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Sample records for exocrine pancreatic acinar

  1. Acinar-to-ductal metaplasia accompanies c-myc-induced exocrine pancreatic cancer progression in transgenic rodents.

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    Grippo, Paul J; Sandgren, Eric P

    2012-09-01

    Several important characteristics of exocrine pancreatic tumor pathogenesis remain incompletely defined, including identification of the cell of origin. Most human pancreatic neoplasms are ductal adenocarcinomas. However, acinar cells have been proposed as the source of some ductal neoplasms through a process of acinar-to-ductal metaplasia. The oncogenic transcription factor c-myc is associated with human pancreatic neoplasms. Transgenic mice overexpressing c-myc under control of acinar cell-specific elastase (Ela) gene regulatory elements not only develop acinar cell carcinomas but also mixed neoplasms that display both acinar-like neoplastic cells and duct-like neoplastic cells. In this report, we demonstrate that, first, c-myc is sufficient to induce acinar hyperplasia, though neoplastic lesions develop focally. Second, cell proliferation remains elevated in the neoplastic duct cell compartment of mixed neoplasms. Third, the proliferation/apoptosis ratio in cells from all lesion types remains constant, suggesting that differential regulation of these processes is not a feature of cancer progression in this model. Fourth, before the development of mixed neoplasms, there is transcriptional activation of the duct cell-specific cytokeratin-19 gene promoter in multicellular foci of amylase-positive acinar neoplasms. This observation provides direct evidence for metaplasia as the mechanism underlying development of ductal neoplastic cells within the context of an acinar neoplasm and suggests that the stimulus for this transformation acts over a multicellular domain or field within a neoplasm. Finally, focal ductal elements develop in some acinar cell carcinomas in Ela-c-myc transgenic rats, indicating that myc-associated acinar-to-ductal metaplasia is not restricted to the mouse. Copyright © 2011 UICC.

  2. Quantitative characterization of the protein contents of the exocrine pancreatic acinar cell by soft x-ray microscopy and advanced digital imaging methods

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    Loo, Jr., Billy W. [Univ. of California, Berkeley, CA (United States)

    2000-06-01

    The study of the exocrine pancreatic acinar cell has been central to the development of models of many cellular processes, especially of protein transport and secretion. Traditional methods used to examine this system have provided a wealth of qualitative information from which mechanistic models have been inferred. However they have lacked the ability to make quantitative measurements, particularly of the distribution of protein in the cell, information critical for grounding of models in terms of magnitude and relative significance. This dissertation describes the development and application of new tools that were used to measure the protein content of the major intracellular compartments in the acinar cell, particularly the zymogen granule. Soft x-ray microscopy permits image formation with high resolution and contrast determined by the underlying protein content of tissue rather than staining avidity. A sample preparation method compatible with x-ray microscopy was developed and its properties evaluated. Automatic computerized methods were developed to acquire, calibrate, and analyze large volumes of x-ray microscopic images of exocrine pancreatic tissue sections. Statistics were compiled on the protein density of several organelles, and on the protein density, size, and spatial distribution of tens of thousands of zymogen granules. The results of these measurements, and how they compare to predictions of different models of protein transport, are discussed.

  3. exocrine pancreatic function

    African Journals Online (AJOL)

    Summary. Background:- Faecal pancreatic elastase-l is a laboratory based test used for the diagnosis or exclusion of exocrine pancreatic insufficiencies. Pancreatic elastase-l, is released into blood circulation during inflammation of the pancreas, but unlike most pancreatic enzymes it is stable during in- testinal passage ...

  4. [Exocrine pancreatic insufficiency (author's transl)].

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    Götze, H

    1980-12-01

    Exocrine pancreatic insufficiency usually does not develop before reduction of enzyme output by more than 90%. Patients with pancreatic insufficiency have a ravenous appetite but fail to thrive from malnutrition. The caloric deprivation is primarily due to fat malabsorption, recognized by the passage of bulky foul smelling greasy stools. Several isolated enzyme deficiencies can be separated from diseases with generalised pancreatic insufficiency. Under replacement therapy with pancreatic enzyme supplements most patients improve and gain weight, although fat and bile acid malabsorption are not abolished.

  5. Pancreatic Exocrine Insufficiency in Pancreatic Cancer

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    Miroslav Vujasinovic

    2017-02-01

    Full Text Available Abstract: Cancer patients experience weight loss for a variety of reasons, commencing with the tumor’s metabolism (Warburg effect and proceeding via cachexia to loss of appetite. In pancreatic cancer, several other factors are involved, including a loss of appetite with a particular aversion to meat and the incapacity of the pancreatic gland to function normally when a tumor is present in the pancreatic head. Pancreatic exocrine insufficiency is characterized by a deficiency of the enzymes secreted from the pancreas due to the obstructive tumor, resulting in maldigestion. This, in turn, contributes to malnutrition, specifically a lack of fat-soluble vitamins, antioxidants, and other micronutrients. Patients with pancreatic cancer and pancreatic exocrine insufficiency have, overall, an extremely poor prognosis with regard to surgical outcome and overall survival. Therefore, it is crucial to be aware of the mechanisms involved in the disease, to be able to diagnose pancreatic exocrine insufficiency early on, and to treat malnutrition appropriately, for example, with pancreatic enzymes.

  6. Pancreatic ductal bicarbonate secretion: challenge of the acinar acid load

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    Peter eHegyi

    2011-07-01

    Full Text Available Acinar and ductal cells of the exocrine pancreas form a close functional unit. Although most studies contain data either on acinar or ductal cells, an increasing number of evidence highlights the importance of the pancreatic acinar-ductal functional unit. One of the best examples for this functional unit is the regulation of luminal pH by both cell types. Protons co-released during exocytosis from acini cause significant acidosis, whereas, bicarbonate secreted by ductal cells cause alkalization in the lumen. This suggests that the first and probably one of the most important role of bicarbonate secretion by pancreatic ductal cells is not only to neutralize the acid chyme entering into the duodenum from the stomach, but to neutralize acidic content secreted by acinar cells. To accomplish this role, it is more than likely that ductal cells have physiological sensing mechanisms which would allow them to regulate luminal pH. To date, four different classes of acid-sensing ion channels have been identified in the gastrointestinal tract (transient receptor potential ion channels, two-pore domain potassium channel, ionotropic purinoceptor and acid-sensing ion channel, however, none of these have been studied in pancreatic ductal cells. In this mini-review, we summarize our current knowledge of these channels and urge scientists to characterize ductal acid-sensing mechanisms and also to investigate the challenge of the acinar acid load on ductal cells.

  7. [Pancreatic acinar neoplasms : Comparative molecular characterization].

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    Bergmann, F

    2016-11-01

    Pancreatic acinar cell carcinomas are biologically aggressive neoplasms for which treatment options are very limited. The molecular mechanisms of tumor initiation and progression are largely not understood and precursor lesions have not yet been identified. In this study, pancreatic acinar cell carcinomas were cytogenetically characterized as well as by molecular and immunohistochemical analyses. Corresponding investigations were carried out on pancreatic ductal adenocarcinomas and pancreatic neuroendocrine neoplasms augmented by functional analyses. We show that pancreatic acinar cell carcinomas display a microsatellite stable, chromosomal unstable genotype, characterized by recurrent chromosomal imbalances that clearly discriminate them from pancreatic ductal adenocarcinomas and neuroendocrine neoplasms. Based on findings obtained from comparative genomic hybridization, candidate genes could be identified, such as deleted in colorectal cancer (DCC) and c-MYC. Furthermore, several therapeutic targets were identified in acinar cell carcinomas and other pancreatic neoplasms, including epidermal growth factor receptor (EGFR), L1 cell adhesion molecule (L1CAM) and heat shock protein 90 (HSP90). Moreover, L1CAM was shown to play a significant role in the tumorigenesis of pancreatic ductal adenocarcinoma. Functional analyses in cell lines derived from pancreatic neuroendocrine neoplasms revealed promising anti-tumorigenic effects using EGFR and HSP90 inhibitors affecting the cell cycle and in the case of HSP90, regulating several other oncogenes. Finally, based on mutational analyses of mitochondrial DNA, molecular evidence is provided that acinar cell cystadenomas (or better cystic acinar transformation) represent non-clonal lesions, suggesting an inflammatory reactive non-neoplastic nature.

  8. Paracrine Secretion of Transforming Growth Factor β by Ductal Cells Promotes Acinar-to-Ductal Metaplasia in Cultured Human Exocrine Pancreas Tissues.

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    Akanuma, Naoki; Liu, Jun; Liou, Geou-Yarh; Yin, Xue; Bejar, Kaitlyn R; Liu, Chengyang; Sun, Lu-Zhe; Storz, Peter; Wang, Pei

    2017-10-01

    We aimed to evaluate the contribution of acinar-to-ductal metaplasia (ADM) to the accumulation of cells with a ductal phenotype in cultured human exocrine pancreatic tissues and reveal the underlying mechanism. We sorted and cultured viable cell populations in human exocrine pancreatic tissues with a flow cytometry-based lineage tracing method to evaluate possible mechanisms of ADM. Cell surface markers, gene expression pattern, and sphere formation assay were used to examine ADM. A large proportion of acinar cells gained CD133 expression during the 2-dimensional culture and showed down-regulation of acinar markers and up-regulation of ductal markers, assuming an ADM phenotype. In a serum-free culture condition, ADM induction was mainly dependent on transforming growth factor β (TGF-β) secreted from cultured ductal cells. Human acinar cells when cultured alone for a week in a serum-free condition do not undergo ADM. However, serum may contain other factors besides TGF-β to induce ADM in human acinar cells. In addition, we found that TGF-β cannot induce ADM of murine acinar cells. Ductal cells are the major source of TGF-β that induces ADM in cultured human exocrine pancreatic tissues. This culture system might be a useful model to investigate the mechanism of ADM in human cells.

  9. Cholinergic intrapancreatic neurons induce Ca²+ signaling and early-response gene expression in pancreatic acinar cells.

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    Turner, D J; cowles, R A; Segura, B J; Romanchuk, G; Barnhart, D C; Mulholland, M W

    2000-01-01

    Pancreatic exocrine function has been demonstrated to be under neuronal regulation. The pathways responsible for this effect, and the long-term consequences of such interactions, are incompletely described. The effects of neuronal depolarization on pancreatic acinar cells were studied to determine whether calcium signaling and c-fos expression were activated. In pancreatic lobules, which contain both neurons and acinar cells, agonists that selectively stimulated neurons increased intracellular calcium in acinar cells. Depolarization also led to the expression of c-fos protein in 24% +/- 4% of the acinar cells. In AR42J pancreatic acinar cells, cholinergic stimulation demonstrated an average increase of 398 +/- 19 nmol/L in intracellular calcium levels, and induced c-fos expression that was time and dose dependent. The data indicate that intrapancreatic neurons induce Ca²+ signaling and early-response gene expression in pancreatic acinar cells.

  10. Papillocystic Variant of Acinar Cell Pancreatic Carcinoma

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    Jasim Radhi

    2010-01-01

    Full Text Available Acinar cell pancreatic carcinoma is a rare solid malignant neoplasm. Recent review of the literature showed occasional cases with papillary or papillocystic growth patterns, ranging from 2 to 5 cm in diameter. We report a large 10 cm pancreatic tumor with papillocystic pathology features involving the pancreatic head. The growth pattern of these tumors could be mistaken for intraductal papillary mucinous tumors or other pancreatic cystic neoplasms.

  11. Exocrine pancreatic carcinogenesis and autotaxin expression.

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    Sandeep Kadekar

    Full Text Available Exocrine pancreatic cancer is an aggressive disease with an exceptionally high mortality rate. Genetic analysis suggests a causative role for environmental factors, but consistent epidemiological support is scarce and no biomarkers for monitoring the effects of chemical pancreatic carcinogens are available. With the objective to identify common traits for chemicals inducing pancreatic tumors we studied the National Toxicology Program (NTP bioassay database. We found that male rats were affected more often than female rats and identified eight chemicals that induced exocrine pancreatic tumors in males only. For a hypothesis generating process we used a text mining tool to analyse published literature for suggested mode of actions (MOA. The resulting MOA analysis suggested inflammatory responses as common feature. In cell studies we found that all the chemicals increased protein levels of the inflammatory protein autotaxin (ATX in Panc-1, MIA PaCa-2 or Capan-2 cells. Induction of MMP-9 and increased invasive migration were also frequent effects, consistent with ATX activation. Testosterone has previously been implicated in pancreatic carcinogenesis and we found that it increased ATX levels. Our data show that ATX is a target for chemicals inducing pancreatic tumors in rats. Several lines of evidence implicate ATX and its product lysophosphatidic acid in human pancreatic cancer. Mechanisms of action may include stimulated invasive growth and metastasis. ATX may interact with hormones or onco- or suppressor-genes often deregulated in exocrine pancreatic cancer. Our data suggest that ATX is a target for chemicals promoting pancreatic tumor development.

  12. Heritability of exocrine pancreatic insufficiency in German Shepherd dogs.

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    Westermarck, E; Saari, S A M; Wiberg, M E

    2010-01-01

    Several studies have revealed that exocrine pancreatic insufficiency (EPI) is an inherited disease in German Shepherd Dogs (GSDs). Pedigree analyses have suggested an autosomal recessive inheritance model. Test mating of 2 dogs with EPI. A sire and dam purebred GSD both with EPI and a litter of 6 puppies. Test mating and long-term follow-up of offspring. The pancreas was biopsied via laparotomy on 26 occasions. Serum trypsin-like immunoreactivity was measured. Study was approved by Animal Ethics Committee. During the 12-year study period only 2 of the 6 offsprings developed pancreatic acinar atrophy (PAA). In 1 puppy, end-stage PAA and in the other puppy partial PAA was diagnosed. PAA is not a congenital disease in GSDs. This study provided evidence that PAA is not inherited in a simple autosomal recessive fashion.

  13. Diagnosis and management of pancreatic exocrine insufficiency.

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    Nikfarjam, Mehrdad; Wilson, Jeremy S; Smith, Ross C

    2017-08-21

    In 2015, the Australasian Pancreatic Club (APC) published the Australasian guidelines for the management of pancreatic exocrine insufficiency (http://pancreas.org.au/2016/01/pancreatic-exocrine-insufficiency-guidelines). Pancreatic exocrine insufficiency (PEI) occurs when normal digestion cannot be sustained due to insufficient pancreatic digestive enzyme activity. This may be related to a breakdown, at any point, in the pancreatic digestive chain: pancreatic stimulation; synthesis, release or transportation of pancreatic enzymes; or synchronisation of secretions to mix with ingested food. Main recommendations: The guidelines provide advice on diagnosis and management of PEI, noting the following: A high prevalence of PEI is seen in certain diseases and conditions, such as cystic fibrosis, acute and chronic pancreatitis, pancreatic cancer and pancreatic surgery. The main symptoms of PEI are steatorrhoea or diarrhoea, abdominal pain, bloating and weight loss. These symptoms are non-specific and often go undetected and untreated. PEI diagnosis is predominantly based on clinical findings and the presence of underlying disease. The likelihood of PEI in suspected patients has been categorised into three groups: definite, possible and unlikely. If left untreated, PEI may lead to complications related to fat malabsorption and malnutrition, and have an impact on quality of life. Pancreatic enzyme replacement therapy (PERT) remains the mainstay of PEI treatment with the recommended adult initial enzyme dose being 25 000-40 000 units of lipase per meal, titrating up to a maximum of 75 000-80 000 units of lipase per meal. Adjunct acid-suppressing therapy may be useful when patients still experience symptoms of PEI on high dose PERT. Nutritional management by an experienced dietitian is essential. Changes in management as a result of these guidelines: These are the first guidelines to classify PEI as being definite, possible or unlikely, and provide a diagnostic algorithm to

  14. Proteoglycans support proper granule formation in pancreatic acinar cells.

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    Aroso, Miguel; Agricola, Brigitte; Hacker, Christian; Schrader, Michael

    2015-10-01

    Zymogen granules (ZG) are specialized organelles in the exocrine pancreas which allow digestive enzyme storage and regulated secretion. The molecular mechanisms of their biogenesis and the sorting of zymogens are still incompletely understood. Here, we investigated the role of proteoglycans in granule formation and secretion of zymogens in pancreatic AR42J cells, an acinar model system. Cupromeronic Blue cytochemistry and biochemical studies revealed an association of proteoglycans primarily with the granule membrane. Removal of proteoglycans by carbonate treatment led to a loss of membrane curvature indicating a supportive role in the maintenance of membrane shape and stability. Chemical inhibition of proteoglycan synthesis impaired the formation of normal electron-dense granules in AR42J cells and resulted in the formation of unusually small granule structures. These structures still contained the zymogen carboxypeptidase, a cargo molecule of secretory granules, but migrated to lighter fractions after density gradient centrifugation. Furthermore, the basal secretion of amylase was increased in AR42J cells after inhibitor treatment. In addition, irregular-shaped granules appeared in pancreatic lobules. We conclude that the assembly of a proteoglycan scaffold at the ZG membrane is supporting efficient packaging of zymogens and the proper formation of stimulus-competent storage granules in acinar cells of the pancreas.

  15. Acinar cell apoptosis in Serpini2-deficient mice models pancreatic insufficiency.

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    Stacie K Loftus

    2005-09-01

    Full Text Available Pancreatic insufficiency (PI when left untreated results in a state of malnutrition due to an inability to absorb nutrients. Frequently, PI is diagnosed as part of a larger clinical presentation in cystic fibrosis or Shwachman-Diamond syndrome. In this study, a mouse model for isolated exocrine PI was identified in a mouse line generated by a transgene insertion. The trait is inherited in an autosomal recessive pattern, and homozygous animals are growth retarded, have abnormal immunity, and have reduced life span. Mice with the disease locus, named pequeño (pq, exhibit progressive apoptosis of pancreatic acinar cells with severe exocrine acinar cell loss by 8 wk of age, while the islets and ductal tissue persist. The mutation in pq/pq mice results from a random transgene insertion. Molecular characterization of the transgene insertion site by fluorescent in situ hybridization and genomic deletion mapping identified an approximately 210-kb deletion on Chromosome 3, deleting two genes. One of these genes, Serpini2, encodes a protein that is a member of the serpin family of protease inhibitors. Reintroduction of only the Serpini2 gene by bacterial artificial chromosome transgenic complementation corrected the acinar cell defect as well as body weight and immune phenotypes, showing that deletion of Serpini2 causes the pequeño phenotype. Dietary supplementation of pancreatic enzymes also corrected body size, body weight, and immunodeficiency, and increased the life span of Serpini2-deficient mice, despite continued acinar cell loss. To our knowledge, this study describes the first characterized genetic animal model for isolated PI. Genetic complementation of the transgene insertion mutant demonstrates that Serpini2 deficiency directly results in the acinar cell apoptosis, malabsorption, and malnutrition observed in pq/pq mice. The rescue of growth retardation, immunodeficiency, and mortality by either Serpini2 bacterial artificial chromosome

  16. Numb regulates acinar cell dedifferentiation and survival during pancreatic damage and acinar-to-ductal metaplasia.

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    Greer, Renee L; Staley, Binnaz K; Liou, Angela; Hebrok, Matthias

    2013-11-01

    Pancreatic ductal adenocarcinoma (PDA) is a leading cause of cancer-related death. Through the process of acinar-to-ductal metaplasia (ADM), pancreatic acinar cells give rise to pancreatic intraepithelial neoplasia (PanIN), the most common precursor of PDA. However, even when Kras is activated in a majority of acinar cells, ADM and subsequent development of PanINs is inefficient in the absence of additional stresses. Numb regulates cell junctions, integrins, and the activity of embryonic signaling pathways; therefore, we investigated its effects on acinar cell dedifferentiation, regeneration, and metaplasia. We used mouse models of pancreatic regeneration and PDA as well as mice with loss-of-function alleles of Numb (p48Cre/p48Cre(ER);Numb(f/f) and p48Cre/p48Cre(ER);Kras(G12D);Numb(f/f) mice) to study the roles of Numb in pancreatic regeneration and ADM. Loss of Numb resulted in premature dedifferentiation of acinar cells in response to injury due to administration of the cholecystokinin analogue cerulein and interfered with acinar cell regeneration. Numb was found to regulate multiple signaling pathways in acinar cells during cerulein-induced pancreatitis. Disruption of Numb accelerated and destabilized ADM in the context of oncogenic Kras (in p48Cre;Kras(G12D);Numb(f/f) and p48Cre(ER);Kras(G12D);Numb(f/f) mice). Numb is an important regulator of acinar cell differentiation and viability during metaplasia. In mice with pancreatitis or pancreatic injury, elimination of Numb causes dedifferentiated acinar cells to undergo apoptosis, and this is not mitigated by oncogenic Kras. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

  17. PD2/Paf1 depletion in pancreatic acinar cells promotes acinar-to-ductal metaplasia.

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    Dey, Parama; Rachagani, Satyanarayana; Vaz, Arokia P; Ponnusamy, Moorthy P; Batra, Surinder K

    2014-06-30

    Pancreatic differentiation 2 (PD2), a PAF (RNA Polymerase II Associated Factor) complex subunit, is overexpressed in pancreatic cancer cells and has demonstrated potential oncogenic property. Here, we report that PD2/Paf1 expression was restricted to acinar cells in the normal murine pancreas, but its expression increased in the ductal cells of KrasG12D/Pdx1Cre (KC) mouse model of pancreatic cancer with increasing age, showing highest expression in neoplastic ductal cells of 50 weeks old mice. PD2/Paf1 was specifically expressed in amylase and CK19 double positive metaplastic ducts, representing intermediate structures during pancreatic acinar-to-ductal metaplasia (ADM). Similar PD2/Paf1 expression was observed in murine pancreas that exhibited ADM-like histology upon cerulein challenge. In normal mice, cerulein-mediated inflammation induced a decrease in PD2/Paf1 expression, which was later restored upon recovery of the pancreatic parenchyma. In KC mice, however, PD2/Paf1 mRNA level continued to decrease with progressive dysplasia and subsequent neoplastic transformation. Additionally, knockdown of PD2/Paf1 in pancreatic acinar cells resulted in the abrogation of Amylase, Elastase and Lipase (acinar marker) mRNA levels with simultaneous increase in CK19 and CAII (ductal marker) transcripts. In conclusion, our studies indicate loss of PD2/Paf1 expression during acinar transdifferentiation in pancreatic cancer initiation and PD2/Paf1 mediated regulation of lineage specific markers.

  18. A novel 2-step culture model for long-term in vitro maintenance of human pancreatic acinar cells.

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    Bläuer, Merja; Sand, Juhani; Nordback, Isto; Laukkarinen, Johanna

    2014-07-01

    Because of rapid loss of functional differentiation that regularly occurs in vitro, culture systems permitting long-term studies on pancreatic acinar cells pose a major technical challenge. We recently described a method for long-term cultivation of mouse acinar cells. Here, we introduce a novel 2-step culture system for human pancreatic acinar cells. The system involves 2 successive culture phases, which are as follows: primary organotypic culture of isolated acinar clusters under soft Matrigel (BD Biosciences, Bedford, Mass; range, 2-3 days) followed by dissociation and secondary monolayer culture of acinar cells (4 days). Basal and agonist-induced amylase secretion was used to assess the secretory capability. Acinar clusters showed excellent morphology and stable basal amylase secretion throughout primary culture. Carbachol (0.1 mM/L) increased amylase secretion 1.4-fold (P = 0.021) versus basal in 3 independent 4-day secondary cultures. Despite the controversy about the presence and roles of cholecystokinin receptors in human acinar cells, one of them also responded to 0.1 and 10 nM/L concentrations of caerulein with 1.9- and 1.4-fold increases in the rate of amylase secretion, respectively. Our technique allows cultured human acinar cells to maintain secretory differentiation for a minimum of 7 days. The technique provides novel prospects for in vitro modeling of the human exocrine pancreas.

  19. ATP release, generation and hydrolysis in exocrine pancreatic duct cells

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    Kowal, Justyna Magdalena; Yegutkin, G.G.; Novak, Ivana

    2015-01-01

    Extracellular adenosine triphosphate (ATP) regulates pancreatic duct function via P2Y and P2X receptors. It is well known that ATP is released from upstream pancreatic acinar cells. The ATP homeostasis in pancreatic ducts, which secrete bicarbonate-rich fluid, has not yet been examined. First, ou...

  20. Loss of acinar cell IKKα triggers spontaneous pancreatitis in mice.

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    Li, Ning; Wu, Xuefeng; Holzer, Ryan G; Lee, Jun-Hee; Todoric, Jelena; Park, Eek-Joong; Ogata, Hisanobu; Gukovskaya, Anna S; Gukovsky, Ilya; Pizzo, Donald P; VandenBerg, Scott; Tarin, David; Atay, Ciǧdem; Arkan, Melek C; Deerinck, Thomas J; Moscat, Jorge; Diaz-Meco, Maria; Dawson, David; Erkan, Mert; Kleeff, Jörg; Karin, Michael

    2013-05-01

    Chronic pancreatitis is an inflammatory disease that causes progressive destruction of pancreatic acinar cells and, ultimately, loss of pancreatic function. We investigated the role of IκB kinase α (IKKα) in pancreatic homeostasis. Pancreas-specific ablation of IKKα (Ikkα(Δpan)) caused spontaneous and progressive acinar cell vacuolization and death, interstitial fibrosis, inflammation, and circulatory release of pancreatic enzymes, clinical signs resembling those of human chronic pancreatitis. Loss of pancreatic IKKα causes defective autophagic protein degradation, leading to accumulation of p62-mediated protein aggregates and enhanced oxidative and ER stress in acinar cells, but none of these effects is related to NF-κB. Pancreas-specific p62 ablation prevented ER and oxidative stresses and attenuated pancreatitis in Ikkα(Δpan) mice, suggesting that cellular stress induced by p62 aggregates promotes development of pancreatitis. Importantly, downregulation of IKKα and accumulation of p62 aggregates were also observed in chronic human pancreatitis. Our studies demonstrate that IKKα, which may control autophagic protein degradation through its interaction with ATG16L2, plays a critical role in maintaining pancreatic acinar cell homeostasis, whose dysregulation promotes pancreatitis through p62 aggregate accumulation.

  1. Pancreatic Fat Accumulation, Fibrosis, and Acinar Cell Injury in the Zucker Diabetic Fatty Rat Fed a Chronic High-Fat Diet

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    Matsuda, Akiko; Makino, Naohiko; Tozawa, Tomohiro; Shirahata, Nakao; Honda, Teiichiro; Ikeda, Yushi; Sato, Hideyuki; Ito, Miho; Kakizaki, Yasuharu; Akamatsu, Manabu; Ueno, Yoshiyuki; Kawata, Sumio

    2014-01-01

    Objective The histological alteration of the exocrine pancreas in obesity has not been clarified. In the present study, we investigated biochemical and histological changes in the exocrine pancreas of obese model rats. Methods Zucker lean rats were fed a standard diet, and Zucker diabetic fatty (ZDF) rats were divided into 2 groups fed a standard diet and a high-fat diet, respectively. These experimental groups were fed each of the diets from 6 weeks until 12, 18, 24 weeks of age. We performed blood biochemical assays and histological analysis of the pancreas. Results In the ZDF rats fed a high-fat diet, the ratio of accumulated pancreatic fat area relative to exocrine gland area was increased significantly at 18 weeks of age in comparison with the other 2 groups (P fat diet, fat accumulates in pancreatic acinar cells, and this fatty change seems to be related to subsequent pancreatic fibrosis and acinar cell injury. PMID:24717823

  2. Pancreatic fat accumulation, fibrosis, and acinar cell injury in the Zucker diabetic fatty rat fed a chronic high-fat diet.

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    Matsuda, Akiko; Makino, Naohiko; Tozawa, Tomohiro; Shirahata, Nakao; Honda, Teiichiro; Ikeda, Yushi; Sato, Hideyuki; Ito, Miho; Kakizaki, Yasuharu; Akamatsu, Manabu; Ueno, Yoshiyuki; Kawata, Sumio

    2014-07-01

    The histological alteration of the exocrine pancreas in obesity has not been clarified. In the present study, we investigated biochemical and histological changes in the exocrine pancreas of obese model rats. Zucker lean rats were fed a standard diet, and Zucker diabetic fatty (ZDF) rats were divided into 2 groups fed a standard diet and a high-fat diet, respectively. These experimental groups were fed each of the diets from 6 weeks until 12, 18, 24 weeks of age. We performed blood biochemical assays and histological analysis of the pancreas. In the ZDF rats fed a high-fat diet, the ratio of accumulated pancreatic fat area relative to exocrine gland area was increased significantly at 18 weeks of age in comparison with the other 2 groups (P fat diet, fat accumulates in pancreatic acinar cells, and this fatty change seems to be related to subsequent pancreatic fibrosis and acinar cell injury.

  3. Activating transcription factor 3 promotes loss of the acinar cell phenotype in response to cerulein-induced pancreatitis in mice.

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    Fazio, Elena N; Young, Claire C; Toma, Jelena; Levy, Michael; Berger, Kurt R; Johnson, Charis L; Mehmood, Rashid; Swan, Patrick; Chu, Alphonse; Cregan, Sean P; Dilworth, F Jeffrey; Howlett, Christopher J; Pin, Christopher L

    2017-09-01

    Pancreatitis is a debilitating disease of the exocrine pancreas that, under chronic conditions, is a major susceptibility factor for pancreatic ductal adenocarcinoma (PDAC). Although down-regulation of genes that promote the mature acinar cell fate is required to reduce injury associated with pancreatitis, the factors that promote this repression are unknown. Activating transcription factor 3 (ATF3) is a key mediator of the unfolded protein response, a pathway rapidly activated during pancreatic insult. Using chromatin immunoprecipitation followed by next-generation sequencing, we show that ATF3 is bound to the transcriptional regulatory regions of >30% of differentially expressed genes during the initiation of pancreatitis. Of importance, ATF3-dependent regulation of these genes was observed only upon induction of pancreatitis, with pathways involved in inflammation, acinar cell differentiation, and cell junctions being specifically targeted. Characterizing expression of transcription factors that affect acinar cell differentiation suggested that acinar cells lacking ATF3 maintain a mature cell phenotype during pancreatitis, a finding supported by maintenance of junctional proteins and polarity markers. As a result, Atf3-/- pancreatic tissue displayed increased tissue damage and inflammatory cell infiltration at early time points during injury but, at later time points, showed reduced acinar-to-duct cell metaplasia. Thus our results reveal a critical role for ATF3 as a key regulator of the acinar cell transcriptional response during injury and may provide a link between chronic pancreatitis and PDAC. © 2017 Fazio et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

  4. Is pancreatic exocrine insufficiency in celiac disease related to structural alterations in pancreatic parenchyma?

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    Rana, Surinder S.; Dambalkar, Arvind; Chhabra, Puneet; Sharma, Ravi; Nada, Ritambhra; Sharma, Vishal; Rana, Satyavati; Bhasin, Deepak K.

    2016-01-01

    Background Although exocrine pancreatic insufficiency (EPI) has been reported in a number of patients with celiac disease (CD), it is not clear if this is primarily a functional or a structural defect. We studied pancreatic structural abnormalities by endoscopic ultrasound (EUS) in adult CD patients with EPI. Methods Pancreatic exocrine function was prospectively assessed in 36 recently diagnosed CD patients (mean age: 29.8 years) by measuring fecal elastase. Pancreatic structural changes wer...

  5. Metabolic profile of pancreatic acinar and islet tissue in culture.

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    Suszynski, T M; Mueller, K R; Gruessner, A C; Papas, K K

    2014-01-01

    The amount and condition of exocrine impurities may affect the quality of islet preparations, especially during culture. In this study, the objective was to determine the oxygen demand and viability of islet and acinar tissue post-isolation and whether they change disproportionately while in culture. We compared the oxygen consumption rate (OCR) normalized to DNA (OCR/DNA, a measure of fractional viability in units of nmol/min/mg DNA), and the percent change in OCR and DNA recoveries between adult porcine islet and acinar tissue from the same preparation (paired) over 6-9 days of standard culture. Paired comparisons were done to quantify differences in OCR/DNA between islet and acinar tissue from the same preparation, at specified time points during culture. The mean (±SE) OCR/DNA was 74.0 ± 11.7 units higher for acinar (vs islet) tissue on the day of isolation (n = 16, P culture. DNA and OCR recoveries decreased at different rates for acinar versus islet tissue over 6-9 days in culture (n = 6). DNA recovery decreased to 24 ± 7% for acinar and 75 ± 8% for islets (P = .002). Similarly, OCR recovery decreased to 16 ± 3% for acinar and remained virtually constant for islets (P = .005). Differences in the metabolic profile of acinar and islet tissue should be considered when culturing impure islet preparations. OCR-based measurements may help optimize pre-islet transplantation culture protocols. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Primary retroperitoneal acinar cell cystadenoma.

    Science.gov (United States)

    Pesci, Anna; Castelli, Paola; Facci, Enrico; Romano, Luigi; Zamboni, Giuseppe

    2012-03-01

    In this report, we describe a case of hitherto unreported primary retroperitoneal acinar cell cystadenoma that morphologically and immunophenotypically resembled pancreatic acinar cell cystadenoma. Pancreatic acinar cell cystadenoma is a very uncommon benign lesion characterized by acinar cell differentiation, the evidence of pancreatic exocrine enzyme production, and the absence of cellular atypia. Our case occurred in a 55-year-old woman presenting a 10-cm multilocular cystic lesion in the retroperitoneum thought to be a mucinous cystic neoplasm. At laparotomy, the cystic mass, which showed no connection with any organ, was completely resected with a clinical diagnosis of cystic lymphangioma. The diagnosis of retroperitoneal acinar cell cystadenoma was based on the recognition of morphological acinar differentiation, the immunohistochemical demonstration of the acinar marker trypsin, and the absence of cellular atypia. These peculiar features can be used in the differential diagnosis with all the other cystic lesions of the retroperitoneum. Copyright © 2012 Elsevier Inc. All rights reserved.

  7. Exocrine Pancreatic Insufficiency in Diabetic Patients: Prevalence, Mechanisms, and Treatment

    Directory of Open Access Journals (Sweden)

    Matteo Piciucchi

    2015-01-01

    Full Text Available Pancreas is a doubled-entity organ, with both an exocrine and an endocrine component, reciprocally interacting in a composed system whose function is relevant for digestion, absorption, and homeostasis of nutrients. Thus, it is not surprising that disorders of the exocrine pancreas also affect the endocrine system and vice versa. It is well-known that patients with chronic pancreatitis develop a peculiar form of diabetes (type III, caused by destruction and fibrotic injury of islet cells. However, less is known on the influence of diabetes on pancreatic exocrine function. Pancreatic exocrine insufficiency (PEI has been reported to be common in diabetics, with a prevalence widely ranging, in different studies, in both type I (25–74% and type II (28–54% diabetes. A long disease duration, high insulin requirement, and poor glycemic control seem to be risk factors for PEI occurrence. The impact of pancreatic exocrine replacement therapy on glycemic, insulin, and incretins profiles has not been fully elucidated. The present paper is aimed at reviewing published studies investigating the prevalence of PEI in diabetic patients and factors associated with its occurrence.

  8. Ca2+ signaling in pancreatic acinar cells: physiology and pathophysiology

    Directory of Open Access Journals (Sweden)

    O.H. Petersen

    2009-01-01

    Full Text Available The pancreatic acinar cell is a classical model for studies of secretion and signal transduction mechanisms. Because of the extensive endoplasmic reticulum and the large granular compartment, it has been possible - by direct measurements - to obtain considerable insights into intracellular Ca2+ handling under both normal and pathological conditions. Recent studies have also revealed important characteristics of stimulus-secretion coupling mechanisms in isolated human pancreatic acinar cells. The acinar cells are potentially dangerous because of the high intra-granular concentration of proteases, which become inappropriately activated in the human disease acute pancreatitis. This disease is due to toxic Ca2+ signals generated by excessive liberation of Ca2+ from both the endoplasmic reticulum and the secretory granules.

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  18. Sirtuin-1 regulates acinar-to-ductal metaplasia and supports cancer cell viability in pancreatic cancer.

    Science.gov (United States)

    Wauters, Elke; Sanchez-Arévalo Lobo, Victor J; Pinho, Andreia V; Mawson, Amanda; Herranz, Daniel; Wu, Jianmin; Cowley, Mark J; Colvin, Emily K; Njicop, Erna Ngwayi; Sutherland, Rob L; Liu, Tao; Serrano, Manuel; Bouwens, Luc; Real, Francisco X; Biankin, Andrew V; Rooman, Ilse

    2013-04-01

    The exocrine pancreas can undergo acinar-to-ductal metaplasia (ADM), as in the case of pancreatitis where precursor lesions of pancreatic ductal adenocarcinoma (PDAC) can arise. The NAD(+)-dependent protein deacetylase Sirtuin-1 (Sirt1) has been implicated in carcinogenesis with dual roles depending on its subcellular localization. In this study, we examined the expression and the role of Sirt1 in different stages of pancreatic carcinogenesis, i.e. ADM models and established PDAC. In addition, we analyzed the expression of KIAA1967, a key mediator of Sirt1 function, along with potential Sirt1 downstream targets. Sirt1 was co-expressed with KIAA1967 in the nuclei of normal pancreatic acinar cells. In ADM, Sirt1 underwent a transient nuclear-to-cytoplasmic shuttling. Experiments where during ADM, we enforced repression of Sirt1 shuttling, inhibition of Sirt1 activity or modulation of its expression, all underscore that the temporary decrease of nuclear and increase of cytoplasmic Sirt1 stimulate ADM. Our results further underscore that important transcriptional regulators of acinar differentiation, that is, Pancreatic transcription factor-1a and β-catenin can be deacetylated by Sirt1. Inhibition of Sirt1 is effective in suppression of ADM and in reducing cell viability in established PDAC tumors. KIAA1967 expression is differentially downregulated in PDAC and impacts on the sensitivity of PDAC cells to the Sirt1/2 inhibitor Tenovin-6. In PDAC, acetylation of β-catenin is not affected, unlike p53, a well-characterized Sirt1-regulated protein in tumor cells. Our results reveal that Sirt1 is an important regulator and potential therapeutic target in pancreatic carcinogenesis. ©2012 AACR.

  19. Let-7b and miR-495 stimulate differentiation and prevent metaplasia of pancreatic acinar cells by repressing HNF6.

    Science.gov (United States)

    Prévot, Pierre-Paul; Augereau, Cécile; Simion, Alexandru; Van den Steen, Géraldine; Dauguet, Nicolas; Lemaigre, Frédéric P; Jacquemin, Patrick

    2013-09-01

    Diseases of the exocrine pancreas are often associated with perturbed differentiation of acinar cells. MicroRNAs (miRNAs) regulate pancreas development, yet little is known about their contribution to acinar cell differentiation. We aimed to identify miRNAs that promote and control the maintenance of acinar differentiation. We studied mice with pancreas- or acinar-specific inactivation of Dicer (Foxa3-Cre/Dicer(loxP/-) mice), combined (or not) with inactivation of hepatocyte nuclear factor (HNF) 6 (Foxa3-Cre/Dicer(loxP/-)/Hnf6-/- mice). The role of specific miRNAs in acinar differentiation was investigated by transfecting cultured cells with miRNA mimics or inhibitors. Pancreatitis-induced metaplasia was investigated in mice after administration of cerulein. Inhibition of miRNA synthesis in acini by inactivation of Dicer and pancreatitis-induced metaplasia were associated with repression of acinar differentiation and with induction of HNF6 and hepatic genes. The phenotype of Dicer-deficient acini depends on the induction of HNF6; overexpression of this factor in developing acinar cells is sufficient to repress acinar differentiation and to induce hepatic genes. Let-7b and miR-495 repress HNF6 and are expressed in developing acini. Their expression is inhibited in Dicer-deficient acini, as well as in pancreatitis-induced metaplasia. In addition, inhibiting let-7b and miR-495 in acinar cells results in similar effects to those found in Dicer-deficient acini and metaplastic cells, namely induction of HNF6 and hepatic genes and repression of acinar differentiation. Let-7b, miR-495, and their targets constitute a gene network that is required to establish and maintain pancreatic acinar cell differentiation. Additional studies of this network will increase our understanding of pancreatic diseases. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

  20. NFATc4 Regulates Sox9 Gene Expression in Acinar Cell Plasticity and Pancreatic Cancer Initiation

    National Research Council Canada - National Science Library

    Hessmann, Elisabeth; Zhang, Jin-San; Chen, Nai-Ming; Hasselluhn, Marie; Liou, Geou-Yarh; Storz, Peter; Ellenrieder, Volker; Billadeau, Daniel D; Koenig, Alexander

    2016-01-01

    Acinar transdifferentiation toward a duct-like phenotype constitutes the defining response of acinar cells to external stress signals and is considered to be the initial step in pancreatic carcinogenesis...

  1. Insulin secretion abnormalities in exocrine pancreatic sufficient cystic fibrosis patients.

    Science.gov (United States)

    Wooldridge, Jamie L; Szczesniak, Rhonda D; Fenchel, Matthew C; Elder, Deborah A

    2015-11-01

    The aim of this study is to assess insulin secretion in pediatric cystic fibrosis (CF) patients with exocrine pancreatic sufficiency. Glucose and insulin responses during an oral glucose tolerance test (OGTT) were measured in 146 CF patients. Patients were divided into exocrine sufficient (CF-PS) and insufficient (CF-PI) groups based on pancreatic enzyme usage and fecal elastase. A reference group included healthy, non-diabetic subjects. All CF groups showed reduced insulin secretion as measured by insulinogenic index. The CF-PS patients had normal glucose tolerance. There was a direct correlation between BMI z-score and insulin area under the curve. Patients with CF have reduced insulin secretion during an OGTT regardless of exocrine pancreatic status. The abnormal insulin secretion in all CF patients may predispose them for glucose intolerance, particularly when challenged by inflammation, infection, or nutritional deficiency. In addition, the diminished insulin secretion may contribute to increased catabolism. Lastly, the CF-related diabetes (CFRD) screening guidelines should be followed by all CF patients regardless of pancreatic status. Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

  2. BMP-7 Induces Adult Human Pancreatic Exocrine-to-Endocrine Conversion.

    Science.gov (United States)

    Klein, Dagmar; Álvarez-Cubela, Silvia; Lanzoni, Giacomo; Vargas, Nancy; Prabakar, Kamalaveni R; Boulina, Maria; Ricordi, Camillo; Inverardi, Luca; Pastori, Ricardo L; Domínguez-Bendala, Juan

    2015-12-01

    The exocrine pancreas can give rise to endocrine insulin-producing cells upon ectopic expression of key transcription factors. However, the need for genetic manipulation remains a translational hurdle for diabetes therapy. Here we report the conversion of adult human nonendocrine pancreatic tissue into endocrine cell types by exposure to bone morphogenetic protein 7. The use of this U.S. Food and Drug Administration-approved agent, without any genetic manipulation, results in the neogenesis of clusters that exhibit high insulin content and glucose responsiveness both in vitro and in vivo. In vitro lineage tracing confirmed that BMP-7-induced insulin-expressing cells arise mainly from extrainsular PDX-1(+), carbonic anhydrase II(-) (mature ductal), elastase 3a (acinar)(-) , and insulin(-) subpopulations. The nongenetic conversion of human pancreatic exocrine cells to endocrine cells is novel and represents a safer and simpler alternative to genetic reprogramming. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  3. Bone mineral metabolism, bone mineral density, and body composition in patients with chronic pancreatitis and pancreatic exocrine insufficiency

    DEFF Research Database (Denmark)

    Haaber, Anne Birgitte; Rosenfalck, A M; Hansen, B

    2000-01-01

    Calcium and vitamin D homeostasis seem to be abnormal in patients with exocrine pancreatic dysfunction resulting from cystic fibrosis. Only a few studies have evaluated and described bone mineral metabolism in patients with chronic pancreatitis and pancreatic insufficiency....

  4. Role of pancreatic polypeptide in the regulation of pancreatic exocrine secretion in dogs

    Energy Technology Data Exchange (ETDEWEB)

    Shiratori, Keiko; Lee, K.Y.; Chang, Tamin; Jo, Y.H.; Coy, D.H.; Chey, W.Y. (Genesee Hospital, Rochester, NY (USA) Tulane Univ. School of Medicine, New Orleans, LA (USA))

    1988-11-01

    The effect of intravenous infusion of synthetic human pancreatic polypeptide (HPP) or a rabbit anti-PP serum on pancreatic exocrine secretion was studied in 10 dogs with gastric and Thomas duodenal cannulas. The infusion of HPP, achieved a plasma PP concentration that mimicked the peak plasma concentration of PP in both interdigestive and postprandial states. This dose of HPP significantly inhibited pancreatic secretion in the interdigestive state. By contrast, immunoneutralization of circulating PP by a rabbit anti-PP serum resulted in significant increases in both interdigestive and postprandial pancreatic secretion, including water, bicarbonate, and protein. The increase in the pancreatic secretion paralleled a decrease in circulating PP level, which lasted for as long as 5 days. Furthermore, the anti-PP serum blocked the inhibitory action of exogenous HPP on pancreatic exocrine secretion. The present study indicates that endogenous PP plays a significant role in the regulation of the pancreatic exocrine secretion in both interdigestive and digestive states. Thus the authors conclude that PP is another hormone regulating pancreatic exocrine secretion in dogs.

  5. Pancreatic Exocrine Insufficiency in Patients With Pancreatic or Periampullary Cancer: A Systematic Review

    NARCIS (Netherlands)

    Tseng, Dorine S. J.; Molenaar, I. Quintus; Besselink, Marc G.; van Eijck, Casper H.; Borel Rinkes, Inne H.; van Santvoort, Hjalmar C.

    2016-01-01

    The aim of this study was to determine the prevalence of pancreatic exocrine insufficiency in patients with pancreatic or periampullary cancer, both before and after resection. Systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA guidelines).

  6. Exocrine pancreatic function following proximal small bowel resection in rats.

    Science.gov (United States)

    Gelinas, M D; Morin, C L; Morisset, J

    1982-01-01

    1. In order to assess if proximal enterectomy induces changes in the function of the exocrine pancreas, the exocrine pancreas was studied 1 week, 4 weeks, and 6 months after 50 or 75% proximal small bowel resection. 2. One week after 50 and 75% proximal small bowel resections, basal pancreatic bicarbonate outputs, studied by means of an external pancreatic fistula in conscious rats, were increased significantly over control values by 43 and 78% respectively. Four weeks after a 75% resection, the bicarbonate output was still significantly higher in resected animals than in sham operated animals. 3. The increase of volume and bicarbonate of the basal pancreatic secretion coincided with a 4-fold increase in plasma secretin concentration 1 week after resection. Both increased pancreatic secretion and plasma secretin concentration were transient. 4. The pancreatic hypersecretion was specifically reversed to control values with an I.P. injection of jejunoileal mucosa homogenate. 5. Serum gastrin and somatostatin values in intestinal mucosa and pancreas were not changed 1 and 4 weeks after enterectomy compared with sham operated animals. 6. The weight of the pancreas and its content of DNA were unaltered by resection. Amylase and chymotrypsinogen per gram pancreatic tissue and per microgram DNA were reduced 4 weeks following resections as compared with sham operated rats. After 6 months, chymotrypsinogen appeared further reduced in resected animals. 7. It is concluded that extensive proximal enterectomy in rats produced early, transient and marked increases in basal pancreatic water and bicarbonate secretion and in plasma secretin due to the loss of jejunoileal inhibitor(s), and a selective decrease in certain enzymes in pancreatic tissue. PMID:6121911

  7. Remnant pancreatic parenchymal volume predicts postoperative pancreatic exocrine insufficiency after pancreatectomy.

    Science.gov (United States)

    Okano, Keisuke; Murakami, Yoshiaki; Nakagawa, Naoya; Uemura, Kenichiro; Sudo, Takeshi; Hashimoto, Yasushi; Kondo, Naru; Takahashi, Shinya; Sueda, Taijiro

    2016-03-01

    Pancreatectomy, including pancreatoduodenectomy and distal pancreatectomy, often causes postoperative pancreatic exocrine insufficiency (PEI). Our aim was to clarify a relationship between remnant pancreatic volume and postoperative PEI. A total of 227 patients who underwent pancreatoduodenectomy or distal pancreatectomy were enrolled in this study. All patients underwent a (13)C-labeled mixed triglyceride breath test to assess pancreatic exocrine function and abdominal dynamic computed tomography for assessing remnant pancreatic volume after pancreatectomy at a median of 7 months postoperatively. The percent (13)CO2 cumulative dose at 7 hours (% dose (13)C cum 7 h) pancreatectomy were performed in 174 (76.7%) and 53 (23.3%) patients, respectively. Of the 227 patients, 128 (56.3%) developed postoperative PEI. Postoperative % dose (13)C cum 7 h was strongly correlated with remnant pancreatic volume (r = .509, P pancreatectomy (P pancreatectomy. Remnant pancreatic volume may predict postoperative PEI in patients who undergo pancreatectomy. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Pancreatic acinar cells-derived cyclophilin A promotes pancreatic damage by activating NF-κB pathway in experimental pancreatitis

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Ge [Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai (China); Wan, Rong [Department of Gastroenterology, Shanghai First People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai (China); Hu, Yanling [Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai (China); Ni, Jianbo [Department of Gastroenterology, Shanghai First People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai (China); Yin, Guojian; Xing, Miao [Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai (China); Shen, Jie [Department of Gastroenterology, Shanghai First People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai (China); Tang, Maochun [Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai (China); Chen, Congying [Department of Gastroenterology, Shanghai First People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai (China); Fan, Yuting; Xiao, Wenqin; Zhao, Yan [Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai (China); Wang, Xingpeng, E-mail: wangxingpeng@hotmail.com [Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai (China); Department of Gastroenterology, Shanghai First People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai (China); and others

    2014-01-31

    Highlights: • CypA is upregulated in experimental pancreatitis. • CCK induces expression and release of CypA in acinar cell in vitro. • rCypA aggravates CCK-induced acinar cell death and inflammatory cytokine production. • rCypA activates the NF-κB pathway in acinar cells in vitro. - Abstract: Inflammation triggered by necrotic acinar cells contributes to the pathophysiology of acute pancreatitis (AP), but its precise mechanism remains unclear. Recent studies have shown that Cyclophilin A (CypA) released from necrotic cells is involved in the pathogenesis of several inflammatory diseases. We therefore investigated the role of CypA in experimental AP induced by administration of sodium taurocholate (STC). CypA was markedly upregulated and widely expressed in disrupted acinar cells, infiltrated inflammatory cells, and tubular complexes. In vitro, it was released from damaged acinar cells by cholecystokinin (CCK) induction. rCypA (recombinant CypA) aggravated CCK-induced acinar cell necrosis, promoted nuclear factor (NF)-κB p65 activation, and increased cytokine production. In conclusion, CypA promotes pancreatic damage by upregulating expression of inflammatory cytokines of acinar cells via the NF-κB pathway.

  9. Somatostatin receptor-effector system in rat pancreatic acinar membranes after subtotal enterectomy.

    Science.gov (United States)

    Alvaro-Alonso, I; Colás, B; Esteve, J P; Susini, C; Arilla, E

    1995-02-01

    In the present study we found that exocrine pancreatic hyperplasia observed after proximal small bowel resection is accompanied by an increase in pancreatic somatostatin (SS) content at 1 mo and an increase in the number of SS receptors at 2 wk and 1 mo after intestinal surgery. At 6 mo after small bowel resection SS content and SS receptors had returned to control values. However, the original increase in SS receptor number was accompanied by a decrease in the ability of SS to inhibit forskolin-stimulated adenylyl cyclase (AC) activity. In addition, the ability of 5'-guanylylimidodiphosphate (a nonhydrolyzable GTP analogue) to inhibit SS receptor binding was decreased in pancreatic acinar membranes from enterectomized rats at 2 wk and 1 mo after jejunoileal resection. These data suggest that there is an abnormality in the integrity of SS receptor binding site-G protein interactions and would explain the decreased inactivation of AC by SS at 2 wk and 1 mo after proximal small bowel resection.

  10. File list: NoD.Pan.10.AllAg.Pancreatic_acinar_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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  15. Loss of Ifnar1 in Pancreatic Acinar Cells Ameliorates the Disease Course of Acute Pancreatitis.

    Science.gov (United States)

    Miller, Katharina J; Raulefs, Susanne; Kong, Bo; Steiger, Katja; Regel, Ivonne; Gewies, Andreas; Kleeff, Jörg; Michalski, Christoph W

    2015-01-01

    Type I interferon constitutes an essential component of the combinational therapy against viral disease. Acute pancreatitis is one side effect of type I interferon-based therapy, implying that activation of type I interferon signaling affects the homeostasis and integrity of pancreatic acinar cells. Here, we investigated the role of type I interferon signaling in pancreatic acinar cells using a caerulein-induced murine model of acute pancreatitis. Pancreas-specific ablation of interferon (alpha and beta) receptor 1 (Ifnar1) partially protected animals from caerulein-induced pancreatitis, as demonstrated by reduced tissue damage. Profiling of infiltrating immune cells revealed that this dampened tissue damage response correlated with the number of macrophages in the pancreas. Pharmacologic depletion of macrophages reversed the protective effect of Ifnar1 deficiency. Furthermore, expression of chemokine (C-C motif) ligand 2 (Ccl2), a potent factor for macrophage recruitment, was significantly increased in the Ifnar1-deficient pancreas. Thus, type I interferon signaling in pancreatic acinar cells controls pancreatic homeostasis by affecting the macrophage-mediated inflammatory response in the pancreas.

  16. Loss of Ifnar1 in Pancreatic Acinar Cells Ameliorates the Disease Course of Acute Pancreatitis.

    Directory of Open Access Journals (Sweden)

    Katharina J Miller

    Full Text Available Type I interferon constitutes an essential component of the combinational therapy against viral disease. Acute pancreatitis is one side effect of type I interferon-based therapy, implying that activation of type I interferon signaling affects the homeostasis and integrity of pancreatic acinar cells. Here, we investigated the role of type I interferon signaling in pancreatic acinar cells using a caerulein-induced murine model of acute pancreatitis. Pancreas-specific ablation of interferon (alpha and beta receptor 1 (Ifnar1 partially protected animals from caerulein-induced pancreatitis, as demonstrated by reduced tissue damage. Profiling of infiltrating immune cells revealed that this dampened tissue damage response correlated with the number of macrophages in the pancreas. Pharmacologic depletion of macrophages reversed the protective effect of Ifnar1 deficiency. Furthermore, expression of chemokine (C-C motif ligand 2 (Ccl2, a potent factor for macrophage recruitment, was significantly increased in the Ifnar1-deficient pancreas. Thus, type I interferon signaling in pancreatic acinar cells controls pancreatic homeostasis by affecting the macrophage-mediated inflammatory response in the pancreas.

  17. Non-invasive discrimination between pancreatic islets and exocrine cells using multiphoton microscopy

    Science.gov (United States)

    Wu, Binlin; Li, Ge; Hao, Mingming; Mukherjee, Sushmita

    2015-03-01

    In this study, we propose a non-invasive method to distinguish pancreatic islet cells from exocrine cell clusters using multiphoton (MP) imaging. We demonstrate the principle of distinguishing them based on autofluorescence. The results show that MP imaging has a potential to distinguish pancreatic islets from exocrine cells. This ability to distinguish the two cell types could have many applications, such as the examination of fresh pancreatic biopsies when staining is not possible or desirable.

  18. Beer and its Non-Alcoholic Compounds: Role in Pancreatic Exocrine Secretion, Alcoholic Pancreatitis and Pancreatic Carcinoma

    Directory of Open Access Journals (Sweden)

    Peter Feick

    2010-03-01

    Full Text Available : In this article we provide an overview of the newest data concerning the effect of non-alcoholic constituents of alcoholic beverages, especially of beer, on pancreatic secretion, and their possible role in alcoholic pancreatitis and pancreatic carcinoma. The data indicate that non-alcoholic constituents of beer stimulate pancreatic enzyme secretion in humans and rats, at least in part, by direct action on pancreatic acinar cells. Some non-alcoholic compounds of beer, such as quercetin, resveratrol, ellagic acid or catechins, have been shown to be protective against experimentally induced pancreatitis by inhibiting pancreatic secretion, stellate cell activation or by reducing oxidative stress. Quercetin, ellagic acid and resveratrol also show anti-carcinogenic potential in vitro and in vivo. However, beer contains many more non-alcoholic ingredients. Their relevance in beer-induced functional alterations of pancreatic cells leading to pancreatitis and pancreatic cancer in humans needs to be further evaluated.

  19. Beer and its Non-Alcoholic Compounds: Role in Pancreatic Exocrine Secretion, Alcoholic Pancreatitis and Pancreatic Carcinoma

    Science.gov (United States)

    Gerloff, Andreas; Singer, Manfred V; Feick, Peter

    2010-01-01

    In this article we provide an overview of the newest data concerning the effect of non-alcoholic constituents of alcoholic beverages, especially of beer, on pancreatic secretion, and their possible role in alcoholic pancreatitis and pancreatic carcinoma. The data indicate that non-alcoholic constituents of beer stimulate pancreatic enzyme secretion in humans and rats, at least in part, by direct action on pancreatic acinar cells. Some non-alcoholic compounds of beer, such as quercetin, resveratrol, ellagic acid or catechins, have been shown to be protective against experimentally induced pancreatitis by inhibiting pancreatic secretion, stellate cell activation or by reducing oxidative stress. Quercetin, ellagic acid and resveratrol also show anti-carcinogenic potential in vitro and in vivo. However, beer contains many more non-alcoholic ingredients. Their relevance in beer-induced functional alterations of pancreatic cells leading to pancreatitis and pancreatic cancer in humans needs to be further evaluated. PMID:20617020

  20. Sarcopenia is closely associated with pancreatic exocrine insufficiency in patients with pancreatic disease.

    Science.gov (United States)

    Shintakuya, Ryuta; Uemura, Kenichiro; Murakami, Yoshiaki; Kondo, Naru; Nakagawa, Naoya; Urabe, Kazuhide; Okano, Keisuke; Awai, Kazuo; Higaki, Toru; Sueda, Taijiro

    The loss of skeletal muscle mass (sarcopenia) is associated with the poor prognosis of pancreatic cancer. It has been reported pancreatic exocrine insufficiency (PEI) is associated with serum nutritional markers in chronic pancreatitis. However, there has been no report about the relationship between sarcopenia and PEI. The aim of this study is to determine whether body composition, including skeletal muscle (SM), subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), intramuscular adipose tissue content (IMAC), and serum nutritional markers are associated with pancreatic exocrine function in patients with pancreatic disease. Data were collected prospectively on 132 patients with pancreatic disease. SM, SAT, VAT and IMAC were assessed by computed tomography. Patients underwent a 13 C-labeled mixed triglyceride breath test to measure pancreatic exocrine function. Serum nutritional markers were measured at the same time of 13 C-labeled mixed triglyceride breath test. Patients were stratified by quartiles according to each body component, and for each component the lowest group was defined as the lowest quartile, treating men and women separately. The lowest group for SM was defined as sarcopenia. PEI was defined as a percentage 13 CO 2 cumulative dose at 7 h below 5%. Sarcopenia was associated with PEI in both men (P sarcopenia (P = 0.001) and serum albumin (P = 0.058) were associated with PEI. On multivariate analysis, only sarcopenia remained independently associated with PEI (P Sarcopenia is independently associated with PEI in patients with pancreatic disease. Copyright © 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.

  1. Delayed release pancrelipase for treatment of pancreatic exocrine insufficiency associated with chronic pancreatitis

    Directory of Open Access Journals (Sweden)

    Devi Mukkai Krishnamurty

    2009-07-01

    Full Text Available Devi Mukkai Krishnamurty,1 Atoosa Rabiee,2 Sanjay B Jagannath,1 Dana K Andersen2Johns Hopkins University School of Medicine; 1Department of Medicine; 2Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA; 2Johns Hopkins University School of Medicine, Johns Hopkins Bayview Medical Center, Baltimore, MD, USAAbstract: Pancreatic enzyme supplements (PES are used in chronic pancreatitis (CP for correction of pancreatic exocrine insufficiency (PEI as well as pain and malnutrition. The use of porcine pancreatic enzymes for the correction of exocrine insufficiency is governed by the pathophysiology of the disease as well as pharmacologic properties of PES. Variability in bioequivalence of PES has been noted on in vitro and in vivo testing and has been attributed to the differences in enteric coating and the degree of micro-encapsulation. As a step towards standardizing pancreatic enzyme preparations, the Food and Drug Administration now requires the manufacturers of PES to obtain approval of marketed formulations by April 2010. In patients with treatment failure, apart from evaluating drug and dietary interactions and compliance, physicians should keep in mind that patients may benefit from switching to a different formulation. The choice of PES (enteric coated versus non-enteric coated and the need for acid suppression should be individualized. There is no current standard test for evaluating adequacy of therapy in CP patients and studies have shown that optimization of therapy based on symptoms may be inadequate. Goals of therapy based on overall patient presentation and specific laboratory tests rather than mere correction of steatorrhea are needed.Keywords: pancreatic exocrine insufficiency, chronic pancreatitis, pancreatic enzyme supplement

  2. Is pancreatic exocrine insufficiency in celiac disease related to structural alterations in pancreatic parenchyma?

    Science.gov (United States)

    Rana, Surinder S; Dambalkar, Arvind; Chhabra, Puneet; Sharma, Ravi; Nada, Ritambhra; Sharma, Vishal; Rana, Satyavati; Bhasin, Deepak K

    2016-01-01

    Although exocrine pancreatic insufficiency (EPI) has been reported in a number of patients with celiac disease (CD), it is not clear if this is primarily a functional or a structural defect. We studied pancreatic structural abnormalities by endoscopic ultrasound (EUS) in adult CD patients with EPI. Pancreatic exocrine function was prospectively assessed in 36 recently diagnosed CD patients (mean age: 29.8 years) by measuring fecal elastase. Pancreatic structural changes were assessed in CD patients with EPI by EUS and elastography. Exocrine functions were reassessed after 3 months of gluten-free diet. Of the 36 CD patients included, 30 (83%) had anemia, 21 (58%) diarrhea, and 7 (19%) hypothyroidism. Ten (28%) patients had EPI with mean elastase levels of 141.6 μg/g of stool, of whom only one had a history of recurrent acute pancreatitis while the rest 9 patients had no history of acute or chronic pancreatitis. Of these 10 patients, 8 (80%) had diarrhea, 8 (80%) anemia, and 2 (20%) hypothyroidism. EUS was done in 8 patients which showed: normal pancreas in 5 (50%), hyperechoic strands in 3 (30%), and hyperechoic foci without shadowing in 2 (20%) patients. None had lobularity or parenchymal calcification. All patients except the patient with recurrent pancreatitis had normal strain ratio. Follow-up fecal elastase was within normal range in 6 of 7 (86%) patients. EPI, assessed by fecal elastase levels in adult CD patients, possibly does not relate to structural alterations in the pancreatic parenchyma and may be reversible by following a gluten-free diet.

  3. The Proteomic Analysis of Pancreatic Exocrine Insufficiency Protein Marker in Type 2 Diabetes Mellitus Patients

    Science.gov (United States)

    Srihardyastutie, Arie; Soeatmadji, DW; Fatchiyah; Aulanni’am

    2018-01-01

    Type 2 Diabetes Mellitus (T2D) is the vast majority case of diabetes. Patient with T2D is at higher risk for developing acute or chronic pancreatitis. Prolonged hyperglycemia results in damages to tissue, which also causes dysfunctions of some organ systems, including enzyme or hormone secretions. Commonly, dysfunction or insufficiency of pancreatic exocrine is evaluated by increasing activity of serum pancreatic enzyme, such as amylase and lipase. Although incidence of pancreatitis was found in Indonesian T2D, the pathogenic mechanism still unclear. The aim of this study was to characterize the marker protein that indicated the correlation of pancreatic exocrine insufficiency with progression of T2D. Proteomic analysis using LC-MS/MS was used in identification and characterization of protein marker which indicates insufficiency pancreatic exocrine. First step, protein profile was analyzed by SDS-PAGE methods using serum sample of T2D compared with normal or healthy control, as negative control, and pancreatitis patients, as positive control. Protein with 18 kDa was found as a candidate protein marker which indicated the pancreatic exocrine insufficiency in T2D. The further identification of that protein using LC-MS/MS showed 4 peptide fragments. In silico analysis of the peptide fragment indicated the correlation of pancreatic exocrine insufficiency with progression of T2D was METTL10 – methyltransferase like protein-10.

  4. Acinar cell carcinoma of the pancreas presenting as diffuse pancreatic enlargement: Two case reports and literature review.

    Science.gov (United States)

    Luo, Yaping; Hu, Guilan; Ma, Yanru; Guo, Ning; Li, Fang

    2017-09-01

    Pancreatic acinar cell carcinoma (ACC) is a rare malignant tumor of exocrine pancreas. It is typically a well-marginated large solid mass arising in a certain aspect of the pancreas. Diffuse involvement of ACC in the pancreas is very rare, and may simulate pancreatitis in radiological findings. We report 2 cases of ACC presenting as diffuse enlargement of the pancreas due to tumor involvement without formation of a distinct mass. The patients consisted of a 41-year-old man with weight loss and a 77-year-old man who was asymptomatic. Computed tomography (CT) and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT showed diffuse enlargement of the pancreas forming a sausage-like shape with homogenously increased FDG activity. Endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) biopsy of the pancreatic lesion was performed. Histopathology results from the pancreas confirmed the diagnosis of pancreatic ACC. Because diffuse enlargement of the pancreas is a common imaging feature of pancreatitis, recognition of this rare morphologic pattern of ACC is important for radiological diagnosis of this tumor.

  5. Feline exocrine pancreatic carcinoma: a retrospective study of 34 cases.

    Science.gov (United States)

    Linderman, M J; Brodsky, E M; de Lorimier, L-P; Clifford, C A; Post, G S

    2013-09-01

    Thirty-four cases were reviewed in this retrospective study for information on clinical presentation, prognostic indicators, survival time and response to various therapies. The most common presenting clinical signs were weight loss, decreased appetite, vomiting, palpable abdominal mass and diarrhoea. Metastatic disease was confirmed in 11 cats. The overall median survival was 97 days. The median survival times for patients who received chemotherapy or had their masses surgically removed was 165 days. Those patients who had an abdominal effusion present at the time of diagnosis survived a median of 30 days. Cats that received non-steroidal anti-inflammatory drug therapy had a median survival of 26 days. This study confirms that exocrine pancreatic carcinoma in cats is an aggressive tumour with a high metastatic rate and poor prognosis, although three patients survived over 1 year. Fifteen percent of the patients were diabetic, which raises the question as to what the link between diabetes and pancreatic cancer in people and cats may be. © 2012 John Wiley & Sons Ltd.

  6. Nelfinavir/ritonavir reduces acinar injury but not inflammation during mouse caerulein pancreatitis

    OpenAIRE

    Singh, Vijay P.; Bren, Gary D; Algeciras-Schimnich, Alicia; Schnepple, David; Navina, Sarah; Rizza, Stacey A; DAWRA, RAJINDER K.; Saluja, Ashok K.; Chari, Suresh T.; Vege, Santhi S.; Badley, Andrew D

    2009-01-01

    There is no clinical treatment that reduces acinar injury during pancreatitis. Human immunodeficiency virus (HIV) protease inhibitors (PI), including nelfinavir (NFV) and ritonavir (RTV), may reduce the rate of pancreatitis in HIV-infected patients. Since permeability transition pore (PTPC)-mediated mitochondrial dysfunction occurs during pancreatitis, and we have shown that PI prevents PTPC opening, we studied its effects in a model of pancreatitis. The effect of NFV plus RTV (NFV/RTV) or ve...

  7. Pancreatic endocrine and exocrine function in children following near-total pancreatectomy for diffuse congenital hyperinsulinism.

    Directory of Open Access Journals (Sweden)

    Ved Bhushan Arya

    Full Text Available Congenital hyperinsulinism (CHI, the commonest cause of persistent hypoglycaemia, has two main histological subtypes: diffuse and focal. Diffuse CHI, if medically unresponsive, is managed with near-total pancreatectomy. Post-pancreatectomy, in addition to persistent hypoglycaemia, there is a very high risk of diabetes mellitus and pancreatic exocrine insufficiency.International referral centre for the management of CHI.Medically unresponsive diffuse CHI patients managed with near-total pancreatectomy between 1994 and 2012.Near-total pancreatectomy.Persistent hypoglycaemia post near-total pancreatectomy, insulin-dependent diabetes mellitus, clinical and biochemical (faecal elastase 1 pancreatic exocrine insufficiency.Of more than 300 patients with CHI managed during this time period, 45 children had medically unresponsive diffuse disease and were managed with near-total pancreatectomy. After near-total pancreatectomy, 60% of children had persistent hypoglycaemia requiring medical interventions. The incidence of insulin dependent diabetes mellitus was 96% at 11 years after surgery. Thirty-two patients (72% had biochemical evidence of severe pancreatic exocrine insufficiency (Faecal elastase 1<100 µg/g. Clinical exocrine insufficiency was observed in 22 (49% patients. No statistically significant difference in weight and height standard deviation score (SDS was found between untreated subclinical pancreatic exocrine insufficiency patients and treated clinical pancreatic exocrine insufficiency patients.The outcome of diffuse CHI patients after near-total pancreatectomy is very unsatisfactory. The incidence of persistent hypoglycaemia and insulin-dependent diabetes mellitus is very high. The presence of clinical rather than biochemical pancreatic exocrine insufficiency should inform decisions about pancreatic enzyme supplementation.

  8. Inheritance of pancreatic acinar atrophy in German Shepherd Dogs.

    Science.gov (United States)

    Moeller, E Michael; Steiner, Jörg M; Clark, Leigh Anne; Murphy, Keith E; Famula, Thomas R; Williams, David A; Stankovics, Mary E; Vose, Amy S

    2002-10-01

    To assess the heritability of pancreatic acinar atrophy (PAA) in German Shepherd Dogs (GSDs) in the United States. 135 GSDs belonging to 2 multigenerational pedigrees. Two multigenerational pedigrees of GSDs with family members with PAA were identified. The clinical history of each GSD enrolled in the study was recorded, and serum samples for canine trypsin-like immunoreactivity (cTLI) analysis were collected from 102 dogs. Dogs with a serum cTLI concentration Pedigree I consisted of 59 dogs and pedigree II of 76 dogs. Serum cTLI concentrations were measured in 48 dogs from pedigree I and 54 dogs from pedigree II. A total of 19 dogs (14.1%) were determined to have EPI, 9 in pedigree I (15.3%) and 10 in pedigree II (13.6%). Of the 19 dogs with EPI, 8 were male and 11 were female. Evaluation of data by complex segregation analysis is strongly suggestive of an autosomal recessive mode of inheritance for EPI in GSDs in the United States.

  9. Pancreatic exocrine insufficiency, diabetes mellitus and serum nutritional markers after acute pancreatitis.

    Science.gov (United States)

    Vujasinovic, Miroslav; Tepes, Bojan; Makuc, Jana; Rudolf, Sasa; Zaletel, Jelka; Vidmar, Tjasa; Seruga, Maja; Birsa, Bostjan

    2014-12-28

    To investigate impairment and clinical significance of exocrine and endocrine pancreatic function in patients after acute pancreatitis (AP). Patients with AP were invited to participate in the study. Severity of AP was determined by the Atlanta classification and definitions revised in 2012. Pancreatic exocrine insufficiency (PEI) was diagnosed by the concentration of fecal elastase-1. An additional work-up, including laboratory testing of serum nutritional markers for determination of malnutrition, was offered to all patients with low levels of fecal elastase-1 FE. Hemoglobin A1c or oral glucose tolerance tests were also performed in patients without prior diabetes mellitus, and type 3c diabetes mellitus (T3cDM) was diagnosed according to American Diabetes Association criteria. One hundred patients were included in the study: 75% (75/100) of patients had one attack of AP and 25% (25/100) had two or more attacks. The most common etiology was alcohol. Mild, moderately severe and severe AP were present in 67, 15 and 18% of patients, respectively. The mean time from attack of AP to inclusion in the study was 2.7 years. PEI was diagnosed in 21% (21/100) of patients and T3cDM in 14% (14/100) of patients. In all patients with PEI, at least one serologic nutritional marker was below the lower limit of normal. T3cDM was more frequently present in patients with severe AP (P = 0.031), but was also present in some patients with mild and moderately severe AP. PEI was present in all degrees of severity of AP. There were no statistically significantly differences according to gender, etiology and number of AP attacks. As exocrine and endocrine pancreatic insufficiency can develop after AP, routine follow-up of patients is necessary, for which serum nutritional panel measurements can be useful.

  10. Diabetes mellitus, exocrine pancreatic deficiency, hypertrichosis, hyperpigmentation, and chronic inflammation: confirmation of a syndrome

    NARCIS (Netherlands)

    Hussain, Khalid; Padidela, Raja; Kapoor, Ritika R.; James, Chela; Banerjee, Kausik; Harper, John; Wilson, Louise C.; Hennekam, Raoul C. M.

    2009-01-01

    Type 1 diabetes mellitus is characterized by dysregulation of the immune system leading to inflammation and selective destruction of pancreatic beta cells. Mild to moderate pancreatic exocrine insufficiency is found in patients with type 1 diabetes. Diabetes mellitus may also be part of a syndrome

  11. Exocrine pancreatic insufficiency in the Eurasian dog breed - inheritance and exclusion of two candidate genes

    DEFF Research Database (Denmark)

    Proschowsky, Helle Friis; Fredholm, Merete

    2007-01-01

    Exocrine pancreatic insufficiency is considered an inherited disease in several dog breeds. Affected dogs show polyphagia, weight loss and voluminous faeces of light colour due to the lack of pancreatic enzymes. In the study described herein, we performed a segregation analysis using the SINGLES ...

  12. Protein kinase D1 drives pancreatic acinar cell reprogramming and progression to intraepithelial neoplasia

    Science.gov (United States)

    Liou, Geou-Yarh; Döppler, Heike; Braun, Ursula B.; Panayiotou, Richard; Scotti Buzhardt, Michele; Radisky, Derek C.; Crawford, Howard C.; Fields, Alan P.; Murray, Nicole R.; Wang, Q. Jane; Leitges, Michael; Storz, Peter

    2015-02-01

    The transdifferentiation of pancreatic acinar cells to a ductal phenotype (acinar-to-ductal metaplasia, ADM) occurs after injury or inflammation of the pancreas and is a reversible process. However, in the presence of activating Kras mutations or persistent epidermal growth factor receptor (EGF-R) signalling, cells that underwent ADM can progress to pancreatic intraepithelial neoplasia (PanIN) and eventually pancreatic cancer. In transgenic animal models, ADM and PanINs are initiated by high-affinity ligands for EGF-R or activating Kras mutations, but the underlying signalling mechanisms are not well understood. Here, using a conditional knockout approach, we show that protein kinase D1 (PKD1) is sufficient to drive the reprogramming process to a ductal phenotype and progression to PanINs. Moreover, using 3D explant culture of primary pancreatic acinar cells, we show that PKD1 acts downstream of TGFα and Kras, to mediate formation of ductal structures through activation of the Notch pathway.

  13. MRI and MRCP findings of the pancreas in patients with diabetes mellitus: compared analysis with pancreatic exocrine function determined by fecal elastase 1.

    Science.gov (United States)

    Bilgin, Mehmet; Balci, Numan Cem; Momtahen, Amir Javad; Bilgin, Yaşar; Klör, Hans-Ulrich; Rau, Wigbert S

    2009-02-01

    To review magnetic resonance imaging and magnetic resonance cholangiopancreatography (MRCP) findings in patients with diabetes mellitus (DM), with pancreatic exocrine insufficiency, and with combined pancreatic exocrine insufficiency and DM. MRI/MRCP findings of 82 consecutive patients with DM (n=28), pancreatic exocrine insufficiency (n=25), and combination of both (n=29) were evaluated and compared with MRI/MRCP findings of 21 healthy volunteers with normal pancreatic exocrine function. Pancreatic exocrine function was determined by fecal elastase 1. MRCP images were evaluated according to the Cambridge classification. MRI of the pancreas was assessed for pancreatic size, signal intensity ratio (SIR), and arterial/venous enhancement ratio (A/V). On MRI, significant difference was present in terms of mean values of pancreatic size (P<0.0001), A/V (P<0.02), and SIR (P<0.005) between the control group and groups of patients with DM, pancreatic exocrine insufficiency, and combined DM and pancreatic exocrine insufficiency. No significant difference was observed between groups of patients with DM and pancreatic exocrine function alone in terms of pancreatic size, A/V, and SIR. Chronic pancreatitis MRCP findings were present with increasing frequency in groups of DM, pancreatic exocrine insufficiency, and combination of both. MRI/MRCP findings suggesting chronic pancreatitis may exist in patients with DM comparable to patients with pancreatic exocrine insufficiency. The frequency and severity of MRI/MRCP findings increase when the patients have combined DM and pancreatic exocrine insufficiency.

