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Sample records for acute mouse pancreas

  1. RNA Isolation from Mouse Pancreas: A Ribonuclease-rich Tissue

    PubMed Central

    Azevedo-Pouly, Ana Clara P.; Elgamal, Ola A.; Schmittgen, Thomas D.

    2015-01-01

    Isolation of high-quality RNA from ribonuclease-rich tissue such as mouse pancreas presents a challenge. As a primary function of the pancreas is to aid in digestion, mouse pancreas may contain as much a 75 mg of ribonuclease. We report modifications of standard phenol/guanidine thiocyanate lysis reagent protocols to isolate RNA from mouse pancreas. Guanidine thiocyanate is a strong protein denaturant and will effectively disrupt the activity of ribonuclease under most conditions. However, critical modifications to standard protocols are necessary to successfully isolate RNA from ribonuclease-rich tissues. Key steps include a high lysis reagent to tissue ratio, removal of undigested tissue prior to phase separation and inclusion of a ribonuclease inhibitor to the RNA solution. Using these and other modifications, we routinely isolate RNA with RNA Integrity Number (RIN) greater than 7. The isolated RNA is of suitable quality for routine gene expression analysis. Adaptation of this protocol to isolate RNA from ribonuclease rich tissues besides the pancreas should be readily achievable. PMID:25145327

  2. In vitro pancreas organogenesis from dispersed mouse embryonic progenitors.

    PubMed

    Greggio, Chiara; De Franceschi, Filippo; Figueiredo-Larsen, Manuel; Grapin-Botton, Anne

    2014-01-01

    The pancreas is an essential organ that regulates glucose homeostasis and secretes digestive enzymes. Research on pancreas embryogenesis has led to the development of protocols to produce pancreatic cells from stem cells (1). The whole embryonic organ can be cultured at multiple stages of development (2-4). These culture methods have been useful to test drugs and to image developmental processes. However the expansion of the organ is very limited and morphogenesis is not faithfully recapitulated since the organ flattens. We propose three-dimensional (3D) culture conditions that enable the efficient expansion of dissociated mouse embryonic pancreatic progenitors. By manipulating the composition of the culture medium it is possible to generate either hollow spheres, mainly composed of pancreatic progenitors expanding in their initial state, or, complex organoids which progress to more mature expanding progenitors and differentiate into endocrine, acinar and ductal cells and which spontaneously self-organize to resemble the embryonic pancreas. We show here that the in vitro process recapitulates many aspects of natural pancreas development. This culture system is suitable to investigate how cells cooperate to form an organ by reducing its initial complexity to few progenitors. It is a model that reproduces the 3D architecture of the pancreas and that is therefore useful to study morphogenesis, including polarization of epithelial structures and branching. It is also appropriate to assess the response to mechanical cues of the niche such as stiffness and the effects on cell´s tensegrity. PMID:25079453

  3. GATA4 and GATA6 control mouse pancreas organogenesis

    PubMed Central

    Carrasco, Manuel; Delgado, Irene; Soria, Bernat; Martín, Francisco; Rojas, Anabel

    2012-01-01

    Recently, heterozygous mutations in GATA6 have been found in neonatal diabetic patients with failed pancreatic organogenesis. To investigate the roles of GATA4 and GATA6 in mouse pancreas organogenesis, we conditionally inactivated these genes within the pancreas. Single inactivation of either gene did not have a major impact on pancreas formation, indicating functional redundancy. However, double Gata4/Gata6 mutant mice failed to develop pancreata, died shortly after birth, and displayed hyperglycemia. Morphological defects in Gata4/Gata6 mutant pancreata were apparent during embryonic development, and the epithelium failed to expand as a result of defects in cell proliferation and differentiation. The number of multipotent pancreatic progenitors, including PDX1+ cells, was reduced in the Gata4/Gata6 mutant pancreatic epithelium. Remarkably, deletion of only 1 Gata6 allele on a Gata4 conditional knockout background severely reduced pancreatic mass. In contrast, a single WT allele of Gata4 in Gata6 conditional knockout mice was sufficient for normal pancreatic development, indicating differential contributions of GATA factors to pancreas formation. Our results place GATA factors at the top of the transcriptional network hierarchy controlling pancreas organogenesis. PMID:23006330

  4. In Vitro Pancreas Organogenesis from Dispersed Mouse Embryonic Progenitors

    PubMed Central

    Grapin-Botton, Anne

    2014-01-01

    The pancreas is an essential organ that regulates glucose homeostasis and secretes digestive enzymes. Research on pancreas embryogenesis has led to the development of protocols to produce pancreatic cells from stem cells 1. The whole embryonic organ can be cultured at multiple stages of development 2-4. These culture methods have been useful to test drugs and to image developmental processes. However the expansion of the organ is very limited and morphogenesis is not faithfully recapitulated since the organ flattens. We propose three-dimensional (3D) culture conditions that enable the efficient expansion of dissociated mouse embryonic pancreatic progenitors. By manipulating the composition of the culture medium it is possible to generate either hollow spheres, mainly composed of pancreatic progenitors expanding in their initial state, or, complex organoids which progress to more mature expanding progenitors and differentiate into endocrine, acinar and ductal cells and which spontaneously self-organize to resemble the embryonic pancreas. We show here that the in vitro process recapitulates many aspects of natural pancreas development. This culture system is suitable to investigate how cells cooperate to form an organ by reducing its initial complexity to few progenitors. It is a model that reproduces the 3D architecture of the pancreas and that is therefore useful to study morphogenesis, including polarization of epithelial structures and branching. It is also appropriate to assess the response to mechanical cues of the niche such as stiffness and the effects on cell´s tensegrity. PMID:25079453

  5. MFng Is Dispensable for Mouse Pancreas Development and Function▿ †

    PubMed Central

    Svensson, Per; Bergqvist, Ingela; Norlin, Stefan; Edlund, Helena

    2009-01-01

    Notch signaling regulates pancreatic cell differentiation, and mutations of various Notch signaling components result in perturbed pancreas development. Members of the Fringe family of β1,3-N-acetylglucosaminyltransferases, Manic Fringe (MFng), Lunatic Fringe (LFng), and Radical Fringe (RFng), modulate Notch signaling, and MFng has been suggested to regulate pancreatic endocrine cell differentiation. We have characterized the expression of the three mouse Fringe genes in the developing mouse pancreas between embryonic days 9 and 14 and show that the expression of MFng colocalized with the proendocrine transcription factor Ngn3. In contrast, the expression of LFng colocalized with the exocrine marker Ptf1a, whereas RFng was not expressed. Moreover, we show that expression of MFng is lost in Ngn3 mutant mice, providing evidence that MFng is genetically downstream of Ngn3. Gain- and loss-of-function analyses of MFng by the generation of mice that overexpress MFng in early pancreatic progenitor cells and mice with a targeted deletion of MFng provide, however, evidence that MFng is dispensable for pancreas development and function, since no pancreatic defects in these mice were observed. PMID:19223466

  6. Pancreas.

    PubMed

    Kandaswamy, R; Skeans, M A; Gustafson, S K; Carrico, R J; Prentice, M A; Israni, A K; Snyder, J J; Kasiske, B L

    2016-01-01

    Even though pancreas transplant numbers have steadily declined over the past decade, new listings increased in 2014 compared with the previous year, notably for pancreas transplant alone (PTA) and simultaneous pancreas-kidney transplant. The number of new PTAs also increased over the past two years. Whether this is a sustainable trend remains to be seen. Significant events in 2014 included implementation of a new pancreas allocation system and development of a proposed uniform definition of pancreas graft failure. Meanwhile, overall pancreas transplant rates and outcomes continued to improve. Substantial decline in pancreas after kidney transplants remains a serious concern. SRTR has not published pancreas graft failure data in the program-specific reports for the past two years. While this will not change in the near future, the acceptance of a uniform definition of graft failure is a crucial first step toward resuming graft failure reporting. Continued improvements and innovation, both surgical and immunological, will be critical to keep pancreas transplant as a viable option for treatment of insulin-dependent diabetes. As alternative therapies for diabetes such as islet transplant and artificial pancreas are evolving, improved outcomes with minimizations of complications are more important than ever. PMID:26755263

  7. Endovascular Management of Acute Enteric Bleeding from Pancreas Transplant

    SciTech Connect

    Semiz-Oysu, Aslihan; Cwikiel, Wojciech

    2007-04-15

    Arterioenteric fistula is a rare but serious complication of enteric drained pancreas transplant, which may lead to massive gastrointestinal bleeding. We present 3 patients with failed enteric drained pancreas transplants and massive gastrointestinal bleeding secondary to arterioenteric fistula. One patient was treated by embolization and the 2 others by stent graft placement. Bleeding was successfully controlled in all cases, at follow up of 5 days, 8 months, and 12 months, respectively. One patient died 24 days after embolization, of unknown causes.

  8. p120 catenin is required for normal tubulogenesis but not epithelial integrity in developing mouse pancreas

    PubMed Central

    Hendley, Audrey M.; Provost, Elayne; Bailey, Jennifer M.; Wang, Yue J.; Cleveland, Megan H.; Blake, Danielle; Bittman, Ross W.; Roeser, Jeffrey C.; Maitra, Anirban; Reynolds, Albert B.; Leach, Steven D.

    2015-01-01

    The intracellular protein p120 catenin aids in maintenance of cell-cell adhesion by regulating E-cadherin stability in epithelial cells. In an effort to understand the biology of p120 catenin in pancreas development, we ablated p120 catenin in mouse pancreatic progenitor cells, which resulted in deletion of p120 catenin in all epithelial lineages of the developing mouse pancreas: islet, acinar, centroacinar, and ductal. Loss of p120 catenin resulted in formation of dilated epithelial tubules, expansion of ductal epithelia, loss of acinar cells, and the induction of pancreatic inflammation. Aberrant branching morphogenesis and tubulogenesis were also observed. Throughout development, the phenotype became more severe, ultimately resulting in an abnormal pancreas comprised primarily of duct-like epithelium expressing early progenitor markers. In pancreatic tissue lacking p120 catenin, overall epithelial architecture remained intact; however, actin cytoskeleton organization was disrupted, an observation associated with increased cytoplasmic PKCζ. Although we observed reduced expression of adherens junction proteins E-cadherin, β-catenin, and α-catenin, p120 catenin family members p0071, ARVCF, and δ-catenin remained present at cell membranes in homozygous p120f/f pancreases, potentially providing stability for maintenance of epithelial integrity during development. Adult mice homozygous for deletion of p120 catenin displayed dilated main pancreatic ducts, chronic pancreatitis, acinar to ductal metaplasia (ADM), and mucinous metaplasia that resembles PanIN1a. Taken together, our data demonstrate an essential role for p120 catenin in pancreas development. PMID:25523391

  9. PNA lectin for purifying mouse acinar cells from the inflamed pancreas

    PubMed Central

    Xiao, Xiangwei; Fischbach, Shane; Fusco, Joseph; Zimmerman, Ray; Song, Zewen; Nebres, Philip; Ricks, David Matthew; Prasadan, Krishna; Shiota, Chiyo; Husain, Sohail Z.; Gittes, George K.

    2016-01-01

    Better methods for purifying human or mouse acinar cells without the need for genetic modification are needed. Such techniques would be advantageous for the specific study of certain mechanisms, such as acinar-to-beta-cell reprogramming and pancreatitis. Ulex Europaeus Agglutinin I (UEA-I) lectin has been used to label and isolate acinar cells from the pancreas. However, the purity of the UEA-I-positive cell fraction has not been fully evaluated. Here, we screened 20 widely used lectins for their binding specificity for major pancreatic cell types, and found that UEA-I and Peanut agglutinin (PNA) have a specific affinity for acinar cells in the mouse pancreas, with minimal affinity for other major pancreatic cell types including endocrine cells, duct cells and endothelial cells. Moreover, PNA-purified acinar cells were less contaminated with mesenchymal and inflammatory cells, compared to UEA-I purified acinar cells. Thus, UEA-I and PNA appear to be excellent lectins for pancreatic acinar cell purification. PNA may be a better choice in situations where mesenchymal cells or inflammatory cells are significantly increased in the pancreas, such as type 1 diabetes, pancreatitis and pancreatic cancer. PMID:26884345

  10. Substance P and bradykinin stimulate plasma extravasation in the mouse gastrointestinal tract and pancreas.

    PubMed

    Figini, M; Emanueli, C; Grady, E F; Kirkwood, K; Payan, D G; Ansel, J; Gerard, C; Geppetti, P; Bunnett, N

    1997-04-01

    Neurogenic inflammation is mediated by release of tachykinins from sensory nerves, which stimulate plasma extravasation from postcapillary venules. Because there are conflicting results regarding the importance of neurogenic inflammation in the gastrointestinal tract, we quantified plasma extravasation using Evans blue and identified sites of the leak using Monastral blue in the mouse. Substance P and bradykinin stimulated extravasation from postcapillary venules in the stomach, small and large intestine, pancreas, urinary bladder, trachea, and skin by two- to sevenfold by interacting with NK1 and B2 receptors, respectively. Stimulation of sensory nerves with capsaicin also induced extravasation. Capsaicin- and bradykinin-stimulated extravasation was attenuated by an NK1-receptor antagonist and is thus mediated by release of tachykinins and activation of the NK1 receptor. We conclude that 1) substance P stimulates extravasation in the gastrointestinal tract and pancreas of mice by interacting with the NK1 receptors, and 2) capsaicin and bradykinin induce plasma extravasation by stimulating tachykinin release from sensory nerves. Thus neurogenic mechanisms mediate inflammation in the gastrointestinal tract and pancreas of the mouse. PMID:9142909

  11. Structural similarities and differences between the human and the mouse pancreas

    PubMed Central

    Dolenšek, Jurij; Rupnik, Marjan Slak; Stožer, Andraž

    2015-01-01

    Mice remain the most studied animal model in pancreas research. Since the findings of this research are typically extrapolated to humans, it is important to understand both similarities and differences between the 2 species. Beside the apparent difference in size and macroscopic organization of the organ in the 2 species, there are a number of less evident and only recently described differences in organization of the acinar and ductal exocrine tissue, as well as in the distribution, composition, and architecture of the endocrine islets of Langerhans. Furthermore, the differences in arterial, venous, and lymphatic vessels, as well as innervation are potentially important. In this article, the structure of the human and the mouse pancreas, together with the similarities and differences between them are reviewed in detail in the light of conceivable repercussions for basic research and clinical application. PMID:26030186

  12. The organoid-initiating cells in mouse pancreas and liver are phenotypically and functionally similar

    PubMed Central

    Dorrell, Craig; Tarlow, Branden; Wang, Yuhan; Canaday, Pamela S; Haft, Annelise; Schug, Jonathan; Streeter, Philip R; Finegold, Milton J; Shenje, Lincoln T; Kaestner, Klaus H; Grompe, Markus

    2014-01-01

    Pancreatic Lgr5 expression has been associated with organoid-forming epithelial progenitor populations but the identity of the organoid-initiating epithelial cell subpopulation has remained elusive. Injury causes the emergence of an Lgr5+ organoid-forming epithelial progenitor population in the adult mouse liver and pancreas. Here, we define the origin of organoid-initiating cells from mouse pancreas and liver prior to Lgr5 activation. This clonogenic population was defined as MIC1-1C3+/CD133+/CD26− in both tissues and the frequency of organoid initiation within this population was approximately 5% in each case. The transcriptomes of these populations overlapped extensively and showed enrichment of epithelial progenitor-associated regulatory genes such as Sox9 and FoxJ1. Surprisingly, pancreatic organoid cells also had the capacity to generate hepatocyte-like cells upon transplantation to Fah-/- mice, indicating a differentiation capacity similar to hepatic organoids. Although spontaneous endocrine differentiation of pancreatic progenitors was not observed in culture, adenoviral delivery of fate-specifying factors Pdx1, Neurog3 and MafA induced insulin expression without glucagon or somatostatin. Pancreatic organoid cultures therefore preserve many key attributes of progenitor cells while allowing unlimited expansion, facilitating the study of fate determination. PMID:25151611

  13. The organoid-initiating cells in mouse pancreas and liver are phenotypically and functionally similar.

    PubMed

    Dorrell, Craig; Tarlow, Branden; Wang, Yuhan; Canaday, Pamela S; Haft, Annelise; Schug, Jonathan; Streeter, Philip R; Finegold, Milton J; Shenje, Lincoln T; Kaestner, Klaus H; Grompe, Markus

    2014-09-01

    Pancreatic Lgr5 expression has been associated with organoid-forming epithelial progenitor populations but the identity of the organoid-initiating epithelial cell subpopulation has remained elusive. Injury causes the emergence of an Lgr5(+) organoid-forming epithelial progenitor population in the adult mouse liver and pancreas. Here, we define the origin of organoid-initiating cells from mouse pancreas and liver prior to Lgr5 activation. This clonogenic population was defined as MIC1-1C3(+)/CD133(+)/CD26(-) in both tissues and the frequency of organoid initiation within this population was approximately 5% in each case. The transcriptomes of these populations overlapped extensively and showed enrichment of epithelial progenitor-associated regulatory genes such as Sox9 and FoxJ1. Surprisingly, pancreatic organoid cells also had the capacity to generate hepatocyte-like cells upon transplantation to Fah(-/-) mice, indicating a differentiation capacity similar to hepatic organoids. Although spontaneous endocrine differentiation of pancreatic progenitors was not observed in culture, adenoviral delivery of fate-specifying factors Pdx1, Neurog3 and MafA induced insulin expression without glucagon or somatostatin. Pancreatic organoid cultures therefore preserve many key attributes of progenitor cells while allowing unlimited expansion, facilitating the study of fate determination. PMID:25151611

  14. STAT3 modulates β-cell cycling in injured mouse pancreas and protects against DNA damage.

    PubMed

    De Groef, S; Renmans, D; Cai, Y; Leuckx, G; Roels, S; Staels, W; Gradwohl, G; Baeyens, L; Heremans, Y; Martens, G A; De Leu, N; Sojoodi, M; Van de Casteele, M; Heimberg, H

    2016-01-01

    Partial pancreatic duct ligation (PDL) of mouse pancreas induces a doubling of the β-cell mass mainly through proliferation of pre-existing and newly formed β-cells. The molecular mechanism governing this process is still largely unknown. Given the inflammatory nature of PDL and inflammation-induced signaling via the signal transducer and activator of transcription 3 (STAT3), the activation and the role of STAT3 in PDL-induced β-cell proliferation were investigated. Duct ligation stimulates the expression of several cytokines that can act as ligands inducing STAT3 signaling and phosphorylation in β-cells. β-Cell cycling increased by conditional β-cell-specific Stat3 knockout and decreased by STAT3 activation through administration of interleukin-6. In addition, the level of DNA damage in β-cells of PDL pancreas increased after deletion of Stat3. These data indicate a role for STAT3 in maintaining a steady state in the β-cell, by modulating its cell cycle and protection from DNA damage. PMID:27336716

  15. Clonal identification of multipotent precursors from adult mouse pancreas that generate neural and pancreatic lineages.

    PubMed

    Seaberg, Raewyn M; Smukler, Simon R; Kieffer, Timothy J; Enikolopov, Grigori; Asghar, Zeenat; Wheeler, Michael B; Korbutt, Gregory; van der Kooy, Derek

    2004-09-01

    The clonal isolation of putative adult pancreatic precursors has been an elusive goal of researchers seeking to develop cell replacement strategies for diabetes. We report the clonal identification of multipotent precursor cells from the adult mouse pancreas. The application of a serum-free, colony-forming assay to pancreatic cells enabled the identification of precursors from pancreatic islet and ductal populations. These cells proliferate in vitro to form clonal colonies that coexpress neural and pancreatic precursor markers. Upon differentiation, individual clonal colonies produce distinct populations of neurons and glial cells, pancreatic endocrine beta-, alpha- and delta-cells, and pancreatic exocrine and stellate cells. Moreover, the newly generated beta-like cells demonstrate glucose-dependent Ca(2+) responsiveness and insulin release. Pancreas colonies do not express markers of embryonic stem cells, nor genes suggestive of mesodermal or neural crest origins. These cells represent a previously unidentified adult intrinsic pancreatic precursor population and are a promising candidate for cell-based therapeutic strategies. PMID:15322557

  16. Carvacrol modulates oxidative stress and decreases cell injury in pancreas of rats with acute pancreatitis.

    PubMed

    Kılıç, Yeliz; Geyikoglu, Fatime; Çolak, Suat; Turkez, Hasan; Bakır, Murat; Hsseinigouzdagani, Mirkhalil

    2016-08-01

    Acute pancreatitis (AP) is considered as major problem around the world and the incidence of AP is increasing. Carvacrol (CAR), a monoterpenic phenol, has good antioxidant activity. This in vivo study was designed to evaluate whether CAR provide protection against AP that developed by pancreas injury. The rats were randomised into groups to receive (I) no therapy; (II) 50 µg/kg cerulein at 1 h intervals by four intraperitonally (i.p.) injections; (III) 50, 100 and 200 mg/kg CAR by one i.p. injection; and (IV) cerulein plus CAR after 2 h of cerulein administration. 12 h later, serum samples were obtained to assess pancreatic function, the lipase and amylase values. The oxidative stress markers were evaluated by changes in the amount of lipid peroxides measured as malondialdehyde (MDA) and changes in main tissue antioxidant enzyme levels including SOD, CAT and GSH-PX. Histopathological examination was performed using scoring systems. Additionally, oxidative DNA damage was determined by measuring the increases of 8-hydroxy-deoxyguanosine (8-OH-dG) formations. We found that the increasing doses of CAR decreased AP-induced MDA and 8-OH-dG levels. Moreover, the pancreas antioxidant enzyme activities were higher than that of the rats in the AP group when compared to the AP plus CAR group. In the treatment groups, the lipase and amylase were reduced. Besides, histopathological findings in the pancreatic tissue were alleviated (p < 0.05). We suggest that CAR could be a safe and potent new drug candidate for treating AP through its antioxidative mechanism of action for the treatment of a wide range of disorders related to pancreas. PMID:26093481

  17. Endoscopic sphincterotomy of the major duodenal papilla in acute relapsing pancreatitis associated with pancreas divisum: a case report.

    PubMed

    Spaziani, E; Trentino, P; Picchio, M; Di Filippo, A; Briganti, M; Pietricola, G; Elisei, W; Ceci, F; Coda, S; Pattaro, G; Parisella, F; De Angelis, F; Pecchia, M; Stagnitti, F

    2010-05-01

    We report a case of acute relapsing pancreatitis associated with pancreas divisum, who underwent major papilla sphincterotomy after failed minor papilla cannulation. Long-term results were satisfactory. The possible explanations of the efficacy of major papilla endoscopic resection in this particular case are discussed. PMID:20615366

  18. [A case of chronic hepatitis C with pancreas divisum and acute pancreatitis during combination treatment with telaprevir/peginterferon/ribavirin].

    PubMed

    Morio, Reona; Imamura, Michio; Fukuhara, Takayuki; Kan, Hiromi; Fujino, Hatsue; Kawaoka, Tomokazu; Hiramatsu, Akira; Aikata, Hiroshi; Sasaki, Tamito; Chayama, Kazuaki

    2014-10-01

    A 47-year-old man developed acute pancreatitis during combination treatment with telaprevir/peginterferon/ribavirin for chronic hepatitis C. Cessation of telaprevir, fasting, and gabexate mesilate improved the pancreatitis. Although peginterferon and ribavirin treatment was continued, there was no recurrence of the pancreatitis. Endoscopic retrograde cholangiopancreatography incidentally showed a pancreas divisum. We definitively diagnosed drug-induced acute pancreatitis due to telaprevir. PMID:25283229

  19. Phosphorus-31 nuclear magnetic resonance spectroscopic study of the canine pancreas: applications to acute alcoholic pancreatitis

    SciTech Connect

    Janes, N.; Clemens, J.A.; Glickson, J.D.; Cameron, J.L.

    1988-01-01

    The first nuclear magnetic resonance spectroscopic study of the canine pancreas is described. Both in-vivo, ex-vivo protocols and NMR observables are discussed. The stability of the ex-vivo preparation based on the NMR observables is established for at least four hours. The spectra obtained from the in-vivo and ex-vivo preparations exhibited similar metabolite ratios, further validating the model. Metabolite levels were unchanged by a 50% increase in perfusion rate. Only trace amounts of phosphocreatine were observed either in the intact gland or in extracts. Acute alcoholic pancreatitis was mimicked by free fatty acid infusion. Injury resulted in hyperamylasemia, edema (weight gain), increased hematocrit and perfusion pressure, and depressed levels of high energy phosphates.

  20. Triheptanoin in acute mouse seizure models.

    PubMed

    Thomas, Nicola K; Willis, Sarah; Sweetman, Lawrence; Borges, Karin

    2012-05-01

    Triheptanoin, the triglyceride of heptanoate, is used to treat certain hereditary metabolic diseases in USA because of its anaplerotic potential. In two chronic mouse seizure models this clear tasteless oil was found to be reproducibly anticonvulsant. Here we investigated the effects of triheptanoin feeding in C3H and CD1 mice using standard acute seizure models. Feeding 30-40% triheptanoin (caloric intake) consistently elevated blood propionyl-carnitines, but inconsistent anticonvulsant effects were observed in the fluorothyl, pentylenetetrazole and 6Hz seizure models. A 2mA consistent increase in the maximal electroshock threshold was found after 3 weeks of 35% triheptanoin feeding (p=0.018). In summary, triheptanoin shows a unique anticonvulsant profile in seizure models, compared to other treatments that are in the clinic. Therefore, despite small and/or inconsistent effects of triheptanoin in acute seizure models, triheptanoin remains of interest as a potential add-on treatment for patients with medically refractory epilepsy. PMID:22260920

  1. Acute graft-versus-host disease following simultaneous pancreas-kidney transplantation: report of a case.

    PubMed

    Asari, Sadaki; Matsumoto, Ippei; Toyama, Hirochika; Shinzeki, Makoto; Goto, Tadahiro; Tanaka, Masaki; Shirakawa, Sachiyo; Yamashita, Hironori; Ajiki, Tetsuo; Fukumoto, Takumi; Ku, Yonson

    2015-12-01

    Acute graft-versus-host-disease (aGVHD) is a rare complication in the setting of pancreas-kidney transplantation (PKT). We herein describe the case of a 37-year-old male with severe type 1 diabetes with chronic renal failure who received simultaneous PKT from a female donor. Diarrhea developed on postoperative day (POD) 10. Subsequently, fever and liver dysfunction occurred on POD 32. Skin rashes appeared with pain and itching on his trunk and extremities on POD 40. As pancytopenia occurred on POD 63, bone marrow biopsies demonstrated profound hypoplastic marrow. On POD 69, we eventually made a definitive diagnosis of aGVHD because skin biopsies revealed the XX chromosome signal in a fluorescence in situ hybridization analysis. Thereafter, 100 mg of prednisolone was administered for 5 days. Although every symptom was temporarily improved, on POD 156, the patient expired from the septic pneumonia without any effects of antibiotics. Clinician should be aware that PKT has the potential to induce aGVHD. PMID:25373363

  2. Purification and Characterization of a Population of EGFP-Expressing Cells from the Developing Pancreas of a Neurogenin3/EGFP Transgenic Mouse

    PubMed Central

    Barrow, J; Bernardo, A S; Hay, C W; Blaylock, M; Duncan, L; MacKenzie, A; McCreath, K; Kind, A J; Schnieke, A E; Colman, A; Hart, A W

    2005-01-01

    Neurogenin 3 (ngn3) is a basic helix loop helix transcription factor that is transiently expressed in the developing mouse pancreas with peak expression around E15. In mice lacking the ngn3 gene the endocrine cells of the pancreas fail to develop suggesting that the ngn3-positive cell may represent a progenitor cell for the endocrine pancreas. In order to purify and characterize this cell in detail we have generated a transgenic mouse, in which the ngn3 promoter drives expression of enhanced green fluorescent protein (EGFP). In the E15.5 embryo EGFP was expressed in the dorsal and ventral pancreas, the duodenum, and lower intestine as well as in the brain. This pattern of expression was in keeping with the known expression profile of the endogenous ngn3 gene. Within the pancreas EGFP was localized in close proximity to cells that stained positive for ngn3, insulin, and glucagon, but was absent from regions of the pancreas that stained positive for amylase. EGFP was also present in the pancreas at E18.5, although there was no detectable expression of ngn3. At this stage EGFP did not colocalize with any of the hormones or exocrine markers. EGFP+ cells were FACS purified (96%) from the E15 pancreas yielding ∼ 10,000 cells or 1.6% of the total pancreatic cells from one litter. RT/PCR analysis confirmed that the purified cells expressed EGFP, ngn3, insulin, glucagon, somatostatin and pancreatic polypeptide. The ability to purify ngn3+ cells provides an invaluable source of material for charactering in detail their properties. PMID:19521525

  3. Pancreas transplant

    MedlinePlus

    ... pancreas from a donor into a person with diabetes. Pancreas transplants give the person a chance to ... used as fuel. In people with type 1 diabetes , the pancreas does not make enough, or sometimes ...

  4. Pancreas Transplantation

    MedlinePlus

    The pancreas is a gland behind your stomach and in front of your spine. It produces the juices that ... hormones that help control blood sugar levels. A pancreas transplant is surgery to place a healthy pancreas ...

  5. Pancreas transplant

    MedlinePlus

    ... liver cells, where it can be used as fuel. In people with type 1 diabetes , the pancreas ... and kidney for the rest of your life. Alternative Names Transplant - pancreas; Transplantation - pancreas Images Endocrine glands ...

  6. Progressive Metaplastic and Dysplastic Changes in Mouse Pancreas Induced by Cyclooxygenase-2 Overexpression1

    PubMed Central

    Colby, Jennifer KL; Klein, Russell D; McArthur, Mark J; Conti, Claudio J; Kiguchi, Kaoru; Kawamoto, Toru; Riggs, Penny K; Pavone, Amy I; Sawicki, Janet; Fischer, Susan M

    2008-01-01

    Cyclooxygenase-2 (COX-2) overexpression is an established factor linking chronic inflammation with metaplastic and neoplastic change in various tissues. We generated transgenic mice (BK5.COX-2) in which elevation of COX-2 and its effectors trigger a metaplasia-dysplasia sequence in exocrine pancreas. Histologic evaluation revealed a chronic pancreatitis-like state characterized by acinar-to-ductal metaplasia and a well-vascularized fibroinflammatory stroma that develops by 3 months. By 6 to 8 months, strongly dysplastic features suggestive of pancreatic ductal adenocarcinoma emerge in the metaplastic ducts. Increased proliferation, cellular atypia, and loss of normal cell/tissue organization are typical features in transgenic pancreata. Alterations in biomarkers associated with human inflammatory and neoplastic pancreatic disease were detected using immunohistochemistry. The abnormal pancreatic phenotype can be completely prevented by maintaining mice on a diet containing celecoxib, a well-characterized COX-2 inhibitor. Despite the high degree of atypia, only limited evidence of invasion to adjacent tissues was observed, with no evidence of distant metastases. However, cell lines derived from spontaneous lesions are aggressively tumorigenic when injected into syngeneic or nude mice. The progressive nature of the metaplastic/dysplastic changes observed in this model make it a valuable tool for examining the transition from chronic inflammation to neoplasia. PMID:18670639

  7. A Preliminary Investigation of Normal Pancreas and Acute Pancreatitis Elasticity Using Virtual Touch Tissue Quantification (VTQ) Imaging

    PubMed Central

    Xie, Juan; Zou, Liling; Yao, Minghua; Xu, Guang; Zhao, Lixia; Xu, Huixiong; Wu, Rong

    2015-01-01

    Background The aim of this study was to prospectively evaluate the use of elastometry in healthy volunteers and patients with acute pancreatitis using virtual touch tissue quantification (VTQ) imaging technology performed on the pancreas. Material/Methods We enrolled 210 healthy volunteers and 44 acute pancreatitis patients in the study between March 2012 and June 2013. Healthy subjects were divided into 3 groups: young (18–30 years), middle-aged (30–50 years), and elderly (>50 years). VTQ was performed on the pancreatic head and body regions to obtain shear wave velocity (SWV) measurements, which were used to evaluate the elasticity values of tissues. Results The pancreatic head SWV value in the whole healthy group was 1.18±0.23 m/s, and that in the pancreatic body was 1.21±0.20 m/s. In patients with acute pancreatitis, the mean SWV measurements at the head were 1.18±0.20 m/s, compared to 1.25±0.19 m/s in the pancreatic body. There was no statistically significant difference between whole healthy volunteers and the acute pancreatitis group. Conclusions VTQ is a new method that shows promise for the quantification of pancreatic elasticity, but further studies are warranted. PMID:26062803

  8. Role of large MAF transcription factors in the mouse endocrine pancreas

    PubMed Central

    ABDELLATIF, Ahmed M.; OGATA, Kiyohito; KUDO, Takashi; XIAFUKAITI, Gulibaikelamu; CHANG, Yu-Hsin; KATOH, Megumi C.; EL-MORSY, Salah E.; OISHI, Hisashi; TAKAHASHI, Satoru

    2015-01-01

    The members of the MAF family of transcription factors are homologs of v-Maf –the oncogenic component of the avian retrovirus AS42. The MAF family is subdivided into 2 groups, small and large MAFs. To elucidate the role of the large MAF transcription factors in the endocrine pancreas, we analyzed large MAF gene knockout mice. It has been shown that Mafa−/− mice develop phenotypes including abnormal islet structure soon after birth. This study revealed that Ins1 and Ins2 transcripts and the protein contents were significantly reduced in Mafa−/− mice at embryonic day 18.5. In addition, Mafa−/−;Mafb−/− mice contained less than 10% of the insulin transcript and protein of those of wild-type mice, suggesting that Mafa and Mafb cooperate to maintain insulin levels at the embryonic stage. On the other hand, the number of insulin-positive cells in Mafa−/− mice was comparable to that of wild-type mice, and even under a Mafb-deficient background the number of insulin-positive cells was not decreased, suggesting that Mafb plays a dominant role in embryonic β-cell development. We also found that at 20 weeks of age Mafa−/−;Mafb+/− mice showed a higher fasting blood glucose level than single Mafa−/− mice. In summary, our results indicate that Mafa is necessary for the maintenance of normal insulin levels even in embryos and that Mafb is important for the maintenance of fasting blood glucose levels in the Mafa-deficient background in adults. PMID:25912440

  9. Surgical Injury to the Mouse Pancreas through Ligation of the Pancreatic Duct as a Model for Endocrine and Exocrine Reprogramming and Proliferation.

