http://molecular-ethology.biochem.s.u-tokyo.ac.jp/neuro-seminar/ftp-box/coagonist.pdf

Synaptic and Extrasynaptic NMDA Receptors Are Gated by Different Endogenous Coagonists

Schizophrenia is a complex disorder, where family, twin and adoption studies have been demonstrating a high heritability of the disease and that this disease is not simply defined by several major genes but rather evolves from addition or potentiation of a specific cluster of genes, which subsequently determines the genetic vulnerability of an individual. Linkage and association studies suggest that a genetic vulnerablility, is not forcefully leading to the disease since triggering factors and environmental influences, i.e. birth complications, drug abuse, urban background or time of birth have been identified. This has lead to the assumption that schizophrenia is not only a genetically defined static disorder but a dynamic process leading to dysregulation of multiple pathways. There are several different hypothesis based on several facets of the disease, some of them due to the relatively well-known mechanisms of therapeutic agents. The most widely considered neurodevelopmental hypothesis of schizophrenia integrates environmental influences and causative genes. The dopamine hypothesis of schizophrenia is based on the fact that all common treatments involve antidopaminergic mechanisms and genes such as DRD2, DRD3, DARPP-32, BDNF or COMT are closely related to dopaminergic system functioning. The glutamatergic hypothesis of schizophrenia lead recently to a first successful mGlu2/3 receptor agonistic drug and is underpinned by significant findings in genes regulating the glutamatergic system (SLC1A6, SLC1A2 GRIN1, GRIN2A, GRIA1, NRG1, ErbB4, DTNBP1, DAAO, G72/30, GRM3). Correspondingly, GABA has been proposed to modulate the pathophysiology of the disease which is represented by the involvement of genes like GABRA1, GABRP, GABRA6 and Reelin. Moreover, several genes implicating immune, signaling and networking deficits have been reported to be involved in the disease, i.e. DISC1, RGS4, PRODH, DGCR6, ZDHHC8, DGCR2, Akt, CREB, IL-1B, IL-1RN, IL-10, IL-1B. However, molecular findings suggest that a complex interplay between receptors, kinases, proteins and hormones is involved in schizophrenia. In a unifying hypothesis, different cascades merge into another that ultimately lead to the development of symptoms adherent to schizophrenic disorders.

/pdf/molecular-mechanisms-of-schizophrenia-519uzgf6dp.pdf

Molecular mechanisms of schizophrenia.

We report a unique mutation in the D-amino acid oxidase gene (R199W DAO) associated with classical adult onset familial amyotrophic lateral sclerosis (FALS) in a three generational FALS kindred, after candidate gene screening in a 14.52 cM region on chromosome 12q22-23 linked to disease. Neuronal cell lines expressing R199W DAO showed decreased viability and increased ubiquitinated aggregates compared with cells expressing the wild-type protein. Similarly, lentiviral-mediated expression of R199W DAO in primary motor neuron cultures caused increased TUNEL labeling. This effect was also observed when motor neurons were cocultured on transduced astrocytes expressing R199W, indicating that the motor neuron cell death induced by this mutation is mediated by both cell autonomous and noncell autonomous processes. DAO controls the level of D-serine, which accumulates in the spinal cord in cases of sporadic ALS and in a mouse model of ALS, indicating that this abnormality may represent a fundamental component of ALS pathogenesis.

https://www.pnas.org/content/pnas/107/16/7556.full.pdf

Familial amyotrophic lateral sclerosis is associated with a mutation in D-amino acid oxidase

Background
Intra-aortic balloon pump counterpulsation (IABP) is currently the most commonly used mechanical assist device for patients with cardiogenic shock due to acute myocardial infarction. Although there has been only limited evidence from randomised controlled trials, the previous guidelines of the American Heart Association/American College of Cardiology (AHA/ACC) and the European Society of Cardiology (ESC) strongly recommended the use of the IABP in patients with infarction-related cardiogenic shock on the basis of pathophysiological considerations, non-randomised trials and registry data. The recent guidelines downgraded the recommendation based on a meta-analysis which could only include non-randomised trials showing conflicting results. Up to now, there have been no guideline recommendations and no actual meta-analysis including the results of the large randomised multicentre IABP-SHOCK II Trial which showed no survival benefit with IABP support. This systematic review is an update of the review published in 2011.