  14. Protons released during pancreatic acinar cell secretion acidify the lumen and contribute to pancreatitis in mice.

    Science.gov (United States)

    Behrendorff, Natasha; Floetenmeyer, Matthias; Schwiening, Christof; Thorn, Peter

    2010-11-01

    Secretory granules are acidic; cell secretion will therefore lead to extracellular acidification. We propose that during secretion, protons co-released with proteins from secretory granules of pancreatic acinar cells acidify the restricted extracellular space of the pancreatic lumen to regulate normal physiological and pathophysiological functions in this organ Extracellular changes in pH were quantified in real time using 2-photon microscopy analysis of pancreatic tissue fragments from mouse models of acute pancreatitis (mice given physiological concentrations [10 -20 pM] of cholecystokinin or high concentrations of [100 nM] cerulein). The effects of extracellular changes in pH on cell behavior and structures were measured. With physiological stimulation, secretory granule fusion (exocytosis) caused acidification of the pancreatic lumen. Acidifications specifically affected intracellular calcium responses and accelerated the rate of recovery from agonist-evoked calcium signals. Protons therefore appear to function as negative-feedback, extracellular messengers during coupling of cell stimuli with secretion. At high concentrations of cerulein, large increases in secretory activity were associated with extreme, prolonged acidification of the luminal space. These pathological changes in pH led to disruption of intercellular junctional coupling, measured by movement of occludin and E-cadherin. By measuring changes in extracellular pH in pancreas of mice, we observed that luminal acidification resulted from exocytosis of zymogen granules from acinar cells. This process is part of normal organ function but could contribute to the tissue damage in cases of acute pancreatitis. Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

  15. Inactivation of TGFβ receptor II signalling in pancreatic epithelial cells promotes acinar cell proliferation, acinar-to-ductal metaplasia and fibrosis during pancreatitis.

    Science.gov (United States)

    Grabliauskaite, Kamile; Saponara, Enrica; Reding, Theresia; Bombardo, Marta; Seleznik, Gitta M; Malagola, Ermanno; Zabel, Anja; Faso, Carmen; Sonda, Sabrina; Graf, Rolf

    2016-02-01

    Determining signalling pathways that regulate pancreatic regeneration following pancreatitis is critical for implementing therapeutic interventions. In this study we elucidated the molecular mechanisms underlying the effects of transforming growth factor-β (TGFβ) in pancreatic epithelial cells during tissue regeneration. To this end, we conditionally inactivated TGFβ receptor II (TGFβ-RII) using a Cre-LoxP system under the control of pancreas transcription factor 1a (PTF1a) promoter, specific for the pancreatic epithelium, and evaluated the molecular and cellular changes in a mouse model of cerulein-induced pancreatitis. We show that TGFβ-RII signalling does not mediate the initial acinar cell damage observed at the onset of pancreatitis. However, TGFβ-RII signalling not only restricts acinar cell replication during the regenerative phase of the disease but also limits ADM formation in vivo and in vitro in a cell-autonomous manner. Analyses of molecular mechanisms underlying the observed phenotype revealed that TGFβ-RII signalling stimulates the expression of cyclin-dependent kinase inhibitors and intersects with the EGFR signalling axis. Finally, TGFβ-RII ablation in epithelial cells resulted in increased infiltration of inflammatory cells in the early phases of pancreatitis and increased activation of pancreatic stellate cells in the later stages of pancreatitis, thus highlighting a TGFβ-based crosstalk between epithelial and stromal cells regulating the development of pancreatic inflammation and fibrosis. Collectively, our data not only contribute to clarifying the cellular processes governing pancreatic tissue regeneration, but also emphasize the conserved role of TGFβ as a tumour suppressor, both in the regenerative process following pancreatitis and in the initial phases of pancreatic cancer. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  16. Murine Pancreatic Acinar Cell Carcinoma Growth Kinetics Are Independent of Dietary Vitamin D Deficiency or Supplementation

    OpenAIRE

    James Dooley; Vasiliki Lagou; Nathalie Heirman; Tom Dresselaers; Uwe Himmelreich; Adrian Liston

    2017-01-01

    Vitamin D has been proposed as a therapeutic strategy in pancreatic cancer, yet evidence for an effect of dietary vitamin D on pancreatic cancer is ambiguous, with conflicting data from human epidemiological and intervention studies. Here, we tested the role of dietary vitamin D in the in vivo context of the well-characterized Ela1-TAg transgenic mouse model of pancreatic acinar cell carcinoma. Through longitudinal magnetic resonance imaging of mice under conditions of either dietary vitamin ...

  17. Restoration of CFTR Activity in Ducts Rescues Acinar Cell Function and Reduces Inflammation in Pancreatic and Salivary Glands of Mice.

    Science.gov (United States)

    Zeng, Mei; Szymczak, Mitchell; Ahuja, Malini; Zheng, Changyu; Yin, Hongen; Swaim, William; Chiorini, John A; Bridges, Robert J; Muallem, Shmuel

    2017-10-01

    Sjögren's syndrome and autoimmune pancreatitis are disorders with decreased function of salivary, lacrimal glands, and the exocrine pancreas. Nonobese diabetic/ShiLTJ mice and mice transduced with the cytokine BMP6 develop Sjögren's syndrome and chronic pancreatitis and MRL/Mp mice are models of autoimmune pancreatitis. Cystic fibrosis transmembrane conductance regulator (CFTR) is a ductal Cl- channel essential for ductal fluid and HCO3- secretion. We used these models to ask the following questions: is CFTR expression altered in these diseases, does correction of CFTR correct gland function, and most notably, does correcting ductal function correct acinar function? We treated the mice models with the CFTR corrector C18 and the potentiator VX770. Glandular, ductal, and acinar cells damage, infiltration, immune cells and function were measured in vivo and in isolated duct/acini. In the disease models, CFTR expression is markedly reduced. The salivary glands and pancreas are inflamed with increased fibrosis and tissue damage. Treatment with VX770 and, in particular, C18 restored salivation, rescued CFTR expression and localization, and nearly eliminated the inflammation and tissue damage. Transgenic overexpression of CFTR exclusively in the duct had similar effects. Most notably, the markedly reduced acinar cell Ca2+ signaling, Orai1, inositol triphosphate receptors, Aquaporin 5 expression, and fluid secretion were restored by rescuing ductal CFTR. Our findings reveal that correcting ductal function is sufficient to rescue acinar cell function and suggests that CFTR correctors are strong candidates for the treatment of Sjögren's syndrome and pancreatitis. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

  18. Exocrine pancreatic insufficiency in diabetes mellitus: a complication of diabetic neuropathy or a different type of diabetes?

    Science.gov (United States)

    Hardt, Philip D; Ewald, Nils

    2011-01-01

    Pancreatic exocrine insufficiency is a frequently observed phenomenon in type 1 and type 2 diabetes mellitus. Alterations of exocrine pancreatic morphology can also be found frequently in diabetic patients. Several hypotheses try to explain these findings, including lack of insulin as a trophic factor for exocrine tissue, changes in secretion and/or action of other islet hormones, and autoimmunity against common endocrine and exocrine antigens. Another explanation might be that diabetes mellitus could also be a consequence of underlying pancreatic diseases (e.g., chronic pancreatitis). Another pathophysiological concept proposes the functional and morphological alterations as a consequence of diabetic neuropathy. This paper discusses the currently available studies on this subject and tries to provide an overview of the current concepts of exocrine pancreatic insufficiency in diabetes mellitus.

  19. Pancreatic Reg I and Acinar Cell Differentiation: Influence On Cellular Lineage

    Science.gov (United States)

    Sanchez, Didier; Mueller, Catherine; Zenilman, Michael

    2009-01-01

    Objectives Pancreatic reg I has been implicated in cellular differentiation. Acinar cells can transdifferentiate into other pancreatic-derived cells, and we postulated that changes in intracellular levels of reg I would affect the state of differentiation. Methods We transfected AR42J cells with a plasmid containing the entire coding sequence of reg I, and isolated clones with cDNA in sense (SS) or antisense (AS) orientation. Levels of mRNA and protein expression were examined by Western blotting and Real Time-PCR. Results Expression of reg I was confirmed in sense or antisense clones. AR42J transfected with SS demonstrated more acinar-like phenotype while those transfected with AS showed a less differentiated state. Specifically, amylase mRNA and protein levels increased in SS cells while AS cells showed increased PDX-1 and insulin mRNAs and cytokeratin protein. Conversely, cytokeratin and PDX-1 were depressed in SS cells. Conclusions These data demonstrate that in acinar cells, reg I over-expression is linked to acinar cell differentiation, while inhibition of reg I leads to beta-cell and possibly ductal phenotype. Reg I expression in acinar cells is important in maintaining pancreatic cell lineage, and when decreased, cells can de-differentiate and move towards becoming other pancreatic cells. PMID:19557902

  20. Pancreatic endocrine and exocrine function in children following near-total pancreatectomy for diffuse congenital hyperinsulinism.

    Science.gov (United States)

    Arya, Ved Bhushan; Senniappan, Senthil; Demirbilek, Huseyin; Alam, Syeda; Flanagan, Sarah E; Ellard, Sian; Hussain, Khalid

    2014-01-01

    Congenital hyperinsulinism (CHI), the commonest cause of persistent hypoglycaemia, has two main histological subtypes: diffuse and focal. Diffuse CHI, if medically unresponsive, is managed with near-total pancreatectomy. Post-pancreatectomy, in addition to persistent hypoglycaemia, there is a very high risk of diabetes mellitus and pancreatic exocrine insufficiency. International referral centre for the management of CHI. Medically unresponsive diffuse CHI patients managed with near-total pancreatectomy between 1994 and 2012. Near-total pancreatectomy. Persistent hypoglycaemia post near-total pancreatectomy, insulin-dependent diabetes mellitus, clinical and biochemical (faecal elastase 1) pancreatic exocrine insufficiency. Of more than 300 patients with CHI managed during this time period, 45 children had medically unresponsive diffuse disease and were managed with near-total pancreatectomy. After near-total pancreatectomy, 60% of children had persistent hypoglycaemia requiring medical interventions. The incidence of insulin dependent diabetes mellitus was 96% at 11 years after surgery. Thirty-two patients (72%) had biochemical evidence of severe pancreatic exocrine insufficiency (Faecal elastase 1total pancreatectomy is very unsatisfactory. The incidence of persistent hypoglycaemia and insulin-dependent diabetes mellitus is very high. The presence of clinical rather than biochemical pancreatic exocrine insufficiency should inform decisions about pancreatic enzyme supplementation.

  1. Acinar injury and early cytokine response in human acute biliary pancreatitis.

    Science.gov (United States)

    Jakkampudi, Aparna; Jangala, Ramaiah; Reddy, Ratnakar; Mitnala, Sasikala; Rao, G Venkat; Pradeep, Rebala; Reddy, D Nageshwar; Talukdar, Rupjyoti

    2017-11-10

    Clinical acute pancreatitis (AP) is marked by an early phase of systemic inflammatory response syndrome (SIRS) with multiorgan dysfunction (MODS), and a late phase characterized by sepsis with MODS. However, the mechanisms of acinar injury in human AP and the associated systemic inflammation are not clearly understood. This study, for the first time, evaluated the early interactions of bile acid induced human pancreatic acinar injury and the resulting cytokine response. We exposed freshly procured resected human pancreata to taurolithocolic acid (TLCS) and evaluated for acinar injury, cytokine release and interaction with peripheral blood mononuclear cells (PBMCs). We observed autophagy in acinar cells in response to TLCS exposure. There was also time-dependent release of IL-6, IL-8 and TNF-α from the injured acini that resulted in activation of PBMCs. We also observed that cytokines secreted by activated PBMCs resulted in acinar cell apoptosis and further cytokine release from them. Our data suggests that the earliest immune response in human AP originates within the acinar cell itself, which subsequently activates circulating PBMCs leading to SIRS. These findings need further detailed evaluation so that specific therapeutic targets to curb SIRS and resulting early adverse outcomes could be identified and tested.

  2. Evaluation of new exocrine pancreatic function tests and their application to clinical research 2. Effect of spa-drink therapy on exocrine pancreatic function

    OpenAIRE

    松本,秀次

    1988-01-01

    The effect of spa-drink therapy (Misasa hot spring) on exocrine pancreatic function was studied in 25 patiens after their physical and psychological conditions had stabilized about two weeks following their hospitalization. Patients were randomly divided into the following two groups: nine patients into the control group (continuance of spa-bathing) and 16 patients into the spa-drink therapy group (continuance of spa-bathing plus commencement of spa-drink therapy). Spa-drink therapy refers to...

  3. Nelfinavir/ritonavir reduces acinar injury but not inflammation during mouse caerulein pancreatitis

    Science.gov (United States)

    Singh, Vijay P.; Bren, Gary D.; Algeciras-Schimnich, Alicia; Schnepple, David; Navina, Sarah; Rizza, Stacey A.; Dawra, Rajinder K.; Saluja, Ashok K.; Chari, Suresh T.; Vege, Santhi S.; Badley, Andrew D.

    2009-01-01

    There is no clinical treatment that reduces acinar injury during pancreatitis. Human immunodeficiency virus (HIV) protease inhibitors (PI), including nelfinavir (NFV) and ritonavir (RTV), may reduce the rate of pancreatitis in HIV-infected patients. Since permeability transition pore (PTPC)-mediated mitochondrial dysfunction occurs during pancreatitis, and we have shown that PI prevents PTPC opening, we studied its effects in a model of pancreatitis. The effect of NFV plus RTV (NFV/RTV) or vehicle on caerulein-induced pancreatitis in mice was compared by measuring changes in mitochondrial membrane potential in vitro and cytochrome c leakage in vivo. Histological and inflammatory makers were also compared. NFV/RTV improved DiOC6 retention in acini exposed to caerulein in vitro. In vivo NFV prevented cytosolic leakage of cytochrome c and reduced pancreatic acinar injury, active caspase-3 staining, TUNEL-positive acinar cells, and serum amylase (P cell death in experimental mouse caerulein-induced pancreatitis but does not impact inflammation. PMID:19282375

  4. Src Dependent Pancreatic Acinar Injury Can Be Initiated Independent of an Increase in Cytosolic Calcium.

    Directory of Open Access Journals (Sweden)

    Vivek Mishra

    Full Text Available Several deleterious intra-acinar phenomena are simultaneously triggered on initiating acute pancreatitis. These culminate in acinar injury or inflammatory mediator generation in vitro and parenchymal damage in vivo. Supraphysiologic caerulein is one such initiator which simultaneously activates numerous signaling pathways including non-receptor tyrosine kinases such as of the Src family. It also causes a sustained increase in cytosolic calcium- a player thought to be crucial in regulating deleterious phenomena. We have shown Src to be involved in caerulein induced actin remodeling, and caerulein induced changes in the Golgi and post-Golgi trafficking to be involved in trypsinogen activation, which initiates acinar cell injury. However, it remains unclear whether an increase in cytosolic calcium is necessary to initiate acinar injury or if injury can be initiated at basal cytosolic calcium levels by an alternate pathway. To study the interplay between tyrosine kinase signaling and calcium, we treated mouse pancreatic acinar cells with the tyrosine phosphatase inhibitor pervanadate. We studied the effect of the clinically used Src inhibitor Dasatinib (BMS-354825 on pervanadate or caerulein induced changes in Src activation, trypsinogen activation, cell injury, upstream cytosolic calcium, actin and Golgi morphology. Pervanadate, like supraphysiologic caerulein, induced Src activation, redistribution of the F-actin from its normal location in the sub-apical area to the basolateral areas, and caused antegrade fragmentation of the Golgi. These changes, like those induced by supraphysiologic caerulein, were associated with trypsinogen activation and acinar injury, all of which were prevented by Dasatinib. Interestingly, however, pervanadate did not cause an increase in cytosolic calcium, and the caerulein induced increase in cytosolic calcium was not affected by Dasatinib. These findings suggest that intra-acinar deleterious phenomena may be initiated

  5. Exocrine pancreatic cancer: symptoms at presentation and their relation to tumour site and stage.

    Science.gov (United States)

    Porta, Miquel; Fabregat, Xavier; Malats, Núria; Guarner, Luisa; Carrato, Alfredo; de Miguel, Ana; Ruiz, Laura; Jariod, Manuel; Costafreda, Sergi; Coll, Susana; Alguacil, Juan; Corominas, Josep M; Solà, Ricard; Salas, Antonio; Real, Francisco X

    2005-06-01

    The need to detect pancreatic cancer at earlier stages is undisputed. We recorded the signs and symptoms of patients presenting with exocrine pancreatic cancer and evaluated their association with clinical characteristics such as tumour site and disease stage. All patients (n = 185) with exocrine pancreatic cancer newly diagnosed at five general hospitals in Eastern Spain were prospectively recruited over 5 years. Symptoms were elicited through personal interviews and signs were recorded by the attending physician on admission. At diagnosis, one third of tumours of the pancreas head were in stage I and another third in stage IV. None of the tumours of the body and tail were in stage I, and over 80% were in stage IV (p head (p semiology of pancreatic cancer which could be of use in studies on the potential of proteomic tests in the early detection of this neoplasm.

  6. Pathology of genetically engineered mouse models of pancreatic exocrine cancer: consensus report and recommendations

    NARCIS (Netherlands)

    Hruban, Ralph H.; Adsay, N. Volkan; Albores-Saavedra, Jorge; Anver, Miriam R.; Biankin, Andrew V.; Boivin, Gregory P.; Furth, Emma E.; Furukawa, Toru; Klein, Alison; Klimstra, David S.; Kloppel, Gunter; Lauwers, Gregory Y.; Longnecker, Daniel S.; Luttges, Jutta; Maitra, Anirban; Offerhaus, G. Johan A.; Pérez-Gallego, Lucía; Redston, Mark; Tuveson, David A.

    2006-01-01

    Several diverse genetically engineered mouse models of pancreatic exocrine neoplasia have been developed. These mouse models have a spectrum of pathologic changes; however, until now, there has been no uniform nomenclature to characterize these changes. An international workshop, sponsored by The

  7. Starch Origin and Thermal Processing Affect Starch Digestion in a Minipig Model of Pancreatic Exocrine Insufficiency

    OpenAIRE

    Anne Mößeler; Sandra Vagt; Martin Beyerbach; Josef Kamphues

    2015-01-01

    Although steatorrhea is the most obvious symptom of pancreatic exocrine insufficiency (PEI), enzymatic digestion of protein and starch is also impaired. Low praecaecal digestibility of starch causes a forced microbial fermentation accounting for energy losses and meteorism. To optimise dietetic measures, knowledge of praecaecal digestibility of starch is needed but such information from PEI patients is rare. Minipigs fitted with an ileocaecal fistula with (n = 3) or without (n = 3) pancreatic...

  8. NFATc4 Regulates Sox9 Gene Expression in Acinar Cell Plasticity and Pancreatic Cancer Initiation

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    Elisabeth Hessmann

    2016-01-01

    Full Text Available Acinar transdifferentiation toward a duct-like phenotype constitutes the defining response of acinar cells to external stress signals and is considered to be the initial step in pancreatic carcinogenesis. Despite the requirement for oncogenic Kras in pancreatic cancer (PDAC development, oncogenic Kras is not sufficient to drive pancreatic carcinogenesis beyond the level of premalignancy. Instead, secondary events, such as inflammation-induced signaling activation of the epidermal growth factor (EGFR or induction of Sox9 expression, are required for tumor formation. Herein, we aimed to dissect the mechanism that links EGFR signaling to Sox9 gene expression during acinar-to-ductal metaplasia in pancreatic tissue adaptation and PDAC initiation. We show that the inflammatory transcription factor NFATc4 is highly induced and localizes in the nucleus in response to inflammation-induced EGFR signaling. Moreover, we demonstrate that NFATc4 drives acinar-to-ductal conversion and PDAC initiation through direct transcriptional induction of Sox9. Therefore, strategies designed to disrupt NFATc4 induction might be beneficial in the prevention or therapy of PDAC.

  9. Influence of SPK with Enteric Drainage on the Pancreatic Exocrine Function in Diabetic Patients with Uremia

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    Guanghui Pei

    2017-01-01

    Full Text Available Objective. This study aimed to determine the use of fecal elastase in evaluating the effect of simultaneous pancreas–kidney transplantation with enteric drainage on the pancreatic exocrine function of diabetic patients with uremia. Methods. A total of 19 patients with simultaneous pancreas–kidney transplantation (SPK with enteric drainage, 31 diabetic patients with uremia (chronic renal failure (CRF, 22 diabetic patients with uremia who underwent renal transplantation (RT, and 20 normal individuals (CON were included in the study. Pancreatic exocrine insufficiency was determined using fecal elastase. Results. The fecal pancreatic elastase level in SPK patients with enteric drainage was 479 μg/g, which was significantly higher than 229 μg/g in CRF patients and 197 μg/g in RT patients. Using 200 μg/g as the established threshold, a reduced fecal pancreatic elastase level was found in 14/31 of CRF patients, 12/22 of RT patients, 1/19 of SPK patients with enteric drainage, and 1/20 of CON patients. The correlation analysis revealed a significant association between fecal elastase and glycosylated hemoglobin. Conclusions. The present study indicated that SPK with enteric drainage improves pancreatic endocrine and exocrine functions. Fecal elastase may be a clinically relevant means to determine the therapeutic effects.

  10. Long-term experience with ZENPEP in infants with exocrine pancreatic insufficiency associated with cystic fibrosis.

    Science.gov (United States)

    Wooldridge, Jamie L; Schaeffer, David; Jacobs, David; Thieroff-Ekerdt, Ruth

    2014-11-01

    The objective of our study was to determine whether infants with cystic fibrosis who developed exocrine pancreatic insufficiency in early infancy would tolerate long-term treatment with ZENPEP (pancrelipase) delayed-release capsules, containing 3000 US Pharmacopeia units of lipase/capsule, and demonstrate consistent long-term growth. The most common treatment-emergent adverse events were diarrhea, vomiting, and constipation (mild or moderate). At study completion, median weight-for-age percentiles increased from 22nd to 49th, median length-for-age percentiles increased from 36.5th to 42nd, and median weight-for-length percentiles increased from 41.5th to 55.5th. Long-term treatment (up to 12 months) of infants with exocrine pancreatic insufficiency owing to cystic fibrosis with ZENPEP was well tolerated and associated with improved growth parameters. This is the first long-term study of pancreatic enzyme replacement therapy conducted in this patient population.

  11. Murine Pancreatic Acinar Cell Carcinoma Growth Kinetics Are Independent of Dietary Vitamin D Deficiency or Supplementation

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    James Dooley

    2017-06-01

    Full Text Available Vitamin D has been proposed as a therapeutic strategy in pancreatic cancer, yet evidence for an effect of dietary vitamin D on pancreatic cancer is ambiguous, with conflicting data from human epidemiological and intervention studies. Here, we tested the role of dietary vitamin D in the in vivo context of the well-characterized Ela1-TAg transgenic mouse model of pancreatic acinar cell carcinoma. Through longitudinal magnetic resonance imaging of mice under conditions of either dietary vitamin D deficiency (<5 IU/kg vitamin D or excess (76,500 IU/kg vitamin D, compared to control diet (1,500 IU/kg vitamin D, we measured the effect of variation of dietary vitamin D on tumor kinetics. No measurable impact of dietary vitamin D was found on pancreatic acinar cell carcinoma development, growth or mortality, casting further doubt on the already equivocal data supporting potential therapeutic use in humans. The lack of any detectable effect of vitamin D, within the physiological range of dietary deficiency or supplementation, in this model further erodes confidence in vitamin D as an effective antitumor therapeutic in pancreatic acinar cell carcinoma.

  12. Romanian guidelines on the diagnosis and treatment of exocrine pancreatic insufficiency

    DEFF Research Database (Denmark)

    Gheorghe, Cristian; Seicean, Andrada; Saftoiu, Adrian

    2015-01-01

    In assessing exocrine pancreatic insufficiency (EPI), its diverse etiologies and the heterogeneous population affected should be considered. Diagnosing this condition remains a challenge in clinical practice especially for mild-to-moderate EPI, with the support of the time-consuming breath test o...... indicated in patients with celiac disease, who have chronic diarrhea (in spite of gluten-free diet), and in patients with cystic fibrosis with proven EPI....... on an individual's weight and clinical symptoms. The main indication for PERT is chronic pancreatitis, in patients who have clinically relevant steatorrhea, abnormal pancreatic function test or abnormal function tests associated with symptoms of malabsorption such as weight loss or meteorism. While enzyme...

  13. Romanian guidelines on the diagnosis and treatment of exocrine pancreatic insufficiency.

    Science.gov (United States)

    Gheorghe, Cristian; Seicean, Andrada; Saftoiu, Adrian; Tantau, Marcel; Dumitru, Eugen; Jinga, Mariana; Negreanu, Lucian; Mateescu, Bogdan; Gheorghe, Liana; Ciocirlan, Mihai; Cijevschi, Cristina; Constantinescu, Gabriel; Dima, Simona; Diculescu, Mircea

    2015-03-01

    In assessing exocrine pancreatic insufficiency (EPI), its diverse etiologies and the heterogeneous population affected should be considered. Diagnosing this condition remains a challenge in clinical practice especially for mild-to-moderate EPI, with the support of the time-consuming breath test or the coefficient of fat absorption. The fecal elastase-1 test, less precise for the diagnosis, cannot be useful for assessing treatment efficacy. Pancreatic enzyme replacement therapy (PERT) is the mainstay of treatment, whereby enteric-coated mini-microspheres are taken with every meal, in progressive doses based on an individual's weight and clinical symptoms. The main indication for PERT is chronic pancreatitis, in patients who have clinically relevant steatorrhea, abnormal pancreatic function test or abnormal function tests associated with symptoms of malabsorption such as weight loss or meteorism. While enzyme replacement therapy is not recommended in the initial stages of acute pancreatitis, pancreatic exocrine function should be monitored for at least 6-18 months. In the case of unresectable pancreatic cancer, replacement enzyme therapy helps to maintain weight and improve overall quality of life. It is also indicated in patients with celiac disease, who have chronic diarrhea (in spite of gluten-free diet), and in patients with cystic fibrosis with proven EPI.

  14. Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation, and Homeostasis by PTF1A.

    Science.gov (United States)

    Hoang, Chinh Q; Hale, Michael A; Azevedo-Pouly, Ana C; Elsässer, Hans P; Deering, Tye G; Willet, Spencer G; Pan, Fong C; Magnuson, Mark A; Wright, Christopher V E; Swift, Galvin H; MacDonald, Raymond J

    2016-12-15

    Maintenance of cell type identity is crucial for health, yet little is known of the regulation that sustains the long-term stability of differentiated phenotypes. To investigate the roles that key transcriptional regulators play in adult differentiated cells, we examined the effects of depletion of the developmental master regulator PTF1A on the specialized phenotype of the adult pancreatic acinar cell in vivo Transcriptome sequencing and chromatin immunoprecipitation sequencing results showed that PTF1A maintains the expression of genes for all cellular processes dedicated to the production of the secretory digestive enzymes, a highly attuned surveillance of unfolded proteins, and a heightened unfolded protein response (UPR). Control by PTF1A is direct on target genes and indirect through a ten-member transcription factor network. Depletion of PTF1A causes an imbalance that overwhelms the UPR, induces cellular injury, and provokes acinar metaplasia. Compromised cellular identity occurs by derepression of characteristic stomach genes, some of which are also associated with pancreatic ductal cells. The loss of acinar cell homeostasis, differentiation, and identity is directly relevant to the pathologies of pancreatitis and pancreatic adenocarcinoma. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  15. The novel cytokine interleukin-33 activates acinar cell proinflammatory pathways and induces acute pancreatic inflammation in mice.

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    Duraisamy Kempuraj

    Full Text Available Acute pancreatitis is potentially fatal but treatment options are limited as disease pathogenesis is poorly understood. IL-33, a novel IL-1 cytokine family member, plays a role in various inflammatory conditions but its role in acute pancreatitis is not well understood. Specifically, whether pancreatic acinar cells produce IL-33 when stressed or respond to IL-33 stimulation, and whether IL-33 exacerbates acute pancreatic inflammation is unknown.In duct ligation-induced acute pancreatitis in mice and rats, we found that (a IL-33 concentration was increased in the pancreas; (b mast cells, which secrete and also respond to IL-33, showed degranulation in the pancreas and lung; (c plasma histamine and pancreatic substance P concentrations were increased; and (d pancreatic and pulmonary proinflammatory cytokine concentrations were increased. In isolated mouse pancreatic acinar cells, TNF-α stimulation increased IL-33 release while IL-33 stimulation increased proinflammatory cytokine release, both involving the ERK MAP kinase pathway; the flavonoid luteolin inhibited IL-33-stimulated IL-6 and CCL2/MCP-1 release. In mice without duct ligation, exogenous IL-33 administration induced pancreatic inflammation without mast cell degranulation or jejunal inflammation; pancreatic changes included multifocal edema and perivascular infiltration by neutrophils and some macrophages. ERK MAP kinase (but not p38 or JNK and NF-kB subunit p65 were activated in the pancreas of mice receiving exogenous IL-33, and acinar cells isolated from the pancreas of these mice showed increased spontaneous cytokine release (IL-6, CXCL2/MIP-2α. Also, IL-33 activated ERK in human pancreatic tissue.As exogenous IL-33 does not induce jejunal inflammation in the same mice in which it induces pancreatic inflammation, we have discovered a potential role for an IL-33/acinar cell axis in the recruitment of neutrophils and macrophages and the exacerbation of acute pancreatic inflammation

  16. Pancreatic Exocrine Insufficiency in Type 1 and 2 Diabetes: Therapeutic Implications.

    Science.gov (United States)

    Talukdar, Rupjyoti; Reddy, D Nageshwar

    2017-09-01

    The objective of the present review is to focus on pancreatic exocrine insufficiency that is associated with Type 1 and 2 diabetes, its clinical and therapeutic implications, including the utility and efficacy of pancreatin supplementation. A literature search was conducted on Pubmed / Medline to identify relevant articles using terms pancreatic exocrine insufficiency in diabetes mellitus patients, pathophysiology, prevalence, treatment and management published between 2006-2016 in English language. Meta-analysis has revealed the prevalence of PEI in patients with type-1 and type-2 diabetes mellitus to be 37.7% (CI 27.2-49.5) and 26.2% (CI 19.4-34.3) respectively. Very scanty data are available that evaluates the efficacy of pancreatin in patients with diabetes. In the available studies, pancreatin was found to reduce hypoglycemia in insulin treated patients. Pancreatic exocrine insufficiency in type 1 and 2 diabetes mellitus is not uncommon and correct use of pancreatin may have a positive effect on the glycemic status of the diabetic patients. © Journal of the Association of Physicians of India 2011.

  17. Should we Investigate Gastroenterology Patients for Pancreatic Exocrine Insufficiency? A Dual Centre UK Study.

    Science.gov (United States)

    Campbell, Jennifer A; Sanders, David S; Francis, Katherine A; Kurien, Matthew; Lee, Sai; Taha, Hatim; Ramadas, Arvind; Joy, Diamond; Hopper, Andrew D

    2016-09-01

    Pancreatic exocrine insufficiency may be under recognised in gastroenterological practice. We aimed to identify the prevalence of pancreatic insufficiency in secondary care gastroenterology clinics and determine if co-morbidity or presenting symptoms could predict diagnosis. A secondary aim was to assess response to treatment. A dual centre retrospective analysis was conducted in secondary care gastroenterology clinics. Patients tested for pancreatic exocrine insufficiency with faecal elastase-1 (FEL-1) between 2009 and 2013 were identified in two centres. Demographics, indication and co-morbidities were recorded in addition to dose and response to pancreatic enzyme replacement therapy. Binary logistic regression was used to assess if symptoms or co-morbidities could predict pancreatic insufficiency. 1821 patients were tested, 13.1% had low FEL-1 (<200µg/g). This prevalence was sub-analysed with 5.4% having FEL-1 100-200µg/g (mild insufficiency) and 7.6% having faecal elastase readings <100µg/g. Low FEL-1 was most significantly associated with weight loss or steatorrhoea. Co-morbidity analysis showed that low levels were significantly associated with excess alcohol intake, diabetes mellitus or human immunodeficiency virus; 80.0% treated with enzyme supplements reported symptomatic benefit with no difference in response between high and low dose supplementation (p=0.761). Targeting the use of FEL-1 in individuals with specific symptoms and associated conditions can lead to improved recognition of pancreatic exocrine insufficiency in a significant proportion of secondary care patients. Intervening with lifestyle advice such as smoking cessation and minimising alcohol intake could improve outcomes. In addition, up to 80% of patients with low faecal elastase respond to supplementation.

  18. Raf-1 kinase inhibitory protein (RKIP) mediates ethanol-induced sensitization of secretagogue signaling in pancreatic acinar cells.

    Science.gov (United States)

    Kim, Sung Ok; Ives, Kirk L; Wang, Xiaofu; Davey, Robert A; Chao, Celia; Hellmich, Mark R

    2012-09-28

    Excessive alcohol consumption is associated with most cases of chronic pancreatitis, a progressive necrotizing inflammatory disease that can result in pancreatic insufficiency due to acinar atrophy and fibrosis and an increased risk of pancreatic cancer. At a cellular level acute alcohol exposure can sensitize pancreatic acinar cells to secretagogue stimulation, resulting in dysregulation of intracellular Ca(2+) homeostasis and premature digestive enzyme activation; however, the molecular mechanisms by which ethanol exerts these toxic effects have remained undefined. In this study we identify Raf-1 kinase inhibitory protein as an essential mediator of ethanol-induced sensitization of cholecystokinin- and carbachol-regulated Ca(2+) signaling in pancreatic acinar cells. We show that exposure of rodent acinar cells to ethanol induces protein kinase C-dependent Raf-1 kinase inhibitory protein phosphorylation, sensitization of cholecystokinin-stimulated Ca(2+) signaling, and potentiation of both basal and cholecystokinin-stimulated extracellular signal-regulated kinase activation. Furthermore, we show that either suppression of Raf-1 kinase inhibitory protein expression using short hairpin RNA or gene ablation prevented the sensitizing effects of ethanol on cholecystokinin- and carbachol-stimulated Ca(2+) signaling and intracellular chymotrypsin activation in pancreatic acinar cells, suggesting that the modulation of Raf-1 inhibitory protein expression may have future therapeutic utility in the prevention or treatment of alcohol-associated pancreatitis.

  19. Molecular Ghrelin System in the Pancreatic Acinar Cells: The Role of the Polypeptide, Caerulein and Sensory Nerves.

    Science.gov (United States)

    Bonior, Joanna; Ceranowicz, Piotr; Gajdosz, Ryszard; Kuśnierz-Cabala, Beata; Pierzchalski, Piotr; Warzecha, Zygmunt; Dembiński, Artur; Pędziwiatr, Michał; Kot, Michalina; Leja-Szpak, Anna; Nawrot-Porąbka, Katarzyna; Link-Lenczowski, Paweł; Olszanecki, Rafał; Bartuś, Krzysztof; Jaworek, Jolanta

    2017-05-02

    Ghrelin (GHRL) is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R). Experimental studies showed that GHRL protects the stomach and pancreas against acute damage, but the effect of GHRL on pancreatic acinar cells was still undetermined. To investigate the effect of GHRL and caerulein on the functional ghrelin system in pancreatic acinar cells taking into account the role of sensory nerves (SN). Experiments were carried out on isolated pancreatic acinar cells and AR42J cells. Before acinar cells isolation, GHRL was administered intraperitoneally at a dose of 50 µg/kg to rats with intact SN or with capsaicin deactivation of SN (CDSN). After isolation, pancreatic acinar cells were incubated in caerulein-free or caerulein containing solution. AR42J cells were incubated under basal conditions and stimulated with caerulein, GHRL or a combination of the above. Incubation of isolated acinar cells with caerulein inhibited GHS-R and GHRL expression at the level of mRNA and protein in those cells. Either in rats with intact SN or with CDSN, administration of GHRL before isolation of acinar cells increased expression of GHRL and GHS-R in those cells and reversed the caerulein-induced reduction in expression of those parameters. Similar upregulation of GHS-R and GHRL was observed after administration of GHRL in AR42J cells. GHRL stimulates its own expression and expression of its receptor in isolated pancreatic acinar cells and AR42J cells on the positive feedback pathway. This mechanism seems to participate in the pancreatoprotective effect of GHRL in the course of acute pancreatitis.

  20. The role of Ca2+ influx in endocytic vacuole formation in pancreatic acinar cells.

    Science.gov (United States)

    Voronina, Svetlana; Collier, David; Chvanov, Michael; Middlehurst, Ben; Beckett, Alison J; Prior, Ian A; Criddle, David N; Begg, Malcolm; Mikoshiba, Katsuhiko; Sutton, Robert; Tepikin, Alexei V

    2015-02-01

    The inducers of acute pancreatitis trigger a prolonged increase in the cytosolic Ca(2+) concentration ([Ca(2+)]c), which is responsible for the damage to and eventual death of pancreatic acinar cells. Vacuolization is an important indicator of pancreatic acinar cell damage. Furthermore, activation of trypsinogen occurs in the endocytic vacuoles; therefore the vacuoles can be considered as 'initiating' organelles in the development of the cell injury. In the present study, we investigated the relationship between the formation of endocytic vacuoles and Ca(2+) influx developed in response to the inducers of acute pancreatitis [bile acid taurolithocholic acid 3-sulfate (TLC-S) and supramaximal concentration of cholecystokinin-8 (CCK)]. We found that the inhibitor of STIM (stromal interaction molecule)/Orai channels, GSK-7975A, effectively suppressed both the Ca(2+) influx (stimulated by inducers of pancreatitis) and the formation of endocytic vacuoles. Cell death induced by TLC-S or CCK was also inhibited by GSK-7975A. We documented the formation of endocytic vacuoles in response to store-operated Ca(2+) entry (SOCE) induced by thapsigargin [TG; inhibitor of sarcoplasmic/endoplasmic reticulum (ER) Ca(2+) pumps] and observed strong inhibition of TG-induced vacuole formation by GSK-7975A. Finally, we found that structurally-unrelated inhibitors of calpain suppress formation of endocytic vacuoles, suggesting that this Ca2+-dependent protease is a mediator between Ca(2+) elevation and endocytic vacuole formation.

  1. Derivation and Characterization of a Pig Embryonic-Stem-Cell-Derived Exocrine Pancreatic Cell Line.

    Science.gov (United States)

    Talbot, Neil C; Shannon, Amy E; Phillips, Caitlin E; Garrett, Wesley M

    2017-07-01

    The aim of this study was to identify an epithelial cell line isolated from the spontaneous differentiation of totipotent pig epiblast cells. PICM-31 and its colony-cloned derivative cell line, PICM-31A, were established from the culture and differentiation of an epiblast mass isolated from an 8-day-old pig blastocyst. The cell lines were analyzed by transmission electron microscopy, marker gene expression, and mass spectroscopy-based proteomics. The PICM-31 cell lines were continuously cultured and could be successively colony cloned. They spontaneously self-organized into acinarlike structures. Transmission electron microscopy indicated that the cell lines' cells were epithelial and filled with secretory granules. Candidate gene expression analysis of the cells showed an exocrine pancreatic profile that included digestive enzyme expression, for example, carboxypeptidase A1, and expression of the fetal marker, α-fetoprotein. Pancreatic progenitor marker expression included pancreatic and duodenal homeobox 1, NK6 homeobox 1, and pancreas-specific transcription factor 1a, but not neurogenin 3. Proteomic analysis of cellular proteins confirmed the cells' production of digestive enzymes and showed that the cells expressed cytokeratins 8 and 18. The PICM-31 cell lines provide in vitro models of fetal pig pancreatic exocrine cells. They are the first demonstration of continuous cultures, that is, cell lines, of nontransformed pig pancreas cells.

  2. Glycogen synthase kinase-3β ablation limits pancreatitis-induced acinar-to-ductal metaplasia.

    Science.gov (United States)

    Ding, Li; Liou, Geou-Yarh; Schmitt, Daniel M; Storz, Peter; Zhang, Jin-San; Billadeau, Daniel D

    2017-09-01

    Acinar-to-ductal metaplasia (ADM) is a reversible epithelial transdifferentiation process that occurs in the pancreas in response to acute inflammation. ADM can rapidly progress towards pre-malignant pancreatic intraepithelial neoplasia (PanIN) lesions in the presence of mutant KRas and ultimately pancreatic adenocarcinoma (PDAC). In the present work, we elucidate the role and related mechanism of glycogen synthase kinase-3beta (GSK-3β) in ADM development using in vitro 3D cultures and genetically engineered mouse models. We show that GSK-3β promotes TGF-α-induced ADM in 3D cultured primary acinar cells, whereas deletion of GSK-3β attenuates caerulein-induced ADM formation and PanIN progression in KrasG12D transgenic mice. Furthermore, we demonstrate that GSK-3β ablation influences ADM formation and PanIN progression by suppressing oncogenic KRas-driven cell proliferation. Mechanistically, we show that GSK-3β regulates proliferation by increasing the activation of S6 kinase. Taken together, these results indicate that GSK-3β participates in early pancreatitis-induced ADM and thus could be a target for the treatment of chronic pancreatitis and the prevention of PDAC progression. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  3. A pancreatic exocrine-like cell regulatory circuit operating in the upper stomach of the sea urchin Strongylocentrotus purpuratus larva.

    Science.gov (United States)

    Perillo, Margherita; Wang, Yue Julia; Leach, Steven D; Arnone, Maria Ina

    2016-05-26

    Digestive cells are present in all metazoans and provide the energy necessary for the whole organism. Pancreatic exocrine cells are a unique vertebrate cell type involved in extracellular digestion of a wide range of nutrients. Although the organization and regulation of this cell type is intensively studied in vertebrates, its evolutionary history is still unknown. In order to understand which are the elements that define the pancreatic exocrine phenotype, we have analyzed the expression of genes that contribute to specification and function of this cell-type in an early branching deuterostome, the sea urchin Strongylocentrotus purpuratus. We defined the spatial and temporal expression of sea urchin orthologs of pancreatic exocrine genes and described a unique population of cells clustered in the upper stomach of the sea urchin embryo where exocrine markers are co-expressed. We used a combination of perturbation analysis, drug and feeding experiments and found that in these cells of the sea urchin embryo gene expression and gene regulatory interactions resemble that of bona fide pancreatic exocrine cells. We show that the sea urchin Ptf1a, a key transcriptional activator of digestive enzymes in pancreatic exocrine cells, can substitute for its vertebrate ortholog in activating downstream genes. Collectively, our study is the first to show with molecular tools that defining features of a vertebrate cell-type, the pancreatic exocrine cell, are shared by a non-vertebrate deuterostome. Our results indicate that the functional cell-type unit of the vertebrate pancreas may evolutionarily predate the emergence of the pancreas as a discrete organ. From an evolutionary perspective, these results encourage to further explore the homologs of other vertebrate cell-types in traditional or newly emerging deuterostome systems.

  4. Pancreatic acinar cell carcinoma with intracranial metastasis in a dog.

    Science.gov (United States)

    Chang, Shih-Chieh; Liao, Jiunn-Wang; Lin, Yung-Chang; Liu, Cheng-I; Wong, Min-Liang

    2007-01-01

    This report concerns a case of pancreatic carcinoma with widespread metastases to many organs including intracranial metastasis. An eleven-year-old, male, mixed-breed dog showed emaciation, ataxia, and multiple visible tumors within the neck. A MRI examination of the patient was conducted because of ataxia, and it was found that the intracranial invasive growth had resulted in compression of the brain stem. Necropsy was performed after the patient died. Based on gross and microscopic examination, the primary tumor cells were located in the left lobe of the pancreas and widespread metastasis was found into various organs, including the brain, lungs, liver, kidneys, tonsils, serosal surface of the esophagus, and submandibular, pulmonary hilar, mediastinal, and mesenteric lymph nodes. This case indicates that pancreatic adenocarcinoma should be included in the differential diagnosis list when cervical neck masses are detected.

  5. Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms.

    Science.gov (United States)

    Lowery, Maeve A; Wong, Winston; Jordan, Emmet J; Lee, Jonathan W; Kemel, Yelena; Vijai, Joseph; Mandelker, Diana; Zehir, Ahmet; Capanu, Marinela; Salo-Mullen, Erin; Arnold, Angela G; Yu, Kenneth H; Varghese, Anna M; Kelsen, David P; Brenner, Robin; Kaufmann, Erica; Ravichandran, Vignesh; Mukherjee, Semanti; Berger, Michael F; Hyman, David M; Klimstra, David S; Abou-Alfa, Ghassan K; Tjan, Catherine; Covington, Christina; Maynard, Hannah; Allen, Peter J; Askan, Gokce; Leach, Steven D; Iacobuzio-Donahue, Christine A; Robson, Mark E; Offit, Kenneth; Stadler, Zsofia K; O'Reilly, Eileen M

    2018-02-28

    Identification of pathogenic germline alterations (PGAs) has important clinical and therapeutic implications in pancreas cancer. We performed comprehensive germline testing (GT) in an unselected prospective cohort of patients with exocrine pancreatic neoplasms with genotype and phenotype association to facilitate identification of prognostic and/or predictive biomarkers and examine potential therapeutic implications. Six hundred fifteen unselected patients with exocrine pancreatic neoplasms were prospectively consented for somatic tumor and matched sample profiling for 410-468 genes. GT for PGAs in 76 genes associated with cancer susceptibility was performed in an "identified" manner in 356 (57.9%) patients and in an "anonymized" manner in 259 (42.1%) patients, using an institutional review board-approved protocol. Detailed clinical and pathological features, response to platinum, and overall survival (OS) were collected for the identified cohort. OS was analyzed with Kaplan-Meier curves. PGAs were present in 122 (19.8%) of 615 patients involving 24 different genes, including BRCA1/2, ATM, PALB2, and multiple additional genes associated with the DNA damage response pathway. Of 122 patients with germline alterations, 41.8% did not meet current guidelines for GT. The difference in median OS was not statistically significant between patients with and without PGA (50.8 months, 95% confidence interval = 34.5 to not reached, two-sided P = .94). Loss of heterozygosity was found in 60.0% of BRCA1/2. PGAs frequently occur in pancreas exocrine neoplasms and involve multiple genes beyond those previously associated with hereditary pancreatic cancer. These PGAs are therapeutically actionable in about 5% to 10% of patients. These data support routinely offering GT in all pancreatic ductal adenocarcimona patients with a broad panel of known hereditary cancer predisposition genes.

  6. FDG PET imaging of Ela1-myc mice reveals major biological differences between pancreatic acinar and ductal tumours

    Energy Technology Data Exchange (ETDEWEB)

    Abasolo, Ibane [Institut Municipal d' Investigacio Medica-Hospital del Mar, Parc de Recerca Biomedica de Barcelona, Barcelona (Spain); Universitat Pompeu Fabra, Parc de Recerca Biomedica de Barcelona, Departament de Ciencies Experimentals i de la Salut, Barcelona (Spain); Institut d' Alta Tecnologia - CRC, Parc de Recerca Biomedica de Barcelona, Barcelona (Spain); Pujal, Judit; Navarro, Pilar [Institut Municipal d' Investigacio Medica-Hospital del Mar, Parc de Recerca Biomedica de Barcelona, Barcelona (Spain); Rabanal, Rosa M.; Serafin, Anna [Universitat Autonoma de Barcelona, Departament de Medicina i Cirurgia Animals, Barcelona (Spain); Millan, Olga [Institut d' Alta Tecnologia - CRC, Parc de Recerca Biomedica de Barcelona, Barcelona (Spain); Real, Francisco X. [Institut Municipal d' Investigacio Medica-Hospital del Mar, Parc de Recerca Biomedica de Barcelona, Barcelona (Spain); Universitat Pompeu Fabra, Parc de Recerca Biomedica de Barcelona, Departament de Ciencies Experimentals i de la Salut, Barcelona (Spain); Programa de Patologia Molecular, Centro Nacional de Investigaciones Oncologicas, Madrid (Spain)

    2009-07-15

    The aim was to evaluate FDG PET imaging in Ela1-myc mice, a pancreatic cancer model resulting in the development of tumours with either acinar or mixed acinar-ductal phenotype. Transversal and longitudinal FDG PET studies were conducted; selected tissue samples were subjected to autoradiography and ex vivo organ counting. Glucose transporter and hexokinase mRNA expression was analysed by quantitative reverse transcription polymerase chain reaction (RT-PCR); Glut2 expression was analysed by immunohistochemistry. Transversal studies showed that mixed acinar-ductal tumours could be identified by FDG PET several weeks before they could be detected by hand palpation. Longitudinal studies revealed that ductal - but not acinar - tumours could be detected by FDG PET. Autoradiographic analysis confirmed that tumour areas with ductal differentiation incorporated more FDG than areas displaying acinar differentiation. Ex vivo radioactivity measurements showed that tumours of solely acinar phenotype incorporated more FDG than pancreata of non-transgenic littermates despite the fact that they did not yield positive PET images. To gain insight into the biological basis of the differential FDG uptake, glucose transporter and hexokinase transcript expression was studied in microdissected tumour areas enriched for acinar or ductal cells and validated using cell-specific markers. Glut2 and hexokinase I and II mRNA levels were up to 20-fold higher in ductal than in acinar tumours. Besides, Glut2 protein overexpression was found in ductal neoplastic cells but not in the surrounding stroma. In Ela1-myc mice, ductal tumours incorporate significantly more FDG than acinar tumours. This difference likely results from differential expression of Glut2 and hexokinases. These findings reveal previously unreported biological differences between acinar and ductal pancreatic tumours. (orig.)

  7. Exocrine and endocrine functional reserve in the course of chronic pancreatitis as studied by maximal stimulation tests.

    Science.gov (United States)

    Cavallini, G; Bovo, P; Zamboni, M; Bosello, O; Filippini, M; Riela, A; Brocco, G; Rossi, L; Pelle, C; Chiavenato, A

    1992-01-01

    Thirty patients suffering from chronic alcoholic pancreatitis (18 calcified) were entered into a study of exocrine and endocrine pancreatic function based on two maximal stimulation tests, namely the secretin-cerulein test and the glucagon test with serum assays of C peptide. The glucagon test was also performed in 19 control subjects. In addition, 10 chronic pancreatitis patients and nine controls were subjected to an oral glucose tolerance test (OGTT) with serum insulin determinations. C peptide basal values were decreased only in patients with severe pancreatic exocrine insufficiency (P less than 0.001), while delta C peptide values were also reduced in patients with moderate exocrine insufficiency (P less than 0.001). Lipase output correlated very well with delta C peptide values (P less than 0.001). While serum insulin levels during OGTT and C peptide basal values showed no significant differences between the chronic pancreatitis and control groups, delta C peptide values were significantly reduced in chronic pancreatitis patients (P less than 0.02). Both endocrine and exocrine function are impaired in chronic pancreatitis, as demonstrated by maximal tests, even in early stages of the disease.

  8. Glucagon-like peptide-1 receptor signaling in acinar cells causes growth dependent release of pancreatic enzymes

    DEFF Research Database (Denmark)

    Albrechtsen, Nicolai Jacob Wewer; Albrechtsen, Reidar; Bremholm, l

    2016-01-01

    -like peptide 1 (GLP-1) on the exocrine pancreas. Here, we identify GLP-1 receptors on pancreatic acini and analyze the impact of receptor activation in humans, rodents, isolated acini, and cell lines from the exocrine pancreas. GLP-1 did not directly stimulate amylase or lipase release. However, we saw...... that GLP-1 induces phosphorylation of the epidermal growth factor receptor and activation of Foxo1, resulting in cell growth with concomitant enzyme release. Our work uncovers GLP-1-induced signaling pathways in the exocrine pancreas and suggests that increases in amylase and lipase levels in subjects...

  9. Effects of Baicalin on inflammatory mediators and pancreatic acinar cell apoptosis in rats with sever acute pancreatitis

    Directory of Open Access Journals (Sweden)

    zhang xiping

    2009-02-01

    Full Text Available

    • BACKGROUND: To investigate the effects of Baicalin and Octreotide on inflammatory mediators and pancreatic acinar cells apoptosis of rats with severe acute pancreatitis (SAP.
    • METHODS: SD rats were randomly divided into sham operated group (I group, model control group (II group, Baicalin treated group (III group and Octreotide treated group (IV group. Each group was also divided into subgroup of 3, 6 and 12 h (n = 15. The mortality rate, ascites/body weight ratio as well as the level of endotoxin, NO and ET-1 in blood were measured. The pathological severity score of pancreas, apoptotic indexes, and expression levels of Bax and Bcl-2 proteins in each group were investigated.
    • RESULTS: The survival rate of III and IV group has a significant difference compared with II group (P12 h < 0.05. The ascites volume, contents of inflammatory mediators in blood and pathological severity score of pancreas of III and IV group declined at different degrees compared to II group (P < 0.05, P < 0.01 or P < 0.001. Apoptotic index in III group was significantly higher than that in II group at 3 and 6 h (P3, 6 h < 0.05. Apoptotic index in IV group was significantly higher than that in II group at pancreatic tail at 6 h (P6 h < 0.05. Expression level of Bax in III group was significantly higher than that in II group (pancreatic head P3 h,6 h < 0.01, pancreatic tail P3 h < 0.001.
    • CONCLUSIONS: Compared with Octreotide in the treatment of SAP, the protective mechanisms of Baicalin include reducing the excessive inflammatory mediators’ release, inducing the pancreatic acinar cells apoptosis.
    • KEY WORDS: Severe acute pancreatitis, baicalin, octreotide, inflammatory mediators, apoptosis, tissue microarrays.

  10. Simultaneous assessments of exocrine pancreatic function by cholesteryl-[14C]octanoate breath test and measurement of plasma p-aminobenzoic acid

    NARCIS (Netherlands)

    Bruno, M. J.; Hoek, F. J.; Delzenne, B.; van Leeuwen, D. J.; Schteingart, C. D.; Hofmann, A. F.; Tytgat, G. N.

    1995-01-01

    Two noninvasive tests for assessing pancreatic exocrine function, the cholesteryl-[14C]octanoate breath test and the HPLCN-benzoyl-tyrosyl-p-aminobenzoic acid/p-aminosalicylic acid (NBT-PABA/PAS) test, were simultaneously performed in nine patients with pancreatic exocrine insufficiency due to

  11. Exocrine pancreatic insufficiency, MRI of the pancreas and serum nutritional markers in patients with coeliac disease.

    Science.gov (United States)

    Vujasinovic, Miroslav; Tepes, Bojan; Volfand, Jasna; Rudolf, Sasa

    2015-09-01

    To determine whether exocrine pancreatic function is impaired in patients with coeliac disease (CD) in our population and to evaluate its clinical importance. Pancreatic exocrine function was determined by measuring faecal elastase-1 (FE) concentration. CD was diagnosed by serological testing using IgA anti-tissue transglutaminase antibody (IgAtTg) and small bowel biopsy using the Marsh classification. MRI of the pancreas was performed to evaluate any morphological changes. The study took place from January 2012 to December 2013. 90 patients (73 women and 17 men) of mean age 43.8±17.7 years (range 20-80) were included in the study. Mean time from CD confirmation was 5.8±0.7 years (range 1-25). Exocrine pancreatic insufficiency (EPI) was diagnosed in four (4.4%) patients (one with mild EPI and three with severe EPI). MRI showed no morphological changes in any of the four patients. In all patients with EPI at least one serological nutritional marker was below the lower limit of normal. EPI is present in a small number of patients with CD. EPI should be excluded in all patients with CD in the presence of overt malnutrition or in cases of persistent gastrointestinal symptoms despite a gluten-free diet. Measurement of a serum nutritional panel, regardless of the presence of clinical symptoms of EPI, can be of clinical importance. MRI should be performed to exclude any morphological change in the pancreas. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  12. Genetic ablation of Smoothened in pancreatic fibroblasts increases acinar-ductal metaplasia.

    Science.gov (United States)

    Liu, Xin; Pitarresi, Jason R; Cuitiño, Maria C; Kladney, Raleigh D; Woelke, Sarah A; Sizemore, Gina M; Nayak, Sunayana G; Egriboz, Onur; Schweickert, Patrick G; Yu, Lianbo; Trela, Stefan; Schilling, Daniel J; Halloran, Shannon K; Li, Maokun; Dutta, Shourik; Fernandez, Soledad A; Rosol, Thomas J; Lesinski, Gregory B; Shakya, Reena; Ludwig, Thomas; Konieczny, Stephen F; Leone, Gustavo; Wu, Jinghai; Ostrowski, Michael C

    2016-09-01

    The contribution of the microenvironment to pancreatic acinar-to-ductal metaplasia (ADM), a preneoplastic transition in oncogenic Kras-driven pancreatic cancer progression, is currently unclear. Here we show that disruption of paracrine Hedgehog signaling via genetic ablation of Smoothened (Smo) in stromal fibroblasts in a Kras(G12D) mouse model increased ADM. Smo-deleted fibroblasts had higher expression of transforming growth factor-α (Tgfa) mRNA and secreted higher levels of TGFα, leading to activation of EGFR signaling in acinar cells and increased ADM. The mechanism involved activation of AKT and noncanonical activation of the GLI family transcription factor GLI2. GLI2 was phosphorylated at Ser230 in an AKT-dependent fashion and directly regulated Tgfa expression in fibroblasts lacking Smo Additionally, Smo-deleted fibroblasts stimulated the growth of Kras(G12D)/Tp53(R172H) pancreatic tumor cells in vivo and in vitro. These results define a non-cell-autonomous mechanism modulating Kras(G12D)-driven ADM that is balanced by cross-talk between Hedgehog/SMO and AKT/GLI2 pathways in stromal fibroblasts. © 2016 Liu et al.; Published by Cold Spring Harbor Laboratory Press.

  13. Fine structural analyses of pancreatic acinar cell nuclei from mice fed on genetically modified soybean

    Directory of Open Access Journals (Sweden)

    M Malatesta

    2009-06-01

    Full Text Available We carried out ultrastructural morphometrical and immunocytochemical analyses on pancreatic acinar cell nuclei from mice fed on genetically modified (GM soybean, in order to investigate possible structural and molecular modifications of nucleoplasmic and nucleolar constituents.We found a significant lowering of nucleoplasmic and nucleolar splicing factors as well as a perichromatin granule accumulation in GM-fed mice, suggestive of reduced post-transcriptional hnRNA processing and/or nuclear export. This is in accordance to already described zymogen synthesis and processing modifications in the same animals.

  14. Effect of glucagon on digestive enzyme synthesis, transport and secretion in mouse pancreatic acinar cells.

    Science.gov (United States)

    Singh, M

    1980-09-01

    1. Effect of glucagon on amylase secretion and lactic dehydrogenase (LDH) release from functionally intact dissociated pancreatic acinar cells and acini was studied. 2. In dissociated rat pancreatic acinar cells, the rate of amylase secretion was increased by 70% with bethanechol (maximally effective concentration, 10(-4) M) and 125% with A23187 (10(-5) M), but the response to cholecystokinin-pancreozymin (CCK-PZ) was inconsistent. In dissociated cells from mouse pancreas, the increases amounted to 78% with bethanechol (10(-4) M), 134% with A23187 (10(-5) M) and 82% with CCK-PZ (maximally effective concentration, 0 . 01 u. ml.-1). Glucagon in concentrations ranging from 10(-7) to 10(-4) M increased amylase secretion by 3, 26, 67 and 80%, whereas secretin (10(-8)--10(-5) M) increased amylase secretion by 8, 39, 88 and 138%. LDH release was increased with A23187 in concentrations greater than 10(-6) M. 3. CCK-PZ, bethanechol and A23187 used in maximal concentrations potentiated the effect of a submaximal dose of glucagon whereas secretin did not have an additive or a potentiating effect. 4. Pancreatic acini were approximately 3 times more responsive to secretagogues than cells. The dose--response curves to bethanechol, glucagon and CCK-PZ for increase in amylase secretion were similar. LDH release was not increased by these agents. Cytochalasin B (5 microgram ml.-1) which is known to disrupt the integrity of luminal membrane inhibited the amylase secretion stimulated by glucagon, bethanechol and CCK-PZ. 5. Glucagon inhibited incorporation of a mixture of fifteen 14C-labelled amino acids (algal profile, Schwarz Mann) into perchloric acid precipitable proteins in dissociated mouse pancreatic acini within 30 min. 6. In 'pulse-chase' experiments, glucagon decreased the specific activity of zymogen granules isolated by differential centrifugation, from pancreatic lobules (120 min) and increased the specific activity of radiolabelled proteins in the medium (60 and 120 min

  15. Acinar Cell Cystadenocarcinoma of the Pancreas

    Directory of Open Access Journals (Sweden)

    Keita Aoto

    2017-09-01

    Full Text Available Acinar cell cystadenocarcinoma is a rare malignant epithelial neoplasm of the pancreas with a diffusely cystic, gross architecture in which the cysts are lined with neoplastic epithelial cells that demonstrate evidence of pancreatic exocrine enzyme production. This is the 10th case that has been reported in the literature. A 77-year-old male complaining of left hypochondrial pain was referred to our hospital for treatment of a pancreatic tumor. A huge, honeycomb-structured tumor was detected in the pancreatic tail. Distal pancreatectomy with total resection of the residual stomach and partial resection of the transverse colon were performed. Microscopically, there were variably sized cystic lesions in the tumor. Immunohistochemical examinations revealed that tumor cells were positive for alpha 1-antichymotrypsin and alpha 1-trypsin, showing that tumor cells had features of pancreatic acinar cells. Thus, the tumor was diagnosed as acinar cell cystadenocarcinoma. Herein, we report a rare case with acinar cell cystadenocarcinoma, which is the 10th case reported in the literature based on a PubMed search. We managed to resect the tumor completely by distal pancreatectomy with total resection of the residual stomach and partial resection of the transverse colon. The patient is still alive 26 months after surgery without any recurrence after 1 year of adjuvant chemotherapy with S-1.

  16. Low prevalence of exocrine pancreatic insufficiency in patients with diabetes mellitus.

    Science.gov (United States)

    Vujasinovic, Miroslav; Zaletel, Jelka; Tepes, Bojan; Popic, Betka; Makuc, Jana; Epsek Lenart, Metka; Predikaka, Marjana; Rudolf, Sasa

    2013-01-01

    Exocrine pancreatic insufficiency (EPI) can occur in patients with diabetes mellitus (DM). Incidence of EPI and its clinical significance remain poorly defined. The aim of our study was to determine whether exocrine pancreatic function is impaired in patients with DM. One hundred and fifty consecutive patients, mean age 59.0 (± 12.0 years), with DM lasting at least 5 years were included in the study. We included 50 patients with type 1 DM (DM1), 50 insulin-treated patients DM type 2 (DM2-insulin) and 50 non-insulin treated patients with DM type 2 (DM2 no-insulin). Diagnosis of DM was established from health records, lasting 15.0 ± 9.9 years on average. EPI was diagnosed with a fecal elastase-1 concentration (FE1) of less than 200 μg/g (ELISA). FE1 was reduced in 8 (5.4%) patients: mildly reduced (100-200 μg/g) in 4 patients (2.7%) and markedly reduced (alcohol intake). Copyright © 2013 IAP and EPC. Published by Elsevier B.V. All rights reserved.

  17. Duct- and Acinar-Derived Pancreatic Ductal Adenocarcinomas Show Distinct Tumor Progression and Marker Expression

    Directory of Open Access Journals (Sweden)

    Rute M.M. Ferreira

    2017-10-01

    Full Text Available The cell of origin of pancreatic ductal adenocarcinoma (PDAC has been controversial. Here, we show that identical oncogenic drivers trigger PDAC originating from both ductal and acinar cells with similar histology but with distinct pathophysiology and marker expression dependent on cell of origin. Whereas acinar-derived tumors exhibited low AGR2 expression and were preceded by pancreatic intraepithelial neoplasias (PanINs, duct-derived tumors displayed high AGR2 and developed independently of a PanIN stage via non-mucinous lesions. Using orthotopic transplantation and chimera experiments, we demonstrate that PanIN-like lesions can be induced by PDAC as bystanders in adjacent healthy tissues, explaining the co-existence of mucinous and non-mucinous lesions and highlighting the need to distinguish between true precursor PanINs and PanIN-like bystander lesions. Our results suggest AGR2 as a tool to stratify PDAC according to cell of origin, highlight that not all PanIN-like lesions are precursors of PDAC, and add an alternative progression route to the current model of PDAC development.

  18. No Functional Role for microRNA-342 in a Mouse Model of Pancreatic Acinar Carcinoma

    Directory of Open Access Journals (Sweden)

    James Dooley

    2017-05-01

    Full Text Available The intronic microRNA (miR-342 has been proposed as a potent tumor-suppressor gene. miR-342 is found to be downregulated or epigenetically silenced in multiple different tumor sites, and this loss of expression permits the upregulation of several key oncogenic pathways. In several different cell lines, lower miR-342 expression results in enhanced proliferation and metastasis potential, both in vitro and in xenogenic transplant conditions. Here, we sought to determine the function of miR-342 in an in vivo spontaneous cancer model, using the Ela1-TAg transgenic model of pancreatic acinar carcinoma. Through longitudinal magnetic resonance imaging monitoring of Ela1-TAg transgenic mice, either wild-type or knockout for miR-342, we found no role for miR-342 in the development, growth rate, or pathogenicity of pancreatic acinar carcinoma. These results indicate the importance of assessing miR function in the complex physiology of in vivo model systems and indicate that further functional testing of miR-342 is required before concluding it is a bona fide tumor-suppressor-miR.

  19. Increased Postprandial Response of Glucagon-Like Peptide-2 in Patients with Chronic Pancreatitis and Pancreatic Exocrine Insufficiency

    DEFF Research Database (Denmark)

    Hornum, Mads; Pedersen, Jan F; Larsen, Steen

    2010-01-01

    Background/Aims: Glucagon-like peptide-2 (GLP-2) is a nutrient-released gastrointestinal (GI) hormone that acts as an intestinal growth factor, and exogenous GLP-2 has been shown to increase superior mesenteric artery (SMA) blood flow. We aimed to investigate how assimilation of nutrients affects...... postprandial GLP-2 responses and to correlate these with postprandial SMA blood flow. Methods: Responses of the GI hormone glucose-dependent insulinotropic polypeptide (GIP) and GLP-2 were measured following an 80-min liquid meal test in 8 patients (6 males) with chronic pancreatitis (CP) and pancreatic...... exocrine insufficiency (PEI) and 8 healthy control subjects (5 males). Postprandial GI hormone responses were correlated with change in SMA flow as assessed by the resistance index. Results: Patients with CP and PEI exhibited the greatest postprandial GLP-2 responses (1,870 +/- 249 vs. 1,199 +/- 108 pM.80...

  20. Growth Factor Independence-1 (Gfi1) Is Required for Pancreatic Acinar Unit Formation and Centroacinar Cell Differentiation

    DEFF Research Database (Denmark)

    Qu, Xiaoling; Nyeng, Pia; Xiao, Fan

    2015-01-01

    BACKGROUND & AIMS: The genetic specification of the compartmentalized pancreatic acinar/centroacinar unit is poorly understood. Growth factor independence-1 (Gfi1) is a zinc finger transcriptional repressor that regulates hematopoietic stem cell maintenance, pre-T-cell differentiation, formation...... of pancreatic acinar cells as well as the centroacinar cells (CACs) in Gfi1(-/-) mice when compared with wild-type littermates. Pancreatic endocrine differentiation, islet architecture, and function were unaffected. Organ domain patterning and the formation of ductal cells occurred normally during the murine...... of granulocytes, inner ear hair cells, and the development of secretory cell types in the intestine. As GFI1/Gfi1 is expressed in human and rodent pancreas, we characterized the potential function of Gfi1 in mouse pancreatic development. METHODS: Gfi1 knockout mice were analyzed at histological and molecular...

  1. Noninvasive investigation of exocrine pancreatic function: Feasibility of cine dynamic MRCP with a spatially selective inversion-recovery pulse.

    Science.gov (United States)

    Yasokawa, Kazuya; Ito, Katsuyoshi; Tamada, Tsutomu; Yamamoto, Akira; Hayashida, Minoru; Tanimoto, Daigo; Higaki, Atsushi; Noda, Yasufumi; Kido, Ayumu

    2015-11-01

    To investigate the feasibility of noncontrast-enhanced cine dynamic magnetic resonance cholangiopancreatography (MRCP) with a spatially selective inversion-recovery (IR) pulse for evaluating exocrine pancreatic function in comparison with the N-benzoyl-L-tyrosyl-p-aminobenzoic acid (BT-PABA) test as a pancreatic exocrine function test. Twenty subjects with or without chronic pancreatitis were included. MRCP with a spatially selective IR pulse was repeated every 15 seconds for 5 minutes to acquire a total of 20 images (cine-dynamic MRCP). The median and mean frequency of the observation (the number of times) and the moving distance (mean secretion grading scores) of pancreatic juice inflow on cine-dynamic MRCP were compared with a BT-PABA test. The urinary PABA excretion rate (%) had significant positive correlations with both the mean secretion grade (r = 0.66, P = 0.002) and frequency of secretory inflow (r = 0.62, P = 0.004) in cine dynamic MRCP. Both the mean frequency of observations of pancreatic secretory inflow (1.4 ± 1.6 times vs. 14.3 ± 4.2 times, P Cine dynamic MRCP with a spatially selective IR pulse may have potential for estimating the pancreatic exocrine function noninvasively as a substitute for the BT-PABA test. © 2015 Wiley Periodicals, Inc.

  2. Prevalence and determinants of exocrine pancreatic insufficiency among older adults: results of a population-based study.

    Science.gov (United States)

    Rothenbacher, Dietrich; Löw, Michael; Hardt, Philip D; Klör, Hans-Ulrich; Ziegler, Hartwig; Brenner, Hermann

    2005-06-01

    The prevalence and main determinants of exocrine pancreatic insufficiency were investigated in a large population-based sample of older adults by measuring pancreatic elastase-1 in stool. The study comprised 914 participants aged 50 to 75 years recruited by their general practitioner during a general health examination. All participants and their physicians were asked to fill out a standardized questionnaire which contained information on socio-demographic and lifestyle factors as well as medical history. Native stool was examined for pancreatic elastase-1 with a commercially available ELISA (ScheBo Tech, Giessen, Germany). Overall, 524 women and 390 men aged 50 to 75 years (mean age 61.9 years) were included in the analysis. In total, 105 (11.5%) of the 914 subjects showed signs of exocrine pancreatic insufficiency (EPI) with =200 microg elastase-1/g stool, and 47 (5.1%) subjects showed signs of a severe exocrine pancreatic insufficiency (SEPI, < 100 microg elastase-1/g stool). There was a clear increase in EPI with age. Patients taking angiotensin-converting enzyme (ACE) inhibitors had a lower prevalence than subjects without this medication; these associations persisted after adjustment for covariates. Prevalence of EPI increases with age and seems to be tentatively higher in men than in women. However, smoking seems to be an independent risk factor for EPI and SEPI whereas ACE-inhibitor intake might be a protective factor. The latter finding may even point to new options in the treatment of chronic pancreatitis.

  3. Normal pancreatic exocrine function does not exclude MRI/MRCP chronic pancreatitis findings.

    Science.gov (United States)

    Alkaade, Samer; Cem Balci, Numan; Momtahen, Amir Javad; Burton, Frank

    2008-09-01

    Abnormal pancreatic function tests have been reported to precede the imaging findings of chronic pancreatitis. Magnetic resonance imaging (MRI) with magnetic resonance cholangiopancreatography (MRCP) is increasingly accepted as the primary imaging modality for the detection of structural changes of early mild chronic pancreatitis. The aim of this study was to evaluate MRI/MRCP findings in patients with symptoms consistent with chronic pancreatitis who have normal Secretin Endoscopic Pancreatic Function test. A retrospective study of 32 patients referred for evaluation of chronic abdominal pain consistent with chronic pancreatitis and reported normal standard abdominal imaging (ultrasound, computed tomography, or MRI). All patients underwent Secretin Endoscopic Pancreatic Function testing and pancreatic MRI/MRCP at our institution. We reviewed the MRI/MRCP images in patients who had normal Secretin Endoscopic Pancreatic Function testing. MRI/MRCP images were assessed for pancreatic duct morphology, gland size, parenchymal signal and morphology, and arterial contrast enhancement. Of the 32 patients, 23 had normal Secretin Endoscopic Pancreatic Function testing, and 8 of them had mild to marked spectrum of abnormal MRI/MRCP findings that were predominantly focal. Frequencies of the findings were as follows: pancreatic duct stricture (n=3), pancreatic duct dilatation (n=3), side branch ectasia (n=4), atrophy (n=5), decreased arterial enhancement (n=5), decreased parenchymal signal (n=1), and cavity formation (n=1). The remaining15 patients had normal pancreatic structure on MRI/MRCP. Normal pancreatic function testing cannot exclude abnormal MRI/MRCP especially focal findings of chronic pancreatitis. Further studies needed to verify significance of these findings and establish MRI/MRCP imaging criteria for the diagnosis of chronic pancreatitis.

  4. Polycomb repressor complex 1 promotes gene silencing through H2AK119 mono-ubiquitination in acinar-to-ductal metaplasia and pancreatic cancer cells.

    Science.gov (United States)

    Benitz, Simone; Regel, Ivonne; Reinhard, Tobias; Popp, Anna; Schäffer, Isabell; Raulefs, Susanne; Kong, Bo; Esposito, Irene; Michalski, Christoph W; Kleeff, Jörg

    2016-03-08

    Acinar-to-ductal metaplasia (ADM) occurring in cerulein-mediated pancreatitis or in oncogenic Kras-driven pancreatic cancer development is accompanied by extensive changes in the transcriptional program. In this process, acinar cells shut down the expression of acinar specific differentiation genes and re-express genes usually found in embryonic pancreatic progenitor cells. Previous studies have demonstrated that a loss of acinar-specific transcription factors sensitizes the cells towards oncogenic transformation, ultimately resulting in cancer development. However, the mechanism behind the transcriptional silencing of acinar cell fate genes in ADM and pancreatic cancer is largely unknown. Here, we analyzed whether elevated levels of the polycomb repressor complex 1 (PRC1) components Bmi1 and Ring1b and their catalyzed histone modification H2AK119ub in ADMs and tumor cells, are responsible for the mediation of acinar gene silencing. Therefore, we performed chromatin-immunoprecipitation in in vitro generated ADMs and isolated murine tumor cells against the repressive histone modifications H3K27me3 and H2AK119ub. We established that the acinar transcription factor complex Ptf1-L is epigenetically silenced in ADMs as well as in pancreatic tumor cells. For the first time, this work presents a possible mechanism of acinar gene silencing, which is an important prerequisite in the initiation and maintenance of a dedifferentiated cell state in ADMs and tumor cells.

  5. Inhibitors of ORAI1 Prevent Cytosolic Calcium-Associated Injury of Human Pancreatic Acinar Cells and Acute Pancreatitis in 3 Mouse Models.