    PubMed

    De Groef, Sofie; Leuckx, Gunter; Van Gassen, Naomi; Staels, Willem; Cai, Ying; Yuchi, Yixing; Coppens, Violette; De Leu, Nico; Heremans, Yves; Baeyens, Luc; Van de Casteele, Mark; Heimberg, Harry

    2015-01-01

    Expansion of pancreatic beta cells in vivo or ex vivo, or generation of beta cells by differentiation from an embryonic or adult stem cell, can provide new expandable sources of beta cells to alleviate the donor scarcity in human islet transplantation as therapy for diabetes. Although recent advances have been made towards this aim, mechanisms that regulate beta cell expansion and differentiation from a stem/progenitor cell remain to be characterized. Here, we describe a protocol for an injury model in the adult mouse pancreas that can function as a tool to study mechanisms of tissue remodeling and beta cell proliferation and differentiation. Partial duct ligation (PDL) is an experimentally induced injury of the rodent pancreas involving surgical ligation of the main pancreatic duct resulting in an obstruction of drainage of exocrine products out of the tail region of the pancreas. The inflicted damage induces acinar atrophy, immune cell infiltration and severe tissue remodeling. We have previously reported the activation of Neurogenin (Ngn) 3 expressing endogenous progenitor-like cells and an increase in beta cell proliferation after PDL. Therefore, PDL provides a basis to study signals involved in beta cell dynamics and the properties of an endocrine progenitor in adult pancreas. Since, it still remains largely unclear, which factors and pathways contribute to beta cell neogenesis and proliferation in PDL, a standardized protocol for PDL will allow for comparison across laboratories. PMID:26273954

  10. Mouse models of acute exacerbations of allergic asthma.

    PubMed

    Kumar, Rakesh K; Herbert, Cristan; Foster, Paul S

    2016-07-01

    Most of the healthcare costs associated with asthma relate to emergency department visits and hospitalizations because of acute exacerbations of underlying chronic disease. Development of appropriate animal models of acute exacerbations of asthma is a necessary prerequisite for understanding pathophysiological mechanisms and assessing potential novel therapeutic approaches. Most such models have been developed using mice. Relatively few mouse models attempt to simulate the acute-on-chronic disease that characterizes human asthma exacerbations. Instead, many reported models involve relatively short-term challenge with an antigen to which animals are sensitized, followed closely by an unrelated triggering agent, so are better described as models of potentiation of acute allergic inflammation. Triggers for experimental models of asthma exacerbations include (i) challenge with high levels of the sensitizing allergen (ii) infection by viruses or fungi, or challenge with components of these microorganisms (iii) exposure to environmental pollutants. In this review, we examine the strengths and weaknesses of published mouse models, their application for investigation of novel treatments and potential future developments. PMID:26922049

  11. Annular pancreas

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/001142.htm Annular pancreas To use the sharing features on this page, please enable JavaScript. An annular pancreas is a ring of pancreatic tissue that encircles ...

  12. Pancreas Transplantation

    MedlinePlus

    ... Text Size: A A A Listen En Español Pancreas Transplantation Some patients with type 1 diabetes have ... weigh the potential benefits and risks. Benefits of Pancreas Transplants You may be able to maintain a ...

  13. Polycystic Pancreas.

    PubMed

    Sonavane, Amey D; Amarapurkar, Deepak N; Amarapurkar, Anjali D

    2016-04-01

    Polycystic disease of the pancreas is a very rare entity with very few cases reported in the literature. We report a symptomatic case of polycystic pancreas associated with pheochromocytoma that was treated surgically. PMID:27144204

  14. Polycystic Pancreas

    PubMed Central

    Amarapurkar, Deepak N.; Amarapurkar, Anjali D.

    2016-01-01

    Polycystic disease of the pancreas is a very rare entity with very few cases reported in the literature. We report a symptomatic case of polycystic pancreas associated with pheochromocytoma that was treated surgically. PMID:27144204

  15. Culture and establishment of self-renewing human and mouse adult liver and pancreas 3D organoids and their genetic manipulation.

    PubMed

    Broutier, Laura; Andersson-Rolf, Amanda; Hindley, Christopher J; Boj, Sylvia F; Clevers, Hans; Koo, Bon-Kyoung; Huch, Meritxell

    2016-09-01

    Adult somatic tissues have proven difficult to expand in vitro, largely because of the complexity of recreating appropriate environmental signals in culture. We have overcome this problem recently and developed culture conditions for adult stem cells that allow the long-term expansion of adult primary tissues from small intestine, stomach, liver and pancreas into self-assembling 3D structures that we have termed 'organoids'. We provide a detailed protocol that describes how to grow adult mouse and human liver and pancreas organoids, from cell isolation and long-term expansion to genetic manipulation in vitro. Liver and pancreas cells grow in a gel-based extracellular matrix (ECM) and a defined medium. The cells can self-organize into organoids that self-renew in vitro while retaining their tissue-of-origin commitment, genetic stability and potential to differentiate into functional cells in vitro (hepatocytes) and in vivo (hepatocytes and endocrine cells). Genetic modification of these organoids opens up avenues for the manipulation of adult stem cells in vitro, which could facilitate the study of human biology and allow gene correction for regenerative medicine purposes. The complete protocol takes 1-4 weeks to generate self-renewing 3D organoids and to perform genetic manipulation experiments. Personnel with basic scientific training can conduct this protocol. PMID:27560176

  16. What Is the Pancreas?

    MedlinePlus

    ... Pancreas Function of the Pancreas What is the pancreas? The pancreas is a long flattened gland located ... controller of blood sugar levels. Where is the pancreas? The pancreas is located deep in the abdomen. ...

  17. Quantitative organellar proteomics analysis of rough endoplasmic reticulum from normal and acute pancreatitis rat pancreas

    PubMed Central

    Chen, Xuequn; Sans, Maria Dolors; Strahler, John R.; Karnovsky, Alla; Ernst, Stephen A.; Michailidis, George; Andrews, Philip C.; Williams, John A.

    2010-01-01

    Summary The rough endoplasmic reticulum (RER) is a central organelle for synthesizing and processing digestive enzymes and alteration of ER functions may participate in the pathogenesis of acute pancreatitis (AP). To comprehensively characterize the normal and diseased RER subproteome, this study quantitatively compared the protein compositions of pancreatic RER between normal and AP animals using isobaric tags (iTRAQ) and 2D LC-MALDI-MS/MS. A total of 469 unique proteins were revealed from four independent experiments using two different AP models. These proteins belong to a large number of functional categories including ribosomal proteins, translocon subunits, chaperones, secretory proteins, and glyco- and lipid-processing enzymes. 37 RER proteins (25 unique in arginine-induced, 6 unique in caerulein-induced and 6 common in both models of AP) showed significant changes during AP including translational regulators and digestive enzymes whereas only mild changes were found in some ER chaperones. The six proteins common to both AP models including a decrease in pancreatic triacylglycerol lipase precursor, Erp27, and prolyl 4-hydroxylase beta polypeptide as well as a dramatic increase in fibrinogen alpha, beta and gamma chains. These results suggest that the early stages of AP involve changes of multiple RER proteins that may affect the synthesis and processing of digestive enzymes. PMID:19954227

  18. Pancreas-protective effect of rituximab for acute-onset type 1 diabetes in the honeymoon period: a case report

    PubMed Central

    Kurozumi, Akira; Okada, Yosuke; Arao, Tadashi; Miyazaki, Yusuke; Yoshikawa, Maiko; Torimoto, Keiichi; Kubo, Satoshi; Nakayamada, Shingo

    2016-01-01

    Summary A randomized controlled study of rituximab demonstrated that the drug protects pancreatic function in patients with acute-onset type 1 diabetes mellitus (AOT1DM). However, the mechanism of this protective effect is poorly understood. We examined the effects of rituximab in two patients with AOT1DM in the honeymoon period and the mechanism of these effects. Case 1 was a 40-year-old man and Case 2 was a 45-year-old man, both diagnosed with AOT1DM. Various tests indicated intact capacity for endogenous insulin secretion and that they were in the honeymoon phase of AOT1DM. Treatment with rituximab protected against pancreatic β-cell damage and maintained somewhat the endogenous insulin secretion. In Case 2, HbA1c level was maintained below 6.5% up to 24 months after treatment. However, in Case 1, the patient showed a gradual increase in HbA1c level starting around 9 months but fell at 12 months to >9.0% and required an insulin dose about twice greater than that of Case 2. High spleen tyrosine kinase (Syk) levels were recorded in the two patients before rituximab administration and after the treatment, the levels were further increased in Case 1, but decreased in Case 2. Both patients require continuous careful follow-up for glycemic control, insulin secretion capacity, and adverse reactions in the future. Although the clinical relevance of high Syk levels in AOT1DM patients remains unclear, the difference in the change in Syk level between the two patients may explain the different clinical courses. Learning points We described the pancreas-protective effect of rituximab in two patients with acute-onset type 1 diabetes mellitus in the honeymoon period and investigated the possible mechanism of action. The present study demonstrated that treatment with rituximab maintained endogenous insulin secretion capacity for 2 years in the two patients. The phosphorylated-spleen tyrosine kinase (p-Syk) data suggest that the differences in HbA1c level and the required

  19. Pancreas divisum

    MedlinePlus

    ... to form the pancreas. Each part has a tube, called a duct. When the parts join together, a final duct, called the pancreatic duct, is formed. Fluid and digestive juices (enzymes) produced by the pancreas normally flow through this duct. If the ducts do not ...

  20. PDX-1 mRNA-induced reprogramming of mouse pancreas-derived mesenchymal stem cells into insulin-producing cells in vitro.

    PubMed

    Guo, Xing Rong; Wang, Xiao Li; Li, Man Chol; Yuan, Ya Hong; Chen, Yun; Zou, Dan Dan; Bian, Liu Jiao; Li, Dong Sheng

    2015-11-01

    Pancreatic islet transplantation has remained an effective therapy for type 1 diabetes since 2000. Its widespread use has been prohibited by the shortage of suitable donors. It is critical to explore an applicable alternative for β-cell replacement. This study was performed to generate insulin-producing cells (IPCs) from pancreas-derived mesenchymal stem cells (pMSCs). pMSCs were isolated from discarded pancreatic tissue in the filter liquor during islet isolation procedure in mice and ex vivo expanded in culture. IPCs were induced by transfection of pancreas and duodenal transcription factor 1 (PDX-1) mRNA in vitro. Some islet characteristics were identified on pMSC-derived IPCs in mRNA and protein levels. Our results demonstrated that mouse pMSCs can be transdifferentiated into effective glucose-responsive insulin-producing cells through transfecting synthetic modified PDX-1 mRNA in vitro. The study of PDX-1 mRNA-induced pMSC reprogramming may pave the way toward the development of a novel β-cell source for the treatment of diabetes. PMID:25345580

  1. Acute pancreatitis decreases the sensitivity of pancreas-projecting dorsal motor nucleus of the vagus neurones to group II metabotropic glutamate receptor agonists in rats

    PubMed Central

    Babic, Tanja; Travagli, R Alberto

    2014-01-01

    Recent studies have shown that pancreatic exocrine secretions (PES) are modulated by dorsal motor nucleus of the vagus (DMV) neurones, whose activity is finely tuned by GABAergic and glutamatergic synaptic inputs. Group II metabotropic glutamate receptors (mGluR) decrease synaptic transmission to pancreas-projecting DMV neurones and increase PES. In the present study, we used a combination of in vivo and in vitro approaches aimed at characterising the effects of caerulein-induced acute pancreatitis (AP) on the vagal neurocircuitry modulating pancreatic functions. In control rats, microinjection of bicuculline into the DMV increased PES, whereas microinjections of kynurenic acid had no effect. Conversely, in AP rats, microinjection of bicuculline had no effect, whereas kynurenic acid decreased PES. DMV microinjections of the group II mGluR agonist APDC and whole cell recordings of excitatory currents in identified pancreas-projecting DMV neurones showed a reduced functional response in AP rats compared to controls. Moreover, these changes persisted up to 3 weeks following the induction of AP. These data demonstrate that AP increases the excitatory input to pancreas-projecting DMV neurones by decreasing the response of excitatory synaptic terminals to group II mGluR agonist. PMID:24445314

  2. Artifical Pancreas

    NASA Astrophysics Data System (ADS)

    Fei, Jiangfeng

    2013-03-01

    In 2006, JDRF launched the Artificial Pancreas Project (APP) to accelerate the development of a commercially-viable artificial pancreas system to closely mimic the biological function of the pancreas individuals with insulin-dependent diabetes, particularly type 1 diabetes. By automating detection of blood sugar levels and delivery of insulin in response to those levels, an artificial pancreas has the potential to transform the lives of people with type 1 diabetes. The 6-step APP development pathway serves as JDRF's APP strategic funding plan and defines the priorities of product research and development. Each step in the plan represents incremental advances in automation beginning with devices that shut off insulin delivery to prevent episodes of low blood sugar and progressing ultimately to a fully automated ``closed loop'' system that maintains blood glucose at a target level without the need to bolus for meals or adjust for exercise.

  3. Organ Facts: Pancreas

    MedlinePlus

    ... Home / Before The Transplant / Organ Facts / Pancreas Organ Facts Heart Lung Heart/Lung Kidney Pancreas Kidney/Pancreas Liver ... Receiving "the call" About the Operation Heart Lung Heart/Lung Kidney Pancreas Kidney/Pancreas Liver Intestine Pancreas Facts The pancreas is a five to six inch ...

  4. Proteomic Profiling of Mouse Liver following Acute Toxoplasma gondii Infection.

    PubMed

    He, Jun-Jun; Ma, Jun; Elsheikha, Hany M; Song, Hui-Qun; Zhou, Dong-Hui; Zhu, Xing-Quan

    2016-01-01

    Toxoplasma gondii remains a global public health problem. However, its pathophysiology is still not-completely understood particularly the impact of infection on host liver metabolism. We performed iTRAQ-based proteomic analysis to evaluate early liver protein responses in BALB/c mice following infection with T. gondii PYS strain (genotype ToxoDB#9) infection. Our data revealed modification of protein expression in key metabolic pathways, as indicated by the upregulation of immune response and downregulation of mitochondrial respiratory chain, and the metabolism of fatty acids, lipids and xenobiotics. T. gondii seems to hijack host PPAR signaling pathway to downregulate the metabolism of fatty acids, lipids and energy in the liver. The metabolism of over 400 substances was affected by the downregulation of genes involved in xenobiotic metabolism. The top 10 transcription factors used by upregulated genes were Stat2, Stat1, Irf2, Irf1, Sp2, Egr1, Stat3, Klf4, Elf1 and Gabpa, while the top 10 transcription factors of downregulated genes were Hnf4A, Ewsr1, Fli1, Hnf4g, Nr2f1, Pparg, Rxra, Hnf1A, Foxa1 and Foxo1. These findings indicate global reprogramming of the metabolism of the mouse liver after acute T. gondii infection. Functional characterization of the altered proteins may enhance understanding of the host responses to T. gondii infection and lead to the identification of new therapeutic targets. PMID:27003162

  5. Proteomic Profiling of Mouse Liver following Acute Toxoplasma gondii Infection

    PubMed Central

    He, Jun-Jun; Ma, Jun; Elsheikha, Hany M.; Song, Hui-Qun; Zhou, Dong-Hui; Zhu, Xing-Quan

    2016-01-01

    Toxoplasma gondii remains a global public health problem. However, its pathophysiology is still not-completely understood particularly the impact of infection on host liver metabolism. We performed iTRAQ-based proteomic analysis to evaluate early liver protein responses in BALB/c mice following infection with T. gondii PYS strain (genotype ToxoDB#9) infection. Our data revealed modification of protein expression in key metabolic pathways, as indicated by the upregulation of immune response and downregulation of mitochondrial respiratory chain, and the metabolism of fatty acids, lipids and xenobiotics. T. gondii seems to hijack host PPAR signaling pathway to downregulate the metabolism of fatty acids, lipids and energy in the liver. The metabolism of over 400 substances was affected by the downregulation of genes involved in xenobiotic metabolism. The top 10 transcription factors used by upregulated genes were Stat2, Stat1, Irf2, Irf1, Sp2, Egr1, Stat3, Klf4, Elf1 and Gabpa, while the top 10 transcription factors of downregulated genes were Hnf4A, Ewsr1, Fli1, Hnf4g, Nr2f1, Pparg, Rxra, Hnf1A, Foxa1 and Foxo1. These findings indicate global reprogramming of the metabolism of the mouse liver after acute T. gondii infection. Functional characterization of the altered proteins may enhance understanding of the host responses to T. gondii infection and lead to the identification of new therapeutic targets. PMID:27003162

  6. Microvesicles but Not Exosomes from Pathfinder Cells Stimulate Functional Recovery of the Pancreas in a Mouse Streptozotocin-Induced Diabetes Model.

    PubMed

    McGuinness, Dagmara; Anthony, Diana F; Moulisova, Vladimira; MacDonald, Alasdair I; MacIntyre, Alan; Thomson, Jacqueline; Nag, Abhijeet; Davies, R Wayne; Shiels, Paul G

    2016-06-01

    Pathfinder cells (PCs), a novel cell type derived from the pancreas of adult rats, have been demonstrated to stimulate recovery of tissue structure and function in two animal models of acute tissue damage to date-streptozotocin (STZ)-induced diabetes and ischemia-reperfusion damage to the kidney. In repaired tissue, PCs and their progeny typically represent only 0.02% of the repaired tissue, suggesting that they act via a paracrine mechanism on native cells in the damaged area. Extracellular vesicles are strong candidates for mediating such a paracrine effect. Therefore, we studied the effects of two PC-derived extracellular vesicle fractions on tissue repair in the STZ diabetes model, one containing primarily microvesicles and the second containing predominantly exosomes. Treatment of STZ-induced diabetic mice with the microvesicles preparation led to blood glucose, insulin, glucagon, and C-peptide levels similar to those found with PC treatment. Furthermore, analysis of the histopathology of the pancreas indicated islet regeneration. In contrast, the exosome fraction demonstrated no repair activity, and STZ diabetic mice treated with exosome preparations had blood glucose values that were indistinguishable from those of vehicle-only treated controls. Therefore, we conclude that exosomes play no part in PC action as detected by this assay, whereas microvesicles provide all or a large component of the paracrine activity of PCs. Because they act to stimulate repair of multiple tissues, PC-derived microvesicles may similarly have the potential to stimulate repair of many damaged tissues, identifying a very significant cell-free therapeutic opportunity in regenerative medicine. PMID:26414011

  7. Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP

    PubMed Central

    Mukherjee, Rajarshi; Mareninova, Olga A; Odinokova, Irina V; Huang, Wei; Murphy, John; Chvanov, Michael; Javed, Muhammad A; Wen, Li; Booth, David M; Cane, Matthew C; Awais, Muhammad; Gavillet, Bruno; Pruss, Rebecca M; Schaller, Sophie; Molkentin, Jeffery D; Tepikin, Alexei V; Petersen, Ole H; Pandol, Stephen J; Gukovsky, Ilya; Criddle, David N; Gukovskaya, Anna S; Sutton, Robert

    2016-01-01

    Objective Acute pancreatitis is caused by toxins that induce acinar cell calcium overload, zymogen activation, cytokine release and cell death, yet is without specific drug therapy. Mitochondrial dysfunction has been implicated but the mechanism not established. Design We investigated the mechanism of induction and consequences of the mitochondrial permeability transition pore (MPTP) in the pancreas using cell biological methods including confocal microscopy, patch clamp technology and multiple clinically representative disease models. Effects of genetic and pharmacological inhibition of the MPTP were examined in isolated murine and human pancreatic acinar cells, and in hyperstimulation, bile acid, alcoholic and choline-deficient, ethionine-supplemented acute pancreatitis. Results MPTP opening was mediated by toxin-induced inositol trisphosphate and ryanodine receptor calcium channel release, and resulted in diminished ATP production, leading to impaired calcium clearance, defective autophagy, zymogen activation, cytokine production, phosphoglycerate mutase 5 activation and necrosis, which was prevented by intracellular ATP supplementation. When MPTP opening was inhibited genetically or pharmacologically, all biochemical, immunological and histopathological responses of acute pancreatitis in all four models were reduced or abolished. Conclusions This work demonstrates the mechanism and consequences of MPTP opening to be fundamental to multiple forms of acute pancreatitis and validates the MPTP as a drug target for this disease. PMID:26071131

  8. Nonproliferative and Proliferative Lesions of the Gastrointestinal Tract, Pancreas and Salivary Glands of the Rat and Mouse

    PubMed Central

    Nolte, Thomas; Brander-Weber, Patricia; Dangler, Charles; Deschl, Ulrich; Elwell, Michael R.; Greaves, Peter; Hailey, Richard; Leach, Michael W.; Pandiri, Arun R.; Rogers, Arlin; Shackelford, Cynthia C.; Spencer, Andrew; Tanaka, Takuji; Ward, Jerrold M.

    2016-01-01

    The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) project is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature and diagnostic criteria for nonproliferative and proliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature and diagnostic criteria for classifying lesions in the digestive system including the salivary glands and the exocrine pancreas of laboratory rats and mice. Most lesions are illustrated by color photomicrographs. The standardized nomenclature, the diagnostic criteria, and the photomicrographs are also available electronically on the Internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous and age related lesions as well as lesions induced by exposure to test items. Relevant infectious and parasitic lesions are included as well. A widely accepted and utilized international harmonization of nomenclature and diagnostic criteria for the digestive system will decrease misunderstandings among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists. PMID:26973378

  9. Nonproliferative and Proliferative Lesions of the Gastrointestinal Tract, Pancreas and Salivary Glands of the Rat and Mouse.

    PubMed

    Nolte, Thomas; Brander-Weber, Patricia; Dangler, Charles; Deschl, Ulrich; Elwell, Michael R; Greaves, Peter; Hailey, Richard; Leach, Michael W; Pandiri, Arun R; Rogers, Arlin; Shackelford, Cynthia C; Spencer, Andrew; Tanaka, Takuji; Ward, Jerrold M

    2016-01-01

    The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) project is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature and diagnostic criteria for nonproliferative and proliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature and diagnostic criteria for classifying lesions in the digestive system including the salivary glands and the exocrine pancreas of laboratory rats and mice. Most lesions are illustrated by color photomicrographs. The standardized nomenclature, the diagnostic criteria, and the photomicrographs are also available electronically on the Internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous and age related lesions as well as lesions induced by exposure to test items. Relevant infectious and parasitic lesions are included as well. A widely accepted and utilized international harmonization of nomenclature and diagnostic criteria for the digestive system will decrease misunderstandings among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists. PMID:26973378

  10. Impact of Transient Acute Hypoxia on the Developing Mouse EEG

    PubMed Central

    Zanelli, S.; Goodkin, H.P.; Kowalski, S.; Kapur, J.

    2015-01-01

    Hypoxemic events are common in sick preterm and term infants and represent the most common cause of seizures in the newborn period. Neonatal seizures often lack clinical correlates and are only recognized by electroencephalogram (EEG). The mechanisms leading from a hypoxic/ischemic insult to acute seizures in neonates remain poorly understood. Further, the effects of hypoxia on EEG at various developmental stages have not been fully characterized in neonatal animals, in part due to technical challenges. We evaluated the impact of hypoxia on neonatal mouse EEG to define periods of increased susceptibility to seizures during postnatal development. Hippocampal and cortical electrodes were implanted stereotaxically in C57BL/6 mice from postnatal age 3 (P3) to P15. Following recovery, EEG recording were obtained during baseline, acute hypoxia (4% FiO2 for 4 min) and reoxygenation. In baseline recordings, maturation of EEG was characterized by the appearance of a more continuous background pattern that replaced alternating high and low amplitude activity. Clinical seizures during hypoxia were observed more frequently in younger animals (100% P3-4, 87.5% P5-6, 93% P7-8, 83% P9-10, 33% P11-12, 17% P15, r2=0.81) and also occurred at higher FiO2 in younger animals (11.2±1.1% P3-P6 vs. 8.9±0.8% P7-12, p<0.05). Background attenuation followed the initial hypoxemic seizure; progressive return to baseline during reoxygenation was observed in survivors. Electrographic seizures without clinical manifestations were observed during reoxygenation, again more commonly in younger animals (83% P3-4, 86% P5-6, 75% P7-8, 71% P9-10, 20% P11-12, r2=0.82). All P15 animals died with this duration and degree of hypoxia. Post-ictal abnormalities included burst attenuation and post-anoxic myoclonus and were more commonly seen in older animals. In summary, neonatal mice exposed to brief and severe hypoxia followed by rapid reoxygenation reliably develop seizures and the response to hypoxia

  11. [The pancreas and alcohol].

    PubMed

    Singer, M V

    1985-07-20

    The action of acute and chronic administration of ethanol on pancreatic exocrine secretion in humans and several animal species is reviewed. If the data concerning the secretory action of ethanol on the pancreas are to the property assessed, several experimental variables have to be considered. Acute intravenous administration of ethanol inhibits basal and hormonally stimulated pancreatic secretion of bicarbonate and protein in nonalcoholic humans and most species of animals tested. Oral or intraduodenal ethanol causes moderate stimulation of pancreatic bicarbonate and enzyme secretion. Since anticholinergic agents and truncal vagotomy diminish the ethanol-induced inhibition of pancreatic secretion in the intact animal, it is possible that the action of ethanol on the pancreas is at least partly mediated by inhibitory cholinergic mechanisms. The action of ethanol on the pancreas may also be mediated by release of gastrointestinal hormones. Intravenous and oral administration of ethanol releases gastrin in dogs but not in humans. Pancreatic polypeptide is unlikely to be the hormonal mediator of the ethanol-induced inhibition of exocrine pancreatic secretion in humans and dogs, since ethanol does not release pancreatic polypeptide. The main secretory changes induced by chronic alcoholism in humans and dogs are increased basal secretion of pancreatic enzymes and decreased basal bicarbonate output, and these secretory changes may favour the occurrence of protein precipitates which are believed to be the first lesion of chronic pancreatitis in man. A decrease in the concentration of "pancreatic stone protein" in pancreatic juice may favour the development of protein precipitates in chronic alcoholic patients. PMID:3901251

  12. Efficient and simple production of insulin-producing cells from embryonal carcinoma stem cells using mouse neonate pancreas extract, as a natural inducer.

    PubMed

    Ebrahimie, Marzieh; Esmaeili, Fariba; Cheraghi, Somayeh; Houshmand, Fariba; Shabani, Leila; Ebrahimie, Esmaeil

    2014-01-01

    An attractive approach to replace the destroyed insulin-producing cells (IPCs) is the generation of functional β cells from stem cells. Embryonal carcinoma (EC) stem cells are pluripotent cells which can differentiate into all cell types. The present study was carried out to establish a simple nonselective inductive culture system for generation of IPCs from P19 EC cells by 1-2 weeks old mouse pancreas extract (MPE). Since, mouse pancreatic islets undergo further remodeling and maturation for 2-3 weeks after birth, we hypothesized that the mouse neonatal MPE contains essential factors to induce in vitro differentiation of pancreatic lineages. Pluripotency of P19 cells were first confirmed by expression analysis of stem cell markers, Oct3/4, Sox-2 and Nanog. In order to induce differentiation, the cells were cultured in a medium supplemented by different concentrations of MPE (50, 100, 200 and 300 µg/ml). The results showed that P19 cells could differentiate into IPCs and form dithizone-positive cell clusters. The generated P19-derived IPCs were immunoreactive to proinsulin, insulin and insulin receptor beta. The expression of pancreatic β cell genes including, PDX-1, INS1 and INS2 were also confirmed. The peak response at the 100 µg/ml MPE used for investigation of EP300 and CREB1 gene expression. When stimulated with glucose, these cells synthesized and secreted insulin. Network analysis of the key transcription factors (PDX-1, EP300, CREB1) during the generation of IPCs resulted in introduction of novel regulatory candidates such as MIR17, and VEZF1 transcription factors, as well as MORN1, DKFZp761P0212, and WAC proteins. Altogether, we demonstrated the possibility of generating IPCs from undifferentiated EC cells, with the characteristics of pancreatic β cells. The derivation of pancreatic cells from EC cells which are ES cell siblings would provide a valuable experimental tool in study of pancreatic development and function as well as rapid production of

  13. Acute molecular response of mouse hindlimb muscles to chronic stimulation

    PubMed Central

    Jayaraman, R. C.; Bombach, K. L.; Ankrapp, D. P.; Krill-Burger, J. M.; Sciulli, C. M.; Petrosko, P.; Wiseman, R. W.

    2009-01-01

    Stimulation of the mouse hindlimb via the sciatic nerve was performed for a 4-h period to investigate acute muscle gene activation in a model of muscle phenotype conversion. Initial force production (1.6 ± 0.1 g/g body wt) declined 45% within 10 min and was maintained for the remainder of the experiment. Force returned to initial levels upon study completion. An immediate-early growth response was present in the extensor digitorum longus (EDL) muscle (FOS, JUN, activating transcription factor 3, and musculoaponeurotic fibrosarcoma oncogene) with a similar but attenuated pattern in the soleus muscle. Transcript profiles showed decreased fast fiber-specific mRNA (myosin heavy chains 2A and 2B, fast troponins T3 and I, α-tropomyosin, muscle creatine kinase, and parvalbumin) and increased slow transcripts (myosin heavy chain-1β/slow, troponin C slow, and tropomyosin 3y) in the EDL versus soleus muscles. Histological analysis of the EDL revealed glycogen depletion without inflammatory cell infiltration in stimulated versus control muscles, whereas ultrastructural analysis showed no evidence of myofiber damage after stimulation. Multiple fiber type-specific transcription factors (tea domain family member 1, nuclear factor of activated T cells 1, peroxisome proliferator-activated receptor-γ coactivator-1α and -β, circadian locomotor output cycles kaput, and hypoxia-inducible factor-1α) increased in the EDL along with transcription factors characteristic of embryogenesis (Kruppel-like factor 4; SRY box containing 17; transcription factor 15; PBX/knotted 1 homeobox 1; and embryonic lethal, abnormal vision). No established in vivo satellite cell markers or genes activated in our parallel experiments of satellite cell proliferation in vitro (cyclins A2, B2, C, and E1 and MyoD) were differentially increased in the stimulated muscles. These results indicated that the molecular onset of fast to slow phenotype conversion occurred in the EDL within 4 h of stimulation

  14. Diagnosis and treatment of acute pancreatitis: the position statement of the Italian Association for the study of the pancreas.

    PubMed

    Pezzilli, R; Uomo, G; Zerbi, A; Gabbrielli, A; Frulloni, L; De Rai, P; Delle Fave, G; Di Carlo, V

    2008-10-01

    This medical position statement has been developed by the board of ProInf AISP (Computerized Project on Acute Pancreatitis) Study Group. The evidence and key recommendations were discussed at a dedicated meeting held in Milan on September 2007 and during this meeting the main clinical and therapeutic medical topics were extensively discussed. Each of the proposed recommendations was discussed and an initial consensus was reached. Acute pancreatitis in Italy is a disease of increasing annual incidence. The diagnosis of the disease should be established within 48hours of admission. Early identification of patients at risk of developing a severe attack of acute pancreatitis is of great importance because rapid therapeutic interventions improve outcome. The endoscopic approach seems to be most beneficial measure in patients with acute pancreatitis with jaundice and in those with cholangitis. The development of infected necrosis should be assessed using fine-needle aspiration and the sample should be cultured for germ isolation and characterization. The role of early ERCP in all patients with severe acute pancreatitis of biliary origin is still controversial. The data supporting the efficacy of antibiotic prophylaxis to prevent infection of necrosis are conflicting. The refeeding is a crucial topic in patients who have recovered from an acute episode of mild acute pancreatitis, but there are very few studies on this issue. PMID:18387862

  15. Potential carcinogenic effects of cigarette smoke and Swedish moist snuff on pancreas: a study using a transgenic mouse model of chronic pancreatitis.

