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The lack of a widely accessible method for expressing genes of interest in wild-type embryos is a fundamental obstacle to understanding genetic regulation during embryonic development. In particular, only a few methods are available for introducing gene expression vectors into cells prior to neural tube closure, which is a period of drastic development for many tissues. In this study, we present a simple technique for injecting vectors into the amniotic cavity and allowing them to reach the ectodermal cells and the epithelia of endodermal organs of mouse embryos at E8.0 via in utero injection, using only a widely used optical fiber with an illuminator. Using this technique, retroviruses can be introduced to facilitate the labeling of cells in various tissues, including the brain, spinal cord, epidermis, and digestive and respiratory organs. We also demonstrated in utero electroporation of plasmid DNA into E7.0 and E8.0 embryos. Taking advantage of this method, we reveal the association between Ldb1 and the activity of the Neurog2 transcription factor in the mouse neocortex. This technique can aid in analyzing the roles of genes of interest during endo- and ectodermal development prior to neural tube closure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Psychopharmacotherapy for patients with schizophrenia in Japan has a long history of polypharmacy, which is rare worldwide but remains a critical problem. One reason for this is that clozapine was not available in Japan until 2009. We aimed to investigate the changes in psychopharmacotherapy in patients with schizophrenia over 12 years pre- and post-introduction of clozapine to clarify how psychopharmacotherapy for patients with schizophrenia has changed with the introduction of clozapine. We retrospectively collected data from the medical records of inpatients diagnosed with schizophrenia at the Okayama Psychiatric Medical Center. Chlorpromazine equivalent (CP-eq) decreased from 1276.6 mg/day in 2009 to 613.9 mg/day in 2020. The prescribed daily dose/defined daily dose (PDD/DDD) decreased from 3.0 in 2009 to 1.2 in 2020. The monotherapy rate increased from 24.4 % in 2009 to 74.6 % in 2020. Our institution began using clozapine in 2010, and the prescription rate for clozapine increased to 37.3 % in 2020. The prescription rate for more than three antipsychotics decreased from 27.8 % in 2009 to 0.8 % in 2020. The increase in clozapine prescription has contributed to an increased rate of antipsychotic monotherapy and a decreased rate of polypharmacy, promoting the optimization of schizophrenia medication. Clozapine therapy should be further promoted in Japan to reduce treatment-resistant schizophrenia due to polypharmacy as much as possible., Competing Interests: Declaration of Competing Interest Mr. Kitagawa has received research grants from the Policy-Based Medical Services Foundation, Japan Society for the Promotion of Science; speaker’s honoraria from Novartis Pharma and Otsuka; and manuscript fees from the Japanese Society of Psychiatric Pharmacy, the Pharmaceutical Society of Japan, Jiho, and Nanzando., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Periostin (POSTN) is a matricellular protein that was originally identified in osteoblasts. Past studies have shown that POSTN is also preferentially expressed in cancer-associated fibroblasts (CAFs) in various types of cancer. We previously demonstrated that the increased expression of POSTN in stromal tissues is associated with an unfavorable clinical outcome in esophageal squamous cell carcinoma (ESCC) patients. In this study, we aimed to elucidate the role of POSNT in ESCC progression and its underlying molecular mechanism. We found that POSTN is predominantly produced by CAFs in ESCC tissues, and that CAFs-cultured media significantly promoted the migration, invasion, proliferation, and colony formation of ESCC cell lines in a POSTN-dependent manner. In ESCC cells, POSTN increased the phosphorylation of ERK1/2 and stimulated the expression and activity of a disintegrin and metalloproteinase 17 (ADAM17), which is critically involved in tumorigenesis and tumor progression. The effects of POSTN on ESCC cells were suppressed by interfering with the binding of POSTN to integrin αvβ3 or αvβ5 using neutralizing antibody against POSTN. Taken together, our data show that CAFs-derived POSTN stimulates ADAM17 activity through activation of the integrin αvβ3 or αvβ5-ERK1/2 pathway and thereby contributes to the progression of ESCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The effect of bevacizumab plus mFOLFOX6 on downsizing of liver metastases for curative resection has not been well assessed for patients with advanced colorectal liver metastases (CRLMs). This multicenter phase II trial aimed to examine the efficacy and safety of bevacizumab plus mFOLFOX6 for advanced CRLMs harboring mutant-type KRAS., Methods: Patients with advanced CRLMs (tumor number of ≥5 and/or technically unresectable) harboring mutant-type KRAS were included. Surgical indication was evaluated every 4 cycles of bevacizumab plus mFOLFOX6. Liver resection was planned if the CRLMs were resectable. The primary endpoint was R0 resection rate. The secondary endpoints included overall survival (OS), recurrence-free survival, progression-free survival, and safety., Results: Between 2013 and 2017, 29 patients from six centers were registered. The rates of complete and partial responses were 0% and 62.1%, respectively. R0 and R1 resections were performed in 19 and 1 patient, respectively (R0 resection rate: 65.5%). No mortality occurred. During the median follow-up of 30.7 months, the 3-year OS rate for all the patients was 64.4% with the median survival of 49.1 months., Conclusion: For advanced CRLMs harboring mutant-type KRAS, bevacizumab plus mFOLFOX6 achieved a high R0 resection rate, leading to favorable survival., (Copyright © 2022 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Nalmefene is the only medication marketed to reduce the consumption of alcohol in patients with alcohol dependence, but it remains unclear which patients could most benefit from it. This study aimed to identify clinical moderators that affect treatment response to nalmefene in patients with alcohol dependence., Methods: In a multicenter, randomized, controlled, double-blind, phase 3 study of nalmefene on Japanese patients with alcohol dependence, the relationship between the reduction of heavy drinking days (HDD) and total alcohol consumption (TAC) at 12 and 24 weeks of treatment and baseline variables of the participants were analyzed in a linear regression and multiple adjusted analysis., Results: Age < 65, no family history of problem drinking, age at onset of problem drinking ≥ 25, and not currently smoking were possible positive moderators. Nalmefene showed a significant HDD reduction in patients with age < 65 or no family history of problem drinking, and a significant TAC reduction in patients with age at onset of problem drinking ≥ 25 or who were not currently smoking. After multiple adjusted analyses, age < 65 (p = .028), no family history of problem drinking (p = .047), and age at onset of problem drinking ≥ 25 (p = .030) were statistically significant. Not currently smoking (p = .071) was marginally significant. In combination, these moderators indicated synergistic effects., Conclusions: Alcohol-dependent patients with favorable prognostic factors such as non-smoking status, no family history of problem drinking, and a late-onset of problem drinking selectively benefit from nalmefene. Further research is needed to validate these exploratory results., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Understanding how organs originate is challenging due to the twin problems of explaining how new cell types evolve and how collective interactions between cell types arise and become selectively advantageous. Animals are assemblages of organs and cell types of different antiquities, and among the most rapidly and convergently evolving are exocrine glands and their constituent secretory cell types. Such structures have arisen independently thousands of times across the Metazoa, impacting how animals chemically interact with their environments. The recurrent evolution of exocrine systems provides a paradigm for examining how qualitative phenotypic novelties arise from variation at the cellular level. Here, we take a hierarchical perspective, focusing on the evolutionary assembly of novel biosynthetic pathways and secretory cell types, and how both selection and non-adaptive molecular processes may combine to build the complex, modular architectures of many animal glands., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The purpose of this study was to assess the risk factors for clozapine-induced central nervous system (CNS) abnormalities (i.e., electroencephalogram [EEG] abnormalities, myoclonus, and seizures). We retrospectively analyzed data from 106 patients with schizophrenia who received clozapine treatment through our hospital. A review of the EEG recordings showed that 71 of these patients (67.0 %) developed CNS abnormalities after initiating clozapine treatment. EEG abnormalities, myoclonus, and seizures occurred in 53.8 %, 38.7 %, and 8.5 % of the patients, respectively. Multivariate logistic regression analysis showed that the risk factors for clozapine-induced CNS abnormalities were concomitant lithium usage (odds ratio, 4.560; 95 % confidence interval, 1.750-11.900) and shorter illness durations before clozapine initiation (odds ratio, 0.796; 95 % confidence interval, 0.649-0.976). However, plasma clozapine levels and the usage of antiepileptics did not exhibit associations with the risks of CNS abnormalities. Clinicians should monitor their patients for incident CNS abnormalities when administering lithium in combination with clozapine regardless of plasma clozapine levels or the usage of antiepileptics. This is especially true for patients with short illness durations., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Anti-NMDAR encephalitis is increasingly recognized as one etiology of psychiatric symptoms, but there is not enough evidence on patients with mood disorder. We assayed anti-NR1/NR2B IgG antibodies in serum and/or cerebrospinal fluid of 62 patients initially diagnosed with mood disorder by a cell-based assay. We also investigated the specific patient characteristics and psychotic symptoms. At first admission, the patients showed only psychiatric symptoms without typical neurological signs or abnormal examination findings. Four of the 62 patients had anti-NR1/NR2B IgG antibodies. The anti-NR1/NR2B IgG antibody-positive patients showed more super- or abnormal sensitivity (P = 0.00088), catatonia (P = 0.049), and more conceptual disorganization (P < 0.0001), hostility (P = 0.0010), suspiciousness (P < 0.0001), and less emotional withdrawal (P < 0.0001) and motor retardation (P < 0.0001) on the Brief Psychiatric Rating Scale than the antibody-negative patients. During the clinical course, anti-NR1/NR2B IgG antibody-positive patients showed more catatonia (P = 0.0042) and met Graus's criteria for diagnosis of anti-NMDAR encephalitis, but negative patients did not. Immunotherapy was effective for anti-NR1/NR2B IgG antibody-positive patients, and there was the weak relationship (R² = 0.318) between the anti-NR1/NR2B IgG antibody titer in the cerebrospinal fluid and the Brief Psychiatric Rating Scale score., (Copyright © 2019 Elsevier B.V. and ECNP. All rights reserved.)