    Science.gov (United States)

    Wen, Li; Voronina, Svetlana; Javed, Muhammad A; Awais, Muhammad; Szatmary, Peter; Latawiec, Diane; Chvanov, Michael; Collier, David; Huang, Wei; Barrett, John; Begg, Malcolm; Stauderman, Ken; Roos, Jack; Grigoryev, Sergey; Ramos, Stephanie; Rogers, Evan; Whitten, Jeff; Velicelebi, Gonul; Dunn, Michael; Tepikin, Alexei V; Criddle, David N; Sutton, Robert

    2015-08-01

    Sustained activation of the cytosolic calcium concentration induces injury to pancreatic acinar cells and necrosis. The calcium release-activated calcium modulator ORAI1 is the most abundant Ca(2+) entry channel in pancreatic acinar cells; it sustains calcium overload in mice exposed to toxins that induce pancreatitis. We investigated the roles of ORAI1 in pancreatic acinar cell injury and the development of acute pancreatitis in mice. Mouse and human acinar cells, as well as HEK 293 cells transfected to express human ORAI1 with human stromal interaction molecule 1, were hyperstimulated or incubated with human bile acid, thapsigargin, or cyclopiazonic acid to induce calcium entry. GSK-7975A or CM_128 were added to some cells, which were analyzed by confocal and video microscopy and patch clamp recordings. Acute pancreatitis was induced in C57BL/6J mice by ductal injection of taurolithocholic acid 3-sulfate or intravenous' administration of cerulein or ethanol and palmitoleic acid. Some mice then were given GSK-7975A or CM_128, which inhibit ORAI1, at different time points to assess local and systemic effects. GSK-7975A and CM_128 each separately inhibited toxin-induced activation of ORAI1 and/or activation of Ca(2+) currents after Ca(2+) release, in a concentration-dependent manner, in mouse and human pancreatic acinar cells (inhibition >90% of the levels observed in control cells). The ORAI1 inhibitors also prevented activation of the necrotic cell death pathway in mouse and human pancreatic acinar cells. GSK-7975A and CM_128 each inhibited all local and systemic features of acute pancreatitis in all 3 models, in dose- and time-dependent manners. The agents were significantly more effective, in a range of parameters, when given at 1 vs 6 hours after induction of pancreatitis. Cytosolic calcium overload, mediated via ORAI1, contributes to the pathogenesis of acute pancreatitis. ORAI1 inhibitors might be developed for the treatment of patients with pancreatitis

  6. Lysosome associated membrane proteins maintain pancreatic acinar cell homeostasis : LAMP-2 deficient mice develop pancreatitis

    NARCIS (Netherlands)

    Mareninova, Olga A; Sendler, Matthias; Malla, Sudarshan Ravi; Yakubov, Iskandar; French, Samuel W; Tokhtaeva, Elmira; Vagin, Olga; Oorschot, Viola; Lüllmann-Rauch, Renate; Blanz, Judith; Dawson, David; Klumperman, Judith; Lerch, Markus M; Mayerle, Julia; Gukovsky, Ilya; Gukovskaya, Anna S

    2015-01-01

    BACKGROUND & AIMS: The pathogenic mechanism of pancreatitis is poorly understood. Recent evidence implicates defective autophagy in pancreatitis responses; however, the pathways mediating impaired autophagy in pancreas remain largely unknown. Here, we investigate the role of lysosome associated

  7. Role of the ductal transcription factors HNF6 and Sox9 in pancreatic acinar-to-ductal metaplasia

    Science.gov (United States)

    Prévot, Pierre-Paul; Simion, Alexandru; Grimont, Adrien; Colletti, Marta; Khalaileh, Abed; Van den Steen, Géraldine; Sempoux, Christine; Xu, Xiaobo; Roelants, Véronique; Hald, Jacob; Bertrand, Luc; Heimberg, Harry; Konieczny, Stephen F.; Dor, Yuval; Lemaigre, Frédéric P.; Jacquemin, Patrick

    2014-01-01

    Objective Growing evidence suggests that a phenotypic switch converting pancreatic acinar cells to duct-like cells can lead to pancreatic intraepithelial neoplasia (PanIN) and eventually to invasive pancreatic ductal adenocarcinoma. Histologically, the onset of this switch is characterised by the co-expression of acinar and ductal markers in acini, a lesion called acinar-to-ductal metaplasia (ADM). Transcriptional regulators required to initiate ADM still remain unknown, yet need to be identified to characterise the regulatory networks that drive ADM. Here we investigate the role of the ductal transcription factors Hepatocyte Nuclear Factor 6 (HNF6, also known as Onecut1)and SRY-related HMG box factor 9 (Sox9) in ADM. Design Expression of HNF6 and Sox9 is measured by immunostaining in normal and diseased human pancreas. The function of the factors is tested in cultured cells and in mouse models of ADM by a combination of gain- and loss-of-function experiments. Results Expression of HNF6 and Sox9 is ectopically induced in acinar cells in human ADM, as well as in mouse models of ADM. We show that these factors are required for repression of acinar genes, for modulation of ADM-associated changes in cell polarity, and for activation of ductal genes in metaplastic acinar cells. Conclusions HNF6 and Sox9 are new biomarkers of ADM and constitute candidate targets for preventive therapy in cases when ADM may lead to cancer. Our work also highlights that ectopic activation of transcription factors may underlie metaplastic processes occurring in other organs. PMID:22271799

  8. Mutant KRas-Induced Mitochondrial Oxidative Stress in Acinar Cells Upregulates EGFR Signaling to Drive Formation of Pancreatic Precancerous Lesions

    Directory of Open Access Journals (Sweden)

    Geou-Yarh Liou

    2016-03-01

    Full Text Available The development of pancreatic cancer requires the acquisition of oncogenic KRas mutations and upregulation of growth factor signaling, but the relationship between these is not well established. Here, we show that mutant KRas alters mitochondrial metabolism in pancreatic acinar cells, resulting in increased generation of mitochondrial reactive oxygen species (mROS. Mitochondrial ROS then drives the dedifferentiation of acinar cells to a duct-like progenitor phenotype and progression to PanIN. This is mediated via the ROS-receptive kinase protein kinase D1 and the transcription factors NF-κB1 and NF-κB2, which upregulate expression of the epidermal growth factor, its ligands, and their sheddase ADAM17. In vivo, interception of KRas-mediated generation of mROS reduced the formation of pre-neoplastic lesions. Hence, our data provide insight into how oncogenic KRas interacts with growth factor signaling to induce the formation of pancreatic cancer.

  9. Chronic alcohol exposure inhibits biotin uptake by pancreatic acinar cells: possible involvement of epigenetic mechanisms.

    Science.gov (United States)

    Srinivasan, Padmanabhan; Kapadia, Rubina; Biswas, Arundhati; Said, Hamid M

    2014-11-01

    Chronic exposure to alcohol affects different physiological aspects of pancreatic acinar cells (PAC), but its effect on the uptake process of biotin is not known. We addressed this issue using mouse-derived pancreatic acinar 266-6 cells chronically exposed to alcohol and wild-type and transgenic mice (carrying the human SLC5A6 5'-promoter) fed alcohol chronically. First we established that biotin uptake by PAC is Na(+) dependent and carrier mediated and involves sodium-dependent multivitamin transporter (SMVT). Chronic exposure of 266-6 cells to alcohol led to a significant inhibition in biotin uptake, expression of SMVT protein, and mRNA as well as in the activity of the SLC5A6 promoter. Similarly, chronic alcohol feeding of wild-type and transgenic mice carrying the SLC5A6 promoter led to a significant inhibition in biotin uptake by PAC, as well as in the expression of SMVT protein and mRNA and the activity of the SLC5A6 promoters expressed in the transgenic mice. We also found that chronic alcohol feeding of mice is associated with a significant increase in the methylation status of CpG islands predicted to be in the mouse Slc5a6 promoters and a decrease in the level of expression of transcription factor KLF-4, which plays an important role in regulating SLC5A6 promoter activity. These results demonstrate, for the first time, that chronic alcohol exposure negatively impacts biotin uptake in PAC and that this effect is exerted (at least in part) at the level of transcription of the SLC5A6 gene and may involve epigenetic/molecular mechanisms. Copyright © 2014 the American Physiological Society.

  10. Predictors of Locoregional Failure and Impact on Overall Survival in Patients With Resected Exocrine Pancreatic Cancer

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    Merrell, Kenneth W.; Haddock, Michael G. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Quevedo, J. Fernando [Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota (United States); Harmsen, William S. [Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota (United States); Kendrick, Michael L. [Department of General Surgery, Mayo Clinic, Rochester, Minnesota (United States); Miller, Robert C. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Hallemeier, Christopher L., E-mail: hallemeier.christopher@mayo.edu [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States)

    2016-03-01

    Purpose: Resection of exocrine pancreatic cancer is necessary for cure, but locoregional and distant relapse is common. We evaluated our institutional experience to better understand risk factors for locoregional failure (LRF) and its impact on overall survival (OS). Methods and Materials: We reviewed 1051 consecutive patients with nonmetastatic exocrine pancreatic cancer who underwent resection at our institution between March 1987 and January 2011. Among them, 458 had adequate follow-up and evaluation for study inclusion. All patients received adjuvant chemotherapy (n=80 [17.5%]) or chemoradiation therapy (n=378 [82.5%]). Chemotherapy and chemoradiation therapy most frequently consisted of 6 cycles of gemcitabine and 50.4 Gy in 28 fractions with concurrent 5-fluorouracil, respectively. Locoregional control (LRC) and OS were estimated with the Kaplan-Meier method. Univariate and multivariate analyses were performed with Cox proportional hazards regression models incorporating propensity score. Results: Median patient age was 64.5 years (range: 29-88 years). Median follow-up for living patients was 84 months (range: 6-300 months). Extent of resection was R0 (83.8%) or R1 (16.2%). Overall crude incidence of LRF was 17% (n=79). The 5-year LRC for patients with and without radiation therapy was 80% and 68%, respectively (P=.003; hazard ratio [HR]: 0.45; 95% confidence interval [CI]: 0.28-0.76). Multivariate analysis, incorporating propensity score, indicated radiation therapy (P<.0001; HR: 0.23; 95% CI: 0.12-0.42) and positive lymph node ratio of ≥0.2 (P=.02; HR: 1.78; 95% CI: 1.10-2.9) were associated with LRC. In addition, LRF was associated with worse OS (P<.0001; HR: 5.0; 95% CI: 3.9-6.3). Conclusions: In our analysis of 458 patients with resected pancreatic cancer, positive lymph node ratio of ≥0.2 and no adjuvant chemoradiation therapy were associated with increased LRF risk. LRF was associated with poor OS. Radiation therapy should be considered as

  11. Undiagnosed pancreatic exocrine insufficiency and chronic pancreatitis in functional GI disorder patients with diarrhea or abdominal pain.

    Science.gov (United States)

    Talley, Nicholas J; Holtmann, Gerald; Nguyen, Quoc Nam; Gibson, Peter; Bampton, Peter; Veysey, Martin; Wong, James; Philcox, Stephen; Koloski, Natasha; Bunby, Lisa; Jones, Michael

    2017-11-01

    A previous UK study showed that 6.1% of patients with diarrhea-predominant irritable bowel syndrome (IBS-D) had evidence of severe pancreatic exocrine insufficiency (PEI), but these findings need replication. We aimed to identify the prevalence of PEI based on fecal elastase stool testing in consecutive outpatients presenting with chronic unexplained abdominal pain and/or diarrhea and/or IBS-D. Patients aged over 40 years presenting to hospital outpatient clinics from six sites within Australia with unexplained abdominal pain and/or diarrhea for at least 3 months and/or IBS-D were studied. Patients completed validated questionnaires and donated a stool sample in which elastase concentration was measured by ELISA. A concentration of chronic pancreatitis. One in 50 patients with IBS-D or otherwise unexplained abdominal pain or diarrhea have an abnormal fecal elastase, but unexpected pancreatic insufficiency was detected in only a minority of these. This study failed to confirm the high prevalence of PEI among patients with unexplained GI symptoms previously reported. © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  12. Ichthyosis, exocrine pancreatic insufficiency, impaired neutrophil chemotaxis, growth retardation, and metaphyseal dysplasia (Shwachman syndrome). : Report of a case with extensive skin lesions (clinical, histological, and ultrastructural findings)

    NARCIS (Netherlands)

    M. Goeteyn (M.); A.P. Oranje (Arnold); V.D. Vuzevski (Vojislav); R. de Groot (Ronald); L.W.A. van Suijlekom-Smit (Lisette)

    1991-01-01

    textabstractThe Shwachman syndrome comprises exocrine pancreatic insufficiency, growth retardation, and bone marrow hypoplasia resulting in neutropenia. Clinical, morphological, and ultrastructural studies, as well as hair analysis, were performed in a patient with Shwachman's syndrome and severe

  13. Evidence for a causal relationship between early exocrine pancreatic disease and cystic fibrosis-related diabetes: a Mendelian randomization study.

    Science.gov (United States)

    Soave, David; Miller, Melissa R; Keenan, Katherine; Li, Weili; Gong, Jiafen; Ip, Wan; Accurso, Frank; Sun, Lei; Rommens, Johanna M; Sontag, Marci; Durie, Peter R; Strug, Lisa J

    2014-06-01

    Circulating immunoreactive trypsinogen (IRT), a biomarker of exocrine pancreatic disease in cystic fibrosis (CF), is elevated in most CF newborns. In those with severe CF transmembrane conductance regulator (CFTR) genotypes, IRT declines rapidly in the first years of life, reflecting progressive pancreatic damage. Consistent with this progression, a less elevated newborn IRT measure would reflect more severe pancreatic disease, including compromised islet compartments, and potentially increased risk of CF-related diabetes (CFRD). We show in two independent CF populations that a lower newborn IRT estimate is associated with higher CFRD risk among individuals with severe CFTR genotypes, and we provide evidence to support a causal relationship. Increased loge(IRT) at birth was associated with decreased CFRD risk in Canadian and Colorado samples (hazard ratio 0.30 [95% CI 0.15-0.61] and 0.39 [0.18-0.81], respectively). Using Mendelian randomization with the SLC26A9 rs7512462 genotype as an instrumental variable since it is known to be associated with IRT birth levels in the CF population, we provide evidence to support a causal contribution of exocrine pancreatic status on CFRD risk. Our findings suggest CFRD risk could be predicted in early life and that maintained ductal fluid flow in the exocrine pancreas could delay the onset of CFRD. © 2014 by the American Diabetes Association.

  14. Activation of GLP-1 and gastrin signalling induces in vivo reprogramming of pancreatic exocrine cells into beta cells in mice.

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    Sasaki, Shugo; Miyatsuka, Takeshi; Matsuoka, Taka-aki; Takahara, Mitsuyoshi; Yamamoto, Yuichi; Yasuda, Tetsuyuki; Kaneto, Hideaki; Fujitani, Yoshio; German, Michael S; Akiyama, Haruhiko; Watada, Hirotaka; Shimomura, Iichiro

    2015-11-01

    Lineage conversion of non-beta cells into insulin-producing cells has been proposed as a therapy for the cure of diabetes. Glucagon-like peptide-1 (GLP-1) and its derivatives can induce beta cell neogenesis in vitro and beta cell mass expansion in vivo, but GLP-1 signalling has not been shown to regulate cell fate decisions in vivo. We therefore tested the impact of GLP-1 receptor (GLP1R) expression on beta cell differentiation in vivo. Mice overexpressing GLP1R in pancreatic exocrine cells were generated by Cre-mediated recombination in sex-determining region Y-box 9 (SOX9)-expressing cells and then treated with exendin-4 and/or gastrin. Histological analysis was performed to detect cellular reprogramming from the exocrine lineage into insulin-producing cells. Whereas no newly generated beta cells were detected in the mice treated with exendin-4 alone, treatment with gastrin only induced the conversion of exocrine cells into insulin-producing cells. Furthermore, the overexpression of GLP1R, together with gastrin and exendin-4, synergistically promoted beta cell neogenesis accompanied by the formation of islet-like clusters. These newly generated beta cells expressed beta cell specific transcription factors, such as pancreatic and duodenal homeobox 1 (PDX1), NK6 homeobox 1 (NKX6.1) and musculoaponeurotic fibrosarcoma oncogene family A (MafA). These mice showed no histological evidence of pancreatitis or pancreatic dysplasia in their acini and had normal plasma amylase levels. Activation of GLP-1 and gastrin signalling induces beta cell neogenesis in the exocrine lineage without any deleterious pancreatic changes, which may lead to a potential therapy to cure diabetes by generating surrogate beta cells.

  15. Alcohol oxidizing enzymes and ethanol-induced cytotoxicity in rat pancreatic acinar AR42J cells.

    Science.gov (United States)

    Bhopale, Kamlesh K; Falzon, Miriam; Ansari, G A S; Kaphalia, Bhupendra S

    2014-04-01

    Alcoholic chronic pancreatitis (ACP) is a serious inflammatory disease causing significant morbidity and mortality. Due to lack of a suitable animal model, the underlying mechanism of ACP is poorly understood. Chronic alcohol abuse inhibits alcohol dehydrogenase (ADH) and facilitates nonoxidative metabolism of ethanol to fatty acid ethyl esters (FAEEs) in the pancreas frequently damaged during chronic ethanol abuse. Earlier, we reported a concentration-dependent formation of FAEEs and cytotoxicity in ethanol-treated rat pancreatic tumor (AR42J) cells, which express high FAEE synthase activity as compared to ADH and cytochrome P450 2E1. Therefore, the present study was undertaken to investigate the role of various ethanol oxidizing enzymes in ethanol-induced pancreatic acinar cell injury. Confluent AR42J cells were pre-treated with inhibitors of ADH class I and II [4-methylpyrazole (MP)] or class I, II, and III [1,10-phenanthroline (PT)], cytochrome P450 2E1 (trans-1,2-dichloroethylene) or catalase (sodium azide) followed by incubation with 800 mg% ethanol at 37°C for 6 h. Ethanol metabolism, cell viability, cytotoxicity (apoptosis and necrosis), cell proliferation status, and formation of FAEEs in AR42J cells were measured. The cell viability and cell proliferation rate were significantly reduced in cells pretreated with 1,10-PT + ethanol followed by those with 4-MP + ethanol. In situ formation of FAEEs was twofold greater in cells incubated with 1,10-PT + ethanol and ∼1.5-fold in those treated with 4-MP + ethanol vs. respective controls. However, cells treated with inhibitors of cytochrome P450 2E1 or catalase in combination of ethanol showed no significant changes either for FAEE formation, cell death or proliferation rate. Therefore, an impaired ADH class I-III catalyzed oxidation of ethanol appears to be a key contributing factor in ethanol-induced pancreatic injury via formation of nonoxidative metabolites of ethanol.

  16. Docosahexaenoic acid inhibits IL-6 expression via PPARγ-mediated expression of catalase in cerulein-stimulated pancreatic acinar cells.

    Science.gov (United States)

    Song, Eun Ah; Lim, Joo Weon; Kim, Hyeyoung

    2017-07-01

    Cerulein pancreatitis mirrors human acute pancreatitis. In pancreatic acinar cells exposed to cerulein, reactive oxygen species (ROS) mediate inflammatory signaling by Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3, and cytokine induction. Docosahexaenoic acid (DHA) acts as an agonist of peroxisome proliferator activated receptor γ (PPARγ), which mediates the expression of some antioxidant enzymes. We hypothesized that DHA may induce PPARγ-target catalase expression and reduce ROS levels, leading to the inhibition of JAK2/STAT3 activation and IL-6 expression in cerulein-stimulated acinar cells. Pancreatic acinar AR42J cells were treated with DHA in the presence or absence of the PPARγ antagonist GW9662, or treated with the PPARγ agonist troglitazone, and then stimulated with cerulein. Expression of IL-6 and catalase, ROS levels, JAK2/STAT3 activation, and nuclear translocation of PPARγ were assessed. DHA suppressed the increase in ROS, JAK2/STAT3 activation, and IL-6 expression induced nuclear translocation of PPARγ and catalase expression in cerulein-stimulated AR42J cells. Troglitazone inhibited the cerulein-induced increase in ROS and IL-6 expression, but induced catalase expression similar to DHA in AR42J cells. GW9662 abolished the inhibitory effect of DHA on cerulein-induced increase in ROS and IL-6 expression in AR42J cells. DHA-induced expression of catalase was suppressed by GW9662 in cerulein-stimulated AR42J cells. Thus, DHA induces PPARγ activation and catalase expression, which inhibits ROS-mediated activation of JAK2/STAT3 and IL-6 expression in cerulein-stimulated pancreatic acinar cells. Copyright © 2017. Published by Elsevier Ltd.

  17. Starch Origin and Thermal Processing Affect Starch Digestion in a Minipig Model of Pancreatic Exocrine Insufficiency

    Directory of Open Access Journals (Sweden)

    Anne Mößeler

    2015-01-01

    Full Text Available Although steatorrhea is the most obvious symptom of pancreatic exocrine insufficiency (PEI, enzymatic digestion of protein and starch is also impaired. Low praecaecal digestibility of starch causes a forced microbial fermentation accounting for energy losses and meteorism. To optimise dietetic measures, knowledge of praecaecal digestibility of starch is needed but such information from PEI patients is rare. Minipigs fitted with an ileocaecal fistula with (n=3 or without (n=3 pancreatic duct ligation (PL were used to estimate the rate of praecaecal disappearance (pcD of starch. Different botanical sources of starch (rice, amaranth, potato, and pea were fed either raw or cooked. In the controls (C, there was an almost complete pcD (>92% except for potato starch (61.5% which was significantly lower. In PL pcD of raw starch was significantly lower for all sources of starch except for amaranth (87.9%. Thermal processing increased pcD in PL, reaching values of C for starch from rice, potato, and pea. This study clearly underlines the need for precise specification of starch used for patients with specific dietetic needs like PEI. Data should be generated in suitable animal models or patients as tests in healthy individuals would not have given similar conclusions.

  18. Starch Origin and Thermal Processing Affect Starch Digestion in a Minipig Model of Pancreatic Exocrine Insufficiency.

    Science.gov (United States)

    Mößeler, Anne; Vagt, Sandra; Beyerbach, Martin; Kamphues, Josef

    2015-01-01

    Although steatorrhea is the most obvious symptom of pancreatic exocrine insufficiency (PEI), enzymatic digestion of protein and starch is also impaired. Low praecaecal digestibility of starch causes a forced microbial fermentation accounting for energy losses and meteorism. To optimise dietetic measures, knowledge of praecaecal digestibility of starch is needed but such information from PEI patients is rare. Minipigs fitted with an ileocaecal fistula with (n = 3) or without (n = 3) pancreatic duct ligation (PL) were used to estimate the rate of praecaecal disappearance (pcD) of starch. Different botanical sources of starch (rice, amaranth, potato, and pea) were fed either raw or cooked. In the controls (C), there was an almost complete pcD (>92%) except for potato starch (61.5%) which was significantly lower. In PL pcD of raw starch was significantly lower for all sources of starch except for amaranth (87.9%). Thermal processing increased pcD in PL, reaching values of C for starch from rice, potato, and pea. This study clearly underlines the need for precise specification of starch used for patients with specific dietetic needs like PEI. Data should be generated in suitable animal models or patients as tests in healthy individuals would not have given similar conclusions.

  19. Evaluation of pancreatic exocrine insufficiency by cine-dynamic MRCP using spatially selective inversion-recovery (IR) pulse: Correlation with severity of chronic pancreatitis based on morphological changes of pancreatic duct.

    Science.gov (United States)

    Yasokawa, Kazuya; Ito, Katsuyoshi; Kanki, Akihiko; Yamamoto, Akira; Torigoe, Teruyuki; Sato, Tomohiro; Tamada, Tsutomu

    2017-12-05

    To evaluate the correlation between the pancreatic exocrine insufficiency estimated by cine-dynamic MRCP using spatially selective IR pulse and the severity stages (modified Cambridge classification) based on morphological changes of the pancreatic duct in patients with suspected chronic pancreatitis. Thirty-nine patients with suspected chronic pancreatitis underwent cine-dynamic MRCP with a spatially selective IR pulse. The secretion grading score (5-point scale) based on the moving distance of pancreatic juice inflow on cine-dynamic MRCP was assessed, and compared with the stage of the severity of chronic pancreatitis based on morphological changes of pancreatic duct. The stage of the severity of chronic pancreatitis based on morphological changes had significant negative correlations with the secretion grade (r=-0.698, P0.70 in 2 (33%) of 6 patients showing normal pancreatic exocrine function. It should be noted that the degree of morphological changes of pancreatic duct does not necessarily reflect the severity of pancreatic exocrine insufficiency at cine-dynamic MRCP in stage 2-3 chronic pancreatitis. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Phosphopeptide mapping of cholecystokinin receptors on agonist-stimulated native pancreatic acinar cells.

    Science.gov (United States)

    Ozcelebi, F; Miller, L J

    1995-02-17

    The cholecystokinin (CCK) receptor on the rat pancreatic acinar cell is a G protein-coupled receptor that is phosphorylated in response to homologous and heterologous agonist stimulation. In this work we have studied the stoichiometry of receptor phosphorylation and have utilized one-dimensional phosphopeptide mapping after cyanogen bromide cleavage to demonstrate that the third intracellular loop is the predominant domain of phosphorylation of this receptor in response to these treatments. Of the average 5 mol of phosphate/mol of receptor, greater than 95% was on the third loop, with the remainder residing on the carboxyl-terminal tail. Serine residues were the site of greater than 95% of phosphorylation, with threonine representing the remainder, and no phosphotyrosine was detected. Further, we have utilized two-dimensional phosphopeptide mapping after subtilisin cleavage to identify differing sites of CCK receptor phosphorylation which are dependent on the agonist utilized to stimulate this cell. Both qualitative and quantitative differences in phosphorylation sites were observed after acinar cell stimulation with different protein kinase C agonists. Further, distinct phosphopeptides on the map were identified as representing substrate(s) of a staurosporine-insensitive kinase activity stimulated only by receptor occupation with native CCK and were felt to represent site(s) of action of a member of the G protein-coupled receptor kinase family. This represents a sensitive and powerful approach that is applicable to sparse receptors residing in their native cellular environment to assess possible differences in patterns of phosphorylation which may be important in agonist-specific receptor regulation.

  1. Determinants of exocrine pancreatic function as measured by fecal elastase-1 concentrations (FEC in patients with diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Ewald N

    2009-03-01

    Full Text Available Abstract Objective Recently it has been shown that there is not only endocrine insufficiency in diabetic patients, but a frequent co-morbidity of both, the endocrine and exocrine pancreas. The present study was performed to further analyse the determinants of exocrine pancreatic function in patients with diabetes mellitus. Methods The records of 1992 patients with diabetes mellitus who had been treated in our hospital during a 2-year period were re-evaluated. Defined parameters were documented in standardized data sheets. Records were further checked for the results of imaging procedures of the pancreas. In 307 patients FEC had been performed and documented. Only these patients were included in further evaluation. Results FEC was inversely correlated with diabetes duration and HbA1c-levels but not with age. C-peptide levels correlated positively with FEC. BMI and FEC were also significantly correlated. There was no correlation between diabetes therapy and exocrine pancreatic function as there was no correlation with any concomitant medication. The presence of diabetes-associated antibodies was not related to FEC. According to the documented data 38 were classified as type-1 diabetes (12.4%, 167 as type-2 (54.4%, and 88 patients met the diagnostic criteria of type-3 (28.7%. Fourteen patients could not be classified because of lacking information (4.6%. Conclusions Exocrine insufficiency might be explained as a complication of diabetes mellitus. However, it is more likely that type-3 diabetes is much more frequent than previously believed. Consequently the evaluation of exocrine function and morphology should be included into the clinical workup of any diabetic patient at least at the time of manifestation.

  2. Novel lipophilic probe for detecting near-membrane reactive oxygen species responses and its application for studies of pancreatic acinar cells: effects of pyocyanin and L-ornithine.

    Science.gov (United States)

    Chvanov, Michael; Huang, Wei; Jin, Tao; Wen, Li; Armstrong, Jane; Elliot, Vicky; Alston, Ben; Burdyga, Alex; Criddle, David N; Sutton, Robert; Tepikin, Alexei V

    2015-02-20

    The aim of this study was to develop a fluorescent reactive oxygen species (ROS) probe, which is preferentially localized in cellular membranes and displays a strong change in fluorescence upon oxidation. We also aimed to test the performance of this probe for detecting pathophysiologically relevant ROS responses in isolated cells. We introduced a novel lipophilic ROS probe dihydrorhodamine B octadecyl ester (H2RB-C18). We then applied the new probe to characterize the ROS changes triggered by inducers of acute pancreatitis in pancreatic acinar cells. We resolved ROS changes produced by L-ornithine, L-arginine, cholecystokinin-8, acetylcholine, taurolithocholic acid 3-sulfate, palmitoleic acid ethyl ester, and the bacterial toxin pyocyanin. Particularly prominent ROS responses were induced by pyocyanin and L-ornithine. These ROS responses were accompanied by changes in cytosolic Ca(2+)concentration ([Ca(2+)]i), mitochondrial membrane potential (ΔΨ), and NAD(P)H concentration. The study describes a novel sensitive lipophilic ROS probe. The probe is particularly suitable for detecting ROS in near-membrane regions and therefore for reporting the ROS environment of plasma membrane channels and pumps. In our experimental conditions, the novel probe was more sensitive than 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein (CM-H2DCF) and dihydrorhodamine123 (H2R123) and allowed us to resolve ROS responses to secretagogues, pyocyanin, and L-ornithine. Changes in the fluorescence of the new probe were particularly prominent in the peripheral plasma membrane-associated regions. Our findings suggest that the new probe will be a useful tool in studies of the contribution of ROS to the pathophysiology of exocrine pancreas and other organs/tissues.

  3. Quantification of pancreatic exocrine function with secretin-enhanced magnetic resonance cholangiopancreatography: normal values and short-term effects of pancreatic duct drainage procedures in chronic pancreatitis. Initial results

    Energy Technology Data Exchange (ETDEWEB)

    Bali, M.A.; Sztantics, A.; Metens, T.; Matos, C. [Universite Libre de Bruxelles, Department of Radiology, Hopital Erasme, Brussels (Belgium); Arvanitakis, M.; Delhaye, M.; Deviere, J. [Universite Libre de Bruxelles, Department of Gastroenterology, Hopital Erasme, Brussels (Belgium)

    2005-10-01

    The aim of this study was to quantify pancreatic exocrine function in normal subjects and in patients with chronic pancreatitis (CP) before and after pancreatic duct drainage procedures (PDDP) with dynamic secretin-enhanced magnetic resonance (MR) cholangiopancreatography (S-MRCP). Pancreatic exocrine secretions [quantified by pancreatic flow output (PFO) and total excreted volume (TEV)] were quantified twice in ten healthy volunteers and before and after treatment in 20 CP patients (18 classified as severe, one as moderate, and one as mild according to the Cambridge classification). PFO and TEV were derived from a linear regression between MR-calculated volumes and time. In all subjects, pancreatic exocrine fluid volume initially increased linearly with time during secretin stimulation. In controls, the mean PFO and TEV were 6.8 ml/min and 97 ml; intra-individual deviations were 0.8 ml/min and 16 ml. In 10/20 patients with impaired exocrine secretions before treatment, a significant increase of PFO and TEV was observed after treatment (P<0.05); 3/20 patients presented post-procedural acute pancreatitis and a reduced PFO. The S-MRCP quantification method used in the present study is reproducible and provides normal values for PFO and TEV in the range of those obtained from previous published intubation studies. The initial results in CP patients have demonstrated non-invasively a significant short-term improvement of PFO and TEV after PDDP. (orig.)

  4. The cyan fluorescent protein (CFP) transgenic mouse as a model for imaging pancreatic exocrine cells.

    Science.gov (United States)

    Tran Cao, Hop S; Kimura, Hiroaki; Kaushal, Sharmeela; Snyder, Cynthia S; Reynoso, Jose; Hoffman, Robert M; Bouvet, Michael

    2009-03-09

    The use of fluorescent proteins for in vivo imaging has opened many new areas of research. Among the important advances in the field have been the development of transgenic mice expressing various fluorescent proteins. To report whole-body and organ-specific fluorescence imaging to characterize the transgenic cyan fluorescent protein mouse. Mice were imaged using two devices. Brightfield images were obtained with the OV100 Small Animal Imaging System (Olympus Corp., Tokyo, Japan). Fluorescence imaging was performed under the cyan fluorescent protein filter using the iBox Small Animal Imaging System (UVP, Upland, CA, USA). All animals were sacrificed immediately before imaging. They were imaged before and throughout multiple steps of a complete necropsy. Harvested organs were also imaged with both devices. Selected organs were then frozen and processed for histology, fluorescence microscopy, and H&E staining. Fluorescence microscopy was performed with an Olympus IMT-2 inverted fluorescence microscope. Determination of fluorescence intensity of different organs. Surprisingly, we found that there is differential enhancement of fluorescence among organs; most notably, the pancreas stands out from the rest of the gastrointestinal tract, displaying the strongest fluorescence of all organs in the mouse. Fluorescence microscopy demonstrated that the cyan fluorescent protein fluorescence resided in the acinar cells of the pancreas and not the islet cells. The cyan fluorescent protein mouse should lead to a deeper understanding of pancreatic function and pathology, including cancer.

  5. Calcium signaling induced by angiotensin II in the pancreatic acinar cell line AR42J.

    Science.gov (United States)

    Barnhart, D C; Sarosi, G A; Romanchuk, G; Mulholland, M W

    1999-03-01

    The purpose of this study was to characterize the nature and mechanisms of angiotensin II-evoked calcium signaling in AR42J cells. Cytosolic calcium concentrations were determined using fura-2-based microfluorimetry. Angiotensin II causes elevations in free cytosolic calcium ([Ca2+]i) in the rat pancreatic acinar cell line AR42J. The mechanisms of angiotensin II-evoked calcium signaling were examined using fura-2-based fluorescent digital microscopy. Angiotensin II caused dose-dependent increments in [Ca2+]i over a concentration range of 0.1-1,000 nM, with an average increment of 243 +/- 16 nM at an angiotensin II concentration of 1,000 nM. Dup753, an AT1-specific antagonist, inhibited angiotensin II-evoked signaling, whereas the AT2 antagonist PD123,319 had no effect. Preincubation with the phospholipase C inhibitor U73122 reduced the response in [Ca2+]i to 25% of that of the control. Thapsigargin abolished angiotensin II-evoked calcium signaling. The inositol 1,4,5-trisphosphate receptor antagonist heparin introduced by radiofrequency electroporation inhibited responses to 46 +/- 6% of controls. Angiotensin II-evoked signals were reduced in magnitude and duration by elimination of Ca2+ from the extracellular buffer. Preincubation with pertussis toxin (100 ng/ml) had no effect. Angiotensin II did not stimulate cyclic AMP or suppress vasoactive intestinal peptide stimulated cyclic AMP production over the concentration range that caused Ca2+ signaling.

  6. Three-dimensional structure of peripheral exocrine gland in rat pancreas: reconstruction using transmission electron microscopic examination of serial sections.

    Science.gov (United States)

    Ashizawa, Nobuo; Sakai, Toshio; Yoneyama, Tsunao; Naora, Hiroyuki; Kinoshita, Yoshikazu

    2005-11-01

    The purpose of this study was to elucidate the 3-dimensional structure of the peripheral pancreatic exocrine gland. We observed serial sections of rat pancreatic tissue using a transmission electron microscope and traced the intercalated duct lumina, intra-acinar secretory canaliculi, intercalated duct cells or centroacinar cells, and basement membranes of acini onto a transparent sheet. These traced diagrams were reconstructed. The intra-acinar secretory canaliculus had branches but no anastomosis. The intercellular secretory canaliculus was extended from the central lumen through the space between the lateral surfaces of the acinar cells to the acinar base. Furthermore, the cytoplasmic process of each centroacinar cell was extended along the central lumen and connected to an intercalated duct cell; thus, centroacinar cells with the same structure as intercalated duct cells were not isolated from the intercalated duct cells. In this study, we elucidated the normal 3-dimensional structure of the peripheral pancreatic exocrine gland. To understand the pathogenesis of chronic pancreatitis, in the future we intend to examine the morphologic changes of pancreatic tissue during the onset and advancement of chronic pancreatitis using animal models.

  7. Histopathological and immunohistochemical study of exocrine and endocrine pancreatic lesions in avian influenza A experimentally infected turkeys showing evidence of pancreatic regeneration.

    Science.gov (United States)

    Cavicchioli, Laura; Zappulli, Valentina; Beffagna, Giorgia; Caliari, Diego; Zanetti, Rossella; Nordio, Laura; Mainenti, Marta; Frezza, Federica; Bonfante, Francesco; Patrono, Livia Victoria; Capua, Ilaria; Terregino, Calogero

    2015-01-01

    In order to investigate the pancreatic lesions caused by the infection with either H7N1 or H7N3 low-pathogenicity avian influenza viruses, 28 experimentally infected turkeys were submitted for histopathology, immunohistochemistry, haematobiochemistry and real-time reverse transcriptase polymerase chain reaction after different days post-infection (DPI). The localization of viral antigen and the measurement of insulin and glucagon expression in the pancreas were assessed to verify the progression from pancreatitis to metabolic disorders, such as diabetes. At the early infection phase (4-7 DPI), a severe acute necrotizing pancreatitis was recognized. During the intermediate phase (8-17 DPI), a mixed acute/chronic change associated with regenerative ductular proliferation was observed. A loss of pancreatic islets was detected in most severe cases and viral antigen was found in the pancreas of 11/28 turkeys (4-10 DPI) with the most severe histological damage. In turkeys euthanized at 39 DPI (late phase), a chronic fibrosing pancreatitis was observed with the reestablishment of both the exocrine and the endocrine pancreas. Insulin and glucagon expression manifested a progressive decrease with subsequent ductular positivity. Haematobiochemistry revealed increased lipasemia in the first week post-infection and hyperglycaemia in the second, with a progressive normalization within 21 DPI. This study allowed the identification of progressive virus-associated exocrine and endocrine pancreatic damage, suggesting that influenza virus might be responsible for metabolic derangements. Moreover, it highlighted a remarkable post-damage hyperplastic and reparative process from a presumptive common exocrine/endocrine precursor. This potential regeneration deserves further investigation for its relevance in a therapeutic perspective to replace lost and non-functional cells in diabetes mellitus.

  8. Early to Late Endosome Trafficking Controls Secretion and Zymogen Activation in Rodent and Human Pancreatic Acinar Cells.

    Science.gov (United States)

    Messenger, Scott W; Thomas, Diana Dh; Cooley, Michelle M; Jones, Elaina K; Falkowski, Michelle A; August, Benjamin K; Fernandez, Luis A; Gorelick, Fred S; Groblewski, Guy E

    2015-11-01

    Pancreatic acinar cells have an expanded apical endosomal system, the physiological and pathophysiological significance of which is still emerging. Phosphatidylinositol-3,5-bisphosphate (PI(3,5)P 2 ) is an essential phospholipid generated by PIKfyve, which phosphorylates phosphatidylinositol-3-phosphate (PI(3)P). PI(3,5)P 2 is necessary for maturation of early endosomes (EE) to late endosomes (LE). Inhibition of EE to LE trafficking enhances anterograde endosomal trafficking and secretion at the plasma membrane by default through a recycling endosome (RE) intermediate. We assessed the effects of modulating PIKfyve activity on apical trafficking and pancreatitis responses in pancreatic acinar cells. Inhibition of EE to LE trafficking was achieved using pharmacological inhibitors of PIKfyve, expression of dominant negative PIKfyve K1877E, or constitutively active Rab5-GTP Q79L. Anterograde endosomal trafficking was manipulated by expression of constitutively active and dominant negative Rab11a mutants. The effects of these agents on secretion, endolysosomal exocytosis of lysosome associated membrane protein (LAMP1), and trypsinogen activation in response to high-dose CCK-8, bile acids and cigarette toxin was determined. PIKfyve inhibition increased basal and stimulated secretion. Adenoviral overexpression of PIKfyve decreased secretion leading to cellular death. Expression of Rab5-GTP Q79L or Rab11a-GTP Q70L enhanced secretion. Conversely, dominant-negative Rab11a-GDP S25N reduced secretion. High-dose CCK inhibited endolysosomal exocytosis that was reversed by PIKfyve inhibition. PIKfyve inhibition blocked intracellular trypsin accumulation and cellular damage responses to high CCK-8, tobacco toxin, and bile salts in both rodent and human acini. These data demonstrate that EE-LE trafficking acutely controls acinar secretion and the intracellular activation of zymogens leading to the pathogenicity of acute pancreatitis.

  9. Keratin 8 sequence variants in patients with pancreatitis and pancreatic cancer.

    NARCIS (Netherlands)

    Treiber, M.; Schulz, H.U.; Landt, O.; Drenth, J.P.H.; Castellani, C.; Real, F.X.; Akar, N.; Ammann, R.W.; Bargetzi, M.; Bhatia, E.; Demaine, A.G.; Battagia, C.; Kingsnorth, A.; O'reilly, D.; Truninger, K.; Koudova, M.; Spicak, J.; Cerny, M.; Menzel, H.J.; Moral, P.; Pignatti, P.F.; Romanelli, M.G.; Rickards, O.; Stefano, G.F. De; Zarnescu, N.O.; Choudhuri, G.; Sikora, S.S.; Jansen, J.B.M.J.; Weiss, F.U.; Pietschmann, M.; Teich, N.; Gress, T.M.; Ockenga, J.; Schmidt, H.; Kage, A.; Halangk, J.; Rosendahl, J.; Groneberg, D.A.; Nickel, R.; Witt, H.

    2006-01-01

    Keratin 8 (KRT8) is one of the major intermediate filament proteins expressed in single-layered epithelia of the gastrointestinal tract. Transgenic mice over-expressing human KRT8 display pancreatic mononuclear infiltration, interstitial fibrosis and dysplasia of acinar cells resulting in exocrine

  10. Prevalence of exocrine pancreatic insufficiency in patients with chronic pancreatitis without follow-up. PANCR-EVOL Study.

    Science.gov (United States)

    Marra-Lopez Valenciano, Carlos; Bolado Concejo, Federico; Marín Serrano, Eva; Millastre Bocos, Judith; Martínez-Moneo, Emma; Pérez Rodríguez, Esperanza; Francisco González, María; Del Pozo-García, Andrés; Hernández Martín, Anaiansi; Labrador Barba, Elena; Orera Peña, María Luisa; de-Madaria, Enrique

    2017-09-18

    Exocrine pancreatic insufficiency (EPI) is an important complication of chronic pancreatitis (CP). Guidelines recommend to rule out EPI in CP, to detect those patients who would benefit from pancreatic enzyme replacement therapy. The aim of this study was to evaluate the prevalence of EPI in patients with CP without follow-up in the last 2 years and to describe their nutritional status and quality of life (QoL). This was a cross-sectional, multicenter Spanish study. CP patients without follow-up by a gastroenterologist or surgeon in at least 2 years were included. EPI was defined as fecal elastase test <200mcg/g. For nutritional assessment, laboratory and anthropometric data were obtained. QoL was investigated using the EORTC QLQ-C30 questionnaire. 64 patients (mean age 58.8±10.3 years, 85.9% men) from 10 centers were included. Median time since diagnosis of CP was 58.7 months [37.7-95.4]. Forty-one patients (64.1%) had EPI. Regarding nutritional status, the following differences were observed (EPI vs. Non-EPI): BMI (23.9±3.5kg/m2 vs. 25.7±2.5, p=0.03); glucose (121 [96-189] mg/dL vs. 98 [90-116], p=0.006); HbA1c 6.6% [6.0-8.4] vs. 5.5 [5.3-6.0], p=0.0005); Vitamin A (0.44mg/L [0.35-0.57] vs. 0.53 [0.47-0.63], p=0.048) and Vitamin E (11.2±5.0μg/ml vs. 14.4±4.3, p=0.03). EPI group showed a worse EORTC QLQ-C30 score on physical (93.3 [66.7-100] vs. 100 [93.3-100], p=0.048) and cognitive function (100 [83.3-100] vs. 100 [100-100], p=0.04). Prevalence of EPI is high in patients with CP without follow-up. EPI group had higher levels of glucose, lower levels of vitamins A and E and worse QoL. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

  11. PPARγ regulates exocrine pancreas lipase.

    Science.gov (United States)

    Danino, Hila; Naor, Ronny Peri-; Fogel, Chen; Ben-Harosh, Yael; Kadir, Rotem; Salem, Hagit; Birk, Ruth

    2016-12-01

    Pancreatic lipase (triacylglycerol lipase EC 3.1.1.3) is an essential enzyme in hydrolysis of dietary fat. Dietary fat, especially polyunsaturated fatty acids (PUFA), regulate pancreatic lipase (PNLIP); however, the molecular mechanism underlying this regulation is mostly unknown. As PUFA are known to regulate expression of proliferator-activated receptor gamma (PPARγ), and as we identified in-silico putative PPARγ binding sites within the putative PNLIP promoter sequence, we hypothesized that PUFA regulation of PNLIP might be mediated by PPARγ. We used in silico bioinformatics tools, reporter luciferase assay, PPARγ agonists and antagonists, PPARγ overexpression in exocrine pancreas AR42J and primary cells to study PPARγ regulation of PNLIP. Using in silico bioinformatics tools we mapped PPARγ binding sites (PPRE) to the putative promoter region of PNLIP. Reporter luciferase assay in AR42J rat exocrine pancreas acinar cells transfected with various constructs of the putative PNLIP promoter showed that PNLIP transcription is significantly enhanced by PPARγ dose-dependently, reaching maximal levels with multi PPRE sites. This effect was significantly augmented in the presence of PPARγ agonists and reduced by PPARγ antagonists or mutagenesis abrogating PPRE sites. Over-expression of PPARγ significantly elevated PNLIP transcript and protein levels in AR42J cells and in primary pancreas cells. Moreover, PNLIP expression was up-regulated by PPARγ agonists (pioglitazone and 15dPGJ2) and significantly down-regulated by PPARγ antagonists in non-transfected rat exocrine pancreas AR42J cell line cells. PPARγ transcriptionally regulates PNLIP gene expression. This transcript regulation resolves part of the missing link between dietary PUFA direct regulation of PNLIP. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Oxidative stress and NO generation in the rat pancreatitis induced by pancreatic duct ligation.

    Science.gov (United States)

    Buchwalow, Igor; Schnekenburger, Jürgen; Atiakshin, Dmitri; Samoilova, Vera; Wolf, Eduard; Boecker, Werner; Tiemann, Katharina

    2017-04-01

    The interaction between nitric oxide (NO) and superoxides is critical in the development of an acute pancreatitis. Previously, we reported that the expression of superoxides and of the NO-generating enzyme (NO synthase, NOS) was up-regulated in the human pancreatitis, especially within the exocrine compartment indicating an exceptional susceptibility of the exocrine parenchyma to oxidative stress. The aim of the present study was to compare the regulation of NO signalling pathways in the human pancreatitis and in an animal model of an acute pancreatitis induced by pancreatic duct ligation (PDL) in rats. In the PDL-induced rat pancreatitis, we revealed a similar pattern of oxidative stress and NOS up-regulation in acinar and in ductal compartments, like in the human pancreatitis. This demonstrates that the PDL-induced rat pancreatitis is a proper model for further studies of acute pancreatitis development in humans. Copyright © 2017 Elsevier GmbH. All rights reserved.

  13. Response to long-term enzyme replacement treatment in dogs with exocrine pancreatic insufficiency.

    Science.gov (United States)

    Wiberg, M E; Lautala, H M; Westermarck, E

    1998-07-01

    To study response to long-term enzyme replacement treatment in dogs with exocrine pancreatic insufficiency (EPI). Cross-sectional study. 76 German Shepherd Dogs or rough-coated Collies with EPI and 145 clinically normal dogs of the same breeds. Questionnaires were sent to owners of dogs with EPI and owners of clinically normal dogs. Dogs with EPI had been given dietary enzyme supplements for at least 4 months. Relative frequency distributions of gastrointestinal tract and dermatologic signs, prevalences of typical signs of EPI (e.g., weight loss, ravenous appetite, yellow and pulpy feces, high fecal volume), feeding regimens, and dietary intolerances were compared between dogs with EPI and clinically normal dogs. Gastrointestinal tract signs considered typical for dogs with EPI were almost completely controlled with dietary enzyme supplements in half of the dogs with EPI, and their general health was similar to that of clinically normal dogs. A poor treatment response was found in a fifth of dogs with EPI that had several signs that were typical of EPI. Signs most often persisting were high fecal volume, yellow and pulpy feces, and flatulence. Dermatologic problems were common, especially in German Shepherd Dogs with EPI. Treatment response was irrespective of breed. Nonenteric-coated enzyme supplements, powdered enzyme, and raw chopped pancreas were equally effective in controlling clinical signs. Although dietary sensitivities were common, use of adjunctive dietary treatment was minimal. Antibiotics were occasionally administered to half of the dogs with EPI. Results of this study indicate that, with basically similar treatment regimens, response to long-term enzyme treatment in dogs with EPI varied considerably.

  14. The Combination of Alcohol and Cigarette Smoke Induces Endoplasmic Reticulum Stress and Cell Death in Pancreatic Acinar Cells.

    Science.gov (United States)

    Lugea, Aurelia; Gerloff, Andreas; Su, Hsin-Yuan; Xu, Zhihong; Go, Ariel; Hu, Cheng; French, Samuel W; Wilson, Jeremy S; Apte, Minoti V; Waldron, Richard T; Pandol, Stephen J

    2017-12-01

    Smoking, an independent risk factor for pancreatitis, accelerates the development of alcoholic pancreatitis. Alcohol feeding of mice induces up-regulation of spliced X-box binding protein 1 (XBP1s), which regulates the endoplasmic reticulum (ER) unfolded protein response and promotes cell survival upon ER stress. We examined whether smoking affects the adaptive mechanisms induced by alcohol and accelerates disorders of the ER in pancreatic acinar cells. We studied the combined effects of ethanol (EtOH) and cigarette smoke extract (CSE) on ER stress and cell death responses in mouse and human primary acini and the acinar cell line AR42J. Cells were incubated with EtOH (50 mmol/L), CSE (20-40 μg/mL), or both (CSE+EtOH), and analyzed by immunoblotting, quantitative reverse-transcription polymerase chain reaction, and cell death assays. Some cells were incubated with MKC-3946, an inhibitor of endoplasmic reticulum to nucleus signaling 1 (ERN1, also called IRE1) that blocks XBP1s formation. Male Sprague-Dawley rats were fed isocaloric amounts of an EtOH-containing (Lieber-DeCarli) or control diet for 11 weeks and exposed to cigarette smoke or room air in an exposure chamber for 2 hours each day. During the last 3 weeks, a subset of rats received intravenous injections of lipopolysaccharide (LPS, 3 mg/kg per week) to induce pancreatitis or saline (control). Pancreatic tissues were collected and analyzed by histology and immunostaining techniques. In AR42J and primary acini, CSE+EtOH induced cell death (necrosis and apoptosis), but neither agent alone had this effect. Cell death was associated with a significant decrease in expression of XBP1s. CSE+EtOH, but neither agent alone, slightly decreased adenosine triphosphate levels in AR42J cells, but induced oxidative stress and sustained activation (phosphorylation) of eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3, also called PERK) and increased protein levels of DNA damage inducible transcript 3 (DDIT

  15. Uptake of ascorbic acid by pancreatic acinar cells is negatively impacted by chronic alcohol exposure.

    Science.gov (United States)

    Subramanian, Veedamali S; Srinivasan, Padmanabhan; Said, Hamid M

    2016-07-01

    Vitamin C (ascorbic acid, AA) is indispensable for normal metabolism of all mammalian cells including pancreatic acinar cells (PACs). PACs obtain AA from their surroundings via transport across the cell membrane. Chronic alcohol exposure negatively affects body AA homeostasis; it also inhibits uptake of other micronutrients into PACs, but its effect on AA uptake is not clear. We examined this issue using both in vitro (266-6 cells) and in vivo (mice) models of chronic alcohol exposure. First, we determined the relative expression of the AA transporters 1 and 2 [i.e., sodium-dependent vitamin C transporter-1 (SVCT-1) and SVCT-2] in mouse and human PACs and found SVCT-2 to be the predominant transporter. Chronic exposure of 266-6 cells to alcohol significantly inhibited AA uptake and caused a marked reduction in SVCT-2 expression at the protein, mRNA, and heterogeneous nuclear RNA (hnRNA) levels. Similarly, chronic alcohol feeding of mice significantly inhibited AA uptake and caused a marked reduction in level of expression of the SVCT-2 protein, mRNA, and hnRNA. These findings suggest possible involvement of transcriptional mechanism(s) in mediating chronic alcohol effect on AA uptake by PACs. We also observed significant epigenetic changes (histone modifications) in the Slc23a2 gene (reduction in H3K4me3 level and an increase in H3K27me3 level) in the alcohol-exposed 266-6 cells. These findings show that chronic alcohol exposure inhibits PAC AA uptake and that the effect is mediated, in part, at the level of transcription of the Slc23a2 gene and may involve epigenetic mechanism(s).

  16. MIST1 and PTF1 Collaborate in Feed-forward Regulatory Loops that Maintain the Pancreatic Acinar Phenotype in Adult Mice.

    Science.gov (United States)

    Jiang, Mei; Azevedo-Pouly, Ana; Deering, Tye G; Hoang, Chinh Q; DiRenzo, Daniel; Hess, David A; Konieczny, Stephen F; Swift, Galvin H; MacDonald, Raymond J

    2016-09-19

    Much remains unknown regarding the regulatory networks formed by transcription factors in mature, differentiated mammalian cells in vivo, despite many studies of individual DNA-binding transcription factors. We report a constellation of feed-forward loops formed by the pancreatic transcription factors MIST1 and PTF1 that govern the differentiated phenotype of the adult pancreatic acinar cell. PTF1 is an atypical basic helix-loop-helix transcription factor complex of pancreatic acinar cells and critical to acinar cell fate specification and differentiation. MIST1, also a basic helix-loop-helix transcription factor, enhances the formation and maintenance of the specialized phenotype of professional secretory cells. The MIST1 and PTF1 collaboration controls a wide range of specialized cellular processes, including secretory protein synthesis and processing, exocytosis, and homeostasis of the endoplasmic reticulum. PTF1 drives Mist1 transcription, and MIST1 and PTF1 bind and drive the transcription of over a hundred downstream acinar genes. PTF1 binds two canonical bipartite sites within a 0.7-kb transcriptional enhancer upstream of Mist1 that are essential for the activity of the enhancer in vivo MIST1 and PTF1 co-regulate target genes synergistically or additively, depending on the target transcriptional enhancer. The frequent close binding proximity of PTF1 and MIST1 in pancreatic acinar cell chromatin implies extensive collaboration, although the collaboration is not dependent on a stable physical interaction. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  17. A comparison study of pancreatic acinar cell carcinoma with ductal adenocarcinoma using computed tomography in Chinese patients

    Directory of Open Access Journals (Sweden)

    Wang Q

    2016-09-01

    Full Text Available Qingbing Wang,1,2 Xiaolin Wang,1,2 Rongfang Guo,2,3 Guoping Li1,2 1Department of Interventional Radiology, Zhongshan Hospital, Fudan University, 2Shanghai Institute of Medical Imaging, 3Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China Abstract: Pancreatic acinar cell carcinoma (ACC is a rare tumor that is difficult to diagnose preoperatively. The aim of this study was to evaluate and describe the computed tomography (CT features of ACC and compare the results with pancreatic ductal adenocarcinoma (DAC for improving preoperative diagnosis. The control group consisted of 34 patients with DAC collected from the pathology electronic database. The CT imaging from nine patients with pathologically confirmed ACC was retrospectively reviewed. Two radiologists independently assessed the tumor location, size, texture, and enhancement patterns. We found that 64.3% (9/14 of ACC tumors were homogeneous and 35.7% (5/14 had necrosis. The percentage of common bile duct and pancreatic ductal dilation was 14.3% (2/14 and 7.1% (1/14, respectively. The mean size of ACC was 50.1±24.2 mm. The mean attenuation of ACC was 35.4±3.9 Hounsfield unit (HU before enhancement, 73.1±42.9 HU in arterial phase, and 71.8±15.6 HU in port venous phase. It is difficult to distinguish ACC from DAC preoperatively only based on CT findings. However, compared with DAC, we found that ACC tumors are likely to be larger and contain more heterogeneous intratumoral necrotic hypovascular regions, and less pancreatic ductal and common biliary dilation. Keywords: acinar cell carcinoma, computed tomography, pancreatic ductal carcinoma, pancreas

  18. Reciprocal stimulation of pancreatic acinar and stellate cells in a novel long-term in vitro co-culture model.

    Science.gov (United States)

    Bläuer, Merja; Laaninen, Matias; Sand, Juhani; Laukkarinen, Johanna

    2016-01-01

    Pancreatic stellate cells (PSCs) are the key fibrogenic cells in the pancreas. Acinar cell injury is known to trigger PSC activation. To facilitate the experimental analysis of the crosstalk between acinar cells and PSCs, an in vitro system for their long-term co-cultivation was developed. PSCs and acinar cells capable of retaining their secretory phenotype in long-term in vitro culture were obtained from mouse pancreata. A dual-chamber co-culture model was built in 24-well format with acinar cells seeded in the wells and PSCs in tissue culture inserts. Acinar cell-3T3 fibroblast co-cultures served as controls. After 4-day maintenance, the acinar compartment was analyzed for cell morphology, secretory capability, necrosis (HMGB1), apoptosis (TUNEL) and inflammation (NFκB). PSCs were analyzed for migratory activity and extracellular matrix (ECM) protein expression. The results were compared to parallel monocultures. Acinar cells in monoculture and in co-culture with fibroblasts exhibited a healthy monolayer arrangement and an ability to respond to 0.1 nM caerulein stimulus by increased amylase release. Co-culture with PSCs caused marked changes in acinar cell morphology and rendered them insensitive to secretagogue stimulus. Activation of NFκB and necrotic changes, but not apoptosis, were identified in co-cultured acinar cells. Co-culture increased the migratory activity and ECM protein expression of PSCs. Humoral interactions between acinar and PSCs in co-culture were shown to reciprocally affect their cellular functions. With its two separable cell compartments the co-culture system provides a versatile culture setting that allows independent manipulation and analysis of both cell types. Copyright © 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.

  19. Wnt/β-catenin signaling is required for development of the exocrine pancreas

    Directory of Open Access Journals (Sweden)

    Sklenka Angela

    2007-01-01

    Full Text Available Abstract Background β-catenin is an essential mediator of canonical Wnt signaling and a central component of the cadherin-catenin epithelial adhesion complex. Dysregulation of β-catenin expression has been described in pancreatic neoplasia. Newly published studies have suggested that β-catenin is critical for normal pancreatic development although these reports reached somewhat different conclusions. In addition, the molecular mechanisms by which loss of β-catenin affects pancreas development are not well understood. The goals of this study then were; 1] to further investigate the role of β-catenin in pancreatic development using a conditional knockout approach and 2] to identify possible mechanisms by which loss of β-catenin disrupts pancreatic development. A Pdx1-cre mouse line was used to delete a floxed β-catenin allele specifically in the developing pancreas, and embryonic pancreata were studied by immunohistochemistry and microarray analysis. Results Pdx1-cre floxed β-catenin animals were viable but demonstrated small body size and shortened median survival. The pancreata from knockout mice were hypoplastic and histologically demonstrated a striking paucity of exocrine pancreas, acinar to duct metaplasia, but generally intact pancreatic islets containing all lineages of endocrine cells. In animals with extensive acinar hypoplasia, putative hepatocyte transdifferention was occasionally observed. Obvious and uniform pancreatic hypoplasia was observed by embryonic day E16.5. Transcriptional profiling of Pdx1-cre floxed β-catenin embryonic pancreata at E14.5, before there was a morphological phenotype, revealed significant decreases in the β-catenin target gene N-myc, and the basic HLH transcription factor PTF1, and an increase of several pancreatic zymogens compared to control animals. By E16.5, there was a dramatic loss of exocrine markers and an increase in Hoxb4, which is normally expressed anterior to the pancreas. Conclusion We

  20. Altered distribution of metaplastic Paneth, gastrin and pancreatic acinar cells in atrophic gastritic mucosa with endocrine cell lesions.

    Science.gov (United States)

    Deveci, M Salih; Deveci, Güzin

    2004-01-01

    The mechanism of progression from gastric endocrine cell hyperplasias (ECHs) to carcinoid tumor (GCT) is still unknown. In these lesions, the distribution of metaplastic Paneth, gastrin and pancreatic acinar cells developing due to consequences of corporal mucosal atrophy has not been investigated in detail. In this study, 33 gastric endoscopic biopsies with endocrine cell lesions were examined. In all cases except 6 with solitary GCT, complete-type (small intestine) intestinal metaplasia (IM) with Paneth cells was observed. The density of lysozyme-positive Paneth cells in IMs in cases with GCTs was less than those in ECH alone. The density of gastrin-positive cells in IMs and average number of micronodules of ECHs were similar. Pancreatic acinar metaplasia (PAM) was observed in 6 cases of GCTs with ECH. The size of GCTs with ECH was smaller than those without ECH. By image analysis, the percentage of Ki67 (MIB-1, proliferation marker) expressing cells of GCTs with ECH was 5.1+/-0.6%, and GCT without ECH 7.8+/-1%. Our results indicate that few Paneth cells and many PAMs in atrophic corporal mucosa are seen more frequently in cases of GCTs with ECH, compared to those in ECH alone. Gastrin-positive cells in the corporal IM may stimulate enterochromaffin-like (ECL) cells, which may induce hyperplasia, dysplasia or neoplasia by augmenting the effects of hypergastrinemia through a paracrine mechanism on local gastrin-sensitive cells.

  1. A piglet with surgically induced exocrine pancreatic insufficiency as an animal model of newborns to study fat digestion.

    Science.gov (United States)

    Goncharova, Kateryna; Pierzynowski, Stefan G; Grujic, Danica; Kirko, Siarhei; Szwiec, Katarzyna; Wang, Jing; Kovalenko, Tetiana; Osadchenko, Iryna; Ushakova, Galyna; Shmigel, Halyna; Fedkiv, Olexandr; Majda, Blanka; Prykhodko, Olena

    2014-12-28

    The maldigestion and malabsorption of fat in infants fed milk formula results due to the minimal production of pancreatic lipase. Thus, to investigate lipid digestion and absorption and mimic the situation in newborns, a young porcine exocrine pancreatic insufficient (EPI) model was adapted and validated in the present study. A total of thirteen EPI pigs, aged 8 weeks old, were randomised into three groups and fed either a milk-based formula or a milk-based formula supplemented with either bacterial or fungal lipase. Digestion and absorption of fat was directly correlated with the addition of lipases as demonstrated by a 30% increase in the coefficient of fat absorption. In comparison to the control group, a 40 and 25% reduction in total fat content and 26 and 45% reduction in n-3 and n-6 fatty acid (FA) content in the stool was observed for lipases 1 and 2, respectively. Improved fat absorption was reflected in the blood levels of lipid parameters. During the experiment, only a very slight gain in body weight was observed in EPI piglets, which can be explained by the absence of pancreatic protease and amylase in the gastrointestinal tract. This is similar to newborn babies that have reduced physiological function of exocrine pancreas. In conclusion, we postulate that the EPI pig model fed with infant formula mimics the growth and lipid digestion and absorption in human neonates and can be used to elucidate further importance of fat and FA in the development and growth of newborns, as well as for testing novel formula compositions.

  2. Organellar Dysfunction in the Pathogenesis of Pancreatitis

    Science.gov (United States)

    Pandol, Stephen J.

    2011-01-01

    Abstract Significance Acute pancreatitis is an inflammatory disease of exocrine pancreas that carries considerable morbidity and mortality; its pathophysiology remains poorly understood. During the past decade, new insights have been gained into signaling pathways and molecules that mediate the inflammatory response of pancreatitis and death of acinar cells (the main exocrine pancreas cell type). By contrast, much less is known about the acinar cell organellar damage in pancreatitis and how it contributes to the disease pathogenesis. Recent Advances This review summarizes recent findings from our group, obtained on experimental in vivo and ex vivo models, which reveal disordering of key cellular organelles, namely, mitochondria, autophagosomes, and lysosomes, in pancreatitis. Our results indicate a critical role for mitochondrial permeabilization in determining the balance between apoptosis and necrosis in pancreatitis, and thus the disease severity. We further investigate how the mitochondrial dysfunction (and hence acinar cell death) is regulated by Ca2+, reactive oxygen species, and Bcl-xL, in relation to specific properties of pancreatic mitochondria. Our results also reveal that autophagy, the principal cellular degradative, lysosome-driven pathway, is impaired in pancreatitis due to inefficient lysosomal function, and that impaired autophagy mediates two key pathological responses of pancreatitis—accumulation of vacuoles in acinar cells and the abnormal, intra-acinar activation of digestive enzymes such as trypsinogen. Critical Issues and Future Directions The findings discussed in this review indicate critical roles for mitochondrial and autophagic/lysosomal dysfunctions in the pathogenesis of pancreatitis and delineate directions for detailed investigations into the molecular events that underlie acinar cell organellar damage. Antioxid. Redox Signal. 15, 2699–2710. PMID:21834686

  3. Recent developments in the treatment of alcoholic chronic pancreatitis.

    Science.gov (United States)

    Tsujimoto, Tatsuhiro; Kawaratani, Hideto; Yoshiji, Hitoshi; Uemura, Masahito; Fukui, Hiroshi

    2008-06-01

    Chronic pancreatitis is a progressive inflammatory condition characterized by repeated attacks of abdominal pain, and the destruction and fibrosis of the pancreatic parenchyma which causes to reduced exocrine and endocrine functions. Alcohol is the most common cause of chronic pancreatitis. Although abstinence is usually considered a prerequisite for successful treatment of alcoholic chronic pancreatitis, we often encounter patients who have repeated attacks from the compensated stage through the transitional stage. In alcoholic chronic pancreatitis, continued alcohol consumption causes changes in the digestive hormones and vagal nerve function that induce the pancreatic acinar cells to oversecrete protein, increasing the protein concentration and viscosity of the pancreatic juice. This induces protein sedimentation from the pancreatic juice and formation of protein plugs within the pancreatic duct, triggering repeated attacks of acute pancreatitis. The treatment of alcoholic chronic pancreatitis includes alleviation of symptoms, particularly abdominal pain, elimination of trigger factors, prevention of recurrence and disease progression, adjuvant therapies for pancreatic exocrine and endocrine failure. Recently, the main constituent proteins in these protein plugs have been identified, enabling trials of several therapies, such as the administration of secretin formulations and endoscopic removal. Bromhexine hydrochloride, a bronchial mucolytic, has an affinity for the pancreatic acinar cells, inducing them to secrete pancreatic juice of low viscosity. In this review, we summarize the most recent thoughts about alcoholic chronic pancreatitis, and the new treatments, and in particular, we present our findings concerning the efficacy of bromhexine hydrochloride in the treatment of this disease.

  4. Exocrine pancreatic secretion is stimulated in piglets fed Fish oil compared with those fed Coconut Oil or Lard

    DEFF Research Database (Denmark)

    Hedemann, Mette Skou; Pedersen, Asger Roer; Engberg, Ricarda M.

    2001-01-01

    An experiment was conducted to study the effect of feeding diets containing fat sources with different fatty acid composition (fish oil, coconut oil or lard, 10 g/100 g diet) on exocrine pancreatic secretion in piglets after weaning. A total of 16 barrows were weaned at 4 wk of age; 3 d later...... the coconut oil or lard diets. The output [U/(h. kg(0.75))] of lipase was higher in piglets fed fish oil than in piglets fed lard or coconut oil. The output of colipase was greater in piglets fed fish oil and coconut oil than in those fed lard. The dietary treatments did not affect the output of carboxylester...... hydrolase. The output of trypsin was significantly lower in piglets fed lard than in piglets fed fish oil or coconut oil diets and the output of carboxypeptidase B was greater in those fed the fish oil diet. Protein, chymotrypsin, carboxypeptidase A, elastase and amylase outputs did not differ among...

  5. No Effect of Dietary Aspartame or Stevia on Pancreatic Acinar Carcinoma Development, Growth, or Induced Mortality in a Murine Model.

    Science.gov (United States)

    Dooley, James; Lagou, Vasiliki; Dresselaers, Tom; van Dongen, Katinka A; Himmelreich, Uwe; Liston, Adrian

    2017-01-01

    Pancreatic cancer has an extremely poor prognosis, largely due to a poor record for early detection. Known risk factors for pancreatic cancer include obesity, diet, and diabetes, implicating glucose consumption and regulation as a key player. The role of artificial sweeteners may therefore be pertinent to disease kinetics. The oncogenic impact of artificial sweeteners is a highly controversial area. Aspartame, one of the most studied food additives, is widely recognized as being generally safe, although there are still specific areas where research is incomplete due to study limitations. Stevia, by contrast, has been the subject of relatively few studies, and the potential health benefits are based on extrapolation rather than direct testing. Here, we used longitudinal tracking of pancreatic acinar carcinoma development, growth, and lethality in a sensitized mouse model. Despite exposure to aspartame and stevia from the in utero stage onward, we found no disease modification activity, in either direction. These results contribute to the data on aspartame and stevia safety, while also reducing confidence in several of the purported health benefits.

  6. No Effect of Dietary Aspartame or Stevia on Pancreatic Acinar Carcinoma Development, Growth, or Induced Mortality in a Murine Model

    Science.gov (United States)

    Dooley, James; Lagou, Vasiliki; Dresselaers, Tom; van Dongen, Katinka A.; Himmelreich, Uwe; Liston, Adrian

    2017-01-01

    Pancreatic cancer has an extremely poor prognosis, largely due to a poor record for early detection. Known risk factors for pancreatic cancer include obesity, diet, and diabetes, implicating glucose consumption and regulation as a key player. The role of artificial sweeteners may therefore be pertinent to disease kinetics. The oncogenic impact of artificial sweeteners is a highly controversial area. Aspartame, one of the most studied food additives, is widely recognized as being generally safe, although there are still specific areas where research is incomplete due to study limitations. Stevia, by contrast, has been the subject of relatively few studies, and the potential health benefits are based on extrapolation rather than direct testing. Here, we used longitudinal tracking of pancreatic acinar carcinoma development, growth, and lethality in a sensitized mouse model. Despite exposure to aspartame and stevia from the in utero stage onward, we found no disease modification activity, in either direction. These results contribute to the data on aspartame and stevia safety, while also reducing confidence in several of the purported health benefits. PMID:28232906

  7. Knockdown of GRP78 promotes apoptosis in pancreatic acinar cells and attenuates the severity of cerulein and LPS induced pancreatic inflammation.

    Directory of Open Access Journals (Sweden)

    Yong Liu

    Full Text Available Acute pancreatitis (AP is a potentially lethal disease characterized by inflammation and parenchymal cell death; also, the severity of AP correlates directly with necrosis and inversely with apoptosis. However, mechanisms of regulating cell death in AP remain unclear. The endoplasmic reticulum (ER chaperone protein GRP78 has anti-apoptotic properties, in addition to modulating ER stress responses. This study used RNA interference (RNAi approach to investigate the potential role of GRP78 in regulating apoptosis during AP. In vitro models of AP were successfully developed by treating AR42J cells with cerulein or cerulein plus lipoplysaccharide (LPS. There was more pancreatic inflammation and less apoptosis with the cerulein plus LPS treatment. Furthermore, knockdown of GRP78 expression markedly promoted apoptosis and reduced necrosis in pancreatic acinar cells. This was accomplished by enhancing the activation of caspases and inhibiting the activity of X-linked inhibitor of apoptosis protein (XIAP, as well as a receptor interacting protein kinase-1(RIPK1, which is a key mediator of necrosis. This attenuated the severity of pancreatic inflammation, especially after cerulein plus LPS treatment. In conclusion, these findings indicate that GRP78 plays an anti-apoptotic role in regulating the cell death response during AP. Therefore, GRP78 is a potential therapeutic target for AP.

  8. Prececal digestibility of various sources of starch in minipigs with or without experimentally induced exocrine pancreatic insufficiency.

    Science.gov (United States)

    Mösseler, A; Kramer, N; Becker, C; Gregory, P C; Kamphues, J

    2012-12-01

    Low prececal digestibility of starch leads to a higher starch flux into the hindgut, causing a forced microbial fermentation, energy losses, and meteorism. For exocrine pancreatic insufficiency (EPI), lack of pancreatic amylase can be compensated mostly by hindgut fermentation of starch. Even in pigs with complete loss of pancreatic secretion, starch digestibility over the entire tract is reaching levels of controls. To optimize diets for human patients with EPI, the proportion of starch that is digested by the ileum is important. Minipigs were fitted with an ileocecal reentrant fistula (n = 8) to determine prececal digestibility of starch. In 5 minipigs the pancreatic duct was ligated (PL) to induce EPI; 3 minipigs served as controls (Con). Various starch sources were tested in a 1-d screening test; therefore, disappearance rate (DR) instead of digestibility was used. Test meals consisted of 169 g DM of a basal diet plus 67.5 g DM of the starch (without thermal treatment; purified; starch content of 89 to 94.5%) and Cr(2)O(3). The test meal contained (% of DM) starch, 67; crude fat, 1.69; CP, 15; crude fiber, 2.0; and Cr(2)O(3), 0.25. In PL, prececal DR of starch was lower than in Con (P 90%) but was lower (P < 0.05) for potato (Solanum tuberosum) starch (75.4%). In PL, prececal DR of starch was higher (P < 0.05) for wheat (Triticum aestivum) starch (61.2%) than corn (Zea mays) starch (43.0%) and rice (Oryza sativa) starch (29.2%) and intermediate for potato and field pea (Pisum sativum) starch. For patients with EPI, wheat starch seems favorable due to the higher prececal digestibility whereas raw corn and rice starch should be avoided.

  9. Nicotine promotes initiation and progression of KRAS-induced pancreatic cancer via Gata6-dependent dedifferentiation of acinar cells in mice.

    Science.gov (United States)

    Hermann, Patrick C; Sancho, Patricia; Cañamero, Marta; Martinelli, Paola; Madriles, Francesc; Michl, Patrick; Gress, Thomas; de Pascual, Ricardo; Gandia, Luis; Guerra, Carmen; Barbacid, Mariano; Wagner, Martin; Vieira, Catarina R; Aicher, Alexandra; Real, Francisco X; Sainz, Bruno; Heeschen, Christopher

    2014-11-01

    Although smoking is a leading risk factor for pancreatic ductal adenocarcinoma (PDAC), little is known about the mechanisms by which smoking promotes initiation or progression of PDAC. We studied the effects of nicotine administration on pancreatic cancer development in Kras(+/LSLG12Vgeo);Elas-tTA/tetO-Cre (Ela-KRAS) mice, Kras(+/LSLG12D);Trp53+/LSLR172H;Pdx-1-Cre (KPC) mice (which express constitutively active forms of KRAS), and C57/B6 mice. Mice were given nicotine for up to 86 weeks to produce blood levels comparable with those of intermediate smokers. Pancreatic tissues were collected and analyzed by immunohistochemistry and reverse transcriptase polymerase chain reaction; cells were isolated and assayed for colony and sphere formation and gene expression. The effects of nicotine were also evaluated in primary pancreatic acinar cells isolated from wild-type, nAChR7a(-/-), Trp53(-/-), and Gata6(-/-);Trp53(-/-) mice. We also analyzed primary PDAC cells that overexpressed GATA6 from lentiviral expression vectors. Administration of nicotine accelerated transformation of pancreatic cells and tumor formation in Ela-KRAS and KPC mice. Nicotine induced dedifferentiation of acinar cells by activating AKT-ERK-MYC signaling; this led to inhibition of Gata6 promoter activity, loss of GATA6 protein, and subsequent loss of acinar differentiation and hyperactivation of oncogenic KRAS. Nicotine also promoted aggressiveness of established tumors as well as the epithelial-mesenchymal transition, increasing numbers of circulating cancer cells and their dissemination to the liver, compared with mice not exposed to nicotine. Nicotine induced pancreatic cells to acquire gene expression patterns and functional characteristics of cancer stem cells. These effects were markedly attenuated in K-Ras(+/LSL-G12D);Trp53(+/LSLR172H);Pdx-1-Cre mice given metformin. Metformin prevented nicotine-induced pancreatic carcinogenesis and tumor growth by up-regulating GATA6 and promoting

  10. Effect of octreotide acetate on pancreatic exocrine and endocrine functions after pancreatoduodenal resection.

    Science.gov (United States)

    Petrin, P; Antoniutti, M; Zaramella, D; Da Lio, C; Basso, D; Plebani, M; Panozzo, M P; Costantino, V; Pedrazzoli, S

    1995-01-01

    In view of forecasting the effect of octreotide acetate (Sandostatin) in preventing fistula formation after pancreatic surgery, 9 patients, who had pancreatoduodenectomy 8-12 days before, underwent a 2-day study. The first day, by means of a catheter located in the jejunal loop separately anastomosed to the pancreatic remnant, basal and after secretin stimulation pancreatic secretion was evaluated. During the 2nd day the possible inhibitory effect of octreotide on basal and stimulated secretion was investigated. Under the experimental conditions of the study Sandostatin showed little effect on the water and bicarbonate increase as stimulated by secretin. A greater hormone inhibitory effect on amylase production and pancreatic endocrine function was seen. On the basis of these results the use of Sandostatin can hardly be seen as useful in preventing fistula formation after pancreatic resection.

  11. Acinar-to-Ductal Metaplasia Induced by Transforming Growth Factor Beta Facilitates KRASG12D-driven Pancreatic TumorigenesisSummary

    Directory of Open Access Journals (Sweden)

    Nicolas Chuvin

    2017-09-01

    Full Text Available Background & Aims: Transforming growth factor beta (TGFβ acts either as a tumor suppressor or as an oncogene, depending on the cellular context and time of activation. TGFβ activates the canonical SMAD pathway through its interaction with the serine/threonine kinase type I and II heterotetrameric receptors. Previous studies investigating TGFβ-mediated signaling in the pancreas relied either on loss-of-function approaches or on ligand overexpression, and its effects on acinar cells have so far remained elusive. Methods: We developed a transgenic mouse model allowing tamoxifen-inducible and Cre-mediated conditional activation of a constitutively active type I TGFβ receptor (TβRICA in the pancreatic acinar compartment. Results: We observed that TβRICA expression induced acinar-to-ductal metaplasia (ADM reprogramming, eventually facilitating the onset of KRASG12D-induced pre-cancerous pancreatic intraepithelial neoplasia. This phenotype was characterized by the cellular activation of apoptosis and dedifferentiation, two hallmarks of ADM, whereas at the molecular level, we evidenced a modulation in the expression of transcription factors such as Hnf1β, Sox9, and Hes1. Conclusions: We demonstrate that TGFβ pathway activation plays a crucial role in pancreatic tumor initiation through its capacity to induce ADM, providing a favorable environment for KRASG12D-dependent carcinogenesis. Such findings are highly relevant for the development of early detection markers and of potentially novel treatments for pancreatic cancer patients. Keywords: Pancreas, Cancer, TGFβ, Acinar-to-Ductal Metaplasia, KRASG12D

  12. Splenic vein thrombosis is associated with an increase in pancreas-specific complications and reduced survival in patients undergoing distal pancreatectomy for pancreatic exocrine cancer.