    PubMed

    Song, Zhigang; Bhagat, Govind; Quante, Michael; Baik, Gwang Ho; Marrache, Frederic; Tu, Shui Ping; Zhao, Chun-Mei; Chen, Duan; Dannenberg, Andrew J; Wang, Timothy C

    2010-03-01

    The risk of pancreatic cancer is increased in both Snus (the Swedish variant of oral smokeless tobacco) users and, to a greater extent, in cigarette smokers. Concurrent chronic pancreatitis further increases the risk in cigarette smokers. Little is known about the mechanism by which cigarette smoke or Snus increase the risk of pancreatic cancer in individuals with chronic pancreatitis. This study examined the carcinogenic effects of an aqueous extract of cigarette smoke (tobacco smoke, TS) or Snus in an Elastase-IL-1beta transgenic mouse model of chronic pancreatitis. Both transgenic and wild-type (WT) mice were fed diluted TS water or Snus-containing diet for up to 15 months, and monitored for phenotypic and molecular changes in the pancreas. Both TS- and Snus-treated Elastase-IL-1beta mice, but not WT mice, developed significant pancreatic ductal epithelial flattening and severe glandular atrophy compared with untreated transgenic mice. Ductal epithelial cells displayed a high proliferative index, minimal apoptosis, and induction of COX-2 in the setting of chronic inflammation. Up-regulation of TNF-alpha correlated with the onset of severe glandular atrophy. In comparison with Snus-treated mice, TS-Elastase-IL-1beta mice had an earlier onset and a greater extent of phenotypic changes, which were associated with up-regulation of TNF-alpha and increased expression of IL-6, TGF-beta, and SDF-1. Collectively, these findings provide new insights into the mechanism by which tobacco products are likely to promote carcinogenesis in the setting of chronic pancreatitis. PMID:20065943

  16. Normal Pancreas Anatomy

    MedlinePlus

    ... hyphen, e.g. -historical Searches are case-insensitive Pancreas Anatomy Add to My Pictures View /Download : Small: ... 1586x1534 View Download Large: 3172x3068 View Download Title: Pancreas Anatomy Description: Anatomy of the pancreas; drawing shows ...

  17. Effect of Yi Gong San Decoction on Iron Homeostasis in a Mouse Model of Acute Inflammation

    PubMed Central

    Zheng, Qin; Guan, Yu; Xia, Lemin; Wang, Zhicheng; Jiang, Yiling; Zhang, Xiaofeng; Wang, Jianying; Wang, Guohua; Pu, Yiqiong; Xia, Jing; Luo, Meihong

    2016-01-01

    We investigated the effect of Yi Gong San (YGS) decoction on iron homeostasis and the possible underlying mechanisms in a mouse model of acute inflammation in this study. Our findings suggest that YGS regulates iron homeostasis by downregulating the level of HAMP mRNA, which may depend on regulation of the IL-6/STAT3 or BMP/HJV/SMAD pathway during acute inflammation. PMID:27143982

  18. Mouse models of acute, chemical itch and pain in humans

    PubMed Central

    LaMotte, Robert H.; Shimada, Steven G.; Sikand, Parul

    2011-01-01

    In psychophysical experiments, humans use different verbal responses to pruritic and algesic chemical stimuli to indicate the different qualities of sensation they feel. A major challenge for behavioral models in the mouse of chemical itch and pain in humans is to devise experimental protocols that provide the opportunity for the animal to exhibit a multiplicity of responses as well. One basic criterion is that chemicals that evoke primarily itch or pain in humans should elicit different types of responses when applied in the same way to the mouse. Meeting this criterion is complicated by the fact that the type of behavioral responses exhibited by the mouse depends in part on the site of chemical application such as the nape of the neck which evokes only scratching with the hind paw vs. the hind limb which elicits licking and biting. Here, we review to what extent mice behaviorally differentiate chemicals that elicit itch vs. pain in humans. PMID:21929688

  19. TISSUE DISPOSITION OF DIMETHYLARSINIC ACID IN THE MOUSE AFTER ACUTE ORAL ADMINISTRATION

    EPA Science Inventory

    TISSUE DISPOSITION OF DIMETHYLARSINIC ACID IN THE MOUSE
    AFTER ACUTE ORAL ADMINISTRATION

    Michael F. Hughes, Ph.D., Brenda C. Edwards, Carol T. Mitchell and Elaina M. Kenyon, Ph.D. United States Environmental Protection Agency, Office of Research and Development, Nation...

  20. [MPO-ANCA related vasculitis complicating mucinous cystadenoma of the pancreas and severe acute pancreatitis after steroid pulse therapy: a case report].

    PubMed

    Tsuruoka, Kayori; Sekiya, Syuusuke; Yokoyama, Takeshi; Koitabashi, Kenichirou; Shimazaki, Minako; Sakurada, Tsutomu; Shirai, Sayuri; Yasuda, Takashi; Kimura, Kenjirou

    2008-01-01

    A 72-year-old woman was admitted to our hospital because of massive proteinuria of 2.2 g/day. She had seen a general practitioner for management of Basedow disease, diabetes mellitus and hypertension for 24 years. On admission, she complained of anorexia and nausea. Laboratory data showed serum creatinine of 3.62 mg/dL and MPO-ANCA of 68 EU. Renal biopsy revealed crescentic glomerulonephritis complicated with membranous nephropathy. Thiamazole (MMI), which was being given for Basedow disease for years, was withdrawn on the suspicion as a cause of MPO-ANCA. Three years after the withdrawal of MMI, renal failure slowly progressed to the end-stage, while MPO-ANCA was negative. She was introduced onto hemodialysis. At that time, MPO-ANCA became positive again, the titer being 12.9 EU. Therefore, we suspected a relapse of ANCA-related vasculitis and performed steroid pulse therapy on the patient with methylprednisolone at 0.5 g/day for 3 days. On hospital day 14, MPO-ANCA became negative. On day 25, however, severe acute pancreatitis developed and a pancreatic tumor lesion was found on CT. In spite of amelioration of the pancreatitis by medical treatment, the pancreatic tumor lesion did not show any significant change. On day 48, she died of multiple organ failure. Autopsy showed a mucinous cyst adenoma of pancreas and necrotizing pancreatitis. We suspected steroid therapy as the cause of the pancreatic lesions. PMID:19069154

  1. Clinical imaging of the pancreas

    SciTech Connect

    May, G.; Gardiner, R.

    1987-01-01

    Featuring more than 300 high-quality radiographs and scan images, clinical imaging of the pancreas systematically reviews all appropriate imaging modalities for diagnosing and evaluating a variety of commonly encountered pancreatic disorders. After presenting a succinct overview of pancreatic embryology, anatomy, and physiology, the authors establish the clinical indications-including postoperative patient evaluation-for radiologic examination of the pancreas. The diagnostic capabilities and limitations of currently available imaging techniques for the pancreas are thoroughly assessed, with carefully selected illustrations depicting the types of images and data obtained using these different techniques. The review of acute and chronic pancreatitis considers the clinical features and possible complications of their variant forms and offers guidance in selecting appropriate imaging studies.

  2. Imaging Acute Neuromuscular Explants from Thy1 Mouse Lines.

    PubMed

    Marinković, Petar; Godinho, Leanne; Misgeld, Thomas

    2015-09-01

    Because core facilities that generate transgenic founder mice for a reasonable fee are now available at most major research institutions, generating new Thy1-XFP transgenic animals (in which XFP stands for any fluorescent protein) is an option even for relatively small laboratories. Here, we provide a protocol for screening offspring of Thy1 transgenic founders. Acute neuromuscular explants are obtained from 3-wk-old F1 mice that have been produced by crossing Thy1 transgenic founders and commercially obtained inbred mice. Thy1-driven expression is detected by fluorescence microscopy. PMID:26330628

  3. Getting a New Pancreas: Facts about Pancreas Transplants

    MedlinePlus

    ... 2003 December 2006 March 2012 Getting A New Pancreas Facts About Pancreas Transplants American Society of Transplantation 1120 Route 73, ... the views of the Society. _________________________________________________________________ Getting a New Pancreas Facts About Pancreas Transplants When you get a ...

  4. Acute inflammation stimulates a regenerative response in the neonatal mouse heart

    PubMed Central

    Han, Chunyong; Nie, Yu; Lian, Hong; Liu, Rui; He, Feng; Huang, Huihui; Hu, Shengshou

    2015-01-01

    Cardiac injury in neonatal 1-day-old mice stimulates a regenerative response characterized by reactive cardiomyocyte proliferation, which is distinguished from the fibrotic repair process in adults. Acute inflammation occurs immediately after heart injury and has generally been believed to exert a negative effect on heart regeneration by promoting scar formation in adults; however, little is known about the role of acute inflammation in the cardiac regenerative response in neonatal mice. Here, we show that acute inflammation induced cardiomyocyte proliferation after apical intramyocardial microinjection of immunogenic zymosan A particles into the neonatal mouse heart. We also found that cardiac injury-induced regenerative response was suspended after immunosuppression in neonatal mice, and that cardiomyocytes could not be reactivated to proliferate after neonatal heart injury in the absence of interleukin-6 (IL-6). Furthermore, cardiomyocyte-specific deletion of signal transducer and activator of transcription 3 (STAT3), the major downstream effector of IL-6 signaling, decreased reactive cardiomyocyte proliferation after apical resection. Our results indicate that acute inflammation stimulates the regenerative response in neonatal mouse heart, and suggest that modulation of inflammatory signals might have important implications in cardiac regenerative medicine. PMID:26358185

  5. Pancreas transplant - slideshow

    MedlinePlus

    ... this page: //medlineplus.gov/ency/presentations/100129.htm Pancreas transplant - series—Normal anatomy To use the sharing ... to slide 6 out of 6 Overview The pancreas resides in the back of the abdomen. It ...

  6. Annular pancreas (image)

    MedlinePlus

    Annular pancreas is an abnormal ring or collar of pancreatic tissue that encircles the duodenum (the part of the ... intestine that connects to stomach). This portion of pancreas can constrict the duodenum and block or impair ...

  7. Pancreas transplant - series (image)

    MedlinePlus

    The pancreas resides in the back of the abdomen. It functions to produce digestive enzymes which are delivered to ... of the most important hormones produced by the pancreas is insulin. Insulin is produced by specialized cells ...

  8. The Gene Expression Profile of CD11c+CD8α− Dendritic Cells in the Pre-Diabetic Pancreas of the NOD Mouse

    PubMed Central

    Beumer, Wouter; Welzen-Coppens, Jojanneke M. C.; van Helden-Meeuwsen, Cornelia G.; Gibney, Sinead M.; Drexhage, Hemmo A.; Versnel, Marjan A.

    2014-01-01

    Two major dendritic cell (DC) subsets have been described in the pancreas of mice: The CD11c+CD8α− DCs (strong CD4+ T cell proliferation inducers) and the CD8α+CD103+ DCs (T cell apoptosis inducers). Here we analyzed the larger subset of CD11c+CD8α− DCs isolated from the pancreas of pre-diabetic NOD mice for genome-wide gene expression (validated by Q-PCR) to elucidate abnormalities in underlying gene expression networks. CD11c+CD8α− DCs were isolated from 5 week old NOD and control C57BL/6 pancreas. The steady state pancreatic NOD CD11c+CD8α− DCs showed a reduced expression of several gene networks important for the prime functions of these cells, i.e. for cell renewal, immune tolerance induction, migration and for the provision of growth factors including those for beta cell regeneration. A functional in vivo BrdU incorporation test showed the reduced proliferation of steady state pancreatic DC. The reduced expression of tolerance induction genes (CD200R, CCR5 and CD24) was supported on the protein level by flow cytometry. Also previously published functional tests on maturation, immune stimulation and migration confirm the molecular deficits of NOD steady state DC. Despite these deficiencies NOD pancreas CD11c+CD8α− DCs showed a hyperreactivity to LPS, which resulted in an enhanced pro-inflammatory state characterized by a gene profile of an enhanced expression of a number of classical inflammatory cytokines. The enhanced up-regulation of inflammatory genes was supported by the in vitro cytokine production profile of the DCs. In conclusion, our data show that NOD pancreatic CD11c+CD8α− DCs show various deficiencies in steady state, while hyperreactive when encountering a danger signal such as LPS. PMID:25166904

  9. Pancreas transplantation: review

    PubMed Central

    Meirelles, Roberto Ferreira; Salvalaggio, Paolo; Pacheco-Silva, Alvaro

    2015-01-01

    ABSTRACT Vascularized pancreas transplantation is the only treatment that establishes normal glucose levels and normalizes glycosylated hemoglobin levels in type 1 diabetic patients. The first vascularized pancreas transplant was performed by William Kelly and Richard Lillehei, to treat a type 1 diabetes patient, in December 1966. In Brazil, Edison Teixeira performed the first isolated segmental pancreas transplant in 1968. Until the 1980s, pancreas transplants were restricted to a few centers of the United States and Europe. The introduction of tacrolimus and mycophenolate mofetil in 1994, led to a significant outcome improvement and consequently, an increase in pancreas transplants in several countries. According to the International Pancreas Transplant Registry, until December 31st, 2010, more than 35 thousand pancreas transplants had been performed. The one-year survival of patients and pancreatic grafts exceeds 95 and 83%, respectively. The better survival of pancreatic (86%) and renal (93%) grafts in the first year after transplantation is in the simultaneous pancreas-kidney transplant group of patients. Immunological loss in the first year after transplant for simultaneous pancreas-kidney, pancreas after kidney, and pancreas alone are 1.8, 3.7, and 6%, respectively. Pancreas transplant has 10 to 20% surgical complications requiring laparotomy. Besides enhancing quality of life, pancreatic transplant increases survival of uremic diabetic patient as compared to uremic diabetic patients on dialysis or with kidney transplantation alone. PMID:26154551

  10. Pancreas preservation for pancreas and islet transplantation

    PubMed Central

    Iwanaga, Yasuhiro; Sutherland, David E.R.; Harmon, James V.; Papas, Klearchos K.

    2010-01-01

    Purpose of review To summarize advances and limitations in pancreas procurement and preservation for pancreas and islet transplantation, and review advances in islet protection and preservation. Recent findings Pancreases procured after cardiac death, with in-situ regional organ cooling, have been successfully used for islet transplantation. Colloid-free Celsior and histidine-tryptophan-ketoglutarate preservation solutions are comparable to University of Wisconsin solution when used for cold storage before pancreas transplantation. Colloid-free preservation solutions are inferior to University of Wisconsin solution for pancreas preservation prior to islet isolation and transplantation. Clinical reports on pancreas and islet transplants suggest that the two-layer method may not offer significant benefits over cold storage with the University of Wisconsin solution: improved oxygenation may depend on the graft size; benefits in experimental models may not translate to human organs. Improvements in islet yield and quality occurred from pancreases treated with inhibitors of stress-induced apoptosis during procurement, storage, isolation or culture. Pancreas perfusion may be desirable before islet isolation and transplantation and may improve islet yields and quality. Methods for real-time, noninvasive assessment of pancreas quality during preservation have been implemented and objective islet potency assays have been developed and validated. These innovations should contribute to objective evaluation and establishment of improved pancreas preservation and islet isolation strategies. Summary Cold storage may be adequate for preservation before pancreas transplants, but insufficient when pancreases are processed for islets or when expanded donors are used. Supplementation of cold storage solutions with cytoprotective agents and perfusion may improve pancreas and islet transplant outcomes. PMID:18685343

  11. Mouse models and methods for studying human disease, acute kidney injury (AKI).

    PubMed

    Ramesh, Ganesan; Ranganathan, Punithavathi

    2014-01-01

    Acute kidney injury (AKI) is serious complication in hospitalized patients with high level of mortality. There is not much progress made for the past 50 years in reducing the mortality rate despite advances in understanding disease pathology. Using variety of animal models of acute kidney injury, scientist studies the pathogenic mechanism of AKI and to test therapeutic drugs, which may reduce renal injury. Among them, renal pedicle clamping and cisplatin induced nephrotoxicity in mice are most prominently used, mainly due to the availability of gene knockouts to study specific gene functions, inexpensive and availability of the inbred strain with less genetic variability. However, ischemic mouse model is highly variable and require excellent surgical skills to reduce variation in the observation. In this chapter, we describe a detailed protocol of the mouse model of bilateral renal ischemia-reperfusion and cisplatin induced nephrotoxicity. We also discuss the protocol for the isolation and analysis of infiltrated inflammatory cell into the kidney by flow cytometry. Information provided in this chapter will help scientist who wants to start research on AKI and want to establish the mouse model for ischemic and toxic kidney injury. PMID:25064118

  12. Histopathological studies of acute and chronic effects of Calliandra portoricensis leaf extract on the stomach and pancreas of adult Swiss albino mice

    PubMed Central

    Ofusori, David A; Adejuwon, Adebomi O

    2011-01-01

    Objective To evaluate the consequence of oral administration of Calliandra portoricensis (C. portoricensis) leaf extract on the stomach and pancreas in Swiss albino mice. Methods Three groups of mice (B, C and D) were treated with 4 mg/kg of C. portoricensis extract. Group A was the control and received an equivalent volume of distilled water. Group B received C. portoricensis leaf extract for 7 days, Group C received C. portoricensis leaf extract for 14 days, and Group D received C. portoricensis leaf extract for 28 days. At different stages in the study, the mice were sacrificed and the stomach and pancreas were excised and fixed in 10% formol saline for histological analysis. Results The result showed a normal microstructural outline in groups B and C as compared with the control. However, animals in group D showed disorganization of the mucosa and discontinuation of epithelial lining of the stomach while the islets of Langerans in the pancreas were at various degree of degeneration as compared with the control mice. Conclusions The present finding suggests that chronic administration (28 days as seen in this study) of C. portoricensis leaf extract may inhibit the proper function of the stomach and pancreas. PMID:23569755

  13. Neuroglobin mitigates mitochondrial impairments induced by acute inhalation of combustion smoke in the mouse brain

    PubMed Central

    Gorgun, Falih Murat; Zhuo, Ming; Singh, Shilpee; Englander, Ella W.

    2014-01-01

    Context Acute inhalation of combustion smoke adversely affects brain homeostasis and energy metabolism. We previously showed that overexpressed neuroglobin (neuron specific globin protein) attenuates the formation of smoke inhalation-induced oxidative DNA damage, in vivo, in the mouse brain, while others reported protection by neuroglobin in diverse models of brain injury, mainly involving oxidative stress and hypoxic/ischemic insults. Objective To determine to what extent elevated neuroglobin ameliorates post smoke-inhalation brain bioenergetics and homeostasis in neuroglobin overexpressing transgenic mouse. Methods Smoke inhalation induced changes in bioenergetics were measured in the wild type and neuroglobin transgene mouse brain. Modulations of mitochondrial respiration were analyzed using the Seahorse XF24 flux analyzer and changes in cytoplasmic energy metabolism were assessed by measuring enzymatic activities and lactate in the course of post smoke recovery. Results Cortical mitochondria from neuroglobin transgene, better maintained ATP synthesis-linked oxygen consumption and unlike wild type mitochondria did not increase futile oxygen consumption feeding the proton leak, reflecting lesser smoke-induced mitochondrial compromise. Measurements revealed lesser reduction of mitochondrial ATP content and lesser compensatory increases in cytosolic energy metabolism, involving pyruvate kinase and lactate dehydrogenase activities as well as cytosolic lactate levels. Additionally, induction of c-Fos, the early response gene and key neuronal stress sensor, was attenuated in neuroglobin transgene compared to wild type brain after smoke. Conclusion Considered together, these differences reflect lesser perturbations produced by acute inhalation of combustion smoke in the neuroglobin overexpressing mouse, suggesting that neuroglobin mitigates mitochondrial dysfunction and neurotoxicity and raises the threshold of smoke inhalation-induced brain injury. PMID:24730682

  14. Neurovascular changes in acute, sub-acute and chronic mouse models of Parkinson's disease.

    PubMed

    Sarkar, Sumit; Raymick, James; Mann, Dushyant; Bowyer, John F; Hanig, Joseph P; Schmued, Larry C; Paule, Merle G; Chigurupati, Srinivasulu

    2014-02-01

    Although selective neurodegeneration of nigro-striatal dopaminergic neurons is widely accepted as a cause of Parkinson's disease (PD), the role of vascular components in the brain in PD pathology is not well understood. However, the neurodegeneration seen in PD is known to be associated with neuroinflammatory-like changes that can affect or be associated with brain vascular function. Thus, dysfunction of the capillary endothelial cell component of neurovascular units present in the brain may contribute to the damage to dopaminergic neurons that occurs in PD. An animal model of PD employing acute, sub-acute and chronic exposures of mice to methyl-phenyl-tetrahydropyridine (MPTP) was used to determine the extent to which brain vasculature may be damaged in PD. Fluoro-Turquoise gelatin labeling of microvessels and endothelial cells was used to determine the extent of vascular damage produced by MPTP. In addition, tyrosine hydroxylase (TH) and NeuN were employed to detect and quantify dopaminergic neuron damage in the striatum (CPu) and substantia nigra (SNc). Gliosis was evaluated through GFAP immunohistochemistry. MPTP treatment drastically reduced TH immunoreactive neurons in the SNc (20.68 ± 2.83 in acute; 22.98 ± 2.14 in sub-acute; 10.20 ± 2.24 in chronic vs 34.88 ± 2.91 in controls; p<0.001). Similarly, TH immunoreactive terminals were dramatically reduced in the CPu of MPTP treated mice. Additionally, all three MPTP exposures resulted in a decrease in the intensity, length, and number of vessels in both CPu and SNc. Degenerative vascular changes such as endothelial cell 'clusters' were also observed after MPTP suggesting that vasculature damage may be modifying the availability of nutrients and exposing blood cells and/or toxic substances to neurons and glia. In summary, vascular damage and degeneration could be an additional exacerbating factor in the progression of PD, and therapeutics that protect and insure vascular integrity may be novel treatments for

  15. Validation of a novel, physiologic model of experimental acute pancreatitis in the mouse

    PubMed Central

    Ziegler, Kathryn M; Wade, Terence E; Wang, Sue; Swartz-Basile, Deborah A; Pitt, Henry A; Zyromski, Nicholas J

    2011-01-01

    Background: Many experimental models of acute pancreatitis suffer from lack of clinical relevance. We sought to validate a recently reported murine model of acute pancreatitis that more closely represents the physiology of human biliary pancreatitis. Methods: Mice (C57BL/6J n=6 and CF-1 n=8) underwent infusion of 50μl of 5% sodium taurocholate (NaT) or 50μl of normal saline (NaCl) directly into the pancreatic duct. Twenty-four hours later, pancreatitis severity was graded histologically by three independent observers, and pancreatic tissue concentration of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) were determined by ELISA. Results: Twenty four hours after retrograde injection, the total pancreatitis score was significantly greater in mice infused with NaT than in those infused with NaCl (6.3 ± 1.2 vs. 1.2 ± 0.4, p<0.05). In addition, the inflammatory mediators IL-6 and MCP-1 were increased in the NaT group relative to the NaCl group. Discussion: Retrograde pancreatic duct infusion of sodium taurocholate induces acute pancreatitis in the mouse. This model is likely representative of human biliary pancreatitis pathophysiology, and therefore provides a powerful tool with which to elucidate basic mechanisms underlying the pathogenesis of acute pancreatitis. PMID:21416058

  16. Insulin-positive, Glut2-low cells present within mouse pancreas exhibit lineage plasticity and are enriched within extra-islet endocrine cell clusters.

    PubMed

    Beamish, Christine A; Strutt, Brenda J; Arany, Edith J; Hill, David J

    2016-04-18

    Regeneration of insulin-producing β-cells from resident pancreas progenitors requires an understanding of both progenitor identity and lineage plasticity. One model suggested that a rare β-cell sub-population within islets demonstrated multi-lineage plasticity. We hypothesized that β-cells from young mice (postnatal day 7, P7) exhibit such plasticity and used a model of islet dedifferentiation toward a ductal epithelial-cell phenotype to test this theory. RIPCre;Z/AP(+/+) mice were used to lineage trace the fate of β-cells during dedifferentiation culture by a human placental alkaline phosphatase (HPAP) reporter. There was a significant loss of HPAP-expressing β-cells in culture, but remaining HPAP(+) cells lost insulin expression while gaining expression of the epithelial duct cell marker cytokeratin-19 (Ck19). Flow cytometry and recovery of β-cell subpopulations from whole pancreas vs. islets suggest that the HPAP(+)Ck19(+) cells had derived from insulin-positive, glucose-transporter-2-low (Ins(+)Glut2(LO)) cells, representing 3.5% of all insulin-expressing cells. The majority of these cells were found outside of islets within clusters of <5 β-cells. These insulin(+)Glut2(LO) cells demonstrated a greater proliferation rate in vivo and in vitro as compared to insulin(+)Glut2(+) cells at P7, were retained into adulthood, and a subset differentiated into endocrine, ductal, and neural lineages, illustrating substantial plasticity. Results were confirmed using RIPCre;ROSA- eYFP mice. Quantitative PCR data indicated these cells possess an immature β-cell phenotype. These Ins(+)Glut2(LO) cells may represent a resident population of cells capable of forming new, functional β-cells, and which may be potentially exploited for regenerative therapies in the future. PMID:27010375

  17. Acute effects of corticosterone injection on paternal behavior in California mouse (Peromyscus californicus) fathers.

    PubMed

    Harris, Breanna N; Perea-Rodriguez, Juan Pablo; Saltzman, Wendy

    2011-11-01

    Glucocorticoids are thought to mediate the disruption of parental behavior in response to acute and chronic stress. Previous research supports their role in chronic stress; however, no study has experimentally tested the effects of acute glucocorticoid elevation on paternal behavior. We tested the prediction that acute corticosterone (CORT) increases would decrease paternal behavior in California mouse fathers and would lead to longer-term effects on reproductive success, as even short-term increases in CORT have been shown to produce lasting effects on the hypothalamic-pituitary-adrenal axis. First-time fathers were injected with 30 mg/kg CORT, 60 mg/kg CORT or vehicle, or left unmanipulated. Interactions between the male and its pup(s) were recorded 1.5-2h after injection and scored for paternal and non-paternal behavior. Treatment groups were combined into control (unmanipulated + vehicle, n = 15) and CORT (30 mg/kg + 60 mg/kg, n = 16) for analysis based on resulting plasma CORT concentrations. CORT treatment did not alter paternal or non-paternal behaviors or any long-term measures (male body mass or temperature, pup growth rate, pup survival, interbirth interval, number or mass of pups born in the second litter). Fathers showed a significant rise in body mass at day 30 postpartum, followed by a decrease in body mass after the birth of the second litter; however, this pattern did not differ between the CORT and control groups. In summary, acute elevation of plasma CORT did not alter direct paternal behavior, body mass, or reproductive outcomes, suggesting that acute CORT elevation alone does not overtly disrupt paternal care in this biparental mammal. PMID:21939660

  18. ACUTE ETHANOL DISRUPTS PHOTIC AND SEROTONERGIC CIRCADIAN CLOCK PHASE-RESETTING IN THE MOUSE

    PubMed Central

    Brager, Allison J.; Ruby, Christina L.; Prosser, Rebecca A.; Glass, J. David

    2011-01-01

    Background Alcohol abuse is associated with impaired circadian rhythms and sleep. Ethanol administration disrupts circadian clock phase-resetting, suggesting a mode for the disruptive effect of alcohol abuse on the circadian timing system. In this study, we extend previous work in C57BL/6J mice to: 1) characterize the SCN pharmacokinetics of acute systemic ethanol administration; 2) explore the effects of acute ethanol on photic and non-photic phase-resetting; and 2) determine if the SCN is a direct target for photic effects. Methods First, microdialysis was used to characterize the pharmacokinetics of acute i.p. injections of 3 doses of ethanol (0.5, 1.0 and 2.0 g/kg) in the mouse suprachiasmatic (SCN) circadian clock. Second, the effects of acute i.p. ethanol administration on photic phase-delays and serotonergic ([+]8-OH-DPAT-induced) phase-advances of the circadian activity rhythm were assessed. Third, the effects of reverse-microdialysis ethanol perfusion of the SCN on photic phase-resetting were characterized. Results Peak ethanol levels from the 3 doses of ethanol in the SCN occurred within 20–40 min post-injection with half-lives for clearance ranging from 0.6–1.8 hr. Systemic ethanol treatment dose-dependently attenuated photic and serotonergic phase-resetting. This treatment also did not affect basal SCN neuronal activity as assessed by Fos expression. Intra-SCN perfusion with ethanol markedly reduced photic phase-delays. Conclusions These results confirm that acute ethanol attenuates photic phase-delay shifts and serotonergic phase-advance shifts in the mouse. This dual effect could disrupt photic and non-photic entrainment mechanisms governing circadian clock timing. It is also significant that the SCN clock is a direct target for disruptive effects of ethanol on photic shifting. Such actions by ethanol could underlie the disruptive effects of alcohol abuse on behavioral, physiological, and endocrine rhythms associated with alcoholism. PMID:21463340

  19. Validation of a mouse xenograft model system for gene expression analysis of human acute lymphoblastic leukaemia

    PubMed Central

    2010-01-01

    Background Pre-clinical models that effectively recapitulate human disease are critical for expanding our knowledge of cancer biology and drug resistance mechanisms. For haematological malignancies, the non-obese diabetic/severe combined immunodeficient (NOD/SCID) mouse is one of the most successful models to study paediatric acute lymphoblastic leukaemia (ALL). However, for this model to be effective for studying engraftment and therapy responses at the whole genome level, careful molecular characterisation is essential. Results Here, we sought to validate species-specific gene expression profiling in the high engraftment continuous ALL NOD/SCID xenograft. Using the human Affymetrix whole transcript platform we analysed transcriptional profiles from engrafted tissues without prior cell separation of mouse cells and found it to return highly reproducible profiles in xenografts from individual mice. The model was further tested with experimental mixtures of human and mouse cells, demonstrating that the presence of mouse cells does not significantly skew expression profiles when xenografts contain 90% or more human cells. In addition, we present a novel in silico and experimental masking approach to identify probes and transcript clusters susceptible to cross-species hybridisation. Conclusions We demonstrate species-specific transcriptional profiles can be obtained from xenografts when high levels of engraftment are achieved or with the application of transcript cluster masks. Importantly, this masking approach can be applied and adapted to other xenograft models where human tissue infiltration is lower. This model provides a powerful platform for identifying genes and pathways associated with ALL disease progression and response to therapy in vivo. PMID:20406497

  20. Acute Radiation Syndrome Severity Score System in Mouse Total-Body Irradiation Model.

    PubMed

    Ossetrova, Natalia I; Ney, Patrick H; Condliffe, Donald P; Krasnopolsky, Katya; Hieber, Kevin P

    2016-08-01

    Radiation accidents or terrorist attacks can result in serious consequences for the civilian population and for military personnel responding to such emergencies. The early medical management situation requires quantitative indications for early initiation of cytokine therapy in individuals exposed to life-threatening radiation doses and effective triage tools for first responders in mass-casualty radiological incidents. Previously established animal (Mus musculus, Macaca mulatta) total-body irradiation (γ-exposure) models have evaluated a panel of radiation-responsive proteins that, together with peripheral blood cell counts, create a multiparametic dose-predictive algorithm with a threshold for detection of ~1 Gy from 1 to 7 d after exposure as well as demonstrate the acute radiation syndrome severity score systems created similar to the Medical Treatment Protocols for Radiation Accident Victims developed by Fliedner and colleagues. The authors present a further demonstration of the acute radiation sickness severity score system in a mouse (CD2F1, males) TBI model (1-14 Gy, Co γ-rays at 0.6 Gy min) based on multiple biodosimetric endpoints. This includes the acute radiation sickness severity Observational Grading System, survival rate, weight changes, temperature, peripheral blood cell counts and radiation-responsive protein expression profile: Flt-3 ligand, interleukin 6, granulocyte-colony stimulating factor, thrombopoietin, erythropoietin, and serum amyloid A. Results show that use of the multiple-parameter severity score system facilitates identification of animals requiring enhanced monitoring after irradiation and that proteomics are a complementary approach to conventional biodosimetry for early assessment of radiation exposure, enhancing accuracy and discrimination index for acute radiation sickness response categories and early prediction of outcome. PMID:27356057

  1. Quantitative Evaluation and Selection of Reference Genes for Quantitative RT-PCR in Mouse Acute Pancreatitis

    PubMed Central

    Yan, Zhaoping; Gao, Jinhang; Lv, Xiuhe; Yang, Wenjuan; Wen, Shilei; Tong, Huan; Tang, Chengwei

    2016-01-01

    The analysis of differences in gene expression is dependent on normalization using reference genes. However, the expression of many of these reference genes, as evaluated by quantitative RT-PCR, is upregulated in acute pancreatitis, so they cannot be used as the standard for gene expression in this condition. For this reason, we sought to identify a stable reference gene, or a suitable combination, for expression analysis in acute pancreatitis. The expression stability of 10 reference genes (ACTB, GAPDH, 18sRNA, TUBB, B2M, HPRT1, UBC, YWHAZ, EF-1α, and RPL-13A) was analyzed using geNorm, NormFinder, and BestKeeper software and evaluated according to variations in the raw Ct values. These reference genes were evaluated using a comprehensive method, which ranked the expression stability of these genes as follows (from most stable to least stable): RPL-13A, YWHAZ > HPRT1 > GAPDH > UBC > EF-1α > 18sRNA > B2M > TUBB > ACTB. RPL-13A was the most suitable reference gene, and the combination of RPL-13A and YWHAZ was the most stable group of reference genes in our experiments. The expression levels of ACTB, TUBB, and B2M were found to be significantly upregulated during acute pancreatitis, whereas the expression level of 18sRNA was downregulated. Thus, we recommend the use of RPL-13A or a combination of RPL-13A and YWHAZ for normalization in qRT-PCR analyses of gene expression in mouse models of acute pancreatitis. PMID:27069927

