Fatty Replacement Research Articles

DMD - BIOMARKERS: EP.156 Expression of Periostin in DMD patients and mdx mice

As an X-chromosomal recessively inherited disease, Duchenne muscular dystrophy (DMD) affects boys from early childhood on. First motor milestones might be delayed, and reduced dystrophin protein expression in muscle leads to severe dysfunction and loss of muscle. Along this line, myofibre necrosis, atrophy and inflammatory cell invasion are seen during early stages of disease (∼ age 3-7y), while development of fibrosis and fatty tissue replacement increases in later stages, subsequently leading to progressive loss of mobility in early teens (∼ age 10-15y).

CHANNELOPATHIES AND RELATED DISORDERS: EP.225 Autosomal dominant early onset vacuolar myopathy with granular material, without periodic paralysis, associated with c.1583C>A CACNA1S gene mutation

Dominant mutations in CACNA1S gene mainly causes hypokalemic periodic paralysis (PP)(hypoPP). We report a patient with progressive early onset myopathy associated with heterozygous CACNA1S mutation and aim to extend the description of phenotypical spectrum of CACNA1S-related muscle diseases. A 68-year-old man developed progressive proximal weakness from the age of 35 years. He had four siblings including an affected brother. His mother had PP and became wheelchair bound at 55 years. CK level was elevated (<1.5 upper normal value). Electroneuromyography showed axonal sensorimotor polyneuropathy and myogenic potentials. Thigh magnetic resonance imaging showed extensive muscle fatty replacement and muscle biopsy showed atrophic fibers with vacuoles containing granular material. Clinical exome identified the heterozygous c.1583G>A well-known pathogenic variant in CACNA1S. The patient's brother had PP from the age of 27. Neurological examination was normal at the age of 39. Muscle biopsy showed a vacuolar myopathy with granular material. No further medical information was available. The patient died at the age of 72 yrs. Molecular characterisation was not achieved. CACNA1S-HypoPP evolving to fixed myopathy in late adulthood is well described but isolated progressive myopathy was only exceptionally reported and never with an onset <50 years. We hereby report the earliest “myopathy onset” ever described, enlarging the phenotypical spectrum of CACNA1S-related myopathies and suggest considering it even in young adult-onset myopathies, especially when granular vacuoles are present.

Statin-associated anti-3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) myopathy: Imaging findings on thigh-muscle magnetic resonance imaging (MRI) in six patients.

Anti-3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) myopathy is a rare but serious complication of statin use. The aim of this study was to describe the imaging features of statin-associated anti-HMGCR myopathy on thigh muscle magnetic resonance imaging (MRI). Thigh muscle MRI images of six patients with statin-associated anti-HMGCR myopathy were reviewed for muscle edema, fatty replacement, and fascial edema in four compartments of each thigh: gluteal, anterior, medial, and posterior. Signal intensity ratio (SIR) was calculated in 17 muscles in both thighs on T2-weighted fat-suppressed images. Intracompartmental comparison of T2 SIRs of different muscles were performed. All patients demonstrated bilateral symmetrical pan-compartmental muscle edema. Three patients had fatty infiltration, involving gluteal and/or posterior compartments. In the anterior compartment, rectus femoris and vastus lateralis most frequently demonstrated the highest T2 SIR. In the posterior compartment, semimembranosus most frequently demonstrated the highest T2 SIR. The long head of the biceps femoris always had a higher T2 SIR than the short head. Statin-associated anti-HMGCR myopathy commonly demonstrates bilateral symmetrical pan-compartmental edema on thigh muscle MRI, with anterolateral predilection in the anterior compartment, and greater involvement of the semimembranosus with relative sparing of the short head of the biceps femoris in the posterior compartment. These observations can contribute to the diagnosis of statin-associated anti-HMGCR myopathy.

