Search

General anesthetics have different efficacies and side effect incidences based on their mechanism of action. However, detailed comparative studies of anesthetics are incomplete. In this study, target brain regions and gene expression changes in these brain regions were determined for sevoflurane and propofol to understand the mechanisms that cause differences among anesthetics. Rats were anesthetized with sevoflurane or propofol for 1 hr, and brain regions with anesthesia-induced changes in neuronal activity were examined by immunohistochemistry and

Carbapenemase-producing Enterobacterales (CPE) pose one of the most serious antimicrobial resistance threats to public health worldwide. The outcome of CPE infection differs depending on the resistance mechanism. Therefore, rapid detection of CPE infection is essential for optimizing patient management. The carbapenem inactivation method (CIM) and modified CIM (mCIM) are standard methods for detecting CPE, but they usually require 24 h to generate results. Recently, an immunochromatographic assay, NG-Test CARBA 5, has become commercially available. It detects the five most common carbapenemase producers (KPC, IMP, NDM, VIM, and OXA-48) rapidly and accurately. We aimed to evaluate the diagnostic accuracy of NG-Test CARBA 5 for detecting carbapenemase-producing Gram-negative bacilli (CPGNB). We used 116 carbapenemase-producing strains and 48 non-carbapenemase-producing strains. Of the 116 carbapenemase-producing strains, 107 harboured genes for at least one of the five most common carbapenemases, KPC, IMP, NDM, VIM, and OXA-48-like. Forty-eight non-carbapenemase-producing strains, including carbapenem-resistant Enterobacterales , harboured genes for extended-spectrum β-lactamases (CTX-M groups [n=25] and SHV groups [n=2]) or plasmid-mediated AmpC β-lactamases (DHA [n=3], CMY-2 [n=2], and CFE-1 [n=1]). Antimicrobial susceptibility was tested using the agar dilution method, according to the Clinical and Laboratory Standards Institute guidelines. Of the 116 carbapenemase-producing strains, 79 were resistant to at least meropenem or imipenem. The sensitivity and specificity of the NG-Test CARBA 5 for the strains were 99.1 % (106 strains positive for 107 strains of the five most common carbapenemase producers) and 100 % (60 strains negative for other types of CPGNB [n=10] and non-CPGNB strains [n=48]), respectively. The carbapenemase-producing strain with a false-negative result produced IMP-66. The NG-Test CARBA 5 had high sensitivity and specificity for detecting carbapenemase-producing strains.

The suprachiasmatic nucleus (SCN) of the hypothalamus is a nucleus that regulates circadian rhythms through the cyclic expression of clock genes. It has been suggested that circadian-rhythm-related, adverse postoperative events, including sleep disturbances and delirium, are partly caused by anesthesia-induced disruption of clock-gene expression. We examined the effects of multiple general anesthetics on the expression cycle of Period2 (Per2), one of the clock genes that regulate circadian rhythms in the SCN, and on the behavioral rhythms of animals. Rats were treated with sevoflurane, propofol, and dexmedetomidine for 4 h. The expression of Per2 in SCN was analyzed using in situ hybridization, and the behavioral rhythm before and after anesthesia was analyzed. Per2 expression in the SCN decreased significantly immediately after anesthesia in all groups compared with corresponding control groups. However, Per2 returned to normal levels within 24 h, and there was no phase change in the gene expression cycle or behavioral rhythm. This study suggests that acute suppression of Per2 expression may be a general phenomenon induced by general anesthesia, but that the molecular mechanism of the body clock is resilient to disturbances to some extent.

Objective: Cognitive decline and alopecia after radiotherapy are challenging problems. We aimed to compare whole brain radiotherapy (WBRT) plans reducing radiation dose to the hippocampus and scalp between helical tomotherapy (HT) and intensity-modulated proton therapy (IMPT). Methods: We conducted a planning study of WBRT for 10 patients. The clinical target volume was defined as the whole brain excluding the hippocampus avoidance (HA) region. The prescribed dose was 30 Gy in 10 fractions to cover 95% of the target. Constraint goals were defined for the target and organs at risk (OAR). Results: Both techniques met the dose constraints for the target and OAR. However, the coverage of the target (dose covering 95% [D95%] and 98% [D98%] of the volume) were better in IMPT than HT (HT vs IMPT: D95%, 29.9 Gy vs 30.0 Gy, P