  2. Annular pancreas intra operatively discovered: a case report

    PubMed Central

    Zeineb, Mzoughi; Sadri, Ben Abid; Nizar, Miloudi; Hassen, Hentati; Nafaa, Arfa; Taher, Khalfallah

    2011-01-01

    Annular pancreas is a rare congenital abnormality. This entity can rarely be symptomatic. Patients can present with gastrointestinal obstruction or acute pancreatitis. We report a case with a rich iconography, of an annular pancreas discovered intraoperatively. A 46-year-old woman was operated with the diagnosis of acute cholecystitis with common bile duct stones. At operation, a strip of pancreatic tissue (2 cm) completely encircled the second duodenum. Open cholecytectomy with choledocotomy and stones extractionwas done. Postoperatively, she developed an acute pancreatitis. The post-operative cholangiography showed the annular duct surrounding the second duodenum. Annular pancreas is rare. Symptoms may occur in newborn children. In adults, annular pancreas discovering is radiological or intra operatively. PMID:24765382

  3. Transcriptional changes of mouse splenocyte organelle components following acute infection with Toxoplasma gondii.

    PubMed

    He, Jun-Jun; Ma, Jun; Li, Fa-Cai; Song, Hui-Qun; Xu, Min-Jun; Zhu, Xing-Quan

    2016-08-01

    Toxoplasmosis is a globally spread zoonosis. The pathogen Toxoplasma gondii can hijack cellular organelles of host for replication. Although a number of important cellular life events are controlled by cell organelles, very little is known of the transcriptional changes of host cellular organelles after infection with T. gondii. Herein, we performed RNA-sequencing (RNA-seq) and bioinformatics analyses to study the global organelle component changes. It was found that many transcripts of the mouse spleen cellular organelle components were altered by acute T. gondii infection with the RH strain (Type I). Most differentially expressed transcripts of mitochondrial components were downregulated, especially those involved in biosynthetic and metabolic processes. Moreover, mitochondria based apoptosis process was downregulated. In terms of cytoskeleton, most differentially expressed transcript of cytoskeleton components were also downregulated, including septin cytoskeleton, cytoskeleton organization, centrosome and myosin. For endolysosomal system, ion transporters were downregulated at mRNA level, whereas the cytolytic components were increased, such as granzymes, Rab27a and perforin1 (Prf1). The main transcripts of Golgi apparatus components involved in sialylation or vesicle-mediated transportation were downregulated, while immune related components were upregulated. For endoplasmic reticulum (ER), posttranslational modification, drug metabolism and material transportation related transcripts were downregulated. In addition, T. gondii antigen cross-presentation by MHC-I complex could be downregulated by the downregulation of CD76 and ubiquitination related transcripts. The present study, for the first time, described the transcriptional changes of the mouse spleen cellular organelles following acute T. gondii infection, which provides a foundation to study the interaction between T. gondii and host cells at the sub-cellular level. PMID:27132051

  4. Normothermic Mouse Functional MRI of Acute Focal Thermostimulation for Probing Nociception

    PubMed Central

    Reimann, Henning Matthias; Hentschel, Jan; Marek, Jaroslav; Huelnhagen, Till; Todiras, Mihail; Kox, Stefanie; Waiczies, Sonia; Hodge, Russ; Bader, Michael; Pohlmann, Andreas; Niendorf, Thoralf

    2016-01-01

    Combining mouse genomics and functional magnetic resonance imaging (fMRI) provides a promising tool to unravel the molecular mechanisms of chronic pain. Probing murine nociception via the blood oxygenation level-dependent (BOLD) effect is still challenging due to methodological constraints. Here we report on the reproducible application of acute noxious heat stimuli to examine the feasibility and limitations of functional brain mapping for central pain processing in mice. Recent technical and procedural advances were applied for enhanced BOLD signal detection and a tight control of physiological parameters. The latter includes the development of a novel mouse cradle designed to maintain whole-body normothermia in anesthetized mice during fMRI in a way that reflects the thermal status of awake, resting mice. Applying mild noxious heat stimuli to wildtype mice resulted in highly significant BOLD patterns in anatomical brain structures forming the pain matrix, which comprise temporal signal intensity changes of up to 6% magnitude. We also observed sub-threshold correlation patterns in large areas of the brain, as well as alterations in mean arterial blood pressure (MABP) in response to the applied stimulus. PMID:26821826

  5. Normothermic Mouse Functional MRI of Acute Focal Thermostimulation for Probing Nociception

    NASA Astrophysics Data System (ADS)

    Reimann, Henning Matthias; Hentschel, Jan; Marek, Jaroslav; Huelnhagen, Till; Todiras, Mihail; Kox, Stefanie; Waiczies, Sonia; Hodge, Russ; Bader, Michael; Pohlmann, Andreas; Niendorf, Thoralf

    2016-01-01

    Combining mouse genomics and functional magnetic resonance imaging (fMRI) provides a promising tool to unravel the molecular mechanisms of chronic pain. Probing murine nociception via the blood oxygenation level-dependent (BOLD) effect is still challenging due to methodological constraints. Here we report on the reproducible application of acute noxious heat stimuli to examine the feasibility and limitations of functional brain mapping for central pain processing in mice. Recent technical and procedural advances were applied for enhanced BOLD signal detection and a tight control of physiological parameters. The latter includes the development of a novel mouse cradle designed to maintain whole-body normothermia in anesthetized mice during fMRI in a way that reflects the thermal status of awake, resting mice. Applying mild noxious heat stimuli to wildtype mice resulted in highly significant BOLD patterns in anatomical brain structures forming the pain matrix, which comprise temporal signal intensity changes of up to 6% magnitude. We also observed sub-threshold correlation patterns in large areas of the brain, as well as alterations in mean arterial blood pressure (MABP) in response to the applied stimulus.

  6. Assessment of pancreas cells

    NASA Technical Reports Server (NTRS)

    Vanoss, C. J.

    1978-01-01

    Pancreatic islets were obtained from guinea pig pancreas by the collagenase method and kept alive in tissue culture prior to further studies. Pancreas cell morphology was studied by standard histochemical techniques using light microscopy. Preparative vertical electrophoresis-levitation of dispersed fetal guinea pig pancreas cells was conducted in phosphate buffer containing a heavy water (D20) gradient which does not cause clumping of cells or alter the osmolarity of the buffers. The faster migrating fractions tended to be enriched in beta-cell content. Alpha and delta cells were found to some degree in most fractions. A histogram showing the cell count distribution is included.

  7. Organ Facts: Kidney / Pancreas

    MedlinePlus

    ... the kidneys is to remove waste from the body through the production of urine. They also help to regulate blood pressure, blood volume and the chemical (electrolyte) composition of the blood. The pancreas is a five ...

  8. Cystic Lymphangioma of Pancreas.

    PubMed

    Bihari, Chhagan; Rastogi, Archana; Rajesh, S; Arora, Ankur; Arora, Asit; Kumar, Nikhil

    2016-03-01

    Lymphangiomas are benign hamartomatous malformations which can arise either from congenitally sequestered lymphatic channels or due to acquired obstruction caused by fibrosis of lymph channels. They are common in the pediatric age group in the soft tissue of neck and the axilla. Abdominal lymphangiomas are rare; even rarer is the primary involvement of pancreas. It occurs more frequently in females and is often located in the distal pancreas. The authors report the case of cystic lymphangioma of pancreas in a 26-year old female presenting with recurrent episodes of upper abdominal pain that was treated with laparoscopic cyst excision. Although exceptionally rare, lymphangioma of the pancreas should be considered in the differential diagnosis of pancreatic cystic lesions, especially in young women. PMID:27065694

  9. Deconstructing Pancreas Developmental Biology

    PubMed Central

    Benitez, Cecil M.; Goodyer, William R.

    2012-01-01

    The relentless nature and increasing prevalence of human pancreatic diseases, in particular, diabetes mellitus and adenocarcinoma, has motivated further understanding of pancreas organogenesis. The pancreas is a multifunctional organ whose epithelial cells govern a diversity of physiologically vital endocrine and exocrine functions. The mechanisms governing the birth, differentiation, morphogenesis, growth, maturation, and maintenance of the endocrine and exocrine components in the pancreas have been discovered recently with increasing tempo. This includes recent studies unveiling mechanisms permitting unexpected flexibility in the developmental potential of immature and mature pancreatic cell subsets, including the ability to interconvert fates. In this article, we describe how classical cell biology, genetic analysis, lineage tracing, and embryological investigations are being complemented by powerful modern methods including epigenetic analysis, time-lapse imaging, and flow cytometry-based cell purification to dissect fundamental processes of pancreas development. PMID:22587935

  10. Blocking macrophage migration inhibitory factor activity alleviates mouse acute otitis media in vivo.

    PubMed

    Zhang, Jin; Xu, Min; Zheng, Qingyin; Zhang, Yan; Ma, Weijun; Zhang, Zhaoqiang

    2014-11-01

    This study was to investigate the role of macrophage migration inhibitory factor (MIF) in mouse acute otitis media (AOM), we hypothesize that blocking MIF activity will relieve mouse AOM. A mouse AOM model was constructed by injecting lipopolysaccharide (LPS) into the middle ear of C57BL/6 mice through the tympanic membrane (TM). MIF levels were measured by real-time PCR (RT-PCR) and ELISA after LPS application. Normal or AOM mice were given PBS or ISO-1 (MIF antagonist) every day for 10 days and the hearing levels were determined by measuring auditory brainstem response (ABR) threshold. After the ABR test finished, H&E staining was conducted and the inflammation was also measured by detecting interleukin (IL)-1β, tumor necrosis factor (TNF)-α and vascular endothelial growth factor (VEGF) levels with RT-PCR and ELISA. TLR-4 expression was determined by western blotting and NF-κB activation was determined by electrophoretic mobility shift assays. Compared with the normal control, MIF levels in the middle ear of LPS-induced AOM mice were significant increased. The ABR results showed that mean ABR thresholds in ISO-1 treated AOM mice were significantly reduced compared with PBS treated AOM mice since day 7, indicating that ISO-1 treatment potentially improved the hearing levels of AOM mice. H&E staining showed that ISO-1 treatment could reduce the mucosal thickness of AOM mice. In ISO-1 treated mice, TLR-4 expression and levels of IL-1β, TNF-α and VEGF were significantly lower compared with PBS treated AOM mice. ISO-1 treatment also significantly inhibited NF-κB activation in AOM mice compared with PBS treated AOM mice. These results suggested that blocking the activity of MIF by ISO-1 could reduce the inflammation in AOM mice in which process TLR-4 and NF-κB were involved. The reduction in MIF activity is conducive to alleviate mouse AOM, which may serve as a potential therapeutic target for the treatment of AOM. PMID:25108100

  11. Pancreas and cyst segmentation

    NASA Astrophysics Data System (ADS)

    Dmitriev, Konstantin; Gutenko, Ievgeniia; Nadeem, Saad; Kaufman, Arie

    2016-03-01

    Accurate segmentation of abdominal organs from medical images is an essential part of surgical planning and computer-aided disease diagnosis. Many existing algorithms are specialized for the segmentation of healthy organs. Cystic pancreas segmentation is especially challenging due to its low contrast boundaries, variability in shape, location and the stage of the pancreatic cancer. We present a semi-automatic segmentation algorithm for pancreata with cysts. In contrast to existing automatic segmentation approaches for healthy pancreas segmentation which are amenable to atlas/statistical shape approaches, a pancreas with cysts can have even higher variability with respect to the shape of the pancreas due to the size and shape of the cyst(s). Hence, fine results are better attained with semi-automatic steerable approaches. We use a novel combination of random walker and region growing approaches to delineate the boundaries of the pancreas and cysts with respective best Dice coefficients of 85.1% and 86.7%, and respective best volumetric overlap errors of 26.0% and 23.5%. Results show that the proposed algorithm for pancreas and pancreatic cyst segmentation is accurate and stable.

  12. Molecular determinants of severe acute respiratory syndrome coronavirus pathogenesis and virulence in young and aged mouse models of human disease.

    PubMed

    Frieman, Matthew; Yount, Boyd; Agnihothram, Sudhakar; Page, Carly; Donaldson, Eric; Roberts, Anjeanette; Vogel, Leatrice; Woodruff, Becky; Scorpio, Diana; Subbarao, Kanta; Baric, Ralph S

    2012-01-01

    SARS coronavirus (SARS-CoV) causes severe acute respiratory tract disease characterized by diffuse alveolar damage and hyaline membrane formation. This pathology often progresses to acute respiratory distress (such as acute respiratory distress syndrome [ARDS]) and atypical pneumonia in humans, with characteristic age-related mortality rates approaching 50% or more in immunosenescent populations. The molecular basis for the extreme virulence of SARS-CoV remains elusive. Since young and aged (1-year-old) mice do not develop severe clinical disease following infection with wild-type SARS-CoV, a mouse-adapted strain of SARS-CoV (called MA15) was developed and was shown to cause lethal infection in these animals. To understand the genetic contributions to the increased pathogenesis of MA15 in rodents, we used reverse genetics and evaluated the virulence of panels of derivative viruses encoding various combinations of mouse-adapted mutations. We found that mutations in the viral spike (S) glycoprotein and, to a much less rigorous extent, in the nsp9 nonstructural protein, were primarily associated with the acquisition of virulence in young animals. The mutations in S likely increase recognition of the mouse angiotensin-converting enzyme 2 (ACE2) receptor not only in MA15 but also in two additional, independently isolated mouse-adapted SARS-CoVs. In contrast to the findings for young animals, mutations to revert to the wild-type sequence in nsp9 and the S glycoprotein were not sufficient to significantly attenuate the virus compared to other combinations of mouse-adapted mutations in 12-month-old mice. This panel of SARS-CoVs provides novel reagents that we have used to further our understanding of differential, age-related pathogenic mechanisms in mouse models of human disease. PMID:22072787

  13. Molecular Determinants of Severe Acute Respiratory Syndrome Coronavirus Pathogenesis and Virulence in Young and Aged Mouse Models of Human Disease

    PubMed Central

    Yount, Boyd; Agnihothram, Sudhakar; Page, Carly; Donaldson, Eric; Roberts, Anjeanette; Vogel, Leatrice; Woodruff, Becky; Scorpio, Diana; Subbarao, Kanta; Baric, Ralph S.

    2012-01-01

    SARS coronavirus (SARS-CoV) causes severe acute respiratory tract disease characterized by diffuse alveolar damage and hyaline membrane formation. This pathology often progresses to acute respiratory distress (such as acute respiratory distress syndrome [ARDS]) and atypical pneumonia in humans, with characteristic age-related mortality rates approaching 50% or more in immunosenescent populations. The molecular basis for the extreme virulence of SARS-CoV remains elusive. Since young and aged (1-year-old) mice do not develop severe clinical disease following infection with wild-type SARS-CoV, a mouse-adapted strain of SARS-CoV (called MA15) was developed and was shown to cause lethal infection in these animals. To understand the genetic contributions to the increased pathogenesis of MA15 in rodents, we used reverse genetics and evaluated the virulence of panels of derivative viruses encoding various combinations of mouse-adapted mutations. We found that mutations in the viral spike (S) glycoprotein and, to a much less rigorous extent, in the nsp9 nonstructural protein, were primarily associated with the acquisition of virulence in young animals. The mutations in S likely increase recognition of the mouse angiotensin-converting enzyme 2 (ACE2) receptor not only in MA15 but also in two additional, independently isolated mouse-adapted SARS-CoVs. In contrast to the findings for young animals, mutations to revert to the wild-type sequence in nsp9 and the S glycoprotein were not sufficient to significantly attenuate the virus compared to other combinations of mouse-adapted mutations in 12-month-old mice. This panel of SARS-CoVs provides novel reagents that we have used to further our understanding of differential, age-related pathogenic mechanisms in mouse models of human disease. PMID:22072787

  14. Time-lapse imaging of neuroblast migration in acute slices of the adult mouse forebrain.

    PubMed

    Khlghatyan, Jivan; Saghatelyan, Armen

    2012-01-01

    the stationary and migratory phases is crucial for the unambiguous interpretation of results. We also performed multiple z-step acquisitions to monitor neuroblasts migration in 3D. Wide-field fluorescent imaging has been used extensively to visualize neuronal migration. Here, we describe detailed protocol for labeling neuroblasts, performing real-time video-imaging of neuroblast migration in acute slices of the adult mouse forebrain, and analyzing cell migration. While the described protocol exemplified the migration of neuroblasts in the adult RMS, it can also be used to follow cell migration in embryonic and early postnatal brains. PMID:23007608

  15. In vitro toxicity assay of cisplatin on mouse acute lymphoblastic leukaemia and spermatogonial stem cells.

    PubMed

    Shabani, R; Ashtari, K; Behnam, B; Izadyar, F; Asgari, H; Asghari Jafarabadi, M; Ashjari, M; Asadi, E; Koruji, M

    2016-06-01

    Testicular cancer is the most common cancer affecting men in reproductive age, and cisplatin is one of the major helpful chemotherapeutic agents for treatment of this cancer. In addition, exposure of testes cancer cells to cisplatin could potentially eliminate tumour cells from germ cells in patients. The aim of this study was to evaluate the effect of cisplatin on viability of mouse acute lymphoblastic leukaemia cell line (EL-4) and neonatal mouse spermatogonial cells in vitro. In this study, the isolated spermatogonial stem cells (SSC) and EL-4 were divided into six groups including control (received medium), sham (received DMSO in medium) and experimental groups which received different doses of cisplatin (0.5, 5, 10 and 15 μg ml(-1) ). Cells viability was evaluated with MTT assay. The identity of the cultured cells was confirmed by the expression of specific markers. Our finding showed that viability of both SSC and EL-4 cells was reduced with the dose of 15 μg/ml when compared to the control group (P ≤ 0.05). Also, the differences between the IC50 in doses 10 and 15 μg/ml at different time were significant (P ≤ 0.05). The number of TUNEL-positive cells was increased, and the BAX and caspase-3 expressions were upregulated in EL4 cells for group that received an effective dose of cisplatin). In conclusion, despite the dramatic effects of cisplatin on both cells, spermatogonial stem cells could form colony in culture. PMID:26428408

  16. Portal Annular Pancreas

    PubMed Central

    Harnoss, Jonathan M.; Harnoss, Julian C.; Diener, Markus K.; Contin, Pietro; Ulrich, Alexis B.; Büchler, Markus W.; Schmitz-Winnenthal, Friedrich H.

    2014-01-01

    Abstract Portal annular pancreas (PAP) is an asymptomatic congenital pancreas anomaly, in which portal and/or mesenteric veins are encased by pancreas tissue. The aim of the study was to determine the role of PAP in pancreatic surgery as well as its management and potential complication, specifically, postoperative pancreatic fistula (POPF). On the basis of a case report, the MEDLINE and ISI Web of Science databases were systematically reviewed up to September 2012. All articles describing a case of PAP were considered. In summary, 21 studies with 59 cases were included. The overall prevalence of PAP was 2.4% and the patients' mean (SD) age was 55.9 (16.2) years. The POPF rate in patients with PAP (12 pancreaticoduodenectomies and 3 distal pancreatectomies) was 46.7% (in accordance with the definition of the International Study Group of Pancreatic Surgery). Portal annular pancreas is a quite unattended pancreatic variant with high prevalence and therefore still remains a clinical challenge to avoid postoperative complications. To decrease the risk for POPF, attentive preoperative diagnostics should also focus on PAP. In pancreaticoduodenectomy, a shift of the resection plane to the pancreas tail should be considered; in extensive pancreatectomy, coverage of the pancreatic remnant by the falciform ligament could be a treatment option. PMID:25207658

  17. Cold stress aggravates inflammatory responses in an LPS-induced mouse model of acute lung injury.

    PubMed

    Joo, Su-Yeon; Park, Mi-Ju; Kim, Kyun-Ha; Choi, Hee-Jung; Chung, Tae-Wook; Kim, Yong Jin; Kim, Joung Hee; Kim, Keuk-Jun; Joo, Myungsoo; Ha, Ki-Tae

    2016-08-01

    Although the relationship between environmental cold temperature and susceptibility to respiratory infection is generally accepted, the effect of ambient cold temperature on host reactivity in lung inflammation has not been fully studied. To examine the function of ambient cold temperature on lung inflammation, mice were exposed to 4 °C for 8 h each day for 14 days. In the lungs of mice exposed to cold stress, inflammatory cells in bronchoalveolar lavage (BAL) fluid and lung tissues were slightly increased by about twofold. However, the structures of pulmonary epithelial cells were kept within normal limits. Next, we examined the effect of cold stress on the inflammatory responses in a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. The infiltration of neutrophils and inflammation of lung tissue determined by histology were significantly increased by exposure to ambient cold temperature. In addition, the production of pro-inflammatory cytokines including interleukin (IL)-12, IL-17, and monokine induced by gamma interferon (MIG) was elevated by exposure to cold stress. Therefore, we suggest that cold stress is a factor that exacerbates lung inflammation including ALI. To our knowledge, this is the first report on the relationship between cold stress and severity of lung inflammation. PMID:26617279

  18. Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy

    PubMed Central

    Roy, Achira; Skibo, Jonathan; Kalume, Franck; Ni, Jing; Rankin, Sherri; Lu, Yiling; Dobyns, William B; Mills, Gordon B; Zhao, Jean J; Baker, Suzanne J; Millen, Kathleen J

    2015-01-01

    Mutations in the catalytic subunit of phosphoinositide 3-kinase (PIK3CA) and other PI3K-AKT pathway components have been associated with cancer and a wide spectrum of brain and body overgrowth. In the brain, the phenotypic spectrum of PIK3CA-related segmental overgrowth includes bilateral dysplastic megalencephaly, hemimegalencephaly and focal cortical dysplasia, the most common cause of intractable pediatric epilepsy. We generated mouse models expressing the most common activating Pik3ca mutations (H1047R and E545K) in developing neural progenitors. These accurately recapitulate all the key human pathological features including brain enlargement, cortical malformation, hydrocephalus and epilepsy, with phenotypic severity dependent on the mutant allele and its time of activation. Underlying mechanisms include increased proliferation, cell size and altered white matter. Notably, we demonstrate that acute 1 hr-suppression of PI3K signaling despite the ongoing presence of dysplasia has dramatic anti-epileptic benefit. Thus PI3K inhibitors offer a promising new avenue for effective anti-epileptic therapy for intractable pediatric epilepsy patients. DOI: http://dx.doi.org/10.7554/eLife.12703.001 PMID:26633882

  19. Treatment with 5-Azacytidine Accelerates Acute Promyelocytic Leukemia Leukemogenesis in a Transgenic Mouse Model

    PubMed Central

    Scaglioni, Pier Paolo; Cai, Lu Fan; Majid, Samia M.; Yung, Thomas M.; Socci, Nicholas D.; Kogan, Scott C.; Kopelovich, Levy; Pandolfi, Pier Paolo

    2011-01-01

    A key oncogenic force in acute promyelocytic leukemia (APL) is the ability of the promyelocytic leukemia–retinoic acid receptor α (PML-RARA) oncoprotein to recruit transcriptional repressors and DNA methyltransferases at retinoic acid–responsive elements. Pharmacological doses of retinoic acid relieve transcriptional repression inducing terminal differentiation/apoptosis of the leukemic blasts. APL blasts often harbor additional recurrent chromosomal abnormalities, and significantly, APL prevalence is increased in Latino populations. These observations suggest that multiple genetic and environmental/dietary factors are likely implicated in APL. We tested whether dietary or targeted chemopreventive strategies relieving PML-RARA transcriptional repression would be effective in a transgenic mouse model. Surprisingly, we found that 1) treatment with a demethylating agent, 5-azacytidine, results in a striking acceleration of APL; 2) a high fat, low folate/choline–containing diet resulted in a substantial but nonsignificant APL acceleration; and 3) all-trans retinoic acid (ATRA) is ineffective in preventing leukemia and results in ATRA-resistant APL. Our findings have important clinical implications because ATRA is a drug of choice for APL treatment and indicate that global demethylation, whether through dietary manipulations or through the use of a pharmacologic agent such as 5-azacytidine, may have unintended and detrimental consequences in chemopreventive regimens. PMID:21779489

  20. Mitochondrial energetic defects in muscle and brain of a Hmbs-/- mouse model of acute intermittent porphyria.

    PubMed

    Homedan, Chadi; Schmitt, Caroline; Laafi, Jihane; Gueguen, Naïg; Desquiret-Dumas, Valérie; Lenglet, Hugo; Karim, Zoubida; Gouya, Laurent; Deybach, Jean-Charles; Simard, Gilles; Puy, Hervé; Malthièry, Yves; Reynier, Pascal

    2015-09-01

    Acute intermittent porphyria (AIP), an autosomal dominant metabolic disease (MIM #176000), is due to a deficiency of hydroxymethylbilane synthase (HMBS), which catalyzes the third step of the heme biosynthetic pathway. The clinical expression of the disease is mainly neurological, involving the autonomous, central and peripheral nervous systems. We explored mitochondrial oxidative phosphorylation (OXPHOS) in the brain and skeletal muscle of the Hmbs(-/-) mouse model first in the basal state (BS), and then after induction of the disease with phenobarbital and treatment with heme arginate (HA). The modification of the respiratory parameters, determined in mice in the BS, reflected a spontaneous metabolic energetic adaptation to HMBS deficiency. Phenobarbital induced a sharp alteration of the oxidative metabolism with a significant decrease of ATP production in skeletal muscle that was restored by treatment with HA. This OXPHOS defect was due to deficiencies in complexes I and II in the skeletal muscle whereas all four respiratory chain complexes were affected in the brain. To date, the pathogenesis of AIP has been mainly attributed to the neurotoxicity of aminolevulinic acid and heme deficiency. Our results show that mitochondrial energetic failure also plays an important role in the expression of the disease. PMID:26071363

  1. Cold stress aggravates inflammatory responses in an LPS-induced mouse model of acute lung injury

    NASA Astrophysics Data System (ADS)

    Joo, Su-Yeon; Park, Mi-Ju; Kim, Kyun-Ha; Choi, Hee-Jung; Chung, Tae-Wook; Kim, Yong Jin; Kim, Joung Hee; Kim, Keuk-Jun; Joo, Myungsoo; Ha, Ki-Tae

    2016-08-01

    Although the relationship between environmental cold temperature and susceptibility to respiratory infection is generally accepted, the effect of ambient cold temperature on host reactivity in lung inflammation has not been fully studied. To examine the function of ambient cold temperature on lung inflammation, mice were exposed to 4 °C for 8 h each day for 14 days. In the lungs of mice exposed to cold stress, inflammatory cells in bronchoalveolar lavage (BAL) fluid and lung tissues were slightly increased by about twofold. However, the structures of pulmonary epithelial cells were kept within normal limits. Next, we examined the effect of cold stress on the inflammatory responses in a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. The infiltration of neutrophils and inflammation of lung tissue determined by histology were significantly increased by exposure to ambient cold temperature. In addition, the production of pro-inflammatory cytokines including interleukin (IL)-12, IL-17, and monokine induced by gamma interferon (MIG) was elevated by exposure to cold stress. Therefore, we suggest that cold stress is a factor that exacerbates lung inflammation including ALI. To our knowledge, this is the first report on the relationship between cold stress and severity of lung inflammation.

  2. Cold stress aggravates inflammatory responses in an LPS-induced mouse model of acute lung injury

    NASA Astrophysics Data System (ADS)

    Joo, Su-Yeon; Park, Mi-Ju; Kim, Kyun-Ha; Choi, Hee-Jung; Chung, Tae-Wook; Kim, Yong Jin; Kim, Joung Hee; Kim, Keuk-Jun; Joo, Myungsoo; Ha, Ki-Tae

    2015-11-01

    Although the relationship between environmental cold temperature and susceptibility to respiratory infection is generally accepted, the effect of ambient cold temperature on host reactivity in lung inflammation has not been fully studied. To examine the function of ambient cold temperature on lung inflammation, mice were exposed to 4 °C for 8 h each day for 14 days. In the lungs of mice exposed to cold stress, inflammatory cells in bronchoalveolar lavage (BAL) fluid and lung tissues were slightly increased by about twofold. However, the structures of pulmonary epithelial cells were kept within normal limits. Next, we examined the effect of cold stress on the inflammatory responses in a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. The infiltration of neutrophils and inflammation of lung tissue determined by histology were significantly increased by exposure to ambient cold temperature. In addition, the production of pro-inflammatory cytokines including interleukin (IL)-12, IL-17, and monokine induced by gamma interferon (MIG) was elevated by exposure to cold stress. Therefore, we suggest that cold stress is a factor that exacerbates lung inflammation including ALI. To our knowledge, this is the first report on the relationship between cold stress and severity of lung inflammation.

  3. Acute inflammatory response in the mouse: exacerbation by immunoneutralization of lipocortin 1.

    PubMed Central

    Perretti, M.; Ahluwalia, A.; Harris, J. G.; Harris, H. J.; Wheller, S. K.; Flower, R. J.

    1996-01-01

    1. An immuno-neutralization strategy was employed to investigate the role of endogenous lipocortin 1 (LC1) in acute inflammation in the mouse. 2. Mice were treated subcutaneously with phosphate-buffered solution (PBS), non-immune sheep serum (NSS) or with one of two sheep antisera raised against LC1 (LCS3), or its N-terminal peptide (LCPS1), three times over a period of seven days. Twenty four hours after the last injection several parameters of acute inflammation were measured including zymosan-induced inflammation in 6-day-old air-pouches, zymosan-activated serum (ZAS)-induced oedema in the skin, platelet-activating factor (PAF)-induced neutrophilia and interleukin-1 beta (IL-1 beta)-induced corticosterone (CCS) release. 3. At the 4 h time-point of the zymosan inflamed air-pouch model, treatment with LCS3 did not modify the number of polymorphonuclear leucocytes (PMN) recruited: 7.84 +/- 1.01 and 7.00 +/- 0.77 x 10(6) PMN per mouse for NSS- and LCS3 group, n = 7. However, several other parameters of cell activation including myeloperoxidase (MPO) and elastase activities were increased (2.2 fold, P < 0.05, and 6.5 fold, P < 0.05, respectively) in the lavage fluids of these mice. Similarly, a significant increase in the amount of immunoreactive prostaglandin E2 (PGE2; 1.81 fold, P < 0.05) and IL-1 alpha (2.75 fold, P < 0.05), but not tumour necrosis factor-alpha (TNF-alpha), was also observed in LCS3-treated mice. 4. The recruitment of PMN into the zymosan inflamed air-pouches by 24 h had declined substantially (4.13 +/- 0.61 x 10(6) PMN per mouse, n = 12) in the NSS-treated mice, whereas high values were still measured in those treated with LCS3 (9.35 +/- 1.20 x 10(6) PMN per mouse, n = 12, P < 0.05). A similar effect was also found following sub-chronic treatment of mice with LCPS1: 6.48 +/- 0.10 x 10(6) PMN per mouse, vs. 2.77 +/- 1.20 and 2.64 +/- 0.49 x 10(6) PMN per mouse for PBS- and NSS-treated groups (n = 7, P < 0.05). Most markers of inflammation were

  4. Hippo Signaling Regulates Pancreas Development through Inactivation of Yap

    PubMed Central

    Day, Caroline E.; Boerner, Brian P.; Johnson, Randy L.; Sarvetnick, Nora E.

    2012-01-01

    The mammalian pancreas is required for normal metabolism, with defects in this vital organ commonly observed in cancer and diabetes. Development must therefore be tightly controlled in order to produce a pancreas of correct size, cell type composition, and physiologic function. Through negative regulation of Yap-dependent proliferation, the Hippo kinase cascade is a critical regulator of organ growth. To investigate the role of Hippo signaling in pancreas biology, we deleted Hippo pathway components in the developing mouse pancreas. Unexpectedly, the pancreas from Hippo-deficient offspring was reduced in size, with defects evident throughout the organ. Increases in the dephosphorylated nuclear form of Yap are apparent throughout the exocrine compartment and correlate with increases in levels of cell proliferation. However, the mutant exocrine tissue displays extensive disorganization leading to pancreatitis-like autodigestion. Interestingly, our results suggest that Hippo signaling does not directly regulate the pancreas endocrine compartment as Yap expression is lost following endocrine specification through a Hippo-independent mechanism. Altogether, our results demonstrate that Hippo signaling plays a crucial role in pancreas development and provide novel routes to a better understanding of pathological conditions that affect this organ. PMID:23071096

  5. Prox1-Heterozygosis Sensitizes the Pancreas to Oncogenic Kras-Induced Neoplastic Transformation12

    PubMed Central

    Drosos, Yiannis; Neale, Geoffrey; Ye, Jianming; Paul, Leena; Kuliyev, Emin; Maitra, Anirban; Means, Anna L; Washington, M Kay; Rehg, Jerold; Finkelstein, David B; Sosa-Pineda, Beatriz

    2016-01-01

    The current paradigm of pancreatic neoplastic transformation proposes an initial step whereby acinar cells convert into acinar-to-ductal metaplasias, followed by progression of these lesions into neoplasias under sustained oncogenic activity and inflammation. Understanding the molecular mechanisms driving these processes is crucial to the early diagnostic and prevention of pancreatic cancer. Emerging evidence indicates that transcription factors that control exocrine pancreatic development could have either, protective or facilitating roles in the formation of preneoplasias and neoplasias in the pancreas. We previously identified that the homeodomain transcription factor Prox1 is a novel regulator of mouse exocrine pancreas development. Here we investigated whether Prox1 function participates in early neoplastic transformation using in vivo, in vitro and in silico approaches. We found that Prox1 expression is transiently re-activated in acinar cells undergoing dedifferentiation and acinar-to-ductal metaplastic conversion. In contrast, Prox1 expression is largely absent in neoplasias and tumors in the pancreas of mice and humans. We also uncovered that Prox1-heterozygosis markedly increases the formation of acinar-to-ductal-metaplasias and early neoplasias, and enhances features associated with inflammation, in mouse pancreatic tissues expressing oncogenic Kras. Furthermore, we discovered that Prox1-heterozygosis increases tissue damage and delays recovery from inflammation in pancreata of mice injected with caerulein. These results are the first demonstration that Prox1 activity protects pancreatic cells from acute tissue damage and early neoplastic transformation. Additional data in our study indicate that this novel role of Prox1 involves suppression of pathways associated with inflammatory responses and cell invasiveness. PMID:26992918

  6. National Pancreas Foundation

    MedlinePlus

    ... NPF raises and directs funds to support exemplary research projects in the field of pancreas disease Fellows Symposium A three-day symposium pairing together world class physicians and scientists with medical fellows. ... Research Grant Application Research History Grant Review Committee ...

