[Combined treatment with dacarbazine, nimustine, cisplatin, and tamoxifen plus interferon-beta in a patient with advanced anorectal malignant melanoma].

A 73-year-old man, who was diagnosed as having advanced anorectal malignant melanoma (Stage IV), was treated with combination chemotherapy using dacarbazine, nimustine, cisplatin, and tamoxifen plus interferon-beta. After the first course of chemotherapy, rectal tumor was decreased in size with less anal pain and liver tumor was disappeared. Twenty-four months after the first treatment, the patient is survived. DAC-Tam IFN-beta therapy may improve the management of patients who have advanced MM of the anorectum.

[Episcleritis and erythema nodosum in a patient with ulcerative colitis].

A 62-year-old Japanese woman with ulcerative colitis (UC) had episcleritis and erythema nodosum. Oral administration of corticosteroid with granulocytapheresis improved all these diseases. Extraintestinal manifestations such as ocular and skin complications are infrequent, especially in Japan, in patients with UC. Although concurrent onset of episcleritis and erythema nodosum associated with UC is also extremely rare, clinical course in this case suggests a possible association among ulcerative colitis, episcleritis and erythema nodosum.

Preferential increase of extracellular matrix expression relative to transforming growth factor beta1 in the pancreas during the early stage of acute hemorrhagic pancreatitis in rats.

OBJECTIVES: To elucidate the role of transforming growth factor (TGF) beta1 and extracellular matrix (ECM) after acute necrotizing pancreatitis, we studied the regulation of TGF-beta1 and ECM after induction of pancreatitis. METHODS: We examined the serial changes of levels of plasma TGF-beta1 by enzyme-linked immunoassay and expression of TGF-beta1 and ECM by Northern and Western blot analyses, respectively, in the pancreas after induction of sodium taurocholate-induced acute pancreatitis. RESULTS: Plasma total (active and inactive) TGF-beta1 levels at 3 hours after induction of pancreatitis were significantly increased compared with baseline values. The levels of TGF-beta1 messenger RNA (mRNA) were unaltered by day 2. Levels of fibronectin mRNA at 3 hours after induction of pancreatitis were already higher than the baseline values. Latency-associated peptide-TGF-beta1 showed a peak on day 7. Thus, the expression of ECM mRNA increased earlier than that of TGF-beta1 mRNA. CONCLUSIONS: These results suggest that the increase in plasma TGF-beta1 concentration probably results from the elevated secretion of TGF-beta1 from several cells and/or the redistribution of TGF-beta1 protein and that the increase in expression of ECM probably is associated with the activation of TGF-beta1. It is conceivable that both increased plasma concentration and focal activation of TGF-beta1 play an important role in ECM production during the early stage of acute pancreatitis.

[Congenital absence of the portal vein in an adult woman with liver tumor].

A 30-years-old Japanese woman with a liver tumor was found to have congenital absence of the portal vein (CAPV). Both three-dimensional CT and angiography revealed that the superior mesenteric vein and splenic vein flowed into inferior vena cava and there was us portal vein, CAPV is an extremely rare congenital anomaly and liver tumor. Most cases on diagnosed in childhood, although this case was found in on adult. We reviewed the literature on reported CAPV cases.

Externally applied pressure activates pancreatic stellate cells through the generation of intracellular reactive oxygen species.

Local tissue pressure is higher in chronic pancreatitis than in the normal pancreas. We reported recently that pressure application induces synthesis of extracellular matrix (ECM) and cytokines in pancreatic stellate cells (PSCs) and that epigallocatechin gallate (EGCG), a potent antioxidant, inhibits the transformation of PSCs from quiescent to activated phenotype and ethanol-induced synthesis of ECM and cytokines in PSCs. These results suggest that oxidative stress and reactive oxygen species (ROS) are important in PSC activation. The aim of this study was to clarify the effects of ROS on activation and functions of pressure-stimulated PSCs. We used freshly isolated rat PSCs and culture-activated PSCs. Pressure was applied on rat cultured PSCs by adding compressed helium gas into a pressure-loading apparatus. PSCs were cultured with or without antioxidants (EGCG and N-acetyl cysteine) under normal or elevated pressure. Externally applied high pressure (80 mmHg) resulted in a gradual decrease of superoxide dismutase activity in PSCs and increased intracellular ROS generation as early as 30 s, reaching a peak level at 1 h. Antioxidants significantly inhibited ROS generation. Pressure increased the expression levels of alpha-smooth muscle actin, alpha(1)(I)-procollagen, and TGF-beta1 in PSCs. EGCG suppressed these alterations, abolished pressure-induced phosphorylation of p38 MAPK, and suppressed pressure-induced PSC transformation to activated phenotype. Our results indicated that ROS is a key player in pressure-induced PSC activation and ECM synthesis. Antioxidants could be potentially effective against the development of pancreatic fibrosis in patients with chronic pancreatitis.

