Effects of a synthetic protease inhibitor (gabexate mesilate) and a neutrophil elastase inhibitor (sivelestat sodium) on acid-induced lung injury in rats

The present study was designed to examine the combined effects of a synthetic protease inhibitor, gabexate mesilate, with a specific neutrophil elastase inhibitor, sivelestat sodium, on acid-induced lung injury. Adult male Sprague-Dawley rats weighing 300-350 g were anaesthetised intraperitoneally with pentobarbitone sodium and the right jugular vein was cannulated. Following tracheostomy, rats were ventilated mechanically and underwent intratracheal instillation of hydrochloric acid (HCl, 0.1 N 1.5 ml/kg) or normal saline. Gabexate mesilate (10 mg/kg, i.p.) and/or sivelestat sodium (10 mg/kg/h, i.v.) were administered 30 min before HCl instillation. Bronchoalveolar lavage fluid samples were obtained 5 h after HCl instillation. in bronchoalveolar lavage fluid, the HCl-induced increases in total nucleated cell counts, neutrophil counts, optical density at 412 nm as an index of pulmonary haemorrhage, concentrations of albumin and cytokine-induced neutrophil chemoattractant (CINC) were significantly attenuated by either gabexate mesilate or sivelestat sodium treatment. Gabexate mesilate or sivelestat sodium treatment also significantly attenuated the wet to dry weight ratio induced by HCl. However, combined treatment with both gabexate mesilate and sivelestat sodium did not show additive effects on HO-induced lung injury, compared with single treatments. These findings suggested that gabexate mesilate and sivelestat sodium each exhibited protective effects on acid-induced lung injury, but that synergistic effects of both agents are limited in this acid-induced lung injury model.ArticleEUROPEAN JOURNAL OF PHARMACOLOGY. 641(2-3):220-225 (2010)journal articl

Comparisons of different mean airway pressure settings during high-frequency oscillation in inflammatory response to oleic acid-induced lung injury in rabbits

Koichi Ono1, Tomonobu Koizumi2, Rikimaru Nakagawa1, Sumiko Yoshikawa2, Tetsutarou Otagiri11Department of Anesthesiology and Resuscitation; 2First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, JapanPurpose: The present study was designed to examine effects of different mean airway pressure (MAP) settings during high-frequency oscillation (HFO) on oxygenation and inflammatory responses to acute lung injury (ALI) in rabbits.Methods: Anesthetized rabbits were mechanically ventilated with a conventional mechanical ventilation (CMV) mode (tidal volume 6 ml/kg, inspired oxygen fraction [FIo2] of 1.0, respiratory rate [RR] of 30/min, positive end-expiratory pressure [PEEP] of 5 cmH2O). ALI was induced by intravenous administration of oleic acid (0.08 ml/kg) and the animals were randomly allocated to the following three experimental groups; animals (n = 6) ventilated using the same mode of CMV, or animals ventilated with standard MAP (MAP 10 cmH2O, n = 7), and high MAP (15 cmH2O, n = 6) settings of HFO (Hz 15). The MAP settings were calculated by the inflation limb of the pressure-volume curve during CMV.Results: HFO with a high MAP setting significantly improved the deteriorated oxygenation during oleic acid-induced ALI and reduced wet/dry ratios, neutrophil counts and interleukin-8 concentration in bronchoalveolar lavage fluid, compared to those parameters in CMV and standard MAP-HFO.Conclusions: These findings suggest that only high MAP setting during HFO could contribute to decreased lung inflammation as well as improved oxygenation during the development of ALI.Keywords: lung protective ventilation, open lung ventilation, IL-8, neutrophi

Increased isoprostane levels in oleic acid-induced lung injury

The present study was performed to examine a role of oxidative stress in oleic acid-induced lung injury model. Fifteen anesthetized sheep were ventilated and instrumented with a lung lymph fistula and vascular catheters for blood gas analysis and measurement of isoprostanes (8-epi prostaglandin F2 alpha). Following stable baseline measurements, oleic acid (0.08 ml/kg) was administered and observed 4 h. Isoprostane was measured by gas chromatography mass spectrometry with the isotope dilution method. Isoprostane levels in plasma and lung lymph were significantly increased 2 h after oleic acid administration and then decreased at 4 h. The percent increases in isoprostane levels in plasma and lung lymph at 2 h were significantly correlated with deteriorated oxygenation at the same time point, respectively. These findings suggest that oxidative stress is involved in the pathogenesis of the pulmonary fat embolism-induced acute lung injury model in sheep and that the increase relates with the deteriorated oxygenation.ArticleBIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS. 388(2):297-300 (2009)journal articl

