Neurobiological basis of relapse prediction in stimulant-induced psychosis and schizophrenia: the role of sensitization

A number of consistent clinical observations provide direction for the hypothesis that pathological sensitization of neuronal systems may be an important factor for relapse or the onset of stimulant-induced psychosis (eg, methamphetamine or amphetamine psychosis, cocaine psychosis and phencyclidine psychosis) and schizophrenia. First, psychotic symptoms can be produced in normal subjects by stimulants. Secondly, a large portion of schizophrenic patients exhibit exacerbation of psychotic symptoms in response to stimulants at doses which would not be psychotogenic in normal subjects. Lastly, the ability of stress to precipitate the onset and relapse of schizophrenia is well documented. In this regard, acute responses to stimulants provide useful information for relapse prediction of schizophrenia and substance abuse. This paper addresses the nature and role of pathological sensitization in relapse of stimulant- and phencyclidine-induced psychosis and schizophrenia, and its relation to pathophysiology of schizophrenia.     

Stimulation of bradykinin B2-receptors on endothelial cells induces relaxation and contraction in porcine basilar artery in vitro.

1. The aim of the present study was to characterize the subtypes of bradykinin (BK) receptors that evoke the relaxation and contraction induced by BK and to identify the main contracting and relaxing factors in isolated porcine basilar artery by measuring changes in isometric tension and a thromboxane (TX) metabolite. 2. Endothelial denudation completely abolished both responses. [Thi5,8, D-Phe7]-BK (a B2-receptor antagonist) inhibited the BK-induced relaxation and contraction, whereas des-Arg9, [Leu8]-BK (a B1-receptor antagonist) had no effect. 3. L-nitro-arginine (L-NA, a nitric oxide synthase inhibitor) completely inhibited BK-induced relaxation. Indomethacin (a cyclo-oxygenase inhibitor) completely and ONO-3708 (a TXA2/prostaglandin H2 receptor antagonist) partially inhibited BK-induced contraction, whereas OKY-046 (a TXA2 synthase inhibitor) and nordihydroguaiaretic acid (a lipoxygenase inhibitor) did not. 4. In the presence of L-NA, the contractile response to BK was inhibited by indomethacin or ONO-3708 and was competitively antagonized by [Thi5,8, D-Phe7]-BK (pA2=7.50). In the presence of indomethacin, the relaxant response to BK was inhibited by L-NA and was competitively antagonized by [Thi5,8, D-Phe7]-BK (pA2=7.59). 5. TXA2 release was not induced by BK-stimulation. 6. These results suggest that the endothelium-dependent relaxation and contraction to BK in the porcine basilar artery is mediated via activation of endothelial B2-receptors. The main relaxing factor may be NO and the main contracting factor may be prostaglandin H2.     

Identification of binding sites of bopindolol and its two metabolites with beta1-adrenoceptors by molecular modeling: comparison with beta2 adrenoceptors

This study was designed to examine the importance of interaction in the bindings of nonselective beta-blockers to beta1-adrenoceptors (beta1-ARs) as compared with beta2-ARs, using molecular modeling. The beta-blockers used in this study were bopindolol [4-(benzoyloxy-3-t- butylaminopropyl)-2-methylindol hydrogen malomate], its two metabolites [18-502 - hydrolyzed bopindolol or 4-(3-t-butylamino-2-hydroxypropoxy)-2-methyl indole - and 20-785 - 4-(3-t-butylaminopropoxy)-2-carboxyl indole], and propranolol. Molecular modeling was performed on an Indigo2 workstation (Silicon Graphic) using Discover/Insight II (Molecular Simulations) software. Through molecular modeling, possible binding sites for these drugs were suggested to lie between helices 3, 4, 5, and 6 of the beta1-AR. The amine, benzoic acid, indole methyl, t-butyl, phenyl, and indole functional groups of bopindolol possibly interact with Asp138 (transmembrane - TM - 3), Ser190 (TM 4), Ala343 (TM 6), Val137 (TM 3), Pro339 (TM6), Cys336 (TM 4), Leu237 (TM 5), and Pro236 (TM 5) of beta1-AR, respectively, by either hydrogen bonding or hydrophobic interactions. In addition, 18-502, 20-785, and propranolol also interacted with sites at the same positions as those of beta2-ARs. Thus, the results of the present study suggested that although Ala343 and Val137 of beta1-AR among these amino acids were different from those of beta2-AR, the interactions at the same sites between ligands and amino acids of beta1-AR as those of beta2-ARs may occur because these drugs are nonselective.     

