Biomedical subjects
Publications and source records attributed to H Koga.
We here report a 42-year-old woman diagnosed cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) by age, family history, neurological findings, and neuro imagings. Magnetic resonance imaging well demonstrated the multiple lesions in the cerebrum including the brain stem, which was characteristic findings in CADASIL.
We have evaluated the backgrounds, neurological symptoms, signs, and magnetic resonance images (MRI) in six cases of spinal dural arteriovenous fistula. The subjects were 2 males and 4 females, and the mean age was 67.2 years old. The cardinal subjective symptoms were progressive motor weakness of lower extremities (2 cases), paroxyomal weakness of lower extremities (3 cases), sensory disturbance of polyneuritic type (2 cases), and intermittent claudication (1 case). Administration of beverages and drugs, which might include vasodilators and taking baths, worsened the symptoms and signs in 3 cases and 2 cases respectively. Concerning to MRI findings, high signal intensities or swellings were observed at mid-thoracic area to upper conus of the spinal cord in all cases. These changes, which would be induced by edema caused by high venous pressure, were especially prominent in the central area of the cords. By these mechanisms, sensory disturbance like polyneuritic type caused by the disturbance in deep areas of posterior columns might more prominent than the disorder of spinothalamic tracts placed in superficial areas of cord in the early stage of the disease. These abnormal intensities of MRI were higher than the level of clinical symptoms and signs. The difference was about 6.5 segments. For this reason, the upper border of the spinal cord lesions could not be identified by the neurological symptoms. Although the clinical features and MRI findings are relatively characteristic, flow void signs by high resonance MRI and abnormal blood vessels by spinal angiography will be necessary to diagnose this disease confidently.
Mutant p53 not simply is an inactivated tumor suppressor, as at least some mutant p53 proteins exhibit oncogenic properties. Mutant p53 thus is the most commonly expressed oncogene in human cancer. Accordingly, the expression of mutant p53 in tumors often correlates with bad prognosis, and expression of mutant p53 in p53-negative tumor cells enhances their transformed phenotype. The molecular basis for this "gain of function" is not yet understood. However, the finding that mutant p53 tightly associates with the nuclear matrix in vivo, and with high affinity binds to nuclear matrix attachment region (MAR) DNA in vitro, suggests that these activities are connected and may result in perturbation of nuclear structure and function in tumor cells. MAR-binding of mutant p53 most likely is due to conformation-selective DNA binding by mutant p53, i.e. the specific interaction of a given mutant p53 protein with regulatory or structural genomic DNA elements that are able to adopt specific non-B-DNA conformations. In support to this assumption, human mutant p53 (Gly(245)-->Ser) was shown to bind to repetitive DNA elements in vivo that might be part of MAR elements. This further supports a model according to which mutant p53, by interacting with key structural components of the nucleus, exerts its oncogenic activities through perturbation of nuclear structure and function. J. Cell. Biochem. Suppl. 35:115-122, 2000.
The small GTPase Rac functions as a molecular switch in several important cellular events including cytoskeletal reorganization and activation of the phagocyte NADPH oxidase, the latter of which leads to production of superoxide, a precursor of microbicidal oxidants. During formation of the active oxidase complex at the membrane, the GTP-bound Rac appears to interact with the N-terminal region of p67(phox), another indispensable activator that translocates from the cytosol upon phagocyte stimulation. Here we show that the p67(phox) N terminus lacks the CRIB motif, a well known Rac target, but contains four tetratricopeptide repeat (TPR) motifs with highly alpha-helical structure. Disruption of any of the N-terminal three TPRs, but the last one, results in defective interaction with Rac, while all the four are required for the NADPH oxidase activation. We also find that Arg-102 in the third repeat is likely involved in binding to Rac via an ionic interaction, and that replacement of this residue with Glu completely abrogates the capability of activating the oxidase both in vivo and in vitro. Thus the TPR motifs of p67(phox) are packed to function as a Rac target, thereby playing a crucial role in the active oxidase complex formation.