Influenza virus causes acute respiratory infection in humans, and is a major public health concern globally. Antibodies play a central role in host protection against influenza virus. We isolated human monoclonal antibodies (hMAb) 206-2-4 and 201-6-8 by a human hybridoma protocol that neutralized various but distinct influenza virus (IFV) A/H1N1 strains, including 2009 pandemic strains. The half-inhibitory concentration of 206-2-4 and 201-6-8 against A/H1N1pdm09 strains was 2-100ng/mL and 5-20μg/mL, respectively. Prophylactic and therapeutic potencies of 206-2-4 were demonstrated in a mouse model of IFV infection at i.p. dosages of 0.25 and 2.5mg/kg, respectively, suggesting that 206-2-4 is one of the most potent hnMAbs against IFV reported thus far. The Ig genes of 206-2-4 and 201-6-8 were originated from distinct germ line repertoires, and accompanied by 63 and 23 somatic hypermutations, respectively. The hemagglutination inhibitory activity indicated that the mechanism of neutralization was to interfere the virus-receptor interaction. The binding epitope of the two antibodies was mapped to hemagglutinin 1 (HA1) amino acid residues 111-120. Additional interaction between the antibody and the HA1 globular head was necessary for neutralization. Such hnMAbs bearing distinct binding epitope have been rarely reported. The potency is likely due to the coverage of a wide surface area of HA protein by these hnMABs. IFV is a highly variable. Our knowledge on the mechanisms by which these cross-reactive hnMAbs function should help design a novel immunogen for the development of a vaccine effective against broader spectrum of IFV strains., (Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: The feasibility of salvage hepatectomy for locally recurrent hepatocellular carcinomas (HCCs) is unclear, especially for patients with viable parts of previously multinodular tumors., Methods: We reviewed charts of patients who underwent initial hepatectomies between 2000 and 2014 to select those with local recurrences (LR) after non-surgical treatments. Their postoperative outcomes, including morbidity, recurrence-free survival (RFS), and overall survival (OS) were compared with matched patients who underwent initial hepatectomies for primary HCCs (PR). Their local recurrence patterns were divided into recurrent solitary tumors (Subgroup A); and recurrent parts of multinodular tumors (Subgroup B)., Results: Among 664 patients, hepatectomy for LR was performed in 62 patients. Matched 59 patients were selected as PR. Clinicopathologic profiles at initial surgery were comparable between the LR and PR groups. Incidence of major morbidity (LR vs. PR, 7% vs. 5%, P = 1.00), 5-year RFS (21% vs. 37%, P = 0.28), and 5-year OS (69% vs. 69%, P = 0.62) were comparable. In the LR group, Subgroup B showed worse 5-year RFS (A vs. B, 29% vs. 0%, P < 0.01) and 5-year-OS (80% vs. 53%, P = 0.01). Postoperative recurrence occurred in 46 patients, but local and extrahepatic recurrence was seen only in 2 patients and 2 patients, respectively., Conclusion: Salvage hepatectomy for locally recurrent HCCs is feasible, and results in prognosis comparable with hepatectomy for primary HCCs. Although the risk of postoperative recurrence was high in Subgroup B, rare local recurrence suggests the usefulness of salvaging uncontrolled tumor by nonsurgical treatment., (Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

