Human Rho guanine nucleotide exchange factor 11 gene is associated with schizophrenia in a Japanese population

ObjectiveThe human Rho guanine nucleotide exchange factor 11 (ARHGEF11) gene is one of the candidate genes for type 2 diabetes mellitus (T2DM). ARHGEF11 is mapped to chromosome 1q21, which has susceptible risk loci for T2DM and schizophrenia. We hypothesized that ARHGEF11 contributes to the pathogenesis of schizophrenia. MethodWe selected eight single nucleotide polymorphisms of ARHGEF11 that had significant associations with T2DM for a case-control association study of 490 patients with schizophrenia and 500 age-matched and sex-matched controls. ResultsWe did not find any differences in allelic, genotypic associations, or minor allele frequencies with schizophrenia. Analysis of the rs6427340-rs6427339 haplotype and the rs822585-rs6427340-rs6427339 haplotype combination provided significant evidence of an association with schizophrenia (global permutations p=0.00047 and 0.0032, respectively). C-C of the rs6427340-rs6427339 haplotype and A-C-C of the rs822585-rs6427340-rs6427339 haplotype carried higher risk factors for schizophrenia (permutation p=0.0010 and 0.0018, respectively). A-C-T of the rs822585-rs6427340-rs6427339 haplotype had a possible protective effect (permutation p=0.031). ConclusionThese results provide new evidence that ARHGEF11 may constitute a risk factor for schizophrenia

Urinary Excretion of Inorganic and Organic Fluoride after Inhalation of Sevoflurane

This study was designed to investigate the defluorination of sevoflurane in patients. Five patients, scheduled for orthopedic surgery, were administered sevoflurane for 60 min during NLA-nitrous oxide-oxygen. The end-tidal concentration of sevoflurane was adjusted at 0.6% throughout the entire inhalation period. The serum concentration of inorganic F- increased significantly 15 min after the onset of inhalation and reached a plateau at 45 min with a mean value about 15 μM. The serum organic fluoride level increased significantly 45 min after the onset of inhalation and did not change significantly 4 hr later with a mean value of about 140 μM. The elimination half-lives and rate constants were calculated from urinary data to be 2040 min and 0.00034 for inorganic fluoride and 1800 min and 0.00038 for organic fluoride respectively. The ratio organic/inorganic fluoride was calculated to be 2.3.This study was supported in part by a Grant-in-aid for Science Research from the Ministry of Education, Science and Culture of Japan

Roads of Drug Resistance in Acute Myeloid Leukemia—Is It Dead End?

Acute myeloid leukemia (AML) is a biologically and clinically heterogeneous neoplasm, which is characterized by abnormal proliferation, impaired apoptosis, and differentiation of leukemic immature cells. Nowadays, the first line treatment of AML is the chemotherapy regimen, which combines both cytosine arabinoside and anthracycline. Despite that complete remission (CR) can be achieved in 40–80% of patients depending on age, a considerable number will eventually relapse (acquired resistance) or have refractory disease (primary resistance). Finally, the estimated 5-year overall survival (OS) is less than 30%. Recent investigations reveal various mechanisms, responsible for drug resistance leading to AML persistence and recurrence. In order to improve clinical outcomes and develop successful therapeutic strategies, it is necessary to better explore the major adverse factors for escape from treatment, as well as to explore ways to predict and prevent or target drug resistance

Clinical Evaluation and Metabolism of Sevoflurane in Patients

Sevoflurane was submitted to Phase II studies in patients following Phase I studies. Sevoflurane, 2% inspired during maintenance, was administered with 50% N2O in oxygen to produce surgical anesthesia in 9 orthopedic patients of ASA Physical Status I. Under controlled ventilation, endotracheal concentration of sevoflurane was recorded. The blood concentration of sevoflurane was measured during and after the inhalation. Serum, urinary inorganic fluoride, and glucuronide of hexafluoroisopropanol were analysed with ion chromatographic analyzer. The patient inhaled sevoflurane for 3.5 ± 1.6 hr. All the patients were anesthetized and operated uneventfully. Postoperative laboratory findings showed no unexplainable abnormality. The end expiratory concentration of sevoflurane reached a plateau in 4.0 ± 0.8 min and fell rapidly after discontinuation of sevoflurane. Blood concentration of sevoflurane was about 500 μM during inhalation. It decreased promptly after termination of sevoflurane and was not correlated with anesthetic time. The time for verbal response after discontinuation was 11.8 ± 4.2 min. The serum concentration of inorganic fluoride increased after inhalation and reached a plateau (13.7 ± 8.2 μM) in 120 min. The level lasted for 120 min after anesthesia and fell by half at 12 hr after anesthesia. Urinary fluoride concentration varied from 20 to 3,000 μM during the first 12 hr urine, and showed its maximum in the first postoperative 12 or 24 hr urine. The findings that sevoflurane with nitrous oxide and oxygen produced surgical anesthesia without any sequelae and that the serum fluoride level did not exceed the nephrotoxic level warrent the further clinical evaluation in a wider range of subjects.A part of this work was supported by a Research Grant from the Japanese Ministry of Education, Science and Culture and presented at the 8th European Congress of Anaesthesiology, Vienna, Austria, in September, 1986

