• 【II型和III型脊髓性肌萎缩症的药物治疗。】 复制标题 收藏 收藏
    DOI:10.1002/14651858.CD006282.pub5 复制DOI
    作者列表:Wadman RI,van der Pol WL,Bosboom WM,Asselman FL,van den Berg LH,Iannaccone ST,Vrancken AF
    BACKGROUND & AIMS: BACKGROUND:Spinal muscular atrophy (SMA) is caused by a homozygous deletion of the survival motor neuron 1 (SMN1) gene on chromosome 5, or a heterozygous deletion in combination with a (point) mutation in the second SMN1 allele. This results in degeneration of anterior horn cells, which leads to progressive muscle weakness. Children with SMA type II do not develop the ability to walk without support and have a shortened life expectancy, whereas children with SMA type III develop the ability to walk and have a normal life expectancy. This is an update of a review first published in 2009 and previously updated in 2011. OBJECTIVES:To evaluate if drug treatment is able to slow or arrest the disease progression of SMA types II and III, and to assess if such therapy can be given safely. SEARCH METHODS:We searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and ISI Web of Science conference proceedings in October 2018. In October 2018, we also searched two trials registries to identify unpublished trials. SELECTION CRITERIA:We sought all randomised or quasi-randomised trials that examined the efficacy of drug treatment for SMA types II and III. Participants had to fulfil the clinical criteria and have a homozygous deletion or hemizygous deletion in combination with a point mutation in the second allele of the SMN1 gene (5q11.2-13.2) confirmed by genetic analysis. The primary outcome measure was change in disability score within one year after the onset of treatment. Secondary outcome measures within one year after the onset of treatment were change in muscle strength, ability to stand or walk, change in quality of life, time from the start of treatment until death or full-time ventilation and adverse events attributable to treatment during the trial period. Treatment strategies involving SMN1-replacement with viral vectors are out of the scope of this review, but a summary is given in Appendix 1. Drug treatment for SMA type I is the topic of a separate Cochrane Review. DATA COLLECTION AND ANALYSIS:We followed standard Cochrane methodology. MAIN RESULTS:The review authors found 10 randomised, placebo-controlled trials of treatments for SMA types II and III for inclusion in this review, with 717 participants. We added four of the trials at this update. The trials investigated creatine (55 participants), gabapentin (84 participants), hydroxyurea (57 participants), nusinersen (126 participants), olesoxime (165 participants), phenylbutyrate (107 participants), somatotropin (20 participants), thyrotropin-releasing hormone (TRH) (nine participants), valproic acid (33 participants), and combination therapy with valproic acid and acetyl-L-carnitine (ALC) (61 participants). Treatment duration was from three to 24 months. None of the studies investigated the same treatment and none was completely free of bias. All studies had adequate blinding, sequence generation and reporting of primary outcomes. Based on moderate-certainty evidence, intrathecal nusinersen improved motor function (disability) in children with SMA type II, with a 3.7-point improvement in the nusinersen group on the Hammersmith Functional Motor Scale Expanded (HFMSE; range of possible scores 0 to 66), compared to a 1.9-point decline on the HFMSE in the sham procedure group (P < 0.01; n = 126). On all motor function scales used, higher scores indicate better function. Based on moderate-certainty evidence from two studies, the following interventions had no clinically important effect on motor function scores in SMA types II or III (or both) in comparison to placebo: creatine (median change 1 higher, 95% confidence interval (CI) -1 to 2; on the Gross Motor Function Measure (GMFM), scale 0 to 264; n = 40); and combination therapy with valproic acid and carnitine (mean difference (MD) 0.64, 95% CI -1.1 to 2.38; on the Modified Hammersmith Functional Motor Scale (MHFMS), scale 0 to 40; n = 61). Based on low-certainty evidence from other single studies, the following interventions had no clinically important effect on motor function scores in SMA types II or III (or both) in comparison to placebo: gabapentin (median change 0 in the gabapentin group and -2 in the placebo group on the SMA Functional Rating Scale (SMAFRS), scale 0 to 50; n = 66); hydroxyurea (MD -1.88, 95% CI -3.89 to 0.13 on the GMFM, scale 0 to 264; n = 57), phenylbutyrate (MD -0.13, 95% CI -0.84 to 0.58 on the Hammersmith Functional Motor Scale (HFMS) scale 0 to 40; n = 90) and monotherapy of valproic acid (MD 0.06, 95% CI -1.32 to 1.44 on SMAFRS, scale 0 to 50; n = 31). Very low-certainty evidence suggested that the following interventions had little or no effect on motor function: olesoxime (MD 2, 95% -0.25 to 4.25 on the Motor Function Measure (MFM) D1 + D2, scale 0 to 75; n = 160) and somatotropin (median change at 3 months 0.25 higher, 95% CI -1 to 2.5 on the HFMSE, scale 0 to 66; n = 19). One small TRH trial did not report effects on motor function and the certainty of evidence for other outcomes from this trial were low or very low. Results of nine completed trials investigating 4-aminopyridine, acetyl-L-carnitine, CK-2127107, hydroxyurea, pyridostigmine, riluzole, RO6885247/RG7800, salbutamol and valproic acid were awaited and not available for analysis at the time of writing. Various trials and studies investigating treatment strategies other than nusinersen (e.g. SMN2-augmentation by small molecules), are currently ongoing. AUTHORS' CONCLUSIONS:Nusinersen improves motor function in SMA type II, based on moderate-certainty evidence. Creatine, gabapentin, hydroxyurea, phenylbutyrate, valproic acid and the combination of valproic acid and ALC probably have no clinically important effect on motor function in SMA types II or III (or both) based on low-certainty evidence, and olesoxime and somatropin may also have little to no clinically important effect but evidence was of very low-certainty. One trial of TRH did not measure motor function.