Activations of coagulation and fibrinolysis secondary to bowel inflammation in patients with ulcerative colitis.

BACKGROUND: Recent investigations suggest that activation of coagulation and fibrinolysis occurs in patients with ulcerative colitis (UC). However, the role of the hypercoagulable state in UC has not been determined. On the other hand, there are no reports dealing with coagulation in ischemic colitis (IC), in which acute bowel inflammation and reversible vascular occlusion affect the colon. Thus, our aim was to evaluate the hyper states of coagulation and fibrinolysis in UC by comparing activations of coagulation and fibrinolysis in patients with active UC and in those with IC. METHODS: Twenty-four patients with active UC and 12 patients with IC were studied, with 18 patients with inactive UC serving as controls. We investigated the activation of the coagulation system, including platelet counts, activated partial thromboplastin time (APTT), thrombin time (TT), prothrombin time (PT), serum concentrations of von Willebrand factor (vWF), activated factors XII, XI, X, IX, VIII, VII, V, II, fibrinogen, prothrombin fragments 1+2 (F1+2), thrombin-antithrombin complexes (TAT), protein S, protein C, plasminogen, alpha-2 plasminogen inhibitor (alpha-2PI) and D-dimer (D-D). RESULTS: Median serum vWF concentrations, F1+2, TAT, fibrinogen, activated factor XI, IX, VIII and V were significantly elevated in patients with active UC and IC compared to those in patients with inactive UC. There was no significant difference between active UC and IC patients in the mean values of any of the factors that were measured. CONCLUSION: The results of the present study indicate that the coagulation-fibrinolysis system is activated in patients with active bowel inflammation such as active UC and IC, and that the hyper states of coagulation and fibrinolysis in patients with active UC are secondary to bowel inflammation.

[Influence of job-related factors on the clinical course of chronic hepatitis].

Although many workers suffer from chronic hepatitis, the influence of labor on its clinical course is not clear. We prospectively followed 89 workers with chronic hepatitis for 3 years, and examined the relationship between job-related factors, such as job class, job type, working hours and work effort, and the liver function test. There were no job-related factors that had any influence on the activity of hepatitis. Moreover, no significant relationship was found between job-related factors, including tiredness, and the acute exacerbation of hepatitis. No significant changes of aminotransferase levels and of platelet counts divided by each job-related factor were found during the observation period, but the platelet counts decreased in workers with acute exacerbation, but without clinical significance. These results suggest that job-related factors have little influence on the clinical course of chronic hepatitis during a relatively short observation period.

Nonalcoholic fatty liver disease is a risk factor for type 2 diabetes in middle-aged Japanese men.

OBJECTIVE: To determine the association between nonalcoholic fatty liver disease and the risk for development of diabetes. RESEARCH DESIGN AND METHODS: We conducted an observational cohort study in male workers > or = 40 years old in a Japanese company from 1997 to 2005. We excluded workers with alcohol intake > or = 20 g/day and those with impaired glucose tolerance by a 75-g oral glucose tolerance test. The remaining 3,189 workers were classified into fatty liver (FL) and non-FL group based on the findings of abdominal ultrasonography. Both groups were followed for the development of diabetes. Hazard ratio (HR) was determined in Cox proportional hazard analysis. A nested case-control study was conducted to determine the odds ratio (OR). RESULTS: The average age of participants was 48.0 years at the entry, and the average follow-up period was 4.0 years. The incidence of diabetes in the FL group was 2,073 per 100,000 person-years (65 cases), whereas 452 per 100,000 person-years (44 cases) in the non-FL group. The age- and BMI-adjusted HR of diabetes associated with FL was 5.5 (95% CI 3.6-8.5, P < 0.001). In the nested case-control analysis, the OR adjusted for age and BMI was 4.6 (3.0-6.9, P < 0.001). CONCLUSIONS: Nonalcoholic fatty liver disease significantly increases the risk of diabetes in middle-aged Japanese men.