  7. Acute Inflammation Loci Are Involved in Wound Healing in the Mouse Ear Punch Model

    PubMed Central

    Canhamero, Tatiane; Garcia, Ludmila Valino; De Franco, Marcelo

    2014-01-01

    Significance: Molecular biology techniques are being used to aid in determining the mechanisms responsible for tissue repair without scar formation. Wound healing is genetically determined, but there have been few studies that examine the genes responsible for tissue regeneration in mammals. Research using genetic mapping is extremely important for understanding the molecular mechanisms involved in the different phases of tissue regeneration. This process is complex, but an early inflammatory phase appears to influence lesion closure, and the present study demonstrates that acute inflammation loci influence tissue regeneration in mice in a positive manner. Recent Advances: Mapping studies of quantitative trait loci (QTL) have been undertaken in recent years to examine candidate genes that participate in the regeneration phenotype. Our laboratory has identified inflammation modifier QTL for wound healing. Mouse lines selected for the maximum (AIRmax) or minimum (AIRmin) acute inflammatory reactivity (AIR) have been used to study not only the tissue repair but also the impact of the genetic control of inflammation on susceptibility to autoimmune, neoplasic, and infectious diseases. Murphy Roths Large and AIRmax mice are exclusive in their complete epimorphic regeneration, although middle-aged inbred mice may also be capable of healing. Critical Issues: Inflammatory reactions have traditionally been described in the literature as negative factors in the process of skin injury closure. Inflammation is exacerbated due to the early release of mediators or the intense release of factors that cause cell proliferation after injury. The initial release of these factors as well as the clean-up of the lesion microenvironment are both crucial for following events. In addition, the activation and repression of some genes related to the regeneration phenotype may modulate lesion closure, demonstrating the significance of genetic studies to better understand the mechanisms

  8. Early aberrant DNA methylation events in a mouse model of acute myeloid leukemia

    PubMed Central

    2014-01-01

    Background Aberrant DNA methylation is frequently found in human malignancies including acute myeloid leukemia (AML). While most studies focus on later disease stages, the onset of aberrant DNA methylation events and their dynamics during leukemic progression are largely unknown. Methods We screened genome-wide for aberrant CpG island methylation in three disease stages of a murine AML model that is driven by hypomorphic expression of the hematopoietic transcription factor PU.1. DNA methylation levels of selected genes were correlated with methylation levels of CD34+ cells and lineage negative, CD127-, c-Kit+, Sca-1+ cells; common myeloid progenitors; granulocyte-macrophage progenitors; and megakaryocyte-erythroid progenitors. Results We identified 1,184 hypermethylated array probes covering 762 associated genes in the preleukemic stage. During disease progression, the number of hypermethylated genes increased to 5,465 in the late leukemic disease stage. Using publicly available data, we found a significant enrichment of PU.1 binding sites in the preleukemic hypermethylated genes, suggesting that shortage of PU.1 makes PU.1 binding sites in the DNA accessible for aberrant methylation. Many known AML associated genes such as RUNX1 and HIC1 were found among the preleukemic hypermethylated genes. Nine novel hypermethylated genes, FZD5, FZD8, PRDM16, ROBO3, CXCL14, BCOR, ITPKA, HES6 and TAL1, the latter four being potential PU.1 targets, were confirmed to be hypermethylated in human normal karyotype AML patients, underscoring the relevance of the mouse model for human AML. Conclusions Our study identified early aberrantly methylated genes as potential contributors to onset and progression of AML. PMID:24944583

  9. Mitochondrial Alterations and Oxidative Stress in an Acute Transient Mouse Model of Muscle Degeneration

    PubMed Central

    Ramadasan-Nair, Renjini; Gayathri, Narayanappa; Mishra, Sudha; Sunitha, Balaraju; Mythri, Rajeswara Babu; Nalini, Atchayaram; Subbannayya, Yashwanth; Harsha, Hindalahalli Chandregowda; Kolthur-Seetharam, Ullas; Bharath, Muchukunte Mukunda Srinivas

    2014-01-01

    Muscular dystrophies (MDs) and inflammatory myopathies (IMs) are debilitating skeletal muscle disorders characterized by common pathological events including myodegeneration and inflammation. However, an experimental model representing both muscle pathologies and displaying most of the distinctive markers has not been characterized. We investigated the cardiotoxin (CTX)-mediated transient acute mouse model of muscle degeneration and compared the cardinal features with human MDs and IMs. The CTX model displayed degeneration, apoptosis, inflammation, loss of sarcolemmal complexes, sarcolemmal disruption, and ultrastructural changes characteristic of human MDs and IMs. Cell death caused by CTX involved calcium influx and mitochondrial damage both in murine C2C12 muscle cells and in mice. Mitochondrial proteomic analysis at the initial phase of degeneration in the model detected lowered expression of 80 mitochondrial proteins including subunits of respiratory complexes, ATP machinery, fatty acid metabolism, and Krebs cycle, which further decreased in expression during the peak degenerative phase. The mass spectrometry (MS) data were supported by enzyme assays, Western blot, and histochemistry. The CTX model also displayed markers of oxidative stress and a lowered glutathione reduced/oxidized ratio (GSH/GSSG) similar to MDs, human myopathies, and neurogenic atrophies. MS analysis identified 6 unique oxidized proteins from Duchenne muscular dystrophy samples (n = 6) (versus controls; n = 6), including two mitochondrial proteins. Interestingly, these mitochondrial proteins were down-regulated in the CTX model thereby linking oxidative stress and mitochondrial dysfunction. We conclude that mitochondrial alterations and oxidative damage significantly contribute to CTX-mediated muscle pathology with implications for human muscle diseases. PMID:24220031

  10. Acute fasting decreases the expression of GLUT1 and glucose utilisation involved in mouse oocyte maturation and cumulus cell expansion.

    PubMed

    Han, Yingying; Yan, Jun; Zhou, Jinlian; Teng, Zhen; Bian, Fenghua; Guo, Meng; Mao, Guankun; Li, Junxia; Wang, Jianwei; Zhang, Meijia; Xia, Guoliang

    2012-01-01

    Acute fasting impairs meiotic resumption and glucose consumption in mouse cumulus cell and oocyte complexes (COCs). This study examines the effects of acute fasting on the regulation of glucose transporter 1 (GLUT1) expression and glucose consumption in oocyte maturation. Our results indicate that the restriction of glucose utilisation by 2-deoxyglucose (2-DG) mimicked the inhibitory effects of acute fasting on oocyte meiotic resumption and cumulus cell expansion, effects that were rescued by high glucose concentrations in the culture medium. GLUT1 protein levels were higher in cumulus cells compared with oocytes, and GLUT1 expression in COCs increased with FSH treatment in vitro. However, under acute fasting conditions, GLUT1 expression in COCs decreased and the response to FSH disappeared. Exposure to high glucose conditions (27.5mM and 55mM), significantly increased both glucose consumption and GLUT1 levels in COCs. Inhibition of GLUT1 function using an anti-GLUT1 antibody significantly inhibited FSH-induced oocyte meiotic resumption. Taken together, these results suggest that acute fasting decreases GLUT1 expression and glucose utilisation, inhibiting the processes of oocyte maturation and cumulus cell expansion. PMID:22697123

  11. Neutrophils and their Fcγ receptors are essential in a mouse model of transfusion-related acute lung injury

    PubMed Central

    Looney, Mark R.; Su, Xiao; Van Ziffle, Jessica A.; Lowell, Clifford A.; Matthay, Michael A.

    2006-01-01

    Transfusion-related acute lung injury (TRALI) is the most common cause of transfusion-related mortality. To explore the pathogenesis of TRALI, we developed an in vivo mouse model based on the passive transfusion of an MHC class I (MHC I) mAb (H2Kd) to mice with the cognate antigen. Transfusion of the MHC I mAb to BALB/c mice produced acute lung injury with increased excess lung water, increased lung vascular and lung epithelial permeability to protein, and decreased alveolar fluid clearance. There was 50% mortality at a 2-hour time point after Ab administration. Pulmonary histology and immunohistochemistry revealed prominent neutrophil sequestration in the lung microvasculature that occurred concomitantly with acute peripheral blood neutropenia, all within 2 hours of administration of the mAb. Depletion of neutrophils by injection of anti-granulocyte mAb Gr-1 protected mice from lung injury following MHC I mAb challenge. FcRγ–/– mice were resistant to MHC I mAb–induced lung injury, while adoptive transfer of wild-type neutrophils into the FcRγ–/– animals restored lung injury following MHC I mAb challenge. In conclusion, in a clinically relevant in vivo mouse model of TRALI using an MHC I mAb, the mechanism of lung injury was dependent on neutrophils and their Fcγ receptors. PMID:16710475

  12. Retinoids in the pancreas

    PubMed Central

    Brun, Pierre-Jacques; Wongsiriroj, Nuttaporn

    2016-01-01

    Retinoids (vitamin A and its natural and synthetic analogs) are required by most tissues for maintaining the normal health of the tissue. This is certainly true for the pancreas. The recent literature is convincing that retinoids are needed by the adult to assure normal pancreatic endocrine functions, especially those of the α- and β-cells. It is also well established that retinoids are required to insure normal pancreas development in utero, including the development of the endocrine pancreas. The actions of retinoids for maintaining normal pancreatic islet functions has drawn considerable research interest from investigators interested in understanding and treating metabolic disease. Pancreatic retinoids are also of interest to investigators studying the origins of pancreatic disease, including the development of pancreatic fibrosis and its sequelae. This research interest is focused on pancreatic stellate cells (PSCs) which store retinoids and possess the metabolic machinery needed to metabolize retinoids. The literature on pancreatic disease and retinoids suggests that there is an association between impairments in pancreatic retinoid storage and metabolism and the development of pancreatic disease. These topics will be considered in this review. PMID:26904552

  13. Modified Extracorporeal Photopheresis with Cells from a Healthy Donor for Acute Graft-versus-Host Disease in a Mouse Model

    PubMed Central

    Budde, Holger; Kolb, Susanne; Salinas Tejedor, Laura; Wulf, Gerald; Reichardt, Holger M.; Riggert, Joachim; Legler, Tobias J.

    2014-01-01

    Background Graft-versus-host disease (GvHD) is a major challenge after hematopoietic stem cell transplantation but treatment options for patients are still limited. In many cases first-line treatment with glucocorticoids is not successful. Among second-line therapies the extracorporeal photopheresis (ECP) is frequently performed, due to induction of selective tolerance instead of general immunosuppression. However, for some patients with severe acute GvHD the leukapheresis step of the ECP procedure is physically exhausting and limits the number of ECP cycles. Methods We hypothesized that leukocytes from healthy cell donors could be used as a replacement for ECP leukocytes gained from the GvHD patient. For this purpose we used a well established mouse model of acute GvHD. The ECP therapy was based on cells with the genetic background of the initial donor of the stem cell transplantation. As a precondition we developed a protocol representing conventional ECP in mice equivalent to clinical used ECP setup. Results We could demonstrate that conventional, clinically derived ECP setup is able to alleviate acute GvHD. By using leukocytes obtained from healthy mice with the bone marrow donor’s genetic background we could not observe a statistically significant therapeutic effect. Conclusions Conventional human ECP setup is effective in the mouse model of severe acute GvHD. In addition we could not prove that ECP cells from healthy mice with bone marrow donor’s genetic background are as effective as ECP cells derived from GvHD mice. Based on our findings, new questions arise for further studies, in which the cellular characteristics for ECP mediated immune tolerance are a matter of investigation. PMID:25148404

  14. Human pancreas development.

    PubMed

    Jennings, Rachel E; Berry, Andrew A; Strutt, James P; Gerrard, David T; Hanley, Neil A

    2015-09-15

    A wealth of data and comprehensive reviews exist on pancreas development in mammals, primarily mice, and other vertebrates. By contrast, human pancreatic development has been less comprehensively reviewed. Here, we draw together those studies conducted directly in human embryonic and fetal tissue to provide an overview of what is known about human pancreatic development. We discuss the relevance of this work to manufacturing insulin-secreting β-cells from pluripotent stem cells and to different aspects of diabetes, especially permanent neonatal diabetes, and its underlying causes. PMID:26395141

  15. Cystic lesions of the pancreas

    PubMed Central

    Hruban, Ralph H.; Fukushima, Noriyoshi

    2008-01-01

    Summary In contrast to the relatively uniform pathology and the unyielding dismal outcome associated with infiltrating ductal adenocarcinoma of the pancreas, cystic lesions have a broad spectrum of gross and microscopic pathologies, and a range of clinical outcomes. The common cystic lesions of the pancreas are reviewed with emphasis on practical tips for distinguishing between the main entities. PMID:20953247

  16. Silibinin suppresses astroglial activation in a mouse model of acute Parkinson's disease by modulating the ERK and JNK signaling pathways.

    PubMed

    Lee, Yujeong; Chun, Hye Jeong; Lee, Kyung Moon; Jung, Young-Suk; Lee, Jaewon

    2015-11-19

    Parkinson's disease (PD) is the second-most common neurodegenerative disease after Alzheimer's disease, and is characterized by dopaminergic neuronal loss in midbrain. The MPTP-induced PD model has been well characterized by motor deficits and selective dopaminergic neuronal death accompanied by glial activation. Silibinin is a constituent of silymarin, an extract of milk thistle seeds, and has been proposed to have hepatoprotective, anti-cancer, anti-oxidative, and neuroprotective effects. In the present study, the authors studied the neuroprotective effects of silibinin in an acute MPTP model of PD. Silibinin was administered for 2 weeks, and then MPTP was administered to mice over 1 day (acute MPTP induced PD). Silibinin pretreatment effectively ameliorated motor dysfunction, dopaminergic neuronal loss, and glial activations caused by MPTP. In addition, an in vitro study demonstrated that silibinin suppressed astroglial activation and ERK and JNK phosphorylation in primary astrocytes in response to MPP(+) treatment. These findings show silibinin protected dopaminergic neurons in an acute MPTP-induced mouse model of PD, and suggest its neuroprotective effects might be mediated by the suppression of astrocyte activation via the inhibition of ERK and JNK phosphorylation. In conclusion, the study indicates silibinin should be viewed as a potential treatment for PD and other neurodegenerative diseases associated with neuroinflammation. PMID:26434409

  17. Acute stress enhances the expression of neuroprotection- and neurogenesis-associated genes in the hippocampus of a mouse restraint model

    PubMed Central

    Sannino, Giuseppina; Pasqualini, Lorenza; Ricciardelli, Eugenia; Montilla, Patricia; Soverchia, Laura; Ruggeri, Barbara; Falcinelli, Silvia; Renzi, Alessandra; Ludka, Colleen; Kirchner, Thomas; Grünewald, Thomas G. P.; Ciccocioppo, Roberto; Ubaldi, Massimo; Hardiman, Gary

    2016-01-01

    Stress arises from an external demand placed on an organism that triggers physiological, cognitive and behavioural responses in order to cope with that request. It is thus an adaptive response useful for the survival of an organism. The objective of this study was to identify and characterize global changes in gene expression in the hippocampus in response to acute stress stimuli, by employing a mouse model of short-term restraint stress. In our experimental design mice were subjected to a one time exposure of restraint stress and the regulation of gene expression in the hippocampus was examined 3, 12 and 24 hours thereafter. Microarray analysis revealed that mice which had undergone acute restraint stress differed from non-stressed controls in global hippocampal transcriptional responses. An up-regulation of transcripts contributing directly or indirectly to neurogenesis and neuronal protection including, Ttr, Rab6, Gh, Prl, Ndufb9 and Ndufa6, was observed. Systems level analyses revealed a significant enrichment for neurogenesis, neuron morphogenesis- and cognitive functions-related biological process terms and pathways. This work further supports the hypothesis that acute stress mediates a positive action on the hippocampus favouring the formation and the preservation of neurons, which will be discussed in the context of current data from the literature. PMID:26863456

  18. Acute Pancreatitis and Pregnancy

    MedlinePlus

    ... sudden inflammation of the pancreas manifested clinically by abdominal pain, nausea and dehydration that is usually self-limiting ... room for evaluation should they develop any abnormal abdominal pain symptoms. Conclusions While a rare event, acute pancreatitis ...

  19. SCID mouse models of acute and relapsing chronic Toxoplasma gondii infections.

    PubMed Central

    Johnson, L L

    1992-01-01

    Lymphodeficient scid/scid (SCID) mice died from acute infection with a strain of Toxoplasma gondii that causes chronic infection with mild symptoms in immunocompetent non-SCID mice. However, most SCID mice reconstituted with spleen cells from immunocompetent mice 1 month prior to T. gondii infection survived in good health after a transient period during which they appeared ill. Unreconstituted SCID mice given sulfadiazine in their drinking water from day 10 of Toxoplasma infection onward survived the acute phase of infection and lived for many weeks without overt symptoms. Histological examination revealed Toxoplasma cysts in their brains. However, if sulfadiazine was withdrawn from the drinking water of these chronically infected SCID mice, the mice died within 1 week with large numbers of trophozoites throughout their brains. These findings establish SCID mice as a potentially useful resource with which to study various aspects of immunological control of T. gondii infection during either its acute or chronic phase. Furthermore, the ability to produce chronic infections with avirulent T. gondii in SCID mice and to cause acute relapsing infections at will suggests that SCID mice may be helpful in evaluating potential therapies for acute and chronic T. gondii infections in immunocompromised patients. Images PMID:1500181

  20. Aromatase Inhibition Attenuates Desflurane-Induced Preconditioning against Acute Myocardial Infarction in Male Mouse Heart In Vivo

    PubMed Central

    Jazbutyte, Virginija; Stumpner, Jan; Redel, Andreas; Lorenzen, Johan M.; Roewer, Norbert

    2012-01-01

    The volatile anesthetic desflurane (DES) effectively reduces cardiac infarct size following experimental ischemia/reperfusion injury in the mouse heart. We hypothesized that endogenous estrogens play a role as mediators of desflurane-induced preconditioning against myocardial infarction. In this study, we tested the hypothesis that desflurane effects local estrogen synthesis by modulating enzyme aromatase expression and activity in the mouse heart. Aromatase metabolizes testosterone to 17β- estradiol (E2) and thereby significantly contributes to local estrogen synthesis. We tested aromatase effects in acute myocardial infarction model in male mice. The animals were randomized and subjected to four groups which were pre-treated with the selective aromatase inhibitor anastrozole (A group) and DES alone (DES group) or in combination (A+DES group) for 15 minutes prior to surgical intervention whereas the control group received 0.9% NaCl (CON group). All animals were subjected to 45 minutes ischemia following 180 minutes reperfusion. Anastrozole blocked DES induced preconditioning and increased infarct size compared to DES alone (37.94±15.5% vs. 17.1±3.62%) without affecting area at risk and systemic hemodynamic parameters following ischemia/reperfusion. Protein localization studies revealed that aromatase was abundant in the murine cardiovascular system with the highest expression levels in endothelial and smooth muscle cells. Desflurane application at pharmacological concentrations efficiently upregulated aromatase expression in vivo and in vitro. We conclude that desflurane efficiently regulates aromatase expression and activity which might lead to increased local estrogen synthesis and thus preserve cellular integrity and reduce cardiac damage in an acute myocardial infarction model. PMID:22876297

  1. Entrainment of the mouse circadian clock by sub-acute physical and psychological stress.

    PubMed

    Tahara, Yu; Shiraishi, Takuya; Kikuchi, Yosuke; Haraguchi, Atsushi; Kuriki, Daisuke; Sasaki, Hiroyuki; Motohashi, Hiroaki; Sakai, Tomoko; Shibata, Shigenobu

    2015-01-01

    The effects of acute stress on the peripheral circadian system are not well understood in vivo. Here, we show that sub-acute stress caused by restraint or social defeat potently altered clock gene expression in the peripheral tissues of mice. In these peripheral tissues, as well as the hippocampus and cortex, stressful stimuli induced time-of-day-dependent phase-advances or -delays in rhythmic clock gene expression patterns; however, such changes were not observed in the suprachiasmatic nucleus, i.e. the central circadian clock. Moreover, several days of stress exposure at the beginning of the light period abolished circadian oscillations and caused internal desynchronisation of peripheral clocks. Stress-induced changes in circadian rhythmicity showed habituation and disappeared with long-term exposure to repeated stress. These findings suggest that sub-acute physical/psychological stress potently entrains peripheral clocks and causes transient dysregulation of circadian clocks in vivo. PMID:26073568

  2. Transcriptional Profile of Muscle following Acute Induction of Symptoms in a Mouse Model of Kennedy's Disease/Spinobulbar Muscular Atrophy

    PubMed Central

    Halievski, Katherine; Mo, Kaiguo; Westwood, J. Timothy; Monks, Douglas A.

    2015-01-01

    Background Kennedy’s disease/Spinobulbar muscular atrophy (KD/SBMA) is a degenerative neuromuscular disease affecting males. This disease is caused by polyglutamine expansion mutations of the androgen receptor (AR) gene. Although KD/SBMA has been traditionally considered a motor neuron disease, emerging evidence points to a central etiological role of muscle. We previously reported a microarray study of genes differentially expressed in muscle of three genetically unique mouse models of KD/SBMA but were unable to detect those which are androgen-dependent or are associated with onset of symptoms. Methodology/Principal Findings In the current study we examined the time course and androgen-dependence of transcriptional changes in the HSA-AR transgenic (Tg) mouse model, in which females have a severe phenotype after acute testosterone treatment. Using microarray analysis we identified differentially expressed genes at the onset and peak of muscle weakness in testosterone-treated Tg females. We found both transient and persistent groups of differentially expressed genes and analysis of gene function indicated functional groups such as mitochondrion, ion and nucleotide binding, muscle development, and sarcomere maintenance. Conclusions/Significance By comparing the current results with those from the three previously reported models we were able to identify KD/SBMA candidate genes that are androgen dependent, and occur early in the disease process, properties which are promising for targeted therapeutics. PMID:25719894

  3. Macrophage Migration Inhibitor Factor Upregulates MCP-1 Expression in an Autocrine Manner in Hepatocytes during Acute Mouse Liver Injury

    PubMed Central

    Xie, Jieshi; Yang, Le; Tian, Lei; Li, Weiyang; Yang, Lin; Li, Liying

    2016-01-01

    Macrophage migration inhibitor factor (MIF), a multipotent innate immune mediator, is an upstream component of the inflammatory cascade in diseases such as liver disease. Monocyte chemoattractant protein-1 (MCP-1), a highly representative chemokine, is critical in liver disease pathogenesis. We investigated the role of MIF in regulating hepatocytic MCP-1 expression. MIF and MCP-1 expression were characterized by immunochemistry, RT-PCR, ELISA, and immunoblotting in CCl4-treated mouse liver and isolated hepatocytes. MIF was primarily distributed in hepatocytes, and its expression increased upon acute liver injury. Its expression was also increased in injured hepatocytes, induced by LPS or CCl4, which mimic liver injury in vitro. MIF was expressed earlier than MCP-1, strongly inducing hepatocytic MCP-1 expression. Moreover, the increase in MCP-1 expression induced by MIF was inhibited by CD74- or CD44-specific siRNAs and SB203580, a p38 MAPK inhibitor. Further, CD74 or CD44 deficiency effectively inhibited MIF-induced p38 activation. MIF inhibitor ISO-1 reduced MCP-1 expression and p38 phosphorylation in CCl4-treated mouse liver. Our results showed that MIF regulates MCP-1 expression in hepatocytes of injured liver via CD74, CD44, and p38 MAPK in an autocrine manner, providing compelling information on the role of MIF in liver injury, and implying a new regulatory mechanism for liver inflammation. PMID:27273604

  4. Effect of low-intensity focused ultrasound on the middle ear in a mouse model of acute otitis media.

    PubMed

    Noda, Kanako; Hirano, Takashi; Noda, Kenji; Kodama, Satoru; Ichimiya, Issei; Suzuki, Masashi

    2013-03-01

    We hypothesized that low-intensity focused ultrasound (LIFU) increases vessel permeability and antibacterial drug activity in the mouse middle ear. We determined appropriate settings by applying LIFU to mouse ears with the external auditory canal filled with normal saline and performed histologic and immunohistologic examination. Acute otitis media was induced in mice with nontypable Haemophilus influenzae, and they were given ampicillin (50, 10, or 2 mg/kg) intraperitoneally once daily for 3 days with or without LIFU (1.0 W/cm(2), 20% duty cycle, 30 s). In the LIFU(+) groups receiving the 2- and 10-mg/kg doses, viable bacteria counts, number of inflammatory cells and IL-1β and TNF-α levels in middle ear effusion were significantly lower than in the LIFU(-) groups on the same doses. Severity of AOM also tended to be reduced more in the LIFU(+) groups than in the LIFU(-) groups. LIFU application with antibiotics may be effective for middle ear infection. PMID:23312959

  5. In vitro and in vivo properties of human/mouse chimeric monoclonal antibody specific for common acute lymphocytic leukemia antigen

    SciTech Connect

    Saga, T.; Endo, K.; Koizumi, M.; Kawamura, Y.; Watanabe, Y.; Konishi, J.; Ueda, R.; Nishimura, Y.; Yokoyama, M.; Watanabe, T. )

    1990-06-01

    A human/mouse chimeric monoclonal antibody specific for a common acute lymphocytic leukemia antigen was efficiently obtained by ligating human heavy-chain enhancer element to the chimeric heavy- and light-chain genes. Cell binding and competitive inhibition assays of both radioiodine and indium-111- (111In) labeled chimeric antibodies demonstrated in vitro immunoreactivity identical with that of the parental murine monoclonal antibodies. The biodistribution of the radiolabeled chimeric antibody in tumor-bearing nude mice was similar to that of the parental murine antibody. Tumor accumulation of radioiodinated parental and chimeric antibodies was lower than that of {sup 111}In-labeled antibodies, probably because of dehalogenation of the radioiodinated antibodies. Indium-111-labeled chimeric antibody clearly visualized xenografted tumor. These results suggest that a human/mouse chimeric antibody can be labeled with {sup 111}In and radioiodine without the loss of its immunoreactivity, and that chimeric antibody localizes in vivo in the same way as the parental murine antibody.

  6. Acute toxicity and cytotoxicity of Bacillus thuringiensis and Bacillus sphaericus strains on fish and mouse bone marrow.

    PubMed

    Grisolia, Cesar Koppe; Oliveira-Filho, Eduardo Cyrino; Ramos, Felipe Rosa; Lopes, Madaí Cruz; Muniz, Daphne Heloisa Freitas; Monnerat, Rose Gomes

    2009-01-01

    The insecticidal properties of delta-endotoxins from Bacillus thuringiensis (Bt) serotypes kurstaki and israelensis and crystal proteins of Bacillus sphaericus (Bs) serotype H5 have been used in insect control for decades. The availability of microbial toxins in biopesticides as well as in plants with incorporated protection has been increasing the concerns about biosafety. Acute toxicity to Danio rerio and cytotoxicity on mouse bone marrow cells and peripheral erythrocytes of Oreochromis niloticus were tested with Bt israelensis, Bt kurstaki and Bs H5 strains. The concentration and dose tested were 10(6) and 10(8) spores/ml, respectively. Neither lethality nor effects on mouse bone marrow were promoted by any strain. In necrosis-apoptosis study on peripheral erythrocytes of O. niloticus an increased frequency of necrotic cells caused by exposure to strains of B. thuringiensis was found. Exposure to B. sphaericus did not show cytotoxic effects in either tested system. None of the strains studied induced apoptosis in contrast with the chemical controls. PMID:18670879

  7. Macrophage Migration Inhibitor Factor Upregulates MCP-1 Expression in an Autocrine Manner in Hepatocytes during Acute Mouse Liver Injury.

    PubMed

    Xie, Jieshi; Yang, Le; Tian, Lei; Li, Weiyang; Yang, Lin; Li, Liying

    2016-01-01

    Macrophage migration inhibitor factor (MIF), a multipotent innate immune mediator, is an upstream component of the inflammatory cascade in diseases such as liver disease. Monocyte chemoattractant protein-1 (MCP-1), a highly representative chemokine, is critical in liver disease pathogenesis. We investigated the role of MIF in regulating hepatocytic MCP-1 expression. MIF and MCP-1 expression were characterized by immunochemistry, RT-PCR, ELISA, and immunoblotting in CCl4-treated mouse liver and isolated hepatocytes. MIF was primarily distributed in hepatocytes, and its expression increased upon acute liver injury. Its expression was also increased in injured hepatocytes, induced by LPS or CCl4, which mimic liver injury in vitro. MIF was expressed earlier than MCP-1, strongly inducing hepatocytic MCP-1 expression. Moreover, the increase in MCP-1 expression induced by MIF was inhibited by CD74- or CD44-specific siRNAs and SB203580, a p38 MAPK inhibitor. Further, CD74 or CD44 deficiency effectively inhibited MIF-induced p38 activation. MIF inhibitor ISO-1 reduced MCP-1 expression and p38 phosphorylation in CCl4-treated mouse liver. Our results showed that MIF regulates MCP-1 expression in hepatocytes of injured liver via CD74, CD44, and p38 MAPK in an autocrine manner, providing compelling information on the role of MIF in liver injury, and implying a new regulatory mechanism for liver inflammation. PMID:27273604

  8. Efficient Replication of Severe Acute Respiratory Syndrome Coronavirus in Mouse Cells Is Limited by Murine Angiotensin-Converting Enzyme 2

    PubMed Central

    Li, Wenhui; Greenough, Thomas C.; Moore, Michael J.; Vasilieva, Natalya; Somasundaran, Mohan; Sullivan, John L.; Farzan, Michael; Choe, Hyeryun

    2004-01-01

    Replication of viruses in species other than their natural hosts is frequently limited by entry and postentry barriers. The coronavirus that causes severe acute respiratory syndrome (SARS-CoV) utilizes the receptor angiotensin-converting enzyme 2 (ACE2) to infect cells. Here we compare human, mouse, and rat ACE2 molecules for their ability to serve as receptors for SARS-CoV. We found that, compared to human ACE2, murine ACE2 less efficiently bound the S1 domain of SARS-CoV and supported less-efficient S protein-mediated infection. Rat ACE2 was even less efficient, at near background levels for both activities. Murine 3T3 cells expressing human ACE2 supported SARS-CoV replication, whereas replication was less than 10% as efficient in the same cells expressing murine ACE2. These data imply that a mouse transgenically expressing human ACE2 may be a useful animal model of SARS. PMID:15452268

  9. Resolvin D1 protects against inflammation in experimental acute pancreatitis and associated lung injury.

    PubMed

    Liu, Yong; Zhou, Dan; Long, Fei-Wu; Chen, Ke-Ling; Yang, Hong-Wei; Lv, Zhao-Yin; Zhou, Bin; Peng, Zhi-Hai; Sun, Xiao-Feng; Li, Yuan; Zhou, Zong-Guang

    2016-03-01

    Acute pancreatitis is an inflammatory condition that may lead to multisystemic organ failure with considerable mortality. Recently, resolvin D1 (RvD1) as an endogenous anti-inflammatory lipid mediator has been confirmed to protect against many inflammatory diseases. This study was designed to investigate the effects of RvD1 in acute pancreatitis and associated lung injury. Acute pancreatitis varying from mild to severe was induced by cerulein or cerulein combined with LPS, respectively. Mice were pretreated with RvD1 at a dose of 300 ng/mouse 30 min before the first injection of cerulein. Severity of AP was assessed by biochemical markers and histology. Serum cytokines and myeloperoxidase (MPO) levels in pancreas and lung were determined for assessing the extent of inflammatory response. NF-κB activation was determined by Western blotting. The injection of cerulein or cerulein combined with LPS resulted in local injury in the pancreas and corresponding systemic inflammatory changes with pronounced severity in the cerulein and LPS group. Pretreated RvD1 significantly reduced the degree of amylase, lipase, TNF-α, and IL-6 serum levels; the MPO activities in the pancreas and the lungs; the pancreatic NF-κB activation; and the severity of pancreatic injury and associated lung injury, especially in the severe acute pancreatitis model. These results suggest that RvD1 is capable of improving injury of pancreas and lung and exerting anti-inflammatory effects through the inhibition of NF-κB activation in experimental acute pancreatitis, with more notable protective effect in severe acute pancreatitis. These findings indicate that RvD1 may constitute a novel therapeutic strategy in the management of severe acute pancreatitis. PMID:26702138

  10. Stereotactic Body Radiotherapy (SBRT) Reirradiation for Recurrent Pancreas Cancer

    PubMed Central

    Dagoglu, Nergiz; Callery, Mark; Moser, James; Tseng, Jennifer; Kent, Tara; Bullock, Andrea; Miksad, Rebecca; Mancias, Joseph D.; Mahadevan, Anand

    2016-01-01

    Objectives: After adjuvant or definitive radiation for pancreas cancer, there are limited conventional treatment options for recurrent pancreas cancer. We explored the role of (Stereotactic Body Radiotherapy) SBRT for reirradiation of recurrent pancreas Cancer. Methods: This is a retrospective study of patients reirradiated with SBRT for recurrent pancreas cancer. All patients were deemed unresectable and treated with systemic therapy. Fiducial gold markers were used. CT simulation was performed with oral and IV contrast and patients were treated with respiratory motion tracking in the CyberknifeTM system. Results: 30 patients (17 men and 13 women) with a median age of 67 years were included in the study. The median target volume was 41.29cc. The median prescription dose was 25Gy (24-36Gy) in a median of 5 fractions prescribed to a mean 78% isodose line. The median overall survival was 14 months. The 1 and 2 year local control was 78%. The worst toxicity included 3/30(10%) Grade III acute toxicity for pain, bleeding and vomiting. There was 2/30 (7%) Grade III long-term bowel obstructions. Conclusions: SBRT can be a useful and tolerable option for patients with recurrent pancreas cancer after prior radiation. PMID:26918041

  11. Transcriptomic analysis of global changes in cytokine expression in mouse spleens following acute Toxoplasma gondii infection.