Studies on Iridoid-related Compounds III: Gentiopicral, the Aglucone of Gentiopicroside

Enzymatic hydrolysis of gentiopicroside ( 1) provided the new aglucone, gentiopicral ( 2), the structure of which was firmly elucidated by means of spectroscopic methods.     

CSF phosphorylated tau protein and mild cognitive impairment: a prospective study

Cerebrospinal fluid (CSF) tau protein phosphorylated at both Thr231 and Ser235 sites (CSF/phospho-tau(231-235)) and total tau (CSF/total-tau) were quantified by sandwich ELISA in 20 patients with mild cognitive impairment (MCI) who eventually developed AD on follow-up as well as seven memory complainers with no objective memory loss. 13/20 (65%) of the MCI patients had high CSF/total-tau and detectable levels of CSF/phospho-tau(231-235), whereas these markers were low and under a detectable level in all of the memory complainers. Although either a total-tau, phospho-tau measurement or a combination of these can help in predicting if MCI will develop AD, our results suggest that the pathogenic steps of AD may be at the stage that finally leads to an accumulation of abnormally phosphorylated tau and neuron death, at least in some brain areas, when MCI patients present with the earliest detectable clinical symptoms of dementia.     

Thoracoscopic surgery for pulmonary nodules in patients with previous malignant tumor

We evaluated the clinico-pathological characteristics of thirty-four cases with previous malignant tumor who was operated under thoracoscopy for pulmonary nodules. In twenty-three cases (67.6%), including 20 cases suspected metastatic pulmonary tumor before operation, thoracoscopic surgery was performed without doing the preoperative examinations for the definite diagnosis. The mean diameter of resected tumors was 13.5 mm and the definite diagnosis was determined in all cases by the intraoperative pathological diagnosis. There were 26(76.5%) cases of malignancy, including 20 cases(58.8%) of metastatic pulmonary tumor and 6 cases (17.7%) of primary lung cancer. Accuracy rate of predictive diagnosis before operation was 67.6%. From the analysis of difference between pre- and post-operative diagnoses, inflammatory nodules or tuberculoma in the solitary nodule and intrapulmonary lymph nodes or silicotic nodules in the multiple nodules should have been considered with more carefully attention. Univariate and multivariate analysis showed that patients with metastatic tumor previously was only a predictive factor for metastatic tumor. Age, gender, CT findings, the number of nodules, disease free interval and tumor markers were unreliable factors in this study. In conclusion, there were a lot of cases with previous malignant tumor in which thoracoscopic surgery could become a first choice of modalities for the diagnosis of pulmonary nodules. Early thoracoscopic procedure will be recommended for such patients to perform the immediate treatment.     

Coronary artery bypass grafting for a patient with bronchial asthma seceeded from cardiopulmonary bypass by additional bypass for spasm of radial artery graft: a case report

A 78-year-old male who had a bronchial asthma underwent coronary artery bypass grafting (CABG) using the left internal thoracic artery and the radial artery. The patient could not be weaned from the cardiopulmonary bypass because the radial artery which anastomosed to the obtuse marginal artery (OM) had a spasm after CABG. An additional bypass using a long saphenous vein to OM was carried out immediately. It brought a weaning from cardiopulmonary bypass. If the cardiac function after CABG is insufficient in patients with bronchial asthma, CABG must be re-done immediately, considering that they cause the arterial spasm more than patients without bronchial asthma.     

Minimum alveolar concentration-awake of Xenon alone and in combination with isoflurane or sevoflurane