Objective: We compared radiotherapy plans among helical tomotherapy (HT), volumetric-modulated arc therapy (VMAT), and intensity-modulated proton therapy (IMPT) for angiosarcoma of the scalp (AS). Methods: We conducted a planning study for 19 patients with AS. The clinical target volume (CTV) 1 and CTV2 were defined as the gross tumor volume with a specific margin and total scalp, respectively. For HT and VMAT, the planning target volume (PTV) 1 and PTV2 were defined as CTV1 and CTV2 with 0.5-cm margins, respectively. For IMPT, robust optimization was used instead of a CTV-PTV margin (i.e. CTV robust). The targets of the HT and VMAT plans were the PTV, whereas the IMPT plans targeted the CTV robust. In total, 70 Gy and 56 Gy were prescribed as the D95% (i.e. dose to 95% volume) of PTV1 (or CTV1 robust) and PTV2 (or CTV2 robust), respectively, using the simultaneous integrated boost (SIB) technique. Other constraint goals were also defined for the target and organs at risk (OAR). Results: All dose constraint parameters for the target and OAR met the goals within the acceptable ranges for the 3 techniques. The coverage of the targets replaced by D95% and D98% were almost equivalent among the 3 techniques. The homogeneity index of PTV1 or CTV1 robust was equivalent among the 3 techniques, whereas that of PTV2 or CTV2 robust was significantly higher in the IMPT plans than in the other plans. IMPT reduced the Dmean of the brain and hippocampus by 49% to 95%, and the Dmax of the spinal cord, brainstem, and optic pathway by 70% to 92% compared with the other techniques. Conclusion: The 3 techniques with SIB methods provided sufficient coverage and satisfactory homogeneity for the targets, but IMPT achieved the best OAR sparing.

Carbapenems serve as a last resort for the clinical treatment of multidrug-resistant infections. Therefore, the rapid spread of carbapenemase-producing strains represents a serious public health threat, further limiting antibiotic choices. The current findings of hypervirulent carbapenemase-producing Klebsiella pneumoniae clinical isolates in Japan demonstrate the potential broad spread and transfer of these genes, necessitating close surveillance., Carbapenemase-producing Enterobacteriaceae represent a serious public health threat worldwide. Carbapenemase genes, harbored on a transferable plasmid, have been isolated globally with distinct geographical features. Klebsiella pneumoniae, included in Enterobacteriaceae, also produces carbapenemase and often shows hypervirulence. Overlapping carbapenem resistance and hypervirulence in K. pneumoniae have been reported, but such strains have not yet been found in Japan. Here, we screened 104 carbapenemase-producing K. pneumoniae isolates collected from 37 hospitals and outpatient clinics in Japan between September 2014 and July 2015. PCR and DNA sequencing demonstrated IMP-1 in 21 isolates and IMP-6 in 83 isolates, 77 of which coharbored CTX-M-2. Most of the isolates showed low MICs toward imipenem and meropenem but high MICs toward penicillin and cephalosporins. Conjugation experiments with an Escherichia coli J53 recipient showed that most of the plasmids in IMP-6 producers were transferable, whereas only one-half of the plasmids in IMP-1 producers were transferable. PCR-based replicon typing and multiplex PCR identified five isolates belonging to the CG258 non-tonB79 cluster and no isolate belonging to the CG258-tonB79 cluster or sequence type 307 (ST307). Four K1-ST23 isolates, 10 K2-ST65 isolates, and 7 K2-ST86 isolates were detected that harbored virulence genes. The resistance genes in 85 isolates were transferable, but the virulence genes were not transferred. These results demonstrate the acquisition of IMP-type carbapenemase genes and CTX-M-type genes among hypervirulence isolates in Japan, warranting further attention and countermeasures. In this study, we have determined the molecular characteristics and epidemiology of IMP-6 producers that coharbored various CTX-M genes in Japan. IMPORTANCE Carbapenems serve as a last resort for the clinical treatment of multidrug-resistant infections. Therefore, the rapid spread of carbapenemase-producing strains represents a serious public health threat, further limiting antibiotic choices. The current findings of hypervirulent carbapenemase-producing Klebsiella pneumoniae clinical isolates in Japan demonstrate the potential broad spread and transfer of these genes, necessitating close surveillance.

