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We herein report the case of a 68-year-old man receiving hemodialysis who developed severe hypoglycemia. He became unconscious and exhibited a blood glucose level below 10 mg/dL. We ruled out the possibility of other causes; however, severe hypoglycemia was observed even after starting glucose injections. The patient developed pneumonia and finally died. Although we conducted an autopsy, there were no specific findings explaining the severe hypoglycemia. We believe that carnitine deficiency was possibly involved in the severe hypoglycemia observed in this case. Physicians should be aware of the possibility of carnitine deficiency and/or severe hypoglycemia, especially in hemodialysis patients with malnutrition.

The relationship between pancreatic fibrosis and apoptosis of pancreatic acinar cells has not been fully elucidated. We reported that taurine had an anti-fibrotic effect in a dibutyltin dichloride (DBTC)-chronic pancreatitis model. However, the effect of taurine on apoptosis of pancreatic acinar cells is still unclear. Therefore, we examined apoptosis in DBTC-chronic pancreatitis and in the AR42J pancreatic acinar cell line with/without taurine. Pancreatic fibrosis was induced by a single administration of DBTC. Rats were fed a taurine-containing diet or a normal diet and were sacrificed at day 5. The AR42J pancreatic acinar cell line was incubated with/without DBTC with taurine chloramines. Apoptosis was determined by using terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) assay. The expression of Bad and Bcl-2 proteins in the AR42J cells lysates was detected by Western blot analysis. The apoptotic index of pancreatic acinar cells in DBTC-administered rats was significantly increased. Taurine treatment inhibited pancreatic fibrosis and apoptosis of acinar cells induced by DBTC. The number of TUNEL-positive cells in the AR42J pancreatic acinar cell lines was significantly increased by the addition of DBTC. Incubation with taurine chloramines ameliorated these changes. In conclusion, taurine inhibits apoptosis of pancreatic acinar cells and pancreatitis in experimental chronic pancreatitis.

Plain abdominal radiography is a very basic examination and plays an important role in primary care. The objectives of this study were to clarify colon distributions on plain abdominal radiographs. Forty-three healthy volunteers underwent gastric fluoroscopy, and 2 hours later, plain abdominal radiography in the supine position. A region of interest (ROI) was defined uniformly on each X-ray image to divide the image into 600 zones. The area corresponding to the large bowel within the ROI was divided into 4 segments (ascending colon, transverse colon, descending colon, and sigmoid colon + rectum). The percentage of barium in each segment relative to the total volume of barium used was calculated to evaluate the percent ROI occupancy. The large bowel covered 76.7% of the entire ROI, with the percent duplication being 55%. The duplicated area corresponded to the transverse colon region. When the method proposed by Arhan et al. was used, the percentage of the colon actually present in each segment relative to that determined theoretically was 99.6% for the right colon segment, 92.2for the left colon segment, and 92.2% for the sigmoid/rectal segment. However, in cases in which the transverse colon descended partially from the fifth lumbar vertebra, the percentage occupied by the sigmoid colon + rectum decreased to 57.2%. We applied a new large bowel segmentation method especially for patients with ptosis, by devising a line joining the lateral side of the right lesser pelvis and the lower ends of both sacroiliac joints.

A 27-year-old woman visited our hospital because of high fever. She had been diagnosed as 22q11.2 deletion syndrome (22q11.2DS) due to her cardiac history (tetralogy of Fallot), thymic hypoplasia and 22q11.2 deletion. She had a normal CD4/CD8 ratio, a slightly decreased lymphocyte count and normal serum immunoglobulin levels. Blood cultures were positive for Staphylococcus lugdunensis (S. lugdunensis). Infection route of S. lugdunensis in this case was unclear. The patient was successfully treated with several intravenous antibiotics. Infection should be considered when managing patients with 22q.11.2DS. regardless of whether their immune system is impaired.

