Autophagy induction in atrophic muscle cells requires ULK1 activation by TRIM32 through unanchored K63-linked polyubiquitin chains.

Optimal autophagic activity is crucial to maintain muscle integrity, with either reduced or excessive levels leading to specific myopathies. LGMD2H is a muscle dystrophy caused by mutations in the ubiquitin ligase TRIM32, whose function in muscles remains not fully understood. Here, we show that TRIM32 is required for the induction of muscle autophagy in atrophic conditions using both in vitro and in vivo mouse models. Trim32 inhibition results in a defective autophagy response to muscle atrophy, associated with increased ROS and MuRF1 levels. The proautophagic function of TRIM32 relies on its ability to bind the autophagy proteins AMBRA1 and ULK1 and stimulate ULK1 activity via unanchored K63-linked polyubiquitin. LGMD2H-causative mutations impair TRIM32's ability to bind ULK1 and induce autophagy. Collectively, our study revealed a role for TRIM32 in the regulation of muscle autophagy in response to atrophic stimuli, uncovering a previously unidentified mechanism by which ubiquitin ligases activate autophagy regulators.

Restless Legs Syndrome in NKX2-1-related chorea: An expansion of the disease spectrum.

BACKGROUND: Molecular technologies are expanding our knowledge about genetic variability underlying early-onset non-progressive choreic syndromes. Focusing on NKX2-1-related chorea, the clinical phenotype and sleep related disorders have been only partially characterized. METHODS: We propose a retrospective and longitudinal observational study in 7 patients with non-progressive chorea due to NKX2-1 mutations. In all subjects sleep and awake EEG, brain MRI with study of pituitary gland, chest X-rays, endocrinological investigations were performed. Movement disorders, pattern of sleep and related disorders were investigated using structured clinical evaluation and several validated questionnaires. RESULTS: In patients carrying NKX2-1 mutations, chorea was mainly distributed in the upper limbs and tended to improve with age. All patients presented clinical or subclinical hypothyroidism and delayed motor milestones. Three subjects had symptoms consistent with Restless Legs Syndrome (RLS) that improved with Levodopa. CONCLUSIONS: Patients with NKX2-1 gene mutations should be investigated for RLS, which, similarly to chorea, can sometimes be ameliorated by Levodopa.

Prematurity, ventricular septal defect and dysmorphisms are independent predictors of pathogenic copy number variants: a retrospective study on array-CGH results and phenotypical features of 293 children with neurodevelopmental disorders and/or multiple congenital anomalies.

BACKGROUND: Since 2010, array-CGH (aCGH) has been the first-tier test in the diagnostic approach of children with neurodevelopmental disorders (NDD) or multiple congenital anomalies (MCA) of unknown origin. Its broad application led to the detection of numerous variants of uncertain clinical significance (VOUS). How to appropriately interpret aCGH results represents a challenge for the clinician. METHOD: We present a retrospective study on 293 patients with age range 1 month - 29 years (median 7 years) with NDD and/or MCA and/or dysmorphisms, investigated through aCGH between 2005 and 2016. The aim of the study was to analyze clinical and molecular cytogenetic data in order to identify what elements could be useful to interpret unknown or poorly described aberrations. Comparison of phenotype and cytogenetic characteristics through univariate analysis and multivariate logistic regression was performed. RESULTS: Copy number variations (CNVs) with a frequency < 1% were detected in 225 patients of the total sample, while 68 patients presented only variants with higher frequency (heterozygous deletions or amplification) and were considered to have negative aCGH. Proved pathogenic CNVs were detected in 70 patients (20.6%). Delayed psychomotor development, intellectual disability, intrauterine growth retardation (IUGR), prematurity, congenital heart disease, cerebral malformations and dysmorphisms correlated to reported pathogenic CNVs. Prematurity, ventricular septal defect and dysmorphisms remained significant predictors of pathogenic CNVs in the multivariate logistic model whereas abnormal EEG and limb dysmorphisms were mainly detected in the group with likely pathogenic VOUS. A flow-chart regarding the care for patients with NDD and/or MCA and/or dysmorphisms and the interpretation of aCGH has been made on the basis of the data inferred from this study and literature. CONCLUSION: Our work contributes to make the investigative process of CNVs more informative and suggests possible directions in aCGH interpretation and phenotype correlation.

Corticosteroid treatment in Sydenham's chorea.

