Serum CK Levels Research Articles

Identification of Two Novel LAMA2 Mutations in a Chinese Patient with Congenital Muscular Dystrophy.

Merosin-deficient CMD type 1A (MDC1A), caused by mutations of laminin subunit alpha 2 (LAMA2), is a predominant subtype of congenital muscular dystrophy (CMD). Herein, we described a Chinese patient with MDC1A who was admitted to hospital 17 days after birth because of marasmus and feeding difficulties. Mutations were identified by targeted capture and next generation sequencing (NGS) and further confirmed by Sanger sequencing. Paternity was confirmed by short tandem repeat analysis. Physical examination showed malnutrition, poor suck and appendicular hypotonia. Her serum CK levels were 2483 and 1962 U/L at 2 and 4 months of age, respectively. Brain magnetic resonance imaging performed at 1 month of age presented hyperintensity on T2-weighted images, T1-weighted images in parietal and occipital lobes, and diffusion-weighted image (DWI) as well as hypointensity on fluid attenuated inversion recovery (FLAIR) image; however, the cerebellum and corpus arenaceum were normal. At 7 months of age, delayed developmental milestones were observed, and she failed to turn her body over and raise her head up. A point mutation (c.1782+2T > G) and a frameshift duplication (c.8217dupT) in the LAMA2 gene were identified by targeted capture and NGS and further confirmed by Sanger sequencing. Moreover, genotyping with multiple short tandem repeat markers confirmed paternity to demonstrate that the point mutation is de novo. The frameshift duplication (c.8217dupT), inherited from her mother, was predicted to cause a substitution of Pro (P) to Ser (S) at the 2740th amino-acid residue and generate a prematurely truncated protein. The in silico analysis suggests that the mutation (c.1782+2T > G) may lead to aberrant splicing of LAMA2. Our case further confirms the heterogeneous clinical spectrum of MDC1A and presents two novel LAMA2 mutations to expand the mutation spectrum of MDC1A.

Comparison of serum markers for muscle damage, surgical blood loss, postoperative recovery, and surgical site pain after extreme lateral interbody fusion with percutaneous pedicle screws or traditional open posterior lumbar interbody fusion

BackgroundThe benefits of extreme lateral interbody fusion (XLIF) as a minimally invasive lumbar spinal fusion treatment for lumbar degenerative spondylolisthesis have been unclear. We sought to evaluate the invasiveness and tolerability of XLIF with percutaneous pedicle screws (PPS) compared with traditional open posterior lumbar interbody fusion (PLIF).MethodsFifty-six consecutive patients underwent open PLIF and 46 consecutive patients underwent single-staged treatment with XLIF with posterior PPS fixation for degenerative lumbar spondylolisthesis, and were followed up for a minimum of 1 year. We analyzed postoperative serum makers for muscle damage and inflammation, postoperative surgical pain, and performance status. A Roland–Morris Disability Questionnaire (RDQ) and Oswestry Disability Index (ODI) were obtained at the time of hospital admission and 1 year after surgery.ResultsIntraoperative blood loss (51 ± 41 ml in the XLIF/PPS group and 206 ± 191 ml in the PLIF group), postoperative WBC counts and serum CRP levels in the XLIF/PPS group were significantly lower than in the PLIF group. Postoperative serum CK levels were significantly lower in the XLIF/PPS group on postoperative days 4 and 7. Postoperative recovery of performance was significantly greater in the XLIF/PPS group than in the PLIF group from postoperative days 2 to 7. ODI and visual analog scale (VAS) score (lumbar) 1 year after surgery were significantly lower in the XLIF/PPS group compared with the PLIF group.ConclusionsThe XLIF/PPS procedure is advantageous to minimize blood loss and muscle damage, with consequent earlier recovery of daily activities and reduced incidence of low back pain after surgery than with the open PLIF procedure.

P.44 - A case of severe encephalopathy and movement disorder due to mutations in the TRAPPC11 gene

