Thigh muscle MRI findings in myopathy associated with anti-mitochondrial antibody.

INTRODUCTION: Myopathy associated with anti-mitochondrial antibody (AMA) has recently been characterized as a distinct type of idiopathic inflammatory myopathy. The purpose of this study is to evaluate the pattern of involvement in thigh muscles in AMA myopathy using MRI. METHODS: Six patients with AMA myopathy were identified and their muscle MRI findings evaluated. RESULTS: On thigh muscle MRI, all six patients showed high signal intensity with short-tau inversion recovery that reflected disease activity mostly in the adductor magnus, called a "cuneiform sign." Fatty degeneration was also prominent in the adductor magnus, as well as the semimembranosus muscles. DISCUSSION: These characteristic changes on MRI contrast with those of other inflammatory myopathies. From these observations, we concluded that the localization pattern of the inflammatory changes in muscle MRI can contribute to the diagnosis of AMA myopathy.

The clinical and histopathological features of idiopathic inflammatory myopathies with asymmetric muscle involvement.

The objective is to determine the frequency of idiopathic inflammatory myopathies (IIMs) with asymmetric muscle involvement (IIMs-A) as initial manifestations in total IIMs and to compare the demographic, clinical, histopathological and radiological characteristics of IIMs-A with classical IIMs (IIMs-C). We retrospectively reviewed the clinical, laboratory, muscle images, histopathological features and treatment response of patients at the Qilu hospital who were diagnosed as IIMs from April 2005 to August 2017. We found among 134 IIMs patients, 13(9.2%) patients with IIMs-A were identified, of which 7 patients were diagnosed as dermatomyositis (DM), 2 as polymyositis (PM), 4 as immune-mediated necrotizing myopathy (IMNM) using the European Neuromuscular Centre (ENMC) criteria. The mean age of our group was 59.1 years old. The duration from the initial symptoms to the first examination was less than 12 months in 12 patients (92.3%). 46.2% patients accompanied with weakness of distal limbs and bulbar symptoms. Finger flexion involvement was found in 5 patients (38.5%). There was no patient that finger flexion was weaker than shoulder abduction. The creatine kinase (CK) level in the serum ranged from 41 IU/L to 9125 IU/L (average: 3192.7 ±â€¯2769.9 IU/L). Serum positive anti-mitochondrial antibodies (AMAs) were found in four patients (30.8%). Endomysial fibrosis and inflammatory cell infiltration were detected in 92.3%, 84.6% patients respectively. Mitochondrial abnormalities in histopathological finding of muscle biopsy were seen in 100% cases. The major histocompatibility complex class I (MHC-I) (84.6%) and class II (MHC-II) (92.3%) expressed on muscle biopsies from almost all cases of our patients. MAC antibody, however, was detected in only 20-40% patients. Eight patients (61.5%) had favorable outcomes. The conclusion was that IIMs-A presented mainly in DM, generally with mitochondrial abnormality and highly positive AMAs. The relationship between the presence of AMAs and the asymmetric muscle involvement in DM needs to be further clarified. We should also consider the diagnosis of IIMs when the patient has features of positive AMAs and asymmetric muscle involvement.

Effects of reactive oxygen species and interplay of antioxidants during physical exercise in skeletal muscles.

A large number of researches have led to a substantial growth of knowledge about exercise and oxidative stress. Initial investigations reported that physical exercise generates free radical-mediated damages to cells; however, in recent years, studies have shown that regular exercise can upregulate endogenous antioxidants and reduce oxidative damage. Yet, strenuous exercise perturbs the antioxidant system by increasing the reactive oxygen species (ROS) content. These alterations in the cellular environment seem to occur in an exercise type-dependent manner. The source of ROS generation during exercise is debatable, but now it is well established that both contracting and relaxing skeletal muscles generate reactive oxygen species and reactive nitrogen species. In particular, exercises of higher intensity and longer duration can cause oxidative damage to lipids, proteins, and nucleotides in myocytes. In this review, we summarize the ROS effects and interplay of antioxidants in skeletal muscle during physical exercise. Additionally, we discuss how ROS-mediated signaling influences physical exercise in antioxidant system.

Preventive effects of electrical stimulation on inflammation-induced muscle mitochondrial dysfunction.