Objectives
To evaluate, in terms of efficacy and safety, the effect of IABP versus non-IABP or other assist devices guideline compliant standard therapy on mortality and morbidity in patients with acute myocardial infarction complicated by cardiogenic shock.

Search methods
Searches of CENTRAL, MEDLINE (Ovid) and EMBASE (Ovid), LILACS, IndMed and KoreaMed, registers of ongoing trials and proceedings of conferences were updated in October 2013. Reference lists were scanned and experts in the field contacted to obtain further information. No language restrictions were applied.

Selection criteria
Randomised controlled trials on patients with acute myocardial infarction complicated by cardiogenic shock.

Data collection and analysis
Data collection and analysis were performed according to the published protocol. Individual patient data were provided for six trials and merged with aggregate data. Summary statistics for the primary endpoints were hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs).

Main results
Seven eligible studies were identified from a total of 2314 references. One new study with 600 patients was added to the original review. Four trials compared IABP to standard treatment and three to other percutaneous left assist devices (LVAD). Data from a total of 790 patients with acute myocardial infarction and cardiogenic shock were included in the updated meta-analysis: 406 patients were treated with IABP and 384 patients served as controls; 339 patients were treated without assisting devices and 45 patients with other LVAD. The HR for all-cause 30-day mortality of 0.95 (95% CI 0.76 to 1.19) provided no evidence for a survival benefit. Different non-fatal cardiovascular events were reported in five trials. During hospitalisation, 11 and 4 out of 364 patients from the intervention groups suffered from reinfarction or stroke, respectively. Altogether 5 out of 363 patients from the control group suffered from reinfarction or stroke. Reocclusion was treated with subsequent re-revascularization in 6 out of 352 patients from the intervention group and 13 out of 353 patients of the control group. The high incidence of complications such as moderate and severe bleeding or infection in the control groups has to be attributed to interventions with other LVAD. Possible reasons for bias were more frequent in small studies with high cross-over rates, early stopping and the inclusion of patients with IABP at randomisation.

Authors' conclusions
Available evidence suggests that IABP may have a beneficial effect on some haemodynamic parameters. However, this did not result in survival benefits so there is no convincing randomised data to support the use of IABP in infarct-related cardiogenic shock.

Intra‐aortic balloon pump counterpulsation (IABP) for myocardial infarction complicated by cardiogenic shock

Maternal cardiac arrest and perimortem caesarean delivery: Evidence or expert-based?

Gastric PCO2 monitoring during canine hemorrhagic shock encountered occasional baseline drift to higher direction when conventional PCO2 sensor was used. As a result of chemical analysis of gastric juice of dogs and human, hydrogen sulfide and acetic acid were identified as causative compounds. It was speculated that these weak acid molecules would permeate gas-permeable silicone membrane to be accumulated in the inner solution of Severinghaus-type PCO2 sensors. In order to prevent this phenomenon, double-membrane type PCO2 sensor was constructed. In this sensor, acid-neutralizing solution was installed between the inner and the outer membranes in order to dissociate weak acid molecules into corresponding ions, which can not diffuse into the inner silicone membrane. In addition, Cu2O particles were mixed in the inner silicone membrane to trap hydrogen sulfide in this membrane. It was confirmed by experiments in vitro that the readings of improved gastric PCO2 sensors were not affected by acetic acid or hydrogen sulfide. As a result of a preliminary clinical evaluation, continuous monitoring of gastric PCO2 was carried out for 72 h without detectable baseline drift or the change of sensitivity.