CD4 + Foxp3 + regulatory T cells (Tregs) play a central role in the maintenance of immune tolerance after hematopoietic stem cell transplantation. We previously reported that low-dose interleukin-2 (IL-2) therapy increased circulating Tregs and improved clinical symptoms of chronic graft-versus-host-disease (cGVHD); however, the mechanisms that regulate Treg homeostasis during IL-2 therapy have not been well studied. To elucidate these regulatory mechanisms, we examined the role of inhibitory coreceptors on Tregs during IL-2 therapy in a murine model and in patients with cGVHD. Murine studies demonstrated that low-dose IL-2 selectively increased Tregs and simultaneously enhanced the expression of programmed cell death 1 (PD-1), especially on CD44 + CD62L + central-memory Tregs, whereas expression of other inhibitory molecules, including CTLA-4, LAG-3, and TIM-3 remained stable. PD-1-deficient Tregs showed rapid Stat5 phosphorylation and proliferation soon after IL-2 initiation, but thereafter Tregs became proapoptotic with higher Fas and lower Bcl-2 expression. As a result, the positive impact of IL-2 on Tregs was completely abolished, and Treg levels returned to baseline despite continued IL-2 administration. We also examined circulating Tregs from patients with cGVHD who were receiving low-dose IL-2 and found that IL-2-induced Treg proliferation was promptly followed by increased PD-1 expression on central-memory Tregs. Notably, clinical improvement of GVHD was associated with increased levels of PD-1 on Tregs, suggesting that the PD-1 pathway supports Treg-mediated tolerance. These studies indicate that PD-1 is a critical homeostatic regulator for Tregs by modulating proliferation and apoptosis during IL-2 therapy. Our findings will facilitate the development of therapeutic strategies that modulate Treg homeostasis to promote immune tolerance., (© 2017 by The American Society of Hematology.)

Objective: To confirm the existence of the proposed three-core symptom domains in delirium by analyzing a dataset of nondemented adults using selected core symptoms as measured by the Delirium Rating Scale-Revised-98 (DRS-R98) scale., Methods: Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) of proposed delirium core symptoms were conducted in a pooled international dataset of 592 delirious and nondelirious patients using DSM-IV criteria from 14 studies with comparable methodologies. Using DRS-R98 categorization, 445 had either subsyndromal or full delirium and comprised the delirium group. The dataset was divided into three independent random subsamples to perform a stepwise analysis. First we performed EFA in 100 cases to delineate latent factor loadings of DRS-R98 items selected to represent the three-core domains (circadian, higher level thinking, and cognitive). These items were then assessed using CFA-modeling (n = 246) followed by a CFA-validation (n = 246). Reliability and goodness of fit of these two CFA were assessed statistically., Results: DRS-R98 items representing the proposed delirium core symptoms loaded onto one factor in the EFA, supporting their core nature. The two CFA confirmed the nature of this core factor as comprising three core domains where DRS-R98 items each loaded with high values (>0.7) onto their corresponding core domain (circadian, higher level thinking, and cognitive) with good fit and reliability. Attention was DRS-R98 item with the highest loading in CFA, followed by thought process, and then by sleep-wake cycle and motor behavior., Conclusions: Our EFA and CFA confirm and validate the proposed three-core domains of delirium, where symptoms were highly related to the domain that they were hypothesized to represent. These domains are consistent with delirium being a state of impaired consciousness, and should be considered necessary to assess whether in clinical or research settings., (Copyright © 2013 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of the present study was to differentiate and specify the subtypes of adenomyosis., Study Design: Surgically treated adenomyosis (n = 152) was subcategorized retrospectively into 4 subtypes on the basis of magnetic resonance imaging geography. Subtype I (n = 59) consisted of adenomyosis that occurs in the uterine inner layer without affecting the outer structures. Subtype II (n = 51) consisted of adenomyosis that occurs in the uterine outer layer without affecting the inner structures. Subtype III (n = 22) consisted of adenomyosis that occurs solitarily without relationship to structural components. Adenomyosis that did not satisfy these criteria composed subtype IV (n = 20). Stepwise logistic regression analysis was used for specification of the subtypes., Results: Subtypes I-III were suggested as a product of direct endometrial invasion, endometriotic invasion from the outside, and de novo metaplasia, respectively. Subtype IV was a heterogeneous mixture of far advanced disease., Conclusion: Adenomyosis appears to consist of 3 distinct subtypes of different causes and an additional subtype of indeterminate cause., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Mycobacterium ulcerans causes Buruli ulcer in humans, a progressive ulcerative epidermal lesion due to the mycolactone toxin produced by the bacterium. Molecular analysis of M. ulcerans reveals it is closely related to Mycobacterium marinum, a pathogen of both fish and man. Molecular evidence from diagnostic PCR assays for the insertion sequence IS2404 suggests an association of M. ulcerans with fish. However, fish infections by M. ulcerans have not been well documented and IS2404 has been found in other mycobacteria. We have thus, employed two experimental approaches to test for M. ulcerans in fish. We show here for the first time that M. ulcerans with or without the toxin does not mount acute or chronic infections in Japanese Medaka "Oryzias latipes" even at high doses. Moreover, M. ulcerans-infected medaka do not exhibit any visible signs of infection nor disease and the bacteria do not appear to replicate over time. In contrast, similar high doses of the wild-type M. marinum or a mycolactone-producing M. marinum "DL" strain are able to mount an acute disease with mortality in medaka. Although these results would suggest that M. ulcerans does not mount infections in fish we have evidence that CLC macrophages from goldfish are susceptible to mycolactones., (Copyright © 2012 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