    背景与目标: 背景:脊髓性肌萎缩症(SMA)是由5号染色体上的生存运动神经元1(SMN1)基因纯合缺失或与第二SMN1等位基因中的(点)突变相结合造成的杂合缺失所致。这导致前角细胞变性,从而导致进行性肌无力。 II型SMA儿童在没有支撑的情况下不会发展走路的能力,并且寿命会缩短,而III型SMA儿童会发展出走路的能力并具有正常的预期寿命。这是对2009年首次发布并于2011年更新的评论的更新。
    目的:评估药物治疗是否能够减缓或阻止II型和III型SMA的疾病进展,并评估这种治疗是否可以安全地进行。
    搜索方法:我们搜索了2018年10月的Cochrane神经肌肉专业注册簿,CENTRAL,MEDLINE,Embase和ISI Web of Science会议记录.2018年10月,我们还搜索了两个试验注册中心以识别未发表的试验。
    选择标准:我们寻求所有随机或半随机试验,以研究药物治疗II型和III型SMA的疗效。参加者必须满足临床标准,并通过基因分析确认SMN1基因第二等位基因(5q11.2-13.2)的点突变与纯合缺失或半合缺失相结合。主要结果指标是治疗开始后一年内的残疾评分变化。治疗开始后一年内的次要结局指标是肌肉力量变化,站立或行走能力,生活质量变化,从治疗开始到死亡或全时通气的时间以及在治疗期间可归因于治疗的不良事件试用期。涉及用病毒载体替代SMN1的治疗策略不在本评价的范围内,但附录1给出了摘要。I型SMA的药物治疗是另一项Cochrane评价的主题。
    数据收集和分析:我们遵循标准的Cochrane方法。
    主要结果:该评价的作者发现10项针对SMA II型和III型SMA的随机,安慰剂对照试验纳入了该评价,共有717名参与者。我们在此更新中添加了四个试验。该试验研究了肌酸(55名参与者),加巴喷丁(84名参与者),羟基脲(57名参与者),努森那森(126名参与者),奥索肟(165名参与者),苯丁酸(107名参与者),生长激素(20名参与者),促甲状腺激素释放激素( TRH)(9名参与者),丙戊酸(33名参与者),以及丙戊酸和乙酰基L-肉碱(ALC)的联合疗法(61名参与者)。治疗时间为3至24个月。没有一项研究调查相同的治疗方法,也没有完全没有偏倚。所有研究均具有足够的盲法,序列产生和主要结果的报告。根据中等程度的证据,鞘内注射Nusinersen可改善II型SMA儿童的运动功能(残疾),并且在Hammersmith功能运动量表扩展(HFMSE;可能评分范围为0至66)上,Nusinersen组改善了3.7点。相比,假手术组的HFMSE下降了1.9点(P <0.01; n = 126)。在所有使用的运动功能量表上,分数越高表示功能越好。根据两项研究的中度证据,与安慰剂相比,以下干预措施对SMA II型或III型(或两者)的运动功能评分均无临床重要影响:肌酸(中位数变化1较高,置信区间95%(CI) )-1到2;在总运动功能量度(GMFM)上,从0到264缩放; n = 40);丙戊酸和肉碱的联合疗法(平均差异(MD)0.64,95%CI -1.1至2.38;修改后的Hammersmith功能运动量表(MHFMS),量表0至40; n = 61)。根据来自其他单项研究的不确定性证据,与安慰剂相比,以下干预措施对SMA II型或III型(或两者)的运动功能评分均无临床重要影响:加巴喷丁(加巴喷丁组中位数变化0,-2在SMA功能评定量表(SMAFRS)上的安慰剂组中,量表为0到50; n = 66);羟基脲(GMFM的MD -1.88,95%CI -3.89至0.13,0至264比例; n = 57),丁酸苯酯(MD -0.13,95%CI -0.84至0.58在Hammersmith功能马达电子秤(HFMS)上0至40; n = 90)和丙戊酸的单药治疗(MDAF为0.06,SMAFRS上为95%CI -1.32至1.44,等级0至50; n = 31)。不确定性极低的证据表明,以下干预措施对运动功能的影响很小或没有影响:油酸肟酯(运动功能量度(MFM)D1 D2为MD 2,95%-0.25至4.25,等级0至75; n = 160)和生长激素(3个月时的中位数变化高0.25,HFMSE的95%CI -1至2.5,等级0至66; n = 19)。一项小型TRH试验未报告对运动功能的影响,该试验其他结果的证据确定性较低或非常低。尚待完成9个研究试验,涉及4-氨基吡啶,乙酰基-L-肉碱,CK-2127107,羟基脲,吡啶斯的明,利鲁唑,RO6885247 / RG7800,沙丁胺醇和丙戊酸的研究结果,在撰写本文时尚未提供分析结果。目前正在进行各种研究,以研究除Nusinersen以外的其他治疗策略(例如,SMN2-小分子增强)。
    作者的结论:Nusinersen可根据中度确定性证据改善II型SMA的运动功能。肌酐,加巴喷丁,羟基脲,苯丁酸,丙戊酸以及丙戊酸和ALC的组合可能基于低确定性证据对SMA II型或III型(或两者)的运动功能没有临床重要影响,并且油酸肟和生长激素也可能在临床上几乎没有影响,甚至没有,但是证据的准确性很低。 TRH的一项试验没有测量运动功能。
  • 【p.Ala546> Asp和p.Arg555> TGFBI基因的Trp突变及其在两个中国大型I型角膜营养不良家族中的临床表现。】 复制标题 收藏 收藏
    DOI:10.1089/gte.2008.0005 复制DOI
    作者列表:Yu P,Gu Y,Jin F,Hu R,Chen L,Yan X,Yang Y,Qi M
    BACKGROUND & AIMS: :The aim of this study was to conduct clinical, genetic, and molecular analysis of Chinese patients with granular corneal dystrophy type I (CDGG1). Two large unrelated Chinese families with CDGG1 were clinically and genetically evaluated. Molecular genetic analysis was performed on DNA extracted from peripheral blood. Exons 4, 11, 12, and 14 of the human transforming growth factor beta-induced gene (TGFBI, formerly designated BIGH3) were amplified by PCR, scanned for mutations using the single-strand