    PubMed

    He, Jun-Jun; Ma, Jun; Song, Hui-Qun; Zhou, Dong-Hui; Wang, Jin-Lei; Huang, Si-Yang; Zhu, Xing-Quan

    2016-02-01

    Toxoplasma gondii is a global pathogen that infects a wide range of animals and humans. During T. gondii infection, the spleen plays an important role in coordinating the adaptive and innate immune responses. However, there is little information regarding the changes in global gene expression within the spleen following T. gondii infection. To address this gap in knowledge, we examined the transcriptome of the mouse spleen following T. gondii infection. We observed differential expression of 2310 transcripts under these conditions. Analysis of KEGG and GO enrichment indicated that T. gondii alters multiple immune signaling cascades. Most of differentially expressed GO terms and pathways were downregulated, while immune-related GO terms and pathways were upregulated with response to T. gondii infection in mouse spleen. Most cytokines were upregulated in infected spleens, and all differentially expressed chemokines were upregulated which enhanced the immune cells chemotaxis to promote recruitment of immune cells, such as neutrophils, eosinophils, monocytes, dendritic cells, macrophages, NK cells, basophils, B cells, and T cells. Although IFN-γ-induced IDO (Ido1) was upregulated in the present study, it may not contribute a lot to the control of T. gondii because most differentially expressed genes involved in tryptophan metabolism pathway were downregulated. Innate immunity pathways, including cytosolic nucleic acid sensing pathway and C-type lectins-Syk-Card9 signaling pathways, were upregulated. We believe our study is the first comprehensive attempt to define the host transcriptional response to T. gondii infection in the mouse spleen. PMID:26508008

  12. Hemodynamic and morphologic responses in mouse brain during acute head injury imaged by multispectral structured illumination

    NASA Astrophysics Data System (ADS)

    Volkov, Boris; Mathews, Marlon S.; Abookasis, David

    2015-03-01

    Multispectral imaging has received significant attention over the last decade as it integrates spectroscopy, imaging, tomography analysis concurrently to acquire both spatial and spectral information from biological tissue. In the present study, a multispectral setup based on projection of structured illumination at several near-infrared wavelengths and at different spatial frequencies is applied to quantitatively assess brain function before, during, and after the onset of traumatic brain injury in an intact mouse brain (n=5). For the production of head injury, we used the weight drop method where weight of a cylindrical metallic rod falling along a metal tube strikes the mouse's head. Structured light was projected onto the scalp surface and diffuse reflected light was recorded by a CCD camera positioned perpendicular to the mouse head. Following data analysis, we were able to concurrently show a series of hemodynamic and morphologic changes over time including higher deoxyhemoglobin, reduction in oxygen saturation, cell swelling, etc., in comparison with baseline measurements. Overall, results demonstrates the capability of multispectral imaging based structured illumination to detect and map of brain tissue optical and physiological properties following brain injury in a simple noninvasive and noncontact manner.

  13. EFFECT OF ACUTE MATERNAL TOXICITY ON FETAL DEVELOPMENT IN THE MOUSE

    EPA Science Inventory

    The effects of acute alterations in maternal health status upon fetal development were assessed following exposure of pregnant CD-1 mice on day 8 of gestation to one of ten chemicals at a dose calculated to be the maternal LD10 or LD40. The dams were killed on day 18 of gestation...

  14. In Vivo Assessment of Acute UVB Responses in Normal and Xeroderma Pigmentosum (XP-C) Skin-Humanized Mouse Models

    PubMed Central

    García, Marta; Llames, Sara; García, Eva; Meana, Alvaro; Cuadrado, Natividad; Recasens, Mar; Puig, Susana; Nagore, Eduardo; Illera, Nuria; Jorcano, José Luis; Del Rio, Marcela; Larcher, Fernando

    2010-01-01

    In vivo studies of UVB effects on human skin are precluded by ethical and technical arguments on volunteers and inconceivable in cancer-prone patients such as those affected with Xeroderma Pigmentosum (XP). Establishing reliable models to address mechanistic and therapeutic matters thus remains a challenge. Here we have used the skin-humanized mouse system that circumvents most current model constraints. We assessed the UVB radiation effects including the sequential changes after acute exposure with respect to timing, dosage, and the relationship between dose and degree-sort of epidermal alteration. On Caucasian-derived regenerated skins, UVB irradiation (800 J/m2) induced DNA damage (cyclobutane pyrimidine dimers) and p53 expression in exposed keratinocytes. Epidermal disorganization was observed at higher doses. In contrast, in African descent–derived regenerated skins, physiological hyperpigmentation prevented tissue alterations and DNA photolesions. The acute UVB effects seen in Caucasian-derived engrafted skins were also blocked by a physical sunscreen, demonstrating the suitability of the system for photoprotection studies. We also report the establishment of a photosensitive model through the transplantation of XP-C patient cells as part of a bioengineered skin. The inability of XP-C engrafted skin to remove DNA damaged cells was confirmed in vivo. Both the normal and XP-C versions of the skin-humanized mice proved proficient models to assess UVB-mediated DNA repair responses and provide a strong platform to test novel therapeutic strategies. PMID:20558577

  15. Pyruvate dehydrogenase kinase 2 and 4 gene deficiency attenuates nociceptive behaviors in a mouse model of acute inflammatory pain.

    PubMed

    Jha, Mithilesh Kumar; Rahman, Md Habibur; Park, Dong Ho; Kook, Hyun; Lee, In-Kyu; Lee, Won-Ha; Suk, Kyoungho

    2016-09-01

    Pyruvate dehydrogenase (PDH) kinases (PDKs) 1-4, expressed in peripheral and central tissues, regulate the activity of the PDH complex (PDC). The PDC is an important mitochondrial gatekeeping enzyme that controls cellular metabolism. The role of PDKs in diverse neurological disorders, including neurometabolic aberrations and neurodegeneration, has been described. Implications for a role of PDKs in inflammation and neurometabolic coupling led us to investigate the effect of genetic ablation of PDK2/4 on nociception in a mouse model of acute inflammatory pain. Deficiency in Pdk2 and/or Pdk4 in mice led to attenuation of formalin-induced nociceptive behaviors (flinching, licking, biting, or lifting of the injected paw). Likewise, the pharmacological inhibition of PDKs substantially diminished the nociceptive responses in the second phase of the formalin test. Furthermore, formalin-provoked paw edema formation and mechanical and thermal hypersensitivities were significantly reduced in Pdk2/4-deficient mice. Formalin-driven neutrophil recruitment at the site of inflammation, spinal glial activation, and neuronal sensitization were substantially lessened in the second or late phase of the formalin test in Pdk2/4-deficient animals. Overall, our results suggest that PDK2/4 can be a potential target for the development of pharmacotherapy for the treatment of acute inflammatory pain. © 2016 Wiley Periodicals, Inc. PMID:26931482

  16. Tanshinone IIA Attenuates Renal Fibrosis after Acute Kidney Injury in a Mouse Model through Inhibition of Fibrocytes Recruitment

    PubMed Central

    Jiang, Chunming; Shao, Qiuyuan; Jin, Bo; Zhang, Miao

    2015-01-01

    Acute kidney injury (AKI) is associated with an increased risk of developing advanced chronic kidney disease (CKD). Yet, effective interventions to prevent this conversion are unavailable for clinical practice. In this study, we examined the beneficial effects of Tanshinone IIA on renal fibrosis in a mouse model of folic acid induced AKI. We found that Tanshinone IIA treatment significantly attenuated the folic acid elicited kidney dysfunction on days 3, 14, and 28. This effect was concomitant with a much lessened accumulation of fibronectin and collagen in tubulointerstitium 28 days after folic acid injury, denoting an ameliorated renal fibrosis. The kidney protective and antifibrotic effect of Tanshinone IIA was likely attributable to an early inhibition of renal recruitment of fibrocytes positive for both CD45 and collagen I. Mechanistically, Tanshinone IIA treatment not only markedly diminished renal expression of chemoattractants for fibrocytes such as TGFβ1 and MCP-1, but also significantly reduced circulating fibrocytes at the acute phase of kidney injury. These data suggested that Tanshinone IIA might be a novel therapy for preventing progression of CKD after AKI. PMID:26885500

  17. Common Disorders of the Pancreas

    MedlinePlus

    ... the disease becomes more chronic, patients can develop malnutrition and weight loss. If the pancreas becomes destroyed ... with these disorders may have chronic pain, diarrhea, malnutrition, or diabetes. Treatment focuses on pain control and ...

  18. CXCL9 and CXCL10 accelerate acute transplant rejection mediated by alloreactive memory T cells in a mouse retransplantation model

    PubMed Central

    ZHUANG, JIAWEI; SHAN, ZHONGGUI; MA, TENG; LI, CHUN; QIU, SHUIWEI; ZHOU, XIAOBIAO; LIN, LIANFENG; QI, ZHONGQUAN

    2014-01-01

    C-X-C motif chemokine ligand (CXCL) 9 and CXCL10 play key roles in the initiation and development of acute transplant rejection. Previously, higher levels of RANTES expression and secretion were demonstrated in retransplantation or T-cell memory-transfer models. In the present study, the effect of the chemokines, CXCL9 and CXCL10, were investigated in a mouse retransplantation model. BALB/c mice were used as donors, while C57BL/6 mice were used as recipients. In the experimental groups, a heterotopic heart transplantation was performed six weeks following skin grafting. In the control groups, a heterotopic heart transplantation was performed without skin grafting. Untreated mice served as blank controls. The mean graft survival time of the heterotopic heart transplantations was 7.7 days in the experimental group (n=6), as compared with 3.25 days in the control group (n=6; P<0.001). On day three following cardiac transplantation, histological evaluation of the grafts revealed a higher International Society for Heart & Lung Transplantation grade in the experimental group as compared with the control group. In addition, gene expression and serum concentrations of CXCL9, CXCL10, interferon-γ, and interleukin-2 were markedly higher in the experimental group when compared with the control group. Differences between the levels of CXCL9 and CXCL10 in the pre- and post-transplant mice indicated that the chemokines may serve as possible biomarkers to predict acute rejection. The results of the present study demonstrated that CXCL9 and CXCL10 play a critical role in transplantation and retransplantation. High levels of these cytokines during the pre-transplant period may lead to extensive acute rejection. Thus, the observations enhance the understanding of the mechanism underlying the increased expression and secretion of CXCL9 and CXCL10 by alloreactive memory T cells. PMID:24944628

  19. Multiplex immunoassay characterization and species comparison of inflammation in acute and non-acute ischemic infarcts in human and mouse brain tissue.

    PubMed

    Nguyen, Thuy-Vi V; Frye, Jennifer B; Zbesko, Jacob C; Stepanovic, Kristina; Hayes, Megan; Urzua, Alex; Serrano, Geidy; Beach, Thomas G; Doyle, Kristian P

    2016-01-01

    This study provides a parallel characterization of the cytokine and chemokine response to stroke in the human and mouse brain at different stages of infarct resolution. The study goal was to address the hypothesis that chronic inflammation may contribute to stroke-related dementia. We used C57BL/6 and BALB/c mice to control for strain related differences in the mouse immune response. Our data indicate that in both mouse strains, and humans, there is increased granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin-6 (IL-6), interleukin-12 p70 (IL-12p70), interferon gamma-induced protein-10 (IP-10), keratinocyte chemoattractant/interleukin-8 (KC/IL-8), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), macrophage inflammatory protein-1β (MIP-1β), regulated on activation, normal T cell expressed and secreted (RANTES), and Tumor necrosis factor-α (TNF-α) in the infarct core during the acute time period. Nevertheless, correlation and two-way ANOVA analyses reveal that despite this substantial overlap between species, there are still significant differences, particularly in the regulation of granulocyte colony-stimulating factor (G-CSF), which is increased in mice but not in humans. In the weeks after stroke, during the stage of liquefactive necrosis, there is significant resolution of the inflammatory response to stroke within the infarct. However, CD68+ macrophages remain present, and levels of IL-6 and MCP-1 remain chronically elevated in infarcts from both mice and humans. Furthermore, there is a chronic T cell response within the infarct in both species. This response is differentially polarized towards a T helper 1 (Th1) response in C57BL/6 mice, and a T helper 2 (Th2) response in BALB/c mice, suggesting that the chronic inflammatory response to stroke may follow a different trajectory in different patients. To control for the fact that the average age of the patients used in this study was 80 years, they

  20. Allograft pancreas: pale acinar nodules.

    PubMed

    Troxell, Megan L; Drachenberg, Cinthia

    2016-08-01

    Microscopic pale-staining acinar nodules were characterized in native pancreas in the 1980s under a variety of names but have been infrequently reported since. We retrospectively studied the frequency and characteristics of pale acinar nodules in allograft pancreas biopsies, as compared to a sampling of native pancreas specimens at our center. Pale acinar nodules were present in 13% (9/69) of allograft biopsies from 22% (7/32) of transplant patients, and 23% (5/22) of native pancreas surgical specimens, although more nodules per pancreas area were present in allograft needle biopsies. Acinar nodules had size of 100 to 700 μm, were periodic acid-Schiff pale, were synaptophysin negative, stained more weakly with keratin CAM 5.2 compared to surrounding parenchyma, and had a low proliferative rate. Ultrastructural evaluation revealed paucity of zymogen granules with dilated cistern-like structures. In our experience, pale acinar nodules have similar features in allograft and native pancreas specimens, yet remain of uncertain etiology and significance. PMID:27063474

  1. Acute mouse and chronic dog toxicity studies of danthron, dioctyl sodium sulfosuccinate, poloxalkol and combinations.

    PubMed

    Case, M T; Smith, J K; Nelson, R A

    Because of an apparent typographic error in a US patent, there has been some confusion as to the acute oral toxicity of danthron and danthron in combination with dioctyl sodium sulfosuccinate (DSS). Acute oral toxicity studies in mice revealed LD50 values of greater than 7 gm/kg for danthron, 2.64 gm/kg for DSS and 3.42 gm/kg for danthron/DSS mixture (1:2 ratio). These results indicate that the lethality of these compounds is in the gm/kg range and not in the mg/kg range. A one year chronic toxicity study of danthron, dioctyl sodium sulfosuccinate, poloxalkol and combinations in dogs failed to reveal any toxic effects. In particular, there was no evidence of hepatotoxicity or of any changes in the myenteric plexuses in the chronically treated dogs. PMID:90594

  2. Changes of hepatic lactoferrin gene expression in two mouse models of the acute phase reaction.

    PubMed

    Ahmad, Ghayyor; Sial, Gull Zareen Khan; Ramadori, Pierluigi; Dudas, Jozsef; Batusic, Danko S; Ramadori, Giuliano

    2011-12-01

    Lactoferrin (Ltf), an iron binding glycoprotein, is a pleiotropic molecule whose serum concentration increases under acute phase conditions. The physiological roles of this protein have been well elucidated, but the source and serum regulation of Ltf gene expression have not been investigated in detail as part of the acute phase reaction (APR). In the current work, the changes in hepatic Ltf-gene-expression during turpentine oil- (TO-) or LPS-induced APR were investigated. Ltf was upregulated at both the mRNA and protein levels in the liver of TO- and LPS-treated wild type (WT) mice. The pattern of induction however was different in both animal models indicating distinctive signalling patterns resulting in an acute phase reaction. Cytokines are the core regulators of APR. Among the major cytokines, IL-6 is an important signalling molecule, which also regulates iron homeostasis in response to an inflammatory situation. In this study, the administration of IL-6 induced Ltf gene expression in the liver of WT mice, in murine hepatocytes and in hepa 1-6 cells. Ltf-gene-expression was upregulated also in the liver of TO- and LPS-treated IL-6 knockout (KO) mice. The increase in serum Ltf after LPS injection was greater than after TO-injection both in WT and IL-6-KO mice. To evaluate the contribution of other acute phase cytokines in the regulation of Ltf-gene-expression in the liver, both in vitro and in vivo studies with IL-1β, TNF-α, or IFN-γ were performed. The results demonstrate that TNF-α and IFN-γ also upregulated Ltf-gene-expression, while IL-1β has no role in the regulation of Ltf-gene-expression. PMID:21963450

  3. Pancreas Cell Fate

    PubMed Central

    Guney, Michelle A.; Gannon, Maureen

    2009-01-01

    Diabetes is characterized by decreased function of insulin-producing insulin β cells and insufficient insulin output resulting from an absolute (Type 1) or relative (Type 2) inadequate functional β cell mass. Both forms of the disease would greatly benefit from treatment strategies that could enhance β cell regeneration and/or function. Successful and reliable methods of generatingβ cells or whole islets from progenitor cells in vivo or in vitro could lead to restoration of β cell mass in individuals with Type 1 diabetes and enhanced β cell compensation in Type 2 patients. A thorough understanding of the normal developmental processes that occur during pancreatic organogenesis, e.g., transcription factors, cell signaling molecules, and cell-cell interactions that regulate endocrine differentiation from the embryonic pancreatic epithelium, is required in order to successfully reach these goals. This review summarizes our current understanding of pancreas development, with particular emphasis on factors intrinsic or extrinsic to the pancreatic epithelium that are involved in regulating the development and differentiation of the various pancreatic cell types. We also discuss the recent progress in generating insulin-producing cells from progenitor sources. PMID:19750517

  4. [Intraoperative pancreas puncture cytology].

    PubMed

    Eggert, A; Lattmann, E; Kopf, R; Pfeiffer, M; Klöppel, G

    1984-01-01

    In the case of 10 to 15% of surgical patients with a pancreatic disorder an intraoperative diagnosis had to be made when a preoperative diagnosis had not yielded a definite result. Fine needle aspiration biopsy ( FNAB ) of the pancreas provided the basis for intraoperative differentiation of malignant and benign pancreatic processes. 244 pancreatic biopsies were carried out in 100 patients. It was possible to make a statement in 99% of the cases, with 65 malignant and 35 benign changes. In 83% the cytological diagnosis was correct; the method yielded incorrect-negative results in 7% of the cases. In 9% the presence of tumour cells was only suspected. There were no incorrect positive cancer diagnoses. FNAB caused no postoperative complications. Intraoperative bleeding after FBAB had to be stopped with a suture in one case. Transitory, asymptomatic hyperamylasemy must be expected in 25% of the patients after FNAB . This diagnostic technique is recommended in preference to the histological tissue removal methods because of its low risk factor. At least 2 biopsies of the suspect area with 2 smears are required, as a training in this diagnostic technique. PMID:6730761

  5. Successful Pancreas Transplantation From a Deceased Donor Intoxicated With Oral Antidiabetic Agent: A Case Report.

    PubMed

    Rodríguez-Villar, C; Conget, I; Ferrer-Fàbrega, J; Paredes, D; Ruíz, A; Roque, R; Rull, R; López-Boado, M; Ricart, M J; Garcia, R; Adalia, R

    2015-10-01

    Simultaneous kidney pancreas transplantation (SKP) is a common procedure for the patient with long-term type 1 diabetes mellitus (DM) with terminal renal failure. It is unusual to consider the pancreas from a deceased donor who died after an acute intoxication with oral antidiabetic agent (OAA), which would suggest an abnormal functionality of the organ and preclude the potential use of the graft. We present a case of a successful pancreatic transplantation from a donor who died of acute cerebral edema secondary to severe hypoglycemia induced by OAA acute intoxication. PMID:26518941

  6. Telomerase expression confers cardioprotection in the adult mouse heart after acute myocardial infarction

    PubMed Central

    Serrano, Rosa; Tejera, Agueda; Ayuso, Eduard; Jimenez, Veronica; Formentini, Ivan; Bobadilla, Maria; Mizrahi, Jacques; de Martino, Alba; Gomez, Gonzalo; Pisano, David; Mulero, Francisca; Wollert, Kai C.; Bosch, Fatima; Blasco, Maria A.

    2016-01-01

    Coronary heart disease is one of the main causes of death in the developed world, and treatment success remains modest, with high mortality rates within 1 year after myocardial infarction (MI). Thus, new therapeutic targets and effective treatments are necessary. Short telomeres are risk factors for age-associated diseases, including heart disease. Here we address the potential of telomerase (Tert) activation in prevention of heart failure after MI in adult mice. We use adeno-associated viruses for cardiac-specific Tert expression. We find that upon MI, hearts expressing Tert show attenuated cardiac dilation, improved ventricular function and smaller infarct scars concomitant with increased mouse survival by 17% compared with controls. Furthermore, Tert treatment results in elongated telomeres, increased numbers of Ki67 and pH3-positive cardiomyocytes and a gene expression switch towards a regeneration signature of neonatal mice. Our work suggests telomerase activation could be a therapeutic strategy to prevent heart failure after MI. PMID:25519492

  7. A two-mutation model of radiation-induced acute myeloid leukemia using historical mouse data.

    PubMed

    Dekkers, Fieke; Bijwaard, Harmen; Bouffler, Simon; Ellender, Michele; Huiskamp, René; Kowalczuk, Christine; Meijne, Emmy; Sutmuller, Marjolein

    2011-03-01

    From studies of the atomic bomb survivors, it is well known that ionizing radiation causes several forms of leukemia. However, since the specific mechanism behind this process remains largely unknown, it is difficult to extrapolate carcinogenic effects at acute high-dose exposures to risk estimates for the chronic low-dose exposures that are important for radiation protection purposes. Recently, it has become clear that the induction of acute myeloid leukemia (AML) in CBA/H mice takes place through two key steps, both involving the Sfpi1 gene. A similar mechanism may play a role in human radiation-induced AML. In the present paper, a two-mutation carcinogenesis model is applied to model AML in several data sets of X-ray- and neutron-exposed CBA/H mice. The models obtained provide good fits to the data. A comparison between the predictions for neutron-induced and X-ray-induced AML yields an RBE for neutrons of approximately 3. The model used is considered to be a first step toward a model for human radiation-induced AML, which could be used to estimate risks of exposure to low doses. PMID:20842369

  8. Acute inflammation alters adult hippocampal neurogenesis in a multiple sclerosis mouse model.

    PubMed

    Giannakopoulou, A; Grigoriadis, N; Bekiari, C; Lourbopoulos, A; Dori, I; Tsingotjidou, A S; Michaloudi, H; Papadopoulos, G C

    2013-07-01

    Neural precursor cells (NPCs) located in the subgranular zone (SGZ) of the dentate gyrus (DG) give rise to thousands of new cells every day, mainly hippocampal neurons, which are integrated into existing neuronal circuits. Aging and chronic degenerative disorders have been shown to impair hippocampal neurogenesis, but the consequence of inflammation is somewhat controversial. The present study demonstrates that the inflammatory environment prevailing in the brain of experimental autoimmune encephalomyelitis (EAE) mice enhances the proliferation of NPCs in SGZ of the dorsal DG and alters the proportion between radial glial cells and newborn neuroblasts. The injection protocol of the cell cycle marker bromodeoxyuridine and the immunohistochemical techniques that were employed revealed that the proliferation of NPCs is increased approximately twofold in the SGZ of the dorsal DG of EAE mice, at the acute phase of the disease. However, although EAE animals exhibited significant higher percentage of newborn radial-glia-like NPCs, the mean percentage of newborn neuroblasts rather was decreased, indicating that the robust NPCs proliferation is not followed by a proportional production of newborn neurons. Significant positive correlations were detected between the number of proliferating cells in the SGZ and the clinical score or degree of brain inflammation of diseased animals. Finally, enhanced neuroproliferation in the acute phase of EAE was not found to trigger compensatory apoptotic mechanisms. The possible causes of altered neurogenesis observed in this study emphasize the need to understand more precisely the mechanisms regulating adult neurogenesis under both normal and pathological conditions. PMID:23606574

  9. In vivo Postnatal Electroporation and Time-lapse Imaging of Neuroblast Migration in Mouse Acute Brain Slices

    PubMed Central

    Oudin, Madeleine Julie; Doherty, Patrick; Lalli, Giovanna

    2013-01-01

    The subventricular zone (SVZ) is one of the main neurogenic niches in the postnatal brain. Here, neural progenitors proliferate and give rise to neuroblasts able to move along the rostral migratory stream (RMS) towards the olfactory bulb (OB). This long-distance migration is required for the subsequent maturation of newborn neurons in the OB, but the molecular mechanisms regulating this process are still unclear. Investigating the signaling pathways controlling neuroblast motility may not only help understand a fundamental step in neurogenesis, but also have therapeutic regenerative potential, given the ability of these neuroblasts to target brain sites affected by injury, stroke, or degeneration. In this manuscript we describe a detailed protocol for in vivo postnatal electroporation and subsequent time-lapse imaging of neuroblast migration in the mouse RMS. Postnatal electroporation can efficiently transfect SVZ progenitor cells, which in turn generate neuroblasts migrating along the RMS. Using confocal spinning disk time-lapse microscopy on acute brain slice cultures, neuroblast migration can be monitored in an environment closely resembling the in vivo condition. Moreover, neuroblast motility can be tracked and quantitatively analyzed. As an example, we describe how to use in vivo postnatal electroporation of a GFP-expressing plasmid to label and visualize neuroblasts migrating along the RMS. Electroporation of shRNA or CRE recombinase-expressing plasmids in conditional knockout mice employing the LoxP system can also be used to target genes of interest. Pharmacological manipulation of acute brain slice cultures can be performed to investigate the role of different signaling molecules in neuroblast migration. By coupling in vivo electroporation with time-lapse imaging, we hope to understand the molecular mechanisms controlling neuroblast motility and contribute to the development of novel approaches to promote brain repair. PMID:24326479

  10. Protection of Retinal Ganglion Cells and Retinal Vasculature by Lycium Barbarum Polysaccharides in a Mouse Model of Acute Ocular Hypertension

    PubMed Central

    Mi, Xue-Song; Feng, Qian; Lo, Amy Cheuk Yin; Chang, Raymond Chuen-Chung; Lin, Bin; Chung, Sookja Kim; So, Kwok-Fai

    2012-01-01

    Acute ocular hypertension (AOH) is a condition found in acute glaucoma. The purpose of this study is to investigate the protective effect of Lycium barbarum polysaccharides (LBP) and its protective mechanisms in the AOH insult. LBP has been shown to exhibit neuroprotective effect in the chronic ocular hypertension (COH) experiments. AOH mouse model was induced in unilateral eye for one hour by introducing 90 mmHg ocular pressure. The animal was fed with LBP solution (1 mg/kg) or vehicle daily from 7 days before the AOH insult till sacrifice at either day 4 or day 7 post insult. The neuroprotective effects of LBP on retinal ganglion cells (RGCs) and blood-retinal-barrier (BRB) were evaluated. In control AOH retina, loss of RGCs, thinning of IRL thickness, increased IgG leakage, broken tight junctions, and decreased density of retinal blood vessels were observed. However, in LBP-treated AOH retina, there was less loss of RGCs with thinning of IRL thickness, IgG leakage, more continued structure of tight junctions associated with higher level of occludin protein and the recovery of the blood vessel density when compared with vehicle-treated AOH retina. Moreover, we found that LBP provides neuroprotection by down-regulating RAGE, ET-1, Aβ and AGE in the retina, as well as their related signaling pathways, which was related to inhibiting vascular damages and the neuronal degeneration in AOH insults. The present study suggests that LBP could prevent damage to RGCs from AOH-induced ischemic injury; furthermore, through its effects on blood vessel protection, LBP would also be a potential treatment for vascular-related retinopathy. PMID:23094016

  11. Autophagy and pancreas disease.

    PubMed

    Vaccaro, María I

    2008-01-01

    Autophagy is an evolutionarily preserved degradation process of cytoplasmic cellular constituents, which has been known for its role in protecting cells against stresses such as starvation and in eliminating defective subcellular structures. It is essentially a form of self-cannibalism - hence the name that means 'self-eating' - in which the cell breaks down its own components. By mostly morphological studies, autophagy has been linked to a variety of pathological processes such as neurodegenerative diseases and tumorigenesis, which highlights its biological and medical importance. However, whether autophagy protects from or causes disease is unclear. Autophagic morphology was described in human pancreatitis by Helin et al. in 1980. Actually, acute pancreatitis is one of the earlier pathological processes where autophagy has been described in a human tissue. Autophagy, autodigestion and cell death are early cellular events in acute pancreatitis. The aim of this review is to introduce a description of the autophagic process and to discuss the possible role of autophagy in acute pancreatitis. PMID:18714176

  12. Noninvasive In Vivo Quantification of Neutrophil Elastase Activity in Acute Experimental Mouse Lung Injury

    PubMed Central

    Kossodo, Sylvie; Zhang, Jun; Groves, Kevin; Cuneo, Garry J.; Handy, Emma; Morin, Jeff; Delaney, Jeannine; Yared, Wael; Rajopadhye, Milind; Peterson, Jeffrey D.

    2011-01-01

    We developed a neutrophil elastase-specific near-infrared fluorescence imaging agent, which, combined with fluorescence molecular tomographic imaging, allowed us to detect and quantify neutrophil elastase activity in vivo, in real time, and noninvasively in an acute model of lung injury (ALI). Significantly higher fluorescent signal was quantified in mice with LPS/fMLP-induced ALI as compared to healthy controls, correlating with increases in the number of bronchoalveolar lavage cells, neutrophils, and elastase activity. The agent was significantly activated ex vivo in lung sections from ALI but not from control mice, and this activation was ablated by the specific inhibitor sivelestat. Treatment with the specific inhibitor sivelestat significantly reduced lung signal in mice with ALI. These results underscore the unique ability of fluorescence molecular imaging to quantify specific molecular processes in vivo, crucial for understanding the mechanisms underlying disease progression and for assessing and monitoring novel pharmacological interventions. PMID:21941648

  13. Radionuclide surveillance of the allografted pancreas

    SciTech Connect

    George, E.A.; Salimi, Z.; Carney, K.; Castaneda, M.; Garvin, P.J.

    1988-04-01

    To determine the value of scintigraphy to detect posttransplantation complications of the allografted pancreas, we retrospectively reviewed 209 scintigrams obtained with /sup 99m/Tc-sulfur colloid (/sup 99m/Tc-SC) and /sup 99m/Tc-glucoheptonate (/sup 99m/Tc-GH). The scintigraphic studies were performed in 37 recipients of simultaneous renal and pancreatic allografts harvested from the same donor. /sup 99m/Tc-SC was used as an indicator of thrombotic vasculitis; pancreatic perfusion and blood-pool parameters were monitored with /sup 99m/Tc-GH. In 11 of the 37 recipients, scintigraphic abnormalities suggested posttransplantation infarction. Recurrent episodes of acute rejection of the pancreatic allograft, which always coincided with acute rejection of the renal allograft, were monitored in 24 recipients. Rejection-induced ischemic pancreatitis was suggested in 12 of the 24 recipients and persisted in 10 recipients for several weeks after improvement of renal allograft rejection. Pancreatic atrophy was suggested scintigraphically in 16 of the 24 recipients with recurrent episodes of rejection. Spontaneous pancreatic-duct obstruction and obstructive pancreatitis were associated with a scintigraphic pattern similar to that of rejection-induced ischemic pancreatitis. We concluded that the specific radionuclides used in this series are useful for the surveillance and assessment of posttransplantation pancreatic infarction, acute rejection, pancreatitis, and atrophy

  14. Effects of acute versus repeated cocaine exposure on the expression of endocannabinoid signaling-related proteins in the mouse cerebellum.

