Invited Review Articles
Helicobacter Pylori and Gastric Diseases
HIDEMI GOTO
pg(s) 77- 85
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Helicobacter pylori (H. pylori) infection is a pathogenic agent of gastric diseases, but their mechanisms are unclear. Effects of ammonia, tumor necrosis factor (TNF), and anti-Lewis autoantibodies induced after H. pylori infection on the development of gastric diseases were investigated. Ammonia disturbed the collagen metabolism in the ulcer base. Soluble TNF receptors regulate the action of TNF. The involvement of anti-Lewis autoantibodies in the development of peptic ulcer might be unlikely. Moreover, H. pylori-specific IgA in gastric juice and TNFα gene polymorphism in persons infected with H. pylori were studied. According to H. pylori-specific IgA titer in gastric juice, persons were divided into two histologically and endoscopically different states of disease. TNFA -857 single nucleotide polymorphism (SNP) may be associated with rugal hyperplastic gastritis and gastric carcinomas without severe atrophy. However, complete elucidation of pathogenic mechanisms of H. pylori-induced gastric diseases requires further research.
Transgenic Rat Models of Vasopressin Overexpression
YUTAKA OISO, HIROSHI NAGASAKI and HISASHI YOKOI
pg(s) 87- 93
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Vasopressin has an important role in water metabolism and its impairment induces some clinical disorders such as diabetes insipidus or syndrome of inappropriate antidiuresis (SIAD). SIAD is caused by the overproduction of vasopressin which induces diluting hyponatremia. The accurate diagnosis and appropriate therapy have not settled up to date because its pathophysiology is very complicated. It is meaningful to develop a rat model of SIAD in which human vasopressin gene is overexpressed in order to analyze pathophysiological changes. Several models transgenic for vasopressin including us had been generated. The transgenic rats provide a useful model to investigate various pathophysiological changes resulting from the oversecretion of vasopressin. Some interesting results based on these animal models are reviewed.
Small-for-size Graft in Liver Transplantation
TETSUYA KIUCHI, FUMITAKA OIKE and HIDEKAZU YAMAMOTO
pg(s) 95-102
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Controversies on small-for-size (SFS) graft in liver transplantation have evolved in parallel with the history of living donor liver transplantation for adults. It is true that the liver regenerates rapidly within a limited threshold. But ‘normal’ liver weight itself is variable and the influences of variable liver graft and extrahepatic factors are not negligible in pathological condition. Clinical features of ‘SFS syndrome’ are neither specific nor inevitable in low-weight liver and many other factors than actual graft weight contribute to their occurrence. Among them, early elevation of portal venous pressure highly probably plays a key role. In the clinical trials of surgical modification and local pharmacological manipulation targeting portal hemodynamics and tissue congestion, it may be the time to discard an excessive fear for SFS grafts and to minimize unnecessary withdrawal from the opportunity of transplantation.
Persistent Helicobactor Pylori Infection and Genetic Polymorphisms of the Host
NOBUYUKI HAMAJIMA
pg(s)103-117
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Helicobacter pylori (HP) infection elevates the risk of gastric diseases including peptic ulcer and gastric cancer. The infection induces inflammatory cytokines, which could work both for and against lifetime infection in the human stomach. Genetic polymorphisms of the cytokines and other related ligands, receptors, and enzymes may influence persistent HP infection. This paper summarizes studies done on the associations between anti-HP antibody seropositivity and polymorphism genotypes. To date, the associations with the polymorphisms of fucosyl transferase 2 (FUT2 or secretor gene), FUT3 (Lewis gene), interleukin 1A (IL- 1A), IL-1B, IL-1RN, IL-8, IL-10, myeloperoxidase (MPO), and tumor necrosis factor A (TNF-A) and TNF-B have been reported. Polymorphisms of other related genes, CD14, CXC chemokine receptor 2 (CXCR2), IL- 1RI, nuclear factor KB2 (NF-KB2), and Toll-like receptor 4 (TLR4), have the potential to influence persistent infection. Unpublished results from our datasets are reported here for all these polymorphisms except TLR4. Gene-environment interactions between these genotypes and smoking are reviewed. An effect on OR due to the involvement of unexposed subjects is demonstrated to elucidate a disadvantage in the studies done in areas where the majority of the population is not exposed to HP.
Original Papers
Radiation Therapy for Metastatic Brain Tumors from Lung Cancer : A Review to Devise Individualized Treatment Plans
YOSHIYUKI ITOH, NOBUKAZU FUWA and KOZO MORITA
pg(s)119-128
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We retrospectively analyzed patients with brain metastasis from lung cancer to evaluate treatment modalities for metastatic brain tumors and to devise criteria for individualized treatment plans. Between October, 1986 and December, 1994, 90 patients were selected for this study. The majority (67.8%) received wholebrain radiotherapy (WBRT) alone. WBRT following surgical removal was carried out on 14 patients (15.5%). The median dose of radiation therapy was 43.3 Gy for WBRT. The results were as follows: (1) PS (1 and 2 vs. 3 and 4), which showed a significant difference (p<0.0001) in survival by both univariate analysis and multivariate analysis, (2) brain metastasis alone or concurrent metastases to other sites (p=0.0001) by univariate analysis, (3) the primary lesion controlled or uncontrolled (p=0.0006) by univariate analysis, (4) solitary brain metastasis or multiple brain metastases (p=0.0145) by univariate analysis. Patients were classified into 3 groups, A (PS1, 2, the primary lesion controlled, no distant metastasis and solitary brain metastasis), B (others except for groups A and C), and C (PS 3,4) based on 4 significant factors. The 1-year survival rates and median survival times were, respectively 75% and 1,767 days in Group A, 40.6% and 313 days in Group B, and 7.8% and 121 days in Group C (p<0.0001). Although the possibility of individualized treatment was suggested, based on 4 factors associated with the patient’s condition and disease progression before treatment for brain metastasis, further evaluation by randomized clinical trials is needed.
Cell Death of Human Oral Squamous Cell Carcinoma Cell Line Induced by Herpes Simplex Virus Thymidine Kinase Gene and Ganciclovir
MASAYA NISHIKAWA, YASUSHI HAYASHI, NORIYUKI YAMAMOTO, TAKAFUMI FUKUI, HIROKAZU FUKUHARA, KENJI MITSUDO, IWAI TOHNAI, MINORU UEDA, MASAAKI MIZUNO and JUN YOSHIDA
pg(s)129-137
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Suicide gene therapy combining herpes simplex virus thymidine kinase gene (HSVtk) and ganciclovir (GCV) is one strategy for the treatment of head and neck squamous cell carcinoma (HNSCC). The purpose of this study is to determine the mechanism of cell death that occurs in suicide gene therapy using HSVtk and GCV and to assess the safety of that therapy. The human oral squamous cell carcinoma cell line SAS was treated with adenovirus vector containing HSVtk gene (AdHSVtk) and GCV in vitro. Morphological changes including chromatin condensation, cell shrinkage, blebbing of cell membrane, and ballooning formations were observed. Changes in the localization of phospholipids in the cell membrane were also observed. The results of flow cytometry showed a maximum of about 65% of cells in the early phase of apoptosis. In addition, DNA fragmentation was investigated using the TUNEL method in vivo. Nude mice (BALB/c AJD-nu-, aged 4 weeks) were implanted with SAS and treated with AdHSVtk and GCV. Tumor sections were then observed. The treatment group was confirmed to have DNA fragmentation-positive cells. These results suggest that suicide gene therapy using AdHSVtk and GCV led to apoptosis of the oral squamous cell carcinoma cell line.