conformation polymorphism method, and the mutations identified by nucleotide sequencing. One family segregated the p.Ala546 > Asp mutation, and the other family had a p.Arg555 > Trp mutation. These missense mutations were not found in 53 unrelated, healthy individuals analyzed as controls. Clinical and genetic evaluations revealed the variable severity, symmetry, and age of onset in visual impairment in these families for different mutations. Penetrance of visual impairment in these families was 100% and 75%, respectively. This study confirms that the p.Arg555 > Trp mutation is a frequent cause of CDGG1, and that the p.Ala546 > Asp mutation is also associated with this disease.
    背景与目标: :本研究的目的是对中国I型角膜颗粒性营养不良患者(CDGG1)进行临床,遗传和分子分析。临床和遗传学评估了两个与CDGG1无关的中国大家庭。对从外周血中提取的DNA进行了分子遗传分析。通过PCR扩增人类转化生长因子β诱导基因(TGFBI,以前称为BIGH3)的外显子4、11、12和14,使用单链构象多态性方法扫描突变,并通过核苷酸测序鉴定突变。一个家庭隔离了p.Ala546> Asp突变,另一家庭隔离了p.Arg555> Trp突变。在被分析为对照的53个不相关,健康的个体中未发现这些错义突变。临床和遗传学评估显示,这些家族中因不同突变而导致的视力障碍的严重程度,对称性和发病年龄各不相同。这些家庭的视觉障碍渗透率分别为100%和75%。这项研究证实p.Arg555> Trp突变是CDGG1的常见原因,并且p.Ala546> Asp突变也与此疾病有关。
  • 【[远端脊髓肌肉萎缩症1(DSMA1或SMARD1)]。】 复制标题 收藏 收藏
    DOI:10.1016/j.arcped.2008.07.014 复制DOI
    作者列表:Kaindl AM,Guenther UP,Rudnik-Schöneborn S,Varon R,Zerres K,Gressens P,Schuelke M,Hubner C,von Au K
    BACKGROUND & AIMS: :In this article, we review the clinical, neuropathological and genetic aspects of distal spinal-muscular atrophy 1 (DSMA1; MIM#604320), formerly designated as autosomal recessive spinal muscular atrophy with respiratory distress type 1 (SMARD1) and also known as distal hereditary-motor neuropathy type 6 (dHMN6 or HMN6).
    背景与目标: :在本文中,我们回顾了远端脊髓性肌肉萎缩症1(DSMA1; MIM#604320)的临床,神经病理学和遗传学方面,该疾病以前被称为常染色体隐性隐性脊髓性肌肉萎缩症,伴有呼吸窘迫1型(SMARD1),也被称为远端遗传性运动神经病6型(dHMN6或HMN6)。
  • 【1型强直性肌营养不良症的左室过度束缚。】 复制标题 收藏 收藏
    影响因子 :
    发表时间:2001-06-01
    来源期刊:Herz
    DOI:10.1007/pl00002032 复制DOI
    作者列表:Finsterer J,Stöllberger C,Wegmann R,Jarius C,Janssen B
    BACKGROUND & AIMS: BACKGROUND:Left ventricular hypertrabeculation (LVHT) has not been described in myotonic dystrophy Type I (MD1) before. CASE REPORT:A 42-year-old man developed typical features of MD1 since 1992. Creatinekinase was slightly, but recurrently elevated. Needle electromyograms were myogenic and showed extensive spontaneous activity. Muscle biopsy was compatible with MDI. DNA analysis revealed a heterozygous 300 CTG-repeat expansion in the myotonic-dystrophy proteinkinase gene on chromosome 19q13.3. Cardiac history and clinical cardiologic examination were normal. On ECG, ST elevation and atrial flutter were found. The AECG was normal except for atrial flutter. Surprisingly, transthoracic echocardiography revealed LVHT, previously described only in Becker's muscular dystrophy, mitochondriopathies, and Barth syndrome. CONCLUSION:A rare cardiac manifestation of MD1 may be LVHT which alone has no therapeutic implication.