TRAPPC11 is a component of the transport protein particle complex (TRAPPC) which mediates trafficking of vesicles from the endoplasmic reticulum to the Golgi system. Recently mutations in TRAPPC11 have been described in patients with neurological and neuromuscular diseases ranging from congenital muscular dystrophy to limb-girdle-muscular dystrophy and myopathy with ataxia and intellectual disability. Here we report the case of a 7 years old child with a severe myopathy, central nervous system involvement cause by mutations in TRAPPC11 gene. The patient presented with hypotonia, spasticity and abnormal involuntary movements (hyperkinesia and stereotypia movements ). He was born with microcephaly and showed cortical atrophy on brain MRI. He was never able to stand or walk. He has a severe cognitive delay. Serum CK levels were elevated ( 350 - 2817 UI/L nr < 190). Muscle biopsy performed at the age of 4 showed myopathic changes, reduction of cytochrome c activity in some fibres and normal expression of sarcolemmal proteins except for a mild reduction of α-dystroglycan in some fibres.The patient was included in the MYO-SEQ project and his DNA studied by Whole-exome-sequencing. Two compound heterozygous mutations were identified in the TRAPPC1 gene. One of them has been previously described (c.1287 +5G>A) and results in the skipping of exons 11 and 12 and an in frame deletion of 58 aa. The second mutation (c.3379_3380insT) has not been reported before and is predicted to cause a frameshift in the open reading frame and premature termination of the protein near the C-terminus. Each mutation has been inherited from one of the non-affected parents.TRAPPC11 protein was significantly reduced in the patient's fibroblasts which supports that the identified mutations in the TRAPPC11 gene is the disease cause. Discussion: This case expands the phentotypic and genetic spectrum of TRAPPC11 associated myopathies. TRAPPC11 should be considered in the differential diagnosis of patients with myopathy/movement disorder, elevated CK and central nervous system involvement.

P.359 - Different kinetic profiles of 2 patients presenting with muscle b-enolase deficiency

We describe the kinetic profile of total enolase activity in muscle tissue of two patients presenting with rhabdomyolysis due to muscle b-enolase deficiency. Two patients presenting with recurrent rhabdomyolysis were diagnosed by next generation sequencing with compound heterozygous mutations in ENO3. Baseline CK was normal in both patients. Rhabdomyolysis was confirmed by high serum CK levels (CK 75,000 IU/L and 193,000 IU/L) during acute episodes of muscle pain following exercise. Muscle biopsy showed minimal changes. Other signs and symptoms included exercise related myalgia and low lactate and ammonia production on a non-ischaemic forearm exercise test. Biochemical studies showed differing kinetic profiles in enolase activity. Muscle b-enolase deficiency is a rare cause of rhabdomyolysis. Here we report two cases with different kinetic profiles of total enolase activity in muscle tissue, illustrating that the disease is not always caused by null mutations, but instead can be caused by mutations that lower the maximal work rate of the enzyme (V max).

051 Differences in the response of dermatologic symptoms and muscular strength after intravenous immunoglobulin therapy in dermatomyositis patients

Dermatomyositis (DM) is an auto-immune inflammatory myopathy characterized by muscle weakness and typical skin manifestations. Therapy includes systemic glucocorticoids, immunosuppressants and intravenous immunoglobulin (IVIG). Studies addressing the long-term efficacy of IVIG treatment are sparse. Particularly, studies investigating differences in response patterns of cutaneous and muscular symptoms are lacking. In this retrospective study we analyzed the clinical characteristics and outcomes of 20 DM patients treated between 2000-2017. The average age of patients was 62.5 (range 89-37) years. Six patients (30%) had paraneoplastic DM. Nineteen patients received glucocorticoids in addition to other immunomodulatory drugs: Fifteen patients (75%) were treated with IVIG at a dosage of 2g/kg bodyweight every 4 weeks. Four patients (20%) initially received azathioprine, and one patient was treated with glucocorticoid monotherapy. Response to treatment was individually assessed for cutaneous and muscular symptoms. Data revealed that muscular strength recovered to near baseline levels within the first 4 cycles of IVIG treatment, with the majority of patients experiencing marked improvement after the first cycle. Similarly, serum CK levels dropped from averageinitial=1138.7U/l to average4cycles=82.2U/l within the first 4 treatment cycles. In contrast, skin manifestations did not improve in the majority of DM patients. Regardless of the initial response to therapy, muscular and skin symptoms did not further improve during the course of treatment, but rather remained stable after cycle 4. None of the investigated clinical characteristics predicted a response to IVIG therapy. Similar findings were seen in patients receiving medication other than IVIG. We conclude that the initial response to treatment determines the success of therapy. Additionally, we found that muscular symptoms almost completely resolved in all patients, whereas skin symptoms were barely improved.

