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BACKGROUND: Urinary trypsin inhibitor (UTI, ulinastatin (R)) inhibits proteinases and has been used for the treatment of ulcerative colitis (UC). We investigated the therapeutic effect of UTI in patients with UC and correlated this effect to mast cell (MC) and macrophages (M) counts in the colonic mucosal wall. DESIGN: Patients with UC resistant to corticosteroids (n=16) and normal control subjects (n=10) were included in this study. Biopsy specimens obtained from the sigmoid colon of patients before and after UTI therapy were immunostained with antibodies to tryptase (AA1, MC) and CD68 (M). The number of MC and M in the lamina propria (LP) was determined and expressed per mm2 of LP. RESULTS: Nine patients with UC responded to UTI treatment. The mean number of MC in the upper part of LP in responders(440ﾂｱ51/mm2)was higher than nonresponders (312ﾂｱ76/mm2)and normal controls(200ﾂｱ47/mm2). MC counts in the lower part of the LP were not different in responders and nonresponders, although the counts in both groups were significantly higher than control. The number of M in the lower part of LP was similar in responders and nonresponders, but were higher than control subjects. M counts in the upper part of LP were similar in both groups of patients and control. Effective treatment with UTI in responders was associated with a significant fall in the number of MC in the upper layer of LP but not in M. CONCLUSION. Our results showed that UTI is an effective therapy in steroid-resistant UC. Our results also showed effective therapy with UTI was associated with a reduction in MC counts in the colonic mucosa, suggesting that the control of these cells may mediate, at least in part, the therapeutic effects of UTI in UC., Acta medica Nagasakiensia. 1999, 44(3-4), p.39-44

Two cases of superficial depressed type (IIc) early cancer of the colon are reported. Case 1 was a 65-year-old male and case 2 a 69-year old male. The lesion was located in the descending colon in both cases, and was removed by strip biopsy endoscopically in the former and surgically in the latter. The size of the lesion after resection was 6 mm in case 1 and 5 mm in case 2. Histopathologically, both cases were well differentiated adenocarcinoma without adenomatous components, and carcinoma developed de novo by submucosal (sm) invasion. As to the immunohistochemical staining of the cancer tissue by tumor associated antigen, case 1 showed a strong expression of carcinoembrionic antigen (CEA) and partial expression of sialyl Lewisx, and case 2 showed expressions of both CEA and sialyl Lewisx . The nuclear DNA content by flow cytometry was aneuploid only in case 1. Thus, although the two cases were morphologically the same IIc type cancer, the process of carcinogenesis and secondary phenomena varied., Acta medica Nagasakiensia. 1997, 42(1-2), p.56-59

The functional status of glutathione (GSH), its related enzymes and Cu, Zn-superoxide dismutase (SOD) in colonocytes isolated from trinitrobenzene sulphonic (TNBS)-induced colitis rats was studied. Colitis (T group) was induced in Wistar rats with 42 mg TNBS dissolved in 0.35 ml of 40% (v/v) ethanol instilled into the colon. The animals were sacrificed on day 14 and compared with saline-instilled rats (S group). The GSH concentration and the enzymatic activities of glutathione peroxidase (GPx), glutathione S-transferase (GST), and SOD were spectrophotometrically estimated. The severity of colitis was assessed histologically and by myeloperoxidase activity (MPO) in whole colonic tissue. The body weight loss of the rats in the T group was marked. In colonocytes isolated from rats in the T group, the concentration of GSH (7.9 ±1.4 vs.11.3 ± 0.4 nmol/mg protein, p < 0.05) and the activities of GST (104.4 ± 10.3 vs. 146.2 ± 18.5 mU/mg protein, p < 0.05) and SOD (74.4 ± 8.9 vs. 99.8 ± 7.5U/mg protein, p < 0.05) were lower, but the activity of GPx (430.0 -±14.1 vs. 283.9 ± 10.0 mU/mg protein, p < 0.05) was higher than in the S group. As expected, the activity of MPO in the T group was higher than in the S group (371.2 ± 14.7 vs. 158.9 ± 8.4 mU/mg tissue, p, Acta medica Nagasakiensia. 1996, 41(1-2), p.35-42