    背景与目标: 背景:以前在I型强直性肌营养不良症(MD1)中尚未描述左室超束(LVHT)。
    病例报告:自1992年以来,一名42岁的男性出现了MD1的典型特征。肌酸激酶轻微升高,但反复升高。针状肌电图是肌源性的,并显示出广泛的自发活动。肌肉活检与MDI兼容。 DNA分析显示,染色体19q13.3上的肌强直性营养不良蛋白激酶基因杂合了300个CTG重复序列。心脏病史和临床心脏检查均正常。在ECG上,发现ST抬高和房扑。除心房扑动外,AECG正常。出乎意料的是,经胸超声心动图显示LVHT,以前仅在贝克尔的肌营养不良症,线粒体病和Barth综合征中有所描述。
    结论:MDHT的一种罕见的心脏表现可能是LVHT,仅LVHT就没有治疗意义。
  • 【在癫痫和杜氏肌营养不良症中发现水通道的意义的优先事项。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Benga I
    BACKGROUND & AIMS: :In addition to the priority in the discovery of the first water channel protein in the red blood cell membrane the group of Gheorghe Benga in Cluj-Napoca, Romania, also has a world priority in the discovery of the implications of water channel proteins in epilepsy and Duchenne muscular dystrophy. This priority is briefly presented here. In 1977 Benga and Morariu reported a decreased water permeability of red blood cells in children with idiopathic epilepsy (cases selected by Ileana Benga). This investigation was performed as part of a program of research of hydroelectrolytic alterations in child epilepsy. On the other hand the group of Gheorghe Benga has reported a decreased water permeability of RBC in patients with Duchenne muscular dystrophy. These findings were interpreted as an expression of generalized membrane defects affecting water permeability in epilepsy and Duchenne muscular dystrophy. In recent years this idea was confirmed by reports indicating aquaporin abnormalities in the brain of epileptic patients and in the muscle of Duchenne muscular dystrophy patients.
    背景与目标: :除了优先发现红细胞膜中的第一个水通道蛋白外,罗马尼亚克卢日-纳波卡的Gheorghe Benga小组在发现水通道蛋白在癫痫中的意义方面也具有世界优先地位和杜氏肌营养不良症。在此简要介绍此优先级。 1977年,Benga和Morariu报告了特发性癫痫患儿(Ileana Benga选择的病例)中红细胞的透水性降低。这项研究是儿童癫痫中水电解改变研究计划的一部分。另一方面,Gheorghe Benga小组报告了Duchenne肌营养不良患者的RBC透水性降低。这些发现被解释为影响癫痫和杜氏肌营养不良症中透水性的广义膜缺损的表达。近年来,有报道表明癫痫患者的大脑和杜兴氏肌营养不良患者的肌肉中存在水通道蛋白异常,这一观点得到了证实。
  • 【在癫痫和杜氏肌营养不良症中发现水通道的意义的重点。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Obeid R,Herrmann W
    BACKGROUND & AIMS: :Folate and vitamin B12 are essential cofactors for the methionine/homocysteine cycle in the brain. These vitamins mediate the remethylation of homocysteine (HCY), which affects the production of the universal methyl donor, S-adenosylmethionine (SAM), in the brain among other organs. Acquired or inherited disorders in these metabolic pathways are associated with brain abnormalities and severe neurological symptoms that are mostly irreversible, even after providing the missing cofactors. This review discusses the relationship between brain and blood levels of key vitamins and metabolites related to one carbon metabolism.
    背景与目标: :叶酸和维生素B12是大脑中蛋氨酸/高半胱氨酸循环的重要辅助因子。这些维生素介导高半胱氨酸(HCY)的再甲基化,这会影响大脑其他器官中通用甲基供体S-腺苷甲硫氨酸(SAM)的产生。这些代谢途径中的获得性或遗传性疾病与脑部异常和严重的神经系统症状有关,即使提供了缺失的辅因子后,这些症状通常也是不可逆的。这篇评论讨论了大脑和血液中与一种碳代谢有关的关键维生素和代谢物的水平之间的关系。
  • 【患有终末心力衰竭的患者的皮肤和肌肉微循环,等待移植。】 复制标题 收藏 收藏
    DOI:10.3233/CH-2012-1599 复制DOI
    作者列表:Knaut M,Matschke K,Plötze K,Steinmann C,Mrowietz C,Jung F
    BACKGROUND & AIMS: :Heart failure patients are clinically characterized by extreme cardiomegaly, breathlessness, fluid retention and an early onset of fatigue. Studies have shown generalized restricted blood flow in those patients. Furthermore animal experiments proved an impaired blood flow and a diminished oxygen supply of the skeletal muscle in animals with chronic heart failure. Patients with chronic heart failure are limited to the extent of their ability to regulate their arterial pressure, especially in physical activity. It is however unclear in what way restriction of blood flow in the main arteries correlates with those in capillaries and to what extent. In this study it was examined the depth of capillary circulatory restriction as well as the disregulation of oxygen partial pressure in skeletal muscle in rest and stress conditions, in patients with terminal heart failure.
