Prolonged mitosis causes separase deregulation and chromosome nondisjunction.

During mitotic chromosome segregation, the protease separase severs cohesin between sister chromatids. A probe for separase activity has shown that separase undergoes abrupt activation shortly before anaphase onset, after being suppressed throughout metaphase; however, the relevance of this control remains unclear. Here, we report that separase activates precociously, with respect to anaphase onset, during prolonged metaphase in multiple types of cancer cell lines. The artificial extension of metaphase in chromosomally stable diploid cells leads to precocious activation and, subsequently, to chromosomal bridges in anaphase, which seems to be attributable to incomplete cohesin removal. Conversely, shortening back of a prolonged metaphase restores the activation of separase and ameliorates anaphase bridge formation. These observations suggest that retarded metaphase progression affects the separase activation profile and its enzymatic proficiency. Our findings provide an unanticipated etiology for chromosomal instability in cancers and underscore the relevance of swift mitotic transitions for fail-safe chromosome segregation.

George E. Palade memorial lecture: My life in pancreatic research-unexpected results may open the door.

The Palade Prize is the most distinguished award of the IAP for achievement in pancreatic research. It is named after George E. Palade, who in 1974 was awarded the Nobel Prize for his work on protein trafficking in pancreatic acinar cells. It is a great honor to be awarded the 2016 Palade Prize. While I was in graduate school, I was conducting research on hypothalamo-pituitary-thyroid axis; after finishing graduate school, I began research on amylase isoenzymes. This was the first step of my pancreatic research. Once I discovered that there are close relationships among blood glucose levels, amylase activity, and exocrine pancreatic function, I continued on to the next challenge. I performed research on the relationship between exocrine and endocrine aspects of the pancreas, pancreatic exocrine functions in diabetes mellitus, the role of cholecystokinin (CCK) and its synthetic analogue on exocrine and endocrine pancreas function, the role of CCK on the pathogenesis of pancreatitis, the cellular mechanisms of reversible and irreversible pancreatitis, and pancreatic stellate cell activation. In addition, I established guidelines for the diagnosis and management of acute, chronic and autoimmune pancreatitis as a chief investigator of the Research Committee of Intractable Pancreatic Diseases supported by the Ministry of Health, Labour and Welfare in Japan.

Treatment with atorvastatin attenuates progression of insulin resistance and pancreatic fibrosis in the Otsuka Long-Evans Tokushima fatty rats.

PURPOSE: The effects of statins on insulin resistance (IR) and type 2 diabetes mellitus (T2DM) are still controversial and its effects on pancreatic fibrosis are poorly defined. The purpose of this study is to examine the effects of atorvastatin on these issues using the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, an animal model of IR, T2DM and pancreatic fibrosis. METHODS: Male OLETF rats were divided into 2 groups at 6weeks of age. The first group received a standard diet until the end of experimental period at age 28weeks. The second group was given a diet containing 0.05% atorvastatin from 6weeks of age, before the onset of IR and pancreatic fibrosis. The age-matched Long-Evans Tokushima Otsuka rats without presence of IR, T2DM and pancreatic fibrosis, received a standard diet and were used as a normal control. RESULTS: Atorvastatin slightly decreased serum fasting glucose and insulin levels, but significantly improved index of IR compared with the untreated OLETF rats. In addition, atorvastatin markedly decreased transforming growth factor-ß1 mRNA expression, myeloperoxidase activity and proportion of fibrotic area, and elevated superoxide dismutase activity in the pancreas compared with the untreated OLETF rats. CONCLUSIONS: These findings suggest that atorvastatin exerts favorable influence on progression of IR and pancreatic inflammation and fibrosis via pleiotropic effect such as anti-oxidative property.

Effect of endogenous cholecystokinin on the course of acute pancreatitis in rats.