AIM We aimed to identify the optimal candidates for early salvage radiotherapy (SRT) among patients with biochemical recurrence (BCR) after radical prostatectomy (RP). METHODS This multi-institutional retrospective study included 371 patients treated using SRT after RP. The median (range) PSA level at BCR was 0.36 (0.10-2.00) ng/mL. The association between early SRT (ie, starting PSA level

The safety and efficacy of dose-escalated radiotherapy with intensity-modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT) remain unclear in salvage radiotherapy (SRT) after radical prostatectomy. We examined the impact of these advanced radiotherapy techniques and dose intensification on the toxicity of SRT. This multi-institutional retrospective study included 421 patients who underwent SRT at the median dose of 66 Gy in 2-Gy fractions. IMRT and IGRT were used for 225 (53%) and 321 (76%) patients, respectively. At the median follow-up of 50 months, the cumulative incidence of late grade 2 or higher gastrointestinal (GI) and genitourinary (GU) toxicities was 4.8% and 24%, respectively. Multivariate analysis revealed that the non-use of either IMRT or IGRT, or both (hazard ratio [HR] 3.1, 95% confidence interval [CI] 1.8–5.4, p p = 0.048) were associated with late GI toxicity, whereas a higher dose ≥68 Gy was the only factor associated with GU toxicities (HR 3.1, CI 1.3–7.4, p = 0.012). This study suggested that the incidence of GI toxicities can be reduced by IMRT and IGRT in SRT, whereas dose intensification may increase GU toxicity even with these advanced techniques.

The aim of this study was to examine the resistance genes in clinical isolates which produced IMP-6 type metallo-β-lactamase lactamase (MBL) and had mildly reduced susceptibilities to levofloxacin and/or amikacin. The inoculum size effect was also assessed. A total of 14 Enterobacteriaceae isolates (2 Escherichia coli and 12 Klebsiella pneumoniae) which produced IMP-6 MBL, and had mild increases in their MICs for levofloxacin and amikacin were examined. Thirteen out of 14 isolates harbored CTX-M-2, with the remaining isolate co-harboring CTX-M-2 and CTX-M-1 as ESBLs. All isolates carried one or more PMQRs; aac(6′)-Ib-cr was the most prevalent (92.8%), followed by oqxA (64.3%), qnrS (42.9%), oqxAB (21.4%), and qnrB (14.3%). The inoculum size effects were significant in all strains for meropenem, 13 for imipenem, 7 for levofloxacin, and 3 for amikacin. Conjugation was successfully performed with 8 isolates and 11 strains were obtained. Eleven of the experimental strains (100%), and 8 strains (72.7%) showed inoculum size effects for meropenem and imipenem, respectively. No inoculum size effect was seen for levofloxacin. Four strains harbored qnr genes and 2 strains harbored qnr genes and QRDR mutations concurrently. blaIMP-6 positive Enterobacteriaceae with mildly reduced susceptibilities to levofloxacin and/or amikacin also harbored at least one plasmid-mediated drug resistance gene. These represent an unrecognized threat, capable of compromising the in vitro activity of many classes of antimicrobial agents. We conclude that IMP-6 MBL plays an important role in decreasing the MIC for carbapenems, whereas qnr does not for levofloxacin.

Background Statin use in individuals with chronic obstructive pulmonary disease (COPD) with coexisting cardiovascular disease is associated with a reduced risk of exacerbations. The mechanisms by which statin plays a role in the pathophysiology of COPD have not been defined. To explore the mechanisms involved, we investigated the effect of statin on endothelial cell function, especially endothelial cell tight junctions. Method We primarily assessed whether pitavastatin could help mitigate the development of emphysema induced by continuous cigarette smoking (CS) exposure. We also investigated the activation of liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signaling, which plays a role in maintaining endothelial functions , important tight junction proteins , zonula occludens (ZO)-1 and claudin-5 expression, and lung microvascular endothelial cell permeability. Results We found that pitavastatin prevented the CS-induced decrease in angiomotin-like protein 1 (AmotL1)-positive vessels via the activation of LKB1/AMPK signaling and IFN-γ-induced hyperpermeability of cultured human lung microvascular endothelial cells by maintaining the levels of AmotL1, ZO-1, and claudin-5 expression at the tight junctions. Conclusion Our results indicate that the maintenance of lung microvascular endothelial cells by pitavastatin prevents tight junction protein dysfunctions induced by CS. These findings may ultimately lead to new and novel therapeutic targets for patients with COPD.

