Cells sense and respond to changes in oxygen concentration through gene regulatory processes that are fundamental to survival. Surprisingly, little is known about how anemia affects hypoxia signaling. Because nitric oxide synthases (NOSs) figure prominently in the cellular responses to acute hypoxia, we defined the effects of NOS deficiency in acute anemia. In contrast to endothelial NOS or inducible NOS deficiency, neuronal NOS (nNOS)
−/−
mice demonstrated increased mortality during anemia. Unlike wild-type (WT) animals, anemia did not increase cardiac output (CO) or reduce systemic vascular resistance (SVR) in nNOS
−/−
mice. At the cellular level, anemia increased expression of HIF-1α protein and HIF-responsive mRNA levels (EPO, VEGF, GLUT1, PDK1) in the brain of WT, but not nNOS
−/−
mice, despite comparable reductions in tissue PO
2
. Paradoxically, nNOS
−/−
mice survived longer during hypoxia, retained the ability to regulate CO and SVR, and increased brain HIF-α protein levels and HIF-responsive mRNA transcripts. Real-time imaging of transgenic animals expressing a reporter HIF-α(ODD)-luciferase chimeric protein confirmed that nNOS was essential for anemia-mediated increases in HIF-α protein stability in vivo.
S
-nitrosylation effects the functional interaction between HIF and pVHL. We found that anemia led to nNOS-dependent
S
-nitrosylation of pVHL in vivo and, of interest, led to decreased expression of GSNO reductase. These findings identify nNOS effects on the HIF/pVHL signaling pathway as critically important in the physiological responses to anemia in vivo and provide essential mechanistic insight into the differences between anemia and hypoxia.
The synchronized discharges typical of seizures have a multifactorial origin at molecular, cellular and network levels. During recent years, the functional role of gap-junctional coupling has received increased attention as a mechanism that may participate in seizure generation. We have investigated the possible functional roles of thalamic and hippocampal gap-junctional communication (GJC) in the generation of spike-and-wave discharges in a rodent model of atypical absence seizures. Seizures in this model spread throughout limbic, thalamic and neocortical areas. Rats were chronically implanted with cannulae to deliver drugs or saline, and local field potentials recordings were performed using intracerebral electrodes positioned in distinct brain areas. Initially, the effects on synaptic transmission of the gap-junctional blockers used in this study were determined. Neither carbenoxolone (CBX) nor 18-alpha-glycyrrhetinic acid altered chemical synaptic transmission at the concentrations tested. These two compounds, when injected via cannulae into the reticular nucleus of the thalamus (NRT), decreased significantly the duration of seizures as compared with saline injections or injections of the CBX inactive derivative glycyrrhizic acid. CBX injections into the hippocampus resulted in diminished seizure activity as well. NRT injections of trimethylamine, which presumably causes intracellular alkalinization (thereby promoting gap-junctional opening), enhanced seizures and spindle activity. These observations suggest that, in this rodent model, thalamic and limbic areas are involved in the synchronous paroxysmal activity and that GJC contributes to the spike-and-wave discharges.
A simple serious games skills competition increased voluntary usage and performance on a laparoscopic simulator, despite a majority of participants reporting they were not motivated by competition. Future directions should endeavour to examine other serious gaming modalities to further engage trainees in simulated skills development.
This study does not support the hypothesis that competition alone universally increases voluntary use of simulation-based training, with only the minority of individuals competing at the national level demonstrated significantly higher simulation use. However, simulation training was perceived as a valuable exercise. Lack of time and access to simulators, as opposed to lack of interest, were the most commonly reported to limited use.
Background: There is an important disconnect between surgical programs and primary care physicians (PCP) in the delivery of bariatric care. The objective of this study is to assess PCP knowledge and perception of a provincial bariatric surgery program.Methods: A 32-question, IRB approved, survey was developed by bariatric surgery experts and vetted by local PCPs. A single round of paper surveys was administered to 1,000 PCPs between July and September 2015. Continuous variables were assessed by t-test and categorical variables by Chi-square test.Results: There were 131 survey responses (13.1%). Half (54.2%) of respondents did not feel equipped to counsel their patients on operative management strategies. PCPs counselled on average 11.6%±17.0% of their obese patients on bariatric surgery. Many respondents (58.3%) thought excess weight loss from gastric bypass was less than 40% and most believed there was less than 50% resolution of diabetes (62.4%), hypertension (72.3%), dyslipidemia (77.8%) and obstructive sleep apnea (60.6%). PCPs who referred patients to the bariatric program (71.8%) were more comfortable counselling their patients on bariatric surgery options (56.8% vs. 17.1%, P<0.001) and were more comfortable with post-operative care (67.4% vs.38.2%, P=0.004). Additionally, these PCPs estimated higher rates of diabetes and hypertension resolution post-bariatric surgery. The predominant perceived barrier to accessing bariatric surgery was wait times (33.3%).Conclusions: PCPs appear to underestimate the efficacy of bariatric surgery in the treatment of obesity and feel ill-equipped to counsel patients. Further education related to bariatric surgery may improve PCP comfort in counselling and long-term follow-up.
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