    PubMed

    Palomino, Ana; Pavón, Francisco-Javier; Blanco-Calvo, Eduardo; Serrano, Antonia; Arrabal, Sergio; Rivera, Patricia; Alén, Francisco; Vargas, Antonio; Bilbao, Ainhoa; Rubio, Leticia; Rodríguez de Fonseca, Fernando; Suárez, Juan

    2014-01-01

    Growing awareness of cerebellar involvement in addiction is based on the cerebellum's intermediary position between motor and reward, potentially acting as an interface between motivational and cognitive functions. Here, we examined the impact of acute and repeated cocaine exposure on the two main signaling systems in the mouse cerebellum: the endocannabinoid (eCB) and glutamate systems. To this end, we investigated whether eCB signaling-related gene and protein expression {cannabinoid receptor type 1 receptors and enzymes that produce [diacylglycerol lipase alpha/beta (DAGLα/β) and N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD)] and degrade [monoacylglycerol lipase (MAGL) and fatty acid amino hydrolase (FAAH)] eCB} were altered. In addition, we analyzed the gene expression of relevant components of the glutamate signaling system [glutamate synthesizing enzymes liver-type glutaminase isoform (LGA) and kidney-type glutaminase isoform (KGA), metabotropic glutamatergic receptor (mGluR3/5), NMDA-ionotropic glutamatergic receptor (NR1/2A/2B/2C) and AMPA-ionotropic receptor subunits (GluR1/2/3/4)] and the gene expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, because noradrenergic terminals innervate the cerebellar cortex. Results indicated that acute cocaine exposure decreased DAGLα expression, suggesting a down-regulation of 2-arachidonylglycerol (2-AG) production, as well as gene expression of TH, KGA, mGluR3 and all ionotropic receptor subunits analyzed in the cerebellum. The acquisition of conditioned locomotion and sensitization after repeated cocaine exposure were associated with an increased NAPE-PLD/FAAH ratio, suggesting enhanced anandamide production, and a decreased DAGLβ/MAGL ratio, suggesting decreased 2-AG generation. Repeated cocaine also increased LGA gene expression but had no effect on glutamate receptors. These findings indicate that acute cocaine modulates the expression of the eCB and

  15. Acute inflammation induces immunomodulatory effects on myeloid cells associated with anti-tumor responses in a tumor mouse model.

    PubMed

    Salem, Mohamed L; Attia, Zeinab I; Galal, Sohaila M

    2016-03-01

    Given the self nature of cancer, anti-tumor immune response is weak. As such, acute inflammation induced by microbial products can induce signals that result in initiation of an inflammatory cascade that helps activation of immune cells. We aimed to compare the nature and magnitude of acute inflammation induced by toll-like receptor ligands (TLRLs) on the tumor growth and the associated inflammatory immune responses. To induce acute inflammation in tumor-bearing host, CD1 mice were inoculated with intraperitoneal (i.p.) injection of Ehrlich ascites carcinoma (EAC) (5 × 10(5) cells/mouse), and then treated with i.p. injection on day 1, day 7 or days 1 + 7 with: (1) polyinosinic:polycytidylic (poly(I:C)) (TLR3L); (2) Poly-ICLC (clinical grade of TLR3L); (3) Bacillus Calmette Guerin (BCG) (coding for TLR9L); (4) Complete Freund's adjuvant (CFA) (coding for TLR9L); and (5) Incomplete Freund's Adjuvant (IFA). Treatment with poly(I:C), Poly-ICLC, BCG, CFA, or IFA induced anti-tumor activities as measured by 79.1%, 75.94%, 73.94%, 71.88% and 47.75% decreases, respectively in the total number of tumor cells collected 7 days after tumor challenge. Among the tested TLRLs, both poly(I:C) (TLR3L) and BCG (contain TLR9L) showed the highest anti-tumor effects as reflected by the decrease in the number of EAc cells. These effects were associated with a 2-fold increase in the numbers of inflammatory cells expressing the myeloid markers CD11b(+)Ly6G(+), CD11b(+)Ly6G(-), and CD11b(+)Ly6G(-). We concluded that Provision of the proper inflammatory signal with optimally defined magnitude and duration during tumor growth can induce inflammatory immune cells with potent anti-tumor responses without vaccination. PMID:26966565

  16. Effects of acute versus repeated cocaine exposure on the expression of endocannabinoid signaling-related proteins in the mouse cerebellum

    PubMed Central

    Palomino, Ana; Pavón, Francisco-Javier; Blanco-Calvo, Eduardo; Serrano, Antonia; Arrabal, Sergio; Rivera, Patricia; Alén, Francisco; Vargas, Antonio; Bilbao, Ainhoa; Rubio, Leticia; Rodríguez de Fonseca, Fernando; Suárez, Juan

    2014-01-01

    Growing awareness of cerebellar involvement in addiction is based on the cerebellum’s intermediary position between motor and reward, potentially acting as an interface between motivational and cognitive functions. Here, we examined the impact of acute and repeated cocaine exposure on the two main signaling systems in the mouse cerebellum: the endocannabinoid (eCB) and glutamate systems. To this end, we investigated whether eCB signaling-related gene and protein expression {cannabinoid receptor type 1 receptors and enzymes that produce [diacylglycerol lipase alpha/beta (DAGLα/β) and N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD)] and degrade [monoacylglycerol lipase (MAGL) and fatty acid amino hydrolase (FAAH)] eCB} were altered. In addition, we analyzed the gene expression of relevant components of the glutamate signaling system [glutamate synthesizing enzymes liver-type glutaminase isoform (LGA) and kidney-type glutaminase isoform (KGA), metabotropic glutamatergic receptor (mGluR3/5), NMDA-ionotropic glutamatergic receptor (NR1/2A/2B/2C) and AMPA-ionotropic receptor subunits (GluR1/2/3/4)] and the gene expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, because noradrenergic terminals innervate the cerebellar cortex. Results indicated that acute cocaine exposure decreased DAGLα expression, suggesting a down-regulation of 2-arachidonylglycerol (2-AG) production, as well as gene expression of TH, KGA, mGluR3 and all ionotropic receptor subunits analyzed in the cerebellum. The acquisition of conditioned locomotion and sensitization after repeated cocaine exposure were associated with an increased NAPE-PLD/FAAH ratio, suggesting enhanced anandamide production, and a decreased DAGLβ/MAGL ratio, suggesting decreased 2-AG generation. Repeated cocaine also increased LGA gene expression but had no effect on glutamate receptors. These findings indicate that acute cocaine modulates the expression of the eCB and

  17. Acute inflammation induces immunomodulatory effects on myeloid cells associated with anti-tumor responses in a tumor mouse model

    PubMed Central

    Salem, Mohamed L.; Attia, Zeinab I.; Galal, Sohaila M.

    2015-01-01

    Given the self nature of cancer, anti-tumor immune response is weak. As such, acute inflammation induced by microbial products can induce signals that result in initiation of an inflammatory cascade that helps activation of immune cells. We aimed to compare the nature and magnitude of acute inflammation induced by toll-like receptor ligands (TLRLs) on the tumor growth and the associated inflammatory immune responses. To induce acute inflammation in tumor-bearing host, CD1 mice were inoculated with intraperitoneal (i.p.) injection of Ehrlich ascites carcinoma (EAC) (5 × 105 cells/mouse), and then treated with i.p. injection on day 1, day 7 or days 1 + 7 with: (1) polyinosinic:polycytidylic (poly(I:C)) (TLR3L); (2) Poly-ICLC (clinical grade of TLR3L); (3) Bacillus Calmette Guerin (BCG) (coding for TLR9L); (4) Complete Freund’s adjuvant (CFA) (coding for TLR9L); and (5) Incomplete Freund’s Adjuvant (IFA). Treatment with poly(I:C), Poly-ICLC, BCG, CFA, or IFA induced anti-tumor activities as measured by 79.1%, 75.94%, 73.94%, 71.88% and 47.75% decreases, respectively in the total number of tumor cells collected 7 days after tumor challenge. Among the tested TLRLs, both poly(I:C) (TLR3L) and BCG (contain TLR9L) showed the highest anti-tumor effects as reflected by the decrease in the number of EAc cells. These effects were associated with a 2-fold increase in the numbers of inflammatory cells expressing the myeloid markers CD11b+Ly6G+, CD11b+Ly6G−, and CD11b+Ly6G−. We concluded that Provision of the proper inflammatory signal with optimally defined magnitude and duration during tumor growth can induce inflammatory immune cells with potent anti-tumor responses without vaccination. PMID:26966565

  18. Gemcitabine and AMG 479 in Metastatic Adenocarcinoma of the Pancreas

    ClinicalTrials.gov

    2014-03-28

    Adenocarcinoma of the Pancreas; Advanced Solid Tumors; Cancer; Cancer of Pancreas; Cancer of the Pancreas; Metastases; Metastatic Cancer; Metastatic Pancreatic Cancer; Pancreas Cancer; Pancreatic Cancer; Bone Metastases; Endocrine Cancer; Oncology; Oncology Patients; Solid Tumors; Advanced Malignancy

  19. Diffuse Optical Spectroscopy for the Quantitative Assessment of Acute Ionizing Radiation Induced Skin Toxicity Using a Mouse Model

    PubMed Central

    Chin, Lee; Korpela, Elina; Kim, Anthony; Yohan, Darren; Niu, Carolyn; Wilson, Brian C.; Liu, Stanley K.

    2016-01-01

    Acute skin toxicities from ionizing radiation (IR) are a common side effect from therapeutic courses of external beam radiation therapy (RT) and negatively impact patient quality of life and long term survival. Advances in the understanding of the biological pathways associated with normal tissue toxicities have allowed for the development of interventional drugs, however, current response studies are limited by a lack of quantitative metrics for assessing the severity of skin reactions. Here we present a diffuse optical spectroscopic (DOS) approach that provides quantitative optical biomarkers of skin response to radiation. We describe the instrumentation design of the DOS system as well as the inversion algorithm for extracting the optical parameters. Finally, to demonstrate clinical utility, we present representative data from a pre-clinical mouse model of radiation induced erythema and compare the results with a commonly employed visual scoring. The described DOS method offers an objective, high through-put evaluation of skin toxicity via functional response that is translatable to the clinical setting. PMID:27284926

  20. Molecular magnetic resonance imaging of acute vascular cell adhesion molecule-1 expression in a mouse model of cerebral ischemia.

    PubMed

    Hoyte, Lisa C; Brooks, Keith J; Nagel, Simon; Akhtar, Asim; Chen, Ruoli; Mardiguian, Sylvie; McAteer, Martina A; Anthony, Daniel C; Choudhury, Robin P; Buchan, Alastair M; Sibson, Nicola R

    2010-06-01

    The pathogenesis of stroke is multifactorial, and inflammation is thought to have a critical function in lesion progression at early time points. Detection of inflammatory processes associated with cerebral ischemia would be greatly beneficial in both designing individual therapeutic strategies and monitoring outcome. We have recently developed a new approach to imaging components of the inflammatory response, namely endovascular adhesion molecule expression on the brain endothelium. In this study, we show specific imaging of vascular cell adhesion molecule (VCAM)-1 expression in a mouse model of middle cerebral artery occlusion (MCAO), and a reduction in this inflammatory response, associated with improved behavioral outcome, as a result of preconditioning. The spatial extent of VCAM-1 expression is considerably greater than the detectable lesion using diffusion-weighted imaging (25% versus 3% total brain volume), which is generally taken to reflect the core of the lesion at early time points. Thus, VCAM-1 imaging seems to reveal both core and penumbral regions, and our data implicate VCAM-1 upregulation and associated inflammatory processes in the progression of penumbral tissue to infarction. Our findings indicate that such molecular magnetic resonance imaging (MRI) approaches could be important clinical tools for patient evaluation, acute monitoring of therapy, and design of specific treatment strategies. PMID:20087364

  1. Mucosal immunisation with novel Streptococcus pneumoniae protein antigens enhances bacterial clearance in an acute mouse lung infection model.

    PubMed

    Jomaa, Maha; Kyd, Jennelle M; Cripps, Allan W

    2005-04-01

    Streptococcus pneumoniae contains many proteins that have not been evaluated as potential protective vaccine antigens. In this study we isolated proteins from a serotype 3 strain of S. pneumoniae for use in mouse immunisation studies. Separation of the protein mix was achieved by SDS-PAGE electrophoresis followed by electro-elution to isolate individual proteins. This procedure successfully separated 21 fractions from which six proteins were selected based on purity and quantity and were initially denoted by their molecular masses: 14-, 34-, 38-, 48-, 57- and 75-kDa. The immunogenicity of these proteins was investigated in a mucosal immunisation model in mice involving a primary inoculation to the intestinal Peyer's patches followed by an intra-tracheal boost two weeks later. The immune response was assessed by enhancement of pulmonary clearance of infection, recruitment of phagocytes to the lungs and induction of an antibody response. Two of the proteins, the 14-kDa identified as a L7/L12 ribosomal protein, and the 34-kDa identified as glyceraldehyde-3-phosphate dehydrogenase resulted in up to 99% and 94%, respectively, enhanced clearance of infection within 5 h following pulmonary challenge with S. pneumoniae. This study has shown that novel pneumococcal proteins have the potential to be vaccine candidates to enhance clearance of an acute mucosal S. pneumoniae infection. PMID:15780579

  2. Diffuse Optical Spectroscopy for the Quantitative Assessment of Acute Ionizing Radiation Induced Skin Toxicity Using a Mouse Model.

    PubMed

    Chin, Lee; Korpela, Elina; Kim, Anthony; Yohan, Darren; Niu, Carolyn; Wilson, Brian C; Liu, Stanley K

    2016-01-01

    Acute skin toxicities from ionizing radiation (IR) are a common side effect from therapeutic courses of external beam radiation therapy (RT) and negatively impact patient quality of life and long term survival. Advances in the understanding of the biological pathways associated with normal tissue toxicities have allowed for the development of interventional drugs, however, current response studies are limited by a lack of quantitative metrics for assessing the severity of skin reactions. Here we present a diffuse optical spectroscopic (DOS) approach that provides quantitative optical biomarkers of skin response to radiation. We describe the instrumentation design of the DOS system as well as the inversion algorithm for extracting the optical parameters. Finally, to demonstrate clinical utility, we present representative data from a pre-clinical mouse model of radiation induced erythema and compare the results with a commonly employed visual scoring. The described DOS method offers an objective, high through-put evaluation of skin toxicity via functional response that is translatable to the clinical setting. PMID:27284926

  3. Glutathione Supplementation Attenuates Lipopolysaccharide-Induced Mitochondrial Dysfunction and Apoptosis in a Mouse Model of Acute Lung Injury

    PubMed Central

    Aggarwal, Saurabh; Dimitropoulou, Christiana; Lu, Qing; Black, Stephen M.; Sharma, Shruti

    2012-01-01

    Acute lung injury (ALI) is a life threatening condition associated with hypoxemia, diffuse alveolar damage, inflammation, and loss of lung function. Lipopolysaccharide (LPS; endotoxin) from the outer membrane of Gram-negative bacteria is a major virulence factor involved in the development of ALI. The depletion of glutathione (GSH), an essential intra- and extra-cellular protective antioxidant, by LPS is an important event that contributes to the elevation in reactive oxygen species. Whether restoring GSH homeostasis can effectively ameliorate mitochondrial dysfunction and cellular apoptosis in ALI is unknown and therefore, was the focus of this study. In peripheral lung tissue of LPS-treated mice, hydrogen peroxide and protein nitration levels were significantly increased. Pre-treatment with GSH-ethyl ester (GSH-EE) prevented this increase in oxidative stress. LPS also increased the lactate/pyruvate ratio, attenuated SOD2 protein levels, and decreased ATP levels in the mouse lung indicative of mitochondrial dysfunction. Again, GSH-EE treatment preserved the mitochondrial function. Finally, our studies showed that LPS induced an increase in the mitochondrial translocation of Bax, caspase 3 activation, and nuclear DNA fragmentation and these parameters were all prevented with GSH-EE. Thus, this study suggests that GSH-EE supplementation may reduce the mitochondrial dysfunction associated with ALI. PMID:22654772

  4. Thymus and pulmonary lymph node response to acute and subchronic ozone inhalation in the mouse

    SciTech Connect

    Dziedzic, D.; White, H.J.

    1985-12-01

    Ozone is an oxidant gas which primarily injures the centroacinar portion of the lung. While the classical lesion of oxidant-mediated lung damage is relatively well described, the effect of this form of injury on the lymphocytic arm of the pulmonary defense system is less clear. In the present experiments Cd-1 female mice were exposed to ozone at a level of 0.7 ppm for 20 hr per day for 1-28 days and the lymphocyte response was observed in the pulmonary lymph nodes and the thymus. In the mediastinal lymph nodes a marked hyperplastic response was observed that was prominent in the paracortex and was characterized by the presence of blastic forms. In contrast, the thymus underwent an atrophic response characterized by cellular loss in the cortical region. Prior surgical adrenalectomy of ozone-exposed animals eliminated part, but not all of the thymic atrophy response, indicating that adrenal-mediated stress alone did not account for all the observed effect. Thymectomy of animals prior to ozone exposure produced a 40% reduction in the mediastinal lymph node response, suggesting that a part of the node hyperplasia is thymus dependent. The results of these experiments indicate that lymphoid organs are altered following oxidant-mediated lung damage in the mouse. The changes are observed in the absence of exogenous antigenic stimulation and suggest that lymphoid cells are in integral aspect of the host response to high-level ozone inhalation.

  5. Restoring specific lactobacilli levels decreases inflammation and muscle atrophy markers in an acute leukemia mouse model.

    PubMed

    Bindels, Laure B; Beck, Raphaël; Schakman, Olivier; Martin, Jennifer C; De Backer, Fabienne; Sohet, Florence M; Dewulf, Evelyne M; Pachikian, Barbara D; Neyrinck, Audrey M; Thissen, Jean-Paul; Verrax, Julien; Calderon, Pedro Buc; Pot, Bruno; Grangette, Corinne; Cani, Patrice D; Scott, Karen P; Delzenne, Nathalie M

    2012-01-01

    The gut microbiota has recently been proposed as a novel component in the regulation of host homeostasis and immunity. We have assessed for the first time the role of the gut microbiota in a mouse model of leukemia (transplantation of BaF3 cells containing ectopic expression of Bcr-Abl), characterized at the final stage by a loss of fat mass, muscle atrophy, anorexia and inflammation. The gut microbial 16S rDNA analysis, using PCR-Denaturating Gradient Gel Electrophoresis and quantitative PCR, reveals a dysbiosis and a selective modulation of Lactobacillus spp. (decrease of L. reuteri and L. johnsonii/gasseri in favor of L. murinus/animalis) in the BaF3 mice compared to the controls. The restoration of Lactobacillus species by oral supplementation with L. reuteri 100-23 and L. gasseri 311476 reduced the expression of atrophy markers (Atrogin-1, MuRF1, LC3, Cathepsin L) in the gastrocnemius and in the tibialis, a phenomenon correlated with a decrease of inflammatory cytokines (interleukin-6, monocyte chemoattractant protein-1, interleukin-4, granulocyte colony-stimulating factor, quantified by multiplex immuno-assay). These positive effects are strain- and/or species-specific since L. acidophilus NCFM supplementation does not impact on muscle atrophy markers and systemic inflammation. Altogether, these results suggest that the gut microbiota could constitute a novel therapeutic target in the management of leukemia-associated inflammation and related disorders in the muscle. PMID:22761662

  6. Additional Resection of the Pancreas Body Prevents Postoperative Pancreas Fistula in Patients with Portal Annular Pancreas Who Undergo Pancreaticoduodenectomy

    PubMed Central

    Muto, Jun; Mano, Yohei; Harada, Noboru; Uchiyama, Hideaki; Yoshizumi, Tomoharu; Taketomi, Akinobu; Shirabe, Ken; Maehara, Yoshihiko

    2012-01-01

    Portal annular pancreas (PAP) is a rare variant in which the uncinate process of the pancreas extends to the dorsal surface of the pancreas body and surrounds the portal vein or superior mesenteric vein. Upon pancreaticoduodenectomy (PD), when the pancreas is cut at the neck, two cut surfaces are created. Thus, the cut surface of the pancreas becomes larger than usual and the dorsal cut surface is behind the portal vein, therefore pancreatic fistula after PD has been reported frequently. We planned subtotal stomach-preserving PD in a 45-year-old woman with underlying insulinoma of the pancreas head. When the pancreas head was dissected, the uncinate process was extended and fused to the dorsal surface of the pancreas body. Additional resection of the pancreas body 1 cm distal to the pancreas tail to the left side of the original resection line was performed. The new cut surface became one and pancreaticojejunostomy was performed as usual. No postoperative complications such as pancreatic fistula occurred. Additional resection of the pancreas body may be a standardized procedure in patients with PAP in cases of pancreas cut surface reconstruction. PMID:22532811

  7. Lymphoepithelial Cyst of the Pancreas

    PubMed Central

    Arumugam, Prabhu; Fletcher, Natalie; Kyriakides, Charis; Mears, Lisa; Kocher, Hemant M.

    2016-01-01

    Lymphoepithelial cyst (LEC) of the pancreas is an extremely rare, benign pancreatic cystic lesion that is difficult to differentiate preoperatively from other cystic pancreatic lesions. LEC may have malignant potential. Here, we describe a case of LEC of the pancreas – initially suspected to be a mucinous cyst neoplasm – in an elderly man presenting with abdominal pain, who went on to have a distal pancreatectomy and splenectomy. We also review the relevant literature and discuss implications for the diagnosis and management of this rare lesion. PMID:27403123

  8. Ginsenoside Rd alleviates mouse acute renal ischemia/reperfusion injury by modulating macrophage phenotype

    PubMed Central

    Ren, Kaixi; Jin, Chao; Ma, Pengfei; Ren, Qinyou; Jia, Zhansheng; Zhu, Daocheng

    2015-01-01

    Background Ginsenoside Rd (GSRd), a main component of the root of Panax ginseng, exhibits anti-inflammation functions and decreases infarct size in many injuries and ischemia diseases such as focal cerebral ischemia. M1 Macrophages are regarded as one of the key inflammatory cells having functions for disease progression. Methods To investigate the effect of GSRd on renal ischemia/reperfusion injury (IRI) and macrophage functional status, and their regulatory role on mouse polarized macrophages in vitro, GSRd (10–100 mg/kg) and vehicle were applied to mice 30 min before renal IRI modeling. Renal functions were reflected by blood serum creatinine and blood urea nitrogen level and histopathological examination. M1 polarized macrophages infiltration was identified by flow cytometry analysis and immunofluorescence staining with CD11b+, iNOS+/interleukin-12/tumor necrosis factor-α labeling. For the in vitro study, GSRd (10–100 μg/mL) and vehicle were added in the culture medium of M1 macrophages to assess their regulatory function on polarization phenotype. Results In vivo data showed a protective role of GSRd at 50 mg/kg on Day 3. Serum level of serum creatinine and blood urea nitrogen significantly dropped compared with other groups. Reduced renal tissue damage and M1 macrophage infiltration showed on hematoxylin–eosin staining and flow cytometry and immunofluorescence staining confirmed this improvement. With GSRd administration, in vitro cultured M1 macrophages secreted less inflammatory cytokines such as interleukin-12 and tumor necrosis factor-α. Furthermore, macrophage polarization-related pancake-like morphology gradually changed along with increasing concentration of GSRd in the medium. Conclusion These findings demonstrate that GSRd possess a protective function against renal ischemia/reperfusion injury via downregulating M1 macrophage polarization. PMID:27158241

  9. PAX5 is a tumor suppressor in mouse mutagenesis models of acute lymphoblastic leukemia

    PubMed Central

    Dang, Jinjun; Wei, Lei; de Ridder, Jeroen; Su, Xiaoping; Rust, Alistair G.; Roberts, Kathryn G.; Payne-Turner, Debbie; Cheng, Jinjun; Ma, Jing; Qu, Chunxu; Wu, Gang; Song, Guangchun; Huether, Robert G.; Schulman, Brenda; Janke, Laura; Zhang, Jinghui; Downing, James R.; van der Weyden, Louise; Adams, David J.

    2015-01-01

    Alterations of genes encoding transcriptional regulators of lymphoid development are a hallmark of B-progenitor acute lymphoblastic leukemia (B-ALL) and most commonly involve PAX5, encoding the DNA-binding transcription factor paired-box 5. The majority of PAX5 alterations in ALL are heterozygous, and key PAX5 target genes are expressed in leukemic cells, suggesting that PAX5 may be a haploinsufficient tumor suppressor. To examine the role of PAX5 alterations in leukemogenesis, we performed mutagenesis screens of mice heterozygous for a loss-of-function Pax5 allele. Both chemical and retroviral mutagenesis resulted in a significantly increased penetrance and reduced latency of leukemia, with a shift to B-lymphoid lineage. Genomic profiling identified a high frequency of secondary genomic mutations, deletions, and retroviral insertions targeting B-lymphoid development, including Pax5, and additional genes and pathways mutated in ALL, including tumor suppressors, Ras, and Janus kinase-signal transducer and activator of transcription signaling. These results show that in contrast to simple Pax5 haploinsufficiency, multiple sequential alterations targeting lymphoid development are central to leukemogenesis and contribute to the arrest in lymphoid maturation characteristic of ALL. This cross-species analysis also validates the importance of concomitant alterations of multiple cellular growth, signaling, and tumor suppression pathways in the pathogenesis of B-ALL. PMID:25855603

  10. Yueju Pill Rapidly Induces Antidepressant-Like Effects and Acutely Enhances BDNF Expression in Mouse Brain

    PubMed Central

    Xue, Wenda; Zhou, Xin; Yi, Nan; Jiang, Lihua; Tao, Weiwei; Wu, Runjie; Wang, Dan; Jiang, Jingjing; Ge, Xiaoyin; Wang, Yuyue; Wu, Haoxin; Chen, Gang

    2013-01-01

    The traditional antidepressants have a major disadvantage in delayed onset of efficacy, and the emerging fast-acting antidepressant ketamine has adverse behavioral and neurotoxic effects. Yueju pill, an herb medicine formulated eight hundred years ago by Doctor Zhu Danxi, has been popularly prescribed in China for alleviation of depression-like symptoms. Although several clinical outcome studies reported the relative short onset of antidepressant effects of Yueju, this has not been scientifically investigated. We, therefore, examined the rapid antidepressant effect of Yueju in mice and tested the underlying molecular mechanisms. We found that acute administration of ethanol extract of Yueju rapidly attenuated depressive-like symptoms in learned helpless paradigm, and the antidepressant-like effects were sustained for at least 24 hours in tail suspension test in ICR mice. Additionally, Yueju, like ketamine, rapidly increased the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus, whereas the BDNF mRNA expression remained unaltered. Yueju rapidly reduced the phosphorylation of eukaryotic elongation factor 2 (eEF2), leading to desuppression of BDNF synthesis. Unlike ketamine, both the BDNF expression and eEF2 phosphorylation were revered at 24 hours after Yueju administration. This study is the first to demonstrate the rapid antidepressant effects of an herb medicine, offering an opportunity to improve therapy of depression. PMID:23710213

  11. Acute effects of whole-body proton irradiation on the immune system of the mouse

    NASA Technical Reports Server (NTRS)

    Kajioka, E. H.; Andres, M. L.; Li, J.; Mao, X. W.; Moyers, M. F.; Nelson, G. A.; Slater, J. M.; Gridley, D. S.

    2000-01-01

    The acute effects of proton whole-body irradiation on the distribution and function of leukocyte populations in the spleen and blood were examined and compared to the effects of photons derived from a (60)Co gamma-ray source. Adult female C57BL/6 mice were exposed to a single dose (3 Gy at 0.4 Gy/min) of protons at spread-out Bragg peak (SOBP), protons at the distal entry (E) region, or gamma rays and killed humanely at six different times thereafter. Specific differences were noted in the results, thereby suggesting that the kinetics of the response may be variable. However, the lack of significant differences in most assays at most times suggests that the RBE for both entry and peak regions of the Bragg curve was essentially 1.0 under the conditions of this study. The greatest immunodepression was observed at 4 days postexposure. Flow cytometry and mitogenic stimulation analyses of the spleen and peripheral blood demonstrated that lymphocyte populations differ in radiosensitivity, with B (CD19(+)) cells being most sensitive, T (CD3(+)) cells being moderately sensitive, and natural killer (NK1.1(+)) cells being most resistant. B lymphocytes showed the most rapid recovery. Comparison of the T-lymphocyte subsets showed that CD4(+) T helper/inducer cells were more radiosensitive than the CD8(+) T cytotoxic/suppressor cells. These findings should have an impact on future studies designed to maximize protection of normal tissue during and after proton-radiation exposure.

  12. Exogenous Lipocalin 2 Ameliorates Acute Rejection in a Mouse Model of Renal Transplantation

    PubMed Central

    Ashraf, M. I.; Schwelberger, H. G.; Brendel, K. A.; Feurle, J.; Andrassy, J.; Kotsch, K.; Regele, H.; Pratschke, J.; Maier, H. T.

    2016-01-01

    Abstract Lipocalin 2 (Lcn2) is rapidly produced by damaged nephron epithelia and is one of the most promising new markers of renal injury, delayed graft function and acute allograft rejection (AR); however, the functional importance of Lcn2 in renal transplantation is largely unknown. To understand the role of Lcn2 in renal AR, kidneys from Balb/c mice were transplanted into C57Bl/6 mice and vice versa and analyzed for morphological and physiological outcomes of AR at posttransplantation days 3, 5, and 7. The allografts showed a steady increase in intensity of interstitial infiltration, tubulitis and periarterial aggregation of lymphocytes associated with a substantial elevation in serum levels of creatinine, urea and Lcn2. Perioperative administration of recombinant Lcn2:siderophore:Fe complex (rLcn2) to recipients resulted in functional and morphological amelioration of the allograft at day 7 almost as efficiently as daily immunosuppression with cyclosporine A (CsA). No significant differences were observed in various donor–recipient combinations (C57Bl/6 wild‐type and Lcn2−/−, Balb/c donors and recipients). Histochemical analyses of the allografts showed reduced cell death in recipients treated with rLcn2 or CsA. These results demonstrate that Lcn2 plays an important role in reducing the extent of kidney AR and indicate the therapeutic potential of Lcn2 in transplantation. PMID:26595644

  13. Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexia

    SciTech Connect

    Benny Klimek, Margaret E.; Aydogdu, Tufan; Link, Majik J.; Pons, Marianne; Koniaris, Leonidas G.; Zimmers, Teresa A.

    2010-01-15

    Cachexia, progressive loss of fat and muscle mass despite adequate nutrition, is a devastating complication of cancer associated with poor quality of life and increased mortality. Myostatin is a potent tonic muscle growth inhibitor. We tested how myostatin inhibition might influence cancer cachexia using genetic and pharmacological approaches. First, hypermuscular myostatin null mice were injected with Lewis lung carcinoma or B16F10 melanoma cells. Myostatin null mice were more sensitive to tumor-induced cachexia, losing more absolute mass and proportionately more muscle mass than wild-type mice. Because myostatin null mice lack expression from development, however, we also sought to manipulate myostatin acutely. The histone deacetylase inhibitor Trichostatin A has been shown to increase muscle mass in normal and dystrophic mice by inducing the myostatin inhibitor, follistatin. Although Trichostatin A administration induced muscle growth in normal mice, it failed to preserve muscle in colon-26 cancer cachexia. Finally we sought to inhibit myostatin and related ligands by administration of the Activin receptor extracellular domain/Fc fusion protein, ACVR2B-Fc. Systemic administration of ACVR2B-Fc potently inhibited muscle wasting and protected adipose stores in both colon-26 and Lewis lung carcinoma cachexia, without affecting tumor growth. Enhanced cachexia in myostatin knockouts indicates that host-derived myostatin is not the sole mediator of muscle wasting in cancer. More importantly, skeletal muscle preservation with ACVR2B-Fc establishes that targeting myostatin-family ligands using ACVR2B-Fc or related molecules is an important and potent therapeutic avenue in cancer cachexia.

  14. Characterization of a nose-only inhaled phosgene acute lung injury mouse model

    PubMed Central

    Plahovinsak, Jennifer L.; Perry, Mark R.; Knostman, Katherine A.; Segal, Robert; Babin, Michael C.

    2016-01-01

    Context Phosgene’s primary mode of action is as a pulmonary irritant characterized by its early latent phase where life-threatening, non-cardiogenic pulmonary edema is typically observed 6–24 h post-exposure. Objective To develop an inhaled phosgene acute lung injury (ALI) model in C57BL/6 mice that can be used to screen potential medical countermeasures. Methods A Cannon style nose-only inhalation exposure tower was used to expose mice to phosgene (8 ppm) or air (sham). An inhalation lethality study was conducted to determine the 8 ppm median lethal exposure (LCt50) at 24 and 48 h post-exposure. The model was then developed at 1.2 times the 24 h LCt50. At predetermined serial sacrifice time points, survivors were euthanized, body and lung weights collected, and lung tissues processed for histopathology. Additionally, post-exposure clinical observations were used to assess quality of life. Results and discussion The 24-hour LCt50 was 226ppm*min (8 ppm for 28.2 min) and the 48-hour LCt50 was 215ppm*min (8 ppm for 26.9 min). The phosgene exposed animals had a distinct progression of clinical signs, histopathological changes and increased lung/body weight ratios. Early indicators of a 1.2 times the 24-hour LCt50 phosgene exposure were significant changes in the lung-to-body weight ratios by 4 h post-exposure. The progression of clinical signs and histopathological changes were important endpoints for characterizing phosgene-induced ALI for future countermeasure studies. Conclusion An 8 ppm phosgene exposure for 34 min (1.2 × LCt50) is the minimum challenge recommended for evaluating therapeutic interventions. The predicted higher mortality in the phosgene-only controls will help demonstrate efficacy of candidate treatments and increase the probability that a change in survival rate is statistically significant PMID:26671199

  15. An Intradermal Inoculation Mouse Model for Immunological Investigations of Acute Scrub Typhus and Persistent Infection

    PubMed Central

    Rockx-Brouwer, Dedeke; Xu, Guang; Goez-Rivillas, Yenny; Drom, Claire; Shelite, Thomas R.; Valbuena, Gustavo; Walker, David H.; Bouyer, Donald H.

