A Study on Drug Interaction between Warfarin and Capecitabine with Special Reference to the Co-Administered Term or the Discontinuation Term of Capecitabine.

We used the prothrombin time international normalized ratio(PT-INR)to investigate the change in degree and term of warfarin following co-administration and after discontinuation of capecitabine. In this study, approximately 3 years of medical records of 7 patients receiving co-administration therapy of warfarin and capecitabine were obtained from 4 hospitals. We observed daily increases in PT-INR values up to peak PT-INR levels following co-administration of warfarin and capecitabine. Interestingly, the peak PT-INR values of 4 of the patients remained remarkably high despite discontinuation of capecitabine. The peak PT-INR values for concomitant warfarin and capecitabine were attained after an average of 31.3 days of usage. When compared with the average PT-INR values attained before co-administration, the PT-INR values following co-administration significantly increased by 3 times (p<0.05). After discontinuation of capecitabine for an average of 15.1 days, i. e., for approximately 14 days, the PT-INR values returned to the PT-INR values attained prior to co-administration. These results suggest that capecitabine has influence on the anticoagulant effect of warfarin during not only the co-administered term but also the discontinuation term, and that this influence occasionally continues after discontinuation of capecitabine. These findings also suggest that a period of approximately 14 days after discontinuation is necessary for the interaction of capecitabine to dissipate and the PT-INR values to return the levels attained before receiving concomitant warfarin and capecitabine.

A diagnosis of depression should be considered in patients with multiple physical symptoms in primary care clinics.

Although the vast majority of depressed patients visit primary health care clinics, they often remain undiagnosed and untreated. Therefore, early detection in primary care settings is important. There is a high correlation between number of physical symptoms and the presence of depression, yet little has been reported regarding this relationship in Japanese primary care clinics. We examined number of physical symptoms and depression in a department of general medicine of a Japanese hospital. We included patients with unexplained symptoms after multiple tests to rule out organic diseases. Twenty-one common symptoms were assessed using a symptom checklist. Depression was diagnosed using the Patient Health Questionnaire-9, a self-administered questionnaire designed to diagnose depression. Among 386 patients, 105 (27.2%) (average age: 49.7 ± 20.9 years, 28 men and 77 women) met the criteria for depression. Among the 21 symptoms, 14 were significantly more frequent in patients with depression than in those without depression. When patients had neither general fatigue, nor sleep disturbance nor appetite loss, none met the criteria for depression. Number of symptoms was significantly higher in patients with compared with those without depression. The prevalence of depression increased with number of symptoms: 2% (2/100) for 0 or 1 symptom, 42.4% (42/99) for four to five symptoms and 68.7% (22/32) for more than nine symptoms. Japanese primary care physicians can often rule out depression when patients have neither general fatigue, nor sleep disturbance nor appetite loss. A diagnosis of depression should be considered in patients who report multiple physical symptoms.

Association of helicobacter pylori dupA with the failure of primary eradication.

GOALS: To determine whether the presence of dupA Helicobacter pylori (H. pylori) influences the cure rate of primary eradication therapy. BACKGROUND: Several virulence factors of H. pylori have been reported to affect the efficacy of the eradication rate. However, no study has investigated whether the presence of dupA affects eradication failure. STUDY: The presence of dupA was evaluated in 142 H. pylori strains isolated from 142 patients with gastrointestinal diseases. Of these patients, 104 received primary eradication therapy for 1 week. The risk factors for eradication failure were determined using univariate and multivariate analyses. RESULTS: Among 142 strains, 44 (31.0%) were dupA positive. There was no association between dupA status and gastroduodenal diseases (P>0.05). The clarithromycin (CLR) resistance rate was generally lower in the dupA-positive than in the dupA-negative group (20.4% vs. 35.7%, P=0.06). However, dupA prevalence was higher in the eradication failure group than in the success group (36.3% vs. 21.9%). Among the CLR-resistant H. pylori infected group, the successful eradication rate was significantly lower in patients infected with dupA-positive H. pylori than dupA-negative H. pylori (P=0.04). In multivariate analysis adjusted for age, sex, and type of disease, not only CLR resistance but also dupA presence was independent risk factors for eradication failure (adjusted odds ratio=3.71; 95% confidence interval,1.07-12.83). CONCLUSIONS: Although CLR resistant was more reliable predictor, the presence of dupA may also be an independent risk factor for eradication failure.