The distribution of endocrine cells in the human intestine was studied by immunostaining using the labeled avidinbiotin technique. The total number of endocrine cells was abundant in the proximal portion of the small intestine and the distal portion of the large intestine. Gastrin, cholecystokinin, and motilin immunoreactive cells were localized in the proximal portion of the small intestine. Peptide YY, serotonin, and glucagon/glicentin immunoreactive cells were distributed more abundantly in the lower large intestine. The serotonin and somatostatin concentrations in the colonic mucosa determined by high-performance liquid chromatography and radioimmunoassay were higher in the distal than proximal portion of the large intestine, being in correlation with the distribution of serotonin and somatostatin immunoreactive cells estimated by immunostaining. Therefore, the regional differences in the number of endocrine cells and the mucosal concentrations of the hormones probably reflect differences in the physiological functions of different regions of the gut. Not many endocrine cells with unknown peptides and animes and immature endocrine cells were present in the lower large intestine. Therefore, the frequent occurrence of carcinoids in the rectum is difficult to explain by the quantitative dominance of endocrine cells alone in the rectal mucosa, and other factors are considered to need evaluation., Acta medica Nagasakiensia. 1994, 39(4), p.30-39

We measured colonic mucosal blood flow using a reflectance spectrophotometry in Wistar rats during and after continuous injection of prostaglandins (PGs: PGE1, PGE2 and PGI2), as vasodilators, and thromboxane A2 (TXA2) as a vasoconstrictor. Administration of PGs increased colonic mucosal blood volume and oxyhemoglobin saturation of the colonic mucosal tissue, representing a parameter of mucosal oxygenation. The dose used did not change arterial blood pressure. These results suggest that PGs regulate colonic mucosal hemodynamics and oxygenation, and may thus act as cytoprotective substances. On the other hand, TXA2 injection diminished colonic mucosal blood flow compared with the same dose of PGI2 injection and acted against PGI2. Our results suggest that TXA2 and PGI2 regulate colonic mucosal hemodynamics., Acta medica Nagasakiensia. 1994, 39(4), p.76-81

Dextran sulfate sodium (DSS) solution was orally administered to mice to experimentally induce colitis, and the effects of X-ray irradiation of the spleen on healing or prolongation of inflammation was investigated. Peripheral, splenic and thymic T lymphocyte subsets were also analyzed to assess the underlying morbid conditions. Colitis with inflammatory changes consisting mainly of hemorrhagic erosions at the distal large intestine was induced by the administration of a 2 % DSS solution for 14 consecutive days. The DSS-induced colitis was inhibited by pre-irradiation of the spleen with 20 Gy prior to the development of DSSinduced colitis. Healing of inflammed lesion was accelerated by irradiation with 20 Gy during the induction of colitis with DSS. The proportion of peripheral Thy-1^+ and L3T4^+ cells was higher while the proportion of splenic L3T4^+ cells was significantly lower compared with the control group during the preparation of DSS-induced colitis. At 2 and 7 days after pre-irradiation, peripheral and splenic Thy-1^+ and L3T4^+ cells increased and thymic Lyt-2^- . L3T4^+ cells increased, whereas thymic Lyt-2^+ . L3T4^+ cell decreased. Our results suggest that the effect of splenic irradiation on DSS-induced colitis is due to a stimulation of T cell function, and activation of the immune system., Acta medica Nagasakiensia. 1994, 39(4), p.61-66

Anemia is observed in a considerable number of patients with Chohn's disease (CD). Iron absorption was investigated, using radioactive iron (^FeCl_3), in 12 normal subjects (controls), seven patients with iron deficiency anemia (ID), and 23 patients with CD. After oral administration of 1 μ Ci of ^Fe with 4 mg of FeSO_4 as a carrier, serum ^59Fe levels were determined for approximately three hours with a liquid scintillation counter. The proportion of iron remaining in the body two weeks after administration was also determined as the absorption ratio by whole-body counting. In investigating the factors affecting the absorption ratio, erythrocyte count, hemoglobin, total protein, albumin, serum iron (Fe), serum transferrin (TS), and serum ferritin were used as dependent variables, and were subjected to a multiple regression analysis for the prediction of the absorption ratio. The analysis revealed that hemoglobin and ferritin levels correlated significantly with the absorption ratio. The absorption ratio was not useful in differentiating between ID and CD patient, while both TS and ferritin were useful in differentiating between CD, ID and normal subjects. The time-course change in serum ^Fe after administration of ^Fe showed slightly higher levels in ID and CD than in controls., Acta medica Nagasakiensia. 1994, 39(4), p.131-136

