Tetramethylenedisulfotetramine alters Ca²⁺ dynamics in cultured hippocampal neurons: mitigation by NMDA receptor blockade and GABA(A) receptor-positive modulation.

Tetramethylenedisulfotetramine (TETS) is a potent convulsant that is considered a chemical threat agent. We characterized TETS as an activator of spontaneous Ca²⁺ oscillations and electrical burst discharges in mouse hippocampal neuronal cultures at 13-17 days in vitro using FLIPR Fluo-4 fluorescence measurements and extracellular microelectrode array recording. Acute exposure to TETS (≥ 2 µM) reversibly altered the pattern of spontaneous neuronal discharges, producing clustered burst firing and an overall increase in discharge frequency. TETS also dramatically affected Ca²⁺ dynamics causing an immediate but transient elevation of neuronal intracellular Ca²⁺ followed by decreased frequency of Ca²⁺ oscillations but greater peak amplitude. The effect on Ca²⁺ dynamics was similar to that elicited by picrotoxin and bicuculline, supporting the view that TETS acts by inhibiting type A gamma-aminobutyric acid (GABA(A)) receptor function. The effect of TETS on Ca²⁺ dynamics requires activation of N-methyl-D-aspartic acid (NMDA) receptors, because the changes induced by TETS were prevented by MK-801 block of NMDA receptors, but not nifedipine block of L-type Ca²⁺ channels. Pretreatment with the GABA(A) receptor-positive modulators diazepam and allopregnanolone partially mitigated TETS-induced changes in Ca²⁺ dynamics. Moreover, low, minimally effective concentrations of diazepam (0.1 µM) and allopregnanolone (0.1 µM), when administered together, were highly effective in suppressing TETS-induced alterations in Ca²⁺ dynamics, suggesting that the combination of positive modulators of synaptic and extrasynaptic GABA(A) receptors may have therapeutic potential. These rapid throughput in vitro assays may assist in the identification of single agents or combinations that have utility in the treatment of TETS intoxication

Global Jacquet-Langlands correspondence, multiplicity one and classification of automorphic representations

In this paper we show a local Jacquet-Langlands correspondence for all unitary irreducible representations. We prove the global Jacquet-Langlands correspondence in characteristic zero. As consequences we obtain the multiplicity one and strong multiplicity one theorems for inner forms of GL(n) as well as a classification of the residual spectrum and automorphic representations in analogy with results proved by Moeglin-Waldspurger and Jacquet-Shalika for GL(n).Comment: 49 pages; Appendix by N. Grba

Brief Report: Estimating Differences and Ratios in Median Times to Event

Time differences and time ratios are often more interpretable estimates of effect than hazard ratios for time-to-event data, especially for common outcomes. We developed a SAS macro for estimating time differences and time ratios between baseline-fixed binary exposure groups based on inverse probability weighted Kaplan-Meier curves. The macro uses pooled logistic regression to calculate inverse probability of censoring and exposure weights, draws Kaplan-Meier curves based on the weighted data, and estimates the time difference and time ratio at a user-defined survival proportion. The macro also calculates the risk difference and risk ratio at a user-specified time. Confidence intervals are constructed by bootstrap. We provide an example assessing the effect of exclusive breastfeeding during diarrhea on the incidence of subsequent diarrhea in children followed from birth to 3 years in Vellore, India. The SAS macro provided here should facilitate the wider reporting of time differences and time ratios

2014 Epilepsy Benchmarks Area III: Improve Treatment Options for Controlling Seizures and Epilepsy-Related Conditions Without Side Effects

The Epilepsy Benchmark goals in Area III focus on making progress in understanding and controlling seizures and related conditions as well as on developing biomarkers and new therapies that will reduce seizures and improve outcomes for individuals with epilepsy. Area III emphasizes a need to better understand the ways in which seizures start, propagate, and terminate and whether those network processes are common or unique in different forms of epilepsy. The application of that knowledge to improved seizure prediction and detection will also play a role in improving patient outcomes. Animal models of treatment-resistant epilepsy that are aligned with etiologies and clinical features of human epilepsies are especially encouraged as necessary tools to understand mechanisms and test potential therapies. Antiseizure therapies that target (either alone or in combination) novel or multiple seizure mechanisms are prioritized in this section of the Benchmarks. Area III goals also highlight validation of biomarkers of treatment response and safety risk, effective self-management, and patient-centered outcome measures as important areas of emphasis for the next five to ten years

Reduction in diarrhoeal rates through interventions that prevent unnecessary antibiotic exposure early in life in an observational birth cohort

Antibiotic treatment early in life is often not needed and has been associated with increased rates of subsequent diarrhea. We estimated the impact of realistic interventions, which would prevent unnecessary antibiotic exposures before 6 months of age, on reducing childhood diarrheal rates

Transfer of multidrug-resistant bacteria to healthcare workers’ gloves and gowns after patient contact increases with environmental contamination*

To assess the role of environmental contamination in the transmission of multidrug-resistant bacteria to healthcare workers’ clothing

On limit multiplicites of discrete series representations in spaces of automorphic forms

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46616/1/222_2005_Article_BF01388963.pd