Kousuke Okamoto

Effects of indole on drug resistance and virulence of Salmonella enterica serovar Typhimurium revealed by genome-wide analyses

BackgroundMany Gram-positive and Gram-negative bacteria produce large quantities of indole as an intercellular signal in microbial communities. Indole demonstrated to affect gene expression in Escherichia coli as an intra-species signaling molecule. In contrast to E. coli, Salmonella does not produce indole because it does not harbor tnaA, which encodes the enzyme responsible for tryptophan metabolism. Our previous study demonstrated that E. coli-conditioned medium and indole induce expression of the AcrAB multidrug efflux pump in Salmonella enterica serovar Typhimurium for inter-species communication; however, the global effect of indole on genes in Salmonella remains unknown.ResultsTo understand the complete picture of genes regulated by indole, we performed DNA microarray analysis of genes in the S. enterica serovar Typhimurium strain ATCC 14028s affected by indole. Predicted Salmonella phenotypes affected by indole based on the microarray data were also examined in this study. Indole induced expression of genes related to efflux-mediated multidrug resistance, including ramA and acrAB, and repressed those related to host cell invasion encoded in the Salmonella pathogenicity island 1, and flagella production. Reduction of invasive activity and motility of Salmonella by indole was also observed phenotypically.ConclusionOur results suggest that indole is an important signaling molecule for inter-species communication to control drug resistance and virulence of S. enterica.

Statistical identification of predictors for peripheral neuropathy associated with administration of bortezomib, taxanes, oxaliplatin or vincristine using ordered logistic regression analysis.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major drug-induced adverse reaction that becomes a dose-limiting toxicity. However, effective strategies for preventing or treating CIPN are lacking. Accordingly, this study aimed to statistically identify predictors for CIPN. Retrospective analysis was carried out for 190 patients who had been treated with bortezomib (n=28), taxanes (paclitaxel or docetaxel; n=58), oxaliplatin (n=52) or vincristine (n=52) at our hospital between April 2005 and December 2008. The severity of CIPN was assessed at the time of chemotherapy completion, graded as grade 0–5 in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. Multivariate ordered logistic regression analysis was used to investigate predictors for CIPN. Predictors for CIPN in patients that were administered bortezomib were no co-administration of dexamethasone [odds ratio (OR), 0.455; confidence interval (CI), 0.208–0.955; P=0.0376] and sex (male) (OR, 3.035; CI, 1.356–6.793; P=0.0069). For taxanes (paclitaxel or docetaxel), the predictor for CIPN was a large number of chemotherapy cycles (OR, 2.379; CI, 1.035–5.466; P=0.0412). For oxaliplatin, the predictors for CIPN were a large number of chemotherapy cycles (OR, 3.089; CI, 1.598–5.972; P=0.0008) and no co-administration of non-steroidal anti-inflammatory drugs (OR, 0.393; CI, 0.197–0.785; P=0.0082). For vincristine, predictors for CIPN were a large number of chemotherapy cycles (OR, 6.015; CI, 1.880–19.248; P=0.0025) and co-administration of an analgesic adjuvant (OR, 3.907; CI, 1.383–11.031; P=0.0101). In conclusion, our study indicates that CIPN will be alleviated by the co-administration of dexamethasone with bortezomib and non-steroidal anti-inflammatory drugs with oxaliplatin.

Ethnic difference in patients with type 2 diabetes mellitus in inter‐East Asian populations: A systematic review and meta‐analysis focusing on gene polymorphism

Background:  We previously reported that the fasting serum insulin level was significantly lower in Japanese patients than in Korean and Chinese patients, and showed evidence that a difference in the dietary component would be one of the most influential factors for the ethnic difference. However, it is well known that type 2 diabetes mellitus (T2DM) results from the interaction between genetic predispositions and environmental risk factors. Therefore, we investigated ethnic differences by focusing on gene polymorphism, possibly related to T2DM in Japanese, Korean, and Chinese subjects.

Risk factors for infection in haematology patients treated with rituximab

Objectives:  Although rituximab therapy is not considered to be closely associated with infection, there have been reports of serious infections in patients treated with rituximab. We performed a statistical retrospective analysis to clarify the risk factors for infection in patients receiving rituximab therapy.