AIM: To examine the effects of pancreatic rest, stimulation and rest/stimulation on the natural course of recovery after acute pancreatitis. METHODS: Acute hemorrhagic pancreatitis (AP) was induced in male rats by intraductal infusion of 40 µL/100 g body weight of 3% sodium taurocholate. All rats took food ad libitum. At 24 h after induction of AP, rats were divided into four groups: control (AP-C), pancreas rest (AP-R), stimulation (AP-S), and rest/stimulation (AP-R/S). Rats in the AP-C, AP-R and AP-S groups received oral administration of 2 mL/kg body weight saline, cholecystokinin (CCK)-1 receptor antagonist, and endogenous CCK release stimulant, respectively, twice daily for 10 d, while those in the AP-R/S group received twice daily CCK-1 receptor antagonist for the first 5 d followed by twice daily CCK release stimulant for 5 d. Rats without any treatment were used as control group (Control). Biochemical and histological changes in the pancreas, and secretory function were evaluated on day 12 at 24 h after the last treatment. RESULTS: Feeding ad libitum (AP-C) delayed biochemical, histological and functional recovery from AP. In AP-C rats, bombesin-stimulated pancreatic secretory function and HOMA-ß-cell score were significantly lower than those in other groups of rats. In AP-R rats, protein per DNA ratio and pancreatic exocrine secretory function were significantly low compared with those in Control rats. In AP-S and AP-R/S rats, the above parameters recovered to the Control levels. Bombesin-stimulated pancreatic exocrine response in AP-R/S rats was higher than in AP-S rats and almost returned to control levels. In the pancreas of AP-C rats, destruction of pancreatic acini, marked infiltration of inflammatory cells, and strong expression of α-smooth muscle actin, tumor necrosis factor-α and interleukin-1ß were seen. Pancreatic rest reversed these histological alterations, but not atrophy of pancreatic acini and mild infiltration of inflammatory cells. In AP-S and AP-R/S rats, the pancreas showed almost normal architecture. CONCLUSION: The favorable treatment strategy for AP is to keep the pancreas at rest during an early stage followed by pancreatic stimulation by promoting endogenous CCK release.

Criteria for the diagnosis and severity stratification of acute pancreatitis.

Recent diagnostic and therapeutic progress for severe acute pancreatitis (SAP) remarkably decreased the case-mortality rate. To further decrease the mortality rate of SAP, it is important to precisely evaluate the severity at an early stage, and initiate appropriate treatment as early as possible. Research Committee of Intractable Diseases of the Pancreas in Japan developed simpler criteria combining routinely available data with clinical signs. Severity can be evaluated by laboratory examinations or by clinical signs, reducing the defect values of the severity factors. Moreover, the severity criteria considered laboratory/clinical severity scores and contrast-enhanced computed tomography (CE-CT) findings as independent risk factors. Thus, CE-CT scans are not necessarily required to evaluate the severity of acute pancreatitis. There was no fatal case in mild AP diagnosed by the CE-CT severity score, whereas case-mortality rate in those with SAP was 14.8%. Case-mortality of SAP that fulfilled both the laboratory/clinical and the CE-CT severity criteria was 30.8%. It is recommended, therefore, to perform CE-CT examination to clarify the prognosis in those patients who were diagnosed as SAP by laboratory/clinical severity criteria. Because the mortality rate of these patients with SAP is high, such patients should be transferred to advanced medical units.

Valsartan, a specific angiotensin II receptor blocker, inhibits pancreatic fluid secretion via vagal afferent pathway in conscious rats.

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 25 mg/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 25 mg/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 25 mg/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.

Mild collateral varices and a fundic plexus without perforating veins on EUS predict endoscopic non-recurrence of esophageal varices after EVL.

BACKGROUND/AIMS: This study assessed the risk of recurrence of esophageal varices by evaluating the severity of esophageal collateral and cardiac vascular structures in patients with portal hypertension on EUS before endoscopic variceal ligation (EVL). METHODOLOGY: Twenty-three consecutive patients with esophageal varices at high risk for bleeding were studied. Simultaneous conventional endoscopy and EUS were performed before endoscopic variceal ligation. Based on EUS findings, vascular structures in the esophageal wall and gastric cardia were classified into two grades, mild and severe, and the relationship between the EUS findings and the esophageal varices recurrence rate was analyzed. RESULTS: Recurrence of esophageal varices was detected endoscopically in 16 (69.6%) of the 23 patients within 2 years after EVL. Patients with non-recurrent esophageal varices after EVL were more likely to have mild-grade collateral veins, perforating veins, and a fundic plexus before treatment than those with recurrence. CONCLUSIONS: Mild collateral varices and a fundic plexus without perforating veins on EUS before EVL predict long-term endoscopic non-recurrence of esophageal varices after EVL.