High glucose activates rat pancreatic stellate cells through protein kinase C and p38 mitogen-activated protein kinase pathway.

OBJECTIVE: Hyperglycemia is implicated in fibrosis in many organs. Exocrine and endocrine pancreas are closely linked both anatomically and physiologically, and pathological conditions in the exocrine gland can cause impairment of endocrine function and vice versa. Chronic pancreatitis causes pancreatic fibrosis and sometimes results in diabetes mellitus. Pancreatic stellate cells (PSCs) play a pivotal role in pancreatic fibrogenesis. However, the effects of high glucose concentrations on PSC activation have not been fully elucidated. METHODS: Cultured PSCs were incubated in the presence of various concentrations of glucose. Pancreatic stellate cell proliferation, alpha-smooth muscle actin (alpha-SMA) expression, and collagen production were determined by colorimetric conversion assay, Western blot analysis, and Sirius red dye binding assay, respectively. RESULTS: High glucose concentrations significantly increased PSC proliferation, alpha-SMA expression, and collagen type I production in PSCs. High glucose concentrations activated protein kinase C (PKC) in PSCs, and PKC inhibitor GF109203X inhibited glucose-stimulated PSC proliferation, alpha-SMA expression, and collagen secretion. High glucose also activated p38 mitogen-activated protein kinase (MAPK) in PSCs, and p38 MAPK inhibitor SB203580 inhibited glucose-stimulated collagen secretion. CONCLUSIONS: Our results indicate that high glucose concentrations stimulate PSC activation via PKC-p38 MAP kinase pathway and suggest that high glucose may aggravate pancreatic fibrosis.

4. Chronic pancreatitis and pancreatic cancer, lifestyle-related diseases.

In Japan, the number of patients with both chronic pancreatitis (CP) and pancreatic cancer (PC) is increasing. A nationwide survey on CP revealed that the total number of patients treated for CP in Japan in 2002 was estimated as 45,200 (95% confidence interval, 35,600-54,700), and 20,137 patients died of PC in 2002. Alcoholic pancreatitis was the most common type of pancreatitis (67.5 %). Cigarette smoking was an independent and significant risk factor for CP. The risks of pancreatic and nonpancreatic cancers increased in the course of CP. While alcohol consumption may increase the risk of PC via CP, smoking was important as a risk factor for both CP and PC. The increasing incidence of PC was closely related to the increasing intake of animal fat. Lifestyle in patients with CP appeared to be the same as that in patients with PC. Environmental factors such as lifestyle in combination with genetic factors may increase the risk for both CP and PC. Therefore, changing and improving lifestyle habits such as drinking, smoking and nutrition may reduce the risks for both CP and PC.

Leucine activates pancreatic translational machinery in rats and mice through mTOR independently of CCK and insulin.

Feeding stimulates pancreatic digestive enzyme synthesis at the translational level, and this is thought to be mediated by hormones and neurotransmitters. However, BCAAs, particularly leucine, stimulate protein synthesis in several tissues. We investigated whether BCAA stimulated the translational machinery in murine pancreas and whether their effects were independent of hormones. Rats and mice were administered (i.g. gavage) individual BCAA at 1.35 mg/g (body weight) and rat isolated pancreatic acini were incubated with BCAA under different conditions. Activation of translation initiation factors and total protein synthesis were analyzed. BCAA gavage stimulated the phosphorylation of the initiation factor 4E (eIF4E) binding protein 1 (4E-BP1) and the ribosomal protein S6 kinase (S6K), with leucine being the most effective. Leucine also increased the association of the initiation factors eIF4E and eIF4G, but did not affect the activity of the guanine nucleotide exchange factor eIF2B, nor total protein synthesis. BCAA acted independently of insulin signaling on isolated pancreatic acini from diabetic rats. The ability of leucine to promote phosphorylation of 4E-BP1 and S6K as well as enhance the assembly of the eIF4F complex was unimpaired in CCK-deficient mice. Finally, rapamycin (0.75 mg/kg) administered to rats 2 h before leucine gavage inhibited the phosphorylation of S6 and 4E-BP1 induced by leucine. We conclude that leucine may participate, as a signal as well as a substrate, in activating the translational machinery in pancreatic acinar cells independently of hormonal effects and that this action is through the mTOR pathway.

Comparison of glucagon and scopolamine butylbromide as premedication for colonoscopy in unsedated patients.

