Study Looking at End Expiratory Pressure for Altitude Illness Decrease (SLEEP-AID).

Lipman, Grant S., Nicholas C. Kanaan, Caleb Phillips, Dave Pomeranz, Patrick Cain, Kristin Fontes, Becky Higbee, Carolyn Meyer, Michael Shaheen, Sean Wentworth, and Diane Walsh. Study Looking at End Expiratory Pressure for Altitude Illness Decrease (SLEEP-AID). High Alt Med Biol 16:154-161, 2015.--Acute mountain sickness (AMS) affects 25%-70% of the tens of millions of high altitude travelers annually, with hypoxia and nocturnal desaturations as major contributing factors. This is the first double blind randomized placebo controlled trial to assess expiratory positive airway pressure (EPAP) for AMS prevention and nocturnal hypoxic events. Healthy adult participants trekking in the Khumbu region of the Himalayas were randomized to a single-use EPAP nasal strip, or a visually identical sham device (placebo) prior to first night sleeping between 4371-4530 m (14,340-14,800 ft). The primary outcome was AMS incidence, measured by Lake Louise Questionnaire (LLQ), with secondary outcomes of AMS severity (by LLQ) and physiologic sleep indices measured by continuous sleep monitor. Intent-to-treat analysis included 219 participants with comparable demographic characteristics, of which 115 received EPAP and 104 placebo. There was no decrease in AMS with EPAP intervention (14% EPAP vs. 17% placebo; p=0.65; risk difference (-)3.15%, 95% CI (-)12.85%-6.56%). While overall AMS severity was not different between groups, EPAP reported decreased incidence of headache (64% vs. 76%; p<0.05, OR 0.51, 95% CI 0.27-0.95) and dizziness (81% vs. 98%; p<0.03, OR 0.29, 95% CI 0.09-0.78). During sleep, EPAP resulted in significant improvements in average peripheral oxygenation (Spo(2)) (80% versus 78%; p<0.01, mean difference=2, 95% CI 0.58-3.63) and a reduced percentage of time below 80% Spo(2) (31% vs. 46%; p<0.03, median difference=16, 95% CI 2.22-28.18). This lightweight and inexpensive EPAP device did not prevent acute mountain sickness, but did reduce the subgroup incidence of headache and dizziness while improving average nighttime peripheral oxygenation.

Acute care in Tanzania: epidemiology of acute care in a small community medical centre

Introduction :Without uniform recognition of Emergency Medicine as a specialty in developing sub-Saharan African countries; data are limited on the epidemiology of emergency care needs. The purposes of this study were to quantify the burden of disease presenting as medical or surgical emergencies and describe the patient population at a small community medical centre in the Republic of Tanzania. Methods : An observational study was conducted from March to June 2011 at the University of Arusha (UOA) Medical Centre in Arusha; Tanzania. All consenting patients presenting with acute illness or injury were eligible for inclusion in the study. A standardized form was used to record demographic information; chief complaint; diagnosis/diagnoses; procedure(s); treatment(s); and disposition. Results : Data were collected on 719 patients; with a mean age of 21.8 years (range neonate to 83 years). Fever (19.5); respiratory (17.5); and gastrointestinal complaints (15.0) were the top three chief complaints; 94.9 of chief complaints were atraumatic. The top three diagnoses included respiratory infection (22.1); malaria (21.4); and skin or soft tissue infection (7.9). Forty-three percent of patients required no procedures or tests; and 42 required only one procedure or test. Of treatments administered; 67.6 were analgesics; 51.3 were cough medications; and 47.6 were antipyretics. Ninety-seven percent of patients were discharged home after their visits. Discussion: Respiratory infections; malaria; and skin or soft tissue infections are leading reasons for seeking medical care at a small community medical centre in Arusha; Tanzania; highlighting the burden of infectious diseases in this type of facility. Males may be more likely to present with trauma; burns; and laceration injuries than females. Many patients required one or no procedures to determine their diagnosis; most treatments administered were inexpensive; and most patients were discharged home; suggesting that providing acute care in this setting could be accomplished with limited resources

A novel alternatively spliced isoform of the mu-opioid receptor: functional antagonism.