BACKGROUND: The presence of ganglia within the prostatic capsule (capsular ganglia) is a poorly understood phenomenon. If cancer invasion into or around ganglia is identified in a needle biopsy specimen, such a finding may be diagnosed as an extraprostatic extension. In this study, the presence of capsular ganglia was clarified. Furthermore, we discuss the significance of these ganglia in prostatic cancer patients. METHODS: The study group comprised a total of 42 patients, who had all undergone a radical prostatectomy for prostate adenocarcinoma with a relatively small volume. After surgery, the step-sectioned radical prostatectomy specimens were histologically evaluated. RESULTS: In 22 of 42 cases, capsular ganglia were recognized. With respect to the distribution of the capsular ganglia, the ganglia were most frequently observed at the posteriolateral aspect of the prostatic base. Morphologically there were no obvious differences between the capsular and periprostatic ganglia. Moreover, in 3 of 5 cases with cancer involvement into the capsular ganglia, such involvement was not predictive of extraprostatic extension. CONCLUSIONS: The presence of capsular ganglia needs to be clarified in prostatic cancer patients. Our findings therefore suggest that cancer involvement either in or around the ganglia should not be immediately interpreted as indicating an extraprostatic extension, if such a finding is recognized in a needle biopsy specimen.
The lethal(3)malignant brain tumor (D-l(3)mbt) gene is considered to be one of the tumor suppressor genes of Drosophila, and its recessive mutations are associated with malignant transformation of the neuroblasts in the larval brain. The structure of D-l(3)mbt protein is similar to Drosophila sex comb on midleg (Scm) protein which is a member of Polycomb group (PcG) proteins. We have isolated here the first human homolog of the D-l(3)mbt gene, designated h-l(3)mbt. Radiation hybrid mapping and fluorescence in situ hybridization (FISH) analysis localized the h-l(3)mbt gene to chromosome 20q12. The h-l(3)mbt transcript is expressed in most of the human adult normal tissues and cultured cell lines. However, some cancer cells markedly reduce the h-l(3)mbt protein expression. Immunocytochemical study revealed that the h-l(3)mbt protein shows a speckled and scattered distribution in interphase nuclei and completely associates with condensed chromosomes in mitotic cells. This subcellular localization has been shown to be different from that of Bmi1 protein which is a component of PcG complex. Furthermore, overexpression of h-l(3)mbt protein by using a Cre-mediated gene activation system leads to failures of proper chromosome segregation and cytokinesis, which result in formation of multinuclei in U251MG cells. These observations suggest that h-l(3)mbt protein has functions distinct from those of PcG proteins and may play a role in proper progression of cell division.
The small GTPase Rac participates in various cellular events such as cytoskeletal reorganization. It has remained, however, largely unknown about intracellular signaling pathways for Rac activation because of the lack of a simple and reliable assay to estimate the activation. Here we describe a novel method to detect the GTP-bound, active Rac in cells by pulling it down with the Rac-binding domain of the protein kinase PAK. Experiments using this method reveal that stimulation of human neutrophils with the Gi-coupled receptor agonists N-formyl-methionyl-leucyl-phenylalanine (fMLP) and leukotriene B4 (LTB4) leads to a rapid and transient increase in the GTP-bound state of Rac2, whereas phorbol myristate acetate (PMA) causes a slow but more sustained activation of Rac2. Pretreatment of cells with pertussis toxin results in defective activation of Rac2 in response to fMLP and LTB4, indicating that coupling of the receptors to Gi plays a crucial role in the activation. Furthermore, the phosphoinositide 3-kinase (PI3K) inhibitors wortmannin and LY294002 block Rac2 activation elicited by the receptor agonists, but not that by PMA. Thus the Gi-coupled receptors likely mediate Rac2 activation via PI3K, whereas PMA activates Rac2 in a PI3K-independent manner.