Anatomical-MRI Correlations in Adults and Children with Arrhythmogenic Right Ventricular Cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare disease in which the right ventricular myocardium is replaced by islands of fibro-adipose tissue. Therefore, ventricular re-entry circuits can occur, predisposing the patient to ventricular tachyarrhythmias, as well as dilation of the right ventricle that eventually leads to heart failure. Although it is a rare disease with low prevalence in Europe and the United States, many patients are addressed disproportionately for cardiac magnetic resonance imaging (MRI). The most severe consequence of this condition is sudden cardiac death at a young age due to untreated cardiac arrhythmias. The purpose of this paper is to revise the magnetic resonance characteristics of ARVC, including the segmental contraction abnormalities, fatty tissue replacement, decrease of the ejection fraction, and the global RV dilation. Herein, we also present several recent improvements of the 2010 Task Force criteria that are not included within the ARVC diagnosis guidelines. In our opinion, these features will be considered in a future Task Force Consensus.

Arrhythmogenic right ventricular cardiomyopathy in dogs

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited myocardial disease seen in dogs, cats, and humans. A common entity in Boxers and the related English bulldog, the disease is characterized by fatty or fibrofatty replacement of the myocardium, ventricular arrhythmias, and the potential for syncope or sudden death. In some individuals, concomitant left ventricular involvement results in systolic dysfunction and a progression to congestive heart failure. The clinical and pathological characteristics of ARVC share many similarities in dogs and humans, and Boxers serve as an important spontaneous model of the disease.Although multiple mechanisms have been implicated in the pathogenesis of ARVC, the disease is ultimately considered to be a disorder of the desmosome. Multiple causal genetic mutations have been identified in people, and over 50% of affected humans have an identifiable mutation in desmosomal proteins. To date, only a single genetic mutation has been associated with ARVC in Boxer dogs. Other as-yet-undiscovered genetic mutations and epigenetic modifiers of the disease are likely. Treatment of ARVC in dogs is focused on controlling ventricular arrhythmias and associated clinical signs. This article will review the pathophysiology, clinical diagnosis, treatment, and prognosis of ARVC in the dog.

Water-Fat Separation in MR Fingerprinting for Quantitative Monitoring of the Skeletal Muscle in Neuromuscular Disorders.

Background Quantitative MRI is increasingly proposed in clinical trials related to neuromuscular disorders (NMDs). Purpose To investigate the potential of an MR fingerprinting sequence for water and fat fraction (FF) quantification (MRF T1-FF) for providing markers of fatty replacement and disease activity in patients with NMDs and to establish the sensitivity of water T1 as a marker of disease activity compared with water T2 mapping. Materials and Methods Data acquired between March 2018 and March 2020 from the legs of patients with NMDs were retrospectively analyzed. The MRI examination comprised fat-suppressed T2-weighted imaging, mapping of the FF measured with the three-point Dixon technique (FFDixon), water T2 mapping, and MRF T1-FF, from which the FF measured with MRF T1-FF (FFMRF) and water T1 were derived. Data from the legs of healthy volunteers were prospectively acquired between January and July 2020 to derive abnormality thresholds for FF, water T2, and water T1 values. Kruskal-Wallis tests and receiver operating characteristic curve analysis were performed, and linear models were used. Results A total of 73 patients (mean age ± standard deviation, 47 years ± 12; 45 women) and 15 healthy volunteers (mean age, 33 years ± 8; three women) were evaluated. A linear correlation was observed between FFMRF and FFDixon (R2 = 0.97, P < .001). Water T1 values were higher in muscles with high signal intensity at fat-suppressed T2-weighted imaging than in muscles with low signal intensity (mean value, 1281 msec [95% CI: 1165, 1604] vs 1198 msec [95% CI: 1099, 1312], respectively; P < .001), and a correlation was found between water T1 and water T2 distribution metrics (R2 = 0.66 and 0.79 for the median and 90th percentile values, respectively; P < .001). Water T1 classified the patients' muscles as abnormal based on quantitative water T2, with high sensitivity (93%; 68 of 73 patients) and specificity (80%; 53 of 73 patients) (area under the receiver operating characteristic curve, 0.92 [95% CI: 0.83, 0.97]; P < .001). Conclusion Water-fat separation in MR fingerprinting is robust for deriving quantitative imaging markers of intramuscular fatty replacement and disease activity in patients with neuromuscular disorders. © RSNA, 2021 Online supplemental material is available for this article.

MRI evidence of extraocular muscle atrophy and fatty replacement in myasthenia gravis.

