Direct interaction of insulin-like growth factor-1 receptor with leukemia-associated RhoGEF

Insulin-like growth factor (IGF)-1 plays crucial roles in growth control and rearrangements of the cytoskeleton. IGF-1 binds to the IGF-1 receptor and thereby induces the autophosphorylation of this receptor at its tyrosine residues. The phosphorylation of the IGF-1 receptor is thought to initiate a cascade of events. Although various signaling molecules have been identified, they appear to interact with the tyrosine-phosphorylated IGF-1 receptor. Here, we identified leukemia-associated Rho guanine nucleotide exchange factor (GEF) (LARG), which contains the PSD-95/Dlg/ZO-1 (PDZ), regulator of G protein signaling (RGS), Dbl homology, and pleckstrin homology domains, as a nonphosphorylated IGF-1 receptor-interacting molecule. LARG formed a complex with the IGF-1 receptor in vivo, and the PDZ domain of LARG interacted directly with the COOH-terminal domain of IGF-1 receptor in vitro. LARG had an exchange activity for Rho in vitro and induced the formation of stress fibers in NIH 3T3 fibroblasts. When MDCKII epithelial cells were treated with IGF-1, Rho and its effector Rho-associated kinase (Rho-kinase) were activated and actin stress fibers were enhanced. Furthermore, the IGF-1–induced Rho-kinase activation and the enhancement of stress fibers were inhibited by ectopic expression of the PDZ and RGS domains of LARG. Taken together, these results indicate that IGF-1 activates the Rho/Rho-kinase pathway via a LARG/IGF-1 receptor complex and thereby regulates cytoskeletal rearrangements

Early aggressive intervention for infantile atopic dermatitis to prevent development of food allergy : a multicenter, investigator‑blinded, randomized, parallel group controlled trial (PACI Study) : protocol for a randomized controlled trial

Background: Atopic dermatitis is the first clinical manifestation of the atopic march, with the highest incidence in the first year of life. Those affected often go on to develop other allergic diseases including food allergy, asthma, and allergic rhinitis. Recent evidence suggests that sensitization to foods may occur through a defective skin barrier which is common in atopic dermatitis in early life. We hypothesize that therapeutic aggressive intervention to treat new onset atopic dermatitis may prevent the development of later allergen sensitization, and associated food allergy, asthma, and allergic rhinitis. Methods: This study is a multi-center, pragmatic, two-parallel group, assessor-blind, superiority, individually randomized controlled trial. Atopic dermatitis infants (N = 650) 7–13 weeks old who develop an itchy rash within the previous 28 days are randomly assigned to the aggressive treatment or the conventional treatment in a 1:1 ratio. The primary outcome is oral food challenge-proven IgE-mediated hen’s egg allergy at the age of 28 weeks. Discussion: This is a novel pragmatic RCT study to examine the efficacy of early aggressive treatment for atopic dermatitis to prevent later food allergy. If our hypothesis is correct, we hope that such a strategy might impact on disease prevention in countries where food allergy is common, and that our results might reduce the frequency and associated costs of all food allergies as well as hens egg food allergy. Long-term follow and other similar studies will help to determine whether such a strategy will reduce the burden of other allergic diseases such as asthma and allergic rhinitis

Association between the examination rate of treatment-resistant schizophrenia and the clozapine prescription rate in a nationwide dissemination and implementation study

Background: The decision to initiate clozapine treatment should be made on an individual basis and may be closely related to the early detection of treatment-resistant schizophrenia (TRS), although there is evidence that the early use of clozapine results in a better response to treatment. Therefore, we investigated the relationship between the examination rate of TRS and the prescription rate of clozapine. Methods: After attending a 1-day educational program on schizophrenia based on the "Guidelines for the Pharmacological Treatment of Schizophrenia," we asked the participating facilities to submit records of whether or not TRS was evaluated for each patient. We calculated the clozapine prescription rate from the schizophrenic patients prescribed clozapine and all of the schizophrenic patients. Forty-nine facilities in 2017 were included in the study. Results: There were dichotomous distributions in the examination rate of TRS and a non-normal distribution in the prescription rate of clozapine. There was a significant correlation between the prescription rate of clozapine and the examination rate of TRS (r s = 0.531, P = 1.032 × 10−4). A significant difference was found in the prescription rate of clozapine between the three groups of facilities according to the examination rate of TRS. Conclusion: As a preliminary problem for the use of clozapine, in Japan, the examination rate of TRS varies, and there are many facilities that typically do not consider the possibility of TRS; this trend leads to a low rate of clozapine use. Clearly, further clinician training is needed for the early detection and appropriate management of TRS that includes an explanation of TRS and how to introduce clozapine therapy to patients and their families

