Publications by authors named "Shuhei Ishikawa"

18 Publications

  • Page 1 of 1

The type rather than the daily dose or number of antipsychotics affects the incidence of hyperglycemic progression.

Prog Neuropsychopharmacol Biol Psychiatry 2021 Oct 9:110453. Epub 2021 Oct 9.

Department of Psychiatry, Hokkaido University Graduate School of Medicine, North 15, West 7, Sapporo 060-8638, Japan. Electronic address:

There have been concerns that antipsychotics increase the incidence of hyperglycemic progression. Many factors have been suggested to contribute to the risk of antipsychotic-induced hyperglycemic progression, including the type, daily dose, and number of antipsychotics; however, few studies have examined these relationships. This study aimed to examine the affect of antipsychotic treatment-associated factors on hyperglycemic progression, after adjustment for the affect of background factors suggested to be associated with hyperglycemic progression. This was a nationwide, multicenter, prospective cohort study examining the incidence of hyperglycemic progression during a 12 mo period following the initiation of newly prescribed antipsychotic medication. Demographic data, medication history, and blood test values were collected from 631 study participants with normal blood glucose levels at baseline for 12 mo. The primary endpoint (incidence of hyperglycemic progression) was defined as progression from normal to prediabetic or probable diabetic status, and was evaluated based on the Japanese monitoring guidance in patients with schizophrenia. To further examine the affect of antipsychotics on glucose metabolism over time, we examined changes in HbA1c levels 3, 6, and 12 mo after the initiation of treatment with each antipsychotic. We found that treatment with zotepine and clozapine was associated with a significantly high incidence of hyperglycemic progression. Furthermore, changes in HbA1c levels 6 mo after the initiation of zotepine treatment were significantly higher than those following blonanserin and haloperidol treatments. In contrast, there was no significant difference in the change in total cholesterol, triglycerides, HDL cholesterol, and BMI during the same period. Moreover, the "daily dose" and "number" of antipsychotics did not show an association with the incidence of hyperglycemic progression. However, in a post hoc analysis in which the antipsychotics were divided into two groups according to the strength of blockade of H, M, M, and 5-HT receptors, the incidence of hyperglycemic progression was higher in the medium- and high-daily dose groups than in the low-daily dose group in the antipsychotic group with strong blockade of these receptors. Our study indicated that the type of antipsychotic had a greater affect on the incidence of hyperglycemic progression than the daily dose of antipsychotics or their number. Among these, zotepine was most likely to increase the incidence of hyperglycemic progression, suggesting the need for caution when these antipsychotics are prescribed.
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http://dx.doi.org/10.1016/j.pnpbp.2021.110453DOI Listing
October 2021

Characteristics of discharge prescriptions for patients with schizophrenia or major depressive disorder: Real-world evidence from the Effectiveness of Guidelines for Dissemination and Education (EGUIDE) psychiatric treatment project.

Asian J Psychiatr 2021 Sep 15;63:102744. Epub 2021 Jul 15.

Department of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.

Background: Monopharmacy with antipsychotics and antidepressants is the first-line treatment for schizophrenia and major depressive disorder (MDD) in most clinical guidelines, while polypharmacy with psychotropic agents in the treatment of schizophrenia is common in clinical practice. There are no detailed data on the prescription patterns for inpatients with mental illness with reliable diagnoses made by treating psychiatrists.

Methods: We gathered prescription data at discharge from 2177 patients with schizophrenia and 1238 patients with MDD from October 2016 to March 2018.

Results: The patients with schizophrenia aged between 60 and 79 were prescribed lower doses of antipsychotics and hypnotics/anxiolytics than those aged between 40 and 59. There were significant differences between the prescription rate of antipsychotics in the patients with schizophrenia and that of antidepressants in the patients with MDD. The frequency of concomitant drugs such as anti-Parkinson drugs, anxiolytics/hypnotics and mood stabilizers in the subjects with schizophrenia prescribed antipsychotic polypharmacy was significantly higher than that with monotherapy. For the patients with schizophrenia, olanzapine, risperidone, aripiprazole, quetiapine, and blonanserin were the five most prescribed antipsychotics. For the patients with MDD, mirtazapine, duloxetine, escitalopram, trazodone and sertraline were the five most prescribed antidepressants.

