013-06-01

To report a phenomenon of optical nerve atrophy secondary to lateral occipital lobe infarction. Two successive patients with unilateral occipital lobe infarction who experienced bilateral optical nerve atrophy during the follow-up underwent cranial imaging, fundus photography, and campimetry. Each patient was diagnosed with occipital lobe infarction by cranial MRI. During the follow-up, a bilateral optic atrophy was revealed, and campimetry showed a right homonymous hemianopia of both eyes with concomitant macular division. Bilateral optic atrophy was related to occipital lobe infarction, and a possible explanation for the atrophy was transneuronal degeneration caused by occipital lobe infarction.

Sense of agency is related to gamma band coupling in an inferior parietal-preSMA circuitry

Directory of Open Access Journals (Sweden)

Anina eRitterband-Rosenbaum

2014-07-01

Full Text Available In the present study we tested whether sense of agency (SoA is reflected by changes in coupling between right medio-frontal/supplementary motor area (SMA and inferior parietal cortex (IPC. Twelve healthy adult volunteers participated in the study. They performed a variation of a line-drawing task (Nielsen, 1963;Fourneret and Jeannerod, 1998, in which they moved a cursor on a digital tablet with their right hand without seeing the hand. Visual feedback displayed on a computer monitor was either in correspondence with or deviated from the actual movement. This made participants uncertain as to the agent of the movement and they reported SoA in approximately 50% of trials when the movement was computer-generated. We tested whether IPC-preSMA coupling was associated with SoA, using dynamic causal modelling (DCM for induced responses (Chen et al., 2008;Herz et al., 2012. Nine different DCMs were constructed for the early and late phases of the task, respectively. All models included two regions: a superior medial gyrus (preSMA region and a right supramarginal gyrus (IPC region. Bayesian models selection (Stephan et al., 2009 favoured a model with input to IPC and modulation of the forward connection to SMA in the late task phase, and a model with input to preSMA and modulation of the backward connection was favoured for the early task phase. The analysis shows that IPC source activity in the 50-60Hz range modulated preSMA source activity in the 40-70 Hz range in the presence of SoA compared with no SoA in the late task phase, but the test of the early task phase did not reveal any differences between presence and absence of SoA. We show that SoA is associated with a directionally specific between frequencies coupling from IPC to preSMA in the higher gamma (ɣ band in the late task phase. This suggests that SoA is a retrospective perception, which is highly dependent on interpretation of the outcome of the performed action.

Sense of agency is related to gamma band coupling in an inferior parietal-preSMA circuitry

Science.gov (United States)

Ritterband-Rosenbaum, Anina; Nielsen, Jens B.; Christensen, Mark S.

2014-01-01

In the present study we tested whether sense of agency (SoA) is reflected by changes in coupling between right medio-frontal/supplementary motor area (SMA) and inferior parietal cortex (IPC). Twelve healthy adult volunteers participated in the study. They performed a variation of a line-drawing task (Nielsen, 1963; Fourneret and Jeannerod, 1998), in which they moved a cursor on a digital tablet with their right hand without seeing the hand. Visual feedback displayed on a computer monitor was either in correspondence with or deviated from the actual movement. This made participants uncertain as to the agent of the movement and they reported SoA in approximately 50% of trials when the movement was computer-generated. We tested whether IPC-preSMA coupling was associated with SoA, using dynamic causal modeling (DCM) for induced responses (Chen et al., 2008; Herz et al., 2012). Nine different DCMs were constructed for the early and late phases of the task, respectively. All models included two regions: a superior medial gyrus (preSMA) region and a right supramarginal gyrus (IPC) region. Bayesian models selection (Stephan et al., 2009) favored a model with input to IPC and modulation of the forward connection to SMA in the late task phase, and a model with input to preSMA and modulation of the backward connection was favored for the early task phase. The analysis shows that IPC source activity in the 50–60 Hz range modulated preSMA source activity in the 40–70 Hz range in the presence of SoA compared with no SoA in the late task phase, but the test of the early task phase did not reveal any differences between presence and absence of SoA. We show that SoA is associated with a directionally specific between frequencies coupling from IPC to preSMA in the higher gamma (ɣ) band in the late task phase. This suggests that SoA is a retrospective perception, which is highly dependent on interpretation of the outcome of the performed action. PMID:25076883

Buckling analysis of SMA bonded sandwich structure – using FEM

Science.gov (United States)

Katariya, Pankaj V.; Das, Arijit; Panda, Subrata K.