The aim of the study was to evaluate extraocular muscle (EOM) atrophy and fatty replacement in ocular myasthenia gravis (OMG) and generalized myasthenia gravis (GMG) patients with chronic and untreated ocular symptoms or with inadequate response to immunotherapy and unprovoked ocular exacerbations despite chronic immunotherapy. Nineteen patients with either OMG or GMG and 19 healthy age-matched controls underwent an orbital MRI. Visually obvious muscle atrophy and muscle fatty replacement were evaluated by two raters independently. Maximum thickness of EOM was measured. Measurements of the muscles of each participant were added up, in order to calculate the total thickness. Eleven patients suffered from AChR-positive GMG, and 8 patients from OMG. All patients had chronic ocular symptoms or inadequate response to corticosteroids and unprovoked ocular exacerbations in spite of immunotherapy. Fatty replacement was reported in 6/19 (31.6%) patients and 0/19 (0%) controls (p = 0.02). Obvious atrophy in at least one muscle was reported in 8/19 (42.1%) patients and 1/19 (5.3%) controls (p = 0.019). Statistically significant differences between the two groups were also found in the mean total thickness, as well as in the thickness of superior recti, levator palpebrae, inferior recti, and superior oblique muscles. EOM atrophy and fatty replacement were seen frequently in our series of MG patients with treatment difficulties and frequent relapses of ocular involvement.

NMR-based serum and muscle metabolomics for diagnosis and activity assessment in idiopathic inflammatory myopathies.

Differentiating smoldering disease activity from weakness due to fatty replacement of atrophied muscle can often be a challenge inthe idiopathic inflammatory myositis (IIM).We aimed to identify the metabolic disturbances associated with IIM and if these changes can aid in the assessment of disease activity. Metabolic profiles of sera (N=99) and muscle (N=21) from patients with IIM(ACR-EULAR criteria) were comparedwith healthy control (HC) samples (N=75 for serum and N=12 for muscle tissues) employing 800MHz NMR (Nuclear Magnetic Resonance) spectroscopy. Metabolic disparity between IIM and HC was established based on Partial Least Squares Discriminant Analysis (PLS-DA) and the discriminatory metabolites were identified based on variable importance in projection (VIP) statistics(P-value<.05, corrected for false discovery rate (FDR)). Serum metabolomics profiles were distinctive in IIM as compared to HC, with a visible shift to anaerobic metabolism (increased lactate, low glucose), oxidative defect (high Phenylalanine/tyrosine), decreased muscle mass (low serum creatinine), increased muscle catabolism (increased branched-chain amino acids), and dyslipidemia (higher lipids, higher very low-density lipoprotein [VLDL]/low-density lipoprotein [LDL] ratio, lower polyunsaturated fatty acid [PUFA]). The sera of active IIM patients were characterized by anaerobic metabolism (low glucose), loss of muscle mass (low creatinine, amino acids), and oxidative defect (high Phenylalanine/tyrosine). Three metabolites (isopropanol, succinate, and glycine) were distinctive in muscle tissue metabolomics. NMR-based serum metabolic disparity was lacking between different clinical subsets of IIM. Serumand muscle tissue metabolomics have the potential to distinguish (a) IIM from HC and (b) active IIM from inactive IIM irrespective of disease subtype.

Musculoskeletal Ultrasound in Inclusion Body Myositis: A Comparative Study with Magnetic Resonance Imaging

The objective of this study was to compare the accuracy of ultrasound (US) with that of magnetic resonance imaging (MRI) in identifying muscle abnormalities in patients with inclusion body myositis (IBM). Twelve patients with IBM underwent muscle US and MRI on the same day. Twelve muscle groups were analyzed per patient. On US, a visual grading system was used to detect whether the muscles were affected. On MRI, muscle atrophy, fat infiltration and edema patterns were analyzed. The inter- and intra-reader reproducibility was similar for US and MRI in the evaluation of muscle abnormalities. All patients with muscle abnormalities identified on US presented with fat infiltration on MRI, which was the most common abnormality identified on MRI. Most importantly, the accuracy of US compared with that of MRI for the detection of muscle abnormalities in patients with IBM was 86.8 (κ coefficient = 0.632), with a sensitivity of 84% and specificity of 100%. In conclusion all patients with muscle abnormalities identified on US presented with fat infiltration on MRI, and the marked increase in echo intensity observed in the muscles of IBM patients was related mostly to fatty replacement. Most importantly, US exhibited significant accuracy compared with MRI.

