Ligation plus low-volume sclerotherapy for high-risk esophageal varices: comparisons with ligation therapy or sclerotherapy alone.
Masumoto H. Toyonaga A. Oho K. Iwao T. Tanikawa K.
Second Department of Medicine, Kurume University School of Medicine, Asahi, Japan.
Endoscopic variceal ligation therapy (EVL) seems to be a more effective and safer method than endoscopic injection variceal sclerotherapy (EVS) for treating bleeding esophageal varices. However, EVL may entail a higher recurrence rate than EVS. The aim of this study was to examine whether EVL combined with low-dose EVS reduced the recurrence rate compared to treatment with EVL alone and reduced the complication rate compared to treatment with EVS alone. In this prospective study, 59 patients with cirrhosis and high-risk (F2 or F3, red color sign ++ or ) esophageal varices were enrolled. They were randomly assigned to an EVS group (n = 18), an EVL group (n = 20), and a combination EVL plus low-dose EVS group (n = 21). After the eradication of varices, follow-up endoscopic examinations were carried out for 24 months to determine the recurrence of varices. Complications, e.g., severe dysphagia, fever, renal dysfunction and pleuritis were also evaluated. The recurrence-free rate was significantly lower in the EVL group (60% at 24 months) than in either the EVS group (90%, P < 0.05) or the combination group (88%, P < 0.05). However, no significant difference was found between the EVS group and the combination group. The complication rate was significantly higher in the EVS group (50%) than in either the EVL group (5%, P < 0.01) or the combination group (10%, P < 0.01). The combination therapy seems to be useful to improve the benefits achieved with EVL alone and to reduce the harmful effects induced by EVS alone. EVL plus low-volume EVS is advisable in the treatment of high-risk esophageal varices.
Studies of 13C-urea breath test for diagnosis of Helicobacter pylori infection in Japan.
Ohara S. Kato M. Asaka M. Toyota T.
C-13UBT Study Group, Third Department of Internal Medicine, Tohoku University School of Medicine, Miyagi, Japan.
In recent years Helicobacter pylori infection has been implicated in the etiology of a variety of upper gastrointestinal diseases. The aim of this multi-center trial was to search for the cut-off value of the simple 13C-urea breath test (13C-UBT) for diagnosis of H. pylori infection, and to examine the sensitivity and specificity of 13C-UBT for culture, the rapid urease test (CLO test), histology, and serological tests. Two hundred and forty-eight patients participated in this study after giving their informed consent. Endoscopic biopsy specimens were taken from gastric antrum and corpus for culture (190 patients), CLO test (222 patients), and histology (98 patients). A serological test was carried out for all patients. H. pylori infection was established when culture was positive or more than two of the tests, histology, CLO test, and serological test, were positive, and non-infection status was established when the all tests more than two tests were negative. After baseline breath samples were taken, the patients (who had fasted) were given 100mg of 13C-urea in 100ml water while sitting; they washed out the mouth with water. They were then placed in the left lateral decubitus position for 5 min, and additional breath samples were taken 10, 20, 30, 45, and 60 min after urea administration, with patients in the sitting position. One hundred and sixty-five of the 248 patients were infected, 48 were not infected, and H. pylori infection status was not evaluated in 35 by endoscopic and serological tests. Breath samples at 20 min were employed to determine the cut-off value. Using the receiver operating characteristic (ROC) curve, we determined the cut-off value for a positive UBT at 2.5 delta per thousand. The sensitivities of UBT for culture, CLO test, histology, and serological test were 98.4%, 98.6%, 100.0%, and 92.5%, and the specificities were 78.8%, 82.5%, 83.3%, and 87.3%, respectively. The cut-off value of 13C-UBT for the diagnosis of H. pylori infection was 2.5 delta per thousand; this test is a simple and noninvasive method for the diagnosis of this infection and has high sensitivity and specificity.
Does Helicobacter pylori eradication depend on the period of amoxicillin treatment? A retrospective study.
Tanimura H. Kawano S. Kubo M. Abe T. Goto M. Tanabe J. Asai A. Ito T.
Department of Medicine, Osaka Police Hospital, Japan.
In this study, the effect of different periods of amoxicillin (AMPC) treatment on the eradication rate of Helicobacter pylori in 173 patients with peptic ulcers (gastric ulcer, 109; duodenal ulcer, 64) was investigated. AMPC (1.5 g/day) was administered for 2, 4, or 6 weeks with omeprazole (20mg/day) and plaunotol (240mg/day), a mucoprotective drug, for 8 weeks. The H. pylori eradication rate was 46.7% for 2 weeks' treatment, 83.4% for 4 weeks' treatment, and 100% for 6 weeks' treatment. The eradication rate had a good correlation with the period of AMPC treatment. The healing rates of peptic ulcer at 4 and 8 weeks were 93.3% and 100%, respectively, in the 2-week group, 98.0% and 99.3% in the 4-week group, and 85.7% and 100% in the 6-week group. The recurrence rate of gastric and duodenal ulcers was 3.5% and 0% respectively, in the patients in whom H. pylori was eradicated and 30.0% and 40%, respectively, in the patients in whom H. pylori was not eradicated for 12 months after the H. pylori eradication treatment. Adverse effects of this regimen were observed in 5 (2.9%) of the 173 patients. Diarrhea was observed in 3 patients and eruption in 2. These adverse effects disappeared within a few days after only AMPC was withdrawn. Therefore, these may be caused by AMPC. The eradication rate of H. pylori depends on the period of AMPC treatment. This regiment, AMPC (1.5g/day) + omeprazole (20mg/day) + plaunotol (240mg/day), is safe and well tolerated for eradication of H. pylori.
Induction of major histocompatibility complex class II antigens on human colonic epithelium by interferon-gamma, tumor necrosis factor-alpha, and interleukin-2.
Horie Y. Chiba M. Suzuki T. Kudo T. Kamata A. Iizuka M. Masamune O.
First Department of Internal Medicine, Akita University School of Medicine, Hondo, Japan.