2018-03-01

Thermal buckling strength of smart sandwich composite structure (bonded with shape memory alloy; SMA) examined numerically via a higher-order finite element model in association with marching technique. The excess geometrical distortion of the structure under the elevated environment modeled through Green’s strain function whereas the material nonlinearity counted with the help of marching method. The system responses are computed numerically by solving the generalized eigenvalue equations via a customized MATLAB code. The comprehensive behaviour of the current finite element solutions (minimum buckling load parameter) is established by solving the adequate number of numerical examples including the given input parameter. The current numerical model is extended further to check the influence of various structural parameter of the sandwich panel on the buckling temperature including the SMA effect and reported in details.

Generation of GZKHQi001-A and GZWWTi001-A, two induced pluripotent stem cell lines derived from peripheral blood mononuclear cells of Duchenne muscular dystrophy patients

Directory of Open Access Journals (Sweden)

Xie Yuhuan

2018-04-01

Full Text Available Duchenne muscular dystrophy (DMD is an X-linked disease caused by mutations in the DMD gene, which spans ~2.4 Mb of genomic sequence at locus Xp21. This mutation results in the loss of the protein dystrophin. DMD patients die in their second or third decade due to either respiratory failure or cardiomyopathy, as the absence of dystrophin leads to myofiber membrane fragility and necrosis, eventually resulting in muscle atrophy and contractures. Currently, there is no effective treatment for DMD, therefore induced pluripotent stem cells from DMD patients would be a powerful tool for studying disease mechanisms.

VAPB/ALS8 MSP ligands regulate striated muscle energy metabolism critical for adult survival in caenorhabditis elegans.

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Sung Min Han

Full Text Available Mutations in VAPB/ALS8 are associated with amyotrophic lateral sclerosis (ALS and spinal muscular atrophy (SMA, two motor neuron diseases that often include alterations in energy metabolism. We have shown that C. elegans and Drosophila neurons secrete a cleavage product of VAPB, the N-terminal major sperm protein domain (vMSP. Secreted vMSPs signal through Roundabout and Lar-like receptors expressed on striated muscle. The muscle signaling pathway localizes mitochondria to myofilaments, alters their fission/fusion balance, and promotes energy production. Here, we show that neuronal loss of the C. elegans VAPB homolog triggers metabolic alterations that appear to compensate for muscle mitochondrial dysfunction. When vMSP levels drop, cytoskeletal or mitochondrial abnormalities in muscle induce elevated DAF-16, the Forkhead Box O (FoxO homolog, transcription factor activity. DAF-16 promotes muscle triacylglycerol accumulation, increases ATP levels in adults, and extends lifespan, despite reduced muscle mitochondria electron transport chain activity. Finally, Vapb knock-out mice exhibit abnormal muscular triacylglycerol levels and FoxO target gene transcriptional responses to fasting and refeeding. Our data indicate that impaired vMSP signaling to striated muscle alters FoxO activity, which affects energy metabolism. Abnormalities in energy metabolism of ALS patients may thus constitute a compensatory mechanism counterbalancing skeletal muscle mitochondrial dysfunction.

Stress Relaxation Effects in TiNi SMA During Superelastic Deformation: Experiment and Constitutive Model

Science.gov (United States)

Pieczyska, Elżbieta A.; Kowalewski, Zbigniew L.; Dunić, Vladimir Lj.

