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In 2002, the Japan Pancreas Society (JPS) was the first in the world to propose diagnostic criteria for autoimmune pancreatitis (AIP). Since the concept of AIP has changed with the accumulation of AIP cases, the Research Committee of Intractable Pancreatic Diseases (RCIPD) provided by the Ministry of Health, Labour and Welfare of Japan and the JPS issued revised clinical diagnostic criteria of AIP in 2006. The Asan Medical Center of Korea also proposed diagnostic criteria for AIP in 2006. However, there are subtle but clinically challenging differences between the Japanese and Korean criteria. This inconsistency makes it difficult to compare data in studies from different centers and elucidate the characteristics of AIP. To reach a consensus on AIP, the RCIPD and the Korean Society of Pancreatobiliary Diseases established the following Asian criteria for the diagnosis of AIP: I-1. Imaging studies of pancreatic parenchyma show a diffuse/segmental/focally enlarged gland, occasionally with a mass and/or a hypoattenuation rim. I-2. Imaging studies of pancreaticobiliary ducts show diffuse/segmental/focal pancreatic ductal narrowing, often with stenosis of the bile duct. (Both I-1 and I-2 are required for diagnosis). II. Elevated level of serum IgG or IgG4, and detection of autoantibodies. III. Common lymphoplasmacytic infiltration and fibrosis, with abundant IgG4-positive cell infiltration. AIP should be diagnosed when criterion I and one of the other two criteria are satisfied, or when histology shows the presence of lymphoplasmacytic sclerosing pancreatitis in the resected pancreas. A diagnostic trial of steroid therapy can be applied carefully by expert pancreatologists only in patients fulfilling criterion I alone with negative diagnostic work-up results for pancreatobiliary cancer. [ABSTRACT FROM AUTHOR]

Abstract: RECQL1 and RECQL5 as well as BLM reportedly interact with TOP3α whose defect is lethal for the cell. Therefore in this study, we characterized recql5/recql1/blm triple mutants from DT40 cells to determine whether the triple mutants show a top3α disrupted cell-like phenotype. The triple mutants are viable. Moreover, both blm/recql1 and recql5/blm cells, and recql5/recql1/blm cells grew slightly slower than blm cells, that is, triple mutant cells grew almost the same rate as either of the double mutant cells. The blm cells showed sensitivity to methyl methanesulfonate (MMS) and ultraviolet light (UV), about a 10-fold increase in sister chromatid exchange (SCE), and about a 3-fold increase in damage-induced mitotic chiasma compared to wild-type cells. The triple mutants showed the same sensitivity to MMS or UV and the same frequency of damage-induced mitotic chiasma compared to those of blm cells, indicating that unlike BLM, RECQL1 and RECQL5 play a little role in the repair of or tolerance to DNA damages. However, recql5/blm cells showed higher frequency of SCE than blm cells, whereas the RECQL1 gene disruption had no effect on SCE in blm cells and even in recql5/blm cells. [Copyright &y& Elsevier]

Bloom's syndrome (BS), which is caused by mutations in the BLM gene, is characterized by a predisposition to a wide variety of cancers. BS cells exhibit elevated frequencies of sister chromatid exchanges (SCEs), interchanges between homologous chromosomes (mitotic chiasmata), and sensitivity to several DNA-damaging agents. To address the mechanism that confers these phenotypes in BS cells, we characterize a series of double and triple mutants with mutations in BLM and in other genes involved in repair pathways. We found that XRCC3 activity generates substrates that cause the elevated SCE in blm cells and that BLM with DNA topoisomerase IIIα suppresses the formation of SCE. In addition, XRCC3 activity also generates the ultraviolet (UV)- and methyl methane-sulfonate (MMS)-induced mitotic chiasmata. Moreover, disruption of XRCC3 suppresses MMS and UV sensitivity and the MMS- and UV-induced chromosomal aberrations of blm cells, indicating that BLM acts downstream of XRCC3. [ABSTRACT FROM AUTHOR]

Abstract: We investigated the function of the interaction between WRN (Werner syndrome gene product) and Ku70 and between WRN and DNA-PKcs, which are components of the DNA-PKcs/Ku70/Ku80 complex, by generating KU70 −/− /WRN −/− and DNA-PKcs −/−/− /WRN −/− double-gene knockout chicken DT40 cells. When treated with camptothecin (CPT), an inhibitor of DNA topoisomerase I, WRN −/− cells showed higher sensitivity than wild-type cells, whereas KU70 −/− and DNA-PKcs −/−/− cells showed hyper-resistance. Disruption of KU70 or DNA-PKcs suppressed the sensitivity of WRN −/− cells to CPT, rendering them as resistant to CPT treatment as KU70 −/− and DNA-PKcs −/−/− cells. On the other hand, CPT sensitivity of BLM −/− cells, which are defective in a RecQ helicase similar to WRN, was enhanced by deletion of KU70. The implications for the function of WRN in the non-homologous end-joining pathway of DNA repair involving Ku70 and DNA-PKcs, which may be the cause of lethality in the presence of CPT, will be discussed. [Copyright &y& Elsevier]

Autoimmune pancreatitis (AIP) is a unique form of chronic pancreatitis generally observed in aged people and characterized by the presence of autoantibodies,1–3 elevated levels of immunoglobulins,4 enlargement of the pancreas (diffuse or focal) on ultrasonography (US) or computed tomography (CT),1–3,5 diffuse narrowing of the main pancreatic duct (MPD) with an irregular wall,1,3,5–8 and pathologic features of dense lymphoplasmacytic inflammation and fibrosis, as well as a favorable response to steroid therapy.1–3,5,8 The clinical findings in AIP include obstructive jaundice secondary to biliary stenosis, mild epigastralgia, and diabetes mellitus. The clinical, laboratory, and radiological features respond promptly to oral steroid therapy.1–3,5,6,8 Although prompt response to oral steroid therapy may be helpful in the differential diagnosis of AIP, careful imaging studies are necessary to exclude cancer of the pancreas or common bile duct (CBD). [ABSTRACT FROM AUTHOR]

We aimed to determine the cumulative rate of diabetes mellitus (DM) and the risk factors for DM in patients with chronic pancreatitis (CP) in Japan. We conducted a follow-up survey of CP in 2002 in patients registered as having CP in 1994, and confirmed 656 patients to be checked in regard to the survey items concerning diabetes. We analyzed the cumulative rate of DM and the risk factors for DM over an 8-year follow up period. In 1994, 35.1% of 656 CP patients had DM, and the incidence of diabetes had increased to 50.4% in 2002. Of 418 patients without diabetes in 1994, 28.9% (121/418) were newly diagnosed with DM in 2002. Alcoholic CP was the most common type of CP in patients with newly developed diabetes, accounting for 67.8%. The incidence of DM was highest in those with alcoholic CP (34.3%) followed by idiopathic CP (23.0%). The risk of diabetes increased 1.32-fold after the onset of pancreatic calcification. Of 121 patients with newly diagnosed DM in 2002, 37 (30.6%) had pancreatic stones in 1994 and 49 (40.5%) had a stone in 2002. The highest incidence of newly diagnosed DM was observed in patients with continuous alcoholic intake (40.9%). Patients treated with camostat mesilate developed DM less frequently than those without camostat mesilate. The present study showed that the incidence of DM in patients with CP increased with time. Of 418 CP patients without DM in 1994, 28.9% developed DM over a period of 8 years. Continuous alcoholic intake aggravated CP and increased the risk of DM in those with CP. [ABSTRACT FROM AUTHOR]

