Mirtazapine in the treatment of essential tremor: an open-label, observer-blind study

Essential tremor (ET) is the most common movement disorder in the adult population. At present ET treatment shows limited efficacy, particularly in patients with severe and disabling symptoms. This study evaluates the clinical efficacy of mirtazapine in an untreated ET patient population

Declaración de la Asociación de Estadı́stica Americana Sobre la Significancia Estadı́stica y Los Valores-P

Fil: Laco Mazzone, Fiorella. Universidad Nacional de Río Negro. Instituto de Investigaciones en Recursos Naturales, Agroecología y Desarrollo Rural; Argentina.Fil: Laco Mazzone, Fiorella. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Recursos Naturales, Agroecología y Desarrollo Rural; Argentina.Fil: Grampa, Maria. Universidad Nacional de Río Negro. Instituto de Investigaciones en Recursos Naturales, Agroecología y Desarrollo Rural; Argentina.Fil: Grampa, Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Recursos Naturales, Agroecología y Desarrollo Rural; Argentina.Fil: Goldenberg, Matı́as. Universidad Nacional de Río Negro. Instituto de Investigaciones en Recursos Naturales, Agroecología y Desarrollo Rural; Argentina.Fil: Goldenberg, Matı́as. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Recursos Naturales, Agroecología y Desarrollo Rural; Argentina.Fil: Aristimuño, Francisco. Universidad Nacional de Río Negro. Instituto de Investigaciones en Recursos Naturales, Agroecología y Desarrollo Rural; Argentina.Fil: Aristimuño, Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Recursos Naturales, Agroecología y Desarrollo Rural; Argentina.Fil: Oddi, Facundo. Universidad Nacional de Río Negro. Instituto de Investigaciones en Recursos Naturales, Agroecología y Desarrollo Rural; Argentina.Fil: Oddi, Facundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Recursos Naturales, Agroecología y Desarrollo Rural; Argentina.Fil: Garibaldi, Lucas Alejandro. Universidad Nacional de Río Negro. Instituto de Investigaciones en Recursos Naturales, Agroecología y Desarrollo Rural; Argentina.Fil: Garibaldi, Lucas Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Recursos Naturales, Agroecología y Desarrollo Rural; Argentina.El aumento del número de investigaciones cientı́ficas y la proliferación de largos y complejos conjuntos de datos en los años recientes han expandido el alcance en las aplicaciones de métodos estadı́sticos. Esto ha creado nuevos caminos para el progreso cientı́fico, pero también trae aparejadas preocupaciones acerca de algunas conclusiones obtenidas a partir de datos de investigación. La validez de las conclusiones cientı́ficas, incluyendo su reproducibilidad, no dependen únicamente de los métodos estadı́sticos utilizados. La elección de las técnicas apropiadas, la conducción de los análisis de forma adecuada y la correcta interpretaci ón de los resultados estadı́sticos también juegan un papel importante en garantizar que las conclusiones obtenidas sean confiables y que la incertidumbre asociada a ellas esté representada apropiadamente. Detrás de muchas conclusiones de publicaciones cientı́ficas subyace el concepto de “significancia estadı́stica,” tı́picamente evaluada con el ı́ndice llamado valor- p. Si bien el valor- p puede ser una medida estadı́stica útil, generalmente es utilizado e interpretado incorrectamente. Esto ha llevado a que algunas revistas cientı́ficas desalienten el uso de los valores- p, y a que algunos cientı́ficos y estadı́sticos recomienden su abandono, con ciertos argumentos que prácticamente no han cambiado desde que los valores- p fueron introducidos por primera vez. En este contexto, la Asociación de Estadı́stica Americana (ASA por sus siglas en Inglés) cree que la comunidad cientı́fica podrı́a beneficiarse de una declaración formal que clarifique varios principios ampliamente aceptados subyacentes al adecuado uso e interpretación de los valores- p. Los temas tratados brevemente aquı́ afectan no sólo a la investigación, sino también al financiamiento de la misma, a las prácticas de escritura cientı́fica, al progreso profesional, a la educación cientı́fica, a las polı́ticas públicas, al periodismo y a la ley. Esta declaraci ón no busca resolver todos los problemas relacionados con la práctica estadı́stica sensata, ni tampoco las controversias fundamentales; sino que, articula en términos no técnicos algunos principios que pueden mejorar la conducta o interpretación de la ciencia cuantitativa, de acuerdo con el consenso extendido en la comunidad cientı́fica

