Corticosterone Induces Rapid Spinogenesis via Synaptic Glucocorticoid Receptors and Kinase Networks in Hippocampus

BACKGROUND: Modulation of dendritic spines under acute stress is attracting much attention. Exposure to acute stress induces corticosterone (CORT) secretion from the adrenal cortex, resulting in rapid increase of CORT levels in plasma and the hippocampus. METHODOLOGY/PRINCIPAL FINDINGS: Here we demonstrated the mechanisms of rapid effect (∼1 h) of CORT on the density and morphology of spines by imaging neurons in adult male rat hippocampal slices. The application of CORT at 100-1000 nM induced a rapid increase in the density of spines of CA1 pyramidal neurons. The density of small-head spines (0.2-0.4 µm) was increased even at low CORT levels (100-200 nM). The density of middle-head spines (0.4-0.5 µm) was increased at high CORT levels between 400-1000 nM. The density of large-head spines (0.5-1.0 µm) was increased only at 1000 nM CORT. Co-administration of RU486, an antagonist of glucocorticoid receptor (GR), abolished the effect of CORT. Blocking a single kinase, such as MAPK, PKA, PKC or PI3K, suppressed CORT-induced enhancement of spinogenesis. Blocking NMDA receptors suppressed the CORT effect. CONCLUSIONS/SIGNIFICANCE: These results imply that stress levels of CORT (100-1000 nM) drive the spinogenesis via synaptic GR and multiple kinase pathways

Endogenous Synthesis of Corticosteroids in the Hippocampus

BACKGROUND: Brain synthesis of steroids including sex-steroids is attracting much attention. The endogenous synthesis of corticosteroids in the hippocampus, however, has been doubted because of the inability to detect deoxycorticosterone (DOC) synthase, cytochrome P450(c21). METHODOLOGY/PRINCIPAL FINDINGS: The expression of P450(c21) was demonstrated using mRNA analysis and immmunogold electron microscopic analysis in the adult male rat hippocampus. DOC production from progesterone (PROG) was demonstrated by metabolism analysis of (3)H-steroids. All the enzymes required for corticosteroid synthesis including P450(c21), P450(2D4), P450(11β1) and 3β-hydroxysteroid dehydrogenase (3β-HSD) were localized in the hippocampal principal neurons as shown via in situ hybridization and immunoelectron microscopic analysis. Accurate corticosteroid concentrations in rat hippocampus were determined by liquid chromatography-tandem mass spectrometry. In adrenalectomized rats, net hippocampus-synthesized corticosterone (CORT) and DOC were determined to 6.9 and 5.8 nM, respectively. Enhanced spinogenesis was observed in the hippocampus following application of low nanomolar (10 nM) doses of CORT for 1 h. CONCLUSIONS/SIGNIFICANCE: These results imply the complete pathway of corticosteroid synthesis of 'pregnenolone →PROG→DOC→CORT' in the hippocampal neurons. Both P450(c21) and P450(2D4) can catalyze conversion of PROG to DOC. The low nanomolar level of CORT synthesized in hippocampal neurons may play a role in modulation of synaptic plasticity, in contrast to the stress effects by micromolar CORT from adrenal glands

Investigation of perioperative safety and clinical results of one-stage bilateral total knee arthroplasty in selected low-risk patients

Abstract Background An increased perioperative complication rate has been a concern with one-stage bilateral total knee arthroplasty (TKA). The purpose of this study was to retrospectively investigate the perioperative safety and clinical results of one-stage bilateral TKA in selected low-risk patients. Methods Sixty-seven patients who received one-stage bilateral TKAs for osteoarthritis who were American Society of Anesthesiology (ASA) class 1 or 2 were included in this study. Perioperative complications, blood loss, transfusion rate, blood laboratory results, and clinical results were evaluated up to 1 year after surgery. Results No major complications (deep infection, pulmonary embolism, cerebrovascular accident, myocardial infarction, death, or removal or revision of the implants) were observed. The average total blood loss was 1139.5 ml. The transfusion rate was 95.5%. Postoperative hemoglobin level and C-reactive protein level gradually improved up to postoperative day 21 (P < 0.01). Bilateral knee extension knee angles and clinical scores improved postoperatively as compared with preoperative values (P < 0.01). Conclusions Although total blood loss and transfusion rate can be high, this preliminary case series suggested that the one-stage bilateral TKA in ASA class 1 or 2 patients can have high perioperative safety levels, and good clinical results can be obtained up to 1 year after surgery. If low-risk patients are selected for bilateral TKA, a one-stage procedure can be beneficial for patients, with a minimal increase in the risk of complications

Influence of nitrous oxide on minimum alveolar concentration of sevoflurance for laryngeal mask insertion in children

Background: Inhalational induction with sevoflurane and nitrous oxide is frequently used for Laryngeal Mask Airway ™ (LMA ™; Laryngeal Mask Company, Henley-on-Thames, United Kingdom) insertion in children. The authors determined the influence of nitrous oxide on the minimum alveolar concentration (MAC) of sevoflurane for LMA ™ insertion.\ud \ud Methods: One hundred twenty unpremedicated children (age, 1-9 yr; American Society of Anesthesiologists physical status I) were randomly assigned to receive 1 of 15 end-tidal concentrations of nitrous oxide and sevoflurane for inhalational induction via a facemask: 0% nitrous oxide with 1.2, 1.4, 1.6, 1.8, or 2.0% sevoflurane; 33% nitrous oxide with 0.8, 1.0, 1.2, 1.4, or 1.6% sevoflurane; or 67% nitrous oxide with 0.4, 0.6, 0.8, 1.0, or 1.2% sevoflurane. The LMA ™ was inserted after steady state end-tidal anesthetic concentrations had been maintained for 15 min. The response to insertion was recorded by three independent blinded observers. The interaction between nitrous oxide and sevoflurane was determined using logistic regression analysis.\ud \ud Results: The MAC of sevoflurane for LMA ™ insertion (95% confidence limit) was 1.57% (1.42-1.72%), and the concentration of sevoflurane required to prevent movement in 95% of children was 1.99% (1.81-2.57%). The addition of 33% and 67% nitrous oxide linearly decreased the MAC of sevoflurane for LMA ™ insertion by 22% and 49%, respectively (P < 0.001). The interaction coefficient between nitrous oxide and sevoflurane did not differ from zero (P = 0.7843), indicating that the relation was additive.\ud \ud Conclusions: Nitrous oxide and sevoflurane suppress the responses to LMA ™ insertion in a linear and additive fashion in children.\u

Influence of Nitrous Oxide on Minimum Alveolar Concentration of Sevoflurane for Laryngeal Mask Insertion in Children

Background: Inhalational induction with sevoflurane and nitrous oxide is frequently used for Laryngeal Mask Airway™ (LMA™; Laryngeal Mask Company, Henley-on-Thames, United Kingdom) insertion in children. The authors determined the influence of nitrous oxide on the minimum alveolar concentration (MAC) of sevoflurane for LMA™ insertion. Methods: One hundred twenty unpremedicated children (age, 1-9 yr; American Society of Anesthesiologists physical status I) were randomly assigned to receive 1 of 15 end-tidal concentrations of nitrous oxide and sevoflurane for inhalational induction via a facemask: 0% nitrous oxide with 1.2, 1.4, 1.6, 1.8, or 2.0% sevoflurane; 33% nitrous oxide with 0.8, 1.0, 1.2, 1.4, or 1.6% sevoflurane; or 67% nitrous oxide with 0.4, 0.6, 0.8, 1.0, or 1.2% sevoflurane. The LMA™ was inserted after steady state end-tidal anesthetic concentrations had been maintained for 15 min. The response to insertion was recorded by three independent blinded observers. The interaction between nitrous oxide and sevoflurane was determined using logistic regression analysis. Results: The MAC of sevoflurane for LMA™ insertion (95% confidence limit) was 1.57% (1.42-1.72%), and the concentration of sevoflurane required to prevent movement in 95% of children was 1.99% (1.81-2.57%). The addition of 33% and 67% nitrous oxide linearly decreased the MAC of sevoflurane for LMA™ insertion by 22% and 49%, respectively (P < 0.001). The interaction coefficient between nitrous oxide and sevoflurane did not differ from zero (P = 0.7843), indicating that the relation was additive. Conclusions: Nitrous oxide and sevoflurane suppress the responses to LMA™ insertion in a linear and additive fashion in children

Deciphering Time Scale Hierarchy in Reaction Networks

Markovian dynamics on complex reaction networks are one of the most intriguing subjects in a wide range of research fields including chemical reactions, biological physics, and ecology. To represent the global kinetics from one node (corresponding to a basin on an energy landscape) to another requires information on multiple pathways that directly or indirectly connect these two nodes through the entire network. In this paper we present a scheme to extract a hierarchical set of global transition states (TSs) over a discrete-time Markov chain derived from first-order rate equations. The TSs can naturally take into account the multiple pathways connecting any pair of nodes. We also propose a new type of disconnectivity graph (DG) to capture the hierarchical organization of different time scales of reactions that can capture changes in the network due to changes in the time scale of observation. The crux is the introduction of the minimum conductance cut (MCC) in graph clustering, corresponding to the dividing surface across the network having the “smallest” transition probability between two disjoint subnetworks (superbasins on the energy landscape) in the network. We present a new combinatorial search algorithm for finding this MCC. We apply our method to a reaction network of Claisen rearrangement of allyl vinyl ether that consists of 23 nodes and 66 links (saddles on the energy landscape) connecting them. We compare the kinetic properties of our DG to those of the transition matrix of the rate equations and show that our graph can properly reveal the hierarchical organization of time scales in a network

Effects of inhibitors for protein and mRNA synthesis on changes in the density and morphology of spines by CORT.

<p>(A) Total spine density. Effect of inhibitors for protein or mRNA synthesis in the presence of CORT on CA1 neurons. A 1 h treatment in ACSF without drugs (Control), with 1 µM CORT (CORT), with 1 µM CORT and 20 µM cycloheximide (CORT + CHX), and with 1 µM CORT and 4 µM actinomycin D (CORT + ActD). (B) Histogram of spine head diameters. Abbreviations are same as in (A). Control (open circle), CORT (closed black circle), CORT + CHX (closed red circle), and CORT + ActD (closed blue circle). (C) Density of three subtypes of spines. Abbreviations are same as in (A). From left to right, small-head spines (small), middle-head spines (middle), and large-head spines (large). ACSF without drugs (open column), CORT (black column), CORT + CHX (red column), and CORT + ActD (blue column). Vertical axis is the average number of spines per 1 µm of dendrite. Statistical significance is calculated against CORT treated group in each spine subtypes and comparisons reached significance are indicated by stars. (D) No effect of inhibitors alone for protein and mRNA synthesis on the total spine density in CA1 neurons. Abbreviations are the same as in (A). Vertical axis is the average number of spines per 1 µm of dendrite. In (A) and (C), results are reported as mean ± SEM. In (A) and (C), the significance of CORT or drug effect was examined using the Tukey–Kramer <i>post hoc</i> multiple comparisons test when one way ANOVA tests yielded <i>P</i><0.05. *<i>P</i><0.05, **<i>P</i><0.01. For each drug treatment, we investigated 3 rats, 6 slices, 12 neurons, 24 dendrites and 1100–1800 spines, except for 1 µM CORT which consists of 10 rats, 28 slices, 56 neurons, 113 dendrites and approx. 8000 spines. For control, we used 5 rats, 8 slices, 16 neurons, 31 dendrites and approx. 1700 spines.</p

Effects of blockers of receptors on changes by CORT in the density and morphology of spines.

<p>(A) Effects of treatments by 1 µM CORT and blockers of receptors on the total spine density in CA1 neurons. A 1 h treatment in ACSF without drugs (Control), with 1 µM CORT (CORT), with 1 µM and 10 µM RU486 (CORT + RU), with 1 µM CORT and 50 µM MK-801 (CORT + MK), with 1 µM CORT and 20 µM CNQX (CORT + CNQX). (B) Histogram of spine head diameters after a 1 h treatment in ACSF without drugs (Control, open circle), with 1 µM CORT (CORT, closed black circle), and with 1 µM CORT and 10 µM RU486 (CORT + RU, closed red circle), with 1 µM CORT and 50 µM MK-801 (CORT + MK, closed blue circle), with 1 µM CORT and 20 µM CNQX (CORT + CNQX, closed green circle). Small-head spines (small), middle-head spines (middle), and large-head spines (large) are categorized. (C) Density of three subtypes of spines. Abbreviations are same as in (B). ACSF without drugs (open column), CORT (black column), CORT + RU (red column), CORT + MK (blue column), and CORT + CNQX (green column) are shown. (D) No effect of receptor inhibitors alone on the total spine density in CA1 neurons. Abbreviations are the same as in (A). Vertical axis is the average number of spines per 1 µm of dendrite. In (A) and (C), results are reported as mean ± SEM. In (A) and (C), the significance of CORT or drug effect was examined using the Tukey–Kramer <i>post hoc</i> multiple comparisons test when one way ANOVA tests yielded <i>P</i><0.05. *<i>P</i><0.05, **<i>P</i><0.01. For each drug treatment, we investigated 3 rats, 7 slices, 14 neurons, 28 dendrites and 1400–2000 spines, except for CORT which consists of 10 rats, 28 slices, 56 neurons, 113 dendrites and approx. 8000 spines. For control, we used 5 rats, 8 slices, 16 neurons, 31 dendrites and approx. 1700 spines.</p

Spine density of hippocampal CA1 neurons in sham rat (Control) or adrenalectomized rat (ADX).

<p>(A) Total spine density. For both sham and ADX rats, slices are incubated for 1 h in ACSF without drugs. The Total spine density was not different significantly between Control and ADX rats. (B) Histogram of spine head diameters. Abbreviations are same as in (A). After a 1 h treatment in ACSF without drugs for sham rat (Control, open circle) and ADX (closed black circle). (C) Density of three subtypes of spines. From left to right, small-head spines (small), middle-head spines (middle), and large-head spines (large). Abbreviations are same as in (A). Control (open column) and ADX (black column). Vertical axis is the average number of spines per 1 µm of dendrite. In (A) and (C) results are reported as mean ± SEM. The significance was examined using the Tukey–Kramer <i>post hoc</i> multiple comparisons test when one way ANOVA tests yielded <i>P</i><0.05. For sham and ADX rats, we investigated 3 rats, 6 slices, 12 neurons, 24 dendrites and approx. 1300 spines.</p