A 53-year-old man visited our hospital complaining of high fever. Chest computed tomography showed left pleural effusion and mediastinitis. He developed painful red subcutaneous nodules in his bilateral lower extremities. Thoracoscopy-assisted exploratory excision showed visceral pleura thickening; panniculitis in the periaortic area was histologically proven. The patient was treated with corticosteroid therapy which immediately reduced the fever. Subsequent imaging examinations after corticosteroid therapy showed improvement of mediastinitis and pleural effusion. This case reminds us that Weber-Christian disease (WCD) should be included in the differential diagnosis of mediastinitis although WCD is rarely associated with thoracic involvement.

Heparanase is an endo-beta-glucuronidase that specifically cleaves heparan sulfate (HS) chains. Heparanase is involved in the process of metastasis and angiogenesis through the degradation of HS chains of the extracellular matrix and cell surface. Recently, we demonstrated that heparanase was localized in the cell nucleus of normal esophageal epithelium and esophageal cancer, and that its expression was correlated with cell differentiation. However, the nuclear function of heparanase remains unknown. To elucidate the role of heparanase in esophageal epithelial differentiation, primary human esophageal cells were grown in monolayer as well as organotypic cultures, and cell differentiation was induced. Expression of heparanase, HS, involucrin, and p27 was determined by immunostaining and Western blotting. SF4, a novel pharmacological inhibitor, was used to specifically inhibit heparanase activity. Upon esophageal cell differentiation, heparanase was translocated from the cytoplasm to the nucleus. Such translocation of heparanase appeared to be associated with the degradation of HS chains in the nucleus and changes in the expression of keratinocyte differentiation markers such as p27 and involucrin, whose induction was inhibited by SF4. Furthermore, these in vitro observations agreed with the expression pattern of heparanase, HS, involucrin, cytokeratin 13, and p27 in normal esophageal epithelium. Nuclear translocation of heparanase and its catalytic cleavage of HS may play a critical role in the differentiation of esophageal epithelial cells. Our study provides a novel insight into the role of heparanase in an essential differentiation process.

Sialadenoma papilliferum of the esophagus is an extremely rare benign tumor that derives from the submucosal gland duct of the minor salivary gland. A 45-year-old man underwent upper gastrointestinal series. A 13 mm diameter esophageal polyp was suspected in the mid esophagus. Endoscopy examination revealed a pedunculated polyp arising from the posterior wall of the esophagus. The head of the polyp was covered with exudate and was slightly nodular but the pedicle had normal mucosa. We performed endoscopic mucosal resection (EMR) and the histological examination of the polyp showed that it was compatible with sialadenoma papilliferum of the esophagus.

Background: Disorders of the motor function of the upper gastrointestinal tract have been implicated in the pathogenesis of non-ulcer dyspepsia. Approximately 50% of patients with abdominal symptoms (without ulcer) have normal gastric emptying. Apart from gastric emptying, other mechanisms are very important in the etiology of non-ulcer dyspepsia. Methods: Gastric emptying and gallbladder motility were simultaneously investigated in 16 patients with non-ulcer dyspepsia and in 15 healthy controls. Fasting blood samples were taken, and pepsinogen levels were assayed. Results: Gastric emptying time, fasting antral diameter, and post-prandial antral diameter were not significantly different between the patients with non-ulcer dyspepsia and the controls. Fasting gallbladder volume, the time required to reach minimal gallbladder residual volume, minimal gallbladder residual volume, and the serum levels of pepsinogen were not significantly different. Simple linear regression was used to summarize the relationship between gastric emptying time and time required to reach minimal gallbladder residual volume. In the controls, the gastric emptying time and time required to reach minimal gallbladder residual volume were linearly related. However, in the patients with non-ulcer dyspepsia, they were not related. Conclusions: These observations suggest that disturbance of coordination between gastric emptying and gallbladder emptying is a cause of the symptoms of non-ulcer dyspepsia.

