Tumor cell invasion and metastasis are associated with the proteolytic activity of various types of proteinases. Among them, cathepsins, which are lysosomal proteinases, have received more attention recently. Since elevated expressions of cathepsins and diminished levels of their inhibitors have been observed in several human cancers, including breast, gastric and prostate cancer, especially in aggressive cancer cells, cathepsins have been suggested to be biological markers of malignant tumors and have proved useful for prognosis of the disease. Furthermore, cathepsins have various roles in cancer progression. Cathepsin D has a mitogenic activity independent of its proteolytic activity and it attenuates the anti-tumor immune response of decaying chemokines to inhibit the function of dendritic cells. Cathepsins B and L have been shown to play an important role in matrix degradation and cell invasion. The administration of their inhibitors prevents the invasion and metastasis of cancer cells. These results indicate that cancer cells orchestrate various cathepsins to progress malignant diseases. Cathepsins may be a potential target for cancer therapy. J. Med. Invest. 52: 1-9, February, 2005

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Here we review epidemiologic studies dealing with the dietary intake and the body burden of polychlorinated dibenzo-p-dioxins (PCDDs)/polychlorinated dibenzo-furans (PCDFs)/polychlorinated biphenyls (PCBs) in the general population, and potential adverse health effects of these substances, especially on the risk of diabetes mellitus and endometriosis, and on thyroid function and the neurodevelopment of infants. The mean or median intake of dioxin-related compounds among the general populations of various countries is lower than the maximum tolerable daily intake (TDI) set by the WHO in 1998 (4pg TEQ/kg/day). However, there have been few reports on the distribution of intake and the proportion of subjects whose exposure levels exceed the maximum TDI. At present, it remains unclear whether background exposure to dioxin-related compounds is associated with increased risk of diabetes (because of lack of longitudinal studies), endometriosis (because of lack of studies with sufficient statistical power), or altered thyroid function (because of inconsistent results on humans). Consistent results have been reported for the association between exposure to background levels of PCBs/dioxins, especially trans-placental PCBs, and defective neurodevelopment of infants in the U.S. and Europe. Thus, efforts should be made to further decrease the body burden among women of reproductive age by reducing the release of PCDDs/PCDFs/PCBs into the environment. J. Med. Invest. 52: 10-21, February, 2005

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About 15 years have passed since the first liver transplant from a living donor (living donor liver transplantation: LDLT), and the status of the procedure has since been established as a standard cure for end-stage liver disease in Japan where liver transplantation (LTx) from deceased donors has not yet been accepted. However, the following problems are surfacing with the increase in the number of LDLTs between adults: graft size mismatching, an ABO blood-type incompatible transplantation, the expansion of LDLT indication to hepatocellular carcinoma (HCC), the relapse of hepatitis C after LDLT, marginal donors, and the freedom from immunosuppressive treatment. In this article we outline the present conditions of these problems and the future view of the LDLT. J. Med. Invest. 52: 22-32, February, 2005

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We collected information concerning diagnosed allergy from 2027 school children in Japan, Taiwan and Vietnam. Children were classified according to the age and sex-specific body mass index (BMI) per-age as indicator of weight status. Logistic regression was performed to examine the relationship between percentiles of BMI-per-age and allergy. Compared with children at the lowest percentile group Taiwanese children at>85^th percentile group showed a tendency toward higher risk of allergy (OR=1.79, 95% CI 0.98 to 3.27; p=0.060). When children with rhino-conjunctivitis were excluded from the analysis the association reached statistical significance (OR=2.89, 95% CI 1.08 to 7.75; p=0.035). Vietnamese children at>85^th percentile group showed a significantly higher risk of allergy (OR=2.34, 95% CI 1.06 to 5.17; p=0.035). This association was not observed when children with atopic dermatitis or food allergy were excluded from the analysis, although a tendency toward increased risk of allergy at BMI-per-age>85^th percentile remained. Our study sample of Japanese school children showed no association between being overweight and allergy. J. Med. Invest. 52: 33-40, February, 2005