Sydenham's chorea (SC) is an immune-mediated hyperkinetic movement disorder, developing after group A Beta-hemolytic streptococcal (GABHS) infection. Aside from conventional symptomatic treatment (carbamazepine, valproate, neuroleptics), the use of steroids has also been advocated, mainly in severe, drug-resistant cases or if clinically disabling side effects develop with first line therapies. Based on the description of 5 cases followed in the Child Neurology Unit of Santa Maria Nuova Hospital in Reggio Emilia and on the available medical literature on this topic, we propose considering the use of corticosteroids therapy in children with SC, with the administration of IV methyl-prednisolone followed by oral deflazacort in severe cases and of oral deflazacort alone in mild and moderate degrees of involvement. In our experience this therapy is effective both in the short and long-term period, in different clinical presentations (chorea paralytica, distal chorea, hemichorea, "classic" chorea, association with mood disorder or dyspraxia) and very well tolerated (no significant side effects were recorded).

Neuroimaging Changes in Menkes Disease, Part 2.

This is the second part of a retrospective and review MR imaging study aiming to define the frequency rate, timing, imaging features, and evolution of gray matter changes in Menkes disease, a rare multisystem X-linked disorder of copper metabolism characterized by early, severe, and progressive neurologic involvement. According to our analysis, neurodegenerative changes and focal basal ganglia lesions already appear in the early phases of the disease. Subdural collections are less common than generally thought; however, their presence remains important because they might challenge the differential diagnosis with child abuse and might precipitate the clinical deterioration. Anecdotal findings in our large sample seem to provide interesting clues about the protean mechanisms of brain injury in this rare disease and further highlight the broad spectrum of MR imaging findings that might be expected while imaging a child with the suspicion of or a known diagnosis of Menkes disease.

A 15-year epileptogenic period after perinatal brain injury.

Seizures are a frequent acute neurological event in the neonatal period. Up to 12 to 18% of all seizures in newborns are due to perinatal stroke and up to 39% of affected children can then develop epilepsy in childhood. We report the case of a young patient who presented stroke-related seizures in the neonatal period and then developed focal symptomatic epilepsy at 15 years of age, and in whom the epileptic focus was found to co-localize with the site of his ischemic brain lesion. Such a prolonged silent period before onset of remote symptomatic epilepsy has not previously been reported. This case suggests that newborns with seizures due to a neonatal stroke are at higher risk of epilepsy and that the epileptogenic process in these subjects can last longer than a decade.

Synthesis, High-Resolution Infrared Spectroscopy, and Vibrational Structure of Cubane, C8H8.

Carbon-cage molecules have generated a considerable interest from both experimental and theoretical points of view. We recently performed a high-resolution study of adamantane (C10H16), the smallest hydrocarbon cage belonging to the diamandoid family ( Pirali , O. ; et al. J. Chem. Phys. 2012 , 136 , 024310 ). There exist another family of hydrocarbon cages with additional interesting chemical properties: the so-called platonic hydrocarbons that comprise dodecahedrane (C20H20) and cubane (C8H8). Both possess C-C bond angles that deviate from the tetrahedral angle (109.8°) of the sp(3) hybridized form of carbon. This generates a considerable strain in the molecule. We report a new wide-range high-resolution study of the infrared spectrum of cubane. The sample was synthesized in Bari upon decarboxylation of 1,4-cubanedicarboxylic acid thanks to the improved synthesis of literature. Several spectra have been recorded at the AILES beamline of the SOLEIL synchrotron facility. They cover the 600-3200 cm(-1) region. Besides the three infrared-active fundamentals (ν10, ν11, and ν12), we could record many combination bands, all of them displaying a well-resolved octahedral rotational structure. We present here a preliminary analysis of some of the recorded bands, performed thanks the SPVIEW and XTDS software, based on the tensorial formalism developed in the Dijon group. A comparison with ab initio calculations, allowing to identify some combination bands, is also presented.

Boson peak and Ioffe-Regel criterion in amorphous siliconlike materials: The effect of bond directionality.

The vibrational properties of model amorphous materials are studied by combining complete analysis of the vibration modes, dynamical structure factor, and energy diffusivity with exact diagonalization of the dynamical matrix and the kernel polynomial method, which allows a study of very large system sizes. Different materials are studied that differ only by the bending rigidity of the interactions in a Stillinger-Weber modelization used to describe amorphous silicon. The local bending rigidity can thus be used as a control parameter, to tune the sound velocity together with local bonds directionality. It is shown that for all the systems studied, the upper limit of the Boson peak corresponds to the Ioffe-Regel criterion for transverse waves, as well as to a minimum of the diffusivity. The Boson peak is followed by a diffusivity's increase supported by longitudinal phonons. The Ioffe-Regel criterion for transverse waves corresponds to a common characteristic mean-free path of 5-7 Å (which is slightly bigger for longitudinal phonons), while the fine structure of the vibrational density of states is shown to be sensitive to the local bending rigidity.

