Integrative network and brain expression analysis reveals mechanistic modules in ataxia

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Morphological analysis of the Dolichoderine ants of Madagascar (Hymenoptera: Formicidae)

BACKGROUND AND OBJECTIVES: Cerebellar ataxia can be induced by a large number of drugs. We here conducted a systemic review of the drugs that can lead to cerebellar ataxia as an adverse drug reaction (ADR). METHODS: We performed a systematic literature search in Pubmed (1966 to January 2014) and EMBASE (1988 to January 2014) to identify all of the drugs that can have ataxia as an ADR and to assess the frequency of drug-induced ataxia for individual drugs. Furthermore, we collected reports of drug-induced ataxia over the past 20 years in the Netherlands by querying a national register of ADRs. RESULTS: Drug-induced ataxia was reported in association with 93 individual drugs (57 from the literature, 36 from the Dutch registry). The most common groups were antiepileptic drugs, benzodiazepines, and antineoplastics. For some, the number needed to harm was below 10. Ataxia was commonly reversible, but persistent symptoms were described with lithium and certain antineoplastics. CONCLUSIONS: It is important to be aware of the possibility that ataxia might be drug-induced, and for some drugs the relative frequency of this particular ADR is high. In most patients, symptoms occur within days or weeks after the introduction of a new drug or an increase in dose. In general, ataxia tends to disappear after discontinuation of the drug, but chronic ataxia has been described for some drugs

Law and Peace: A Legal Framework for United Nations Peacekeeping

The hypothesis of this work is that international human rights law and not international humanitarian law is the legal framework that applies to United Nations (UN) peacekeeping operations in collapsed States where the peacekeepers do not become a party to an armed conflict. In order to test this hypothesis the work begins by examining what is meant by peacekeeping and charts the evolution of peacekeeping from its origins as a passive ad hoc activity to the modern highly complex operations capable of providing the foundations for the recreation of civil society. Chapter two of the work builds on the first chapter by analysing the UNâs theoretical approach to peacekeeping through its major reports. This chapter provides insight into the development of peacekeeping as a theoretical construct and then into a central tool in the UNâs attempt to implement the Charter. Chapters three and four analyse peacekeeping as practiced by the UN in operations conducted under Chapters VI and VII of the UN Charter. This analysis leads to the conclusion that as a matter of practice the UN and the State parties that have provided the troops to perform peacekeeping under UN control have acted in accordance with international human rights law and that as a result there is evidence of State practice to support an argument that as a matter of customary international law international human rights law applies as the framework for peacekeeping in collapsed States. With a clear grounding in the practice and theory of peacekeeping the work then examines the competing claims of international humanitarian law and international human rights law as the legal framework for peacekeeping operations. Suggestions are made with regard to the triggers for international humanitarian law to apply and the conclusion is drawn that the vast majority of UN operations between 1949 and 2003 were conducted beneath the threshold for the application of international humanitarian law. The final chapter of the work analyses the practical application of a human rights framework to peacekeeping and concludes that it provides a flexible and adaptive tool for the restoration of peace and the reconstruction of civil society. As a result of the analysis of UN peacekeeping theory, practice and the competing claims of international humanitarian law and international human rights law, the work concludes that international human rights law provides the framework for UN peacekeeping in collapsed States and that international humanitarian law will only apply where peacekeepers cross the threshold into armed conflict

Human induced pluripotent stem cell-based modelling of spinocerebellar ataxias

Dominant spinocerebellar ataxias (SCAs) constitute a large group of phenotypically and genetically heterogeneous disorders that mainly present with dysfunction of the cerebellum as their main hallmark. Although animal and cell models have been highly instrumental for our current insight into the underlying disease mechanisms of these neurodegenerative disorders, they do not offer the full human genetic and physiological context. The advent of human induced pluripotent stem cells (hiPSCs) and protocols to differentiate these into essentially every cell type allows us to closely model SCAs in a human context. In this review, we systematically summarize recent findings from studies using hiPSC-based modelling of SCAs, and discuss what knowledge has been gained from these studies. We conclude that hiPSC-based models are a powerful tool for modelling SCAs as they contributed to new mechanistic insights and have the potential to serve the development of genetic therapies. However, the use of standardized methods and multiple clones of isogenic lines are essential to increase validity and reproducibility of the insights gained.Functional Genomics of Muscle, Nerve and Brain Disorder

Clinical spectrum of POLR3-related leukodystrophy caused by biallelic POLR1C pathogenic variants