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For understanding of the resistance to topoisomerase II inhibitors, 50 sublines were isolated as single clones from parental glioma cell lines by exposure to VP-16 or m-AMSA. The quantitative aspects of topoisomerase IIα, multidrug resistant gene (MDR)-1, breast cancer resistance protein (BCRP), and multidrug resistant associated protein (MRP) 1-5 were studied by Northern blotting in 50 resistant cell lines. By understanding the function of MRP2, we picked up three drug resistant sublines (T98G-m1, T98G-m2, and gli36-VP1) that overexpressed MRP2, but did not overexpress MDR-1 or MRP1-5 except 2. Moreover, in the results of northern blot analysis of mRNA for topoisomerase IIα identical results are observed in parental cell lines and their resistant cell lines, suggesting that alterations in topoisomerase II do not account for the resistance in these cells. To determine whether the cellular sensitivity to anticancer agents was closely associated with the cellular levels of MRP2, we established cell lines with the same levels of MRP2 as their parental cells by introducing the MRP2 antisense expression plasmid into resistant cells. Etoposide (VP-16) accumulation and efflux studies were carried out in the parental cell lines and their drug resistant cell lines. Decreases in the H³-VP-16 accumulation and increases in the efflux were observed in these drug resistant cell lines. In the cytotoxicity assay, these drug resistant cell lines were resistant to multiple topoisomerase II inhibitors with little cross resistance to vincristine, and display efflux of VP-16. We found that the resistant cells transfected with MRP2 antisense cDNA displayed increased cellular levels of VP-16 and enhanced sensitivities to topoisomerase II inhibitors. In this study on the T98G-m1, T98G-m2, and gli36-VP1 cell lines, we showed a high correlation between MRP2 mRNA and VP-16 efflux, suggesting that MRP2 could be a new transporter for topoisomerase II inhibitors. J. Med. Invest. 52: 41-48, February, 2005

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The aim of this study is confirmation of an abnormal regional cerebral blood flow (rCBF) pattern in high-functioning autism (HFA). Confirmation of an abnormal rCBF pattern in HFA may be useful for elucidate of its pathophysiology and a differential diagnosis, such as with attention-deficit / hyperactivity disorder (AD/HD). Brain ^99mTc-ECD SPECT was performed in 16 cases of HFA. The HFA group consisted of 16 cases of HFA. They were all male, with an IQ of 76∼126. They had normal brain MRI findings, and had an age of 9∼14 years. We examined abnormal rCBF in HFA by comparing the results to those in the control group. The control group consisted of 1 male and 4 females cryptogenic epilepsy patients with normal intelligence. They have no problems in learning at school or mental or behavioral traits. They had normal brain MRI or SPECT findings, and had an age of 7∼15 years. 3-dimensional stereotactic ROI template (3DSRT) was used to analyze SPECT data. We calculated the ‘relative rCBF (%)’ (RI count of each segment ×100 / Sum of RI count of the corresponding hemisphere), and compared the values between the two groups. We found a significantly low ‘relative rCBF (%)’ in the left temporal region in the HFA group. We also calculated the ‘L/R ratio’ (the ‘relative rCBF (%)’ of a segment on the left side / the ‘relative rCBF (%)’ of the corresponding segment on the right side), and compared the value for each segment between the two groups. There were no significant differences in any segments between the two groups. We also checked for differences in the ‘relative rCBF (%)’ between segments on the right side and corresponding segments on the left side in both the HFA and control groups. We found significant right<left perfusion in the angular region and significant left<right perfusion in the pericallosal, thalamus, and hippocampus region in the HFA group. We also found significant right<left perfusion in the temporal region in the control group. Significant hypoperfusion in the left temporal region due to an unidentified underlying brain pathology and abnormal laterality in the angular, temporal (lack of right<left perfusion), pericallosal, thalamus, and hippocampus regions may influence the symptoms of autism. J. Med. Invest. 52: 49-56, February, 2005

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Objective: This study was conducted to address the question of whether the β3-adrenergic receptor gene mutation (Trp 64 Arg) is associated with metabolic disease in Japanese patients with schizophrenia.
Methods: In a cross-sectional study, 89 participants were grouped into three genotypes. The 64 Arg allelic frequency in patients with or without metabolic disease was analyzed. Anthropometrics variables and biochemical parameters were compared among the genotypes.
Results: The 64 Arg allele, which had a frequency of 0.22, was not associated with obesity, type 2 diabetes mellitus, dyslipidemias, or hypertension. No significant differences among the genotypes were found in current age, age at diagnosis with schizophrenia, body mass index, waist-hip ratio, plasma glucose, plasma insulin, triglycerides, free fatty acids. Patients with the 64 Arg allele had greater 24-h excretion of norepinephrine than those lacking the variant (p=0.019).
Conclusion: The 64 Arg allelic mutation is not associated with obesity, type 2 diabetes mellitus, lipid metabolism dysfunction, or hypertension in Japanese patients with schizophrenia. J. Med. Invest. 52: 57-64, February, 2005