Predictive factors for postherpetic neuralgia using ordered logistic regression analysis.

Objectives:To identify predictive factors for the occurrence of postherpetic neuralgia (PHN). Methods:The participants were 73 herpes zoster patients who had been treated at the pain clinic of our hospital between January 2008 and June 2010. Variables present at the initial visit were extracted from the clinical records for regression analysis of factors related to the occurrence of PHN. The following scores for response were used: 0=no PHN after 3 months; 1=PHN present after 3 months but absent after 6 months; and 2=PHN present after 6 months. Multivariate ordered logistic regression analysis was performed to identify the predictive factors for PHN. Results:Advanced age [odds ratio (OR)=2.740, confidence interval (CI)=1.110-6.761; P=0.0288] and deep pain (OR=4.244, CI=1.114-16.163; P=0.0341) at the initial visit to our outpatient pain clinic were found to be significant predictive factors for the occurrence of PHN. Diabetes mellitus (OR=3.075) and pain reduced by bathing (OR=3.389) also had high OR, although they were not significant. Discussion:Our study indicates that advanced age and deep pain at the initial visit are significant predictors for PHN. Our results are considered likely to contribute to the establishment of evidence-based medicine in the optimal treatment of PHN.

Ethnic difference in patients with type 2 diabetes mellitus in inter-East Asian populations: A systematic review and meta-analysis focusing on fasting serum insulin

AIMS To investigate ethnic difference by focusing on fasting serum insulin (FSI) in inter-East Asian patients with type 2 diabetes. METHODS Data sources included MEDLINE and EMBASE between 2001 and 2006. We conducted a search for articles containing mean or geometric mean values of FSI in East Asian patients with type 2 diabetes. The Monte Carlo method was used for simulation of the mean and standard deviation of individual measures in each ethnic group; calculation of the median ratio and 95% confidence interval of individual measures between ethnic groups. RESULTS The initial search identified a total of 996 journal articles. After reviewing the titles and abstracts of these articles, 201 studies were selected for further screening and the complete papers on these studies were then reviewed in detail. Of these, seven articles fully met our pre-determined criteria and were included in the meta-analysis. Results of the meta-analysis revealed that FSI level is significantly lower in Japanese patients than in Korean and Chinese patients. CONCLUSIONS Results from our review of ethnic differences in dietary habit in the inter-East Asian population suggested that difference in dietary component was one of the most influential factors for the ethnic difference.

Factors predicting requirement of high-dose transdermal fentanyl in opioid switching from oral morphine or oxycodone in patients with cancer pain.

ObjectivesTo identify predictive factors requiring high-dose transdermal fentanyl in opioid switching from oral morphine or oxycodone to transdermal fentanyl in patients with cancer pain. MethodsThe participants were 76 hospitalized terminal cancer patients who underwent opioid switching from oxycodone or morphine sustained-release tablet to transdermal fentanyl at our hospital between January 2009 and June 2010. The conversion dose was calculated as transdermal fentanyl (25 &mgr;g/h)/oral morphine (60 mg) or oxycodone (40 mg)=1. The response evaluated was the dose conversion ratio [transdermal fentanyl/oral morphine or oxycodone (conversion dose to fentanyl)]=Y and was taken to be 0 for Y⩽1, 1 for 1<Y⩽2, 2 for 2<Y⩽3, and 3 for 3<Y. Predictors evaluated were factors potentially impacting pain. Ordered logistic regression analysis was carried out to identify the predictive factors requiring high-dose transdermal fentanyl in opioid switching. ResultsBreast cancer [odds ratio (OR)=8.218; 95% confidence interval (CI), 1.219-55.407; P=0.0305], total protein level (OR=0.630; 95% CI, 0.408-0.974; P=0.0377), alanine aminotransferase level (OR=1.017; 95% CI, 1.001-1.033; P=0.0390), advanced age (OR=3.700; 95% CI, 1.360-10.063; P=0.0104), and male sex (OR=3.702; 95% CI, 1.355-10.115; P=0.0107) were found to be significant predictive factors requiring high-dose transdermal fentanyl in opioid switching. DiscussionOur study indicates that breast cancer, total protein, alanine aminotransferase, advanced age, and male sex are significant predictors of a need for higher dose transdermal fentanyl in opioid switching. Our results are considered likely to contribute to the establishment of evidence-based medicine in pain relief and palliative care.