Conclusions: Our results showed the use of high doses of antipsychotics, high percentages of antipsychotic polypharmacy and concurrent use of hypnotics/anxiolytics in patients with schizophrenia. Notably, these data were collected before intensive instruction regarding the guidelines; therefore, we need to assess the change in the prescription pattern post guideline instruction.
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http://dx.doi.org/10.1016/j.ajp.2021.102744DOI Listing
September 2021

Presenteeism and Associated Factors Among Nursing Personnel with Low Back Pain: A Cross-Sectional Study.

J Pain Res 2020 19;13:2979-2986. Epub 2020 Nov 19.

Department of Medical Research and Management for Musculoskeletal Pain, 22nd Century Medical & Research Center, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.

Background: A decrease in work productivity due to presenteeism among healthcare workers with low back pain (LBP) is a major problem in the workplace. It is important to determine the factors associated with presenteeism to successfully manage work productivity among nursing staff with LBP. This study aimed to identify the factors associated with presenteeism among nursing personnel with LBP through the evaluation of several aspects, including individual, occupational, and psychological factors.

Methods: We conducted a cross-sectional study with 668 nursing personnel who had experienced LBP within the 4 weeks before study enrollment at a tertiary hospital in Japan. Information on demographics (eg, sex, age, height, weight, etc.), LBP intensity (Numerical Rating Scale, NRS), kinesiophobia (Tampa Scale for Kinesiophobia-11, TSK-11), depressive condition (K6), workaholism, overworking hours, frequency of shift work, sleep problem, work-related stress, and presenteeism (Work Productivity and Activity Impairment-General Health) were collected using a self-administered questionnaire. Multiple linear regressions were applied to examine the factors related to presenteeism. We further used a multiple imputation by chained equations for missing data in the model.

Results: Multiple linear regression analysis after adjusting for covariates showed that NRS (regression coefficient β = 2.275), TSK-11 (1.112), K6 (0.616), and sleep duration (-1.990) were significantly associated with presenteeism. These results with complete-case analyses were similar to those with multiple imputation analyses.

Conclusion: Psychological factors, such as kinesiophobia and depressive symptoms, were associated with presenteeism independently of LBP intensity among nursing staff with LBP. Our findings suggest that the above-mentioned factors may need to be considered for the development of strategies to increase work productivity among nursing staff with LBP.
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http://dx.doi.org/10.2147/JPR.S269529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682615PMC
November 2020

Unusual etiology of persistent fever after urinary tract infection: Papillary renal cell carcinoma.

J Gen Fam Med 2020 Sep 13;21(5):193-194. Epub 2020 May 13.

Department of Nephrology Teine Keijinkai Medical Center Sapporo Japan.

This manuscript presents a case report of type 2 papillary renal cell carcinoma presenting with persistent fever and abdominal tenderness after treatment for urinary tract infection. The purpose of this article is to aid physicians in understanding that papillary renal cell carcinomas should be considered in patients with a persistent fever after urinary tract infection and computed tomography was useful to diagnose this entity.
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http://dx.doi.org/10.1002/jgf2.327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521785PMC
September 2020

Association Between -Desmethylclozapine and Clozapine-Induced Sialorrhea: Involvement of Increased Nocturnal Salivary Secretion via Muscarinic Receptors by -Desmethylclozapine.

J Pharmacol Exp Ther 2020 11 29;375(2):376-384. Epub 2020 Aug 29.

Laboratory of Clinical Pharmaceutics and Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences (S.I., M.K., H.M., K.N., A.F., K.I.) and Education Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences (M.K.), Hokkaido University, Sapporo, Japan; Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan (S.I.); Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan (N.H., I.K.); and Department of Pharmacology, School of Dentistry, Health Sciences University of Hokkaido, Sapporo, Japan (A.T.).