Background: Soluble mesothelin (SM) and megakaryocyte potentiating factor (MPF) are serum biomarkers of mesothelioma. This study examined the effect of clinical covariates on biomarkers levels and their diagnostic and prognostic value., Methods: Five hundred ninety-four participants were enrolled in a multicenter study, including 106 patients with mesothelioma and 488 control subjects. Multiple linear regression analyses were used to identify which covariates were independently associated with SM and MPF levels. The effect of these covariates on the diagnostic accuracy was evaluated with receiver operating characteristics curve analysis. In patients with mesothelioma, survival analysis was performed with Cox regression., Results: SM and MPF levels were independently associated with age, glomerular filtration rate (GFR), and BMI in control subjects and with GFR and tumor stage in patients with mesothelioma. The diagnostic accuracy of SM and MPF was significantly affected by the distribution of these covariates in the study population. The patients with mesothelioma were best discriminated from the control subjects with either the youngest age, the highest GFR, or the largest BMI. Furthermore, the control subjects were significantly better differentiated from stage II to IV than from stage I mesothelioma. MPF, not SM, was an independent negative prognostic factor, but only if adjusted for the biomarker-associated covariates., Conclusions: SM and MPF levels were affected by the same clinical covariates, which also had a significant impact on their diagnostic and prognostic value. To improve the interpretation of biomarker results, age, GFR, and BMI should be routinely recorded. Approaches to account for these covariates require further validation, as does the prognostic value of SM and MPF.

Introduction: Soluble mesothelin (SM), megakaryocyte potentiating factor (MPF), and osteopontin (OPN) are blood biomarkers of mesothelioma. This study evaluates their use as markers of response to therapy and outcome., Methods: Sixty-two patients with malignant pleural mesothelioma were included in an observational multicenter study. Blood samples and matched computed tomography scans were collected at diagnosis and, when possible, during and after therapy. For each patient, the best overall radiological response was compared with the changes in serum SM, MPF, and plasma OPN levels across corresponding time points., Results: In five patients, blood sampling was done shortly before and after extrapleural pneumonectomy. SM and MPF levels markedly decreased after surgery, whereas OPN levels showed a median increase. Fifty-seven patients were surveilled during (and after) chemotherapy, of whom 27 (47%) had stable disease, 14 (25%) partial response, and 16 (28%) progressive disease. In patients with stable disease, SM and MPF levels did not change significantly across the corresponding time points, whereas OPN levels significantly decreased. In those with partial response, SM and MPF levels significantly decreased, whereas OPN levels showed no significant change. In patients with progressive disease, all three biomarker levels significantly increased. Patient responses correlated with a 15% change in all three biomarkers, although SM and MPF appeared more accurate than OPN. Low baseline OPN levels were independently associated with favorable progression-free survival and overall survival. Neither SM nor MPF showed prognostic value., Conclusions: SM and MPF levels were more closely associated with disease course than OPN and might prove useful in monitoring patient response in mesothelioma. Baseline OPN levels were an independent negative predictor of survival. These promising results require further validation.

Introduction: Soluble mesothelin (SM) and megakaryocyte potentiating factor (MPF) are serum biomarkers of mesothelioma. This study aims to examine the longitudinal behavior of SM and MPF in controls to gain insight in the optimal use of these biomarkers in screening., Methods: Asbestos-exposed individuals, with no malignant disease at inclusion, were surveilled for 2 years with annual measurements of SM and MPF. Fixed thresholds were set at 2.10 nmol/L for SM and 13.10 ng/ml for MPF. Longitudinal biomarker analysis, using a random intercept model, estimated the association with age and glomerular filtration rate (GFR), and the intraclass correlation. The latter represents the proportion of total biomarker variance accounted for by the between-individual variance., Results: A total of 215 participants were included, of whom 179 and 137 provided a second sample and third sample, respectively. Two participants with normal SM and MPF levels presented afterward with mesothelioma and lung cancer, respectively. Participants with elevated biomarker levels were typically older and had a lower GFR. During follow-up, biomarker levels significantly increased. Longitudinal analysis indicated that this was in part due to aging, while changes in GFR had a less pronounced effect on serial biomarker measurements. SM and MPF had a high intraclass correlation of 0.81 and 0.78, respectively, which implies that a single biomarker measurement and fixed threshold are suboptimal in screening., Conclusions: The longitudinal behavior of SM and MPF in controls indicates that a biomarker-based screening approach can benefit from the incorporation of serial measurements and individual-specific screening rules, adjusted for age and GFR. Large-scale validation remains nevertheless mandatory to elucidate whether such an approach can improve the early detection of mesothelioma.