Class II antigens are strongly expressed on the inflamed colonic epithelium in inflammatory bowel disease. However, the mechanism of this epithelial class II antigen induction is not fully understood. Increased activities of interferon (IFN)gamma, tumor necrosis factor (TNF)alpha, and interleukin (IL)2 have been shown in the inflamed mucosa of inflammatory bowel disease. Therefore, we studied whether these cytokines could induce class II antigens on the human colonic epithelium. By an organ culture technique, 284 normal colonic biopsy specimens obtained from 49 individuals were cultured in media containing different concentrations of cytokines with/without anti-IFNgamma R antibody. Colonic epithelial class II antigens were identified by the indirect immunoperoxidase staining method with anti-human leukocyte antigen (HLA)-DR, DP, and DQ monoclonal antibodies. IFNgamma, TNFalpha, and IL2 induced epithelial class II antigens in 16 of 16 cases (100%), 2 of 16 cases (12.5%), and 6 of 17 cases (35%), respectively. Epithelial class II antigen expression in response to TNFalpha was induced via IFNgamma but not via IL2. This is the first demonstration that: (i) the induction of class II antigens on the colonic epithelium in response to TNFalpha is mediated via IFNgamma, and (ii) that IL2 induces class II antigens.
Role of non-adrenergic non-cholinergic inhibitory nerves in the colon of patients with ulcerative colitis.
Tomita R. Munakata K. Tanjoh K.
First Department of Surgery, Nihon University School of Medicine, Tokyo, Japan.
The cause of impaired colonic motility in patients with ulcerative colitis (UC) is unknown. The non-adrenergic non-cholinergic (NANC) inhibitory nervous system is one of the most important factors in the enteric nervous system of human gut. To assess the physiological significance of NANC inhibitory nerves in the colon of patients with UC, we investigated the enteric nerve responses of colonic tissues from patients with this disease. Colonic tissues were obtained from the lesional sigmoid colons of six patients with UC. Normal sigmoid colonic tissues obtained from ten patients with colonic cancer were used as controls. A mechanographic technique was used to evaluate in-vitro muscle responses to the electrical field stimulation (EFS) of adrenergic and cholinergic nerves before and after treatment with various autonomic nerve blockers. NANC inhibitory nerves were found to act on both normal colon and the lesional colon of patients with UC, but colon with UC was more strongly innervated by NANC inhibitory nerves than was the normal colon. These findings suggest that NANC inhibitory nerves play an important role in the impaired motility observed in the colon of patients with UC.
Icteric type hepatocellular carcinoma: revisited 20 years later.
Huang GT. Sheu JC. Lee HS. Lai MY. Wang TH. Chen DS.
Department of Internal Medicine, Graduate Institute of Clinical Medicine, National Taiwan University Hospital, Taipei.
Icteric type hepatocellular carcinoma is rare, and a poor prognosis has been demonstrated in the past. We performed this study to re-evaluate prognosis since the availability of modern diagnostic modalities. Of 3921 patients with hepatocellular carcinoma in our hospital, 9 patients who presented with tumor fragments in common bile duct and had a patent portal vein were submitted for analysis. Cholangiocarcinoma was suspected in 7 patients before the study was completed, and icteric type hepatocellular carcinoma was diagnosed in all 9 patients after serial studies that included serum alpha-fetoprotein levels, computed tomography, angiography, and histology. The prognosis was better in the 4 resectable patients (survival time 16, 31, 33, and 63 months, respectively), and was extremely poor for the 5 patients who received palliative treatment only (mean survival time, 4.5 months). Because of the apparently discrepant outcomes, this specific type of hepatocellular carcinoma should be kept in mind in areas where hepatocellular carcinomas are prevalent, and the suspected cases should be thoroughly investigated, because prognosis may be improved when resection is done at an earlier stage.
HGV/GBV-C infection in patients with acute hepatitis of different etiology and in patients with chronic hepatitis C.
Fabris P. Infantolino D. Biasin MR. Benedetti P. Tositti G. Bettini C. Marchelle G. de Lalla F.
Department of Infectious Diseases, Ospedale S. Bortolo, Vicenza, Italy.
To investigate the prevalence of hepatitis G virus (HGV/GBV-C) in patients with liver disease and to confirm its hypothesized ability to cause liver damage, we studied 130 subjects; 61 had chronic hepatitis C virus infection and 69 had acute hepatitis of either defined etiology (n = 57) or of unknown origin (n = 12). Positivity for HGV/GBV-C RNA was detected in 10 of the 61 subjects with chronic hepatitis C (16.3%) and in 11 of the 57 subjects with acute hepatitis of defined etiology (19%), whereas we failed to detect HGV/ GBV-C viremia in subjects with hepatitis of nonestablished etiology. Patients exhibiting positivity for HGV/GBV-C RNA were found to be comparable to those exhibiting negativity for HGV/GBV-C RNA in terms of both liver function tests and Knodell's score (in liver biopsies); the affect of HGV/GBV-C infection on the biohumoral and histological activity in patients with chronic hepatitis C therefore appears to be minimal or absent. Similar clinical features were observed in patients with acute hepatitis of known etiology whether they were positive or negative for HGV/GBV-C RNA. However, long-term clinical studies are still required to clarify the actual impact of HGV/GBV-C co-infection. In our geographic, i.e., a region or north-east Italy, HGV/GBV-C infection appears to be strictly related to intravenous drug use, and this agent does not seem to be responsible for acute hepatitis of unknown etiology; other etiological agents are probably involved.
Outcome of patients with cirrhosis requiring intensive care unit support: prospective assessment of predictors of mortality.
Singh N. Gayowski T. Wagener MM. Marino IR.
Division of Transplantation and Infectious Diseases Section, Veterans Affairs Medical Center, Pittsburgh, PA 15240, USA.
Determinants of outcome and the utility of the Child-Pugh score and the acute physiology and chronic health evaluation (APACHE) II score as predictors of outcome were prospectively assessed in 54 consecutive patients with cirrhosis requiring intensive care unit (ICU) management. Overall mortality in the ICU was 43% (23/54). Child-Pugh scores did not differ between survivors or nonsurvivors (12.8 versus 12.3, P = 0.26), however APACHE II scores (P = 0.007), acute physiology scores (P = 0.006), and Karnofsky scores (P = 0.001) were significant predictors of outcome. By univariate analysis, requirement of mechanical ventilation analysis (P = 0.001), duration of mechanical ventilation (P = 0.001), pulmonary infiltrates (P = 0.0001), infections (P = 0.047), gastrointestinal bleeding (P = 0.005), and serum creatinine >1.5mg/dl (P = 0.0005) were significantly associated with mortality. By logistic regression analysis only pulmonary infiltrates (P = 0.0001) and renal dysfunction (P = 0.041) were independent predictors of mortality. When controlled for the severity of illness (APACHE II scores), the mortality in patients with cirrhosis caused by alcohol was significantly lower than that in patients with liver disease not caused by alcohol (P = 0.01). Our study not only identified predictors of poor outcome in patients with cirrhosis requiring ICU care but also provided data that may have implications for optimal timing for transplantation.
