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

Addendum to `Fake Projective Planes'

The addendum updates the results presented in the paper `Fake Projective Plane, Invent Math 168, 321-370 (2007)' and makes some additions and corrections. The fake projective planes are classified into twenty six classes. Together with a recent work of Donald Cartwright and Tim Steger, there is now a complete list of fake projective planes. There are precisely one hundred fake projective planes as complex surfaces classified up to biholomorphism.Comment: A more refined classification is given in the new versio

Mechanisms of action of currently used antiseizure drugs

Antiseizure drugs (ASDs) prevent the occurrence of seizures; there is no evidence that they have disease-modifying properties. In the more than 160 years that orally administered ASDs have been available for epilepsy therapy, most agents entering clinical practice were either discovered serendipitously or with the use of animal seizure models. The ASDs originating from these approaches act on brain excitability mechanisms to interfere with the generation and spread of epileptic hyperexcitability, but they do not address the specific defects that are pathogenic in the epilepsies for which they are prescribed, which in most cases are not well understood. There are four broad classes of such ASD mechanisms: (1) modulation of voltage-gated sodium channels (e.g. phenytoin, carbamazepine, lamotrigine), voltage-gated calcium channels (e.g. ethosuximide), and voltage-gated potassium channels [e.g. retigabine (ezogabine)]; (2) enhancement of GABA-mediated inhibitory neurotransmission (e.g. benzodiazepines, tiagabine, vigabatrin); (3) attenuation of glutamate-mediated excitatory neurotransmission (e.g. perampanel); and (4) modulation of neurotransmitter release via a presynaptic action (e.g. levetiracetam, brivaracetam, gabapentin, pregabalin). In the past two decades there has been great progress in identifying the pathophysiological mechanisms of many genetic epilepsies. Given this new understanding, attempts are being made to engineer specific small molecule, antisense and gene therapies that functionally reverse or structurally correct pathogenic defects in epilepsy syndromes. In the near future, these new therapies will begin a paradigm shift in the treatment of some rare genetic epilepsy syndromes, but targeted therapies will remain elusive for the vast majority of epilepsies until their causes are identified

Blocks of cyclotomic Hecke algebras and Khovanov-Lauda algebras

We construct an explicit isomorphism between blocks of cyclotomic Hecke algebras and (sign-modified) Khovanov-Lauda algebras in type A. These isomorphisms connect the categorification conjecture of Khovanov and Lauda to Ariki's categorification theorem. The Khovanov-Lauda algebras are naturally graded, which allows us to exhibit a non-trivial Z-grading on blocks of cyclotomic Hecke algebras, including symmetric groups in positive characteristic.Comment: 32 pages; minor changes to section

Costs analysis of a population level rabies control programme in Tamil Nadu, India

The study aimed to determine costs to the state government of implementing different interventions for controlling rabies among the entire human and animal populations of Tamil Nadu. This built upon an earlier assessment of Tamil Nadu’s efforts to control rabies. Anti-rabies vaccines were made available at all health facilities. Costs were estimated for five different combinations of animal and human interventions using an activity-based costing approach from the provider perspective. Disease and population data were sourced from the state surveillance data, human census and livestock census. Program costs were extrapolated from official documents. All capital costs were depreciated to estimate annualized costs. All costs were inflated to 2012 Rupees. Sensitivity analysis was conducted across all major cost centres to assess their relative impact on program costs. It was found that the annual costs of providing Anti-rabies vaccine alone and in combination with Immunoglobulins was \$0.7 million (Rs 36 million) and \$2.2 million (Rs 119 million), respectively. For animal sector interventions, the annualised costs of rolling out surgical sterilisation-immunization, injectable immunization and oral immunizations were estimated to be \$ 44 million (Rs 2,350 million), \$23 million (Rs 1,230 million) and \$ 11 million (Rs 590 million), respectively. Dog bite incidence, health systems coverage and cost of rabies biologicals were found to be important drivers of costs for human interventions. For the animal sector interventions, the size of dog catching team, dog population and vaccine costs were found to be driving the costs. Rabies control in Tamil Nadu seems a costly proposition the way it is currently structured. Policy makers in Tamil Nadu and other similar settings should consider the long-term financial sustainability before embarking upon a state or nation-wide rabies control programme

Psychosocial and environmental determinants of child cognitive development in rural south africa and tanzania: findings from the mal-ed cohort

Background Approximately 66% of children under the age of 5 in Sub-Saharan African countries do not reach their full cognitive potential, the highest percentage in the world. Because the majority of studies investigating child cognitive development have been conducted in high-income countries (HICs), there is limited knowledge regarding the determinants of child development in low- and middle-income countries (LMICs). Methods This analysis includes 401 mother-child dyads from the South Africa and Tanzania sites of the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) longitudinal birth cohort study. We investigated the effect of psychosocial and environmental determinants on child cognitive development measured by the Wechsler Preschool Primary Scales of Intelligence (WPPSI) at 5 years of age using multivariable linear regression. Results Socioeconomic status was most strongly associated with child cognitive development (WPSSI Score Difference (SD):14.27, 95% CI:1.96, 26.59). Modest associations between the organization of the home environment and its opportunities for cognitive stimulation and child cognitive development were also found (SD: 3.08, 95% CI: 0.65, 5.52 and SD: 3.18, 95% CI: 0.59, 5.76, respectively). Conclusion This study shows a stronger association with child cognitive development at 5 years of age for socioeconomic status compared to more proximal measures of psychosocial and environmental determinants. A better understanding of the role of these factors is needed to inform interventions aiming to alleviate the burden of compromised cognitive development for children in LMICs.publishedVersio