BACKGROUND: We investigated whether a new marker of bone turnover, pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP), could be useful in the assessment of bone metastasis and in monitoring of the response to treatment in patients with prostate cancer with bone metastasis. METHODS: In all, 58 patients with prostate cancer (25 with bone metastasis and 33 without bone metastasis) and 52 patients with benign prostate hypertrophy who were treated between June 1994-August 1997 were included in this study. All patients were newly diagnosed. RESULTS: Serum ICTP levels in patients with prostate cancer with bone metastasis were significantly higher than those in patients with prostate cancer without bone metastasis (P<0.0001) or with benign prostate hypertrophy (P<0.0001). No significant differences were observed in serum ICTP levels between patients with prostate cancer without bone metastasis and those with benign prostate hypertrophy. Serum ICTP levels correlated significantly with Soloway's grading system for bone scans. Serum ICTP levels in patients with bone metastasis showed a significant downward trend in response to hormonal treatment. CONCLUSIONS: The determination of serum ICTP levels is useful in the assessment of bone metastasis and in monitoring the response of bone metastasis to treatment to prostate cancer.
Cyclooxygenase (COX) is a key enzyme in the synthesis of prostanoids. Two isoforms of this enzyme have been identified: COX-1 and COX-2. Recent studies have suggested that COX-2, but not COX-1, may play a role in colorectal tumorigenesis. In the present study, we investigated the expression of COX-2 as well as COX-1 in human hepatocellular carcinoma (HCC) tissues using immunohistochemistry and immunoblotting. Forty-four surgically resected HCC tissues with adjacent nontumorous livers (NTs), involving 17 cases of chronic viral hepatitis and 27 cases of cirrhosis, and 7 surgically resected, histologically normal liver tissues were used. The well-differentiated HCC expressed COX-2 more frequently and strongly than less-differentiated HCC or hepatocytes of NTs. Less-differentiated HCCs expressed less COX-2 than hepatocytes of NTs, which showed scattered, strong COX-2 expression. Histologically normal liver was weakly positive for COX-2. The expression of COX-1 was weaker than that of COX-2 in hepatic neoplastic and non-neoplastic parenchymal cells. An enhanced expression of COX-1 was not observed in well-differentiated HCCs. Immunoblotting also confirmed up-regulation of COX-2, but not COX-1, in well-differentiated HCCs. The present study is the first to demonstrate a high expression of COX-2 in well-differentiated HCC and a low expression in advanced HCC, in contrast to its continuous expression during colorectal carcinogenesis. These findings suggested that COX-2 may play a role in the early stages of hepatocarcinogenesis, but not in the advanced stages, and may consequently be related to HCC dedifferentiation.
PURPOSE: This study was undertaken to demonstrate that quinolones may cause acute colitis resembling penicillin-induced hemorrhagic colitis. METHODS: We reviewed the medical records of patients with acute colitis in our institutes. Twenty-eight patients with acute hemorrhagic colitis in which no pathogenic microorganisms were identified were the subjects of this study. Pseudomembranous colitis caused by Clostridium difficile was excluded. Ulcerative colitis, Crohn's disease, and radiation proctocolitis were also excluded. RESULTS: Among these patients, 25 had a history of recent administration of penicillin derivatives. The remaining three patients had never been given any penicillin derivatives, but had ingested quinolones approximately four weeks before the developing colitis had been identified. Klebsiella oxytoca was also isolated in these three patients. CONCLUSIONS: Quinolones may cause acute hemorrhagic colitis. The time interval from antibiotic ingestion to onset of the condition may be much longer in quinolones than in penicillin derivatives.
PURPOSE: To study the structure and expression of the cyclin D1 and the epidermal growth factor receptor (EGFR) genes in a cohort of 298 non-small-cell lung cancer (NSCLC) specimens. METHODS: Gene structure was studied by Southern analysis, and gene expression was studied by Northern analysis and immunohistochemical analysis. RESULTS: Amplification of the cyclin D1 locus was found in 14/298 (5%) specimens. All 12/12 specimens with amplification of the cyclin D1 gene for which RNA was available were found to express the cyclin D1 transcript, and 11/12 overexpressed the transcript to levels higher than that of uninvolved lung. The EGFR gene was amplified in 17/286 samples of NSCLC tested, and was overexpressed in 22/169 (13%) cases tested, including 12/13 cases with amplification of the gene for which RNA was available. Cyclin D1 gene amplification was associated with advanced lymph node involvement (P = 0.043), but not with larger tumor size or adverse outcome. Cyclin D1 gene amplification and overexpression occurred independently of retinoblastoma tumor-suppressor gene (RB) inactivation, but tumors with amplification of the cyclin D1 gene were more likely to have EGFR gene amplification (P < 0.005). No correlation of EGFR gene amplification or overexpression with tumor size, lymph node involvement, patient demographic data, or survival was identified. CONCLUSIONS: These data indicate that the cyclin D1 and EGFR genes are amplified and overexpressed in NSCLC, and amplification of the cyclin D1 gene occurs frequently in conjunction with amplification of the EGFR gene.