Gastric plasmacytoma coexistent with plasma cell granuloma in a patient with gastric cancer.
Kitayama Y. Sugimura H. Nakamura SI.
First Department of Pathology, Hamamatsu University School of Medicine, Japan.
We report a rare case of multiple gastric plasmacytomatous lesions at an early stage found incidentally in a stomach resected because of gastric cancer. The three lesions had different macroscopic features, showing depressed, submucosal, and nodular tumor-forming types. The smallest, a depressed lesion, produced IgG of the lambda and kappa types, and had a plasma-cell granuloma-like appearence, whereas the largest, a submucosal tumor, was formed by the monoclonal proliferation of atypical plasma cells containing IgA-kappa type immunoglobulin, and the nodular lesion exhibited histological features intermediate between those of the other two lesions. From their microscopic features and the profile of immunoglobulin production, we believe that these lesions may represent different stages in the possible course of development of plasmacytoma from the early stage of plasma cell granuloma. All three lesions were located far from the gastric carcinoma and it was unclear whether they had any causal relationship with it.
Retroperitoneal extrarenal angiomyolipoma with early gastric carcinoma.
Mogi Y. Takimoto R. Kura T. Tamakawa M. Sakamaki S. Niitsu Y.
Department of Internal Medicine, Naganuma Municipal Hospital, Hokkaido, Japan.
We present a very rare case of a retroperitoneal extrarenal angiomyolipoma accompanied by early gastric cancer. A 41-year-old Japanese man, who had undergone surgery for a type IIc early gastric cancer 2 years earlier, was admitted to hospital presenting with back pain and abdominal fullness. Computed tomographic scanning and magnetic resonance imaging of the abdomen disclosed a massive fatty tumor extending from the hepatic hilus to the retroperitoneum. A large retroperitoneal tumor mass with no sign of involvement in the kidney was totally resected by radical surgery. Histologically, the tumor was classified as an angiomyolipoma.
Malignant transformation of Nakamura type IV gastric polyp with CA 19-9 production.
Nagai K. Ishii K. Matsumaru K. Kohra T. Okajima T. Yamamuro W. Hatori T. Sugimoto M. Sumino Y. Nonaka H.
Department of Internal Medicine, Saiseikai Yokohama-shi Nanbu Hospital, Yokohama, Japan.
In a 68-year-old Japanese man, a gastric polyp 24mm in diameter with a stalk 15 mm in diameter was diagnosed as well differentiated adenocarcinoma and treated by endoscopic polypectomy. Histologically, most of the resected tissue was adenoma, and atypical cells were papillarily proliferating to form adenocarcinoma in adenoma, a Nakamura type IV gastric polyp. Infiltration of carcinoma was limited to within the mucosal layer. Immunohistochemical study with anti-CA19-9 antibody revealed positive staining in carcinoma cells. Serum CA19-9 level, which showed slight elevation, returned to the normal range 1 month after the polypectomy. The proliferating cell nuclear antigen (PCNA) labeling index and DNA ploidy pattern were analyzed in the resected tissue. The PCNA labeling index was 30% in carcinoma, 17% in adenoma, and 0.1% in the normal tissue. The DNA ploidy pattern was diploid in adenoma and aneuploid in adenocarcinoma. These findings suggest that gastric adenoma, as well as colonic adenoma, may have the potential for malignant transformation.
Lymphoma arising in mucosa-associated lymphoid tissue of the duodenal bulb.
Kawai T. Tada T. Yokoyama Y. Joh T. Itoh M.
Department of Internal Medicine, Nagoya Municipal Johsai Hospital, Japan.
We report a case of low-grade B-cell lymphoma of the duodenal bulb arising from mucosa-associated lymphoid tissue. A barium swallow and an endoscopic examination showed multiple elevated, irregularly contoured lesions limited to the duodenal bulb. Endoscopic biopsy specimens were highly suggestive of non-Hodgkin's lymphoma. The resected specimen showed a gyriform mucosal elevation measuring 3 x 2cm in extent, with multiple small polypoid elevations scattered around it. Histologically, the small lymphocytes constituting the tumor infiltrated the duodenal mucosa and submucosa. The neoplastic centrocyte-like cells tended to grow around reactive lymphoid follicles and to invade epithelial structures, forming characteristic lymphoepithelial lesions. Monoclonal proliferation of the lymphoid tissue was demonstrated by the polymerase chain reaction method. The histologic appearance and the demonstration of monoclonality fulfilled the criteria for malignant lymphoma arising from mucosa-associated lymphoid tissue, which is extremely rare in the duodenum.
Computed tomography in the diagnosis of adult midgut rotational anomalies: a report of two cases.
Wang TK. Yeh CH.
Department of Surgery, Far Eastern Memorial Hospital, Taipei, Taiwan.
Adult midgut rotational anomalies are difficult to diagnose. Any symptoms present in adults may be the result of intermittent volvulus of the midgut. Successful outcome of this clinical condition depends on prompt diagnosis and timely surgical intervention. Computed tomography (CT) is useful in early identification of these lesions in the abdomen. However, the specific CT signs, the "superior mesenteric vein rotation" sign and the "whirl" sign, are easy to overlook if not kept in mind, as occurred in one of our two patients. In the other patient, CT played the major role in preoperative diagnosis.
Lymphangioma of the jejunum and mesentery presenting with acute abdomen in an adult.
Seki H. Ueda T. Kasuya T. Kotanagi H. Tamura T.
Department of Surgery, Hokusyu Central Hospital, Akita, Japan.
We describe a patient, 54-year-old woman, with lymphangiomas of the jejunum and mesentery presenting as acute abdomen. She had sudden onset of severe abdominal pain with guarding and fever. Physical examination revealed an elastic hard mass, with marked tenderness in the right abdominal region. Ultrasonography and computed tomography revealed a heterogenous mass, 20 x 15 x 8cm in size, in the mesentery. An emergency operation was performed with the diagnosis of diffuse peritonitis due to an inflammatory tumor in the mesentery. At operation, the tumor was found in the mesentery, adhering to a 60-cm segment of the jejunum. Multiple small tumors were seen in the submucosal layer of jejunum. The tumor was excised with a 60cm length of the jejunum. Histologically, the tumors were diagnosed as cavernous lymphangiomas. Although lymphangioma in the abdomen is rare in adults, we should consider it as one of the causes of acute abdomen.