Abnormal Calcium Handling in Duchenne Muscular Dystrophy: Mechanisms and Potential Therapies.

Duchenne muscular dystrophy (DMD) is an X-linked muscle-wasting disease caused by the loss of dystrophin. DMD is associated with muscle degeneration, necrosis, inflammation, fatty replacement, and fibrosis, resulting in muscle weakness, respiratory and cardiac failure, and premature death. There is no curative treatment. Investigations on disease-causing mechanisms offer an opportunity to identify new therapeutic targets to treat DMD. An abnormal elevation of the intracellular calcium () concentration in the dystrophin-deficient muscle is a major secondary event, which contributes to disease progression in DMD. Emerging studies have suggested that targeting Ca2+-handling proteins and/or mechanisms could be a promising therapeutic strategy for DMD. Here, we provide an updated overview of the mechanistic roles the sarcolemma, sarcoplasmic/endoplasmic reticulum, and mitochondria play in the abnormal and sustained elevation of levels and their involvement in DMD pathogenesis. We also discuss current approaches aimed at restoring Ca2+ homeostasis as potential therapies for DMD.

Therapeutic management of immune-mediated necrotizing myositis.

The idiopathic inflammatory myopathies are a heterogeneous group of autoimmune disorders characterized by skeletal muscle inflammation leading to chronic muscle weakness. Immune-mediated necrotizing myopathy (IMNM) is a distinct subgroup of inflammatory myopathy typically characterized by myofiber necrosis with minimal inflammatory infiltrates on muscle biopsy, highly elevated creatine kinase levels, and infrequent extra-muscular involvement. This review provides an overview of currently recommended treatment strategies for IMNM, including discussion of disease activity monitoring and recommended first-line immunomodulatory agents depending on clinical phenotype and autoantibody status. IMNM can be divided into three subtypes based on autoantibody positivity: anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) IMNM, anti-signal recognition particle (SRP) IMNM, and antibody negative IMNM. Autoantibody status in IMNM has considerable correlation with clinical phenotype, prognosis, and recommended choice of immunosuppressive agent. Patients with anti-HMGCR IMNM tend to respond well to intravenous immunoglobulin (IVIG), and IVIG monotherapy may be sufficient treatment for certain patients. In anti-SRP IMNM, early rituximab is commonly favored. More generally, prompt initiation of aggressive immunosuppression is often indicated, as both anti-SRP and anti-HMGCR IMNM can potentially cause debilitating weakness, and muscle atrophy and irreversible fatty replacement happen early in the disease course. Patients with IMNM frequently require combination therapy to achieve disease control, and have a high rate of relapse when tapering immunosuppression. Young age of onset is a poor prognostic factor. IMNM can be severely disabling and often requires aggressive immunosuppression. For any given patient, the treatment strategy should be informed by the severity of their presenting features and autoantibody status. While our ability to treat IMNM has certainly improved, there remains a need for more prospective trials to inform optimal treatment strategies.

Modic Change: An Emerging Complication in the Aging Population.

This was a literature review. The objective of this study was to review the pathogenesis, prevalence, clinical associations, diagnostic modalities, and treatment options for patients with lower back pain (LBP) associated with Modic change (MC). Vertebral body endplates are located between the intervertebral disk and adjacent vertebral body. Despite their crucial roles in nutrition and biomechanical stability, vertebral endplates are extremely susceptible to mechanical failure. Studies examining the events leading to disk degeneration have shown that failure often begins at the endplates. Endplate degeneration with subchondral bone marrow changes were originally noticed on magnetic resonance imaging. These magnetic resonance imaging signal changes were classified as MC. A literature review was conducted on the history, etiology, risk factors, diagnostic modalities, and treatment of LBP with MC. Type 1 MC refers to the presence of increased vascularization and bone marrow edema within the vertebral body. Type 2 MC involves fatty marrow replacement within the vertebral body. Type 3 MC reflects subchondral bone sclerosis. Despite the original classification, research has supported the notion that MCs possess a transitional nature. Furthermore, type 1 MCs have been strongly associated with inflammation and severe LBP, while types 2 and 3 tend to be more stable and demonstrate less refractory pain. With a strong association to LBP, understanding the etiology of MC is crucial to optimal treatment planning. Various etiologic theories have been proposed including autoimmunity, mechanics, infection, and genetic factors. With the aging nature of the population, MC has emerged as an extremely prevalent issue. Research into the pathogenesis of MC is important for planning preventative and therapeutic strategies. Such strategies may include rehabilitation, surgical fixation, stabilization, steroid or cement injection, or antibiotics. Improved diagnostic methods in clinical practice are thus critical to properly identify patients suffering from MC, plan early intervention, and hasten return to functioning.

