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.

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.

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.

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.

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.

Nurses are the key to improving mental health services in low- and middle-income countries.

Mental health nursing is a critical issue for most countries. Nurses in low- and middle-income countries are often the primary providers of care for people with mental disorders. Some are highly qualified professionals who train other providers to identify and treat mental disorders. However, in other instances, particularly in low-income countries, nurses have had very little or no mental health training and receive no support from mental health professionals. The lack of sufficient mental health professionals in these countries creates an environment where nurses without training are often the only providers available to care for people with mental disorders. In September 2007 the World Health Organization and the International Council of Nurses produced a report summarizing the responses to some of the questions on a survey of nursing mental health practices in 177 countries and territories. The summary of the open-ended questions (e.g. what are the key issues for nurses providing mental health care in your country?) is reported for the first time in this article. Subsequent to the release of the Nurses in Mental Health Atlas, an online forum was held. There were 615 subscribers to this forum from over 80 countries. This article summarizes the rich insights and recommendations from both the survey's open-ended comments and the online forum. The issues discussed include: the varied and complex roles for nurses in mental health care; nursing education; prescribing practices; nurse recruitment and retention; human rights; research; and technical expertise.

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.

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.

Exercises reduce the progression rate of adolescent idiopathic scoliosis: results of a comprehensive systematic review of the literature.

BACKGROUND: A previously published systematic review (Ped.Rehab.2003 - DARE 2004) documented the existence of the evidence of level 2a (Oxford EBM Centre) on the efficacy of specific exercises to reduce the progression of AIS (Adolescent Idiopathic Scoliosis). AIM: To confirm whether the indication for treatment with specific exercises for AIS has changed in recent years. STUDY DESIGN: Systematic review. METHODS: A bibliographic search with strict inclusion criteria (patients treated exclusively with exercises, outcome Cobb degrees, all study designs) was performed on the main electronic databases and through extensive manual searching. We retrieved 19 studies, including one RCT and eight controlled studies; 12 studies were prospective. A methodological and clinical evaluation was performed. RESULTS: The 19 papers considered included 1654 treated patients and 688 controls. The highest-quality study (RCT) compared two groups of 40 patients, showing an improvement of curvature in all treated patients after six months. We found three papers on Scoliosis Intensive Rehabilitation (Schroth), five on extrinsic autocorrection-based methods (Schroth, side-shift), four on intrinsic autocorrection-based approaches (Lyon and SEAS) and five with no autocorrection (three asymmetric, two symmetric exercises). Apart from one (no autocorrection, symmetric exercises, very low methodological quality), 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. CONCLUSION: In five years, eight more papers have been published to the indexed literature coming from throughout the world (Asia, the US, Eastern Europe) and proving that interest in exercises is not exclusive to Western Europe. This systematic review confirms and strengthens the previous ones. The actual evidence on exercises for AIS is of level 1b.

Clinical and postural behaviour of scoliosis during daily brace weaning hours.

UNLABELLED: What happens to scoliosis when the brace is daily weaned is not described in the literature, even if this can have a significant clinical impact. Our aim was to evaluate the postural and clinical changes at brace weaning. We developed a pre-post trial in 10 adolescent idiopathic scoliosis female patients 12.6 years old, with 42.8+/-7.4 degrees Cobb curves. INCLUSION CRITERIA: more than 30 degrees Cobb; TLSO worn at least 20 hours/day. Patients have been divided according to the hours of brace wearing per day: group 23H (6 patients, 23 hours per day) and group 20H (20-21 hours per day). We evaluated the patients at brace weaning and every hour per 4 hours, clinically (Bunnell degrees, hump and plumbline distances through usual clinical instruments) and posturally (scoliosis degree), by means of a non-ionising instrument that allow a 3D reconstruction of the spine. Paired ANOVA and t-test were used for statistical analysis. Group 23H showed statistically significant variations in 1 to 3 hours in all clinical parameters, and a tendency to progression of scoliosis. Group 20H did not show any statistically significant variation in 4 hours, a part from slight improvements. These results could be explained in terms of scoliosis reactions to usual/unusual daily load on the spine. Moreover, these data show the possible existence of the "concertina effect" due to brace weaning, and the importance of standardizing clinical examination with respect to the daily brace weaning hours.

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).

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.

Novel Munc13-4 mutations in children and young adult patients with haemophagocytic lymphohistiocytosis.

