[Progress in the study of physiopathology, diagnosis, and treatment of digestive system diseases].
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Digestive System Diseases↗
Biomedical subjects
H Asakura
Publications and source records attributed to H Asakura.
Regulation by chemokines of circulating dendritic cell precursors, and the formation of portal tract-associated lymphoid tissue, in a granulomatous liver disease.
We have studied the recruitment and roles of distinct dendritic cell (DC) precursors from the circulation into Propionibacterium acnes-induced granulomas in mouse liver. During infection, F4/80(-)B220(-)CD11c(+) DC precursors appeared in the circulation, migrated into the perisinusoidal space, and matured within newly formed granulomas. Recruited DCs later migrated to the portal area to interact with T cells in what we term "portal tract-associated lymphoid tissue" (PALT). Macrophage inflammatory protein 1alpha attracted blood DC precursors to the sinusoidal granuloma, whereas secondary lymphoid organ chemokine (SLC) attracted mature DCs to the newly identified PALT. Anti-SLC antibody diminished PALT expansion while exacerbating granuloma formation. Therefore, circulating DC precursors can migrate into a solid organ like liver, and participate in the granulomatous reaction in response to specific chemokines.
Animals↗
Safety and efficacy of granulocyte and monocyte adsorption apheresis in patients with active ulcerative colitis: a multicenter study.
Active ulcerative colitis (UC) is characterized by activation and infiltration of granulocytes and monocytes/macrophages into the colonic mucosa. The infiltrated leukocytes can cause mucosal damage by releasing degradative proteases, reactive oxygen derivatives, and proinflammatory cytokines. The aim of this trial (conducted in 14 specialist centers) was to assess safety and efficacy of granulocyte and monocyte adsorption apheresis in patients with active UC most of whom were refractory to conventional drug therapy. We used a new adsorptive type extracorporeal column (G-1 Adacolumn) filled with cellulose acetate beads (carriers) of 2 mm in diameter, which selectively adsorb granulocytes and monocytes/macrophages. Patients (n = 53) received five apheresis sessions, each of 60 minutes duration, flow rate 30 ml per minute for 5 consecutive weeks in combination with 24.4 +/- 3.60 mg prednisolone (mean +/- SE per patient per day, baseline dose). During 60 minutes apheresis, 26% of granulocytes, 19.5% of monocytes and 2% of lymphocytes adsorbed to the carriers. At week 7, 58.5% of patients had remission or improved, the dose of prednisolone was reduced to 14.2 +/- 2.25 mg (n = 37). The apheresis treatment was fairly safe, only eight non-severe side effects (in 5 patients) were reported. Based on our results, we believe that in patients with active severe UC, patients who are refractory to conventional drugs, granulocyte and monocyte adsorption apheresis is a useful adjunct to conventional therapy. This procedure should have the potential to allow tapering the dose of corticosteroids, shorten the time to remission and delay relapse.
Adult↗
One missense mutation in the factor X gene causing factor X deficiency--factor X Kanazawa.
We investigated the molecular basis of factor X deficiency in a Japanese patient whose factor X activity and antigen level were 45% and 50% of normal control values, respectively. All exons and intron/exon junctions of the factor X gene were studied using a strategy combining polymerase chain reaction (PCR) amplification and nonradioactive single-strand conformational polymorphism (SSCP) analysis. Exon 5, containing the DNA fragment of the proband, showed aberrant migration by SSCP analysis. All exon-containing DNA fragments amplified by PCR were sequenced, and it was revealed that the proband was a heterozygote for a G --> A substitution in exon 5 of the factor X gene of the proband. This mutation predicts an amino acid replacement of arginine (Arg) for glycine (Gly) at codon 114 in the second EGF-like domain.
Aged↗
Prevalence of deep venous thrombosis in the lower limbs and the pelvis and pulmonary embolism in patients with positive antiphospholipid antibodies.