Cachexia is a complex metabolic syndrome associated with underlying chronic diseases and is characterized by the overexpression of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), which impair muscle oxidative metabolism. We hypothesized that electrical stimulation (ES) would prevent decrement in muscle oxidative metabolism by suppressing the phosphorylation of p38 MAPK, a critical regulator of inflammatory response. Therefore, the purpose of the present study was to verify the effects of ES on inflammatory-induced decrement of oxidative metabolism in mice tibialis anterior muscles. ICR mice were randomly divided into three groups: control, lipopolysaccharide (LPS) injection for 4days, and LPS injection plus ES (LPS+ES). Cachexia was induced in the animals in the LPS groups via LPS injection (10mg/kg body weight/day, i.p.) during the intervention period. The animals in the LPS+ES group were stimulated electrically (carrier frequency, 2500Hz; modulation frequency, 100Hz; duration, 240s/day; type of contraction, isometric) during the intervention period. LPS injection resulted in decreased body and muscle wet weight and increased expression of TNF-α in plasma and skeletal muscle. In addition, LPS injection decreased indicators of mitochondrial function such as succinate dehydrogenase (SDH) and citrate synthase (CS) activity as well as the expression of PGC-1ɑ, and increased the phosphorylation of p38 MAPK. On the other hand, the intervention of ES attenuated the changes in muscle wet weight, SDH activity, CS activity, p38 MAPK, and PGC-1ɑ. These results suggest that ES could prevent decrement in muscle oxidative metabolism induced by pro-inflammatory cytokines in cachexia.

[Clinical and histopathological features of myositis associated with anti-mitochondrial antibodies].

Anti-mitochondrial antibodies (AMA) are known to be characteristic markers of primary biliary cirrhosis (PBC). The association of PBC with myositis has been reported mainly as case reports, and comprehensive studies of the clinical and histopathological features of patients with myositis and AMAs or PBC have not been conducted thus far. We retrospectively reviewed 212 patients with inflammatory myopathies in our laboratory and found 24 patients with AMA-positive myositis (11%) (seven patients with PBC and 17 patients without PBC). The analysis of clinical and histopathological features revealed that myositis associated with AMAs frequently include patients with a clinically chronic disease course, muscle atrophy, cardiopulmonary involvement and granulomatous inflammation, regardless of the presence or absence of PBC. We also reviewed and analyzed the clinical features of previously reported patients. The analysis of 75 patients, which have been described in previous case reports including the ones of meeting abstracts, also showed the similar results about clinical features of myositis associated with AMAs and supported our findings. Our study suggests that myositis associated with AMAs form a characteristic subgroup.

Neurophysiological and mitochondrial abnormalities in MuSK antibody seropositive myasthenia gravis compared to other immunological subtypes.

OBJECTIVE: To compare the electrophysiological and histopathological features of immunological myasthenia gravis (MG) subtypes. METHODS: Fifty MG patients underwent clinical examination, MuSK-Ab and AChR-Ab analysis. The majority underwent quantitative and single-fiber electromyography (QEMG, SFEMG), repetitive nerve stimulation and deltoid muscle biopsy. From muscle specimens with histological mitochondrial dysfunction, we amplified mitochondrial DNA (mtDNA). In specimens with mtDNA deletions, the nuclear gene POLG1 was sequenced. RESULTS: Five AChR-Ab seropositive [AChR(+)] and 5 seronegative [AChR(-)] patients were MuSK-Ab seropositive [MuSK(+)]. Five of 7 neurophysiologically examined MuSK(+) patients (71%) had proximal myopathic pattern, compared to 7 of 31 MuSK(-)/AChR(+) patients (23%) (P=0.012). SFEMG was abnormal in all examined MuSK(+) patients. All 7 biopsied MuSK(+) and 32 MuSK(-) patients (89%) had cytochrome c oxidase (COX) negative fibers. Three of five MuSK(+) and 13 of 20 MuSK(-) patients analyzed had multiple mtDNA deletions but no POLG1 mutations. CONCLUSIONS: Similar degree of SFEMG abnormalities was present in proximal muscles among MuSK(+) and AChR(+) patients. Proximal myopathy was over-represented in MuSK(+) patients; however, both MuSK(+) and MuSK(-) patients had mild myopathy with frequent mitochondrial abnormalities. SIGNIFICANCE: The weakness in MuSK(+) patients is most likely due to disturbed neuromuscular transmission. The frequently encountered mitochondrial dysfunction in MG warrants further study.