The prevalence of hepatitis C virus (HCV) genotypes in Myanmar in comparison with the rest of Southeast Asia is not well known. Serum samples were obtained from 201 HCV antibody-positive volunteer blood donors in and around the Myanmar city of Yangon. Of these, the antibody titers of 101 samples were checked by serial dilution using HCV antibody PA test II and Terasaki microplate as a low-cost method. To compare antibody titers by this method and RNA identification, we also checked HCV-RNA using the Amplicor 2.0 test. Most high-titer groups were positive for HCV-RNA. Of the 201 samples, 110 were successfully polymerase chain reaction (PCR) amplified. Among them, 35 (31.8%) were of genotype 1, 52 (47.3%) were of genotype 3, and 23 (20.9%) were of type 6 variants, and phylogenetic analysis of these type 6 variants revealed that 3 new type 6 subgroups exist in Myanmar. We named the subgroups M6-1, M6-2, and M6-3. M6-1 and M6-2 were relatively close to types 8 and 9, respectively. M6-3, though only found in one sample, was a brand-new subgroup. These subtypes were not seen in Vietnam, where type 6 group variants are widely spread. These findings may be useful for analyzing how and when these subgroups were formed.

INTRODUCTION Matrix metalloproteinase-2 (MMP-2) has an activity to degrade type IV collagen and is associated with invasion angiogenesis of malignant tumor. AIM A diagnostic value of MMP-2 in pancreatic juice was studied in the diagnosis of pancreatic cancer. METHODOLOGY Using gelatin zymography, active MMP-2 and proMMP-2 were determined in pancreatic juice obtained endoscopically from 12 patients with pancreatic cancer, 11 with chronic pancreatitis, and 7 control subjects. RESULTS ProMMP-2 was detected in 12 of 12 patients (100%) with pancreatic cancer, 6 of 11 (54.5%) with chronic pancreatitis, and 3 of 7 (42.9%) controls. Active MMP-2 was detected in 11 patients (91.6%) with pancreatic cancer, 2 (18.2%) with chronic pancreatitis, and none of the control subjects. An activation ratio of MMP-2 (active MMP-2/total MMP-2) in pancreatic juice is significantly higher in pancreatic cancer (23.4 +/- 4.4%, mean +/- SE) than in chronic pancreatitis (2.1 +/- 1.7%) and controls (0%) (p < 0.01). Active MMP-2 was also detected in pancreatic juice from three cases of small pancreatic cancer (tumor

A combination of diet therapy, nutritional support with medium-chain triglycerides (MCT), and well-planned preterm Cesarean delivery on demand is an effective measure to prevent gestational hyperlipidemic pancreatitis and leads to successful childbirth. Prevention and therapy of gestational hyperlipidemic pancreatitis are important, although difficult, because the condition carries a high maternal and fetal morbidity and mortality. We describe a 32-yr-old female with lipoprotein lipase-deficient familial hypertriglyceridemia who had recurrent episodes of acute pancreatitis. The third episode occurred with worsened hyperlipidemia 7 yr earlier at 32 wk of her first pregnancy and resulted in fetal death. The fourth and fifth episodes were also accompanied by marked hyperlipidemia probably caused by drug discontinuance and dietary noncompliance. She became pregnant. Serum triglyceride levels were controlled below 2000 mg/dL by strict monitoring with low-fat, low-calorie diet and MCT nutritional support. A premature but healthy infant was born by Cesarean delivery at 36 wk of gestation when the mother presented with mild abdominal pain and was found to have uterine contractions. The ensuing clinical course has been uneventful.

Prolyl hydroxylase is a key enzyme in collagen synthesis, and tissue inhibitor of metalloproteinase (TIMP) is known to suppress collagenolytic enzymes. To see whether the levels of these two enzymes in serum and human pure pancreatic juice (PPJ) are good indicators of pancreatic fibrosis in chronic pancreatitis (CP), we examined 15 controls, 14 alcoholics without evident pancreatic diseases (7 current drinkers and 7 former drinkers), and 19 patients with CP. Levels of the two enzymes were determined by a sandwich enzyme immunoassay method. TIMP-1 levels in PPJ were significantly higher in patients with CP than in controls and alcoholics, with overlap in only a few exceptional patients. A significant inverse correlation between TIMP-1 and bicarbonate output in PPJ was observed. Prolyl hydroxylase levels in PPJ, in contrast, were significantly higher in current drinkers than in patients with CP, controls, and former drinkers, with overlap in only a few exceptional patients with relapsing CP. Identical results were obtained even when the enzyme levels were expressed as nanograms per milligram of protein. Serum levels of prolyl hydroxylase and TIMP-1 showed no significant differences among controls, current alcoholics, former alcoholics, and patients with CP. These results indicate that the raised level of TIMP-1 in PPJ, unlike that of prolyl hydroxylase, is a good indicator of pancreatic fibrosis in CP.

