During embryonic development, innervation induces the anatomical and biochemical specialization of a defined region of the muscle cell membrane immediately under the motor nerve ending. A prominent aspect of this specialization is the accumulation of high densities of nicotinic acetylcholine receptors (AChR) 1 at these sites (1, 2). The aggregation of AChR and other synaptic components is mediated by agrin, a heparansulfated proteoglycan that is synthesized by motor neurons and secreted into the synaptic cleft (3, 4). The recruitment of AChR into clusters in postsynaptic membranes ensures high efficiency synaptic transmission at neuromuscular junctions.Agrin-induced redistribution of surface AChR involves the co-clustering of multiple associated proteins, several of which have been identified to date (2, 5). These include the musclespecific receptor tyrosine kinase (MuSK) (6), the linker protein rapsyn (7), and the scaffolding proteins dystroglycan and utrophin (8). The clustering of MuSK upon its activation by agrin, the formation of AChR complexes with rapsyn, as well as the aggregation of these complexes and their stabilization upon the formation of dystroglycan-utrophin scaffolds appear to be sequential events that are to some extent independently regulated (9 -11). Although the signaling mechanisms that couple agrin activation of MuSK to the clustering of postsynaptic components are incompletely characterized, there is recent evidence for the participation of Src tyrosine kinases (12, 13), the Rho GTPases Rac and Cdc42 (14), and Dishevelled, a component of the Wnt signaling pathway (15).Focal changes in the peripheral actin-based cytoskeleton are thought to underlie the aggregation of AChR at neuromuscular junctions (16 -18). The monomeric G proteins Rac and Rho function to link extracellular signals to dynamic changes in actin cytoskeleton organization leading to the assembly of lamellipodia and actin-myosin filaments, respectively (19 -22). Rac activation induces actin polymerization at the plasma membrane, causing the appearance of lamellipodia with resultant stimulation of cell spreading and motility (23,24). Rho exerts the opposite effect by stimulating actin stress fiber appearance and focal adhesion complex formation to promote cell adhesion and contractility (25,26). As several recent studies have shown, Rac and Rho are mutually inhibitory in several cell types, and the balance between their antagonistic activities is responsible for the dynamic changes in cell morphology, adhesion, and motility (27,28). In other systems Rac serves as an upstream activator of Rho (29).We have recently shown that agrin triggers the activation of Rac and Cdc42 and that this activation is necessary but not sufficient for formation of full size AChR clusters (14). In this study we present evidence that Rho plays a crucial role in agrin-initiated signaling that is complementary to the contribution of Rac/Cdc42 and that together these Rho family GTPases serve to couple signaling initiated by extracellular agrin to the for...
Borges, L. S. and Ferns, M. (2001).
BACKGROUND: Early morning patient discharge from the hospital is increasingly being recognized as a key dimension of quality of care. At our institution, there is a significantly lower early discharge rate on the teaching hospitalist teams in comparison with the non-teaching teams. OBJECTIVE: To implement a resident-driven intervention in the teaching medical services to increase overall discharge order rate before 11 am (DOB-11) and assess the effect of this intervention on hospital length of stay (LOS), 30-day readmission rates (RR), and resident perception. DESIGN: Interrupted time series as well as controlled before-after designs. PARTICIPANTS: All inpatients discharged from general medicine units. INTERVENTIONS:We implemented an educational didactic in conjunction with resident-attending daily walk rounds followed by resident-led multidisciplinary discharge huddles to identify next-day discharges. MAIN MEASURES: The primary outcome was DOB-11 rates 18 months pre-and 12 months post-intervention. Secondary outcomes: LOS and RR. Additionally, we assessed residents' perception of the early discharge protocol. KEY RESULTS: The DOB-11 rate increased from 12 to 29% (p < 0.001), LOS increased by 1.47 days (P < 0.001), and RR increased by 0.32% (P = 0.84), respectively, on the teaching teams. Compared with the non-teaching (control) teams, the teaching teams registered a greater increase in DOB-11 rate (by 17%, p < 0.001; ratio of adjusted ORs 2.16; 95% CI, 1.65, 2.85; p value < 0.001), small increase in LOS (by 0.74 day, p = 0.39; ratio of adjusted post-/pre-intervention ratio [teaching] and post-/ pre-intervention ratio [non-teaching] = 1.05, 95% CI, 0.97, 1.14, p = 0.23), and relative increase in RR (by 3.98%, p = 0.07, and ratio of ORs = 1.35, 95% CI, 1.03, 1.8), p = 0.03). Approximately 55% (16/29) of the residents agreed that the early discharge initiative helped in understanding the importance of prioritizing patients for early discharge. Additionally, 55% (20/36) of the residents "agreed" that the early discharge initiative compromised their learning during teaching rounds. CONCLUSION: Our study demonstrates that DOB-11 is an achievable goal, not only for non-teaching teams but also for resident-run teaching teams.
Patient: Male, 40Final Diagnosis: Patent foramen ovaleSymptoms: Dyspnea exertional • hemoptysis • shortness of breathMedication: —Clinical Procedure: Airway pressure release ventilationSpecialty: Critical Care MedicineObjective:Rare co-existance of disease or pathologyBackground:Patent foramen ovale (PFO) are common, normally resulting in a left to right shunt or no net shunting. Pulmonary embolism (PE) can cause sustained increased pulmonary vascular resistance (PVR) and right atrial pressure. Increasing positive end-expiratory pressure (PEEP) improves oxygenation at the expense of increasing intrathoracic pressures (ITP). Airway pressure release ventilation (APRV) decreases shunt fraction, improves ventilation/perfusion (V/Q) matching, increases cardiac output, and decreases right atrial pressure by facilitating low airway pressure.Case Report:A 40-year-old man presented with dyspnea and hemoptysis. Oxygen saturation (SaO2) 80% on room air with A a gradient of 633 mmHg. Post-intubation SaO2 dropped to 71% on assist control, FiO2 100%, and PEEP of 5 cmH20. Successive PEEP dropped SaO2 to 60–70% and blood pressure plummeted. APRV was initaiated with improvement in SaO2 to 95% and improvement in blood pressure. Hemiparesis developed and CT head showed infarction. CT pulmonary angiogram found a large pulmonary embolism. Transthoracic echocardiogram detected right-to left intracardiac shunt, with large PFO.Conclusions:There should be suspicion for a PFO when severe hypoxemia paradoxically worsens in response to increasing airway pressures. Concomitant venous and arterial thromboemboli should prompt evaluation for intra cardiac shunt. Patients with PFO and hypoxemia should be evaluated for causes of sustained right-to left pressure gradient, such as PE. Management should aim to decrease PVR and optimize V/Q matching by treating the inciting incident (e.g., thrombolytics in PE) and by minimizing ITP. APRV can minimize PVR and maximize V/Q ratios and should be considered in treating patients similar to the one whose case is presented here.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.