Background: Delirium is a common neuropsychiatric disorder in medical and surgical inpatients of all ages. It is associated with increased long-term mortality, longer length of hospital stay, poor functional recovery, and increased likelihood of nursing home placement., Objective: The aim of this study was to investigate the reliability and the validity of the Japanese translation of the Delirium Rating Scale, Revised-98 (DRS-R-98)., Method: Psychiatric-consultation patients were assessed to compare groups of delirium, dementia, and non-delirium., Results: Mean Total and Severity scores significantly distinguished delirium from the other groups. The scale had high interrater reliability and high internal consistency. Mean Severity scores during delirium differed from the posttreatment scores. Stratum-specific likelihood ratios showed that the DRS-R98-J is a reliable diagnostic tool., Conclusion: This study indicates that the Japanese version of the DRS-R-98 has high reliability and validity, and is a useful tool for assessing delirium among Japanese medically ill populations.

It is unclear how changes in the content and number of news reports over time affect the impressions made in the minds of newspaper readers. This study targeted news reports in major newspapers regarding an incident of mass nosocomial Serratia infection that occurred at one clinic. The trends in the total number of articles and total number of characters contained in the articles were congruent, with a peak on the day after the incident was disclosed and a rapid decrease thereafter. The numbers of articles and characters that appeared during the first 3 days corresponded to 45 and 51% of those that appeared during the entire study period. On day 9, it was published that Serratia liquefaciens propagated on medical instruments, and both the number of articles and the number of characters increased by approximately 40% in comparison to those published on the day after the initial report of the incident. The individual articles were deemed to be medically accurate; however, the main problem was that only part of the specific medical issue had been emphasized because of a poor balance in the number of news reports on this topic.

Total synthesis and structure assignment of the minor metabolite present in lipid extracts of the frog pathogen Mycobacterium liflandii are reported.

We propose a simple and practical modeling approach for analysis of the data for myelosuppression after cancer chemotherapy, which can be applied when pharmacokinetic data are not available and several anticancer drugs were simultaneously administered. The model equation is based on the probability density function for the Erlang distribution. The data for cell counts of leukocytes (white blood cell, WBC), platelets (PLT), and reticulocytes (RET) obtained in routine clinical laboratory tests after the ICE (ifosfamide/carboplatin/etoposide) regimen for cancer chemotherapy were retrospectively collected from 28 patients, and a population analysis was applied. The time course profiles could be well explained by the proposed model. The individual values of the time to reach the nadir were obtained by the Bayesian method, and their medians (days) were 16.8 for WBC, 12.8 for PLT, and 8.2 for RET. Such information would be useful to determine the day of visit for outpatients especially for additional treatment to prevent side effects such as infections. The model is simple and applicable to explain the time course profiles for myelosuppression irrespective of cell types, and also practical because it requires only the data from routine clinical laboratory tests without any additional burden to patients., (c) 2009 Wiley-Liss, Inc. and the American Pharmacists Association)

The authors examined the factors associated with referral errors in which the presence of delirium was ostensibly not recognized by medical staff personnel. Medical records of 541 university-hospital patients consecutively referred for psychiatric consultation were scrutinized for extant delirium. The data indicated that a greater likelihood of a missed diagnosis was associated with younger age; referrals outside of family practice service; orientation as to person, place, and time; and a history of bipolar affective disorder or psychosis. The ramifications of failure to diagnose existing delirium include increased morbidity and mortality, longer length of hospital stay, and increased healthcare costs.

A highly effective procedure is reported to synthesize 1,2-aminoalcohols by regio- and chemo-selective ammonolysis of monosubstituted epoxides. Additive- and concentration-effects were studied, revealing that: (1) methanesulfonic acid is most effective among the additives tested and (2) formation of bis-adducts is practically eliminated at [C]

The authors investigated psychiatric consultation in two hospitals, one in the United States, the other in Japan. They examined similarities and differences, and drew inferences on possible cross-cultural values and/or temporary cultural conditions. As compared with the Japanese consultation patients, the Americans had more mood disorders, including anxiety and chemical-dependency problems, in respective diagnostic classifications. Patients in the United States also showed more acute as well as more serious chronic conditions. These differences may relate to disorder base-rates in the respective countries. In general, psychosocial problems emerged as ascendant in Japan, as compared with chemical-dependency difficulties among American patients. The results are discussed in terms of current conditions in Japan that affect the mental health professions, together with attempts by Japanese clinicians to protect collective mores by ascribing causation for disorders to the individual, rather than the societal conditions often invoked in the United States.

To investigate clinicopathological features of pyothorax-associated lymphoma (PAL), we examined medical records of 98 patients (88 males and 10 females) with PAL at a median age of 70 years (range 51-86). Seventy-nine patients had a history of artificial pneumothorax. Median interval between diagnosis and artificial pneumothorax was 43 years (range 19-64). At diagnosis, performance status (PS) was 0-1 (n=56) and 2-4 (n=42). Clinical stages were I (n=42), II (n=26), III (n=8) and IV (n=22). Pathological diagnosis comprised diffuse large-B-cell (n=78) and peripheral T-cell lymphoma (n=1). Seventeen were treated supportively. The other 81 received aggressive treatments; chemotherapy (n=52), radiotherapy (n=7), surgery (n=4) and combination (n=18). Five-year overall survival (OS) was 0.35 (95% confidence interval, 24% to 45%). Causes of deaths were PAL (n=39), respiratory failure (n=13) and others (n=12). Multivariate analysis identified prognostic factors for OS; lactate dehydrogenase levels [hazard ratio (HR)=2.36; P=0.013], sex (female versus male) (HR=0.15; P=0.01), PS (2-4 versus 0-1) (HR=2.20; P=0.02), clinical stages (III/IV versus I/II) (HR=1.95; P=0.037) and chemotherapy (HR=0.31; P=0.01). Most patients with PAL are elderly and have comorbidities, while some of them achieve durable remission with appropriate treatments. These findings prompt us to establish an optimal treatment strategy on the basis of risk stratification of individual patients.