2017-12-01

This paper presents an investigation of thermomechanical effects related to the phenomena of stress relaxation occurring in TiNi SMA subjected to modified program of displacement-controlled tension. The deformation data were taken from testing machine, whereas the temperature changes accompanying the exothermic/endothermic martensite forward/reverse transformation were measured by infrared camera. At the advanced stages of the transformations, the strain was kept constant for a few minutes and the SMA load and temperature were recorded continuously. As a consequence, the stress and temperature changed significantly during the loading stops. A large stress drop, caused by the transformation, was observed during the relaxation stage in both courses of the SMA loading and unloading. Moreover, the non-uniform temperature distribution, reflecting macroscopically inhomogeneous transformation, lapsed while the strain was kept constant, yet restarted at the end of the relaxation stop and developed at the reloading stage. Along with the experimental results, the mechanical and thermal responses induced by the transformation were obtained by 3D coupled thermomechanical numerical analysis, realized in partitioned approach. Latent heat production was correlated with an amount of the martensitic volume fraction. The stress and temperature drops recorded during the experiment were satisfactorily reproduced by the model proposed for the SMA thermomechanical coupling.

Characterization of disuse skeletal muscle atrophy and the efficacy of a novel muscle atrophy countermeasure during spaceflight and simulated microgravity

Science.gov (United States)

Hanson, Andrea Marie

Humans are an integral part of the engineered systems that will enable return to the Moon and eventually travel to Mars. Major advancements in countermeasure development addressing deleterious effects of microgravity and reduced gravity on the musculoskeletal system need to be made to ensure mission safety and success. The primary objectives of this dissertation are to advance the knowledge and understanding of skeletal muscle atrophy, and support development of novel countermeasures for disuse atrophy to enable healthy long-duration human spaceflight. Models simulating microgravity and actual spaceflight were used to examine the musculoskeletal adaptations during periods of unloading. Myostatin inhibition, a novel anti-atrophy drug therapy, and exercise were examined as a means of preventing and recovering from disuse atrophy. A combination of assays was used to quantify adaptation responses to unloading and examine efficacy of the countermeasures. Body and muscle masses were collected to analyze systemic changes due to treatments. Hindlimb strength and individual muscle forces were measured to demonstrate functional adaptations to treatments. Muscle fiber morphology and myosin heavy chain (MHC) expression was examined to identify adaptations at the cellular level. Protein synthesis signals insulin-like growth factor-1 (IGF-1), Akt, and p70s6 kinase; and the degradation signals Atrogin-1 and MuRF-1 were examined to identify adaptations at the molecular level that ultimately lead to muscle hypertrophy and atrophy. A time course study provided a thorough characterization of the adaptation of skeletal muscle during unloading in C57BL/6 mice, and baseline data for comparison to and evaluation of subsequent studies. Time points defining the on-set and endpoints of disuse muscle atrophy were identified to enable characterization of rapid vs. long-term responses of skeletal muscle to hindlimb suspension. Unloading-induced atrophy primarily resulted from increased protein

X-linked spinal and bulbar muscular atrophy (Kennedy's disease with long-term electrophysiological evaluation: case report Atrofia muscular bulbo-espinal ligada ao cromossomo X (doença de Kennedy com seguimento eletrofisiológico de longo prazo: relato de caso

Directory of Open Access Journals (Sweden)