Genomic profiling of submucosal-invasive gastric cancer by array-based comparative genomic hybridization.

Genomic copy number aberrations (CNAs) in gastric cancer have already been extensively characterized by array comparative genomic hybridization (array CGH) analysis. However, involvement of genomic CNAs in the process of submucosal invasion and lymph node metastasis in early gastric cancer is still poorly understood. In this study, to address this issue, we collected a total of 59 tumor samples from 27 patients with submucosal-invasive gastric cancers (SMGC), analyzed their genomic profiles by array CGH, and compared them between paired samples of mucosal (MU) and submucosal (SM) invasion (23 pairs), and SM invasion and lymph node (LN) metastasis (9 pairs). Initially, we hypothesized that acquisition of specific CNA(s) is important for these processes. However, we observed no significant difference in the number of genomic CNAs between paired MU and SM, and between paired SM and LN. Furthermore, we were unable to find any CNAs specifically associated with SM invasion or LN metastasis. Among the 23 cases analyzed, 15 had some similar pattern of genomic profiling between SM and MU. Interestingly, 13 of the 15 cases also showed some differences in genomic profiles. These results suggest that the majority of SMGCs are composed of heterogeneous subpopulations derived from the same clonal origin. Comparison of genomic CNAs between SMGCs with and without LN metastasis revealed that gain of 11q13, 11q14, 11q22, 14q32 and amplification of 17q21 were more frequent in metastatic SMGCs, suggesting that these CNAs are related to LN metastasis of early gastric cancer. In conclusion, our data suggest that generation of genetically distinct subclones, rather than acquisition of specific CNA at MU, is integral to the process of submucosal invasion, and that subclones that acquire gain of 11q13, 11q14, 11q22, 14q32 or amplification of 17q21 are likely to become metastatic.

The relationship between Helicobacter pylori infection and Alzheimer's disease in Japan.

Although two studies have indicated a possible link between Alzheimer's disease (AD) and Helicobacter pylori (H. pylori) infection, these were reported from Europe, where the prevalence of H. pylori infection is not very high. In this study, the prevalence of H. pylori infection was examined in AD patients in Japan, where there is a high prevalence of H. pylori. Consecutive patients referred to the Memory and Dementia Outpatient Clinic from August 2002 to March 2009 were studied. H. pylori infection status was determined by measuring urinary levels of anti-H. pylori antibody (RAPIRUN(®)). Multiple stepwise logistic regression analyses were used to examine the associations of AD with the main predictor variables. Of the 917 patients who visited the clinic, 385 were diagnosed as having AD. Ninety-seven patients did not have dementia and were considered controls. On univariate analysis, average age and the proportion of males were significantly higher in AD patients than in controls. There was no difference in the prevalence of H. pylori infection between patients with AD and controls (62.0% vs. 59.7%, p = 0.67, crude odds ratio (OR), 1.10). Multiple logistic regression analysis showed that older age and male sex, but not H. pylori status, were significantly associated with AD (p < 0.001, p = 0.01, p = 0.83, respectively). The prevalence of H. pylori infection did not differ between AD patients and controls among Japanese subjects. The high prevalence of H. pylori in controls may contribute to the discrepancy with previous reports.

Genomic profiling of gastric carcinoma in situ and adenomas by array-based comparative genomic hybridization.

