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During status epilepticus (SE), synaptic γ-aminobutyric acid A receptors (GABAA Rs) become internalized and inactive, whereas spare N-methyl-d-aspartate receptors (NMDARs) assemble, move to the membrane, and become synaptically active. When treatment of SE is delayed, the number of synaptic GABAA Rs is drastically reduced, and a GABAA agonist cannot fully restore inhibition. We used a combination of low-dose diazepam (to stimulate the remaining GABAA Rs), ketamine (to mitigate the effect of the NMDAR increase), and valproate (to enhance inhibition at a nonbenzodiazepine site) to treat seizures in a model of severe cholinergic SE. High doses of diazepam failed to stop electrographic SE, showing that benzodiazepine pharmacoresistance had developed. The diazepam-ketamine-valproate combination was far more effective in stopping SE than triple-dose monotherapy using the same individual drugs. Isobolograms showed that this drug combination's therapeutic actions were synergistic, with positive cooperativity between drugs, whereas drug toxicity was simply additive, without positive or negative cooperativity. As a result, the therapeutic index was improved by this drug combination compared to monotherapy. These results suggest that synergistic drug combinations that target receptor changes can control benzodiazepine-refractory SE.

Cholinergic status epilepticus (CSE) quickly becomes self-sustaining, independent of its initial trigger, and resistant to benzodiazepines and other antiepileptic drugs. We review a few of the many physiological changes associated with CSE, with an emphasis on receptor trafficking. Time-dependent internalization of synaptic GABAA receptors explains, in part, the loss of inhibition and the loss of response to benzodiazepines in the early stages of CSE. The increase in NMDA receptors may contribute to the runaway excitation and excitotoxicity of CSE. These changes have therapeutic implications. The time-dependent increase in maladaptive changes points to the importance of early treatment. The involvement of both inhibitory and excitatory systems challenges current therapeutic guidelines, which recommend treating only one system, and questions the rationale for monotherapy. It suggests that polytherapy may be needed, especially when treatment is delayed, so that drugs can only reach a much reduced number of GABAA receptors. Finally, it raises the possibility that the current practice of waiting for one treatment to fail before starting the next drug may need to be re-evaluated.

O progresso das pesquisas relacionadas à perda auditiva genética tem provocado um importante avanço do entendimento dos mecanismos moleculares que governam o desenvolvimento, a função, a resposta ao trauma e o envelhecimento do ouvido interno. Em países desenvolvidos, mais de 50% dos casos de surdez na infância é causada por alterações genéticas e as perdas auditivas relacionadas à idade têm sido associadas com mecanismos genéticos. OBJETIVO: O objetivo desta revisão é relatar as informações mais recentes relacionadas às perdas audtivas de origem genética. FORAMA DE ESTUDO: Revisão sistemática. MATERIAL E MÉTODO: A revisão da literatura inclui artigos indexados à MEDLINE (Biblioteca Nacional de Saúde, NIH-USA) e publicados nos últimos 3 anos, além das informações disponíveis na Hereditary Hearing Loss Home Page. CONCLUSÃO: Os recentes avanços no entendimento das perdas auditivas de origem genética têm favorecido a nossa compreensão da função auditiva e tornado o diagnóstico mais apurado. Possivelmente, no futuro, este conhecimento também proporcionará o desenvolvimento de novas terapias para o tratamento das causas genéticas das perdas auditivas.The progress in the research of genetic hearing loss has advanced our understanding of the molecular mechanisms that govern inner ear development, function and response to injury and aging. In the developed world, over 50% of childhood deafness is attributable to genetic causes and even age-related hearing loss has been associated with genetic mechanisms. AIM: The objective of this review is to summarize recent knowledge in genetic hearing loss. STUDY DESIGN: Sistematic review. MATERIAL AND METHODS: The literature review included articles indexed at MEDLINE (The National Library of Medicine, The National Institute of Health - USA) focusing on publications from the past 3 years plus the information available at the Hereditary Hearing Loss Home Page. CONCLUSION: Advances in the genetics of hearing loss have enhanced our comprehension of auditory function and have enabled more accurate diagnosis. Hopefully, as we further understand the molecular elements of the auditory system, this knowledge will help in the development of new therapies for the treatment of the underlying genetic defects.

Posttraumatic epilepsy (PTE) is a major long-term complication of traumatic brain injury (TBI). PTE usually develops within 5 years of head injury. The risk for developing PTE varies with TBI type. Both Korean and Vietnam war veterans with penetrating TBI had a 53% risk of developing PTE. The risk of developing PTE is between 10% and 25% in combat-associated closed-head trauma with positive brain imaging and about 5% in moderately severe closed-head injury without imaging finding. We do not know the risk of PTE among Operation Iraqi Freedom/Operation Enduring Freedom veterans with minimal TBI because of blast exposure.Partial seizures may manifest with subtle behavioral alterations that can be mistaken for manifestations of posttraumatic stress disorder and improperly treated. Accidents and medical complications commonly occur during seizures. Sudden unexpected death in epilepsy is most frequent among 20- to 40-year-olds. Seizures increase the likelihood of refractory seizures years after TBI. Seizures are also a social stigma that compromise veterans' reintegration into society. People with uncontrolled epilepsy are not allowed to drive and have difficulty obtaining or maintaining employment. Optimal seizure control is essential to the physical and emotional health of veterans with TBI and to their ability to lead productive lives.

A method for pediatric airway support was evaluated for the situation when mask ventilation or intubation is impossible. Mongrel dogs were sedated, intubated, and allowed to breathe room air for 30 min. Baseline variables were recorded, and the airway obstructed. After 2 to 3 min of hypoxia, arterial blood gas and hemodynamic data were again recorded. A percutaneous cricothyroid membrane puncture (PCMP) was then performed with a 12-ga iv catheter. Studies were carried out both in the presence and absence of spontaneous ventilatory efforts. With spontaneous ventilation, continuous low flow (1.0 L/min) oxygen insufflation provided oxygenation for 30 min and reversed increases in mean arterial pressure, pulmonary artery pressure (PAP), and systemic and pulmonary vascular resistance that had been produced by the obstruction. Respiratory acidosis occurred but was well tolerated. With paralyzed animals, whose ventilation was supported by a self-inflating bag with 10.0 L/min of oxygen, all hemodynamic variables except PAP returned to normal, oxygenation was excellent, and PaCO2 values were maintained at steady, but elevated levels. Complications included bilateral tension pneumothorax in one animal. This experimental study supports anecdotal experiences where PCMP has been used and has proven lifesaving when standard resuscitative measures to establish a clear airway have failed.