Large Genomic Deletions in CACNA1A Cause Episodic Ataxia Type 2

Episodic ataxia (EA) syndromes are heritable diseases characterized by dramatic episodes of imbalance and incoordination. EA type 2 (EA2), the most common and the best characterized subtype, is caused by mostly nonsense, splice site, small indel, and sometimes missense mutations in CACNA1A. Direct sequencing of CACNA1A fails to identify mutations in some patients with EA2-like features, possibly due to incomplete interrogation of CACNA1A or defects in other EA genes not yet defined. Previous reports described genomic deletions between 4 and 40 kb in EA2. In 47 subjects with EA (26 with EA2-like features) who tested negative for mutations in the known EA genes, we used multiplex ligation-dependent probe amplification to analyze CACNA1A for exonic copy number variations. Breakpoints were further defined by long-range PCR. We identified distinct multi-exonic deletions in three probands with classic EA2-like features: episodes of prolonged vertigo and ataxia triggered by stress and fatigue, interictal nystagmus, with onset during infancy or early childhood. The breakpoints in all three probands are located in Alu sequences, indicating errors in homologous recombination of Alu sequences as the underlying mechanism. The smallest deletion spanned exons 39 and 40, while the largest deletion spanned 200 kb, missing all but the first three exons. One deletion involving exons 39 through 47 arose spontaneously. The search for mutations in CACNA1A appears most fruitful in EA patients with interictal nystagmus and onset early in life. The finding of large heterozygous deletions suggests haploinsufficiency as a possible pathomechanism of EA2

Practice Parameter: Therapies for Benign Paroxysmal Positional Vertigo (An Evidence-Based Review): Report of the Quality Standards Subcommittee of the American Academy of Neurologysymbol Symbol

American Academy of Neurology; BPPV = benign paroxysmal positional vertigo; CONSORT = Consolidated Standards of Reporting Trials; CRP = canalith repositioning procedure; NNT = number needed to treat

Residual cognitive deficits 50 years after lead poisoning during childhood

The long term neurobehavioural consequences of childhood lead poisoning are not known. In this study adult subjects with a documented history of lead poisoning before age 4 and matched controls were examined with an abbreviated battery of neuropsychological tests including measures of attention, reasoning, memory, motor speed, and current mood. The subjects exposed to lead were inferior to controls on almost all of the cognitive tasks. This pattern of widespread deficits resembles that found in children evaluated at the time of acute exposure to lead rather than the more circumscribed pattern typically seen in adults exposed to lead. Despite having completed as many years of schooling as controls, the subjects exposed to lead were lower in lifetime occupational status. Within the exposed group, performance on the neuropsychological battery and occupational status were related, consistent with the presumed impact of limitations in neuropsychological functioning on everyday life. The results suggest that many subjects exposed to lead suffered acute encephalopathy in childhood which resolved into a chronic subclinical encephalopathy with associated cognitive dysfunction still evident in adulthood. These findings lend support to efforts to limit exposure to lead in childhood

Vestibular Perception following Acute Unilateral Vestibular Lesions.

Little is known about the vestibulo-perceptual (VP) system, particularly after a unilateral vestibular lesion. We investigated vestibulo-ocular (VO) and VP function in 25 patients with vestibular neuritis (VN) acutely (2 days after onset) and after compensation (recovery phase, 10 weeks). Since the effect of VN on reflex and perceptual function may differ at threshold and supra-threshold acceleration levels, we used two stimulus intensities, acceleration steps of 0.5°/s(2) and velocity steps of 90°/s (acceleration 180°/s(2)). We hypothesised that the vestibular lesion or the compensatory processes could dissociate VO and VP function, particularly if the acute vertiginous sensation interferes with the perceptual tasks. Both in acute and recovery phases, VO and VP thresholds increased, particularly during ipsilesional rotations. In signal detection theory this indicates that signals from the healthy and affected side are still fused, but result in asymmetric thresholds due to a lesion-induced bias. The normal pattern whereby VP thresholds are higher than VO thresholds was preserved, indicating that any 'perceptual noise' added by the vertigo does not disrupt the cognitive decision-making processes inherent to the perceptual task. Overall, the parallel findings in VO and VP thresholds imply little or no additional cortical processing and suggest that vestibular thresholds essentially reflect the sensitivity of the fused peripheral receptors. In contrast, a significant VO-VP dissociation for supra-threshold stimuli was found. Acutely, time constants and duration of the VO and VP responses were reduced - asymmetrically for VO, as expected, but surprisingly symmetrical for perception. At recovery, VP responses normalised but VO responses remained shortened and asymmetric. Thus, unlike threshold data, supra-threshold responses show considerable VO-VP dissociation indicative of additional, higher-order processing of vestibular signals. We provide evidence of perceptual processes (ultimately cortical) participating in vestibular compensation, suppressing asymmetry acutely in unilateral vestibular lesions

Toward a More Comprehensive Understanding of organizational influences On Implementation: the organization theory For Implementation Science Framework

INTRODUCTION: Implementation is influenced by factors beyond individual clinical settings. Nevertheless, implementation research often focuses on factors related to individual providers and practices, potentially due to limitations of available frameworks. Extant frameworks do not adequately capture the myriad organizational influences on implementation. Organization theories capture diverse organizational influences but remain underused in implementation science. to advance their use among implementation scientists, we distilled 70 constructs from nine organization theories identified in our previous work into theoretical domains in the Organization Theory for Implementation Science (OTIS) framework. METHODS: The process of distilling organization theory constructs into domains involved concept mapping and iterative consensus-building. First, we recruited organization and implementation scientists to participate in an online concept mapping exercise in which they sorted organization theory constructs into domains representing similar theoretical concepts. Multidimensional scaling and hierarchical cluster analyses were used to produce visual representations (clusters) of the relationships among constructs in concept maps. Second, to interpret concept maps, we engaged members of the Cancer Prevention and Control Research Network (CPCRN) OTIS workgroup in consensus-building discussions. RESULTS: Twenty-four experts participated in concept mapping. Based on resulting construct groupings\u27 coherence, OTIS workgroup members selected the 10-cluster solution (from options of 7-13 clusters) and then reorganized clusters in consensus-building discussions to increase coherence. This process yielded six final OTIS domains: organizational characteristics (e.g., size; age); governance and operations (e.g., organizational and social subsystems); tasks and processes (e.g., technology cycles; excess capacity); knowledge and learning (e.g., tacit knowledge; sense making); characteristics of a population of organizations (e.g., isomorphism; selection pressure); and interorganizational relationships (e.g., dominance; interdependence). DISCUSSION: Organizational influences on implementation are poorly understood, in part due to the limitations of extant frameworks. to improve understanding of organizational influences on implementation, we distilled 70 constructs from nine organization theories into six domains. Applications of the OTIS framework will enhance understanding of organizational influences on implementation, promote theory-driven strategies for organizational change, improve understanding of mechanisms underlying relationships between OTIS constructs and implementation, and allow for framework refinement. Next steps include testing the OTIS framework in implementation research and adapting it for use among policymakers and practitioners

Prognostic significance of the expression of GFRα1, GFRα3 and Syndecan-3, Proteins binding ARTEMIN, In mammary carcinoma

10.1186/1471-2407-13-34BMC Cancer13-BCMA