Epidemiological data suggest an increase in both developed and undeveloped countries of inflammatory bowel disease. Furthermore, its etiology and pathophysiology remain unknown. Appropriated animal models are needed. We have studied a rat model of hapten-induced chronic colitis. In Wistar rats, intracolonic instillation of 20 mg or 42 mg of the hapten trinitrobenzene sulfonic acid in 30 % and 40 % ethanol proved to induce chronic colitis after 14 to 21 days of administration, in dose-dependent fashion when compared with ethanol alone that induced only acute colitis after three days of administration. This chronic colitis shares some characteristics with inflammatory bowel disease in humans, specially with Crohn's disease, such as transmural inflammation, development of strictures, ulcerations and infiltration of inflammatory cells throughout the colonic wall. These features make this model suitable for further studies of intestinal inflammation., Acta medica Nagasakiensia. 1994, 39(4), p.1-10

The effect of intravenous administration of various gastrointestinal hormones or peptides on the colonic mucosal blood flow was investigated by a reflex spectrum apparatus (TS-200, Sumitomo Denko Co). Various gastrointestinal hormones (pentagastrin, secretin, substance P, vasoactive intestinal polypeptide) were administered via the femoral vein at different doses. The hormones were administered over 30 minutes using a chronofuser at a rate of 0.1 ml/min. Serial measurements of cecal mucosal blood flow were performed. Saline was administered to the control group. 1) Pentagastrin was administered at doses of 1μg/kg/hr, 50μg/kg/hr, 100μg/kg/hr, and 200μg/kg/hr. Cecal mucosal blood flow decreased when the dose of pentagastrin was increased. The intravascular supply of oxygen also decreased in a dose dependent manner. Each dose of the gastrointestinal hormone caused a reduction in blood pressure. 2) Secretin was administered at doses of 5μg/kg/hr, 50μg/ kg/hr, and 100μg/kg/hr. Each tested dose of this gastrointestinal hormone acted to maintain cecal mucosal blood flow. The blood pressure remained unchanged throughout the experiment. 3) Substance P was administered at doses of 1μg/kg/hr and 5μg/kg/hr. Cecal mucosal blood flow and the intravascular oxygen supply increased after administration of this gastrointestinal hormone. The blood pressure decreased transiently at the start of administration, but later gradually returned to the baseline values. 4) Vasoactive intestinal polypeptide (VIP) was administered at doses of 1μg/kg/hr, 5μg/kg/hr, and 10μg/kg/hr. VIP caused the cecal mucosal blood flow to increase in a dosedependent manner. The intravascular oxygen, supply also increased signific antly after administration of this gastrointestinal hormone. The blood pressure initially de creased after administration of each test dose of VIP, after which it gradually started to increase. 5) To identify the factors responsible for the increase in cecal mucosal blood flow at the start of VIP administration at a dose of 5μg/kg/h of VIP, the blood concentrations of VIP, cyclic AMP, phospholipase, prostaglandin E_2, prostaglandin: E, and 6 keto-prostaglandin:F_1α were examined at regular intervals. However, no significant changes with regard to these substances were noted., Acta medica Nagasakiensia. 1994, 39(4), p.125-130