BACKGROUND: Antiphospholipid antibodies (AA) are immunoglobulins that cross-react with phospholipid on cell membrane, and are therefore associated with a hypercoagulable state manifested by arterial/venous thromboses. We aimed to determine the prevalence of deep venous thrombosis in the lower limbs and the pelvic region (DVT) and pulmonary embolism (PE) in patients with positive AA. METHODS: Sixty-six patients (48 female, 18 male) with positive lupus anticoagulant (LA) and/or positive anticardiolipin antibody (aCL) underwent radionuclide (RN) venography with 370 MBq of 99mTc-MAA. Pulmonary perfusion scintigraphy was performed in 58 patients. Fifteen patients had positive LA and positive aCL (LA+/aCL+), 33 patients had positive LA only (LA+/ aCL-) and 18 patients had positive aCL only (LA-/aCL+). 43 patients were diagnosed with primary antiphospholipid syndrome (APS) and 19 were diagnosed with APS associated with SLE. RESULTS: DVT was detected in 21 of 66 patients (32%). Patients with LA+/aCL+ showed higher prevalence of DVT (53%) as compared to LA+/aCL- (27%) and LA-/aCL+ (22%). PE was found in 13 of 58 patients (22%). The prevalence of PE was higher in patients with positive aCL (33% in LA+/aCL+; 36% in LA-/aCL+) than in patients with negative aCL (10%). CONCLUSION: Because of the high prevalence of DVT and PE in patients with AA, RN scintigraphy must be recommended in screening for these clinical troubles. These results indicate that the prevalence of DVT and PE may vary in subgroups of AA.
Adolescent↗
Vitamin K administration to elderly patients with osteoporosis induces no hemostatic activation, even in those with suspected vitamin K deficiency.
The administration of menaquinone-4 (MK-4), one of subclasses of vitamin K2, significantly reduces bone loss in postmenopausal osteoporotic women. However, concerns have been raised about whether vitamin K administration alters the hemostatic balance by inducing a thrombotic tendency. We investigated were whether the administration of vitamin K in the form of MK-4 induced a thrombotic tendency in 29 elderly patients with osteoporosis (5 men, 24 women; age range 78.7+/-5.1 years). Patients were administered 45 mg/day (three times a day, 30 min after each meal) of MK-4 for 12 weeks. Blood samples were obtained from the patients at 0, 4 and 12 weeks after the start of MK-4 administration. A number of hemostatic parameters remained stable under the markedly increased plasma levels of MK-4. However, in patients with suspected vitamin K deficiency, whose plasma levels of vitamin K or factor VII were low, vitamin-K-dependent clotting factors such as factor VII and prothrombin were gradually increased after administration of MK-4. No changes in the sensitive molecular markers such as TAT and F1+2, which reflect the amount of thrombin generated in the blood stream, were observed, even in those patients with suspected vitamin K deficiency. These results indicate that MK-4 can be administered safely, with regard to maintaining the hemostatic balance, to osteoporotic patients receiving no anticoagulant therapy.
Aged↗
Heterogeneity of p53 mutational status in the superficial spreading type of early gastric carcinoma.
BACKGROUND: The superficial spreading type of gastric carcinoma may originate from either a single cellular clone or from several different clones; this issue remains controversial. Indeed, the p53 gene has been shown to play an important role in gastric carcinogenesis, but there have been only a few reports on the heterogeneity of gastric carcinoma with respect to the p53 gene. METHODS: We analyzed seven cases of the superficial spreading type of gastric submucosal carcinomas (80 lesions; 10 to 17 per case) which showed different histological types and/or different p53 protein staining patterns. Direct sequences of polymerase chain reaction products were used for the analysis. RESULTS: p53 Gene heterogeneity in mucosal carcinoma lesions was detected in three cases. However, in all of the cases, the p53 mutational pattern was identical to that found in the submucosal carcinoma lesions. In the heterogeneous cases, the mutation in the submucosal carcinoma was one of the mutation patterns found among the mucosal carcinoma lesions. More precisely, the mutational pattern of both submucosal carcinoma lesions and the mucosal lesions located just above them, was identical. CONCLUSION: These data suggest that, with regard to the p53 gene, in some superficial spreading types of gastric carcinomas, there are various subclones in the mucosal carcinoma; one of these subclones becomes predominant through clonal selection, and, thus, invades the submucosa.