Chronic pancreatitis is a chronic clinical disorder characterized by irreversible damage to the pancreas and the development of histologic evidence of inflammation and fibrosis, and eventually the destruction and permanent loss of exocrine and endocrine tissue. A nationwide survey in Japan revealed an increase in the total number of patients treated for chronic pancreatitis from 32000 in 1994 to 42000 in 1999. The overall prevalence and the incidence rate of chronic pancreatitis also increased, from 28.5 and 5.4, respectively, in 1994 to 32.91 and 5.77 per 100000 population, respectively, in 1999. Diagnostic criteria for chronic pancreatitis in Japan were proposed by the Japan Pancreas Society in 1995 and revised in 2001. The criteria were established to rule out false-positive cases and to confidently diagnose definite and probable cases of chronic pancreatitis, and thus easily detect advanced chronic pancreatitis, but the criteria are unable to lead to the early diagnosis of chronic pancreatitis. Cancer is the major cause of death in patients with chronic pancreatitis in Japan (49.6% of all deaths in patients with chronic pancreatitis). Clarification of the mechanisms by which possible chronic pancreatitis progresses to probable or definite chronic pancreatitis, and to pancreatic cancer, is an important research goal. Because even chronic pancreatitis defined as irreversible appears to be reversible for some time in its clinical course, there is an urgent need to develop methods for diagnosing reversible chronic pancreatitis, and to prevent the transition from chronic pancreatitis to pancreatic cancer. [ABSTRACT FROM AUTHOR]

Two cases with duodenal carcinoma successfully treated by endoscopic mucosal resection are reported. Case 1 had a semipedunculate polyp, and case 2 had a flat elevated lesion with a central depression in the second portion of the duodenum. Histologic examination showed tubular adenocarcinoma in adenoma in case 1 and an intramucosal adenocarcinoma in case 2, indicating that complete endoscopic resection had been achieved in both cases. Endoscopic mucosal resection appears to be a safe and efficient method for management of early carcinoma of the duodenum as well as in other regions of the gastrointestinal tract. [ABSTRACT FROM AUTHOR]

Abstract Cholecystokinin (CCK) is a major gastrointestinal hormone that plays an important role in stimulation of pancreatic secretion and gall-bladder contraction, regulation of gastrointestinal motility and induction of satiety. Ingestion of fat and protein induces significant increases in plasma CCK. Intraluminal mediators of CCK secretion, luminal CCK releasing factor and diazepam-binding inhibitor, were purified from rat intestinal secretion. These CCK-releasing factors (RF) are secreted tonically by the small intestine and stimulate CCK release. Another kind of CCK-RF named ‘monitor peptide’ was purified from the rat pancreatic juice that stimulates CCK secretion when introduced into rat intestine. Bile exclusion from the duodenum causes an increase in basal CCK and enhances stimulated plasma CCK release, and bile salt replacement reverses these effects. Thus, the CCK-RF are spontaneously secreted into the intestinal lumen in humans, while the CCK-producing cells are under constant suppression by intraduodenal bile acids. In acute pancreatitis, plasma CCK levels are high in patients with gallstone pancreatitis, but not in patients with pancreatitis from other causes, such as alcoholic and idiopathic pancreatitis. A transient disturbance of bile flow into the duodenum by stones or oedema of the pancreas together with impairment of pancreatic exocrine function might cause the increase in plasma CCK release in gallstone pancreatitis. Patients with chronic pancreatitis with mild to moderate impairment of exocrine function and abdominal pain, had significantly higher plasma CCK concentrations, whereas patients with pancreatic insufficiency had a significantly lower plasma CCK response to a test meal than the healthy subjects. The increased CCK may further aggravate pancreatitis and worsen the prognosis of pancreatitis by stimulating the injured pancreas, resulting in the vicious circle via endogenous CCK release. The CCK-A receptor antagonist might be therapeutically useful in acute pancreatitis by stopping the vicious circle. [ABSTRACT FROM AUTHOR]

Discusses the loss of sensitivity to cholecystokinin (CCK) stimulation of isolated pancreatic acini from genetically diabetic rats. Responsiveness to fluoride; Selective defect in the binding of CCK to its receptors on the acinar cell surface; Enzyme activities in serum and pancreas; Response to secretagogues.

Investigates the effects of an oral dose of the synthetic trypsin inhibitor camostat on pancreatic exocrine function in rats. Feeding of camostat to fed and fasted rats; Increase in plasma cholecystokinin bioactivity; Immediate and delayed effects of camostat on pancreatic exocrine secretory function.

The article discusses the current problems of the diagnostic criteria of chronic pancreatitis. Chronic pancreatitis is a chronic continuing inflammatory disease of the pancreas. The diagnosis of chronic pancreatitis can be confirmed only at the advanced end stage of chronic pancreatitis which is common to all etiologies.

Editorial. Provides details on the interaction among fat, lipase, cholecystokinin (CCK) and gastric emptying. Stimulator of CCK release; Feedback system made possible by the interaction of CCK and gastric emptying; Effect of triglycerides on plasma CCK levels and gastric emptying in young and elderly subjects in the presence or absence of lipase.

Abstract: Objective: In patients with liver cirrhosis (LC), the incidence of diabetes mellitus (DM) is high, whereas that of hypertension and ischemic heart diseases is low. We measured carotid artery intima-media thickness (IMT) to determine the incidence of atherosclerosis in patients with LC+DM and to compare it with that in patients with type 2 DM, and evaluated the risk factors for atherosclerosis in these patients. Research design and methods: We determined IMT of the common carotid artery by B-mode ultrasound, serum lipid levels, C-reactive protein (CRP), plasma levels of fasting and postprandial glucose, glycated hemoglobin (HbA1c), fibrinogen and platelet counts in 14 patients of the LC+DM group, 16 patients with type 2 DM (DM group) and 14 patients with LC without impaired glucose tolerance (LC group). Results: The IMT in the LC+DM group (0.694±0.175mm) was similar to that in the LC group (0.693±0.151mm) but significantly smaller than the DM group (0.904±0.337mm). There were no significant differences between the LC+DM group and DM group in the duration of DM, proportion of smokers, arterial blood pressure, fasting and postprandial plasma glucose levels, and CRP, but HbA1c, platelet counts and fibrinogen were significantly lower in the LC+DM group than in the DM group. Conclusions: Our study suggests that the development of atherosclerosis in patients with DM is suppressed by the presence of LC, probably due to reduced platelet counts and fibrinogen levels. [Copyright &y& Elsevier]