Clozapine-induced sialorrhea (CIS) is a common side effect of clozapine. There is no established standard treatment of CIS since the underlying mechanism remains unknown. This study aimed to elucidate the mechanisms involved in CIS. In our clinical study, a prospective observational study evaluated the association between serum and saliva concentrations of clozapine or its metabolites and Drooling Severity and Frequency Scale (DSFS) score. In our in vivo study, we first developed a new CIS animal model; subsequently, we measured salivary secretion and concentrations of clozapine or its metabolites in the animal model. In our in vitro study, we measured the calcium ion (Ca) response to evaluate the effect of clozapine or its metabolites on human salivary gland cell line (HSY cells) and then examined whether their effect was inhibited by atropine. In our clinical study, serum and saliva -desmethylclozapine concentrations were significantly correlated with nocturnal DSFS score. In our in vivo study, daily single oral administration of 100 mg/kg clozapine for 7 days significantly increased salivary secretion in rats. Furthermore, -desmethylclozapine concentrations in serum and submandibular glands of the rats were higher than clozapine concentrations. In our in vitro study, -desmethylclozapine only elicited an increase in the intracellular Ca in HSY cells. -desmethylclozapine-induced Ca responses were inhibited by atropine. These results suggest that -desmethylclozapine is implicated in CIS by increasing nocturnal salivation via the muscarinic receptors. Moreover, our developed animal model that reflects CIS in clinical condition plays a key role as a bridge between basic and clinical research. SIGNIFICANCE STATEMENT: Clozapine-induced sialorrhea (CIS) is a severe and frequent adverse reaction, but the mechanism underlying CIS is less well understood. This paper reports that -desmethylclozapine, a metabolite of clozapine, is implicated in CIS by increasing nocturnal salivation via the muscarinic receptors and that oral administration of clozapine at 100 mg/kg once daily for 7 days to rat is the optimum method for establishing the new animal model reflecting the clinical scenario of CIS.
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http://dx.doi.org/10.1124/jpet.120.000164DOI Listing
November 2020

Evaluation of Daptomycin-Induced Cellular Membrane Injury in Skeletal Muscle.

Biol Pharm Bull 2020 Sep 23;43(9):1338-1345. Epub 2020 Jun 23.

Department of Pharmacy, Hokkaido University Hospital.

Daptomycin, a cyclic lipopeptide antibiotic, has bactericidal activity against Gram-positive organisms and is especially effective against methicillin-resistant Staphylococcus aureus. Although daptomycin causes unique adverse drug reactions such as elevation of creatine phosphokinase or rhabdomyolysis, the detailed mechanisms underlying these adverse drug reactions in skeletal muscle are unclear. This study aimed to elucidate whether daptomycin causes direct skeletal muscle cell toxicity and investigate the relationship between daptomycin exposure and musculoskeletal toxicity. First, we evaluated the relationship between daptomycin exposure and skeletal muscle toxicity. Of the 38 patients who received daptomycin intravenously, an elevation in creatine phosphokinase levels was observed in five. The median plasma trough concentration of daptomycin in patients with elevated creatine phosphokinase levels was significantly higher than that in patients whose creatine phosphokinase levels were within the normal range, suggesting that increased exposure to daptomycin is related to elevation in creatine phosphokinase levels. In an in vitro study using human rhabdomyosarcoma cells, daptomycin reduced cell viability and increased membrane damage. These effects were more marked under hypoxic conditions. A necroptotic pathway seemed to be involved because phosphorylated mixed lineage kinase domain-like protein expression was enhanced following daptomycin exposure, which was significantly enhanced under hypoxic conditions. These findings indicate that daptomycin elicits cytotoxic effects against skeletal muscle cells via the necroptotic pathway, and the extent of toxicity is enhanced under hypoxic conditions.
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http://dx.doi.org/10.1248/bpb.b20-00217DOI Listing
September 2020

Factors associated with disabling low back pain among nursing personnel at a medical centre in Japan: a comparative cross-sectional survey.

BMJ Open 2019 09 27;9(9):e032297. Epub 2019 Sep 27.