Characteristics of pancreatic diabetes in patients with autoimmune pancreatitis.

OBJECTIVE: Although patients with autoimmune pancreatitis (AIP) tend to have concurrent diverse disorders, very few studies have focused on diabetes mellitus (DM) coexisting with AIP. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Treatment with pravastatin attenuates progression of chronic pancreatitis in rat.

As appropriate therapies for pancreatic fibrosis and inflammation are limited, prognosis of chronic pancreatitis has not improved to date. Recent studies have shown that statins improve inflammation and fibrosis in several organs. We therefore examined the therapeutic effect of pravastatin on progression of chronic pancreatitis by starting this treatment after induction of pancreatic fibrosis in rats. Chronic pancreatitis was induced by continuous pancreatic ductal hypertension (PDH) for 14 days according to our previous study. Pravastatin at a dose of 10 mg/kg/day was administrated directly into the duodenum via cannula from 2 days after induction of PDH. Progression of pancreatic fibrosis and expression levels of transforming growth factor-ß1 and tumor necrosis factor-α mRNA were markedly attenuated after commencement of pravastatin compared with untreated group with PDH. In addition, pravastatin treatment markedly improved pancreatic exocrine function and significantly elevated expression level of interleukin (IL)-10 and superoxide dismutase activity in the pancreas compared with the untreated group with PDH. These results revealed that pravastatin substantially attenuates the progression of pancreatic inflammation, fibrosis and exocrine dysfunction probably by its anti-oxidative property and overproduction of IL-10 in animal model of chronic pancreatitis. These results provide an experimental evidence that pravastatin exerts beneficial effect for progression of chronic pancreatitis.

Transient stasis of pancreatic fluid flow together with mild injury of the pancreatic duct cause chronic pancreatitis.

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.

Gastric mucosal cancer smaller than 7mm can be treated with conventional endoscopic mucosal resection as effectively as with endoscopic submucosal dissection.

BACKGROUND/AIMS: Recently, endoscopic submucosal dissection (ESD) has been accepted for the treatment of gastrointestinal mucosal neoplasms because of the higher en bloc resection rate. However, ESD is technically more difficult, requires a longer procedure time and has more frequent complications compared with conventional endoscopic mucosal resection (EMR). We evaluated retrospectively the clinical outcomes of ESD compared with EMR to determine the size of the lesion for choosing EMR rather than ESD. METHODOLOGY: Three hundred and sixty-five lesions of early gastric cancer were treated endoscopically (146 by EMR and 219 by ESD). We compared en bloc resection, residual tumor and recurrence-free rates between EMR and ESD. RESULTS: En bloc resection rate was significantly higher with ESD (88.5%) than EMR (45.2%). With regard to lesions < or = 7mm in size, en bloc resection, residual tumor and recurrence-free rates did not differ. CONCLUSIONS: Gastric mucosal cancer < or = 7mm can be treated with EMR as effectively as with ESD.

Salt sensitivity is associated with insulin resistance, sympathetic overactivity, and decreased suppression of circulating renin activity in lean patients with essential hypertension.