Summary This article reviews the evolution of functional testing of the pancreas in Japan for the diagnosis and treatment of chronic pancreatitis (CP), contrasting the pre- with the post-secretin test (S test) era. In the pre-S test era, the diagnosis was based on symptoms, clinical findings, fasting serum diastase levels, and the vagostigmin- and ether-stimulation test unless morphologic evidence was available. The S test and CCK-pancreozymin (PZ) test (PS test) were introduced into Japan around 1963 and have been used as the gold standard of the exocrine pancreatic-function test. Through a series of attempts at standardization in 1971, 1985, and 1987, the method was standardized to collect duodenal juice for 60 min through a double- or triple-lumen tube after a bolus or during a continu-ous i.v. injection of secretin (100 U). The S test, however, is an invasive and cumbersome procedure. As a result, N-benzoyl-L-tyrosal-paminobenzoic acid (BT-PABA) testing and fecal chymotrypsin testing were introduced into Japan in the middle and late 1970s, respectively. Although simple and noninvasive, these two methods were found have lower sensitivity and specificity than the conventional S test. These two methods, therefore, are presently used more often for monitoring the course of disease and therapeutic effects. Additionally, the glucose tolerance test can be performed to detect endocrine pancreatic insufficiency.

We assessed the clinical usefulness of the intraductal secretin test in order to ascertain whether it can substitute for the conventional duodenal secretin test. Duodenal juice was obtained with a triple-lumen tube and pure pancreatic juice was obtained by retrograde cannulation of the main pancreatic duct using a duodenofiberscope. Pancreatic secretion was stimulated by a bolus intravenous injection of secretin (100 units). The two tests showed comparable interindividual coefficients of variation, significantly good correlations, and comparable diagnostic efficiencies. The intraductal secretin test showed no less reproducibility than that of the duodenal secretin test as reported in the literature. In the intraductal secretin test, secretory volume, peak flow rate, bicarbonate output, and lipase output yielded the best diagnostic efficiency, followed by amylase output and maximal bicarbonate concentration. In the intraductal secretin test, a 10-min collection provided as much information as a 20-min collection. We conclude, therefore, that the 10-min intraductal secretin test is as useful as the conventional duodenal secretin test in assessing exocrine pancreatic function and that the most discriminatory parameters are secretory volume, bicarbonate output, and amylase (or lipase) output.

The concept of Team-Based Learning (TBL) was developed in the late 1970s by Larry Michaelsen, who wanted students to enjoy the benefits of small group learning within large classes in the business school environment. In contrast to problem-based learning (PBL), which is student centered, TBL is typically instructor centered. Recently, TBL is being used as a teaching method in over 60 health science professional schools in the US and other countries. In the present study, the impact of adopting TBL in teaching pharmaceutical care practices to students was evaluated. Students were required to answer a set of multiple-choice questions individually in individual readiness assessment test (IRAT) before the TBL sessions to assess their level of preparation. The same set of questions was then reattempted by the group readiness assessment test (GRAT) during TBL. Comparing the scores obtained in the GRAT and IRAT before the first TBL session, the scores from the GRAT were always higher than those of the IRAT, indicating that TBL has encouraged active learning. In addition, students were surveyed about their level of satisfaction with TBL and written comments about TBL were solicited. The results of the questionnaire showed that 87.3±9.3% of the students were satisfied. Moreover, no student commented that TBL was in any way inferior to the PBL. Implementation of a TBL approach was successfully integrated into the pharmaceutical care education course. In order to further improve the usefulness of TBL in teaching pharmaceutical care, a hybrid teaching approach that also comprises PBL and a lecture-based course is desirable.

A 46-year-old Japanese man visited our hospital for chronic abdominal pain, persistent diarrhea and discharge of proglottids for 7 years. He had been living in Lao People's Democratic Republic. Ileography using meglumine/diatrizoate sodium (Gastrografin) revealed a long tapeworm. A Taenia saginata including the scolex was excreted through the intestinal tract by the administration of total 780 ml of Gastrografin. Taeniasis is an important disease in the differential diagnosis of imported diseases in Japan. Parasite infection should be suspected in patients with chronic abdominal pain or persistent diarrhea regardless of the findings for small bowel obstruction when there is a history of overseas travel.