    背景与目标: 心力衰竭患者的临床特征是极端的心脏肥大,呼吸困难,体液retention留和疲劳的早期发作。研究表明,这些患者的血流普遍受限。此外,动物实验证明,患有慢性心力衰竭的动物的血流量受损,骨骼肌的氧气供应减少。患有慢性心力衰竭的患者被限制在调节其动脉压的能力范围内,特别是在体育锻炼中。然而,尚不清楚主要动脉中的血流限制与毛细血管中的血流以何种方式相关以及在何种程度上相关。在这项研究中,检查了患有终末心力衰竭的患者中毛细血管循环限制的深度,以及在休息和压力条件下骨骼肌中氧分压的失调。
  • 【脊柱肌肉萎缩的新兴疗法和挑战。】 复制标题 收藏 收藏
    DOI:10.1002/ana.24864 复制DOI
    作者列表:Farrar MA,Park SB,Vucic S,Carey KA,Turner BJ,Gillingwater TH,Swoboda KJ,Kiernan MC
    BACKGROUND & AIMS: :Spinal muscular atrophy (SMA) is a hereditary neurodegenerative disease with severity ranging from progressive infantile paralysis and premature death (type I) to limited motor neuron loss and normal life expectancy (type IV). Without disease-modifying therapies, the impact is profound for patients and their families. Improved understanding of the molecular basis of SMA, disease pathogenesis, natural history, and recognition of the impact of standardized care on outcomes has yielded progress toward the development of novel therapeutic strategies and are summarized. Therapeutic strategies in the pipeline are appraised, ranging from SMN1 gene replacement to modulation of SMN2 encoded transcripts, to neuroprotection, to an expanding repertoire of peripheral targets, including muscle. With the advent of preliminary trial data, it can be reasonably anticipated that the SMA treatment landscape will transform significantly. Advancement in presymptomatic diagnosis and screening programs will be critical, with pilot newborn screening studies underway to facilitate preclinical diagnosis. The development of disease-modifying therapies will necessitate monitoring programs to determine the long-term impact, careful evaluation of combined treatments, and further acceleration of improvements in supportive care. In advance of upcoming clinical trial results, we consider the challenges and controversies related to the implementation of novel therapies for all patients and set the scene as the field prepares to enter an era of novel therapies. Ann Neurol 2017;81:355-368.
    背景与目标: :脊髓性肌萎缩症(SMA)是一种遗传性神经退行性疾病,其严重程度从进行性婴儿瘫痪和过早死亡(I型)到有限的运动神经元丧失和正常预期寿命(IV型)不等。如果没有改善疾病的疗法,对患者及其家属的影响将是深远的。对SMA分子基础,疾病发病机制,自然病史以及对标准化治疗对预后的影响的认识得到了更好的理解,这为新型治疗策略的发展带来了进步,并对其进行了总结。评估中的治疗策略包括SMN1基因替换,SMN2编码转录物的调节,神经保护以及包括肌肉在内的周围靶标的扩展库。随着初步试验数据的出现,可以合理地预期SMA治疗前景将发生重大变化。症状前诊断和筛查计划的进展将至关重要,目前正在进行试点新生儿筛查研究以促进临床前诊断。疾病缓解疗法的发展将需要制定监测计划,以确定长期影响,对联合治疗进行认真评估,并进一步加速支持治疗的改善。在即将到来的临床试验结果公布之前,我们考虑了为所有患者实施新疗法带来的挑战和争议,并为该领域准备进入新疗法时代做好了准备。 Ann Neurol 2017; 81:355-368。
  • 【Myostatin阻滞剂可改善肢带型肌营养不良症2C小鼠模型的功能,但不能改善组织病理学。】 复制标题 收藏 收藏
    DOI:10.1002/mus.20920 复制DOI
    作者列表:Bogdanovich S,McNally EM,Khurana TS
    BACKGROUND & AIMS: :Myostatin is a negative regulator of skeletal muscle growth. Myostatin mutations and pharmacological strategies increase muscle mass in vivo, suggesting that myostatin blockade may prove useful in diseases characterized by muscle wasting, such as the muscular dystrophies. We subjected the gamma-sarcoglycan-deficient (Sgcg(-/-)) mouse model of limb-girdle muscular dystrophy (LGMD) 2C to antibody-mediated myostatin blockade in vivo. Myostatin inhibition led to increased fiber size, muscle mass, and absolute force. However, no clear improvement in muscle histopathology was evident, demonstrating discordance between physiological and histological improvement. These results and previous studies on the dyw/dyw mouse model of congenital muscular dystrophy and in the late-stage delta-sarcoglycan-deficient (Sgcd(-/-)) mouse model of LGMD2F document disease-specific limitations to therapeutic strategies based on myostatin blockade in the more severe mouse models of different muscular dystrophies.