Study of Serum Irisin in Patients with Thyroid Dysfunction

Background: irisin, identified as a proteolytic cleavage product of the fibronectin type III domain-containing protein 5 (FNDC5), It is a novel myokine secreted by contracting skeletal muscle, possibly mediating some exercise health benefits via ‘browning’ of white adipose tissue. Irisin causes a significant increase in total body energy expenditure and resistance to obesity-associated insulin resistance in mice, while controversy still exists concerning irisin origin, regulation and function in humans. Aim of the work: our study aimed to detect relation of thyroid status (hypo, hyperthyroid) with serum irisin, ck and peripheral neuropathy. Patient and methods: this study was conducted on 60 candidates consisted of 40 patients with thyroid dysfunction selected from Endocrine outpatient Clinic and Inpatient Department of Ain Shams University Hospitals and 20 healthy volunteers from April 2016 to October 2016. Informed consent was obtained from all participants. Patients of both genders, age more than 18 years old, 20 patients with hypothyroidism, 20 patients with hyperthyroidism and 20 healthy volunteers. We excluded significant renal, hepatic and cardiac disease, severe associated acute illness or depression, pregnant females, diabetes, hypercortisolism, hypocortisolism, muscular or neurological disorders, routinely taking drugs as statins, intensively involved in a sport or any strenuous physical activity. All participants were subjected to full medical history taking, general clinical examination and laboratory investigations as thyroid and thyroid-related hormone concentrations as well as a thyroid ultrasound examination and thyroid scan for patients with hyperthyroidism. Serum irisin level, CK and nerve conduction velocity were measured. Results: irisin level was higher in hyperthyroid group than euthyroid group with a significant difference. In comparison with normal NCV candidates and reduced NCV candidates with other variables there was only border line significant difference with irisin p-value. Non significant value of irisin and CK level were detected for diagnosis of hypothyroidism. Irisin has highly significant value for diagnosis of hyperthyroidism with (sen 95%, sp 42.5). Increased BMI is the only independent predictor for hypothyroidism by using multivariable binary logistic regression analysis. Decreased BMI and irisin are independent predictors for hyperthyroidism. Conclusion: serum irisin level is one of predictors for hyperthyroidism, on the other hand irisin does not have a significant value to predict hypothyroidism. Serum irisin was found to be higher in patients with hyperthyroidism in comparison with euthyroid participant with non statistically significant difference between hypo and hyperthyroidism. Serum CK level does not have a significant value in diagnosis of thyroid dysfunction (hypothyroidism or hyperthyroidism). Serum irisin level was low in thyroid dysfunction cases with delayed NCV compared to thyroid dysfunction cases and normal NCV with border line significant difference.

Gender-differences in the associations between circulating creatine kinase, blood pressure, body mass and non-alcoholic fatty liver disease in asymptomatic asians.

BackgroundCreatine kinase (CK) is a pivotal regulatory enzyme in energy metabolism linked to both blood pressure and cardio-metabolic components. However, data is lacking in a large population of asymptomatic Asians.Methods and resultsCardio-metabolic assessment including anthropometric measures and non-alcoholic fatty liver disease (NAFLD) were evaluated by abdominal echo in 4,562 consecutive subjects who underwent an annual health survey. Serum CK levels were related to blood pressure components [systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP)], anthropometric measures, and excessive adiposity in liver as indicated by NAFLD. Circulating CK levels ranged from 4 to 1842 IU/L (mean [SE]: 108.7 [1.1] IU/L) in the study population which consisted of 2522 males (mean age: 48.7 ± 11.2) and 2040 females (mean age: 49.4±11.5). In general, male subjects presented with higher circulating CK levels than females (mean ± SE: 127.3 ± 1.5 vs. 85.5 ± 1.3 IU/L, respectively, p < .001). Gender-differences in circulating CK levels were also observed with increasing age, which showed a more pronounced positive relationship with age in female subjects (gender interaction: p < .05). Furthermore, an elevated circulating CK level was independently associated with higher blood pressure, waist circumference and fat mass (FM), greater body mass index (BMI), increased lower estimated glomerular filtration rate (eGFR) and presence of NAFLD in multivariate analysis (all p < .05), with CK elevation more pronounced with greater BMI and FM in males compared with females (sex interaction: p < .05).ConclusionIn a large asymptomatic Asian population, circulating CK levels were increased with more advanced age, higher blood pressure, and greater body mass with gender differences. Our findings may be useful in interpreting elevated CK from subjects free of ongoing myocardial damage.

Circulating serum CK level vs. muscle impairment for in situ monitoring burden ofdiseaseinMdx-mice.

