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Early maladaptive internalization of synaptic GABAA receptors (GABAAR) and externalization of NMDA receptors (NMDAR) may explain the time-dependent loss of potency of standard anti-epileptic drugs (AED) in refractory status epilepticus (SE). We hypothesized that correcting the effects of changes in GABAAR and NMDAR would terminate SE, even when treatment is delayed 40 minutes. SE was induced in adult Sprague-Dawley rats with a high dose of lithium and pilocarpine. The GABAAR agonist midazolam, the NMDAR antagonist ketamine and the AED valproate were injected 40 min after SE onset in combination or as monotherapy. The midazolam-ketamine-valproate combination was more efficient than triple-dose midazolam, ketamine or valproate monotherapy or higher-dose dual therapy in reducing several parameters of SE severity. Triple therapy also reduced SE-induced acute neuronal injury and spatial memory deficits. In addition, simultaneous triple therapy was more efficient than sequential triple therapy: giving the three drugs simultaneously was more efficient at stopping seizures than the standard practice of giving them sequentially. Furthermore, midazolam-ketamine-valproate therapy suppressed seizures far better than the midazolam-fosphenytoin-valproate therapy, which follows evidence-based AES guidelines. These results show that a treatment aimed at correcting maladaptive GABAAR and NMDAR trafficking can reduce the severity of SE and its long-term consequences.

ObjectivePharmacoresistance remains an unsolved therapeutic challenge in status epilepticus (SE) and in cholinergic SE induced by nerve agent intoxication. SE triggers a rapid internalization of synaptic γ-aminobutyric acid A (GABAA ) receptors and externalization of N-methyl-d-aspartate (NMDA) receptors that may explain the loss of potency of standard antiepileptic drugs (AEDs). We hypothesized that a drug combination aimed at correcting the consequences of receptor trafficking would reduce SE severity and its long-term consequences.MethodsA severe model of SE was induced in adult Sprague-Dawley rats with a high dose of lithium and pilocarpine. The GABAA receptor agonist midazolam, the NMDA receptor antagonist ketamine, and/or the AED valproate were injected 40 min after SE onset in combination or as monotherapy. Measures of SE severity were the primary outcome. Secondary outcomes were acute neuronal injury, spontaneous recurrent seizures (SRS), and Morris water maze (MWM) deficits.ResultsMidazolam-ketamine dual therapy was more efficient than double-dose midazolam or ketamine monotherapy or than valproate-midazolam or valproate-ketamine dual therapy in reducing several parameters of SE severity, suggesting a synergistic mechanism. In addition, midazolam-ketamine dual therapy reduced SE-induced acute neuronal injury, epileptogenesis, and MWM deficits.SignificanceThis study showed that a treatment aimed at correcting maladaptive GABAA receptor and NMDA receptor trafficking can stop SE and reduce its long-term consequences. Early midazolam-ketamine dual therapy may be superior to monotherapy in the treatment of benzodiazepine-refractory SE.

A literature review on Parkinson disease was conducted to acquaint dentists with the latest medical advancements in the treatment of the disorder. Findings indicate that the oral health of patients may decline because of tremors, muscle rigidity, and cognitive deficits. The importance of limiting the administration of local anesthetic agents is also discussed.

Epidemiology, pathophysiology and medical management of Alzheimer's disease with relation to efficient dental treatment are discussed.

Intravital microscopy (IVM) enables the study of cellular and molecular events in living organisms. Confocal microscopy permits images to be collected from narrow focal planes without interference from out-of-focus regions, and multi-photon microscopy produces high-resolution images from deep (several hundred micrometers) within opaque organs and tissues. Lasers that are targeted through microscope objectives can injure individual microvessels and induce thrombi that can be studied in detail. The marriage of these technologies provides exciting possibilities for investigating the inflammation and coagulation that is associated with disseminated intravascular coagulation (DIC). In this review, I consider some of the new technology associated with microscopy, give examples of discoveries that have been made using this technology and speculate on how the study of DIC might be advanced using IVM.

Government cost analysts must often construct models using production data that are limited by a contract between the producer and the government. The producer usually does not share cost data with the government unless the contract requires that data are reported. Also, the data that are rep are often not in the proper form for constructing mathematical models; that is, cost data are often provided by production unit or lot, while economic and accounting data are usually reported by time period. This paper provides a mathematical link between unit or lot data and time series data; that between the units domain and the time domain. The analysis is relevant for made-to-order production, the case where a relatively small number of specialized items are produced to contractual order, as defense and other government contract situations. Keywords: System analysis; Learning curves; Progress functions; Production planning, A mathematical link between time series data and lot or unit data can be applied in government contract situations, such as when ordering a small quantity of tailored products. Models are often built by government cost analysts using production information that is restricted to a contract between the government and manufacturer. Cost data is not generally imparted to the government by the manufacturer unless specifically required under contract. Cost data is also not usually supplied by production lot or unit.

The production of illicit drugs at clandestine laboratory operations is a world‐wide problem with many associated public health hazards. This review describes many laboratory types that might be encountered by the clandestine laboratory response personnel, describing the materials and processes associated with different clandestine laboratories to aid in awareness and hazard identification. Clandestine laboratories generally create products according to market forces, including the end‐user expectations with regard to product appearance (e.g., as solid or liquid, in powder or tablet formulation) and potency. The clandestine laboratories use different materials, and processes depending on the laboratory's access to precursors, their ability to produce quantities sufficient to meet market demands, and also their ability to circumvent local, national and international laws and regulations. The information presented here is aimed at both laboratory‐based scientists and analysts who have to understand the classical methods for production, which are still used, and consider novel methods using alternative precursors. It is important to be cognizant of the emerging drugs and drug analogues, how these are considered under the law, and how they can be safely collected for analysis. Clandestine laboratory responders must consider the information presented here from the perspective of the risks associated with the drugs, precursors, waste materials and equipment. As clandestine laboratories and drug markets are constantly evolving, responders need to consistently pursue ongoing education, research, and collaboration with the constant review and assessment of the emerging drugs and precursors seized during operations and reported on regional and international forums. This article is categorized under:Forensic Chemistry and Trace Evidence > Controlled and Emerging Drug CompoundsToxicology > Drug AnalysisCrime Scene Investigation > Crime Scene Examination [ABSTRACT FROM AUTHOR]