COVID-19-associated Guillain-Barré syndrome in the early pandemic experience in Lombardia (Italy)

Objective To estimate the incidence and describe clinical characteristics and outcome of GBS in COVID-19 patients (COVID19-GBS) in one of the most hit regions during the frst pandemic wave, Lombardia. Methods Adult patients admitted to 20 Neurological Units between 1/3–30/4/2020 with COVID19-GBS were included as part of a multi-center study organized by the Italian society of Hospital Neuroscience (SNO). Results Thirty-eight COVID19-GBS patients had a mean age of 60.7 years and male frequency of 86.8%. CSF albuminocytological dissociation was detected in 71.4%, and PCR for SARS-CoV-2 was negative in 19 tested patients. Based on neurophysiology, 81.8% of patients had a diagnosis of AIDP, 12.1% of AMSAN, and 6.1% of AMAN. The course was favorable in 76.3% of patients, stable in 10.5%, while 13.2% worsened, of which 3 died. The estimated occurrence rate in Lombardia ranges from 0.5 to 0.05 GBS cases per 1000 COVID-19 infections depending on whether you consider positive cases or estimated seropositive cases. When we compared GBS cases with the pre-pandemic period, we found a reduction of cases from 165 to 135 cases in the 2-month study period in Lombardia. Conclusions We detected an increased incidence of GBS in COVID-19 patients which can refect a higher risk of GBS in COVID-19 patients and a reduction of GBS events during the pandemic period possibly due to a lower spread of more common respiratory infectious diseases determined by an increased use of preventive measures

Clinical pregenetic screening for stroke monogenic diseases: Results from lombardia GENS registry

BACKGROUND AND PURPOSE: Lombardia GENS is a multicentre prospective study aimed at diagnosing 5 single-gene disorders associated with stroke (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, Fabry disease, MELAS [mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes], hereditary cerebral amyloid angiopathy, and Marfan syndrome) by applying diagnostic algorithms specific for each clinically suspected disease METHODS: We enrolled a consecutive series of patients with ischemic or hemorrhagic stroke or transient ischemic attack admitted in stroke units in the Lombardia region participating in the project. Patients were defined as probable when presenting with stroke or transient ischemic attack of unknown etiopathogenic causes, or in the presence of <3 conventional vascular risk factors or young age at onset, or positive familial history or of specific clinical features. Patients fulfilling diagnostic algorithms specific for each monogenic disease (suspected) were referred for genetic analysis. RESULTS: In 209 patients (57.4\ub114.7 years), the application of the disease-specific algorithm identified 227 patients with possible monogenic disease. Genetic testing identified pathogenic mutations in 7% of these cases. Familial history of stroke was the only significant specific feature that distinguished mutated patients from nonmutated ones. The presence of cerebrovascular risk factors did not exclude a genetic disease. CONCLUSIONS: In patients prescreened using a clinical algorithm for monogenic disorders, we identified monogenic causes of events in 7% of patients in comparison to the 1% to 5% prevalence reported in previous series

The role of clinical and neuroimaging features in the diagnosis of CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common familial cerebral small vessel disease, caused by NOTCH3 gene mutations. The aim of our study was to identify clinical and neuroradiological features which would be useful in identifying which patients presenting with lacunar stroke and TIA are likely to have CADASIL. METHODS: Patients with lacunar stroke or TIA were included in the present study. For each patient, demographic and clinical data were collected. MRI images were centrally analysed for the presence of lacunar infarcts, microbleeds, temporal lobe involvement, global atrophy and white matter hyperintensities. RESULTS: 128 patients (mean age 56.3 ± 12.4 years) were included. A NOTCH3 mutation was found in 12.5% of them. A family history of stroke, the presence of dementia and external capsule lesions on MRI were the only features significantly associated with the diagnosis of CADASIL. Although thalamic, temporal pole gliosis and severe white matter hyperintensities were less specific for CADASIL diagnosis, the combination of a number of these factors together with familial history for stroke result in a higher positive predictive value and specificity. CONCLUSIONS: A careful familial history collection and neuroradiological assessment can identify patients in whom NOTCH3 genetic testing has a higher yield.The Lombardia GENS project has received funding from the Regione Lombardia Government as a Research Independent Project (DGR n°VIII/006128-12/12/2007). Lombardia GENS is an investigator-driven, academic, non-profit consortium and is publicly funded. Hugh Markus is supported by an NIHR Senior Investigator award and his work is supported by the Cambridge University Hospitals NIHR Biomedical Research Centr

