Anti-HMGCR myopathy overlaps with dermatomyositis-like rash: a distinct subtype of idiopathic inflammatory myopathy

Journal of Neurology - To characterize the clinical and pathological features of anti-HMGCR myopathy. The presence of anti-HMGCR antibody in the serum of 227 patients with idiopathic inflammatory...     

肾移植患者用他克莫司替换环孢素A后的疗效及不良反应的回顾性分析

目的 研究肾移植患者用基础免疫抑制剂他克莫司替换环孢素A后的疗效与不良反应。方法 收集他克莫司替换环孢素A的肾移植患者随访资料,使用SPSS17.0分析替换后1年内相关药源性疾病（DIDs）和急性排异反应（AR）的改善情况。结果 肾移植患者用他克莫司替换环孢素A后的1年内,慢性爬行肌酐升高（CScr）者和AR者的血肌酐（Scr）及尿素氮（BUN）均逐渐下降,两者有显著性差异（P<0.05或P<0.01）;药物性肝损伤（DILI）者的总胆红素（TB）和直接胆红素（DB）逐渐下降,并呈显著性差异（P<0.05或P<0.01）,第12个月转氨酶（ALT）显著降低（P<0.05）;牙龈增生（GO）现象停止。然而,空腹血糖（FBG）在第12个月显著升高（P<0.05）。结论 使用环孢素A的肾移植患者,若发生环孢素相关的AR和（或）其所致DIDs,可用他克莫司替换,但需警惕换药所致的肾移植后新发糖尿病。     

Defect in degradation of glycogenin-exposed residual glycogen in lysosomes is the fundamental pathomechanism of Pompe disease

Pompe disease is a lysosomal storage disorder that preferentially affects muscles, and it is caused by GAA mutation coding acid alpha-glucosidase in lysosome and glycophagy deficiency. While the initial pathology of Pompe disease is glycogen accumulation in lysosomes, the special role of the lysosomal pathway in glycogen degradation is not fully understood. Hence, we investigated the characteristics of accumulated glycogen and the mechanism underlying glycophagy disturbance in Pompe disease. Skeletal muscle specimens were obtained from the affected sites of patients and mouse models with Pompe disease. Histological analysis, immunoblot analysis, immunofluorescence assay, and lysosome isolation were utilized to analyze the characteristics of accumulated glycogen. Cell culture, lentiviral infection, and the CRISPR/Cas9 approach were utilized to investigate the regulation of glycophagy accumulation. We demonstrated residual glycogen, which was distinguishable from mature glycogen by exposed glycogenin and more α-amylase resistance, accumulated in the skeletal muscle of Pompe disease. Lysosome isolation revealed glycogen-free glycogenin in wild type mouse lysosomes and variously sized glycogenin in Gaa^−/− mouse lysosomes. Our study identified that a defect in the degradation of glycogenin-exposed residual glycogen in lysosomes was the fundamental pathological mechanism of Pompe disease. Meanwhile, glycogenin-exposed residual glycogen was absent in other glycogen storage diseases caused by cytoplasmic glycogenolysis deficiencies. In vitro, the generation of residual glycogen resulted from cytoplasmic glycogenolysis. Notably, the inhibition of glycogen phosphorylase led to a reduction in glycogenin-exposed residual glycogen and glycophagy accumulations in cellular models of Pompe disease. Therefore, the lysosomal hydrolysis pathway played a crucial role in the degradation of residual glycogen into glycogenin, which took place in tandem with cytoplasmic glycogenolysis. These findings may offer a novel substrate reduction therapeutic strategy for Pompe disease. © 2024 The Pathological Society of Great Britain and Ireland.     