João Aris Kouyoumdjian

2005-03-01

Full Text Available X-linked spinal and bulbar muscular atrophy or Kennedy's disease is an adult-onset motor neuronopathy caused by a CAG repeat expansion within the first exon of an androgen receptor gene. We report the case of a 66-year-old man, previously diagnosed with motor neuron disease (MND, who presented acute and reversible left vocal fold (dysphonia and pharyngeal paresis, followed by a slowly progressive weakness and also bouts of weakness, wasting and fasciculation on tongue, masseter, face, pharyngeal, and some proximal more than distal upper limb muscles, associated to bilateral hand tremor and mild gynecomastia. There were 5 electroneuromyography exams between 1989 and 2003 that revealed chronic reinnervation, some fasciculations (less than clinically observed and rare fibrillation potentials, and slowly progressive sensory nerve action potentials (SNAP abnormality, leading to absent/low amplitude potentials. PCR techniques of DNA analysis showed an abnormal number of CAG repeats, found to be 44 (normal 11-34. Our case revealed an acute and asymmetric clinical presentation related to bulbar motoneurons; low amplitude/absent SNAP with mild asymmetry; a sub-clinical or subtle involvement of proximal/distal muscles of both upper and lower limbs; and a probable evolution with bouts of acute dennervation, followed by an efficient reinnervation.Atrofia muscular bulbo-espinal ligada ao cromossomo X (doença de Kennedy é uma neuronopatia motora em adultos causada por expansões na repetição CAG no gene do receptor andrógeno. Neste relato, descreve-se o caso de homem de 66 anos, com diagnóstico prévio de doença do neurônio motor (DNM que apresentou quadro agudo e reversível de paresia de prega vocal (disfonia e de músculos faríngeos à esquerda; posteriormente seguiram-se surtos de fraqueza lentamente progressiva, atrofia e fasciculações em língua, masseter, face, faringe e membros superiores predominantemente proximal, associada a tremor

A fuzzy PID-controlled SMA actuator for a two-DOF joint

Directory of Open Access Journals (Sweden)

Shi Zhenyun

2014-04-01

Full Text Available Shape memory alloy (SMA actuator is a potential advanced component for servo-systems of aerospace vehicles and aircraft. This paper presents a joint with two degrees of freedom (DOF and a mobility range close to ±60° when driven by SMA triple wires. The fuzzy proportional-integral-derivative (PID-controlled actuator drive was designed using antagonistic SMA triple wires, and the resistance feedback signal made a closed loop. Experiments showed that, with the driving responding frequency increasing, the overstress became harder to be avoided at the position under the maximum friction force. Furthermore, the hysteresis gap between the heating and cooling paths of the strain-to-resistance curve expanded under this condition. A fuzzy logic control was considered as a solution, and the curves of the wires were then modeled by fitting polynomials so that the measured resistance was used directly to determine the control signal. Accurate control was demonstrated through the step response, and the experimental results showed that under the fuzzy PID-control program, the mean absolute error (MAE of the rotation angle was about 3.147°. In addition, the investigation of the external interference to the system proved the controllable maximum output.

Perancangan Sistem Informasi SMA Negeri 1 Babalan Dengan Menggunakan Pemrograman PHP Dan MySQL

OpenAIRE

Yulita, Devi

2014-01-01

Tulisan ini bertujuan untuk membangun suatu sistem informasi pada SMA Negeri 1 Babalan. Sistem ini dikembangkan dengan menggunakan perangkat lunak PHP, MySQL, Apache, dan Mozilla Firefox juga software pembantu lainnya seperti Adobe Dreamweaver CS5. Tujuan dari sistem informasi ini adalah untuk menyajikan informasi profil sekolah, visi, misi dan tujuan, daftar siswa, daftar guru. Merancang sebuah website untuk membantu siswa dalam memperoleh informasi SMA Negeri 1 Babalan dan website ini dapat...

FRECUENCIAS NATURALES EN VIGAS ACTIVAMENTE TORSIONADAS USANDO ALAMBRES DE ALEACIÓN CON MEMORIA DE FORMA (SMA | NATURAL FREQUENCIES IN ACTVELY TWISTED BEAMS USING SHAPE MEMORY ALLOY (SMA WIRES

Directory of Open Access Journals (Sweden)

Gaetano Starlacci

2016-08-01

Full Text Available Changes in the geometry and stiffness of structural members can be obtained using Shape Memory Alloys (SMA wires, previously stretched, and externally attached to the member in a helical pattern. The wire was modeled assuming transformation from a pure martensitic phase to a pure austenitic phase. Natural frequency values before and after the SMA wire activation attached to the beam were calculated using the finite element method and these values were compared with those obtained from a model developed for pre-twisted stress-free cantilever members. The results obtained showed the active torsion influence over the structural element in the values of natural frequencies calculated.