Department of Medical Research and Management for Musculoskeletal Pain, The University of Tokyo, Bunkyo-ku, Japan.

Objectives: Low back pain (LBP) is a common cause of disability among nursing personnel. Although many studies regarding the risk factors for LBP among nursing staff have focused on the physical load at work, multidimensional assessments of risk factors are essential to identify appropriate preventive strategies. We aimed to investigate the association of multidimensional factors (individual, physical, psychological and occupational) with disabling LBP among nursing personnel in Japan.

Design: Observational study with comparative cross-sectional design.

Setting: Data were collected using the self-administered questionnaire at a tertiary medical centre.

Participants: After excluding participants with missing variables, 718 nursing personnel were included in the analysis.

Outcome Measures: A self-administered questionnaire assessed individual characteristics, rotating night shift data, severity of LBP, previous episode of LBP, sleep problem, kinesiophobia (Tampa Scale for Kinesiophobia), depressive condition (K6), physical flexibility and frequency of lifting at work. A logistic regression model was used to evaluate the factors associated with disabling LBP (LBP interfering with work) among nursing personnel.

Results: Of all participants, 110 (15.3%) reported having disabling LBP. The multivariable logistic regression analysis after adjustment for several confounding factors showed that kinesiophobia (highest tertile, adjusted OR (aOR): 6.13, 95% CI : 3.34 to 11.27), previous episode of LBP (aOR: 4.31, 95% CI: 1.50 to 12.41) and insomnia (aOR: 1.66, 95% CI: 1.05 to 2.62) were significantly associated with disabling LBP.

Conclusions: The present study indicated that kinesiophobia, a previous episode of LBP, and sleep problems were associated with disabling LBP among nursing personnel. In the future, workplace interventions considering assessments of these factors may reduce the incidence of disabling LBP in nursing staff, although further prospective studies are needed.
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http://dx.doi.org/10.1136/bmjopen-2019-032297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773308PMC
September 2019

Comparison of the paralogous transcription factors AraR and XlnR in Aspergillus oryzae.

Curr Genet 2018 Dec 13;64(6):1245-1260. Epub 2018 Apr 13.

Department of Biological Mechanisms and Functions, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi, 464-8601, Japan.

The paralogous transcription factors AraR and XlnR in Aspergillus regulate genes that are involved in degradation of cellulose and hemicellulose and catabolism of pentose. AraR and XlnR target the same genes for pentose catabolism but target different genes encoding enzymes for polysaccharide degradation. To uncover the relationship between these paralogous transcription factors, we examined their contribution to regulation of the PCP genes and compared their preferred recognition sequences. Both AraR and XlnR are involved in induction of all the pentose catabolic genes in A. oryzae except larA encoding L-arabinose reductase, which was regulated by AraR but not by XlnR. DNA-binding studies revealed that the recognition sequences of AraR and XlnR also differ only slightly; AraR prefers CGGDTAAW, while XlnR prefers CGGNTAAW. All the pentose catabolic genes possess at least one recognition site to which both AraR and XlnR can bind. Cooperative binding by the factors was not observed. Instead, they competed to bind to the shared sites. XlnR bound to the recognition sites mentioned above as a monomer, but bound to the sequence TTAGSCTAA on the xylanase promoters as a dimer. Consequently, AraR and XlnR have significantly similar, but not the same, DNA-binding properties. Such a slight difference in these paralogous transcription factors may lead to complex outputs in enzyme production depending on the concentrations of coexisting inducer molecules in the natural environment.
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http://dx.doi.org/10.1007/s00294-018-0837-5DOI Listing
December 2018

Possible modulation of the amygdala on metaplasticity deficits in the hippocampal CA1 field in early postnatally stressed rats.

J Pharmacol Sci 2012 28;119(1):64-72. Epub 2012 Apr 28.

Department of Pharmacology, School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan.

