Circadian and ultradian rhythms in normal mice and in a mouse model of Huntington's disease.

Circadian rhythms in core body temperature (CBT) have been widely studied, but fewer studies have explored higher-frequency (ultradian) rhythms in detail. We analyzed CBT recordings from young and middle-aged wild-type mice as well as from the Q175 model of Huntington's disease (HD), at sufficient temporal resolution to address the question of ultradian rhythms. We used model selection methods to show that the overall circadian pattern was better fit by a square wave than a sine wave. Then, using Fourier analysis of the CBT rhythms, we identified the spectral signature of an 8-hour oscillation that occurs in the night but not the day, an observation that can be confirmed by direct inspection of the rhythms. This diurnal amplitude modulation of the 8-hour rhythm was lost with aging as well as in the HD model. Thus, the impact of aging and disease is seen here in the loss of the ability to separate rhythms into a daytime phase and a nighttime phase. These findings raise the possibility that ultradian rhythms in CBT may be a useful biomarker for the pathology within the central nervous system.

Needs Assessment and Identification of the Multifaceted COPD Care Bundle in the Emergency Department of a Tertiary Hospital in Nepal.

PURPOSE: Acute care of patients with exacerbation of chronic obstructive pulmonary disease (AECOPD) in the emergency department (ED) is crucial, however not studied extensively in Nepal. The purpose of this study is to identify the opportunities for succinct measures to optimize the AECOPD care in ED with a multifaceted bundle care approach in a resource-limited setting. METHODS: We conducted a prospective cross-sectional observational study as an initial baseline stage of the quality improvement project. Demographic data, clinical characteristics, the current diagnosis and treatment performances of AECOPD were recorded. The primary outcome measures were 30-day ED revisit and near-fatal events which were compared with other variables and performances with binary and logistic regression. The multidisciplinary team performed the root cause and Pareto analysis to identify the potential gaps in the AECOPD care. RESULTS: The AECOPD performance measures were suboptimal. Written AECOPD emergency management clinical guidelines and advice regarding pulmonary rehabilitation were absent. Among the 249 AECOPD encounters, bilevel positive-airway pressure ventilation was started in 6.4%. At discharge, 11.8% and 39.7% were given oral steroids and antibiotics respectively; 2.2% were advised vaccination. Near-fatal events and 30-day revisit occurred in 19% and 38.2% of the encounters respectively. Those who required domiciliary oxygen had significantly higher 30-day revisits (OR=2.5; 95% CI=1.43-4.4; P value =0.001) as did those who were previously admitted (OR=1.98; 95% CI 1.11-3.59; P value =0.022). Those who had a 30-day revisit had increased near-fatal events (OR=2.86; 95% CI=1.362-6.18; P value =0.006). The opportunities for improving the ED care were identified and feasible interventions and their indicators are summarized for future implementation. CONCLUSION: The current COPD performance measures were suboptimal with high 30-day revisit and near-fatal outcomes. We suggest the urgent implementation of the enlisted feasible bundles-care involving multifaceted team and protocol-based management plans for AECOPD in a busy resource-limited ED.

Cardiac TRPV1 afferent signaling promotes arrhythmogenic ventricular remodeling after myocardial infarction.

Chronic sympathoexcitation is implicated in ventricular arrhythmogenesis (VAs) following myocardial infarction (MI), but the critical neural pathways involved are not well understood. Cardiac adrenergic function is partly regulated by sympathetic afferent reflexes, transduced by spinal afferent fibers expressing the transient receptor potential cation subfamily V member 1 (TRPV1) channel. The role of chronic TRPV1 afferent signaling in VAs is not known. We hypothesized that persistent TRPV1 afferent neurotransmission promotes VAs after MI. Using epicardial resiniferatoxin (RTX) to deplete cardiac TRPV1-expressing fibers, we dissected the role of this neural circuit in VAs after chronic MI in a porcine model. We examined the underlying mechanisms using molecular approaches, IHC, in vitro and in vivo cardiac electrophysiology, and simultaneous cardioneural mapping. Epicardial RTX depleted cardiac TRPV1 afferent fibers and abolished functional responses to TRPV1 agonists. Ventricular tachycardia/fibrillation (VT/VF) was readily inducible in MI subjects by programmed electrical stimulation or cesium chloride administration; however, TRPV1 afferent depletion prevented VT/VF induced by either method. Mechanistically, TRPV1 afferent depletion did not alter cardiomyocyte action potentials and calcium transients, the expression of ion channels, or calcium handling proteins. However, it attenuated fibrosis and mitigated electrical instability in the scar border zone. In vivo recordings of cardiovascular-related stellate ganglion neurons (SGNs) revealed that MI enhances SGN function and disrupts integrated neural processing. Depleting TRPV1 afferents normalized these processes. Taken together, these data indicate that, after MI, TRPV1 afferent-induced adrenergic dysfunction promotes fibrosis and adverse cardiac remodeling, and it worsens border zone electrical heterogeneity, resulting in electrically unstable ventricular myocardium. We propose targeting TRPV1-expressing afferent to reduce VT/VF following MI.