A proportion of patients with Hodgkin lymphoma carry Epstein-Barr virus (EBV), an oncogenic herpesvirus, in their tumor cells. Although it is generally assumed that EBV contributes to the malignant phenotype of Hodgkin lymphoma cells, direct evidence in support of this is lacking. Here we show that EBV infection of Hodgkin lymphoma cells results in the induction of autotaxin, a secreted tumor-associated factor with lysophospholipase-D activity. Up-regulation of autotaxin increased the generation of lysophosphatidic acid (LPA) and led to the enhanced growth and survival of Hodgkin lymphoma cells, whereas specific down-regulation of autotaxin decreased LPA levels and reduced cell growth and viability. In lymphoma tissues, autotaxin expression was mainly restricted to CD30+ anaplastic large-cell lymphomas and Hodgkin lymphoma; in the latter, high levels of autotaxin were strongly associated with EBV positivity (P = .006). Our results identify the induction of autotaxin and the subsequent generation of LPA as key molecular events that mediate the EBV-induced growth and survival of Hodgkin lymphoma cells and suggest that this pathway may provide opportunities for novel therapeutic intervention.

The purpose of this study was to examine the factors affecting the timing of psychiatric consultations and length of stay in the current managed care era. It also assessed the relationships between the timing of consultations and demographic/clinical characteristics. Medical records of 541 consecutive psychiatric consultation patients at a university teaching hospital in 2001 were reviewed for demographic characteristics, lengths of stay, number of days from admission to consultation, specialty services requesting consultations, reasons for the referral given by the referring physicians, and all five axes of DSM-IV. Earlier consultations independently predicted shorter lengths of stay. Delayed consultations were seen more often in women; surgical patients; those seen with a request to assess depression; and those seen with a diagnosis of adjustment disorder, delirium, or no psychiatric disorder. Delay in psychiatric consultations continues to be associated with longer lengths of stay in the current managed care environment. It is now possible that early detection strategies for high-risk patients with behavioral health problems in the medical setting, such as use of the INTERMED, may lead to reduction in delayed psychiatric consultations and thus shorter lengths of stay.

Study Objective: To investigate the influence of diabetes mellitus on the hemodynamic-stabilizing effect of clonidine during off-pump coronary artery bypass (OPCAB) surgery., Design: Prospective study., Setting: Public, university-affiliated hospital., Patients: 40 patients (32 male, 8 female) scheduled for OPCAB surgery., Interventions and Measurements: Patients were divided into equal groups of diabetic and nondiabetic patients. All patients were given 150 microg oral clonidine 1 hour before induction. Anesthesia was induced and maintained with fentanyl, propofol, and sevoflurane. Propranolol was administered intermittently to maintain an adequate heart rate (HR; 50 to 70 bpm). Preoperative demographic data (fasting blood glucose concentration and hemoglobin A1c), dose of intraoperative drugs (propofol and propranolol), and outcome data (duration of intubation and duration of hospital stay after surgery) were analyzed., Main Results: In the diabetic and nondiabetic groups, the mean (+/-SD) plasma glucose values were 7.8 +/- 2.3 mmoL. L(-1) and 5.4 +/- 0.7 mmoL. L(-1), respectively (p < 0.05), and the mean (+/-SD) HbA1c values were 7.1 +/- 1.3% and 5.2 +/- 0.4%, respectively (p < 0.05). The mean propofol infusion rate was 2.8 +/- 0.9 mg. kg(-1). h(-1) in diabetic patients and 3.1 +/- 1.0 mg. kg(-1). h(-1) in nondiabetics (NS, p > 0.05). The total requirement for propranolol was 5.1 +/- 2.4 mg in diabetic patients and 1.6 +/- 1.1 mg in nondiabetics (p < 0.05)., Conclusions: Diabetes attenuates the hemodynamic stabilizing effects of preanesthetic oral clonidine in the clinical setting.

Study Objective: To investigate whether intraoperative fluid management contributes to postoperative respiratory disturbances in esophagectomy for carcinoma., Design: Retrospective study., Setting: Operating room and postanesthetic care unit of the cancer center., Patients: From 1997 to 2000, 112 ASA physical status I, II, and III patients with primary carcinoma of the esophagus undergoing transthoracic esophagectomy., Interventions and Measurements: As of 1998, we altered fluid management during esophagectomy to save intraoperative fluid administration. Then, we investigated postoperative respiratory disturbances after esophagectomy in the period from 1998 to 2000 (late period) compared with the period from 1997 to 1998 (early period). We also investigated the relationship between perioperative risk factors and postoperative respiratory disturbances. The need for frequent (>10) bronchoscopic suctioning of sputum during postoperative period, the need for tracheostomy, and failure in the removal of endotracheal tube (ETT) (extubation) on the first postoperative day (1 POD) were investigated for respiratory disturbances after surgery., Main Results: Intraoperative volume balance decreased more so in the late period compared with early period (p < 0.0,001). The need for tracheostomy, bronchoscopic suctioning, and extubation failure on 1 POD were more frequent in the early period than in the late period (p = 0.0083, p = 0.0319, and p = 0.0024, respectively). The hospital recovery period after surgery was shortened during the late period (p = 0.032). Intraoperative volume balance affected the need for tracheostomy and frequent bronchoscopy postoperatively., Conclusions: Careful intraoperative fluid administration may decrease postoperative respiratory disturbances.

Activation of platelets by acute vigorous exercise has been demonstrated by various parameters, including an increase in agonist-induced platelet [Ca2+]i levels. However, direct evidence is lacking regarding how acute exercise affects platelet-derived NO. Twenty-three healthy male non-smokers (21-59 years) underwent a symptom-limited treadmill exercise test. Washed platelets were prepared from blood samples obtained before and immediately after exercise. All subjects completed at least Bruce stage 2 and were each negative for ischemia. With a low dose (2 microg/ml) of collagen, NO release from washed platelets, detected by the NO-selective microelectrode, was significantly increased after exercise (pmols/10(8) platelets, before: 0.64+/-0.11, after: 1.03+/-0.18; P<0.005) without changes in aggregation ability. This enhanced NO release was accompanied by increased platelet [Ca2+]i levels (before: 232+/-25, after: 296+/-37; P<0.01). With a high dose (5 or 10 microg/ml) of collagen, NO release and aggregation were both modestly, but significantly, enhanced after exercise. The exercise-induced enhancement of platelet NO release in response to collagen was also suggested by increase in platelet cyclic guanosine monophosphate accumulation and augmenting effect of N(G)-monomethyl-L-arginine on platelet aggregation. In summary, acute strenuous exercise primes enhanced NO release and may play a protective role against exercise-induced activation of platelets in normal subjects.