    Science.gov (United States)

    Dedania, Nishi; Agrawal, Nidhi; Winter, Jordan M; Koniaris, Leonidas G; Rosato, Ernest L; Sauter, Patricia K; Leiby, Ben; Pequignot, Edward; Yeo, Charles J; Lavu, Harish

    2013-08-01

    Distal pancreatectomy and splenectomy (DPS) is the procedure of choice for the surgical treatment of pancreatic exocrine cancer localized to the body and tail of the pancreas. Splenic vein thrombosis (SVT) can occur in patients with malignant pancreatic exocrine tumors secondary to direct tumor invasion or compression of the splenic vein by mass effect. This study examines the effect of preoperative SVT on postoperative outcomes. In this retrospective cohort study, we queried our pancreatic surgery database to identify patients who underwent DPS from October 2005 to June 2011. These cases were evaluated for evidence of preoperative SVT on clinical records and cross-sectional imaging (CT,MRI, endoscopic US). Outcomes for patients with and without SVT were compared. From an overall cohort of 285 consecutive patients who underwent DPS during the study period, data were evaluated for 70 subjects who underwent surgery for pancreatic exocrine cancer (27 with SVT, 43 without SVT). The preoperative demographics and co-morbidities were similar between the groups, except the average age was higher for those without SVT (pSVT group (675 versus 250 ml, p=SVT versus 56% no SVT, p=NS), the group with SVT had a significantly higher rate of pancreas-specific complications, including pancreatic fistula (33 versus 7 %,pSVT had a trend toward longer median survival (40 versus 20.8 months),although the difference was not statistically significant (p=0.1). DPS for pancreatic ductal adenocarcinoma can be performed safely in patients with SVT, but with higher intraoperative blood loss, increased pancreas-specific complications, and a trend towards lower long-term survival rates. This paper was presented as a poster at the 53rd annual meeting of the Society for Surgery of the Alimentary Tract and at the 46th annual meeting of the Pancreas Club, San Diego, CA, May 2012.

  13. Delayed release pancrelipase for the treatment of pancreatic exocrine insufficiency associated with cystic fibrosis

    Directory of Open Access Journals (Sweden)

    Susan S Baker

    2008-10-01

    Full Text Available Susan S BakerDepartment of Pediatrics, University at Buffalo, Buffalo, NY, USAAbstract: Pancreatic enzyme replacement therapy (PERT is the only treatment for malabsorption in cystic fi brosis (CF caused by pancreatic insufficiency (PI. PI occurs in approximately 85% of patients with CF. PERT overcomes some, but not all the signs and symptoms of malabsorption. Clinical parameters such as growth, abdominal pain, diarrhea and gassiness, commonly used to adjust PERT dosing, are shown not to be good indicators of their effectiveness. The FDA does not provide oversight of preparations of pancreatic enzymes consistent with the oversight it provides for all other drugs. The FDA intends to rectify this situation. Measures of the effectiveness of PERT are limited to the coefficient of fat absorption, a difficult and unpleasant exercise for patients.Keywords: pancrelipase, cystic fibrosis, malabsorption, pancreatic enzymes

  14. Metastatic pancreatic acinar cell carcinoma in a younger male with marked AFP production: A potential pitfall on fine needle aspiration biopsy.

    Science.gov (United States)

    Valente, Kari; Yacoub, George; Cappellari, James O; Parks, Graham

    2017-02-01

    A 30-year-old male presented to his doctor with complaints of abdominal pain and was found to have retroperitoneal as well as multiple hepatic masses. A serum alpha-fetoprotein (AFP) level was significantly elevated (17,373 ng mL(-1) ), raising suspicions for a metastatic germ cell tumor. Fine needle aspiration biopsy of the pancreatic lesion revealed atypical epithelioid cells with round nuclei, large prominent nucleoli, and granular cytoplasm. The morphologic differential diagnosis included pancreatic neoplasm, metastatic germ cell tumor, other metastatic carcinoma, and melanoma. An extensive panel of immunohistochemical stains confirmed the diagnosis of acinar cell carcinoma. The diagnosis of acinar cell carcinoma could be confounded by the markedly increased AFP level, particularly in the setting of a retroperitoneal mass in a younger male. The increased AFP level in the setting of an acinar cell tumor is a potential pitfall to correct diagnosis by cytology. As the treatment for these two entities differs considerably, acute awareness of the phenomenon is important. We present a case of pancreatic ACC with an increased AFP level diagnosed on a cytology specimen. Diagn. Cytopathol. 2017;45:133-136. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  15. Impact of nutrition on pancreatic exocrine and endocrine secretion in ruminants: a review.

    Science.gov (United States)

    Harmon, D L

    1992-04-01

    Because of the unique features of the ruminant digestive system, variations in diet composition and intake produce dramatic changes in ruminal fermentation. Optimizing nutritional management requires an understanding of how these variations and changes influence digestion and metabolism. Although the pancreas plays a central role in digestion and subsequent nutrient metabolism, relatively little is known about pancreatic adaptation to nutritional changes in the ruminant. Increasing starch intake has been suggested to increase pancreatic alpha-amylase; however, recent work suggests that dietary energy per se may drive these changes, and interactions with other nutrients, such as protein, may exist. Studies describing the influence of altered protein and lipid intakes on pancreatic adaptation in ruminants are lacking. Pancreatic secretion of both insulin and glucagon respond to the intravenous infusion of VFA in a dramatic fashion; however, feeding studies suggest that the influence of VFA on insulin and glucagon may be more subtle. Interactions exist between stimulatory signals and physiological state, such as lactation. Assessment of pancreatic endocrine secretion is further complicated by a variable removal of insulin and glucagon by hepatic tissues. These studies point out that pancreatic hormone secretion is controlled by integrated and complex mechanisms. Studies of these controlling mechanisms should consider the entire array to more fully understand hormone secretion.

  16. Bile acid effects are mediated by ATP release and purinergic signalling in exocrine pancreatic cells

    DEFF Research Database (Denmark)

    Kowal, Justyna Magdalena; Haanes, Kristian Agmund; Christensen, Nynne

    2015-01-01

    BACKGROUND: In many cells, bile acids (BAs) have a multitude of effects, some of which may be mediated by specific receptors such the TGR5 or FXR receptors. In pancreas systemic BAs, as well as intra-ductal BAs from bile reflux, can affect pancreatic secretion. Extracellular ATP and purinergic si...

  17. Derivation and characterization of a pig embryonic stem cell-derived exocrine pancreatic cell line

    Science.gov (United States)

    The establishment and initial characterization of a pig embryonic stem cell-derived pancreatic cell line, PICM-31, and a colony-cloned derivative cell line, PICM-31A, is described. The cell lines were propagated for several months at split ratios of 1:3 or 1:5 at each passage on STO feeder cells af...

  18. PET in diagnosing exocrine pancreatic cancer; PET bei Tumoren des exokrinen Pankreas

    Energy Technology Data Exchange (ETDEWEB)

    Bares, R.; Besenfelder, H.; Dohmen, B.M. [Abt. Nuklearmedizin, Radiologische Klinik des Universitaetsklinikums Tuebingen (Germany)

    2003-06-01

    Despite dramatic improvements in diagnostic imaging (ultrasonography, in particular endoscopic ultrasound, CT, MRI) treatment results of pancreatic cancer are still poor. Due to the lack of early symptoms, most tumors are diagnosed at an advanced stage of disease which excludes curative surgical treatment. FDG-PET has been shown to be effective in detecting pancreatic cancer as well as differentiating benign from malignant pancreatic tumors. Results might be further improved by applying quantitative analyses, in particular kinetic modelling of FDG metabolism. Nevertheless false negative as well as false positive findings may occur. Small lesions (lymphnode or liver metastases < 1 cm) might be missed, furthermore hyperglycemia often present in patients with pancreatic disease might reduce tumor uptake and subsequently tumor detectability by PET. False positive findings were reported in active pancreatitis and some benign tumors. Although PET proved to be superior to CT or ERCP in detecting cancer, clinical relevance of PET is limited due to the absence of therapeutic consequences to be derived from PET. As a consequence PET should only be used in patients with equivocal findings of morphological imaging (CT, ERCP) who are potential candidates for surgical treatment. (orig.) [German] Trotz verbesserter diagnostischer Moeglichkeiten (endoskopischer Ultraschall, Spiral-CT, MRT) sind die Behandlungsergebnisse bei Tumoren des exokrinen Pankreas nach wie vor unbefriedigend. Aufgrund der spaet einsetzenden klinischen Symptomatik wird die Diagnose meist erst bei lokaler Inoperabilitaet gestellt. Die FDG-PET has sich sowohl im Nachweis von Pankreaskarzinomen als auch bei der Differenzialdiagnose pankreatischer Raumforderungen bewaehrt und den etablierten bildgebenden Verfahren (Ultraschall, CT) als ueberlegen erwiesen. Weitere Verbesserungen erscheinen durch absolute Quantifizierung der FDG-Kinetik moeglich. Dennoch koennen falsch negative wie auch falsch positive Ergebnisse

  19. Silencing Mist1 Gene Expression Is Essential for Recovery from Acute Pancreatitis.

    Directory of Open Access Journals (Sweden)

    Anju Karki

    Full Text Available Acinar cells of the exocrine pancreas are tasked with synthesizing, packaging and secreting vast quantities of pro-digestive enzymes to maintain proper metabolic homeostasis for the organism. Because the synthesis of high levels of hydrolases is potentially dangerous, the pancreas is prone to acute pancreatitis (AP, a disease that targets acinar cells, leading to acinar-ductal metaplasia (ADM, inflammation and fibrosis-events that can transition into the earliest stages of pancreatic ductal adenocarcinoma. Despite a wealth of information concerning the broad phenotype associated with pancreatitis, little is understood regarding specific transcriptional regulatory networks that are susceptible to AP and the role these networks play in acinar cell and exocrine pancreas responses. In this study, we examined the importance of the acinar-specific maturation transcription factor MIST1 to AP damage and organ recovery. Analysis of wild-type and Mist1 conditional null mice revealed that Mist1 gene transcription and protein accumulation were dramatically reduced as acinar cells underwent ADM alterations during AP episodes. To test if loss of MIST1 function was primarily responsible for the damaged status of the organ, mice harboring a Cre-inducible Mist1 transgene (iMist1 were utilized to determine if sustained MIST1 activity could alleviate AP damage responses. Unexpectedly, constitutive iMist1 expression during AP led to a dramatic increase in organ damage followed by acinar cell death. We conclude that the transient silencing of Mist1 expression is critical for acinar cells to survive an AP episode, providing cells an opportunity to suppress their secretory function and regenerate damaged cells. The importance of MIST1 to these events suggests that modulating key pancreas transcription networks could ease clinical symptoms in patients diagnosed with pancreatitis and pancreatic cancer.

  20. A highly stable Yarrowia lipolytica lipase formulation for the treatment of pancreatic exocrine insufficiency.

    Science.gov (United States)

    Turki, Saoussen; Mrabet, Ghada; Jabloun, Zeineb; Destain, Jacqueline; Thonart, Philippe; Kallel, Héla

    2010-12-01

    Yarrowia lipolytica lipase has been assumed to be a good candidate for the treatment of fat malabsorption in patients with pancreatic insufficiency. Nevertheless, no systematic studies on its stability under physiological conditions pertaining to the human GI (gastrointestinal) tract have been published. Stability of various Y. lipolytica lipase powder formulations at various physiological pH values as well as the effect of digestive proteases and bile salts on enzyme activity were investigated. Results were compared with those obtained from another competing fungal lipase sourced from Candida rugosa. Among the studied formulations, Y. lipolytica lipase stabilized with gum arabic and skimmed milk powder was the most promising powder formulation. Under acidic conditions (pH 3-5), this formulation showed higher stability than those observed with the other Y. lipolytica lipase formulations and C. rugosa lipase. In addition, in the presence of gum arabic and skimmed milk powder as additives, Y. lipolytica lipase exhibited markedly higher resistance to pepsin, trypsin and chymotrypsin actions. Resistance to proteolytic degradation by digestive proteases was also by far higher than that observed with C. rugosa lipase. Similar behaviour was, however, observed when these two fungal lipases were incubated with increased concentrations of bile salts. Residual lipase activity of both fungal lipases showed a slight decrease in NaTDC (sodium taurodeoxycholate) concentration above 4 mM. Consequently, Y. lipolytica lipase formulated with gum arabic and milk powder seemed to have great potential for use as a therapeutic tool for patients with pancreatic insufficiency.

  1. Free cytosolic calcium and secretagogue-stimulated initial pancreatic exocrine secretion.

    Science.gov (United States)

    Krims, P E; Pandol, S J

    1988-01-01

    In order to establish the role of secretagogue-induced changes in free cytosolic Ca2+ ([Ca2+]i) in pancreatic enzyme secretion, we measured the effects of carbachol, cholecystokinin-octapeptide (CCK-OP), bombesin, substance P, and bromo-A23187 on amylase release and [Ca2+]i in guinea pig pancreatic acini loaded with the Ca2+-selective fluorescent indicator, fura-2. Evaluation of time courses and dose-response curves indicated that carbachol, CCK-OP, bombesin, and substance P cause extracellular Ca2+-independent transient increases in [Ca2+]i and transient bursts in amylase release (initial secretion). The potencies for the secretagogues to increase [Ca2+]i and initial amylase release were similar. Bromo-A23187 also caused an extracellular Ca2+-independent transient increase in [Ca2+]i and amylase release. In the absence of extracellular Ca2+, sequential additions of substance P followed by carbachol caused transient increases in [Ca2+]i correlating with transient bursts in amylase release. In contrast, in acini first treated with carbachol, the ability of substance P to increase [Ca2+]i and amylase release was blocked. Sustained secretion caused by the secretagogues was dependent on extracellular Ca2+ but occurred at basal [Ca2+]i. Increasing [Ca2+]i during the sustained phase of stimulation by increasing the extracellular Ca2+ concentration or with bromo-A23187 did not increase the rate of sustained secretion.

  2. Determination of the exocrine pancreatic function with the NBT-PABA test using a novel dual isotope technique and gas chromatography-mass spectrometry.

    Science.gov (United States)

    Larsen, B; Ekelund, S; Jørgensen, L; Bremmelgaard, A

    1997-04-01

    We describe a tubeless test of exocrine pancreatic function based on a new dual isotope technique, using N-benzoyl-L-tyrosyl-p-aminobenzoic acid (NBT-PABA) as a substrate for intestinal chymotrypsin activity and the stable isotope, 13C-PABA as marker. Gas chromatography-mass spectrometry (GC-MS) was used for the quantification of PABA and 13C-PABA in blood. The method involves hydrolysis, extractions, separation by HPLC, and methyl ester formation of the test substances before GC-MS analysis. The test is precise and shows good separation of healthy volunteers from patients with pancreatic insufficiency. The PABA/13C-PABA ratios in serum after 1.5 h were 2.64 +/- 0.14 (mean +/- SEM) in 10 healthy volunteers and 1.26 +/- 0.22 in 10 patients with exocrine pancreatic insufficiency. We present a sensitive and specific assay, which is free of analytical interference and radiation hazards and, additionally, it illuminates extrapancreatic pharmacokinetic conditions. This test can eliminate the need for duodenal intubation, which makes it very acceptable to the patients.

  3. 915-MHz continuous wave electromagnetic radiation alters the kinetics of zymogen processing by pancreatic acinar cells

    Energy Technology Data Exchange (ETDEWEB)

    Downs, M.B.

    1987-01-01

    Two aspects of the secretory process were examined: (1) exocytosis, as measured by amylase release, and (2) the kinetics of the intracellular transport and packaging of secretory proteins, as assessed by electron microscopic autoradiographic analysis of the intracellular distribution of pulse-labelled secretory proteins. The exocytotic response was evaluated by measuring the discharge of amylase from pancreatic tissue slices. Under nonstimulated conditions, there was no difference in the kinetics of amylase discharge from tissue slices kinetically heated to 37/sup 0/C or 40/sup 0/C, indicating that a thermally induced increase in the metabolic rate of the tissue does not significantly alter the basal rate of exocytosis. Analysis of the release of both pulse-labelled secretory proteins and amylase from CC-stimulated tissue indicated that irradiation in a 25 mW/cm/sup 2/ field altered the kinetics of intracellular transport of newly synthesized secretory proteins in a manner not duplicated by kinetic heating. Electron microscopic autoradiography and morphometric analysis failed to elucidate the mechanism by which protein processing was altered.

  4. Duodenal application of Li+ in a submaximal therapeutic dose inhibits exocrine pancreatic secretion and modulates gastro-duodenal myoelectrical activity in a conscious pig model

    DEFF Research Database (Denmark)

    Naughton, Violetta; Hedemann, Mette Skou; Naughton, Patrick Joseph

    2013-01-01

    for electromyography of smooth muscles, and with a pancreatic duct catheter and a duodenal T-cannula for collection and re-entrant flow of pancreatic juice. After the recovery period, on alternative days, each animal was tested once with an intraduodenal infusion of Li+ (100 mmol·L–1 C3H5LiO3, 10 mL·kg−1·h−1) for 1 h......This study tested whether duodenal application of lithium inhibits gastroduodenal motility, and whether it suppresses secretion from the exocrine pancreas. Five suckling pigs, 16–18 days old, were surgically fitted with 3 serosal electrodes on the wall of the gastric antrum and the duodenum...

  5. Pancreatic proteome profiling of type 1 diabetic mouse: Differential expression of proteins involved in exocrine function, stress response, growth, apoptosis and metabolism.

    Science.gov (United States)

    Chakravarti, Bulbul; Sherpa, Chheten; Bose, Devasrie; Paul Chowdhury, Kakoli; Khadar, Kavita; Zhang, Yuan Clare; Chakravarti, Deb N

    2017-06-10

    Type 1 diabetes (T1D) is a chronic autoimmune disease in which the pancreatic β-cells fail to produce insulin. In addition to such change in the endocrine function, the exocrine function of the pancreas is altered as well. To understand the molecular basis of the changes in both endocrine and exocrine pancreatic functions due to T1D, the proteome profile of the pancreas of control and diabetic mouse was compared using two dimensional gel electrophoresis (2D-GE) and the differentially expressed proteins identified by electrospray ionization liquid chromatography-tandem mass spectrometry (ESI-LC-MS/MS). Among several hundred protein spots analyzed, the expression levels of 27 protein spots were found to be up-regulated while that of 16 protein spots were down-regulated due to T1D. We were able to identify 23 up-regulated and 9 down-regulated protein spots and classified them by bioinformatic analysis into different functional categories: (i) exocrine enzymes (or their precursors) involved in the metabolism of proteins, lipids, and carbohydrates; (ii) chaperone/stress response; and (iii) growth, apoptosis, amino acid metabolism or energy metabolism. Several proteins were found to be present in multiple forms, possibly resulting from proteolysis and/or post-translational modifications. Succinate dehydrogenase [ubiquinone] flavoprotein subunit, which is the major catalytic subunit of succinate dehydrogenase (SDH), was found to be one of the proteins whose expression was increased in T1D mouse pancreata. Since altered expression of a protein can modify its functional activity, we tested and observed that the activity of SDH, a key metabolic enzyme, was increased in the T1D mouse pancreata as well. The potential role of the altered expression of different proteins in T1D associated pathology in mouse is discussed. Copyright © 2016. Published by Elsevier Inc.

  6. Efficacy and Safety of a New Formulation of Pancrelipase (Ultrase MT20 in the Treatment of Malabsorption in Exocrine Pancreatic Insufficiency in Cystic Fibrosis

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    Michael W. Konstan

    2010-01-01

    Full Text Available Background. Pancreatic enzyme replacement therapy is the standard of care for treatment of malabsorption in patients with cystic fibrosis (CF and exocrine pancreatic insufficiency (PI. Aim. To evaluate efficacy and safety of a new formulation of pancrelipase (Ultrase MT20 in patients with CF and PI. Coefficients of fat absorption (CFA% and nitrogen absorption (CNA% were the main efficacy parameters. Safety was evaluated by monitoring laboratory analyses, adverse events (AEs, and overall signs and symptoms. Methods. Patients (n=31 were randomized in a crossover design comparing this pancrelipase with placebo during 2 inpatient evaluation periods (6-7 days each. Fat and protein/nitrogen ingestion and excretion were measured from food diaries and 72-hour stool collections. CFA% and CNA% were calculated for each period and compared. Results. Twenty-four patients provided analyzable data. This pancrelipase increased mean CFA% and CNA% (+34.7% and +25.7%, resp., P<.0001 for both, reduced stool frequency, and improved stool consistency compared with placebo. Placebo-treated patients reported more AEs, with gastrointestinal symptoms being the most frequently reported AE. Conclusions. This pancrelipase is a safe and effective treatment for malabsorption associated with exocrine PI in patients with CF.

  7. New insights into alcoholic pancreatitis and pancreatic cancer.

    Science.gov (United States)

    Apte, Minoti; Pirola, Romano; Wilson, Jeremy

    2009-10-01

    Pancreatitis and pancreatic cancer represent two major diseases of the exocrine pancreas. Pancreatitis exhibits both acute and chronic manifestations. The commonest causes of acute pancreatitis are gallstones and alcohol abuse; the latter is also the predominant cause of chronic pancreatitis. Recent evidence indicates that endotoxinemia, which occurs in alcoholics due to increased gut permeability, may trigger overt necroinflammation of the pancreas in alcoholics and one that may also play a critical role in progression to chronic pancreatitis (acinar atrophy and fibrosis) via activation of pancreatic stellate cells (PSCs). Chronic pancreatitis is a major risk factor for the development of pancreatic cancer, which is the fourth leading cause of cancer-related deaths in humans. Increasing attention has been paid in recent years to the role of the stroma in pancreatic cancer progression. It is now well established that PSCs play a key role in the production of cancer stroma and that they interact closely with cancer cells to create a tumor facilitatory environment that stimulates local tumor growth and distant metastasis. This review summarizes recent advances in our understanding of the pathogenesis of alcoholic pancreatitis and pancreatic cancer, with particular reference to the central role played by PSCs in both diseases. An improved knowledge of PSC biology has the potential to provide an insight into pathways that may be therapeutically targeted to inhibit PSC activation, thereby inhibiting the development of fibrosis in chronic pancreatitis and interrupting stellate cell-cancer cell interactions so as to retard cancer progression.

  8. Pancreatic Exocrine Tumors

    Science.gov (United States)

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  9. Manual ventilation therapy and aggressive potassium supplementation in the management of respiratory failure secondary to severe hypokalaemia in a cat with exocrine pancreatic insufficiency.

    Science.gov (United States)

    Daste, Thomas; Dossin, Olivier; Reynolds, Brice S; Aumann, Marcel

    2014-04-01

    A domestic shorthair cat was referred for progressive muscle weakness and dyspnoea. The cat had a 2-month history of severe weight loss, small intestinal diarrhoea, polyphagia and polyuria/polydipsia. Biochemical analysis and venous blood gas evaluation revealed severe hypokalaemia [1.7 mmol/l; reference interval (RI): 3.5-5.1 mmol/l] and hypoventilation (partial pressure of carbon dioxide = 68 mmHg; RI: 34-38 mmHg). Aggressive potassium supplementation was initiated. The cat was manually ventilated until serum potassium increased to 3 mmol/l. A diagnosis of exocrine pancreatic insufficiency (EPI) was made based on clinical signs and serum feline trypsin-like immunoreactivity (0.1 μg/l; RI: 12-82 μg/l). Medical management of the EPI resulted in clinical recovery.

  10. Ichthyosis, exocrine pancreatic insufficiency, impaired neutrophil chemotaxis, growth retardation, and metaphyseal dysplasia (Shwachman syndrome). Report of a case with extensive skin lesions (clinical, histological, and ultrastructural findings)

    Science.gov (United States)

    Goeteyn, M; Oranje, A P; Vuzevski, V D; de Groot, R; van Suijlekom-Smit, L W

    1991-02-01

    The Shwachman syndrome comprises exocrine pancreatic insufficiency, growth retardation, and bone marrow hypoplasia resulting in neutropenia. Clinical, morphological, and ultrastructural studies, as well as hair analysis, were performed in a patient with Shwachman's syndrome and severe ichthyosis. Clinical findings were lamellar ichthyosiform desquamation on the extremities. The hair was scanty and short on the scalp, in the eyelashes, and in the eyebrows. The nails were hyperkeratotic. Morphologic findings were slight, regular acanthosis and severe diffuse hyperkeratosis with variable parakeratosis. The granular layer was thickened. The papillary dermis showed very slight perivascular lymphocyte infiltration. The most prominent ultrastructural finding was the presence of solitary or multiple droplets of varying size in the cytoplasm of the keratinocytes. Hair analysis revealed no abnormalities; the cystine concentration in hair specimens was normal.

  11. Efficient and persistent transduction of exocrine and endocrine pancreas by adeno-associated virus type 8.

    Science.gov (United States)

    Cheng, Henrique; Wolfe, Stephanie H; Valencia, Valery; Qian, Keping; Shen, Leping; Phillips, M Ian; Chang, Lung-Ji; Zhang, Y Clare

    2007-09-01

    Efficient delivery of therapeutic proteins into the pancreas represents a major obstacle to gene therapy of pancreatic disorders. The current study compared the efficiency of recombinant lentivirus and adeno-associated virus (AAV) serotypes 1, 2, 5, 8 vectors delivered by intrapancreatic injection for gene transfer in vivo. Our results indicate that lentivirus and AAV 1, 2, 8 are capable of transducing pancreas with the order of efficiency AAV8 >AAV1 > AAV2 >/= lentivirus, whereas AAV5 was ineffective. AAV8 resulted in an efficient, persistent (150 days) and dose-dependent transduction in exocrine acinar cells and endocrine islet cells. Pancreatic ducts and blood vessels were also transduced. Extrapancreatic transduction was restricted to liver. Leukocyte infiltration was not observed in pancreas and blood glucose levels were not altered. Thus, AAV8 represents a safe and effective vehicle for therapeutic gene transfer to pancreas in vivo.

  12. [Effectiveness of panzytrat--modern physiological enzyme preparation in complex therapy of pancreatic exocrine secretory insufficiency in cholelithiasis].

    Science.gov (United States)

    Petukhov, V A; Mironov, A V; Semenov, Zh S; Ustinov, F S

    2009-01-01

    In the article the analysis of the survey with 102 patients with gallstone disease involved, 68 of whom underwent cholecystectomy and 34 were treated conservatively, is made. The content of fecal elastase 1 in stool was estimated for diagnostics of exocrine enzyme insufficiency of pancreas by immune-enzyme analysis. It was stated that 90% of patients possess secondary exocrine insufficiency of pancreas in case of gallstone disease. It is the result of complex metabolic liver abnormalities, portal and mesenterial haemodynamics, dysbiosis of large intestine which are the components of a syndrom of maldigestion and appear during gallstone disease progressing long time before hospitalization. Cholecystectomy doesn't eliminate enzyme insufficiency of pancreas. The effectiveness of using new physiological enzymatic drug Panzytrat in a complex therapy of a syndrom of maldigestion in case of gallstone disease is shown.

  13. Light and Electron Microscopic Studies on Prenatal Differentiation of Exocrine Pancreas in Buffalo

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    Divya Gupta

    2016-01-01

    Full Text Available The study was conducted on pancreas of 24 buffalo fetuses collected from abattoir and Veterinary clinics, GADVASU, Ludhiana. The buffalo fetuses were divided into three groups after measuring their CVRL, namely, group I (CVRL between 0 and 20 cm, group II (CVRL above 20 cm and up to 40 cm, and group III (CVRL above 40 cm and their approximate age was calculated. The tissues were processed for light and ultrastructural studies. In group I, at 1.2 cm CVRL (34 days, the pancreas comprised tubules and solid nest of undifferentiated epithelial cells. At 7.5 cm CVRL (63 days acinar cells with zymogen granules were observed. These acinar cells varied in shape from columnar to pyramidal. At 12.8 cm CVRL (86 days, parenchyma began to organize into lobes and lobules. The centroacinar cells were observed at 12.8 cm CVRL (86 days. In group II, at 28.3 cm CVRL (137 days, there was extensive branching of tubules that resulted in highly branched ductal tree connecting exocrine secretary units to the duct system. The interlobular and intralobular ducts were well observed at this age yet the intercalated ducts were not completely developed. In group III, exocrine pancreas showed a massive growth at 48 cm CVRL (182 days with distinct pancreatic lobes and lobules. At 54 cm CVRL (195 days, well developed pancreatic architecture was seen with the presence of extensive development of exocrine part organized in lobes and lobules with interlobular and intralobular ducts whereas the intercalated ducts were observed in 80 cm CVRL (254 days.

  14. Pathology review of proliferative lesions of the exocrine pancreas in two chronic feeding studies in rats with ammonium perfluorooctanoate

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    Jessica M. Caverly Rae

    2014-01-01

    Full Text Available Two chronic dietary studies, conducted years apart, with ammonium perfluorooctanoate (APFO in Sprague Dawley rats have been previously reported. Although both included male 300 ppm dietary dose groups, only the later study, conducted in 1990–1992 by Biegel et al., reported an increase in proliferative lesions (hyperplasia and adenoma of the acinar pancreas. An assessment of the significance of the differences between both studies requires careful consideration of: the diagnostic criteria for proliferative acinar cell lesions of the rat pancreas (for example, the diagnosis of pancreatic acinar cell hyperplasia versus adenoma is based on the two-dimensional size of the lesion rather than distinct morphological differences; the basis for those criteria in light of their relevance to biological behavior; and the potential diagnostic variability between individual pathologists for difficult-to-classify lesions. A pathology peer review of male exocrine pancreatic tissues from the earlier study, conducted in 1981–1983 by Butenhoff et al., was undertaken. This review identified an increase in acinar cell hyperplasia but not adenoma or carcinoma in the earlier study. Both studies observed a proliferative response in the acinar pancreas which was more pronounced in the study by Biegel et al. Definitive reasons for the greater incidence of proliferative lesions in the later study were not identified, but some possible explanations are presented herein. The relevance of this finding to human risk assessment, in the face of differences in the biological behavior of human and rat pancreatic proliferative lesions and the proposed mechanism of formation of these lesions, are questionable.

  15. Obestatin Accelerates the Recovery in the Course of Ischemia/Reperfusion-Induced Acute Pancreatitis in Rats.

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    Jakub Bukowczan

    Full Text Available Several previous studies have shown that obestatin exhibits protective and regenerative effects in some organs including the stomach, kidney, and the brain. In the pancreas, pretreatment with obestatin inhibits the development of cerulein-induced acute pancreatitis, and promotes survival of pancreatic beta cells and human islets. However, no studies investigated the effect of obestatin administration following the onset of experimental acute pancreatitis.The aim of this study was to evaluate the impact of obestatin therapy in the course of ischemia/reperfusion-induced pancreatitis. Moreover, we tested the influence of ischemia/reperfusion-induced acute pancreatitis and administration of obestatin on daily food intake and pancreatic exocrine secretion.Acute pancreatitis was induced by pancreatic ischemia followed by reperfusion of the pancreas. Obestatin (8 nmol/kg/dose was administered intraperitoneally twice a day, starting 24 hours after the beginning of reperfusion. The effect of obestatin in the course of necrotizing pancreatitis was assessed between 2 and 14 days, and included histological, functional, and biochemical analyses. Secretory studies were performed on the third day after sham-operation or induction of acute pancreatitis in conscious rats equipped with chronic pancreatic fistula.Treatment with obestatin ameliorated morphological signs of pancreatic damage including edema, vacuolization of acinar cells, hemorrhages, acinar necrosis, and leukocyte infiltration of the gland, and led to earlier pancreatic regeneration. Structural changes were accompanied by biochemical and functional improvements manifested by accelerated normalization of interleukin-1β level and activity of myeloperoxidase and lipase, attenuation of the decrease in pancreatic DNA synthesis, and by an improvement of pancreatic blood flow. Induction of acute pancreatitis by pancreatic ischemia followed by reperfusion significantly decreased daily food intake and

  16. Obestatin Accelerates the Recovery in the Course of Ischemia/Reperfusion-Induced Acute Pancreatitis in Rats

    Science.gov (United States)

    Bukowczan, Jakub; Warzecha, Zygmunt; Ceranowicz, Piotr; Kuśnierz-Cabala, Beata; Tomaszewska, Romana

    2015-01-01

    Objective Several previous studies have shown that obestatin exhibits protective and regenerative effects in some organs including the stomach, kidney, and the brain. In the pancreas, pretreatment with obestatin inhibits the development of cerulein-induced acute pancreatitis, and promotes survival of pancreatic beta cells and human islets. However, no studies investigated the effect of obestatin administration following the onset of experimental acute pancreatitis. Aim The aim of this study was to evaluate the impact of obestatin therapy in the course of ischemia/reperfusion-induced pancreatitis. Moreover, we tested the influence of ischemia/reperfusion-induced acute pancreatitis and administration of obestatin on daily food intake and pancreatic exocrine secretion. Methods Acute pancreatitis was induced by pancreatic ischemia followed by reperfusion of the pancreas. Obestatin (8nmol/kg/dose) was administered intraperitoneally twice a day, starting 24 hours after the beginning of reperfusion. The effect of obestatin in the course of necrotizing pancreatitis was assessed between 2 and 14 days, and included histological, functional, and biochemical analyses. Secretory studies were performed on the third day after sham-operation or induction of acute pancreatitis in conscious rats equipped with chronic pancreatic fistula. Results Treatment with obestatin ameliorated morphological signs of pancreatic damage including edema, vacuolization of acinar cells, hemorrhages, acinar necrosis, and leukocyte infiltration of the gland, and led to earlier pancreatic regeneration. Structural changes were accompanied by biochemical and functional improvements manifested by accelerated normalization of interleukin-1β level and activity of myeloperoxidase and lipase, attenuation of the decrease in pancreatic DNA synthesis, and by an improvement of pancreatic blood flow. Induction of acute pancreatitis by pancreatic ischemia followed by reperfusion significantly decreased daily food

  17. Yarrowia lipolytica Lipase 2 Is Stable and Highly Active in Test Meals and Increases Fat Absorption in an Animal Model of Pancreatic Exocrine Insufficiency.

    Science.gov (United States)

    Aloulou, Ahmed; Schué, Mathieu; Puccinelli, Delphine; Milano, Stéphane; Delchambre, Chantal; Leblond, Yves; Laugier, René; Carrière, Frédéric

    2015-12-01

    Pancreatic exocrine insufficiency (PEI) reduces pancreatic secretion of digestive enzymes, including lipases. Oral pancreatic enzyme replacement therapy (PERT) with pancreatin produces unsatisfactory results. The lipase 2 produced by the yeast Yarrowia lipolytica (YLLIP2; GenBank: AJ012632) might be used in PERT. We investigated its ability to digest triglycerides in a test meal and its efficacy in reducing fecal fat in an animal model of PEI. YLLIP2 was produced by genetically engineered Y lipolytica and purified from culture media. YLLIP2 or other gastric (LIPF) and pancreatic (PNLIPD) lipases were added to a meal paste containing dietary triglycerides, at a range of pH values (pH 2-7), with and without pepsin or human bile and incubated at 37°C. We collected samples at various time points and measured lipase activities and stabilities. To create an animal model of PEI, steatorrhea was induced by embolization of the exocrine pancreas gland and pancreatic duct ligation in minipigs. The animals were given YLLIP2 (1, 4, 8, 40, or 80 mg/d) or pancreatin (100,000 US Pharmacopeia lipase units/d, controls) for 9 days. We then collected stool samples, measured fat levels, and calculated coefficient of fat absorption (CFA) values. YLLIP2 was highly stable and poorly degraded by pepsin, and had the highest activity of all lipases tested on meal triglyceride at pH 4-7 (pH 6 with bile: 94 ± 34 U/mg; pH 4 without bile: 43 ± 13 U/mg). Only gastric lipase was active and stable at pH 3, whereas YLLIP2 was sensitive to pepsin hydrolysis after pH inactivation. From in vitro test meal experiments, the lipase activity of YLLIP2 (10 mg) was estimated to be equivalent to that of pancreatin (1200 mg; 100,000 US Pharmacopeia units) at pH 6. In PEI minipigs, CFA values increased from 60.1% ± 9.3% before surgery to 90.5% ± 3.2% after administration of 1200 mg pancreatin (P < .05); CFA values increased to a range of 84.6% ± 3.0% to 90.0% ± 3.8% after administration of 4-80 mg YLLIP

  18. Treatment of pancreatic exocrine insufficiency after pancreatic resection - Results of a randomized, double-blind, placebo-controlled, crossover study of high vs standard dose pancreatin

    NARCIS (Netherlands)

    Neoptolemos, JP; Ghaneh, P; Andren-Sandberg, A; Bramhall, S; Patankar, R; Kleibeuker, JH; Johnson, CD

    Background: Steatorrhea following major;pancreatic resection can be difficult to control, requiring high doses of pancreatic enzyme supplements. The aim of this study was to demonstrate equivalent efficacy of high-dose and standard-dose pancreatin in treating steatorrhea after pancreatectomy.

  19. Multimodal Treatment of Hepatic Metastasis in the Form of a Bile Duct Tumor Thrombus from Pancreatic Acinar Cell Carcinoma: Case Report of Successful Resection after Chemoradiation Therapy

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    Hirotada Kittaka

    2012-07-01

    Full Text Available Pancreatic acinar cell carcinoma (ACC is a rare tumor, and its pathophysiology has not been well understood. Treatment strategies for hepatic metastasis originating from ACC remain controversial. We report the case of a 66-year-old woman who had undergone total pancreatectomy from ACC 7 years prior to clinical presentation. Contrast-enhanced computed tomography imaging revealed a tumorous lesion measuring 7 cm in length and 1 cm in diameter and extending along the intrahepatic bile duct (B6, which showed mild enhancement in the early phase and modest washout in the late phase. This lesion was diagnosed as hepatic metastasis primarily in the form of a bile duct tumor thrombus originating from the prior ACC by the pathological evaluation of the fine needle biopsy specimen. The patient underwent preoperative gemcitabine-based chemoradiation therapy followed by subsequent surgical resection, which included subsegmentectomy (S6 of the liver and complete removal of the bile duct tumor thrombus. The patient has had no recurrence during the past 8 months since her last surgery. Multimodal treatment including preoperative chemoradiation therapy might be beneficial especially for marginally resectable cases of ACC.

  20. Regeneration of the exocrine pancreas is delayed in telomere-dysfunctional mice.

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    Guido von Figura

    Full Text Available INTRODUCTION: Telomere shortening is a cell-intrinsic mechanism that limits cell proliferation by induction of DNA damage responses resulting either in apoptosis or cellular senescence. Shortening of telomeres has been shown to occur during human aging and in chronic diseases that accelerate cell turnover, such as chronic hepatitis. Telomere shortening can limit organ homeostasis and regeneration in response to injury. Whether the same holds true for pancreas regeneration in response to injury is not known. METHODS: In the present study, pancreatic regeneration after acute cerulein-induced pancreatitis was studied in late generation telomerase knockout mice with short telomeres compared to telomerase wild-type mice with long telomeres. RESULTS: Late generation telomerase knockout mice exhibited impaired exocrine pancreatic regeneration after acute pancreatitis as seen by persistence of metaplastic acinar cells and markedly reduced proliferation. The expression levels of p53 and p21 were not significantly increased in regenerating pancreas of late generation telomerase knockout mice compared to wild-type mice. CONCLUSION: Our results indicate that pancreatic regeneration is limited in the context of telomere dysfunction without evidence for p53 checkpoint activation.

  1. Both Exocrine Pancreatic Insufficiency and Signs of Pancreatic Inflammation Are Prevalent in Children with Complicated Severe Acute Malnutrition: An Observational Study

    NARCIS (Netherlands)

    Bartels, Rosalie H.; Meyer, Sophie L.; Stehmann, Tijs A.; Bourdon, Céline; Bandsma, Robert H. J.; Voskuijl, Wieger P.

    2016-01-01

    Objectives To assess whether pancreatic function is impaired in children with severe acute malnutrition, is different between edematous vs nonedematous malnutrition, and improves by nutritional rehabilitation. Study design We followed 89 children with severe acute malnutrition admitted to Queen

  2. Both Exocrine Pancreatic Insufficiency and Signs of Pancreatic Inflammation Are Prevalent in Children with Complicated Severe Acute Malnutrition : An Observational Study

    NARCIS (Netherlands)

    Bartels, Rosalie H.; Meyer, Sophie L.; Stehmann, Tijs A.; Bourdon, Celine; Bandsma, Robert H. J.; Voskuijl, Wieger P.

    Objectives To assess whether pancreatic function is impaired in children with severe acute malnutrition, is different between edematous vs nonedematous malnutrition, and improves by nutritional rehabilitation. Study design We followed 89 children with severe acute malnutrition admitted to Queen

  3. Oral Supplementation with a Special Additive of Retinyl Palmitate and Alpha Tocopherol Reduces Growth Retardation in Young Pancreatic Duct Ligated Pigs Used as a Model for Children Suffering from Exocrine Pancreatic Insufficiency

    Directory of Open Access Journals (Sweden)

    Anne Mößeler

    2016-09-01

    Full Text Available Pancreatic exocrine insufficiency (PEI is a disease of diverse aetiology—e.g., majority of patients suffering from cystic fibrosis (CF show PEI congenitally. Malnutrition and malabsorption of nutrients impair growth and nutritional status. As reduced fat digestion leads to a deficiency of fat-soluble vitamins the supplementation is standard, but absorption is a critical point in PEI-patients. The pancreatic duct ligated (PL pig is an established model for PEI in humans and has been proven to be a suitable model to compare different vitamin additives for supplementation. In a former study, PEI caused distinct growth retardation in young piglets, but did not affect growth in older ones. Our study hypothesised that this age-dependent effect is caused by exhausted body reserves of fat-soluble vitamins and, therefore, extra supply reduces growth retardation. PEI was induced by PL at the age of seven (PL-7 or 16 weeks (PL-16. Controls (C underwent a sham surgery. Some PL-7 pigs (PL-7 + Vit were fed a special vitamin additive. PEI reduced the mean final body weight (kg at 26 weeks of age significantly with lower effect in PL-16-pigs (C:117; PL-7:49.5; PL-7 + Vit:77.1; PL-16:96.4. Extra vitamin supply resulted in an increased growth and normalised serum concentration of alpha-tocopherol, underlining the importance of special supplementation in PEI-patients.

  4. Angiotensin-converting enzyme 2-angiotensin (1-7)-Mas axis prevents pancreatic acinar cell inflammatory response via inhibition of the p38 mitogen-activated protein kinase/nuclear factor-κB pathway.

    Science.gov (United States)

    Yu, Xiaozheng; Cui, Lijian; Hou, Fei; Liu, Xiaoya; Wang, Yan; Wen, Yan; Chi, Cheng; Li, Chunyun; Liu, Ruixia; Yin, Chenghong

    2017-11-13

    The aim of the present study was to investigate the role of the angiotensin-converting enzyme (ACE)2-angiotensin‑(Ang)-(1-7)-Mas axis in the pathogenesis of pancreatitis and the association between this axis and the p38 mitogen-activated protein kinase (p38 MAPK)/nuclear factor (NF-κB) signaling pathway in pancreatic acinar cells. Mouse pancreatic acinar cancer (MPC-83) cells were stimulated with 10 nM caerulein (CAE) to create an in vitro model of acute pancreatitis, and collected for analysis at 2, 6, 12, 24 and 48 h post stimulation. In addition, cells were pretreated with different concentrations of Ang‑(1‑7), Ang‑(1‑7) antagonist A779, p38 MAPK inhibitor SB203580 or ACE2 inhibitor DX600 for 30 min, and then stimulated with CAE for 24 h. The ACE2, Mas receptor, p38 MAPK, phosphorylated (p)-p38 MAPK and NF-κB expression levels were evaluated using western blotting and immunofluorescence. p38 MAPK, NF-κB, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-8 and IL-10 mRNA expression levels were assessed using reverse transcription-quantitative polymerase chain reaction. The results of the immunofluorescence assay demonstrated that ACE2 and p38 MAPK were present mainly in the cytoplasm, while the Mas receptor was located mainly in the cell membrane. ACE2, p38 MAPK and p-p38 MAPK protein levels were significantly increased (PMas receptor protein levels were significantly upregulated (PMas axis significantly inhibits pancreatitis by inhibition of the p38 MAPK/NF-κB signaling pathway.

  5. Acinar Cell Cyst adenoma (Acinar Cystic Transformation) of the Pancreas: the Radiologic-Pathologic Features

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    Gumus, Mehmet; Algin, Oktay; Gundogdu, Haldun [Ataturk Training and Research Hospital, Ankara (Turkmenistan); Ugras, Serdar [Selcuk University, Selcuklu Medical Faculty, Konya (Turkmenistan)

    2011-02-15

    Acinar cystic transformation of the pancreas is also known as acinar cell cystadenoma (ACC), and this is an extremely rare benign lesion that was first described in April 2002. We report here on a case of a previously asymptomatic patient with pancreatic ACC and this was diagnosed by computed tomography (CT) and magnetic resonance imaging (MRI). To the best of our knowledge, there is no previous report concerning the CT or MRI features of ACC in the medical literature. We present here the CT, MRI and pathological findings of pancreatic ACC

  6. Acinar cell cystadenoma (acinar cystic transformation) of the pancreas: the radiologic-pathologic features.

    Science.gov (United States)

    Gumus, Mehmet; Ugras, Serdar; Algin, Oktay; Gundogdu, Haldun

    2011-01-01

    Acinar cystic transformation of the pancreas is also known as acinar cell cystadenoma (ACC), and this is an extremely rare benign lesion that was first described in April 2002. We report here on a case of a previously asymptomatic patient with pancreatic ACC and this was diagnosed by computed tomography (CT) and magnetic resonance imaging (MRI). To the best of our knowledge, there is no previous report concerning the CT or MRI features of ACC in the medical literature. We present here the CT, MRI and pathological findings of pancreatic ACC.

  7. Sjögren-like pluriglandular exocrine insufficiency after drug-induced toxic epidermal necrolysis.

    Science.gov (United States)

    Sabán, J.; Pais, J. R.; Rodríguez, J. L.; Boixeda, D.

    1991-01-01

    We present the case of a patient that progressively developed xerophthalmia, xerostomia, cutaneous xerosis and exocrine pancreatic insufficiency 3 months after metamizole-induced toxic epidermal necrolysis. Though the association of Sjögren's syndrome and exocrine pancreatic impairment is well established, the Sjögren-like syndrome after drug-induced toxic epidermal necrolysis in association with such a wide exocrine glandular insufficiency has not been previously described, to our knowledge. PMID:2041854

  8. Dynamic landscape of pancreatic carcinogenesis reveals early molecular networks of malignancy.

    Science.gov (United States)

    Kong, Bo; Bruns, Philipp; Behler, Nora A; Chang, Ligong; Schlitter, Anna Melissa; Cao, Jing; Gewies, Andreas; Ruland, Jürgen; Fritzsche, Sina; Valkovskaya, Nataliya; Jian, Ziying; Regel, Ivonne; Raulefs, Susanne; Irmler, Martin; Beckers, Johannes; Friess, Helmut; Erkan, Mert; Mueller, Nikola S; Roth, Susanne; Hackert, Thilo; Esposito, Irene; Theis, Fabian J; Kleeff, Jörg; Michalski, Christoph W

    2016-09-19

    The initial steps of pancreatic regeneration versus carcinogenesis are insufficiently understood. Although a combination of oncogenic Kras and inflammation has been shown to induce malignancy, molecular networks of early carcinogenesis remain poorly defined. We compared early events during inflammation, regeneration and carcinogenesis on histological and transcriptional levels with a high temporal resolution using a well-established mouse model of pancreatitis and of inflammation-accelerated KrasG12D-driven pancreatic ductal adenocarcinoma. Quantitative expression data were analysed and extensively modelled in silico. We defined three distinctive phases-termed inflammation, regeneration and refinement-following induction of moderate acute pancreatitis in wild-type mice. These corresponded to different waves of proliferation of mesenchymal, progenitor-like and acinar cells. Pancreas regeneration required a coordinated transition of proliferation between progenitor-like and acinar cells. In mice harbouring an oncogenic Kras mutation and challenged with pancreatitis, there was an extended inflammatory phase and a parallel, continuous proliferation of mesenchymal, progenitor-like and acinar cells. Analysis of high-resolution transcriptional data from wild-type animals revealed that organ regeneration relied on a complex interaction of a gene network that normally governs acinar cell homeostasis, exocrine specification and intercellular signalling. In mice with oncogenic Kras, a specific carcinogenic signature was found, which was preserved in full-blown mouse pancreas cancer. These data define a transcriptional signature of early pancreatic carcinogenesis and a molecular network driving formation of preneoplastic lesions, which allows for more targeted biomarker development in order to detect cancer earlier in patients with pancreatitis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  9. Maintenance of acinar cell organization is critical to preventing Kras-induced acinar-ductal metaplasia.

    Science.gov (United States)

    Shi, G; DiRenzo, D; Qu, C; Barney, D; Miley, D; Konieczny, S F

    2013-04-11

    Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers owing to a number of characteristics including difficulty in establishing early diagnosis and the absence of effective therapeutic regimens. A large number of genetic alterations have been ascribed to PDAC with mutations in the KRAS2 proto-oncogene thought to be an early event in the progression of disease. Recent lineage-tracing studies have shown that acinar cells expressing mutant Kras(G12D) are induced to transdifferentiate, generating duct-like cells through a process known as acinar-ductal metaplasia (ADM). ADM lesions then convert to precancerous pancreatic intraepithelial neoplasia (PanIN) that progresses to PDAC over time. Thus, understanding the earliest events involved in ADM/PanIN formation would provide much needed information on the molecular pathways that are instrumental in initiating this disease. As studying the transition of acinar cells to metaplastic ductal cells in vivo is complicated by analysis of the entire organ, an in vitro three dimensional (3D) culture system was used to model ADM outside the animal. Kras(G12D)-expressing acinar cells rapidly underwent ADM in 3D culture, forming ductal cysts that silenced acinar genes and activated duct genes, characteristics associated with in vivo ADM/PanIN lesions. Analysis of downstream KRAS signaling events established a critical importance for the Raf/MEK/ERK pathway in ADM induction. In addition, forced expression of the acinar-restricted transcription factor Mist1, which is critical to acinar cell organization, significantly attenuated Kras(G12D)-induced ADM/PanIN formation. These results suggest that maintaining MIST1 activity in Kras(G12D)-expressing acinar cells can partially mitigate the transformation activity of oncogenic KRAS. Future therapeutics that target both the MAPK pathway and Mist1 transcriptional networks may show promising efficacy in combating this deadly disease.

  10. The Crucial Role of Early Mitochondrial Injury in L-Lysine-Induced Acute Pancreatitis

    Science.gov (United States)

    Biczó, György; Hegyi, Péter; Dósa, Sándor; Shalbuyeva, Natalia; Berczi, Sándor; Sinervirta, Riitta; Hracskó, Zsuzsanna; Siska, Andrea; Kukor, Zoltán; Jármay, Katalin; Venglovecz, Viktória; Varga, Ilona S.; Iványi, Béla; Alhonen, Leena; Wittmann, Tibor; Gukovskaya, Anna; Takács, Tamás

    2011-01-01

    Abstract Aims Large doses of intraperitoneally injected basic amino acids, L-arginine, or L-ornithine, induce acute pancreatitis in rodents, although the mechanisms mediating pancreatic toxicity remain unknown. Another basic amino acid, L-lysine, was also shown to cause pancreatic acinar cell injury. The aim of the study was to get insight into the mechanisms through which L-lysine damages the rat exocrine pancreas, in particular to characterize the kinetics of L-lysine-induced mitochondrial injury, as well as the pathologic responses (including alteration of antioxidant systems) characteristic of acute pancreatitis. Results We showed that intraperitoneal administration of 2 g/kg L-lysine induced severe acute necrotizing pancreatitis. L-lysine administration caused early pancreatic mitochondrial damage that preceded the activation of trypsinogen and the proinflammatory transcription factor nuclear factor-κB (NF-κB), which are commonly thought to play an important role in the development of acute pancreatitis. Our data demonstrate that L-lysine impairs adenosine triphosphate synthase activity of isolated pancreatic, but not liver, mitochondria. Innovation and Conclusion Taken together, early mitochondrial injury caused by large doses of L-lysine may lead to the development of acute pancreatitis independently of pancreatic trypsinogen and NF-κB activation. PMID:21644850

  11. Keratins provide virus-dependent protection or predisposition to injury in coxsackievirus-induced pancreatitis

    Directory of Open Access Journals (Sweden)

    DM Toivola, SE Ostrowski

    2009-08-01

    Full Text Available DM Toivola1, SE Ostrowski2, H Baribault3, TM Magin4, AI Ramsingh2, MB Omary51Åbo Akademi University, Dept. Biology, BioCity, Turku, Finland and Stanford University School of Medicine and Digestive Disease Center; 2New York State Department of Health, Albany, NY, USA; 3Amgen, South San Francisco, CA, USA; 4University of Bonn, Bonn, Germany; 5Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Mi, USAAbstract: Keratins 8 and 18 (K8/K18 are the two major intermediate filament proteins in hepatocytes and pancreatic acinar cells. Acinar cell keratins are organized as cytoplasmic and apicolateral filaments. An important role of hepatocyte K8/K18 is to maintain cellular integrity, while this cytoprotective function of K8/K18 is not evident in the pancreas since keratin-deficient mice cope well with pancreatitis models. To further study the roles of keratins in the exocrine pancreas, we used coxsackievirus B4-models, CVB4-V and CVB4-P, to induce severe acute/chronic pancreatitis and acute pancreatitis, respectively, in K8-null (which lack acinar keratins and K18-null (which lack cytoplasmic keratins mice. Despite similar virus titers in all mice, CVB4-V resulted in 40% mortality of the K8-null mice 14 days post-infection compared to no lethality of WT and K18-null mice. In contrast, K8-null mice were far less susceptible to CVB4-P-induced damage as determined by histology and serology analysis, and they recover faster than WT and K18-null mice. After CVB4 virus infection, keratins aggregated during acinar degranulation, and K8/K18 site-specific phosphorylation was observed during degranulation and recovery. Hence, keratins significantly affect CVB4 virulence, positively or negatively, depending on the virus subtype and keratin makeup, in a virus replication-independent manner.Keywords: keratin, pancreatitis, coxsackievirus

  12. High fat diet and GLP-1 drugs induce pancreatic injury in mice

    Energy Technology Data Exchange (ETDEWEB)

    Rouse, Rodney, E-mail: rodney.rouse@fda.hhs.gov; Xu, Lin; Stewart, Sharron; Zhang, Jun

    2014-04-15

    Glucagon Like Peptide-1 (GLP-1) drugs are currently used to treat type-2 diabetes. Safety concerns for increased risk of pancreatitis and pancreatic ductal metaplasia have accompanied these drugs. High fat diet (HFD) is a type-2 diabetes risk factor that may affect the response to GLP-1 drug treatment. The objective of the present study was to investigate the effects of diet and GLP-1 based drugs on the exocrine pancreas in mice. Experiments were designed in a mouse model of insulin resistance created by feeding a HFD or standard diet (STD) for 6 weeks. The GLP-1 drugs, sitagliptin (SIT) and exenatide (EXE) were administered once daily for additional 6 weeks in both mice fed HFD or STD. The results showed that body weight, blood glucose levels, and serum levels of pro-inflammatory cytokines (TNFα, IL-1β, and KC) were significantly greater in HFD mice than in STD mice regardless of GLP-1 drug treatment. The semi-quantitative grading showed that pancreatic changes were significantly greater in EXE and SIT-treated mice compared to control and that HFD exacerbated spontaneous exocrine pancreatic changes seen in saline-treated mice on a standard diet. Exocrine pancreatic changes identified in this study included acinar cell injury (hypertrophy, autophagy, apoptosis, necrosis, and atrophy), vascular injury, interstitial edema and inflammation, fat necrosis, and duct changes. These findings support HFD as a risk factor to increased susceptibility/severity for acute pancreatitis and indicate that GLP-1 drugs cause pancreatic injury that can be exacerbated in a HFD environment.

  13. High Volume Washing of the Abdomen in Increasing Survival After Surgery in Patients With Pancreatic Cancer That Can Be Removed by Surgery

    Science.gov (United States)

    2017-10-25

    Acinar Cell Carcinoma; Ampulla of Vater Adenocarcinoma; Cholangiocarcinoma; Duodenal Adenocarcinoma; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraductal Papillary Mucinous Neoplasm, Pancreatobiliary-Type; Periampullary Adenocarcinoma

  14. Latest advances in chronic pancreatitis

    National Research Council Canada - National Science Library

    Domínguez Muñoz, J Enrique

    2015-01-01

    .... These advances mainly concern the early diagnosis of the disease, the treatment of symptoms and complications, mainly pain and pancreatic exocrine insufficiency, and the diagnosis and therapy of autoimmune pancreatitis...

  15. AN EMBRYONIC CHICK PANCREAS ORGAN CULTURE MODEL: CHARACTERIZATION AND NEURAL CONTROL OF EXOCRINE RELEASE

    Science.gov (United States)

    An embryonic chick (Gallus domesticus) whole-organ pancreas culture system was developed for use as an in vitro model to study cholinergic regulation of exocrine pancreatic function. The culture system was examined for characteristic exocrine function and viability by measuring e...

  16. The Relation Between Malnutrition and the Exocrine Pancreas: A Systematic Review

    NARCIS (Netherlands)

    Bartels, Rosalie H.; van den Brink, Deborah A.; Bandsma, Robert H.; Boele van Hensbroek, Michael; Tabbers, Merit M.; Voskuijl, Wieger P.

    2018-01-01

    The relation between malnutrition and exocrine pancreatic insufficiency (EPI) has been described previously, but it is unclear if malnutrition leads to EPI or vice versa. We systematically synthesized current evidence evaluating the association between malnutrition and EPI in children. Pubmed,

  17. Combined endocrine and exocrine tumours of the pancreas

    Directory of Open Access Journals (Sweden)

    Alzein Abdulhalem

    2007-09-01

    Full Text Available Abstract Background Cystic neoplasms of the pancreas comprise 10%–15% of pancreatic cystic lesions, with the serous cystadenoms being the commonest. The association of exocrine and endocrine tumours of the pancreas unrelated to Von Hipple Lindau disease is very rare. Very few cases have been reported in the literature. We present another case of both these tumours in one patient. Case presentation A female patient was seen in the surgical clinic for a pain in the right groin. Clinical examination and investigations confirmed a diagnosis of combined endocrine and exocrine tumours of the pancreas. She underwent surgery and is under regular follow-up in the surgical clinic. Conclusion Biphasic differentiation of pancreatic stem cell during embryological development could happen and may result in combined endocrine and exocrine tumours of the pancreas. Imaging studies are excellent in diagnosing theses lesions. Surgery has a central role and could be curative.

  18. The cystic fibrosis of exocrine pancreas

    DEFF Research Database (Denmark)

    Wilschanski, Michael; Novak, Ivana

    2013-01-01

    The cystic fibrosis transmembrane conductance regulator (CFTR) protein is highly expressed in the pancreatic duct epithelia and permits anions and water to enter the ductal lumen. This results in an increased volume of alkaline fluid allowing the highly concentrated proteins secreted by the acinar...... cells to remain in a soluble state. This work will expound on the pathophysiology and pathology caused by the malfunctioning CFTR protein with special reference to ion transport and acid-base abnormalities both in humans and animal models. We will also discuss the relationship between cystic fibrosis...

  19. Exocrine drainage in vascularized pancreas transplantation in the new millennium

    Science.gov (United States)

    El-Hennawy, Hany; Stratta, Robert J; Smith, Fowler

    2016-01-01

    The history of vascularized pancreas transplantation largely parallels developments in immunosuppression and technical refinements in transplant surgery. From the late-1980s to 1995, most pancreas transplants were whole organ pancreatic grafts with insulin delivery to the iliac vein and diversion of the pancreatic ductal secretions to the urinary bladder (systemic-bladder technique). The advent of bladder drainage revolutionized the safety and improved the success of pancreas transplantation. However, starting in 1995, a seismic change occurred from bladder to bowel exocrine drainage coincident with improvements in immunosuppression, preservation techniques, diagnostic monitoring, general medical care, and the success and frequency of enteric conversion. In the new millennium, pancreas transplants are performed predominantly as pancreatico-duodenal grafts with enteric diversion of the pancreatic ductal secretions coupled with iliac vein provision of insulin (systemic-enteric technique) although the systemic-bladder technique endures as a preferred alternative in selected cases. In the early 1990s, a novel technique of venous drainage into the superior mesenteric vein combined with bowel exocrine diversion (portal-enteric technique) was designed and subsequently refined over the next ≥ 20 years to re-create the natural physiology of the pancreas with first-pass hepatic processing of insulin. Enteric drainage usually refers to jejunal or ileal diversion of the exocrine secretions either with a primary enteric anastomosis or with an additional Roux limb. The portal-enteric technique has spawned a number of newer and revisited techniques of enteric exocrine drainage including duodenal or gastric diversion. Reports in the literature suggest no differences in pancreas transplant outcomes irrespective of type of either venous or exocrine diversion. The purpose of this review is to examine the literature on exocrine drainage in the new millennium (the purported

  20. Extended exenatide administration enhances lipid metabolism and exacerbates pancreatic injury in mice on a high fat, high carbohydrate diet.

    Directory of Open Access Journals (Sweden)

    Rodney Rouse

    Full Text Available This study expanded upon a previous study in mice reporting a link between exenatide treatment and exocrine pancreatic injury by demonstrating temporal and dose responses and providing an initial mechanistic hypothesis. The design of the present study included varying lengths of exenatide exposure (3, 6 weeks to 12 weeks at multiple concentrations (3, 10, or 30 µg/kg with multiple endpoints (histopathology evaluations, immunoassay for cytokines, immunostaining of the pancreas, serum chemistries and measurement of trypsin, amylase, and, lipase, and gene expression profiles. Time- and dose-dependent exocrine pancreatic injury was observed in mice on a high fat diet treated with exenatide. The morphological changes identified in the pancreas involved acinar cell injury and death (autophagy, apoptosis, necrosis, and atrophy, cell adaptations (hypertrophy and hyperplasia, and cell survival (proliferation/regeneration accompanied by varying degrees of inflammatory response leading to secondary injury in pancreatic blood vessels, ducts, and adipose tissues. Gene expression profiles indicated increased signaling for cell survival and altered lipid metabolism in exenatide treated mice. Immunohistochemistry supported gene expression findings that exenatide caused and/or exacerbated pancreatic injury in a high fat diet environment potentially by further increasing high fat diet exacerbated lipid metabolism and resulting oxidative stress. Further investigation is required to confirm these findings and determine their relevance to human disease.

  1. Extended exenatide administration enhances lipid metabolism and exacerbates pancreatic injury in mice on a high fat, high carbohydrate diet.

    Science.gov (United States)

    Rouse, Rodney; Zhang, Leshuai; Shea, Katherine; Zhou, Hongfei; Xu, Lin; Stewart, Sharron; Rosenzweig, Barry; Zhang, Jun

    2014-01-01

    This study expanded upon a previous study in mice reporting a link between exenatide treatment and exocrine pancreatic injury by demonstrating temporal and dose responses and providing an initial mechanistic hypothesis. The design of the present study included varying lengths of exenatide exposure (3, 6 weeks to 12 weeks) at multiple concentrations (3, 10, or 30 µg/kg) with multiple endpoints (histopathology evaluations, immunoassay for cytokines, immunostaining of the pancreas, serum chemistries and measurement of trypsin, amylase, and, lipase, and gene expression profiles). Time- and dose-dependent exocrine pancreatic injury was observed in mice on a high fat diet treated with exenatide. The morphological changes identified in the pancreas involved acinar cell injury and death (autophagy, apoptosis, necrosis, and atrophy), cell adaptations (hypertrophy and hyperplasia), and cell survival (proliferation/regeneration) accompanied by varying degrees of inflammatory response leading to secondary injury in pancreatic blood vessels, ducts, and adipose tissues. Gene expression profiles indicated increased signaling for cell survival and altered lipid metabolism in exenatide treated mice. Immunohistochemistry supported gene expression findings that exenatide caused and/or exacerbated pancreatic injury in a high fat diet environment potentially by further increasing high fat diet exacerbated lipid metabolism and resulting oxidative stress. Further investigation is required to confirm these findings and determine their relevance to human disease.

  2. Black-Box Gastrointestinal Tract—Needs and Prospects of Gaining Insights of Fate of Fat, Protein, and Starch in Case of Exocrine Pancreatic Insufficiency by Using Fistulated Pigs

    Science.gov (United States)

    Mößeler, Anne; Kamphues, Josef

    2017-01-01

    Exocrine pancreatic insufficiency (EPI) results in the maldigestion and malabsorption of nutrients. The digestive processes in humans and other monogastric species like rat and pig are characterized by a predominantly enzymatic digestion within the small intestine and microbial fermentation located in the hindgut. For protein, it is doctrine that only prececally absorbed amino acids can be transferred to the amino acid pool of the host, while postileal absorption of nitrogen-containing compounds occurs mainly in the form of ammonia, being a burden rather than a benefit for the organism. The pig is an established animal model for humans to study digestive processes. As digestion is markedly impaired in case of EPI the use of an appropriate animal model to study the effects of this disease and to optimize treatment and dietetic measures is of special interest. By using an animal model of experimentally-induced EPI allowing differentiating between digestive processes in the small as well as in the large intestine by use of ileo-cecal fistulated animals, marked effects of EPI on prececal digestion of starch and protein could be shown. The data indicate that estimation of digestibility of nutrients over the entire digestive tract results in a distinct overestimation of enzymatic digestion of starch and protein. Therefore, this model clearly shows that protein and starch digestion are significantly reduced in case of EPI although this cannot be detected on a fecal level. As postileal fermentation of starch is associated not only with energy losses but also with intensive gas production, this is of special interest to minimize meteorism and improve wellbeing of patients. PMID:28212351

  3. Decreased α-cell mass and early structural alterations of the exocrine pancreas in patients with type 1 diabetes: An analysis based on the nPOD repository.

    Directory of Open Access Journals (Sweden)

    Fidéline Bonnet-Serrano

    Full Text Available Abnormal glucagon secretion and functional alterations of the exocrine pancreas have been described in patients with type 1 diabetes (T1D, but their respective anatomical substrata have seldom been investigated. Our aim was to develop an automated morphometric analysis process to characterize the anatomy of α-cell and exocrine pancreas in patients with T1D, using the publicly available slides of the Network for Pancreatic Organ Donors (nPOD.The ratio of β- and α-cell area to total tissue area were quantified in 75 patients with T1D (thereafter patients and 66 control subjects (thereafter controls, on 2 insulin-stained and 4 glucagon-stained slides from both the head and the tail of the pancreas. The β- and α-cell masses were calculated in the 66 patients and the 50 controls for which the pancreas weight was available. Non-exocrine-non-endocrine tissue area (i.e. non-acinar, non-insular tissue to total tissue area ratio was evaluated on both insulin- and glucagon-stained slides. Results were expressed as mean ±SD.An automated quantification method was set up using the R software and was validated by quantification of β-cell mass, a well characterized parameter. β-cell mass was 29.6±112 mg in patients and 628 ±717 mg in controls (p<0.0001. α-cell mass was 181±176 mg in patients and 349 ±241mg in controls (p<0.0001. Non-exocrine-non-endocrine area to total tissue area ratio was 39±9% in patients and 29± 10% in controls (p<0.0001 and increased with age in both groups, with no correlation with diabetes duration in patients.The absolute α-cell mass was lower in patients compared to controls, in proportion to the decrease in pancreas weight observed in patients. Non-exocrine-non-endocrine area to total tissue area ratio increased with age in both groups but was higher in patients at all ages.

  4. Effects of Melatonin and Its Analogues on Pancreatic Inflammation, Enzyme Secretion, and Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Jolanta Jaworek

    2017-05-01

    Full Text Available Melatonin is an indoleamine produced from the amino acid l-tryptophan, whereas metabolites of melatonin are known as kynuramines. One of the best-known kynuramines is N1-acetyl-N1-formyl-5-methoxykynuramine (AFMK. Melatonin has attracted scientific attention as a potent antioxidant and protector of tissue against oxidative stress. l-Tryptophan and kynuramines share common beneficial features with melatonin. Melatonin was originally discovered as a pineal product, has been detected in the gastrointestinal tract, and its receptors have been identified in the pancreas. The role of melatonin in the pancreatic gland is not explained, however several arguments support the opinion that melatonin is probably implicated in the physiology and pathophysiology of the pancreas. (1 Melatonin stimulates pancreatic enzyme secretion through the activation of entero-pancreatic reflex and cholecystokinin (CCK release. l-Tryptophan and AFMK are less effective than melatonin in the stimulation of pancreatic exocrine function; (2 Melatonin is a successful pancreatic protector, which prevents the pancreas from developing of acute pancreatitis and reduces pancreatic damage. This effect is related to its direct and indirect antioxidant action, to the strengthening of immune defense, and to the modulation of apoptosis. Like melatonin, its precursor and AFMK are able to mimic its protective effect, and it is commonly accepted that all these substances create an antioxidant cascade to intensify the pancreatic protection and acinar cells viability; (3 In pancreatic cancer cells, melatonin and AFMK activated a signal transduction pathway for apoptosis and stimulated heat shock proteins. The role of melatonin and AFMK in pancreatic tumorigenesis remains to be elucidated.

  5. an extended pancreatic normal subjects and ~in pancreatItIs In ...

    African Journals Online (AJOL)

    Exocrine pancreatic response was evaluated in patients with varying degrees of pancreatic damage and in control subjects by means of an extended pancreatic function test (PFT). A second injection of secretin and pancreozymin was given after com- pletion of the standard test. The discriminatory value of the standard PFT ...

  6. Pancreatitis

    Science.gov (United States)

    ... the hormones insulin and glucagon into the bloodstream. Pancreatitis is inflammation of the pancreas. It happens when digestive enzymes start digesting the pancreas itself. Pancreatitis can be acute or chronic. Either form is ...

  7. Pancreatitis

    Science.gov (United States)

    ... be present. How is pancreatitis diagnosed? How is pancreatitis treated? Treatment mainly consists of putting the pancreas to rest ( ... not as a definitive basis for diagnosis or treatment in any particular case. It is very ... pancreatitis is suspected, laboratory tests search for higher than ...

  8. Growth Factor Mediated Signaling in Pancreatic Pathogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Nandy, Debashis; Mukhopadhyay, Debabrata, E-mail: mukhopadhyay.debabrata@mayo.edu [Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic, 200 First Street SW, Guggenheim 1321C, Rochester, MN 55905 (United States)

    2011-02-24

    Functionally, the pancreas consists of two types of tissues: exocrine and endocrine. Exocrine pancreatic disorders mainly involve acute and chronic pancreatitis. Acute pancreatitis typically is benign, while chronic pancreatitis is considered a risk factor for developing pancreatic cancer. Pancreatic carcinoma is the fourth leading cause of cancer related deaths worldwide. Most pancreatic cancers develop in the exocrine tissues. Endocrine pancreatic tumors are more uncommon, and typically are less aggressive than exocrine tumors. However, the endocrine pancreatic disorder, diabetes, is a dominant cause of morbidity and mortality. Importantly, different growth factors and their receptors play critical roles in pancreatic pathogenesis. Hence, an improved understanding of how various growth factors affect pancreatitis and pancreatic carcinoma is necessary to determine appropriate treatment. This chapter describes the role of different growth factors such as vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), platelet derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), and transforming growth factor (TGF) in various pancreatic pathophysiologies. Finally, the crosstalk between different growth factor axes and their respective signaling mechanisms, which are involved in pancreatitis and pancreatic carcinoma, are also discussed.

  9. [Latest advances in chronic pancreatitis].

    Science.gov (United States)

    Domínguez Muñoz, J Enrique

    2015-09-01

    This article summarizes some of the recent and clinically relevant advances in chronic pancreatitis. These advances mainly concern the early diagnosis of the disease, the treatment of symptoms and complications, mainly pain and pancreatic exocrine insufficiency, and the diagnosis and therapy of autoimmune pancreatitis. The multimodal dynamic endoscopic ultrasound-guided secretin-stimulated evaluation of the pancreas provides relevant morphological and functional information for the diagnosis of chronic pancreatitis at early stages. Extracorporeal shock wave lithotripsy in patients with calcifying pancreatitis and endoscopic pancreatic stent placement are effective alternatives for pain therapy in patients with chronic pancreatitis. Presence of pancreatic exocrine insufficiency in patients with chronic pancreatitis is associated with a significantly increase of mortality rate. Despite that, pancreatic enzyme replacement therapy is not prescribed in the majority of patients with pancreatic exocrine insufficiency, or it is prescribed at a low dose. The newly developed and commercialized needles for endoscopic ultrasound-guided pancreatic biopsy are effective in retrieving appropriate tissue samples for the histological diagnosis of autoimmune pancreatitis. Maintenance therapy with azathioprine is effective and safe to prevent relapses in patients with autoimmune pancreatitis. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

  10. Transcriptome analysis of pancreatic cells across distant species highlights novel important regulator genes.

    Science.gov (United States)

    Tarifeño-Saldivia, Estefania; Lavergne, Arnaud; Bernard, Alice; Padamata, Keerthana; Bergemann, David; Voz, Marianne L; Manfroid, Isabelle; Peers, Bernard

    2017-03-21

    Defining the transcriptome and the genetic pathways of pancreatic cells is of great interest for elucidating the molecular attributes of pancreas disorders such as diabetes and cancer. As the function of the different pancreatic cell types has been maintained during vertebrate evolution, the comparison of their transcriptomes across distant vertebrate species is a means to pinpoint genes under strong evolutionary constraints due to their crucial function, which have therefore preserved their selective expression in these pancreatic cell types. In this study, RNA-sequencing was performed on pancreatic alpha, beta, and delta endocrine cells as well as the acinar and ductal exocrine cells isolated from adult zebrafish transgenic lines. Comparison of these transcriptomes identified many novel markers, including transcription factors and signaling pathway components, specific for each cell type. By performing interspecies comparisons, we identified hundreds of genes with conserved enriched expression in endocrine and exocrine cells among human, mouse, and zebrafish. This list includes many genes known as crucial for pancreatic cell formation or function, but also pinpoints many factors whose pancreatic function is still unknown. A large set of endocrine-enriched genes can already be detected at early developmental stages as revealed by the transcriptomic profiling of embryonic endocrine cells, indicating a potential role in cell differentiation. The actual involvement of conserved endocrine genes in pancreatic cell differentiation was demonstrated in zebrafish for myt1b, whose invalidation leads to a reduction of alpha cells, and for cdx4, selectively expressed in endocrine delta cells and crucial for their specification. Intriguingly, comparison of the endocrine alpha and beta cell subtypes from human, mouse, and zebrafish reveals a much lower conservation of the transcriptomic signatures for these two endocrine cell subtypes compared to the signatures of pan

  11. Peculiarities of death and regeneration of pancreas cells at early stages of alcoholic chronic pancreatitis

    Directory of Open Access Journals (Sweden)

    N. Y. Oshmyanska

    2014-10-01

    Full Text Available The study has been conducted on 39 white laboratory male rats which formed 5 groups: experimental occlusal pancreatitis caused by ligation of the main pancreatic duct (n = 6, experimental alcoholic pancreatitis caused by oral intake of alcohol (n = 6, against the background of an excess (n = 6 or deficiency (n = 6 of nitric oxide, as well as a control group (n = 15. This study provides the detailed description of the processes of death and regeneration in the islets of Langerhans, typical for early stages of the disease. The expression of the proliferation markers (PCNA and Neurogenin-3 has been analyzed using histological and immunohistochemical methods along with the changes of morphological structure, that led to initiation of the alcoholic chronic pancreatitis against the background of imbalance in NO-ergic regulatory system caused by an excess or deficiency of nitric oxide. It has been found that ligation of the pancreatic duct in the experiment reconstructedthe circumstances of chronic pancreatitis in rats and caused the activation of fibrosis and regeneration of endocrine and exocrine tissue. Compared with occlusion, the effects of ethanol on the pancreas also manifested in the activation of fibrogenesis, but the structural changes were negligible and could unlikely lead to advanced fibrosis and chronic pancreatitis in the future. On the other side, an imbalance of NO-system in alcoholic rats leads to disruption of the zymogens secretion in the acinar cells and dilatation of the capillary network in islets. Uneven distribution of zymogen granules may lead to their intracellular activation as evidenced by the deformation of acini and focal apoptosis without inflammatory response. In this case, violation of the key adaptive responses in the pancreas makes it more vulnerable to the effects of ethanol, its metabolites, and other environmental factors, and may increase the probability of chronic pancreatitis development. At the same time

  12. Total pancreatectomy for metachronous mixed acinar-ductal carcinoma in a remnant pancreas.

    Science.gov (United States)

    Shonaka, Tatsuya; Inagaki, Mitsuhiro; Akabane, Hiromitsu; Yanagida, Naoyuki; Shomura, Hiroki; Yanagawa, Nobuyuki; Oikawa, Kensuke; Nakano, Shiro

    2014-09-07

    In October 2009, a 71-year-old female was diagnosed with a cystic tumor in the tail of the pancreas with an irregular dilatation of the main pancreatic duct in the body and tail of the pancreas. A distal pancreatectomy with splenectomy, and partial resection of the duodenum, jejunum and transverse colon was performed. In March 2011, a follow-up computed tomography scan showed a low density mass at the head of the remnant pancreas. We diagnosed it as a recurrence of the tumor and performed a total pancreatectomy for the remnant pancreas. In the histological evaluation of the resected specimen of the distal pancreas, the neoplastic cells formed an acinar and papillary structure that extended into the main pancreatic duct. Mucin5AC, α1-antitrypsin (α-AT) and carcinoembryonic antigen (CEA) were detected in the tumor cells by immunohistochemistry. In the resected head of the pancreas, the tumor was composed of both acinar and ductal elements with a mottled pattern. The proportions of each element were approximately 40% and 60%, respectively. Strongly positive α-AT cells were detected in the acinar element. Some tumor cells were also CEA positive. However, the staining for synaptophysin and chromogranin A was negative in the tumor cells. Ultimately, we diagnosed the tumor as a recurrence of mixed acinar-ductal carcinoma in the remnant pancreas. In conclusion, we report here a rare case of repeated pancreatic resection for multicentric lesions of mixed acinar-ductal carcinoma of the pancreas.

