Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

O ensino de história da enfermagem nos cursos de graduação de Santa Catarina Nursing history education on graduation courses in Santa Catarina

Partindo da idéia de que o ensino da história da enfermagem é fundamental para a formação dos alunos do curso de graduação e de que a forma como se ministra o seu conteúdo proporciona ou não a aderência a este conhecimento, esta pesquisa pretende estabelecer uma rede de contatos com todas as escolas de enfermagem de Santa Catarina para traçar um diagnóstico do ensino de história da enfermagem. Este poderá subsidiar a criação de uma política para nortear a reformulação curricular da disciplina, face às necessidades do Estado. A metodologia é qualitativa e a coleta de dados inicial identificou, a partir de 15 escolas de enfermagem do Estado, o modus operandi do desenvolvimento da disciplina ao longo do curso. Uma análise inicial indica que as estratégias educacionais e curriculares são variadas, havendo interfaces entre elas. Percebe-se um avanço relativo à carga horária e às estratégias de ensino-aprendizagem, porém a inserção do conteúdo em questão ainda carece de reflexão coletiva sobre a sua importância no currículo dos cursos.<br>Concerning to the idea that the nursing history education is fundamental to the development of students of graduation course and that the way this instruction is given determines if its content provides or not the adherence to this information, this research aims to establish a network with all Nursing Schools of Santa Catarina to determine a education diagnosis of nursing history education. This may be a subsidy for a policy creation to guide the curricular reformulation of this subject, in view of the State needs. The methodology is qualitative and the initial data collection identified, from 15 nursing schools of the State, the modus operandi of the subject development along the course. An initial analysis indicates that the educational and curricular strategies are varied, and there are interfaces between them. We note an advance related to the grade hours and to learning-education strategies, however the insertion of said content still needs a collective reflection about its importance on the courses curriculum

Next-generation sequencing for the diagnosis of MYH9-RD: Predicting pathogenic variants

The heterogeneous manifestations of MYH9-related disorder (MYH9-RD), characterized by macrothrombocytopenia, Döhle-like inclusion bodies in leukocytes, bleeding of variable severity with, in some cases, ear, eye, kidney, and liver involvement, make the diagnosis for these patients still challenging in clinical practice. We collected phenotypic data and analyzed the genetic variants in more than 3,000 patients with a bleeding or platelet disorder. Patients were enrolled in the BRIDGE-BPD and ThromboGenomics Projects and their samples processed by high throughput sequencing (HTS). We identified 50 patients with a rare variant in MYH9. All patients had macrothrombocytes and all except two had thrombocytopenia. Some degree of bleeding diathesis was reported in 41 of the 50 patients. Eleven patients presented hearing impairment, three renal failure and two elevated liver enzymes. Among the 28 rare variants identified in MYH9, 12 were novel. HTS was instrumental in diagnosing 23 patients (46%). Our results confirm the clinical heterogeneity of MYH9-RD and show that, in the presence of an unclassified platelet disorder with macrothrombocytes, MYH9-RD should always be considered. A HTS-based strategy is a reliable method to reach a conclusive diagnosis of MYH9-RD in clinical practice.status: publishe

Next-generation sequencing for the diagnosis of MYH9-RD: Predicting pathogenic variants.

The heterogeneous manifestations of MYH9-related disorder (MYH9-RD), characterized by macrothrombocytopenia, Döhle-like inclusion bodies in leukocytes, bleeding of variable severity with, in some cases, ear, eye, kidney, and liver involvement, make the diagnosis for these patients still challenging in clinical practice. We collected phenotypic data and analyzed the genetic variants in more than 3,000 patients with a bleeding or platelet disorder. Patients were enrolled in the BRIDGE-BPD and ThromboGenomics Projects and their samples processed by high throughput sequencing (HTS). We identified 50 patients with a rare variant in MYH9. All patients had macrothrombocytes and all except two had thrombocytopenia. Some degree of bleeding diathesis was reported in 41 of the 50 patients. Eleven patients presented hearing impairment, three renal failure and two elevated liver enzymes. Among the 28 rare variants identified in MYH9, 12 were novel. HTS was instrumental in diagnosing 23 patients (46%). Our results confirm the clinical heterogeneity of MYH9-RD and show that, in the presence of an unclassified platelet disorder with macrothrombocytes, MYH9-RD should always be considered. A HTS-based strategy is a reliable method to reach a conclusive diagnosis of MYH9-RD in clinical practice.National Institute for Health Research. Grant Numbers: RBAG/181, RG65966 NIHR BioResource ‐ Rare Diseases British Heart Foundation. Grant Numbers: RBAG/245, 208, 226 European Commission. Grant Number: RBAG/344 MRC. Grant Numbers: RBAG/285, 295 NHS Blood and Transplant. Grant Number: RBAG/142 Wellcome Trust. Grant Number: RBAG/342 MIUR‐FIRB Telethon Foundation Grant Fondazione Umberto Veronesi NIHR Imperial College Biomedical Research Centre FIS‐Fondos FEDER NIH