Several lines of evidence have shown that early life experiences have a profound impact on fear-related behavior, but the detailed mechanisms are unknown. The present study examined the possible involvement of the amygdala in behavioral deficits associated with fear memory in a juvenile stress model, with a focus on hippocampal synaptic function. Adult rats exposed to footshock (FS) stress during the second postnatal period (2wFS group) exhibited low levels of freezing in response to contextual fear conditioning (CFC). The CFC-induced suppression of long-term potentiation (LTP) in the CA1 field was not found in the 2wFS group. Additionally, synaptic metaplasticity, that is, low-frequency stimulation-induced suppression of subsequent LTP, did not occur in the 2wFS group; instead, LTP was induced. These synaptic changes mimicked the impairment in metaplasticity induced by reversible inactivation of the basolateral amygdala (BLA). Inactivation of the BLA markedly decreased freezing behavior in non-FS controls, similar to the 2wFS group. Furthermore, extracellular signal-regulated kinase activation in the BLA in response to CFC did not occur in the 2wFS group. These findings suggest that early postnatal stress may cause long-term dysfunction of the modulatory effect of the amygdala on hippocampal function associated with fear memory.
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http://dx.doi.org/10.1254/jphs.12023fpDOI Listing
November 2012

Phase-dependent synaptic changes in the hippocampal CA1 field underlying extinction processes in freely moving rats.

Neurobiol Learn Mem 2012 May 4;97(4):361-9. Epub 2012 Mar 4.

Department of Pharmacology, School of Pharmaceutical Science, Health Sciences University of Hokkaido, Ishikari-Tobetsu 061-0293, Japan.

Recent studies focus on the functional significance of a novel form of synaptic plasticity, low-frequency stimulation (LFS)-induced synaptic potentiation in the hippocampal CA1 area. In the present study, we elucidated dynamic changes in synaptic function in the CA1 field during extinction processes associated with context-dependent fear memory in freely moving rats, with a focus on LFS-induced synaptic plasticity. Synaptic transmission in the CA1 field was transiently depressed during each extinction trial, but synaptic efficacy was gradually enhanced by repeated extinction trials, accompanied by decreases in freezing. On the day following the extinction training, synaptic transmission did not show further changes during extinction retrieval, suggesting that the hippocampal synaptic transmission that underlies extinction processes changes in a phase-dependent manner. The synaptic potentiation produced by extinction training was mimicked by synaptic changes induced by LFS (0.5 Hz) in the group that previously received footshock conditioning. Furthermore, the expression of freezing during re-exposure to footshock box was significantly reduced in the LFS application group in a manner similar to the extinction group. These results suggest that LFS-induced synaptic plasticity may be associated with the extinction processes that underlie context-dependent fear memory. This hypothesis was supported by the fact that synaptic potentiation induced by extinction training did not occur in a juvenile stress model that exhibited extinction deficits. Given the similarity between these electrophysiological and behavioral data, LFS-induced synaptic plasticity may be related to extinction learning, with some aspects of neuronal oscillations, during the acquisition and/or consolidation of extinction memory.
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http://dx.doi.org/10.1016/j.nlm.2012.02.006DOI Listing
May 2012

Tumor endothelial cells acquire drug resistance by MDR1 up-regulation via VEGF signaling in tumor microenvironment.

Am J Pathol 2012 Mar 13;180(3):1283-1293. Epub 2012 Jan 13.

Department of Vascular Biology, Graduate School of Dental Medicine, University of Hokkaido, Hokkaido, Japan. Electronic address:

Tumor endothelial cells (TECs) are therapeutic targets in anti-angiogenic therapy. Contrary to the traditional assumption, TECs can be genetically abnormal and might also acquire drug resistance. In this study, mouse TECs and normal ECs were isolated to investigate the drug resistance of TECs and the mechanism by which it is acquired. TECs were more resistant to paclitaxel with the up-regulation of multidrug resistance (MDR) 1 mRNA, which encodes the P-glycoprotein, compared with normal ECs. Normal human microvascular ECs were cultured in tumor-conditioned medium (CM) and became more resistant to paclitaxel through MDR1 mRNA up-regulation and nuclear translocation of Y-box-binding protein 1, which is an MDR1 transcription factor. Vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) and Akt were activated in human microvascular ECs by tumor CM. We observed that tumor CM contained a significantly high level of VEGF. A VEGFR kinase inhibitor, Ki8751, and a phosphatidylinositol 3-kinase-Akt inhibitor, LY294002, blocked tumor CM-induced MDR1 up-regulation. MDR1 up-regulation, via the VEGF-VEGFR pathway in the tumor microenvironment, is one of the mechanisms of drug resistance acquired by TECs. We observed that VEGF secreted from tumors up-regulated MDR1 through the activation of VEGFR2 and Akt. This process is a novel mechanism of the acquisition of drug resistance by TECs in the tumor microenvironment.
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http://dx.doi.org/10.1016/j.ajpath.2011.11.029DOI Listing
March 2012