Caractérisation des mécanismes physiopathologiques associés aux mutations NEK8 / NPHP9 identifiées chez des patients atteints de ciliopathies rénales sévères

Les ciliopathies sont un groupe de maladies génétiques multi-systémiques liées à un dysfonctionnement du cil primaire, une structure sensorielle présente à la surface des cellules qui régule des voies de signalisation clés au cours du développement et de l'homéostasie tissulaire. Afin d'identifier de nouveaux gènes responsables de ciliopathies développementales sévères, ~ 500 patients / fétus ont été analysés par une approche de séquençage à haut débit de l'exome ciblant > 1 200 gènes ciliaires ("ciliome"). Nous avons identifié huit nouvelles mutations dans le gène NEK8/NPHP9 chez cinq familles dont les syndromes se chevauchent. NEK8/NPHP9 code une protéine kinase de la famille des NIMA qui se localise au niveau du compartiment Inversine du cil primaire et agit comme un régulateur de la signalisation Hippo, une voie essentielle contrôlant la taille des organes. Nous montrons pour la première fois que les mutations du gène NEK8 sont associées à une agénésie rénale et une hypodysplasie. De plus, notre travail met en évidence une corrélation génotype/phénotype: les mutations "perte de fonction" de NEK8 conduisant à reins élargies et kystiques, des kystes pancréatiques et hépatique, alors que les mutations faux-sens de NEK8 causent une hypodysplasie/agénésie rénale associée à une cardiopathie et une paucité des canaux biliaires. La première partie de mon projet de thèse porte sur l'étude de l'impact des mutations faux-sens de NEK8 sur divers processus cellulaires et des voies de signalisation dépendantes de NEK8. Nous avons démontré un effet "gain de fonction" des mutations faux-sens de NEK8 puisqu'elles affectent la ciliogenèse et la composition du compartiment Inversine (localisation ciliaire de ANKS6). De plus, ces mutations altèrent la localisation nucléaire de YAP, le principal acteur de la voie Hippo, ainsi que l'expression des gènes cibles de YAP dans les fibroblastes de patients et dans la lignée cellulaire rénale (mIMCD3) invalidée pour NEK8. De même, nous avons montré une accumulation anormale de YAP nucléaire dans les reins polykystiques de la souris Jck, porteuse d'une mutation faux-sens de Nek8. Un déséquilibre de la voie Hippo serait donc à l'origine des défauts de morphogenèses épithéliales. En effet, les cellules mIMCD3 invalidées pour NEK8 forment en culture 3D des structures anormales et/ou des sphères élargies qui s'accompagnent d'une persistance du marquage nucléaire de YAP et Ki-67 et forment de grandes sphères par rapport aux cellules contrôles. Des défauts plus sévères ont été observés pour les cellules ré-exprimant les différents mutants de NEK8, confirmant la pathogénicité de ces mutations et leur effet "gain de fonction". Enfin, le traitement par la Vertéporfine, un inhibiteur spécifique de l'activité transcriptionnelle de YAP, améliore non seulement le phénotype des fibroblastes de patients et des cellules rénales invalidées pour NEK8 en culture 3D, mais également in vivo les anomalies observées chez les embryons de poisson zèbre dues à la surexpression de la forme NEK8 humaine, confirmant ainsi l'implication d'une dérégulation de YAP dans les mécanismes physiopathologiques. Par ailleurs, nous avons observé que les mutants de NEK8 s'accumulent de manière anormale au niveau de l'appareil de Golgi dans les fibroblastes de patients, et que cet appareil de Golgi apparait dispersé. Nos résultats montrent que le recrutement de NEK8 au Golgi est sensible à la Brefeldine A et dépendrait donc de ARF1, une petite GTPase impliquée dans le trafic de protéines entre les compartiments du Golgi et du réticulum endoplasmique. Nous avons démontré que NEK8 interagit et co-localise préférentiellement avec la forme d'ARF1 liée au GDP, suggérant pour NEK8 une possible fonction de facteur d'échange d'ARF1 à des sites