Background: Radiofrequency ablation (RFA) is used to treat early-stage hepatocellular carcinoma (HCC), but is sometimes avoided in patients with decompensated liver cirrhosis because of the possible side effect of deterioration of liver function. Aims: In this study, we report the safety and effects of RFA for treating HCC patients with Child-Pugh B/C liver cirrhosis. Methods: Sixty-six consecutive HCC patients with Child-Pugh B/C cirrhosis, who were treated by RFA, were enrolled in this study. We analyzed patient outcomes, the complications of RFA, and changes in liver function and tumor markers. Results: Fifty-six patients were classified as Child-Pugh class B, and 10 were classified as class C. The overall survival rates in patients with Child-Pugh B and C cirrhosis were 82 and 83% at 1 year and 47 and 31% at 3 years, respectively. Serum total bilirubin (T.Bil), albumin, prothrombin time, ascites, and encephalopathy were unchanged at 1, 3, and 6 months after RFA in patients with Child-Pugh B cirrhosis; however, serum T.Bil levels increased significantly at 6 months after RFA in 6/10 (60%) patients with Child-Pugh C cirrhosis. Hemothorax and rupture of esophageal varices were observed in 2 patients; however, there were no complications related to poor liver function. Conclusion: RFA is a useful modality for treating HCC in patients with poor liver function such as Child-Pugh B and C, but careful monitoring after RFA must be needed.

Alcoholic intake has increased in society in recent years. gamma-GTP is used as a marker of liver damage by alcohol intake, but there is no reliable marker of pancreatic fibrosis. We used animal experiments and clinical data to identify a new reliable marker of early-stage pancreatic fibrosis. Pancreatic fibrosis is induced by intra-peritoneal injection of diethyldithiocarbamate. Pancreas tissue was extracted and measured. Human pure pancreatic juice was collected by endoscopic procedures. Prolyl hydroxylase in pancreas tissue is increased in the early stage of pancreatic fibrosis. Secretion of matrix metalloproteinase from pancreatic stellate cells is increased by diethyldithiocarbamate stimulation. Pancreatic stellate cells, prolyl hydroxylase and a tissue inhibitor of metalloproteinase in human pure pancreatic juice is increased in heavy alcohol drinkers and normalized in former alcohol drinkers. Active matrix metalloproteinase 2 is detected in pure pancreatic juice of chronic pancreatitis patients. Treatment with oral camostat increases pancreatic secretory trypsin inhibitor in chronic pancreatitis patients. Experimental and clinical data indicated that matrix metalloproteinase 2 and prolyl hydroxylase are candidates as markers of early-stage pancreatic fibrosis. Clinical data showed that tissue inhibitor of metalloproteinase and pancreatic secretory trypsin inhibitor in pure pancreatic juice had potential as markers of early-stage pancreatic fibrosis.

Background and Aim: The mechanism of pancreatic fibrosis is unclear. Taurine is used in the clinical treatment of a wide variety of diseases, but its effect on improving pancreatic fibrosis is unknown. We examined whether a diet with added taurine improves pancreatic fibrosis induced by dibutyltin dichloride (DBTC) in an experimental chronic pancreatitis rat model. In addition, we examined the influence of taurine on pancreatic stellate cells. Methods: Pancreatic fibrosis was induced by DBTC. Rats were fed a taurine-containing diet or a normal diet and were killed at 4 weeks. Pancreatic stellate cells were isolated from male Wistar rats. Cultured pancreatic stellate cells were incubated with or without taurine chloramine. Type I collagen and transforming growth factor-β1 secretion was evaluated by ELISA, and matrix metalloproteinase activity was assessed by gelatin zymography. Interleukin-6, interleukin-2, and transforming growth factor-β1 levels in the supernatants of pancreatic tissue homogenates were measured. Results: Pancreatic fibrosis induced by DBTC was improved remarkably by the oral administration of the taurine-containing diet. Taurine chloramine decreased type I collagen, transforming growth factor-β1, and matrix metalloproteinases 2 of the pancreatic stellate cell culture supernatant. Increased interleukin-6 and decreased interleukin-2 were found in the supernatants of the pancreatic tissue homogenates of DBTC-induced pancreatitis rats compared with other groups. Conclusion: The oral administration of taurine improves pancreatic fibrosis. Taurine chloramine inhibits transforming growth factor-β1 produced from activated pancreatic stellate cells and improves pancreatic fibrosis.