HLA-B*38:55Q: a new alternatively expressed allele identified in a three-generation Italian family.

The new allelic variant HLA-B*38:55Q differs from the closest related B*38:01:01 by one nucleotide substitution at position 373 in exon 3 (TGC>CGC). This results in a difference of one amino acid at residue 101 of the HLA-B heavy chain, from a neutral-polar Cys to a basic-polar Arg, thus impairing disulphide bridge formation in the alpha-2 domain. This alteration of the secondary structure probably affects the maturation of the heavy chain and the level of surface expression, making the HLA-B*38:55Q undetectable by standard serological typing.

Rheological properties vs. local dynamics in model disordered materials at low temperature.

We study the rheological response at low temperature of a sheared model disordered material as a function of the bond rigidity. We find that the flow curves follow a Herschel-Bulkley law, whatever is the bond rigidity, with an exponent close to 0.5. Interestingly, the apparent viscosity can be related to a single relevant time scale t rel, suggesting a strong connection between the local dynamics and the global mechanical behaviour. We propose a model based on the competition between the nucleation and the avalanche-like propagation of spatial strain heterogeneities. This model can explain the Herschel-Bulkley exponent on the basis of the size dependence of the heterogeneities on the shear rate.

The molecular causes of thyroid dysgenesis: a systematic review.

BACKGROUND: Congenital hypothyroidism (CH) is a frequent disease occurring with an incidence of about 1/2500 newborns/year. In 80-85% of the cases CH is caused by alterations in thyroid morphogenesis, generally indicated by the term "thyroid dysgenesis" (TD). TD is generally a sporadic disease, but in about 5% of the cases a genetic origin has been demonstrated. In these cases, mutations in genes playing a role during thyroid morphogenesis (NKX2-1, PAX8, FOXE1, NKX2-5, TSHR) have been reported. AIM: This work reviews the main steps of thyroid morphogenesis and all the genetic alterations associated with TD and published in the literature.

A 1.3-mb 7q11.23 atypical deletion identified in a cohort of patients with williams-beuren syndrome.

Williams-Beuren syndrome is a rare multisystem neurodevelopmental disorder caused by a 1.55-1.84-Mb hemizygous deletion on chromosome 7q11.23. The classical phenotype consists of characteristic facial features, supravalvular aortic stenosis, intellectual disability, overfriendliness, and visuospatial impairment. So far, 26-28 genes have been shown to contribute to the multisystem phenotype associated with Williams-Beuren syndrome. Among them, haploinsufficiency of the ELN gene has been shown to cause the cardiovascular anomalies. Identification of patients with atypical deletions has provided valuable information for genotype-phenotype correlation, in which other genes such as LIMK1,CLIP2, GTF2IRD1, or GTF2I have been correlated with specific cognitive profiles or craniofacial features. Here, we report the clinical and molecular characteristics of a patient with an atypical deletion that does not include the GTF2I gene and only partially includes the GTF2IRD1 gene.

Report of the First Clinical Case of a Moroccan Kabuki Patient with a Novel MLL2 Mutation.

Kabuki syndrome (also known as Niikawa-Kuroki syndrome) is a rare autosomal disorder, characterized by an unusual face, short stature, skeletal, visceral and dermatoglyphic abnormalities, cardiac anomalies, mental retardation, and immunological defects. Point mutations and large intragenic deletions and duplications of the mixed lineage leukemia 2 (MLL2) and exons deletions of lysine demethylase 6A (-KDM6A) genes have been identified as its underlying causes. We report on the first description of a Moroccan Kabuki syndrome patient with typical facial features, developmental delay, finger pads, and other anomalies carrying a novel splice site mutation in the MLL2 gene that produces a truncated and likely pathogenetic form of MLL2 protein.

Long-time damage under creep experiments in disordered materials: transition from exponential to logarithmic fracture dynamics.

Some materials, and in particular some polymer materials, can display an important range of stress levels for which slow and progressive damage can be observed before they finally break. In creep or fatigue experiments, final rupture can happen after very long times, during which the mechanical properties have progressively decayed. We model here some generic features of the long-time damage evolution of disordered elastic materials under constant load, characterized by a progressive decrease of the elastic modulus. We do it by studying a two-dimensional electric random fuse network with quenched disorder and thermal noise. The time evolution of global quantities (conductivity or, equivalently, elastic modulus) is characterized by different regimes ranging from faster than exponential to slower than logarithmic, which are governed by the stress level and the relative magnitude of disorder with respect to temperature. A region of widely distributed rupture times exists where the modulus decays (more slowly than) logarithmically for not too small values of the disorder and for not too large values of the load. A detailed analysis of the dynamical regimes is performed and presented through a phase diagram.