Duchenne muscular dystrophy (DMD) consists of alack in the expression of the subsarcolemmal protein dystrophin causing progressive muscle dysfunction. Among the widely applied animal models in DMD research is the C57BL/1010ScSn-Dmdmdx mouse, commonly referred to as the "mdx mouse". The potential benefit of novel interventions in this model is often assessed by variables such as functional improvement, histological changes, and creatine kinase (CK) serum levels as an indicator for the extent of in situ muscle damage. Our objective was to determine to what extent the serum CK-level serves asurrogate for muscle dysfunction. In this trial mdx mice were subjected to afour-limb wire-hanging test (WHT) to assess the physical performance as areference for muscle function. As CK is acomponent of the muscle fiber cytosol, its serum activity is supposed to positively correlate with progressing muscle damage. Hence serum CK levels were measured to detect the degree of muscle impairment. The functional tests and the serum CK levels were analyzed for their specific correlation. Although physical performance decreased during the course of the experiment, latency to fall times in the WHT did not correlate with the CK level in mdx mice. Our data suggests that the serum CK activity might be acritical parameter to monitor the progression of muscle impairment in mdx mice. Further this study emphasizes the complexity of the DMD phenotype in the mdx mouse, and the care with which isolated parameters in this model should be interpreted.

Safety and Free Testosterone Boosting Efficacy of a Novel Curculigo orchioides Extract (Blamus™) in Male Rats

Curculigo orchioides Gaertn (family Hypoxidaceae, also known as black or kali musli), is an endangered medicinal plant used for diverse medicinal purposes including impotency, aphrodisiac, tonic, jaundice, and skin ailments. phytochemical investigations of rhizomes revealed the presence of a novel phenolic glycoside, curculigoside, triterpenoid, saponins, flavones, cellulose, hemicellulose, and calcium oxalate. We developed a novel extract of Curculigo orchioides (commercially known as Blamus™) and assessed its dose‐dependent efficacy (0‐, 10‐, 25‐ and 50 mg/kg body weight p.o.) in male rats (200–230 grams; n = 6) over a period of 28 days. Dose‐ and time‐dependent efficacy of Blamus™ was evaluated on body weight, serum free and total testosterone levels. Furthermore, extensive histopathological analyses and blood chemistry analyses were performed to assess the liver function (SGOT and SGPT), kidney function (BUN) and heart function (creatinine) as the beginning and end of the study. Blamus™ didn't cause any marked elevation in serum free testosterone levels at either10‐ or 25 mg/kg body weight doses, however, a 50 mg/kg body weight dose of Blamus showed a significant increase in serum free testosterone level (*p &lt; 0.0001). However, no significant increases were observed in serum total testosterone levels at 0‐, 10‐, 25‐ or 50 mg/kg body weight doses of Blamus™. No significant changes were observed in serum SGOT, SGPT, BUN and CK levels following treatment with either 0‐, 10‐, 25‐ or 50 mg/kg body weight doses of Blamus™, which demonstrated its broad spectrum safety. Histopathological analyses including investigations on the seminiferous tubules, spermatogenesis, sperm cell morphology, Leydig cells and Sertoli cells following treatment with either 0‐, 10‐, 25‐ or 50 mg/kg body weight doses of Blamus™ demonstrated dose‐dependent improvement in structural integrity. These data demonstrated that Blamus™ may serve as a safe and novel, natural testosterone booster and provide broad spectrum application is sports nutrition, muscle building and exercise pathophysiology.Support or Funding InformationThis project was funded by Cepham Inc, Piscataway, NJ

DISTRIBUTION OF POLYMORPHISMS OF GENES OF STATINS METABOLISM AND TRANSPORT IN THE LIVER IN PATIENTS WITH CORONARY ARTERY DISEASE ETHNIC UZBEKS WITH SIMVASTATIN INTOLERANCE