A 62-year-old man with large cell carcinoma of the lung underwent a right upper lobectomy and four months later demonstrated a relapse in the stomach and duodenum. He received systemic chemotherapy consisting of carboplatin and gemcitabine. After the first cycle of chemotherapy, the duodenal lesion disappeared, however, the gastric lesion demonstrated no response. Considering the risk of bleeding or perforation, a partial gastroduodenal resection was therefore performed. Subsequently, he received adjuvant chemotherapy with the same regimen. He has since been doing well for 24 months after the recurrence. Although the prognosis for patients with gastrointestinal metastases from lung cancer tends to be extremely poor, treatment with chemotherapy and a metastasectomy have resulted in this patient, achieving a long survival.

We report a 74-yr-old woman who was referred to our hospital because of abdominal fullness. ERP showed a questionable irregularity of the main pancreatic duct at the body. Examination of pure pancreatic juice was positive for K-ras point mutation at codon 12 and negative for cytology. Because neither US nor CT showed apparent lesions in the pancreas, we decided to follow up the patient with serial ERP and pure pancreatic juice studies at 3-month intervals. No changes had been seen up to 18 months later, when cytology was conclusive for malignancy with an apparent stenosis of the main pancreatic duct at the body. Distal pancreatectomy with splenectomy was performed. A round mass, 12 mm in diameter, was found in the body, which proved to be an adenocarcinoma at histological examination. No extrapancreatic extension and metastases were noted. Although positive K-ras point mutation has been reported in some cases of adenoma or mucinous cell hyperplasia of the pancreas and chronic pancreatitis, our case, along with previous reports, indicated the importance of testing K-ras point mutation in pure pancreatic juices for the diagnosis of pancreatic cancer at an early stage.

Background and Aim: Free radicals are reported to be associated with fibrosis in the pancreas. It is generally accepted that pancreatic stellate cells (PSC) play an important role in pancreatic fibrosis. However, the exact role of free radicals in activation of PSC has not been fully elucidated. In the present study, using a superoxide dismutase (SOD) inhibitor, diethyldithiocarbamate (DDC) with cultured PSC, we investigated how free radicals act on the activation of PSC. Methods: PSC were isolated from male Wister rats. Cultured rat PSC were incubated with DDC for 48 h. Intracellular SOD activity and lipid peroxidation were examined in DDC-treated PSC. Activation of PSC was examined by determining the expression of α-smooth muscle actin (α-SMA) by immunocytochemistry. The number of PSC using a hemocytometer, type I collagen secretion with ELISA and matrix metalloproteinases (MMP) activities with gelatin zymography were also examined. Secretion of transforming growth factor-β1 (TGF-β1) was evaluated by ELISA. The effects of the allopurinol, a xanthine oxidase (XOD) inhibitor, on PSC were also examined. Results: DDC decreased SOD activity and increased lipid peroxidation products in PSC. DDC activated PSC, increasing the number of α-SMA positive cells, enhancing secretion of type I collagen and MMP, inhibiting PSC proliferation. Secretion of TGF-β1, which is known to activate PSC, was increased by DDC treatment. These alterations were prevented by allopurinol. Conclusion: These results suggest that free radicals generated by XOD might directly activate PSC.