Familial haemophagocytic lymphohistiocytosis (FHL) is a genetically heterogeneous disorder characterised by constitutive defects in cellular cytotoxicity resulting in fever, hepatosplenomegaly and cytopenia, and the outcome is fatal unless treated by chemoimmunotherapy followed by haematopoietic stem-cell transplantation. Since 1999, mutations in the perforin gene giving rise to this disease have been identified; however, these account only for 40% of cases. Lack of a genetic marker hampers the diagnosis, suitability for transplantation, selection of familial donors, identification of carriers, genetic counselling and prenatal diagnosis. Mutations in the Munc13-4 gene have recently been described in patients with FHL. We sequenced the Munc13-4 gene in all patients with haemophagocytic lymphohistiocytosis not due to PRF1 mutations. In 15 of the 30 families studied, 12 novel and 4 known Munc13-4 mutations were found, spread throughout the gene. Among novel mutations, 2650C-->T introduced a stop codon; 441del A, 532del C, 3082del C and 3226ins G caused a frameshift, and seven were mis sense mutations. Median age of diagnosis was 4 months, but six patients developed the disease after 5 years of age and one as a young adult of 18 years. Involvement of central nervous system was present in 9 of 15 patients, activity of natural killer cells was markedly reduced or absent in 13 of 13 tested patients. Chemo-immunotherapy was effective in all patients. Munc13-4 mutations were found in 15 of 30 patients with FHL without PRF1 mutations. Because these patients may develop the disease during adolescence or even later, haematologists should include FHL2 and FHL3 in the differential diagnosis of young adults with fever, cytopenia, splenomegaly and hypercytokinaemia.

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.

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.

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.

[Fabry nephropathy in a female with superposed IgA glomerulonephritis]. / Nefropatia da malattia di Fabry in donna eterozigote con sovraimposta glomerulonefrite da IgA.

BACKGROUND: In Anderson-Fabry disease (AFd), the kidney is affected in all hemizygous males and in some heterozygous females. Female carriers can present subtle renal abnormalities due to glycosphingolipid (GSL) accumulation within renal cells. Renal biopsy is rarely performed in female Fabry patients because clinical renal manifestations are usually lacking. However, female carriers can accumulate GSL in their renal cells despite the absence of clinically evident kidney disease. CASE REPORT: We performed a kidney biopsy in a 52-year-old female patient, a Fabry disease carrier. The patient showed normal glomerular filtration rate, persistent microhematuria and proteinuria (about 1.7 g/24 hr), cornea "verticillata", and evident left ventricular hypertrophy. The molecular study documented a missense mutation R227Q in exon 5 of the alpha-galactosidase A gene. Optical microscopy showed electron-dense mesangial deposits due IgA glomerulonephritis, as confirmed by immunofluorescence. We decided to start therapy with angiotensin-converting enzyme inhibitors (ACE-I). After 8 months of treatment, the patient demonstrated proteinuria of 0.9 g/24 hr. To decide when to start treatment using enzyme replacement therapy (ERT) with human recombinant GAL A (Fabrazyme), we decided to perform an electron microscopy study of the renal biopsy. The renal ultrastructural findings were typical GSL inclusions in all kinds of glomerular cells, in tubular epithelial cells and in endothelial cells of interstitial capillaries, confirming the hypothesis of Fabry nephropathy. Consequently, Fabrazyme was given at a standard dose of 1 mg/kg every 2 weeks. After 24 months of combined treatment (ACE-I-Fabrazyme), proteinuria decreased to 0.2 g/24 hr. CONCLUSIONS: The importance of performing the ultrastructural examination of the kidney biopsy is stressed, especially in heterozygous Fabry patients to evaluate the need to treat them with ERT and to evaluate the degree of renal involvement.

Post-fertilization changes in Discoglossus pictus (Anura) eggs result in the formation of a capsular chamber where the egg rotates.

Discoglossus pictus is one of the few anurans with an egg where a capsular chamber forms as a consequence of fertilization; the egg with its vitelline envelope rotates in this chamber according to gravity. We investigated the formation of the capsular chamber through various experimental cytochemical and ultrastructural approaches, and found that it is the product of plug liquefaction. The plug is a lens-shaped jelly coat typical of Discoglossus, and covering only part of the egg animal half. About 15 min after fertilization, granular material coming from the egg enters the plug, which gradually dissolves and, once liquefied, reorganizes itself around the entire egg, thus forming the chamber. This process goes through stages of rearrangement of the 25-A- and 250-A-thick filaments which constitute the plug matrix. The material entering the plug derives from the exocytosis of two vacuole types, with electron transparent and granular PAS-positive contents. Liquefaction of the plug correlates with the reduction of disulfide bonds present in its matrix. Furthermore, in vitro tests showed that the substances released from the egg are active in selectively dissolving only the plug, and lose activity upon boiling.