Overview of JET results

High density and high confinement operation in ELMy H-mode is confirmed at or above the normalized parameters foreseen for the ITER operating point (H98(y,2) 3c 1, n/nGW 3c 1, \u3b2N > 1.8 at q95 3c 3). The scaling of the ELMy H-mode with \u3b2N could be more favourable than that predicted by the IPB98(y,2) scaling. In ELMy H-mode, ion cyclotron current drive (ICCD) control of large sawteeth stabilized by fast particle has been demonstrated and the underlying neo-classical tearing modes (NTMs) and sawtooth physics is being refined. At high-density, Type I ELMy H-modes show trends that would lead to marginally acceptable ELMs on ITER. Type II ELM regime has been produced, though under very restrictive conditions. Type III ELMy operation with radiation fractions up to 95% has been demonstrated by seeding of N2 in H-modes and could extrapolate to Q = 10 ITER operation, albeit at high current (17 MA). The mitigation of Type I ELMs, nevertheless, remains a challenge. Considerable progress has been obtained in internal transport barrier (ITB) plasmas, with operation at central densities close to the Greenwald density or/and low toroidal rotation or/and high triangularity. Demonstrations of full current drive and successful simultaneous real time control of safety factor and temperature profiles have been achieved in ITB plasmas. Physics of resistive wall modes (RWMs) has been compared with theory, showing favourable scaling for ITER. High \u3b2N 3c 2.8 operation of hybrid modes (also called improved H-modes) has been obtained with dominant neutral beam heating. Hybrid modes with dominant ion cyclotron resonance heating (ICRH) have also been achieved. Trace tritium experiments yielded valuable information on particle transport in H-mode, ITB and hybrid regimes. In Type I ELMy plasmas, successful tests of the conjugate-T ICRH scheme have been achieved as well as lower hybrid coupling at ITER-relevant 10\u201311 cm distances. Reduced D and T fuel retention has been observed, which could relate to operation with vertical targets in the divertor and/or lower (ITER-like) vessel temperature. It is confirmed that erosion occurs predominantly on the main chamber surfaces, with possible benefits for T retention in ITER, although consequences for the metallic first wall lifetime need to be assessed. Disruption and ELM studies indicate that transient power deposition could be less constraining than expected for the ITER divertor, but more challenging for the metallic first wall. Alpha particle tomography and direct observation of alpha particle slowing down have been made possible by \u3b3 -spectroscopy. Measurements of Alfve \u301n cascades have been improved by a new interferometric technique. Promising tests of ITER relevant neutron counting detectors have been conducted

Overview of JET results

Since the last IAEA conference, the scientific programme of JET has focused on the qualification of the integrated operating scenarios for ITER and on physics issues essential for the consolidation of design choices and the efficient exploitation of ITER. Particular attention has been given to the characterization of the edge plasma, pedestal energy and edge localized modes (ELMs), and their impact on plasma facing components (PFCs). Various ELM mitigation techniques have been assessed for all ITER operating scenarios using active methods such as resonant magnetic field perturbation, rapid variation of the radial field and pellet pacing. In particular, the amplitude and frequency of type I ELMs have been actively controlled over a wide parameter range (q95 = 3-4.8, βN ≥ 3.0) by adjusting the amplitude of the n = 1 external perturbation field induced by error field correction coils. The study of disruption induced heat loads on PFCs has taken advantage of a new wide-angle viewing infrared system and a fast bolometer to provide a detailed account of time, localization and form of the energy deposition. Specific ITER-relevant studies have used the unique JET capability of varying the toroidal field (TF) ripple from its normal low value δBT = 0.08% up to δBT = 1% to study the effect of TF ripple on high confinement-mode plasmas. The results suggest that δBT < 0.5% is required on ITER to maintain adequate confinement to allow QDT = 10 at full field. Physics issues of direct relevance to ITER include heat and toroidal momentum transport, with experiments using power modulation to decouple power input and torque to achieve first experimental evidence of inward momentum pinch in JET and determine the threshold for ion temperature gradient driven modes. Within the longer term JET programme in support of ITER, activities aiming at the modification of the JET first wall and divertor and the upgrade of the neutral beam and plasma control systems are being conducted. The procurement of all components will be completed by 2009 with the shutdown for the installation of the beryllium wall and tungsten divertor extending from summer 2009 to summer 2010