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Background: We investigated the performance of an ELISA for the detection of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) IgG antibodies in immune-mediated necrotizing myopathies (IMNM)., Methods: Patients positive for HMGCR antibodies (n=61) or negative (n=78) by protein immunoprecipitation (IP), and healthy controls (n=100) were used to evaluate the ELISA. Unique consecutive serum samples (n=155) received at ARUP Laboratories for HMGCR IgG testing by ELISA were also investigated and analysed for serum muscle enzymes (aldolase, creatine kinase, and myoglobin). The ELISA's sensitivity, specificity, and percentage agreement were assessed relative to IP. Correlation between specific muscle enzyme concentration and the presence of HMGCR antibody was determined., Results: Overall agreement between ELISA and IP was 93.4%. Using the IP as reference, the sensitivity and specificity of the ELISA was 95.1%, and 100%, respectively. Inter- and intra-assay coefficient of variation of the ELISA was <10.0%, and ≤15.0%, respectively. In the consecutive cohort, 21 (13.6%) samples tested positive for HMGCR IgG. Concentrations of aldolase, creatine kinase, and myoglobin were significantly higher (all p<0.0001) in patients positive for HMGCR antibodies at the time of evaluation., Conclusions: We confirm significant reliability of HMGCR antibodies as measured by the ELISA for the evaluation of IMNM., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Nitric oxide (NO) is a multifunctional signaling molecule involved in plant-induced resistance to disease. The present study aimed to investigate the relationship between disease resistance induced by NO and the phenylpropanoid pathway in peach fruit. The present study investigated the effect of NO on the main enzymes and metabolites of the phenylpropanoid pathway of harvested peach, which are probably related to disease resistance against Monilinia fructicola., Results: The results showed that treatment with 15 µmol L -1 NO significantly (P < 0.05) enhanced the activities of phenylalanine ammonia-lyase, cinnamate-4-hydroxylase, 4-coumaroyl-CoA ligase, chalcone synthase and chalcone isomerase and the expression of their genes. Furthermore, NO treatment significantly (P < 0.05) increased the contents of total phenolics, flavonoids and lignin over the entire storage period and maintained higher total anthocyanin, phenolic acid and anthocyanin contents during the earlier storage period., Conclusion: These results suggest that NO treatment could activate the phenylpropanoid pathway to enhance the activity of related enzymes and the contents of phenylpropanoid metabolites in peach to improve disease resistance and prevent pathogenic invasion. © 2016 Society of Chemical Industry., (© 2016 Society of Chemical Industry.)

Introduction: The patient presenting with proximal muscle weakness, elevated serum creatinine kinase and myopathic electromyography and biopsy findings has a wide differential diagnosis that includes toxic, autoimmune, paraneoplastic and congenital myopathies. Autoimmune myopathies are important to identify because they may respond to immunosuppressive therapies., Methods: We describe two cases of immune-mediated necrotizing myopathy each associated with a novel antibody., Results: Case 1 describes a progressive myopathy in a statin user. Antibodies to 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase were identified and the patient responded to steroid therapy. Case 2 describes an aggressive myopathy associated with antibodies to signal recognition particle. There was no response to steroids. Clinical improvement followed treatment with rituximab and cyclophosphamide., Conclusion: The identification of myositis-specific antibodies is important because they are associated with distinct clinical phenotypes and may guide the physician in terms of treatment strategies.

It is well known that statins can have a toxic effect on musculature, but less widely known that they can also trigger progressive autoimmune myopathy. Statin-associated autoimmune myopathy is characterised by proximal muscle weakness, antibodies to 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) in serum, and necrosis without lymphocytic infiltration on muscle biopsy.

