Prospective Double-Blinded Randomized Field-Based Clinical Trial of Metoclopramide and Ibuprofen for the Treatment of High Altitude Headache and Acute Mountain Sickness.

INTRODUCTION: High altitude headache (HAH) and acute mountain sickness (AMS) are common pathologies at high altitudes. There are similarities between AMS and migraine headaches, with nausea being a common symptom. Several studies have shown ibuprofen can be effective for AMS prophylaxis, but few have addressed treatment. Metoclopramide is commonly administered for migraine headaches but has not been evaluated for HAH or AMS. We aimed to evaluate metoclopramide and ibuprofen for treatment of HAH and AMS. METHODS: We performed a prospective, double-blinded, randomized, field-based clinical trial of metoclopramide and ibuprofen for the treatment of HAH and AMS in 47 adult subjects in the Mount Everest region of Nepal. Subjects received either 400 mg ibuprofen or 10 mg metoclopramide in a 1-time dose. Lake Louise Score (LLS) and visual analog scale of symptoms were measured before and at 30, 60, and 120 min after treatment. RESULTS: Subjects in both the metoclopramide and ibuprofen arms reported reduced headache severity and nausea compared to pretreatment values at 120 min. The ibuprofen group reported 22 mm reduction in headache and 6 mm reduction in nausea on a 100 mm visual analog scale at 120 min. The metoclopramide group reported 23 mm reduction in headache and 14 mm reduction in nausea. The ibuprofen group reported an average 3.5-point decrease on LLS, whereas the metoclopramide group reported an average 2.0-point decrease on LLS at 120 min. CONCLUSIONS: Metoclopramide and ibuprofen may be effective alternative treatment options in HAH and AMS, especially for those patients who additionally report nausea.

Altitude Sickness in Climbers and Efficacy of NSAIDs Trial (ASCENT): randomized, controlled trial of ibuprofen versus placebo for prevention of altitude illness.

OBJECTIVE: To study the effectiveness of ibuprofen versus placebo in preventing acute mountain sickness (AMS) and high altitude headache (HAH). METHODS: Double-blind, randomized, placebo-controlled trial. RESULTS: Two hundred ninety-four healthy Western trekkers were recruited on the Everest approach at 4280 m or 4358 m and randomly assigned to receive either 600 mg of ibuprofen or placebo 3 times daily before and during ascent to 4928 m. One hundred eighty-three of 294 participants completed the trial. Of the participants who did not complete the trial, 62 were lost to follow-up and another 49 broke trial protocol. In an intent-to-treat analysis (232 participants), ibuprofen was found to be more effective than placebo in reducing the incidence of AMS (24.4% vs 40.4%; P = .01) and the incidence of HAH (42.3% vs 60.5%; P < .01). Ibuprofen was also superior to placebo in reducing the severity of HAH (4.9% vs 14.7%; P = .01). The end point of oxygen saturation was also higher in the ibuprofen group (80.8 % vs 82.4%; P = .035). For the 183 participants who completed the trial and conformed to the protocol, the incidence of AMS between placebo and treatment groups was not significant (32.9% vs 22.7%; P = .129 for AMS incidence, 9.6% vs 8.2%; P = .74 for AMS severity, 54.8% vs 42.7%; P = .11 for HAH incidence, and 8.2% vs 3.6%; P = .18 for HAH severity). CONCLUSIONS: Ibuprofen was found to be effective in preventing AMS in the intent-to-treat analysis group but not in those who completed the trial. This loss of significance in the subjects who completed the trial may be explained by persons in the placebo group having a higher burden of illness and associated decreased compliance with the protocol. An important limitation of this study may be the possibility that ibuprofen can mask headache, which is a compulsory criterion for the diagnosis of AMS.

Stem cells and bioactive scaffolds as a treatment for traumatic brain injury.