Churg-Strauss syndrome (allergic granulomatous angitis) presenting with ileus caused by ischemic ileal ulcer.
Kaneki T. Kawashima A. Hayano T. Honda T. Kubo K. Koizumi T. Sekiguchi M. Ichikawa H. Matsuzawa K. Katsuyama T.
First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
We report a rare case of Churg-Strauss syndrome (CSS) in a 41-year-old Japanese man with a history of middle-age onset of bronchial asthma who had severe abdominal pain. He presented with ileus caused by an annular ulcer of the ileum, attributable to mucosal ischemia resulting from necrotizing vasculitis of the mesenteric artery. He also had marked hypereosinophilia (51.5%), elevated serum IgE levels (34040 IU/ml), and generalized enlargement of the superficial cervical lymph nodes, containing eosinophilic granulomas. A stenotic lesion caused by an annular ulcer in the ileum was found and resected by laparotomy. Microscopic examination of the resected specimen revealed luminal narrowing or occlusion of small arteries in the ulcer base, subserosa, and mesenterium resulting from marked fibrotic intimal thickening with fragmentation or lack of the internal elastic lamina. These findings were diagnosed as vasculitis, scar stage. The postoperative course was uneventful, with the patient receiving a maintenance dose of prednisolone (10-15 mg/day) for 7 years subsequently. We must carefully diagnose and treat patients with middle-age onset asthma, because the symptom may be a lung manifestation of CSS, in which various organs including gastrointestinal tract are involved as a result of systemic necrotizing vasculitis.
A new approach to dynamic graciloplasty.
Shatari T. Kawahara H. Inoue S. Sakurai T. Kawachi S. Teramoto T. Kitajima M.
Municipal Ida Hospital, Kawasaki City, Kawasaki, Japan.
The reestablishment of anal function by transposition of the gracilis muscle, combined with the implantation of electrodes and a neuromuscular stimulator (dynamic graciloplasty), has recently been developed. With this method, the transposed muscle maintains contraction by electrical stimulation to maintain neoanal pressure without fatigue. It is necessary to convert the fatigue-prone gracilis muscle to fatigue-resistant muscle by long-term electrical stimulation (conditioning). In most patients receiving dynamic graciloplasty, the conditioning is accomplished after the transposition. However, conditioning before graciloplasty should reduce the risk of ischemia in the transposed muscle after the graciloplasty and improve the outcome. This new sequence of procedures is described, in combination with J-pouch construction, in a patient who required abdominoperineal excision of the rectum for lower rectal cancer. The graciloplasty was performed after conditioning of the gracilis muscle in situ; the conditioning did not cause the patient discomfort and resulted in good anal function.
Severe muscle damage induced by high carbohydrate intake from elemental diet in a patient with Crohns disease.
Waki S. Kawanami C. Kanda F. Uenoyama Y. Maekawa T. Fukui H. Okada A. Matsushima Y. Kishi K. Kinoshita Y. Chiba T.
Department of Medicine, Kobe University School of Medicine, Japan.
Crohn's disease is associated with complications in multiple organs. However, there are very few reported cases of patients with Crohn's disease with muscle symptoms and/or high serum creatine phospho-kinase (CPK) levels. We report here a patient with Crohn's disease who experienced skeletal muscle damage with extremely high serum CPK level during treatment with an elemental diet. The non-parenteral administration of large amounts of carbohydrate and limited glycogen degradation capability may be a possible causative mechanism for this elemental diet-induced muscle damage.
Islet-cell hyperplasia causing hyperinsulinemic hypoglycemia in an adult.
Ueda Y. Kurihara K. Kondoh T. Okanoue T. Chiba T.
Department of Internal Medicine, Uwajima City Hospital, Ehime, Japan.
We report a patient, a 23-year-old man, who had clinical and laboratory findings suggestive of insulinoma. Although imaging studies did not reveal any tumors in the pancreas, distal pancreatectomy was performed because the possibility of small insulinoma could not be completely excluded. Grossly, the surgically removed pancreas did not reveal any tumors. Microscopically, the pancreas exhibited islet cell hyperplasia and nesidioblastosis. To our knowledge, this is the first authentic reported case of islet-cell hyperplasia occurring in a Japanese adult.
Small non-functioning endocrine tumor of pancreas: comparison with solid cystic tumor.
Kitajima T. Tomioka T. Tajima Y. Yamamoto O. Sasaki M. Kanematsu T.
Second Department of Surgery, Nagasaki University School of Medicine, Sakamoto, Japan.
A small non-functioning islet-cell tumor of the pancreas in a 79-year-old man is reported. Ultrasonography showed a solid small mass in the body of the pancreas. All laboratory data, including serum hormones and tumor markers, were within normal limits. A distal pancreatectomy was performed. Cut sections of the specimen revealed a small, hard, solid mass measuring 2.8 x 2.2 x 2.0 cm. Histologically, the tumor consisted of large acidophilic cells with round nuclei, and these cells were similar to those normally found in solid and cystic tumors (SCT) of the pancreas. However, the tumor cells were slightly positive for somatostatin and neuron-specific enolase. Ultrastructural studies revealed clear nuclei with no zymogen but immature neurosecretory granules in the cytoplasm of the tumor cells. These findings were consistent with those of non-functioning islet-cell tumors. We describe the clinical and histological differences between non-functioning islet-cell tumors and SCT based on an analysis of the literature.
Role of extravariceal collateral channels in the development of portal-hypertensive gastropathy before and after sclerotherapy.
Nakayama M. Iwao T. Oho K. Toyonaga A. Tanikawa K.
Second Department of Medicine, Kurume University School of Medicine, Asahi, Japan.
We investigated whether extravariceal collateral pattern contributed to the development of portal-hypertensive gastropathy (PHG) before and after sclerotherapy. Ninety-nine patients with cirrhosis and large esophageal varices were examined in this retrospective study. They were divided into four groups according to transhepatic portographic findings: group A (with neither paraesophageal veins nor gastrorenal shunt; n = 46), group B (with paraesophageal veins; n = 27), group C (with gastrorenal shunt; n = 14), and group D (with paraesophageal veins and gastrorenal shunt; n = 12). To assess PHG, endoscopic examinations were carried out before and 1 week and 1 month after sclerotherapy. The severity of PHG was classified according to a modified McCormack's classification and scored as: absence, 0; mild, 1; severe, 2. There were no significant differences in age, sex, cause of cirrhosis, severity of liver dysfunction, and extent of esophageal varices in the four groups. The PHG score before sclerotherapy was significantly higher in group A than in either group C (P < 0.05) or group D patients (P < 0.05). The calculated, integrated incremental change in PHG score after sclerotherapy was significantly higher in group A than in group C (P < 0.01) and group D patients (P < 0.01). Although the integrated change in PHG score was lower in group B than in group A patients, the difference was not significant (P = 0.68). These results suggest that gastrorenal shunt, but not paraesophageal veins, may play a protective role in the development of PHG before and after sclerotherapy.