Mast cell (MC)- and basophil-associated inflammatory diseases are a considerable burden to society. A significant portion of patients have symptoms despite standard-of-care therapy. Statins, used to lower serum cholesterol, have immune-modulating activities. We tested the in vitro and in vivo effects of statins on IgE-mediated MC and basophil activation. Fluvastatin showed the most significant inhibitory effects of the six statins tested, suppressing IgE-induced cytokine secretion among mouse MCs and basophils. The effects of fluvastatin were reversed by mevalonic acid or geranylgeranyl pyrophosphatase, and mimicked by geranylgeranyl transferase inhibition. Fluvastatin selectively suppressed key FcεRI signaling pathways, including Akt and ERK. Although MCs and basophils from the C57BL/6J mouse strain were responsive to fluvastatin, those from 129/SvImJ mice were completely resistant. Resistance correlated with fluvastatin-induced upregulation of the statin target HMG-CoA reductase. Human MC cultures from eight donors showed a wide range of fluvastatin responsiveness. These data demonstrate that fluvastatin is a potent suppressor of IgE-mediated MC activation, acting at least partly via blockade of geranyl lipid production downstream of HMG-CoA reductase. Importantly, consideration of statin use for treating MC-associated disease needs to incorporate genetic background effects, which can yield drug resistance., (Copyright © 2016 by The American Association of Immunologists, Inc.)

Statins are some of the most widely prescribed medications, and though generally well tolerated, can lead to a self-limited myopathy in a minority of patients. Recently, these medications have been associated with a necrotizing autoimmune myopathy (NAM). Statin-associated NAM is characterized by irritable myopathy on electromyography (EMG) and muscle necrosis with minimal inflammation on muscle biopsy. The case presented is a 63-year-old woman who has continued elevation of creatine kinase (CK) after discontinuation of statin therapy. She has irritable myopathy on EMG and NAM is confirmed by muscle biopsy. She subsequently tests positive for an experimental anti-3-hydroxy-3-methylglutaryl-coenzyme A (anti-HMGCoA) antibody that is found to be present in patients with statin-associated NAM. Though statin-associated NAM is a relatively rare entity, it is an important consideration for the general internist in patients who continue to have CK elevation and weakness after discontinuation of statin therapy. Continued research is necessary to better define statin-specific and dose-dependent risk, as well as optimal treatment for this condition.

Necrotizing myopathy is defined by the predominant pathological feature of necrosis of muscle fibers in the absence of substantial lymphocytic inflammatory infiltrates. Most commonly necrotizing myopathies are divided into immune mediated (IMNM) and nonimmune mediated (NIMNM). IMNM has been associated with anti-signal recognition particle antibodies, connective tissue diseases, cancer, post-statin exposure with 3-hydroxy-3-methylglutaryl-coenzyme A antibodies, and viral infections including HIV and hepatitis C. NIMNM is linked to medications and toxic exposures. Both IMNM and NIMNM are typically characterized by proximal weakness, although the severity can vary substantially. Myalgias are reported by some, but not all, patients. Pathological findings on muscle biopsy include predominant fiber necrosis with little or no inflammatory infiltrate. In IMNM, there is variable evidence for the deposition of membrane attack complex on capillaries and muscle fibers, although membrane attack complex deposition on capillaries is typically less than is seen in dermatomyositis; class I major histocompatibility complex expression on muscle fibers is variable but typically less than is seen in polymyositis. Immunohistochemical abnormalities are not typically seen in NIMNM. Treatment of IMNM involves immunosuppressive therapy, although there are no controlled trials to guide particular treatment choices. Treatment of NIMNM involves removal of the toxic exposure.