SummaryBackground Several gene variants identified in bronchial asthmatic patients are associated with a decrease in pulmonary function. The effects of this intervention on pulmonary function have not been fully researched. Objective We determined the effects of high-dose inhaled corticosteroids (ICSs) on decreased pulmonary function in asthmatic Japanese patients with variants of IL13 and STAT4 during long-term treatments with low to mild doses of ICS. Methods In this study, 411 patients with bronchial asthma who were receiving ICSs and living in Japan were recruited, were genotyped, and underwent pulmonary function tests and fibreoptic examinations. The effects of 2 years of high-dose ICSs administered to asthmatic patients who were homozygous for IL13 AA of rs20541 or STAT4 TT of rs925847 and who progressed to airway remodelling were investigated. Results High-dose ICS treatment increased the pulmonary function of patients homozygous for IL13 AA of rs20541 but not of patients homozygous for STAT4 TT of rs925847. The increased concentrations of the mediators IL23, IL11, GMCSF, hyaluronic acid, IL24, and CCL8 in bronchial lavage fluid (BLF) were diminished after high-dose ICS treatment in patients homozygous for IL13 AA of rs20541. Conclusion and Clinical Relevance IL13 AA of rs20541 and STAT4 TT of rs925847 are potential genomic biomarkers for predicting lower pulmonary function. The administration of high-dose ICSs to asthmatic patients with genetic variants of IL13 AA may inhibit the advancement of airway remodelling. The genetic variants of STAT4 TT did not respond to high-dose ICSs. Therefore, using medications other than ICSs must be considered even during the initial treatment of bronchial asthma. These genetic variants may aid in the realization of personalized and phenotype-specific therapies for bronchial asthma.

Sir,Carbapenemase-producing Enterobacteriaceae show multi-antibiotic resistance; thus, infections with these bacteria are difficult to treat, representing a growing problem worldwide. Carbapenemase...

SUMMARY Improving the reusability of models and increasing automatic code generation efficiency are problems in model-driven development. In order to solve these problems, we apply component-based development technologies that have mainly been developed at the software implementation level to the modeling level. In the proposed approach, functionally relevant model elements are packaged as a component, and the modeling of software is performed by associating them with the model components. The role of a model becomes clear by introducing the concept of a component, and the reusability of model components is improved by externalizing the dependencies between the components. In addition, flexible model transformation rules united with the roles of models can be designed. As a result, the proposed method is able to generate more source code automatically. The validity of the proposed approach is verified through application experiments.

Background Several gene variants are associated with a response to an inhaled corticosteroids (ICSs) treatment in patients with bronchial asthma. A variant of the glucocorticoid-induced transcript 1 (GLCCI1) genes has previously been associated with decreased lung function improvement upon treatment with inhaled corticosteroids in patients with bronchial asthma. Another report has also demonstrated that this genetic biomarker did not influence the change in flow volume in one second. However, no studies have considered the treatment content and the GLCCI1 variants. We were able to determine the relationship between the pulmonary function and clinical features and the variant of the GLCCI1 in Japanese asthmatic patients receiving long-term ICS treatment. Materials and Methods In this study, 405 patients with bronchial asthma, who were receiving ICS and living in Japan, were recruited, genotyped, and underwent pulmonary function tests. To identify the GLCCI1 protein expression cells, endobronchial biopsy specimens were examined. Results We found that the pulmonary function was not significantly different in the homozygotes compared to the wild types. Also, the homozygotes increased the risk of a sustained step-up of the asthma treatment when compared to the wild type and heterozygotes. GLCCI1-positive cells were localized to the bronchial epithelial cells. The amount of GLCCI1 protein that cultured epithelial cells harboring GLCCI1 variants produced was less than the GLCCI1 wild type in the presence of a corticosteroid. Conclusions A worsening of pulmonary function caused by GLCCI1 variants might be prevented due to recently used medications based on new action mechanisms. This article is protected by copyright. All rights reserved.

