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The prevalence of burnout and depressive symptoms is high among physician trainees.

Hartford Hospital''s Meditation Garden, dedicated on October 30, 1997, is a beautiful focal point on the campus. Its location affords patients and staff the ability to take in its beauty and is part of our healing environment. The garden was made possible by generous donors including the Hartford Hospital Auxiliary. A few years later, the garden became the site for the placement of a bronze statue depicting a student nurse and serving to recognize the century long contribution of the Hospital''s former School of Nursing (1877–1976). [Copyright &y& Elsevier]

Ion channels are membrane proteins that flicker open and shut to regulate the flow of ions down their electrochemical gradient across the membrane and consequently regulate cellular excitability. Every living cell expresses ion channels, as they are critical life-sustaining proteins. Ion channels are generally either activated by voltage or by ligand interaction. For each group of ion channels the channels’ molecular biology and biophysics will be introduced and the pharmacology of that group of channels will be reviewed. The in vitro and in vivo literature will be reviewed and, for ion channel groups in which clinical trials have been conducted, the efficacy and therapeutic potential of the neuroprotective compounds will be reviewed. A large part of this article will deal with glutamate receptors, focusing specifically on N-methyl-D-aspartate (NMDA) receptors. Although the outcome of clinical trials for NMDA receptor antagonists as therapeutics for acute stroke is disappointing, the culmination of these failed trials was preceded by a decade of efforts to develop these agents. Sodium and calcium channel antagonists will be reviewed and the newly emerging efforts to develop therapeutics targeting potassium channels will be discussed. The future development of stroke therapeutics targeting ion channels will be discussed in the context of the failures of the last decade in hopes that this decade will yield successful stroke therapeutics.

Minor stab wounding of rodent brain by needle or razor blade is a standard model for immunohistochemical investigations of secondary neuronal degeneration and scarring. Opening of the bloodbrain barrier (BBB) to plasma molecules and inflammatory cells is integral to the secondary injury process. To facilitate quantitative study of these BBB phenomena, we tested the utility of a stereotaxic wire knife as a minimally invasive way for modeling of focal trauma and bleeding in brain parenchyma and substantial, reproducible BBB damage. Adult rats were anesthetized, and through a skull burr hole, the 0.3-mm dia guide cannula housing a laterally extendable tungsten wire (0.13 mm dia) was inserted into the right striatum. A layering of horizontal disk-like cuts (3 mm dia) was made, producing a cylindrical lesion of ∼18 mm3 volume, ∼2.7% of the cerebral hemisphere. Transfer constants (Ki) for blood to brain permeation of [3H]sucrose measured from 30 min to 2 weeks postlesion showed sustained BBB leakiness; for example, mean Ki ± SEM (nL.g-1.s-1) for a standard, matrix-dissected forebrain sample enclosing the lesion were 7.2 ± 1.2 (day 1 postlesion), 8.1 ± 1.4 (day 3), 5.4 ± 0.8 (day 14) compared with values for contralateral nonlesioned forebrain ranging from 1.3 ± 0.05 to 1.6 ± 0.3 (n = 3-4 samples per time point). Analysis of the simultaneous transport of [14C]sucrose (MW = 342 Da) and [3H]inulin (MW ∼5,000) showed significantly larger upward increments in Ki for sucrose than inulin, indicating a pore-like opening mechanism. Significant edema was measured 3 days postlesion. A reactive glial response was indicated by an increase in S100β by 6 h and a glial scar forming around the lesion by 7 days. Secondary brain injury was indicated by a 10% loss of hemisphere mass, measured at 2 months. The wire knife enabled tailoring of interstitial trauma with a minimum of extraneous injury and supported reproducible measurements of sustained BBB injury using relatively few animals.

Animal models of cerebral ischaemia mimic at best less than 25% of all strokes. Compounds which prove efficacious in animal models should, therefore, only be expected to improve outcome in a quarter of all strokes. If trials for acute stroke are to succeed, stroke subgroups represented by the animal models should be targeted. For the other subgroups, e.g. lacunar stroke, appropriate animal models need to be developed. Moreover, thrombolysis should be included in animal models because it is likely to be used as a first line treatment for ischaemic stroke and any future therapeutics will need to be compatible with it.