This study was designed to examine whether continuous pancreatic ductal hypertension (PDH) plays an important role in the onset and development of chronic pancreatitis (CP). Pancreatic, biliary, and duodenal cannulas were implanted in male Wistar rats. PDH was induced by vertically raising the free end of the pancreatic duct cannula to exert a hydrostatic pressure and maintained for 2 wk. PDH was gradually increased, but when the pancreatic juice (PJ) flow was interrupted, PDH was decreased to restore PJ flow. The induction of PDH resulted in a marked reduction of amylase activity in PJ and an increase in serum amylase activity. At 2 wk after persistent PDH, pancreatic exocrine function was markedly decreased in response to a bolus injection of secretin (100 pmol/kg) compared with the controlgroup. Histological examination revealed interlobular as well as intralobular fibrosis in the form of nodular pancreatitis at 2 wk after the induction of PDH. Immunohistochemistry revealed the expression of fibronectin and collagen types I and Ill. Quantitative real-time RT-PCR showed an increase in transforming growth factor-β1 mRNA expression in the pancreas during PDH. The present results suggest that PDH plays an important role in the onset and development of CP. Furthermore, our animal model seems useful for investigating the mechanisms of CP in rats. [ABSTRACT FROM AUTHOR]

Bloom syndrome (BS) and ataxia-telangiectasia (A-T) are rare autosomal recessive diseases associated with chromosomal instability. The genes responsible for BS and A-T have been identified as BLM and ATM, respectively, whose products were recently found to be components of BRCA1-associated genome surveillance complex (BASC), a supercomplex possibly involved in the recognition and repair of aberrant DNA structures. Based on experiments using BLM−/− DT40 cells and BLM−/−/RAD54−/− DT40 cells, we previously suggested that BLM functions to reduce the formation of double-strand breaks (DSBs) during DNA replication. To examine whether ATM is involved in the recognition and/or repair of DSBs generated in BLM−/− DT40 cells and to address the functional relationship between the two BASC components, we generated BLM−/−/ATM−/− DT40 cells and characterized their properties as well as those of ATM−/− and BLM−/− DT40 cells. BLM−/−/ATM−/− cells proliferated slightly more slowly than either BLM−/− or ATM−/− cells. The sensitivity of BLM−/−/ATM−/− cells to γ-irradiation was similar to that of ATM−/− cells, while BLM−/− cells were slightly resistant to γ-irradiation compared with wild-type cells. BLM−/− cells showed sensitivity to methyl methanesulfonate (MMS) and UV irradiation while ATM−/− cells did not show sensitivity to either agent. The sensitivity of BLM−/−/ATM−/− cells to MMS and UV was similar to that of BLM−/− cells. Disrupting the function of ATM reduced the targeted integration frequency in BLM−/− DT40 cells. However, a defect in ATM only slightly reduced the increased sister chromatid exchanges (SCEs) in BLM−/− DT40 cells. [Copyright &y& Elsevier]

Studies Plasma cholecystokinin- (CCK), secretin-, and cholinergic-independent pancreatic fluid hypersecretion in protease inhibitor-treated rats. Elevation in pancreatic fluid secretion; Acinar cell proliferation; Endogenous cholecystokinin release.

Focuses on CCK secretin and cholinergic-independent pancreatic fluid hypersecretion in protease inhibitor-treated rats. Methodology used in the treatment of the animals; Examination of basal pancreatic secretion; Discussion on data analysis used to prepare animals.

Because autoimmune pancreatitis is a new disease entity, there are no data with regard to its prevalence. To estimate the number of patients with autoimmune pancreatitis in Japan, we randomly selected hospitals using stratification and asked them how many patients they had with pancreatitis in 2002 who fulfilled the diagnostic criteria for autoimmune pancreatitis as proposed by the Japan Pancreas Society. The number of patients with autoimmune pancreatitis who visited hospitals in Japan in 2002 was approximately 900 (95% confidence interval; range 670–1100). The male : female ratio was 2.85 : 1, and the age of disease onset in 95% of the patients was over 45 years. The prevalence of patients with autoimmune pancreatitis in Japan was estimated to be 0.82 per 100 000. Autoimmune pancreatitis was predominantly seen in men past middle age (over the age of 45 years). [ABSTRACT FROM AUTHOR]

Abstract: Background/aim: The renin–angiotensin system (RAS) exists in the pancreas, but the role of RAS in the regulation of pancreatic exocrine secretion under physiological conditions has been little known. The present study addressed the RAS''s effect on the pancreatic secretion by using valsartan, a specific angiotensin II receptor blocker, in conscious rats. Method: Male Wistar rats prepared with pancreatic, biliary, duodenal and jugular vein cannulas were used. To examine the role of RAS in the pancreatic secretion, valsartan at 1, 5, or 25mg/kg was administered into the duodenum via cannula, and volume of pancreatic juice and protein concentration were determined. In addition, to examine the role of RAS in hormone-stimulated pancreatic hypersecretion, pancreatic secretion was examined in response to stimulation of secretin or cholecystokinin after intraduodenal infusion of valsartan at 25mg/kg. Furthermore, to examine the mechanism of action of RAS on pancreatic secretion, intravenous infusion of atropine or perivagal application of capsaicin was conducted and then the pancreatic secretion was examined following intraduodenal infusion of valsartan at 25mg/kg. Results: Volume of pancreatic juice, but not protein output, significantly decreased after administration of valsartan. However, administration of valsartan did not exert significant effects on secretin- or cholesystokinin-stimulated pancreatic secretion. Treatment with atropine and perivagal application of capsaicin completely abolished the suppressive effect of valsartan on pancreatic juice secretion. Conclusion: Present results suggest that RAS plays a stimulatory role in pancreatic juice secretion via cholinergic afferent pathway without affecting protein secretion and hormonally stimulated pancreatic secretion under physiological conditions. [Copyright &y& Elsevier]

Background: Little is known about the etiopathogenesis of chronic pancreatitis, due mainly to the lack of simple animal models suitable to study inflammatory and fibrogenetic processes in the pancreas.Aims: The purpose of this study was to examine whether transient congestion of pancreatic fluid flow alone or slight ductal injury alone is sufficient, or where both are required, to induce chronic pancreatic injury.Methods: Three different models of pancreatitis were tested in rats induced by retrograde intraductal infusion of 40 μl/100 g body weight of 0.01% agarose (group A), 40 μl/100 g body weight of 0.1% sodium taurocholate (group T), or a mixture of the two solutions (group M). Histological alterations of the pancreas were examined by hematoxylin-eosin staining, changes in type IV collagen structure were studied by immunostaining, and the gelatinolytic activity of latent and active matrix metalloproteinase-2 (MMP-2) was analyzed by zymography.Results: In group A and T rats, histological alterations of the pancreas and the gelatinolytic activity of MMP-2 returned to baseline levels by day 14, and immunoreactivity for type IV collagen appeared as continuous lines along the basement membrane. In group M rats, however, acinar damage, fibrosis and fatty degeneration were observed even on day 56, and type IV collagen was detected as discontinuous lines until day 56. MMP-2 was significantly elevated from day 5 to day 42.Conclusions: Co-existence of transient stasis of pancreatic fluid flow, together with mild damage to the pancreatic duct and acinar cells, exert synergistic effects on the development of persistent pancreatic injury with continuous disorganization of type IV collagen in the basement membrane of the ducts. [ABSTRACT FROM AUTHOR]