Cardiac involvement in patients with limb-girdle muscular dystrophy type 2 and Becker muscular dystrophy

DEFF Research Database (Denmark)

Sveen, Marie-Louise; Thune, Jens Jakob; Køber, Lars

2008-01-01

OBJECTIVE: To investigate the extent of cardiac involvement in patients with 1 of the 12 groups of recessively inherited limb-girdle muscular dystrophy type 2 (LGMD2A-L) and Becker muscular dystrophy (BMD). DESIGN: Prospective screening. SETTING: Neuromuscular Clinic and Department of Cardiology...

Self-repairing performance of concrete beams strengthened using superelastic SMA wires in combination with adhesives released from hollow fibers

International Nuclear Information System (INIS)

Kuang Yachuan; Ou Jinping

2008-01-01

By taking advantage of the superelastic effect of shape memory alloy (SMA) and the cohering characteristic of repairing adhesive, a smart self-repairing concrete beam with damage self-repairing performance has been developed. In order to verify the potential self-repairing capacity of smart concrete beams reinforced with SMA wires and brittle fibers containing adhesives, static loading tests were conducted. Experimental results show that the superelastic SMA wires added self-restoration capacity to concrete beams, the deflection of the beams reversed and the crack closed almost completely after unloading. After the release of adhesive from the broken-open fibers into the cracks from the first loading, stress was redistributed to the uncracked section where a new crack was formed, while the sealed crack remained closed during reloading for the smart concrete beams reinforced with SMA wires and brittle fibers containing adhesives. While the original cracks experienced reopening, the load was carried directly by the wires during reloading for concrete beams reinforced with SMA wires

Efeitos da fadiga muscular induzida por exercícios no tempo de reação muscular dos fibulares em indivíduos sadios Efectos de la fatiga muscular inducida por ejercicios sobre el tiempo de reacción muscular peronea en individuos sanos Effects of the exercise-induced muscular fatigue on the time of muscular reaction of the fibularis in healthy individuals

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Bruno Araújo Rego Santos Silva

2006-04-01

Full Text Available A fadiga muscular (FM é um fenômeno comum nas atividades esportivas e diárias, resultando numa piora da performance motora. Ela é considerada um dos fatores causadores de lesões músculo-esqueléticas. A entorse de tornozelo é um exemplo: a FM afetaria tanto o sistema aferente quanto o eferente. Vários estudos têm analisado a influência da FM no controle neuromuscular (CNM; entretanto, existe pouca pesquisa sobre essa influência na velocidade de reação dos músculos. O objetivo deste estudo foi verificar os efeitos da FM no tempo de reação muscular (TRM dos músculos fibulares, que são os primeiros a responder a um estresse em inversão do tornozelo. Foram estudados 14 indivíduos saudáveis masculinos (idade: 20-35 anos, que tiveram seus TRM avaliados por meio de eletromiografia (EMG de superfície. O início da atividade muscular foi definido como a média de repouso + 3x o desvio-padrão (DP. O TRM dos fibulares foi mensurado após uma inversão súbita de 20º realizada numa plataforma. A inversão súbita foi realizada antes e depois da fadiga muscular, que foi induzida por exercícios localizados dos fibulares até a exaustão. Os resultados mostraram que houve um aumento significativo do tempo de reação muscular após a fadiga (p La fatiga muscular (FM es un fenómeno común en las actividades diarias, produciendo un empeoramiento de la actuación. Se la considera una de las causas de factores lesionantes musculares de esqueleto. El esguince del tobillo es un ejemplo: La FM afectaría tanto el sistema aferente cuanto el eferente. Varios estudios han estado analizando la influencia de FM en el comando neuromuscular (CNM, sin embargo, la existen pocas investigaciones sobre la influencia en la velocidad de reacción de los músculos. El objetivo de ese estudio era verificar los efectos de FM en el tiempo de reacción muscular (TRM de los músculos peroneos, que son los primeros en responder a una tensión en la inversi