Glutamate plays an important role in brain development, physiological function, and neurodegeneration. Astrocytes control synaptic concentration of glutamate via the high affinity glutamate transporters, GLT-1 and GLAST, and the glutamate catabolizing enzyme, glutamine synthetase. In this study we show that astrocytes cultured from rat brain in various stages of development including embryonic (E18), postnatal (P1–P21) and mature (P50), show distinct patterns of GLT-1 and GLAST expression, glutamine synthetase activity, and phenotypic changes induced by dibutyryl-cyclic adenosine monophosphate. The transcripts for GLT-1 message were detectable in embryonic astrocytes only, whereas the GLAST message was highly expressed in E18 and P1–P4 astrocyte cultures, declined in P10–P21, and was undetectable in P50 astrocytes. Uptake of 3H-glutamate correlated well with GLAST expression in astrocyte cultures of all developmental stages. Glutamine synthetase activity significantly declined from high embryonic levels in P4 astrocytes and remained low throughout postnatal maturation. Exposure of astrocyte cultures to the differentiating agent, db-cAMP (250–500 µM; 6 days), resulted in a pronounced stellation, up-regulation of GLT-1 and GLAST in E18, and GLAST in P4 cultures, while it was ineffective in P10 astrocytes. By contrast, db-cAMP induced a more pronounced stimulation of glutamine synthetase activity (up to 10-fold above basal) in P10 than in E18 cultures (up to 2 times above basal). The differences in expression/inducibility of glutamate transporters and glutamine synthetase observed in astrocyte cultures derived from various stages of fetal and postnatal development suggest that astrocytes in vivo might also respond differently to environmental or injurious stimuli during development and maturation.

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QUINOXALINEDIONES such as NBQX are neuroprotective in most models of cerebral ischemia but their poor solubility results in nephrotoxicity limiting their clinical utility. We have investigated the neuroprotective effects of a water soluble AMPA receptor antagonist, YM872, using two in vitromodels. The viability of cortical cultures exposed to 400 μM AMPA for 15 min (16.4 ± 2.6; n= 10) was significantly (p< 0.05) increased (84.7 ± 4.6; n= 6) with YM872 (10 μM) in a concentration-dependent manner. Evoked post-synaptic response amplitudes in oxygen-glucose deprived hippocampal slices treated with 10 μM YM872 (3.5 ± 0.3 mV; n= 27) were significantly different from untreated deprived slices (0.3 ± 0.1 mV; n= 31, p< 0.05) and the CA1 neurons appeared viable using a confocal live/dead fluorescence assay with confocal microscopy. The neuroprotection seen with YM872 in vitrowarrants further investigation in vivo.

Brain insults, including cerebral ischemia, can alter glutamate receptor subunit expression in vulnerable neurons. Understanding these post-ischemic changes in glutamate receptors could enhance our ability to identify specific, novel neuroprotective compounds. Reverse transcription-polymerase chain reaction (RT-PCR) amplification was used to quantify the altered expression of the N-methyl-d-aspartate (NMDA) NR2A, NR2B and NR2C subunits relative to one another in rat hippocampal slices in resistant and vulnerable regions following in vitro oxygen-glucose deprivation. Ninety minutes after re-oxygenation and return to 10 mM glucose, there was a significant increase in the expression of NR2C relative to NR2B and NR2A in the slice as a whole, as well as in the selectively vulnerable CA1 region and the resistant CA3 and dentate gyrus regions.

Excitatory amino acids can modify the tone of cerebral vessels and permeability of the blood-brain barrier (BBB) by acting directly on endothelial cells of cerebral vessels or indirectly by activating receptors expressed on other brain cells. In this study we examined whether rat or human cerebromicrovascular endothelial cells (CEC) express ionotropic and metabotropic glutamate receptors. Glutamate and the glutamate receptor agonists N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA), and kainate failed to increase [Ca2+]iin either rat or human microvascular and capillary CEC but elicited robust responses in primary rat cortical neurons, as measured by fura-2 fluorescence. The absence of NMDA and AMPA receptors in rat and human CEC was further confirmed by the lack of immunocytochemical staining of cells by antibodies specific for the AMPA receptor subunits GluR1, GluR2/3, and GluR4 and the NMDA receptor subunits NR1, NR2A, and NR2B. We failed to detect mRNA expression of the AMPA receptor subunits GluR1 to GluR4 or the NMDA receptor subunits NR11XX, NR10XX, and NR2A to NR2C in both freshly isolated rat and human microvessels and cultured CEC using reverse transcriptase polymerase chain reaction (RT-PCR). Cultured rat CEC expressed mRNA for KA1 or KA2 and GluR5 subunits. Primary rat cortical neurons were found to express GluR1 to GluR3 and NR1, NR2A, and NR2B by both immunocytochemistry and RT-PCR and KA1, KA2, GluR5, GluR6, and GluR7 by RT-PCR. Moreover, the metabotropic glutamate receptor agonist 1-amino-cyclopentyl-1S, 3R-dicorboxylate (1S,3R-trans-ACPD), while eliciting both inositol trisphosphate and [Ca2+]iincreases and inhibiting forskolin-stimulated cyclic AMP in cortical neurons, was unable to induce either of these responses in rat or human CEC. These results strongly suggest that both rat and human CEC do not express functional glutamate receptors. Therefore, excitatory amino acid-induced changes in the cerebral microvascular tone and BBB permeability must be affected indirectly, most likely by mediators released from the adjacent glutamate-responsive cells.

This corrects the article DOI: 10.1038/39062