Aged↗
Elevated plasma levels of free-form of TFPI antigen in hypercholesterolemic patients.
Several studies have previously reported high levels of total tissue factor pathway inhibitor (TFPI) antigen in patients with hypercholesterolemia. The relationship between serum lipid concentrations and total and free-form TFPI antigen in 32 patients with primary type II hypercholesterolemia and 38 age- and gender-matched normolipemic control subjects was studied (Study Group I). Plasma concentrations of total TFPI (tTFPI) antigen, free-form TFPI (fTFPI) antigen, tissue factor antigen, factor VII activity (FVIIc), and prothrombin fragment 1+2 (F1+2) were measured. The median levels of tTFPI, fTFPI, FVIIc, and F1+2 were higher in hyperlipidemic patients compared with those in healthy subjects. The effect of lowering total cholesterol on hypercoagulability in 25 patients with type II hyperlipoproteinemia (Study Group II) were also studied. The median levels of tTFPI, FVIIc, and F1+2 decreased significantly after 6 months of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor therapy in the hypercholesterolemic patients. On the other hand, fTFPI did not change after therapy. Plasma tTFPI was strongly correlated with total cholesterol and low density lipoprotein (LDL)-cholesterol in hyperlipidemic patients. In contrast to the strong correlation between tTFPI and total cholesterol, the correlation between plasma fTFPI and total cholesterol was relatively poor. These results suggest that the activation of the anticoagulant system as well as the activation of the coagulation system may occur in association with hypercholesterolemia. Furthermore, the results of this study may suggest that lowering of total cholesterol in hyperlipidemic patients reduces the thrombin generation in plasma and that down-regulation of LDL does not affect the anticoagulant potency of TFPI in plasma.
Adult↗
Spontaneous intracranial hypotension during pregnancy.
BACKGROUND: Spontaneous intracranial hypotension is characterized by postural headache associated with low cerebrospinal fluid pressure. CASE: A 37-year-old Japanese woman, gravida 3, para 2, had sudden onset of severe postural headache at 8 weeks' gestation, accompanied by nausea and vomiting. Results of medical and neurologic examinations were normal, and there was no measurable cerebrospinal fluid pressure on lumbar puncture. Brain magnetic resonance imaging showed diffuse subdural fluid collection and a narrowing of the ambient cistern, confirming the diagnosis of spontaneous intracranial hypotension. After a month of bed rest and intravenous fluid infusion, all symptoms subsided gradually and did not recur. CONCLUSION: Obstetricians should be aware that spontaneous intracranial hypotension can occur in pregnancy.
Adult↗
Phylogenetic diversity and similarity of active sites of Shiga toxin (stx) in Shiga toxin-producing Escherichia coli (STEC) isolates from humans and animals.
Nucleotide sequences of Shiga toxin (Stx) genes in STEC from various origins were determined and characterized by phylogenetic analysis based on Shiga toxin (Stx) with those deposited in GenBank. The phylogenetic trees placed Stx1 and Stx2 into two and five groups respectively, and indicated that Stx1 in sheep-origin STEC were placed into a different group from those in other STEC, and that Stx2 of deer-origin STEC also belonged to the unique group and appeared to be distantly related to human-origin STEC. On the other hand, Stx of STEC isolated from cattle, seagulls and flies were closely related to those of human-origin STEC. Such a diversity of Stx suggested that STEC might be widely disseminated in many animal species, and be dependent on their host species or their habitat. In addition, the active sites in both toxins were compared; the active sites in both subunits of Stx in all the animal-origin STEC were identical to those in human-origin STEC, suggesting that all the toxin of STEC from animals might be also cytotoxic, and therefore, such animal-origin STEC might have potential pathogenicity for humans.
Amino Acid Sequence↗
Mechanisms involved in enteropathy induced by administration of nonsteroidal antiinflammatory drugs (NSAIDS).
