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1.  Effect of angiotension II on voltage-gated sodium currents in aortic baroreceptor neurons and arterial baroreflex sensitivity in heart failure rats 
Journal of hypertension  2015;33(7):1401-1410.
Impairment of arterial baroreflex sensitivity is associated with mortality in patients with chronic heart failure (CHF). Elevation of plasma angiotension II (Ang II) contributes to arterial baroreflex dysfunction in CHF. A reduced number of voltage-gated sodium (Nav) channels in aortic baroreceptor neurons are involved in CHF-blunted arterial baroreflex. In this study, we investigated acute effect of Ang II on Nav currents in the aortic baroreceptor neuron and on arterial baroreflex in sham and coronary artery ligation-induced CHF rats. Using Ang II 125I radioimmunoassay, real-time RT-PCR and western blot, we found that Ang II levels, and mRNA and protein expression of angiotension II type 1 receptor (AT1R) in nodose ganglia (NG) from CHF rats were higher than that from sham rats. Local microinjection of Ang II (0.2 nmol) into the NG decreased the arterial baroreflex sensitivity in sham rats, whereas losartan (1 nmol, an AT1R antagonist) improved the arterial baroreflex sensitivity in CHF rats. Data from patch-clamp recording showed that Ang II (100 nM) acutely inhibited Nav currents in the aortic baroreceptor neurons from sham and CHF rats. In particular, inhibitory effect of Ang II on Nav currents in the aortic baroreceptor neurons was larger in CHF rats than that in sham rats. Losartan (1 μM) totally abolished the inhibitory effect of Ang II on Nav currents in sham and CHF aortic baroreceptor neurons. These results suggest that elevation of endogenous Ang II in the NG contributes to impairment of the arterial baroreflex function in CHF rats through inhibiting Nav channels.
doi:10.1097/HJH.0000000000000563
PMCID: PMC4702522  PMID: 25827427
Angiotensin II; autonomic nervous system; baroreceptor neuron; baroreflex sensitivity; heart failure; nodose ganglia; patch-clamp; sodium channel
2.  In-vivo transfection of manganese superoxide dismutase gene or NFκB shRNA in nodose ganglia improves aortic baroreceptor function in heart failure rats 
Hypertension  2013;63(1):88-95.
Arterial baroreflex sensitivity is attenuated in chronic heart failure (CHF) state, which is associated with cardiac arrhythmias and sudden cardiac death in the patients with CHF. Our previous study showed that CHF-induced sodium channel dysfunction in the baroreceptor neurons was involved in the blunted baroreflex sensitivity in CHF rats. Mitochondria-derived superoxide overproduction decreased expression and activation of the sodium channels in the baroreceptor neurons from CHF rats. However, the molecular mechanisms responsible for the sodium channel dysfunction in the baroreceptor neurons from CHF rats remain unknown. We tested the involvement of NFκB in the sodium channel dysfunction and evaluated the effects of in-vivo transfection of manganese superoxide dismutase gene and NFκB shRNA on the baroreflex function in CHF rats. CHF was developed at 6–8 weeks after left coronary artery ligation in adult rats. Western bolt and chromatin immunoprecipitation data showed that phosphorylated NFκB p65 and ability of NFκB p65 binding to the sodium channel promoter were increased in the nodose ganglia from CHF rats. In-vivo transfection of adenoviral manganese superoxide dismutase gene or lentiviral NFκB p65 shRNA into the nodose ganglia partially reversed CHF-reduced sodium channel expression and cell excitability in the baroreceptor neurons and improved CHF-blunted arterial baroreflex sensitivity. Additionally, transfection of adenoviral manganese superoxide dismutase also inhibited the augmentation of phosphorylated NFκB p65 in the nodose neurons from CHF rats. The present study suggests that superoxide-NFκB signaling contributes to CHF-induced baroreceptor dysfunction and resultant impairment of baroreflex function.
doi:10.1161/HYPERTENSIONAHA.113.02057
PMCID: PMC3893036  PMID: 24101667
baroreceptor; baroreflex; heart failure; NFκB; sodium channel; superoxide
3.  Angiotensin II-superoxide-NFκB signaling and aortic baroreceptor dysfunction in chronic heart failure 
Chronic heart failure (CHF) affects approximately 5.7 million people in the United States. Increasing evidence from both clinical and experimental studies indicates that the sensitivity of arterial baroreflex is blunted in the CHF state, which is a predictive risk factor for sudden cardiac death. Normally, the arterial baroreflex regulates blood pressure and heart rate through sensing mechanical alteration of arterial vascular walls by baroreceptor terminals in the aortic arch and carotid sinus. There are aortic baroreceptor neurons in the nodose ganglion (NG), which serve as the main afferent component of the arterial baroreflex. Functional changes of baroreceptor neurons are involved in the arterial baroreflex dysfunction in CHF. In the CHF state, circulating angiotensin II (Ang II) and local Ang II concentration in the NG are elevated, and AT1R mRNA and protein are overexpressed in the NG. Additionally, Ang II-superoxide-NFκB signaling pathway regulates the neuronal excitability of aortic baroreceptors through influencing the expression and activation of Nav channels in aortic baroreceptors, and subsequently causes the impairment of the arterial baroreflex in CHF. These new findings provide a basis for potential pharmacological interventions for the improvement of the arterial baroreflex sensitivity in the CHF state. This review summarizes the mechanisms responsible for the arterial baroreflex dysfunction in CHF.