Although patients with autoimmune pancreatitis (AIP) tend to have concurrent diverse disorders, very few studies have focused on diabetes mellitus (DM) coexisting with AIP. In total 102 AIP patients with DM were divided into three groups. Those with DM before the onset of AIP were labeled group A ( n = 35), those who developed DM and AIP simultaneously were labeled group B ( n = 58) and those who developed DM after steroid therapy for AIP were labeled group C ( n = 9). The characteristics of DM among the three groups were evaluated. No significant differences were noted in the age of DM onset among the three groups. However, the mean duration of DM was significantly longer in group A (8.7 years) than in groups B and C. AIP developed 6.8 years after DM onset in group A, whereas it developed 1.8 years after steroid therapy in group C. Group A had the highest rate (25.7%) of family members with a history of AIP. Levels of serum albumin, total cholesterol and triglyceride were significantly lower in group A. No correlations were found between glycated hemoglobin and benzoyl-tyrosyl para-aminobenzoic acid. Hypoglycemia was observed in 20% of patients under insulin therapy. Most of them were habitual drinkers and received no pancreatic enzymes. Group A showed a high prevalence of retinopathy, nephropathy and macrovascular disorders than group B. Aspects of AIP-associated pancreatic diabetes were clarified. AIP-associated DM must be controlled by a full assessment of the pancreatic endocrine and exocrine function. [ABSTRACT FROM AUTHOR]

In Japan, we are now using the clinical diagnostic criteria for chronic pancreatitis (CP) that were revised in 2001 to add the findings of magnetic resonance cholangiopancreatography to the criteria compiled by the Japan Pancreas Society (JPS) in 1995. Because the current criteria are set for diagnosing advanced CP, they are unlikely to improve patients’ prognoses. In addition, they seem unsuitable for current clinical practice because exocrine pancreatic function tests, which have become obsolete in Japan, are included in the diagnostic factors. For these reasons, the Research Committee on Intractable Pancreatic Diseases supported by the Ministry of Health, Labour and Welfare of Japan, the JPS and the Japanese Society of Gastroenterology have revised the criteria. The revised criteria are unique in that they contain an introduction to the concept of early CP. It is a challenge aimed at improvement of the long-term prognosis of CP patients by early diagnosis and therapeutic intervention in this disease. We need to determine and clarify the clinico-pathological outcome of early CP by a prospective long-term follow-up of the patients in this category. [ABSTRACT FROM AUTHOR]

Background: Excessive consumption of alcohol is involved in the onset of pancreatitis. However, most of heavy drinkers do not always develop chronic pancreatitis. Various genetic factors appear to be involved in these individual differences in onset of chronic alcoholic pancreatitis. Here we investigated a possible association of alcoholic pancreatitis with polymorphisms of the various genes belong to the phase II detoxification enzymes responsible for metabolism of the oxidative compounds, and the several genes that have relevance to inherited pancreatitis. Methods: The subjects consisted of 53 patients with chronic alcoholic pancreatitis, 54 alcoholic patients without pancreatic dysfunction, and 42 healthy individuals. DNA was extracted from the peripheral nucleated blood cells of all subjects and genetic mutations and subtypes were analyzed by the PCR and RFLP methods. We examined the correlation between chronic alcoholic pancreatitis and variants of the phase II detoxification enzymes such as Glutathione S-transferase M1 (GSTM1), glutathione S-transferase theta 1 (GSTT1), NADPH-quinone oxidoreductase 1 (NQO1), and N-acetyl transferase (NAT2). In addition, genes of lipoprotein lipase (LPL), cationic trypsinogen (PRSS1), pancreatic secretory trypsin inhibitor (PSTI), and cystic fibrosis transmembrane conductance regulator (CFTR) were also analyzed. Results: Frequencies of the gene deletion of GSTM1 and GSTT1 in addition to the C-allele frequency of NQO1 tended to be higher in the alcoholic patients with (AlCP) or without pancreatic dysfunction (Alc) than in the healthy controls although the difference was not significant. The NAT2 gene showed no relation with Alc and AlCP patients. PSTI, LPL, PRSS1, and CFTR genes presented no association with chronic alcoholic pancreatitis. Conclusions: All genes analyzed in the present study lacked association with chronic alcoholic pancreatitis. However, the gene deletion of GSTM1 and GSTT1, and the C-allele of NQO1 cannot be ruled out for association with alcoholism. [ABSTRACT FROM AUTHOR]

Autoimmune pancreatitis (AIP) is a rare type of chronic pancreatitis caused by an autoimmune abnormality. It is well known that high serum concentrations of IgG4 are helpful for making a diagnosis of AIP; however, it is unclear whether there are abnormalities in the production of other immunoglobulins in AIP. We examined the immune condition of AIP patients before and after glucocorticoid treatment, focusing on serum levels of IgG, IgG4, IgM and IgA, and compared the results with those in other hepato-pancreatic diseases, such as autoimmune hepatitis, primary biliary cirrhosis, chronic pancreatitis and pancreatic carcinoma. IgM and IgA were decreased in patients with untreated AIP. IgM and IgG or IgG4 were negatively correlated in patients with AIP. The ratios of IgG to IgM and IgG to IgA in patients with AIP were significantly increased compared with the other diseases. The diagnostic sensitivity of IgG to IgM and IgG to IgA was 0.800 and 0.950, and the specificity of each ratio was 0.703 and 0.728, respectively, in the differentiation of AIP from the other diseases. IgM was not significantly changed after glucocorticoid treatment in the patients with AIP, while IgG, IgG4 and IgA decreased. The ratios of IgG to IgM and IgG to IgA may serve as novel diagnostic markers to differentiate AIP from other hepato-pancreatic diseases. Furthermore, low concentrations of IgM and IgA may be involved in the pathogenesis of AIP. [ABSTRACT FROM AUTHOR]