Explore the source record for details and available documents.
PURPOSE: To examine the relationship of instant coffee and brewed coffee with serum lipids and lipoproteins in Japanese men. METHODS: Study subjects were 4587 male self-defense officials aged 48-56 years who had a preretirement health examination at one of the three hospitals of the Self-Defense Forces from October 1986 to December 1992. A self-administered questionnaire ascertained lifestyle characteristics including consumption of a limited number of foods and beverages by all of the men. Serum concentrations of total cholesterol (TC), triglycerides (TG), and high density lipoprotein (HDL) cholesterol were measured, and low density lipoprotein (LDL) cholesterol levels were calculated from the values of TC, TG, and HDL cholesterol. RESULTS: While the consumption of brewed coffee was unrelated to any parameter of serum lipids and lipoproteins, instant coffee consumption showed a highly significant positive association with serum LDL cholesterol levels and an inverse association with serum TG levels. After adjustment for body mass index, smoking, alcohol use, green tea consumption, rank, and hospital, for each cup of instant coffee per day, LDL cholesterol levels were 0.82 mg/dl (95% confidence interval (CI) 0.29-1.35) higher, and TG levels in a natural log-scale were 0.014 mg/dl (95% CI 0.006-0.022) lower. There was also a tendency for a positive association between instant coffee intake and serum TC levels (trend p = 0.09). HDL cholesterol levels were unrelated to instant coffee consumption. These associations did not change after additional adjustment for selected foods and beverages associated with serum lipids and lipoproteins. CONCLUSIONS: The findings suggest that instant coffee, not brewed coffee, may be associated with raised levels of serum LDL cholesterol and decreased levels of serum TG.
Optimal therapeutic strategy for malignant brain tumors is controversial. Recent studies of viral or nonviral gene therapy in rats emphasize the need for a selective delivery system. We examined whether phosphorothioate oligodeoxynucleotides (lacZ 2157, 5'-GTGGCGTCTGGCGGAAAACC-3') could be selectively delivered transvascularly into experimental brain tumors following intracarotid infusion of bradykinin, a specific blood-tumor barrier opener. The specificity of 32P-labeled complementary antisense lacZ 2157 and the stability of lacZ 2157 in vivo were confirmed using slot-blotting hybridization method and polyacrylamide gel electrophoresis. Concentrations of lacZ 2157 after intracarotid injection (2 mg/kg, 10 microg/kg/min) with or without bradykinin were determined in the brain, tumor tissue, liver, kidney, and plasma. The transfer ratio of lacZ 2157 from the plasma to the tissues was calculated and expressed as tissue content relative to plasma content of lacZ 2157 per mg tissue (Do, microl/mg). Delivery of lacZ 2157 to tumor tissue increased 3.24 times with bradykinin over delivery in controls (0.0243 +/- 0.0176 vs. 0.00750 +/- 0.00389; p < 0.05). Delivery of lacZ 2157 to ipsilateral and contralateral cerebral cortex to the tumor, and delivery to the contralateral basal ganglia, did not increase significantly with bradykinin. These results indicate that such transvascular delivery with bradykinin can deliver a relatively large amount of oligodeoxynucleotide selectively to brain tumors without affecting normal brain.