Increased Interleukin-8 in Epithelial Lining Fluid of Collapsed Lungs During One-Lung Ventilation for Thoracotomy

The present study was designed to evaluate inflammatory changes in collapsed lungs during one-lung ventilation using the assistance of a bronchoscopic microsampling probe. Serial albumin and interleukin (IL)-8 concentrations in epithelial lining fluid (ELF) were measured in seven patients undergoing resection of lung tumors. The samples were taken after induction of anesthesia (baseline), 30 min after one-lung ventilation was started (point 2), just before resuming two-lung ventilation (point 3), and 30 min after two-lung ventilation was restarted (point 4). The albumin and IL-8 concentrations in ELF were significantly increased at point 2 and point 3, respectively, and remained to be high, compared to the baseline. The increase in IL-8 at point 3 was correlated with the interval of one-lung ventilation; however, none developed specific acute lung injury. These findings suggest that inflammatory changes can occur on the epithelium of a collapsed lung even in patients who underwent successful and standard thoracic surgery.ArticleINFLAMMATION. 35(6):1844-1850 (2012)journal articl

Prospective Study of Gefitinib Readministration After Chemotherapy in Patients With Advanced Non-Small-Cell Lung Cancer Who Previously Responded to Gefitinib

The present study was designed to prospectively evaluate the clinical efficacy of gefitinib readministration in patients with advanced non-small cell lung cancer who responded well to initial gefitinib, followed by cytotoxic chemotherapy. Twenty subjects were enrolled, and 3 and 6 patients achieved partial response and stable disease, respectively. These findings provide valuable information for the management of previous gefitinib responders. Introduction: Salvage treatment for acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor in patients with non-small-cell lung cancer is a matter of clinical concern. Several retrospective reports have indicated the usefulness of epidermal growth factor receptor tyrosine kinase inhibitor readministration; however, there have been few prospective studies. Materials and Methods: This study was designed to prospectively evaluate the clinical efficacy of gefitinib readministration in patients with advanced or metastatic non-small-cell lung cancer who responded well to initial gefitinib treatment. The subjects received at least 1 regimen of cytotoxic chemotherapy after progressive disease with the initial gefitinib therapy. Gefitinib administration (250 mg/d, orally) was started after progressive disease with the previous chemotherapeutic regimen. The primary endpoint in the present study was the response rate. Results: Twenty patients were enrolled between April 2007 and May 2011. Three patients achieved partial response, and 6 showed stable disease. Thus, the overall response rate and disease control rate of gefitinib readministration were 15% (95% Cl, 3.21-37.9) and 45% (95% Cl, 23.1-68.5), respectively. Median progression-free survival and overall survival from the start of gefitinib readministration were 2.0 months (95% Cl, 0.9-3.1 months) and 12.0 months (95% Cl, 8.0-16.0 months), respectively. Conclusion: These results suggest that gefitinib readministration may be an option, albeit with a low response rate and short progression-free survival, for patients who responded well to initial gefitinib followed by systemic chemotherapy. These findings provide valuable information for the management of previous gefitinib responders.ArticleCLINICAL LUNG CANCER. 13(6):458-463 (2012)journal articl

Topoisomerase II, scaffold component, promotes chromatin compaction in vitro in a linker-histone H1-dependent manner