Heterogeneity of tumor endothelial cells: comparison between tumor endothelial cells isolated from high- and low-metastatic tumors.

Am J Pathol 2012 Mar 12;180(3):1294-1307. Epub 2012 Jan 12.

Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Hokkaido, Japan. Electronic address:

An important concept in tumor angiogenesis is that tumor endothelial cells (TECs) are genetically normal and homogeneous. However, we previously reported that TECs differ from normal ECs. Whether the characteristics of TECs derived from different tumors differ remains unknown. To elucidate this, in this study, we isolated two types of TECs from high-metastatic (HM) and low-metastatic (LM) tumors and compared their characteristics. HM tumor-derived TECs (HM-TECs) showed higher proliferative activity and invasive activity than LM tumor-derived TECs (LM-TECs). Moreover, the mRNA expression levels of pro-angiogenic genes, such as vascular endothelial growth factor (VEGF) receptors 1 and 2, VEGF, and hypoxia-inducible factor-1α, were higher in HM-TECs than in LM-TECs. The tumor blood vessels themselves and the surrounding area in HM tumors were exposed to hypoxia. Furthermore, HM-TECs showed higher mRNA expression levels of the stemness-related gene stem cell antigen and the mesenchymal marker CD90 compared with LM-TECs. HM-TECs were spheroid, with a smoother surface and higher circularity in the stem cell spheroid assay. HM-TECs differentiated into osteogenic cells, expressing activated alkaline phosphatase in an osteogenic medium at a higher rate than either LM-TECs or normal ECs. Furthermore, HM-TECs contained more aneuploid cells than LM-TECs. These results indicate that TECs from HM tumors have a more pro-angiogenic phenotype than those from LM tumors.
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http://dx.doi.org/10.1016/j.ajpath.2011.11.035DOI Listing
March 2012

Early postnatal stress alters extracellular signal-regulated kinase signaling in the corticolimbic system modulating emotional circuitry in adult rats.

Eur J Neurosci 2012 Jan 15;35(1):135-45. Epub 2011 Dec 15.

Department of Pharmacology, School of Pharmaceutical Science, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaida 061-0293, Japan.

The present study elucidated whether early life stress alters the extracellular signal-regulated kinase (ERK) pathway that underlies fear retrieval and fear extinction based on a contextual fear conditioning paradigm, using a juvenile stress model. Levels of phospho-ERK (pERK), the active form of ERK, increased after fear retrieval in the hippocampal CA1 region but not in the medial prefrontal cortex (mPFC). ERK activation in the CA1 following fear retrieval was not observed in adult rats who received aversive footshock (FS) stimuli during the second postnatal period (2wFS), which exhibited low levels of freezing. In fear extinction, pERK levels in the CA1 were increased by repeated extinction trials, but they were not altered after extinction retrieval. In contrast, pERK levels in the mPFC did not change during extinction training, but were enhanced after extinction retrieval. These findings were compatible in part with electrophysiological data showing that synaptic transmission in the CA1 field and mPFC was enhanced during extinction training and extinction retrieval, respectively. ERK activation in the CA1 and mPFC associated with extinction processes did not occur in rats that received FS stimuli during the third postnatal period (3wFS), which exhibited sustained freezing behavior. The repressed ERK signaling and extinction deficit observed in the 3wFS group were ameliorated by treatment with the partial N-methyl-D-aspartate receptor agonist D-cycloserine. These findings suggest that early postnatal stress induced the downregulation of ERK signaling in distinct brain regions through region-specific regulation, which may lead to increased behavioral abnormalities or emotional vulnerabilities in adulthood.
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http://dx.doi.org/10.1111/j.1460-9568.2011.07921.xDOI Listing
January 2012

Impact of diagnostic ureteroscopy on intravesical recurrence and survival in patients with urothelial carcinoma of the upper urinary tract.