PURPOSE: Premedication with glucagon or hyoscyamine is reported to be effective in reducing colonic spasm. However, these drugs can be associated with unfavorable events. This prospective study was designed to compare the effects of premedication with glucagon with those of scopolamine butylbromide on cardiopulmonary parameters, intubation time, and patient discomfort in unsedated patients undergoing diagnostic colonoscopy. METHODS: One hundred consecutive adult patients (65 males) undergoing colonoscopy without sedation were randomized to receive 1 mg of glucagon (n = 50) or 20 mg of scopolamine butylbromide (n = 50), intramuscularly. Physiologic changes, including systolic blood pressure, heart rate, and oxygen saturation, were monitored before colonoscope insertion and at three-minute intervals during colonoscopy. The percentages of completed procedure and time to cecal intubation were recorded. Patients were asked to rate pain by using a five-point pain score (0 = no pain; 4 = severe pain). RESULTS: The percentages of completed procedure (96 vs. 98 percent), time to cecal intubation (16.3 vs. 14.5 minutes), and pain score (1.7 vs. 1.5) did not differ significantly between two groups. An increase in heart rate of more than ten beats per minute from baseline during colonoscopy occurred significantly more often in scopolamine group (44 percent of 50 patients) than in the glucagon group (12 percent of 50 patients; P = 0.0004). There were no significant differences between the two study groups with regard to changes in systolic blood pressure and decrease in oxygen saturation during colonoscopy. CONCLUSIONS: Premedication with 1 mg of glucagon facilitates favorable examination with respect to physiologic changes compared with 20 mg of scopolamine. These features favor glucagon as the preferred premedication for patients undergoing colonoscopy.

Calcineurin-dependent and calcineurin-independent signal transduction pathways activated as part of pancreatic growth.

OBJECTIVE: We have recently reported that pancreatic growth driven by cholecystokinin released endogenously by feeding the synthetic trypsin inhibitor camostat requires the Ca-activated phosphatase calcineurin. In the present study, we evaluated a number of signal transduction pathways for their activation as part of the growth response and whether their activation was dependent on calcineurin. METHODS: Male ICR mice were fed with either chow or chow plus 1 mg/g of camostat. FK506 was administered at 3 mg/kg. After various times from 12 hours to 10 days, pancreatic samples were prepared and assayed for activity of various signal transduction pathway components. RESULTS: Camostat feeding increased the activation of extracellular signal-regulated kinases, c-Jun NH2-terminal kinases, and phosphorylation of the translation factor eukaryotic initiation factor 4E and activated the mammalian target of rapamycin pathway that leads to phosphorylation of the ribosomal protein S6 and of the eukaryotic initiation factor 4E binding protein but with different time courses. Treatment of mice with the calcineurin inhibitor FK506 totally blocked c-Jun NH2-terminal kinase activation, partially blocked the mammalian target of rapamycin pathway, and had no effect on extracellular signal-regulated kinase activation or the phosphorylation of eukaryotic initiation factor 4E. CONCLUSIONS: The pancreatic growth response is accompanied by activation of a number of signaling pathways regulating transcription and translation, some of which are dependent on and some independent of calcineurin.

Persistent destruction of the basement membrane of the pancreatic duct contributes to progressive acinar atrophy in rats with experimentally induced pancreatitis.

BACKGROUND AND AIMS: The imbalance between synthesis and degradation of extracellular matrix (ECM) proteins is a characteristic feature in chronic pancreatitis. We evaluated the relationship between type IV collagen structure in the basement membrane (BM) and the development of acinar atrophy or the regeneration from acinar injury. METHODS: Three different models of pancreatitis were induced in rats by repetitive intraperitoneal injections of 500 mg/100 g body weight of arginine (Arg) or 20 microg/kg body weight of caerulein (Cn) or a single retrograde intraductal infusion of 40 microL/100 g body weight of 3% sodium taurocholate (NaTc). We examined the changes in type IV collagen structure by immunostaining, and the serial changes in the gelatinolytic activity of pro- and active matrix metalloproteinase-2 by zymography in these models of pancreatitis. RESULTS: The pancreas appeared to be histologically normal on day 35 after the first intraperitoneal Cn injection and on day 42 after intraductal infusion of NaTc, whereas 85% to 90% of acinar tissue was replaced by fatty tissue and dilated pancreatic ducts on day 54 after the first intraperitoneal Arg injection. Immunoreactivity for type IV collagen appeared as a discontinuous line along the BM of ducts, vessels, tubular complexes, and acinar cells on day 40 in Arg-induced pancreatitis, whereas it was detected as a continuous line along the BM on day 35 in Cn-induced pancreatitis and on day 42 in NaTc-induced pancreatitits. Gelatinolytic activity of active MMP-2 increased significantly from day 13 to day 40 after the first intraperitoneal Arg injection, whereas it decreased to the baseline level on day 35 after the first intraperitoneal Cn injection and on day 42 after intraductal infusion of NaTc. CONCLUSIONS: Our findings indicate that a long-term increase in gelatinolytic activity of active MMP-2 in Arg-induced pancreatitis causes continuous disorganization of type IV collagen in the BM and progressive acinar atrophy, whereas a transient increase in gelatinolytic activity of active MMP-2 is involved in the regeneration of type IV collagen structure in the BM and recovery from acinar injury.