Gastric PCO2 monitoring system based on a double membrane type PCO2 sensor

BACKGROUND The visibility and quality of the tracheal intubation may be improved by the video intubating laryngoscope (VIL). However, the efficacy using VIL among novice residents has not been reported. METHODS Total of 154 cases of tracheal intubation experienced by 5 novice residents in 8 weeks were divided into VIL (X-Lite: Rusch, Germany) group (n = 59) and ordinary laryngoscope group (OL: n = 95), retrospectively. Number of attempts, success and failure were recorded in both groups. In VIL group, video image of the entire procedure was recorded. Success rates were compared between OL and VIL. In VIL group, elapsed time for intubation and findings during laryngoscopic procedure were examined retrospectively. RESULTS In the first attempt, the success rate was significantly higher in VIL (83%) than OL (68%). Including secondary attempt, the rate increased to 85% in OL and 97% in VIL, and the difference was also significant. In VIL group, elapsed time for entire intubation was 42 +/- 18 seconds (mean +/- SD). It was significantly decreased in 4, 6 and 7th week compared in the first week. Residents showed different pattern of findings during their laryngoscopic procedure. CONCLUSIONS The use of VIL improved success rate of tracheal intubation compared with OL. Retrospective analysis of video image revealed their progress and characteristics features in their laryngoscopic procedure. VIL was efficient in the education of the novice residents.

The efficacy of video intubating laryngoscope for novice residents

We evaluated three different tracheal tubes, Portex Profile Soft-Seal Cuff (PSSC), Portex Profile Cuff (PC) and Mallincrodt Lo-Contour (LC), when they are used in the artificial trachea and in anesthetized patients. When a cuff was inflated in the artificial trachea, PSSC with a cuff of high N2O gas-barrier property, and PC could achieve air-tight sealing with a smaller amount of injected air, compared with LC. This finding suggests that the inflated cuff-shape and cuff-fold formation are important to block the airway leakage with small volume of air. Either of three tubes was used randomly in thirty adult patients for general anesthesia using nitrous oxide 65%. Intracuff pressures were increased significantly with the passage of time. In PSSC group, however, intracuff pressure was 25 +/- 6 mmHg (mean +/- SD) at two hours, and in other two groups it was between 32 and 48 mmHg. The use of a tracheal tube with gas-barrier cuff is recommended to prevent a high tracheal wall pressure.

[Usefulness of tracheal tube with N2O gas-barrier cuff].

Intestinal mucosal ischemia is one of the earliest manifestations of impaired core tissue perfusion in critically ill patients. The aim of this study was to investigate the effects of dobutamine and dopamine on intestinal ischemia in ten anesthetized dogs. Intestinal intramural pH (pHi) by tonometry is an early reliable marker of assessing the adequacy of tissue oxygenation. A tonometer was inserted into the midjejunum through enterotomy. The superior mesenteric artery (SMA) blood flow was measured by a transit-time ultrasonic flowmeter. A vascular screw clamp for blood flow reduction was placed at the origin of the SMA, proximal to the flow probe. The SMA blood flow was maintained at 70% of baseline flow for three hours. After two hours of decreased blood flow, intravenous dobutamine or dopamine was infused at a rate of 5 micrograms.kg-1.min-1 for one hour. The pHi fell significantly from 7.16 +/- 0.04 to 7.08 +/- 0.04 in dobutamine group, and from 7.18 +/- 0.04 to 7.06 +/- 0.05 in dopamine group two hours after induction of intestinal ischemia. Treatments with dobutamine and dopamine increased the SMA blood flow to near baseline levels. Dobutamine caused a significant increase in pHi to 7.11 +/- 0.04. On the contrary, dopamine tended to decrease pHi further to 7.01 +/- 0.09. These results suggest that dobutamine may improve intestinal tissue oxygenation. However, dopamine even at lower doses, may induce constriction of the intestinal mucosal arterioles.

[How should we treat intestinal ischemia?--1: Effects of dobutamine and dopamine].

救急・集中治療領域では診療参加型の卒前教育の実施が困難な場合が多い. その対応策として患者実体シミュレータを用いる臨床実習の有用性が強調されている. 本学救急医学講座では, 研究室の一角を改築して実習専用のシミュレーションセンターを新設した. 実施環境の整備, 教育プログラムの充実により, 現実性があり緊張感をもったシミュレーションが実施可能となった. 実習終了後には録画映像を用いた討論会を開いて, 種々の問題点などを学生に指導している. 本学での患者実体シミュレータ使用状況の概略を紹介する.

Hideaki Sakio

Papers

Gastric PCO2 monitoring system based on a double membrane type PCO2 sensor

The efficacy of video intubating laryngoscope for novice residents

[Usefulness of tracheal tube with N2O gas-barrier cuff].

[How should we treat intestinal ischemia?--1: Effects of dobutamine and dopamine].

Clinical Training System Using Mannequin-Based Simulator in the Field of Critical Care Management