EGUIDE project and treatment guidelines

Background Clinical practice guidelines for schizophrenia and major depressive disorder have been published. However, these have not had sufficient penetration in clinical settings. We developed the Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE) project as a dissemination and education programme for psychiatrists. Aims The aim of this study is to assess the effectiveness of the EGUIDE project on the subjective clinical behaviour of psychiatrists in accordance with clinical practice guidelines before and 1 and 2 years after participation in the programmes. Method A total of 607 psychiatrists participated in this study during October 2016 and March 2019. They attended both 1-day educational programmes based on the clinical practice guidelines for schizophrenia and major depressive disorder, and answered web questionnaires about their clinical behaviours before and 1 and 2 years after attending the programmes. We evaluated the changes in clinical behaviours in accordance with the clinical practice guidelines between before and 2 years after the programme. Results All of the scores for clinical behaviours in accordance with clinical practice guidelines were significantly improved after 1 and 2 years compared with before attending the programmes. There were no significant changes in any of the scores between 1 and 2 years after attending. Conclusions All clinical behaviours in accordance with clinical practice guidelines improved after attending the EGUIDE programme, and were maintained for at least 2 years. The EGUIDE project could contribute to improved guideline-based clinical behaviour among psychiatrists

Impurity emission characteristics of long pulse discharges in Large Helical Device

Line spectra from intrinsic impurity ions have been monitored during the three kinds of long-pulse discharges (ICH, ECH, NBI). Constant emission from the iron impurity shows no preferential accumulation of iron ion during the long-pulse operations. Stable Doppler ion temperature has been also measured from Fe XX, C V and C III spectra

Bisphenol A Does Not Affect Memory Performance in Adult Male Rats

Bisphenol A (BPA) is an estrogenic endocrine disruptor used for producing polycarbonate plastics and epoxy resins. This study investigated the effects of oral BPA administration on memory performance, general activity, and emotionality in adult male Sprague Dawley rats using a battery of behavioral tests, including an appetite-motivated maze test (MAZE test) used to assess spatial memory performance. In addition, in order to confirm the effects of BPA on spatial memory performance, we examined whether intrahippocampal injection of BPA affects spatial memory consolidation. In the MAZE test, although oral BPA administration at 10 mg/kg significantly altered the number of entries into the incorrect area compared to those of vehicle-treated rats, male rats given BPA through either oral administration or intrahippocampal injection failed to show significant differences in latencies to reach the reward. Also, oral BPA administration did not affect fear-motivated memory performance in the step-through passive avoidance test. Oral BPA administration at 0.05 mg/kg, the lowest dose used in this study, was correlated with a decrease in locomotor activity in the open-field test, whereas oral administration at 10 mg/kg, the highest dose used in this study, was correlated with a light anxiolytic effect in the elevated plus-maze test. The present study suggests that BPA in adulthood has little effect on spatial memory performance in male rats

Recent Results from LHD Experiment with Emphasis on Relation to Theory from Experimentalist’s View

he Large Helical Device (LHD) has been extending an operational regime of net-current free plasmas towardsthe fusion relevant condition with taking advantage of a net current-free heliotron concept and employing a superconducting coil system. Heating capability has exceeded 10 MW and the central ion and electron temperatureshave reached 7 and 10 keV, respectively. The maximum value of β and pulse length have been extended to 3.2% and 150 s, respectively. Many encouraging physical findings have been obtained. Topics from recent experiments, which should be emphasized from the aspect of theoretical approaches, are reviewed. Those are (1) Prominent features in the inward shifted configuration, i.e., mitigation of an ideal interchange mode in the configuration with magnetic hill, and confinement improvement due to suppression of both anomalous and neoclassical transport, (2) Demonstration ofbifurcation of radial electric field and associated formation of an internal transport barrier, and (3) Dynamics of magnetic islands and clarification of the role of separatrix

A flat-lying dimer as a key intermediate in NO reduction on Cu(100)

The reaction of nitric oxide (NO) on Cu(100) is studied by scanning tunneling microscopy, electron energy loss spectroscopy and density functional theory calculations. The NO molecules adsorb mainly as monomers at 64 K, and react and dissociate to yield oxygen atoms on the surface at ∼70 K. The temperature required for the dissociation is significantly low for Cu(100), compared to those for Cu(111) and Cu(110). The minimum energy pathway of the reaction is via (NO)₂ formation, which converts into a flat-lying ONNO and then dissociates into N₂O and O with a considerably low activation energy. We propose that the formation of (NO)₂ and flat-lying ONNO is the key to the exceptionally high reactivity of NO on Cu(100)