TopoisomeraseII (Topo II) is a major component of chromosomal scaffolds and essential for mitotic chromosome condensation, but the mechanism of this action remains unknown. Here, we used an in vitro chromatin reconstitution system in combination with atomic force and fluorescence microscopic analyses to determine how Topo II affects chromosomal structure. Topo II bound to bare DNA and clamped the two DNA strands together, even in the absence of ATP. In addition, Topo II promoted chromatin compaction in a manner dependent on histone H1 but independent of ATP. Histone H1-induced 30-nm chromatin fibers were converted into a large complex by Topo II. Fluorescence microscopic analysis of the Brownian motion of chromatin stained with 4′,6-diamidino-2-phenylindole showed that the reconstituted chromatin became larger following the addition of Topo II in the presence but not the absence of histone H1. Based on these findings, we propose that chromatin packing is triggered by histone H1-dependent, Topo II-mediated clamping of DNA strands

Insulinoma with symptoms of suspected transient ischemic attack : A case report

We report the case of a６７-year-old woman who had symptoms suggestive of a transient ischemic attack（TIA）, such as lightheadedness and transient visual changes before meals for ４ months. She experienced altered consciousness before lunch and was taken to the emergency room２weeks ago. She had repeated hypoglycemia with a blood glucose level of ３１ mg/dL. Insulin secretion was not suppressed, with an immunoreactive insulin level of １４．０ μU/mL and connecting peptide immunoreactivity of １．８３ ng/mL for occasional blood glucose levels of ４９ mg/dL. Dynamic CT revealed a １７‐mm mass enhanced during the arterial phase in the pancreatic uncinate process, suggestive of a pancreatic neuroendocrine tumor. A selective arterial secretagogue（calcium）injection test revealed the localization of insulinoma in the head of the pancreas. Therefore, pancreatoduodenectomy was performed. Hyperglycemia occurred after the surgery, and it was judged that the insulinoma was resected. This case showed TIA-like symptoms without signs of sympathetic overdrive associated with hypoglycemia. Thus, the diagnosis was delayed. Insulinoma may present with symptoms of neuroglycopenia but not autonomic activity due to hypoglycemia. Insulinoma should be distinguished in patients with unknown neurological symptoms since neuroglycopenia caused by insulinoma is diverse

Criterion and Construct Validity of the CogState Schizophrenia Battery in Japanese Patients with Schizophrenia

BACKGROUND: The CogState Schizophrenia Battery (CSB), a computerized cognitive battery, covers all the same cognitive domains as the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery but is briefer to conduct. The aim of the present study was to evaluate the criterion and construct validity of the Japanese language version of the CSB (CSB-J) in Japanese patients with schizophrenia. METHODOLOGY/PRINCIPAL FINDINGS: Forty Japanese patients with schizophrenia and 40 Japanese healthy controls with matching age, gender, and premorbid intelligence quotient were enrolled. The CSB-J and the Brief Assessment of Cognition in Schizophrenia, Japanese-language version (BACS-J) were performed once. The structure of the CSB-J was also evaluated by a factor analysis. Similar to the BACS-J, the CSB-J was sensitive to cognitive impairment in Japanese patients with schizophrenia. Furthermore, there was a significant positive correlation between the CSB-J composite score and the BACS-J composite score. A factor analysis showed a three-factor model consisting of memory, speed, and social cognition factors. CONCLUSIONS/SIGNIFICANCE: This study suggests that the CSB-J is a useful and rapid automatically administered computerized battery for assessing broad cognitive domains in Japanese patients with schizophrenia

The hierarchical structure of chromatin : Nucleosomal array reconstitution with ring and linear DNA(Knots and soft-matter physics: Topology of polymers and related topics in physics, mathematics and biology)

この論文は国立情報学研究所の電子図書館事業により電子化されました。真核生物で見られる階層的な折りたたみの基本構造としてヌクレオソーム(長さ50nmのDNAがコアヒストンと呼ばれる直径7nmのタンパクに巻きついた構造)が知られている。DNAの長さ、ねじれ、大域的な構造(環状等)がヌクレオソーム形成に与える影響は未だ十分に理解されていない。本研究ではDNAの両端がつながっている環状構造がヌクレオソーム形成に与える影響を明らかにするために、全長1マイクロメートルの線状・環状DNAを用いて再構成を行い、その効率とヌクレオソーム間相互作用の検討を行った。その結果、環状のDNAを用いた場合の方が環状構造に由来して再構成の効率が高くなることが明らかになった