Type 1 diabetes of both the human and NOD mouse is associated with autoimmunity directed against insulin which is the only β cell specific autoantigen. Variable number of tandem repeats in the 5′ region of insulin gene on chromosome 11 is associated with the risk of type 1 diabetes in human. Mice have two insulin genes including the insulin 1 gene (chromsome 19) and the insulin 2 gene (chromsome 7). The insulin 2 gene knockout when bred onto NOD mice accelerates diabetes. In contrast to insulin 2, diabetes and insulitis were markedly reduced in insulin 1 knockout mice with decreased and delayed diabetes. Autoantibodies to insulin can predict diabetes in man and NOD mice. Insulin peptides can be used to induce insulitis and diabetes in non-diabetic strain mice. Our results suggest that insulin molecule is a possible “primary” autoantigen that initiates a pathogenesis of type 1 diabetes. An administration of insulin or its peptide can prevent the development of diabetes in NOD mice but we cannot at present safely prevent type 1 diabetes in humans. A series of clinical trials are under way and planned.

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With increased longevity, the elderly constitute a growing segment of the community. Bone mineral density (BMD) decreases with aging, and osteoporosis (low bone mass or density) is one of the most prevalent chronic health conditions among the elderly. Since fractures due to osteoporosis lead to considerable disability and many premature deaths, osteoporosis and osteoporotic fractures are major public health concerns. Vertebral deformities are very common among the elderly, and are associated with back pain and impairment. The incidence rates of hip fracture increase with age, and show a significant increase after ages 70. Post-fracture disability at multiple skeletal sites, especially the hip and vertebrae has been reported, and clinical vertebral fractures and hip fractures are associated with a substantial increase in mortality. The appropriate lifestyles for people of all ages, such as adequate intake of calcium, vitamin D and vitamin K should be recommended, in order to maintain bone strength (bone mass and bone quality). Physical activity increases BMD and decreases the risk of falls and fractures. In contrast, excess intake of caffeine and alcohol, as well as smoking, which is associated with low bone density and increased fracture risk, should be avoided. Although obesity is associated with higher BMD, adequate BMI (prevention of leanness) is recommended for general health. Furthermore, a simple risk assessment questionnaire helps to target high-risk women for BMD measurements. Effective drug treatment and prevention of falls are required for high-risk patients. Patients with both low BMD and susceptibility to falls should consider using a hip protector.

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The antiarrhythmic amiodarone is known to cause hepatic toxicity. Recently, much attention has been devoted to the role of apoptosis in the pathogenesis of drug-induced cytotoxicity. The aim of this study is to investigate whether apoptosis contributes to hepatic toxicity caused by amiodarone and, if so, by which mechanism. HepG2 human hepatoblastoma cells were incubated for 48 hours with various concentration of amiodarone. To determine apoptotic cells, concentration of cytochrome c in the cytosol fraction, caspase-9 and -3 activities, and the percentage of the cells with hypodiploid DNA were measured quantitatively by flow cytometric assay or ELISA. The expression of Bcl-2-related proteins was examined by Western blot analysis. Amiodarone induced cytochrome c release into the cytosol fraction, activation of caspase-9 and caspase-3, and the occurrence of hypodiploid cells beginning at 10 μg/ml in the HepG2 cells. However, 2.5 μg/ml of amiodarone, a clinically attainable serum level, did not significantly. The expression of Bcl-xL but neither Bcl-2 nor Bax was decreased in the amiodarone-treated cells. Thus, amiodarone-induced cell death related with cytochrome c release and caspases in the HepG2 cells, suggesting that the drug causes hepatic toxicity in part through the induction of apoptosis. It is our conclusion that the amiodarone-induced apoptosis of HepG2 cells proceeds via the mitochondrial pathway, and is mediated by the downregulation of Bcl-xL.