Immune-mediated necrotizing myopathy (IMNM) associated with statin use and anti 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibody is a new and emerging entity that supports a link between statin use and IMNM and raises the questions of distinct clinical phenotypes and treatment strategy. We describe the clinical and histopathological characteristics of a patient and discuss the spectrum of IMNM and statin-induced myopathies. A 65-year-old man was suffering from proximal muscle weakness and elevated CK levels, following exposure to statin therapy. The symptoms worsened despite discontinuation of the drug. At that point, no myositis-specific or -associated antibodies were detected. Malignancy screening did not reveal abnormalities. Muscle biopsy demonstrated a predominantly necrotizing myopathy with minimal lymphocytic infiltrates, MHC class I expression in necrotic muscle fibers, and complement deposition on scattered non-necrotic muscle fibers. Muscle protein analysis by western blot was normal. The patient did not improve with steroid and methotrexate and required monthly intravenous immunoglobulin (IVIG) therapy. Muscle strength gradually improved, CK levels normalized and IVIG were stopped 1 year later. Screening for anti-HMGCR antibodies, not available at the time of presentation, was highly positive. Identification of anti-HMGCR antibodies in statin-exposed patients with myopathy appears to be helpful both for differential diagnosis and for treatment strategy. In patients who did not improve after discontinuation of the statin treatment, a muscle biopsy should be performed as well as screening for anti-HMGCR antibodies. Patients with this disorder require aggressive immunosuppressive treatment., (Copyright © 2013 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

Idiopathic inflammatory myopathies are a group of acquired skeletal muscle diseases that include polymyositis, dermatomyositis, and inclusion body myositis. Studies have shown many myositis-specific autoantibodies (MSAs) that are useful for the diagnoses as well as classification of idiopathic inflammatory myopathies, because they have been shown to correlate with distinct clinical phenotypes. Anti-Jo-1, anti-PL-7, anti-PL-12, anti-EJ, anti-KS, anti-OJ, anti-Ha, and anti-Zo antibodies target aminoacyl tRNA synthetases, and represent anti-synthetase syndrome. Anti-synthetase syndrome is characterized by myositis, interstitial lung disease, arthritis, fever, Raynaud's phenomenon, and mechanic's hands. Anti-Mi-2, anti-MDA5 (anti-CADM140), anti-TIF1 (anti-155/140, anti-p155), anti-NXP-2 (anti-MJ), and anti-SAE antibodies are specific for dermatomyositis. In particular, anti-MDA5 antibodies are clinically associated with amyopathic dermatomyositis developing into rapidly progressive interstitial lung disease, whereas anti-TIF1 and anti-NXP-2 antibodies are closely correlated with cancer-associated dermatomyositis in adults. In addition, anti-TIF1 and anti-NXP-2 antibodies are predominant MSAs found in juvenile dermatomyositis, and the latter was correlated with a high incidence of calcinosis. Furthermore, anti-SRP and anti-3-hydroxy-3-methylglutaryl-coenzyme A (anti-HMG-CoA) antibodies have been found in patients with necrotizing myopathy. Moreover, a recent study suggested the presence of autoantibodies to a 43-kDa muscle protein in patients with inclusion body myositis. Although the pathogenic role of MSAs remains unknown, recent studies have shown that myositis autoantigens are expressed at high levels in regenerating muscle fibers, which may initiate or amplify autoimmune responses in idiopathic inflammatory myopathies.

Anti-acyl-Coenzyme A (acyl-CoA) antibodies were used to detect fatty acyl-CoAs in cultured rat hippocampal neurons, in which important lipid metabolism and transport occur. Hippocampus was chosen because of his involvement in many cerebral functions and diseases. Immunofluorescence experiments showed an intense labelling within neurites and cell bodies. Labelling seems to be associated with vesicles and membrane domains. We have shown by immunoblot experiments that the labelling corresponded to acyl-CoAs which were in strong interaction with proteins, without being covalently bound to them. Immunoprecipitation experiments, followed by proteomic analysis, showed that anti-acyl-CoA antibodies were also able to immunoprecipitate multiprotein complexes, principally related to vesicle trafficking and/or to membrane rafts.

Antibodies directed against long chain acyl-CoAs (having 16 and 18 carbon atoms) have been prepared and are reported for the first time. A modified ELISA procedure adapted to these amphiphilic molecules has been developed: it is a rapid, simple and sensitive test permitting to detect as little as 3 pmol of acyl-CoA. These antibodies represent a new tool for studying long-chain acyl-CoAs. Their use in an immunochemical approach for the study of protein-acyl-CoA interactions is presented.