Novel Mitochondrial C15620A Variant may Modulate the Phenotype of Mitochondrial G11778A Mutation in a Chinese Family with Leigh Syndrome

We report a case of 3-year-old boy who presented with Leigh syndrome but carried a mitochondrial G11778A mutation in the fourth subunit of the NADH dehydrogenase gene (MTND4). Additional to G11778A mutation, a novel C15620A variant was detected, which resulted in the conversion from leucine to isoleucine in the mitochondrial cytochrome b gene. As G11778A mutation is the most common mutation associated with Leber’s hereditary optic neuropathy (LHON), given the unusual phenotype, the C15620A mutation was postulated to influence the pathogenicity of the G11778A mutation. This case further expands the clinical spectrum associated with the primary G11778A LHON mutation.     

Clinical features and ETFDH mutation spectrum in a cohort of 90 Chinese patients with late-onset multiple acyl-CoA dehydrogenase deficiency

The major cause of lipid storage myopathies (LSM) in China is multiple acyl-CoA dehydrogenase deficiency (MADD) caused by ETFDH mutations. We here present an analysis of the spectrum of ETFDH mutations in the largest cohort of patients with MADD (90 unrelated patients). We identified 61 ETFDH mutations, including 31 novel mutations, which were widely distributed within the coding sequence. Three frequent mutations were identified: c.250G?>?A (most common in South China), c.770A?>?G and c.1227A?>?C (most common in both South and North China). Regional differences of allele frequency and further haplotype analysis suggest the possibility of founder effects of c.250G?>?A and c.770A?>?G. These findings promise to provide the basis for implementing a rapid and economical strategy for diagnosing MADD.     

Changes in metalloproteinase and tissue inhibitor of metalloproteinase during tachycardia-induced cardiomyopathy by rapid atrial pacing in dogs

BACKGROUND: It was the aim of this study to investigate the variation in metalloproteinase and tissue inhibitor of metalloproteinase (TIMP) connexin levels during tachycardia-induced cardiomyopathy (TIC). METHODS: Canine models of TIC were established by rapid right atrial pacing at 350-400 beats per min for 8 weeks in 11 dogs, with another 6 dogs acting as sham operation group. Echocardiography, left ventricular pressure and its first derivation with time (positive and negative maximum, dp/dt(max) and -dp/dt(max)), as well as intracardiac electrograms were recorded before and after rapid pacing at 1, 4 and 8 weeks. Data were acquired in sinus rhythm. Ultrastructural changes in left ventricular tissue were observed by transmission electron microscope. The relative abundance of matrix metalloproteinase (MMP)-9 and TIMP-1 was studied by immunoblotting. RESULTS: The following hemodynamic changes were detected after 8 weeks of rapid pacing: the TIC group had decreased dp/dt(max) (p < 0.05), the left ventricular relaxation time constant (tau) was prolonged (p < 0.05), both left ventricular end-diastolic volume and left ventricular end-systolic volume were decreased (p <0.05), left ventricular end-diastolic pressure was significantly increased (p <0.05), and -dp/dt(max) was significantly decreased (p <0.001) compared with the control group; no statistical differences in the left ventricular ejection fraction between weeks 1, 4 or 8 (p >0.05) were observed, but left ventricular ejection fraction was significantly decreased after 1 week of pacing (p < 0.05). The left ventricular end-diastolic volume was increased after 1 week of pacing compared with the control group (24.15 +/- 8.15 vs.11.19 +/- 4.41 ml; p <0.05), as shown by echocardiography. Compared with the control group, MMP-9 was significantly higher (0.217 +/- 2.16 E-02 vs. 0.314 +/- 5.263 E-02; p < 0.001), while TIMP-1 was decreased (0.230 +/- 8.944 E-02 vs. 0.120 +/- 9.258 E-03; p < 0.001). CONCLUSIONS: Ventricular dilatation and systolic dysfunction occurred after 1 week of rapid right atrial pacing. Enlarged and disarrayed fibers and mitochondria with disintegrated crystal and an anarchic pattern were observed. Additionally, moderate dilation of the rough endoplasmic reticulum and intercalated disk discontinuity were seen after 8 weeks of pacing, and MMP-9 was increased and TIMP-1 was decreased after the same time period.     