Detection of genes of RNA viruses from freshly biopsied gastric mucosa by reverse transcription polymerase chain reaction.
Hayase Y. Tobita K.
Department of Virology, Jichi Medical School, Tochigi, Japan.
The reverse transcription polymerase chain reaction (RT-PCR) was performed to detect genes of RNA viruses in the freshly biopsied gastric mucosa of seven patients with low gastric acidity. Although nucleoprotein genes of Sendai virus and hemmaglutinin genes of influenza virus A were not detected, nucleoprotein genes of influenza virus B were detected in samples from three of the seven patients. The first patient had had antrectomy and vagotomy for gastric ulcer, the second patient was receiving a histamine type 2 receptor blocker for gastritis, and the third patient was receiving a proton pump inhibitor for gastric ulcer. Virus isolation from gastric mucosa and from gargles was negative for all seven patients. These findings suggest that genes of influenza viruses may exist in the gastric mucosa of patients with low gastric acidity.
Enhancement of reactivity of anti-MUC1 core protein antibody and killing activity of anti-MUC1 cytotoxic T cells by deglycosylation of target tissues or cells.
Hinoda Y. Takahashi T. Hayashi T. Suwa T. Makiguchi Y. Itoh F. Adachi M. Imai K.
First Department of Internal Medicine, Sapporo Medical University, Japan.
MUC1 mucin core protein contains an important tumor-associated peptide antigen that can induce cytotoxic T cells (CTLs) in vivo, although this antigen is generally masked by mucin-type glycans. To reveal the precise expression pattern of MUC1 protein in normal and neoplastic gastric tissues, we performed immunohistochemical staining of periodic acid-treated tissue sections with an anti-MUC1 core protein monoclonal antibody (mAb), MUSE11. In non-cancerous tissues, the deep portion of fundic glands and the luminal surface were predominantly immunostained in normal and metaplastic glands, respectively. In cancerous tissues, the incidence of positivity for MUC1 protein varied from 67% to 88%, depending on histological type. This frequent expression of MUC1 protein in cancer tissues after periodic acid treatment suggested that deglycosylation may be of use for exposing the target antigen of anti-MUC1 CTLs. Accordingly, we then examined the effect of benzyl-alpha-GalNAc, an inhibitor of O-glycan biosynthesis, on the expression of MUC1 protein and sensitivity to an anti-MUC1 CTL line, designated TS, in gastric cancer JRST cells. After incubation with benzyl-alpha-GalNAc, the reactivity of mAb MUSE11 with JRST cells and their sensitivity of TS were clearly increased. These findings suggest that deglycosylation may offer an important strategy for enhancing anti-tumor immunity in patients with gastric cancer.
Infiltration of peroxidase-producing eosinophils into the lamina propria of patients with ulcerative colitis.
Nishitani H. Okabayashi M. Satomi M. Shimoyama T. Dohi Y.
Fourth Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.
Little information is available to explain the pathogenesis of ulcerative colitis (UC). In this study, we focused on eosinophils in the lamina propria of the mucosa of patients with UC in the active phase. Biopsy specimens were taken from 17 patients with UC in the active phase, 17 in the inactive phase, and 20 control patients, and submitted for histochemical staining for peroxidase and chloroacetate esterase for microscopic examination. Both peroxidase-producing and chloroacetate esterase-producing cells in the lamina propria increased markedly in the active phase (8.3 +/- 3.1/0.01 mm2 and 6.6 +/- 2.7/0.01 mm2, respectively), compared with values in the inactive phase (0.8 +/- 0.6/0.01 mm2 and 1.3 +/- 0.6/0.01 mm2) or in the controls (1.3 +/- 0.8/0.01 mm2 and 1.3 +/- 0.4/0.01 mm2). Triple staining for peroxidase, chloroacetate esterase, and nonspecific esterase in the specimens revealed that the peroxidase-producing cells constituted a different population from that of neutrophils, macrophages/monocytes, or basophils. A monoclonal antibody specific for eosinophil peroxidase stained almost all infiltrated peroxidase-producing cells. These results indicated that eosinophils with strong peroxidase activity had infiltrated the lamina propria in UC, suggesting an allergic background and the involvement of released peroxidase in the mucosal damage characteristic of UC.
Steroid complications and surgery in intractable ulcerative colitis.
Shinozaki M. Suzuki K. Sawada T. Tsuno N. Higuchi Y. Muto T.
Department of Surgery, School of Medicine, the University of Tokyo, Japan.
The major operative indication for ulcerative colitis is intractability. Although steroid side effects appear to be closely associated with surgical indications for intractable ulcerative colitis, this relationship has yet to be analyzed in detail. To elucidate this relationship, we investigated 39 surgical patients with intractable ulcerative colitis, as defined by the Research Committee for Intractable Diseases of the Ministry of Health and welfare of Japan, and 66 conservatively treated patients with ulcerative colitis, of whom 6 had intractable disease. All patients with major steroid side effects and 17/24 (71%) patients with minor side effects underwent surgery. The median number of admissions was higher in patients with major side effects than in those with less severe or no side effects in the operative series, while this value was lower in the non-operative series than in the operative series. This tendency was similar for the total duration of hospitalization and the number of relapses. In the operative series, markedly higher steroid doses were administered to patients with side effects than to those without, and lower doses were given in the non-operative series. On multivariate regression analysis, the presence of steroid side effects, disease extent, and disease duration were significantly associated with surgery. Patients without side effects had a higher postoperative complication rate than those with minor side effects. We conclude that major side effects are a surgical indication for patients with intractable ulcerative colitis, and that even minor side effects should be taken as a surgical indication in view of the patient's quality of life.
Colorectal perforation with barium enema in the elderly: case analysis with the POSSUM scoring system.
Wang TK. Tu HH.
Department of Surgery, Far Eastern Memorial Hospital, Taipei, Taiwan, Republic of China.