Background and Aim: Upper gastrointestinal endoscopy is generally accepted as the gold standard for the clinical evaluation of gastric cancer (GC). However, the efficacy of endoscopic screening for asymptomatic GC remains controversial. The present study is designed to clarify the efficacy of endoscopic screening for the detection of early GC by investigating the clinicopathological features. Methods: A total of 17 522 patients who had underwent endoscopic screening as a part of their annual health checkup at the Seirei Center for Health Promotion and Preventive Medicine between April 2002 and March 2006 were enrolled in this study. We investigated the clinicopathological findings of GC detected by endoscopy. Furthermore, in accordance with the screening interval at our center, patients with GC were categorized into two groups: group A, patients with repeated endoscopic screening within the last 2 years, and group B, patients without endoscopic screening within the last 2 years. Results: Thirty-nine GC (mean age of patients: 62.2 ± 8.0 years, 36 males and three females) were detected in total (0.22%). The proportion of early GC was 87.2%. Notable differences between groups A and B were not found in the rate of early GC ( P = 0.6342). However, eight of 27 cases (29.6%) in group A were treated by endoscopic resection, but none in group B ( P = 0.0344). In six of 26 cases (23.1%) in group A, the recorded images from the previous endoscopic examination indicated some macroscopic abnormalities at the same location, suggesting GC or premalignant lesions. Conclusion: Endoscopic screening is useful for detecting GC at the early stages, and repeated examinations at short-time intervals contribute to the detection of resectable lesions by endoscopy. Further studies are needed to decrease the false negative rate of endoscopic screening. [ABSTRACT FROM AUTHOR]

Chronic and excessive consumption of alcohol is an important factor responsible for the onset of pancreatitis. However, the incidence of chronic pancreatitis in heavy drinkers differs in individuals, suggesting that these individual differences may involve various genetic and environmental factors. In the present study, we investigated an association of alcoholic pancreatitis with polymorphisms of the various genes related to metabolism of the oxidative compounds. We analyzed polymorphisms of NADPH-quinone oxidoreductase 2 (NQO2), multidrug resistance 1 (MDR1), alcohol dehydrogenase 1B (ADH1B) and lipoprotein lipase (LPL). The subjects consisted of 53 patients with chronic alcoholic pancreatitis (AlCP), 54 alcoholic patients without pancreatic dysfunction (Alc), and 42 healthy individuals. DNA samples were prepared from the peripheral blood of all subjects, and the genetic mutations were analyzed by polymerase chain reaction and restriction fragment length polymorphism methods. The ADH1B gene frequencies were significantly different between healthy controls and Alc patients ( P < 0.001), and also between AlCP and Alc patients ( P < 0.05). However, no significant difference was found between healthy controls and AlCP patients. The gene frequencies of MDR1 (3435C > T) and MDR1 (2677G > A/T) of patients with AlCP or Alc were different when compared with healthy controls, although the difference was not significant. The NQO2 and LPL genes showed no relation with Alc and AlCP patients. The ADH1B* 1 gene frequency in AlCP was significantly lower compared with Alc. We speculate that the ADH1B* 1 gene may function by reducing vulnerability to the onset of alcoholic pancreatitis. Other genes analyzed in the present study lacked association with AlCP. [ABSTRACT FROM AUTHOR]

Background: Placement of self-expandable metallic stents has become the preferred palliative treatment for patients with unresectable malignant biliary obstruction. Metallic stents provide longer patency compared with plastic stents. Distal malposition or migration of metallic stents sometimes occurs, but it is often difficult to remove them. We evaluated the efficacy and safety of argon plasma coagulation (APC), and the optimum conditions for cutting metallic stents (Wallstent). Methods: We wrapped porcine small intestines around a metallic Wallstent with and without silicon lining membrane (Permulume®), leaving the distal portion unwrapped to resemble the protrusion of the biliary metallic stent from the ampulla of Vater. APC irradiation was applied to the metallic stent at 1 cm from the edge of the wrapped small intestine at 30, 60 and 99 watts (W) for 3 or 6 s. Results: Metallic Wallstent with the silicone-based membrane Permalume® was cut at 30 W power, whereas more than 60 W power was required to cut the bare metallic wire. The irradiation of APC (flow rate at 2.0 L/min) at 30 W to the covered metallic stent transected the metallic mesh stent not only under dry but also under wet conditions (moisturized stent). Irradiation of APC caused no gross damage to the small intestines irrespective of the power applied and duration of irradiation. Conclusions: Our results suggest that APC is efficacious and safe for endoscopic sectioning of wire mesh stents at low power (30 W) without gross damage to the surrounding pancreaticobiliary tissues. [ABSTRACT FROM AUTHOR]

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 a-smooth muscle actin, α1(I)-procollagen, and TGF-β1 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. [ABSTRACT FROM AUTHOR]

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 ≥40 years old in a Japanese company from 1997 to 2005. We excluded workers with alcohol intake ≥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. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Liver steatosis is frequently observed in patients with chronic hepatitis C (CHC) and is an identified risk factor for progression of liver fibrosis. This study aimed to evaluate the relationship between steatosis and host/viral factors, and the correlation between steatosis and insulin secretion in CHC patients with normal glucose tolerance (NGT). METHODS: A total of 212 CHC patients were enrolled in this study. Insulin resistance and insulin secretion were determined in response to oral loading of 75 g glucose. Liver fibrosis and steatosis were quantified by the image analysis. RESULTS: Of the 212 CHC patients, 165 (78%) had steatosis, mostly of a mild degree. Multiple ordinal regression analysis revealed body mass index (BMI) ( P= 0.011) as the main factor associated with severe steatosis. Of the 212 CHC patients, 148 (61%) showed NGT, and the serum insulin response to oral glucose loading in these NGT patients with steatosis was significantly different from that in patients with NGT but no steatosis. The peak insulin response occurred at 60 min in cases of mild steatosis, and at 90 min in patients with moderate or severe steatosis. The insulin level at 120 min in patients with severe steatosis was higher than that in those without steatosis. The total area under the response curve of insulin during OGTT in the patients with steatosis is higher than that in those without steatosis. CONCLUSION: Exaggerated insulin secretion was observed even in CHC patients with mild steatosis and NGT, suggesting the presence of insulin resistance. Exaggerated insulin secretion may accelerate the progression of liver fibrosis in CHC patients. [ABSTRACT FROM AUTHOR]

Autoimmune pancreatitis (AIP) has been characterized by unique clinical imaging, immunological findings, and the effectiveness of steroid therapy. A set of clinicopathological criteria for AIP was proposed by the Japan Pancreatic Society in 2002, and AIP has come to be widely recognized among general digestive clinicians. However, the indication of steroid therapy for AIP is still not well established, and furthermore the therapeutic doses and method of administration of steroid therapy is also unclear. Recently, an epidemiological survey of all the treatments used for AIP in Japan was conducted by the Research Committee of Intractable Pancreatic Diseases, and their report “Consensus for a Treatment of Autoimmune Pancreatitis” was produced. In a comparison of the results of steroid therapy and nonsteroid therapy for AIP in relation to the rate of complete remission, the recurrence rate, and the period needed to guarantee complete remission, it was thought that the administration of a steroid should be a standard therapy for AIP. However, if the diagnosis of AIP is still uncertain, steroid therapy should be given with caution. In addition, even when AIP still appears to be possible after a course of steroid therapy, a re-evaluation should be carried out taking pancreatic carcinoma into consideration. An initial steroid dose of 30–40 mg per day is recommended. With continuous and careful observations of the clinical manifestations, laboratory data, and imaging findings after administration of the initial dose of steroid for 2–4 weeks, the quantity of steroid can be reduced gradually to a maintenance dose in 2–3 months, and then reduced to 2.5–5 mg per day after remission. The recommended period of maintenance treatment is still unclear, but the administration of the steroid could be stopped after a period of about 6–12 months of treatment, although the patient should be monitored for clinical manifestations of improvement. In addition, the patient's progress should be followed taking recurrence into consideration. In order to evaluate the effectiveness of steroid therapy, follow-up observations should include biochemical examinations of blood findings such as serum γ-globulin, IgG, and IgG 4, imaging findings, and clinical manifestations such as jaundice and abdominal discomfort. [ABSTRACT FROM AUTHOR]

