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 Ca²⁺ rise during adenosine 5′-triphosphate (ATP) depletion. We studied the effect of ATP depletion on Ca²⁺ 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 Ca²⁺ extrusion, which was accompanied by a remarkably synchronous inhibition of store-operated Ca²⁺ influx. Alternative inhibition of Ca²⁺ extrusion by carboxyeosin had a much smaller effect on Ca²⁺ influx. The coordinated metabolic inhibition of Ca²⁺ influx and extrusion suggests the existence of a common ATP-dependent master regulator of both processes. ATP-depletion also suppressed acetylcholine (ACh)-induced Ca²⁺ oscillations, which was due to the inhibition of Ca²⁺ release from internal stores. This could be particularly important for limiting Ca²⁺ toxicity during periods of hypoxia. In contrast, metabolic control of Ca²⁺ influx and Ca²⁺ release from internal stores spectacularly failed to prevent large toxic Ca²⁺ 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 Ca²⁺ release from internal stores nor Ca²⁺ influx triggered by bile acids were inhibited by ATP depletion, emphasising the danger of these pathological mechanisms. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Presynaptic and postsynaptic actions of halothane at glutamatergic synapses in the mouse hippocampus

1. Whole-cell patch-clamp recordings in adult mouse hippocampal slices were used to test the mechanism by which the volatile anesthetic halothane inhibits glutamate receptor-mediated synaptic transmission. Non-N-methyl-D-aspartate (nonNMDA) and NMDA receptor-mediated currents in CA1 pyramidal cells were pharmacologically isolated by bath application of D,L-2-amino-5-phosphonovaleric acid (APV; 100 μM) or 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX; 5 μM), respectively.
2. Halothane blocked both nonNMDA and NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) to a similar extent (IC₅₀ values of 0.66 and 0.57 mM, respectively).
3. Partial blockade of the EPSCs by lowering the extracellular concentration of calcium ([Ca²⁺]_o), but not by application of CNQX (1 μM), was accompanied by an increase in paired-pulse facilitation (PPF). Halothane-induced blockade of the EPSCs also was associated with an increase in PPF.
4. The effects of halothane on α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and NMDA receptor-mediated currents induced by agonist iontophoresis, were compared. AMPA-induced currents were blocked with an IC₅₀ of 1.7 mM. NMDA-induced currents were significantly less sensitive to halothane (IC₅₀ of 5.9 mM).
5. The effect of halothane on iontophoretic AMPA dose-response curves was tested. Halothane suppressed the maximal response to AMPA without affecting its EC₅₀, suggesting a noncompetitive mechanism of inhibition.
6. All effects of halothane were reversible upon termination of the exposure to the drug.
7. These data suggest that halothane blocks central glutamatergic synaptic transmission by presynaptically inhibiting glutamate release and postsynaptically blocking the AMPA subtype of glutamate receptors.

     

Constructing past,present, and future communities: Exploring the experiences of community among last‐dollar scholarship students

This study explores sense of community (SOC) among low‐income college students. The development of a SOC among college students, especially low‐income students, may be particularly vital because of its implications for student success. Six low‐income Arizona State University students were selected based on receipt of a prestigious last‐dollar scholarship. Using narrative inquiry, participants were interviewed about their understanding and experiences with communities. Interviews were audio recorded and transcribed. Participant narratives were created to provide context and in‐depth understanding of experiences. We identified the following themes: (a) mutual support and caring; (b) shared values and goals; (c) interaction and intentionality; and (d) community as self‐constructed, intersecting, and nonlinear. These findings expand existing literature on SOC, with an emphasis on low‐income students in university settings. This research offers an opportunity to examine ways in which universities and student services can provide students an opportunity to better understand their own SOC.     

Learning curves in minimally invasive esophagectomy

Surgical innovation and pioneering are important for improving patient outcome, but can be associated with learning curves. Although learning curves in surgery are a recognized problem, the impact of surgical learning curves is increasing, due to increasing complexity of innovative surgical procedures, the rapid rate at which new interventions are implemented and a decrease in relative effectiveness of new interventions compared to old interventions. For minimally invasive esophagectomy(MIE), there is now robust evidence that implementation can lead to significant learning associated morbidity(morbidity during a learning curve, that could have been avoided if patients were operated by surgeons that have completed the learning curve). This article provides an overview of the evidence of the impact of learning curves after implementation of MIE. In addition, caveats for implementation and available evidence regarding factors that are important for safe implementation and safe pioneering of MIE are discussed.