Few studies have investigated the relation between glucose tolerance status and ultrasonographically determined gallstone disease. Using a 75-g oral glucose tolerance test, we examined the association of impaired glucose tolerance (IGT) and non-insulin-dependent diabetes mellitus (NIDDM) with gallstone disease in Japanese men. Subjects were men aged 48 to 59 of the Japan Self-Defense Forces who received a preretirement health examination between October 1986 to December 1994. After exclusion of 12 men under insulin treatment in the consecutive series of 7637 men, 174 were found to have gallstones; 103 were at the state of postcholecystectomy, and 6899 had normal gallbladder. IGT and NIDDM were associated with a modestly increased risk of gallstone disease; adjusted odds ratios were 1.3 (95% confidence interval [CI]: 0.9-1.8) for IGT and 1.3 (95% CI: 0.8-2.0) for NIDDM after adjustment for hospital, rank, smoking, alcohol use, and body mass index. Adjusted odds ratio for IGT and NIDDM combined was 1.3 (95% CI: 1.0-1.7, p=0.08). When prevalent gallstones and postcholecystectomy were considered separately, NIDDM showed a significant, positive association with postcholecystectomy, but not with prevalent gallstones. The findings add to evidence that glucose intolerance is associated with a modest increase in the risk of gallstone disease.
OBJECTIVE: To examine the relation of body mass index (BMI) and waist-to-hip ratio (WHR) to gallstones and postcholecystectomy risk in middle-aged Japanese men. DESIGN: Cross-sectional study. SUBJECTS: We used 174 men with prevalent gallstones, 104 with postcholecystectomy and 6909 with normal gallbladder in the consecutive series of 7637 men aged 48-59y receiving a preretirement health examination at four hospitals of the Japan Self-Defense Forces between 1986 and 1994. MEASUREMENTS: Gallbladder status was assessed by abdominal ultrasonography after an overnight fast. BMI was calculated as weight in kilogram divided by height in square meters, and WHR was used as a measure of central obesity. Analysis of the WHR was limited to a subset of data for the period 1991-1994 (gallstones 113, postcholecystectomy 66 and normal gallbladder 4410). RESULTS: After adjustment for hospital, rank in the Self-Defense Forces, cigarette smoking, alcohol use and glucose tolerance, BMI was significantly associated with an increased risk of both prevalent gallstones and postcholecystectomy. WHR also showed a significant positive association with each of the two conditions. When BMI and WHR were mutually adjusted for, both of the obesity indices tended to be associated positively with prevalent gallstones and postcholecystectomy. CONCLUSION: These findings indicate that obesity is associated with increased gallstone risk in men.
BACKGROUND: Dad1, the defender against apoptotic cell death, comprises the oligosaccharyltransferase complex and is well conserved among eukaryotes. In hamster BHK21-derived tsBN7 cells, loss of Dad1 causes apoptosis which cannot be prevented by Bcl-2. RESULTS: To determine the role of Dad1 function in vivo, we prepared by gene targeting, mice harbouring a disrupted Dad1 gene. Homozygous mutants died shortly after they were implanted with the characteristic features of apoptosis. In an in vitro blastocyst culture system, Dad1-null cells displayed abnormalities which were comparable to those obtained in vivo. However, oligosaccharyltransferase activity was apparently retained even after the Dad1-null cells were destined to die. Some live-born heterozygous mutants displayed soft-tissue syndactyly. Mild thymic hypoplasia was also indicated in heterozygotes. CONCLUSION: These results suggest the involvement of the Dad1 gene in the acquisition of a common syndactyly phenotype, as well as in the control of programmed cell death during development.
To investigate the mode of action of the newly synthesized optically active imidazole compound, NND-502, (-)-(E)-[4-(2, 4-dichlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolylacetonit rile, its effect on ergosterol biosynthesis in cell-free extracts of Candida albicans was examined and compared with that of the (S)-enantiomer of NND-502 in addition to lanoconazole and bifonazole, both of which are clinically used for the treatment of dermatomycoses. NND-502 was found to interfere with ergosterol biosynthesis by inhibition of sterol 14alpha-demethylase, while no interference due to the (S)-enantiomer of NND-502 was found, indicating that the stereochemical orientation of the 2, 4-dichlorophenyl group plays an important role in the interaction with the enzyme. In terms of drug concentration exerting 50% inhibition of ergosterol biosynthesis, NND-502 was 2.5 and 28 times more effective than that of lanoconazole and bifonazole, respectively.