The purpose of this study was to assess the usefulness of nuclear DNA analysis in early cancer detection in patients with ulcerative colitis. The results of flow cytometric nuclear DNA anaiysis of tissue specimens from patients with ulcerative colitis, colonic adenoma, and colorectal carcinoma were compared. DNA aneuploidy was observed in 53.1 % of patients with ulcerative colitis and 16.7 % of patients with colonic adenoma. The degree of atypism of the tumor cells was related to the incidence of DNA aneuploidy. DNA aneuploidy was noted in 48.6 % of the patient with ulcerative colitis and coexistent colorectal carcinoma. The degree of dysplasia of the tumor cells was also correlated with the incidence of DNA aneuploidy. DNA aneuploidy was found in 14.3 % of specimens of mucosal tissue that were without cancerous or dysplastic cells. DNA aneuploidy was found in 8.5 % of specimens of mucosal tissue collected from patients with ulcerative colitis alone. Our findings showed that abnormalities in DNA content was closely correlated with histological atypism. In addition, our findings suggested that DNA aneuploidy may precede dysplastic changes in some cases of ulcerative colitis. We concluded that DNA analysis using flow cytometry is a useful method for identification of patients with ulcerative colitis at high risk for the development of cancer., Acta medica Nagasakiensia. 1994, 39(4), p.87-94

The phenotype of, and the production of interleukinl-β(Ｉ L-1β)and interleukin 6(IL、-6)by lamina propria mononuclear cells (LPMNC) were studied in 25 patients with ulcerative colitis (UC) (11 with untreated active disease and 14 inactive disease), and 18 control subjects. The percentage of CD4+ cells, CD20+ cells, CD3+, CD25+ cells and CD3+, HLA-DR+ cells was significantly higher in patients with active UC than in control patients, however, the percentage of CD8+ cells was significantly lower in patients with active UC than in patients with inactive UC and controls. IL-1 β was detected in nine of the ll patients(82%) with active UC but in only two of the 14 patients (14 %) with inactive UC and three of the 18 control subjects (17 %). The amount of IL-6 in patients with active UC was significantly higher than in patients with inactive UC and in controls. These results suggest that IL-1β and IL-6 mediate immune responses, and may be associated with inflammation and the etiopathogenesis of UC., Acta medica Nagasakiensia. 1994, 39(4), p.55-60

One of the eosinophil granule proteins is eosinophil cationic protein (ECP) which is basic and cytotoxic. The association of ECP in ulcerative colitis (UC) was studied by immunohistochemical method and RIA. ECP was localized in the lamina propria and the interstitium of the UC colon mucosa, showing a significant increase in distribution compared to the control. The ECP content, which was compared among the three groups according to the severity of UC classified by Matts' histopathological classification, disclosed an increasing tendency as the histological severity increased. The serum ECP level in active UC 17.68±12.25μg/L (n = 21) was significantly higher than that in inactive UC. In view of these findings, it was speculated that ECP has a role, though partial, in the damage of the colonic mucosa in UC on the basis of its biological features., Acta medica Nagasakiensia. 1994, 39(4), p.67-71

Lamina propria mononuclear cells (LPMNC) were isolated from 20 untreated patients with active ulcerative colitis (UC) and 11 patients with inactive UC. All patients with active UC were first attacks, and were not being treated with any drugs. The effects of dexamethasone on production of interleukin-6 (IL-6) and immunoglobulins by LPMNC were assessed. IL-6 production by LPMNC, stimulated by pokeweed mitogen (PWM), was higher in patients with active UC (663.3±213.1 pg/ml) compared with normal controls (129.0 ±39.0 pg/ml) and patients with inactive UC (219.6 ± 63.4 pg/ ml). IgG was produced in greater amount by the LPMNC from patients with active UC (1395.5 ± 876.6 ng/ml) than by those from controls (413.0 ± 471.2 ng/ml) and patients with inactive UC (488.3±552.0 ng/ml) (p < 0.001). The amount of IgA and IgM did not vary among three groups. Dexamethasone suppressed the production of IL-6 and IgA, IgG and IgM by PWM-stimulated LPMNC in a dose-dependent manner in the dose range between 10-5and 10-2 mg/dl. We speculate that the suppression of IL-6 production by dexamethasone will contribute to the suppression of UCassociated inflammation, Acta medica Nagasakiensia. 1994, 39(4), p.50-54