BACKGROUND: The mechanisms by which a derangement of glucose metabolism causes high blood pressure are not fully understood. OBJECTIVES: This study aimed to clarify the relation between salt sensitivity of blood pressure and insulin resistance, which are important subcharacteristics of hypertension and impaired glucose metabolism, respectively. Effects on the renin-angiotensin and sympathetic nervous systems were also studied. DESIGN: The state of glucose metabolism was assessed by a hyperinsulinemic euglycemic glucose clamp technique and a 75-g oral-glucose-tolerance test in 24 essential hypertensive patients who were lean and without diabetes or chronic kidney disease. The subjects were classified as salt-sensitive or salt-resistant on the basis of the difference (Delta mean blood pressure > or =5%) between 24-h ambulatory blood pressure monitoring results on the seventh day of low-salt (34 mmol/d) and high-salt (252 mmol/d) diets. Urine and blood samples were collected for analyses. RESULTS: There was a robust inverse relation between the glucose infusion rate (GIR) and the salt sensitivity index. The GIR correlated directly with the change in urinary sodium excretion and was inversely related to the change in hematocrit when the salt diet was changed from low to high, which is indicative of salt and fluid retention in salt-sensitive subjects. The GIR also showed an inverse correlation compared with the changes in urinary norepinephrine excretion, plasma renin activity, and plasma aldosterone concentration. CONCLUSIONS: Salt sensitivity of blood pressure is strongly associated with insulin resistance in lean, essential hypertensive patients. Hyperinsulinemia, sympathetic overactivation, and reduced suppression of the renin-angiotensin system may play a role in this relation.

The revised Japanese clinical diagnostic criteria for chronic pancreatitis.

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.

Epidemiological study of pancreatic diabetes in Japan in 2005: a nationwide study.

OBJECTIVES: There have been few epidemiological studies on pancreatic diabetes. In this study, we determined the incidence and pathology of pancreatic diabetes in Japan. METHODS: We examined the epidemiology of pancreatic diabetes in Japan in 2005 by using a nationwide stratified random-sampling method. Especially, we focused on newly developed diabetes in association with the occurrence of pancreatic disease (true pancreatic diabetes). RESULTS: A total of 19,500 individuals received treatment for true pancreatic diabetes, accounting for 0.8% of patients with diabetes. Prevalence was estimated to be 15.2 per 100,000 with an annual onset incidence of 1.1 per 100,000. With regard to the complications in true pancreatic diabetes, the incidence of retinopathy was lower than that in types 1 and 2 diabetes. Among true pancreatic diabetes with chronic pancreatitis, alcoholic pancreatitis was found in the largest sector. Furthermore, as many as 53.7% were continuous drinkers, and 66.7% received insulin therapy. The frequency of hypoglycemia was high in regular drinkers treated with insulin. Hypoglycemia was a major cause of death in patients who were on insulin and continuous drinkers. CONCLUSION: We clarified the epidemiology of pancreatic diabetes in Japan. Patients with chronic pancreatitis-associated pancreatic diabetes should receive lifestyle guidance focused on drinking cessation.

Animal models of chronic pancreatitis.

Animal models for CP in rats can be classified into 2 groups: one is noninvasive or nonsurgical models and the other is invasive or surgical models. Pancreatic injury induced by repetitive injections of supramaximal stimulatory dose of caerulein (Cn) or by intraductal infusion of sodium taurocholate (NaTc) recovered within 14 days, whereas that caused by repetitive injection of arginine or by intraductal infusion of oleic acid was persistent. However, the destroyed acinar tissues were replaced by fatty tissues without fibrosis. Transient stasis of pancreatic fluid flow by 0.01% agarose and minimum injury of the pancreatic duct by 0.1% NaTc solution induced progressive pancreatic injury although one alone is insufficient to cause persistent pancreatic injury. However, the damaged tissue was replaced by fatty tissue without fibrosis. Continuous pancreatic ductal hypertension (PDH) caused diffuse interlobular and intralobular fibrosis closely resembling human CP.

Overexpression of Smad6 exacerbates pancreatic fibrosis in murine caerulein-induced chronic pancreatic injuries.

OBJECTIVES: We examined the effect of the overexpression of Smad6 on pancreatic fibrosis after chronic pancreatic injury. METHODS: Chronic pancreatic injury was induced in transgenic mice overexpressing Smad6 (Tg mice) in acini and wild-type (Wt) mice by 3 episodes of acute pancreatitis per week for 1 to 4 consecutive weeks. Acute pancreatitis was elicited by 6 intraperitoneal injections of caerulein (Cn) at 50 microg/kg of body weight at hourly intervals. Pancreatic fibrosis was evaluated by histological examination and hydroxyproline content before and 1, 2, 3, and 4 weeks of repetitive episodes of Cn-induced acute pancreatitis. We further determined transforming growth factor beta1 (TGF-beta1) messenger RNA expression and trypsin activity in the pancreas. RESULTS: After repetitive episodes of acute pancreatitis, pancreatic fibrosis in Tg mice was significantly severer than that in Wt mice at all time points (weeks 1-4). The expression of TGF-beta1 messenger RNA and the activity of trypsin in the pancreas in the Tg mice were significantly high compared with those in the Wt mice at all corresponding time points after repetitive episodes of acute pancreatitis. CONCLUSIONS: These results demonstrated that overexpression of Smad6 in acini enhanced the development of pancreatic fibrosis after chronic pancreatic injury.