spécifiques (appareil de Golgi, membranes, cil) afin de promouvoir le trafic vésiculaire de protéines telles que les protéine ciliaires. (...)Ciliopathies are a group of genetic multi-systemic disorders related to dysfunction of the primary cilium, a sensory organelle present at the cell surface that regulates key signaling pathways during development and tissue homeostasis. In order to identify novel genes whose mutations would cause severe developmental ciliopathies, ~500 patients/fetuses were analyzed by a targeted high throughput sequencing approach allowing exome sequencing of > 1200 ciliary genes. We have identified eight novel mutations in NEK8/NPHP9 in five independent families with severe overlapping syndromic disorders. NEK8/NPHP9 encodes a NIMA-related kinase that localizes at the inversin compartment of the primary cilium and acts as a regulator of Hippo signaling, a pathway that is essential for control of organ size during development. We show for the first time that NEK8 mutations are associated with renal agenesis and hypodysplasia, and our work highlights a genotype/phenotype correlation with NEK8 loss-of-function mutations leading to enlarged cystic kidney, pancreas and liver, whereas NEK8 gain-of-function (missense) mutations cause renal hypodysplasia, cardiopathy and paucity of bile ducts. The first part of my thesis project focuses on the study of the impact of these NEK8 missense mutations on various cellular processes and NEK8-dependent signaling pathways. We demonstrate that NEK8 missense mutations impair the Inversin (INVS) compartment composition and ciliogenesis, and also alter the nuclear localization of the main Hippo signalling effector, YAP, as well as expression of its target genes in patient fibroblasts and renal cell lines. We also demonstrated that this Hippo pathway imbalance causes epithelial morphogenesis defects in 3D matrigel culture. Indeed, mIMCD3 cells depleted for NEK8 showed persistent YAP and Ki-67 staining and formed bigger spheres compared to control cells. Abnormal sphere volume was also observed in cells re-expressing NEK8-GFP mutations, suggesting their pathogenicity. We confirm these data in vivo in Jck mice, a model of polycystic kidney disease bearing a Nek8 missense mutation. Finally, treatment with Verteporfin, a specific inhibitor of YAP transcriptional activity, improves the mutant phenotype of both cellular models and zebrafish embryos overexpressing human NEK8, further supporting the involvement of YAP dysregulation in the pathogenic cellular mechanisms. Surprisingly, in patient fibroblasts, we showed that mutated NEK8 accumulates at the Golgi that appeared dispersed. NEK8 recruitment at the Golgi apparatus is dependent on ARF1 (Brefeldin A sensitive), a small GTPase involved in protein trafficking between Golgi compartments and ER. We notably demonstrated that NEK8 mostly interacts and localizes with the dominant negative form of ARF1 (T31N), suggesting that NEK8 could act as an activator (GEF) of ARF1 to promote vesicular trafficking of ciliary proteins. The second part of my project focuses on a new candidate gene for which a missense homozygous mutation has been identified in 3 individuals presenting a late onset NPH with hepatic fibrosis. This gene encodes ANKS3, an evolutionarily conserved protein whose function is still poorly characterized. Interestingly, ANKS3 has been reported to be a partner of NEK8, even though we showed it does not localize at the INVS compartment with NEK8 but is rather present at the base of cilia in fibroblasts. We showed that the missense mutation does not affect ANKS3 localization but leads to longer cilia and abnormal accumulation of NEK8 at the cilium base in patient fibroblasts and kidney tubules. Altogether, my work focused on NEK8 and its partners, ANKS6 and ANKS3, each of whose related gene is mutated in patients presenting a broad clinical spectrum of phenotypes. (...