    背景与目标: :肌生长抑制素是骨骼肌生长的负调节剂。肌肉生长抑制素的突变和药理学方法会增加体内肌肉的质量,这表明肌肉生长抑制素的阻断可能在以肌肉萎缩为特征的疾病(如肌肉营养不良)中被证明是有用的。我们经历了肢带肌肉萎缩症(LGMD)2C的γ-肌糖蛋白缺乏(Sgcg(-/-))小鼠模型体内抗体介导的肌生长抑制素阻断作用。抑制肌生长抑制素导致纤维大小,肌肉质量和绝对力增加。但是,肌肉组织病理学没有明显改善,表明生理和组织学改善之间不一致。这些结果和关于先天性肌营养不良的dyw / dyw小鼠模型以及LGMD2F的晚期δ-肌糖缺乏症(Sgcd(-/-))小鼠模型的先前研究记录了基于肌肉生长抑制素的疾病特异性治疗策略的局限性在不同肌肉营养不良的更严重的小鼠模型中具有阻断作用。
  • 【RCS大鼠视网膜营养不良基因的人类直系同源基因MERTK中的突变导致色素性视网膜炎。】 复制标题 收藏 收藏
    DOI:10.1038/81555 复制DOI
    作者列表:Gal A,Li Y,Thompson DA,Weir J,Orth U,Jacobson SG,Apfelstedt-Sylla E,Vollrath D
    BACKGROUND & AIMS: :Mutation of a receptor tyrosine kinase gene, Mertk, in the Royal College of Surgeons (RCS) rat results in defective phagocytosis of photoreceptor outer segments by the retinal pigment epithelium (RPE) and retinal degeneration. We screened the human orthologue, MERTK, located at 2q14.1 (ref. 10), in 328 DNA samples from individuals with various retinal dystrophies and found three mutations in three individuals with retinitis pigmentosa (RP). Our findings are the first conclusive evidence implicating the RPE phagocytosis pathway in human retinal disease.
    背景与目标: :在皇家外科医学院(RCS)大鼠中酪氨酸受体激酶基因Mertk的突变导致视网膜色素上皮(RPE)和视网膜变性导致光感受器外部节段的吞噬功能缺陷。我们在来自患有各种视网膜营养不良的个体的328个DNA样本中筛选了位于2q14.1(参考文献10)的人类直向同源基因MERTK,并在三个患有色素性视网膜炎(RP)的个体中发现了三个突变。我们的发现是人类视网膜疾病中涉及RPE吞噬途径的第一个确凿证据。
  • 【日本的2型强直性肌营养不良:祖先血统不同于白种人。】 复制标题 收藏 收藏
    DOI:10.1007/s10048-007-0110-4 复制DOI
    作者列表:Saito T,Amakusa Y,Kimura T,Yahara O,Aizawa H,Ikeda Y,Day JW,Ranum LP,Ohno K,Matsuura T
    BACKGROUND & AIMS: :Myotonic dystrophy type 2 (DM2) is caused by expansion of a tetranucleotide CCTG repeat in intron 1 of the ZNF9 gene on chromosome 3q21. All studied DM2 mutations have been reported in Caucasians and share an identical haplotype, suggesting a common founder. We identified a Japanese patient with DM2 and showed that the affected haplotype is distinct from the previously identified DM2 haplotype shared among Caucasians. These data strongly suggest that DM2 expansion mutations originate from separate founders in Europe and Japan and are more widely distributed than previously recognized.
    背景与目标: :2型肌强直性营养不良(DM2)是由3q21号染色体上ZNF9基因内含子1中四核苷酸CCTG重复序列的扩增引起的。所有已研究的DM2突变均已在高加索人中报道,并具有相同的单倍型,表明是一个共同的创始人。我们确定了一名患有DM2的日本患者,并表明受影响的单倍型与之前在高加索人中共享的DM2单倍型不同。这些数据有力地表明,DM2扩展突变来自欧洲和日本的不同创始人,并且比以前公认的分布更广泛。
  • 【麻醉和强直性肌营养不良症(施泰纳特综合征)。异丙酚,西沙曲库铵和瑞芬太尼全静脉麻醉的作用。案例报告。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Catena V,Del Monte DD,Rubini A,Guccione C,Ricagna F,Gangeri G,De Zen GF
    BACKGROUND & AIMS: :Anesthesia for patients with Steinert's syndrome (myotonic dystrophy, MD) is a challenge for the anaesthetist. MD is a multisystemic disease and the neuromuscular symptoms can be associated with sleep apnea, endocrine disorders (diabetes, hypogonadism, hypothyroidism), cardiac, gastroenteric or cognitive disorders (mental deficiency, attention disorders). The diagnosis is facilitated when one or more of these symptoms are associated with the neuromuscular symptoms; however, the latter are not always present at the onset, which makes the diagnosis of MD a difficult and often late one. The choice of drugs and the choice of anesthesia in these patients can be very challenging for many reasons. A myotonic crisis can be triggered by several factors including hypothermia, shivering and mechanical or electrical stimulation. These patients are very sensitive to the usual anesthetics such as hypnotics and paralyzing agents (both depolarizing and nondepolarizing). The following case report describes pathophysiological considerations and a technique for anaesthesia during thoracic surgery that has been able to assure hemodynamic peroperative stability, early extubation and prolonged respiratory autonomy in a patient affected by this genetic disorder.