Correlation Between Respiratory Accessory Muscles and Diaphragm Pillars MRI and Pulmonary Function Test in Late-Onset Pompe Disease Patients.

Objectives: Pompe disease is a rare genetic disease produced by mutations in the GAA gene leading to progressive skeletal and respiratory muscle weakness. T1-weighted magnetic resonance imaging is useful to identify fatty replacement in skeletal muscles of late-onset Pompe disease (LOPD) patients. Previous studies have shown that replacement by fat correlates with worse results of muscle function tests. Our aim was to investigate if fat replacement of muscles involved in the ventilation process correlated with results of the spirometry and predicted respiratory muscle impairment in LOPD patients over time.Materials and Methods: We studied a cohort of 36 LOPD patients followed up annually in our center for a period of 4 years. We quantified muscle fat replacement using Mercuri score of the thoracic paraspinal and abdominal muscles and the pillars of the diaphragm. We correlated the combined Mercuri scores of these areas with spirometry results and the need of respiratory support.Results: We found a statistically significant correlation (Spearman test, p < 0.05; coefficient of correlation > 0.6) between forced vital capacity seated and lying and fat fraction score of all muscle groups studied. The group of patients who needed respiratory support had higher fat fraction scores than patients not requiring ventilatory support. Higher fat replacement in these areas correlated with worse progression in spirometry values over time.Conclusions: Fat replacement of paraspinal, abdominal, and trunk muscles correlates with results of spirometry and is able to predict worsening in respiratory muscle function tests that could lead to an emerging ventilatory dysfunction. Therefore, the identification of fat replacement in these muscle groups should lead to a closer monitorization of patients. Radiologic evaluation of diaphragm pillars in T1-weighted imaging axial sequences could also be helpful to predict respiratory insufficiency.

Distinct MR features in scleroderma associated myopathy.

To compare the MRI features in patients with fibrosing [FM] versus non-fibrosing [NFM] systemic sclerosis [SSc]-associated myopathy. 10 patients with FM and 14 with NFM underwent bilateral thigh MRI [T1-weighted, STIR and DW/ADC mapping]. Three observers, blinded to histology evaluated 36 muscles per patient for presence of intramuscular edema, fascial edema, fatty replacement and atrophy and measured ADC values. Fisher's exact test and student's t-test were used to compare MRI findings of FM [endomysial/ perimysial fibrosis] and NFM [necrosis/inflammation] on histology. Intramuscular edema [p < 0.0001] and fascial edema [p = 0.07] were more common in FM. On DWI, elevated intramuscular signal was more common in FM, [low b-value: p < 0.0001 and high b-value: p < 0.0001]. On T1, NFM exhibited more fatty replacement [p = < 0.0001] and atrophy [p = < 0.0001]. Intramuscular and fascial edema on MRI are more common in SSc-associated FM, while markers of chronic muscle damage are more often associated with NFM.

The value of qualitative muscle MRI in the diagnostic procedures of myopathies: a biopsy-controlled study in 191 patients.