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Asiatic acid is a pentacyclic triterpene contained in medicinal plants. The cytotoxic effect of this compound and its augmentative effect on the anticancer drug irinotecan hydrochloride (CPT-11) were investigated in the human colon adenocarcinoma cell line HT-29. Asiatic acid dose-dependently showed cytotoxicity in HT-29 cells. DNA fragmentation, annexin-positive apoptotic cells, and caspase-3 activation were observed in a dose-dependent manner. A caspase-3 inhibitor suppressed the DNA ladder formation in a concentration-dependent manner. Bcl-2 and Bcl-x_L proteins were decreased by asiatic acid treatment. These results indicate that asiatic acid induced apoptosis in HT-29 cells via caspase-3 activation. Cytotoxic effects of combined treatment with CPT-11 and asiatic acid on HT-29 cells were further examined. Simultaneous treatment or sequential exposure first to asiatic acid and then to CPT-11 showed an additive effect. Synergism was observed when cells were first exposed to CPT-11 and then to asiatic acid. These results suggest that asiatic acid can be used as an agent for increasing sensitivity of colon cancer cells to treatment with CPT-11 or as an agent for reducing adverse effects of CPT-11. J. Med. Invest. 52: 65-73, February, 2005

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Lower axillary lymph node dissection (lower parts of both the level I and II elements below the second intracostobrachial nerve) and level I and II lymph node dissection were performed on breast cancer patients (n=54), and the results with the two methods were compared in terms of the status of detected lymph node metastases. For Stage I, N0 cases, the results for pathological classification lymph node metastases (pN) were in agreement between the two dissection methods. And, the occurrence of operated arm swelling wasn’t recognized when a side effect was examined with the case (n=28) that only lower axillary dissection was carried out in case of an operation for breast cancer. Accordingly, it was surmised that lower axillary dissection provides accurate pN information for Stage I, N0 cases. These results indicate that lower axillary dissection has the potential to become an effective, standard surgical procedure for breast cancer patients whose preoperative disease stage is Stage I. J. Med. Invest. 52: 74-79, February, 2005

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The aim of the study was to characterize patients at risk for exacerbations of their asthma as a result of the Tottori-Ken Seibu earthquake and to identify factors that predict exacerbation of asthma after an earthquake. A retrospective cohort study-analysis was conducted of 156 asthmatic patients, aged 18 to 89 years, who were out-patients of Tottori University Hospital and who had completely recorded their asthmatic symptoms and measured their peak expiratory flow (PEF) rates for more than one year prior to the earthquake. Seventeen (11%) patients who experienced the earthquake were identified as having an exacerbation within one month after the earthquake. Diurnal variability of PEF during the month after the earthquake was compared to values during a matched month one year previously. When factors associated with exacerbation were identified by a review of the medical case notes and the contribution of these factors to the exacerbation was determined using multivariate analysis, airflow limitation was shown to be independently associated with exacerbation after the earthquake. Acute asthma attacks are more likely to occur within the first week after the earthquake event without diurnal PEF variability. Asthma is likely to worsen after an earthquake. J. Med. Invest. 52: 80-84, February, 2005

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Macrophage-derived chemokine (MDC/CCL22) and thymus-and activation-regulated chemokine (TARC/CCL17) are ligands for CC chemokine receptor 4. Recently, TARC has been reported to play a role in the pathogenesis of idiopathic eosinophilic pneumonia (IEP). The purpose of this study was to evaluate the role of MDC in IEP and other interstitial lung diseases (ILDs). MDC and TARC in the bronchoalveolar lavage fluid (BALF) were measured by enzyme-linked immunosorbent assay in patients with ILDs and healthy volunteers (HV). We also examined the expression of MDC mRNA in alveolar macrophages (AM) by real-time quantitative reverse transcriptase-polymerase chain reaction. Both MDC and TARC were detected only in BALF obtained from IEP patients. The concentration of MDC was higher than that of TARC in all cases. The level of MDC in IEP correlated with that of TARC. AM from IEP patients expressed a significantly higher amount of MDC than that from HV at the levels of protein and mRNA. MDC in BALF from IEP dramatically decreased when patients achieved remission. These findings suggest that MDC, in addition to TARC, might be involved in the pathogenesis of IEP, and AM play a role in the elevation of MDC in IEP. J. Med. Invest. 52: 85-92, February, 2005

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To determine the significance of proteases in interstitial lung diseases, we examined the activity of cathepsins, thrombin, and aminopeptidase in bronchoalveolar lavage (BAL) fluid from patients with these disorders. Significantly increased activities of cathepsin H and aminopeptidase were detected in BAL fluid from patients with idiopathic pulmonary fibrosis (IPF), cryptogenic organizing pneumonia (COP), chronic eosinophilic pneumonia (CEP) and hypersensitivity pneumonitis (HP). Significantly higher activity of cathepsin B was found in BAL fluid from patients with CEP. The activity of thrombin was significantly higher in patients with IPF and CEP. In patients with IPF, there were significant correlations between neutrophil number and the activity of cathepsin B, cathepsin H or aminopeptidase. In patients with COP and HP, the activity of the proteases was significantly higher in patients with higher number of lymphocytes than in those with lower number of lymphocytes. The present study suggests that the activity of the proteases is a useful marker in activity of the interstitial lung diseases, and may have a role in the pathogenesis of these disorders. J. Med. Invest. 52: 93-100, February, 2005