EFEKTIVITAS FOCUS GROUP DISCUSSION UNTUK MENGURANGI STRES PADA SISWA SMA YANG AKAN MENGHADAPI UJIAN AKHIR NASIONAL

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Dina Aprilia

2016-10-01

Full Text Available This research is aimed to find the effectivity of Focus Group Discussion (FGD to decrease the feeling stress for senior high school students (SMA who will face the national final examination (UAN. Stress on SMA students is a circumstance which gets negative assessment. It intimidates and pushes the students, in this case is UAN would appear a reaction such as emotional disorder, cognition, physiology and behavior disorder of SMA students. This research concerned 21 SMA students in grade XII, who had high stress level in facing UAN. The subjects were divided into two groups. First group was the experiment group (include 11 students and it was the group who got the FGD treatment. The second group was control group (include 10 students and this group didn’t get the FGD treatment. Collecting data was done by using Stress Scale in facing UAN. It was given (a before FGD (pre-test and (b after FGD (post-test. The hypothesis is examined by using difference examination (t-test by comparing mean pre-test and post-test. The result showed that there was a significant influence to decrease the stress in SMA students who were in experiment group (t = 6,540, p < 0,01 after they got FGD treatment. Experiment group had decreased the stress score to face UAN (Mean=7,476.

Faktor Penghambat Proses Layanan Konseling Individual di SMA se-Kota Cilacap

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Fenti Nurindahsari

2015-12-01

Full Text Available Berdasarkan penuturan guru BK di salah satu SMA di kota Cilacap yang pernah menjadi tempat observasi oleh peneliti, ditemukan fenomena terkait dengan layanan konseling individual di sekolah tersebut yang tidak sesuai dengan teori-teori mengenai konseling individual yang ada dalam bimbingan konseling. Contoh yang tidak sesuai dengan teori  ketika proses konseling berakhir guru BK di sekolah tersebut tidak ada upaya tindak lanjut. Tujuan penelitian ini untuk mengetahui faktor penghambat proses layanan konseling individual di SMA sekota Cilacap. Jenis penelitian deskriptif kuantitatif. Populasi dalam penelitian ini adalah konselor yang ada di SMA sekota Cilacap. Teknik sampel untuk konselor yang dipilih praktikan adalah sampling jenuh. Instrumen yang digunakan adalah angket. Validitas menggunakan rumus Product Moment. Uji reliabitilitas menggunakan rumus Alpha. Metode analisis data menggunakan deskriptif persentase. Hasil penelitian menunjukan faktor internal penghambat berasal dari konselor dalam kriteria tinggi (71,74% faktor eksternal penghambat termasuk kriteria tinggi yaitu norma (71,59%, sarpras (71,38% dan lingkungan fisik (72,39%. Dapat disimpulkan hambatan yang ada dalam proses layanan konseling individual di SMA sekota Cilacap berasal dari faktor internal dan eksternal yang memiliki kriteria yang sama yaitu dalam kategori tinggi. Based the narrative counseling teacher in one high school in Cilacap town that  once a place observation, discovered the phenomenon associated with individual counseling services in the school is not in accordance with the theories about the existing individual counseling in counseling. Examples that don’t fit with theory when the counseling process ends counseling teacher the school is’n follow-up effort. The purpose of this study to determine inhibiting factors individual counseling service process In senior high school Cilacap derby. Pupolasi in research is senior high school counselors. Technical

Muscular dystrophy

Science.gov (United States)

... are no known cures for the various muscular dystrophies. The goal of treatment is to control symptoms. Physical therapy may help maintain muscle strength and function. Leg braces and a wheelchair ...

PENGARUH LINGKUNGAN KELUARGA, LINGKUNGAN SEKOLAH, DISIPLIN BELAJAR DAN MOTIVASI BELAJAR TERHADAP PRESTASI BELAJAR EKONOMI SISWA SMA KELAS XI IPS SMA PGRI 1 TAMAN PEMALANG