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?

Exaggerated responses to chronic nociceptive stimuli and enhancement of N-methyl-D-aspartate receptor-mediated synaptic transmission in mutant mice lacking D-amino-acid oxidase.

This study compared the hemodynamic effects of enhanced external counterpulsation and intra-aortic counterpulsation in patients with acute myocardial infarction. Results demonstrated similarity between these 2 methods, except enhanced external counterpulsation had a transient effect of increasing right atrial pressure, pulmonary capillary wedge pressure, and cardiac index.

Comparison of hemodynamic effects of enhanced external counterpulsation and intra-aortic balloon pumping in patients with acute myocardial infarction.

A 75-year-old woman with amyotrophic lateral sclerosis (ALS) underwent surgical gastrostomy and repair of incisional hernia Anesthesia was induced with propofol and high concentrations of sevoflurane Tracheal intubation was performed without muscle relaxants Anesthesia was maintained with sevoflurane and thoracic epidural anesthesia (bupivacaine and fentanyl) Surgery, emergence and extubation were completed uneventfully She was transferred to ICU for postoperative observation On the 2 nd POD, however, she was re-intubated due to sudden dyspnea and desaturation caused by failed sputum exhaustion Simultaneously, her ECG showed ischemic change in leads I, III, aVF, and V3-6 Left ventriculogram showed an "Ampulla" or so called "Takotsubo" shape with intact coronary angiogram After medication with nitroglycerin and diltiazem, her ECG returned to normal She showed no deterioration of neurological symptoms No respiratory and cardiac events were reported until her discharge from hospital We conclude that an extreme care is required in patient with ALS to avoid perioperative complications

["Takotsubo" cardiomyopathy developed in the postoperative period in a patient with amyotrophic lateral sclerosis].

IMPLICATIONS We measured plasma propofol levels by head space-gas chromatography analysis using solid-phase microextraction. This method saves time, and does not require elimination of interfering substances in the plasma. The coefficient variation was +/-5% to +/-30%. The detection limit was 10 ng/mL.

A simple method for detecting plasma propofol.

A 23-year-old woman at 35 weeks of gestation was scheduled for emergency cesarean section because of preeclampsia. Anesthesia was induced with thiopental 250 mg, and her trachea was intubated following administration of vecuronium 7 mg. Anesthesia was maintained with oxygen and sevoflurane (0.5%). Immediately after the start of the surgical procedure, she developed severe bradycardia and hypotension followed by cardiac arrest. She was resuscitated, and her heart beat resumed 30 min after the start of the resuscitation. Her babies were delivered without sequela during resuscitation. She was transferred to the intensive care unit of our university hospital. She was diagnosed as having peripartum cardiomyopathy from her history and echocardiography. She was discharged from the hospital with only slight disturbance of consciousness two months after surgery.

Hideaki Sakio

Papers

Exaggerated responses to chronic nociceptive stimuli and enhancement of N-methyl-D-aspartate receptor-mediated synaptic transmission in mutant mice lacking D-amino-acid oxidase.

Comparison of hemodynamic effects of enhanced external counterpulsation and intra-aortic balloon pumping in patients with acute myocardial infarction.

["Takotsubo" cardiomyopathy developed in the postoperative period in a patient with amyotrophic lateral sclerosis].

A simple method for detecting plasma propofol.

[Cardiac arrest during emergency cesarean section due to peripartum cardiomyopathy--a case report].