Background. It is well-known that in majority of cases treatment with statins can be safe and well tolerated, but in some patients observed statin-induced adverse liver or muscle symptoms - the main reasons for statin discontinuation. Asian ethnicity - is one of the predisposing factors for statin-associated adverse effects. Objective. To study possible effects of CYP3A5 (6986A&gt;G), CYP2C9 (430C&gt;T), CYP2C9 (1075A&gt;C), SLCO1B1 (521T&gt;C) and BCRP (ABCG2, 421C&gt;A) genetic polymorphism on simvastatin tolerance and safety in ethnic Uzbek patients with Coronary Artery Disease (CAD).Material and methods. The prospective case-control research included 100 patients with CAD. Group "case" were 50 patients who demonstrated statin-induced adverse liver effects (transaminase level increases 3 times and more - in 37 cases) or statin-induced elevations in serum CK (of &gt;3*UNL - in 4 cases) at treatment with simvastatin with the dose of 20 mg/day for 3 months of treatment and 13 with myopathy, associated with increased levels of total creatine phosphokinase (CPK) 3 times or more. In 4 patients with adverse effects on the liver, along with an increase in the enzymes, while there was an increase of CPK levels. Control group contained 50 patient with CAD treated with simvastatin with the dose of 20-40 mg/day for one year without side effects. The both groups of patients were similar in gender, age, original index of kidney function and serum CK level. The comparison group consisted of healthy ethnic Uzbeks (n = 41) of comparable age and sex, with the absence of a family history of coronary artery disease. The research was performed by means of PCR-RFLP method.Results. As a whole, all genotypes (except for CYP2C9 * 2 in patients) were in Hardy-Weinberg equilibrium. Among patients with simvastatin intolerance, compared to the control group, the following genotypes were observed more frequently with high level of confidence: CYP3A5 *3/*3, compared to genotype variants *1/*3 and *1/*1 (OR 9.33; 95% CI 3,37-25,9; P = 0.0001) and BCRP CA (patients with BCRP CC genotype were not observed among those examined) (OR 3.22; 95% CI 1,258,30, P = 0.024).Conclusions. Genotypes CYP3A5 *3/*3 (6986A&gt;G) and BCRP CA (ABCG2, 421C&gt;A) are accompanied with the increase of statin-induced adverse effects in ethnic Uzbek patients with Coronary artery disease.

筋ジストロフィーとの鑑別を要した，慢性経過の小児期発症抗HMGCR（3-hydroxy-3-methyl-glutaryl-CoA reductase）抗体陽性壊死性ミオパチーの1例

A 24-year-old woman visited our hospital with a complaint of walking disability. She had no family history of consanguineous marriage, and her developmental history was unremarkable, with good physical performance just before the onset. At the age of 13, she developed difficulty in walking and visited a pediatrician. Her serum CK level was 10,000 IU/l and she was diagnosed with muscular dystrophy by muscle biopsy. At the age of 16, she became wheelchair dependent and was admitted to our hospital. Physical examination revealed diffuse muscle atrophy and proximal weakness, with no calf hypertrophy or selectivity of muscle involvement. Needle EMG and MR images indicated inflammatory myopathy. Muscle biopsy revealed necrotic and regenerating fibers and lymphocyte infiltration. She was re-diagnosed with inflammatory myopathy and recovered walking capacity after immunotherapy. Subsequently, she was tested positive for anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies. To distinguish treatable inflammatory myopathy from muscular dystrophy, a comprehensive assessment of patient history, family history, selectivity of muscle involvement, findings suggestive of inflammation in EMG and CT/MR imaging, and muscle pathology is necessary.

N-of-1 Trials for Myalgia in People Taking a Statin

About 1 in 5 patients taking statins report some degree of muscular pain or other musculoskeletal symptom, but there is great controversy over what proportion is due to statin therapy. This uncertainty has considerable clinical significance, given the importance of adherence to statins and the increasing number of therapies available for statin intolerance. N-of-1 trials provide the most reliable assessment of causality for an individual person. However, only 8 N-of-1 trials have been reported for patients with possible statin-related myalgia, and for all 8 there was no evidence that the statin was causal 1DOI:10.7326/M13-19211DOI:10.7326/M13-1921. This study aims to evaluate the feasibility and sustainability of an information technology-enhanced N-of-1 trial service to improve the diagnosis of statin-induced myalgia in Australian general practice setting. N-of-1 (single-patient multiple crossover) trials (n = 15) of patients with prior history of intolerance of both atorvastatin 10 mg and rosuvastatin 5 mg monotherapy, who had myalgia occurring within three weeks of starting statin therapy and consequently discontinued statin use. Each person will go through 3 double-blind, crossover comparisons of statin versus matching placebo for a total of 27 weeks. Myalgia scores and Brief Pain Inventory Questionnaire will be recorded on a weekly basis during the study period. Blood sample collection will be done at baseline and at the end of each active treatment and control period to measure serum CK, ALT, AST, FGF21 and creatinine levels. To avoid unblinding of treatment allocation during the trial period, additional blood samples will be stored to measure lipid levels upon study completion. Genotype analysis will also be done at the end of the study to determine if genotype is associated with statin-induced myalgia. Patient and prescriber intentions to continue statin therapy at the end of the trial will also be assessed.

Dendrobium officinale Kimura et Migo attenuates diabetic cardiomyopathy through inhibiting oxidative stress, inflammation and fibrosis in streptozotocin-induced mice.