To evaluate the activity level of eosinophils in patients with ulcerative colitis (UC), we analyzed peripheral blood eosinophil counts, serum levels of eosinophil cationic protein (ECP) and the percentage of hypodense eosinophils among all eosinophils in peripheral blood. Patients with active UC had significantly higher serum ECP levels and eosinophil counts, compared with patients in remission and healthy controls. Serum ECP levels correlated positively with eosinophil counts. In patients who could be followed from the active stage of UC to remission, ECP decreased significantly over time and eventually reached approximately normal levels, while eosinophil counts showed no significant change. The mean percentage of hypodense eosinophils (specific gravity < 1.082 g/ml) in peripheral blood was 5% or less in patients in remission and healthy controls, but it was 31.7 % in patients with active UC. These results suggest that eosinophils are activated in patients with UC, and that they are involved in injury to the colorectal mucosa by inducing the release of cytotoxic proteins such as ECP., Acta medica Nagasakiensia. 1994, 39(4), p.40-44

The serum pepsinogen (PG) level was determined in 81 patients undergoing gastric examination, and the results were clinically compared with the results of the conventional primary screening for gastric cancer based on the inquiry and radiography of the upper digestive tract. The values of PG I and PG II in patients whose stomach was found to be normal (normal group) were almost the same as the reported values, but their PG I /PG II ratio was somewhat smaller than the reported value. The PG levels in the gastric ulcer, erosive gastritis and gastric polyp groups did not significantly differ from those in the normal group, while the screening based on the PG level was suggested to be potentially useful for discovery of atrophic gastritis, post-gastrectomy abnormality and duodenal ulcer. Gastric cancer was discovered in four of the 81 cases (early cancer in one case and advanced cancer in three cases), and all were poorly-differentiated adenocarcinoma. When compared with the normal group, only the PG I, II ratio was smaller in this group. If this PG method is employed for the primary screening, the false-positive rate is 35.5% (falsenegative rate:75% ), an 46.9% of subjects undergoing this screening will require a second examination. The discrepancy between the results of this study and those reported earlier was surmised to be partly attributable to the facts that histological type was poorly-differentiated adenocarcinoma in all the patients with gastric cancer in this study and the mean age of all subjects was more than 10 year higher than that in the earlier report. Compared with the conventional screening method, the percentage of subjects requiring a second examination was higher by more than 20%. It was concluded that further studies are necessary, including review of the criteria for judgment of gastric cancer., Acta medica Nagasakiensia. 1994, 39(1-3), p.16-20

Using two-color immunofluorescence, multiparameter flow cytometry has been used to examine the antigenic characteristics of the nature of changes due to aging in lymphocyte subests. The percentage and absolute numbers of T cells (CD3+T) declined in the aging humans. This decline was associated with a decreasing trend of CD8+T (cytotoxic/suppressor) cells in aging. The aged men had a slight but non-significant increased proportion of CD4+Leu8-T cells, which mediate the helper functions in B cell differentiation in association with an increasing tendency in the number of CD4+ T cells. A wide variety of changes took place in activated T cells expressing antigens such as Leu17(CD38), HLA-DR, or HLA-DQ, Although the decrease in the number of total CD8+ T cells was only slight, the proportion of CD8+ cell bearing Leu7 (CD57) antigen was strikingly increased in the elderly. For NK cells, a total number of NK cells (Leu19+CD3-) in the aged subjects was increased, but a subpopulation of cells having the high NK activity (Leu19+CD57-cells) decreased in the elderly men. The present study revealed various changes in lymphocyte subsets in aging humans., Acta Medica Nagasakiensia. 1992, 37(1-4), p.190-194

Acta Medica Nagasakiensia. 1992, 37(1-4), p.1-4

Clinicopathological significance of strip biopsy was evaluated in 23 gastric lesions in 22 patients. The 23 lesions consisted of 16 adenomas, 4 adenomas with focal carcinoma, 1 carcinoma, and 2 "no atypical cell"l. Strip biopsy provided precise information for accurate histological diagnosis and the depth of cancer invasion. Eleven % of lesions diagnosed as Group III by forceps biopsy and 66.7% of Group IV lesions had focal carcinoma in adenoma. Sixteen of 23 lesions were completely resected by strip biopsy. Seven lesions resulted in incomplete resection. One patient of the 7 cases underwent piece-meal resection because the lesion was too large to be resected by single strip biopsy. Four of the 7 lesions received additional endoscopic coagulation by laser or heater probe. All lesions except for 2 lesions which were resected by operation were followed by repeated endoscopy and all remained disappeared. The combination of strip biopsy and coagulation therapy appears to give great benefit in eradicating lesions., Acta Medica Nagasakiensia. 1992, 37(1-4), p.66-70