Autoimmune pancreatitis with IgG4-positive plasma cell infiltration in salivary glands and biliary tract.

A 62-year-old male was referred to our hospital because of liver dysfunction, diffuse pancreatic swelling, and trachelophyma. At admission, the patient was free of pain. Physical examination showed enlarged and palpable bilateral submandibular masses, but no palpable mass or organomegaly in the abdomen. Laboratory findings were as follows: total protein 90 g/L with gamma-globulin of 37.3% (33 g/L), total bilirubin 4 mg/L, aspartate aminotransferase 39 IU/L, alanine aminotransferase 67 IU/L, gamma-glutamyl transpeptidase 1 647 IU/L, and amylase 135 IU/L. Autoantibodies were negative, and tumor markers were within the normal range. Serum IgG4 level was markedly elevated (18 900 mg/L). Computed tomography (CT) showed diffuse swelling of the pancreas and dilatation of both common and intra-hepatic bile ducts. Endoscopic retrograde pancreatography (ERP) revealed diffuse irregular and narrow main pancreatic duct and stenosis of the lower common bile duct. Biopsy specimens from the pancreas, salivary gland and liver showed marked periductal IgG4-positive plasma cell infiltration with fibrosis. We considered this patient to be autoimmune pancreatitis (AIP) with fibrosclerosis of the salivary gland and biliary tract, prescribed prednisolone at an initial dose of 40 mg/d. Three months later, the laboratory data improved almost to normal. Abdominal CT reflected prominent improvement in the pancreatic lesion. Swelling of the salivary gland also improved. At present, the patient is on 10 mg/d of prednisolone without recurrence of the pancreatitis. We present here a case of AIP with fibrosclerosis of salivary gland and biliary tract.

Inhibition of transforming growth factor beta decreases pancreatic fibrosis and protects the pancreas against chronic injury in mice.

Transforming growth factor-beta (TGF-beta) is an important cytokine in the fibrogenesis in many organs, including the pancreas. Using an adenoviral vector expressing the entire extracellular domain of type II human TGF-beta receptor (AdTbeta-ExR), we investigated whether inhibition of TGF-beta action is effective against persistent pancreatic fibrosis, and whether it exerts a beneficial effect on the pancreas in the process of chronic injury. To induce chronic pancreatic injury and pancreatic fibrosis, mice were subjected to three episodes of acute pancreatitis induced by six intraperitoneal injections of 50 microg/kg body weight cerulein at hourly intervals, per week for 3 consecutive weeks. Mice were infected once with AdTbeta-ExR, or with a control adenoviral vector expressing bacterial beta-galactosidase (AdLacZ). Pancreatic fibrosis was evaluated by histology and hydroxyproline content. Activation of pancreatic stellate cells (PSCs) was assessed by immunostaining for alpha-smooth muscle actin. Apoptosis and proliferation of acinar cells were assessed by immunostaining of ssDNA and Ki-67, respectively. Three-week cerulein injection induced pancreatic fibrosis and pancreatic atrophy with proliferation of activated PSCs. In AdTbeta-ExR-injected mice, but not AdLacZ-injected mice, pancreatic fibrosis was significantly attenuated. This finding was accompanied by a reduction of activated PSCs. AdTbeta-ExR, but not AdLacZ, significantly increased pancreas weight after chronic pancreatic injury. AdTbeta-ExR did not change the proportion of proliferating acinar cells, whereas it reduced the number of apoptotic acinar cells. Our results demonstrate that inhibition of TGF-beta action not only decreases pancreatic fibrosis but also protects the pancreas against chronic injury by preventing acinar cell apoptosis.