Objective: To determine the clinical, radiologic, and molecular characteristics of RNA polymerase III-related leukodystrophy (POLR3-HLD) caused by biallelic POLR1C pathogenic variants. Methods: A cross-sectional observational study involving 25 centers worldwide was conducted. Clinical and molecular information was collected on 23 unreported and previously reported patients with POLR3-HLD and biallelic pathogenic variants in POLR1C. Brain MRI studies were reviewed. Results: Fourteen female and 9 male patients aged 7 days to 23 years were included in the study. Most participants presented early in life (birth to 6 years), and motor deterioration was seen during childhood. A notable proportion of patients required a wheelchair before adolescence, suggesting a more severe phenotype than previously described in POLR3-HLD. Dental, ocular, and endocrine features were not invariably present (70%, 50%, and 50%, respectively). Five patients (22%) had a combination of hypomyelinating leukodystrophy and abnormal craniofacial development, including 1 individual with clear Treacher Collins syndrome (TCS) features. Brain MRI revealed hypomyelination in all cases, often with areas of pronounced T2 hyperintensity corresponding to T1 hypointensity of the white matter. Twenty-nine different pathogenic variants (including 12 new disease-causing variants) in POLR1C were identified. Conclusions: This study provides a comprehensive description of POLR3-HLD caused by biallelic POLR1C pathogenic variants based on the largest cohort of patients to date. These results suggest distinct characteristics of POLR1C-related disorder, with a spectrum of clinical involvement characterized by hypomyelinating leukodystrophy with or without abnormal craniofacial development reminiscent of TCS.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.This study was supported by grants from the Canadian Institutes of Health Research (201610PJT-377869, MOP-G2-341146-159133-BRIDG), Fondation Les Amis d'Elliot, Leuco-Action, Fondation Lueur d'Espoir pour Ayden, Fondation le Tout pour Loo, and Réseau de Médecine Génétique Appliquée of the Fonds de Recherche en Santé du Québec. This research was enabled in part by support provided by Compute Canada (computecanada.ca). The authors acknowledge the McGill University and Genome Quebec Innovation Center. Dr. Bernard has received the New Investigator Salary Award from the Canadian Institutes of Health Research (2017–2022). Dr. Gauquelin has received grants from the Canadian Gene Cure Advanced Therapies for Rare Disease (Can-GARD) and from the R.S. McLaughlin and Teva Canada Innovation funds from the Faculty of Medicine, Université Laval. Dr. Fribourg is supported by INSERM, CNRS, and the Université de Bordeaux.published version, accepted version, submitted versio

Износ кругов из СТМ при зубошлифовании

The problems of increasing the efficiency of grinding highly precision gearwheels of the 3–4 degree of precision using superhard material tools are discussed. The efficiency of cubic boron nitride dish grinding wheels in various bonds has been studied. Recommendations how to use cubic boron nitride wheels in gear grinding are given

De novo SPAST mutations may cause a complex SPG4 phenotype

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Легочная гипертензия при диастолической дисфункции левого желудочка у больных с ишемической кардиомиопатией

На основании данных эхокардиографического исследования выявлена взаимосвязь между степенью легочной гипертензии и тяжестью диастолической дисфункции левого желудочка у больных с ишемической кардиомиопатией. Показано, что рестриктиное наполнение левого желудочка наблюдается в основном при выраженной легочной гипертензии.The findings of echocardiography were used to reveal interrelation between the degree of pulmonary hypertension and severity of diastolic dysfunction of the left ventricle in patients with ischemic cardiomyopathy. Restrictive filling of the left ventricle is shown to be observed in marked pulmonary hypertension

Network localization of cervical dystonia based on causal brain lesions

Cervical dystonia is a neurological disorder characterized by sustained, involuntary movements of the head and neck. Most cases of cervical dystonia are idiopathic, with no obvious cause, yet some cases are acquired, secondary to focal brain lesions. These latter cases are valuable as they establish a causal link between neuroanatomy and resultant symptoms, lending insight into the brain regions causing cervical dystonia and possible treatment targets. However, lesions causing cervical dystonia can occur in multiple different brain locations, leaving localization unclear. Here, we use a technique termed lesion network mapping', which uses connectome data from a large cohort of healthy subjects (resting state functional MRI, n = 1000) to test whether lesion locations causing cervical dystonia map to a common brain network. We then test whether this network, derived from brain lesions, is abnormal in patients with idiopathic cervical dystonia (n = 39) versus matched controls (n = 37). A systematic literature search identified 25 cases of lesion-induced cervical dystonia. Lesion locations were heterogeneous, with lesions scattered throughout the cerebellum, brainstem, and basal ganglia. However, these heterogeneous lesion locations were all part of a single functionally connected brain network. Positive connectivity to the cerebellum and negative connectivity to the somatosensory cortex were specific markers for cervical dystonia compared to lesions causing other neurological symptoms. Connectivity with these two regions defined a single brain network that encompassed the heterogeneous lesion locations causing cervical dystonia. These cerebellar and somatosensory regions also showed abnormal connectivity in patients with idiopathic cervical dystonia. Finally, the most effective deep brain stimulation sites for treating dystonia were connected to these same cerebellar and somatosensory regions identified using lesion network mapping. These results lend insight into the causal neuroanatomical substrate of cervical dystonia, demonstrate convergence across idiopathic and acquired dystonia, and identify a network target for dystonia treatment

Genome-wide association and Meta-analysis of age at onset in Parkinson Disease

Background and Objectives Considerable heterogeneity exists in the literature concerning genetic determinants of the age at onset (AAO) of Parkinson disease (PD), which could be attributed to a lack of well-powered replication cohorts. The previous largest genome-wide association studies (GWAS) identified SNCA and TMEM175 loci on chromosome (Chr) 4 with a significant influence on the AAO of PD; these have not been independently replicated. This study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations. Methods A meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) Consortium. This was followed by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson Disease Genomics Consortium (IPDGC). Results The COURAGE-PD Consortium included a cohort of 8,535 patients with PD (91.9%: Europeans and 9.1%: East Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD = 11.6), with an underrepresentation of females (40.2%). The heritability estimate for AAO in COURAGE-PD was 0.083 (SE = 0.057). None of the loci reached genome-wide significance (p < 5 × 10−8). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published TMEM175 variant as a genetic determinant of the AAO of PD with Bonferroni-corrected nominal levels of significance (p < 0.025): (rs34311866: β(SE)COURAGE = 0.477(0.203), pCOURAGE = 0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (Ntotal = 25,950) led to the identification of 2 genome-wide significant association signals on Chr 4, including the previously reported SNCA locus (rs983361: β(SE)COURAGE+IPDGC = 0.720(0.122), pCOURAGE+IPDGC = 3.13 × 10−9) and a novel BST1 locus (rs4698412: β(SE)COURAGE+IPDGC = −0.526(0.096), pCOURAGE+IPDGC = 4.41 × 10−8). Discussion Our study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of BST1 as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD