The neurobiological mechanisms underlying the induction and remission of depressive episodes over time are not well understood. Through repeated longitudinal imaging of medial prefrontal ...microcircuits in the living brain, we found that prefrontal spinogenesis plays a critical role in sustaining specific antidepressant behavioral effects and maintaining long-term behavioral remission. Depression-related behavior was associated with targeted, branch-specific elimination of postsynaptic dendritic spines on prefrontal projection neurons. Antidepressant-dose ketamine reversed these effects by selectively rescuing eliminated spines and restoring coordinated activity in multicellular ensembles that predict motivated escape behavior. Prefrontal spinogenesis was required for the long-term maintenance of antidepressant effects on motivated escape behavior but not for their initial induction.
Tic disorders affect ~5% of the population and are frequently comorbid with obsessive-compulsive disorder, autism, and attention deficit disorder. Histamine dysregulation has been identified as a ...rare genetic cause of tic disorders; mice with a knockout of the histidine decarboxylase (Hdc) gene represent a promising pathophysiologically grounded model. How alterations in the histamine system lead to tics and other neuropsychiatric pathology, however, remains unclear. We found elevated expression of the histamine H3 receptor in the striatum of Hdc knockout mice. The H3 receptor has significant basal activity even in the absence of ligand and thus may modulate striatal function in this knockout model. We probed H3R function using specific agonists. The H3 agonists R-aminomethylhistamine (RAMH) and immepip produced behavioral stereotypies in KO mice, but not in controls. H3 agonist treatment elevated intra-striatal dopamine in KO mice, but not in controls. This was associated with elevations in phosphorylation of rpS6, a sensitive marker of neural activity, in the dorsal striatum. We used a novel chemogenetic strategy to demonstrate that this dorsal striatal activity is necessary and sufficient for the development of stereotypy: when RAMH-activated cells in the dorsal striatum were chemogenetically activated (in the absence of RAMH), stereotypy was recapitulated in KO animals, and when they were silenced the ability of RAMH to produce stereotypy was blocked. These results identify the H3 receptor in the dorsal striatum as a contributor to repetitive behavioral pathology.
Summary Background Surgical site infection (SSI) after colorectal surgery is the leading cause of postoperative morbidity. Opioids induce immunosuppression through activation of μ-opioid receptors ...expressed on leucocytes, and through opioid withdrawal. A high dose of opioid administered as remifentanil during surgery may induce immunosuppression, leading to the development of SSI. Aim The purpose of this study was to investigate the influence of remifentanil on the development of SSI. Methods Adult patients who underwent elective colorectal surgery from January 2009 to December 2012 ( N = 286) were prospectively investigated according to the guidelines of the US Centers for Disease Control and Prevention. After exclusion of 51 patients, propensity matching was performed in 235 patients. To reduce the influence of selection on SSIs, propensity score pairwise matching was performed for patients maintained with remifentanil and for patients maintained with fentanyl. Findings The number of patients who developed SSI was higher after remifentanil-based anaesthesia compared with fentanyl-based anaesthesia 11.6% (17/146) vs 3.4% (3/89), remifentanil vs fentanyl, P = 0.03 before propensity matching. Propensity matching yielded 61 pairs of patients anaesthetized with remifentanil or fentanyl, and corrected several biases in the preoperative patient characteristics. After propensity matching, the number of patients who developed SSI was still higher after remifentanil-based anaesthesia than after fentanyl-based anaesthesia 16.4% (10/61) vs 3.3% (2/61), remifentanil vs fentanyl, P = 0.029. Conclusion Remifentanil-based anaesthesia increased the incidence of SSI. A possible reason may be opioid-induced immunosuppression or opioid withdrawal-induced immunosuppression.
The spatial resolution along the pad-row direction was measured with a GEM-based TPC prototype for the future linear collider experiment in order to understand its performance for tracks with finite ...projected angles with respect to the pad-row normal. The degradation of the resolution due to the angular pad effect was confirmed to be consistent with the prediction of a simple calculation taking into account the cluster-size distribution and the avalanche fluctuation.
Polarization of the neuronal cell body and initiation of the first neuritic process represent the starting point of a series of dynamic metamorphic events by which the newly acquired identity of a ...group of neurons can be translated into a morphologically complex web of three-dimensional neuronal circuit. Despite the critical importance of these events, little is known about the molecular signaling mechanisms that either regulate the temporal sequence of these steps or ensure the accuracy and the spatial consistency of the resulting circuits. In this review, based on recent findings from our group and others, we present a working model on how the initial events in neuronal morphogenesis in the CNS may be controlled by multiple Rho pathways.
The molecular mechanisms that govern the coordinated programs of axonogenesis and cell body migration of the cerebellar granule cell are not well understood. In Pax6 mutant rats (rSey2/rSey2), ...granule cells in the external germinal layer (EGL) fail to form parallel fiber axons and to migrate tangentially along these fibers despite normal expression of differentiation markers. In culture, mutant cells sprout multiple neurites with enlarged growth cones, suggesting that the absence of Pax6 function perturbs cytoskeletal organization. Some of these alterations are cell-autonomous and rescuable by ectopic expression of Pax6 but not by co-culture with wild-type EGL cells. Cell-autonomous control of cytoskeletal dynamics by Pax6 is independent of the ROCK-mediated Rho small GTPase pathway. We propose that in addition to its roles during early patterning of the CNS, Pax6 is involved in a novel regulatory step of cytoskeletal organization during polarization and migration of CNS neurons.
Sevoflurane reacts with CO2 absorbents, resulting in the generation of breakdown products. The concentrations of sevoflurane breakdown products in a low-flow system within 5 h have been reported, but ...concentrations in low-flow anesthesia exceeding 5 h or in closed-circuit anesthesia have not. In this study, the breakdown products of sevoflurane in closed-circuit anesthesia exceeding 5 h were examined.
Closed-circuit sevoflurane anesthesia was administered to ten patients. Laboratory tests of hepatic and renal function were performed before and after anesthesia. Gas samples were obtained from the inspiratory limb of the anesthesia circuit, and breakdown products were analyzed by gas chromatography. The temperature of the soda lime was measured during anesthesia.
Among the breakdown products of sevoflurane, two products, CF2 = C(CF3)-O-CH2F (compound A) and CH3OCF2CH(CF3)OCH2F (compound B), were detected. Compound A was detected in all measurements, and its concentration reached 19.5 +/- 5.4 ppm 1 h after anesthesia and decreased after 5 h. The highest concentration observed for compound A was 30.0 ppm. Compound B was detected in seven of the ten patients; its concentration was 0.17 +/- 0.37 ppm after 0.5 h of anesthesia and remained at similar concentrations thereafter. The highest mean temperature of the soda lime was 46.0 +/- 1.7 degrees C. Postanesthetic clinical laboratory tests showed no abnormalities in hepatic or renal function associated with anesthesia.
Two breakdown products were detected in the patients anesthetized with sevoflurane using a closed-circuit technique. No abnormalities were observed during anesthesia, and no evidence of hepatic or renal dysfunction was noted in postoperative laboratory tests.
The cDNA for a platelet-activating factor (PAF) receptor was cloned from a human leukocyte cDNA library using a 0.8-kilobase
pair fragment of the guinea pig lung PAF receptor cDNA (Honda, Z., ...Nakamura, M., Miki, I., Minami, M., Watanabe, T., Seyama,
Y., Okado, H., Toh, H., Ito, K., Miyamoto, T., and Shimizu, T. (1991) Nature 349, 342-346). The cDNA (1.8-kilobase pairs)
had an open reading frame encoding 342 amino acid residues with a calculated Mr of 39,203. The clone was shown to code for
a PAF receptor based on the following criteria: 1) the amino acid sequence possesses seven putative membrane spanning domains
with 83% identity to the guinea pig lung PAF receptor, 2) Xenopus laevis oocytes injected with the transcript of the clone
showed an electrophysiological response to PAF, and 3) COS-7 cells expressing the encoded receptor showed ligand binding with
the pharmacological properties of the PAF receptor. Activation of the PAF receptor yielded inositol 1,4,5-trisphosphate production
in both COS-7 cells and oocytes, and guanosine 5'-O-(2-thio)bisphosphate injection into the oocytes inhibited PAF-induced
Cl- current, providing an evidence that PAF stimulates phosphoinositide turnover via G-protein(s). PAF receptor mRNA was abundant
in leukocytes and less so in an undifferentiated human eosinophilic cell line (EoL-1 cells) or human erythroleukemia cells
(HEL cells). The production of the mRNA was prominently increased when EoL-1 cells were treated with granulocyte macrophage
colony stimulating factor, interleukin-5, and n-butyrate.
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