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Bacteroides species, saccharolytic Gram-negative obligate anaerobes, are frequently isolated from human infections such as peritonitis, abscesses and bacteremia. Among the species in the genus Bacteroides, the species called “B. fragilis group” are particularly involved in human infections and are medically important because they account for a major part of anaerobic isolates from clinical specimens. The purpose of this study was to develop PCR primers that specifically and simultaneously amplify the β-isopropylmalate dehydrogenase gene leuB in B. fragilis group species. We determined partial nucleotide sequences of leuB genes and compared them in seventeen strains of nine B. fragilis group species, and the regions that are conserved among Bacteroides strains but different from other species were used as a B. fragilis group-specific PCR primer set, BacLBF-BacLBR. Specificity tests of the primer set using 52 phenotypically characterized strains and 75 isolates from rat feces showed only one case each of false-positive and false-negative. The detection limit of the leuB-directed PCR using BacLBF and BacLBR was 3.9×10³ colony-forming units. These results indicate that leuB amplification using BacLBF and BacLBR is a useful tool for rapid diagnosis of Bacteriodes infection and for rapid differential diagnosis of anaerobic infections. J. Med. Invest. 52: 101-108, February, 2005

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Linkage analysis previously identified a hyperglycemic quantitative trait locus (QTL), Nidd2/of, on rat Chromosome 14 in crosses utilizing OLETF (Otsuka Long Evans Tokushima Fatty) rat, a model for type2 diabetes. A separate QTL study mapped an obesity QTL, Obs5, to the same chromosomal region. A congenic strain placing ca. 38 cM OLETF-derived segments containing both Nidd2/of and Obs5 on the F344 background was shown to possess mild diabetic and obese phenotypes, suggesting the presence of mutations affecting the glucose metabolism and fat accumulation. In order to localize the loci more precisely, we generated a series of deletion-subcongenic strains in which OLETF-segments were shortened from either ends. We found that there are at least two hyperglycemic QTLs within the Nidd2/of locus. We predict that they are localized towards both ends of the Nidd2/of region. In contrast, Obs5 QTL was further narrowed down to a single region of ca. 10 cM fragment. J. Med. Invest. 52: 109-113, February, 2005

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We reported two cases of retroperitoneal hematoma in patients who received a combination of anticoagulant therapy and 5-fluorouracil (5-FU). We should be aware of the possible interaction of this combination therapy and monitor prothrombin time (PT) prolongation. CT is useful for evaluation of the disease. J. Med. Invest. 52: 114-117, February, 2005

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A 51-year-old man with a history of gingival cancer two years previously was referred to our hospital for further examination of chest abnormal shadow. Bilateral hilar and mediastinal lymphadenopathy, diffuse small nodular opacities and pleural nodules were observed in chest high resolution CT. Serum angiotensin converting enzyme and lysozyme were elevated. Transbronchial lung biopsy specimens demonstrated non-caseous granuloma. CD4-positive lymphocytes were increased in broncho-alveolar lavage (CD4/CD8 ratio 5.47).The patient was diagnosed as having sarcoidosis. Radiological findings were improved and serum angiotensin converting enzyme level was decreased to within the normal range by corticosteroid therapy (prednisolone 30mg/day). This is the first report of sarcoidosis accompanying the gingival cancer. J. Med. Invest. 52: 118-121, February, 2005

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A 71-year-old male was admitted for abdominal fullness. The condition rapidly deteriorated in a short period (3 weeks), and the patient died. Autopsy revealed a protruding lesion measuring about 3 cm with erosion measuring 5 mm in diameter immediately below the esophago-gastric conjugation site, suggesting primary cardial undifferentiated adenocarcinoma. In the primary focus, changes on the mucosal surface were almost normal. However, below the mucosa, infiltration of cancer cells was observed in an approximately 3 cm area along the gastric wall. Simultaneously, the site of infiltration was markedly increased in deep areas. Extraserous infiltration was observed. The morphology was special, and resembled an octopus pot, a trap used to catch octopuses in Japan, with a narrow top and a broad base. In our patient, metastatic lesions were detected in multiple organs, including the stomach. J. Med. Invest. 52: 122-125, February, 2005

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