Automated MRI quantification of volumetric per-muscle fat fractions in the proximal leg of patients with muscular dystrophies

Muscular dystrophies (MD) are a class of rare genetic diseases resulting in progressive muscle weakness affecting specific muscle groups, depending on the type of disease. Disease progression is characterized by the gradual replacement of muscle tissue by fat, which can be assessed with fat-sensitive magnetic resonance imaging (MRI) and objectively evaluated by quantifying the fat fraction percentage (FF%) per muscle. Volumetric quantification of fat replacement over the full 3D extent of each muscle is more precise and potentially more sensitive than 2D quantification in few selected slices only, but it requires an accurate 3D segmentation of each muscle individually, which is time consuming when this has to be performed manually for a large number of muscles. A reliable, largely automated approach for 3D muscle segmentation is thus needed to facilitate the adoption of fat fraction quantification as a measure of MD disease progression in clinical routine practice, but this is challenging due to the variable appearance of the images and the ambiguity in the discrimination of the contours of adjacent muscles, especially when the normal image contrast is affected and diminished by the fat replacement. To deal with these challenges, we used deep learning to train AI-models to segment the muscles in the proximal leg from knee to hip in Dixon MRI images of healthy subjects as well as patients with MD. We demonstrate state-of-the-art segmentation results of all 18 muscles individually in terms of overlap (Dice score, DSC) with the manual ground truth delineation for images of cases with low fat infiltration (mean overall FF%: 11.3%; mean DSC: 95.3% per image, 84.4–97.3% per muscle) as well as with medium and high fat infiltration (mean overall FF%: 44.3%; mean DSC: 89.0% per image, 70.8–94.5% per muscle). In addition, we demonstrate that the segmentation performance is largely invariant to the field of view of the MRI scan, is generalizable to patients with different types of MD and that the manual delineation effort to create the training set can be drastically reduced without significant loss of segmentation quality by delineating only a subset of the slices

Enterocolitis: an adverse event in refractory epilepsy patients treated with levetiracetam?

AbstractIntroduction: Levetiracetam (LEV) is a recently marketed novel anti-epileptic drug with a promising efficacy and safety profile. In this report we describe two patients who presented with enterocolitis and discuss the possible relationship with concurrent LEV intake.Patients: In two patients, LEV was initiated to control refractory complex partial seizures (CPS). The first patient was treated with 1500mg/day and complained of abdominal pain and weight loss 6 months later. Internal examination and colonoscopy revealed a punctate colitis. The second patient presented with bloody stool 1 month after LEV initiation. Colonoscopy showed punctate colitis. In both patients gastrointestinal symptoms disappeared following tapering of LEV.Discussion: There are no reports in the literature describing colitis related to LEV intake. Three possible mechanisms of action are discussed. Colitis may be part of a hypersensitivity syndrome caused by LEV. Pharmacodynamic interactions with other anti-epileptic drugs, for example, carbamazepine may play a role. A haematological adverse event is another possibility since piracetam, a related molecule, has a known impact on erythrocytes and platelets.Conclusion: The close temporal relationship between initiation of LEV intake, symptomatic colitis and clinical improvement following LEV tapering, suggests that colitis may be a possible and previously undescribed adverse effect of LEV

Національні інтереси держави в інформаційній сфері

На сьогодні Україна перебуває в умовах протиборства, в яких саме забезпечення інформаційної безпеки грає ключовий аспект в формуванні національних інтересів держави. В даній роботі розглянуто сучасний стан інформаційної сфери як пріоритетний напрямок національних інтересів України

Impact of Monetary Uncertainty and Economic Uncertainty on Money Demand in Africa

This dissertation investigates the role that economic uncertainties and monetary uncertainties play in the money demand function for 21 African countries. The Auto-regressive Distributive Lag (ARDL) and F-test approach are employed using quarterly time series data covering the period from 1971I-2012IV. In particular, this paper aims to demonstrate both short and long-run relationships between the dependent variables, Real Money Aggregate (M2), and the independent variables that include real income (Y), inflation rate nominal effective exchange rate (NEX), output uncertainty (VY), and monetary uncertainty (VM). We apply GARCH methodology to approximate the uncertainty measures. The empirical results show that except for Egypt, monetary VM and VY have significant short-run as well as long-run effects on money demand in all the countries, with some variables carrying negative or positive coefficient. We find that the coefficients of Y in all the countries is positive while that of and NEX are negative, implying depreciation of domestic currency decreases demand for money. The results also indicate that CUSUM and CUSUMSQ test are stable, thus M2 is stable in all the countries except Egyp