  13. Pancreatic function and enzyme synthesis rates in mild chronic pancreatitis.

    Science.gov (United States)

    Hamilton, I; Boyd, E J; Jacyna, M R; Penston, J G; Soutar, J S; Bouchier, I A

    1986-06-01

    Incorporation of intravenous 75Se-methionine into duodenal juice proteins during pancreatic stimulation was measured as an index of pancreatic enzyme synthesis rates in 12 patients with a normal pancreatogram and in 6 with mild chronic pancreatitis. Isotope incorporation was significantly greater in subjects with mild chronic pancreatitis than in those with a normal pancreatogram. Thus in most patients in whom pancreatography demonstrates the characteristic radiological features of 'mild chronic pancreatitis' pancreatic acinar function is abnormal. The coexistence of morphological and functional abnormality implies that such patients do have chronic pancreatitis.

  14. What difference exists in the pancreas of mammals with sanguivorous diet? A morphological, stereological and immunohistochemical study of the pancreatic islets of the hematophagous bat Diphylla ecaudata.

    Science.gov (United States)

    Machado-Santos, Clarice; Aquino, Júlio César Fraulob; Mikalauka, Jefferson Simanas; Abidu-Figueiredo, Marcelo; Mendes, Rosa Maria Marcos; Sales, Armando

    2013-05-10

    Diphylla ecaudata is a vampire bat that mainly feeds on the blood of birds. This highly specialized diet - hematophagy - is accompanied by a series of morphological changes in the gastro-entero-pancreatic system, since the distribution and relative proportions of different pancreatic endocrine cell types can vary between species due to different physiological conditions and eating habits. The aim of this study was to examine for the first time the pancreas of the vampire bat D. ecaudata using morphological, stereological and immunohistochemical techniques. The pancreas of the D. ecaudata has an exocrine acinar portion in which the highest concentration of pancreatic islets is scattered. These pancreatic islets have irregular size and a mean diameter of 56.94 μm. The total number of islets in the pancreas was 23,900, with a volumetric density of 4.1%. Insulin-immunoreactive (IR) cells were located in the central pancreatic islet region and had the largest density (54.8%). Glucagon-IR cells were located mainly in the peripheral mantle region (16.2%), along with somatostatin-IR (SS) cells (14.3%). Cells immunoreactive to insulin, glucagon and somatostatin were also observed to have spread in isolated places in the exocrine pancreas. In the connective tissue near the pancreatic ducts, a high concentration was identified of insulin-IR cells and a low concentration of glucagon-IR and somatostatin-IR cells. These results indicate that although the pancreas of D. ecaudata has morphological similarities with that of other mammals, it has a differentiated islet structure, because there were a large number of islets and different volumetric densities of α, β and δ cells. Copyright © 2013 Elsevier B.V. All rights reserved.

  15. Bcl-2 expression in pancreas development and pancreatic cancer progression.

    Science.gov (United States)

    Campani, D; Esposito, I; Boggi, U; Cecchetti, D; Menicagli, M; De Negri, F; Colizzi, L; Del Chiaro, M; Mosca, F; Fornaciari, G; Bevilacqua, G

    2001-08-01

    Apoptosis is important for both tissue development and differentiation; its deregulation may contribute to tumourigenesis. In order to clarify the role of Bcl-2, an apoptosis-inhibiting protein, in pancreatic morphogenesis and tumour progression, its immunohistochemical expression was evaluated in 12 samples of fetal pancreas, in 10 samples of adult pancreas with ductal hyperplastic lesions, in 120 cases of primary pancreatic ductal adenocarcinoma, and in 43 synchronous metastatic lymph nodes. To evaluate the role of apoptosis in pancreatic cancer, p53 expression was also studied in tumour samples. Bcl-2 cytoplasmic acinar and ductal immunostaining was found in all fetal and adult tissue samples; ductal hyperplastic lesions were constantly negative. Thirty out of 120 (25%) tumours and 3 out of 43 (7%) lymph nodes expressed Bcl-2, whereas 67 out of 120 (56%) expressed nuclear p53. Well-differentiated tumours (G1) were more frequently Bcl-2-positive (p=0.002); furthermore, there was an inverse correlation between Bcl-2 and p53 expression in primary tumours (p=0.02). Neither Bcl-2 nor p53 influenced patients' prognosis, which was instead affected by N (p=0.02) and M (p<0.0001) status and stage of the disease (p=0.002). It is concluded that Bcl-2 regulates pancreatic morphogenesis and tissue homeostasis from early fetal to adult life and can be considered a phenotypic marker of normal exocrine pancreas. On the other hand, the lack of expression in preneoplastic lesions and the low positivity found in primary tumours and lymph node metastases suggest that Bcl-2 does not play a centralrole in pancreatic tumourigenesis and cancer progression. Copyright 2001 John Wiley & Sons, Ltd.

  16. Latest advances in chronic pancreatitis.

    Science.gov (United States)

    Enrique Domínguez-Muñoz, J

    2016-09-01

    This article summarizes some of the recent and clinically relevant advances in chronic pancreatitis. These advances mainly concern the definition of the disease, the etiological diagnosis of idiopathic disease, the correlation between fibrosis degree and pancreatic secretion in the early stages of chronic pancreatitis, the treatment of the disease and of pain, the clinical relevance of pancreatic exocrine insufficiency, and the diagnosis of autoimmune pancreatitis. A new mechanistic definition of chronic pancreatitis has been proposed. Genetic testing is mainly of help in patients with relapsing idiopathic pancreatitis. A significant correlation has been shown between the degree of pancreatic fibrosis as evaluated by elastography and pancreatic secretion of bicarbonate. New data supports the efficacy of antioxidants and simvastatin for the therapy of chronic pancreatitis. The pancreatoscopy-guided intraductal lithotripsy is an effective alternative to extracorporeal shock wave lithotripsy in patients with chronic calcifying pancreatitis. The presence of pancreatic exocrine insufficiency in patients with chronic pancreatitis is associated with a significant risk of cardiovascular events. Fine needle biopsy and contrast enhanced harmonic endoscopic ultrasonography are of help for the diagnosis of autoimmune pancreatitis and its differential diagnosis with pancreatic cancer. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  17. Mesenchymal Stem Cells Derived from Human Exocrine Pancreas Spontaneously Express Pancreas Progenitor-Cell Markers in a Cell-Passage-Dependent Manner

    Directory of Open Access Journals (Sweden)

    Song Lee

    2016-01-01

    Full Text Available Mesenchymal stem cells (MSCs derived from bone marrow, adipose tissue, and most connective tissues have been recognized as promising sources for cell-based therapies. MSCs have also been detected in human pancreatic tissue, including endocrine and exocrine cells. These adult human pancreas-derived MSCs have generated a great deal of interest owing to their potential use in the differentiation of insulin-producing cells for diabetes treatment. In the present study, we isolated MSCs from the adult human exocrine pancreas to determine whether isolated MSCs have the potential to differentiate into pancreatic endocrine cells and, therefore, whether they can be used in stem cell-based therapies. Pancreatic tissue was digested by collagenase and an enriched exocrine-cell fraction was obtained by density-gradient separation. Crude exocrine cells were methodically cultured in suspension and then in adherent culture. We expanded the human pancreatic exocrine-derived MSCs (hpMSCs by cell passaging in culture and confirmed by flow cytometry that >90% expressed human classic surface markers of MSCs. Interestingly, these cells expressed pancreatic transcription factors, such as Pdx1, Ngn3, and MafA, similar to pancreatic progenitor cells. These results indicated that hpMSCs can be used for the differentiation of pancreatic endocrine cells and may be used in type 1 diabetes treatment.

  18. Autoimmune Pancreatitis.

    Science.gov (United States)

    Majumder, Shounak; Takahashi, Naoki; Chari, Suresh T

    2017-07-01

    Autoimmune pancreatitis (AIP) is a chronic fibroinflammatory disease of the pancreas that belongs to the spectrum of immunoglobulin G-subclass4-related diseases (IgG4-RD) and typically presents with obstructive jaundice. Idiopathic duct-centric pancreatitis (IDCP) is a closely related but distinct disease that mimics AIP radiologically but manifests clinically most commonly as recurrent acute pancreatitis in young individuals with concurrent inflammatory bowel disease. IgG4 levels are often elevated in AIP and normal in IDCP. Histologically, lymphoplasmacytic acinar inflammation and storiform fibrosis are seen in both. In addition, the histologic hallmark of IDCP is the granulocyte epithelial lesion: intraluminal and intraepithelial neutrophils in medium-sized and small ducts with or without granulocytic acinar inflammation often associated with destruction of ductal architecture. Initial treatment of both AIP and IDCP is with oral corticosteroids for duration of 4 weeks followed by a gradual taper. Relapses are common in AIP and relatively uncommon in IDCP, a relatively rare disease for which the natural history is not well understood. For patients with relapsing AIP, treatment with immunomodulators and more recently rituximab has been recommended. Although rare instances of pancreaticobiliary malignancy has been reported in patients with AIP, overall the lifetime risk of developing pancreatic cancer does not appear to be elevated.

  19. Adenoviral vectors stimulate glucagon transcription in human mesenchymal stem cells expressing pancreatic transcription factors

    National Research Council Canada - National Science Library

    Zaldumbide, Arnaud; Carlotti, Françoise; Gonçalves, Manuel A; Knaän-Shanzer, Shoshan; Cramer, Steve J; Roep, Bart O; Wiertz, Emmanuel J H J; Hoeben, Rob C

    2012-01-01

    .... Forced expression of key regulators of pancreatic differentiation in stem cells, liver cells, pancreatic duct cells, or cells from the exocrine pancreas, can lead to the initiation of endocrine...

  20. Type 3c (pancreatogenic) diabetes mellitus secondary to chronic pancreatitis and pancreatic cancer

    Science.gov (United States)

    Hart, Phil A; Bellin, Melena D; Andersen, Dana K; Bradley, David; Cruz-Monserrate, Zobeida; Forsmark, Christopher E; Goodarzi, Mark O; Habtezion, Aida; Korc, Murray; Kudva, Yogish C; Pandol, Stephen J; Yadav, Dhiraj; Chari, Suresh T

    2017-01-01

    Diabetes mellitus is a group of diseases defined by persistent hyperglycaemia. Type 2 diabetes, the most prevalent form, is characterised initially by impaired insulin sensitivity and subsequently by an inadequate compensatory insulin response. Diabetes can also develop as a direct consequence of other diseases, including diseases of the exocrine pancreas. Historically, diabetes due to diseases of the exocrine pancreas was described as pancreatogenic or pancreatogenous diabetes mellitus, but recent literature refers to it as type 3c diabetes. It is important to note that type 3c diabetes is not a single entity; it occurs because of a variety of exocrine pancreatic diseases with varying mechanisms of hyperglycaemia. The most commonly identified causes of type 3c diabetes are chronic pancreatitis, pancreatic ductal adenocarcinoma, haemochromatosis, cystic fibrosis, and previous pancreatic surgery. In this Review, we discuss the epidemiology, pathogenesis, and clinical relevance of type 3c diabetes secondary to chronic pancreatitis and pancreatic ductal adenocarcinoma, and highlight several important knowledge gaps. PMID:28404095

  1. Dimethyl fumarate protects pancreatic islet cells and non-endocrine tissue in L-arginine-induced chronic pancreatitis.

    Directory of Open Access Journals (Sweden)

    Lourdes Robles

    Full Text Available Chronic pancreatitis (CP is a progressive disorder resulting in the destruction and fibrosis of the pancreatic parenchyma which ultimately leads to impairment of the endocrine and exocrine functions. Dimethyl Fumarate (DMF was recently approved by FDA for treatment of patients with multiple sclerosis. DMF's unique anti-oxidant and anti-inflammatory properties make it an interesting drug to test on other inflammatory conditions. This study was undertaken to determine the effects of DMF on islet cells and non-endocrine tissue in a rodent model of L-Arginine-induced CP.Male Wistar rats fed daily DMF (25 mg/kg or vehicle by oral gavage were given 5 IP injections of L-Arginine (250 mg/100 g × 2, 1 hr apart. Rats were assessed with weights and intra-peritoneal glucose tolerance tests (IPGTT, 2 g/kg. Islets were isolated and assessed for islet mass and viability with flow cytometry. Non-endocrine tissue was assessed for histology, myeloperoxidase (MPO, and lipid peroxidation level (MDA. In vitro assessments included determination of heme oxygenase (HO-1 protein expression by Western blot.Weight gain was significantly reduced in untreated CP group at 6 weeks. IPGTT revealed significant impairment in untreated CP group and its restoration with DMF therapy (P <0.05. Untreated CP rats had pancreatic atrophy, severe acinar architectural damage, edema, and fatty infiltration as well as elevated MDA and MPO levels, which were significantly improved by DMF treatment. After islet isolation, the volume of non-endocrine tissue was significantly smaller in untreated CP group. Although islet counts were similar in the two groups, islet viability was significantly reduced in untreated CP group and improved with DMF treatment. In vitro incubation of human pancreatic tissue with DMF significantly increased HO-1 expression.Administration of DMF attenuated L-Arginine-induced CP and islet function in rats. DMF treatment could be a possible strategy to improve clinical

  2. Simultaneous characterization of pancreatic stellate cells and other pancreatic components within three-dimensional tissue environment during chronic pancreatitis

    Science.gov (United States)

    Hu, Wenyan; Fu, Ling

    2013-05-01

    Pancreatic stellate cells (PSCs) and other pancreatic components that play a critical role in exocrine pancreatic diseases are generally identified separately by conventional studies, which provide indirect links between these components. Here, nonlinear optical microscopy was evaluated for simultaneous characterization of these components within a three-dimensional (3-D) tissue environment, primarily based on multichannel detection of intrinsic optical emissions and cell morphology. Fresh rat pancreatic tissues harvested at 1 day, 7 days, and 28 days after induction of chronic pancreatitis were imaged, respectively. PSCs, inflammatory cells, blood vessels, and collagen fibers were identified simultaneously. The PSCs at day 1 of chronic pancreatitis showed significant enlargement compared with those in normal pancreas (ppancreatic components coincidently within 3-D pancreatic tissues. It is a prospect for intravital observation of dynamic events under natural physiological conditions, and might help uncover the key mechanisms of exocrine pancreatic diseases, leading to more effective treatments.

  3. PKD signaling and pancreatitis.

    Science.gov (United States)

    Yuan, Jingzhen; Pandol, Stephen J

    2016-07-01

    Acute pancreatitis is a serious medical disorder with no current therapies directed to the molecular pathogenesis of the disorder. Inflammation, inappropriate intracellular activation of digestive enzymes, and parenchymal acinar cell death by necrosis are the critical pathophysiologic processes of acute pancreatitis. Thus, it is necessary to elucidate the key molecular signals that mediate these pathobiologic processes and develop new therapeutic strategies to attenuate the appropriate signaling pathways in order to improve outcomes for this disease. A novel serine/threonine protein kinase D (PKD) family has emerged as key participants in signal transduction, and this family is increasingly being implicated in the regulation of multiple cellular functions and diseases. This review summarizes recent findings of our group and others regarding the signaling pathway and the biological roles of the PKD family in pancreatic acinar cells. In particular, we highlight our studies of the functions of PKD in several key pathobiologic processes associated with acute pancreatitis in experimental models. Our findings reveal that PKD signaling is required for NF-κB activation/inflammation, intracellular zymogen activation, and acinar cell necrosis in rodent experimental pancreatitis. Novel small-molecule PKD inhibitors attenuate the severity of pancreatitis in both in vitro and in vivo experimental models. Further, this review emphasizes our latest advances in the therapeutic application of PKD inhibitors to experimental pancreatitis after the initiation of pancreatitis. These novel findings suggest that PKD signaling is a necessary modulator in key initiating pathobiologic processes of pancreatitis, and that it constitutes a novel therapeutic target for treatments of this disorder.

  4. An update on pancreatic pathophysiology (do we have to rewrite pancreatic pathophysiology?).

    Science.gov (United States)

    Hammer, Heinz F

    2014-02-01

    This review focuses on seven aspects of physiology and pathophysiology of the exocrine pancreas that have been intensively discussed and studied within the past few years: (1) the role of neurohormonal mechanisms like melatonin, leptin, or ghrelin in the stimulation of pancreatic enzyme secretion; (2) the initiation processes of acute pancreatitis, like fusion of zymogen granules with lysosomes leading to intracellular activation of trypsinogen by the lysosomal enzyme cathepsin B, or autoactivation of trypsinogen; (3) the role of genes in the pathogenesis of acute pancreatitis; (4) the role of alcohol and constituents of alcoholic beverages in the pathogenesis of acute pancreatitis; (5) the role of pancreatic hypertension, neuropathy, and central mechanisms for the pathogenesis of pain in chronic pancreatitis; (6) the relation between exocrine pancreatic function and diabetes mellitus; and (7) pathophysiology, diagnosis and treatment of pancreatic steatorrhea.

  5. Imaging in the diagnosis of chronic pancreatitis

    Directory of Open Access Journals (Sweden)

    Vasile D. Balaban

    2014-12-01

    Full Text Available Chronic pancreatitis is characterised by progressive and irreversible damage of the pancreatic parenchyma and ductal system, which leads to chronic pain, loss of endocrine and exocrine functions. Clinically, pancreatic exocrine insufficiency becomes apparent only after 90% of the parenchima has been lost. Despite the simple definition, diagnosing chronic pancreatitis remains a challenge, especially for early stage disease. Because pancreatic function tests can be normal until late stages and have significant limitations, there is an incresing interest in the role of imaging techniques for the diagnosis of chronic pancreatitis. In this article we review the utility and accuracy of different imaging methods in the diagnosis of chronic pancreatitis, focusing on the role of advanced imaging (magnetic resonance imaging, endoscopic retrograde cholangiopancreatography and endoscopic ultrasound.

  6. Evaluation of an extended pancreatic function test in normal ...

    African Journals Online (AJOL)

    Exocrine pancreatic response was evaluated in patients with varying degrees of pancreatic damage and in control subjects by means of an extended pancreatic function test (PFT). A second injection of secretin and pancreozymin was given after completion of the standard test. The discriminatory value of the standard PFT ...

  7. Time-course proteomic analysis of taurocholate-induced necrotizing acute pancreatitis.

    Science.gov (United States)

    Fétaud-Lapierre, Vanessa; Pastor, Catherine M; Jorge-Costa, Manuel; Hochstrasser, Denis F; Morel, Denis R; Frossard, Jean-Louis; Lescuyer, Pierre

    2013-06-24

    Acute pancreatitis is an inflammatory disease of the pancreas, which varies greatly in course and severity. Severe forms are associated with serious local and/or systemic complications, and eventually death. The pathobiology of acute pancreatitis is complex. Animal models have been developed to investigate pathobiological processes and identify factors determining disease course. We performed a time-course proteomic analysis using a rat model of severe necrotizing acute pancreatitis induced by taurocholate perfusion in the pancreatic ducts. Results showed that levels of proteins associated to a given biological process changed in a coordinated fashion after disease onset. It was possible to follow the response of a particular pathobiological process to pancreatitis induction and to compare the course of protein pathways. Proteins involved in acinar cell secretion were found to follow a different kinetics than other cellular processes. After an initial decrease, secretory pathway-associated proteins raised again at 18 h post-induction. This phenomenon coincided with a burst in the expression of pancreatitis-associated protein (REG3A), an acute phase protein produced by the exocrine pancreas, and with the decrease of classical markers of pancreatic injury, suggesting that the expression of proteins associated to the secretory pathway may be a modulating factor of pancreas injury. Acute pancreatitis (AP) is a complex inflammatory disease, the pathobiology of which is not yet fully understood. Various animal models, relying on different mechanisms of disease induction, have been developed in order to investigate pathobiological processes of AP. In this study, we performed a time-course proteomic analysis to investigate changes of the pancreas proteome occurring in an experimental model of AP induced by perfusion of taurocholate, a bile acid, into the pancreatic duct. This experimental model is characterized by a severe disease with pancreatic necrosis and systemic

  8. New Insights into the Pathogenesis of Pancreatitis

    Science.gov (United States)

    Sah, Raghuwansh P.; Dawra, Rajinder K.; Saluja, Ashok K.

    2014-01-01

    Purpose of review In this article, we review important advances in our understanding of the mechanisms of pancreatitis. Recent Findings The relative contribution of intra-pancreatic trypsinogen activation and NFκB activation, the two major early independent cellular events in the etiology of pancreatitis, have been investigated using novel genetic models. Trypsinogen activation has traditionally held the spotlight for many decades as it is believed to be the central pathogenic event of pancreatitis However, recent experimental evidence points to the role of trypsin activation in early acinar cell damage but not in the inflammatory response of acute pancreatitis through NFκB activation. Further, chronic pancreatitis in the caerulein model develops independently of typsinogen activation. Sustained activation of the NFκB pathway, but not persistent intra-acinar expression of active trypsin, was shown to result in chronic pancreatitis. Calcineurin-NFAT signaling was shown to mediate downstream effects of pathologic rise in intracellular calcium. IL-6 was identified as a key cytokine mediating pancreatitis-associated lung injury. Summary Recent advances challenge the long-believed trypsin-centered understanding of pancreatitis. It is becoming increasingly clear that activation of intense inflammatory signaling mechanisms in acinar cells is crucial to the pathogenesis of pancreatitis, which may explain the strong systemic inflammatory response in pancreatitis. PMID:23892538

  9. Pancreas Volume and Fat Deposition in Diabetes and Normal Physiology: Consideration of the Interplay Between Endocrine and Exocrine Pancreas

    Science.gov (United States)

    Saisho, Yoshifumi

    2016-01-01

    The pancreas is comprised of exocrine and endocrine components. Despite the fact that they are derived from a common origin in utero, these two compartments are often studied individually because of the different roles and functions of the exocrine and endocrine pancreas. Recent studies have shown that not only type 1 diabetes (T1D), but also type 2 diabetes (T2D), is characterized by a deficit in beta-cell mass, suggesting that pathological changes in the pancreas are critical events in the natural history of diabetes. In both patients with T1D and those with T2D, pancreas mass and exocrine function have been reported to be reduced. On the other hand, pancreas volume and pancreatic fat increase with obesity. Increased beta-cell mass with increasing obesity has also been observed in humans, and ectopic fat deposits in the pancreas have been reported to cause beta-cell dysfunction. Moreover, neogenesis and transdifferentiation from the exocrine to the endocrine compartment in the postnatal period are regarded as a source of newly formed beta-cells. These findings suggest that there is important interplay between the endocrine and exocrine pancreas throughout life. This review summarizes the current knowledge on physiological and pathological changes in the exocrine and endocrine pancreas (i.e., beta-cell mass), and discusses the potential mechanisms of the interplay between the two compartments in humans to understand the pathophysiology of diabetes better. PMID:28012279

  10. Hereditary pancreatitis: current perspectives

    Directory of Open Access Journals (Sweden)

    Raphael KL

    2016-07-01

    Full Text Available Kara L Raphael, Field F Willingham Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA Abstract: Hereditary pancreatitis (HP is a rare cause of acute, recurrent acute, and chronic pancreatitis. It may present similarly to other causes of acute and chronic pancreatitis, and often there has been a protracted evaluation prior to the diagnosis of HP. Since it was first described in 1952, multiple genetic defects that affect the action of digestive enzymes in the pancreas have been implicated. The most common mutations involve the PRSS1, CFTR, SPINK1, and CTRC genes. New mutations in these genes and previously unrecognized mutations in other genes are being discovered due to the increasing use of next-generation genomic sequencing. While the inheritance pathways of these genetic mutations may be variable and complex, sometimes involving coinheritance of other mutations, the clinical presentation of patients tends to be similar. Interactions with environmental triggers often play a role. Patients tend to present at an early age (prior to the second decade of life and have a significantly increased risk for the development of pancreatic adenocarcinoma. Patients with HP may develop sequelae of chronic pancreatitis such as strictures and fluid collections as well as exocrine and endocrine insufficiency. Management of patients with HP involves avoidance of environmental triggers, surveillance for pancreatic adenocarcinoma, medical therapy for endocrine and exocrine insufficiency, pain management, and endoscopic or surgical treatment for complications. Care for affected patients should be individualized, with an emphasis on early diagnosis and multidisciplinary involvement to develop a comprehensive treatment strategy. Keywords: pancreatic cancer, chronic pancreatitis, idiopathic pancreatitis, pancreatitis, familial pancreatitis, genetic mutations

  11. Black-Box Gastrointestinal Tract-Needs and  Prospects of Gaining Insights of Fate of Fat, Protein,  and Starch in Case of Exocrine Pancreatic  Insufficiency by Using Fistulated Pigs.

    Science.gov (United States)

    Mößeler, Anne; Kamphues, Josef

    2017-02-16

    Exocrine pancreatic insufficiency (EPI) results in the maldigestion and malabsorption of nutrients. The digestive processes in humans and other monogastric species like rat and pig are characterized by a predominantly enzymatic digestion within the small intestine and microbial fermentation located in the hindgut. For protein, it is doctrine that only prececally absorbed amino acids can be transferred to the amino acid pool of the host, while postileal absorption of nitrogen-containing compounds occurs mainly in the form of ammonia, being a burden rather than a benefit for the organism. The pig is an established animal model for humans to study digestive processes. As digestion is markedly impaired in case of EPI the use of an appropriate animal model to study the effects of this disease and to optimize treatment and dietetic measures is of special interest. By using an animal model of experimentally-induced EPI allowing differentiating between digestive processes in the small as well as in the large intestine by use of ileo-cecal fistulated animals, marked effects of EPI on prececal digestion of starch and protein could be shown. The data indicatethat estimation of digestibility of nutrients over the entire digestive tract results in a distinct overestimation of enzymatic digestion of starch and protein. Therefore, this model clearly shows that protein and starch digestion are significantly reduced in case of EPI although this cannot be detected on a fecal level. As postileal fermentation of starch is associated not only with energy losses but also with intensive gas production, this is of special interest to minimize meteorism and improve wellbeing of patients.

  12. Black‐Box Gastrointestinal Tract—Needs and  Prospects of Gaining Insights of Fate of Fat, Protein,  and Starch in Case of Exocrine Pancreatic  Insufficiency by Using Fistulated Pigs

    Directory of Open Access Journals (Sweden)

    Anne Mößeler

    2017-02-01

    Full Text Available Exocrine pancreatic insufficiency (EPI results in the maldigestion and malabsorption of nutrients. The digestive processes in humans and other monogastric species like rat and pig are characterized by a predominantly enzymatic digestion within the small intestine and microbial fermentation located in the hindgut. For protein, it is doctrine that only prececally absorbed amino acids can be transferred to the amino acid pool of the host, while postileal absorption of nitrogen‐containing compounds occurs mainly in the form of ammonia, being a burden rather than a benefit for the organism. The pig is an established animal model for humans to study digestive processes. As digestion is markedly impaired in case of EPI the use of an appropriate animal model to study the effects of this disease and to optimize treatment and dietetic measures is of special interest. By using an animal model of experimentally‐induced EPI allowing differentiating between digestive processes in the small as well as in the large intestine by use of ileo‐cecal fistulated animals, marked effects of EPI on prececal digestion of starch and protein could be shown. The data indicatethat estimation of digestibility of nutrients over the entire digestive tract results in a distinct overestimation of enzymatic digestion of starch and protein. Therefore, this model clearly shows that protein and starch digestion are significantly reduced in case of EPI although this cannot be detected on a fecal level. As postileal fermentation of starch is associated not only with energy losses but also with intensive gas production, this is of special interest to minimize meteorism and improve wellbeing of patients.

  13. Elevation of serum pancreatic amylase and distortion of pancreatic ...

    African Journals Online (AJOL)

    Background: Diabetes mellitus has been shown to cause severe impairment in exocrine pancreatic function and cyto-architecture. Ocimum grattissimum has been reported to lower blood glucose levels in experimental diabetic animals. This study, therefore, aims to investigate if treatment with O. grattissimum can alleviate ...

  14. Are pancreatic autoantibodies associated with azathioprine-induced pancreatitis in Crohn's disease?

    NARCIS (Netherlands)

    Weersma, Rinse K; Batstra, Manou R; Kleibeuker, Jan H; van Dullemen, Hendrik M

    2008-01-01

    CONTEXT: Azathioprine is frequently used in the treatment of Crohn's disease. A severe side effect is acute pancreatitis, which is specific for Crohn's disease. Autoantibodies against exocrine pancreas occur in about 30% of Crohn's disease cases but not in other inflammatory diseases. Pancreatic

  15. Pancreatic Cancer Genetics.

    Science.gov (United States)

    Amundadottir, Laufey T

    2016-01-01

    Although relatively rare, pancreatic tumors are highly lethal [1]. In the United States, an estimated 48,960 individuals will be diagnosed with pancreatic cancer and 40,560 will die from this disease in 2015 [1]. Globally, 337,872 new pancreatic cancer cases and 330,391 deaths were estimated in 2012 [2]. In contrast to most other cancers, mortality rates for pancreatic cancer are not improving; in the US, it is predicted to become the second leading cause of cancer related deaths by 2030 [3, 4]. The vast majority of tumors arise in the exocrine pancreas, with pancreatic ductal adenocarcinoma (PDAC) accounting for approximately 95% of tumors. Tumors arising in the endocrine pancreas (pancreatic neuroendocrine tumors) represent less than 5% of all pancreatic tumors [5]. Smoking, type 2 diabetes mellitus (T2D), obesity and pancreatitis are the most consistent epidemiological risk factors for pancreatic cancer [5]. Family history is also a risk factor for developing pancreatic cancer with odds ratios (OR) ranging from 1.7-2.3 for first-degree relatives in most studies, indicating that shared genetic factors may play a role in the etiology of this disease [6-9]. This review summarizes the current knowledge of germline pancreatic cancer risk variants with a special emphasis on common susceptibility alleles identified through Genome Wide Association Studies (GWAS).

  16. Epithelial: Endothelial cross-talk regulates exocrine differentiation in developing pancreas.

    Science.gov (United States)

    Pierreux, Christophe E; Cordi, Sabine; Hick, Anne-Christine; Achouri, Younes; Ruiz de Almodovar, Carmen; Prévot, Pierre-Paul; Courtoy, Pierre J; Carmeliet, Peter; Lemaigre, Frédéric P

    2010-11-01

    Endothelial cells are required to initiate pancreas development from the endoderm. They also control the function of endocrine islets after birth. Here we investigate in developing pancreas how the endothelial cells become organized during branching morphogenesis and how their development affects pancreatic cell differentiation. We show that endothelial cells closely surround the epithelial bud at the onset of pancreas morphogenesis. During branching morphogenesis, the endothelial cells become preferentially located near the central (trunk) epithelial cells and remain at a distance from the branch tips where acinar cells differentiate. This correlates with predominant expression of the angiogenic factor vascular endothelial growth factor-A (VEGF-A) in trunk cells. In vivo ablation of VEGF-A expression by pancreas-specific inactivation of floxed Vegfa alleles results in reduced endothelial development and in excessive acinar differentiation. On the contrary, acinar differentiation is repressed when endothelial cells are recruited around tip cells that overexpress VEGF-A. Treatment of embryonic day 12.5 explants with VEGF-A or with VEGF receptor antagonists confirms that acinar development is tightly controlled by endothelial cells. We also provide evidence that endothelial cells repress the expression of Ptf1a, a transcription factor essential for acinar differentiation, and stimulate the expression of Hey-1 and Hey-2, two repressors of Ptf1a activity. In explants, we provide evidence that VEGF-A signaling is required, but not sufficient, to induce endocrine differentiation. In conclusion, our data suggest that, in developing pancreas, epithelial production of VEGF-A determines the spatial organization of endothelial cells which, in turn, limit acinar differentiation of the epithelium. Copyright © 2010 Elsevier Inc. All rights reserved.

  17. Hereditary pancreatitis for the endoscopist

    Science.gov (United States)

    Patel, Milan R.; Eppolito, Amanda L.

    2013-01-01

    Hereditary pancreatitis shares a majority of clinical and morphologic features with chronic alcoholic pancreatitis, but may present at an earlier age. The term hereditary pancreatitis has primarily been associated with mutations in the serine protease 1 gene (PRSS1) which encodes for cationic trypsinogen. PRSS1 mutations account for approximately 68–81% of hereditary pancreatitis. Mutations in other genes, primarily serine protease inhibitor Kazal type 1 (SPINK1) and the cystic fibrosis transmembrane conductance regulator (CFTR) are also associated with hereditary pancreatitis. While chronic alcoholic pancreatitis may develop in the fourth or fifth decades, patients with hereditary pancreatitis may develop symptoms in the first or second decades of life. Hereditary pancreatitis is diagnosed either by detecting a causative gene mutation or by the presence of chronic pancreatitis in two first-degree or three second-degree relatives, in two or more generations, without precipitating factors and with a negative workup for known causes. Patients with hereditary pancreatitis may have recurrent acute pancreatitis and may develop pancreatic exocrine and endocrine insufficiency. Hereditary pancreatitis may involve premature trypsinogen activation or decreased control of trypsin. Recurrent inflammation can lead to acute pancreatitis and subsequently to chronic pancreatitis with parenchymal calcification. There is a markedly increased risk of pancreatic carcinoma compared with the general population. Patients are often referred for evaluation of pancreatitis, biliary or pancreatic ductal dilatation, jaundice, biliary obstruction, pancreatic duct stone or stricture, pancreatic pseudocysts, and for evaluation for malignancy. Medical treatment includes pancreatic enzyme supplementation, nutritional supplementation, diabetes management, and palliation of pain. Patients should avoid tobacco use and alcohol exposure. Hereditary pancreatitis is reviewed and recommendations for

  18. Chronic ethanol administration selectively impairs endocytosis in the rat exocrine pancreas.

    Science.gov (United States)

    Tenner, S; Freedman, S D

    1998-08-01

    Release of GP2, a glycosyl phosphatidylinositol-linked protein on the apical plasma membrane of the pancreatic acinar cell, is associated with activation of endocytosis. Released GP2 is also an integral component of intraductal plugs in patients with alcohol-induced chronic pancreatitis. Our purpose was to determine the effect of ethanol on exocytosis and endocytosis and its association with release of membrane-bound GP2. Rats were fed Lieber-DeCarli diets with and without ethanol for 2 weeks. Endocytosis was then assessed in acini by measuring horseradish peroxidase (HRP) uptake, GP2 release by Western blotting, and exocytosis by measuring amylase release. In ethanol-fed rats, HRP uptake was inhibited by 90% compared to that in control rats. In contrast, no significant difference in cholecystokinin-stimulated amylase secretion was found. In vitro, ethanol inhibited HRP uptake in a dose-dependent manner, with 50% inhibition at 50 mM ethanol. Despite the inhibition of endocytosis, GP2 release increased linearly over 60 min and was significantly higher from acini incubated with ethanol compared to controls. These data indicate that ethanol selectively inhibits endocytosis in pancreatic acinar cells. The release of GP2 into the pancreatic duct was no longer coupled to endocytosis in animals fed ethanol.

  19. Nutritional and Metabolic Derangements in Pancreatic Cancer and Pancreatic Resection.

    Science.gov (United States)

    Gilliland, Taylor M; Villafane-Ferriol, Nicole; Shah, Kevin P; Shah, Rohan M; Tran Cao, Hop S; Massarweh, Nader N; Silberfein, Eric J; Choi, Eugene A; Hsu, Cary; McElhany, Amy L; Barakat, Omar; Fisher, William; Van Buren, George

    2017-03-07

    Pancreatic cancer is an aggressive malignancy with a poor prognosis. The disease and its treatment can cause significant nutritional impairments that often adversely impact patient quality of life (QOL). The pancreas has both exocrine and endocrine functions and, in the setting of cancer, both systems may be affected. Pancreatic exocrine insufficiency (PEI) manifests as weight loss and steatorrhea, while endocrine insufficiency may result in diabetes mellitus. Surgical resection, a central component of pancreatic cancer treatment, may induce or exacerbate these dysfunctions. Nutritional and metabolic dysfunctions in patients with pancreatic cancer lack characterization, and few guidelines exist for nutritional support in patients after surgical resection. We reviewed publications from the past two decades (1995-2016) addressing the nutritional and metabolic status of patients with pancreatic cancer, grouping them into status at the time of diagnosis, status at the time of resection, and status of nutritional support throughout the diagnosis and treatment of pancreatic cancer. Here, we summarize the results of these investigations and evaluate the effectiveness of various types of nutritional support in patients after pancreatectomy for pancreatic adenocarcinoma (PDAC). We outline the following conservative perioperative strategies to optimize patient outcomes and guide the care of these patients: (1) patients with albumin 10% should postpone surgery and begin aggressive nutrition supplementation; (2) patients with albumin pancreatic insufficiency alongside implementation of appropriate treatment to improve the patient's quality of life.

  20. Hereditary Pancreatitis Associated With the N29T Mutation of the PRSS1 Gene in a Brazilian Family: A Case-Control Study.

    Science.gov (United States)

    Dytz, Marcio Garrison; Mendes de Melo, Julia; de Castro Santos, Olga; da Silva Santos, Isabel Durso; Rodacki, Melanie; Conceição, Flavia Lucia; Ortiga-Carvalho, Tania Maria

    2015-09-01

    Hereditary pancreatitis (HP) is an autosomal-dominant disease with incomplete penetrance manifesting as early-onset chronic relapsing pancreatitis. A mutation in the PRSS1 gene is present in greater than 70% of HP kindreds and leads to a gain-of-function characterized by the increased autocatalytic conversion of trypsinogen to active trypsin, promoting autodigestion and damage to acinar cells. Other genetic defects observed in the pathogenic mechanism of pancreatitis include mutations in the genes encoding SPINK1, CTRC, and CPA1. There are few reports of HP in Latin America, and no families have been investigated in Brazil. A case-control observational study was conducted at Clementino Fraga Filho University Hospital in Brazil. Patients with suspected HP and healthy controls were enrolled in this study, and a detailed questionnaire was administered to patients with HP. PRSS1 and SPINK1 genes were analyzed by DNA sequencing, and a family that fit the HP diagnostic criteria was identified. The neutral polymorphism c.88-352A > G in the SPINK1 gene was found to be prevalent in the individuals studied, but no important alterations were found in this gene. Ten out of 16 individuals in this family carried the N29T mutation in the PRSS1 gene, with 2 clinically unaffected mutation carriers. The median age of HP onset was 6 years. Pancreatic exocrine failure occurred in 6 patients, 5 of whom also had diabetes mellitus. Surgical procedures were performed on 3 affected members, and no cases of pancreatic cancer have been reported thus far. This study identified the first PRSS1 gene mutation in a Brazilian family with HP.

  1. Mixed acinar-endocrine carcinoma of the pancreas: new clinical and pathological features in a contemporary series.

    Science.gov (United States)

    Yu, Run; Jih, Lily; Zhai, Jing; Nissen, Nicholas N; Colquhoun, Steven; Wolin, Edward; Dhall, Deepti

    2013-04-01

    The objective of this study was to characterize the novel clinical and pathological features of mixed acinar-endocrine carcinoma of the pancreas. This was a retrospective review of medical records and surgical pathology specimens of patients with a diagnosis of mixed acinar-endocrine carcinoma of the pancreas at Cedars-Sinai Medical Center between 2005 and 2011. Additional immunohistochemistry was performed on the specimens of some patients. Five patients were identified. The median age at presentation was 74 years (range, 59-89 years), and all patients were male. The presenting symptoms were all related to tumor mass effects. The median size of the tumor was 10 cm (range, 3.9-16 cm). Preoperative clinical diagnosis aided by fine-needle aspiration biopsy was incorrect in all 5 cases. Most tumors (3/5) exhibited predominantly endocrine differentiation without hormonal production. Only 10% to 30% of cells were truly amphicrine, whereas most were differentiated into either endocrine or acinar phenotype. The clinical behavior ranged from moderate to aggressive with postoperative survival from 2.5 months to more than 3 years. Four patients received neoadjuvant or adjuvant chemotherapy with variable responses. Mixed acinar-endocrine carcinoma of the pancreas appears to be not uncommon in men, may harbor predominantly endocrine component, is often misdiagnosed by cytology, and exhibits variable clinical behavior. Mixed acinar-endocrine carcinoma of the pancreas should be considered in older patients with sizable pancreatic mass and may warrant aggressive surgical resection and chemotherapy.

  2. Pharmacological approach to acute pancreatitis

    DEFF Research Database (Denmark)

    Bang, U.C.; Semb, S.; Nøjgaard, Camilla

    2008-01-01

    The aim of the present review is to summarize the current knowledge regarding pharmacological prevention and treatment of acute pancreatitis (AP) based on experimental animal models and clinical trials. Somatostatin (SS) and octreotide inhibit the exocrine production of pancreatic enzymes and may...... be useful as prophylaxis against post endoscopic retrograde cholangiopancreatography pancreatitis (PEP). The protease inhibitor gabexate mesilate (GM) is used routinely as treatment to AP in some countries, but randomized clinical trials and a meta-analysis do not support this practice. Nitroglycerin (NGL...

  3. Human pluripotent stem cell-derived acinar/ductal organoids generate human pancreas upon orthotopic transplantation and allow disease modelling.

    Science.gov (United States)

    Hohwieler, Meike; Illing, Anett; Hermann, Patrick C; Mayer, Tobias; Stockmann, Marianne; Perkhofer, Lukas; Eiseler, Tim; Antony, Justin S; Müller, Martin; Renz, Susanne; Kuo, Chao-Chung; Lin, Qiong; Sendler, Matthias; Breunig, Markus; Kleiderman, Susanne M; Lechel, André; Zenker, Martin; Leichsenring, Michael; Rosendahl, Jonas; Zenke, Martin; Sainz, Bruno; Mayerle, Julia; Costa, Ivan G; Seufferlein, Thomas; Kormann, Michael; Wagner, Martin; Liebau, Stefan; Kleger, Alexander

    2017-03-01

    The generation of acinar and ductal cells from human pluripotent stem cells (PSCs) is a poorly studied process, although various diseases arise from this compartment. We designed a straightforward approach to direct human PSCs towards pancreatic organoids resembling acinar and ductal progeny. Extensive phenotyping of the organoids not only shows the appropriate marker profile but also ultrastructural, global gene expression and functional hallmarks of the human pancreas in the dish. Upon orthotopic transplantation into immunodeficient mice, these organoids form normal pancreatic ducts and acinar tissue resembling fetal human pancreas without evidence of tumour formation or transformation. Finally, we implemented this unique phenotyping tool as a model to study the pancreatic facets of cystic fibrosis (CF). For the first time, we provide evidence that in vitro , but also in our xenograft transplantation assay, pancreatic commitment occurs generally unhindered in CF. Importantly, cystic fibrosis transmembrane conductance regulator (CFTR) activation in mutated pancreatic organoids not only mirrors the CF phenotype in functional assays but also at a global expression level. We also conducted a scalable proof-of-concept screen in CF pancreatic organoids using a set of CFTR correctors and activators, and established an mRNA-mediated gene therapy approach in CF organoids. Taken together, our platform provides novel opportunities to model pancreatic disease and development, screen for disease-rescuing agents and to test therapeutic procedures. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  4. Faecal pancreatic elastase - l a non invasive measure of

    African Journals Online (AJOL)

    whether by cancer, ampullary or panceatic calculi or inflam- mation, is a cause of pancreatic insufficiency and malabsorp- tion. However, the diagnosis of chronic exocrine pancreatic. insufficiency is hampered by the absence of easily available histological confirmation and is therefore based on the mor- phology and ...

  5. Animal Models of Chronic Pancreatitis

    Directory of Open Access Journals (Sweden)

    Makoto Otsuki

    2010-01-01

    Full Text Available 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.

  6. Nutritional and Metabolic Derangements in Pancreatic Cancer and Pancreatic Resection

    Directory of Open Access Journals (Sweden)

    Taylor M. Gilliland

    2017-03-01

    Full Text Available Pancreatic cancer is an aggressive malignancy with a poor prognosis. The disease and its treatment can cause significant nutritional impairments that often adversely impact patient quality of life (QOL. The pancreas has both exocrine and endocrine functions and, in the setting of cancer, both systems may be affected. Pancreatic exocrine insufficiency (PEI manifests as weight loss and steatorrhea, while endocrine insufficiency may result in diabetes mellitus. Surgical resection, a central component of pancreatic cancer treatment, may induce or exacerbate these dysfunctions. Nutritional and metabolic dysfunctions in patients with pancreatic cancer lack characterization, and few guidelines exist for nutritional support in patients after surgical resection. We reviewed publications from the past two decades (1995–2016 addressing the nutritional and metabolic status of patients with pancreatic cancer, grouping them into status at the time of diagnosis, status at the time of resection, and status of nutritional support throughout the diagnosis and treatment of pancreatic cancer. Here, we summarize the results of these investigations and evaluate the effectiveness of various types of nutritional support in patients after pancreatectomy for pancreatic adenocarcinoma (PDAC. We outline the following conservative perioperative strategies to optimize patient outcomes and guide the care of these patients: (1 patients with albumin < 2.5 mg/dL or weight loss > 10% should postpone surgery and begin aggressive nutrition supplementation; (2 patients with albumin < 3 mg/dL or weight loss between 5% and 10% should have nutrition supplementation prior to surgery; (3 enteral nutrition (EN should be preferred as a nutritional intervention over total parenteral nutrition (TPN postoperatively; and, (4 a multidisciplinary approach should be used to allow for early detection of symptoms of endocrine and exocrine pancreatic insufficiency alongside implementation of

  7. Protein kinase D regulates cell death pathways in experimental pancreatitis

    Directory of Open Access Journals (Sweden)

    Jingzhen eYuan

    2012-03-01

    Full Text Available Inflammation and acinar cell necrosis are two major pathological responses of acute pancreatitis, a serious disorder with no current therapies directed to its molecular pathogenesis. Serine/threonine protein kinase D family, which includes PKD/PKD1, PKD2, and PKD3, has been increasingly implicated in the regulation of multiple physiological and pathophysiological effects. We recently reported that PKD/PKD1, the predominant PKD isoform expressed in rat pancreatic acinar cells, mediates early events of pancreatitis including NF-kappaB activation and inappropriate intracellular digestive enzyme activation. In current studies, we investigated the role and mechanisms of PKD/PKD1 in the regulation of necrosis in pancreatic acinar cells by using two novel small molecule PKD inhibitors CID755673 and CRT0066101 and molecular approaches in in vitro and in vivo experimental models of acute pancreatitis. Our results demonstrated that both CID755673 and CRT0066101 are PKD-specific inhibitors and that PKD/PKD1 inhibition by either the chemical inhibitors or specific PKD/PKD1 siRNAs attenuated necrosis while promoting apoptosis induced by pathological doses of cholecystokinin-octapeptide (CCK in pancreatic acinar cells. Conversely, upregulation of PKD expression in pancreatic acinar cells increased necrosis and decreased apoptosis. We further showed that PKD/PKD1 regulated several key cell death signals including inhibitors of apoptotic proteins (IAPs, caspases, receptor-interacting protein kinase 1 (RIP1 to promote necrosis. PKD/PKD1 inhibition by CID755673 significantly ameliorated necrosis and severity of pancreatitis in an in vivo experimental model of acute pancreatitis. Thus, our studies indicate that PKD/PKD1 is a key mediator of necrosis in acute pancreatitis and that PKD/PKD1 may represent a potential therapeutic target in acute pancreatitis.

  8. The Presence of Interleukin-13 at Pancreatic ADM/PanIN Lesions Alters Macrophage Populations and Mediates Pancreatic Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Geou-Yarh Liou

    2017-05-01

    Full Text Available The contributions of the innate immune system to the development of pancreatic cancer are still ill defined. Inflammatory macrophages can initiate metaplasia of pancreatic acinar cells to a duct-like phenotype (acinar-to-ductal metaplasia [ADM], which then gives rise to pancreatic intraepithelial neoplasia (PanIN when oncogenic KRas is present. However, it remains unclear when and how this inflammatory macrophage population is replaced by tumor-promoting macrophages. Here, we demonstrate the presence of interleukin-13 (IL-13, which can convert inflammatory into Ym1+ alternatively activated macrophages, at ADM/PanIN lesions. We further show that Ym1+ macrophages release factors, such as IL-1ra and CCL2, to drive pancreatic fibrogenesis and tumorigenesis. Treatment of mice expressing oncogenic KRas under an acinar cell-specific promoter with a neutralizing antibody for IL-13 significantly decreased the accumulation of alternatively activated macrophages at these lesions, resulting in decreased fibrosis and lesion growth.

  9. Islet-selectivity of G-protein coupled receptor ligands evaluated for PET imaging of pancreatic {beta}-cell mass

    Energy Technology Data Exchange (ETDEWEB)

    Cline, Gary W., E-mail: gary.cline@yale.edu [Yale University School of Medicine (United States); Zhao, Xiaojian [Yale University School of Medicine (United States); Jakowski, Amy B.; Soeller, Walter C.; Treadway, Judith L. [Pfizer Global Research and Development, Pfizer Inc., Groton CT (United States)

    2011-09-02

    Highlights: {yields} We screened G-protein coupled receptors for imaging pancreatic. {yields} Database mining and immunohistochemistry identified GPCRs enriched in {beta}-cells. {yields} In vitro and in vivo assays were used to determine exocrine vs endocrine specificity. {yields} GPCR candidates for imaging of {beta}-cell mass are Prokineticin-1R, mGluR5, and GLP-1R. -- Abstract: A critical unmet need exists for methods to quantitatively measure endogenous pancreatic {beta}-cell mass (BCM) for the clinical evaluation of therapies to prevent or reverse loss of BCM and diabetes progression. Our objective was to identify G-protein coupled receptors (GPCRs) that are expressed with a high degree of specificity to islet {beta}-cells for receptor-targeted imaging of BCM. GPCRs enriched in pancreatic islets relative to pancreas acinar and hepatic tissue were identified using a database screen. Islet-specific expression was confirmed by human pancreas immunohistochemistry (IHC). In vitro selectivity assessment was determined from the binding and uptake of radiolabeled ligands to the rat insulinoma INS-1 832/13 cell line and isolated rat islets relative to the exocrine pancreas cell-type, PANC-1. Tail-vein injections of radioligands into rats were used to determine favorable image criteria of in vivo biodistribution to the pancreas relative to other internal organs (i.e., liver, spleen, stomach, and lungs). Database and IHC screening identified four candidate receptors for further in vitro and in vivo evaluation for PET imaging of BCM: prokineticin-1 receptor (PK-1R), metabotropic glutamate receptor type-5 (mGluR5), neuropeptide Y-2 receptor (NPY-2R), and glucagon-like peptide 1 receptor (GLP-1R). In vitro specificity ratios gave the following receptor rank order: PK-1R > GLP-1R > NPY-2R > mGluR5. The biodistribution rank order of selectivity to the pancreas was found to be PK-1R > VMAT2 {approx} GLP-1R > mGluR5. Favorable islet selectivity and biodistribution

  10. Silencing of the Fibroblast growth factor 21 gene is an underlying cause of acinar cell injury in mice lacking MIST1.

    Science.gov (United States)

    Johnson, Charis L; Mehmood, Rashid; Laing, Scott W; Stepniak, Camilla V; Kharitonenkov, Alexei; Pin, Christopher L

    2014-04-15

    Fibroblast growth factor 21 (FGF21) is a key regulator of metabolism under conditions of stress such as starvation, obesity, and hypothermia. Rapid induction of FGF21 is also observed in experimental models of pancreatitis, and FGF21 reduces tissue damage observed in these models, suggesting a nonmetabolic function. Pancreatitis is a debilitating disease with significant morbidity that greatly increases the risk of pancreatic ductal adenocarcinoma. The goals of this study were to examine the regulation and function of FGF21 in acinar cell injury, specifically in a mouse model of pancreatic injury (Mist1(-/-)). Mist1(-/-) mice exhibit acinar cell disorganization, decreased acinar cell communication and exocytosis, and increased sensitivity to cerulein-induced pancreatitis (CIP). Examination of Fgf21 expression in Mist1(-/-) mice by qRT-PCR, Northern blot, and Western blot analyses showed a marked decrease in pancreatic Fgf21 expression before and after induction of CIP compared with C57Bl/6 mice. To determine whether the loss of FGF21 accounted for the Mist1(-/-) phenotypes, we generated Mist1(-/-) mice overexpressing human FGF21 from the ApoE promoter (Mist1(-/-)ApoE-FGF21). Reexpression of FGF21 partially mitigated pancreatic damage in Mist1(-/-) tissue based on reduced intrapancreatic enzyme activation, reduced expression of genes involved in fibrosis, and restored cell-cell junctions. Interestingly, alteration of Fgf21 expression in Mist1(-/-) tissue was not simply due to a loss of direct transcriptional regulation by MIST1. Chromatin immunopreciptation indicated that the loss of Fgf21 in the Mist1(-/-) pancreas is due, in part, to epigenetic silencing. Thus, our studies identify a new role for FGF21 in reducing acinar cell injury and uncover a novel mechanism for regulating Fgf21 gene expression.

  11. Total pancreatic lipomatosis with malabsorption syndrome

    Directory of Open Access Journals (Sweden)

    Rama Anand

    2011-01-01

    Full Text Available Total fat replacement of the pancreas is rare. Focal fatty replacement is the most common degenerative lesion of pancreas. Focal fatty deposits have no major clinical significance; however, extreme fat replacement is of pathologic significance, as it is associated with marked reduction in exocrine function of pancreas, resulting in malabsorption due to pancreatic enzyme insufficiency.

  12. Pharmacological challenges in chronic pancreatitis

    DEFF Research Database (Denmark)

    Olesen, Anne Estrup; Brokjaer, Anne; Fischer, Iben Wendelboe Deleuran

    2014-01-01

    Drug absorption in patients with chronic pancreatitis might be affected by the pathophysiology of the disease. The exocrine pancreatic insufficiency is associated with changes in gastrointestinal intraluminal pH, motility disorder, bacterial overgrowth and changed pancreatic gland secretion....... Together these factors can result in malabsorption and may also affect the efficacy of pharmacological intervention. The lifestyle of chronic pancreatitis patients may also contribute to gastrointestinal changes. Many patients limit their food intake because of the pain caused by eating and in some cases...... are often prescribed as pain treatment. Opioids have intrinsic effects on gastrointestinal motility and hence can modify the absorption of other drugs taken at the same time. Furthermore, the increased fluid absorption caused by opioids will decrease water available for drug dissolution and may hereby...

  13. Chronic pancreatitis

    Science.gov (United States)

    Chronic pancreatitis - chronic; Pancreatitis - chronic - discharge; Pancreatic insufficiency - chronic; Acute pancreatitis - chronic ... abuse over many years. Repeated episodes of acute pancreatitis can lead to chronic pancreatitis. Genetics may be ...

  14. Inflammation, autophagy, and obesity: common features in the pathogenesis of pancreatitis and pancreatic cancer.

    Science.gov (United States)

    Gukovsky, Ilya; Li, Ning; Todoric, Jelena; Gukovskaya, Anna; Karin, Michael

    2013-06-01

    Inflammation and autophagy are cellular defense mechanisms. When these processes are deregulated (deficient or overactivated) they produce pathologic effects, such as oxidative stress, metabolic impairments, and cell death. Unresolved inflammation and disrupted regulation of autophagy are common features of pancreatitis and pancreatic cancer. Furthermore, obesity, a risk factor for pancreatitis and pancreatic cancer, promotes inflammation and inhibits or deregulates autophagy, creating an environment that facilitates the induction and progression of pancreatic diseases. However, little is known about how inflammation, autophagy, and obesity interact to promote exocrine pancreatic disorders. We review the roles of inflammation and autophagy, and their deregulation by obesity, in pancreatic diseases. We discuss the connections among disordered pathways and important areas for future research. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

  15. Acinar cystadenoma of the pancreas: a clinicopathologic study of 10 cases including multilocular lesions with mural nodules.

    Science.gov (United States)

    Khor, Tze S; Badizadegan, Kamran; Ferrone, Cristina; Fernández-del Castillo, Carlos; Desai, Gaurav S; Saenz, Adam; Le, Long; Lauwers, Gregory Y; Deshpande, Vikram

    2012-11-01

    Pancreatic acinar cystadenomas (ACAs) are rare cystic lesions showing acinar differentiation with benign outcome. Although debated, ACAs are favored to be neoplastic and potentially the benign counterpart of acinar cystadenocarcinoma. We present the largest single institution series to date comprising 10 cases. The mean age was 49 years with a female predominance (M:F=1:2.3). Abdominal/flank pain was the most common presentation (n=6). Serum amylase/lipase and cyst fluid amylase were often elevated. All lesions had a benign outcome on follow-up (5 to 67 mo). The lesions were unilocular (n=3) or multilocular (n=7) with mean size of 3.8 cm (range, 2.9 to 5.0 cm) and 5.1 cm (range, 2.0 to 7.5 cm), respectively. Eight lesions were unifocal with locations as follows: head (n=2), head/neck (n=2), body (n=1), tail (n=1), predominantly extrapancreatic with a microscopic intrapancreatic component (n=1), and unspecified location (n=1). Two lesions were multifocal, involving the head/uncinate/body and pancreatic head, respectively. Two aspects of ACAs that may represent a diagnostic pitfall include the propensity for acinar epithelium to appear as nondescript flat/cuboidal epithelium (trypsin/chymotrypsin immunopositive) and epithelial heterogeneity, with focal mucinous and squamous epithelium, the latter particularly in multilocular variants. In addition, 2 cases with intracystic nodules were observed. Array comparative genomic hybridization performed on 1 of these cases showed multiple chromosomal gains involving 1p, 3p, 5q, 6p, 7q, 8, 10q, 11, 14, 20, and X. These findings provide preliminary evidence that ACAs represent a cystic neoplastic lesion.

  16. Effects of a diet high in fish oil (MaxEPA) on the formation of micronucleated erythrocytes in blood and on the number of atypical acinar cell foci induced in rat pancreas by Azaserine

    NARCIS (Netherlands)

    Appel, M.J.; Woutersen, R.A.

    2004-01-01

    The present study was performed to investigate the influence of fish oil on the genotoxic effects of azaserine, using the formation of micronucleated erythrocytes as a measure for the degree of initiating potency and the number and size of putative preneoplastic pancreatic atypical acinar cell foci

  17. Type 1 autoimmune pancreatitis: case scenario and review of the disease.

    Science.gov (United States)

    Donet, Jean A; Czul, Frank; Peña, Nathalie A; Barkin, Jamie S

    2016-01-01

    Autoimmune pancreatitis (AIP) is an uncommon disease that represents a diagnostic challenge unless it is considered as a cause of acute pancreatitis, pancreatic exocrine insufficiency and a pancreatic mass. This entity is under diagnosed and successful medical therapy is available. In this paper, we will describe a case of a 59 year-old, Hispanic woman diagnosed with autoimmune pancreatitis, a disease previously believed to affect typically older men. We will review the definition, types, clinical manifestations, radiological features, serology, histopathological findings, treatment strategies and diagnostic criteria of autoimmune pancreatitis.

  18. Role of autophagy in development and progression of acute pancreatitis

    Directory of Open Access Journals (Sweden)

    YANG Shuli

    2014-08-01

    Full Text Available Acute pancreatitis is considered an autodigestive disorder in which inappropriate activation of trypsinogen to trypsin within pancreatic acinar cells leads to the development of pancreatitis. Autophagy is an evolutionarily preserved degradation process of cytoplasmic cellular constituents, and it is one of the early pathological processes in acute pancreatitis. Autophagic flux is impaired in acute pancreatitis, which mediates the key pathologic responses of this disease. Impaired autophagy, dysfunction of lysosomes, and dysregulation of autophagy suggest a disorder of the endolysosomal pathway in acute pancreatitis. The role of autophagy in acute pancreatitis is discussed from the aspects of autophagic process, autophagy and activation of trypsinogen, impaired autophagy and acute pancreatitis, and defective autophagy promoting inflammation.

  19. Successful Salvage Chemotherapy with FOLFIRINOX for Recurrent Mixed Acinar Cell Carcinoma and Ductal Adenocarcinoma of the Pancreas in an Adolescent Patient

    Directory of Open Access Journals (Sweden)

    Sarah Pfrommer

    2013-09-01

    Full Text Available Pancreatic tumors are rare in children and adolescents. Here, we report the case of a 15-year-old boy who presented with a mixed acinar cell carcinoma/ductal adenocarcinoma with blastomatous components. He received multimodal treatment including various chemotherapy regimens and multistep surgery including liver transplantation. Introduction of FOLFIRINOX after relapse repeatedly achieved a durable metabolic and clinical response with good quality of life.

  20. Purinergic receptors in the endocrine and exocrine pancreas

    DEFF Research Database (Denmark)

    Novak, I

    2008-01-01

    The pancreas is a complex gland performing both endocrine and exocrine functions. In recent years there has been increasing evidence that both endocrine and exocrine cells possess purinergic receptors, which influence processes such as insulin secretion and epithelial ion transport. Most commonly......, there is also evidence for other P2 and adenosine receptors in beta cells (P2Y(2), P2Y(4), P2Y(6), P2X subtypes and A(1) receptors) and in glucagon-secreting alpha cells (P2X(7), A(2) receptors). In the exocrine pancreas, acini release ATP and ATP-hydrolysing and ATP-generating enzymes. P2 receptors...

  1. Pancreatitis - discharge

    Science.gov (United States)

    Chronic pancreatitis - discharge; Pancreatitis - chronic - discharge; Pancreatic insufficiency - discharge; Acute pancreatitis - discharge ... You were in the hospital because you have pancreatitis. This is a swelling of the pancreas. You ...

  2. Hereditary Pancreatitis

    Science.gov (United States)

    ... E-News Sign-Up Home Hereditary Pancreatitis Hereditary Pancreatitis Hereditary Pancreatitis (HP) is a rare genetic condition characterized by ... of pancreatic attacks, which can progress to chronic pancreatitis . Symptoms include abdominal pain, nausea, and vomiting. Onset ...

  3. Pancreatic Enzymes

    Science.gov (United States)

    ... NOW HONOR/MEMORIAL GENERAL DONATION MONTHLY PURPLESTRIDE Pancreatic enzymes Home Facing Pancreatic Cancer Living with Pancreatic Cancer ... and see a registered dietitian. What are pancreatic enzymes? Pancreatic enzymes help break down fats, proteins and ...

  4. Assessment of quality of life in patients with chronic pancreatitis

    OpenAIRE

    Mokrowiecka, Anna; Pi?kowski, Dominik; Ma?ecka-Panas, Ewa

    2011-01-01

    Summary Background Quality of life (QOL) has increasingly become a factor in management decisions in patients with chronic diseases. Chronic pancreatitis (CP) is a debilitating disorder that causes not only pain and endo/exocrine insufficiency but is also connected with some social issues. The aim of this study was to assess QOL in patients with chronic pancreatitis in correlation with the disease activity or the environmental/social factors that can influence their well-being. Material/Metho...

  5. Pancreatitis and pancreatic trauma.

    Science.gov (United States)

    Stringer, Mark D

    2005-11-01

    Many pancreatic disorders in children benefit from a multidisciplinary approach. This is especially true for acute and chronic pancreatitis which has numerous and diverse etiologies. The current management of pancreatitis is reviewed, focusing on recent advances. Children with pancreatitis must be fully investigated, not least to select out those who benefit from specific surgical interventions. The treatment of pancreas divisum, pseudocysts, and fibrosing pancreatitis deserve particular consideration. Management of pancreatic injuries involving the main pancreatic duct is both variable and controversial. Treatment should be individualized depending on the site of injury, timing of referral, presence of associated injuries, and institutional expertise.

  6. Generation of Functional Beta-Like Cells from Human Exocrine Pancreas.

    Directory of Open Access Journals (Sweden)

    Maria J Lima

    Full Text Available Transcription factor mediated lineage reprogramming of human pancreatic exocrine tissue could conceivably provide an unlimited supply of islets for transplantation in the treatment of diabetes. Exocrine tissue can be efficiently reprogrammed to islet-like cells using a cocktail of transcription factors: Pdx1, Ngn3, MafA and Pax4 in combination with growth factors. We show here that overexpression of exogenous Pax4 in combination with suppression of the endogenous transcription factor ARX considerably enhances the production of functional insulin-secreting β-like cells with concomitant suppression of α-cells. The efficiency was further increased by culture on laminin-coated plates in media containing low glucose concentrations. Immunocytochemistry revealed that reprogrammed cultures were composed of ~45% islet-like clusters comprising >80% monohormonal insulin+ cells. The resultant β-like cells expressed insulin protein levels at ~15-30% of that in adult human islets, efficiently processed proinsulin and packaged insulin into secretory granules, exhibited glucose responsive insulin secretion, and had an immediate and prolonged effect in normalising blood glucose levels upon transplantation into diabetic mice. We estimate that approximately 3 billion of these cells would have an immediate therapeutic effect following engraftment in type 1 diabetes patients and that one pancreas would provide sufficient tissue for numerous transplants.

  7. Alcohol and pancreatic cancer.

    Science.gov (United States)

    Go, Vay Liang W; Gukovskaya, Anna; Pandol, Stephen J

    2005-04-01

    Findings obtained from numerous prospective cohort and case-control studies on alcohol consumption and pancreatic cancer risk have been inconsistent, with many confounding variables present in various investigations. However, heavy alcohol consumption has been known to be a major cause of chronic pancreatitis and a risk factor for type 2 diabetes mellitus, both of which are linked to pancreatic cancer. It has been established that an extensive normal interaction exists between the exocrine and endocrine pancreas, as well as in inflammatory processes and carcinogenesis. Alcohol and its metabolites (acetaldehyde and fatty acid ethyl esters) can alter metabolic pathways involved in the inflammatory response and carcinogenesis, and they are mediated by one or more of the following mechanisms: (1) premature activation of zymogens; (2) induction of the inflammatory response through activation of nuclear transcription factors, including nuclear factor-kappa and activation protein 1; (3) increased production of reactive oxygen species, resulting in oxidative DNA damage and altered effect of dietary antioxidants; (4) activation of pancreatic stellate cells, which leads to fibrosis; (5) gene mutation in enzymes related to cytochrome P450, glutathione S-transferase, aldehyde dehydrogenase, cationic trypsinogen, and pancreatic secretory trypsin inhibitor; (6) synergistic effects of ethanol and tobacco carcinogen on NNK [nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone] metabolism; and (7) dysregulation of proliferation and apoptosis. These various metabolic effects of alcohol can lead to or interact with other risk factors (genetic, dietary, environmental, and lifestyle factors) that result in acute and chronic pancreatitis and diabetes mellitus and, ultimately, affect the multistep process of carcinogenesis toward the development of pancreatic cancer.

  8. [Recent Advances in Management of Chronic Pancreatitis].

    Science.gov (United States)

    Park, Seon Mee

    2015-09-01

    Treatment for chronic pancreatitis (CP) should be started early to prevent further pancreatic fibrosis and managed with a multidisciplinary approach to prevent complications and to maintain a good quality of life. The management strategies of CP can be divided into medical, endoscopic, and surgical treatment. The role of pancreatic enzymes and antioxidants for pain relief is not clearly defined, but their role in maintaining nutritional support by correcting exocrine insufficiency is well established. Endoscopic treatment is applied for resolution of pancreatic or bile duct strictures, clearance of pancreatic duct stones, and pseudocyst drainage. Endosonography-guided celiac plexus or celiac ganglia block for pain relief are known to be safe procedures but evidence for their effectiveness is still lacking. Surgery is commonly recommended when endoscopic therapy fails or there is suspicion of malignancy. New evidence-based guidelines for the management of CP are needed.

  9. Fine needle aspiration cytology of acinar cell cystadenoma of the pancreas.

    Science.gov (United States)

    Yergiyev, Oleksandr; Krishnamurti, Uma; Mohanty, Alok; Thakkar, Shyam; Gurram, Krishna; Silverman, Jan F

    2014-01-01

    Acinar cell cystadenoma (ACC) is a recently recognized cystic lesion of the pancreas that demonstrates acinar differentiation and is currently believed to behave in a benign fashion. ACC enters the differential diagnosis of pancreatic cystic lesions alongside better recognized entities such as mucinous cystic and intraductal papillary mucinous neoplasms. Although uncommon, patients with ACC can undergo fine needle aspiration (FNA) of the lesion. However, the diagnosis is rarely made on cytologic examination due to sparse cellularity. Furthermore, the eosinophilic amorphous material in the cyst lumen may be mistaken for mucin, resulting in an incorrect diagnosis of a mucinous cyst. To date, there is a paucity of literature on the cytomorphology of ACC, both in peer-reviewed publications and cytopathology texts. To our knowledge, we present the first detailed case report of FNA of ACC in a 22-year-old asymptomatic female. The FNA cytology specimen was hypocellular, and the presence of amorphous secretions led to the initial diagnosis of a mucinous-type neoplasm. Following surgical resection, the cytology specimen was reviewed. We discuss the cytomorphologic features of ACC along with the potential pitfalls and diagnostic implications. © 2014 S. Karger AG, Basel.

  10. Pancreatic Agenesis with Congenital Diaphragmatic Hernia and Congenital Heart Disease: A Case Report

    OpenAIRE

    Nakao, Atsushi; Takeda, Tomohiro; Hisaeda, Yoshiya; Hirota, Atsushi; Amagata, Syusuke; Sakurai, Yuko; Kawakami, Tadashi

    2013-01-01

    Pancreatic agenesis is a rare disease that causes neonatal diabetes mellitus and exocrine pancreatic insufficiency. We report the case of a very low birth weight infant with congenital diaphragmatic hernia, and congenital heart disease (ventricular septal defect and patent ductus arteriosus). Failure to gain weight, despite well-managed respiratory and heart failure, was improved by infusion of subcutaneous insulin, administration of pancreatic enzyme, and nutrition of medium-chain-triglyceri...

  11. Nutrition treatment of deficiency and malnutrition in chronic pancreatitis: a review.

    LENUS (Irish Health Repository)

    Duggan, SN

    2010-08-01

    Chronic pancreatitis results in exocrine and endocrine dysfunction, affecting normal digestion and absorption of nutrients. In individuals with chronic pancreatitis, nutrition status may be further affected by poor dietary intake, often related to alcoholism. However, some deficiencies may be overlooked, potentially leading to nutrition-related problems with bone health and fatigue. The aim of this article is to describe the deficiencies that occur and to propose an evidence-based algorithm for the nutrition assessment and treatment of patients with chronic pancreatitis.

  12. [Chronic pancreatitis: Retrospective review of 121 cases].

    Science.gov (United States)

    Berger F, Zoltán; Mancilla A, Carla

    2016-12-01

    Chronic pancreatitis (CP) is a rare disease in Chile, without a clear explanation for this low prevalence. To analyze the characteristics of our patients with pancreatitis. Retrospective analysis of a database of patients with pancreatitis of a clinical hospital. Morphological proof of diagnosis (calcifications/calculi, alterations of ducts, local complication or histology) was obtained for every patient. History of acute pancreatitis was recorded and exocrine-endocrine function was assessed. We retrieved information of 121 patients with pancreatitis (86 males) in a period of 20 years. The number of cases increased markedly every five years. The calculated incidence and prevalence was 0.8/100,000/year and 6/100,000, respectively. Pancreatic calcifications were initially observed in 93 patients and became evident during the follow-up in another six patients. Severe pain or local complications occurred in 27 patients, requiring surgery in 10 or endoscopic treatment in 15. During the years of follow-up, 55 patients were free of symptoms. Exocrine and endocrine insufficiency was demonstrated and treated in 81 and 67 patients, respectively. Alcoholic etiology was evident in 40% of patients. In 29% no etiology was identified. Mapuche origin was exceptional. Late diagnosis of CP is common, since most of our patients presented with advanced stages. Even though CP is increasingly diagnosed in our hospitals, the number of cases is still far fewer when compared to other countries. Underdiagnosis alone cannot explain this difference and genetic factors might be of importance.

  13. Epidermal growth factor receptor expression in pancreatic lesions induced in the rat by azaserine.

    Science.gov (United States)

    Visser, C. J.; de Weger, R. A.; van Blokland, W. T.; Seifert-Bock, I.; Kobrin, M. S.; Korc, M.; Woutersen, R. A.

    1996-01-01

    In the present study, the expression of the epidermal growth factor receptor (EGFR) was investigated in putative preneoplastic and neoplastic acinar cell lesions induced in the rat pancreas by azaserine, using Northern blotting, in situ hybridisation (ISH) and immunohistochemistry. EGFR protein levels were decreased in putative preneoplastic eosinophilic acinar cell lesions (atypical acinar cell nodules, AACN) in comparison with normal acinar cells of the pancreas. However, EGFR mRNA expression correlated positively with the volume of AACN in pancreatic homogenates and ISH showed equal or stronger EGFR mRNA expression in AACN than in the surrounding normal acinar cells. Neither EGFR protein nor EGFR mRNA was detected in more advanced lesions such as acinar adenocarcinomas (in situ). Moreover, EGFR protein expression showed an inverse relationship with the mitotic rate of the acinar cells. These findings suggest that down-regulation of EGFR at the protein level may abrogate negative constraints on cell growth, which may stimulate the development of putative preneoplastic AACN to more advanced lesions and, ultimately, acinar adenocarcinomas. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:8679465

  14. The Scandinavian baltic pancreatic club (SBPC) database

    DEFF Research Database (Denmark)

    Olesen, Søren Maagaard; Poulsen, Jakob L; Drewes, Asbjørn M.

    2017-01-01

    , we describe the design of the database and characteristics of the study cohort. METHODS: Nine centres from six different countries in the Scandinavian-Baltic region joined the database. Patients with definitive or probable CP (M-ANNHEIM diagnostic criteria) were included. Standardised case report......: The study cohort comprised of 910 patients (608 men: 302 women; median age 58 (IQR: 48-67) years with definite 848 (93%) or probable CP 62 (7%). Nicotine (70%) and alcohol (59%) were the most frequent aetiologies and seen in combination in 44% of patients. A history of recurrent acute pancreatitis was seen...... in 49% prior to the development of CP. Pain (69%) and exocrine pancreatic insufficiency (68%) were the most common complications followed by diabetes (43%). Most patients (30%) were classified as clinical stage II (symptomatic CP with exocrine or endocrine insufficiency). Less than 10% of the patients...

  15. Translating Discovery in Zebrafish Pancreatic Development to Human Pancreatic Cancer: Biomarkers, Targets, Pathogenesis, and Therapeutics

    Science.gov (United States)

    Kazi, Abid A.; Yee, Rosemary K.

