Partial and full deletion of nicotinic acetylcholine receptor α4 and ß2 subunits reduces sensitivity to acute nicotine administration and development of tolerance following chronic nicotine administration.

The diversity of nicotinic cholinergic receptor (nAChR) subunits underlies the complex responses to nicotine. Mice differing in the expression of α4 and ß2 subunits, which are most widely expressed in brain, were evaluated for the responses to acute nicotine administration on Y-maze crossings and rears, open-field locomotion and body temperature following chronic treatment with nicotine (0, 0.25, 1.0 and 4.0 mg/kg/h). Deletion or partial deletion of the α4, ß2 or both nAChR subunits reduced the sensitivity of mice to acute nicotine administration. This reduced sensitivity was gene dose-dependent. Modification of α4 subunit expression elicited a greater reduction in sensitivity than the modification of ß2 subunit expression. No measurable tolerance was observed for mice of any genotype following chronic treatment with 0.25 mg/kg/h nicotine. Modest tolerance was noted following treatment with 1.0 mg/kg/h. Greater tolerance was observed following treatment with 4.0 mg/kg/h. The extent of tolerance differed among the mice depending on genotype: wild-type (α4 and ß2) developed measurable tolerance for all four tests. Heterozygotes (α4, ß2 and α4/ß2) developed tolerance for only Y-maze crossings and body temperature. Null mutants (α4 and ß2) did not become tolerant. However, following chronic treatment with 4.0 mg/kg/h nicotine, wild type, α4 and α4 mice displayed increased Y-maze crossings following acute administration of 0.5 mg/kg nicotine that may reflect the activity of α6ß2*-nAChR. These results confirm the importance of the α4 and ß2 nAChR subunits in mediating acute and chronic effects of nicotine on locomotion and body temperature in the mouse.

Comparison of a Novel Trainer to a Traditional Swine Model for Training Providers in Lateral Canthotomy and Cantholysis.

RESEARCH OBJECTIVE: Military personnel are at greater risks of head and facial traumas and permanent blindness from orbital compartment syndrome in modern warfare. Rapid treatment must be implemented with a low-risk surgical remedy: lateral canthotomy and cantholysis (LCC). Traditional training of LCC is primarily performed using an animal tissue trainer (ATT); however, limitations to these types of trainers exist. Therefore, our research objectives were focused on highlighting the effectiveness, benefits, and vision-saving potential of learning LCC on a synthetic trainer. METHODS: Participants included 22 second-year medical students and 6 healthcare professionals. A pre-quiz assessed baseline knowledge. Next, an experienced ophthalmologist provided an overview and instruction. Subjects were randomized to either the synthetic trainer or the ATT and then switched to the other model for comparison. After performing LCC procedures on both models, a post-quiz and survey were administered. RESULTS: Participants found the synthetic trainer easier to use than the ATT model (p < 0.01). There was no statistically significant preference (p = 0.23), or preference of practical eye anatomy (p = 0.26) between the trainers. Post-quiz results demonstrated an overall improvement from pre-quiz scores for participants (p < 0.001). CONCLUSIONS: The synthetic trainer is comparable to the traditional swine model for training LCC procedures, and should be considered as a future training platform.

Surgery at Sea: The Effect of Simulated High Sea States on Surgical Performance.

BACKGROUND: The US Navy initiated design concepts for a Medical Mission Module Support Container (M3SC), a mobile operating room capable of rapid installation aboard maneuverable ships within proximity of active combat units. The M3SC provides an alternative echelon of care in the current trauma system by decreasing the time between point of injury, arrival, and surgical intervention. The mobile ships used as M3SC platforms, however, are more susceptible to oceanic conditions that can induce detrimental physiologic motion sickness in medical personnel and patients aboard the vessels. This study investigated the effects of different sea-state motion conditions on the performance of surgical teams. METHODS: Six four-person surgical teams performed 144 procedures in an M3SC aboard a Stewart motion table that simulated motion profiles of sea states 0, 3, and 4. A modified human-worn partial- task surgical simulator was used as a surgical surrogate to simulate the four most common, wartime, improvised explosive device injuries in the past 10 years. Electroencephalographs and heart rate variability (HRV) data were collected from surgeons and surgical technologists during each procedure to assess real-time physiologic responses to motion. Two postprocedure surveys, a Surgical Task Load Index and a Motion Sickness Assessment Questionnaire, were given to assess subjective responses of workload stress and motion-induced kinetosis. Surgical subject matter experts quantified surgical performance after each procedure by measuring blood loss and orthopedic pin placement to evaluate each intervention. RESULTS: Motion did not significantly influence overall performance (ρ = .002). Surgical procedure was the strongest predictor of performance. HRV was used to measure stress and was increased in surgical technologists; however, HRV was decreased for surgeons and technologists in motion. There was a significant interaction between role and motion (ρ = .002): Surgeons had higher workloads than did surgical technologists and neither demonstrated differences between motion and no motion. Surgeons demonstrated significantly decreased workloads under motion conditions (ρ = 0.002); however, surgeons perceived their workload to be higher. We attribute this to their increased critical thinking and physical execution of procedures. Surgeons and surgical technologists showed a trend toward HRV suppression within the motion conditions. This may indicate a coping response to the increased stress of the motion setting. Procedure and team dynamic were the strongest predictors of overall performance, suggesting a learning curve exists and that added focus on training should be enforced. CONCLUSION: Based on data collected in this study, similar surgical procedures should be implemented aboard these classes of ships. By doing so, injured military personnel would have more timely access to care. Surgical team members were aware of craft motion, used compensatory measures, and exhibited some physiological response.

Impact of human D398N single nucleotide polymorphism on intracellular calcium response mediated by α3ß4α5 nicotinic acetylcholine receptors.

The human CHRNA5 D398N polymorphism (rs16969968) causes an aspartic acid to asparagine change in the nicotinic acetylcholine receptor (nAChR) α5 subunit gene. The N398 variant of CHRNA5 is linked to increased risk for nicotine dependence. In this study, we explored the effect of the CHRNA5 D398N polymorphism on the properties of human α3ß4* nicotinic acetylcholine receptors in human embryonic kidney (HEK) cells. Addition of either D398 or N398 variant of α5 subunit in the α3ß4* receptor did not affect total [(125)I]-epibatidine binding or surface expression of the receptor. However, addition of α5(D398) into α3ß4* receptor decreased the maximal response to agonist without significantly affecting EC(50) in aequorin intracellular calcium assay. α3ß4α5(N398) nAChRs showed further decreased maximal response. The differences in agonist efficacy between the receptor subtypes were found to be dependent upon the concentration of external calcium but independent of external sodium. Moreover, activation of α3ß4α5 nAChRs led to significantly greater intracellular calcium release from IP(3) stores relative to α3ß4 nAChRs although no effect of the α5 polymorphism was observed. Finally, inclusion of the α5 variant caused a small shift to the left in IC(50) for some of the antagonists tested, depending upon α5 variant but did not affect sensitivity of α3ß4* receptors to desensitization in response to incubation with nicotine. In conclusion, addition of either variant of α5 into an α3ß4α5 receptor similarly effects receptor pharmacology and function. However, the N398 variant exhibits a reduced response to agonists when extracellular calcium is high and it may lead to distinct downstream cellular signaling.