Influence of barium on rectification in rat neocortical neurons

The effect of low concentrations of barium on the membrane properties of rat neocortical neurons was studied in vitro. Potassium currents were examined using single-electrode current- and voltage-clamp techniques. Neurons responded to bath application of barium (10–100 μM) with a membrane depolarization associated with an increase in input resistance. Under voltage clamp conditions, an inward shift in holding current was observed. The effects of barium were rapidly reversible upon washing and persisted in the presence of TTX. The equilibrium potential for the barium-induced inward current was near −110 mV, suggesting that barium inhibited a tonically active potassium conductance. Measurements of current voltage relationships indicated an inward rectification of this conductance between −50 and −130 mV. These results provide strong evidence that barium blocks a persistent potassium ‘leak’ current in neocortical neurons that contributes to the resting potential of these cells

Multimodal sensory reliance in the nocturnal homing of the amblypygid \u3ci\u3ePhrynus pseudoparvulus\u3c/i\u3e (Class Arachnida, Order Amblypygi)?

Like many other nocturnal arthropods, the amblypygid Phrynus pseudoparvulus is capable of homing. The environment through which these predators navigate is a dense and heterogeneous tropical forest understory and the mechanism(s) underlying their putatively complex navigational abilities are presently unknown. This study explores the sensory inputs that might facilitate nocturnal navigation in the amblypygid P. pseudoparvulus. Specifically, we use sensory system manipulations in conjunction with field displacements to examine the potential involvement of multimodal—olfactory and visual—stimuli in P. pseudoparvulus’ homing behavior. In a first experiment, we deprived individuals of their olfactory capacity and displaced them to the opposite side of their home trees (\u3c5 m). We found that olfaction-intact individuals were more likely to be re-sighted in their home refuges than olfaction-deprived individuals. In a second experiment, we independently manipulated both olfactory and visual sensory capacities in conjunction with longer-distance displacements (8 m) from home trees. We found that sensory-intact individuals tended to be re-sighted on their home tree more often than sensory-deprived individuals, with a stronger effect of olfactory deprivation than visual deprivation. Comparing across sensory modality manipulations, olfaction-manipulated individuals took longer to return to their home trees than vision-manipulated individuals. Together, our results indicate that olfaction is important in the nocturnal navigation of P. pseudoparvulus and suggest that vision may also play a more minor role

The impact of hypsarrhythmia on infantile spasms treatment response: Observational cohort study from the National Infantile Spasms Consortium

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141801/1/epi13937_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141801/2/epi13937.pd

International Veterinary Epilepsy Task Force Consensus Proposal: Outcome of therapeutic interventions in canine and feline epilepsy

Common criteria for the diagnosis of drug resistance and the assessment of outcome are needed urgently as a prerequisite for standardized evaluation and reporting of individual therapeutic responses in canine epilepsy. Thus, we provide a proposal for the definition of drug resistance and partial therapeutic success in canine patients with epilepsy. This consensus statement also suggests a list of factors and aspects of outcome, which should be considered in addition to the impact on seizures. Moreover, these expert recommendations discuss criteria which determine the validity and informative value of a therapeutic trial in an individual patient and also suggest the application of individual outcome criteria. Agreement on common guidelines does not only render a basis for future optimization of individual patient management, but is also a presupposition for the design and implementation of clinical studies with highly standardized inclusion and exclusion criteria. Respective standardization will improve the comparability of findings from different studies and renders an improved basis for multicenter studies. Therefore, this proposal provides an in-depth discussion of the implications of outcome criteria for clinical studies. In particular ethical aspects and the different options for study design and application of individual patient-centered outcome criteria are considered

Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2)

BACKGROUND Deficiency of adenosine deaminase 2 (DADA2) is a syndrome with pleiotropic manifestations including vasculitis and hematologic compromise. A systematic definition of the relationship between ADA2 mutations and clinical phenotype remains unavailable. OBJECTIVE We tested whether the impact of ADA2 mutations on enzyme function correlates with clinical presentation. METHODS DADA2 patients with severe hematologic manifestations were compared with vasculitis-predominant patients. Enzymatic activity was assessed using expression constructs reflecting all 53 missense, nonsense, insertion and deletion genotypes from 152 patients across the DADA2 spectrum. RESULTS We identified DADA2 patients presenting with pure red cell aplasia (PRCA, n = 5) or bone marrow failure syndrome (BMF, n = 10). Most patients did not exhibit features of vasculitis. Recurrent infection, hepatosplenomegaly and gingivitis were common in patients with BMF, of whom half died from infection. Unlike DADA2 patients with vasculitis, patients with PRCA and BMF proved largely refractory to tumor necrosis factor inhibitors. ADA2 variants associated with vasculitis predominantly reflected missense mutations with at least 3% residual enzymatic activity. By contrast, PRCA and BMF were associated with missense mutations with minimal residual enzyme activity, nonsense variants, and insertions / deletions resulting in complete loss of function. CONCLUSION Functional interrogation of ADA2 mutations reveals an association of subtotal function loss with vasculitis, typically responsive to TNF blockade, whereas more extensive loss is observed in hematologic disease which may be refractory to treatment. These findings establish a genotype-phenotype spectrum in DADA2

Opportunities for improving animal welfare in rodent models of epilepsy and seizures

Animal models of epilepsy and seizures, mostly involving mice and rats, are used to understand the pathophysiology of the different forms of epilepsy and their comorbidities, to identify biomarkers, and to discover new antiepileptic drugs and treatments for comorbidities. Such models represent an important area for application of the 3Rs (replacement, reduction and refinement of animal use). This report provides background information and recommendations aimed at minimising pain, suffering and distress in rodent models of epilepsy and seizures in order to improve animal welfare and optimise the quality of studies in this area. The report includes practical guidance on principles of choosing a model, induction procedures, in vivo recordings, perioperative care, welfare assessment, humane endpoints, social housing, environmental enrichment, reporting of studies and data sharing. In addition, some model-specific welfare considerations are discussed, and data gaps and areas for further research are identified. The guidance is based upon a systematic review of the scientific literature, survey of the international epilepsy research community, consultation with veterinarians and animal care and welfare officers, and the expert opinion and practical experience of the members of a Working Group convened by the United Kingdom's National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs)

Postnatal Proteasome Inhibition Induces Neurodegeneration and Cognitive Deficiencies in Adult Mice: A New Model of Neurodevelopment Syndrome

Defects in the ubiquitin-proteasome system have been related to aging and the development of neurodegenerative disease, although the effects of deficient proteasome activity during early postnatal development are poorly understood. Accordingly, we have assessed how proteasome dysfunction during early postnatal development, induced by administering proteasome inhibitors daily during the first 10 days of life, affects the behaviour of adult mice. We found that this regime of exposure to the proteasome inhibitors MG132 or lactacystin did not produce significant behavioural or morphological changes in the first 15 days of life. However, towards the end of the treatment with proteasome inhibitors, there was a loss of mitochondrial markers and activity, and an increase in DNA oxidation. On reaching adulthood, the memory of mice that were injected with proteasome inhibitors postnatally was impaired in hippocampal and amygdala-dependent tasks, and they suffered motor dysfunction and imbalance. These behavioural deficiencies were correlated with neuronal loss in the hippocampus, amygdala and brainstem, and with diminished adult neurogenesis. Accordingly, impairing proteasome activity at early postnatal ages appears to cause morphological and behavioural alterations in adult mice that resemble those associated with certain neurodegenerative diseases and/or syndromes of mental retardation