    2013-01-01

    Abstract Experimental studies in the zebrafish have greatly facilitated understanding of genetic regulation of the early developmental events in the pancreas. Various approaches using forward and reverse genetics, chemical genetics, and transgenesis in zebrafish have demonstrated generally conserved regulatory roles of mammalian genes and discovered novel genetic pathways in exocrine pancreatic development. Accumulating evidence has supported the use of zebrafish as a model of human malignant diseases, including pancreatic cancer. Studies have shown that the genetic regulators of exocrine pancreatic development in zebrafish can be translated into potential clinical biomarkers and therapeutic targets in human pancreatic adenocarcinoma. Transgenic zebrafish expressing oncogenic K-ras and zebrafish tumor xenograft model have emerged as valuable tools for dissecting the pathogenetic mechanisms of pancreatic cancer and for drug discovery and toxicology. Future analysis of the pancreas in zebrafish will continue to advance understanding of the genetic regulation and biological mechanisms during organogenesis. Results of those studies are expected to provide new insights into how aberrant developmental pathways contribute to formation and growth of pancreatic neoplasia, and hopefully generate valid biomarkers and targets as well as effective and safe therapeutics in pancreatic cancer. PMID:23682805

  16. Nutrition in chronic pancreatitis.

    Science.gov (United States)

    Rasmussen, Henrik Højgaard; Irtun, Oivind; Olesen, Søren Schou; Drewes, Asbjørn Mohr; Holst, Mette

    2013-11-14

    The pancreas is a major player in nutrient digestion. In chronic pancreatitis both exocrine and endocrine insufficiency may develop leading to malnutrition over time. Maldigestion is often a late complication of chronic pancreatic and depends on the severity of the underlying disease. The severity of malnutrition is correlated with two major factors: (1) malabsorption and depletion of nutrients (e.g., alcoholism and pain) causes impaired nutritional status; and (2) increased metabolic activity due to the severity of the disease. Nutritional deficiencies negatively affect outcome if they are not treated. Nutritional assessment and the clinical severity of the disease are important for planning any nutritional intervention. Good nutritional practice includes screening to identify patients at risk, followed by a thoroughly nutritional assessment and nutrition plan for risk patients. Treatment should be multidisciplinary and the mainstay of treatment is abstinence from alcohol, pain treatment, dietary modifications and pancreatic enzyme supplementation. To achieve energy-end protein requirements, oral supplementation might be beneficial. Enteral nutrition may be used when patients do not have sufficient calorie intake as in pylero-duodenal-stenosis, inflammation or prior to surgery and can be necessary if weight loss continues. Parenteral nutrition is very seldom used in patients with chronic pancreatitis and should only be used in case of GI-tract obstruction or as a supplement to enteral nutrition.

  17. Acinar cell cystadenoma of the pancreas: report of three cases and literature review.

    Science.gov (United States)

    Wolf, Andrea M; Shirley, L Andrew; Winter, Jordan M; Prestipino, Anthony J; Palazzo, Juan P; Yeo, Charles J; Lavu, Harish

    2013-07-01

    Acinar cell cystadenoma (ACC) of the pancreas was first described as a distinct pancreatic cystic neoplasm in 2002. We have encountered three cases of ACC at our institution in addition to the 15 cases reported to date in the world literature. The gender distribution in the total cohort of patients with ACC slightly favored females (61 % female), and the median age was 49.5 years. Almost half (53 %) of the cases were identified incidentally, while the remainder presented with abdominal pain. The median tumor diameter was 5 cm in size, and no patients have had documented disease recurrence or progression, even in the setting of an incomplete resection. These findings suggest a relatively indolent biology, and that complete resections are curative. As we will show, surgical resection is warranted to treat symptoms and prevent local extension or malignant transformation.

  18. Stromal ETS2 Regulates Chemokine Production and Immune Cell Recruitment during Acinar-to-Ductal Metaplasia.

    Science.gov (United States)

    Pitarresi, Jason R; Liu, Xin; Sharma, Sudarshana M; Cuitiño, Maria C; Kladney, Raleigh D; Mace, Thomas A; Donohue, Sydney; Nayak, Sunayana G; Qu, Chunjing; Lee, James; Woelke, Sarah A; Trela, Stefan; LaPak, Kyle; Yu, Lianbo; McElroy, Joseph; Rosol, Thomas J; Shakya, Reena; Ludwig, Thomas; Lesinski, Gregory B; Fernandez, Soledad A; Konieczny, Stephen F; Leone, Gustavo; Wu, Jinghai; Ostrowski, Michael C

    2016-09-01

    Preclinical studies have suggested that the pancreatic tumor microenvironment both inhibits and promotes tumor development and growth. Here we establish the role of stromal fibroblasts during acinar-to-ductal metaplasia (ADM), an initiating event in pancreatic cancer formation. The transcription factor V-Ets avian erythroblastosis virus E26 oncogene homolog 2 (ETS2) was elevated in smooth muscle actin-positive fibroblasts in the stroma of pancreatic ductal adenocarcinoma (PDAC) patient tissue samples relative to normal pancreatic controls. LSL-Kras(G12D/+); LSL-Trp53(R172H/+); Pdx-1-Cre (KPC) mice showed that ETS2 expression initially increased in fibroblasts during ADM and remained elevated through progression to PDAC. Conditional ablation of Ets-2 in pancreatic fibroblasts in a Kras(G12D)-driven mouse ADM model decreased the amount of ADM events. ADMs from fibroblast Ets-2-deleted animals had reduced epithelial cell proliferation and increased apoptosis. Surprisingly, fibroblast Ets-2 deletion significantly altered immune cell infiltration into the stroma, with an increased CD8+ T-cell population, and decreased presence of regulatory T cells (Tregs), myeloid-derived suppressor cells, and mature macrophages. The mechanism involved ETS2-dependent chemokine ligand production in fibroblasts. ETS2 directly bound to regulatory sequences for Ccl3, Ccl4, Cxcl4, Cxcl5, and Cxcl10, a group of chemokines that act as potent mediators of immune cell recruitment. These results suggest an unappreciated role for ETS2 in fibroblasts in establishing an immune-suppressive microenvironment in response to oncogenic Kras(G12D) signaling during the initial stages of tumor development. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  19. Is there adaptation of the exocrine pancreas in wild animal? The case of the Roe Deer

    Directory of Open Access Journals (Sweden)

    Guilloteau Paul

    2012-05-01

    Full Text Available Abstract Background Physiology of the exocrine pancreas has been well studied in domestic and in laboratory animals as well as in humans. However, it remains quite unknown in wildlife mammals. Roe deer and cattle (including calf belong to different families but have a common ancestor. This work aimed to evaluate in the Roe deer, the adaptation to diet of the exocrine pancreatic functions and regulations related to animal evolution and domestication. Results Forty bovine were distributed into 2 groups of animals either fed exclusively with a milk formula (monogastric or fed a dry feed which allowed for rumen function to develop, they were slaughtered at 150 days of age. The 35 Roe deer were wild animals living in the temperate broadleaf and mixed forests, shot during the hunting season and classified in two groups adult and young. Immediately after death, the pancreas was removed for tissue sample collection and then analyzed. When expressed in relation to body weight, pancreas, pancreatic protein weights and enzyme activities measured were higher in Roe deer than in calf. The 1st original feature is that in Roe deer, the very high content in pancreatic enzymes seems to be related to specific digestive products observed (proline-rich proteins largely secreted in saliva which bind tannins, reducing their deleterious effects on protein digestion. The high chymotrypsin and elastase II quantities could allow recycling of proline-rich proteins. In contrast, domestication and rearing cattle resulted in simplified diet with well digestible components. The 2nd feature is that in wild animal, both receptor subtypes of the CCK/gastrin family peptides were present in the pancreas as in calf, although CCK-2 receptor subtype was previously identified in higher mammals. Conclusions Bovine species could have lost some digestive capabilities (no ingestion of great amounts of tannin-rich plants, capabilities to secrete high amounts of proline-rich proteins

  20. Long-Term Outcomes of Pancreatic Function Following Pancreatic Trauma.

    Science.gov (United States)

    Morita, Toshio; Takasu, Osamu; Sakamoto, Teruo; Mori, Shinjirou; Nakamura, Atsuo; Nabeta, Masakazu; Hirayu, Nobuhisa; Moroki, Mariko; Yamashita, Norio

    2017-05-08

    The objective of this study is to retrospectively assess long-term outcomes and late complications of pancreatic trauma. We studied 14 patients with pancreatic trauma who were treated at the Advanced Emergency Medical Service Center, Kurume University Hospital, between 1981 and 2012 and discharged alive. Relevant data were extracted from patient records and a retrospective patient questionnaire and blood test were completed to evaluate pancreatic function. The median patient age at the time of the survey was 49 years; the median post-injury period was 23 years and 5 months. The comorbidity rates for pancreatic endocrine and exocrine dysfunctions were 35.7% and 33.3%, respectively. No new-onset diabetes mellitus (DM) was seen within 3 years of trauma, except in 1 patient who underwent pancreaticoduodenectomy. DM developed >15 years after trauma in 2 patients each in the pancreatectomy and non-pancreatectomy groups. Diarrhea exacerbated by fat intake was seen in 3 and 1 patient in the pancreatectomy and non-pancreatectomy groups, respectively. Both complications were more common in the pancreatectomy group, but without statistical significance. Although post-surgical pancreatic dysfunction may be absent at discharge, treatment for pancreatic trauma should take into account the possibility that pancreatectomy may accelerate DM onset.

  1. Pancreatic agenesis with congenital diaphragmatic hernia and congenital heart disease: a case report.

    Science.gov (United States)

    Nakao, Atsushi; Takeda, Tomohiro; Hisaeda, Yoshiya; Hirota, Atsushi; Amagata, Syusuke; Sakurai, Yuko; Kawakami, Tadashi

    2013-10-01

    Pancreatic agenesis is a rare disease that causes neonatal diabetes mellitus and exocrine pancreatic insufficiency. We report the case of a very low birth weight infant with congenital diaphragmatic hernia, and congenital heart disease (ventricular septal defect and patent ductus arteriosus). Failure to gain weight, despite well-managed respiratory and heart failure, was improved by infusion of subcutaneous insulin, administration of pancreatic enzyme, and nutrition of medium-chain-triglyceride -enriched formula. This is the first case of pancreatic agenesis with both malformations where the patient is discharged from the hospital. Early diagnosis and adequate treatments to compensate pancreatic function may prevent mortality and improve growth.

  2. Pancreatic Agenesis with Congenital Diaphragmatic Hernia and Congenital Heart Disease: A Case Report

    Directory of Open Access Journals (Sweden)

    Atsushi Nakao

    2013-10-01

    Full Text Available Pancreatic agenesis is a rare disease that causes neonatal diabetes mellitus and exocrine pancreatic insufficiency. We report the case of a very low birth weight infant with congenital diaphragmatic hernia, and congenital heart disease (ventricular septal defect and patent ductus arteriosus. Failure to gain weight, despite well-managed respiratory and heart failure, was improved by infusion of subcutaneous insulin, administration of pancreatic enzyme, and nutrition of medium-chain-triglyceride -enriched formula. This is the first case of pancreatic agenesis with both malformations where the patient is discharged from the hospital. Early diagnosis and adequate treatments to compensate pancreatic function may prevent mortality and improve growth.

  3. Collision of extensive exocrine and neuroendocrine neoplasms in multiple endocrine neoplasia type 1 revealed by cytogenetic analysis of loss of heterozygosity: a case report.

    Science.gov (United States)

    Moriyoshi, Koki; Minamiguchi, Sachiko; Miyagawa-Hayashino, Aya; Fujimoto, Masakazu; Kawaguchi, Michiya; Haga, Hironori

    2013-09-01

    The combination of exocrine and neuroendocrine neoplasms is rarely found in the pancreas. These combined lesions vary from a clonal tumor with mixed differentiation to the incidental co-existence of two or more independent tumors, but the differential diagnosis is sometimes difficult. Here we report a case of multiple endocrine neoplasia type 1 (MEN1) with extensive ductal and neuroendocrine neoplastic changes. These two types of tumors admixed markedly in some parts, which made it difficult to determine the pathological diagnosis based on histological findings. Cytogenetic analysis showed that loss of heterozygosity (LOH) of the MEN1 locus exists in neuroendocrine but not in exocrine neoplasms, indicating that independent mechanisms of tumorigenesis may occur in these two types of tumors. This case shows the usefulness of cytogenetic analysis for the diagnosis of combined tumors of the pancreas. Extensive exocrine neoplastic change, including pancreatic intraepithelial neoplasia (PanIN) in virtually all pancreatic ducts and a focus of intraductal papillary mucinous neoplasm (IPMN) with focal invasion, was a distinguishing feature of the present case. The possible association of ductal tumorigenesis and a MEN1 background is discussed. © 2013 The Authors. Pathology International © 2013 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.

  4. Lymphotoxin β receptor signaling promotes development of autoimmune pancreatitis.

    Science.gov (United States)

    Seleznik, Gitta M; Reding, Theresia; Romrig, Franziska; Saito, Yasuyuki; Mildner, Alexander; Segerer, Stephan; Sun, Li-Kang; Regenass, Stephan; Lech, Maciej; Anders, Hans-Joachim; McHugh, Donal; Kumagi, Teru; Hiasa, Yoichi; Lackner, Carolin; Haybaeck, Johannes; Angst, Eliane; Perren, Aurel; Balmer, Maria Luisa; Slack, Emma; MacPherson, Andrew; Manz, Markus G; Weber, Achim; Browning, Jeffrey L; Arkan, Melek Canan; Rülicke, Thomas; Aguzzi, Adriano; Prinz, Marco; Graf, Rolf; Heikenwalder, Mathias

    2012-11-01

    Little is known about the pathogenic mechanisms of autoimmune pancreatitis (AIP), an increasingly recognized, immune-mediated form of chronic pancreatitis. Current treatment options are limited and disease relapse is frequent. We investigated factors that contribute to the development of AIP and new therapeutic strategies. We used quantitative polymerase chain reaction, immunohistochemical, and enzyme-linked immunosorbent analyses to measure the expression of cytokines and chemokines in tissue and serum samples from patients with and without AIP. We created a mouse model of human AIP by overexpressing lymphotoxin (LT)α and β specifically in acinar cells (Ela1-LTab mice). Messenger RNA levels of LTα and β were increased in pancreatic tissues from patients with AIP, compared with controls, and expression of chemokines (CXCL13, CCL19, CCL21, CCL1, and B-cell-activating factor) was increased in pancreatic and serum samples from patients. Up-regulation of these factors was not affected by corticosteroid treatment. Acinar-specific overexpression of LTαβ (Ela1-LTαβ) in mice led to an autoimmune disorder with various features of AIP. Chronic inflammation developed only in the pancreas but was sufficient to cause systemic autoimmunity. Acinar-specific overexpression of LTαβ did not cause autoimmunity in mice without lymphocytes (Ela1-LTab/Rag1(-/-)); moreover, lack of proinflammatory monocytes (Ela1-LTab/Ccr2(-/-)) failed to prevent AIP but prevented early pancreatic tissue damage. Administration of corticosteroids reduced pancreatitis but did not affect production of autoantibodies, such as antipancreatic secretory trypsin inhibitor in Ela1-LTab mice. In contrast, inhibition of LTβR signaling reduced chemokine expression, renal immune-complex deposition, and features of AIP in Ela1-LTab mice. Overexpression of LTαβ specifically in acinar cells of mice causes features of AIP. Reagents that neutralize LTβR ligands might be used to treat patients with AIP

  5. Acinar cell cystadenoma of the pancreas: a benign neoplasm or non-neoplastic ballooning of acinar and ductal epithelium?

    Science.gov (United States)

    Singhi, Aatur D; Norwood, Stephanie; Liu, Ta-Chiang; Sharma, Rajni; Wolfgang, Christopher L; Schulick, Richard D; Zeh, Herbert J; Hruban, Ralph H

    2013-09-01

    Acinar cell cystadenoma (ACA) of the pancreas was initially described as a non-neoplastic cyst of the pancreas and, at that time, referred to as "acinar cystic transformation." In subsequent studies, these lesions were given the designation of "-oma," despite the relative lack of evidence supporting a neoplastic process. To characterize these lesions further, we examined the clinical, pathologic, and immunohistochemical features of 8 ACAs. The majority of patients were female (7 of 8, 88%) and ranged in age from 18 to 57 years (mean, 43 y). Grossly, the cysts involved the head (n=5), body (n=1), or the entire pancreas (n=2). ACAs were either multilocular (n=4) or unilocular (n=4) and ranged in size from 1.8 to 15 cm (mean, 6.8 cm). Histologically, multilocular ACAs were lined by patches of acinar and ductal epithelium. Immunolabeling, including double-labeling for cytokeratin 19 and chymotrypsin, highlighted the patchy pattern of the ductal and acinar cells lining the cysts. In some areas, the cysts with patches of acinar and ductal differentiation formed larger locules with incomplete septa as they appeared to fuse with other cysts. In contrast, the unilocular cases were lined by 1 to 2 cell layers of acinar cells with little intervening ductal epithelium. Nuclear atypia, mitotic figures, necrosis, infiltrative growth, and associated invasive carcinoma were absent in all cases. In addition, we assessed the clonal versus polyclonal nature of ACAs, occurring in women, using X-chromosome inactivation analysis of the human androgen receptor (AR) gene. Five of 7 cases were informative and demonstrated a random X-chromosome inactivation pattern. Clinical follow-up information was available for all patients, and follow-up ranged from 10 months to 7.8 years (mean, 3.6 y), with no evidence of recurrence or malignant transformation. We hypothesize that early lesions are marked by acinar dilatation that expands into and incorporates smaller ductules and later larger ducts

  6. Smoking, alcohol, coffee, and tea intake and incidence of cancer of the exocrine pancreas: the Iowa Women's Health Study.

    Science.gov (United States)

    Harnack, L J; Anderson, K E; Zheng, W; Folsom, A R; Sellers, T A; Kushi, L H

    1997-12-01

    To assess the relationship of smoking and coffee, tea, and alcohol intake to the risk of cancer of the exocrine pancreas, analyses were performed using data from a prospective cohort study of 33,976 postmenopausal Iowa women who responded to a mailed questionnaire in 1986 and were followed through 1994 for cancer incidence and total mortality. At baseline, information on cigarette smoking, consumption of tea, coffee, and alcoholic beverages, and other dietary and lifestyle factors was obtained. Age-adjusted relative risks of pancreatic cancer (n = 66 cases) showed a dose-response association with smoking. Those with fewer than 20 pack-years and those with 20 or more pack-years of smoking exposure were 1.14 (95% confidence interval, 0.53-2.45) and 1.92 (95% confidence interval, 1.12-2.30) times more likely, respectively, to develop pancreatic cancer than were nonsmokers. Current smokers were twice as likely as were nonsmokers to develop pancreatic cancer. Relative risks of pancreatic cancer increased with the amount of alcohol consumed (Ptrend = 0.11) after adjustment for age, smoking status, and pack-years of smoking. Relative risks of pancreatic cancer according to alcoholic beverage intake were as strong among never-smokers as they were in the total cohort. After the data were adjusted for age, smoking status, and pack-years of smoking, there was a statistically significant 2-fold (95% confidence interval, 1.08-4.30) elevated risk of pancreatic cancer for those who drank > 17.5 cups of coffee per week, compared to those who consumed cancer incidence. In summary, these findings provide evidence of an association of both alcoholic beverage and coffee consumption with pancreatic cancer incidence that is independent of age and cigarette smoking.

  7. Nitric oxide-induced signalling in rat lacrimal acinar cells

    DEFF Research Database (Denmark)

    Looms, Dagnia Karen; Tritsaris, K.; Dissing, S.

    2002-01-01

    The aim of the present study was to investigate the physiological role of nitric oxide (NO) in mediating secretory processes in rat lacrimal acinar cells. In addition, we wanted to determine whether the acinar cells possess endogenous nitric oxide synthase (NOS) activity by measuring NO productio...... using the fluorescent NO indicator 4,5-diaminofluorescein (DAF-2). We initiated investigations by adding NO from an external source by means of the NO-donor, S-nitroso-N-acetyl-penicillamine (SNAP). Cellular concentrations of cyclic guanosine 5'-phosphate (cGMP) ([cGMP]) were measured...... by radioimmunoassay (RIA), and we found that SNAP induced a fast increase in the [cGMP], amounting to 350% of the [cGMP] in resting cells. Moreover, addition of SNAP and elevating [cGMP] in fura-2 loaded lacrimal acinar cells, resulted in a cGMP-dependent protein kinase-mediated release of Ca2+ from intracellular...

  8. Genetic alterations in pancreatic carcinoma

    Directory of Open Access Journals (Sweden)

    Schmid Roland M

    2003-01-01

    Full Text Available Abstract Cancer of the exocrine pancreas represents the fifth leading cause of cancer death in the Western population with an average survival after diagnosis of 3 to 6 months and a five-year survival rate under 5%. Our understanding of the molecular carcinogenesis has improved in the last few years due to the development of novel molecular biological techniques. Pancreatic cancer is a multi-stage process resulting from the accumulation of genetic changes in the somatic DNA of normal cells. In this article we describe major genetic alterations of pancreatic cancer, mutations in the proto-oncogene K-RAS and the tumor suppressors INK4A, TP53 and DPC4/SMAD4. The accumulation of these genetic changes leads to a profound disturbance in cell cycle regulation and continuous growth. The knowledge of the underlying molecular mechanisms will offer new therapeutic and diagnostic options and hopefully improve the outcome of this aggressive disease.

  9. Early postoperative and late metabolic morbidity after pancreatic resections: An old and new challenge for surgeons - A review.

    Science.gov (United States)

    Beger, Hans G; Mayer, Benjamin

    2018-02-16

    The metrics for measuring early postoperative morbidity after resection of pancreatic neoplastic tumors are overall morbidity, severe surgery-related morbidity, frequency of reoperation and reintervention, in-hospital, 30-day and 90-day mortality and length of hospital stay. Thirty-day readmission after discharge is additionally an indispensable criterion to assess quality of surgery. The metrics for surgery-associated long-term results after pancreatic resections are survival times, new onset of diabetes (DM), impaired glucose tolerance, exocrine pancreatic insufficiency, body mass index and GI motility dysfunctions. Following pancreaticoduodenectomy (PD) performed on pancreatic normo-glycemic patients for malignant and benign tumors, 4-30% develop postoperative new onset of diabetes. Long-term persistence of diabetes mellitus is observed after surgery for benign tumors in 14% and in 15.5% of patients after cancer resection. Pancreatic exocrine insufficiency after PD is observed in the early postoperative period in 23-80% of patients. Persistence of exocrine dysfunctions exists in 25% and 49% of patients. Following left-sided pancreatic resection, new onset DM is observed in 14% of cases; an exocrine insufficiency persisting in the long-term outcome is observed in 16-28% of patients. Copyright © 2018 Elsevier Inc. All rights reserved.

  10. Lnx2 ubiquitin ligase is essential for exocrine cell differentiation in the early zebrafish pancreas.

    Science.gov (United States)

    Won, Minho; Ro, Hyunju; Dawid, Igor B

    2015-10-06

    The gene encoding the E3 ubiquitin ligase Ligand of Numb protein-X (Lnx)2a is expressed in the ventral-anterior pancreatic bud of zebrafish embryos in addition to its expression in the brain. Knockdown of Lnx2a by using an exon 2/intron 2 splice morpholino resulted in specific inhibition of the differentiation of ventral bud derived exocrine cell types, with little effect on endocrine cell types. A frame shifting null mutation in lnx2a did not mimic this phenotype, but a mutation that removed the exon 2 splice donor site did. We found that Lnx2b functions in a redundant manner with its paralog Lnx2a. Inhibition of lnx2a exon 2/3 splicing causes exon 2 skipping and leads to the production of an N-truncated protein that acts as an interfering molecule. Thus, the phenotype characterized by inhibition of exocrine cell differentiation requires inactivation of both Lnx2a and Lnx2b. Human LNX1 is known to destabilize Numb, and we show that inhibition of Numb expression rescues the Lnx2a/b-deficient phenotype. Further, Lnx2a/b inhibition leads to a reduction in the number of Notch active cells in the pancreas. We suggest that Lnx2a/b function to fine tune the regulation of Notch through Numb in the differentiation of cell types in the early zebrafish pancreas. Further, the complex relationships among genotype, phenotype, and morpholino effect in this case may be instructive in the ongoing consideration of morpholino use.

  11. Animal models for investigating chronic pancreatitis

    Science.gov (United States)

    2011-01-01

    Chronic pancreatitis is defined as a continuous or recurrent inflammatory disease of the pancreas characterized by progressive and irreversible morphological changes. It typically causes pain and permanent impairment of pancreatic function. In chronic pancreatitis areas of focal necrosis are followed by perilobular and intralobular fibrosis of the parenchyma, by stone formation in the pancreatic duct, calcifications in the parenchyma as well as the formation of pseudocysts. Late in the course of the disease a progressive loss of endocrine and exocrine function occurs. Despite advances in understanding the pathogenesis no causal treatment for chronic pancreatitis is presently available. Thus, there is a need for well characterized animal models for further investigations that allow translation to the human situation. This review summarizes existing experimental models and distinguishes them according to the type of pathological stimulus used for induction of pancreatitis. There is a special focus on pancreatic duct ligation, repetitive overstimulation with caerulein and chronic alcohol feeding. Secondly, attention is drawn to genetic models that have recently been generated and which mimic features of chronic pancreatitis in man. Each technique will be supplemented with data on the pathophysiological background of the model and their limitations will be discussed. PMID:22133269

  12. Epithelial NEMO/IKKγ limits fibrosis and promotes regeneration during pancreatitis.

    Science.gov (United States)

    Chan, Lap Kwan; Gerstenlauer, Melanie; Konukiewitz, Björn; Steiger, Katja; Weichert, Wilko; Wirth, Thomas; Maier, Harald Jakob

    2017-11-01

    Inhibitory κB kinase (IKK)/nuclear factor κB (NF-κB) signalling has been implicated in the pathogenesis of pancreatitis, but its precise function has remained controversial. Here, we analyse the contribution of IKK/NF-κB signalling in epithelial cells to the pathogenesis of pancreatitis by targeting the IKK subunit NF-κB essential modulator (NEMO) (IKKγ), which is essential for canonical NF-κB activation. Mice with a targeted deletion of NEMO in the pancreas were subjected to caerulein pancreatitis. Pancreata were examined at several time points and analysed for inflammation, fibrosis, cell death, cell proliferation, as well as cellular differentiation. Human samples were used to corroborate findings established in mice. In acute pancreatitis, NEMO deletion in the pancreatic parenchyma resulted in minor changes during the early phase but led to the persistence of inflammatory and fibrotic foci in the recovery phase. In chronic pancreatitis, NEMO deletion aggravated inflammation and fibrosis, inhibited compensatory acinar cell proliferation, and enhanced acinar atrophy and acinar-ductal metaplasia. Gene expression analysis revealed sustained activation of profibrogenic genes and the CXCL12/CXCR4 axis in the absence of epithelial NEMO. In human chronic pancreatitis samples, the CXCL12/CXCR4 axis was activated as well, with CXCR4 expression correlating with the degree of fibrosis. The aggravating effects of NEMO deletion were attenuated by the administration of the CXCR4 antagonist AMD3100. Our results suggest that NEMO in epithelial cells exerts a protective effect during pancreatitis by limiting inflammation and fibrosis and improving acinar cell regeneration. The CXCL12/CXCR4 axis is an important mediator of that effect and may also be of importance in human chronic pancreatitis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  13. Mixed acinar-neuroendocrine carcinoma of the pancreas

    DEFF Research Database (Denmark)

    Jakobsen, Mark; Klöppel, Günter; Detlefsen, Sönke

    2016-01-01

    of the English-language literature revealed 44 previously published cases of resected MAECs. We found that, compared to pure acinar cell carcinoma, patients with MAEC have a slightly higher age and are less frequently males, as the male / female ratio was almost equal. The histogenesis of MAEC is still...

  14. Adrenoceptor-activated nitric oxide synthesis in salivary acinar cells

    DEFF Research Database (Denmark)

    Looms, Dagnia; Dissing, Steen; Tritsaris, Katerina

    2000-01-01

    We investigated the cellular regulation of nitric oxide synthase (NOS) activity in isolated acinar cells from rat parotid and human labial salivary glands, using the newly developed fluorescent nitric oxide (NO) indicator, DAF-2. We found that sympathetic stimulation with norepinephrine (NE) caused...

  15. The risk for immediate postoperative complications after pancreaticoduodenectomy is increased by high frequency of acinar cells and decreased by prevalent fibrosis of the cut edge of pancreas.

    Science.gov (United States)

    Laaninen, Matias; Bläuer, Merja; Vasama, Kaija; Jin, Haitao; Räty, Sari; Sand, Juhani; Nordback, Isto; Laukkarinen, Johanna

    2012-08-01

    Soft pancreas is considered as a factor for pancreatitis after pancreaticoduodenectomy, which in turn constitutes a high risk for local complications. The aim was to analyze the proportion of different cell types in the cut edge of pancreas (CEP) in relation to postoperative pancreatitis and other complications after pancreaticoduodenectomy. Data from postoperative follow-up was collected on 40 patients who had undergone pancreaticoduodenectomy. Positive urine trypsinogen-2, an early detector of pancreatitis, was checked on days 1 to 6 after operation. Drain amylase was measured on postoperative day 3. Anastomotic leakages, delayed gastric emptying, and other complications were registered. The areas of different cell types were calculated from the entire hematoxylin-eosin-stained section of CEP. High frequency of acinar cells in the CEP significantly increased positive urine trypsinogen-2 days, drain amylase values, and delayed gastric emptying. In a subgroup of patients with more than 40% acini in the CEP, there were significantly more postoperative complications. Increased fibrosis correlated with a small number of positive urine trypsinogen-2 days and postoperative complications. A large number of acinar cells in the CEP increases, whereas extensive fibrosis in the CEP decreases, the risk for postoperative complications after pancreaticoduodenectomy. These results emphasize the importance of acini in the development of postoperative complications.

  16. Inhibition of human pancreatic and biliary output but not intestinal motility by physiological intraileal lipid loads

    DEFF Research Database (Denmark)

    Keller, Jutta; Holst, Jens Juul; Layer, Peter

    2005-01-01

    Lipid perfusion into the distal ileal lumen at supraphysiological loads inhibits pancreatic exocrine secretion and gastrointestinal motility in humans. In the present study, we sought to determine the effects of physiological postprandial intraileal lipid concentrations on endogenously stimulated....... Physiological postprandial ileal lipid concentrations dose dependently inhibited human digestive pancreatic protease and bile acid output, but not intestinal motor activity. Thus physiological postprandial ileal nutrient exposure may be of importance for the termination of digestive secretory responses...

  17. Pancreatic Cancer

    Science.gov (United States)

    ... hormones that help control blood sugar levels. Pancreatic cancer usually begins in the cells that produce the juices. Some risk factors for developing pancreatic cancer include Smoking Long-term diabetes Chronic pancreatitis Certain ...

  18. The Value of Secretin-Enhanced MRCP in Patients With Recurrent Acute Pancreatitis.

    Science.gov (United States)

    Sandrasegaran, Kumar; Tahir, Bilal; Barad, Udaykamal; Fogel, Evan; Akisik, Fatih; Tirkes, Temel; Sherman, Stuart

    2017-02-01

    The purpose of this study is to assess the additional value of secretin-enhanced MRCP over conventional (non-secretin-enhanced) MRCP in diagnosing disease in patients with recurrent acute pancreatitis. A retrospective review of a radiology database found 72 patients with recurrent acute pancreatitis who had secretin-enhanced MRCP and ERCP correlation within 3 months of each other between January 2007 and December 2011. Of these patients, 54 had no history of pancreatic tumor or surgery and underwent MRI more than 3 months after an episode of acute pancreatitis. In addition, 57 age- and sex-matched control subjects with secretin-enhanced MRCP and ERCP correlation and without a diagnosis of recurrent acute pancreatitis or chronic pancreatitis were enrolled as the control group. All studies were anonymized, and secretin-enhanced MRCP images (image set A) were separated from conventional 2D and 3D MRCP and T2-weighted images (image set B). Image sets A and B for each patient were assigned different and randomized case numbers. Two blinded reviewers independently assessed both image sets for ductal abnormalities and group A image sets for exocrine response to secretin. There were statistically significantly more patients with recurrent acute pancreatitis with reduced exocrine function compared with patients in the control group (32% vs 9%; p pancreatitis were more likely to have side branch dilation (p = 0.02; odds ratio, 3.6), but not divisum, compared with the control group. Secretin-enhanced images were superior to non-secretin-enhanced images for detecting ductal abnormalities in patients with recurrent acute pancreatitis, with higher sensitivity (76% vs 56%; p = 0.01) and AUC values (0.983 vs 0.760; p pancreatitis showed exocrine functional abnormalities. Secretin-enhanced MRCP had a significantly higher yield for ductal abnormalities than did conventional MRI and should be part of the MRCP protocol for investigation of patients with recurrent acute pancreatitis.

  19. Activated wnt signaling in stroma contributes to development of pancreatic mucinous cystic neoplasms.

    Science.gov (United States)

    Sano, Makoto; Driscoll, David R; De Jesus-Monge, Wilfredo E; Klimstra, David S; Lewis, Brian C

    2014-01-01

    Pancreatic mucinous cystic neoplasm (MCN), a cystic tumor of the pancreas that develops most frequently in women, is a potential precursor to pancreatic ductal adenocarcinoma. MCNs develop primarily in the body and tail of the pancreas and are characterized by the presence of a mucinous epithelium and ovarian-like subepithelial stroma. We investigated the involvement of Wnt signaling in KRAS-mediated pancreatic tumorigenesis and development of MCN in mice, and Wnt activation in human MCN samples. LSL-Kras(G12D), Ptf1a-cre mice were crossed with elastase-tva mice to allow for introduction of genes encoded by the replication-competent avian sarcoma-leukosis virus long-terminal repeat with splice acceptor viruses to pancreatic acinar cells and acinar cell progenitors, postnatally and sporadically. Repeat with splice acceptor viruses that expressed Wnt1 were delivered to the pancreatic epithelium of these mice; pancreatic lesions were analyzed by histopathology and immunohistochemical analyses. We analyzed levels of factors in Wnt signaling pathways in 19 MCN samples from patients. Expression of Wnt1 in the pancreatic acinar cells and acinar cell progenitors of female mice led to development of unilocular or multilocular epithelial cysts in the pancreas body and tail, similar to MCN. The cystic lesions resembled the estrogen receptor- and progesterone receptor-positive ovarian-like stroma of MCN, but lacked the typical mucinous epithelium. Activated Wnt signaling, based on nuclear localization of β-catenin, was detected in the stroma but not cyst epithelium. Wnt signaling to β-catenin was found to be activated in MCN samples from patients, within the ovarian-like stroma, consistent with the findings in mice. Based on studies of mice and pancreatic MCN samples from patients, the canonical Wnt signaling pathway becomes activated and promotes development of the ovarian-like stroma to contribute to formation of MCNs. Copyright © 2014 AGA Institute. Published by Elsevier

  20. Comparing acid steatocrit and faecal elastase estimations for use in M-ANNHEIM staging for pancreatitis.

    Science.gov (United States)

    Kamath, M Ganesh; Pai, C Ganesh; Kamath, Asha; Kurien, Annamma

    2017-03-28

    To compare two tests for exocrine pancreatic function (EPF) for use in M-ANNHEIM staging for pancreatitis. One hundred and ninety four consecutive patients with acute pancreatitis (AP; n = 13), recurrent acute pancreatitis (RAP; n = 65) and chronic pancreatitis (CP; n = 116) were enrolled. EPF was assessed by faecal elastase-1 (FE-1) estimation and stool fat excretion by the acid steatocrit method. Patients were classified as per M-ANNHEIM stages separately based on the results of the two tests for comparison. Independent Student's t-test, χ2 test, Kruskal-Wallis test, Mann-Whitney U test and McNemar's test were used as appropriate. Sixty-one (52.5%) patients with CP had steatorrhoea when assessed by the acid steatocrit method; 79 (68.1%) with CP had exocrine insufficiency by the FE-1 test (χ2 test, P pancreatitis by the M-ANNHEIM classification since it diagnosed a higher proportion of patients with exocrine insufficiency.

  1. Pancreatic Stellate Cells : A Starring Role in Normal and Diseased Pancreas

    Directory of Open Access Journals (Sweden)

    Minoti eApte

    2012-08-01

    Full Text Available While the morphology and function of cells of the exocrine and endocrine pancreas have been studied over several centuries, one important cell type in the gland, the pancreatic stellate cell (PSC, had remained undiscovered until as recently as twenty years ago. Even after its first description in 1982, it was to be another 16 years before its biology could begin to be studied, because it was only in 1998 that methods were developed to isolate and culture PSCs from rodent and human pancreas. PSCs are now known to play a critical role in pancreatic fibrosis, a consistent histological feature of two major diseases of the pancreas - chronic pancreatitis and pancreatic cancer. In health, PSCs maintain normal tissue architecture via regulation of the synthesis and degradation of extracellular matrix (ECM proteins. Recent studies have also implied other additional functions for PSCs as progenitor cells, immune cells or intermediaries in exocrine pancreatic secretion in humans.During pancreatic injury, PSCs transform from their quiescent phase into an activated, myofibroblast-like phenotype that secretes excessive amounts of ECM proteins leading to the fibrosis of chronic pancreatitis and pancreatic cancer. An ever increasing number of factors that stimulate and/or inhibit PSC activation via paracrine and autocrine pathways are being identified and characterized. It is also now established that PSCs interact closely with pancreatic cancer cells to facilitate cancer progression. Based on these findings, several therapeutic strategies have been examined in experimental models of chronic pancreatitis as well as pancreatic cancer, in a bid to inhibit/retard PSC activation and thereby alleviate chronic pancreatitis or reduce tumour growth in pancreatic cancer. The challenge that remains is to translate these pre-clinical developments into clinically applicable treatments for patients with chronic pancreatitis and pancreatic cancer.

  2. Acute Pancreatitis and Pregnancy

    Science.gov (United States)

    ... Pancreatitis Acute Pancreatitis and Pregnancy Acute Pancreatitis and Pregnancy Timothy Gardner, MD Acute pancreatitis is defined as ... pancreatitis in pregnancy. Reasons for Acute Pancreatitis and Pregnancy While acute pancreatitis is responsible for almost 1 ...

  3. Effect of P2X(7) receptor knockout on exocrine secretion of pancreas, salivary glands and lacrimal glands

    DEFF Research Database (Denmark)

    Novak, Ivana; Jans, Ida M; Wohlfahrt, Louise

    2010-01-01

    the P2X(7) receptors affect fluid secretion in pancreas, salivary glands and tear glands. We monitored gland secretions in in vivo preparations of wild-type and P2X(7)(-/-) (Pfizer) mice stimulated with pilocarpine. In cell preparations from pancreas, parotid and lacrimal glands we measured ATP release......The purinergic P2X(7) receptors are expressed in different cell types where they have varied functions, including regulation of cell survival. The P2X(7) receptors are also expressed in exocrine glands, but their integrated role in secretion is unclear. The aim of our study was to determine whether...... and intracellular Ca(2+) activity using Fura-2. The data showed that pancreatic secretion and salivary secretions were reduced in P2X(7)(-/-) mice, and in contrast, tear secretion was increased in P2X(7)(-/-) mice. The secretory phenotype was also dependent on the sex of the animal, such that males were more...

  4. Anatomic variants of the pancreatic duct and their clinical relevance: an MR-guided study in the general population

    Energy Technology Data Exchange (ETDEWEB)

    Buelow, Robin; Thiel, Robert; Thamm, Patrick; Messner, Philip; Hosten, Norbert; Kuehn, Jens-Peter [University Medicine, Ernst Moritz Arndt University Greifswald, Department of Radiology and Neuroradiology, Greifswald (Germany); Simon, Peter; Lerch, Markus M.; Mayerle, Julia [University Medicine, Ernst Moritz Arndt University Greifswald, Division of Gastroenterology and Department of Medicine A, Greifswald (Germany); Voelzke, Henry [University Medicine, Ernst Moritz Arndt University Greifswald, Institute for Community Medicine, Greifswald (Germany)

    2014-12-15

    To investigate the frequency of pancreatic duct (PD) variants and their effect on pancreatic exocrine function in a population-based study using non-invasive secretin-stimulated magnetic resonance cholangiopancreatography (sMRCP). Nine hundred and ninety-five volunteers, 457 women and 538 men, aged 51.9 ± 13.4 years, underwent navigator-triggered, T2-weighted, 3D turbo spin echo MRCP on a 1.5 T system after 1 unit/kg secretin administration. Two readers evaluated images for PD variants. Pancreatic exocrine function and morphological signs of chronic pancreatitis such as abnormalities of the main PD, side branch dilatation, and pancreatic cysts were evaluated and related to PD variants using a Kruskal-Wallis test and post hoc analysis. Of all sMRCP, 93.2 % were of diagnostic quality. Interobserver reliability for detection of PD variants was found to be kappa 0.752 (95 %CI, 0.733 - 0.771). Normal PD variants were observed in 90.4 % (n = 838/927). Variants of pancreas divisum was identified in 9.6 % (n = 89/927). Abnormalities of the main PD, side branch dilatation, and pancreatic cysts were observed in 2.4 %, 16.6 %, and 27.7 %, respectively, and were not significantly different between pancreas divisum and non-divisum group (P = 0.122; P = 0.152; P = 0.741). There was no association between PD variants and pancreatic exocrine function (P = 0.367). PD variants including pancreas divisum are not associated with morphological signs of chronic pancreatitis or restriction of pancreatic exocrine function. (orig.)

  5. COMPUTER-AIDED DETECTION OF ACINAR SHADOWS IN CHEST RADIOGRAPHS

    Directory of Open Access Journals (Sweden)

    Tao Xu

    2013-05-01

    Full Text Available Despite the technological advances in medical diagnosis, accurate detection of infectious tuberculosis (TB still poses challenges due to complex image features and thus infectious TB continues to be a public health problem of global proportions. Currently, the detection of TB is mainly conducted visually by radiologists examining chest radiographs (CXRs. To reduce the backlog of CXR examination and provide more precise quantitative assessment, computer-aided detection (CAD systems for potential lung lesions have been increasingly adopted and commercialized for clinical practice. CADs work as supporting tools to alert radiologists on suspected features that could have easily been neglected. In this paper, an effective CAD system aimed for acinar shadow regions detection in CXRs is proposed. This system exploits textural and photometric features analysis techniques which include local binary pattern (LBP, grey level co-occurrence matrix (GLCM and histogram of oriented gradients (HOG to analyze target regions in CXRs. Classification of acinar shadows using Adaboost is then deployed to verify the performance of a combination of these techniques. Comparative study in different image databases shows that the proposed CAD system delivers consistent high accuracy in detecting acinar shadows.

  6. A common variant of PNPLA3 (p.I148M) is not associated with alcoholic chronic pancreatitis.

    NARCIS (Netherlands)

    Rosendahl, J.; Tonjes, A.; Schleinitz, D.; Kovacs, P.; Wiegand, J.; Ruffert, C.; Jesinghaus, M.; Schober, R.; Herms, M.; Grutzmann, R.; Schulz, H.U.; Stickel, F.; Werner, J.; Bugert, P.; Bluher, M.; Stumvoll, M.; Bohm, S.; Berg, T. van den; Wittenburg, H.; Mossner, J.; Morsche, R.H.M. te; Derikx, M.; Keim, V.; Witt, H.; Drenth, J.P.H.

    2012-01-01

    BACKGROUND: Chronic pancreatitis (CP) is an inflammatory disease that in some patients leads to exocrine and endocrine dysfunction. In industrialized countries the most common aetiology is chronic alcohol abuse. Descriptions of associated genetic alterations in alcoholic CP are rare. However, a

  7. Membrane potential and conductance of frog skin gland acinar cells in resting conditions and during stimulation with agonists of macroscopic secretion

    DEFF Research Database (Denmark)

    Sørensen, Jakob B.; Larsen, Erik Hviid

    1999-01-01

    Adrenaline; carbachol; Cl- secretion; exocrine gland; isoproterenol; noradrenaline; prostaglandin E*U2......Adrenaline; carbachol; Cl- secretion; exocrine gland; isoproterenol; noradrenaline; prostaglandin E*U2...

  8. The Content of Free Amino Acids in Blood Serum of Patients with Chronic Pancreatitis

    OpenAIRE

    RUSYN V.I.; Ye.S. Sirchak; N.Yu. Kurchak

    2013-01-01

    The results of examination of 48 patients with chronic pancreatitis are given. We had stablished imbalance in content of free amino acids of blood serum with preferential reduction of the levels of methionine (up to (0.63 ± 0.10) mg%), tryptophan (up to (0.74 ± 0.15) mg%), leucine and isoleucine (up to (0.41 ± 0.06) mg%). Amino acid imbalance in patients with chronic pancreatitis promotes development of significant clinical manifestations of exocrine pancreatic insufficiency.

  9. The Content of Free Amino Acids in Blood Serum of Patients with Chronic Pancreatitis

    Directory of Open Access Journals (Sweden)

    V.I. Rusyn

    2013-05-01

    Full Text Available The results of examination of 48 patients with chronic pancreatitis are given. We had stablished imbalance in content of free amino acids of blood serum with preferential reduction of the levels of methionine (up to (0.63 ± 0.10 mg%, tryptophan (up to (0.74 ± 0.15 mg%, leucine and isoleucine (up to (0.41 ± 0.06 mg%. Amino acid imbalance in patients with chronic pancreatitis promotes development of significant clinical manifestations of exocrine pancreatic insufficiency.

  10. Sorting of a HaloTag protein that has only a signal peptide sequence into exocrine secretory granules without protein aggregation.

    Science.gov (United States)

    Fujita-Yoshigaki, Junko; Matsuki-Fukushima, Miwako; Yokoyama, Megumi; Katsumata-Kato, Osamu

    2013-11-15

    The mechanism involved in the sorting and accumulation of secretory cargo proteins, such as amylase, into secretory granules of exocrine cells remains to be solved. To clarify that sorting mechanism, we expressed a reporter protein HaloTag fused with partial sequences of salivary amylase protein in primary cultured parotid acinar cells. We found that a HaloTag protein fused with only the signal peptide sequence (Met(1)-Ala(25)) of amylase, termed SS25H, colocalized well with endogenous amylase, which was confirmed by immunofluorescence microscopy. Percoll-density gradient centrifugation of secretory granule fractions shows that the distributions of amylase and SS25H were similar. These results suggest that SS25H is transported to secretory granules and is not discriminated from endogenous amylase by the machinery that functions to remove proteins other than granule cargo from immature granules. Another reporter protein, DsRed2, that has the same signal peptide sequence also colocalized with amylase, suggesting that the sorting to secretory granules is not dependent on a characteristic of the HaloTag protein. Whereas Blue Native PAGE demonstrates that endogenous amylase forms a high-molecular-weight complex, SS25H does not participate in the complex and does not form self-aggregates. Nevertheless, SS25H was released from cells by the addition of a β-adrenergic agonist, isoproterenol, which also induces amylase secretion. These results indicate that addition of the signal peptide sequence, which is necessary for the translocation in the endoplasmic reticulum, is sufficient for the transportation and storage of cargo proteins in secretory granules of exocrine cells.

  11. Acute pancreatitis.

    Science.gov (United States)

    Munsell, Melissa A; Buscaglia, Jonathan M

    2010-04-01

    Acute pancreatitis is a common disease most frequently caused by gallstone disease or excess alcohol ingestion. Diagnosis is usually based on characteristic symptoms, often in conjunction with elevated serum pancreatic enzymes. Imaging is not always necessary, but may be performed for many reasons, such as to confirm a diagnosis of pancreatitis, rule out other causes of abdominal pain, elucidate the cause of pancreatitis, or to evaluate for complications such as necrosis or pseudocysts. Though the majority of patients will have mild, self-limiting disease, some will develop severe disease associated with organ failure. These patients are at risk to develop complications from ongoing pancreatic inflammation such as pancreatic necrosis, fluid collections, pseudocysts, and pancreatic duct disruption. Validated scoring systems can help predict the severity of pancreatitis, and thus, guide monitoring and intervention.Treatment of acute pancreatitis involves supportive care with fluid replacement, pain control, and controlled initiation of regular food intake. Prophylactic antibiotics are not recommended in acute pancreatitis if there is no evidence of pancreatic infection. In patients who fail to improve, further evaluation is necessary to assess for complications that require intervention such as pseudocysts or pancreatic necrosis. Endoscopy, including ERCP and EUS, and/or cholecystectomy may be indicated in the appropriate clinical setting. Ultimately, the management of the patient with severe acute pancreatitis will require a multidisciplinary approach. (c) 2010 Society of Hospital Medicine.

  12. Complicated Pancreatitis

    NARCIS (Netherlands)

    Bakker, O.J.

    2015-01-01

    Research questions addressed in this thesis: What is the accuracy of serum blood urea nitrogen as early predictor of complicated pancreatitis? ; What is difference in clinical outcome between patients with pancreatic parenchymal necrosis and patients with extrapancreatic necrosis without necrosis

  13. Pancreatitis - children

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/007679.htm Pancreatitis - children To use the sharing features on this page, please enable JavaScript. Pancreatitis in children occurs when the pancreas becomes swollen ...

  14. [Nutritional repercussions and management of chronic pancreatitis].

    Science.gov (United States)

    Botella Romero, F; Alfaro Martínez, J J

    2008-05-01

    The pancreas is a retroperitoneal organ that releases water, bicarbonate and digestive enzymes by the main pancreatic duct (MPD) into the duodenum. Chronic pancreatitis (CP) is typically caused, in adults, by chronic alcohol abuse and, less frequently hypertriglyceridemia, primary hyperparathyroidism or cystic fibrosis. Exocrine dysfunction results in malabsorption of fat and subsequent steatorrhea. Damage to pancreatic endocrine function is a late finding in CP and results in hyperglycaemia or overt diabetes mellitus. Care of patients with CP principally involves management of pain. A significant change in the pain pattern or the sudden onset of persistent symptoms suggests the need to rule out other potential etiologies, including peptic ulcer disease, biliary obstruction, pseudocysts, pancreatic carcinoma, and pancreatic duct stricture or stones, then is important to establish a secure diagnosis. Management of pain should then proceed in a judicious stepwise approach avoiding opioids dependence. Patients should be advised to stop alcohol intake. Fat malabsorption and other complications may also arise. Management of steatorrhea should begin with small meals and restriction in fat intake. Pancreatic enzyme supplements can relieve symptoms and reduce malabsorption in patients who do not respond to dietary restriction. Enzymes at high doses should be used with meals. Treatment with acid suppression to reduce inactivation of the enzymes from gastric acid are recommended. Supplementation with medium chain triglycerides and fat soluble vitamin replacement may be required. Management of other complications (such as pseudocysts, bile duct or duodenal obstruction, pancreatic ascites, splenic vein thrombosis and pseudoaneurysms) often requires aggressive approach with the patient kept on total parenteral nutrition to minimize pancreatic stimulation.

  15. Heterotopic pancreatic tissue obstructing the gallbladder neck: a case report.

    Science.gov (United States)

    Weppner, Justin L; Wilson, Matthew R; Ricca, Robert; Lucha, Paul A

    2009-09-04

    Heterotopic pancreatic tissue is defined as pancreatic tissue outside the boundaries of the pancreas that has neither anatomic nor vascular continuity with the pancreas. Heterotopic pancreatic tissue in the gallbladder is uncommon and has rarely been reported to cause symptoms. We report a case of heterotopic pancreatic tissue obstructing the gallbladder neck resulting in cholecystitis. A 26-year-old female presented with right upper quadrant abdominal pain and fever. On physical examination the right upper quadrant was tender to palpation with a positive Murphy's sign. Laboratory tests were significant for elevated aspartate aminotransferase and alanine aminotransferase. Transabdominal sonography showed gallbladder wall thickening, a positive sonographic Murphy's sign, and an apparent large non-mobile stone at the gallbladder neck. Pathologic examination revealed cholecystitis but instead of a large stone there was a tan-yellow necrotic mass at the gallbladder neck. Microscopically, the mass consisted of heterotopic pancreatic tissue containing exocrine pancreatic acini, ducts, and islets of Langerhans. The final diagnosis was acute cholecystitis secondary to obstruction by heterotopic pancreatic tissue. Although heterotopic pancreatic tissue is usually an incidental finding on pathologic exam, one should not exclude it in the differential diagnosis of symptomatic gallbladder disease of indefinite etiology.

  16. The evolution of the surgical treatment of chronic pancreatitis.

    Science.gov (United States)

    Andersen, Dana K; Frey, Charles F

    2010-01-01

    To establish the current status of surgical therapy for chronic pancreatitis, recent published reports are examined in the context of the historical advances in the field. The basis for decompression (drainage), denervation, and resection strategies for the treatment of pain caused by chronic pancreatitis is reviewed. These divergent approaches have finally coalesced as the head of the pancreas has become apparent as the nidus of chronic inflammation. The recent developments in surgical methods to treat the complications of chronic pancreatitis and the results of recent prospective randomized trials of operative approaches were reviewed to establish the current best practices. Local resection of the pancreatic head, with or without duct drainage, and duodenum-preserving pancreatic head resection offer outcomes as effective as pancreaticoduodenectomy, with lowered morbidity and mortality. Local resection or excavation of the pancreatic head offers the advantage of lowest cost and morbidity and early prevention of postoperative diabetes. The late incidences of recurrent pain, diabetes, and exocrine insufficiency are equivalent for all 3 surgical approaches. Local resection of the pancreatic head appears to offer best outcomes and lowest risk for the management of the pain of chronic pancreatitis.

  17. Pancreatic mesenchyme regulates epithelial organogenesis throughout development.

    Directory of Open Access Journals (Sweden)

    Limor Landsman

    2011-09-01

    Full Text Available The developing pancreatic epithelium gives rise to all endocrine and exocrine cells of the mature organ. During organogenesis, the epithelial cells receive essential signals from the overlying mesenchyme. Previous studies, focusing on ex vivo tissue explants or complete knockout mice, have identified an important role for the mesenchyme in regulating the expansion of progenitor cells in the early pancreas epithelium. However, due to the lack of genetic tools directing expression specifically to the mesenchyme, the potential roles of this supporting tissue in vivo, especially in guiding later stages of pancreas organogenesis, have not been elucidated. We employed transgenic tools and fetal surgical techniques to ablate mesenchyme via Cre-mediated mesenchymal expression of Diphtheria Toxin (DT at the onset of pancreas formation, and at later developmental stages via in utero injection of DT into transgenic mice expressing the Diphtheria Toxin receptor (DTR in this tissue. Our results demonstrate that mesenchymal cells regulate pancreatic growth and branching at both early and late developmental stages by supporting proliferation of precursors and differentiated cells, respectively. Interestingly, while cell differentiation was not affected, the expansion of both the endocrine and exocrine compartments was equally impaired. To further elucidate signals required for mesenchymal cell function, we eliminated β-catenin signaling and determined that it is a critical pathway in regulating mesenchyme survival and growth. Our study presents the first in vivo evidence that the embryonic mesenchyme provides critical signals to the epithelium throughout pancreas organogenesis. The findings are novel and relevant as they indicate a critical role for the mesenchyme during late expansion of endocrine and exocrine compartments. In addition, our results provide a molecular mechanism for mesenchymal expansion and survival by identifying β-catenin signaling as an

  18. Effects of Benzodiazepines on Acinar and Myoepithelial Cells.

    Science.gov (United States)

    Mattioli, Tatiana M F; Alanis, Luciana R A; Sapelli, Silvana da Silva; de Lima, Antonio A S; de Noronha, Lucia; Rosa, Edvaldo A R; Althobaiti, Yusuf S; Almalki, Atiah H; Sari, Youssef; Ignacio, Sergio A; Johann, Aline C B R; Gregio, Ana M T

    2016-01-01

    Benzodiazepines (BZDs), the most commonly prescribed psychotropic drugs with anxiolytic action, may cause hyposalivation. It has been previously shown that BZDs can cause hypertrophy and decrease the acini cell number. In this study, we investigated the effects of BZDs and pilocarpine on rat parotid glands, specifically on acinar, ductal, and myoepithelial cells. Ninety male Wistar rats were divided into nine groups. Control groups received a saline solution for 30 days (C30) and 60 days (C60), and pilocarpine (PILO) for 60 days. Experimental groups received lorazepam (L30) and midazolam (M30) for 30 days. Another group (LS60 or MS60) received lorazepam or midazolam for 30 days, respectively, and saline for additional 30 days. Finally, other groups (LP60 or MP60) received either lorazepam or midazolam for 30 days, respectively, and pilocarpine for additional 30 days. The expression of calponin in myoepithelial cells and the proliferating cell nuclear antigen (PCNA) in acinar and ductal cells were evaluated. Animals treated with lorazepam showed an increase in the number of positive staining cells for calponin as compared to control animals (p glands.

  19. Reappraisal of xenobiotic-induced, oxidative stress-mediated cellular injury in chronic pancreatitis: A systematic review

    Science.gov (United States)

    Siriwardena, Ajith K

    2014-01-01

    AIM: To reappraise the hypothesis of xenobiotic induced, cytochrome P450-mediated, micronutrient-deficient oxidative injury in chronic pancreatitis. METHODS: Individual searches of the Medline and Embase databases were conducted for each component of the theory of oxidative-stress mediated cellular injury for the period from 1st January 1990 to 31st December 2012 using appropriate medical subject headings. Boolean operators were used. The individual components were drawn from a recent update on theory of oxidative stress-mediated cellular injury in chronic pancreatitis. RESULTS: In relation to the association between exposure to volatile hydrocarbons and chronic pancreatitis the studies fail to adequately control for alcohol intake. Cytochrome P450 (CYP) induction occurs as a diffuse hepatic and extra-hepatic response to xenobiotic exposure rather than an acinar cell-specific process. GSH depletion is not consistently confirmed. There is good evidence of superoxide dismutase depletion in acute phases of injury but less to support a chronic intra-acinar depletion. Although the liver is the principal site of CYP induction there is no evidence to suggest that oxidative by-products are carried in bile and reflux into the pancreatic duct to cause injury. CONCLUSION: Pancreatic acinar cell injury due to short-lived oxygen free radicals (generated by injury mediated by prematurely activated intra-acinar trypsin) is an important mechanism of cell damage in chronic pancreatitis. However, in contemporary paradigms of chronic pancreatitis this should be seen as one of a series of cell-injury mechanisms rather than a sole mediator. PMID:24659895

  20. Occupational exposures and risk of pancreatic cancer.

    Science.gov (United States)

    Santibañez, Miguel; Vioque, Jesús; Alguacil, Juan; de la Hera, Manuela García; Moreno-Osset, Eduardo; Carrato, Alfredo; Porta, Miquel; Kauppinen, Timo

    2010-10-01

    The objective was to analyze the relationship between occupation (and specific occupational exposures) and risk of exocrine pancreatic cancer (EPC). We conducted a multicenter hospital-based case-control study in Eastern Spain. We included 161 incident cases of EPC (59.6% men, 94 with histological confirmation, of whom 80% had ductal adenocarcinoma). Cases were frequency-matched with 455 controls by sex, age and province of residence. Information was elicited using structured questionnaires. Occupations were coded according to the Spanish version of the International Standard Classification of Occupations 1988. Occupational exposure to a selection of carcinogenic substances was assessed with the Finnish Job-Exposure Matrix (FINJEM). Odds ratios (OR) and 95% confidence intervals (CI) were estimated by multiple logistic regression, adjusting for sex, age, province, education, alcohol and smoking. A higher risk of EPC was associated with having worked as 'Miners, shotfirers, stone cutters and carvers', 'Machinery mechanics and fitters', 'Building trades workers' and 'Motor vehicle drivers' in men, 'Office Clerks' in women, and 'Waiters' in both sexes. Cases with ductal adenocarcinomas were more likely to have been exposed to chlorinated hydrocarbon solvents (OR = 4.1, 95% CI: 1.1-15.2, p-trend = 0.04). We also observed significant associations with exposure to 'synthetic polymer dust exposure' and 'ionizing radiation'. Suggestive increases in risk were observed for 'pesticides', 'diesel and gasoline engine exhaust', and 'hydrocarbon solvents'. Results support the hypothesis that occupational exposure to chlorinated hydrocarbon solvents is associated with exocrine pancreatic cancer.

  1. Role of bile acids in carcinogenesis of pancreatic cancer: An old topic with new perspective.

    Science.gov (United States)

    Feng, Hui-Yi; Chen, Yang-Chao

    2016-09-07

    The role of bile acids in colorectal cancer has been well documented, but their role in pancreatic cancer remains unclear. In this review, we examined the risk factors of pancreatic cancer. We found that bile acids are associated with most of these factors. Alcohol intake, smoking, and a high-fat diet all lead to high secretion of bile acids, and bile acid metabolic dysfunction is a causal factor of gallstones. An increase in secretion of bile acids, in addition to a long common channel, may result in bile acid reflux into the pancreatic duct and to the epithelial cells or acinar cells, from which pancreatic adenocarcinoma is derived. The final pathophysiological process is pancreatitis, which promotes dedifferentiation of acinar cells into progenitor duct-like cells. Interestingly, bile acids act as regulatory molecules in metabolism, affecting adipose tissue distribution, insulin sensitivity and triglyceride metabolism. As a result, bile acids are associated with three risk factors of pancreatic cancer: obesity, diabetes and hypertriglyceridemia. In the second part of this review, we summarize several studies showing that bile acids act as cancer promoters in gastrointestinal cancer. However, more question are raised than have been solved, and further oncological and physiological experiments are needed to confirm the role of bile acids in pancreatic cancer carcinogenesis.

  2. Autoimmune pancreatitis

    Directory of Open Access Journals (Sweden)

    Davorin Dajčman

    2007-05-01

    Full Text Available Background: Autoimmune pancreatitis is a recently described type of pancreatitis of presumed autoimmune etiology. Autoimmune pancreatitis is often misdiagnosed as pancreatic cancer difficult, since their clinical presentations are often similar. The concept of autoimmune pancreatitis was first published in 1961. Since then, autoimmune pancreatitis has often been treated not as an independent clinical entity but rather as a manifestation of systemic disease. The overall prevalence and incidence of the disease have yet to be determined, but three series have reported the prevalence as between 5 and 6 % of all patients with chronic pancreatitis. Patient vary widely in age, but most are older than 50 years. Patients with autoimmune pancreatitis usually complain of the painless jaundice, mild abdominal pain and weight loss. There is no laboratory hallmark of the disease, even if cholestatic profiles of liver dysfunction with only mild elevation of amylase and lipase levels have been reported.Conclusions: Proposed diagnostic criteria contains: (1 radiologic imaging, diffuse enlargement of the pancreas and diffusely irregular narrowing of the main pancreatic duct, (2 laboratory data, elevated levels of serum ã-globulin and/or IgG, specially IgG4, or the presence of autoantibodies and (3 histopathologic examination, fibrotic change with dense lymphoplasmacytic infiltration in the pancreas. For correct diagnosis of autoimmune pancreatitis, criterion 1 must be present with criterion 2 and/or 3. Autoimmune pancreatitis is frequently associated with rheumatoid arthritis, Sjogren’s syndrome, inflammatory bowel disease, tubulointersticial nephritis, primary sclerosing cholangitis and idiopathic retroperitoneal fibrosis. Pancreatic biopsy using an endoscopic ultrasound-guided fine needle aspiration biopsy is the most important diagnostic method today. Treatment with corticosteroids leads to the and resolution of pancreatic inflamation, obstruction and

  3. Effect of buprenorphine on pancreatic enzyme synthesis and secretion in normal rats and rats with acute edematous pancreatitis.

    Science.gov (United States)

    Ogden, J M; Modlin, I M; Gorelick, F S; Marks, I N

    1994-11-01

    Pancreatic enzyme secretion is inhibited during acute pancreatitis, resulting in an increase in acinar zymogen content. Since the premature activation of zymogens has been assigned a central role in the pathogenesis of acute pancreatitis, minimizing the amount of stored zymogens might lead to less severe acute pancreatitis. Inhibition of enzyme synthesis or stimulation of enzyme secretion would result in reduction of zymogen stores. Opiates have a varying effect on pancreatic secretion, depending on the dosage, site of administration, and presence of pancreatic stimulants. The effect of opiates and acute pancreatitis on individual pancreatic enzyme synthesis is unknown. The following study was undertaken in order to examine the effects of an opiate on pancreatic enzyme secretion and synthesis during experimental acute pancreatitis. Four groups of rats were studied. Group I received cerulein (25 micrograms/kg); group II received an opiate, buprenorphine (BPN, 0.5 mg/kg); and group III received cerulein and BPN. Drugs were dissolved in gelatin/saline and injected subcutaneously. A control group (group IV) received only gelatin/saline. Rats were sacrificed 4 hr after injection, and pancreatic mass was measured. Pancreatic acini were prepared and assayed for amylase and DNA content. Amylase, trypsinogen, chymotrypsinogen and lipase synthesis, and amylase secretion were measured for 2 hr. Results showed that, compared to controls, acini of rats with AP had increased amylase content, a finding consistent with decreased in vivo amylase secretion. Total protein and individual enzyme synthesis rates were significantly lower in the acini of the rats with AP than in those of the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. Genetic inhibition of protein kinase Cε attenuates necrosis in experimental pancreatitis

    Science.gov (United States)

    Liu, Yannan; Tan, Tanya; Jia, Wenzhuo; Lugea, Aurelia; Mareninova, Olga; Waldron, Richard T.; Pandol, Stephen J.

    2014-01-01

    Understanding the regulation of death pathways, necrosis and apoptosis, in pancreatitis is important for developing therapies directed to the molecular pathogenesis of the disease. Protein kinase Cε (PKCε) has been previously shown to regulate inflammatory responses and zymogen activation in pancreatitis. Furthermore, we demonstrated that ethanol specifically activated PKCε in pancreatic acinar cells and that PKCε mediated the sensitizing effects of ethanol on inflammatory response in pancreatitis. Here we investigated the role of PKCε in the regulation of death pathways in pancreatitis. We found that genetic deletion of PKCε resulted in decreased necrosis and severity in the in vivo cerulein-induced pancreatitis and that inhibition of PKCε protected the acinar cells from CCK-8 hyperstimulation-induced necrosis and ATP reduction. These findings were associated with upregulation of mitochondrial Bak and Bcl-2/Bcl-xL, proapoptotic and prosurvival members in the Bcl-2 family, respectively, as well as increased mitochondrial cytochrome c release, caspase activation, and apoptosis in pancreatitis in PKCε knockout mice. We further confirmed that cerulein pancreatitis induced a dramatic mitochondrial translocation of PKCε, suggesting that PKCε regulated necrosis in pancreatitis via mechanisms involving mitochondria. Finally, we showed that PKCε deletion downregulated inhibitors of apoptosis proteins, c-IAP2, survivin, and c-FLIPs while promoting cleavage/inactivation of receptor-interacting protein kinase (RIP). Taken together, our findings provide evidence that PKCε activation during pancreatitis promotes necrosis through mechanisms involving mitochondrial proapoptotic and prosurvival Bcl-2 family proteins and upregulation of nonmitochondrial pathways that inhibit caspase activation and RIP cleavage/inactivation. Thus PKCε is a potential target for prevention and/or treatment of acute pancreatitis. PMID:25035113

  5. Assessment of Nutritional Status, Digestion and Absorption, and Quality of Life in Patients with Locally Advanced Pancreatic Cancer

    Science.gov (United States)

    Lochtenberg-Potjes, C. M.; Wierdsma, N. J.; Scheffer, H. J.; Kazemier, G.; Ottens-Oussoren, K.; Meijerink, M. R.; de van der Schueren, M. A. E.

    2017-01-01

    Background and Aim To provide a comprehensive quantitative assessment of nutritional status, digestion and absorption, and quality of life (QoL) in patients with locally advanced pancreatic cancer (LAPC). Methods Sixteen patients with LAPC were prospectively assessed for weight loss (WL), body mass index (BMI), fat-free mass index (FFMI), handgrip strength (HGS), dietary macronutrient intake, serum vitamin levels, resting and total energy expenditure (REE and TEE, indirect calorimetry), intestinal absorption capacity and fecal losses (bomb calorimetry), exocrine pancreatic function (fecal elastase-1 (FE1)), and gastrointestinal quality of life (GIQLI). Results Two patients had a low BMI, 10 patients had WL > 10%/6 months, 8 patients had a FFMI carbohydrates was observed in, respectively, 9, 8, 12, and 10 patients. FE1 levels were low (nutritional status, most likely as a result of an increased REE and malabsorption due to exocrine pancreatic insufficiency. The trial is registered with PANFIRE clinicaltrials.gov NCT01939665. PMID:28912804

  6. Chronic pancreatitis.

    Science.gov (United States)

    Yang, Dennis; Forsmark, Chris E

    2017-09-01

    Summarize key clinical advances in chronic pancreatitis reported in 2016. Early diagnosis of chronic pancreatitis remains elusive. Recent studies suggest that endoscopic ultrasound may be less accurate than previously thought and new MRI techniques may be helpful. Genetic predisposition may independently affect the clinical course of chronic pancreatitis and the risk for pancreatic cancer. Cigarette smoking may have a greater negative impact on chronic pancreatitis than previously thought and moderate alcohol consumption may be protective. A multidisciplinary approach is necessary for the treatment of type 3 diabetes and nutritional deficiencies in chronic pancreatitis. Although endoscopic therapy remains a reasonable first-line option in treating chronic pancreatitis and its complications, early surgical intervention may be indicated for pain in select patients. Newer endoscopic ultrasound and MRI techniques are being evaluated to help with the early diagnosis of chronic pancreatitis. Both genetic predisposition and cigarette smoking are increasingly recognized as having a major impact in the course of the disease and the risk for pancreatic cancer. Endoscopic therapy is well tolerated and effective for the treatment of chronic pancreatitis and its complications although an early surgical approach for pain may be associated with improved clinical outcomes.

  7. Differential regulation of pancreatic digestive enzymes during chronic high-fat diet-induced obesity in C57BL/6J mice

    NARCIS (Netherlands)

    Birk, R.Z.; Rubio-Aliaga, I.; Boekschoten, M.V.; Danino, H.; Müller, M.R.; Daniel, H.

    2014-01-01

    Exocrine pancreatic digestive enzymes are essential for the digestion of dietary components and are regulated by them. Chronic excess dietary high fat (HF) consumption is a contributing factor of diet-induced obesity (DIO) and associated chronic diseases and requires adaptation by the pancreas. The

  8. Chronic pancreatitis in a patient with malnutrition due to anorexia nervosa.

    Science.gov (United States)

    Wesson, Russell N; Sparaco, Anna; Smith, Martin D

    2008-05-08

    Both acute and chronic pancreatitis are associated with eating disorders, including malnutrition found in anorexia, bulimia, and major depression. We report a case of a female patient suffering from severe malnutrition and anorexia with repeated attacks of pancreatic pain and an enlarging cystic lesion in the pancreatic head. Due to a progressively enlarging lesion on CT, a pancreaticoduodenectomy was performed. Histology demonstrated chronic pancreatitis. The pathogenesis of chronic pancreatitis remains to be well defined. There is evidence that an imbalance between oxidative stress and antioxidant capacity results in pancreatic inflammation and activation of periacinar myofibroblasts. It has been demonstrated that protein energy malnutrition is associated with increased levels of proinflammatory cytokines as well as pancreatic acinar cell damage and ductal disruption. Furthermore, it has been shown that protein energy malnutrition including anorexia nervosa is associated with a depleted antioxidant status. Thus there is a possible pathogenic basis for severe malnutrition leading to chronic pancreatitis. Our patient underwent surgery based on the presumption that she had a symptomatic cystic neoplasm. Chronic pancreatitis was demonstrated. Patients presenting with malnutrition and recurrent epigastric pain should be investigated for pancreatic pathology and the possibility of pancreatitis and the presence of pseudocysts entertained.

  9. A Mini-Review on the Effect of Docosahexaenoic Acid (DHA) on Cerulein-Induced and Hypertriglyceridemic Acute Pancreatitis.

    Science.gov (United States)

    Jeong, Yoo Kyung; Kim, Hyeyoung

    2017-10-25

    Acute pancreatitis refers to the sudden inflammation of the pancreas. It is associated with premature activation and release of digestive enzymes into the pancreatic interstitium and systemic circulation, resulting in pancreatic tissue autodigestion and multiple organ dysfunction, as well as with increased cytokine production, ultimately leading to deleterious local and systemic effects. Although mechanisms involved in pathogenesis of acute pancreatitis have not been completely elucidated, oxidative stress is regarded as a major risk factor. In human acute pancreatitis, lipid peroxide levels in pancreatic tissues increase. Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid (C22:6n-3), exerts anti-inflammatory and antioxidant effects on various cells. Previous studies have shown that DHA activates peroxisome proliferator-activated receptor-γ and induces catalase, which inhibits oxidative stress-mediated inflammatory signaling required for cytokine expression in experimental acute pancreatitis using cerulein. Cerulein, a cholecystokinin analog, induces intra-acinar activation of trypsinogen in the pancreas, which results in human acute pancreatitis-like symptoms. Therefore, DHA supplementation may be beneficial for preventing or inhibiting acute pancreatitis development. Since DHA reduces serum triglyceride levels, addition of DHA to lipid-lowering drugs like statins has been investigated to reduce hypertriglyceridemic acute pancreatitis. However, high DHA concentrations increase cytosolic Ca2+, which activates protein kinase C and may induce hyperlipidemic acute pancreatitis. In this review, effect of DHA on cerulein-induced and hypertriglyceridemic acute pancreatitis has been discussed. The relation of high concentration of DHA to hyperlipidemic acute pancreatitis has been included.

  10. Therapeutic Effect of Low Doses of Acenocoumarol in the Course of Ischemia/Reperfusion-Induced Acute Pancreatitis in Rats

    Science.gov (United States)

    Warzecha, Zygmunt; Sendur, Paweł; Ceranowicz, Piotr; Cieszkowski, Jakub; Dembiński, Marcin; Sendur, Ryszard; Bonior, Joanna; Jaworek, Jolanta; Ambroży, Tadeusz; Olszanecki, Rafał; Kuśnierz-Cabala, Beata; Tomasz, Kaczmarzyk; Tomaszewska, Romana; Dembiński, Artur

    2017-01-01

    Intravascular activation of coagulation is observed in acute pancreatitis and is related to the severity of this inflammation. The aim of our study was to evaluate the impact of acenocoumarol therapy on the course of acute pancreatitis induced in male rats by pancreatic ischemia followed by reperfusion. Acenocoumarol at a dose of 50, 100, or 150 µg/kg/dose was administered intragastrically once a day, starting the first dose 24 h after the initiation of pancreatic reperfusion. Results: Histological examination showed that treatment with acenocoumarol reduces pancreatic edema, necrosis, and hemorrhages in rats with pancreatitis. Moreover, the administration of acenocoumarol decreased pancreatic inflammatory infiltration and vacuolization of pancreatic acinar cells. These findings were accompanied with a reduction in the serum activity of lipase and amylase, concentration of interleukin-1β, and plasma d-Dimer concentration. Moreover, the administration of acenocoumarol improved pancreatic blood flow and pancreatic DNA synthesis. Acenocoumarol given at a dose of 150 µg/kg/dose was the most effective in the treatment of early phase acute pancreatitis. However later, acenocoumarol given at the highest dose failed to exhibit any therapeutic effect; whereas lower doses of acenocoumarol were still effective in the treatment of acute pancreatitis. Conclusion: Treatment with acenocoumarol accelerates the recovery of ischemia/reperfusion-induced acute pancreatitis in rats. PMID:28430136

  11. Therapeutic Effect of Low Doses of Acenocoumarol in the Course of Ischemia/Reperfusion-Induced Acute Pancreatitis in Rats.

    Science.gov (United States)

    Warzecha, Zygmunt; Sendur, Paweł; Ceranowicz, Piotr; Cieszkowski, Jakub; Dembiński, Marcin; Sendur, Ryszard; Bonior, Joanna; Jaworek, Jolanta; Ambroży, Tadeusz; Olszanecki, Rafał; Kuśnierz-Cabala, Beata; Tomasz, Kaczmarzyk; Tomaszewska, Romana; Dembiński, Artur

    2017-04-21

    Intravascular activation of coagulation is observed in acute pancreatitis and is related to the severity of this inflammation. The aim of our study was to evaluate the impact of acenocoumarol therapy on the course of acute pancreatitis induced in male rats by pancreatic ischemia followed by reperfusion. Acenocoumarol at a dose of 50, 100, or 150 µg/kg/dose was administered intragastrically once a day, starting the first dose 24 h after the initiation of pancreatic reperfusion. Histological examination showed that treatment with acenocoumarol reduces pancreatic edema, necrosis, and hemorrhages in rats with pancreatitis. Moreover, the administration of acenocoumarol decreased pancreatic inflammatory infiltration and vacuolization of pancreatic acinar cells. These findings were accompanied with a reduction in the serum activity of lipase and amylase, concentration of interleukin-1β, and plasma d-Dimer concentration. Moreover, the administration of acenocoumarol improved pancreatic blood flow and pancreatic DNA synthesis. Acenocoumarol given at a dose of 150 µg/kg/dose was the most effective in the treatment of early phase acute pancreatitis. However later, acenocoumarol given at the highest dose failed to exhibit any therapeutic effect; whereas lower doses of acenocoumarol were still effective in the treatment of acute pancreatitis. Treatment with acenocoumarol accelerates the recovery of ischemia/reperfusion-induced acute pancreatitis in rats.