Impact of sensory differences on consumer acceptability of yoghurt and yoghurt-like products

8 pages, 5 tables, 6 figures.-- Available online 7 October 2010.The aim of this work was to obtain information about how perceptible sensory differences affect consumer acceptability for yoghurt and a yoghurt-like product. Descriptive sensory profiles of six commercial samples, three of plain yoghurt and three of plain fermented milk, were determined using a trained panel (n = 10). Sample acceptance was determined by a group of consumers (n = 120). Initially, two groups of consumers were identified using Cluster analyses. For one group 46 (38%) of the consumers, variability in sensory attributes did not affect sample acceptability. For the second group, of 74 (62%) of the consumers, variability in sensory attributes had a significant effect and three consumer subgroups with different preference criteria were detected. Partial least squares regression was used to determine the sensory factors driving liking/disliking for each consumer subgroup. The information obtained can be important in predicting or explaining the market response to these types of products.MICINN of Spain for financial support (Project AGL 2007-63444) and Fondo Social Europeo for financing the contract of author S. Bayarri in the program I3P from CSIC.Peer reviewe

Unusual multisystemic involvement and a novel BAG3 mutation revealed by NGS screening in a large cohort of myofibrillar myopathies

Myofibrillar myopathies (MFM) are a group of phenotypically and genetically heterogeneous neuromuscular disorders, which are characterized by protein aggregations in muscle fibres and can be associated with multisystemic involvement.Methods We screened a large cohort of 38 index patients with MFM for mutations in the nine thus far known causative genes using Sanger and next generation sequencing (NGS). We studied the clinical and histopathological characteristics in 38 index patients and five additional relatives (n = 43) and particularly focused on the associated multisystemic symptoms.Results We identified 14 heterozygous mutations (diagnostic yield of 37%), among them the novel p.Pro209Gln mutation in the BAG3 gene, which was associated with onset in adulthood, a mild phenotype and an axonal sensorimotor polyneuropathy, in the absence of giant axons at the nerve biopsy. We revealed several novel clinical phenotypes and unusual multisystemic presentations with previously described mutations: hearing impairment with a FLNC mutation, dysphonia with a mutation in DES and the first patient with a FLNC mutation presenting respiratory insufficiency as the initial symptom. Moreover, we described for the first time respiratory insufficiency occurring in a patient with the p.Gly154Ser mutation in CRYAB. Interestingly, we detected a polyneuropathy in 28% of the MFM patients, including a BAG3 and a MYOT case, and hearing impairment in 13%, including one patient with a FLNC mutation and two with mutations in the DES gene. In four index patients with a mutation in one of the MFM genes, typical histological findings were only identified at the ultrastructural level (29%).Conclusions We conclude that extraskeletal symptoms frequently occur in MFM, particularly cardiac and respiratory involvement, polyneuropathy and/or deafness. BAG3 mutations should be considered even in cases with a mild phenotype or an adult onset. We identified a genetic defect in one of the known genes in less than half of the MFM patients, indicating that more causative genes are still to be found. Next generation sequencing techniques should be helpful in achieving this aim

Expanding the importance of HMERF titinopathy : new mutations and clinical aspects

ObjectiveHereditary myopathy with early respiratory failure (HMERF) is caused by titin A-band mutations in exon 344 and considered quite rare. Respiratory insufficiency is an early symptom. A collection of families and patients with muscle disease suggestive of HMERF was clinically and genetically studied.MethodsAltogether 12 new families with 19 affected patients and diverse nationalities were studied. Most of the patients were investigated using targeted next-generation sequencing; Sanger sequencing was applied in some of the patients and available family members. Histological data and muscle MRI findings were evaluated.ResultsThree families had several family members studied while the rest were single patients. Most patients had distal and proximal muscle weakness together with respiratory insufficiency. Five heterozygous TTN A-band mutations were identified of which two were novel. Also with the novel mutations the muscle pathology and imaging findings were compatible with the previous reports of HMERF.ConclusionsOur collection of 12 new families expands mutational spectrum with two new mutations identified. HMERF is not that rare and can be found worldwide, but maybe underdiagnosed. Diagnostic process seems to be complex as this study shows with mostly single patients without clear dominant family history.Peer reviewe

NEB mutations disrupt the super-relaxed state of myosin and remodel the muscle metabolic proteome in nemaline myopathy