Dendrobium officinale Kimura et Migo (Dendrobium catenatum Lindley), a prized traditional Chinese Medicine, has been used in China and Southeast Asian countries for centuries. The present study was aimed to investigate the effects and the possible mechanisms of the Dendrobium officinale extracts (DOE) on diabetic cardiomyopathy in mice. The diabetic model was induced by intraperitoneal injection of streptozotocin at the dose of 50mg/kg body weight for 5 consecutive days. After 8 weeks treatment of DOE, mice were sacrificed, blood sample and heart tissues were collected. Our results showed that Streptozotocin-induced diabetic model was effectively achieved and serum CK and LDH levels were significantly increased in mice with diabetic cardiomyopathy. Pretreatment with DOE decreased the heart-to-body weight ratio (HW/BW) and showed an evident hypoglycemic effect. DOE pretreatment significantly decreased CK, LDH, TC and TG levels, limited the production of MDA and increased the activities of T-SOD. The histological analysis of Oil red O staining and Sirius red staining showed an obvious amelioration of cardiac injury, inhibition of cardiac lipid accumulation and deposition of collagen when pretreatment with DOE. In addition, Western blot detection and analysis showed that DOE down-regulated the expression of TGF-β, collegan-1, fibronectin, NF-κB, TNF-α and IL-1β. In conclusion, our study suggested that DOE possesses the cardioprotective potential against diabetic cardiomyopathy, which may be due to the inhibition of oxidative stress, cardiac lipid accumulation, pro-inflammatory cytokines and cardiac fibrosis.

P.191 - Rituximab for the treatment of anti-HMGCR necrotizing autoimmune myopathy

The effectiveness of rituximab in refractory myositis has been suggested by case reports and case series. Recently, anti-HMGCR, a new autoantibody associated with necrotizing autoimmune myopathy and related to statin exposure was discovered. Our objective was to address the effectiveness of rituximab in the subgroup of anti-HMGCR necrotizing autoimmune myopathy. We identified 4 patients with anti-HMGCR necrotizing autoimmune myopathy that were treated with rituximab. Medical records were reviewed to assess their clinical presentation, muscle testing, serum CK levels, corticosteroid doses and associated immunosuppressant agents while receiving rituximab, and their evolution at last follow-up. Only one patient had previous statin exposure. Two patients had a slowly-progressive dystrophic-like presentation over 20 years. All patients had a relapsing disease and needed multiple therapy trials and combination to maintain remission. Two patients were resistant to rituximab and clearly IVIg-dependent, requiring long-term treatment with IVIg to maintain remission. One patient had a thrombotic event while on IVIg and was successfully switched to rituximab. Another patient experienced a biological flare with an isolated CK rise following IVIg discontinuation yet subsequent slowly-progressive CK lowering with rituximab re-infusion and introduction of methotrexate. At last follow-up all patients were in clinical remission. Two of them were still on IVIg with low-dose prednisone +/− azathioprine. Two patients were adequately controlled with rituximab and low-dose prednisone +/− methotrexate. Our patients with anti-HMGCR necrotizing autoimmune myopathy had a refractory disease with multiple relapses. Larger prospective trials are needed to confirm potential efficacy of rituximab in this subgroup of patients.

P.192 - Autoimmune myopathy with cardiac involvement associated with antimitochondrial antibodies

Antimitochondrial antibodies (AMA) are associated with primary biliary cirrhosis (PBC). They act against autoantigens situated in the inner membrane of mitochondria. AMA M2, directed against the proteins of the 2–oxo acid dehydrogenase family, is the subtype most frequently associated with hepatic disease. The relation of AMA M2 with inflammatory myopathies has recently been reported by Hashimoto et al, who described 24 patients among 212 patients with seronegative inflammatory myopathy associated with AMA antibodies. We aim to describe a series of patients suffering from immunomediated myopathy (IMM) associated with AMA. We identified 8 patients with IMM. We determined serum CK levels and excluded other specific myositis antibodies. We performed a complete cardiological examination in all patients focused on the presence of arrhythmias. The patients were 7 females and 1 male. Age at onset varied from 31 to 71 years, and diagnosis delay ranged from 1 to 10 years. All patients presented with subacute progressing limb girdle weakness. 6 patients suffered cardiac involvement at onset with supraventricular arrhythmias; 3 of them eventually developed a dilated cardiomyopathy. One patient presented hypercapnic respiratory failure. Three patients presented PBC. Serum CK levels were elevated. Muscle biopsy revealed muscle fiber necrosis in 6 patients. Only in one were perivascular inflammatory infiltrates observed. MHC class I was up-regulated in 6 patients. All patients received immunomodulatory therapy. Muscle weakness improved with steroid treatment but cardiac involvement didn't respond. AMA must be determined in patients suffering with autoimmune myopathy, especially when cardiac manifestations are present. A detailed cardiological examination may be performed in patients with limb girdle weakness associated with AMA. Arrhythmias and dilated cardiomyopathy often fail to respond to conventional immunomodulatory therapy.