Colorectal perforation is a serious complication of barium-enema examination, as the resultant contamination of the intraperitoneal or extraperitoneal space may result in a severe septic course. Between 1 October 1993 and 30 September 1996, four patients had colorectal injuries after barium-enema examinations at the Far Eastern Memorial Hospital, Taipei, Taiwan. Their mean age was 80 years and three of them died, despite the implementation of early and aggressive treatment. To examine the differences between this high crude mortality rate and reports of zero mortality, we retrospectively analyzed the data with the well established predictive surgical scoring system, the Physiological and Operative Severity Score for the enUmeration of Morbidity and mortality (POSSUM), to estimate the potential risk of death in these four patients.
Increased mRNA expression of a novel prostacyclin-stimulating factor in human colon cancer.
Umeda F. Ono Y. Sekiguchi N. Hashimoto T. Masakado M. Nakamura K. Chijiiwa Y. Nawata H.
Third Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
We recently cloned a prostacyclin (PGl2)-stimulating factor (PSF), which stimulates PGl2 production by cultured vascular endothelial cells. Immunohistochemistry and Northern blot analysis demonstrated that PSF was highly expressed in colon cancer sites compared with normal colon mucosa obtained from the same patient, as well as in cultured adenocarcinoma cell lines compared with cultured normal colon mucosal cell lines. Increased levels of the PSF protein were detected in the culture media of these adenocarcinoma cells compared with levels in the culture media of normal mucosal cells. These results suggest that PSF is closely associated with carcinogenesis of colon mucosa.
Sero-epidemiologic study of hepatitis C virus infection in Fukuoka, Japan.
Sata M. Nakano H. Suzuki H. Noguchi S. Yamakawa Y. Tanaka E. Fukuizumi K. Tanaka K. Yoshida H. Tanikawa K.
Second Department of Medicine, Kurume University School of Medicine, Japan.
We conducted an epidemiological study of 509 residents of H town, Fukuoka, Japan, to investigate the high mortality rate from liver disease. Antibodies to hepatitis C virus (HCV) (anti-HCV) were detected in 120 residents (23.6%); HCV RNA in 91 (17.9%), and hepatitis B surface antigen (HBsAg) in 13 (2.6%). Multivariate logistic regression analyses showed that presence of anti-HCV, male gender, and history of liver disease were associated with the presence of liver dysfunction, and that age of more than 40 years and a particular district were associated with the presence of anti-HCV. HCV RNA was more frequently detected in anti-HCV-positive men than women (41, or 85.4% versus 50, or 69.4%) (P < 0.05). The incidence of liver dysfunction was significantly higher in HCV RNA-positive men than women (32, or 66.7% versus 22, or 30.6%) (P < 0.05). These findings suggest that: (1) HCV was correlated with the high mortality rate from liver diseases, (2) there were district-related differences in the incidence of HCV, and (3) the lower frequency of elimination of HCV from men may explain why they showed a high mortality from liver disease.
Usefulness of hepatitis C virus RNA counts by second generation HCV bDNA-probe in chronic hepatitis C based on the HCV genotype.
Kobayashi M. Kumada H. Arase Y. Chayama K. Kobayashi M. Tsubota A. Koida I. Saitoh S. Suzuki Y. Murashima N. Ikeda K. Miyano Y. Mizoshita K. Matsuda M. Koike H. Hashimoto M.
Liver Research Laboratory, Toranomon Hospital, Kawasaki, Kanagawa, Japan.
Detection of hepatitis C virus (HCV) RNA by a second generation (ver 2) HCV bDNA-probe method (bDNA-probe) was compared with detection by the first generation (ver 1) assay. The two assays were performed simultaneously with the same serum samples of HCV genotypes 1b, 2a, 2b, 3a, and 3b. The positive rates with ver 1 were 82% for HCV genotype 1b (type 1b), 57.6% for HCV genotype 2a (type 2a), 75.0% for HCV genotype 2b (type 2b), 55.6% for HCV genotype 3a (type 3a), and 93.8% for HCV genotype 3b (type 3b). The positive rates with ver 2 were 95.0% for type 1b, 93.9% for type 2a, 83.3% for type 2b, 100% for type 3a, and 93.8% for type 3b. With Fisher's exact test, the detection rate for type 2a was significantly higher (P = 0.001) with ver 2 than with ver 1. We obtained regression lines using the HCV counts measured by bDNA-probe on the y axis and the HCV counts obtained by an HCV reverse transcriptase (RT)-competitive polymerase chain reaction method (competitive PCR) on the x axis. The gradients for types 1b, 2a, and 3b were greater with ver 2 compared to ver 1. The gradients for types 2a and 3b were the highest: for type 2a, y = 0.135x + 0.6 with ver 1 and y = 0.248x + 0.1 with ver 2; for type 3b, y = 0.366x + 0.1 with ver 1 and y = 0.727x + 0.3 for ver 2. In addition, HCV-RNA counts for all the genotypes tested in this study were significantly higher with ver 2 than with ver 1. Hence, we conclude that ver 2 of the bDNA-probe measures HCV-RNA counts closer to those obtained with competitive PCR than the ver 1 assay.
Multiple regression analysis for assessing the growth of small hepatocellular carcinoma: the MIB-1 labeling index is the most effective parameter.
Saito Y. Matsuzaki Y. Doi M. Sugitani T. Chiba T. Abei M. Shoda J. Tanaka N.
Department of Internal Medicine, Tsukuba Medical Center, Ibaraki, Japan.
The aim of this study was to clarify whether histological parameters reflected tumor aggressiveness in patients with hepatocellular carcinoma (HCC). The tumor volume doubling times (TVDTs) of 21 HCCs, less than 3 cm in diameter at the start of the observation period, were calculated in 21 patients in whom the natural progression of the lesion was observed by ultrasonography. Paraffin-embedded sections were prepared from samples obtained by ultrasound-guided fine-needle liver biopsy at the end of the observation period. The histological parameters examined were the MIB-1 labeling index (LI), for which we performed immunohistochemical staining with the MIB-1 monoclonal antibody, using an antigen retrieval method; the nucleo-cytoplasmic (N/C ratio), cellularity, and the nuclear form factor (NFF), were calculated with an imaging analyzer. We performed multiple regression analysis for estimating the growth of small HCCs. With the N/C ratio (0.154 +/- 0.068; mean +/- SD), cellularity (453 +/- 21.8 cells/10(4) microm2), NFF (1.150 +/- 0.096), and degree of HCC differentiation as independent variables, only the MIB-1 LI (11.8 +/- 6.1%) showed a significant correlation with TVDT (207.5 +/- 162.6 days) (r = -0.658; P < 0.05). Compared to the conventional indices of histological atypism tested, i.e., N/C ratio, cellularity NFF, and degree of HCC differentiation, only MIB-1 LI was significantly correlated with small HCC growth rate. The MIB-1 LI may therefore be a simple and useful index of tumor aggressiveness.
