以脾胃为中心的葛根相关配伍对糖尿病心肌病大鼠受损心肌线粒体的改善作用

目的:观察葛根及其配伍对糖尿病心肌病(DCM)大鼠心肌线粒体质量变化的影响,探寻治疗糖尿病心肌病的最优配伍及机制。方法:采用链脲佐菌素腹腔注射进行模型大鼠制备,并将60只成模大鼠随机分为模型组6.5 g/(kg·d)、达美康组16.7 mg/(kg·d)、葛根组1.04 g/(kg·d)、葛芪组2.6 g/(kg·d)、葛参组2.6 g/(kg·d)、葛蒌组4.48g/(kg·d)及葛芪参蒌组7.6 g/(kg·d)各8只,同时选取空白大鼠8只,为对照组6.5 g/(kg·d)。各组依据上述剂量,以相应药物持续灌胃9周后,对比各组心肌线粒体超微结构变化、心肌线粒体膜电位变化及心肌ATP变化情况。结果:电镜显示各药物干预组心肌线粒体超微结构较模型组均有不同程度的改善,其中葛芪参蒌组改善效果最为明显,与空白组无明显差异; 流式细胞仪检测显示:各干预组波峰均在模型组、空白组之间; 其中葛芪参蒌组、葛参组、葛根组波峰位于达美康组右侧; 葛芪组、葛蒌组则位于达美康组左侧; 以葛芪参蒌组波峰与空白组最为接近。心肌ATP浓度检测显示:各中药干预组心肌ATP浓度均较模型组有所提升(P<0.05),其中葛芪参蒌组ATP值较其余各干预组提升最为明显(P<0.05),但仍低于空白组(P>0.05)。结论:葛根相关配伍均能够对心肌线粒体结构、心肌线粒体膜电位进行正向调控,进而使因糖尿病心肌病导致的心肌线粒体受损得以恢复,其中以益气、化瘀、祛痰三法合用的组方原则进行配伍的葛芪参蒌方改善效果最优。可见其治疗机制可能是通过益气、化瘀、祛痰的协同作用,正向调控心肌线粒体质量而达到治疗目的。     

New advances in Amyotrophic Lateral Sclerosis genetics: Towards gene therapy opportunities for familial and young cases

Due to novel gene therapy opportunities, genetic screening is no longer restricted to familial cases of ALS (FALS) cases but also aplies to the sporadic populations (SALS). Screening of four main genes (C9orf72, SOD1, TARDBP and FUS) identified the causes in 15% of Amyotrophic Lateral Sclerosis (ALS) patients (two third of the familial cases and 8% of the sporadic ones) but their respective contribution to ALS phenotype varies according the age of disease onset. The genetic overlap between ALS and other diseases is expanding and includes frontotemporal dementia, Paget's Disease of Bone, myopathy for adult cases, HSP and CMT for young cases highlighing the importance of retrieving the exhaustive familial history for each indivdual with ALS. Incomplete disease penetrance, diversity of the possible phenotypes, as well as the lack of confidence concerning the pathogenicity of most identified variants and/or possible oligogenic inheritance are burdens of ALS genetic counseling to be delivered to patients and at risk individuals. The multitude of rare ALS genetic causes identifed seems to converge to similar cellular pathways leading to inapropriate response to stress emphacising new potential therapeutic options for the disease.     

The neurophysiology of deforming spastic paresis: A revised taxonomy

This paper revisits the taxonomy of the neurophysiological consequences of a persistent impairment of motor command execution in the classic environment of sensorimotor restriction and muscle hypo-mobilization in short position. Around each joint, the syndrome involves 2 disorders, muscular and neurologic. The muscular disorder is promoted by muscle hypo-mobilization in short position in the context of paresis, in the hours and days after paresis onset: this genetically mediated, evolving myopathy, is called spastic myopathy. The clinician may suspect it by feeling extensibility loss in a resting muscle, although long after the actual onset of the disease. The neurologic disorder, promoted by sensorimotor restriction in the context of paresis and by the muscle disorder itself, comprises 4 main components, mostly affecting antagonists to desired movements: the first is spastic dystonia, an unwanted, involuntary muscle activation at rest, in the absence of stretch or voluntary effort; spastic dystonia superimposes on spastic myopathy to cause visible, gradually increasing body deformities; the second is spastic cocontraction, an unwanted, involuntary antagonist muscle activation during voluntary effort directed to the agonist, aggravated by antagonist stretch; it is primarily due to misdirection of the supraspinal descending drive and contributes to reducing movement amplitude; and the third is spasticity, one form of hyperreflexia, defined by an enhancement of the velocity-dependent responses to phasic stretch, detected and measured at rest (another form of hyperreflexia is “nociceptive spasms”, following flexor reflex afferent stimulation, particularly after spinal cord lesions). The 3 main forms of overactivity, spastic dystonia, spastic cocontraction and spasticity, share the same motor neuron hyperexcitability as a contributing factor, all being predominant in the muscles that are more affected by spastic myopathy. The fourth component of the neurologic disorder affects the agonist: it is stretch-sensitive paresis, which is a decreased access of the central command to the agonist, aggravated by antagonist stretch. Improved understanding of the pathophysiology of deforming spastic paresis should help clinicians select meaningful assessments and refined treatments, including the utmost need to preserve muscle tissue integrity as soon as paresis sets in.     

Myopathy associated with homozygous PYROXD1 pathogenic variants detected by genome sequencing

Biallelic pathogenic variants in the gene PYROXD1 have recently been described to cause early-onset autosomal recessive myopathy. Myopathy associated with PYROXD1 pathogenic variants is rare and reported in only 17 individuals. Known pathogenic variants in PYROXD1 include missense, insertion and essential splice-site variants. Here we describe a consanguineous family of individuals affected with late-onset myopathy and homozygous PYROXD1 missense variants (NM_024854.5:c.464A>G [p.Asn155Ser]) expanding our understanding of the possible disease phenotypes of PYROXD1-associated myopathy.     

Current pharmacological treatment of idiopathic inflammatory myopathies

The idiopathic inflammatory myopathies are uncommon and heterogeneous disorders. Their classification is based on distinct clinicopathologic features. Although idiopathic inflammatory myopathies share some similarities, different subtypes may have variable responses to therapy, so it is very important to distinguish the correct subtype.

There are few randomised, double blind placebo controlled studies to support the current treatment. High dose corticosteroids continue to be the first-line therapy and other immunosupressive drugs are used in refractory cases, as well as steroid-sparing agents.

Some novel therapeutic approaches have emerged as potential treatment including tacrolimus, intravenous immunoglobulin and rituximab, following good outcomes reported in case studies. However, more randomised controlled trials are needed.

This review considers the current and the potential future therapies for inflammatory myopathies.