A mitochondrial encephalomyopathy with specific deficiencies of two respiratory chain polypeptides and a circulating autoantibody to a mitochondrial matrix protein.

A 15-yr-old boy with mitochondrial encephalomyopathy and NADH CoQ reductase (Complex I) deficiency is presented. Immunoblotting demonstrated specific deficiencies of the 24 kDa FeS protein of Complex I and subunit II of Complex IV. The patient's serum contained an antibody to a specific mitochondrial matrix polypeptide of apparent Mr 41 kDa. The specific polypeptide deficiencies involve products of nuclear (24 kDa FeS protein) and mitochondrial (subunit II) genes and suggest some intergenomic regulation. The relevance of the circulating antibody to the pathogenesis of the patient's Complex I deficiency is discussed.

Fatal infantile mitochondrial myopathy and renal dysfunction caused by cytochrome c oxidase deficiency: immunological studies in a new patient.

A 3-month-old female infant had profound generalized weakness, de Toni-Fanconi-Debre syndrome, and lactic acidosis. She required assisted ventilation and died at the age of 8 months. Muscle biopsy showed accumulation of mitochondria, glycogen, and lipid droplets. Histochemical reaction and immunocytochemical stain for cytochrome c oxidase showed very weak results, but both reactions were normal in intrafusal fibers of the muscle spindle. In crude extracts of the patient's muscle, cytochrome c oxidase activity was undetectable and enzyme-linked immunosorbent assay showed decreased reaction at all dilutions of antiserum. These data indicate that the amount of immunoreactive enzyme protein is markedly decreased in muscle of patients with fatal infantile cytochrome c oxidase deficiency and renal dysfunction.

Elevated levels of smooth muscle autoantibodies in patients with acromegaly.

Screening of sera from patients with central nervous system (CNS) tumors for serum antibodies to tumor and normal tissue antigens revealed that the sera from a significant percentage of patients with pituitary adenoma demonstrated reactivity for smooth muscle antibodies (SMA) at a serum titer (1/25) at which other CNS tumors are devoid of this reaction. The sera were assessed by an indirect immunofluorescent antibody assay on fresh cryostat sections of rat kidney, liver, diaphragm, and stomach tissue. Absorption of SMA-positive sera with extracts containing smooth muscle tissue abolished the reaction. The overall incidence of SMA among patients harboring pituitary tumors was 30% (12/40). Assessment of the functional types of the tumor revealed a distinct predilection for such findings among patients with clinical acromegaly. Among patients with hypersecretion of growth hormone (CA) 90% (9/10) have SMA (both IgG and IgM type) whereas SMA was positive in only 10% (3/30) of corresponding group of patients with pituitary tumors resulting in hypercortisolemia or those that did not result in a hyperfunctional endocrine state.

Chronic carriers of hepatitis B antigen (HBsAg). Histological, biochemical, and immunological findings in 31 voluntary blood donors.

Among 289 HBsAg carriers detected by the Montreal Red Cross Blood Transfusion Service and seen by our group, 31 submitted voluntarily to liver biopsy. These 31 carriers have now been followed for 10-33 months (mean: 23) and all remained positive for HBsAg. 15 of these 31 subjects had lived in institutions during infancy or childhood and none were drug users. Histological examinations revealed 24 cases of chronic persistent hepatitis (CPH), 2 cases of chronic aggressive hepatitis, 2 with steatosis, and 3 with normal liver. On repeated determination, 16 of the 31 subjects had at least one elevated transaminase level. Transaminases levels could not be correlated with the histological diagnosis. 4 cases had positive antinuclear antibodies, all in the CPH group, a finding that could not be correlated with any clinical, biological, or histological findings. The search for other autoantibodies and the immunoglobulin determinations were totally unrewarding. Thus, it appears that chronic HBsAg carriers in Montreal voluntary blood donors often have chronic hepatitis, usually persistent, occasionally aggressive; liver biopsy still remains the most useful approach in the evaluation of these HBsAg carriers. The HBsAg-carrier state seems to be well tolerated, but further long-term studies are needed to understand the natural history of this condition.