Nemaline myopathy (NM) is one of the most common non-dystrophic genetic muscle disorders. NM is often associated with mutations in the NEB gene. Even though the exact NEB-NM pathophysiological mechanisms remain unclear, histological analyses of patients' muscle biopsies often reveal unexplained accumulation of glycogen and abnormally shaped mitochondria. Hence, the aim of the present study was to define the exact molecular and cellular cascade of events that would lead to potential changes in muscle energetics in NEB-NM. For that, we applied a wide range of biophysical and cell biology assays on skeletal muscle fibres from NM patients as well as untargeted proteomics analyses on isolated myofibres from a muscle-specific nebulin-deficient mouse model. Unexpectedly, we found that the myosin stabilizing conformational state, known as super-relaxed state, was significantly impaired, inducing an increase in the energy (ATP) consumption of resting muscle fibres from NEB-NM patients when compared with controls or with other forms of genetic/rare, acquired NM. This destabilization of the myosin super-relaxed state had dynamic consequences as we observed a remodeling of the metabolic proteome in muscle fibres from nebulin-deficient mice. Altogether, our findings explain some of the hitherto obscure hallmarks of NM, including the appearance of abnormal energy proteins and suggest potential beneficial effects of drugs targeting myosin activity/conformations for NEB-NM.Peer reviewe

PLEKHG5 deficiency leads to an intermediate form of autosomal-recessive Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease (CMT) comprises a clinically and genetically heterogeneous group of peripheral neuropathies characterized by progressive distal muscle weakness and atrophy, foot deformities and distal sensory loss. Following the analysis of two consanguineous families affected by a medium to late-onset recessive form of intermediate CMT, we identified overlapping regions of homozygosity on chromosome 1p36 with a combined maximum LOD score of 5.4. Molecular investigation of the genes from this region allowed identification of two homozygous mutations in PLEKHG5 that produce premature stop codons and are predicted to result in functional null alleles. Analysis of Plekhg5 in the mouse revealed that this gene is expressed in neurons and glial cells of the peripheral nervous system, and that knockout mice display reduced nerve conduction velocities that are comparable with those of affected individuals from both families. Interestingly, a homozygous PLEKHG5 missense mutation was previously reported in a recessive form of severe childhood onset lower motor neuron disease (LMND) leading to loss of the ability to walk and need for respiratory assistance. Together, these observations indicate that different mutations in PLEKHG5 lead to clinically diverse outcomes (intermediate CMT or LMND) affecting the function of neurons and glial cell

SIL1 mutations and clinical spectrum in patients with Marinesco-Sjögren syndrome

Marinesco-Sjögren syndrome is a rare autosomal recessive multisystem disorder featuring cerebellar ataxia, early-onset cataracts, chronic myopathy, variable intellectual disability and delayed motor development. More recently, mutations in the SIL1 gene, which encodes an endoplasmic reticulum resident co-chaperone, were identified as the main cause of Marinesco-Sjögren syndrome. Here we describe the results of SIL1 mutation analysis in 62 patients presenting with early-onset ataxia, cataracts and myopathy or combinations of at least two of these. We obtained a mutation detection rate of 60% (15/25) among patients with the characteristic Marinesco-Sjögren syndrome triad (ataxia, cataracts, myopathy) whereas the detection rate in the group of patients with more variable phenotypic presentation was below 3% (1/37). We report 16 unrelated families with a total of 19 different SIL1 mutations. Among these mutations are 15 previously unreported changes, including single- and multi-exon deletions. Based on data from our screening cohort and data compiled from the literature we found that SIL1 mutations are invariably associated with the combination of a cerebellar syndrome and chronic myopathy. Cataracts were observed in all patients beyond the age of 7 years, but might be missing in infants. Six patients with SIL1 mutations had no intellectual disability, extending the known wide range of cognitive capabilities in Marinesco-Sjögren syndrome to include normal intelligence. Modestly constant features were somatic growth retardation, skeletal abnormalities and pyramidal tract signs. Examination of mutant SIL1 expression in cultured patient lymphoblasts suggested that SIL1 mutations result in severely reduced SIL1 protein levels irrespective of the type and position of mutations. Our data broaden the SIL1 mutation spectrum and confirm that SIL1 is the major Marinesco-Sjögren syndrome gene. SIL1 patients usually present with the characteristic triad but cataracts might be missing in young children. As cognitive impairment is not obligatory, patients without intellectual disability but a Marinesco-Sjögren syndrome-compatible phenotype should receive SIL1 mutation analysis. Despite allelic heterogeneity and many families with private mutations, the phenotype related to SIL1 mutations is relatively homogenous. Based on SIL1 expression studies we speculate that this may arise from a uniform effect of different mutations on protein expressio