Fatty acid binding protein 3 is associated with skeletal muscle strength in polymyositis and dermatomyositis.

To determine serum levels and histopathological characteristics of fatty acid binding protein 3 (FABP3) in patients with polymyositis (PM) and dermatomyositis (DM), and to evaluate the correlation between the FABP3 and muscle strength. The study population included 24 subjects with PM/DM, 12 subjects with asymptomatic or minimally symptomatic hyper-creatine kinase-emia (AMSH), and 10 healthy control subjects. Muscle strength was measured by using the Manual Muscle Test (MMT8). Serum CK, myoglobin and FABP3 levels were tested. Correlations between variables were studied by using Spearman's rank and partial correlation analysis methods. Immunohistochemical and double immunofluorescent stainings of FABP3 were performed to investigate its distribution in skeletal muscle. PM/DM patients had significantly higher (P < 0.05) serum FABP3 levels (35.46 ± 38.45 ng/mL) than did AMSH patients (3.77 ± 1.21 ng/mL) and healthy control subjects (4.30 ± 3.18 ng/mL). MMT8 scores correlated negatively with CK, myoglobin and FABP3 levels. Partial correlation analysis was performed and showed that the correlation coefficients between MMT8 score and serum CK, myoglobin and FABP3 levels were -0.276 (P > 0.05), -0.228 (P > 0.05) and -0.927 (P < 0.001), respectively. Immunohistochemical and double immunofluorescent staining showed that FABP3 expression increased in the skeletal muscle of PM/DM patients and was mainly distributed in slow twitch muscle fibers. Serum levels of FABP3 in PM/DM patients were significantly increased and were mainly distributed in slow twitch muscle fibers, displaying a closer association with muscle weakness than did serum levels of CK and myoglobin. FABP3 is likely to be a useful serum biomarker in PM/DM patients.

Notch1 Pathway Protects against Burn-Induced Myocardial Injury by Repressing Reactive Oxygen Species Production through JAK2/STAT3 Signaling.

Oxidative stress plays an important role in burn-induced myocardial injury, but the cellular mechanisms that control reactive oxygen species (ROS) production and scavenging are not fully understood. This study demonstrated that blockade of Notch signaling via knockout of the transcription factor RBP-J or a pharmacological inhibitor aggravated postburn myocardial injury, which manifested as deteriorated serum CK, CK-MB, and LDH levels and increased apoptosis in vitro and in vivo. Interruption of Notch signaling increased intracellular ROS production, and a ROS scavenger reversed the exacerbated myocardial injury after Notch signaling blockade. These results suggest that Notch signaling deficiency aggravated postburn myocardial injury through increased ROS levels. Notch signaling blockade also decreased MnSOD expression in vitro and in vivo. Notably, Notch signaling blockade downregulated p-JAK2 and p-STAT3 expression. Inhibition of JAK2/STAT3 signaling with AG490 markedly decreased MnSOD expression, increased ROS production, and aggravated myocardial injury. AG490 plus GSI exerted no additional effects. These results demonstrate that Notch signaling protects against burn-induced myocardial injury through JAK2/STAT3 signaling, which activates the expression of MnSOD and leads to decreased ROS levels.

Muscle hypertrophy induced by myostatin inhibition accelerates degeneration in dysferlinopathy.

Myostatin is a secreted signaling molecule that normally acts to limit muscle growth. As a result, there is extensive effort directed at developing drugs capable of targeting myostatin to treat patients with muscle loss. One potential concern with this therapeutic approach in patients with muscle degenerative diseases like muscular dystrophy is that inducing hypertrophy may increase stress on dystrophic fibers, thereby accelerating disease progression. To investigate this possibility, we examined the effect of blocking the myostatin pathway in dysferlin-deficient (Dysf−/−) mice, in which membrane repair is compromised, either by transgenic expression of follistatin in skeletal muscle or by systemic administration of the soluble form of the activin type IIB receptor (ACVR2B/Fc). Here, we show that myostatin inhibition by follistatin transgene expression in Dysf−/− mice results in early improvement in histopathology but ultimately exacerbates muscle degeneration; this effect was not observed in dystrophin-deficient (mdx) mice, suggesting that accelerated degeneration induced by follistatin transgene expression is specific to mice lacking dysferlin. Dysf−/− mice injected with ACVR2B/Fc showed significant increases in muscle mass and amelioration of fibrotic changes normally seen in 8-month-old Dysf−/− mice. Despite these potentially beneficial effects, ACVR2B/Fc treatment caused increases in serum CK levels in some Dysf−/− mice, indicating possible muscle damage induced by hypertrophy. These findings suggest that depending on the disease context, inducing muscle hypertrophy by myostatin blockade may have detrimental effects, which need to be weighed against the potential gains in muscle growth and decreased fibrosis.