Ethnic difference in inter-East Asian subjects with normal glucose tolerance and impaired glucose regulation: A systematic review and meta-analysis focusing on fasting serum insulin

AIMS To investigate ethnic difference by focusing on fasting serum insulin (FSI) in inter-East Asian subjects with normal glucose tolerance (NGT) and impaired glucose regulation (IGR). METHODS Data sources included MEDLINE and EMBASE between 2001 and 2007. We conducted a search for articles containing mean or geometric mean values of FSI in East Asian subjects with NGT, IGR, or type 2 diabetes (T2DM). The Monte Carlo method was used for simulation of the mean and standard deviation of individual measures in each ethnic group; calculation of the median ratio and 95% confidence interval of individual measures between ethnic groups. RESULTS Twenty-two articles fully met our pre-determined criteria and were included in the meta-analysis. Results of the meta-analysis revealed that FSI level is significantly lower in Japanese subjects with NGT, IGR, or T2DM than in Korean and Chinese subjects. CONCLUSIONS Ethnic difference in FSI level between East Asians was observed in not only T2DM patients but also subjects with NGT or IGR. The lower FSI level in Japanese subjects was accompanied by lower triglyceride level. These results suggest that ethnic difference in dietary habit was one of the most influential factors for the ethnic difference in FSI.

Population pharmacokinetics of itraconazole solution used as prophylaxis for febrile neutropenia

Although administration of antifungal agents, such as itraconazole (ITC) solution, for prophylaxis is the most promising strategy for the treatment of haematological malignancies, little is known about the population pharmacokinetic (PK) parameters. A clinical study was conducted to identify PK parameters for the administration of 200mg/day ITC solution used as prophylaxis for febrile neutropenia in patients undergoing treatment. The study population comprised six patients. NONMEM software was used to estimate PK parameters. Clearance, volume of distribution and the absorption rate constant were 12.7 L/h, 333 L and 1.72 h(-1), respectively. These parameters were different from a previous study to large extent, which may be due to differences in intended patients. These differences strongly suggest that establishment of population pharmacokinetics is essential for planning a prospective clinical trial. Assuming a normal distribution, we predicted the trough concentrations of 94.5% of the patients receiving 200 mg/day ITC solution to be >250 ng/mL, indicating that administration of 200mg/day might be suitable for prophylaxis. This pilot study presents a basic PK model of ITC solution in Japanese haematological patients for the establishment of optimal administration. Large-scale studies will be necessary in the future to determine population PK parameters with covariates.

Statistical validation of the relationships of cancer pain relief with various factors using ordered logistic regression analysis.

Objective To clarify the relationships of cancer pain with various factors that prevent pain control statistically. Methods The participants were 71 terminal cancer patients admitted to the Department of Hematology/Oncology or Department of Gastroenterology/Hepatology, University Hospital, Kyoto Prefectural University of Medicine in whose pain control a pharmacist was involved as part of her clinical duties from January 2004 to November 2006. The effectiveness of pain control was evaluated using a 5-point verbal rating scale (0=excellent, 1=good, 2=moderate, 3=poor, and 4=very poor) by interviewing the patients. As pain was rated using a graded scale and as many factors were involved in pain, analysis was performed using ordered logistic regression analysis. Moreover, prediction of an optimal model was performed by leave-one-out cross-validation to eliminate unnecessary variables. A program to perform leave-one-out cross-validation by ordered logistic regression analysis was prepared, independent variables used in the model were increased one by one, and calculation was performed in all combinations. Then, the optimal model was predicted by calculating the percent accuracy of predictions and Spearman rank correlation coefficient. Results Nausea [odds ratio (OR)=1.948, P=0.0232], sex (OR=2.322, P=0.0030), and bone metastasis (OR=2.367, P=0.0017) remained as variables significantly correlated with pain when the number of independent variables was 5, and sex (OR=2.167, P=0.006) and bone metastasis (OR=2.093, P=0.005) remained when the number of variables was 6. Discussion The statistical identification of factors preventing pain control is considered to contribute to the establishment of an evidence-based approach to cancer pain relief.