The article discusses the proposed amendments for clinical diagnostic criteria of autoimmune pancreatitis (AIP) by the Research Committee of Intractable Diseases of the Pancreas. The extrapancreatic lesions that may be associated with AIP include biliary lesions, sialadenitis, retroperitoneal fibrosis, enlarged celiac and hilar lymph nodes, and chronic thyroiditis. Patients with AIP demonstrate infiltration of lymphocytes and plasma cells, and obliterative phlebitis.

Background and Aim: The aim of the present study was to determine whether a 24-week course of combination therapy with ribavirin and high-dose interferon-α2b (IFN-α2b) could provide an acceptable treatment efficacy in chronic hepatitis C (CHC). Methods: Seventy-six patients with CHC whose serum hepatitis C virus (HCV) RNA levels were more than 100 kIU/mL on quantitative polymerase chain reaction (PCR) assay were included. The patients were assigned to two different dose groups of IFN-α2b: group A ( n = 39) received 6 MU and group B ( n = 37) received 10 MU. Each group received the dose daily for 14 days then three times per week for a total of 24 weeks. In addition, HCV genotype 1b patients in group A and group B were classified into group C ( n = 20) and D ( n = 29), respectively. All patients received 600 or 800 mg ribavirin per day. Results: Sustained response rates in group A were significantly higher than those in group B (66.7% vs 35.1%, intent-to-treat, P = 0.0060). However, sustained response rates in group C were not different from those in group D (45.0% vs 20.7%, intent-to-treat, P = 0.0696). The proportion of patients who discontinued the treatment or reduced drug dosage because of adverse events was significantly higher in group B than in group A (27.0% vs 7.69%, P = 0.0224). Conclusion: A 24-week course of combination therapy with ribavirin and 6 MU IFN-α2b had an acceptable efficacy with fewer adverse events than that with ribavirin and 10 MU IFN-α2b in CHC. [ABSTRACT FROM AUTHOR]

Endoscopic therapy is often difficult to achieve particularly when the field of view of the lesion is poor due to contamination of mucus and blood. We developed five different types of end hoods that facilitate endoscopic procedures by simultaneously allowing various treatments and irrigation of the site.The end-hood pieces were fabricated by drilling a side hole in the cap portion of conventional transparent hoods, then the irrigation tube was glued to the exterior surface of the hole. The fabricated transparent hood was placed at the tip of the endoscope.Types 1 and 2 were useful for upper-gastrointestinal (GI) hemorrhage, type 3 for lower-GI hemorrhage, type 4 for endoscopic submucosal dissection and type 5 for endoscopic mucosal resection.With this method, endoscopic procedure is easy and economical, as therapeutic procedures can be performed under irrigation using a conventional endoscopy. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor about the pseudomalignant erosion in hyperplastic polyp at esophago-gastric juntion.

BACKGROUND AND AIMS: The efficacy of interferon (IFN)-based antiviral therapy for chronic hepatitis C (CHC) varies depending on predictive factors such as hepatitis C virus (HCV) genotype and viral load. For patients with good predictive factors, a low dose and short course of IFN-based therapy may be adequate. However, there is no evidence about the optimal duration of IFN-based therapy for these patients. The aim of this study was to clarify whether the duration of IFN therapy could be shortened to less than the conventional treatment period for patients with good predictive factors.METHODS: A total of 25 treatment-naive CHC patients with genotype 2a were randomized to receive either IFN monotherapy for 24 wks (group A: long-term IFN therapy, n= 13) or for 6 wks (group B: short-term IFN therapy, n= 12). Patients were monitored for HCV RNA and routine liver function tests during and following treatment, and data were examined according to intention-to-treat analysis.RESULTS: Eleven of 13 patients in group A and all patients in group B completed IFN therapy according to the original planned schedule. At the end of the treatment, viral clearance occurred in all patients. However, 4 patients in group A and 5 in group B relapsed within 6 months of follow-up. There was no significant difference of sustained response rate between group A (53.8%) and group B (58.3%). Among patients who had HCV viral load of<100 kIU/ml, the sustained response rate was 83.3% (5/6) in group A and 100% (5/5) in group B.CONCLUSIONS: In this study, our results suggest that the duration of IFN therapy can be shortened to less than 24 wks in patients with good predictive factors. Further studies, however, should examine the optimal regimen of IFN therapy based on the backgrounds of patients.(Am J Gastroenterol 2005;100:1-6) [ABSTRACT FROM AUTHOR]

Pancreatic stellate cells (PSCs) play a central role in development of pancreatic fibrosis. In chronic pancreatitis, pancreatic tissue pressure is higher than that of the normal pancreas. We here evaluate the effects of pressure on the activation of rat PSCs. PSCs were isolated from the pancreas of Wistar rat using collagenase digestion and centrifugation with Nycodenz gradient. Pressure was applied to cultured rat PSCs by adding compressed helium gas into the pressure-loading apparatus to raise the internal pressure. Cell proliferation rate was assessed by 5-bromo-2'-deoxyuridine (BrdU) incorporation. MAPK protein levels and α-smooth muscle actin (α-SMA) expression were evaluated by Western blot analysis. Concentration of activated transforming growth factor-β1 (TGF-β1) secreted from PSCs into culture medium was determined by ELISA. Collagen type I mRNA expression and collagen secretion were assessed by quantitative PCR and Sirius red dye binding assay, respectively. Application of pressure significantly increased BrdU incorporation and α-SMA expression. In addition, pressure rapidly increased the phosphorylation of p44/42 and p38 MAPK. Treatment of PSCs with an MEK inhibitor and p38 MAPK inhibitor suppressed pressure-induced cell proliferation and α-SMA expression, respectively. Moreover, pressure significantly promoted activated TGF-β1 secretion, collagen type I mRNA expression, and collagen secretion. Our results demonstrate that pressure itself activates rat PSCs and suggest that increased pancreatic tissue pressure may accelerate the development of pancreatic fibrosis in chronic pancreatitis. [ABSTRACT FROM AUTHOR]