Purpose: To investigate whether continuous epidural droperidol and intravenous (IV) intraoperative droperidol inhibit pruritus and postoperative nausea and vomiting (PONV) during epidural morphine analgesia., Design: Randomized, double-blinded, controlled study., Setting: Metropolitan cancer center., Patients: 120 ASA physical status I and II patients undergoing thoracic or abdominal surgery with general anesthesia combined with epidural anesthesia., Interventions: Patients received an intraoperative epidural injection of 2 mg morphine hydrochloride, followed postoperatively by a continuous epidural infusion of morphine hydrochloride 4 mg/day for 4 days. Patients were randomly allocated to four groups: Group A = control group, Group B = intraoperative single IV injection of droperidol (2.5 mg), Group C = postoperative continuous epidural droperidol infusion (2.5 mg/day), and Group D = intraoperative IV injection of droperidol (2.5 mg) and postoperative continuous epidural droperidol infusion (2.5 mg/day)., Measurements and Main Results: The frequency and severity of pruritus and PONV in each group were evaluated during the postoperative period. Continuous epidural infusion of droperidol significantly reduced the frequency and severity of pruritus and PONV induced by epidural morphine without causing significant side effects. Intraoperative single IV injection of droperidol was effective for PONV (p < 0.05) but not for pruritus., Conclusion: Postoperative epidural droperidol infusion significantly decreased both the frequency and severity of pruritus and PONV during postoperative continuous epidural morphine analgesia. IV intraoperative droperidol significantly reduced the frequency and the severity of PONV but not pruritus.

Suicide is one of the leading causes of death in the community. The risk of suicide is greater among patients with physical illnesses than among the general population. This study was undertaken to evaluate the clinical characteristics and correlates of suicidal ideation in patients with acute life-threatening physical illnesses and to assess the duration of suicidal ideation. The study included a consecutive series of patients admitted with stroke, traumatic brain injury, myocardial infarction, or spinal cord injury (n=496). Study participants were administered a semistructured psychiatric interview as well as a series of standardized quantitative scales of mood, cognitive function, physical impairment, social ties, and social functioning. Follow-up evaluations of up to 24 months were also carried out. This study found that 36 (7.3%) patients with acute medical illness had clinically significant suicidal ideation. The suicidal ideation occurred mostly among patients with major depression and sometimes in those with minor depression. About 25% of patients with major depression and acute physical illnesses developed suicidal ideation. After the improvement of depressive disorders, suicidal ideations were ameliorated. These findings suggest that the detection and treatment of depressive disorders is the most important factor in preventing suicide among this patient population.

Study Objective: To examine the relationship between the duration of the preoperative smoke-free period and the development of postoperative pulmonary complications (PPCs) in patients who underwent pulmonary surgery, and the optimal timing of quitting smoking., Design: Retrospective cohort study., Setting: Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan., Patients: Two hundred eighty-eight consecutive patients who underwent pulmonary surgery between January 1997 and December 1998., Measurements and Results: We collected information on the preoperative characteristics, intraoperative conditions, and occurrence of PPCs by reviewing the medical records. Study subjects were classified into four groups based on their smoking status. A current smoker was defined as one who smoked within 2 weeks prior to the operation. Recent smokers and ex-smokers were defined as those whose duration of abstinence from smoking was 2 to 4 weeks and > 4 weeks prior to the operation, respectively. A never-smoker was defined as one who had never smoked. The incidence of PPCs among the current smokers and recent smokers was 43.6% and 53.8%, respectively, and each was higher than that in the never-smokers (23.9%; p < 0.05). The moving average of the incidence of PPCs gradually decreased in patients whose smoke-free period was 5 to 8 weeks or longer. After controlling for sex, age, results of pulmonary function tests, and duration of surgery, the odds ratios for PPCs developing in current smokers, recent smokers, and ex-smokers in comparison with never-smokers were 2.09 (95% confidence interval [CI], 0.83 to 5.25), 2.44 (95% CI, 0.67 to 8.89), and 1.03 (95% CI, 0.47 to 2.26), respectively., Conclusions: These findings indicate that preoperative smoking abstinence of at least 4 weeks is necessary for patients who undergo pulmonary surgery, to reduce the incidence of PPCs.

Study Objective: To investigate whether oral omeprazole 20 mg decreases the risk of aspiration pneumonia in patients with gastric tube reconstruction., Design: Consecutive study., Setting: Operation room of cancer center., Patients: Thirteen patients with gastric tube reconstruction for esophageal cancer., Interventions: Oral omeprazole 20 mg was given the night before surgery. A rapid-sequence induction with cricoid pressure was employed for induction of anesthesia. After tracheal intubation, a nasogastric catheter was inserted into the gastric tube and the contents were aspirated., Measurements and Main Results: The pH and volume of the gastric contents were measured. The pH and volume of the gastric tube contents were 4.5 +/- 1.6 (range from 2.5 to 7.0) and 9.5 +/- 10.2 mL (range from 0 to 30 mL), respectively. Food residue was recognized in nine patients. There was no patient with a pH below 2.5 and a volume of 25 mL or greater., Conclusions: Omeprazole 20 mg decreased the acidity and volume of the gastric tube contents and reduced the risk of aspiration pneumonia in patients with a gastric tube in place.