BACKGROUND: Opioids are the most widely used analgesics for the treatment of clinical pain. They produce their therapeutic effects by binding to mu-opioid receptors (MORs), which are 7 transmembrane domain (7TM) G-protein-coupled receptors (GPCRs), and inhibiting cellular activity. However, the analgesic efficacy of opioids is compromised by side-effects such as analgesic tolerance, dependence and opioid-induced hyperalgesia (OIH). In contrast to opioid analgesia these side effects are associated with cellular excitation. Several hypotheses have been advanced to explain these phenomena, yet the molecular mechanisms underlying tolerance and OIH remain poorly understood. RESULTS: We recently discovered a new human alternatively spliced isoform of MOR (MOR1K) that is missing the N-terminal extracellular and first transmembrane domains, resulting in a 6TM GPCR variant. To characterize the pattern of cellular transduction pathways activated by this human MOR1K isoform, we conducted a series of pharmacological and molecular experiments. Results show that stimulation of MOR1K with morphine leads to excitatory cellular effects. In contrast to stimulation of MOR1, stimulation of MOR1K leads to increased Ca2+ levels as well as increased nitric oxide (NO) release. Immunoprecipitation experiments further reveal that unlike MOR1, which couples to the inhibitory Galphai/o complex, MOR1K couples to the stimulatory Galphas complex. CONCLUSION: The major MOR1 and the alternative MOR1K isoforms mediate opposite cellular effects in response to morphine, with MOR1K driving excitatory processes. These findings warrant further investigations that examine animal and human MORK1 expression and function following chronic exposure to opioids, which may identify MOR1K as a novel target for the development of new clinically effective classes of opioids that have high analgesic efficacy with diminished ability to produce tolerance, OIH, and other unwanted side-effects.

Characterization of NF-kB-mediated inhibition of catechol-O-methyltransferase.

BACKGROUND: Catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, has recently been implicated in the modulation of pain. Specifically, low COMT activity is associated with heightened pain perception and development of musculoskeletal pain in humans as well as increased experimental pain sensitivity in rodents. RESULTS: We report that the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) downregulates COMT mRNA and protein in astrocytes. Examination of the distal COMT promoter (P2-COMT) reveals a putative binding site for nuclear factor kappaB (NF-kappaB), the pivotal regulator of inflammation and the target of TNFalpha. Cell culture assays and functional deletion analyses of the cloned P2-COMT promoter demonstrate that TNFalpha inhibits P2-COMT activity in astrocytes by inducing NF-kappaB complex recruitment to the specific kappaB binding site. CONCLUSION: Collectively, our findings provide the first evidence for NF-kappaB-mediated inhibition of COMT expression in the central nervous system, suggesting that COMT contributes to the pathogenesis of inflammatory pain states.

Bilateral entorhinal cortex lesions impair acquisition of delayed spatial alternation in rats.

Entorhinal cortex lesions induce significant reorganization of several homotypic and heterotypic inputs to the hippocampus. This investigation determined whether surviving heterotypic inputs after bilateral entorhinal lesions would support the acquisition of a learned alternation task. Rats with entorhinal lesions or sham operations were trained to acquire a spatial alternation task. Although the sham-operated rats acquired the task within about 3 weeks postsurgery, rats with bilateral entorhinal lesions failed to learn the task after 12 consecutive weeks of training despite heterotypic sprouting of the cholinergic septodentate pathway and the expansion of the commissural/associational fiber plexus within the dentate gyrus. Thus, heterotypic sprouting failed to ameliorate significantly the effects of bilateral entorhinal lesions. Rather, entorhinal lesions produced a persistent impairment of spatial memory, characterized by a mixture of random error production and perseverative responding.