The reninangiotensin system (RAS) plays important roles in various pathophysiological processes. However, the role of the RAS in pancreatic fibrosis has not been established. We investigated the role of angiotensin II (ANG II)-ANG II type 1 (AT1) receptor pathway in the development of pancreatic fibrosis with AT1a receptor-deficient [AT1a(-/-)] mice. To induce pancreatic fibrosis, AT1a(-/-) and wild-type (WT) mice were submitted to three episodes of acute pancreatitis induced by six intraperitoneal injections of 50 µg/kg body wt cerulein at hourly intervals, per week, for four consecutive weeks. Pancreatic fibrosis was assessed by histology and hydroxyproline content. Pancreatic stellate cell (PSC) activation and the localization of AT1 receptors were assessed by Western blot analysis for α-smooth muscle actin and immunostaining. Transforming growth factor-β1 (TGF-β1) mRNA expression in the pancreas was assessed by RTPCR. Six intraperitoneal injections of cerulein induced acute pancreatitis in both AT1a(-/-) and WT mice. There were no significant differences between two groups with regard to serum amylase and histological changes. Pancreatic fibrosis induced by repeated episodes of acute pancreatitis was significantly attenuated in AT1a(-/-) mice compared with that in WT mice. This finding was accompanied by a reduction of activated PSCs. Dual-immunofluorescence staining in WT mice revealed that activated PSCs express AT1 receptors. The level of TGF-β1 mRNA was lower in AT1a(-/-) mice than in WT mice. Our results demonstrate that the ANG II-AT1 receptor pathway is not essential for the local pancreatic injury in acute pancreatitis but plays an important role in the development of pancreatic fibrosis through PSC activation and proliferation. [ABSTRACT FROM AUTHOR]

Background/Aims: Diabetes mellitus (DM) is frequently observed in patients with chronic hepatitis caused by hepatitis C virus infection (CHC). The present study was designed to determine the pathogenic factors responsible for glucose intolerance in CHC patients.Methods: A total of 131 patients with CHC were enrolled in this study. Insulin resistance and β-cell function were determined after 75 g oral glucose tolerance tests.Results: Glucose intolerance was detected in 27.5% (36/131) of CHC patients; 10 had DM and 26 impaired glucose tolerance. HOMA-R [insulin 0×glucose 0/22.5] was greater in patients with both impaired glucose tolerance and DM than in those with normal glucose tolerance (P<0.01). Matsuda index [104/√(mean insulin×mean glucose×glucose 0×insulin 0)] was lower in diabetic patients than in those with normal glucose tolerance (P<0.05). The insulinogenic index [Δinsulin 30-0/Δglucose 30-0] and ΔC-peptide 30 [ΔC-peptide 30-0/Δglucose 30-0] were significantly lower even in patients with impaired glucose tolerance than in patients with normal glucose tolerance (P<0.01).Conclusions: Both insulin resistance and β-cell dysfunction contribute to glucose intolerance in CHC patients. [Copyright &y& Elsevier]

Background Methods. We retrospectively examined the serum levels of N-terminal peptide of type III procollagen (P-III-NP) and 7S domain of type IV collagen (IV-7S) in 56 patients with CHC who were revealed to be IFN-nonresponders. We measured these markers before (T0) and 1 month (T1) after the commencement of IFN therapy, at the end of 24 weeks’ IFN therapy (T24), and 1 year (T24-1) and more than 2 years (T24-2) after the cessation of IFN therapy. We also measured these markers twice, at intervals of more than 2 years, in 43 IFN-untreated patients with CHC as controls. Results. In nonresponders, both P-III-NP and IV-7S levels at T24-2 were significantly decreased compared with those at T0. P-III-NP levels at T1 were significantly decreased compared with those at T0, and remained at significantly low levels until the end of the observation period. IV-7S levels at T1 were not significantly different from those at T0. In patients whose IV-7S levels at T24-2 were decreased compared with those at T0, IV-7S levels at T1 were significantly lower than those at T0. In patients whose IV-7S levels at T24-2 were elevated or unchanged compared with those at T0, IV-7S levels at T1 were significantly higher than those at T0. In unteated patients, both P-III-NP and IV-7S levels at more than 2 years after the initial time were significantly increased compared with those at the initial time. Conclusions. An early decrease in IV-7S levels after IFN treatment is a useful indicator of anti-fibrogenic effects in nonresponders. We evaluated whether early changes in serum levels of fibrogenic markers during interferon (IFN) treatment can predict long-term anti-fibrogenic effects in patients with chronic hepatitis C (CHC). [ABSTRACT FROM AUTHOR]

Recent studies demonstrated that cholecystokinin (CCK) at physiological levels stimulates pancreatic enzyme secretion via a capsaicin-sensitive afferent vagal pathway. This study examined whether chemical ablation of afferent vagal fibers influences pancreatic growth and secretion in rats. Bilateral subdiaphragmatic vagal trunks were exposed, and capsaicin solution was applied. Pancreatic wet weight and pancreatic secretion and growth in response to endogenous and exogenous CCK were examined 7 days after capsaicin treatment. Perivagal application of capsaicin increased plasma CCK levels and significantly increased pancreatic wet weight compared with those in the control rats. Oral administration of CCK-1 receptor antagonist loxiglumide prevented the increase in pancreatic wet weight after capsaicin treatment. In addition, continuous intraduodenal infusion of trypsin prevented the increase in plasma CCK levels and pancreatic wet weight after capsaicin treatment. There were no significant differences in the expression levels of CCK-1 receptor mRNA and protein in the pancreas in capsaicin-treated and control rats. Intraduodenal administration of camostat or intravenous infusion of CCK-8 stimulated pancreatic secretion in control rats but not in capsaicin-treated rats. In contrast, repeated oral administrations of camostat or intraperitoneal injections of CCK-8 significantly increased pancreatic wet weight in both capsaicin-treated and control rats. Present results suggest that perivagal application of capsaicin stimulates pancreatic growth via an increase in endogenous CCK and that exogenous and endogenous CCK stimulate pancreatic growth not via vagal afferent fibers but directly in rats. [ABSTRACT FROM AUTHOR]

Fatty livers are vulnerable to ischemia/reperfusion (I/R) injury. We investigated the role of hepatic macrophages in the I/R injury in the fatty liver. Rats with alcoholic or nonalcoholic fatty liver were subjected to hepatic warm ischemia for 30 min. A bolus of gadolinium chloride (GdCl3) was injected intravenously twice before I/R to block hepatic macrophage activity. Alcoholic fatty liver developed more extensive hepatic necrosis with neutrophil infiltration in association with a higher production of cytokine-induced neutrophil chemoattractant (CINC)-1, a potent neutrophil chemokine in rat, after I/R than the nonalcoholic fatty liver or control liver without steatosis. Hepatic apoptosis after I/R increased to a similar degree (3-fold) in each of the two fatty liver models, compared with the control liver. Alcoholic fatty liver exposed to I/R showed a rapid increase in nuclear factor-kappa B (NF-κB) binding activity. The GdCl3 pretreatment significantly reduced NF-κB binding activity, CINC-1 level and necrosis in alcoholic fatty liver, despite no significant decrease in the extent of apoptosis. Our results suggest that the activation of hepatic macrophages in alcoholic fatty liver may contribute to hepatic necrosis after I/R, and that the apoptosis might be less dependent on the macrophage activity. [Copyright &y& Elsevier]

