Risk factors for admission at three urban emergency departments in England: a cross-sectional analysis of attendances over 1 month.

OBJECTIVE: To investigate factors associated with unscheduled admission following presentation to emergency departments (EDs) at three hospitals in England. DESIGN AND SETTING: Cross-sectional analysis of attendance data for patients from three urban EDs in England: a large teaching hospital and major trauma centre (site 1) and two district general hospitals (sites 2 and 3). Variables included patient age, gender, ethnicity, deprivation score, arrival date and time, arrival by ambulance or otherwise, a variety of ED workload measures, inpatient bed occupancy rates and admission outcome. Coding inconsistencies in routine ED data used for this study meant that diagnosis could not be included. OUTCOME MEASURE: The primary outcome for the study was unscheduled admission. PARTICIPANTS: All adults aged 16 and older attending the three inner London EDs in December 2013. Data on 19 734 unique patient attendances were gathered. RESULTS: Outcome data were available for 19 721 attendances (>99%), of whom 6263 (32%) were admitted to hospital. Site 1 was set as the baseline site for analysis of admission risk. Risk of admission was significantly greater at sites 2 and 3 (adjusted OR (AOR) relative to site 1 for site 2 was 1.89, 95% CI 1.74 to 2.05, p<0.001) and for patients of black or black British ethnicity (AOR 1.29, 1.16 to 1.44, p<0.001). Deprivation was strongly associated with admission. Analysis of departmental and hospital-wide workload pressures gave conflicting results, but proximity to the "4-hour target" (a rule that limits patient stays in EDs to 4 hours in the National Health Service in England) emerged as a strong driver for admission in this analysis (AOR 3.61, 95% CI 3.30 to 3.95, p<0.001). CONCLUSION: This study found statistically significant variations in odds of admission between hospital sites when adjusting for various patient demographic and presentation factors, suggesting important variations in ED-level and clinician-level behaviour relating to admission decisions. The 4-hour target is a strong driver for emergency admission.

Positive feedback regulation between gamma-aminobutyric acid type A (GABA(A)) receptor signaling and brain-derived neurotrophic factor (BDNF) release in developing neurons.

During the early development of the nervous system, γ-aminobutyric acid (GABA) type A receptor (GABA(A)R)-mediated signaling parallels the neurotrophin/tropomyosin-related kinase (Trk)-dependent signaling in controlling a number of processes from cell proliferation and migration, via dendritic and axonal outgrowth, to synapse formation and plasticity. Here we present the first evidence that these two signaling systems regulate each other through a complex positive feedback mechanism. We first demonstrate that GABA(A)R activation leads to an increase in the cell surface expression of these receptors in cultured embryonic cerebrocortical neurons, specifically at the stage when this activity causes depolarization of the plasma membrane and Ca(2+) influx through L-type voltage-gated Ca(2+) channels. We further demonstrate that GABA(A)R activity triggers release of the brain-derived neurotrophic factor (BDNF), which, in turn by activating TrkB receptors, mediates the observed increase in cell surface expression of GABA(A)Rs. This BDNF/TrkB-dependent increase in surface levels of GABA(A)Rs requires the activity of phosphoinositide 3-kinase (PI3K) and protein kinase C (PKC) and does not involve the extracellular signal-regulated kinase (ERK) 1/2 activity. The increase in GABA(A)R surface levels occurs due to an inhibition of the receptor endocytosis by BDNF, whereas the receptor reinsertion into the plasma membrane remains unaltered. Thus, GABA(A)R activity is a potent regulator of the BDNF release during neuronal development, and at the same time, it is strongly enhanced by the activity of the BDNF/TrkB/PI3K/PKC signaling pathway.

ATP depletion inhibits Ca2+ release, influx and extrusion in pancreatic acinar cells but not pathological Ca2+ responses induced by bile.

Here, we describe novel mechanisms limiting a toxic cytosolic Ca(2+) rise during adenosine 5'-triphosphate (ATP) depletion. We studied the effect of ATP depletion on Ca(2+) signalling in mouse pancreatic acinar cells. Measurements of ATP in isolated cells after adenovirus-mediated expression of firefly luciferase revealed that the cytosolic ATP concentration fell from approximately 1 mM to near zero after treatment with oligomycin plus iodoacetate. ATP depletion resulted in the inhibition of Ca(2+) extrusion, which was accompanied by a remarkably synchronous inhibition of store-operated Ca(2+) influx. Alternative inhibition of Ca(2+) extrusion by carboxyeosin had a much smaller effect on Ca(2+) influx. The coordinated metabolic inhibition of Ca(2+) influx and extrusion suggests the existence of a common ATP-dependent master regulator of both processes. ATP-depletion also suppressed acetylcholine (ACh)-induced Ca(2+) oscillations, which was due to the inhibition of Ca(2+) release from internal stores. This could be particularly important for limiting Ca(2+) toxicity during periods of hypoxia. In contrast, metabolic control of Ca(2+) influx and Ca(2+) release from internal stores spectacularly failed to prevent large toxic Ca(2+) responses induced by bile acids-activators of acute pancreatitis (a frequent and often fatal disease of the exocrine pancreas). The bile acids taurolithocholic acid 3-sulphate (TLC-S), taurochenodeoxycholic acid (TCDC) and taurocholic acid (TC) were used in our experiments. Neither Ca(2+) release from internal stores nor Ca(2+) influx triggered by bile acids were inhibited by ATP depletion, emphasising the danger of these pathological mechanisms.