The efficacy of endoscopic laser irradiation for gastric tumors was evaluated on 130 patients. The patients consisted of 51 cases with advanced cancer, 30 with early cancer, 33 with adenoma and 16 with hyperplastic polyp. In 14 of 22 patients with advanced cancer complicated by stricture of the cardiac region, palliation of the stricture was successfully obtained by laser therapy. The survival rate of patients who obtained an effective improvement of the stricture was greater than that of the patients without palliation. Moreover, relief of the stricture enabled the patients to aquire a better quality of life. Significant tumor reduction by the laser did not affect the survival rate. As for early cancer, 12 of the 30 patients were cured by laser therapy. Adequate eradication of early cancer was possible in lesions of 10mm or less in diameter, which were confined to the mucosal layer with differentiated type of histology, and were without ulcer. The indication of curative laser irradiation should be restricted to highly selected patients, and careful follow-up study by restricted endoscopic examination is required. Adenomas were eradicated in 29 of 33 patients. However, cancer developed within a few years of the laser therapy in 3 of these, possibly indicating an adverse effect of the laser. Recently in Japan, endoscopic mucosal resection (EMR) has become the preferred treatment for early cancer and adenoma. Laser therapy, however, is useful when EMR is impossible because of the location or size of lesions, and when the lesions remain after EMR., Acta Medica Nagasakiensia. 1992, 37(1-4), p.9-15

Flow cytometric analysis of the cellular DNA content was conducted using paraffin-embedded liver tissues. Of the 488 cases examined, 413 (84.6%) cases were suitable for analysis. Of these, 296 (88.9%) were diploid and 37 (11.1%) were aneuploid. The ploidy pattern was unaffected by patients' sex and age. Long-term stored tissues were as suitable for analysis as short-term stored ones. An aneuploid pattern was more frequently found in hepatocellular carcinoma (HCC) (17/43,39.5%) than in non-neoplastic liver conditions (20/284,7.0%) (p, Acta Medica Nagasakiensia. 1992, 37(1-4), p.5-8

181 gastric polyps obtained by endoscopic polypectomy were studied clinico-pathologically. The polyps occurred most frequently in the lower portion, and the incidence of the polyps tended to increase with age. 91% (164/181) of the polyps were occupied by hyperplastic polyps, and 3 polyps and one polyp respectively with dysplastic and carcinomatous foci were detected in 164 hyperplastic polyps. Although hyperplastic polyps rarely transform into dysplasia or carcinoma, careful follow-up is recommended., Acta medica Nagasakiensia. 1991, 36(1-4), p.238-242

Twenty-seven patients with Crohn's disease who were operated on at the First Department of Surgery, Nagasaki University School of Medicine and followed-up after surgery were reviewed. Involved portion of intestinal tract were 10 in small bowel only, 14 in both small and large bowels, and 3 in large bowel. Major indication for surgery were obstruction, fistula, peritonitis and intractability of medical therapy. Twenty-two patients underwent radical resection and the other 5 patients had the disease left behind at anastomosis. The recurrence rate was 25.9% (7 out of 22), and early recurrence was found in small bowel diseases with longitudinal ulcerations or multiple aphthoid ulcers. Initial recurrence occured near the suture line, which showed no wide spreading in subsequent periods. Two cases with both small and large bowel disease required reoperation over 5 years after initial surgery because of stenosis. Three out of five cases with residual disease at the intestinal resection margin had a good condition, but the other three cases with skip sigmoid disease were intractable for medical therapy. Most suture line recurrence and residual disease at anastomosis were sufficiently managed by postoperative medication for long periods of time. Long-term follow-up study showed a good quality of life in about 75% of these cases. In conclusion, conservative resection rather than the sacrifice of normal bowel should be recommended for an extended disease of small bowel., Acta medica Nagasakiensia. 1989, 34(2-4), p.126-133