Human RECQL1 and RECQL5 belong to the RecQ family that includes Bloom syndrome, Werner syndrome, and Rothmund-Thomson syndrome causative genes. Cells derived from individuals suffering from these syndromes show significant levels of genomic instability. However, neither RECQL1 nor RECQL5 has been related to a disease, and nothing is known about the functions of RecQL1 and RecQL5. We generated here RECQL1[sup -/-], RECQL5[sup -/-], RECQL1[sup -/-]/RECQL5[sup -/-], RECQL1[sup -/-]/BLM[sup -/-], and RECQL5[sup -/-]/BLM[sup -/-] cells from chicken B-lymphocyte line DT40 cells. Although BLM[sup -/-] DT40 cells showed a slow-growth phenotype, a higher sensitivity to methyl methanesulfonate than the wild type, and an ∼10-fold increase in the frequency of sister chromatid exchange (SCE) compared to wild-type cells, RECQL1[sup -/-], RECQL5[sup -/-], and RECQL1[sup -/-]/ RECQL5[sup -/-] cells showed no significant difference from the wild-type cells in growth, sensitivity to DNAdamaging agents, and the frequency of SCE. However, both RECQL1[sup -/-]/BLM[sup -/-] and RECQL5[sup -/-]/BLM[sup -/-] cells grew more slowly than BLM[sup -/-] cells because of the increase in the population of dead cells, indicating that RecQL1 and RecQL5 are somehow involved in cell viability under the BLM function-impaired condition. Surprisingly, RECQL5[sup -/-]/BLM[sup -/-] cells showed a higher frequency of SCE than BLM[sup -/-] cells, indicating that RecQL5 suppresses SCE under the BLM function-impaired condition. [ABSTRACT FROM AUTHOR]

Background. Mutations in the pancreatic secretory trypsin inhibitor (PSTI) gene have been reported in patients suffering from chronic pancreatitis. The aim of the present study was to investigate whether similar gene mutations are present in familial and juvenile pancreatitis patients in Japan. Methods. All four exons of the PSTI gene and their flanking intronic sequences were amplified by polymerase chain reaction and sequenced for 37 familial pancreatitis patients (24 families) and 15 juvenile pancreatitis patients, distributed throughout Japan. Results. Three types of exonic mutation in the PSTI gene were observed. The N34S mutation was found in six familial pancreatitis patients (three families) and in one juvenile pancreatitis patient, and the R67C mutation was found in one familial pancreatitis patient and one juvenile pancreatitis patient. We also found a 272C>T mutation in the 3' untranslated region of exon 4 in one familial pancreatitis patient and four juvenile pancreatitis patients. It should be noted that the N34S mutation was cosegregated with two intronic mutations, specifically, IVS1-37T>C and IVS369insTTTT. Conclusions. The same set of N34S mutations (N34S + IVS1-37T>C + IVS3-69insTTTT) that exists in other countries was found in the PSTI gene in Japanese familial and juvenile pancreatitis patients. Another unique mutation (R67C) was also observed in two patients; 272C>T was suggested to be a normal polymorphism. [ABSTRACT FROM AUTHOR]

We examined the levels of serum N-terminal peptide of type III procollagen (P-III-NP) and the 7S domain of type IV collagen (IV-7S) as fibrogenesis markers in patients with chronic hepatitis C to clarify whether high-dose interferon-α (IFN-α) therapy has a suppressive effect on hepatic fibrogenesis for a long period (over 5 years) after the cessation of IFN therapy. Eighty patients with CHC were given 10 million units of IFN-α2b daily for 14 days followed by three times per week for a total of 24 weeks. Patients were divided into the following three groups according to the highest serum alanine aminotransferase levels during 1 year observation after the end of IFN therapy: complete responders (CR), partial responders (PR), and nonresponders (NR). We measured serum fibrogenesis markers before and at the end of IFN therapy, and again 1 year and more than 5 years after the end of IFN therapy. Liver biopsies were performed before IFN therapy in all patients and again over long-term observation in 10 patients (PR; 5 and NR; 5). Serum P-III-NP levels significantly decreased after IFN therapy in all three groups of patients, and further decreased in CR and PR over long-term observation. Serum IV-7S levels in CR significantly decreased after IFN therapy and further decreased over long-term observation. Serum IV-7S levels over long-term observation were significantly lower than those at the end of IFN therapy in CR and PR and significantly lower than the initial values in all three groups of patients. The progression of fibrosis was not significant over long-term observation in liver biopsy specimens of 10 patients. The results of the present study suggest that high-dose IFN-α therapy for 6 months suppresses the progression of hepatic fibrosis for more than 5 years not only in CR but also in PR. [Copyright &y& Elsevier]

OBJECTIVES:Application of a new variable stiffness colonoscope (VSC) is expected to control loop formation and to lessen patient discomfort. The aim of this prospective study was to compare the efficacy of VSC with a conventional colonoscope (CC) in unsedated colonoscopy, based on the experience of examiners.METHODS:Four-hundred sixty-seven patients were randomly assigned to undergo colonoscopy with either VSC or CC by an endoscopist, including experienced and less-experienced examiners. The percentages of completed procedure and time to cecal intubation were recorded. Patients were asked to rate pain on a 5-point pain score.RESULTS:The percentages of completed procedure with VSC and CC were 98% and 95%, respectively, by less-experienced hands, and 99% and 98%, respectively, by experienced hands. Time for cecal intubation with VSC and CC was 15.7 and 18.5 min, respectively, by less-experienced hands, and 9.8 and 10.6 min, respectively, by experienced hands. A significantly lower mean pain score was noted in VSC patients compared with CC patients, irrespective of experience of the examiner. The percent of patients rating the procedure as moderately or severely painful was significantly lower with VSC than with CC, both in less-experienced (19% vs 40%; p < 0.01) and experienced hands (15% vs 26%; p < 0.05).CONCLUSIONS:Our results indicated that VSC allows favorable examination compared with CC regarding completeness, time to cecal intubation, and comfort of patients undergoing unsedated colonoscopy, irrespective of the examiner’s experience. These features suggest VSC as the preferred colonoscope for patients undergoing unsedated colonoscopy. [Copyright &y& Elsevier]

Determines the pathogenic role of transforming growth factor-beta1 (TGF-beta1) in the development of pancreatic fibrosis in Otsuka Long-Evans Tokushima Fatty rats. Histological findings; Quantitative analysis of pancreatic fibrosis; Northern blot analysis; Immunohistochemistry.