Almost all cases of carbapenemase-producing Enterobacteriaceae infections in Japan are caused by blaIMP-positive Enterobacteriaceae (especially blaIMP-6) and infections caused by other types of carbapenemase-producing Enterobacteriaceae are quite rare. We examined drug resistance genes co-harboring with blaIMP-6 and their inoculum size effects. We screened β-lactamase genes, plasmid-mediated quinolone resistance (PMQR) genes, and aminoglycoside-modifying enzyme genes by PCR and performed sequencing for 14 blaIMP-6-positive Enterobacteriaceae. Further, all PMQR-positive isolates were submitted to conjugation and inoculum effect evaluation. Our data showed that 13 of the 14 isolates harbored CTX-M-2 and one co-harbored CTX-M-2 and CTX-M-1 as extended-spectrum β-lactamases. All isolates carried one or more PMQRs; aac(6')-Ib-cr was the most prevalent (92.8%), and was followed by oqxA (64.3%), qnrS (50%), oqxAB (21.4%), and qnrB (14.3%). However, Klebsiella pneumoniae contains chromosomal OqxAB. Inoculum size effects were significant in all strains for meropenem, 13 strains for imipenem, 7 for levofloxacin, and 3 for amikacin. We observed that 11 of the experimental strains (100%), 8 strains (72.7%), and 1 strain showed inoculum size effects for meropenem, imipenem, and amikacin, respectively. However, four strains harbored qnr genes and two strains harbored qnr genes and QRDR mutations concurrently; no inoculum size effect was seen for levofloxacin. The blaIMP-6-positive Enterobacteriaceae that we studied was found to harbor at least one plasmid-mediated drug resistance gene. The inoculum size effect for carbapenems was thought to be mainly due to IMP-6-type metallo-β-lactamase; however qnrB and qnrS also had a minimal impact on the inoculum size effect for levofloxacin.

Traditionally, Management Information Systems (MIS) have been developed without using formal methods. By informal methods, MIS are developed over their lifecycle without having any models. This causes many problems, such as lack of reliability of the system design specifications. In order to overcome these problems, a model theory approach has been proposed. The approach is based on the idea that a system can be modeled by automata and set theory. However, it is very difficult to generate automata of the system to be developed right from the start. On the other hand, there is a model-driven development method that can flexibly adapt to changes of business logics or implementing technologies. In model-driven development, a system is modeled using a modeling language such as UML. This paper proposes a new development method for management information systems, applying the model-driven development method to a component of the model theory approach. Experiments have shown that the reduction in the amount of efforts is more than 30%. © 2013 Wiley Periodicals, Inc. Electron Comm Jpn, 96(2): 16–24, 2013; Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/ecj.11445

Objectives: (1) To examine criterion validity of the Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) using obstructive sleep apnea (OSA), periodic limb movement disorder (PLMD), rapid eye movement sleep behavior disorder (RBD), and narcolepsy as criterion standard. (2) To summarize the evidence for criterion validity of the ESS for the diagnosis of OSA by a meta-analysis that combines the current and previous studies. (3) To investigate the determinants of the PSQI and ESS scores. Methods: The PSQI and ESS as well as the Hospital Anxiety and Depression Scale (HADS), which measures anxiety and depression levels, were administered to 367 patients consecutively referred to a sleep clinic. They underwent overnight polysomnography (PSG) and the multiple sleep latency test if narcolepsy was suspected. Results: The area under the receiver operating characteristic curves for the ESS and PSQI (and its subscale) were

Almost every information system is built assuming that it is to be modified during operation. It costs very much to transplant the system to change requirement specifications or implementing technologies. For this purpose, there is a model theory approach that is based on a theory that a system can be modeled by automata and set theory. However, it is very difficult to generate automata of the system to be developed right from the start. In addition, there is a model-driven development method that can flexibly correspond to changes of business logics or implementing technologies. In the model-driven development, a system is modeled using a modeling language. This paper proposes a new development method applying the model-driven development method to a component of the model theory approach. The experiment has shown that a reduced amount of workloads is more than 30% of all the workloads.