Background and aims:The role of muscle magnetic resonance imaging (MRI) in the diagnostic procedures of myopathies is still controversially discussed. The current study was designed to analyze the status of qualitative muscle MRI, electromyography (EMG), and muscle biopsy in different cases of clinically suspected myopathy.Methods:A total of 191 patients (male: n = 112, female: n = 79) with suspected myopathy who all received muscle MRI, EMG, and muscle biopsy for diagnostic reasons were studied, with the same location of biopsy and muscle MRI (either upper or lower extremities or paravertebral muscles). Muscle MRIs were analyzed using standard rating protocols by two different raters independently.Results:Diagnostic findings according to biopsy results and genetic testing were as follow: non-inflammatory myopathy: n = 65, inflammatory myopathy (myositis): n = 51, neurogenic: n = 18, unspecific: n = 23, and normal: n = 34. The majority of patients showed myopathic changes in the EMG. Edema, atrophy, muscle fatty replacement, and contrast medium enhancement (CM uptake) in MRI were observed across all final diagnostic groups. Only 30% of patients from the myositis group (n = 15) showed CM uptake.Discussion and conclusion:The study provides guidance in the definition of the impact of muscle MRI in suspected myopathy: despite being an important diagnostic tool, qualitative MRI findings could not distinguish different types of neuromuscular diagnostic groups in comparison with the gold standard histopathologic diagnosis and/or genetic testing. The results suggest that neither muscle edema nor gadolinium enhancement are able to secure a diagnosis of myositis. The current results do not support qualitative MRI as aiding in the diagnostic distinction of various myopathies. Quantitative muscle MRI is, however, useful in the diagnostic procedure of a suspected neuromuscular disease, especially with regard to assessing progression of a chronic myopathy by quantification of the degree of atrophy and fatty replacement and in exploring patterns of muscle group involvements in certain genetic myopathies.

Solid pseudopapillary neoplasm in the pancreatic head with fat replacement of the pancreas

Fat replacement of the pancreas is rare. Obstruction of the main pancreatic duct by a tumor in the head of the pancreas may cause fatty degeneration of the pancreatic parenchyma. We describe the case of a pancreatic solid pseudopapillary neoplasm, associated with fat replacement of the remaining pancreas. A 44-year-old woman presented with epigastric discomfort since one week and was admitted to our hospital. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed a 4cm sized tumor in the head of the pancreas with calcification and fatty replacement of the parenchyma in the body and tail.

Pancreatic steatosis: a giant step forward or recognition of ignorance

This review analyzes the terminology of pancreatic steatosis, the data about the prevalence of non-alcoholic fatty pancreas disease (NAFPD) were given.&#x0D; The etiological factors of NAFPD are usually subdivided into hereditary, metabolic, and toxic ones. The main etiopathogenetic factor of pancreatic fatty infiltration is obesity: it causes pancreatic infiltration by adipocytes, leading to the development of NAFPD. The pathogenesis of the disease is associated with adipocytic tissue dysfunction, which induces local and systemic inflammatory response with corresponding clinical consequences. Insulin resistance and oxidative stress play major role in the pathogenesis of NAFPD. From a histological point of view, NAFPD is a heterogeneous process, characterized by excessive intracellular accumulation of lipids and fatty infiltration followed by fatty replacement of the pancreas.&#x0D; NAFPD clinical picture is asymptomatic and nonspecific. Diagnosis of NAFPD is based primarily on the results of imaging methods (ultrasound, CT, MRI). A consequence of NAFPD is exocrine pancreatic insufficiency requiring enzyme replacement therapy. One of the NAFPD complications is the development of pancreatic adenocarcinoma.&#x0D; Currently, standards for the diagnosis, treatment and management of patients with NAFPD have not been developed yet, but on used the guidelines for the treatment of non-alcoholic fatty liver disease (rational diet, exercises, weight loss). The “gold standard” of enzyme replacement therapy, such as Creon®, is used for correction of exocrine pancreatic insufficiency. The detailed analysis of the clinical case of total pancreatic steatosis with severe exocrine pancreatic insufficiency was done in this article.

Intensive Teenage Activity Is Associated With Greater Muscle Hyperintensity on T1W Magnetic Resonance Imaging in Adults With Dysferlinopathy.