Hippocampal metabotropic glutamate receptor long-term depression in health and disease: focus on mitogen-activated protein kinase pathways

YesGroup I metabotropic glutamate receptor (mGluR) dependent long-term depression (LTD) is a major form of synaptic plasticity underlying learning and memory. The molecular mechanisms involved in mGluR-LTD have been investigated intensively for the last two decades. In this 60th anniversary special issue article, we review the recent advances in determining the mechanisms that regulate the induction, transduction and expression of mGluR-LTD in the hippocampus, with a focus on the mitogen-activated protein kinase (MAPK) pathways. In particular we discuss the requirement of p38 MAPK and extracellular signal-regulated kinase 1/2 (ERK 1/2) activation. The recent advances in understanding the signaling cascades regulating mGluR-LTD are then related to the cognitive impairments observed in neurological disorders, such as fragile X syndrome and Alzheimer's disease

Application of ALPIDE pixel detector for heavy-ion nuclear experiment and ion therapy

International audienceWe present computer simulation data for the dielectric constant of a system of uniform polarizable spheres randomly distributed in a homogeneous background. The deviations from the Clausius-Mossotti formula are found for seven values of the volume fraction. In addition, the spectral density which appears in the Bergman representation of the dielectric constant is determined. The spectrum obtained with a sufficient number of higher-order multipoles differs significantly from that found with just dipolar or dipole-quadrupolar interactions

Performance and application of heavy ion nuclear microbeam facility at the Nuclear Physics Institute in Řež, Czech Republic

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ELIMAIA-ELIMED: a new user platform for radiobiological research utilizing laser-driven protons

The ELIMAIA-ELIMED beamline, powered by the L3 HAPLS petawatt laser, enables the irradiation of biological samples with intermediate-energy laser-driven protons (LDP) in a multi-shot regime. In the pilot radiobiological experiment, protons with a mean energy of similar to 24 MeV and doses up to similar to 14 mGy per shot, with similar to 4 ns bunch duration, were used to irradiate AG01522 normal human skin fibroblasts. The shortest irradiation time achieved was down to similar to 17 min/Gy, while the mean and peak dose rates reached similar to 1 x 10-3 and 3.5 x 106 Gy/s, respectively. The cells were exposed to doses ranging from similar to 0.4 to 1.5 Gy and analyzed for DNA damage, with double-strand breaks visualized as 53BP1 foci. Despite the differences in shot exposures between the multi-shot LDP and the previous experiments (at other facility) with single-shot LDP, similar DNA damage responses were observed. Results with conventionally accelerated protons align closely with the corresponding single-shot LDP samples. These experimental results were achieved as part of the flagship experiment FLAIM (within the IMPULSE EU-funded project) and serve as an initial demonstration of the ELIMAIA-ELIMED platform's potential for advanced radiobiological research, creating new opportunities for such studies utilizing laser-driven ion sources

Mitochondrial ROS control neuronal excitability and cell fate in frontotemporal dementia.

INTRODUCTION: The second most common form of early-onset dementia-frontotemporal dementia (FTD)-is often characterized by the aggregation of the microtubule-associated protein tau. Here we studied the mechanism of tau-induced neuronal dysfunction in neurons with the FTD-related 10+16 MAPT mutation. METHODS: Live imaging, electrophysiology, and redox proteomics were used in 10+16 induced pluripotent stem cell-derived neurons and a model of tau spreading in primary cultures. RESULTS: Overproduction of mitochondrial reactive oxygen species (ROS) in 10+16 neurons alters the trafficking of specific glutamate receptor subunits via redox regulation. Increased surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors containing GluA1 and NR2B subunits leads to impaired glutamatergic signaling, calcium overload, and excitotoxicity. Mitochondrial antioxidants restore the altered response and prevent neuronal death. Importantly, extracellular 4R tau induces the same pathological response in healthy neurons, thus proposing a mechanism for disease propagation. DISCUSSION: These results demonstrate mitochondrial ROS modulate glutamatergic signaling in FTD, and suggest a new therapeutic strategy