Mice received oral indomethacin (1 mg/mouse) daily for five days. It was found that severe gastroenteropathy (ie, paralytic stomach and necrotic intestine) was induced on the sixth day. Ulcer formation was also seen at many sites in the digestive tract, especially in the colon. In parallel with the increase in the number of leukocytes in the digestive tract, the proportion of granulocytes increased at various sites, for example, in the intraepithelium and lamina propria of the colon and the lamina propria of the appendix. The number of extrathymic T cells at these sites in the digestive tract, especially gammadelta T cells in the colon, increased. A functional assay revealed that granulocytes isolated from mice injected with indomethacin were activated in terms of their superoxide production upon stimulation. In conjunction with the data on the simultaneous activation of granulocytes in the liver and blood, the present results suggest that nonsteroidal antiinflammatory drugs (NSAIDs) have the potential to induce severe granulocytosis in specific sites of the body, possibly via their stimulatory effect on the sympathetic nervous system (ie, granulocytes bear adrenergic receptors on their surface).
Animals↗
A close relationship of triplet repeat polymorphism in MHC class I chain-related gene A (MICA) to the disease susceptibility and behavior in ulcerative colitis.
Major histocompatibility complex (MHC) class I chain-related gene A (MICA) has been found near the HLA-B gene. The MICA molecule is exclusively expressed on gastrointestinal epithelium and recognized by intestinal epithelial gamma delta T cells, where it exhibits a triplet repeat polymorphism in the transmembrane region. We investigated the possible correlation between MICA genetic polymorphism and ulcerative colitis (UC). Eighty-three patients with UC and 132 unrelated controls were included in this study. All subjects were Japanese. A triplet repeat polymorphism in the transmembrane region of the MICA was determined by direct sequencing procedures after amplification by a polymerase chain reaction. A significantly higher allele and phenotype frequencies of MICA A6 allele were observed in patients with UC than controls (allele frequency: P(c)=0.000011, phenotype frequency: P(c)=0.0049 odds ratio=2.62). A6 homozygous patients with UC showed significantly earlier onset of UC than patients without the A6 allele ((P)c=0.0042). Phenotypes of MICA A6 allele in Japanese are closely related to the disease susceptibility and behavior in UC. Examinations of MICA polymorphism in other ethnic groups may provide important information about the locus of primary responsible gene for UC.
Adolescent↗
Stratification analysis of MICA triplet repeat polymorphisms and HLA antigens associated with ulcerative colitis in Japanese.
We previously reported a conserved haplotype of HLA B52-DR2 and a significantly high frequency of the major histocompatibility complex (MHC) class I chain-related gene A (MICA) transmembrane-short tandem repeat (TM-STR) 6 allele in Japanese patients with ulcerative colitis (UC). To examine the predominance of the MICA TM-STR 6 allele as a marker of the susceptibility to UC within the susceptible haplotype, the association of each allele with UC was estimated following stratification of the patients to control for any possible confounding effects of other alleles positively associated with UC. Sixty-four patients with UC and 236 unrelated healthy controls were included in this study. All subjects were Japanese. HLA-A, -B, -C, and -DR antigens were determined serologically. A triplet repeat polymorphism of the MICA was determined by direct sequencing. To control for the effect of linkage disequilibrium, Mantel-Haenszel weighed odds ratios were calculated. Significantly higher phenotype frequencies of B52, MICA TM-STR 6, and DR2 were observed in patients with UC. Linkage disequilibria among alleles associated with UC revealed that a B52 - MICA TM-STR 6 - DR2 haplotype was conserved in patients with UC, as in controls. When the association of HLA-B52 was estimated after patient stratification for the possible confounding effect of MICA TM-STR 6 or DR2, a strong significant association of B52 with UC was still observed. In contrast, no association with UC was observed for MICA TM-STR 6 or DR2, after stratification of the possible confounding effect of HLA-B52. These results imply that the significant increase in MICA TM-STR 6 in Japanese patients with UC is attributable to linkage disequilibrium with HLA-B52.