Association analyses of genetic polymorphisms of GSTM1, GSTT1, NQO1, NAT2, LPL, PRSS1, PSTI, and CFTR with chronic alcoholic pancreatitis in Japan.

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.

Long-term treatment with proton pump inhibitor is associated with undesired weight gain.

AIM: To examine the effects of long-term proton pump inhibitor (PPI) therapy on body weight (BW) and body mass index (BMI) in patients with gastroesophageal reflux disease (GERD). METHODS: The subjects were 52 patients with GERD and 58 sex- and age-matched healthy controls. GERD patients were treated with PPI for a mean of 2.2 years (range, 0.8-5.7 years), and also advised on lifestyle modifications (e.g. selective diet, weight management). BW, BMI and other parameters were measured at baseline and end of study. RESULTS: Twenty-four GERD patients were treated daily with 10 mg omeprazole, 12 with 20 mg omeprazole, 8 with 10 mg rabeprazole, 5 with 15 mg lansoprazole, and 3 patients with 30 mg lansoprazole. At baseline, there were no differences in BW and BMI between reflux patients and controls. Patients with GERD showed increases in BW (baseline: 56.4 +/- 10.4 kg, end: 58.6 +/- 10.8 kg, mean +/- SD, P < 0.0001) and BMI (baseline: 23.1 +/- 3.1 kg/m(2), end: 24.0 +/- 3.1 kg/m(2), P < 0.001), but no such changes were noted in the control group. Mean BW increased by 3.5 kg (6.2% of baseline) in 37 (71%) reflux patients but decreased in only 6 (12%) patients during treatment. CONCLUSION: Long-term PPI treatment was associated with BW gain in patients with GERD. Reflux patients receiving PPI should be encouraged to manage BW through lifestyle modifications.

Decreased production of immunoglobulin M and A in autoimmune pancreatitis.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Interactions between the endocrine and exocrine pancreas and their clinical relevance.

In consequence of the close anatomical and functional links between the exocrine and endocrine pancreas, any disease affecting one of these parts will inevitably affect the other. Pancreatic conditions which might cause diabetes mellitus include acute and chronic pancreatitis, pancreatic surgery, cystic fibrosis and pancreatic cancer. The development of diabetes greatly influences the prognosis and quality of life of patients with exocrine pancreatic diseases. It may cause life-threatening complications, such as hypoglycemia, due to the lack of glucagon and the impaired absorption of nutrients, or the micro- and macrovascular complications may impair the organ functions. Diabetes mellitus is an independent risk factor of mortality in those with exocrine pancreatic diseases. The treatment of pancreatic diabetes, a distinct metabolic and clinical form of diabetes, requires special knowledge. Diet and pancreatic enzyme replacement therapy may be sufficient in the early stages. Oral antidiabetic drugs are not recommended. If the diet proves inadequate to reach the glycemic goals, insulin treatment with multiple injections is required. Impairments of the exocrine pancreatic function and morphology in diabetic patients are frequent and well known. Atrophy of the exocrine tissue may be caused by the lack of trophic insulin, whereas pancreatic fibrosis can result from activation of stellate cells by hyperglycemia, or from microangiopathy and neuropathy. The regulation of the exocrine pancreatic function is also damaged because of the impaired effect of islet hormones. In the event of a proven impairment of the pancreatic exocrine function in diabetes mellitus, pancreatic enzyme replacement therapy is indicated. This may improve the nutritional condition of the patient and decrease the metabolic instability.