Practice of sports during childhood or adolescence correlates with an earlier onset and more rapidly progressing phenotype in dysferlinopathies. To determine if this correlation relates to greater muscle pathology that persists into adulthood, we investigated the effect of exercise on the degree of muscle fatty replacement measured using muscle MRI. We reviewed pelvic, thigh and leg T1W MRI scans from 160 patients with genetically confirmed dysferlinopathy from the Jain Foundation International clinical outcomes study in dysferlinopathy. Two independent assessors used the Lamminen-Mercuri visual scale to score degree of fat replacement in each muscle. Exercise intensity for each individual was defined as no activity, minimal, moderate, or intensive activity by using metabolic equivalents and patient reported frequency of sports undertaken between the ages of 10 and 18. We used ANCOVA and linear modeling to compare the mean Lamminen-Mercuri score for the pelvis, thigh, and leg between exercise groups, controlling for age at assessment and symptom duration. Intensive exercisers showed greater fatty replacement in the muscles of the pelvis than moderate exercisers, but no significant differences of the thigh or leg. Within the pelvis, Psoas was the muscle most strongly associated with this exercise effect. In patients with a short symptom duration of <15 years there was a trend toward greater fatty replacement in the muscles of the thigh. These findings define key muscles involved in the exercise-phenotype effect that has previously been observed only clinically in dysferlinopathy and support recommendations that pre-symptomatic patients should avoid very intensive exercise.

Petri Net modelling approach for analysing the behaviour of Wnt/[inline-formula removed]-catenin and Wnt/Ca2+ signalling pathways in arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease that may result in arrhythmia, heart failure and sudden death. The hallmark pathological findings are progressive myocyte loss and fibro fatty replacement, with a predilection for the right ventricle. This study focuses on the adipose tissue formation in cardiomyocyte by considering the signal transduction pathways including Wnt/[inline-formula removed]-catenin and Wnt/Ca2+ regulation system. These pathways are modelled and analysed using stochastic petri nets (SPN) in order to increase our comprehension of ARVC and in turn its treatment regimen. The Wnt/[inline-formula removed]-catenin model predicts that the dysregulation or absence of Wnt signalling, inhibition of dishevelled and elevation of glycogen synthase kinase 3 along with casein kinase I are key cytotoxic events resulting in apoptosis. Moreover, the Wnt/Ca2+ SPN model demonstrates that the Bcl2 gene inhibited by c-Jun N-terminal kinase protein in the event of endoplasmic reticulum stress due to action potential and increased amount of intracellular Ca2+ which recovers the Ca2+ homeostasis by phospholipase C, this event positively regulates the Bcl2 to suppress the mitochondrial apoptosis which causes ARVC.

Advanced imaging for quantification of abnormalities in the salivary glands of patients with primary Sjögren's syndrome.

ObjectivesTo assess non-invasive imaging for detection and quantification of gland structure, inflammation and function in patients with primary Sjogren's syndrome (pSS) using PET-CT with 11C-Methionine (11C-MET; radiolabelled amino acid), and 18F-fluorodeoxyglucose (18F-FDG; glucose uptake marker), to assess protein synthesis and inflammation, respectively; multiparametric MRI evaluated salivary gland structural and physiological changes.MethodsIn this imaging/clinical/histology comparative study (GSK study 203818; NCT02899377) patients with pSS and age- and sex-matched healthy volunteers underwent MRI of the salivary glands and 11C-MET PET-CT. Patients also underwent 18F-FDG PET-CT and labial salivary gland biopsies. Clinical and biomarker assessments were performed. Primary endpoints were semi-quantitative parameters of 11C-MET and 18F-FDG uptake in submandibular and parotid salivary glands and quantitative MRI measures of structure and inflammation. Clinical and minor salivary gland histological parameter correlations were explored.ResultsTwelve patients with pSS and 13 healthy volunteers were included. Lower 11C-MET uptake in parotid, submandibular and lacrimal glands, lower submandibular gland volume, higher MRI fat fraction, and lower pure diffusion in parotid and submandibular glands were observed in patients vs healthy volunteer, consistent with reduced synthetic function. Disease duration correlated positively with fat fraction and negatively with 11C-MET and 18F-FDG uptake, consistent with impaired function, inflammation and fatty replacement over time. Lacrimal gland 11C-MET uptake positively correlated with tear flow in patients, and parotid gland 18F-FDG uptake positively correlated with salivary gland CD20+ B-cell infiltration.ConclusionMolecular imaging and MRI may be useful tools to non-invasively assess loss of glandular function, increased glandular inflammation and fat accumulation in pSS.