Longitudinal changes of bone mineral content with age in patients with cirrhosis of the liver.
Masaki K. Shiomi S. Kuroki T. Tanaka T. Monna T. Ochi H.
Third Department of Internal Medicine, Osaka City University Medical School, Osaka, Japan.
Bone disorders are associated with cirrhosis. Knowledge of the natural course of bone changes in cirrhosis could help in decision-making about medical treatment. We carried out one measurement of bone mineral density (BMD) in 184 Japanese patients (98 men and 86 women) with cirrhosis by dual-energy X-ray absorptiometry. Differences in BMD values means +/- SD between the 98 cirrhotic men and 283 healthy men of the same age reported in another study were not significant. In the 86 cirrhotic women, BMD tended to show a greater decrease with age than in healthy controls reported elsewhere. Differences in BMD values (means +/- SD) between 622 healthy women reported elsewhere and our patients were not significant for women up to age 60 years, but at 60 years or more, the mean BMD in cirrhotic women (0.692 +/- 0.100) was lower than that in healthy women (0.749 +/- 0.101; P < 0.01). In 61 of the 184 patients (31 men and 30 women), the bone mineral content (BMC) of lumbar vertebrae was measured at least twice, at intervals of 10-72 months. In this longitudinal part of the study, the group mean of estimated annual change for cirrhotic men was -0.4%, close to that of healthy men (-0.2%). This mean in cirrhotic women was -2.8%, significantly different from that of healthy women (-1.1%; P < 0.05). As expected, cirrhotic women were the most likely to lose BMC, and many needed prompt treatment.
Long-term prognosis of non-shunt operation for idiopathic portal hypertension.
Ohashi K. Kojima K. Fukazawa M. Beppu T. Futagawa S.
Second Department of Surgery, Juntendo University, Faculty of Medicine, Tokyo, Japan.
This report presents 46 Japanese patients with idiopathic portal hypertension (IPH) in whom non-shunt operation was performed for the management of esophageal varices. Non-shunt operation included transthoracic esophageal transection (Sugiura's procedure) in 37 patients, transabdominal esophageal transection (TAET) in 3 patients, and Hassab's procedure in 6 patients. Rates of postoperative variceal eradication were: 78.4% by Sugiura's procedure; 100% by TAET; and 50% by Hassab's procedure. The cumulative rates for recurrent varices and recurrent bleeding were 3.9%, and 5.1%, respectively, at 5 years, and 8.9% and 9.8% at both 10 and 15 years. Only 3 patients required additional endoscopic injection sclerotherapy to treat recurrent varices. Although 3 patients developed upper gastrointestinal bleeding, the source of hemorrhage was esophageal varices in 1, and portal hypertensive gastropathy in 2; none of the patients died from bleeding. Actuarial survival for all patients was 87.5% at 5 years, 77.9% at 10 years, and 58.8% at 15 years. There were no deaths within the first 30 days after surgery. These results show that non-shunt operation is useful in preventing bleeding from esophageal varices in patients with IPH.
Clinical assessment of pancreatic diabetes caused by chronic pancreatitis.
Wakasugi H. Funakoshi A. Iguchi H.
National Kyushu Cancer Center, Fukuoka, Japan.
Despite the high prevalence of diabetes mellitus in patients with chronic pancreatitis, few studies of pancreatic diabetes have been reported. We investigated 154 patients with chronic pancreatitis, of whom 50% were diabetics, with special reference to the features and clinical course of pancreatic diabetes. We arrived to clarify the features of pancreatic diabetes by comparing pancreatic exocrine function in 112 patients with primary diabetes with findings in a separate group of 80 patients with chronic pancreatitis. Pancreatic diabetes is proposed as a type of diabetes in which exocrine pancreatic function is markedly decreased. Progressive and fatal angiopathies were found in patients with pancreatic diabetes after a long duration of diabetes. The present investigation suggests that treatment of malnutrition is necessary in patients with pancreatic diabetes and that control of blood glucose is often difficult in these patients because of the high incidence of insulin-induced hypoglycemic episodes.
Duodenal secretion of phospholipase A2, amylase, and bicarbonate in chronic pancreatitis.
Makela A. Kuusi T. Seppala K. Schoder T.
Department of Surgery, University of Helsinki, Finland.
Phospholipase A2 has been suggested to be involved in the pathogenesis and pathophysiology of acute pancreatitis. We determined phospholipase A2 and amylase activities in duodenal juice collected during a secretin test from 30 consecutive patients who were suspected to have chronic pancreatitis or biliary disease. The patients underwent endoscopic retrograde cholangiopancreatography (ERCP) the following day. In the 8 patients with ERCP findings of advanced chronic pancreatitis, the mean outputs of phospholipase A2, amylase, and bicarbonate were reduced by 74%, 72%, and 60% compared to the respective values in the 13 (control) patients without a diagnosis of any pancreatic disorder or jaundice. In the 3 patients with recurrent pancreatitis but normal ERCP findings and in the 6 patients with jaundice the output values were not significantly reduced compared to those in the patients without any pancreatic disorder or jaundice. The outputs of amylase and phospholipase A2 were not significantly interrelated, whereas the outputs of phospholipase A2 and bicarbonate correlated well. Receiver characteristic (ROC) curves confirmed the high specificity and sensitivity of phospholipase A2 or bicarbonate output in patients with ERCP findings of advanced chronic pancreatitis compared to those with no changes in pancreatic ducts, with similar probability values of 0.880 +/- 0.111 (SEM), compared to the respective lower value of amylase, 0.676 +/- 0.118. Phospholipase A2 and bicarbonate output proved of equal value as markers of chronic pancreatitis and were superior to amylase output in the secretin test.
Gastrojejunal fistula caused by gastric ulcer.
Matsuoka M. Yoshida Y. Hayakawa K. Fukuchi S.
Department of Gastroenterology, Mishuku Hospital, Tokyo, Japan.