Communication about psychotic symptoms in long-term psychiatric illness.

BACKGROUND: Communicating about psychotic symptoms can be challenging. This study aimed to identify (1) how psychiatrists and patients communicate about psychotic symptoms from a research and clinical perspective and (2) whether communication patterns depend on patients' symptom levels. SAMPLING AND METHODS: Consultations between 27 psychiatrists and 100 patients with long-term schizophrenia/schizoaffective disorder in outpatient clinics were video-recorded, transcribed and coded. Symptoms were assessed on the Positive and Negative Syndrome Scale. Avoidance or engagement with psychotic symptoms was coded separately by researchers and three clinical psychiatrists. RESULTS: Psychotic symptoms were not mentioned in 27% of consultations. Patients reported their absence in 34% of consultations and avoided talking about symptoms in 6%. Researchers rated psychiatrists as engaged in talking about psychotic symptoms in 15% of consultations and avoiding talking about them in 18% of consultations. Psychiatrists identified somewhat less avoidance (10%) and more engagement (23%). Psychiatrist avoidance was seen when the patient raised the topic and the psychiatrist gave brief responses and/or changed the topic. When psychiatrists engaged, they asked specific questions about symptoms, responded to patient concerns and provided explanations about symptoms. Psychotic symptoms were more often discussed with patients with more negative and general symptoms. CONCLUSIONS: There is considerable variation in whether psychotic symptoms are discussed or not in outpatient consultations. Whether psychiatrists discuss psychotic symptoms is influenced by patients' symptoms; however, not by their psychotic symptoms but rather by the presence of negative and general symptoms. Psychiatrists' ratings of communication identify broadly similar patterns as detailed research analyses.

Physical exercises in the treatment of adolescent idiopathic scoliosis: an updated systematic review.

Two years ago we published an update of another of our previous systematic reviews about the effectiveness of physical exercises (PEs), and we found that the evidence on exercises for AIS was of level 1b. Now we have updated these results in the field of exercises for AIS with the final aim to find the strongest evidence as possible about PEs. Our goal was to verify if treatment with specific exercises for AIS has changed in these years. The study design was a systematic review. A bibliographic search with strict inclusion criteria (patients treated exclusively with exercises, outcome Cobb degrees, all study designs) has been performed on the main electronic databases. We found a new paper about active autocorrection (Negrini et al, 2008 b), a prospective controlled cohort observational study on patients never treated before so the number of manuscripts considered in the systematic review was 20. The highest quality study (RCT) compared 2 groups of 40 patients, showing an improvement of the curve in all treated patients after 6 months. All studies confirmed the efficacy of exercises in reducing the progression rate (mainly in early puberty) and/or improving the Cobb angles (around the end of growth). Exercises were also shown to be effective in reducing brace prescription. Appendices of the popular exercise protocols that have been used in the research studies that are examined are included with detailed description and illustrations. This study (like the previously published systematic reviews) showed that PEs can improve the Cobb angles of individuals with AIS and can improve strength, mobility, and balance. The level of evidence remains 1b according to the Oxford Centre for Evidence-based Medicine, as previously documented.

7th SOSORT consensus paper: conservative treatment of idiopathic & Scheuermann's kyphosis.

UNLABELLED: : Thoracic hyperkyphosis is a frequent problem and can impact greatly on patient's quality of life during adolescence. This condition can be idiopathic or secondary to Scheuermann disease, a disease disturbing vertebral growth. To date, there is no sound scientific data available on the management of this condition. Some studies discuss the effects of bracing, however no guidelines, protocols or indication's of treatment for this condition were found. The aim of this paper was to develop and verify the consensus on managing thoracic hyperkyphosis patients treated with braces and/or physiotherapy. METHODS: The Delphi process was utilised in four steps gradually modified according to the results of a set of recommendations: we involved the SOSORT Board twice, then all SOSORT members twice, with a Pre-Meeting Questionnaire (PMQ), and during a Consensus Session at the SOSORT Lyon Meeting with a Meeting Questionnaire (MQ). RESULTS: There was an unanimous agreement on the general efficacy of bracing and physiotherapy for this condition. Most experts suggested the use of 4-5 point bracing systems, however there was some controversy with regards to physiotherapeutic aims and modalities. CONCLUSION: The SOSORT panel of experts suggest the use of rigid braces and physiotherapy to correct thoracic hyperkyphosis during adolescence. The evaluation of specific braces and physiotherapy techniques has been recommended.