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We examined whether 55 isolates of erythromycin-resistant Streptococcus pneumoniae (MIC≥1 μg/mL) carrying mefA and/or ermB genes would develop resistance to telithromycin. Fifteen isolates, carrying only the mefA gene, had the M resistance phenotype by their susceptibility pattern and their susceptibility to rokitamycin did not change after exposure to 0.1 μg/mL of erythromycin. Of the other 40 isolates, 25 carried the ermB gene and 15 carried the both mefA and ermB genes, all of them showed high resistance to clindamycin (MIC≥128 μg/mL) and were resistant to macrolides, lincosamides and streptogramin B (MLS_B resistance phenotype). Twenty six isolates with the MLS_B resistance phenotype showed decreased sensitivity to telithromycin after exposure to erythromycin, although the elevated MICs of telithromycin remained below 1 μg/mL, the remaining 14 isolates did not showed an obvious decrease of their sensitivity to telithromycin (only two-fold dilution). However, by adding the telithromycin disk to the erythromycin-rokitamycin double disk diffusion test, the zone of inhibition around the telithromycin disk was blunted proximal to the erythromycin disk in all isolates with the MLS_B resistance phenotype including the 25 isolates which were considered to have a true cMLS_B phenotype because of their constitutive resistance to rokitamycin (MIC≥4 μg/mL). Furthermore, in 16 isolates, highly resistance to rokitamycin (MIC≥64 μg/mL), the zone of inhibition around the telithromycin disk was blunted to both erythromycin and rokitamycin disks. These results indicate that the expression of telithromycin resistance was induced even in S. pneumoniae isolates with a true cMLS_B resistance phenotype.

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To clarify the relationship with development of colorectal cancer, we investigated chromosomal aberrations in 715 specimens of the colorectal neoplasm by cytogenetic analysis. A gain of chromosome 17 was observed in the transitional epithelium around non-polypoid carcinomas, although the normal epithelium exhibited diploidy. Most tubular adenomas were diploid, however, loss of chromosome 11 and gain of chromosome 17 were increased in adenomas in association with an increased villous component. DNA aneuploidy, aneusomy and p53 deletion were predominantly observed in carcinomas, even in early cancers. Alterations of chromosomes 11 and 18 reflected different tumor morphologies in the early carcinomas. Gains of chromosomes 11, 17 and 18, and deletion of chromosomes 11 and 17p and p53 became more frequent following an increase in the depth of invasion. Aneusomy of chromosome 11 was a risk factor for patient survival after operation. Gains of chromosome 20 and 20q13.2 were associated with liver metastasis. Aneusomy and translocations of chromosome 17 and the p53 locus were predominantly observed in patients with multiple cancers and hereditary non-polyposis colorectal cancer. Our results indicate that in the process of development of colorectal carcinomas, specific chromosomal aberrations might be related to each step of development, or an alternative pathway of de novo carcinogenesis.

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This study was designed to provide quantitative analysis using flow cytometry (FCM) and immunohistochemical analysis (IH) for p53 protein in 85 patients who underwent pulmonary resection for non-small cell lung carcinoma (NSCLC). We also examined the relationship among numerical aberrations of chromosome 17 and p53 locus, clinicopathological parameters and patient prognosis in NSCLC. PAb 1801 was used as the primary antibody for p53 and the Fluorescence Index (F.I.) was calculated by FCM. Fifty-six patients (66%) showed a higher F.I. (≥0.5), and had a higher rate of lymph node metastasis, more advanced stage and poor survival, while a positive expression of p53 protein by IH was associated with no clinicopathologic factors or patient survival. The F.I. of p53 protein was significantly higher in cases with imbalanced numbers between chromosome 17 and the p53 locus, particularly in patients with higher F.I. This indicated that quantitative analysis by FCM was the most useful method to detect the over-expression of p53 protein compared to that by IH. Higher F.I. (≥0.5) is a prognostic indicator for predicting malignant behavior and poor survival in patients with NSCLC.

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To escape from reactive oxygen species generated in response to infection, intracellular pathogens, such as Salmonellae and Anaplasma phagocytophilum, can modulate the expression and distribution of the phagocyte NADPH oxidase components. In the present study, we analyzed the effect of Ehrlichia chaffeensis infection on the ability of human monocytic THP-1 cells to produce superoxide anion. Phorbol ester-stimulated superoxide generation and mRNAs for gp91^phox, p47^phox, and p67^phox were significantly increased in E. chaffeensis-infected THP-1 cells. These increases were also achieved in THP-1 cells cultured in medium conditioned by the E. chaffeensis-infected cells, indicating that bystander cells can be activated for superoxide generation and implicating soluble factors in the response. Heat-stable and -unstable factors represented one-third and two-thirds of this activity, respectively. These results suggest that immature human monocytic cells increase their ability to generate superoxide anion in response to E. chaffeensis infection regardless they have been directly invaded or not.