    背景与目标: Steinert综合征(强直性营养不良,MD)患者的麻醉对于麻醉师而言是一项挑战。 MD是一种多系统疾病,其神经肌肉症状可能与睡眠呼吸暂停,内分泌失调(糖尿病,性腺功能减退,甲状腺功能减退),心脏,胃肠道或认知障碍(精神缺陷,注意障碍)有关。当这些症状中的一种或多种与神经肌肉症状相关时,有助于诊断。然而,后者并不总是在发病时就出现,这使得MD的诊断非常困难,而且常常是晚期。由于许多原因,这些患者的药物选择和麻醉选择可能非常具有挑战性。强直性危机可由多种因素触发,包括体温过低,发抖以及机械或电刺激。这些患者对常规麻醉剂(例如催眠药和麻痹剂(去极化和非去极化))非常敏感。以下病例报告描述了在胸外科手术期间麻醉的病理生理学考虑和一种技术,该技术已能够确保受这种遗传病影响的患者的血流动力学稳定性,早期拔管和延长的呼吸自主性。
  • 【杜氏肌营养不良症的治疗策略:更新。】 复制标题 收藏 收藏
    DOI:10.3390/genes11080837 复制DOI
    作者列表:Sun C,Shen L,Zhang Z,Xie X
    BACKGROUND & AIMS: :Neuromuscular disorders encompass a heterogeneous group of conditions that impair the function of muscles, motor neurons, peripheral nerves, and neuromuscular junctions. Being the most common and most severe type of muscular dystrophy, Duchenne muscular dystrophy (DMD), is caused by mutations in the X-linked dystrophin gene. Loss of dystrophin protein leads to recurrent myofiber damage, chronic inflammation, progressive fibrosis, and dysfunction of muscle stem cells. Over the last few years, there has been considerable development of diagnosis and therapeutics for DMD, but current treatments do not cure the disease. Here, we review the current status of DMD pathogenesis and therapy, focusing on mutational spectrum, diagnosis tools, clinical trials, and therapeutic approaches including dystrophin restoration, gene therapy, and myogenic cell transplantation. Furthermore, we present the clinical potential of advanced strategies combining gene editing, cell-based therapy with tissue engineering for the treatment of muscular dystrophy.
    背景与目标: 神经肌肉疾病包括一组异类疾病,这些疾病会损害肌肉,运动神经元,周围神经和神经肌肉接头的功能。杜兴氏肌营养不良症(DMD)是最常见,最严重的肌营养不良症,是由X连锁肌营养不良蛋白基因的突变引起的。肌营养不良蛋白的丢失会导致肌纤维复发,慢性炎症,进行性纤维化和肌肉干细胞功能障碍。在过去的几年中,DMD的诊断和治疗方法有了长足的发展,但是目前的治疗方法不能治愈该疾病。在这里,我们将回顾DMD发病机理和治疗方法的当前状态,重点关注突变谱,诊断工具,临床试验以及包括肌营养不良蛋白修复,基因治疗和成肌细胞移植在内的治疗方法。此外,我们介绍了结合基因编辑,基于细胞的治疗与组织工程技术治疗肌肉营养不良的先进策略的临床潜力。
  • 【英国消防员的体力劳动标准:最低肌肉强度和耐力要求。】 复制标题 收藏 收藏
    DOI:10.1097/JOM.0000000000000926 复制DOI
    作者列表:Stevenson RD,Siddall AG,Turner PF,Bilzon JL
    BACKGROUND & AIMS: OBJECTIVE:The aim of this study was to assess sensitivity and specificity of surrogate physical ability tests as predictors of criterion firefighting task performance and to identify corresponding minimum muscular strength and endurance standards. METHODS:Fifty-one (26 male; 25 female) participants completed three criterion tasks (ladder lift, ladder lower, ladder extension) and three corresponding surrogate tests [one-repetition maximum (1RM) seated shoulder press; 1RM seated rope pull-down; repeated 28 kg seated rope pull-down]. Surrogate test standards were calculated that best identified individuals who passed (sensitivity; true positives) and failed (specificity; true negatives) criterion tasks. RESULTS:Best sensitivity/specificity achieved were 1.00/1.00 for a 35 kg seated shoulder press, 0.79/0.92 for a 60 kg rope pull-down, and 0.83/0.93 for 23 repetitions of the 28 kg rope pull-down. CONCLUSIONS:These standards represent performance on surrogate tests commensurate with minimum acceptable performance of essential strength-based occupational tasks in UK firefighters.