Colitis, Ulcerative↗
Decreased plasma activity of antithrombin or protein C is not due to consumption coagulopathy in septic patients with disseminated intravascular coagulation.
We investigated whether depressed plasma antithrombin and protein C activity, considered as a specific finding of disseminated intravascular coagulation (DIC), is due to consumption coagulopathy in septic patients with DIC. An analysis of hemostatic parameters was performed in 139 septic patients (68 with DIC and 71 without DIC). Plasma activity of antithrombin and protein C tended to be significantly decreased in septic patients with DIC but not in those without DIC (p < 0.001). However, when the septic patients were classified into three groups according to the albumin (or choline esterase) level, no significant differences in antithrombin activity or protein C activity were observed between the patients with and without DIC in any of the subgroups. Notably, neither the plasma activity of antithrombin nor protein C was decreased even in septic patients with DIC who had normal plasma levels of albumin (or choline esterase). No significant correlation was observed between plasma levels of thrombin-antithrombin complex (TAT) and antithrombin activity, or between plasma levels of TAT and protein C activity either in septic patients with DIC or without DIC. It is reasonable to conclude that the markedly reduced plasma activity of antithrombin and protein C is not due to consumption coagulopathy in septic patients with DIC.
Aged↗
Improved survival with oral administration of enteric-coated tegafur/uracil for advanced stage IV-A hepatocellular carcinoma.
BACKGROUND AND AIMS: There is currently no proven chemotherapy regimen for hepatocellular carcinoma (HCC). The principal chemotherapeutic approach in most cases is infusion therapy into the hepatic arteries feeding the tumors. However, the clinical effects of chemotherapy are extremely poor. Therefore, in the present study, we conducted a prospective randomized trial of the efficacy of oral administration of enteric-coated tegafur/uracil for advanced HCC. METHODS: From 1994 to 1999, a total of 56 consecutive patients with unresectable stage IV-A HCC were studied prospectively to examine the efficacy of enteric-coated tegafur/uracil in HCC and to determine the significant prognostic factors. Twenty-eight patients were treated only with enteric-coated tegafur/uracil without other anticancer treatment. Another 20 patients were given conservative management only. The remaining eight patients withdrew from the study. RESULTS: In the group treated only with enteric-coated tegafur/uracil, the median survival time and 1 and 2 year survival rates were 12.13 months and 55.3 and 36.9%, respectively. In the control group, the median survival time and 1 year survival rate were 6.20 months and 5.5%, respectively. By both univariate analysis and multivariate analysis using Cox's proportional hazards model, treatment with enteric-coated tegafur/uracil was shown to be the factor most significantly favoring a better prognosis. CONCLUSIONS: Although the prognosis of most patients with stage IV-A HCC is poor, administration of enteric-coated tegafur/uracil induces long-term survival and is an effective treatment for stage IV-A HCC.
Administration, Oral↗
Difference in quasispecies of the hypervariable region 1 of hepatitis C virus between alcoholic and non-alcoholic patients.
BACKGROUND: Habitual alcohol intake is known to aggravate the clinical outcome of hepatitis C virus (HCV)-related chronic liver diseases and to increase the risk of hepatocellular carcinoma. METHODS: To investigate the possible mechanism of these effects by alcohol, we examined 31 cases of HCV-related chronic liver diseases of which 17 cases were drinking just before admission and the remaining 14 cases were non-drinkers. The studied cases included 18 patients with chronic hepatitis, six with liver cirrhosis and seven with hepatocellular carcinoma. The quasispecies of the hypervariable region 1 of the HCV genome were analyzed by using polymerase chain reaction single strand conformation polymorphism (PCR-SSCP). Hepatitis C virus viral load was quantitated by using multicyclic PCR after reverse transcription of the 5' non-coding region of the genome. RESULTS: The mean PCR-SSCP band number that reflected the quasispecies complexity in hypervariable region 1 was more significantly increased in alcoholics than in non-alcoholics (5.5 +/- 1.4 vs 3.9 +/- 1.1, P< 0.01). The significant increase in alcoholics remained, even if the cases were restricted to males (P < 0.01), to HCV genotype 1b (P < 0.05) or to chronic hepatitis (P < 0.05). The HCV viral load was not statistically different between alcoholic and non-alcoholic HCV-related chronic liver diseases (5.02 x 10(6) +/- 5.16 x 10(6) copies/mL vs 9.00 x 10(7) +/- 2.75 x 10(8) copies/mL, P = 0.28). Mutation events seemed to occur randomly when amino acid sequences of hypervariable region 1 were compared between four drinkers and four non-drinkers. CONCLUSIONS: The enhanced quasispecies complexity in hypervariable region 1 of HCV in alcoholics may be the main cause of more progressive HCV-related chronic liver diseases, and may provide the disease the resistance against any therapeutic modalities including interferon.