Although genomic copy number aberrations (CNAs) of gastric carcinoma at the advanced stage have already been extensively characterized by array comparative genomic hybridization (array CGH) analysis, those of gastric carcinoma in situ (CIS) are still poorly understood. Furthermore, no reports have demonstrated correlations between CNAs and histopathological features of gastric adenoma. In this study, we investigated CNAs of 20 gastric CISs (Vienna category 4.2) and 20 adenomas including seven low-grade adenomas (LGA; Vienna category 3) and 13 high-grade adenomas (HGA; Vienna category 4.1), using oligonucleotide-based array CGH. The most frequent aberrations in CIS were gains at 8q (85%) and 20q (50%), and losses at 5q (50%) and 17p (50%), suggesting that these CNAs are involved in the development of CIS. We found that the pattern of CNAs in HGA was quite different from that in LGA. The most frequent CNAs in HGA were gains at 8q (62%) and 7pq (54%), whereas those in LGA were gain at 7q21.3-q22.1 (57%) and loss at 5q (43%). Interestingly, gains at 8q and 7pq, both of which occurred most frequently in HGA, were not detected in any cases of LGA. Of note, 8q gain was detected most frequently in both HGA and CIS but was undetected in LGA. Since HGA is believed to have a higher risk of progression to invasive carcinoma than LGA, these data suggest that 8q gain is important for the malignant transformation of gastric adenoma.

Evaluation of the anti-East Asian CagA-specific antibody for CagA phenotyping.

The determination of the cagA genotype is generally based on sequencing the variable 3' region of the cagA gene. In a previous study, we successfully generated an anti-East Asian CagA-specific antibody (anti-EAS Ab) immunoreactive only with the East Asian CagA and not with the Western CagA. In a small number of Japanese patients, anti-EAS Ab appeared to be a useful tool for phenotyping CagA immunohistochemically. The present study was conducted to validate the anti-EAS Ab immunohistochemistry method in a larger number of patients from Vietnam and Thailand. A total of 385 Vietnamese and Thais were recruited. Helicobacter pylori status was determined by a combination of three methods, including culture, histology, and immunohistochemistry with anti-H. pylori antibody. The sensitivity, specificity, and accuracy of the anti-EAS Ab immunohistochemistry method for the diagnosis of CagA phenotype were calculated based on the results of the cagA sequencing as the gold standard. The sensitivity, specificity, and accuracy of our immunohistochemistry method were 96.7%, 97.9%, and 97.1%, respectively. Moreover, anti-EAS Ab was not cross-reactive with noninfected gastric mucosa. In conclusion, immunohistochemistry with anti-EAS Ab appears to be a good method for determination of CagA phenotype.

Intramuscular transplantation of G-CSF-mobilized CD34(+) cells in patients with critical limb ischemia: a phase I/IIa, multicenter, single-blinded, dose-escalation clinical trial.

A number of preclinical studies have indicated the therapeutic potential of endothelial progenitor cells for vascular regeneration in ischemic diseases. A phase I/IIa clinical trial of transplantation of autologous CD34(+) cells, the endothelial and hematopoietic progenitor-enriched fraction, was performed in no-option patients with atherosclerotic peripheral artery disease or Buerger's disease with critical limb ischemia (CLI). CD34(+) cells were isolated from the G-CSF-mobilized apheresis product using a magnetic cell sorting system. CD34(+) cells (10(5)/kg, n = 6; 5 x 10(5)/kg, n = 8; or 10(6)/kg, n = 3) were injected i.m. into the leg with more severe ischemia. The Efficacy Score, representing changes in the toe brachial pressure index (TBPI), Wong-Baker FACES pain rating scale, and total walking distance 12 weeks after cell transplantation, the primary endpoint, was positive, indicating improvement in limb ischemia in all patients, although no significant dose-response relationship was observed. During the 12-week observation after cell therapy, the Wong-Baker FACES pain rating scale, TBPI, transcutaneous partial oxygen pressure, total or pain-free walking distance, and ulcer size serially improved in all patients. No death or major amputation occurred, and severe adverse events were rare, although mild to moderate events relating to G-CSF and leukapheresis were frequent during the 12-week follow-up. In conclusion, the outcomes of this prospective clinical study indicate the safety and feasibility of CD34(+) cell therapy in patients with CLI. Favorable trends in efficacy parameters encourage a randomized and controlled trial in the future.