Abstract 104: Vasonatrin Peptide Inhibits Endoplasmic Reticulum Stress and Attenuates Myocardial Ischemia/reperfusion Injury in Diabetic Rats

Aims: Diabetes mellitus (DM) increases morbidity/mortality of ischemic heart disease. Although the ability of the natriuretic peptides to modulate cardiac function and cell proliferation has been recognized, their effects on myocardial ischemia/reperfusion (MI/R) injury is still unclear. This study was to investigate the effects of the artificial synthetic natriuretic peptide — vasonatrin peptide (VNP) on MI/R injury in diabetic rats, and underlying mechanisms. Method: The high-fat diet-fed streptozotocin induced diabetic rats were subjected to MI/R (30 min/4 h) and VNP treatment (100 μg/kg, i.v., 10 min before R). In vitro study was performed using H9c2 cardiomyocytes subjected to hypoxia/reoxygenation (H/R, 3 h/6 h) and incubated with or without VNP (10 -8 mol/L). Result: The diabetic state aggravated MI/R injury and showed more severe myocardial functional impairment than normal state. VNP treatment (100 μg/kg, i.v., 10 min before R) significantly improved ± LV d P /dt max and LVSP, and decreased infarct size, apoptosis index, caspase-3 activity, serum CK and LDH levels (n=8, P &lt;0.05). Moreover, VNP inhibited endoplasmic reticulum (ER) stress by suppressing GRP78 and CHOP, and consequently increased Akt and ERK1/2 expression and phosphorylation levels (n=3, P &lt;0.05). These effects were mimicked by 8-Br-cGMP (1 mg/kg, i.p., 20 min before R), a cGMP analogue, whereas inhibited by KT-5823 (0.5 mg/kg, i.p.), the selective inhibitor of PKG ( P &lt;0.05). Pretreated DM rats with TUDCA (50 mg/kg, i.p.), an inhibitor of ER stress, couldn’t further promote the VNP’s cardioprotective effect. Additionally, gene knockdown of PKG1α with siRNA blunted VNP’s inhibition of ER stress and apoptosis, while overexpression of PKG1α resulted in significant decreased ER stress and apoptosis in H/R H9c2 cardiomyocytes (n=6, P &lt;0.05). Conclusion: We demonstrated that VNP protects diabetic heart against MI/R injury by inhibiting ER stress via cGMP-PKG signaling pathway.

Clinical characteristics of megaconial congenital muscular dystrophy due to choline kinase beta gene defects in a series of 15 patients.

A new form of congenital muscular dystrophy (CMD) with multisystem involvement and characteristic mitochondrial structural changes, due to choline kinase beta (CHKB) gene defects has been characterized by intellectual disability, autistic features, ichthyosis-like skin changes, and dilated cardiomyopathy. We define the clinical characteristics in 15 patients, from 14 unrelated families with so-called 'megaconial CMD', all having mutations in CHKB. Core clinical phenotype included global developmental delay prominent in gross-motor and language domains, severe intellectual disability (ID), and/or muscle weakness in all cases. Muscle biopsies were equivocally 'megaconial' in all. Other peculiarities were: ichthyosis-like skin changes (n = 11), increased serum CK levels (n = 12), microcephaly (n = 6), dysmorphic facial features (n = 7), neonatal hypotonia (n = 3), seizures (n = 3), epileptiform activity without clinically overt seizures (n = 2), dilated cardiomyopathy (n = 2), decreased left ventricular systolic function (n = 2), congenital heart defects (n = 3), sensorineural (n = 1), and conductive hearing loss (n = 1). Ten patients had cranial neuroimaging (MRI-MRS) study, which was notably normal in all, other than one patient having a decreased choline: creatine peak. Intra-familial variability in clinical expression of the disease is noted in four families. Two siblings from the same family, one presenting with global developmental delay and dilated cardiomyopathy, and the other with ichthyosis, ID and proximal weakness without cardiomyopathy died at the ages of 2 years 1 month, and 7 years 4 months respectively. Evolution was progressive (n = 13) and static (n = 2).