  12. Acinar cell cystadenoma of the pancreas in a cat.

    Science.gov (United States)

    Yoshimura, H; Matsuda, Y; Kawamoto, Y; Michishita, M; Ohkusu-Tsukada, K; Takahashi, K; Naito, Z; Ishiwata, T

    2013-01-01

    Cystic tumours of the pancreas are heterogeneous lesions with a spectrum of morphology and biological behaviour in people. These are poorly characterized in animals. A multicystic tumour of the pancreas was identified in an 11-year-old, female, mixed breed cat. The tumour was 5.5 cm in diameter and the largest cysts were 1.5 cm in diameter. Microscopically, the cysts were lined by single layered or pseudostratified, flat, cuboidal or columnar epithelial cells that occasionally formed papillary structures with a thin fibrous core. The tumour cells had eosinophilic granules in the apical cytoplasm, similar to zymogen granules, and the nuclei were uniform in size and shape. Mitotic figures were not observed. Immunohistochemically, the tumour cells expressed trypsin, but not cytokeratin 7. A diagnosis of acinar cell cystadenoma of the pancreas was made and this is the first report of this tumour in a cat. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. Pentoxifylline Treatment in Acute Pancreatitis (AP)

    Science.gov (United States)

    2016-09-14

    Acute Pancreatitis (AP); Gallstone Pancreatitis; Alcoholic Pancreatitis; Post-ERCP/Post-procedural Pancreatitis; Trauma Acute Pancreatitis; Hypertriglyceridemia Acute Pancreatitis; Idiopathic (Unknown) Acute Pancreatitis; Medication Induced Acute Pancreatitis; Cancer Acute Pancreatitis; Miscellaneous (i.e. Acute on Chronic Pancreatitis)

  14. Type I interferons mediate pancreatic toxicities of PERK inhibition.

    Science.gov (United States)

    Yu, Qiujing; Zhao, Bin; Gui, Jun; Katlinski, Kanstantsin V; Brice, Angela; Gao, Yan; Li, ChangHong; Kushner, Jake A; Koumenis, Constantinos; Diehl, J Alan; Fuchs, Serge Y

    2015-12-15

    The great preclinical promise of the pancreatic endoplasmic reticulum kinase (PERK) inhibitors in neurodegenerative disorders and cancers is marred by pancreatic injury and diabetic syndrome observed in PERK knockout mice and humans lacking PERK function and suffering from Wolcott-Rallison syndrome. PERK mediates many of the unfolded protein response (UPR)-induced events, including degradation of the type 1 interferon (IFN) receptor IFNAR1 in vitro. Here we report that whole-body or pancreas-specific Perk ablation in mice leads to an increase in IFNAR1 protein levels and signaling in pancreatic tissues. Concurrent IFNAR1 deletion attenuated the loss of PERK-deficient exocrine and endocrine pancreatic tissues and prevented the development of diabetes. Experiments using pancreas-specific Perk knockouts, bone marrow transplantation, and cultured pancreatic islets demonstrated that stabilization of IFNAR1 and the ensuing increased IFN signaling in pancreatic tissues represents a major driver of injury triggered by Perk loss. Neutralization of IFNAR1 prevented pancreatic toxicity of PERK inhibitor, indicating that blocking the IFN pathway can mitigate human genetic disorders associated with PERK deficiency and help the clinical use of PERK inhibitors.

  15. Diagnosing Chronic Pancreatitis: Comparison and Evaluation of Different Diagnostic Tools.

    Science.gov (United States)

    Issa, Yama; van Santvoort, Hjalmar C; van Dieren, Susan; Besselink, Marc G; Boermeester, Marja A; Ahmed Ali, Usama

    2017-10-01

    This study aims to compare the M-ANNHEIM, Büchler, and Lüneburg diagnostic tools for chronic pancreatitis (CP). A cross-sectional analysis of the development of CP was performed in a prospectively collected multicenter cohort including 669 patients after a first episode of acute pancreatitis. We compared the individual components of the M-ANNHEIM, Büchler, and Lüneburg tools, the agreement between tools, and estimated diagnostic accuracy using Bayesian latent-class analysis. A total of 669 patients with acute pancreatitis followed-up for a median period of 57 (interquartile range, 42-70) months were included. Chronic pancreatitis was diagnosed in 50 patients (7%), 59 patients (9%), and 61 patients (9%) by the M-ANNHEIM, Lüneburg, and Büchler tools, respectively. The overall agreement between these tools was substantial (κ = 0.75). Differences between the tools regarding the following criteria led to significant changes in the total number of diagnoses of CP: abdominal pain, recurrent pancreatitis, moderate to marked ductal lesions, endocrine and exocrine insufficiency, pancreatic calcifications, and pancreatic pseudocysts. The Büchler tool had the highest sensitivity (94%), followed by the M-ANNHEIM (87%), and finally the Lüneburg tool (81%). Differences between diagnostic tools for CP are mainly attributed to presence of clinical symptoms, endocrine insufficiency, and certain morphological complications.

  16. Obesity, pancreatitis, and pancreatic cancer.

    Science.gov (United States)

    Gumbs, Andrew A

    2008-09-01

    The only universally accepted risk factors for the development of pancreatic cancer are a positive family history or a history of smoking. Although the contribution of pancreatitis to pancreatic carcinogenesis has been debated for decades in the epidemiology literature, the actual mechanism is still unclear. With the rising epidemic of obesity, scientists have begun to focus on the contribution of chronic inflammatory state of morbidly obese patients in an effort to better understand the contribution of inflammation to the comorbidities of obesity. Notably, population studies are beginning to show that one of the most serious potential comorbidities of obesity is an increased lifetime risk of developing cancer. In this article, the current literature that exists supporting this Chronic Inflammatory Hypothesis as it pertains to obesity and pancreatic carcinogenesis is reviewed. To date, studies have focused on interleukin-6, a cytokine known to play a role in obesity, chronic pancreatitis and pancreatic cancer. The anti-inflammatory adipocytokine, adiponectin, has also shown promise as a key player in this mechanism and has recently been found to be more specific than standard tumor markers in differentiating pancreatic cancer from chronic pancreatitis. If the pathogenesis of pancreatic cancer is related to hormone levels associated with obesity, such as adipocytokines, and cytokines associated with chronic inflammation, this could potentially lead to the development of new pancreatic cancer tumor markers and ultimately new therapies and methods of prevention.

  17. Recent advances in the investigation of pancreatic inflammation induced by large doses of basic amino acids in rodents.

    Science.gov (United States)

    Kui, Balázs; Balla, Zsolt; Végh, Eszter T; Pallagi, Petra; Venglovecz, Viktória; Iványi, Béla; Takács, Tamás; Hegyi, Péter; Rakonczay, Zoltán

    2014-02-01

    It has been known for approximately 30 years that large doses of the semi-essential basic amino acid L-arginine induce severe pancreatic inflammation in rats. Recently, it has been demonstrated that L-arginine can also induce pancreatitis in mice. Moreover, other basic amino acids like L-ornithine and L-lysine can cause exocrine pancreatic damage without affecting the endocrine parenchyma and the ducts in rats. The utilization of these noninvasive severe basic amino acid-induced pancreatitis models is becoming increasingly popular and appreciated as these models nicely reproduce most laboratory and morphological features of human pancreatitis. Consequently, the investigation of basic amino acid-induced pancreatitis may offer us a better understanding of the pathogenesis and possible treatment options of the human disease.

  18. Pancreatic stellate cells and CX3CR1: occurrence in normal pancreas, acute and chronic pancreatitis and effect of their activation by a CX3CR1 agonist

    Science.gov (United States)

    Uchida, Masahiko; Ito, Tetsuhide; Nakamura, Taichi; Hijioka, Masayuki; Igarashi, Hisato; Oono, Takamasa; Kato, Masaki; Nakamura, Kazuhiko; Suzuki, Koichi; Takayanagi, Ryoichi; Jensen, Robert T.

    2014-01-01

    Objectives Numerous studies suggest important roles of the chemokine, fractalkine (CX3CL1) in acute/chronic pancreatitis, however the possible mechanisms of the effects are unclear. Pancreatic stellate cells (PSCs) can play important roles in pancreatitis, secreting inflammatory cytokines/chemokines, as well as proliferation. Therefore, we investigated CX3CL1 receptor (CX3CR1) occurrence in normal pancreas and pancreatitis (acute/chronic) tissues, and the effects of CX3CL1 on activated-PSCs. Methods CX3CR1 expression/localization in normal pancreas and pancreatitis (acute/chronic) tissues were evaluated with immunohistochemical analysis. CX3CR1 expression and effects of CX3CL1 on activated-PSCs were examined with realtime-PCR, BrdU assays and Western Blotting. Results In normal pancreas, acinar cells expressed CX3CR1 within granule-like-formations in the cytoplasm, whereas in acute/chronic pancreatitis, acinar, ductal and activated-PSCs expressed CX3CR1 on cell membranes. With activation of normal PSCs, CX3CR1 is increased. CX3CL1 activated multiple signaling cascades in PSCs. CX3CL1, did not induce inflammatory-genes expression in activated-PSCs, but induced proliferation. Conclusions CX3CR1s are expressed in normal pancreas. Expression is increased in acute/chronic pancreatitis and the CX3CR1s are activated. CX3CL1 induces proliferation of activated-PSCs without increasing release of inflammatory-mediators. These results suggest that CX3CR1 activation of PSCs could be important in their effects in pancreatitis, especially to PSCs proliferation in pancreatitis where CX3CL1 levels are elevated. PMID:24681877

  19. Cyclooxygenase-2 expression in feline pancreatic adenocarcinomas.

    Science.gov (United States)

    Newman, Shelley Joy; Mrkonjich, Ladonna

    2006-11-01

    Cyclooxygenase-2 (COX-II) is an inducible enzyme that is responsible for the production of prostaglandin E2 (PGE2), which is often upregulated in neoplastic conditions. Expression of COX-II is documented in the majority of human pancreatic adenocarcinomas and in many epithelial neoplasms in humans and animals. The purpose of this study was to assess a series of feline pancreatic adenocarcinomas for the expression of COX-II. Eight feline pancreatic adenocarcinomas (5 poorly differentiated ductular variants and 3 well-differentiated acinar variants) were included. Immunohistochemical staining showed that COX-II was expressed in 2 (both poorly differentiated ductular variants) of the 8 neoplasms (25%). Approximately 10% of the epithelial cells from these 2 neoplasms expressed intense cytoplasmic staining. However, because feline pancreatic adenocarcinoma does not appear to consistently express COX-II, it is not a useful prognostic indicator for this group of feline neoplasms. In addition, COX-II inhibitors are not likely to be effective therapeutics for cats with this neoplasm.

  20. Congenital Acinar Dysplasia: Report of a Case and Review of Literature

    Directory of Open Access Journals (Sweden)

    Mary Langenstroer

    2013-05-01

    Full Text Available Objective - Describe a case of congenital acinar dysplasia and review the literature. Study Design - Retrospective chart review and literature search. Results - Congenital acinar dysplasia is a rare malformation of growth arrest of the lower respiratory tract resulting in critical respiratory insufficiency at birth. It is a form of pulmonary hypoplasia that is characterized by diffuse maldevelopment and derangement of the acinar and alveolar architecture of the lungs, resulting in the complete absence of gas exchanging units. The growth-arrested lung tissue resembles the pseudoglandular phase of 16 weeks' gestation. The etiology is unknown. It is diagnosed by exclusion of all other causes of pulmonary hypoplasia and a summation of clinical, imaging, and histopathologic findings. Conclusion - There is no cure and clinical treatment is supportive until death of the infant. We present a case of congenital acinar dysplasia in a male infant who lived 20 days with intensive support.

  1. Small amounts of tissue preserve pancreatic function

    Science.gov (United States)

    Lu, Zipeng; Yin, Jie; Wei, Jishu; Dai, Cuncai; Wu, Junli; Gao, Wentao; Xu, Qing; Dai, Hao; Li, Qiang; Guo, Feng; Chen, Jianmin; Xi, Chunhua; Wu, Pengfei; Zhang, Kai; Jiang, Kuirong; Miao, Yi

    2016-01-01

    Abstract Middle-segment preserving pancreatectomy (MPP) is a novel procedure for treating multifocal lesions of the pancreas while preserving pancreatic function. However, long-term pancreatic function after this procedure remains unclear. The aims of this current study are to investigate short- and long-term outcomes, especially long-term pancreatic endocrine function, after MPP. From September 2011 to December 2015, 7 patients underwent MPP in our institution, and 5 cases with long-term outcomes were further analyzed in a retrospective manner. Percentage of tissue preservation was calculated using computed tomography volumetry. Serum insulin and C-peptide levels after oral glucose challenge were evaluated in 5 patients. Beta-cell secreting function including modified homeostasis model assessment of beta-cell function (HOMA2-beta), area under the curve (AUC) for C-peptide, and C-peptide index were evaluated and compared with those after pancreaticoduodenectomy (PD) and total pancreatectomy. Exocrine function was assessed based on questionnaires. Our case series included 3 women and 2 men, with median age of 50 (37–81) years. Four patients underwent pylorus-preserving PD together with distal pancreatectomy (DP), including 1 with spleen preserved. The remaining patient underwent Beger procedure and spleen-preserving DP. Median operation time and estimated intraoperative blood loss were 330 (250–615) min and 800 (400–5500) mL, respectively. Histological examination revealed 3 cases of metastatic lesion to the pancreas, 1 case of chronic pancreatitis, and 1 neuroendocrine tumor. Major postoperative complications included 3 cases of delayed gastric emptying and 2 cases of postoperative pancreatic fistula. Imaging studies showed that segments representing 18.2% to 39.5% of the pancreas with good blood supply had been preserved. With a median 35.0 months of follow-ups on pancreatic functions, only 1 patient developed new-onset diabetes mellitus of the 4

  2. CONTRAST-ENHANCED ULTRASONOGRAPHY OF THE PANCREAS IN HEALTHY DOGS AND IN DOGS WITH ACUTE PANCREATITIS.

    Science.gov (United States)

    Rademacher, Nathalie; Schur, David; Gaschen, Frédéric; Kearney, Michael; Gaschen, Lorrie

    2016-01-01

    Pancreatitis is the most frequent disease affecting the exocrine pancreas in dogs and reliable diagnostic techniques for predicting fatal complications are lacking. Contrast-enhanced ultrasound (CEUS) improves detection of tissue perfusion as well as organ lesion vascular pattern. Objectives of this prospective case control study were to compare perfusion characteristics and enhancement patterns of the pancreas in healthy dogs and dogs with pancreatitis using CEUS. Ten healthy dogs and eight dogs with pancreatitis were selected based on physical examination, abdominal ultrasound, and blood analysis findings. A CEUS study of the pancreas was performed for each dog and two observers who were aware of clinical status used advanced ultrasound quantification software to analyze time-intensity curves. Perfusion patterns were compared between healthy and affected dogs. In dogs with acute pancreatitis, mean pixel and peak intensity of the pancreatic parenchyma was significantly higher than that of normal dogs (P = 0.05) in between 6 and 60 s (P = dogs with acute pancreatitis compared to healthy dogs. Wash-in rates were greater and had a consistently steeper slope to peak in dogs with pancreatitis as opposed to healthy dogs. All dogs with pancreatitis showed a decrease in pixel intensity 10-15 days after the initial examination (P = 0.011) and their times to peak values were prolonged compared to the initial exam. Findings from the current study supported the use of CEUS for diagnosing pancreatitis, pancreatic necrosis, and disease monitoring following therapy in dogs. © 2015 American College of Veterinary Radiology.

  3. Effect of parenteral and early intrajejunal nutrition on pancreatic digestive enzyme synthesis, storage and discharge in dog models of acute pancreatitis.

    Science.gov (United States)

    Qin, Huan-Long; Su, Zhen-Dong; Hu, Lei-Guang; Ding, Zai-Xian; Lin, Qing-Tian

    2007-02-21

    To study the effect of early intrajejunal nutrition on enzyme-protein synthesis and secretion during acute pancreatitis. Fifteen dogs were randomly divided into parenteral nutrition (n = 7) and early intrajejunal nutrition groups (n = 8). An acute pancreatitis model was induced by injecting 5% sodium taurocholate and trypsin into the pancreas via the pancreatic duct. Intrajejunal nutrition was delivered with a catheter via a jejunostomy tube after the model was established for 24 h. On d 1 and 7 and at the beginning of nutritional support, radioactive tracing and electron microscopes were used to evaluate the enzyme-protein synthesis in acinar cells, the subcellular fractionation and the change in zymogen granules after 1.85 x 10(6) Bq L-(3)H phenylalanine was infused at 30, 60, 120, and 180 min. The 3H radioactivity in pancreatic acinar cells reached its peak level at 60 min, and the contents in the early intrajejunal nutrition group were higher than those in the parenteral nutrition group, which were then decreased. The mean number and area of zymogen granules did not show any significant statistical difference in both groups on d 1 or on d 7 (P > 0.05). Early intrajejunal nutrition might be effective in dogs with acute pancreatitis.

  4. English language version of the S3-consensus guidelines on chronic pancreatitis: Definition, aetiology, diagnostic examinations, medical, endoscopic and surgical management of chronic pancreatitis.

    Science.gov (United States)

    Hoffmeister, A; Mayerle, J; Beglinger, C; Büchler, M W; Bufler, P; Dathe, K; Fölsch, U R; Friess, H; Izbicki, J; Kahl, S; Klar, E; Keller, J; Knoefel, W T; Layer, P; Loehr, M; Meier, R; Riemann, J F; Rünzi, M; Schmid, R M; Schreyer, A; Tribl, B; Werner, J; Witt, H; Mössner, J; Lerch, M M

    2015-12-01

    Chronic pancreatitis is a disease of the pancreas in which recurrent inflammatory episodes result in replacement of pancreatic parenchyma by fibrous connective tissue. This fibrotic reorganization of the pancreas leads to a progressive exocrine and endocrine pancreatic insufficiency. In addition, characteristic complications arise, such as pseudocysts, pancreatic duct obstructions, duodenal obstruction, vascular complications, obstruction of the bile ducts, malnutrition and pain syndrome. Pain presents as the main symptom of patients with chronic pancreatitis. Chronic pancreatitis is a risk factor for pancreatic carcinoma. Chronic pancreatitis significantly reduces the quality of life and the life expectancy of affected patients. These guidelines were researched and compiled by 74 representatives from 11 learned societies and their intention is to serve evidence-based professional training as well as continuing education. On this basis they shall improve the medical care of affected patients in both the inpatient and outpatient sector. Chronic pancreatitis requires an adequate diagnostic workup and systematic management, given its severity, frequency, chronicity, and negative impact on the quality of life and life expectancy. © Georg Thieme Verlag KG Stuttgart · New York.

  5. Role of parathyroid hormone-related protein in the pro-inflammatory and pro-fibrogenic response associated with acute pancreatitis.

    Science.gov (United States)

    Bhatia, Vandanajay; Kim, Sung O K; Aronson, Judith F; Chao, Celia; Hellmich, Mark R; Falzon, Miriam

    2012-04-10

    Pancreatitis is a common and potentially lethal necro-inflammatory disease with both acute and chronic manifestations. Current evidence suggests that the accumulated damage incurred during repeated bouts of acute pancreatitis (AP) can lead to chronic disease, which is associated with an increased risk of pancreatic cancer. While parathyroid hormone-related protein (PTHrP) exerts multiple effects in normal physiology and disease states, its function in pancreatitis has not been previously addressed. Here we show that PTHrP levels are transiently elevated in a mouse model of cerulein-induced AP. Treatment with alcohol, a risk factor for both AP and chronic pancreatitis (CP), also increases PTHrP levels. These effects of cerulein and ethanol are evident in isolated primary acinar and stellate cells, as well as in the immortalized acinar and stellate cell lines AR42J and irPSCc3, respectively. Ethanol sensitizes acinar and stellate cells to the PTHrP-modulating effects of cerulein. Treatment of acinar cells with PTHrP (1-36) increases expression of the inflammatory mediators interleukin-6 (IL-6) and intracellular adhesion protein (ICAM-1), suggesting a potential autocrine loop. PTHrP also increases apoptosis in AR42J cells. Stellate cells mediate the fibrogenic response associated with pancreatitis; PTHrP (1-36) increases procollagen I and fibronectin mRNA levels in both primary and immortalized stellate cells. The effects of cerulein and ethanol on levels of IL-6 and procollagen I are suppressed by the PTH1R antagonist, PTHrP (7-34). Together these studies identify PTHrP as a potential mediator of the inflammatory and fibrogenic responses associated with alcoholic pancreatitis. Copyright © 2011 Elsevier B.V. All rights reserved.

  6. Mixed acinar-neuroendocrine carcinoma of the pancreas

    DEFF Research Database (Denmark)

    Jakobsen, Mark; Klöppel, Günter; Detlefsen, Sönke

    2016-01-01

    A 62-year-old woman presented with abdominal discomfort. Imaging studies showed a tumor in the pancreatic tail. At contrast-enhanced CT and macroscopy, the tumor showed cystic, solid and hemorrhagic areas. Histologically, the tumor was well-circumscribed and entirely encapsulated. Some of the tum...

  7. Biliary versus alcohol-related infected pancreatic necrosis: similarities and differences in the follow-up.

    Science.gov (United States)

    Reszetow, Jacek; Hać, Stanisław; Dobrowolski, Sebastian; Stefaniak, Tomasz; Wajda, Zdzisław; Gruca, Zbigniew; Sledziński, Zbigniew; Studniarek, Michał

    2007-10-01

    Infected pancreatic necrosis (IPN) is a serious complication of acute pancreatitis. Data concerning survivors' quality of life and pancreatic functions are scarce. Follow-up of the patients with alcohol and biliary etiology of IPN treated with open necrosectomy was performed. Twenty-eight survivors after operative treatment (Bradley procedure) of IPN were followed up 24 to 96 months after discharge from the hospital (10 biliary and 18 alcohol patients). Their exocrine and endocrine pancreatic functions and quality of life (Functional Assessment of Chronic Illness Therapy scale) were evaluated. Pancreatic tissue remaining after necrosectomy was visualized by use of contrast-enhanced computed tomography (CT). In 44.4% of alcohol-induced IPN patients, the presence of the whole pancreas was shown on the follow-up CT, contrary to the biliary group, where the partial lack of the pancreas was observed in all cases. Pancreatic tissue calcifications were present on CT in 8 patients of alcohol-induced acute pancreatitis group only. Median stool elastase 1 concentrations were 318.1 U/mL in the biliary group and 238.3 U/mL in the alcohol-induced group (not significant). The Functional Assessment of Chronic Illness Therapy scale showed significantly higher social/family and emotional well-being in patients with biliary acute necrotizing pancreatitis. Patients after alcohol-induced IPN had lower quality of life compared with biliary etiology. Biliary and alcohol-induced IPN patients after surgical treatment have nonsignificant differences of endocrine and exocrine pancreatic functions.

  8. Gelatin-Enabled Microsensor for Pancreatic Trypsin Sensing

    Directory of Open Access Journals (Sweden)

    George Banis

    2018-01-01

    Full Text Available Digestive health is critically dependent on the secretion of enzymes from the exocrine pancreas to the duodenum via the pancreatic duct. Specifically, pancreatic trypsin is a major protease responsible for breaking down proteins for absorption in the small intestine. Gelatin-based hydrogels, deposited in the form of thin films, have been studied as potential sensor substrates that hydrolyze in the presence of trypsin. In this work, we (1 investigate gelatin as a sensing material; (2 develop a fabrication strategy for coating sensor surfaces; and (3 implement a miniaturized impedance platform for measuring activity levels of pancreatic trypsin. Using impedance spectroscopy, we evaluate gelatin’s specificity and rate of degradation when exposed to a combination of pancreatic enzymes in neutral solution representative of the macromolecular heterogeneity present in the duodenal environment. Our findings suggest gelatin’s preferential degradation to trypsin compared to enzymes such as lipase and amylase. We further observe their interference with trypsin behavior in equivalent concentrations, reducing film digestion by as much as 83% and 77%, respectively. We achieve film patterns in thicknesses ranging from 300–700 nm, which we coat over interdigitated finger electrode sensors. Finally, we test our sensors over several concentrations to emulate the range of pancreatic secretions. Ultimately, our microsensor will serve as the foundation for developing in situ sensors toward diagnosing pancreatic pathologies.

  9. Diagnosis and treatment of diabetes mellitus in chronic pancreatitis.

    Science.gov (United States)

    Ewald, Nils; Hardt, Philip D

    2013-11-14

    Diabetes secondary to pancreatic diseases is commonly referred to as pancreatogenic diabetes or type 3c diabetes mellitus. It is a clinically relevant condition with a prevalence of 5%-10% among all diabetic subjects in Western populations. In nearly 80% of all type 3c diabetes mellitus cases, chronic pancreatitis seems to be the underlying disease. The prevalence and clinical importance of diabetes secondary to chronic pancreatitis has certainly been underestimated and underappreciated so far. In contrast to the management of type 1 or type 2 diabetes mellitus, the endocrinopathy in type 3c is very complex. The course of the disease is complicated by additional present comorbidities such as maldigestion and concomitant qualitative malnutrition. General awareness that patients with known and/or clinically overt chronic pancreatitis will develop type 3c diabetes mellitus (up to 90% of all cases) is rather good. However, in a patient first presenting with diabetes mellitus, chronic pancreatitis as a potential causative condition is seldom considered. Thus many patients are misdiagnosed. The failure to correctly diagnose type 3 diabetes mellitus leads to a failure to implement an appropriate medical therapy. In patients with type 3c diabetes mellitus treating exocrine pancreatic insufficiency, preventing or treating a lack of fat-soluble vitamins (especially vitamin D) and restoring impaired fat hydrolysis and incretin secretion are key-features of medical therapy.

  10. CT and MR imaging of multilocular acinar cell cystadenoma: comparison with branch duct intraductal papillary mucinous neoplasia (IPMNs)

    Energy Technology Data Exchange (ETDEWEB)

    Delavaud, Christophe; Assignies, Gaspard d' ; Vilgrain, Valerie; Vullierme, Marie-Pierre [Hopital Beaujon, Service de Radiologie, Clichy (France); Cros, Jerome [Hopital Beaujon, Service d' Anatomopathologie, Clichy (France); Ruszniewski, Philippe; Hammel, Pascal; Levy, Philippe [Hopital Beaujon, Service de Pancreato-Gastro-Enterologie, Clichy (France); Couvelard, Anne [Hopital Bichat, Service d' Anatomopathologie, Paris (France); Sauvanet, Alain; Dokmak, Safi [Hopital Beaujon, Service de Chirurgie Hepato-Pancreato-Biliaire, Clichy (France)

    2014-09-15

    To describe CT and MR imaging findings of acinar cell cystadenoma (ACC) of the pancreas and to compare them with those of branch duct intraductal papillary mucinous neoplasia (BD-IPMN) to identify distinctive elements. Five patients with ACC and the 20 consecutive patients with histologically proven BD-IPMN were retrospectively included. Clinical and biological information was collected and histological data reviewed. CT and MR findings were analysed blinded to pathological diagnosis in order to identify imaging diagnostic criteria of ACC. Patients with ACC were symptomatic in all but one case and were younger than those with BD-IPMN (p = 0.006). Four radiological criteria allowed for differentiating ACC from IPMN: five or more cysts, clustered peripheral small cysts, presence of cyst calcifications and absence of communication with the main pancreatic duct (p < 0.05). Presence of at least two or three of these imaging criteria had a strong diagnostic value for ACC with a sensitivity of 100 % and 80 % and a specificity of 85 % and 100 %, respectively. Preoperative differential diagnosis between ACC and BD-IPMN can be achieved using a combination of four CT and/or MR imaging criteria. Recognition of ACC patients could change patient management and lead to more conservative treatment. (orig.)

  11. [Autoimmune pancreatitis].

    Science.gov (United States)

    Beyer, G; Menzel, J; Krüger, P-C; Ribback, S; Lerch, M M; Mayerle, J

    2013-11-01

    Autoimmune pancreatitis is a relatively rare form of chronic pancreatitis which is characterized by a lymphoplasmatic infiltrate with a storiform fibrosis and often goes along with painless jaundice and discrete discomfort of the upper abdomen. Clinically we distinguish between two subtypes, which differ in terms of their histology, clinical picture and prognosis. Type 1 autoimmune pancreatitis is the pancreatic manifestation of the IgG4-associated syndrome which also involves other organs. About one third of the patients can only be diagnosed after either histological prove or a successful steroid trail. Type 2 is IgG4-negative with the histological picture of an idiopathic duct centric pancreatitis and is to higher degree associated with inflammatory bowel disease. A definitive diagnosis can only be made using biopsy. Usually both forms show response to steroid treatment, but in type 1 up to 50 % of the patients might develop a relapse. The biggest challenge and most important differential diagnosis remains the discrimination of AIP from pancreatic cancer, because also AIP can cause mass of the pancreatic head, lymphadenopathy and ductal obstruction. This article summarizes recent advances on epidemiology, clinical presentation, diagnostic strategy, therapy and differential diagnosis in this relatively unknown disease. © Georg Thieme Verlag KG Stuttgart · New York.

  12. Molecular Mechanism of Pancreatic and Salivary Glands Fluid and HCO3− Secretion

    Science.gov (United States)

    Lee, Min Goo; Ohana, Ehud; Park, Hyun Woo; Yang, Dongki; Muallem, Shmuel

    2013-01-01

    Fluid and HCO3− secretion is a vital function of all epithelia and is required for the survival of the tissue. Aberrant fluid and HCO3− secretion is associated with many epithelial diseases, such as cystic fibrosis, pancreatitis, Sjögren’s syndrome and other epithelial inflammatory and autoimmune diseases. Significant progress has been made over the last 20 years in our understanding of epithelial fluid and HCO3− secretion, in particular by secretory glands. Fluid and HCO3− secretion by secretory glands is a two step process. Acinar cells secrete isotonic fluid in which the major salt is NaCl. Subsequently, the duct modifies the volume and electrolyte composition of the fluid to absorb the Cl− and secrete HCO3−. The relative volume secreted by acinar and duct cells and modification of electrolyte composition of the secreted fluids varies among secretory glands to meet their physiological functions. In the pancreas, acinar cells secrete small amount of NaCl-rich fluid, while the duct absorbs the Cl− and secretes HCO3− and the bulk of the fluid in the pancreatic juice. Fluid secretion appears to be driven by active HCO3− secretion. In the salivary glands, acinar cells secrete the bulk of the fluid in the saliva that contains high concentrations of Na+ and Cl− and fluid secretion is mediated by active Cl− secretion. The salivary glands duct absorbs both the Na+ and Cl− and secretes K+ and HCO3−. In this review, we focus on the molecular mechanism of fluid and HCO3− secretion by the pancreas and salivary glands, to highlight the similarities of the fundamental mechanisms of acinar and duct cell functions, and point the differences to meet glands specific secretions. PMID:22298651

  13. Lacrimal gland primary acinar cell culture: the role of insulin

    Directory of Open Access Journals (Sweden)

    Leonardo Tannus Malki

    2016-04-01

    Full Text Available ABSTRACT Purpose: The goal of the present study was to establish a protocol for primary culture of lacrimal gland acinar cells (LGACs and to assess the effect of adding insulin to the culture media. Methods: LGACs were isolated and cultured from lacrimal glands of Wistar male rats. The study outcomes included cell number, viability, and peroxidase release over time and in response to three concentrations of insulin (0.5, 5.0, and 50.0 μg/mL. Results: In LGAC primary culture, cells started to form clusters by day 3. There was a time-response pattern of peroxidase release, which rose by day 6, in response to carbachol. Culture viability lasted for 12 days. An insulin concentration of 5.0 μg/mL in the culture medium resulted in higher viability and secretory capacity. Conclusions: The present method simplifies the isolation and culture of LGACs. The data confirmed the relevance of adding insulin to maintain LGACs in culture.

  14. Acute Pancreatitis in Children

    Science.gov (United States)

    ... an episode of pancreatitis. How do you treat pancreatitis? The treatment of pancreatitis is supportive care. There is no ... and Diagnosis Risks and Treatment Complementary Therapies Chronic Pancreatitis ... and Diagnosis Pain Management/Treatment Pediatric Pancreatitis
 ...

  15. Chronic Pancreatitis in Children

    Science.gov (United States)

    ... Information Children/Pediatric Chronic Pancreatitis in Children Chronic Pancreatitis in Children What symptoms would my child have? ... will develop diabetes in adolescence. Who gets chronic pancreatitis? Those at risk for chronic pancreatitis are children ...

  16. Pancreatic duct replication is increased with obesity and type 2 diabetes in humans.

    Science.gov (United States)

    Butler, A E; Galasso, R; Matveyenko, A; Rizza, R A; Dry, S; Butler, P C

    2010-01-01

    In a high-fat-fed rat model of type 2 diabetes we noted increased exocrine duct replication. This is a predisposing factor for pancreatitis and pancreatic cancer, both of which are more common in type 2 diabetes. The aim of the study reported here was to establish if obesity and/or type 2 diabetes are associated with increased pancreatic ductal replication in humans. We obtained pancreas at autopsy from 45 humans, divided into four groups: lean (BMI obese (BMI >27 kg/m(2)); non-diabetic; and with type 2 diabetes. Pancreases were evaluated after immunostaining for the duct cell marker cytokeratin and Ki67 for replication. We show for the first time that both obesity and type 2 diabetes in humans are associated with increased pancreatic ductal replication. Specifically, we report that (1) replication of pancreatic duct cells is increased tenfold by obesity, and (2) lean subjects with type 2 diabetes demonstrate a fourfold increase in replication of pancreatic duct cells compared with their lean non-diabetic controls. Pancreatic duct cell replication is increased in humans in response to both obesity and type 2 diabetes, potentially providing a mechanism for the increased risk of pancreatitis and pancreatic cancer in those with obesity and/or type 2 diabetes.

  17. Chronic pancreatitis: challenges and advances in pathogenesis, genetics, diagnosis, and therapy.

    Science.gov (United States)

    Witt, Heiko; Apte, Minoti V; Keim, Volker; Wilson, Jeremy S

    2007-04-01

    Chronic pancreatitis (CP) is characterized by progressive pancreatic damage that eventually results in significant impairment of exocrine as well as endocrine functions of the gland. In Western societies, the commonest association of chronic pancreatitis is alcohol abuse. Our understanding of the pathogenesis of CP has improved in recent years, though important advances that have been made with respect to delineating the mechanisms responsible for the development of pancreatic fibrosis (a constant feature of CP) following repeated acute attacks of pancreatic necroinflammation (the necrosis-fibrosis concept). The pancreatic stellate cells (PSCs) are now established as key cells in fibrogenesis, particularly when activated either directly by toxic factors associated with pancreatitis (such as ethanol, its metabolites or oxidant stress) or by cytokines released during pancreatic necroinflammation. In recent years, research effort has also focused on the genetic abnormalities that may predispose to CP. Genes regulating trypsinogen activation/inactivation and cystic fibrosis transmembrane conductance regulator (CFTR) function have received particular attention. Mutations in these genes are now increasingly recognized for their potential 'disease modifier' role in distinct forms of CP including alcoholic, tropical, and idiopathic pancreatitis. Treatment of uncomplicated CP is usually conservative with the major aim being to effectively alleviate pain, maldigestion and diabetes, and consequently, to improve the patient's quality of life. Surgical and endoscopic interventions are reserved for complications such as pseudocysts, abscess, and malignancy.

  18. A Serous Cystic Neoplasm of the Pancreas Coexisting with High-Grade Pancreatic Intraepithelial Neoplasia Mimicking an Intraepithelial Papillary Mucinous Neoplasm: A Case Report.

    Science.gov (United States)

    Kawanishi, Aya; Hirabayashi, Kenichi; Kono, Hirotaka; Takanashi, Yumi; Hadano, Atsuko; Kawashima, Yohei; Ogawa, Masami; Kawaguchi, Yoshiaki; Yamada, Misuzu; Nakagohri, Toshio; Nakamura, Naoya; Mine, Tetsuya

    2017-01-01

    Serous cystic neoplasms of the pancreas are rare exocrine pancreatic neoplasms, most of which are benign and do not communicate with the pancreatic duct. Pancreatic intraepithelial neoplasm (PanIN) is considered a precursor of ductal adenocarcinoma that is microscopically recognized in pancreatic ducts. A 67-year-old Japanese woman presented with a 10-mm multilocular cystic lesion at the pancreatic body. Magnetic resonance pancreatography showed stenosis of the main pancreatic duct at the pancreatic body and dilatation of the distal side of the main pancreatic duct. Furthermore, communication between the cystic lesion and the main pancreatic duct was suspected based on magnetic resonance pancreatography findings. Distal pancreatectomy was performed under the preoperative diagnosis of intraductal papillary mucinous neoplasm. Histologically, the cystic lesion was lined with a non-atypical cuboidal or flat epithelium with clear cytoplasm and was thus diagnosed as a serous cystic neoplasm. High-grade PanIN lesions with stromal fibrosis were observed at the main and branch pancreatic ducts. Histological examination revealed no communication between the serous cystic neoplasm and the pancreatic ducts. Immunohistochemically, the epithelium of the serous cystic neoplasm showed positive anti-von Hippel-Lindau antibody staining, whereas the epithelium of the PanIN showed negative staining. A serous cystic neoplasm coexisting with another pancreatic neoplasm is rare. When dilatation of the main or branch pancreatic ducts coexists with a serous cystic neoplasm, as in this case, the lesion clinically mimics an intraductal papillary mucinous neoplasm.

  19. Lipotoxicity Causes Multisystem Organ Failure and Exacerbates Acute Pancreatitis in Obesity

    Science.gov (United States)

    Navina, Sarah; Acharya, Chathur; DeLany, James P.; Orlichenko, Lidiya S.; Baty, Catherine J.; Shiva, Sruti S.; Durgampudi, Chandra; Karlsson, Jenny M.; Lee, Kenneth; Bae, Kyongtae T.; Furlan, Alessandro; Behari, Jaideep; Liu, Shiguang; McHale, Teresa; Nichols, Larry; Papachristou, Georgios Ioannis; Yadav, Dhiraj; Singh, Vijay P.

    2012-01-01

    Obesity increases the risk of adverse outcomes during acute critical illnesses such as burns, severe trauma, and acute pancreatitis. Although individuals with more body fat and higher serum cytokines and lipase are more likely to experience problems, the roles that these characteristics play are not clear. We used severe acute pancreatitis as a representative disease to investigate the effects of obesity on local organ function and systemic processes. In obese humans, we found that an increase in the volume of intrapancreatic adipocytes was associated with more extensive pancreatic necrosis during acute pancreatitis and that acute pancreatitis was associated with multisystem organ failure in obese individuals. In vitro studies of pancreatic acinar cells showed that unsaturated fatty acids were proinflammatory, releasing intracellular calcium, inhibiting mitochondrial complexes I and V, and causing necrosis. Saturated fatty acids had no such effects. Inhibition of lipolysis in obese (ob/ob) mice with induced pancreatitis prevented a rise in serum unsaturated fatty acids and prevented renal injury, lung injury, systemic inflammation, hypocalcemia, reduced pancreatic necrosis, and mortality. Thus, therapeutic approaches that target unsaturated fatty acid–mediated lipotoxicity may reduce adverse outcomes in obese patients with critical illnesses such as severe acute pancreatitis. PMID:22049070

  20. Genetic, epidemiological, and clinical aspects of hereditary pancreatitis: a population-based cohort study in Denmark

    DEFF Research Database (Denmark)

    Brusgaard, Klaus

    2010-01-01

    OBJECTIVES: In a population-based, well-defined group of patients first regarded as having pancreatitis of unknown origin (PUO), we identified, described, and compared the clinical and genetic aspects of patients with hereditary pancreatitis (HP) and with cystic fibrosis transmembrane conductance...... regulator gene (CFTR) and serine protease inhibitor Kazal type 1 gene (SPINK1) mutations with patients who retained the diagnosis of true idiopathic pancreatitis (tIP) after genetic testing for HP, SPINK1, and CFTR mutations. METHODS: Patients with PUO were identified in the Danish National Registry......, respectively, and among tIP patients 9 and 12%, respectively. Pancreatic cancer was diagnosed in 5% of the HP families. CONCLUSIONS: The genotype of the Danish population with HP differs from that of previously described cohorts. The occurrence of exocrine and endocrine insufficiency is higher among patients...

  1. Pancreatic Cysts

    Science.gov (United States)

    ... Pancreatic cysts Symptoms & causes Diagnosis & treatment Doctors & departments Advertisement Mayo Clinic does not endorse companies or products. ... a Job Site Map About This Site Twitter Facebook Google YouTube Pinterest Mayo Clinic is a not- ...

  2. Chronic pancreatitis

    NARCIS (Netherlands)

    Bruno, Marco J.

    2005-01-01

    In the past 20 years, endoscopic ultrasonography has been added to the already large armamentarium of diagnostic tests for chronic pancreatitis. This article discusses its potential and possible limitations

  3. Pancreatitis - slideshow

    Science.gov (United States)

    ... gov/ency/presentations/100149.htm Pancreatitis - series—Normal anatomy To use the sharing features on this page, ... Bethesda, MD 20894 U.S. Department of Health and Human Services National Institutes of Health Page last updated: ...

  4. CD1d expression in paneth cells and rat exocrine pancreas revealed by novel monoclonal antibodies which differentially affect NKT cell activation.

    Directory of Open Access Journals (Sweden)

    Elisa Monzon-Casanova

    2010-09-01

    Full Text Available CD1d is a nonpolymorphic MHC class I-like molecule which presents nonpeptide ligands, e.g. glycolipids, to NKT cells. These cells are known to have multiple effects on innate and adaptive immune responses and on the development of pathological conditions. In order to analyze CD1d expression and function in the rat, the first rat CD1d-specific monoclonal antibodies (mAbs were generated.Two mAbs, WTH-1 and WTH-2, were generated which bound equally well to cell surface-expressed rat and mouse CD1d. Their non-overlapping epitopes were mapped to the CD1d heavy chain. Flow cytometry and immunohistological analyses revealed a nearly identical degree and pattern of CD1d expression for hematopoieitic cells of both species. Notable is also the detection of CD1d protein in mouse and rat Paneth cells as well as the extremely high CD1d expression in acinar exocrine cells of the rat pancreas and the expression of CD4 on rat marginal zone B cells. Both mAbs blocked α-galactosylceramide recognition by primary rat and mouse NKT cells. Interestingly, the two mAbs differed in their impact on the activation of various autoreactive T cell hybridomas, including the XV19.2 hybridoma whose activation was enhanced by the WTH-1 mAb.The two novel monoclonal antibodies described in this study, allowed the analysis of CD1d expression and CD1d-restricted T cell responses in the rat for the first time. Moreover, they provided new insights into mechanisms of CD1d-restricted antigen recognition. While CD1d expression by hematopoietic cells of mice and rats was extremely similar, CD1d protein was detected at not yet described sites of non-lymphatic tissues such as the rat exocrine pancreas and Paneth cells. The latter is of special relevance given the recently reported defects of Paneth cells in CD1d(-/- mice, which resulted in an altered composition of the gut flora.

  5. Role of cholecystokinin in dietary fat-promoted azaserine-induced pancreatic carcinogenesis in rats.

    Science.gov (United States)

    Appel, M. J.; Meijers, M.; Van Garderen-Hoetmer, A.; Lamers, C. B.; Rovati, L. C.; Sprij-Mooij, D.; Jansen, J. B.; Woutersen, R. A.

    1992-01-01

    The role of cholecystokinin in dietary fat-promoted pancreatic carcinogenesis was investigated in azaserine-treated rats, using lorglumide, a highly specific cholecystokinin-receptor antagonist. The animals were killed 8 months after the start of treatment. Cholecystokinin, but not dietary unsaturated fat, increased pancreatic weight. Rats treated with cholecystokinin developed more acidophilic atypical acinar cell nodules, adenomas and adenocarcinomas than control animals. Rats maintained on the high-fat diet developed significantly more adenomas and adenocarcinomas than controls given a diet low in unsaturated fat. Lorglumide largely inhibited the enhancing effect of cholecystokinin, but not of dietary fat, on pancreatic carcinogenesis indicating that it is unlikely that the promoting effect of dietary unsaturated fat on pancreatic carcinogenesis is mediated via cholecystokinin. PMID:1637675

  6. [The role of fecal elastase-1 in pancreatic diseases].

    Science.gov (United States)

    Yang, Xiao-ou; Li, Jing-nan; Qian, Jia-ming

    2006-04-01

    To determine the average concentration and its ranges of fecal elastase-1 (FE1) in healthy controls; to calculate the sensitivity and specificity of FE1 in the assay of pancreatic insufficiency; and to evaluate the diagnosing and differentiating value of FE1 in pancreatic diseases. Used the FE1 ELISA kit to quantitate the concentrations of FE1 in 73 healthy controls with different age groups, and 30 patients with chronic pancreatitis, 17 patients with pancreatic cancer and 24 patients with non-pancreatic digestive diseases. Urine N-benzoyl-tyrosyl-para-aminobenzoic acid (BT-PABA) was measured in those patients as a comparison simultaneously. (1) FE1 concentration in healthy controls ranged from 136 to 1380 (966.93 +/- 256.17) microg/g. There were no statistical significances between the different age groups (P > 0.05). (2) The FE1 of both groups of chronic pancreatitis [(208.80 +/- 197.72) microg/g, ranged from 15 to 900 microg/g] and pancreatic cancer [(175.00 +/- 172.25) microg/g, ranged from 15 to 460 microg/g] compare to that in non-pancreatic digestive diseases [(502.63 +/- 210.28) microg/g] were significantly low (P specificity of FE1 for diagnosing pancreatic diarrhea were 77.8% and 89.5% as well as 50.0% and 42.9% of urine BT-PABA. (4) The sensitivity and specificity of FE1 for diagnosing chronic pancreatitis were 63.3% and 97.3% respectively, the sensitivity of urine BT-PABA was 83.3%. FE1 concentration is (966.93 +/- 256.17) microg/g in healthy controls. Our study clearly showed that there are no changes of FE1 concentration in different age groups. FE1 showed the higher specificity for chronic pancreatitis than urine BT-PABA. The test is noninvasive and can assist in diagnosing exocrine pancreatic insufficiency, and is better than the BT-PABA in differentiating pancreatic and non-pancreatic diarrhea.

  7. Predictive factors for post-ERCP pancreatitis: a large-scale single expertized endoscopist study.

    Science.gov (United States)

    Katsinelos, Panagiotis; Lazaraki, Georgia; Gkagkalis, Stergios; Chatzimavroudis, Grigoris; Fasoulas, Kostas; Zavos, Christos; Pilpilidis, Ioannis; Germanidis, George; Kountouras, Jannis

    2014-12-01

    Pancreatitis remains the most common and feared complication of therapeutic endoscopic cholangiopancreatography (ERCP) associated with substantial morbidity. The patient-related and procedure-related independent risk factors for post-ERCP pancreatitis (PEP) in a large case volume by a single experienced endoscopist have been investigated only by few studies. The aim of the study was to investigate patient-related and procedure-related risk factors for PEP collected by a defined protocol on patients who underwent therapeutic ERCP in a single endoscopic unit during the last 8 years. Our retrospective cohort study included a total of 2688 therapeutic ERCPs enrolled in the final analysis. The impact of the risk factors on PEP development was investigated by univariate and multivariate analysis. PEP was diagnosed and its severity was graded according to the consensus criteria. With the exception of history of pancreatitis, there was no other statistically significant difference of patients' characteristics between patients with and without PEP. Female sex, age, difficult cannulation, suspected sphincter of Oddi dysfunction, metal stent placement, opacification of main pancreatic duct, and suprapapillary fistulotomy were not found to be risk factors for PEP by univariate and multivariate analysis. Both univariate and multivariate analysis showed history of acute pancreatitis, needle-knife papillotomy, transpancreatic sphincterotomy, opacification of first-class and second-class pancreatic ductules, and acinarization as independent risk factors for PEP. History of acute pancreatitis, needle-knife papillotomy, transpancreatic sphincterotomy, opacification of first-class and second-class pancreatic ductules, and acinarization were all identified as independent risk factors for PEP.

  8. Effect of α1-adrenergic stimulation of Cl- secretion and signal transduction in exocrine glands (RANA esculenta)

    DEFF Research Database (Denmark)

    Gudme, Charlotte Nini; Nielsen, Morten S.; Nielsen, Robert

    2000-01-01

    cAMP, cellular Ca2+, Cl- secretion, exocrine gland, fura-2, inositol 1,4,5-trisphospate, noradrenaline......cAMP, cellular Ca2+, Cl- secretion, exocrine gland, fura-2, inositol 1,4,5-trisphospate, noradrenaline...

  9. Extended Exenatide Administration Enhances Lipid Metabolism and Exacerbates Pancreatic Injury in Mice on a High Fat, High Carbohydrate Diet

    OpenAIRE

    Rouse, Rodney; Zhang, Leshuai; Shea, Katherine; Zhou, Hongfei; Xu, Lin; Stewart, Sharron; Rosenzweig, Barry; Zhang, Jun

    2014-01-01

    This study expanded upon a previous study in mice reporting a link between exenatide treatment and exocrine pancreatic injury by demonstrating temporal and dose responses and providing an initial mechanistic hypothesis. The design of the present study included varying lengths of exenatide exposure (3, 6 weeks to 12 weeks) at multiple concentrations (3, 10, or 30 µg/kg) with multiple endpoints (histopathology evaluations, immunoassay for cytokines, immunostaining of the pancreas, serum chemist...

  10. Treatment with H2S-releasing diclofenac protects mice against acute pancreatitis-associated lung injury.

    Science.gov (United States)

    Bhatia, Madhav; Sidhapuriwala, Jenab N; Sparatore, Anna; Moore, Philip K

    2008-01-01

    Impaired lung function in severe acute pancreatitis is the primary cause of morbidity and mortality in this condition. Hydrogen sulfide (H(2)S) is a naturally occurring gas that has been shown to be a potent vasodilator. Diclofenac is a nonsteroidal anti-inflammatory drug and has been shown to have anti-inflammatory, analgesic, and antipyretic activity. ACS15 is an H(2)S-releasing derivative of diclofenac. Little is known about its effectiveness as an anti-inflammatory drug. In this report, we describe the effect of diclofenac and its H(2)S-releasing derivative on acute pancreatitis and associated lung injury in the mouse. Acute pancreatitis was induced in mice by hourly i.p. injections of cerulein. Diclofenac and ACS15 were administered either 1 hour before or 1 hour after starting cerulein injections, and the severity of acute pancreatitis and associated lung injury was assessed. The severity of acute pancreatitis was determined by hyperamylasemia, neutrophil sequestration in the pancreas (pancreatic myeloperoxidase activity), and pancreatic acinar cell injury/necrosis on histological examination of pancreas sections. The severity of acute pancreatitis-associated lung injury was assessed by neutrophil sequestration in the lungs (lung myeloperoxidase activity) and by histological examination of lung sections. ACS15, given prophylactically and therapeutically, significantly reduced lung inflammation without having any significant effect on pancreatic injury. These results suggest the usefulness of H(2)S-releasing nonsteroidal anti-inflammatory drugs as potential treatments for pancreatitis-associated lung injury.

  11. Enzyme replacement therapy for pancreatic insufficiency: present and future

    Directory of Open Access Journals (Sweden)

    Fieker A

    2011-05-01

    Full Text Available Aaron Fieker1, Jessica Philpott1, Martine Armand21Division of Digestive Diseases, University of Oklahoma, OKC, OK, USA; 2INSERM, U476 "Nutrition Humaine et Lipides", Marseille, F-13385 France; Univ Méditerranée Aix-Marseille 2, Faculté de Médecine, IPHM-IFR 125, Marseille, F-13385 FranceAbstract: Pancreatic enzyme replacement therapy is currently the mainstay of treatment for nutrient malabsorption secondary to pancreatic insufficiency. This treatment is safe and has few side effects. Data demonstrate efficacy in reducing steatorrhea and fat malabsorption. Effective therapy has been limited by the ability to replicate the physiologic process of enzyme delivery to the appropriate site, in general the duodenum, at the appropriate time. The challenges include enzyme destruction in the stomach, lack of adequate mixing with the chyme in the duodenum, and failing to deliver and activate at the appropriate time. Treatment is begun when clinically significant malabsorption occurs resulting in steatorrhea and weight loss. Treatment failure is addressed in a sequential fashion. Current research is aimed at studying new enzymes and delivery systems to improve the efficiency of action in the duodenum along with developing better means to monitor therapy.Keywords: exocrine pancreatic insufficiency, chronic pancreatitis, cystic fibrosis, pancreatic enzyme replacement therapy, lipase, lipids

  12. CXCL12 chemokine expression suppresses human pancreatic cancer growth and metastasis.

    Directory of Open Access Journals (Sweden)

    Ishan Roy

    Full Text Available Pancreatic ductal adenocarcinoma is an unsolved health problem with nearly 75% of patients diagnosed with advanced disease and an overall 5-year survival rate near 5%. Despite the strong link between mortality and malignancy, the mechanisms behind pancreatic cancer dissemination and metastasis are poorly understood. Correlative pathological and cell culture analyses suggest the chemokine receptor CXCR4 plays a biological role in pancreatic cancer progression. In vivo roles for the CXCR4 ligand CXCL12 in pancreatic cancer malignancy were investigated. CXCR4 and CXCR7 were consistently expressed in normal and cancerous pancreatic ductal epithelium, established cell lines, and patient-derived primary cancer cells. Relative to healthy exocrine ducts, CXCL12 expression was pathologically repressed in pancreatic cancer tissue specimens and patient-derived cell lines. To test the functional consequences of CXCL12 silencing, pancreatic cancer cell lines stably expressingthe chemokine were engineered. Consistent with a role for CXCL12 as a tumor suppressor, cells producing the chemokine wereincreasingly adherent and migration deficient in vitro and poorly metastatic in vivo, compared to control cells. Further, CXCL12 reintroduction significantly reduced tumor growth in vitro, with significantly smaller tumors in vivo, leading to a pronounced survival advantage in a preclinical model. Together, these data demonstrate a functional tumor suppressive role for the normal expression of CXCL12 in pancreatic ducts, regulating both tumor growth andcellulardissemination to metastatic sites.

  13. Pathomorphological feature of chronic pancreatitis (CP is the development of pancreatic fibrosis with the accumulation of various collagen types, tubulin, fibronectin, laminin, and also intermediate filament proteins produced by activated pancreatic stel

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    T. V. Turovskaya

    2013-04-01

    Full Text Available T. V. Turovskaya, A. M. Gnilorybov, L. V. Vasilyeva Pathomorphological feature of chronic pancreatitis (CP is the development of pancreatic fibrosis with the accumulation of various collagen types, tubulin, fibronectin, laminin, and also intermediate filament proteins produced by activated pancreatic stellate cells (PSCs, which express the cytoskeletal α-smooth muscle actin (α-SMA. The aim of the research: determination of immunophenotype and proliferative activity of pancreatic stellate cells as well as the main histotopographic components of severe pancreatic fibrosis and accumulation of collagen I, III and IV types in pancreas at CP. Materials and methods. Histological, histochemical (Van Gieson's and Masson's trichrome staining, immunohistochemical (α-SMA, vimentin, desmin, fibronectin, Ki-67, collagen I, III and IV types and morphometric studies (Image J program of accumulation of various collagen types, represented in standard unit of optical density (SUOD, were held at pancreas biopsies of 30 patients (35-72 years old with CP. Results. It was found that development of severe pancreatic fibrosis is promoted by proliferation and increase of α-SMA+, vimentin+, desmin+ activated stellate cells and deposition of significant amount of collagen I, III, IV types and fibronectin in pancreas that are synthesized by PSCs. In areas of severe fibrosis Ki-67 expression is detected in the nuclei of at least 25% of PSCs, that corresponds to relatively low levels of proliferation. Four components of severe pancreatic fibrosis: circular-periductal fibrosis involving the large ducts of the pancreas, laminar fibrosis in extensive fibrous fields between large ducts and acinar tissue, as well as tape-like interlobular and septal-periacinar intralobular pancreatic fibrosis are identified in patients with CP. Conclusion. Morphological manifestation of severe circular-periductal pancreatic fibrosis is the presence of significant concentric fibrosis around the

  14. Assessment of Toxicological Perturbations and Variants of Pancreatic Islet Development in the Zebrafish Model

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    Karilyn E. Sant

    2016-09-01

    Full Text Available The pancreatic islets, largely comprised of insulin-producing beta cells, play a critical role in endocrine signaling and glucose homeostasis. Because they have low levels of antioxidant defenses and a high perfusion rate, the endocrine islets may be a highly susceptible target tissue of chemical exposures. However, this endpoint, as well as the integrity of the surrounding exocrine pancreas, is often overlooked in studies of developmental toxicology. Disruption of development by toxicants can alter cell fate and migration, resulting in structural alterations that are difficult to detect in mammalian embryo systems, but that are easily observed in the zebrafish embryo model (Danio rerio. Using endogenously expressed fluorescent protein markers for developing zebrafish beta cells and exocrine pancreas tissue, we documented differences in islet area and incidence rates of islet morphological variants in zebrafish embryos between 48 and 96 h post fertilization (hpf, raised under control conditions commonly used in embryotoxicity assays. We identified critical windows for chemical exposures during which increased incidences of endocrine pancreas abnormalities were observed following exposure to cyclopamine (2–12 hpf, Mono-2-ethylhexyl phthalate (MEHP (3–48 hpf, and Perfluorooctanesulfonic acid (PFOS (3–48 hpf. Both islet area and length of the exocrine pancreas were sensitive to oxidative stress from exposure to the oxidant tert-butyl hydroperoxide during a highly proliferative critical window (72 hpf. Finally, pancreatic dysmorphogenesis following developmental exposures is discussed with respect to human disease.

  15. [Pancreatic ultrasonography].

    Science.gov (United States)

    Fernández-Rodríguez, T; Segura-Grau, A; Rodríguez-Lorenzo, A; Segura-Cabral, J M

    2015-04-01

    Despite the recent technological advances in imaging, abdominal ultrasonography continues to be the first diagnostic test indicated in patients with a suspicion of pancreatic disease, due to its safety, accessibility and low cost. It is an essential technique in the study of inflammatory processes, since it not only assesses changes in pancreatic parenchyma, but also gives an indication of the origin (bile or alcoholic). It is also essential in the detection and tracing of possible complications as well as being used as a guide in diagnostic and therapeutic punctures. It is also the first technique used in the study of pancreatic tumors, detecting them with a sensitivity of around 70% and a specificity of 90%. Copyright © 2014 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España. All rights reserved.

  16. Pancreatic injury in hepatic alcohol dehydrogenase-deficient deer mice after subchronic exposure to ethanol.

    Science.gov (United States)

    Kaphalia, Bhupendra S; Bhopale, Kamlesh K; Kondraganti, Shakuntala; Wu, Hai; Boor, Paul J; Ansari, G A Shakeel

    2010-08-01

    Pancreatitis caused by activation of digestive zymogens in the exocrine pancreas is a serious chronic health problem in alcoholic patients. However, mechanism of alcoholic pancreatitis remains obscure due to lack of a suitable animal model. Earlier, we reported pancreatic injury and substantial increases in endogenous formation of fatty acid ethyl esters (FAEEs) in the pancreas of hepatic alcohol dehydrogenase (ADH)-deficient (ADH(-)) deer mice fed 4% ethanol. To understand the mechanism of alcoholic pancreatitis, we evaluated dose-dependent metabolism of ethanol and related pancreatic injury in ADH(-) and hepatic ADH-normal (ADH(+)) deer mice fed 1%, 2% or 3.5% ethanol via Lieber-DeCarli liquid diet daily for 2months. Blood alcohol concentration (BAC) was remarkably increased and the concentration was ∼1.5-fold greater in ADH(-) vs. ADH(+) deer mice fed 3.5% ethanol. At the end of the experiment, remarkable increases in pancreatic FAEEs and significant pancreatic injury indicated by the presence of prominent perinuclear space, pyknotic nuclei, apoptotic bodies and dilation of glandular ER were found only in ADH(-) deer mice fed 3.5% ethanol. This pancreatic injury was further supported by increased plasma lipase and pancreatic cathepsin B (a lysosomal hydrolase capable of activating trypsinogen), trypsinogen activation peptide (by-product of trypsinogen activation process) and glucose-regulated protein 78 (endoplasmic reticulum stress marker). These findings suggest that ADH-deficiency and high alcohol levels in the body are the key factors in ethanol-induced pancreatic injury. Therefore, determining how this early stage of pancreatic injury advances to inflammation stage could be important for understanding the mechanism(s) of alcoholic pancreatitis. Copyright © 2010 Elsevier Inc. All rights reserved.

  17. Rapidly Progressive Pancreatic Lipomatosis in a Young Adult Patient with Transfusion-dependent Myelodysplastic Syndrome

    Directory of Open Access Journals (Sweden)

    Wei-Ching Lin

    2007-08-01

    Full Text Available Pancreatic lipomatosis is defined as deposition of fat cells in pancreatic parenchyma. Although the etiology of this condition is still unclear, it is not uncommon in the elderly obese individuals, and a variety of transfusion-dependent hematologic diseases such as β-thalassemia major. Pancreatic lipomatosis associated with transfusion-dependent myelodysplastic syndrome (MDS has never been reported. We present a 17-year-old male patient with transfusion-dependent MDS. He received transfusion of a total of 345 units of blood in a period of 18 months but without iron chelating agent. Progressive fatty replacement of the pancreas parenchyma was found by a series of computed tomography images over seven hospital admissions due to repeated infections. Bone marrow biopsy revealed hemosiderin deposition. Because of his poor response to induction chemotherapy, stem cell transplantation was suggested, but the patient died of sepsis before the therapeutic procedure could take place. Although most patients with pancreatic lipomatosis have neither clinical symptoms nor abnormal laboratory data, it may cause endocrine and exocrine pancreas dysfunction. In this reported case, mild exocrine dysfunction was noted on the last admission. Clinicians should be cautious of hemosiderin deposition after large amount of blood transfusion and chelating therapy should be given to avoid iron overload.

  18. Acute Pancreatitis

    DEFF Research Database (Denmark)

    Bertilsson, Sara; Håkansson, Anders; Kalaitzakis, Evangelos

    2017-01-01

    Aims: We aimed to evaluate the potential relation between the incidence of (alcoholic and non-alcoholic) acute pancreatitis (AP) and alcohol consumption in the general population, and whether the occurrence of AP shows any seasonal variation, particularly in relation to periods with expected...... consumption in the general population do not appear to be related to changes in the incidence of AP and there are no significant seasonal differences in the occurrence of AP in Sweden. Short summary: The incidence of acute pancreatitis (AP) is increasing, and alcohol is still recognized as one of the most...

  19. Comparison of reg I and reg III Levels During Acute Pancreatitis in the Rat

    Science.gov (United States)

    Zenilman, Michael E.; Tuchman, David; Zheng, Qing-hu; Levine, Joshua; Delany, Harry

    2000-01-01

    Objective To study alterations of serum levels of the pancreatic reg family of proteins in two models of acute pancreatitis. Summary Background Data The pancreatic reg family of proteins is expressed in the acinar pancreas. Reg I (pancreatic stone protein, PSP) and reg III (pancreatitis-associated protein, PAP) are induced after the onset of acute pancreatitis, and both have been proposed as potential markers of pancreatitis. Methods Pancreatitis was induced in rats by either retrograde infusion of sodium taurocholate or by direct trauma. Serum samples were obtained daily for 4 days after the procedure, and the animals were then killed. Twelve animals underwent sham procedure and six underwent daily analysis without surgery. Levels of reg I/PSP and reg III/PAP were estimated by enzyme-linked immunosorbent assay. Results Reg III/PAP levels increased significantly the first day after induction of both types of pancreatitis and rapidly returned to baseline in all survivors. Even animals who received retrograde infusion of saline showed a mild increase in reg III/PAP on the first day, whereas control animals that did not undergo surgery showed no variations. Reg I/PSP serum levels remained unchanged throughout all experimental periods. Postinjury reg III/PAP levels significantly correlated with severity of the pancreatic injury and animal survival;reg I/PSP levels did not. Conclusion After induction of pancreatitis, serum levels of reg I and III protein differ significantly. Reg III/PAP levels are a sensitive marker of pancreatic injury and early in the disease may be a useful prognostic indicator for disease severity. PMID:11066135

  20. Spontaneous Pancreatitis Caused by Tissue-Specific Gene Ablation of Hhex in MiceSummary

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    Mark J. Ferreira

    2015-09-01

    Full Text Available Background & Aims: Perturbations in pancreatic ductal bicarbonate secretion cause chronic pancreatitis. The physiologic mechanism of ductal secretion is known, but its transcriptional control is not. We determine the role of the transcription factor hematopoietically expressed homeobox protein (Hhex in ductal secretion and pancreatitis. Methods: We derived mice with pancreas-specific, Cre-mediated Hhex gene ablation to determine the requirement of Hhex in the pancreatic duct in early life and in adult stages. Histologic and immunostaining analyses were used to detect the presence of pathology. Pancreatic primary ductal cells were isolated to discover differentially expressed transcripts upon acute Hhex ablation on a cell autonomous level. Results: Hhex protein was detected throughout the embryonic and adult ductal trees. Ablation of Hhex in pancreatic progenitors resulted in postnatal ductal ectasia associated with acinar-to-ductal metaplasia, a progressive phenotype that ultimately resulted in chronic pancreatitis. Hhex ablation in adult mice, however, did not cause any detectable pathology. Ductal ectasia in young mice did not result from perturbation of expression of Hnf6, Hnf1β, or the primary cilia genes. RNA-seq analysis of Hhex-ablated pancreatic primary ductal cells showed mRNA levels of the G-protein coupled receptor natriuretic peptide receptor 3 (Npr3, implicated in paracrine signaling, up-regulated by 4.70-fold. Conclusions: Although Hhex is dispensable for ductal cell function in the adult, ablation of Hhex in pancreatic progenitors results in pancreatitis. Our data highlight the critical role of Hhex in maintaining ductal homeostasis in early life and support ductal hypersecretion as a novel etiology of pediatric chronic pancreatitis. Keywords: Npr3, Pancreatic Ducts, Primary Cilia

  1. Pancreatic stellate cells and CX3CR1: occurrence in normal pancreas and acute and chronic pancreatitis and effect of their activation by a CX3CR1 agonist.

    Science.gov (United States)

    Uchida, Masahiko; Ito, Tetsuhide; Nakamura, Taichi; Hijioka, Masayuki; Igarashi, Hisato; Oono, Takamasa; Kato, Masaki; Nakamura, Kazuhiko; Suzuki, Koichi; Takayanagi, Ryoichi; Jensen, Robert T

    2014-07-01

    Numerous studies suggest important roles of the chemokine, fractalkine (CX3CL1), in acute/chronic pancreatitis; however, the possible mechanisms of the effects are unclear. Pancreatic stellate cells (PSCs) can play important roles in pancreatitis, secreting inflammatory cytokines/chemokines, as well as proliferation. Therefore, we investigated CX3CL1 receptor (CX3CR1) occurrence in normal pancreas and pancreatitis (acute/chronic) tissues and the effects of CX3CL1 on activated PSCs. CX3CR1 expression/localization in normal pancreas and pancreatitis (acute/chronic) tissues was evaluated with immunohistochemical analysis. CX3CR1 expression and effects of CX3CL1 on activated PSCs were examined with real-time polymerase chain reaction, BrdU (5-bromo-2-deoxyuridine) assays, and Western blotting. In normal pancreas, acinar cells expressed CX3CR1 within granule-like formations in the cytoplasm, whereas in acute/chronic pancreatitis, acinar, ductal, and activated PSCs expressed CX3CR1 on cell membranes. With activation of normal PSCs, CX3CR1 is increased. CX3CL1 activated multiple signaling cascades in PSCs. CX3CL1 did not induce inflammatory genes expression in activated PSCs, but induced proliferation. CX3CR1s are expressed in normal pancreas. Expression is increased in acute/chronic pancreatitis, and the CX3CR1s are activated. CX3CL1 induces proliferation of activated PSCs without increasing release of inflammatory mediators. These results suggest that CX3CR1 activation of PSCs could be important in their effects in pancreatitis, especially to PSC proliferation in pancreatitis where CX3CL1 levels are elevated.

  2. Cirugías Conservadoras del Parénquima Pancreático / Converving Parenchyma Pancreatic Surgeries

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    Giunippero Alejandro

    2015-11-01

    Full Text Available After a classical pancreatic resection the risk of endocrine and exocrine insufficiency is in the order of : 8-20 % and 20-50 % respectively 1. Conservative surgery of pancreatic parenchyma decrease the risk of insufficiency and represents the clearest benefits of this type of surgery. They are optional techniques that help the surgeon to evaluate the decision which is best for each patient and each type of lesion. Among them we will approach three of them: uncinate process resection, enucleation, median pancreatectomy.

  3. In vitro secretion of zymogens by bovine pancreatic acini and ultra-structural analysis of exocytosis

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    Sivalingam Jayaveni

    2016-03-01

    Full Text Available The aim of this study is to establish a bovine pancreatic acinar cell culture model with longer viability and functionality. The cells could be maintained in a functional state for upto 20 days with normal morphology. Cells were positive for amylase as observed by immunofluorescence staining. Acinar cells are spherical and range about 2–3 µm in diameter. The porosome formed by exocytosis and heterogenous enzyme granules of size ranging 100–300 nm were seen on the surface of cells by electron microscopy. The activity of the enzymes was high on day 15 and the activity profile of the enzymes is in the order: protease>lipase>amylase and the enzymes were identified by SDS-PAGE. Long-term culture of bovine pancreatic acini could be useful in studying the pathogenesis of pancreatitis. Since the bovine genome shares about 80% identity with the human genome, the cells derived from bovine pancreas can be engineered and used as a potential xenotransplant to treat conditions like pancreatitis as the tissue source is abundantly available.

  4. Subclinical zinc deficiency impairs pancreatic digestive enzyme activity and digestive capacity of weaned piglets.

    Science.gov (United States)

    Brugger, Daniel; Windisch, Wilhelm M

    2016-08-01

    This study investigated the effects of short-term subclinical Zn deficiency on exocrine pancreatic activity and changes in digestive capacity. A total of forty-eight weaned piglets were fed ad libitum a basal diet (maize and soyabean meal) with adequate Zn supply (88 mg Zn/kg diet) during a 2-week acclimatisation phase. Animals were then assigned to eight dietary treatment groups (n 6) according to a complete randomised block design considering litter, live weight and sex. All pigs were fed restrictively (450 g diet/d) the basal diet but with varying ZnSO4.7H2O additions, resulting in 28·1, 33·6, 38·8, 42·7, 47·5, 58·2, 67·8 and 88·0 mg Zn/kg diet for a total experimental period of 8 d. Pancreatic Zn concentrations and pancreatic activities of trypsin, chymotrypsin, carboxypeptidase A and B, elastase and α-amylase exhibited a broken-line response to stepwise reduction in dietary Zn by declining beneath thresholds of 39·0, 58·0, 58·0, 41·2, 47·5, 57·7 and 58·0 mg Zn/kg diet, respectively. Furthermore, carboxypeptidase B and α-amylase activities were significantly lower in samples with reduced pancreatic Zn contents. Coefficients of faecal digestibility of DM, crude protein, total lipids and crude ash responded similarly to pancreatic enzyme activities by declining below dietary thresholds of 54·7, 45·0, 46·9 and 58·2 mg Zn/kg diet, respectively. In conclusion, (1) subclinical Zn deficiency impaired pancreatic exocrine enzymes, (2) this response was connected to pancreatic Zn metabolism and (3) the decline in catalytic activity impaired faecal digestibility already after 1 week of insufficient alimentary Zn supply and very early before clinical deficiency symptoms arise.

  5. Endosonography of groove pancreatitis

    NARCIS (Netherlands)

    Tio, T. L.; Luiken, G. J.; Tytgat, G. N.

    1991-01-01

    Groove pancreatitis is a rare form of chronic pancreatitis. Distinction between pancreatitis and pancreatic carcinoma is often difficult. Two cases of groove pancreatitis diagnosed by endosonography are described. A hypoechoic pattern between the duodenal wall and pancreas was clearly imaged in both

  6. Pancreatic cystadenoma

    Energy Technology Data Exchange (ETDEWEB)

    Aspestrand, F.; Oppedal, B.R.; Eide, T.J.

    1984-05-01

    Two cases of pancreatic cystadenoma are presented, demonstrating the typical angiographic and histologic pattern as given in previous literature. Although computed tomography and ultrasound examinations may be useful, angiography seems to play a decisive role in establishing the diagnosis, demonstrating the localization and extent of the tumor, and permitting the possible differentiation of benign and malignant lesions.

  7. Pancreatitis aguda

    National Research Council Canada - National Science Library

    ALARCÓN O, CLAUDIA; ÁVILA B, MARÍA LORETO; TAJMUCH V, VIRGINIA

    2008-01-01

    .... La mayoría de los casos en niños son cuadros autolimitados y de buen pronóstico. La clasificación de Atlanta de 1992 define los conceptos de pancreatitis aguda leve, grave, necrosis, colecciones...

  8. Serglycin proteoglycan is not implicated in localizing exocrine pancreas enzymes to zymogen granules

    DEFF Research Database (Denmark)

    Niemann, Carsten U; Cowland, Jack B; Ralfkiaer, Elisabeth

    2009-01-01

    Storage and release of proteins from granules forms the basis of cellular functions as diverse as cell mediated cytotoxicity, neuronal communication, activation of muscle fibres, and release of hormones or digestive enzymes from endocrine and exocrine glands, such as the pancreas. Serglycin...

  9. Hydrogen-rich saline ameliorates the severity of L-arginine-induced acute pancreatitis in rats

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Han; Sun, Yan Ping; Li, Yang [Department of General Surgery, Shanghai Chang Zheng Hospital, Second Military Medical University, Shanghai 200003 (China); Liu, Wen Wu [Department of Diving Medicine, Faculty of Naval Medicine, Second Military Medical University, Shanghai 200433 (China); Xiang, Hong Gang [Department of General Surgery, Shanghai Chang Zheng Hospital, Second Military Medical University, Shanghai 200003 (China); Fan, Lie Ying [Department of Clinical Laboratory, Shanghai East Hospital, Tong Ji University, Shanghai 200120 (China); Sun, Qiang [Department of Diving Medicine, Faculty of Naval Medicine, Second Military Medical University, Shanghai 200433 (China); Xu, Xin Yun [Department of General Surgery, Shanghai Chang Zheng Hospital, Second Military Medical University, Shanghai 200003 (China); Cai, Jian Mei [Department of Diving Medicine, Faculty of Naval Medicine, Second Military Medical University, Shanghai 200433 (China); Ruan, Can Ping; Su, Ning; Yan, Rong Lin [Department of General Surgery, Shanghai Chang Zheng Hospital, Second Military Medical University, Shanghai 200003 (China); Sun, Xue Jun, E-mail: sunxjk@hotmail.com [Department of Diving Medicine, Faculty of Naval Medicine, Second Military Medical University, Shanghai 200433 (China); Wang, Qiang, E-mail: wang2929@hotmail.com [Department of General Surgery, Shanghai Chang Zheng Hospital, Second Military Medical University, Shanghai 200003 (China)

    2010-03-05

    Molecular hydrogen, which reacts with the hydroxyl radical, has been considered as a novel antioxidant. Here, we evaluated the protective effects of hydrogen-rich saline on the L-arginine (L-Arg)-induced acute pancreatitis (AP). AP was induced in Sprague-Dawley rats by giving two intraperitoneal injections of L-Arg, each at concentrations of 250 mg/100 g body weight, with an interval of 1 h. Hydrogen-rich saline (>0.6 mM, 6 ml/kg) or saline (6 ml/kg) was administered, respectively, via tail vein 15 min after each L-Arg administration. Severity of AP was assessed by analysis of serum amylase activity, pancreatic water content and histology. Samples of pancreas were taken for measuring malondialdehyde and myeloperoxidase. Apoptosis in pancreatic acinar cell was determined with terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling technique (TUNEL). Expression of proliferating cell nuclear antigen (PCNA) and nuclear factor kappa B (NF-{kappa}B) were detected with immunohistochemistry. Hydrogen-rich saline treatment significantly attenuated the severity of L-Arg-induced AP by ameliorating the increased serum amylase activity, inhibiting neutrophil infiltration, lipid oxidation and pancreatic tissue edema. Moreover, hydrogen-rich saline treatment could promote acinar cell proliferation, inhibit apoptosis and NF-{kappa}B activation. These results indicate that hydrogen treatment has a protective effect against AP, and the effect is possibly due to its ability to inhibit oxidative stress, apoptosis, NF-{kappa}B activation and to promote acinar cell proliferation.

  10. Effect of nicotine on exocytotic pancreatic secretory response: role of calcium signaling

    Directory of Open Access Journals (Sweden)

    Chowdhury Parimal

    2013-01-01

    Full Text Available Abstract Background Nicotine is a risk factor for pancreatitis resulting in loss of pancreatic enzyme secretion. The aim of this study was to evaluate the mechanisms of nicotine-induced secretory response measured in primary pancreatic acinar cells isolated from Male Sprague Dawley rats. The study examines the role of calcium signaling in the mechanism of the enhanced secretory response observed with nicotine exposure. Methods Isolated and purified pancreatic acinar cells were subjected to a nicotine exposure at a dose of 100 μM for 6 minutes and then stimulated with cholecystokinin (CCK for 30 min. The cell’s secretory response was measured by the percent of amylase released from the cells in the incubation medium Calcium receptor antagonists, inositol trisphosphate (IP3 receptor blockers, mitogen activated protein kinase inhibitors and specific nicotinic receptor antagonists were used to confirm the involvement of calcium in this process. Results Nicotine exposure induced enhanced secretory response in primary cells. These responses remained unaffected by mitogen activated protein kinases (MAPK’s inhibitors. The effects, however, have been completely abolished by nicotinic receptor antagonist, calcium channel receptor antagonists and inositol trisphosphate (IP3 receptor blockers. Conclusions The data suggest that calcium activated events regulating the exocytotic secretion are affected by nicotine as shown by enhanced functional response which is inhibited by specific antagonists… The results implicate the role of nicotine in the mobilization of both intra- and extracellular calcium in the regulation of stimulus-secretory response of enzyme secretion in this cell system. We conclude that nicotine plays an important role in promoting enhanced calcium levels inside the acinar cell.