Effect of care manager support on health-related quality of life of caregivers of impaired elderly: one-year longitudinal study.

The aim of this study was to identify factors related to the health-related quality of life (HRQOL) of caregivers providing continuing home care for the impaired elderly focusing mainly on care managers' support given to caregivers. Two interviews over a course of 12 months were conducted with 42 caregivers. The questionnaire items for the caregivers included demographic variables, HRQOL, the satisfaction level of care managers, coping ability, and depressive state. For the impaired elderly, the questionnaire items included demographic variables, abilities of activities of daily living, dementia assessment, and depressive state. The mean age of the caregivers was 66.1+/-8.8. By logistic regression analysis with HRQOL as a dependent variable, the caregivers' physical QOL was significantly related to the depressive state of impaired elderly and the caregivers' satisfaction with their care manager, whereas the caregivers' mental QOL was significantly related to the caregivers' sense of coherence and satisfaction with their care manager. These results suggest that the care managers' support to caregivers who provide continuing home care is important for caregivers' HRQOL.

[Health-related quality of life assessed by EuroQol in caregivers of home care stroke patients].

The purpose of this study was to identify significant factors influencing health-related quality of life (HRQOL) of caregivers for home care patients with stroke. Subjects were 150 caregivers and 167 stroke patients who required help in activities of daily living (ADL) after discharge. HRQOL of caregivers and patients was assessed using a EuroQol utility score obtained by mailed questionnaire. The questionnaire also included the following items; caregiver's relationship to the patient, age, nursing care hours, family support, patient's functional changes after discharge, stroke recurrence, ADL, public nursing care insurance, care levels, and number of services patients received. The mean QOL score of 0.82 +/- 0.18 for caregivers was significantly higher than that of 0.57 +/- 0.20 for patients. Multiple regression analysis revealed that the significant factors influencing caregiver's QOL were caregiver's age and family support for caregivers, and anxious/depressed state, pain/discomfort state, and failure of memory of the patients. In addition, a significant correlation of QOL score was observed between patients and caregivers in the pain/discomfort and anxious/depressed states. The results of our study suggested that the alleviation of the patient's depressive state after stroke and the family's active support to caregivers played an important role for improving caregiver's QOL.

Effects of polymerization and hydrolysis degrees of poly(vinyl alcohol) (PVA) on the efficiency of the PVA-solid substrate for room-temperature phosphorimetry.

Several kinds of poly(vinyl alcohols) (PVAs) having different degrees of polymerization and hydrolysis were tested as a material of a solid substrate for room-temperature phosphorimetry (RTP). Effects of these differences on the efficiency of the solid substrate were investigated. Completely hydrolyzed PVAs acquired a luminescence property in the grinding process of substrate preparation, but partially hydrolyzed PVAs did not acquire this property. When the completely hydrolyzed PVA substrates were prepared by drying their aqueous solutions, their luminescence property almost disappeared. However, very weak background emission remained on the surface of a completely dried substrate which had been treated with an analyte aqueous solution. This residual background affected the spectrum of the analyte, especially at low concentrations. Stability of the phosphorescence intensity with the passage of time was superior on the partially hydrolyzed PVAs than on the completely hydrolyzed PVAs. On the other hand, the RTP intensity and reproducibility were superior on the completely hydrolyzed PVAs. Practically, partially hydrolyzed PVAs were more suitable as a material of the substrate because of the stability of its RTP intensity and the weakness of its background emission. The linear dynamic range of the analytical curve for p-aminobenzoic acid on the substrate of partially hydrolyzed PVA having a degree of polymerization of 3,500 was 5-2,000 pmol/spot (20 microL) and its correlation coefficient was 0.963 for 30 data points.