    背景与目标: 目的:本研究的目的是评估替代体力测试的敏感性和特异性,以作为标准消防任务表现的预测指标,并确定相应的最低肌力和耐力标准。
    方法:51名(男26名;女25名)参与者完成了三个标准任务(梯子抬高,梯子下降,梯子伸展)和三个相应的替代测试[最大重复坐姿(1RM),肩部推举; 1RM落座式绳索下拉;重复28 kg坐下的绳索下拉]。计算替代测试标准可以最好地识别通过(敏感性;真阳性)和失败(特异性;真阴性)标准任务的人员。
    结果:最佳的灵敏度/特异度是:35 kg的肩部推举时为1.00 / 1.00,60 kg的拉绳器为0.79 / 0.92,23次重复28 kg的拉绳器为0.83 / 0.93。
    结论:这些标准代表在替代测试中的性能,与在英国消防员中基于强度的基本职业任务的最低可接受性能相当。
  • 【L-瓜氨酸和二甲双胍在Duchenne肌营养不良症中的治疗:单中心,随机,安慰剂对照试验的研究方案。】 复制标题 收藏 收藏
    DOI:10.1186/s13063-016-1503-1 复制DOI
    作者列表:Hafner P,Bonati U,Rubino D,Gocheva V,Zumbrunn T,Gueven N,Fischer D
    BACKGROUND & AIMS: BACKGROUND:Duchenne muscular dystrophy (DMD) is an X-linked recessive disease that affects 1 in 3500-6000 male births. Despite broad research aiming to improve muscle function as well as heart and brain function, sufficient therapeutic efficacy has not yet been achieved and current therapeutic management is still supportive. In a recent pilot trial, oral treatment with L-arginine and metformin showed consistent changes of muscular metabolism both in vitro and in vivo by raising NO levels and expression of mitochondrial proteins in the skeletal muscle tissue of patients with DMD. This randomised, double-blind, placebo-controlled trial aims to demonstrate the superiority of L-citrulline and metformin therapy over placebo in DMD patients with regard to the Motor Function Measure (MFM) D1 subscore (primary endpoint) as well as additional clinical and subclinical tests. METHODS/DESIGN:A total of 40-50 ambulant patients with DMD will be recruited at the outpatient department of the University of Basel Children's Hospital (Switzerland), as well as from the DMD patient registries of Switzerland, Germany and Austria. Patients will be randomly allocated to one of the two arms of the study and will receive either a combination of L-citrulline and metformin or placebo for 26 weeks. Co-medication with glucocorticoids is allowed. The primary endpoint is the change of the MFM D1 subscore from baseline to week 26 under L-citrulline and metformin therapy. Secondary endpoints will include the motor function measure (MFM) and its items and subscores, the 6-minute walking test, timed function tests and quantitative muscle testing. Furthermore, quantitative muscle MRI assessment to evaluate the muscle fat fraction as well as safety and biomarker laboratory analyses from blood will be included. For comparison, muscle metabolism and mitochondrial function will be analysed in 10-20 healthy age-matched male children. DISCUSSION:The aim of this study is to test if a 6-month treatment of a combination of L-citrulline and metformin is more effective than placebo in preventing loss of motor function and muscle degeneration in DMD. The MFM D1 subscore is used as a clinical outcome measure and a quantitative muscle MRI assessment as the surrogate outcome measure of fatty muscle degeneration. TRIAL REGISTRATION:ClinicalTrials.gov: NCT01995032 . Registered on 20 November 2013.
    背景与目标: 背景:杜氏肌营养不良症(DMD)是一种X连锁隐性疾病,影响3500-6000名男性出生中的1名。尽管有旨在改善肌肉功能以及心脏和脑功能的广泛研究,但尚未获得足够的治疗效果,并且目前的治疗管理仍是支持性的。在最近的一项先导试验中,口服L-精氨酸和二甲双胍治疗通过提高DMD患者骨骼肌组织中的NO水平和线粒体蛋白的表达,显示出体内和体外肌肉代谢的持续变化。这项随机,双盲,安慰剂对照试验旨在证明在运动功能量度(MFM)D1子评分(主要终点)以及其他临床和研究方面,DMD患者中L-瓜氨酸和二甲双胍治疗优于安慰剂。亚临床测试。
    方法/设计:将在瑞士巴塞尔儿童医院大学的门诊部以及瑞士,德国和奥地利的DMD患者登记处招募40-50名DMD流动患者。患者将被随机分配至研究的两个部门之一,并将接受L-瓜氨酸和二甲双胍的组合或安慰剂治疗26周。允许与糖皮质激素合用。主要终点是在L-瓜氨酸和二甲双胍治疗下MFM D1子评分从基线到第26周的变化。次要终点包括运动功能量度(MFM)及其项目和分项,6分钟步行测试,定时功能测试和定量肌肉测试。此外,将包括定量肌肉MRI评估以评估肌肉脂肪含量以及血液中的安全性和生物标志物实验室分析。为了进行比较,将对10至20名年龄匹配的健康男孩进行肌肉代谢和线粒体功能分析。
    讨论:这项研究的目的是检验L-瓜氨酸和二甲双胍联合治疗6个月是否比安慰剂更有效,以防止DMD的运动功能丧失和肌肉变性。 MFM D1子评分被用作临床结果测量指标,定量肌肉MRI评估被用作脂肪肌肉变性的替代结果指标。
    试验注册:ClinicalTrials.gov:NCT01995032。 2013年11月20日注册。

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