doi:10.3389/fnins.2015.00382
PMCID: PMC4607814  PMID: 26528122
angiotensin II; baroreflex; baroreceptor; heart failure; nodose ganglion; nuclear factor κB; sodium channel; superoxide
4.  Fatalities of Pedestrians, Bicycle Riders, and Motorists Due to Distracted Driving Motor Vehicle Crashes in the U.S., 2005–2010 
Public Health Reports  2013;128(6):436-442.
Objective
Distracted driving is an increasingly deadly threat to road safety. This study documents trends in and characteristics of pedestrian, bicycle rider, and other victim deaths caused by distracted drivers on U.S. public roads.
Methods
We obtained data from the Fatality Analysis Reporting System database from 2005 to 2010 on every crash that resulted in at least one fatality within 30 days occurring on public roads in the U.S. Following the definition used by the National Highway Traffic Safety Administration, we identified distracted driving based on whether police investigators determined that a driver had been using a technological device, including a cell phone, onboard navigation system, computer, fax machine, two-way radio, or head-up display, or had been engaged in inattentive or careless activities.
Results
The rate of fatalities per 10 billion vehicle miles traveled increased from 116.1 in 2005 to 168.6 in 2010 for pedestrians and from 18.7 in 2005 to 24.6 in 2010 for bicyclists. Pedestrian victims of distracted driving crashes were disproportionately male, 25–64 years of age, and non-Hispanic white. They were also more likely to die at nighttime, be struck by a distracted driver outside of a marked crosswalk, and be in a metro location. Bicycling victims of distracted crashes were disproportionately male, non-Hispanic white, and struck by a distracted driver outside of a crosswalk. Compared with pedestrians, bicyclists were less likely to be hit in early morning.
Conclusions
Distracted drivers are the cause of an increasing share of fatalities found among pedestrians and bicycle riders. Policies are needed to protect pedestrians and bicycle riders as they cross intersections or travel on roadways.
PMCID: PMC3804087  PMID: 24179255
5.  Mitochondria-Derived Superoxide Links to Tourniquet-Induced Apoptosis in Mouse Skeletal Muscle 
PLoS ONE  2012;7(8):e43410.
Our previous study has reported that superoxide mediates ischemia-reperfusion (IR)-induced necrosis in mouse skeletal muscle. However, it remains poorly understood whether IR induces apoptosis and what factors are involved in IR-induced apoptosis in skeletal muscle. Using a murine model of tourniquet-induced hindlimb IR, we investigated the relationship between mitochondrial dysfunction and apoptosis in skeletal muscle. Hindlimbs of C57/BL6 mice were subjected to 3 h ischemia and 4 h reperfusion via placement and release of a rubber tourniquet at the greater trochanter. Compared to sham treatment, tourniquet-induced IR significantly elevated mitochondria-derived superoxide production, activated opening of mitochondrial permeability transition pore (mPTP), and caused apoptosis in the gastrocnemius muscles. Pretreatment with a superoxide dismutase mimetic (tempol, 50 mg/kg) or a mitochondrial antioxidant (co-enzyme Q10, 50 mg/kg) not only decreased mitochondria-derived superoxide production, but also inhibited mPTP opening and apoptosis in the IR gastrocnemius muscles. Additionally, an inhibitor of mPTP (cyclosporine A, 50 mg/kg) also inhibited both mPTP opening and apoptosis in the IR gastrocnemius muscles. These results suggest that mitochondria-derived superoxide overproduction triggers the mPTP opening and subsequently causes apoptosis in tourniquet-induced hindlimb IR.
doi:10.1371/journal.pone.0043410
PMCID: PMC3422247  PMID: 22912870
6.  Tourniquet-induced acute ischemia-reperfusion injury in mouse skeletal muscles: involvement of superoxide 
European journal of pharmacology  2010;650(1):328-334.