We report a case of gastrojejunal fistula caused by benign gastric ulcer, a very rare condition. The patient was an 81-year-old-woman who had had multiple recurrences of gastric ulcer. She also had diabetes mellitus. She was admitted to our hospital because of a left femoral head fracture, necessitating a mechanical bone head exchange operation. She had severe abdominal pain and anemia on the 48th postoperative day. Gastroendoscopic examination revealed a giant ulcer with a long-axis diameter of more than 5cm on the lesser curvature of the gastric body. She was treated with intravenous famotidine and all oral intake was restricted; her symptoms were alleviated. Two weeks later, a fistula had formed between the stomach and the jejunum just anal to the duodeno-jejunal flexure. She was placed on an ulcer diet, and was discharged with no symptoms on the 151st postoperative day. She has remained asymptomatic for 1 1/2, years to date. Lack of H2-antagonist administration, operative stress, and administration of ipriflavone appeared to have induced gastric ulcer recurrence, and formation of the fistula between the stomach and the jejunum seemed to have been facilitated by the patient being very lean and having minimal mesenteric adipose tissue.
Ileo-abdominal wall fistula caused by diverticulum of the ileum.
Eriguchi N. Aoyagi S. Nakayama T. Emi Y. Saku M. Yoshida K.
Department of Surgery, Kurume University School of Medicine, Japan.
We report a very rare case of ileo-abdominal fistula caused by penetration of the ileal diverticulum. Small bowel diverticulosis is generally considered to be an innocuous condition. In this report, we describe a case of ileal diverticulitis associated with an abdominal wall abscess.
Carcinosarcoma of the colon: report of a case and review of the literature.
Nakao A. Sakagami K. Uda M. Mitsuoka S. Ito H.
Department of Surgery, Shobara Red Cross Hospital, Hiroshima, Japan.
We report a case of carcinosarcoma in the transverse colon in a 60-year-old woman. She was admitted to our hospital for further examination of occult blood in October, 1995. Colonoscopy disclosed an elevated lesion with ulceration in the transverse colon, and she underwent right hemicolectomy. Histopathological examination revealed the tumor to consist of both carcinomatous and sarcomatous elements, the latter being more predominant. Immunohistochemistry revealed vimentin immunoreactivity in most of the sarcomatous cells, and S-100 and myoglobin in a few carcinomatous cells. Distinct carcinomatous features were noted in one superficial portion of the tumor, and these carcinomatous cells showed immunoreactivity for epithelial membrane antigen. The patient is alive 14 months after surgery without evidence of recurrence. To our knowledge, this is the fourth reported case of carcinosarcoma of the colon. Our review of the literature disclosed poor prognosis in colonic carcinosarcoma.
Aggressive jejunal gamma deltaT-cell lymphoma derived from intraepithelial lymphocytes: an autopsy case report.
Tsujikawa T. Itoh A. Bamba M. Andoh A. Hodohara K. Inoue H. Fujiyama Y. Bamba T.
Second Department of Internal Medicine, Shiga University of Medical Science, Otsu, Japan.
A 69-year-old man with massive ascites was referred to our hospital. Paracentesis revealed exudative ascites with many abnormal lymphocytes, which expressed T-natural killer (T-NK) cell surface markers and gamma deltaT-cell receptor (TCR). Although the ascites resolved for a short time with chemotherapy, gastrointestinal bleeding occurred and acute retention of ascites was observed. The patient died of panperitonitis. At autopsy, part of the jejunum revealed ulceration and marked mucosal thickening, and was perforated at the site of the severe ulceration. Histological examination showed massive infiltration of abnormal lymphocytes that were positive for CD45RO. Therefore, the cells responsible for the jejunal lymphoma and ascites were thought to be derived from gamma deltaIEL.
Segmental groove pancreatitis accompanied by protein plugs in Santorinis duct.
Shudo R. Obara T. Tanno S. Fujii T. Nishino N. Sagawa M. Ura H. Kohgo Y.
Third Department of Internal Medicine, Asahikawa Medical College, Hokkaido, Japan.
"Groove pancreatitis", a form of segmental pancreatitis affecting the head of the pancreas, is localized within the "groove" between pancreas head, duodenum, and common bile duct. Differentiation between groove pancreatitis and pancreatic head carcinoma is often difficult. We report a case of groove pancreatitis in which a hypoechoic mass between the duodenal wall and pancreas was clearly imaged, and narrowing of the second portion of the duodenum and bile duct stenosis were also found. The diagnosis was confirmed by surgery (pylorus-preserving pancreato duodenectomy). The patient was relieved from abdominal pain post operation. Up to the present, the patient has been good condition. We review the clinicopathologic and radiologic features of groove pancreatitis in the Japanese literature and discuss the possible role of Santorini's duct in its pathogenesis. We consider that impacted protein plugs in Santorini's duct are a pathogenic factor in the development of groove pancreatitis. Therefore, the findings of Santorini's duct on endoscopic retrograde pancreatography are very important in the diagnosis of groove pancreatitis. Groove pancreatitis presents various clinical features, such as biliary stenosis, duodenal stenosis, and pancreatic mass, and often masquerades as pancreatic head carcinoma. This condition should be kept in mind in the differential diagnosis of pancreatic head carcinoma.
Hepatic fibrosis as wound repair: a progress report.
Department of Medicine and Liver Core Center, University of California, San Francisco 94143, USA.
The injury response of the liver fits within the general paradigm of wound repair. The overall repair response requires close coordination of several cell types and synthetic processes and is orchestrated by an interacting group of cytokines, extracellular matrix (ECM) proteins, and products of metabolism such as oxygen radicals. Many cytokines act over short distances, engaging specific receptors on their parent cell (autocrine) or on immediately adjacent cells (paracrine). The most prominent of these is transforming growth factor-beta (TGFbeta). The ECM also mediates cellular crosstalk and does so in two ways. Firstly, as a binder of cytokines, it is capable of concentrating, presenting, or sequestering these factors at specific locations. Secondly, like cytokines, individual ECM proteins interact with cells via specific receptors, many of which belong to the integrin family. Engagement of a receptor leads to its activation, followed by intracellular signaling events and modification of cell behavior. Recent work has identified a specific integrin on stellate cells (alpha1beta1) as critical to the contractility of these cells. Finally, contrary to the view once held of ECM as relatively inert "ground substance", this extracellular complex is highly dynamic, its cytokine- and cell-binding activities being subject to rapid change. Therefore, matrix proteinases also are important, both during the initiation of fibrosis in association with stellate cell activation, and during the resolution of the injury. As current research reveals the key elements of this regulatory network, new therapeutic modalities are emerging. The goal of therapy is to modify the extent of the repair response without deleting it. Strategies directed at several levels of regulation are under consideration, including agents that block cytokine effects (e.g., TGFbeta receptor antagonists) and direct inhibitors of stellate cell activation or contraction.