Indistinguishable synaptic pharmacodynamics of the N-methyl-D-aspartate receptor channel blockers memantine and ketamine.

Memantine and ketamine, voltage- and activation-dependent channel blockers of N-methyl-d-aspartate (NMDA) receptors (NMDARs), have enjoyed a recent resurgence in clinical interest. Steady-state pharmacodynamic differences between these blockers have been reported, but it is unclear whether the compounds differentially affect dynamic physiologic signaling. In this study, we explored nonequilibrium conditions relevant to synaptic transmission in hippocampal networks in dissociated culture and hippocampal slices. Equimolar memantine and ketamine had indistinguishable effects on the following measures: steady-state NMDA currents, NMDAR excitatory postsynaptic current (EPSC) decay kinetics, progressive EPSC inhibition during repetitive stimulation, and extrasynaptic NMDAR inhibition. Therapeutic drug efficacy and tolerability of memantine have been attributed to fast kinetics and strong voltage dependence. However, pulse depolarization in drug presence revealed a surprisingly slow and similar time course of equilibration for the two compounds, although memantine produced a more prominent fast component (62% versus 48%) of re-equilibration. Simulations predicted that low gating efficacy underlies the slow voltage-dependent relief from block. This prediction was empirically supported by faster voltage-dependent blocker re-equilibration with several experimental manipulations of gating efficacy. Excitatory postsynaptic potential-like voltage commands produced drug differences only with large, prolonged depolarizations unlikely to be attained physiologically. In fact, we found no difference between drugs on measures of spontaneous network activity or acute effects on plasticity in hippocampal slices. Despite indistinguishable synaptic pharmacodynamics, ketamine provided significantly greater neuroprotection from damage induced by oxygen glucose deprivation, consistent with the idea that under extreme depolarizing conditions, the biophysical difference between drugs becomes detectable. We conclude that despite subtle differences in voltage dependence, during physiologic activity, blocker pharmacodynamics are largely indistinguishable and largely voltage independent.

The Protective Role of Social Support Sources and Types Against Depression in Caregivers: A Meta-Analysis.

The protective effects of social support for caregiver mental health are well documented, however the differential impact of support providers (partner, child, family, siblings, friends, professionals) and types (perceived, received) remain unclear. Observational data from 21 independent studies, involving a pooled sample of 2273 parents, stepparents and grandparents of children (aged ≤ 19) with autism spectrum disorder (ASD) were examined. Pearson's r, publication bias and heterogeneity were calculated using random effects modelling. Significant associations were noted between lowered depressive symptoms and positive sources of support, regardless of support type. Parental mental health can be enhanced by strengthening close personal relationships alongside connections with formal support services. Longitudinal research is needed to explore support need and perceived helpfulness over time.

Responses and Injuries to PMHS in Side-Facing and Oblique Seats in Horizontal Longitudinal Sled Tests per FAA Emergency Landing Conditions.

The objective of the present exploratory study is to understand occupant responses in oblique and side-facing seats in the aviation environment, which are increasingly installed in modern aircrafts. Sled tests were conducted using intact Post Mortem Human Surrogates (PMHS) seated in custom seats approximating standard aircraft geometry. End conditions were selected to represent candidate aviation seat and restraint configurations. Three-dimensional head center-of-gravity linear accelerations, head angular velocities, and linear accelerations of the T1, T6, and T12 spinous processes, and sacrum were obtained. Three-dimensional kinematics relative to the seat were obtained from retroreflective targets attached to the head, T1, T6, T12, and sacrum. All specimens sustained spinal injuries, although variations existed by vertebral level. While the tension mechanism was associated with cervical spine injuries, complex distraction-coupled with bending and tension was attributed to thoracolumbar spine injuries. Skeletal fractures to the ribcage were attributed to compression induced by the restraint from the seatbelt, the presence of the armrest, and/or severe motions of the unconstrained torso. Pelvic injuries were also attributed to restraint offered by the lap belt on the accelerating torso-pelvis complex in the absence of the armrest. Lower extremity injuries occurred due to the unconstrained motion (flailing mechanism). These results serve as an initial dataset to understand the kinematics of different body regions, injuries and patterns, and potential injury mechanisms describing PMHS responses in the aviation environment.