This study compares the treatment of patients with comorbid medical and psychiatric illness admitted to a high-acuity (Type IV) integrated medicine and psychiatry inpatient program with patients having psychiatric symptoms on general internal medicine wards (IMWs). More patients in the Type IV program had agitation, suicidal ideation, or psychosis as psychiatric admission behaviors when compared to IMW patients. Medical symptom improvement was comparable in the two settings, whereas, psychiatric symptoms improved more in the Type IV Program than on the IMWs despite more significant illness and comparable lengths of stay. Integrated care on the Type IV unit allowed shorter total lengths of stay for medical patients with serious psychiatric illness than would have occurred had the traditional sequential approach to care been used. The integrated Type IV medicine and psychiatry treatment program represents an efficient and effective process improvement in the way that medical patients with comorbid medical and psychiatric illness can be treated.

Study Objective: To investigate the effects of preanesthetic oral clonidine on total propofol requirement for uniform minor surgery (breast conservative surgery: breast cancer removal with axillary lymph node dissection), and to compare the action of clonidine with that of preanesthetic oral diazepam, a commonly used benzodiazepine., Design: Randomized double-blinded study., Setting: Operating room ASA physical status I and II room and recovery room of the cancer center., Patients: 80 breast cancer patients scheduled for surgery., Interventions: Patients were randomized to one of four treatment groups (placebo, clonidine 75 micrograms, or 150 micrograms of clonidine, or 10 mg of diazepam were orally administered 60 min before induction of anesthesia); n = 20 per group. After evaluating the sedation and anxiety levels of patients using a visual analog scale, anesthesia was induced with propofol (1.5 mg/kg), and maintained with oxygen (O2): nitrous oxide (N2O) (30:70) with a continuous infusion of propofol. The propofol infusion was started at 10 mg/kg/h for 10 minutes, then decreased to 8 mg/kg/h, and 6 mg/kg/h thereafter, and the rate of infusion was adjusted to obtain adequate anesthesia (maintaining hemodynamic parameters within 20% of that prior to premedication). Fentanyl 0.2 mg (each 0.1 mg was given for intubation and axillary lymph node dissection, respectively) was administered., Measurements and Main Results: Preanesthetic oral clonidine (150 micrograms) and diazepam (10 mg) induced anxiolysis without sedation. The total requirement (the mean infusion rates) of propofol in placebo, clonidine 75 micrograms, clonidine 150 micrograms, and 10 mg of diazepam groups were 841 +/- 70 (9.0 +/- 0.3), 720 +/- 63 (7.1 +/- 0.4), 491 +/- 39 (5.6 +/- 0.2), and 829 +/- 77 mg (7.9 +/- 0.4 mg/kg/h), respectively. The cost of propofol in these groups was $51.0 +/- 3.8, $45.5 +/- 3.2, $33.5 +/- 2.3, and $50.5 +/- 4.4, respectively., Conclusions: Preanesthetic oral clonidine (150 micrograms) but not diazepam (10 mg) reduced the total requirement of propofol while stabilizing hemodynamic parameters. In addition, 150 micrograms of oral clonidine attenuates the hemodynamic responses associated with tracheal intubation.

We present a case of 'subclavian steal syndrome' secondary to Takayasu arteritis, in a 32-year-old, Japanese woman, whose clinical manifestations result from severe ocular and brain ischemia, refractory to high dose systemic corticosteroids. Surgical management using two bypass-grafts was carried out. The first one, a GoreTex, 8 mm in diameter, thin wall, stretch type with ring-bypass graft, from the left external iliac artery to the ipsilateral axillary artery. The second one, an autologous reverse saphenous vein graft from the left subclavian artery to the ipsilateral common carotid artery. The result was a remarkable improvement of the patient's general condition and symptoms. Patency of the extra-anatomic conduits was established by digital subtraction angiography (DSA), and transcranial Doppler evaluation, as well as flow velocity assessment revealed an objective improvement of the blood supply to the ischemic areas. The present surgical approach was justified since the inflammatory process extended to the aortic arch. The development of new and efficient operatory techniques, and continuous improvement of the graft-materials provide better expectations for the long-term outcome of refractory syndromes.

We have previously shown that aggregated human platelets elicited a decrease in intracellular adenosine triphosphate (ATP), enhanced adenosine egress and damage to mitochondria in bovine aortic endothelial cells (ECs). To test whether such metabolic and ultrastructural changes could be associated with functional impairment of ECs, we investigated the effects of activated platelets on nitric oxide (NO) and prostacyclin release, and on the antiaggregation property of ECs. Pretreatment of ECs with aggregated platelets transiently stimulated basal NO release while prolonged (> or = 30 min) exposure dose-dependently inhibited NO release, both basal and in response to ATP or serotonin, with NO synthase activity being attenuated in these cells. Supplementary L-arginine (L-A) restored NO release completely. Prostacyclin release was also stimulated transiently but not affected by prolonged pretreatment. The antiaggregation property of ECs was attenuated by pretreatment with activated platelets but restored with L-A supplement. Although the effects of activated platelets and 0.5 mM acetylsalicylic acid (ASA) to attenuate the antiaggregation property of ECs were additive, activated platelets had no effect on ECs treated with 0.2 mM N omega-nitro-L-arginine (L-NA), suggesting a common mechanism. We conclude that prolonged exposure to aggregated platelets may affect the antiaggregation property of ECs by directly inhibiting NO synthesis, which may be normalized by L-A supplementation.

15 kinds of recombinant semi-synthetic aequorins and a recombinant fluorescein-conjugated aequorin were prepared and their properties in Ca(2+)-triggered luminescence were studied. The semi-synthetic aequorins showed a wide range of Ca(2+)-sensitivity. The luminescence intensity of a high-sensitivity type (hcp-aequorin) was greater than 10(4)-times that of a low-sensitivity type (n-aequorin) at pCa 6.0-6.5. The fluorescein-conjugated aequorin exhibited fluorescence in addition to the Ca(2+)-triggered luminescence, thus it can be used to visualize the diffusion and distribution of aequorin in cells. The data obtained, particularly the Ca(2+)-sensitivity curves, are useful in selecting a suitable semi-synthetic aequorin for an experiment.