Although arterial limb tourniquet is one of the first-line treatments to prevent exsanguinating hemorrhage in both civilian pre-hospital and battlefield casualty care, prolonged application of a limb tourniquet can lead to serious ischemia-reperfusion injury. However, the underlying pathomechanisms of tourniquet-induced ischemia-reperfusion injury are still poorly understood. Using a murine model of acute limb ischemia-reperfusion, we investigated if acute limb ischemia-reperfusion injury is mediated by superoxide overproduction and mitochondrial dysfunction. Hind limbs of C57/BL6 mice were subjected to 3 h ischemia and 4 h reperfusion via placement and release of a rubber tourniquet at the greater trochanter. Approximately 40% gastrocnemius muscle suffered infarction in this model. Activities of mitochondrial electron transport chain complexes including complex I, II, III, and IV in gastrocnemius muscle were decreased in the ischemia-reperfusion group compared to sham. Superoxide production was increased while activity of manganese superoxide dismutase (MnSOD, the mitochondria-targeted SOD isoform) was decreased in the ischemia-reperfusion group compared to sham group. Pretreatment with tempol (a SOD mimetic, 50 mg/kg) or co-enzyme Q10 (50 mg/kg) not only decreased the superoxide production, but also reduced the infarct size and normalized mitochondrial dysfunction in the gastrocnemius muscle. Our results suggest that tourniquet-induced skeletal muscle ischemia-reperfusion injuries including infarct size and mitochondrial dysfunction may be mediated via the superoxide over-production and reduced antioxidant activity. In the future, this murine ischemia-reperfusion model can be adapted to mechanistically evaluate anti-ischemic molecules in tourniquet-induced skeletal muscle injury.
doi:10.1016/j.ejphar.2010.10.037
PMCID: PMC3008320  PMID: 21036124
Infarct size; Ischemia-reperfusion injury; Mitochondria; Superoxide; Tourniquet
7.  Reduced expression and activation of voltage-gated sodium channels contributes to blunted baroreflex sensitivity in heart failure rats 
Journal of neuroscience research  2010;88(15):3337-3349.
Voltage-gated sodium (Nav) channels are responsible for initiation and propagation of action potential in the neurons. To explore the mechanisms for chronic heart failure (CHF)-induced baroreflex dysfunction, we measured the expression and current density of Nav channel subunits (Nav1.7, Nav1.8, and Nav1.9) in the aortic baroreceptor neurons and investigated the role of Nav channels on aortic baroreceptor neuron excitability and baroreflex sensitivity in sham and CHF rats. CHF was induced by left coronary artery ligation. The development of CHF (6–8 weeks after the coronary ligation) was confirmed by hemodynamic and morphological characteristics. Immunofluorescent data indicated that Nav1.7 was expressed in A-type (myelinated) and C-type (unmyelinated) nodose neurons but Nav1.8 and Nav1.9 were expressed only in C-type nodose neurons. Real-time RT-PCR and western blot data showed that CHF reduced mRNA and protein expression levels of Nav channels in nodose neurons. In addition, using the whole cell patch-clamp technique, we found that Nav current density and cell excitability of the aortic baroreceptor neurons were lower in CHF rats than that in sham rats. Aortic baroreflex sensitivity was blunted in anesthetized CHF rats, compared with that in sham rats. Furthermore, Nav channel activator (rATX II, 100 nM) significantly enhanced Nav current density and cell excitability of aortic baroreceptor neurons and improved aortic baroreflex sensitivity in CHF rats. These results suggest that reduced expression and activation of the Nav channels is involved in the attenuation of baroreceptor neuron excitability, which subsequently contributes to the impairment of baroreflex in CHF state.
doi:10.1002/jnr.22483
PMCID: PMC2953570  PMID: 20857502
Aortic baroreceptor neuron; Baroreflex; Heart failure; Sodium channel
8.  Assessment of a Chief Complaint–Based Curriculum for Resident Education in Geriatric Emergency Medicine 
Introduction
We hypothesized that a geriatric chief complaint–based didactic curriculum would improve resident documentation of elderly patient care in the emergency department (ED).
Methods
A geriatric chief complaint curriculum addressing the 3 most common chief complaints—abdominal pain, weakness, and falls—was developed and presented. A pre- and postcurriculum implementation chart review assessed resident documentation of the 5 components of geriatric ED care: 1) differential diagnosis/patient evaluation considering atypical presentations, 2) determination of baseline function, 3) chronic care facility/caregiver communication, 4) cognitive assessment, and 5) assessment of polypharmacy. A single reviewer assessed 5 pre- and 5 postimplementation charts for each of 18 residents included in the study. We calculated 95% confidence and determined that statistical significance was determined by a 2-tailed z test for 2 proportions, with statistical significance at 0.003 by Bonferroni correction.
Results
For falls, resident documentation improved significantly for 1 of 5 measures. For abdominal pain, 2 of 5 components improved. For weakness, 3 of 5 components improved.
Conclusion
A geriatric chief complaint–based curriculum improved emergency medicine resident documentation for the care of elderly patients in the ED compared with a non–age-specific chief complaint–based curriculum.
doi:10.5811/westjem.2010.10.1722
PMCID: PMC3236144  PMID: 22224144

Results 1-8 (8)