中低度近视眼Trans-PRK术中使用丝裂霉素C对术后haze影响的研究

目的探讨中低度近视眼行经上皮准分子激光角膜切削术(Trans-PRK)中使用0.02%丝裂霉素C(MMC)预防术后角膜上皮下雾状混浊(haze)的临床效果。方法回顾性队列研究。纳入行Trans-PRK的近视眼患者295例(588只眼), 其中低度近视眼(近视度数<3.00 D)45例(90只眼), 年龄(20.53±4.95)岁(18～41岁);男性37例, 女性8例;32只眼术中使用MMC浸润角膜基质床。中度近视眼(近视度数≥3.00 D)患者250例(498只眼), 年龄(23.66±6.12)岁(18～46岁);男性168例, 女性82例;261只眼术中使用MMC。低度和中度近视眼患者术中MMC的作用时间分别为15和30 s。所有患者随访6个月, 观察指标包括最佳矫正视力、等效球镜度数及haze情况。正态分布资料的比较用两独立样本t检验, 非正态分布资料的比较采用Mann-WhitneyU检验, 术后haze的发生情况比较采用χ2检验。结果按照Fantes分级, 将0.5～4级均纳入标准进行haze评估。术中使用MMC的低度近视眼患者术后haze发生率为6.25%(2/32...     

Oculopharyngeal Muscular Dystrophy: Phenotypic and Genotypic Studies in a Chinese Population

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant late-onset neuromuscular degenerative disease characterized by ptosis, dysphagia, and proximal muscle weakness. The genetic basis has been identified as an abnormal (GCN) expansion encoding the polyalanine tract in exon 1 of the polyadenylate-binding protein nuclear 1 gene (PABPN1). OPMD is worldwide distributed, but has rarely been reported in East Asians. In this study, we summarized the clinical and genetic characteristics of 34 individuals from 13 unrelated families in Chinese population. In our cohort, the mean age at onset was 47.2 years. Dysphagia, rather than ptosis, was the most common initial symptom. Genetically, we identified seven genotypes in our patients, including one compound heterozygote of (GCN)₁₁/(GCN)₁₂. The genetic heterogeneity implies that there is no single founder effect in Chinese population, and our data also support that the (GCN)₁₁ polymorphism may have a disease-modifying effect. Additionally, the clinical features showed homogeneity within families, which suggests that other genetic factors apart from the already known genotype also play a role in modifying the phenotype.     

Changes in connexin 43, metalloproteinase and tissue inhibitor of metalloproteinase during tachycardia-induced cardiomyopathy in dogs

OBJECTIVE: To study changes in connexin, metalloproteinase and tissue inhibitor of metalloproteinase levels during tachycardia-induced cardiomyopathy (TIC). METHODS: Canine models of TIC were established by rapid right atrial pacing at 350-400 beats per min for 8 weeks in 11 dogs, six dogs acted as a sham operation group. Echocardiography, left ventricular pressure and its first derivation with time (positive and negative maximum, dp/dtmax, -dp/dtmax), and intracardiac electrograms were recorded before and after rapid pacing at 1, 4 and 8 weeks. Data were acquired in sinus rhythm. Ultrastructural changes in left ventricular tissue were observed by transmission electron microscope. Connexin 43 (Cx43) levels in the left ventricular myocardium were measured by confocal laser microscopy. The relative abundance of matrix metalloproteinase (MMP-2) and tissue inhibitor of metalloproteinase (TIMP-2) were studied by immunoblotting. RESULT AND CONCLUSIONS: (1) Ventricular dilatation and systolic dysfunction occurred after 1 week of rapid right atrial pacing. (2) There was structural damage to the myofibrils, mitochondria, and the sarcoplasmic reticulum with intercalated disk discontinuity. (3) Levels of Cx43 decreased significantly and gap junction remodelling occurred during TIC. (4) TIC may result from several mechanisms, such as ultrastructural changes or gap junction and matrix remodelling.