  11. In vivo spectroscopic photoacoustic tomography imaging of a far red fluorescent protein expressed in the exocrine pancreas of adult zebrafish

    Science.gov (United States)

    Liu, Mengyang; Schmitner, Nicole; Sandrian, Michelle G.; Zabihian, Behrooz; Hermann, Boris; Salvenmoser, Willi; Meyer, Dirk; Drexler, Wolfgang

    2014-03-01

    Fluorescent proteins brought a revolution in life sciences and biological research in that they make a powerful tool for researchers to study not only the structural and morphological information, but also dynamic and functional information in living cells and organisms. While green fluorescent proteins (GFP) have become a common labeling tool, red-shifted or even near infrared fluorescent proteins are becoming the research focus due to the fact that longer excitation wavelengths are more suitable for deep tissue imaging. In this study, E2-Crimson, a far red fluorescent protein whose excitation wavelength is 611 nm, was genetically expressed in the exocrine pancreas of adult zebrafish. Using spectroscopic all optical detection photoacoustic tomography, we mapped the distribution of E2-Crimson in 3D after imaging the transgenic zebrafish in vivo using two different wavelengths. With complementary morphological information provided by imaging the same fish using a spectral domain optical coherence tomography system, the E2-Crimson distribution acquired from spectroscopic photoacoustic tomography was confirmed in 2D by epifluorescence microscopy and in 3D by histology. To the authors' knowledge, this is the first time a far red fluorescent protein is imaged in vivo by spectroscopic photoacoustic tomography. Due to the regeneration feature of zebrafish pancreas, this work preludes the longitudinal studies of animal models of diseases such as pancreatitis by spectroscopic photoacoustic tomography. Since the effective penetration depth of photoacoustic tomography is beyond the transport mean free path length, other E2-Crimson labeled inner organs will also be able to be studied dynamically using spectroscopic photoacoustic tomography.

  12. Acinar autolysis and mucous extravasation in human sublingual glands: a microscopic postmortem study

    Directory of Open Access Journals (Sweden)

    Luciana Reis AZEVEDO-ALANIS

    2015-10-01

    Full Text Available Although some morphological investigations on aged human sublingual glands (HSG found eventual phenomena identified as autolysis and mucous extravasation, the exact meaning of these findings has not been elucidated.Objective The aim of this work is to investigate whether acinar autolysis and mucous extravasation are related to the aging process in human sublingual glands. We also speculate if autolytic changes may assist forensic pathologists in determining time of death.Material and Methods 186 cadavers’ glands were allocated to age groups: I (0–30 years; II (31–60, and III (61–90. Time and mode of death were also recorded. Acinar autolysis and mucous extravasation were classified as present or absent. Ultrastructural analysis was performed using transmission electron microscopy (TEM. Data were compared using Mann-Whitney U, Spearman’s correlation coefficient, Kruskal-Wallis, and Dunn tests (p<0.05.Results There was correlation between age and acinar autolysis (r=0.38; p=0.0001. However, there was no correlation between autolysis and time of death. No differences were observed between genders. TEM showed mucous and serous cells presenting nuclear and membrane alterations and mucous cells were more susceptible to autolysis.Conclusion Acinar autolysis occurred in all age groups and increased with age while mucous extravasation was rarely found. Both findings are independent. Autolysis degrees in HSG could not be used to determine time of death.

  13. Role of Ca2+-independent phospholipase A2 in exocytosis of amylase from parotid acinar cells.

    Science.gov (United States)

    Takuma, T; Ichida, T

    1997-06-01

    We evaluated the role of cytosolic phospholipase A2 (PLA2) in the exocytosis of amylase from parotid acinar cells. The exocytosis stimulated by isoproterenol was dose-dependently inhibited by bromoenol lactone (BEL), a potent suicide inhibitor of Ca2+-independent cytosolic PLA2. The IC50 value of BEL was approximately 7 microM. AACOCF3, a selective inhibitor of Ca2+-dependent cytosolic PLA2, did not inhibit the exocytosis at least up to 30 microM. BEL also inhibited amylase release evoked by forskolin and membrane-permeable cAMP, but it did not inhibit cAMP-dependent protein kinase activity. PLA2 activity in parotid acinar cells was found to be predominantly Ca2+-independent, and was strongly inhibited by BEL, whose IC50 value was approximately 2 microM when it was applied to intact acini. Although isoproterenol scarcely enhanced [3H]arachidonic acid release from intact acinar cells, BEL dose-dependently decreased the basal arachidonic acid release to approximately one half of the control value. These results suggest that the cytosolic Ca2+-independent PLA2 activity plays a role in the membrane fusion process of exocytosis in parotid acinar cells.

  14. The pattern of fibrosis in the acinar zone 3 areas in early alcoholic liver disease

    DEFF Research Database (Denmark)

    Junge, Jette; Horn, T; Vyberg, M

    1991-01-01

    . The results suggest that the initial liver fibrosis in alcoholics is slightly asymmetrical distributed in each acinar zone 3 area. With progression, the fibrosis tends to be more uniformly distributed and septa appear, eventually linking THV with portal tracts. Apparently, thickening of the THV walls does...

  15. Differential regulation of pancreatic digestive enzymes during chronic high-fat diet-induced obesity in C57BL/6J mice.

    Science.gov (United States)

    Birk, Ruth Z; Rubio-Aliaga, Isabel; Boekschoten, Mark V; Danino, Hila; Müller, Michael; Daniel, Hannelore

    2014-07-28

    Exocrine pancreatic digestive enzymes are essential for the digestion of dietary components and are regulated by them. Chronic excess dietary high fat (HF) consumption is a contributing factor of diet-induced obesity (DIO) and associated chronic diseases and requires adaptation by the pancreas. The aim of the present study was to investigate the effects of chronic HF diet feeding on exocrine pancreatic digestive enzyme transcript levels in DIO C57BL/6J mice. C57BL/6J mice were fed diets containing either 10 or 45% energy (E%) derived from fat for 12 weeks (n 10 mice per diet group). Pancreatic tissue and blood samples were collected at 0, 4 and 12 weeks. The expression of a panel of exocrine pancreatic digestive enzymes was analysed using quantitative RT-PCR and Western blot analysis. The HF (45 E%) diet-fed C57BL/6J mice developed obesity, hyperleptinaemia, hyperglycaemia and hyperinsulinaemia. The transcript levels of pancreatic lipase (PL), pancreatic lipase-related protein 2 (PLRP2) and pancreatic phospholipase A2 (PLA2) were initially elevated; however, they were down-regulated to basal control levels at week 12. The transcript levels of colipase were significantly affected by diet and time. The protein levels of PL and PLRP2 responded to HF diet feeding. The transcript levels of amylase and proteases were not significantly affected by diet and time. The transcript levels of specific lipases in hyperinsulinaemic, hyperleptinaemic and hyperglycaemic DIO C57BL/6J mice are down-regulated. However, these mice compensate for this by the post-transcriptional regulation of the levels of proteins that respond to dietary fat. This suggests a complex regulatory mechanism involved in the modulation of fat digestion.

  16. Pancreatic tuberculosis masquerading as pancreatic serous cystadenoma

    Science.gov (United States)

    Hong, Seung Goun; Kim, Jae Seon; Joo, Moon Kyung; Lee, Kwang Gyun; Kim, Key Hyeon; Oh, Cho Rong; Park, Jong-Jae; Bak, Young-Tae

    2009-01-01

    Solitary pancreatic involvement of tuberculosis is rare, especially in an immunocompetent individual, and it may be misdiagnosed as pancreatic cystic neoplasms. Pancreatic cystic neoplasms are being identified in increasing numbers, probably because of the frequent use of radiology and advances in endoscopic techniques. However, they are composed of a variety of neoplasms with a wide range of malignant potential, and it is often difficult to differentiate pancreatic tuberculosis mimicking cystic neoplasms from benign or malignant pancreatic cystic neoplasms. Non-surgical diagnosis of pancreatic tuberculosis is inconclusive and continues to be a challenge in many cases. If so, then laparotomy should be employed to establish the diagnosis. Therefore, pancreatic tuberculosis should be kept in mind during the differential diagnosis of solitary cystic masses in the pancreas. We report a patient who had solitary pancreatic tuberculosis masquerading as pancreatic serous cystadenoma. PMID:19248204

  17. Hypoxic vasoconstriction of partial muscular intra-acinar pulmonary arteries in murine precision cut lung slices

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    Goldenberg Anna

    2006-06-01

    Full Text Available Abstract Background Acute alveolar hypoxia causes pulmonary vasoconstriction (HPV which serves to match lung perfusion to ventilation. The underlying mechanisms are not fully resolved yet. The major vascular segment contributing to HPV, the intra-acinar artery, is mostly located in that part of the lung that cannot be selectively reached by the presently available techniques, e.g. hemodynamic studies of isolated perfused lungs, recordings from dissected proximal arterial segments or analysis of subpleural vessels. The aim of the present study was to establish a model which allows the investigation of HPV and its underlying mechanisms in small intra-acinar arteries. Methods Intra-acinar arteries of the mouse lung were studied in 200 μm thick precision-cut lung slices (PCLS. The organisation of the muscle coat of these vessels was characterized by α-smooth muscle actin immunohistochemistry. Basic features of intra-acinar HPV were characterized, and then the impact of reactive oxygen species (ROS scavengers, inhibitors of the respiratory chain and Krebs cycle metabolites was analysed. Results Intra-acinar arteries are equipped with a discontinuous spiral of α-smooth muscle actin-immunoreactive cells. They exhibit a monophasic HPV (medium gassed with 1% O2 that started to fade after 40 min and was lost after 80 min. This HPV, but not vasoconstriction induced by the thromboxane analogue U46619, was effectively blocked by nitro blue tetrazolium and diphenyleniodonium, indicating the involvement of ROS and flavoproteins. Inhibition of mitochondrial complexes II (3-nitropropionic acid, thenoyltrifluoroacetone and III (antimycin A specifically interfered with HPV, whereas blockade of complex IV (sodium azide unspecifically inhibited both HPV and U46619-induced constriction. Succinate blocked HPV whereas fumarate had minor effects on vasoconstriction. Conclusion This study establishes the first model for investigation of basic characteristics of HPV

  18. Is Pancreatic Cancer Hereditary?

    Science.gov (United States)

    ... Board Patient Education / Basics of Pancreatic Cancer Is pancreatic cancer hereditary? Cancer of the pancreas is a genetic ... found in cigarette smoke. The genetics of hereditary pancreatic cancer is a focus of research at Johns Hopkins. ...

  19. Comparative histological and histochemical studies on the pancreas of Labeo rohita (Hamilton, 1822, Mystus vittatus (Bloch, 1790 and Notopterus notopterus (Pallas, 1769

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    Padmanabha Chakrabarti

    2015-01-01

    Full Text Available The histological analysis, disposition and histochemical localization of tryptophan were investigated in the pancreas to compare the cellular organization and histochemical characterization in the pancreas of Labeo rohita (Hamilton, 1822, Mystus vittatus (Bloch, 1790 and Notopterus notopterus (Pallas, 1769 having different feeding habits. Histological analysis demonstrated that the exocrine pancreatic tissues were dispersed within the hepatic parenchyma and spleen in L. rohita. Thin septa of connective tissue separated parenchyma of liver and also the spleen from exocrine pancreatic cells. However, in M. vittatus, the discrete pancreatic tissue formed distinct oval or elongated acini interspersed with small area of islet of Langerhans and blood vessels. In N. notopterus, the rhomboidal acinar cells of discrete pancreatic tissue intercalated with comparatively clear and large islet of Langerhans. The exocrine acinar cells in all the three species were provided with prominent nuclei and densely packed zymogen granules. Histochemical localization revealed that the zymogen granules of exocrine acinar cells of all species exhibited varied intensities of tryptophan reaction, the precursor of various pancreatic enzymes which may be related to the food and feeding habits of the fishes under study.

  20. Biomarkers for pancreatic cancer: promising new markers and options beyond CA 19-9.

    Science.gov (United States)

    Ballehaninna, Umashankar K; Chamberlain, Ronald S

    2013-12-01

    Pancreatic adenocarcinoma accounts for nearly 90-95% of exocrine malignant tumors of the pancreas. Traditionally, overexpressed proteins/epitopes such as CA 19-9, CA-50, CEA, and many others were being used as pancreatic cancer tumor markers. The main utility of these biomarkers was in the diagnosis of pancreatic cancer as well as to assess response to chemotherapy and to determine prognosis and to predict tumor recurrence. However, these markers had significant limitations such as lack of sensitivity, false-negative results in certain blood groups, as well as false-positive elevation in the presence of obstructive jaundice. To circumvent these limitations, an extraordinary amount of research is being performed to identify an accurate tumor marker or a panel of markers that could aid in the management of the pancreatic cancer. Although this research has identified a large number and different variety of biomarkers, few hold future promise as a preferred marker for pancreatic cancer. This review provides an insight into exciting new areas of pancreatic biomarker research such as salivary, pancreatic juice, and stool markers that can be used as a noninvasive test to identify pancreatic cancer. This manuscript also provides a discussion on newer biomarkers, the role of microRNAs, and pancreatic cancer proteomics, which have the potential to identify a preferred tumor marker for pancreatic adenocarcinoma. This review further elaborates on important genetic changes associated with the development and progression of pancreatic cancer that holds the key for the identification of a sensitive biomarker and which could also serve as a therapeutic target.

  1. G protein-coupled receptor 39 deficiency is associated with pancreatic islet dysfunction

    DEFF Research Database (Denmark)

    Holst, Birgitte; Egerod, Kristoffer L; Jin, Chunyu

    2009-01-01

    tolerance both during oral and iv glucose tolerance tests, and Gpr39(-/-) mice had decreased plasma insulin response to oral glucose. Islet architecture was normal in the Gpr39 null mice, but expression of Pdx-1 and Hnf-1alpha was reduced. Isolated, perifused islets from Gpr39 null mice secreted less......alpha, and in the present study, we addressed the importance of GPR39 for glucose homeostasis and pancreatic islets function. The expression and localization of GPR39 were characterized in the endocrine pancreas and pancreatic cell lines. Gpr39(-/-) mice were studied in vivo, especially in respect...... of glucose tolerance and insulin sensitivity, and in vitro in respect of islet architecture, gene expression, and insulin secretion. Gpr39 was down-regulated on differentiation of the pluripotent pancreatic cell line AR42J cells toward the exocrine phenotype but was along with Pdx-1 strongly up...

  2. Description of the use of contrast-enhanced ultrasonography in four dogs with pancreatic tumours.

    Science.gov (United States)

    Vanderperren, K; Haers, H; Van der Vekens, E; Stock, E; Paepe, D; Daminet, S; Saunders, J H

    2014-03-01

    Canine pancreatic tumours are rare compared to human medicine and the detection and differentiation of pancreatic neoplasia is challenging with B-mode ultrasonography, which often leads to late clinical diagnosis and poor prognosis. This case report describes the findings of contrast-enhanced ultrasonography in four dogs with pancreatic adenocarcinoma or insulinoma. B-mode ultrasonography of the pancreas revealed a hypoechoic nodule in three dogs and heterogenous tissue in one dog. Contrast-enhanced ultrasonography was able to differentiate between two tumour types: adenocarcinomas showed hypoechoic and hypovascular lesions, whereas insulinomas showed uniformly hypervascular lesions. Contrast-enhanced ultrasonography findings were confirmed by cytology and/or histopathology. The results demonstrated that contrast-enhanced ultrasonography was able to establish different enhancement patterns between exocrine (adenocarcinoma) and endocrine (insulinoma) tumours in dogs.

  3. Role of Biomarkers in Diagnosis and Prognostic Evaluation of Acute Pancreatitis

    Science.gov (United States)

    Meher, Susanta; Mishra, Tushar Subhadarshan; Sasmal, Prakash Kumar; Rath, Satyajit; Sharma, Rakesh; Rout, Bikram; Sahu, Manoj Kumar

    2015-01-01

    Acute pancreatitis is a potentially life threatening disease. The spectrum of severity of the illness ranges from mild self-limiting disease to a highly fatal severe necrotizing pancreatitis. Despite intensive research and improved patient care, overall mortality still remains high, reaching up to 30–40% in cases with infected pancreatic necrosis. Although little is known about the exact pathogenesis, it has been widely accepted that premature activation of digestive enzymes within the pancreatic acinar cell is the trigger that leads to autodigestion of pancreatic tissue which is followed by infiltration and activation of leukocytes. Extensive research has been done over the past few decades regarding their role in diagnosis and prognostic evaluation of severe acute pancreatitis. Although many standalone biochemical markers have been studied for early assessment of severity, C-reactive protein still remains the most frequently used along with Interleukin-6. In this review we have discussed briefly the pathogenesis and the role of different biochemical markers in the diagnosis and severity evaluation in acute pancreatitis. PMID:26345247

  4. Pancreatitis in hyperlipemic mink (Mustela vison).

    Science.gov (United States)

    Nordstoga, K; Sørby, R; Olivecrona, G; Smith, A J; Christophersen, B

    2012-05-01

    In both man and animals, inflammatory changes in the pancreas often occur with disturbances in lipid metabolism, including hypertriglyceridemia and an excess of free fatty acids. Hyperlipoproteinemia type I is a human condition caused by a deficiency of lipoprotein lipase. A similar metabolic disturbance that occurs in mink is of considerable comparative interest, as it is also followed by pancreatitis. Pancreatic lesions in hyperlipoproteinemic mink included overt variably sized nodules with hemorrhage and necrosis. These lesions began as intralobular necrosis of exocrine cells and progressed to total lobular destruction, with eventual involvement of interlobular tissue. Remnants of epithelial cells and lipid-filled macrophages were seen in necrotic areas, along with other types of inflammatory cells scattered in a lipid-rich exudate. Granulation tissue developed rapidly in necrotic areas. Additional observations included ductal proliferation, replacement of epithelial cells with fat, and mural arterial thickening, most conspicuously with vacuolated cells and endothelial proliferation. Extravasation of lipid-rich plasma is thought to be a major intensifier of the inflammatory response.

  5. On the Structure of Bovine Pancreatic Ribonuclease B. Isolation of a Glycopeptide

    Energy Technology Data Exchange (ETDEWEB)

    Plummer, Jr., T. H.; Hirs, C. H.W.

    Ribonuclease B is a constituent of the zymogen granules of bovine pancreatic acinar cells and is secreted in the pancreatic juice of cattle. Its isolation from bovine pancreatic juice has been described. The enzyme is a glycoprotein that possesses an amino acid composition indistinguishable from that of ribonuclease A and contains carbohydrate to the extent of six residues of mannose and two residues of glucosamine per molecule. The experiments to be described in the present communication were designed to provide preliminary structural information about the protein, and, in particular, to furnish an understanding of the distribution of the carbohydrate in the molecule. The experiments have demonstrated that the carbohydrate content is accounted for by a single covalently-bonded oligosaccharide moiety attached at an aspartic acid or asparagine residue, and have provided further presumptive evidence that the structure of the protein is otherwise identical to that of ribonuclease A. (auth)

  6. Targeting of the P2X7 receptor in pancreatic cancer and stellate cells

    DEFF Research Database (Denmark)

    Giannuzzo, Andrea; Saccomano, Mara; Napp, Joanna

    2016-01-01

    The ATP-gated receptor P2X7 (P2X7R) is involved in regulation of cell survival and has been of interest in cancer field. Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer and new markers and therapeutic targets are needed. PDAC is characterized by a complex tumour microenvironment, which...... includes cancer and pancreatic stellate cells (PSCs), and potentially high nucleotide/side turnover. Our aim was to determine P2X7R expression and function in human pancreatic cancer cells in vitro as well as to perform in vivo efficacy study applying P2X7R inhibitor in an orthotopic xenograft mouse model...... into nude mice and tumour growth was followed noninvasively by bioluminescence imaging. AZ10606120-treated mice showed reduced bioluminescence compared to saline-treated mice. Immunohistochemical analysis confirmed P2X7R expression in cancer and PSC cells, and in metaplastic/neoplastic acinar and duct...

  7. PANCREATIC CANCER

    Directory of Open Access Journals (Sweden)

    Alojz Pleskovič

    2003-12-01

    Full Text Available Background. The pancreatic cancer is quite common malignant tumor of gastointestinal tract and its incidence is increasing in well developed part of the world. Despite of all advanced diagnostic methods the disease is in most cases recognised too late when the tumor is not resectable.Conclusions. Only in 20–30% of patients with pancreatic cancer surgical resection is possible, and even in this group 5year survival is very low. In the patients where the tumor is not resectable, sometimes only palliative procedures are indicated and sometimes only simptomatic therapy is possible. The average survival period in this group of patients is 12–20 months. Adjuvant chemo and radiotherapy has not shown much of benefit and the prognosis is still very bad.

  8. Morphometric Measurements to Quantify the Cerulein Induced Hyperstimulatory Pancreatitis of Rats under the Protective Effect of Lectins

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    Ludwig Jonas

    1998-01-01

    Full Text Available In preceding papers we demonstrated an inhibitory effect of wheat germ agglutinin (WGA and Ulex europaeus agglutinin (UEA on the cholecystokinin (CCK binding to the CCK receptor of rat pancreatic cells and also on the CCK induced Ca2+ release and α-amylase secretion in vitro as well as on pancreatic secretion of intact rats in vivo. In the present study we show the same inhibitory effect of both lectins on the cerulein pancreatitis of rats. This acute pancreatitis was induced by supramaximal injections (5 µg/kg/h iv or 10 µg/kg/h ip of the CCK analogue cerulein in rats every hour. To monitor the degree of pancreatitis, we measured the number and diameter of injury vacuoles in the pancreatic acinar cells as one of the most important signs of this type of pancreatitis by light microscopic morphometry with two different systems on paraffin sections. Furthermore, the serum α-amylase activity was measured biochemically. We found a correlation between the diameter of vacuoles inside the acinar cells and the serum enzyme activity up to 24 h. The simultaneous ip administration of cerulein and WGA or UEA in a dosage of 125 µg/kg/h for 8 h led to a reduction of vacuolar diameter from 13.1 ± 2.0 µm (cerulein to 7.5 ± 1.1 µm (cerulein + WGA or 7.2 ± 1.3 µm (cerulein + UEA. The serum amylase activity was reduced from 63.7 ± 15.8 mmol/l \\times min (cerulein to 37.7 ± 11.8 (cerulein + WGA or 39.4; +52.9; -31.1 (cerulein + UEA-I. Both parameters allow the grading this special type of pancreatitis to demonstrate the protective effect of the lectins.

  9. Scolopendra subspinipes mutilans protected the cerulein-induced acute pancreatitis by inhibiting high-mobility group box protein-1.

    Science.gov (United States)

    Jo, Il-Joo; Bae, Gi-Sang; Park, Kyoung-Chel; Choi, Sun Bok; Jung, Won-Seok; Jung, Su-Young; Cho, Jung-Hee; Choi, Mee-Ok; Song, Ho-Joon; Park, Sung-Joo

    2013-03-14

    To evaluate the inhibitory effects of Scolopendra subspinipes mutilans (SSM) on cerulein-induced acute pancreatitis (AP) in a mouse model. SSM water extract (0.1, 0.5, or 1 g/kg) was administrated intraperitoneally 1 h prior to the first injection of cerulein. Once AP developed, the stable cholecystokinin analogue, cerulein was injected hourly, over a 6 h period. Blood samples were taken 6 h later to determine serum amylase, lipase, and cytokine levels. The pancreas and lungs were rapidly removed for morphological examination, myeloperoxidase assay, and real-time reverse transcription polymerase chain reaction. To specify the role of SSM in pancreatitis, the pancreatic acinar cells were isolated using collagenase method. Then the cells were pre-treated with SSM, then stimulated with cerulein. The cell viability, cytokine productions and high-mobility group box protein-1 (HMGB-1) were measured. Furthermore, the regulating mechanisms of SSM action were evaluated. The administration of SSM significantly attenuated the severity of pancreatitis and pancreatitis associated lung injury, as was shown by the reduction in pancreatic edema, neutrophil infiltration, vacuolization and necrosis. SSM treatment also reduced pancreatic weight/body weight ratio, serum amylase, lipase and cytokine levels, and mRNA expression of multiple inflammatory mediators such as tumor necrosis factor-α and interleukin-1β. In addition, treatment with SSM inhibited HMGB-1 expression in the pancreas during AP. In accordance with in vivo data, SSM inhibited the cerulein-induced acinar cell death, cytokine, and HMGB-1 release. SSM also inhibited the activation of c-Jun NH2-terminal kinase, p38 and nuclear factor (NF)-κB. These results suggest that SSM plays a protective role during the development of AP and pancreatitis associated lung injury via deactivating c-Jun NH2-terminal kinase, p38 and NF-κB.

  10. Synchronous pancreatic solid pseudopapillary neoplasm and intraductal papillary mucinous neoplasm.

    Science.gov (United States)

    Hirabayashi, Kenichi; Zamboni, Giuseppe; Ito, Hiroyuki; Ogawa, Masami; Kawaguchi, Yoshiaki; Yamashita, Tomohiro; Nakagohri, Toshio; Nakamura, Naoya

    2013-06-07

    Solid pseudopapillary neoplasm (SPN) is a rare and low-grade malignant pancreatic neoplasm composed of poorly cohesive monomorphic neoplastic cells forming solid and pseudopapillary structures with frequent hemorrhagic-cystic degeneration. Intraductal papillary mucinous neoplasm (IPMN) is a pancreatic exocrine tumor composed of intraductal papillary growth of mucin containing neoplastic cells in the main pancreatic duct or its major branches. In the case presented here, a 53-year-old, Japanese man was found to have multiple cystic lesions and dilatation of the main pancreatic duct in the neck of the pancreas. Histological examination revealed a main-duct and branch-duct type IPMN, of the gastric-type, involving the neck of the pancreas, associated with a 0.5 cm SPN in the caudal side of the IPMN. We diagnosed this case as synchronous SPN and IPMN. As far as we know, only one other case of synchronous SPN and IPMN has been reported. Both the present case and the previously reported case showed abnormal nuclear expression of β-catenin in SPN, whereas IPMN showed no abnormal nuclear expression. These results suggest that β-catenin abnormality is not a common pathogenetic factor of synchronous SPN and IPMN.

  11. Pancreatitis in dogs and cats: definitions and pathophysiology.

    Science.gov (United States)

    Watson, P

    2015-01-01

    Pancreatitis, or inflammation of the pancreas, is commonly seen in dogs and cats and presents a spectrum of disease severities from acute to chronic and mild to severe. It is usually sterile, but the causes and pathophysiology remain poorly understood. The acute end of the disease spectrum is associated with a high mortality but the potential for complete recovery of organ structure and function if the animal survives. At the other end of the spectrum, chronic pancreatitis in either species can cause refractory pain and reduce quality of life. It may also result in progressive exocrine and endocrine functional impairment. There is confusion in the veterinary literature about definitions of acute and chronic pancreatitis and there are very few studies on the pathophysiology of naturally occurring pancreatitis in dogs and cats. This article reviews histological and clinical definitions and current understanding of the pathophysiology and causes in small animals by comparison with the much more extensive literature in humans, and suggests many areas that need further study in dogs and cats. © 2015 British Small Animal Veterinary Association.

  12. A Mini-Review on the Effect of Docosahexaenoic Acid (DHA on Cerulein-Induced and Hypertriglyceridemic Acute Pancreatitis

    Directory of Open Access Journals (Sweden)

    Yoo Kyung Jeong

    2017-10-01

    Full Text Available Acute pancreatitis refers to the sudden inflammation of the pancreas. It is associated with premature activation and release of digestive enzymes into the pancreatic interstitium and systemic circulation, resulting in pancreatic tissue autodigestion and multiple organ dysfunction, as well as with increased cytokine production, ultimately leading to deleterious local and systemic effects. Although mechanisms involved in pathogenesis of acute pancreatitis have not been completely elucidated, oxidative stress is regarded as a major risk factor. In human acute pancreatitis, lipid peroxide levels in pancreatic tissues increase. Docosahexaenoic acid (DHA, an omega-3 polyunsaturated fatty acid (C22:6n-3, exerts anti-inflammatory and antioxidant effects on various cells. Previous studies have shown that DHA activates peroxisome proliferator-activated receptor-γ and induces catalase, which inhibits oxidative stress-mediated inflammatory signaling required for cytokine expression in experimental acute pancreatitis using cerulein. Cerulein, a cholecystokinin analog, induces intra-acinar activation of trypsinogen in the pancreas, which results in human acute pancreatitis-like symptoms. Therefore, DHA supplementation may be beneficial for preventing or inhibiting acute pancreatitis development. Since DHA reduces serum triglyceride levels, addition of DHA to lipid-lowering drugs like statins has been investigated to reduce hypertriglyceridemic acute pancreatitis. However, high DHA concentrations increase cytosolic Ca2+, which activates protein kinase C and may induce hyperlipidemic acute pancreatitis. In this review, effect of DHA on cerulein-induced and hypertriglyceridemic acute pancreatitis has been discussed. The relation of high concentration of DHA to hyperlipidemic acute pancreatitis has been included.

  13. Chronic pancreatitis: An international draft consensus proposal for a new mechanistic definition.

    Science.gov (United States)

    Whitcomb, David C; Frulloni, Luca; Garg, Pramod; Greer, Julia B; Schneider, Alexander; Yadav, Dhiraj; Shimosegawa, Tooru

    2016-01-01

    A definition of chronic pancreatitis (CP) is needed for diagnosis and distinguishing CP from other disorders. Previous definitions focused on morphology. Advances in epidemiology, genetics, molecular biology, modeling and other disciplines provide new insights into pathogenesis of CP, and allow CP to be better defined. Expert physician-scientists from the United States, India, Europe and Japan reviewed medical and scientific literature and clinical experiences. Competing views and approaches were debated until a new consensus definition was reached. CP has been defined as 'a continuing inflammatory disease of the pancreas, characterized by irreversible morphological change, and typically causing pain and/or permanent loss of function'. Focusing on abnormal morphology makes early diagnosis challenging and excludes inflammation without fibrosis, atrophy, endocrine and exocrine dysfunction, pain syndromes and metaplasia. A new mechanistic definition is proposed--'Chronic pancreatitis is a pathologic fibro-inflammatory syndrome of the pancreas in individuals with genetic, environmental and/or other risk factors who develop persistent pathologic responses to parenchymal injury or stress.' In addition, "Common features of established and advanced CP include pancreatic atrophy, fibrosis, pain syndromes, duct distortion and strictures, calcifications, pancreatic exocrine dysfunction, pancreatic endocrine dysfunction and dysplasia." This definition recognizes the complex nature of CP, separates risk factors from disease activity markers and disease endpoints, and allows for a rational approach to early diagnosis, classification and prognosis. Initial agreement on a mechanistic definition of CP has been reached. This definition should be debated in rebuttals and endorsements, among experts and pancreatic societies until international consensus is reached. Copyright © 2016 IAP and EPC. Published by Elsevier India Pvt Ltd. All rights reserved.

  14. Pancreatic enzyme synthesis in pancreatic disease.

    Science.gov (United States)

    Boyd, E J; Clark, G; Dunbar, J; Wormsley, K G

    1985-08-01

    In a prospective evaluation of patients suspected of having chronic pancreatitis, synthesis of pancreatic enzymes was measured by means of the incorporation of selenium-75-labelled methionine into the proteins of duodenal aspirate during stimulation of pancreatic secretion with secretin (1 CU X kg-1 X h-1) plus cholecystokinin (CCK) (1 IDU X kg-1 X h-1). The rate of pancreatic enzyme synthesis was increased in patients with chronic pancreatitis. Measurement of pancreatic enzyme synthesis was more sensitive in the detection of chronic pancreatitis than either the bicarbonate or the trypsin secretory response to secretin plus CCK. A combination of the bicarbonate secretory response with measurement of the rate of enzyme synthesis provided a positive predictive power of 100% when both tests were abnormal and a negative predictive power of 100% when both tests were normal, so that the combined test can be recommended both for excluding and confirming the presence of chronic pancreatitis.

  15. Inactivation of Brca2 cooperates with Trp53(R172H) to induce invasive pancreatic ductal adenocarcinomas in mice: a mouse model of familial pancreatic cancer.

    Science.gov (United States)

    Feldmann, Georg; Karikari, Collins; dal Molin, Marco; Duringer, Stephanie; Volkmann, Petra; Bartsch, Detlef K; Bisht, Savita; Koorstra, Jan-Bart; Brossart, Peter; Maitra, Anirban; Fendrich, Volker

    2011-06-01

    An inactivating germline mutation in BRCA2 is the most common known genetic basis for familial pancreatic cancer (FPC), accounting for 5-10% of inherited cases. A genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC) arising on the backdrop of Brca2 deficiency is likely to elucidate valuable diagnostic and therapeutic insights for FPC. Both Brca2 alleles were conditionally deleted during development within the pancreatic epithelium by generating Pdx1-Cre; Brca2(f/f) (CB) mice; in addition, triple transgenic Pdx1-Cre; Brca2(f/f); LSL-Trp53(R172H) (CBP) mice were generated, in order to determine the impact of p53 deregulation on Brca2-deficient carcinogenesis. Both CB and CBP mice developed non-invasive ductal precursor lesions (murine pancreatic intraepithelial neoplasia or mPanIN), although these were observed at an earlier time point (5 versus 8 months) and with higher prevalence in CBP mice. A minority of CB mice (15%) developed invasive and metastatic PDAC at a latency of 15 months or greater; in contrast, CBP mice of comparable age uniformly developed PDAC with variable histological features. Mortality in the absence of neoplasia in CB and CBP mice was associated with profound loss of pancreatic parenchyma, consistent with progressive elimination of Brca2-deficient cells. Widespread DNA damage, as evidenced by overexpression of the phosphorylated histone H(2)AX(Ser139), was observed in the non-neoplastic exocrine pancreas, as well as in the mPanIN and PDAC lesions of Brca2-deficient mice, independent of p53 status. Loss of Brca2 function predisposes the exocrine pancreas to profound DNA damage, and the frequency of invasive neoplasia is accentuated by the concomitant deregulation of p53.

  16. Identification of miRNAs Involved in Reprogramming Acinar Cells into Insulin Producing Cells.

    Directory of Open Access Journals (Sweden)

    Joan Teichenne

    Full Text Available Reprogramming acinar cells into insulin producing cells using adenoviral (Ad-mediated delivery of Pdx1, Ngn3 and MafA (PNM is an innovative approach for the treatment of diabetes. Here, we aimed to investigate the molecular mechanisms involved in this process and in particular, the role of microRNAs. To this end, we performed a comparative study of acinar-to-β cell reprogramming efficiency in the rat acinar cell line AR42J and its subclone B13 after transduction with Ad-PNM. B13 cells were more efficiently reprogrammed than AR42J cells, which was demonstrated by a strong activation of β cell markers (Ins1, Ins2, IAPP, NeuroD1 and Pax4. miRNome panels were used to analyze differentially expressed miRNAs in acinar cells under four experimental conditions (i non-transduced AR42J cells, (ii non-transduced B13 cells, (iii B13 cells transduced with Ad-GFP vectors and (iv B13 cells transduced with Ad-PNM vectors. A total of 59 miRNAs were found to be differentially expressed between non-transduced AR42J and B13 cells. Specifically, the miR-200 family was completely repressed in B13 cells, suggesting that these cells exist in a less differentiated state than AR42J cells and as a consequence they present a greater plasticity. Adenoviral transduction per se induced dedifferentiation of acinar cells and 11 miRNAs were putatively involved in this process, whereas 8 miRNAs were found to be associated with PNM expression. Of note, Ad-PNM reprogrammed B13 cells presented the same levels of miR-137-3p, miR-135a-5p, miR-204-5p and miR-210-3p of those detected in islets, highlighting their role in the process. In conclusion, this study led to the identification of miRNAs that might be of compelling importance to improve acinar-to-β cell conversion for the future treatment of diabetes.

  17. Neural plasticity in pancreatitis and pancreatic cancer.

    Science.gov (United States)

    Demir, Ihsan Ekin; Friess, Helmut; Ceyhan, Güralp O

    2015-11-01

    Pancreatic nerves undergo prominent alterations during the evolution and progression of human chronic pancreatitis and pancreatic cancer. Intrapancreatic nerves increase in size (neural hypertrophy) and number (increased neural density). The proportion of autonomic and sensory fibres (neural remodelling) is switched, and are infiltrated by perineural inflammatory cells (pancreatic neuritis) or invaded by pancreatic cancer cells (neural invasion). These neuropathic alterations also correlate with neuropathic pain. Instead of being mere histopathological manifestations of disease progression, pancreatic neural plasticity synergizes with the enhanced excitability of sensory neurons, with Schwann cell recruitment toward cancer and with central nervous system alterations. These alterations maintain a bidirectional interaction between nerves and non-neural pancreatic cells, as demonstrated by tissue and neural damage inducing neuropathic pain, and activated neurons releasing mediators that modulate inflammation and cancer growth. Owing to the prognostic effects of pain and neural invasion in pancreatic cancer, dissecting the mechanism of pancreatic neuroplasticity holds major translational relevance. However, current in vivo models of pancreatic cancer and chronic pancreatitis contain many discrepancies from human disease that overshadow their translational value. The present Review discusses novel possibilities for mechanistically uncovering the role of the nervous system in pancreatic disease progression.

  18. Autoimmune pancreatitis can develop into chronic pancreatitis

    Science.gov (United States)

    2014-01-01

    Autoimmune pancreatitis (AIP) has been recognized as a distinct type of pancreatitis that is possibly caused by autoimmune mechanisms. AIP is characterized by high serum IgG4 and IgG4-positive plasma cell infiltration in affected pancreatic tissue. Acute phase AIP responds favorably to corticosteroid therapy and results in the amelioration of clinical findings. However, the long-term prognosis and outcome of AIP remain unclear. We have proposed a working hypothesis that AIP can develop into ordinary chronic pancreatitis resembling alcoholic pancreatitis over a long-term course based on several clinical findings, most notably frequent pancreatic stone formation. In this review article, we describe a series of study results to confirm our hypothesis and clarify that: 1) pancreatic calcification in AIP is closely associated with disease recurrence; 2) advanced stage AIP might have earlier been included in ordinary chronic pancreatitis; 3) approximately 40% of AIP patients experience pancreatic stone formation over a long-term course, for which a primary risk factor is narrowing of both Wirsung’s and Santorini’s ducts; and 4) nearly 20% of AIP patients progress to confirmed chronic pancreatitis according to the revised Japanese Clinical Diagnostic Criteria, with independent risk factors being pancreatic head swelling and non-narrowing of the pancreatic body duct. PMID:24884922

  19. Detection, evaluation and treatment of diabetes mellitus in chronic pancreatitis: recommendations from PancreasFest 2012.

    Science.gov (United States)

    Rickels, Michael R; Bellin, Melena; Toledo, Frederico G S; Robertson, R Paul; Andersen, Dana K; Chari, Suresh T; Brand, Randall; Frulloni, Luca; Anderson, Michelle A; Whitcomb, David C

    2013-01-01

    Diabetes and glucose intolerance are common complications of chronic pancreatitis, yet clinical guidance on their detection, classification, and management is lacking. A working group reviewed the medical problems, diagnostic methods, and treatment options for chronic pancreatitis-associated diabetes for a consensus meeting at PancreasFest 2012. Guidance Statement 1.1: Diabetes mellitus is common in chronic pancreatitis. While any patient with chronic pancreatitis should be monitored for development of diabetes, those with long-standing duration of disease, prior partial pancreatectomy, and early onset of calcific disease may be at higher risk. Those patients developing diabetes mellitus are likely to have co-existing pancreatic exocrine insufficiency. Guidance Statement 1.2: Diabetes occurring secondary to chronic pancreatitis should be recognized as pancreatogenic diabetes (type 3c diabetes). Guidance Statement 2.1: The initial evaluation should include fasting glucose and HbA1c. These tests should be repeated annually. Impairment in either fasting glucose or HbA1c requires further evaluation. Guidance Statement 2.2: Impairment in either fasting glucose or HbA1c should be further evaluated by a standard 75 g oral glucose tolerance test. Guidance Statement 2.3: An absent pancreatic polypeptide response to mixed-nutrient ingestion is a specific indicator of type 3c diabetes. Guidance Statement 2.4: Assessment of pancreatic endocrine reserve, and importantly that of functional beta-cell mass, should be performed as part of the evaluation and follow-up for total pancreatectomy with islet autotransplantation (TPIAT). Guidance Statement 3: Patients with pancreatic diabetes shall be treated with specifically tailored medical nutrition and pharmacologic therapies. Physicians should evaluate and treat glucose intolerance in patients with pancreatitis. Copyright © 2013 IAP and EPC. All rights reserved.

  20. Antioxidants and chronic pancreatitis: theory of oxidative stress and trials of antioxidant therapy.

    Science.gov (United States)

    Grigsby, Brianna; Rodriguez-Rilo, Horacio; Khan, Khalid

    2012-04-01

    Chronic pancreatitis (CP) is an inflammatory disease characterized by the progressive destruction of pancreatic tissue and resulting in pancreatic exocrine and endocrine insufficiency. Increased oxidative stress has been implicated as a potential mechanism in its etiology and pathology. A number of studies have demonstrated that CP patients have a compromised antioxidant status, which may be a contributing factor to the enhanced oxidative state associated with the disease. Nutrition is an essential consideration in the treatment of CP, especially since diet is a source of several antioxidants and cofactors required for the production of cellular antioxidant enzymes. Many CP patients have an inadequate intake of macro and micronutrients because of abdominal pain and discomfort, which often increase postprandially and discourage eating. Exocrine insufficiency leads to further complications by preventing adequate digestion and absorption of ingested food, thus causing even greater deficiencies and impairment of antioxidant status. The aims of this article are to review the oxidative stress model of CP and to examine the evidence for nutrition, and, particularly, antioxidants, in the treatment of CP.

  1. Fecal pancreatic elastase-1 levels in older individuals without known gastrointestinal diseases or diabetes mellitus.

    Science.gov (United States)

    Herzig, Karl-Heinz; Purhonen, Anna-Kaisa; Räsänen, Kati M; Idziak, Joanna; Juvonen, Petri; Phillps, Ryszard; Walkowiak, Jaroslaw

    2011-01-25

    Structural changes occur in the pancreas as a part of the natural aging process. With aging, also the incidence of maldigestive symptoms and malnutrition increases, raising the possibility that these might be caused at least in part by inadequate pancreatic enzyme secretion due to degenerative processes and damage of the gland. Fecal elastase-1 is a good marker of pancreatic exocrine secretion. The aim of this study was to investigate the fecal elastase-1 levels among over 60 years old Finnish and Polish healthy individuals without any special diet, known gastrointestinal disease, surgery or diabetes mellitus. A total of 159 patients participated in this cross-sectional study. 106 older individuals (aged 60-92 years) were recruited from outpatient clinics and elderly homes. They were divided to three age groups: 60-69 years old (n = 31); 70-79 years old (n = 38) and over 80 years old (n = 37). 53 young subjects (20-28 years old) were investigated as controls. Inclusion criteria were age over 60 years, normal status and competence. Exclusion criteria were any special diet, diabetes mellitus, any known gastrointestinal disease or prior gastrointestinal surgery. Fecal elastase-1 concentration was measured from stool samples with an ELISA that uses two monoclonal antibodies against different epitopes of human elastase-1. Fecal elastase-1 concentrations correlated negatively with age (Pearson r = -0,3531, P gastrointestinal disorder, surgery or diabetes mellitus suffer from pancreatic exocrine insufficiency and might benefit from enzyme supplementation therapy.

  2. Framework for interpretation of trypsin-antitrypsin imbalance and genetic heterogeneity in pancreatitis.

    Science.gov (United States)

    Lin, Kun; Gao, Feng; Chen, Qingquan; Liu, Qicai; Chen, Shu

    2015-01-01

    Early intracellular premature trypsinogen activation was interpreted as the key initiator of pancreatitis. When the balance in the homeostasis of trypsin and antitrypsin system is disequilibrated, elevated aggressive enzymes directly attack the pancreatic tissue, which leads to pancreatic destruction and inflammation. However, trypsin alone is not enough to cause complications in pancreatitis, which may play a crucial role in modulating signaling events in the initial phase of the disease. NFκB activation is the major inflammatory pathway involved in the occurrence and development of pancreatitis and it can be induced by intrapancreatic activation of trypsinogen. Synthesis of trypsinogen occurs in endoplasmic reticulum (ER), and ER stress is an important early acinar cell event. Components of ER stress response are known to be able to trigger cell death as well as NFκB signaling cascade. The strongest evidence supporting the trypsin-centered theory is that gene mutations, which lead to the generation of more trypsin, or reduce the activity of trypsin inhibitors or trypsin degradation, are associated with pancreatitis. Thus, trypsin-antitrypsin imbalance may be the first step leading to pancreatic autodigestion and inducing other pathways. Continued experimental studies are necessary to determine the specific relationships between trypsin-antitrypsin imbalance and genetic heterogeneity in pancreatitis. In this article, we review the latest advances that contributed to the understanding of the basic mechanisms behind the occurrence and development of pancreatitis with a focus on the interpretation of trypsin-antitrypsin imbalance and their relationships with other inflammation pathways. We additionally highlight genetic predispositions to pancreatitis and possible mechanisms associated with them.

  3. Framework for Interpretation of Trypsin–antitrypsin Imbalance and Genetic Heterogeneity in Pancreatitis

    Science.gov (United States)

    Lin, Kun; Gao, Feng; Chen, Qingquan; Liu, Qicai; Chen, Shu

    2015-01-01

    Early intracellular premature trypsinogen activation was interpreted as the key initiator of pancreatitis. When the balance in the homeostasis of trypsin and antitrypsin system is disequilibrated, elevated aggressive enzymes directly attack the pancreatic tissue, which leads to pancreatic destruction and inflammation. However, trypsin alone is not enough to cause complications in pancreatitis, which may play a crucial role in modulating signaling events in the initial phase of the disease. NFκB activation is the major inflammatory pathway involved in the occurrence and development of pancreatitis and it can be induced by intrapancreatic activation of trypsinogen. Synthesis of trypsinogen occurs in endoplasmic reticulum (ER), and ER stress is an important early acinar cell event. Components of ER stress response are known to be able to trigger cell death as well as NFκB signaling cascade. The strongest evidence supporting the trypsin-centered theory is that gene mutations, which lead to the generation of more trypsin, or reduce the activity of trypsin inhibitors or trypsin degradation, are associated with pancreatitis. Thus, trypsin–antitrypsin imbalance may be the first step leading to pancreatic autodigestion and inducing other pathways. Continued experimental studies are necessary to determine the specific relationships between trypsin–antitrypsin imbalance and genetic heterogeneity in pancreatitis. In this article, we review the latest advances that contributed to the understanding of the basic mechanisms behind the occurrence and development of pancreatitis with a focus on the interpretation of trypsin–antitrypsin imbalance and their relationships with other inflammation pathways. We additionally highlight genetic predispositions to pancreatitis and possible mechanisms associated with them. PMID:26228362

  4. Dorsal Pancreatic Agenesis

    OpenAIRE

    Oya Uygur-Bayramiçli; Can Dolapçioglu; Derya Öztas; Resat Dabak; Gamze Kiliçoglu

    2007-01-01

    Context Agenesis of the dorsal pancreas is a rare entity and might present with various symptoms. We report a case which presented with chronic pancreatitis. Case report The patient presented with epigastric pain and we found dorsal pancreatic agenesis causing chronic pancreatitis. Conclusions Dorsal pancreatic agenesis can be easily diagnosed with new techniques and its association with clinical syndromes can be better understood.

  5. Mechanisms of disease: chronic inflammation and cancer in the pancreas--a potential role for pancreatic stellate cells?

    Science.gov (United States)

    Algül, Hana; Treiber, Matthias; Lesina, Marina; Schmid, Roland M

    2007-08-01

    Late diagnosis and ineffective therapeutic options mean that pancreatic ductal adenocarcinoma (PDA) is one of the most lethal forms of human cancer. The identification of genetic alterations facilitated the launch of the Pancreatic Intraepithelial Neoplasm nomenclature, a standardized classification system for pancreatic duct lesions, but the factors that contribute to the development of such lesions and their progression to high-grade neoplasia remain obscure. Age, smoking, obesity and diabetes confer increased risk of PDA, and the presence of chronic pancreatitis is a consistent risk factor for pancreatic cancer. It is hypothesized that chronic inflammation generates a microenvironment that contributes to malignant transformation in the pancreas, as is known to occur in other organs. Pancreatic stellate cells (PSCs) are the main mediator of fibrogenesis during chronic pancreatitis, but their contribution to the development of PDA has not been elucidated. Data now suggest that PSCs might assume a linking role in inflammation-associated carcinogenesis through their ability to communicate with inflammatory cells, acinar cells, and pancreatic cancer cells in a complicated network of interactions. In this Review, the role of PSCs in the process of inflammation-associated carcinogenesis is discussed and new potential treatment options evaluated.

  6. Autoimmune Pancreatitis - A Riddle Wrapped in an Enigma.

    Science.gov (United States)

    Webster, George J

    Autoimmune pancreatitis (AIP) was recognized as a clinical entity, at least in the West little more than 10 years ago. Since then, studies globally, and international collaboration, have led to important advances in our understanding of its clinical features, disease course, and management, although the aetiopathogenesis of this curious disease remains to be fully elucidated. Types 1 and 2 AIP have been described, of which type 1 is the commonest form, and best defined. International consensus now recognizes it as one of the many clinical manifestations of IgG4-related disease, and is now termed IgG4-related pancreatitis (IgG4-RP). The disease is not confined to a particular race, gender, or age, but often presents after the fifth decade in men. A common presentation is with jaundice due to low bile duct obstruction related to diffuse pancreatic enlargement (historically often leading to a misdiagnosis of cancer). Acute pancreatitis is unusual. Other organ involvement is a particular feature, including biliary disease, retroperitoneal fibrosis, generalized lymphadenopathy, renal, and lung involvement. No single test makes the diagnosis, and diagnostic criteria for type 1 AIP/IgG4-RP, which incorporate clinical, laboratory, radiological, pathological, and therapeutic parameters should be applied. A particular attempt should be made to make a histological diagnosis, which is characterized by an IgG4-positive lymphoplasmacytic infiltrate. Management is not based on randomized studies, but corticosteroids are the mainstay of treatment, providing rapid clinical and radiological benefit. However, clinical relapse is common (particularly in type 1 AIP, and in those with associated other organ involvement). Additional immunosuppression may be required, including azathioprine, and rituximab may play an emerging role. The disease course is variable, but loss of organ function (especially pancreatic exocrine failure and pancreatic atrophy) may occur. © 2016 S. Karger AG

  7. General Information about Pancreatic Cancer

    Science.gov (United States)

    ... History Committees of Interest Legislative Resources Recent Public Laws Careers Visitor Information Search Search Home Cancer Types Pancreatic Cancer Patient Pancreatic Cancer Patient Pancreatic ...

  8. [Pancreatic cysts].

    Science.gov (United States)

    Varola, F; Beccaria, A; Oliaro, A; Sasso, D; Villata, E; Cirillo, R

    1975-02-15

    True and pseudo-cysts of the pancreas are described and their aetiology, pathology, laboratory tests, radiological examination, differential diagnosis, symptomatology and surgical management are illustrated. A series of 22 cases of pancreatic cyst is presented. Surgical management consisted of 14 cystogastrostomies, 3 cystoduodenostomies, 2 resections of the tail of the pancreas, 1 internal drainage between the fistular segment of the gland and the gastric cavity, and 2 external drainages with a Pezzer tube. It is felt that internal drainage is the operation of choice. Of the surgical techniques available, a preference is expressed for cystogastrostomy and cystoduodenostomy.

  9. The pattern of fibrosis in the acinar zone 3 areas in early alcoholic liver disease

    DEFF Research Database (Denmark)

    Junge, Jette; Horn, T; Vyberg, M

    1991-01-01

    The degree of fibrosis and the pattern of collagen distribution in the acinar zone 3, as well as the thickness of the terminal hepatic vein walls (THV) were analyzed in 48 consecutive liver needle biopsies from 48 alcoholics with preserved liver architecture. The fibrosis occurred to more or less....... No relationship was found between TTHV and PSF. The results were compared to similar data obtained in liver biopsies from 117 non-alcoholics with normal morphology or slight non-specific changes. No significant difference concerning TTHV and THV diameter was found between alcoholic and non-alcoholic patients....... The results suggest that the initial liver fibrosis in alcoholics is slightly asymmetrical distributed in each acinar zone 3 area. With progression, the fibrosis tends to be more uniformly distributed and septa appear, eventually linking THV with portal tracts. Apparently, thickening of the THV walls does...

  10. [Changes in serous acinar cells of the tracheal gland in diabetic rats].

    Science.gov (United States)

    Tsuda, T

    1993-08-01

    Histochemical and ultrastructural changes in tracheal glands of rats with artificially induced diabetes were studied. The diabetic condition was induced by streptozotocin. The tracheal gland is composed of a duct and secretory units, mucus tubules and serous acini in diabetic as well as normal rats. In normal rats, the serous acinar cells contained only neutral polysaccharides. In diabetic rats, on the other hand, the serous acinar cells contained not only neutral but also moderate amounts of what appeared to be sialic acid containing compounds. On the ultrastructural level, two kinds of serous cells were observed in diabetic rats, one of which contained homogeneous granules while the other containing heterogeneous granules. The ratio between the number of cells containing heterogeneous granules and cells with homogeneous granules increased with the duration of the diabetic condition in the rat. Changes within the serous cells of diabetic rats might depress tracheal host defense mechanisms and could explain why airway infections are common in patients suffering from diabetes.

  11. A Novel Biosensor for Evaluation of Apoptotic or Necrotic Effects of Nitrogen Dioxide during Acute Pancreatitis in Rat

    Directory of Open Access Journals (Sweden)

    Dagmara Jacewicz

    2009-12-01

    Full Text Available The direct and accurate estimation of nitric dioxide levels is an extremely laborious and technically demanding procedure in the molecular diagnostics of inflammatory processes. The aim of this work is to demonstrate that a stop-flow technique utilizing a specific spectroscopic biosensor can be used for detection of nanomolar quantities of NO2 in biological milieu. The use of novel compound cis-[Cr(C2O4(AaraNH2(OH22]+ increases NO2 estimation accuracy by slowing down the rate of NO2 uptake. In this study, an animal model of pancreatitis, where nitrosative stress is induced by either 3g/kg bw or 1.5 g/kg bw dose of L-arginine, was used. Biochemical parameters and morphological characteristics of acute pancreatitis were monitored, specifically assessing pancreatic acinar cell death mode, NO2 generation and cellular glutathione level. The severity of the process correlated positively with NO2 levels in pancreatic acinar cell cytosol samples, and negatively with cellular glutathione levels.

  12. Functional differences in the acinar cells of the murine major salivary glands.

    Science.gov (United States)

    Kondo, Y; Nakamoto, T; Jaramillo, Y; Choi, S; Catalan, M A; Melvin, J E

    2015-05-01

    In humans, approximately 90% of saliva is secreted by the 3 major salivary glands: the parotid (PG), the submandibular (SMG), and the sublingual glands (SLG). Even though it is known that all 3 major salivary glands secrete saliva by a Cl(-)-dependent mechanism, salivary secretion rates differ greatly among these glands. The goal of this study was to gain insight into the properties of the ion-transporting pathways in acinar cells that might account for the differences among the major salivary glands. Pilocarpine-induced saliva was simultaneously collected in vivo from the 3 major salivary glands of mice. When normalized by gland weight, the amount of saliva secreted by the PG was more than 2-fold larger than that obtained from the SMG and SLG. At the cellular level, carbachol induced an increase in the intracellular [Ca(2+)] that was more than 2-fold larger in PG and SMG than in SLG acinar cells. Carbachol-stimulated Cl(-) efflux and the protein levels of the Ca(2+)-activated Cl(-) channel TMEM16A, the major apical Cl(-) efflux pathway in salivary acinar cells, were significantly greater in PG compared with SMG and SLG. In addition, we evaluated the transporter activity of the Na(+)-K(+)-2Cl(-) cotransporters (NKCC1) and anion exchangers (AE), the 2 primary basolateral Cl(-) uptake mechanisms in acinar cells. The SMG NKCC1 activity was about twice that of the PG and more than 12-fold greater than that of the SLG. AE activity was similar in PG and SLG, and both PG and SLG AE activity was about 2-fold larger than that of SMG. In summary, the salivation kinetics of the 3 major glands are distinct, and these differences can be explained by the unique functional properties of each gland related to Cl(-) movement, including the transporter activities of the Cl(-) uptake and efflux pathways, and intracellular Ca(2+) mobilization. © International & American Associations for Dental Research 2015.

  13. Steady streaming: A key mixing mechanism in low-Reynolds-number acinar flows

    Science.gov (United States)

    Kumar, Haribalan; Tawhai, Merryn H.; Hoffman, Eric A.; Lin, Ching-Long

    2011-01-01

    Study of mixing is important in understanding transport of submicron sized particles in the acinar region of the lung. In this article, we investigate transport in view of advective mixing utilizing Lagrangian particle tracking techniques: tracer advection, stretch rate and dispersion analysis. The phenomenon of steady streaming in an oscillatory flow is found to hold the key to the origin of kinematic mixing in the alveolus, the alveolar mouth and the alveolated duct. This mechanism provides the common route to folding of material lines and surfaces in any region of the acinar flow, and has no bearing on whether the geometry is expanding or if flow separates within the cavity or not. All analyses consistently indicate a significant decrease in mixing with decreasing Reynolds number (Re). For a given Re, dispersion is found to increase with degree of alveolation, indicating that geometry effects are important. These effects of Re and geometry can also be explained by the streaming mechanism. Based on flow conditions and resultant convective mixing measures, we conclude that significant convective mixing in the duct and within an alveolus could originate only in the first few generations of the acinar tree as a result of nonzero inertia, flow asymmetry, and large Keulegan–Carpenter (KC) number. PMID:21580803

  14. [A Case of Invasive Ductal Carcinoma in the Fat Replacement of the Pancreatic Body and Tail].

    Science.gov (United States)

    Ebihara, Takeshi; Yamamoto, Tameyoshi; Hoshino, Hiromitsu; Yoshimura, Jumpei; Sasamatsu, Shingo; Hiraki, Yoko; Nishi, Hidemi; Shimizu, Katsushu; Kawada, Masahiro; Inoue, Toshiya; Kato, Fumitaka; Amano, Koji; Mikami, Jota; Yamamura, Jun; Makari, Yoichi; Nakata, Ken; Ikeda, Naoki; Kamigaki, Shunji; Tsujie, Masaki; Kimura, Yutaka; Nakata, Yasuki; Munakata, Satoru; Ohzato, Hiroki

    2015-11-01

    A 56 year-old woman with obesity (BMI3 2) and diabetes mellitus was diagnosed with right renal cell carcinoma. She underwent right nephrectomy 1 year ago. Seven months after surgery, CT revealed a rapidly growing mass near the spleen. The mass showed slight accumulation of FDG (SUVmax=2.4) on PET-CT. Since the lesion grew rapidly and was not enhanced in the early phase of enhanced CT, we diagnosed pancreatic cancer. Distal pancreatectomy and splenectomy were performed. The final pathological diagnosis was invasive ductal carcinoma in the fat replacement of the pancreatic body and tail. Postoperatively, the patient had no complications such as pancreatic fistula or aggravation of glucose intolerance. She received postoperative chemotherapy with gemcitabine. Since she developed pulmonary artery thrombosis, postoperative chemotherapy was interrupted after 8 courses. Thirty-two months after the surgery, she was still living without any recurrence. Acinar cells were absent in the fat replacement of the pancreas, but the pancreatic duct cells were still present. There was carcinoma in situ in the main pancreatic duct surrounding chronic inflammation. Fat replacement itself could be potentially precursor of the pancreatic cancer.

  15. Protective Effect of Pretreatment with Acenocoumarol in Cerulein-Induced Acute Pancreatitis

    Science.gov (United States)

    Warzecha, Zygmunt; Sendur, Paweł; Ceranowicz, Piotr; Dembiński, Marcin; Cieszkowski, Jakub; Kuśnierz-Cabala, Beata; Olszanecki, Rafał; Tomaszewska, Romana; Ambroży, Tadeusz; Dembiński, Artur

    2016-01-01

    Coagulation is recognized as a key player in inflammatory and autoimmune diseases. The aim of the current research was to examine the effect of pretreatment with acenocoumarol on the development of acute pancreatitis (AP) evoked by cerulein. Methods: AP was induced in rats by cerulein administered intraperitoneally. Acenocoumarol (50, 100 or 150 µg/kg/dose/day) or saline were given once daily for seven days before AP induction. Results: In rats with AP, pretreatment with acenocoumarol administered at the dose of 50 or 100 µg/kg/dose/day improved pancreatic histology, reducing the degree of edema and inflammatory infiltration, and vacuolization of acinar cells. Moreover, pretreatment with acenocoumarol given at the dose of 50 or 100 µg/kg/dose/day reduced the AP-evoked increase in pancreatic weight, serum activity of amylase and lipase, and serum concentration of pro-inflammatory interleukin-1β, as well as ameliorated pancreatic DNA synthesis and pancreatic blood flow. In contrast, acenocoumarol given at the dose of 150 μg/kg/dose did not exhibit any protective effect against cerulein-induced pancreatitis. Conclusion: Low doses of acenocoumarol, given before induction of AP by cerulein, inhibit the development of that inflammation. PMID:27754317

  16. Long-Term Culture of Self-renewing Pancreatic Progenitors Derived from Human Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Jamie Trott

    2017-06-01

    Full Text Available Pluripotent stem cells have been proposed as an unlimited source of pancreatic β cells for studying and treating diabetes. However, the long, multi-step differentiation protocols used to generate functional β cells inevitably exhibit considerable variability, particularly when applied to pluripotent cells from diverse genetic backgrounds. We have developed culture conditions that support long-term self-renewal of human multipotent pancreatic progenitors, which are developmentally more proximal to the specialized cells of the adult pancreas. These cultured pancreatic progenitor (cPP cells express key pancreatic transcription factors, including PDX1 and SOX9, and exhibit transcriptomes closely related to their in vivo counterparts. Upon exposure to differentiation cues, cPP cells give rise to pancreatic endocrine, acinar, and ductal lineages, indicating multilineage potency. Furthermore, cPP cells generate insulin+ β-like cells in vitro and in vivo, suggesting that they offer a convenient alternative to pluripotent cells as a source of adult cell types for modeling pancreatic development and diabetes.

  17. [Obesity and pancreatic diseases].

    Science.gov (United States)

    Kim, Ho Gak; Han, Jimin

    2012-01-01

    Obesity is defined as BMI (calculated as weight in kg divided by height in m2) more than 30, and overweight is defined as BMI of 25-29.9. Obesity has been considered as a risk factor for pancreatic diseases, including pancreatitis and pancreatic cancer. Severe acute pancreatitis is significantly more frequent in obese patients. Furthermore, obese patients develop systemic and local complications of acute pancreatitis more frequently. The underlying mechanisms are increased inflammation and necrosis from increased amount of intra- and peri-pancreatic fat. In addition, obesity is a poor prognostic factor in acute pancreatitis, and overweight before disease onset appears to be a risk factor for chronic pancreatitis. Overweight and/or obesity are associated with greater risk of pancreatic cancer and younger age of onset. Physical activity appears to decrease the risk of pancreatic cancer, especially among those who are overweight. Long-standing diabetes increases the risk of pancreatic cancer. The pathogenic mechanism is that obesity and physical inactivity increase insulin resistance. In a state of hypersinulinemia, increased circulating level of insulin-like growth factor-1 induces cellular proliferation of pancreatic cancer. Obesity is associated with negative prognostic factor and increased mortality in pancreatic cancer. However, there are controversies regarding the effects of obesity on long-term post-operative results in the patient with pancreatic cancer.

  18. Pancreatic Pseudocyst Pleural Fistula in Gallstone Pancreatitis

    Directory of Open Access Journals (Sweden)

    Sala Abdalla

    2016-01-01

    Full Text Available Extra-abdominal complications of pancreatitis such as pancreaticopleural fistulae are rare. A pancreaticopleural fistula occurs when inflammation of the pancreas and pancreatic ductal disruption lead to leakage of secretions through a fistulous tract into the thorax. The underlying aetiology in the majority of cases is alcohol-induced chronic pancreatitis. The diagnosis is often delayed given that the majority of patients present with pulmonary symptoms and frequently have large, persistent pleural effusions. The diagnosis is confirmed through imaging and the detection of significantly elevated amylase levels in the pleural exudate. Treatment options include somatostatin analogues, thoracocentesis, endoscopic retrograde cholangiopancreatography (ERCP with pancreatic duct stenting, and surgery. The authors present a case of pancreatic pseudocyst pleural fistula in a woman with gallstone pancreatitis presenting with recurrent pneumonias and bilateral pleural effusions.

  19. The variable phenotype of the p.A16V mutation of cationic trypsinogen (PRSS1) in pancreatitis families

    DEFF Research Database (Denmark)

    Grocock, Christopher J; Rebours, Vinciane; Delhaye, Myriam

    2010-01-01

    Pancreatic Cancer or via a collaborator. DNA samples were tested for mutations in PRSS1, SPINK1, CFTR and CTRC. PATIENTS: Participants were recruited on the basis of either family history of pancreatitis (acute or chronic), or the results of genetic testing. Families were categorised as having Hereditary.......A16V mutations were identified (22 affected individuals); six HP families, three with idiopathic disease and one with only a single generation affected. The median age of onset, ignoring non-penetrants, was 10 years (95% CI: 5,25). There were 8 confirmed cases of exocrine failure, 4 of whom also had......OBJECTIVE: To characterise the phenotypes associated with the p.A16V mutation of PRSS1. DESIGN: Clinical and epidemiological data were collected for any family in which a p.A16V mutation was identified, either referred directly to the European Registry of Hereditary Pancreatitis and Familial...

  20. LAPAROSCOPIC PANCREATIC RESECTION. FROM ENUCLEATION TO PANCREATODUODENECTOMY. 11-YEAR EXPERIENCE

    Directory of Open Access Journals (Sweden)

    Marcel Autran Cesar MACHADO

    2013-09-01

    Full Text Available Context Our experience with laparoscopic pancreatic resection began in 2001. During initial experience, laparoscopy was reserved for selected cases. With increasing experience more complex laparoscopic procedures such as central pancreatectomy and pancreatoduodenectomies were performed. Objectives The aim of this paper is to review our personal experience with laparoscopic pancreatic resection over 11-year period. Methods All patients who underwent laparoscopic pancreatic resection from 2001 through 2012 were reviewed. Preoperative data included age, gender, and indication for surgery. Intraoperative variables included operative time, bleeding, blood transfusion. Diagnosis, tumor size, margin status were determined from final pathology reports. Results Since 2001, 96 patients underwent laparoscopic pancreatectomy. Median age was 55 years old. 60 patients were female and 36 male. Of these, 88 (91.6% were performed totally laparoscopic; 4 (4.2% needed hand-assistance, 1 robotic assistance. Three patients were converted. Four patients needed blood transfusion. Operative time varied according type of operation. Mortality was nil but morbidity was high, mainly due to pancreatic fistula (28.1%. Sixty-one patients underwent distal pancreatectomy, 18 underwent pancreatic enucleation, 7 pylorus-preserving pancreatoduodenectomies, 5 uncinate process resection, 3 central and 2 total pancreatectomies. Conclusions Laparoscopic resection of the pancreas is a reality. Pancreas sparing techniques, such as enucleation, resection of uncinate process and central pancreatectomy, should be used to avoid exocrine and/or endocrine insufficiency that could be detrimental to the patient's quality of life. Laparoscopic pancreatoduodenectomy is a safe operation but should be performed in specialized centers by highly skilled laparoscopic surgeons.

  1. Environmental risk factors for pancreatic cancer: an update.

    Science.gov (United States)

    Barone, Elisa; Corrado, Alda; Gemignani, Federica; Landi, Stefano

    2016-11-01

    Pancreatic cancer (PC) is one of the most aggressive diseases. Only 10 % of all PC cases are thought to be due to genetic factors. Here, we analyzed the most recently published case-control association studies, meta-analyses, and cohort studies with the aim to summarize the main environmental factors that could have a role in PC. Among the most dangerous agents involved in the initiation phase, there are the inhalation of cigarette smoke, and the exposure to mutagenic nitrosamines, organ-chlorinated compounds, heavy metals, and ionizing radiations. Moreover, pancreatitis, high doses of alcohol drinking, the body microbial infections, obesity, diabetes, gallstones and/or cholecystectomy, and the accumulation of asbestos fibers seem to play a crucial role in the progression of the disease. However, some of these agents act both as initiators and promoters in pancreatic acinar cells. Protective agents include dietary flavonoids, marine omega-3, vitamin D, fruit, vegetables, and the habit of regular physical activity. The identification of the factors involved in PC initiation and progression could be of help in establishing novel therapeutic approaches by targeting the molecular signaling pathways responsive to these stimuli. Moreover, the identification of these factors could facilitate the development of strategies for an early diagnosis or measures of risk reduction for high-risk people.

  2. [Advances in the role of autophagy in acute pancreatitis].

    Science.gov (United States)

    Xia, He; Zhao, Liang; Wang, Weixing

    2017-10-01

    Autophagy is a self-protect cellular mechanism by which the unneeded cellular structure or impaired protein are targeted to degeneration. Acute pancreatitis (AP) is associated with autophagy tightly. This article is aimed to mainly elaborate the phenomenon that AP can be triggered by impaired autophagy and the mechanism of AP exacerbation by damaged autophagy. In AP, the reasons of impaired autophagy is dysfunction of cathepsins and lysosome associated membrane protein, which present as vacuoles accumulation in acinar cells and combination disorder of autophagolysosome, finally to activation of trypsin. By the relocation of high mobility group box 1 (HMGB1) and promotion of mitochondrial permeability transition (MPT), impaired autophagy aggravates AP. Understanding the above mechanism has certain significance to the prevention and treatment of AP.

  3. Species- and dose-specific pancreatic responses and progression in single- and repeat-dose studies with GI181771X: a novel cholecystokinin 1 receptor agonist in mice, rats, and monkeys.

    Science.gov (United States)

    Myer, James R; Romach, Elizabeth H; Elangbam, Chandikumar S

    2014-01-01

    Compound-induced pancreatic injury is a serious liability in preclinical toxicity studies. However, its relevance to humans should be cautiously evaluated because of interspecies variations. To highlight such variations, we evaluated the species- and dose-specific pancreatic responses and progression caused by GI181771X, a novel cholecystokinin 1 receptor agonist investigated by GlaxoSmithKline for the treatment of obesity. Acute (up to 2,000 mg/kg GI181771X, as single dose) and repeat-dose studies in mice and/or rats (0.25-250 mg/kg/day for 7 days to 26 weeks) showed wide-ranging morphological changes in the pancreas that were dose and duration dependent, including necrotizing pancreatitis, acinar cell hypertrophy/atrophy, zymogen degranulation, focal acinar cell hyperplasia, and interstitial inflammation. In contrast to rodents, pancreatic changes were not observed in cynomolgus monkeys given GI181771X (1-500 mg/kg/day with higher systemic exposure than rats) for up to 52 weeks. Similarly, no GI181771X treatment-associated abnormalities in pancreatic structure were noted in a 24-week clinical trial with obese patients (body mass index >30 or >27 kg/m(2)) as assessed by abdominal ultrasound or by magnetic resonance imaging. Mechanisms for interspecies variations in the pancreatic response to CCK among rodents, monkeys, and humans and their relevance to human risk are discussed.

  4. Pancreatic Cancer Genetics

    National Research Council Canada - National Science Library

    Amundadottir, Laufey T

    2016-01-01

    Although relatively rare, pancreatic tumors are highly lethal [1]. In the United States, an estimated 48,960 individuals will be diagnosed with pancreatic cancer and 40,560 will die from this disease in 2015 [1...

  5. Pancreatitis-imaging approach

    Science.gov (United States)

    Busireddy, Kiran K; AlObaidy, Mamdoh; Ramalho, Miguel; Kalubowila, Janaka; Baodong, Liu; Santagostino, Ilaria; Semelka, Richard C

    2014-01-01

    Pancreatitis is defined as the inflammation of the pancreas and considered the most common pancreatic disease in children and adults. Imaging plays a significant role in the diagnosis, severity assessment, recognition of complications and guiding therapeutic interventions. In the setting of pancreatitis, wider availability and good image quality make multi-detector contrast-enhanced computed tomography (MD-CECT) the most used imaging technique. However, magnetic resonance imaging (MRI) offers diagnostic capabilities similar to those of CT, with additional intrinsic advantages including lack of ionizing radiation and exquisite soft tissue characterization. This article reviews the proposed definitions of revised Atlanta classification for acute pancreatitis, illustrates a wide range of morphologic pancreatic parenchymal and associated peripancreatic changes for different types of acute pancreatitis. It also describes the spectrum of early and late chronic pancreatitis imaging findings and illustrates some of the less common types of chronic pancreatitis, with special emphasis on the role of CT and MRI. PMID:25133027

  6. Surgery for pancreatic cancer

    Science.gov (United States)

    ... medlineplus.gov/ency/article/007649.htm Surgery for pancreatic cancer To use the sharing features on this page, ... surgeries are used in the surgical treatment of pancreatic cancer. Whipple procedure: This is the most common surgery ...

  7. Pathogenic mechanisms of pancreatitis

    Science.gov (United States)

    Manohar, Murli; Verma, Alok Kumar; Venkateshaiah, Sathisha Upparahalli; Sanders, Nathan L; Mishra, Anil

    2017-01-01

    Pancreatitis is inflammation of pancreas and caused by a number of factors including pancreatic duct obstruction, alcoholism, and mutation in the cationic trypsinogen gene. Pancreatitis is represented as acute pancreatitis with acute inflammatory responses and; chronic pancreatitis characterized by marked stroma formation with a high number of infiltrating granulocytes (such as neutrophils, eosinophils), monocytes, macrophages and pancreatic stellate cells (PSCs). These inflammatory cells are known to play a central role in initiating and promoting inflammation including pancreatic fibrosis, i.e., a major risk factor for pancreatic cancer. A number of inflammatory cytokines are known to involve in promoting pancreatic pathogenesis that lead pancreatic fibrosis. Pancreatic fibrosis is a dynamic phenomenon that requires an intricate network of several autocrine and paracrine signaling pathways. In this review, we have provided the details of various cytokines and molecular mechanistic pathways (i.e., Transforming growth factor-β/SMAD, mitogen-activated protein kinases, Rho kinase, Janus kinase/signal transducers and activators, and phosphatidylinositol 3 kinase) that have a critical role in the activation of PSCs to promote chronic pancreatitis and trigger the phenomenon of pancreatic fibrogenesis. In this review of literature, we discuss the involvement of several pro-inflammatory and anti-inflammatory cytokines, such as in interleukin (IL)-1, IL-1β, IL-6, IL-8 IL-10, IL-18, IL-33 and tumor necrosis factor-α, in the pathogenesis of disease. Our review also highlights the significance of several experimental animal models that have an important role in dissecting the mechanistic pathways operating in the development of chronic pancreatitis, including pancreatic fibrosis. Additionally, we provided several intermediary molecules that are involved in major signaling pathways that might provide target molecules for future therapeutic treatment strategies for

  8. Autoimmune pancreatitis: a review.

    Science.gov (United States)

    Zandieh, Iman; Byrne, Michael-F

    2007-12-21

    Autoimmune pancreatitis has emerged over the last 40 years from a proposed concept to a well established and recognized entity. As an efficient mimicker of pancreatic carcinoma, its early and appropriate recognition are crucial. With mounting understanding of its pathogenesis and natural history, significant advances have been made in the diagnosis of autoimmune pancreatitis. The characteristic laboratory features and imaging seen in autoimmune pancreatitis are reviewed along with some of the proposed diagnostic criteria and treatment algorithms.

  9. Autoimmune pancreatitis: A review

    OpenAIRE

    Zandieh, Iman; Michael F Byrne

    2007-01-01

    Autoimmune pancreatitis has emerged over the last 40 years from a proposed concept to a well established and recognized entity. As an efficient mimicker of pancreatic carcinoma, its early and appropriate recognition are crucial. With mounting understanding of its pathogenesis and natural history, significant advances have been made in the diagnosis of autoimmune pancreatitis. The