An oral trypsin inhibitor, camostat (CM), has a beneficial effect on chronic pancreatitis, but its mechanism is not yet fully understood. Recently, pancreatic stellate cells (PSC) have been reported to play an essential role in pancreatic fibrosis. An experimental model of pancreatic fibrosis induced by a superoxide dismutase (SOD) inhibitor (diethyldithiocarbamate [DDC]) was developed in rats. Thus, the effect of an oral trypsin inhibitor on pancreatic fibrosis and PSC was investigated.Pancreatic fibrosis was induced in rats using DDC (DDC rats). DDC + CM rats were administered DDC, and subsequently were fed a diet containing CM. Immunohistochemistry of the pancreas was performed with monoclonal anti-alpha-smooth muscle actin (alpha-SMA) antibody and anti-desmin antibody.The DDC rats showed a significant increase in alpha-SMA-positive cells or desmin-positive cells compared with control rats. These significant increases in the fibrotic area improved after treatment with CM. The level of prolyl hydroxylase in the pancreas, which significantly increased as a result of DDC, decreased after treatment with CM.Camostat has a beneficial effect on pancreatic fibrosis induced by the administration of a SOD inhibitor, which inhibits the proliferation and activation of PSC.

Disorders of the motor function of the upper gastrointestinal tract have been implicated in the pathogenesis of non-ulcer dyspepsia. Approximately 50% of patients with abdominal symptoms (without ulcer) have normal gastric emptying. Apart from gastric emptying, other mechanisms are very important in the etiology of non-ulcer dyspepsia.Gastric emptying and gallbladder motility were simultaneously investigated in 16 patients with non-ulcer dyspepsia and in 15 healthy controls. Fasting blood samples were taken, and pepsinogen levels were assayed.Gastric emptying time, fasting antral diameter, and post-prandial antral diameter were not significantly different between the patients with non-ulcer dyspepsia and the controls. Fasting gallbladder volume, the time required to reach minimal gallbladder residual volume, minimal gallbladder residual volume, and the serum levels of pepsinogen were not significantly different. Simple linear regression was used to summarize the relationship between gastric emptying time and time required to reach minimal gallbladder residual volume. In the controls, the gastric emptying time and time required to reach minimal gallbladder residual volume were linearly related. However, in the patients with non-ulcer dyspepsia, they were not related.These observations suggest that disturbance of coordination between gastric emptying and gallbladder emptying is a cause of the symptoms of non-ulcer dyspepsia.

Acute pancreatitis has been reported in several studies to increase the catabolism and proteolysis of skeletal muscle in comparison with normal controls. Decreased levels of total plasma proteins and rapid turnover proteins and a marked decrease of the ratio of branched-chain to aromatic amino acid further characterize the hypercatabolic state. Significant decreases in plasma essential amino acids, with marked reductions of almost all amino acids in the liver and increased uptake of endogenous amino acids by the skeletal muscle mass, have been reported clinically and experimentally. Gluconeogenesis increases, and glucose clearance and oxidation diminish, leading to glucose intolerance in 40% to 90% of cases. As a consequence, insulin canbe required in as many as 81% of patients.

The epidermal growth factor receptor (EGFR) activates several signaling cascades in response to epidermal growth factor stimulation. One of these signaling events involves tyrosine phosphorylation of signal transducer and activator of transcription (STAT), whereas another involves activation of the phosphatidylinositol 3-OH kinase pathway. Two possibilities for STAT activation exist: a janus kinase (JAK)-dependent and a JAK-independent mechanism. Herein, we demonstrate that EGFR overexpression in primary esophageal keratinocytes activates STAT in a JAK-dependent fashion with the functional consequence of enhanced cell migration, which can be abolished by use of a JAK-specific inhibitor, AG-490. We determined the mechanisms underlying the signal transduction pathway responsible for increased cell migration. Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min. In addition, we found that activation of this signaling pathway results in matrix metalloproteinase-1 (MMP-1) activity. By contrast, Akt activation does not impact the EGFR-STATs-JAKs complex formation and nuclear translocation of the STATs with subsequent MMP-1 activity, although Akt activation may contribute to cell migration through an independent mechanism. Taken together, we find that the recruitment of the STAT-JAK complex by EGFR is responsible for keratinocyte migration that, in turn, might be mediated by MMP-1 activation.