Zetética e dogmática, um diálogo (im)possível?: uma crítica antropológica ao decisionismo jurídico ocidental

O problema central desta pesquisa se sintetiza em “é possível o diálogo entre Direito e Antropologia enquanto ciências modernas?” e, caso seja, “quais os aportes possíveis nesse diálogo e possíveis obstáculos epistemológicos?”. São veiculadas duas hipóteses, uma na qual “não é possível o diálogo, tendo em vista duas espécies distintas de enfoques: o zetético e o dogmático”; como segunda hipótese tem-se que “é possível o diálogo entre essas áreas, com algumas relativizações, numa divisão não tão categórica entre esses enfoques (zetético/dogmático)”, garantida uma terceira hipótese geral que seria um meio termo entre as outras duas. O objetivo geral da pesquisa é: “analisar aproximações e distanciamentos entre a Antropologia e o Direito, enquanto ciências, e eventuais aportes”, sendo objetivos específicos: “verificar a implicação desses aportes sobre as áreas” e “analisar criticamente a inter-relação dessas áreas do saber e razões pelas quais ocorrem em maior ou menor grau, se forem possíveis”. Utilizou-se o método científico em pesquisa de revisão bibliográfica crítica. O referencial teórico utilizado foi, em síntese: Tércio Sampaio Ferraz Júnior, Orlando Villas Bôas Filho (em sua leitura de Niklas Luhmann e sobre Antropologia Jurídica) e Pierre Clastres. O problema de pesquisa está situado em uma região problemática de alta relevância em face das dificuldades do pluralismo cultural e jurídico: “a dificuldade de interlocução do direito com a pluralidade cultural, em especial com os aportes pluralistas da Antropologia, muitas vezes ignorados na decidibilidade jurídica”. Essa situação leva ao problema de pesquisa, posto que é necessário verificar se é possível esse diálogo ou não e suas implicações. Num primeiro capítulo procurou-se estruturar a “constituição científica dessas áreas, com a discussão entre zetética e dogmática”, com apoio na obra de Ferraz Júnior e Luhmann; num segundo capítulo fez-se alguns recortes históricos entre o Direito e a Antropologia do século XIX ao século XXI”, com base na obra de Eric J. Hobsbawm e Villas Bôas Filho, e finalmente procurou-se verificar “alguns aportes possíveis para o direito a partir da constituição do campo da Antropologia Social e Jurídica, com os impactos sobre o poder político ocidental e as estruturas pluralistas, como os estados plurinacionais”, com apoio na obra de Pierre Clastres e de teóricos indigenistas. Concluiu-se que “sim, é possível uma aproximação entre direito e antropologia” e que os óbices epistemológicos, ainda que existentes, derivam de uma estruturação da sociedade moderna, sobretudo da conceituação do poder político enquanto comando-obediência e as finalidades dessa racionalidade, e não de algum obstáculo epistemológico apriorístico.This paper seeks to find out whether "the dialogue between the sciences of Law and Anthropology is possible", and if so, "what are the possible contributions from such dialogue and its potential epistemological obstacles?” Three hypotheses are presented from this: 1) "the dialogue is not possible considering two different views, i.e., zetetic and dogmatic"; 2) "as long as some relativization is considered, the dialogue between those two fields is possible in a less categorical division between both zetetic and dogmatic views"; and 3) a middle ground between the two first ones. The main objective of this research is to "analyze distances and proximities between the sciences of Anthropology and Law and their possible contributions." The specific objectives are to "verify the implication of such contributions on the aforementioned fields," and to "critically analyze how such fields of knowledge interrelate as well as the reasons why they occur to a greater or lesser extent, if possible." This research used the critical literature review as the scientific method for analysis. In summary, the theoretical reference is Tércio Sampaio Ferraz Júnior, Orlando Villas Bôas Filho (in his reading of Niklas Luhmann and Legal Anthropology), and Pierre Clastres. The research problem lies in a challenging area that is highly relevant due to the difficulties found in cultural and legal pluralism: "the difficulty of communication between Law and cultural pluralism, especially with the pluralist contributions of Anthropology, which are often not taken into account in the legal decision-making. This situation leads to the research problem, since it is necessary to find out whether such dialogue is possible or not and what are its implications. In one of the chapters, we seek to structure the "scientific constitution of these fields through the discussion between zetetic and dogmatic theories," supported by Ferraz Júnior and Luhmann’s work. In the next chapter, we delimited some historical periods between both Law and Anthropology from the 19th to 21st century," based on Eric J. Hobsbawm and Villas Bôas Filho's work. Then we sought to verify "some possible contributions to Law through the constitution of Social and Legal Anthropology, considering the impacts on Western political power and the pluralist structures, such as the plurinational states," based on the work of Pierre Clastres and indigenist theorists. Finally, we conclude, "it is possible to bring Law and Anthropology close", and, although the epistemological obstacles exist, they derive from a structuring of the modern society, especially from the conceptualization of political power as command-obedience and the purposes of such rationality, rather than from some a priori epistemological obstacle