Successful repair of the injured brain is critical, as traumatic brain injury pathology often involves a secondary cascade of insults that may ultimately lead to worsened neurologic dysfunction. Damage is balanced by the brain's attempt to repair itself, the genetic profile of the person, underlying health issues, and age, among other factors. The challenge in using a tissue engineering approach to repair and regeneration is centered at the heterogeneous and complex environment, variables that are difficult to measure and interpret. The brain must be in a state that minimizes rejection, inflammation, immune response, and donor cell death to maximize the intended benefit. Tissue engineering, using a bioactive based scaffold to both counter some of the hostile factors and to chaperone donor cells into the brain, has merit, yet the complexity of transplanting a combination biologic construct to the brain has yet to be successfully transferred to the clinic. Several options, such as cell source, scaffold composition, as well as delivery methods will be discussed.

Synapse-to-neuron ratio is inversely related to neuronal density in mature neuronal cultures.

Synapse formation is a fundamental process in neurons that occurs throughout development, maturity, and aging. Although these stages contain disparate and fluctuating numbers of mature neurons, tactics employed by neuronal networks to modulate synapse number as a function of neuronal density are not well understood. The goal of this study was to utilize an in vitro model to assess the influence of cell density and neuronal maturity on synapse number and distribution. Specifically, cerebral cortical neurons were plated in planar culture at densities ranging from 10 to 5000 neurons/mm², and synapse number and distribution were evaluated via immunocytochemistry over 21 days in vitro (DIV). High-resolution confocal microscopy revealed an elaborate three-dimensional distribution of neurites and synapses across the heights of high-density neuronal networks by 21 DIV, which were up to 18 µm thick, demonstrating the complex degree of spatial interactions even in planar high-density cultures. At 7 DIV, the mean number of synapses per neuron was less than 5, and this did not vary as a function of neuronal density. However, by 21 DIV, the number of synapses per neuron had jumped 30- to 80-fold, and the synapse-to-neuron ratio was greatest at lower neuronal densities (< 500 neurons/mm²; mean approximately 400 synapses/neuron) compared to mid and higher neuronal densities (500-4500 neurons/mm²; mean of approximately 150 synapses/neuron) (p<0.05). These results suggest a relationship between neuronal density and synapse number that may have implications in the neurobiology of developing neuronal networks as well as processes of cell death and regeneration.

Three-dimensional neural constructs: a novel platform for neurophysiological investigation.

Morphological and electrophysiological properties of neural cells are substantially influenced by their immediate extracellular surroundings, yet the features of this environment are difficult to mimic in vitro. Therefore, there is a tremendous need to develop a new generation of culture systems that more closely model the complexity of nervous tissue. To this end, we engineered novel electrophysiologically active 3D neural constructs composed of neurons and astrocytes within a bioactive extracellular matrix-based scaffold. Neurons within these constructs exhibited extensive 3D neurite outgrowth, expressed mature neuron-specific cytoskeletal proteins, and remained viable for several weeks. Moreover, neurons assumed complex 3D morphologies with rich neurite arborization and clear indications of network connectivity, including synaptic junctures. Furthermore, we modified whole-cell patch clamp techniques to permit electrophysiological probing of neurons deep within the 3D constructs, revealing that these neurons displayed both spontaneous and evoked electrophysiological action potentials and exhibited functional synapse formation and network properties. This is the first report of individual patch clamp recordings of neurons deep within 3D scaffolds. These tissue engineered cellular constructs provide an innovative platform for neurobiological and electrophysiological investigations, serving as an important step towards the development of more physiologically relevant neural tissue models.

High rate shear insult delivered to cortical neurons produces heterogeneous membrane permeability alterations.

Traumatic brain injury (TBI) occurs when brain tissue is subjected to stresses and strains at high rates and magnitudes, yet the mechanisms of injury and cellular thresholds are not well understood. The events that occur at the time of and immediately after an insult are hypothesized to initiate cell dysfunction or death following a critical cell strain and strain rate. We analyzed neuronal plasma membrane disruption in two in vitro injury models-fluid shear stress delivered to planar cultures and shear strain induction of 3-D neural cultures. We found that insult severity positively correlated with the degree of membrane disruptions in a heterogeneous fashion in both cell configurations. Furthermore, increased membrane permeability led to increases in electrophysiological disturbance. Specifically, cells that exhibited increased membrane permeability did not fire random action potentials, in contrast to neighboring cells that had intact plasma membranes. This approach provides an experimental framework to investigate injury tolerance criteria as well as mechanistically driven therapeutic strategies.