J Urol 2010 Sep;184(3):883-7

Department of Urology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Purpose: We determined whether diagnostic ureteroscopy for upper urinary tract cancer affects intravesical recurrence and cancer specific mortality.

Materials And Methods: In a retrospective, multi-institutional study we evaluated 208 patients undergoing nephroureterectomy for upper urinary tract cancer who had no perioperative systemic chemotherapy, history of invasive bladder cancer, distant metastasis or incomplete followup data. Of these 208 patients 55 who composed the study group underwent diagnostic ureteroscopy before nephroureterectomy while 153 serving as controls did not. We analyzed intravesical recurrence and cancer specific survival using the Kaplan-Meier method with the log rank test used to assess significance.

Results: There was no significant difference between the 2 groups in patient characteristics or upper urinary tract cancer stage and grade while followup, and the proportion of multiple tumors and lymphovascular invasion positive tumors were significantly greater in controls. The 2-year bladder recurrence-free survival rate was 60.0% in the study group and 58.7% in controls. There was no significant difference in the intravesical recurrence rate between the 2 groups (log rank test p = 0.972). Estimated Kaplan-Meier cancer specific survival was 88.3% and 78.1% at 5 years in the study and control groups, respectively (log rank test p = 0.0687).

Conclusions: Diagnostic ureteroscopy did not affect intravesical recurrence or cancer specific survival in patients with upper urinary tract cancer undergoing nephroureterectomy.
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http://dx.doi.org/10.1016/j.juro.2010.05.027DOI Listing
September 2010

Pathological characteristics and clinical course of bladder tumour developing after nephroureterectomy.

BJU Int 2010 Apr 2;105(8):1102-6. Epub 2009 Sep 2.

Department of Urology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Objectives: To determine the pathological features and clinical course of intravesical recurrence after nephroureterectomy (NU) for upper urinary tract (UUT) cancer.

Patients And Methods: Among 325 patients undergoing NU with bladder cuff excision for UUT cancer, in this retrospective multi-institutional study we evaluated 113 who developed bladder tumour after NU. Excluding patients with (i) perioperative systemic chemotherapy or radiotherapy for UUT cancer; (ii) a history of previous or synchronous bladder cancer at the time of NU; (iii) distant metastasis at the time of NU; (iv) a follow-up of <1 year after the initial bladder cancer recurrence; or (v) missing data, 74 patients were included in this study. We compared the pathology between UUT cancer and the first bladder cancer recurrence, using Fisher's exact test. Further intravesical recurrence and bladder cancer progression was analysed using the Kaplan-Meier method, with the log-rank test used to assess significance. A Cox proportional hazard model was used for multivariate analysis.

Results: The grade of the first bladder cancer recurrence strongly correlated with that of the UUT tumour (P < 0.001) and the carcinoma in situ (CIS) lesion with the first bladder cancer recurrence correlated with high grade (grade 3) UUT tumour (P < 0.001). In all, 56 of the assessable 70 patients further developed intravesical recurrence at a median interval of 7 months after the first bladder cancer recurrence. There were no clinicopathological factors that predicted the second recurrence. Progression occurred in 14 patients, at a median interval of 25 months. A CIS lesion with the first bladder cancer recurrence was a risk factor for progression on multivariate analysis.

Conclusions: A large proportion of the patients who developed bladder tumour after NU had further intravesical recurrence, which indicated its refractory nature. Especially when a CIS lesion is detected in the initial intravesical recurrence, a careful follow-up is mandatory to detect bladder cancer progression.
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http://dx.doi.org/10.1111/j.1464-410X.2009.08836.xDOI Listing
April 2010

The role of lymph-node dissection in the treatment of upper urinary tract cancer: a multi-institutional study.