In this study we evaluated the efficacy and toxicities of combination chemotherapy consisting of continuous 5-fluorouracil (5-FU) infusion and low-dose cisplatin infusion (low-dose FP therapy) in the treatment of advanced hepatocellular carcinoma (HCC).Thirty-eight patients with advanced HCC in whom local treatment was not indicated were enrolled. The low-dose FP therapy consisted of 5-FU (170 mg/m2/day on days 1 to 7/week, continuous infusion) and cisplatin (3 mg/m2/day in 100 ml normal saline, infusion more than 30 minutes, on days 1 to 5/weeks). The patients were treated for 4 consecutive weeks with a subsequent one-week rest period.Thirty-seven of the 38 patients (97%) completed this therapy. A partial response was obtained in 18 (47%), no change in 10 and progressive disease in 9. The time to progression was 211 days. The most common toxicity was nausea/vomiting (13.2%).Low-dose FP therapy has a substantial effect on low-grade toxicity in long-term treatment. Low-dose FP therapy is useful for the treatment of advanced HCC.

Epidermal growth factor receptor (EGFR) overexpression is observed in a number of malignancies, especially those of esophageal squamous cell origin. However, little is known about the biological functions of EGFR in primary esophageal squamous epithelial cells. Using newly established primary human esophageal squamous epithelial cells as a platform, we overexpressed EGFR through retroviral transduction and established novel three-dimensional organotypic cultures. Additionally, EGFR was targeted in a cell type- and tissue-specific fashion to the esophageal epithelium in transgenic mice. EGFR overexpression in primary esophageal keratinocytes resulted in the biochemical activation of Akt and STAT pathways and induced enhanced cell migration and cell aggregation. When established in organotypic culture, EGFR-overexpressing cells had evidence of epithelial cell hyperproliferation and hyperplasia. These effects were also observed in EGFR-overexpressing transgenic mice and the esophageal cell lines established thereof. In particular, EGFR-induced effects upon aggregation appear to be mediated through the relocalization of p120 from the cytoplasm to the membrane and increased interaction with E-cadherin. EGFR modulates cell migration through the up-regulation of matrix metalloproteinase 1. Taken together, the functional effects of EGFR overexpression help to explain its role in the initiating steps of esophageal squamous carcinogenesis.

beta-Catenin plays an important role in signal transduction pathways that regulate cellular differentiation and proliferation. The increased concentration of this protein in the cytoplasm favors its binding to the T-cell factor (TCF) family of DNA-binding proteins, and it subsequently translocates to the nucleus, where it induces transcription of specific genes. We explored mechanisms that lead to activation of beta-catenin/TCF-dependent transcription in esophageal squamous cell carcinoma (ESCC) independent of adenomatous polyposis coli and beta-catenin mutation. Electrophoresis mobility shift assay demonstrated that TCF4 and beta-catenin form a complex and have DNA binding activity. However, there was no constitutive activation of beta-catenin/TCF-dependent transcription. Coculture experiments demonstrated that Wnt-1, but not Wnt-5A and Wnt-7A, activated the TCF reporter gene. Additionally, when cultured with Wnt-1-conditioned media, ESCC cell lines showed an accumulation of beta-catenin in the cytoplasm. Although both Wnt and epidermal growth factor inactivate glycogen synthase kinase 3beta, activation of epidermal growth factor receptor did not stabilize beta-catenin. A comparison of extracellular stimuli suggests that specific Wnt family members stabilize beta-catenin with resulting activation of TCF-dependent transcription in ESCC.

A 78-year-old woman visited our hospital complaining of high fever. Since the fever did not improve with antibiotics and nonsteroidal anti-inflammatory drugs, she was admitted to the hospital. On admission a test for C reactive protein demonstrated 17.0 mg/dL. She did not have tenderness or swelling in temporal arteries. She showed laterality in radial pulse and her left radial pulse was weakened. Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) identified uptake of FDG in the aortic arch, abdominal aorta and left brachial artery, etc. (Picture 1). Magnetic resonance angiography (MRA) revealed left brachial artery stenosis (Picture 2). The presumable diagnosis of a giant cell arteritis (GCA) developing into brachial artery stenosis was made. The patient was treated with 30 mg/day of prednisolone, which immediately reduced the fever. Subsequent MRA after steroid therapy showed improvement of brachial artery stenosis (Picture 3). GCA may cause severe complications such as aortic aneurysm, dissec