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The study was set out to elucidate whether there are detectable differences in the molecular features of mitochondrial DNA (mtDNA) from peripheral blood lymphocytes (PBLs) between individuals possibly exposed to radiation due to fallouts from Semipalatinsk Nuclear Test Site and those who lived in non-contaminated area in Kazakhstan. Subjects were residents of three villages in Kazakhstan considered to be affected with radionuclides in the past. Control individuals were from one non-contaminated settlement in Kazakhstan and age-matched Japanese volunteers. Two parameters, the relative mtDNA content and abundance of large-scale deletions (LSDs) in mtDNA were estimated by real-time PCR and a PCR adjusted to sensitively reveal the LSDs, respectively. Relative content of mtDNA as well as the abundance of LSDs were found to differ non-significantly both in Kazakhstan radiation exposed, control Kazakhstan and Japanese individuals. LSD scores displayed no regular or statistically significant association with the mtDNA content in any group tested. Lack of correlation between the number of LSDs and mtDNA level occurred irrespectively the radiation history of a blood donor or individual's age. We conclude that the molecular parameters of PBL mtDNA measured in this work are unlikely to be informative as a bioindicator of radiation exposure.

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A six-year-old girl with biliary atresia underwent a living donor liver transplantation because of deteriorating intrapulmonary shunting related to portal hypertension. Following transplantation, the patient's oxygenation improved after the tenth postoperative day and returned to normal within thirty days. The important points of early post-transplantation management for intrapulmonary shunting are as follows: 1) coping with large volume of sputum and thus, if necessary, a prompt tracheotomy should be performed; 2) when dealing with persistent hypoxemia, it is essential to maintain the preoperative oxygenation levels and avoid any outflow disturbance of the graft liver; and 3) the prevention of the fatal vascular thrombosis. Phlebotomy to correct the presence of underlying polycythemia is also required.

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We herein present two cases of solitary fibrous tumor (SFT) of the pleura. In case 1, a 66-year-old female was admitted with a nodule in the left lung field gradually inceasing in size for a period of two years. During video-assisted thoracoscopic surgery (VATS), the tumor showed a pedunculated tumor arised from the visceral pleura. Resected specimens were diagnosed to be SFT of the pleura with a malignant potential. In case 2, a 69-year-old female was admitted with a mass lesion in the left lower lung field. MRI showed a tumor with very low signal intensity on T2 weighted images, which was compatible with SFT of the pleura. During VATS, the tumor adhered to the parietal pleura with some fibrous bands but was easily removed. Resected specimens were diagnosed to be a benign SFT of the pleura. MRI was considered to be a helpful modality for the preoperative diagnosis of SFT.

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Bile duct cystadenocarcinomas are rare cystic neoplasms of the liver. A 70-year-old woman with a cystadenocarcinoma with the invasion to the stomach as a submucosal tumor is presented. There were unrepresentative findings in a pre-operative examination, and it was difficult to distinguish whether this cystic tumor was malignant or benign. The tumor in the stomach was diagnosed as submucosal prior to operation, but was revealed as an invasive tumor from a bile duct cystadenocarcinoma in a left lobe of the liver during surgery. As it metastasized to the stomach and spread intraductally, a left lobectomy was performed. The operation was noncurative but the patient has been alive for 19 months since.

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Gastrointestinal stromal tumors (GISTs) are common form of submucosal tumors of the stomach. Treatment of recurrent GISTs had been unsuccessful because of resistance to chemotherapy and radiotherapy. Recently, GISTs were reported to markedly respond to the molecular target agent, imatinib mesylate. We present here a patient with recurrent GIST and c-kit mutation who was successfully treated with imatinib mesylate. A 66-year-old man underwent partial gastrectomy because of GIST. The tumor was 3 cm in size and positive for KIT expression. One year after the excision, spiral computed tomography (CT) scan revealed four intra-peritoneal recurrence lesions measuring 7, 4, 3 and 2 cm in diameter. One week after the CT scan, we started treatment with imatinib mesylate at 400 mg/day, which resulted within two months in 40% decrease in the sum of the longest diameter. The reduction of tumor size continued for more than 6 months. Analysis of the c-kit mutation of the primary tumor revealed the deletion of 18 bases in exon 11 (codon 551-557), while other exons showed no mutation. In this report, we showed the effectiveness of imatinib mesylate therapy for the recurrence of GIST, especially with c-kit mutation in exon 11.

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