BJU Int 2008 Aug 11;102(5):576-80. Epub 2008 Apr 11.

Department of Urology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Objectives: To determine the role of lymph-node (LN) dissection in patients undergoing surgery for upper urinary tract (UUT) cancer.

Patients And Methods: We reviewed the clinicopathological data from 312 patients with UUT cancer treated predominantly by nephroureterectomy. The relationship between clinical characteristics and cancer-specific survival (CSS) was analysed, focusing on node-related information.

Results: In all, 166 patients had LN dissection while 146 did not (pNx). Multivariate analysis showed that T stage, grade and pN status were significant variables for CSS. The difference in survival between the pN0 and pNx groups remained significant in a multivariate analysis. The median (range) number of LNs removed was 6 (1-65). There was no significant difference in CSS between the 72 patients with fewer than six LNs removed and the 78 with six or more removed.

Conclusions: LN dissection is important for postoperative stratification of patients with UUT cancer because node-positive disease was one of the variables with a significant adverse effect on survival. In addition, the significant difference in survival between the pN0 and pNx groups might indicate a therapeutic benefit of LN dissection, although removing more LNs did not uniformly increase the probability of CSS.
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http://dx.doi.org/10.1111/j.1464-410X.2008.07673.xDOI Listing
August 2008

[A case of small cell carcinoma of the ureter with SIADH-like symptoms].

Nihon Hinyokika Gakkai Zasshi 2004 Jul;95(5):725-8

Department of Urology, Teine Keijinkai Hospital.

Primary small cell carcinoma of the ureter is very rare. We report a case associated with SIADH (syndrome of inappropriate secretion of ADH) -like symptoms. A 53-year-old man presented to our hospital with lower back and left lower quadrant abdominal pain. Computed tomography revealed left hydronephrosis, a peri-ureteral left lower quadrant mass, and retroperitoneal (RP) lymphadenopathy. Transduodendal biopsy of a RP lymph node revealed small cell carcinoma. He was referred to urology for further evaluation. Urography showed an obstructing mass invading the left ureter. Comprehensive metastatic evaluation revealed no other lesions. Thus, we diagnosed primary small cell carcinoma of the ureter with RP lymph node metastases. In addition, he developed SIADH-like symptoms, and we strongly suspected that it was due to ectopic production of ADH from this carcinoma. He was treated with systemic chemotherapy (methotrexate, epirubicin, and cisplatin). Following this, we performed radical nephroureterectomy with RP lymph node resection. However, he died of recurrent disease five months later.
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http://dx.doi.org/10.5980/jpnjurol1989.95.725DOI Listing
July 2004

Medical management of recurrent aggressive angiomyxoma with gonadotropin-releasing hormone agonist.

Int J Urol 2004 Jun;11(6):432-5

Department of Urology, Graduate School of Medicine, Hokkaido University, Kitaku, Sapporo, Japan.

Patients with aggressive angiomyxoma may experience local recurrences. We report a case of recurrent aggressive angiomyxoma medically treated successfully with a gonadotropin-releasing hormone agonist. A 34-year-old woman with a huge perineal tumor underwent an extensive resection of the abdominoperineal tumor combined with total pelvic exenteration. Histology showed aggressive angiomyxoma and the tumor cells were immunoreactive for estrogen and progesterone receptors. Although the patient had experienced no local recurrence for 12 months under adjuvant therapy with a gonadotropin-releasing hormone agonist, a recurrence occurred 3 months after the completion of adjuvant therapy. The patient underwent medical treatment with a gonadotropin-releasing hormone agonist and had a complete resolution of the recurrent tumor again. Hormonal treatment with a gonadotropin-releasing hormone agonist can be applied for small primary aggressive angiomyxomas in addition to adjuvant therapy for residual tumors.
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http://dx.doi.org/10.1111/j.1442-2042.2004.00816.xDOI Listing
June 2004
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