BACKGROUND: The minimum alveolar concentration (MAC)-awake is a traditional index of hypnotic potency of an inhalational anesthetic. The MAC-awake of xenon, an inert gas with anesthetic properties (MAC = 71%), has not been determined. It is also unknown how xenon interacts with isoflurane or sevoflurane on the MAC-awake. METHODS: In the first part of the study, 90 female patients received xenon, nitrous oxide (N2O), isoflurane, or sevoflurane supplemented with epidural anesthesia (n = 36 for xenon and n = 18 per group for other anesthetics). In the second part, 72 additional patients received either xenon or N2O combined with the 0.5 times MAC-awake concentration of isoflurane or sevoflurane (0.2% and 0.3%, respectively, based on the results of the first part; n = 18 per group). During emergence, the concentration of an assigned anesthetic (xenon or N2O only in the second part) was decreased in 0. 1 MAC decrements every 15 min from 0.8 MAC or from 70% in the case of N2O until the patient followed the command to either open her eyes or to squeeze and release the investigator's hand. The concentration midway between the value permitting the first response to command and that just preventing it was defined as the MAC-awake. RESULTS: The MAC-awake were as follows: xenon, 32.6 +/- 6.1% (mean +/- SD) or 0.46 +/- 0.09 MAC; N2O, 63.3 +/- 7.1% (0.61 +/- 0.07 MAC); isoflurane, 0.40 +/- 0.07% (0.35 +/- 0.06 MAC); and sevoflurane, 0.59 +/- 0.10% (0.35 +/- 0.06 MAC). Addition of the 0.5 MAC-awake concentrations of isoflurane and sevoflurane reduced the MAC-awake of xenon to 0.50 +/- 0.15 and 0.51 +/- 0.16 times its MAC-awake as a sole agent, but that of N2O to the values significantly greater than 0.5 times its MAC-awake as a sole agent (0.68 +/- 0.12 and 0.66 +/- 0.14 times MAC-awake; P < 0.01, analysis of variance and Dunnett's test). CONCLUSIONS: The MAC-awake of xenon is 33% or 0.46 times its MAC. In terms of the MAC-fraction, this is smaller than that for N2O but greater than those for isoflurane and sevoflurane. Unlike N2O, xenon interacts additively with isoflurane and sevoflurane on MAC-awake.     

Influx and efflux transport of H1-antagonist epinastine across the blood-brain barrier.

We investigated influx and efflux transporters involved in blood-brain barrier transport of the nonsedative H1-antagonist epinastine. The basal-to-apical transport of [14C]epinastine was markedly higher than that in the opposite direction in LLC-GA5-COL150 cells stably transfected with human multidrug resistance (MDR)1 gene. The brain-to-plasma concentration ratio of [14C]epinastine in mdr1a/b(-/-) mice was 3.2 times higher than that in wild-type mice. The uptake of both [3H]mepyramine and [14C]epinastine into immortalized rat brain capillary endothelial cells (RBEC)1 showed temperature and concentration dependence. The kinetic parameters, K(m), V(max), and uptake clearance (V(max)/K(m)), of the initial uptake of [3H]mepyramine and [14C]epinastine by RBEC1 were 150 microM, 41.8 nmol/min/mg protein, and 279 microl/min/mg protein for mepyramine and 10.0 mM, 339 nmol/min/mg protein, and 33.9 microl/min/mg protein for epinastine, respectively. The uptake of [3H]mepyramine and [14C]epinastine by RBEC1 was inhibited by organic cations such as quinidine, amantadine, and verapamil, but not by other organic cations, tetraethyl ammonium, guanidine, and carnitine. Organic anions such as benzoic acid, estrone-3-sulfate, taurocholate, and neutral digoxin were not inhibitory. Furthermore, some cationic H1 antagonists (chlorpheniramine, cyproheptadine, ketotifen, and desloratadine) inhibited the [3H]mepyramine and [14C]epinastine uptake into RBEC1. In conclusion, the present study demonstrated that the combination of efficient efflux transport by P-glycoprotein and poor uptake by the influx transporter, which is identical with that responsible for the uptake of mepyramine, account for the low brain distribution of epinastine.     

A new method of reconstruction for chest wall resection

Sixteen patients who involved in chest wall disease underwent major chest wall resection between April 1995 and January 1999. The underlying diseases were 6 recurrence of breast cancers, 4 direct invasion by primary lung cancer, 2 metastatic chest wall tumor, one direct invasion by metastatic lung tumor, one direct invasion by metastatic mediastinal tumor, one radio-induced-necrosis of the chest wall, and one chest wall infection. In 9 patients, the thoracic cage reconstruction was performed using double sheets of absorbable mesh (Dexon mesh), cross string sutures and autologous ribs grafts. None of the patients had major respiratory failure and chest wall unstability. No late complications including infections, pains, recurrence and others related to reconstruction materials have been observed.