Aged↗
Efficacy of treatment with chimeric monoclonal antibody (Infliximab) to tumor necrosis factor-alpha for Crohn's disease in Japan: evaluation by rapid turnover proteins, and radiologic and endoscopic findings.
BACKGROUND: Several studies have reported that the chimeric monoclonal antibody to tumor necrosis factor (TNF)-alpha (Infliximab) is extremely valuable in the treatment of Crohn's disease. The aim of this study was to clarify the efficacy of this treatment in Japanese patients with Crohn's disease. METHODS: A 12-week multicenter, open trial of Infliximab was carried out and involved 25 patients with moderate to severe Crohn's disease who were resistant to conventional treatment. Patients received a single 2-h intravenous infusion of Infliximab at a dose of 1, 3, 5 or 10 mg/kg bodyweight. Clinical evaluation of this treatment response was defined as a reduction in the index of the inflammatory bowel disease (IOIBD) and of the Crohn's disease activity index scores (CDAI), and in serum levels of C-reactive protein (CRP) at 2, 4, 8 and 12 weeks, and as an increase in serum levels of rapid turnover proteins as well as improvement of radiologic and endoscopic findings at 4 weeks. RESULTS: The IOIBD score was reduced after 4 weeks in 66.7% of the group receiving 1 mg/kg Infliximab, 71.4% in the group receiving 3 mg/kg, 80.0% in the group receiving 5 mg/kg, and 85.7% in the group receiving 10 mg/kg. Improvement was better maintained over 12 weeks in the 5 and 10 mg/kg groups compared with the 1 and 3 mg/kg groups. Similar results were obtained for the CDAI scores. Serum levels of rapid turnover proteins significantly increased to within the normal ranges after infusion in all groups. Seven of the 11 (63.6%) patients evaluated showed improvement of radiologic and endoscopic findings. CONCLUSIONS: A single infusion of Infliximab was effective for the treatment of Japanese patients with Crohn's disease. Serum rapid turnover proteins reflected the clinical response to antibody for TNF-alpha well.
Adult↗
A female with asymptomatic primary biliary cirrhosis associated with pernicious anemia.
We experienced a female case with asymptomatic primary biliary cirrhosis that was associated with pernicious anemia after 16 years from the onset. She was 52 years old when she first visited a clinic in 1981 for liver dysfunction treatment. Antimitochondrial antibody was negative and antipyruvate dehydrogenase complex antibody was positive in a low titer in its immunoglobulin (Ig)M type. Histological examination of her liver revealed a presence of definite chronic non-suppurative destructive cholangitis with numerous epithelioid cell granuloma. She had been given 600 mg of the oral daily dose of ursodeoxycholic acid since 1992. Macrocytic anemia incidiously appeared in September 1999. An immunological examination detected negative antiparietal cell antibodies and positive anti-intrinsic factor antibodies. Her bone marrow smear showed numerous megaloblasts and serum vitamin B12 in her blood was low at 99 pg/mL. Severe reversed atrophic-type gastritis (type A gastritis) was demonstrated by the use of dye-endoscopy with Congo red. Her macrocytic anemia dramatically improved after intramuscular administration of vitamin B12. In conclusion, attention should be given to the association of pernicious anemia during the follow up of primary biliary cirrhosis.
Anemia, Pernicious↗