The mammalian circadian clock in the suprachiasmatic nucleus (SCN) is a heterogeneous structure. Two key populations of cells that receive retinal input and are believed to participate in circadian responses to light are cells that contain vasoactive intestinal polypeptide (VIP) and gastrin-releasing peptide (GRP). VIP acts primarily through the VPAC2 receptor, while GRP works primarily through the BB2 receptor. Both VIP and GRP phase shift the circadian clock in a manner similar to light when applied to the SCN, both in vivo and in vitro, indicating that they are sufficient to elicit photic-like phase shifts. However, it is not known if they are necessary signals for light to elicit phase shifts. Here we test the hypothesis that GRP and VIP are necessary signaling components for the photic phase shifting of the hamster circadian clock by examining two antagonists for each of these neuropeptides. The BB2 antagonist PD176252 had no effect on light-induced delays on its own, while the BB2 antagonist RC-3095 had the unexpected effect of significantly potentiating both phase delays and advances. Neither of the VIP antagonists ([d-p-Cl-Phe6, Leu17]-VIP, or PG99-465) altered phase shifting responses to light on their own. When the BB2 antagonist PD176252 and the VPAC2 antagonist PG99-465 were delivered together to the SCN, phase delays were significantly attenuated. These results indicate that photic phase shifting requires participation of either VIP or GRP; phase shifts to light are only impaired when signalling in both pathways are inhibited. Additionally, the unexpected potentiation of light-induced phase shifts by RC-3095 should be investigated further for potential chronobiotic applications.
Background Subglottic stenosis (SGS) is a reportedly rare disease that causes recurrent severe airway obstruction. Etiologies reported for SGS include idiopathic, iatrogenic, autoimmune, congenital, and traumatic, with variable ratios among different centres. From empiric observation, southern and central Alberta was hypothesized to have a disproportionate distribution of SGS driven by increased idiopathic SGS (iSGS) compared to previous literature. Identification of causative agents of iSGS will help understand and guide future management options, so this study aimed to characterize the demographics of SGS subtypes, define prevalence and incidence rates of iSGS in southern Alberta, and geographically analyze for clustering of iSGS prevalence. Methods SGS patients from Alberta census divisions No. 1–9 and 15 were retrospectively reviewed. Patients were subtyped according to etiology of SGS and characterized. Idiopathic SGS prevalence and incidence was assessed; prevalence was further geographically segregated by census division and forward sortation area (FSA). Significant clustering patterns were assessed for using a Global Moran’s I analysis. Results From 2010 to 2019 we identified 250 SGS patients, who were substantially overrepresented by idiopathic patients (80.4%) compared to autoimmune (10.0%), iatrogenic (7.6%), congenital (1.2%), and traumatic (0.8%). The total iSGS prevalence was 9.28/100,000 with a mean annual incidence rate of 0.71/100,000 per year. Significant clustering was observed (Moran’s index 0.125; z-score 2.832; p = 0.0046) and the highest rates of prevalence were observed in southern Alberta and in rural communities heterogeneously dispersed around Calgary FSAs. Conclusion In southern and central Alberta, iSGS patients were disproportionately over-represented in contrast to other subtypes with the highest prevalence in southern Alberta. There was a three-fold higher annual incidence compared to previous literature demonstrating the highest rates of disease reported worldwide. Future research aims to expand the geographical scope and to assess for demographic or environmental differences within significant clusters that may contribute to disease pathophysiology. Level of evidence III. Graphical Abstract
A 34-year-old man with end-stage kidney disease presented with new onset blood pressure lability, acute gait difficulties, bilateral leg weakness, hypersomnia, fecal incontinence, and urinary retention within 2 weeks of starting dialysis. His maximum urea was 40 mmol/L, and he was gently dialyzed with three short runs, leading to a 50% reduction in his urea over 3 days. His initial mild hyponatremia (132 mmol/L) was slowly corrected.Examination revealed proximal hip flexor weakness (4/5), mild vibration loss distally, 1 + Achilles and patellar reflexes, and equivocal plantar reflexes with no saddle anesthesia. Upper extremities and coordination were normal. A computed tomography (CT) of the brain was unremarkable (Figure 1A). Full spinal magnetic resonance imaging (MRI) was performed, revealing mild radicular involvement in L4-L5 (Figure 1B), inconsistent with cauda equina syndrome (CES).Given his proximal-predominant weakness, blood pressure lability, and urinary/bowel involvement, differential diagnosis
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