    2016-01-01

    Scrub typhus is a neglected tropical disease, caused by Orientia tsutsugamushi, a Gram-negative bacterium that is transmitted to mammalian hosts during feeding by Leptotrombidium mites and replicates predominantly within endothelial cells. Most studies of scrub typhus in animal models have utilized either intraperitoneal or intravenous inoculation; however, there is limited information on infection by the natural route in murine model skin or its related early host responses. Here, we developed an intradermal (i.d.) inoculation model of scrub typhus and focused on the kinetics of the host responses in the blood and major infected organs. Following ear inoculation with 6 x 104 O. tsutsugamushi, mice developed fever at 11–12 days post-infection (dpi), followed by marked hypothermia and body weight loss at 14–19 dpi. Bacteria in blood and tissues and histopathological changes were detected around 9 dpi and peaked around 14 dpi. Serum cytokine analyses revealed a mixed Th1/Th2 response, with marked elevations of MCP-1/CCL2, MIP-1α/CCL3 and IL-10 at 9 dpi, followed by increased concentrations of pro-inflammatory markers (IL-6, IL-12, IFN-γ, G-CSF, RANTES/CCL5, KC/CCL11, IL-1α/β, IL-2, TNF-α, GM-CSF), as well as modulatory cytokines (IL-9, IL-13). Cytokine levels in lungs had similar elevation patterns, except for a marked reduction of IL-9. The Orientia 47-kDa gene and infectious bacteria were detected in several organs for up to 84 dpi, indicating persistent infection. This is the first comprehensive report of acute scrub typhus and persistent infection in i.d.-inoculated C57BL/6 mice. This is a significant improvement over current murine models for Orientia infection and will permit detailed studies of host immune responses and infection control interventions. PMID:27479584

  16. An Intradermal Inoculation Mouse Model for Immunological Investigations of Acute Scrub Typhus and Persistent Infection.

    PubMed

    Soong, Lynn; Mendell, Nicole L; Olano, Juan P; Rockx-Brouwer, Dedeke; Xu, Guang; Goez-Rivillas, Yenny; Drom, Claire; Shelite, Thomas R; Valbuena, Gustavo; Walker, David H; Bouyer, Donald H

    2016-08-01

    Scrub typhus is a neglected tropical disease, caused by Orientia tsutsugamushi, a Gram-negative bacterium that is transmitted to mammalian hosts during feeding by Leptotrombidium mites and replicates predominantly within endothelial cells. Most studies of scrub typhus in animal models have utilized either intraperitoneal or intravenous inoculation; however, there is limited information on infection by the natural route in murine model skin or its related early host responses. Here, we developed an intradermal (i.d.) inoculation model of scrub typhus and focused on the kinetics of the host responses in the blood and major infected organs. Following ear inoculation with 6 x 104 O. tsutsugamushi, mice developed fever at 11-12 days post-infection (dpi), followed by marked hypothermia and body weight loss at 14-19 dpi. Bacteria in blood and tissues and histopathological changes were detected around 9 dpi and peaked around 14 dpi. Serum cytokine analyses revealed a mixed Th1/Th2 response, with marked elevations of MCP-1/CCL2, MIP-1α/CCL3 and IL-10 at 9 dpi, followed by increased concentrations of pro-inflammatory markers (IL-6, IL-12, IFN-γ, G-CSF, RANTES/CCL5, KC/CCL11, IL-1α/β, IL-2, TNF-α, GM-CSF), as well as modulatory cytokines (IL-9, IL-13). Cytokine levels in lungs had similar elevation patterns, except for a marked reduction of IL-9. The Orientia 47-kDa gene and infectious bacteria were detected in several organs for up to 84 dpi, indicating persistent infection. This is the first comprehensive report of acute scrub typhus and persistent infection in i.d.-inoculated C57BL/6 mice. This is a significant improvement over current murine models for Orientia infection and will permit detailed studies of host immune responses and infection control interventions. PMID:27479584

  17. Sesamol treatment reduces plasma cholesterol and triacylglycerol levels in mouse models of acute and chronic hyperlipidemia.

    PubMed

    Kumar, Nitesh; Mudgal, Jayesh; Parihar, Vipan K; Nayak, Pawan G; Kutty, N Gopalan; Rao, C Mallikarjuna

    2013-06-01

    The active constituents of Sesamum indicum, sesamin and sesamolin, have already been explored for hypolipidemic action. In this study we have explored the anti-dyslipidemic activity of another active component and metabolite of sesamolin (sesamol), by using acute models of hyperlipidemia viz., a fat tolerance test, a tyloxapol-induced hyperlipidemia model and a chronic model of hyperlipidemia viz., a high-fat diet-induced hyperlipidemia model in Swiss albino mice. Sesamol (100 and 200 mg/kg) significantly (P < 0.05) decreased triacylglycerol absorption in the fat tolerance test by showing a dose-dependent decrease in triacylglycerol levels. The hypolipidemic effect of sesamol at 200 mg/kg was equivalent to 10 mg/kg of orlistat. In the tyloxapol-induced hyperlipidemia model, Sesamol at 200 mg/kg reversed the elevated levels of cholesterol and triacylglycerol compared with the tyloxapol group at 12 and 24 h, which indicates its probable effect on cholesterol synthesis. Chronic hyperlipidemia in mice was produced by feeding a high-diet, a mixture of cholesterol (2 % w/w), cholic acid (1 % w/w) and coconut oil 30 % (v/w) with standard powdered standard animal chow (up to 100 g). Niacin (100 mg/kg) and sesamol (100 mg/kg) significantly (P < 0.05) reduced the elevated body weight compared with the high fat diet control group. Elevated levels of cholesterol and triacylglycerol were significantly (P < 0.05) reversed by the sesamol (50 and 100 mg/kg), implying that it might reduce the absorption and increase the excretion of cholesterol as well. PMID:23504268

  18. Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexia.

    PubMed

    Benny Klimek, Margaret E; Aydogdu, Tufan; Link, Majik J; Pons, Marianne; Koniaris, Leonidas G; Zimmers, Teresa A

    2010-01-15

    Cachexia, progressive loss of fat and muscle mass despite adequate nutrition, is a devastating complication of cancer associated with poor quality of life and increased mortality. Myostatin is a potent tonic muscle growth inhibitor. We tested how myostatin inhibition might influence cancer cachexia using genetic and pharmacological approaches. First, hypermuscular myostatin null mice were injected with Lewis lung carcinoma or B16F10 melanoma cells. Myostatin null mice were more sensitive to tumor-induced cachexia, losing more absolute mass and proportionately more muscle mass than wild-type mice. Because myostatin null mice lack expression from development, however, we also sought to manipulate myostatin acutely. The histone deacetylase inhibitor Trichostatin A has been shown to increase muscle mass in normal and dystrophic mice by inducing the myostatin inhibitor, follistatin. Although Trichostatin A administration induced muscle growth in normal mice, it failed to preserve muscle in colon-26 cancer cachexia. Finally we sought to inhibit myostatin and related ligands by administration of the Activin receptor extracellular domain/Fc fusion protein, ACVR2B-Fc. Systemic administration of ACVR2B-Fc potently inhibited muscle wasting and protected adipose stores in both colon-26 and Lewis lung carcinoma cachexia, without affecting tumor growth. Enhanced cachexia in myostatin knockouts indicates that host-derived myostatin is not the sole mediator of muscle wasting in cancer. More importantly, skeletal muscle preservation with ACVR2B-Fc establishes that targeting myostatin-family ligands using ACVR2B-Fc or related molecules is an important and potent therapeutic avenue in cancer cachexia. PMID:20036643

  19. Flaxseed Mitigates Acute Oxidative Lung Damage in a Mouse Model of Repeated Radiation and Hyperoxia Exposure Associated with Space Exploration

    PubMed Central

    Pietrofesa, Ralph A.; Solomides, Charalambos C.; Christofidou-Solomidou, Melpo

    2015-01-01

    Background Spaceflight missions may require crewmembers to conduct extravehicular activities (EVA). Pre-breathe protocols in preparation for an EVA entail 100% hyperoxia exposure that may last for a few hours and be repeated 2-3 times weekly. Each EVA is associated with additional challenges such as low levels of total body cosmic/galactic radiation exposure that may present a threat to crewmember health. We have developed a mouse model of total body radiation and hyperoxia exposure and identified acute damage of lung tissues. In the current study we evaluated the usefulness of dietary flaxseed (FS) as a countermeasure agent for such double-hit exposures. Methods We evaluated lung tissue changes 2 weeks post-initiation of exposure challenges. Mouse cohorts (n=5/group) were pre-fed diets containing either 0% FS or 10% FS for 3 weeks and exposed to: a) normoxia (Untreated); b) >95% O2 (O2); c) 0.25Gy single fraction gamma radiation (IR); or d) a combination of O2 and IR (O2+IR) 3 times per week for 2 consecutive weeks, where 8-hour hyperoxia treatments were spanned by normoxic intervals. Results At 2 weeks post challenge, while control-diet fed mice developed significant lung injury and inflammation across all challenges, FS protected lung tissues by decreasing bronchoalveolar lavage fluid (BALF) neutrophils (p<0.003) and protein levels, oxidative tissue damage, as determined by levels of malondialdehyde (MDA) (p<0.008) and nitrosative stress as determined by nitrite levels. Lung hydroxyproline levels, a measure of lung fibrosis, were significantly elevated in mice fed 0% FS (p<0.01) and exposed to hyperoxia/radiation or the combination treatment, but not in FS-fed mice. FS also decreased levels of a pro-inflammatory, pro-fibrogenic cytokine (TGF-β1) gene expression levels in lung. Conclusion Flaxseed mitigated adverse effects in lung of repeat exposures to radiation/hyperoxia. This data will provide useful information in the design of countermeasures to early

  20. Gadolinium induced recurrent acute pancreatitis.

    PubMed

    Blasco-Perrin, H; Glaser, B; Pienkowski, M; Peron, J M; Payen, J L

    2013-01-01

    Acute pancreatitis is a sudden swelling and inflammation of the pancreas. The two most common causes are alcohol use and biliary stones. Drug-induced acute pancreatitis are rare (1.4-2%). In this present study, we present a case of recurrent acute pancreatitis induced by a specific magnetic-resonance-imaging (MRI) contrast agent called gadobenate dimeglumine. PMID:23395575

  1. Acute TrkB inhibition rescues phenobarbital-resistant seizures in a mouse model of neonatal ischemia.

    PubMed

    Kang, S K; Johnston, M V; Kadam, S D

    2015-11-01

    Neonatal seizures are commonly associated with hypoxic-ischemic encephalopathy. Phenobarbital (PB) resistance is common and poses a serious challenge in clinical management. Using a newly characterized neonatal mouse model of ischemic seizures, this study investigated a novel strategy for rescuing PB resistance. A small-molecule TrkB antagonist, ANA12, used to selectively and transiently block post-ischemic BDNF-TrkB signaling in vivo, determined whether rescuing TrkB-mediated post-ischemic degradation of the K(+)-Cl(-) co-transporter (KCC2) rescued PB-resistant seizures. The anti-seizure efficacy of ANA12 + PB was quantified by (i) electrographic seizure burden using acute continuous video-electroencephalograms and (ii) post-treatment expression levels of KCC2 and NKCC1 using Western blot analysis in postnatal day (P)7 and P10 CD1 pups with unilateral carotid ligation. ANA12 significantly rescued PB-resistant seizures at P7 and improved PB efficacy at P10. A single dose of ANA12 + PB prevented the post-ischemic degradation of KCC2 for up to 24 h. As anticipated, ANA12 by itself had no anti-seizure properties and was unable to prevent KCC2 degradation at 24 h without follow-on PB. This indicates that unsubdued seizures can independently lead to KCC2 degradation via non-TrkB-dependent pathways. This study, for the first time as a proof-of-concept, reports the potential therapeutic value of KCC2 modulation for the management of PB-resistant seizures in neonates. Future investigations are required to establish the mechanistic link between ANA12 and the prevention of KCC2 degradation. PMID:26452067

  2. Increase in cocaine- and amphetamine-regulated transcript (CART) in specific areas of the mouse brain by acute caffeine administration.

    PubMed

    Cho, Jin Hee; Cho, Yun Ha; Kim, Hyo Young; Cha, Seung Ha; Ryu, Hyun; Jang, Wooyoung; Shin, Kyung Ho

    2015-04-01

    Caffeine produces a variety of behavioral effects including increased alertness, reduced food intake, anxiogenic effects, and dependence upon repeated exposure. Although many of the effects of caffeine are mediated by its ability to block adenosine receptors, it is possible that other neural substrates, such as cocaine- and amphetamine-regulated transcript (CART), may be involved in the effects of caffeine. Indeed, a recent study demonstrated that repeated caffeine administration increases CART in the mouse striatum. However, it is not clear whether acute caffeine administration alters CART in other areas of the brain. To explore this possibility, we investigated the dose- and time-dependent changes in CART immunoreactivity (CART-IR) after a single dose of caffeine in mice. We found that a high dose of caffeine (100 mg/kg) significantly increased CART-IR 2 h after administration in the nucleus accumbens shell (AcbSh), dorsal bed nucleus of the stria terminalis (dBNST), central nucleus of the amygdala (CeA), paraventricular hypothalamic nucleus (PVN), arcuate hypothalamic nucleus (Arc), and locus coeruleus (LC), and returned to control levels after 8 h. But this increase was not observed in other brain areas. In addition, caffeine administration at doses of 25 and 50 mg/kg appears to produce dose-dependent increases in CART-IR in these brain areas; however, the magnitude of increase in CART-IR observed at a dose of 50 mg/kg was similar or greater than that observed at a dose of 100 mg/kg. This result suggests that CART-IR in AcbSh, dBNST, CeA, PVN, Arc, and LC is selectively affected by caffeine administration. PMID:25820086

  3. HLA-A, -B, -C, -DR, and -DQ Matching in Pancreas Transplantation: Effect on Graft Rejection and Survival.

    PubMed

    Rudolph, E N; Dunn, T B; Mauer, D; Noreen, H; Sutherland, D E R; Kandaswamy, R; Finger, E B

    2016-08-01

    To enhance selection of appropriate deceased donors for pancreas transplants, we sought to determine whether HLA matching improved posttransplantation outcomes. In this single-center study of 1219 pancreas transplants, we correlated posttransplantation outcomes with HLA-A, -B, -C, -DR, and -DQ matches and mismatches. Rejection was linearly correlated with the number of mismatches. The individual number of HLA mismatches reached significance at four or more with a 2.3- to 2.9-fold increase in rejection. The effect was most predominant with HLA-B (1.8-fold with one mismatch and 2.0-fold with two mismatches) and -DR (1.9-fold with two mismatches) loci, whereas HLA-A, -C, and -DQ matches or mismatches did not independently predict acute rejection. The affect was strongest in solitary pancreas transplants, with little impact for simultaneous pancreas and kidney (SPK). In contrast, HLA matching did not affect graft or patient survival rates but was associated with a reduced risk of opportunistic infection. Avoidance of acute rejection saved an estimated $32 000 for solitary pancreas recipients and $52 000 for SPK recipients in hospital costs. Our data do not support the use of HLA matching for predicting pancreas graft survival but do support its significance for the reduction of acute rejection, particularly for solitary pancreas recipients. PMID:26814363

  4. Pancreas donation for islet transplantation.

    PubMed

    Frutos, M A; Ruiz, P; Mansilla, J J

    2005-04-01

    Islet transplantation, though still in the experimental phase, is a therapeutic option that has opened new expectations for the control of diabetes mellitus. Initial results are encouraging for the significant advantages compared with whole pancreas transplantation for selected patients with type 1 diabetes mellitus, with or without kidney failure. However, the success of transplantation, both at centers with more experience and others with less, is limited by the difficulty in obtaining a suitable number of donors and by laboratory isolation techniques. Significant advances require changes in donor selection, perfusion, oxygenation, and transfer of the pancreas, and in the process of isolation, purification, and culture in the laboratory. Of the 32 pancreases sent to the islet isolation laboratory from different hospitals in Andalusia, a viable percentage of islets was finally available in 19. However, in only 4 (18%) procedures were the preparations considered optimal for implantation in 2 recipients. PMID:15866673

  5. Wearable and implantable pancreas substitutes.

    PubMed

    Ricotti, Leonardo; Assaf, Tareq; Dario, Paolo; Menciassi, Arianna

    2013-03-01

    A lifelong-implanted and completely automated artificial or bioartificial pancreas (BAP) is the holy grail for type 1 diabetes treatment, and could be a definitive solution even for other severe pathologies, such as pancreatitis and pancreas cancer. Technology has made several important steps forward in the last years, providing new hope for the realization of such devices, whose feasibility is strictly connected to advances in glucose sensor technology, subcutaneous and intraperitoneal insulin pump development, the design of closed-loop control algorithms for mechatronic pancreases, as well as cell and tissue engineering and cell encapsulation for biohybrid pancreases. Furthermore, smart integration of the mentioned components and biocompatibility issues must be addressed, bearing in mind that, for mechatronic pancreases, it is most important to consider how to recharge implanted batteries and refill implanted insulin reservoirs without requiring periodic surgical interventions. This review describes recent advancements in technologies and concepts related to artificial and bioartificial pancreases, and assesses how far we are from a lifelong-implanted and self-working pancreas substitute that can fully restore the quality of life of a diabetic (or other type of) patient. PMID:22990986

  6. Quercetin Aglycone Is Bioavailable in Murine Pancreas and Pancreatic Xenografts

    PubMed Central

    Zhang, Lifeng; Angst, Eliane; Park, Jenny L.; Moro, Aune; Dawson, David W.; Reber, Howard A.; Eibl, Guido; Hines, O. Joe; Go, Vay-Liang W.; Lu, Qing-Yi

    2010-01-01

    Quercetin is a potential chemopreventive and chemotherapeutic agent for pancreatic and other cancers. This study was to examine the distribution of quercetin in plasma, lung, liver, pancreas and pancreatic cancer xenografts in a murine in vivo model and the uptake of quercetin in pancreatic cancer MiaPaCa-2 cells in cellular in vitro model. Mice were randomly allocated to control diet, 0.2 and 1% quercetin diet groups utilizing the AIN93G-based diet (n=12 per group) for 6 weeks. In addition, 6 mice from each group were injected weekly with chemotherapeutic drug gemcitabine (120 mg/kg mouse, i.p.). MiaPaCa cells were collected from culture medium after cells were exposed to 30 µM of quercetin for 0.5, 1, 2, 4, 8, and 24 hrs. Levels of quercetin and 3-O’-methyl-quercetin in mice tissues and MiaPaCa-2 cells were measured by high-pressure liquid chromatography following enzymatic hydrolysis and then extraction. Our study showed that quercetin is accumulated in pancreatic cancer cells, and is absorbed in the circulating system, tumors and tissues of pancreas, liver and lung in vivo. A higher proportion of total quercetin found in tumors and pancreas are aglycones. Gemcitabine co-treatment with quercetin reduced absorption of quercetin in mice circulatory system and liver. Results from the study provide important information on the interpretation of chemo-therapeutic efficacy of quercetin. PMID:20499918

  7. Acute and Chronic Plasma Metabolomic and Liver Transcriptomic Stress Effects in a Mouse Model with Features of Post-Traumatic Stress Disorder

    PubMed Central

    Gautam, Aarti; D’Arpa, Peter; Donohue, Duncan E.; Muhie, Seid; Chakraborty, Nabarun; Luke, Brian T.; Grapov, Dmitry; Carroll, Erica E.; Meyerhoff, James L.; Hammamieh, Rasha; Jett, Marti

    2015-01-01

    Acute responses to intense stressors can give rise to post-traumatic stress disorder (PTSD). PTSD diagnostic criteria include trauma exposure history and self-reported symptoms. Individuals who meet PTSD diagnostic criteria often meet criteria for additional psychiatric diagnoses. Biomarkers promise to contribute to reliable phenotypes of PTSD and comorbidities by linking biological system alterations to behavioral symptoms. Here we have analyzed unbiased plasma metabolomics and other stress effects in a mouse model with behavioral features of PTSD. In this model, C57BL/6 mice are repeatedly exposed to a trained aggressor mouse (albino SJL) using a modified, resident-intruder, social defeat paradigm. Our recent studies using this model found that aggressor-exposed mice exhibited acute stress effects including changed behaviors, body weight gain, increased body temperature, as well as inflammatory and fibrotic histopathologies and transcriptomic changes of heart tissue. Some of these acute stress effects persisted, reminiscent of PTSD. Here we report elevated proteins in plasma that function in inflammation and responses to oxidative stress and damaged tissue at 24 hrs post-stressor. Additionally at this acute time point, transcriptomic analysis indicated liver inflammation. The unbiased metabolomics analysis showed altered metabolites in plasma at 24 hrs that only partially normalized toward control levels after stress-withdrawal for 1.5 or 4 wks. In particular, gut-derived metabolites were altered at 24 hrs post-stressor and remained altered up to 4 wks after stress-withdrawal. Also at the 4 wk time point, hyperlipidemia and suppressed metabolites of amino acids and carbohydrates in plasma coincided with transcriptomic indicators of altered liver metabolism (activated xenobiotic and lipid metabolism). Collectively, these system-wide sequelae to repeated intense stress suggest that the simultaneous perturbed functioning of multiple organ systems (e.g., brain, heart

  8. Stromal reengineering to treat pancreas cancer

    PubMed Central

    Stromnes, Ingunn M.; DelGiorno, Kathleen E.; Greenberg, Philip D.; Hingorani, Sunil R.

    2014-01-01

    Pancreatic ductal adenocarcinoma co-opts multiple cellular and extracellular mechanisms to create a complex cancer organ with an unusual proclivity for metastasis and resistance to therapy. Cell-autonomous events are essential for the initiation and maintenance of pancreatic ductal adenocarcinoma, but recent studies have implicated critical non-cell autonomous processes within the robust desmoplastic stroma that promote disease pathogenesis and resistance. Thus, non-malignant cells and associated factors are culprits in tumor growth, immunosuppression and invasion. However, even this increasing awareness of non-cell autonomous contributions to disease progression is tempered by the conflicting roles stromal elements can play. A greater understanding of stromal complexity and complicity has been aided in part by studies in highly faithful genetically engineered mouse models of pancreatic ductal adenocarcinoma. Insights gleaned from such studies are spurring the development of therapies designed to reengineer the pancreas cancer stroma and render it permissive to agents targeting cell-autonomous events or to reinstate immunosurveillance. Integrating conventional and immunological treatments in the context of stromal targeting may provide the key to a durable clinical impact on this formidable disease. PMID:24908682

  9. Gravity in mammalian organ development: differentiation of cultured lung and pancreas rudiments during spaceflight

    NASA Technical Reports Server (NTRS)

    Spooner, B. S.; Hardman, P.; Paulsen, A.

    1994-01-01

    Organ culture of embryonic mouse lung and pancreas rudiments has been used to investigate development and differentiation, and to assess the effects of microgravity on culture differentiation, during orbital spaceflight of the shuttle Endeavour (mission STS-54). Lung rudiments continue to grow and branch during spaceflight, an initial result that should allow future detailed study of lung morphogenesis in microgravity. Cultured embryonic pancreas undergoes characteristic exocrine acinar tissue and endocrine islet tissue differentiation during spaceflight, and in ground controls. The rudiments developing in the microgravity environment of spaceflight appear to grow larger than their ground counterparts, and they may have differentiated more rapidly than controls, as judged by exocrine zymogen granule presence.

  10. Imaging of Acute Pancreatitis.

    PubMed

    Thoeni, Ruedi F

    2015-11-01

    Acute pancreatitis is an acute inflammation of the pancreas. Several classification systems have been used in the past but were considered unsatisfactory. A revised Atlanta classification of acute pancreatitis was published that assessed the clinical course and severity of disease; divided acute pancreatitis into interstitial edematous pancreatitis and necrotizing pancreatitis; discerned an early phase (first week) from a late phase (after the first week); and focused on systemic inflammatory response syndrome and organ failure. This article focuses on the revised classification of acute pancreatitis, with emphasis on imaging features, particularly on newly-termed fluid collections and implications for the radiologist. PMID:26526433

  11. Cybersecurity in Artificial Pancreas Experiments.

    PubMed

    O'Keeffe, Derek T; Maraka, Spyridoula; Basu, Ananda; Keith-Hynes, Patrick; Kudva, Yogish C

    2015-09-01

    Medical devices have transformed modern health care, and ongoing experimental medical technology trials (such as the artificial pancreas) have the potential to significantly improve the treatment of several chronic conditions, including diabetes mellitus. However, we suggest that, to date, the essential concept of cybersecurity has not been adequately addressed in this field. This article discusses several key issues of cybersecurity in medical devices and proposes some solutions. In addition, it outlines the current requirements and efforts of regulatory agencies to increase awareness of this topic and to improve cybersecurity. PMID:25923544

  12. Cybersecurity in Artificial Pancreas Experiments

    PubMed Central

    O'Keeffe, Derek T.; Maraka, Spyridoula; Basu, Ananda; Keith-Hynes, Patrick

    2015-01-01

    Abstract Medical devices have transformed modern health care, and ongoing experimental medical technology trials (such as the artificial pancreas) have the potential to significantly improve the treatment of several chronic conditions, including diabetes mellitus. However, we suggest that, to date, the essential concept of cybersecurity has not been adequately addressed in this field. This article discusses several key issues of cybersecurity in medical devices and proposes some solutions. In addition, it outlines the current requirements and efforts of regulatory agencies to increase awareness of this topic and to improve cybersecurity. PMID:25923544

  13. Design of a bioartificial pancreas+

    PubMed Central

    Opara, Emmanuel C.; Mirmalek-Sani, Sayed-Hadi; Khanna, Omaditya; Moya, Monica L; Brey, Eric M.

    2010-01-01

    Introduction In Type 1 diabetes, the β-cells that secrete insulin have been destroyed such that daily exogenous insulin administration is required for the control of blood sugar in individuals afflicted with the disease. Following the development of reliable techniques for the isolation of islets from the human pancreas, islet transplantation has emerged as a therapeutic option, albeit, for only a few selected patients largely because there are not enough islets for the millions of patients requiring the treatment, and there is also the need to use immunosuppressive drugs to prevent transplant rejection. In 1980, the concept of islet immunoisolation by microencapsulation was introduced as a technique to overcome these two major barriers to islet transplantation. Microencapsulation of islets and transplantation in the peritoneal cavity was then described as a bioartificial pancreas. However, it is difficult to retrieve encapsulated islets transplanted in the peritoneal cavity, thus making it difficult to meet all the criteria for a bioartificial pancreas. A new design of a bioartificial pancreas comprising islets co-encapsulated with angiogenic protein in perm-selective multilayer alginate-poly-L-ornithine-alginate (APA) microcapsules and transplanted in an omentum pouch is described in this paper. Materials & Methods The multilayer APA microcapsules are made with ultrapure alginate using poly-L-ornithine as a semi-permeable membrane separating the two alginate layers. The inner alginate layer is used to encapsulate the islets and the outer layer is used to encapsulate angiogenic protein, which would induce neovascularization around the graft within the omentum pouch. Results In in vitro studies, we found that both the wild-type and the heparin binding-growth associated molecule (HBGAM)-FGF-1 chimera can be encapsulated and released in a controlled and sustained manner from the outer alginate layer with a mean diameter in the range of 113–164 microns when 1

  14. Nutrition, Inflammation, and Acute Pancreatitis

    PubMed Central

    Petrov, Max

    2013-01-01

    Acute pancreatitis is acute inflammatory disease of the pancreas. Nutrition has a number of anti-inflammatory effects that could affect outcomes of patients with pancreatitis. Further, it is the most promising nonspecific treatment modality in acute pancreatitis to date. This paper summarizes the best available evidence regarding the use of nutrition with a view of optimising clinical management of patients with acute pancreatitis. PMID:24490104

  15. Acute over-the-counter pharmacological intervention does not adversely affect behavioral outcome following diffuse traumatic brain injury in the mouse.

    PubMed

    Harrison, Jordan L; Rowe, Rachel K; O'Hara, Bruce F; Adelson, P David; Lifshitz, Jonathan

    2014-09-01

    Following mild traumatic brain injury (TBI), patients may self-treat symptoms of concussion, including post-traumatic headache, taking over-the-counter (OTC) analgesics. Administering one dose of OTC analgesics immediately following experimental brain injury mimics the at-home treated population of concussed patients and may accelerate the understanding of the relationship between brain injury and OTC pharmacological intervention. In the current study, we investigate the effect of acute administration of OTC analgesics on neurological function and cortical cytokine levels after experimental diffuse TBI in the mouse. Adult, male C57BL/6 mice were injured using a midline fluid percussion (mFPI) injury model of concussion (6-10 min righting reflex time for brain-injured mice). Experimental groups included mFPI paired with either ibuprofen (60 mg/kg, i.p.; n = 16), acetaminophen (40 mg/kg, i.p.; n = 9), or vehicle (15% ethanol (v/v) in 0.9% saline; n = 13) and sham injury paired OTC medicine or vehicle (n = 7-10 per group). At 24 h after injury, functional outcome was assessed using the rotarod task and a modified neurological severity score. Following behavior assessment, cortical cytokine levels were measured by multiplex ELISA at 24 h post-injury. To evaluate efficacy on acute inflammation, cortical cytokine levels were measured also at 6 h post-injury. In the diffuse brain-injured mouse, immediate pharmacological intervention did not attenuate or exacerbate TBI-induced functional deficits. Cortical cytokine levels were affected by injury, time, or their interaction. However, levels were not affected by treatment at 6 or 24 h post-injury. These data indicate that acute administration of OTC analgesics did not exacerbate or attenuate brain-injury deficits which may inform clinical recommendations for the at-home treated mildly concussed patient. PMID:24760409

  16. Bisphenol A down-regulates rate-limiting Cyp11a1 to acutely inhibit steroidogenesis in cultured mouse antral follicles

    PubMed Central

    Peretz, Jackye; Flaws, Jodi A.

    2013-01-01

    Bisphenol A (BPA) is the backbone of polycarbonate plastic products and the epoxy resin lining of aluminum cans. Previous studies have shown that exposure to BPA decreases sex steroid hormone production in mouse antral follicles. The current study tests the hypothesis that BPA first decreases the expression levels of the steroidogenic enzyme cytochrome P450 side-chain cleavage (Cyp11a1) and steroidogenic acute regulatory protein (StAR) in mouse antral follicles, leading to a decrease in sex steroid hormone production in vitro. Further, the current study tests the hypothesis that these effects are acute and reversible after removal of BPA. Exposure to BPA (10μg/mL and 100μg/mL) significantly decreased expression of Cyp11a1 and StAR beginning at 18h and 72h, respectively, compared to controls. Exposure to BPA (10μg/mL and 100μg/mL) significantly decreased progesterone levels beginning at 24h and decreased androstenedione, testosterone, and estradiol levels at 72h and 96h compared to controls. Further, after removing BPA from the culture media at 20h, expression of Cyp11a1 and progesterone levels were restored to control levels by 48h and 72h, respectively. Additionally, expression of StAR and levels of androstenedione, testosterone, and estradiol never decreased compared to controls. These data suggest that BPA acutely decreases expression of Cyp11a1 as early as 18h and this reduction in Cyp11a1 may lead to a decrease in progesterone production by 24h, followed by a decrease in androstenedione, testosterone, and estradiol production and expression of StAR at 72h. Therefore, BPA exposure likely targets Cyp11a1 and steroidogenesis, but these effects are reversible with removal of BPA exposure. PMID:23707772

  17. Effect of Acute Swim Stress on Plasma Corticosterone and Brain Monoamine Levels in Bidirectionally Selected DxH Recombinant Inbred Mouse Strains Differing in Fear Recall and Extinction

    PubMed Central

    Browne, Caroline A.; Hanke, Joachim; Rose, Claudia; Walsh, Irene; Foley, Tara; Clarke, Gerard; Schwegler, Herbert; Cryan, John F.; Yilmazer-Hanke, Deniz

    2015-01-01

    Stress-induced changes in plasma corticosterone and central monoamine levels were examined in mouse strains that differ in fear-related behaviors. Two DxH recombinant inbred mouse strains with a DBA/2J background, which were originally bred for a high (H-FSS) and low fear-sensitized acoustic startle reflex (L-FSS), were used. Levels of noradrenaline, dopamine, and serotonin and their metabolites (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were studied in the amygdala, hippocampus, medial prefrontal cortex, striatum, hypothalamus, and brainstem. H-FSS mice exhibited increased fear levels and a deficit in fear extinction (within-session) in the auditory fear-conditioning test, and depressive-like behavior in the acute forced swim stress test. They had higher tissue noradrenaline and serotonin levels and lower dopamine and serotonin turnover under basal conditions, although they were largely insensitive to stress-induced changes in neurotransmitter metabolism. In contrast, acute swim stress increased monoamine levels but decreased turnover in the less fearful L-FSS mice. L-FSS mice also showed a trend toward higher basal and stress-induced corticosterone levels and an increase in noradrenaline and serotonin in the hypothalamus and brainstem 30 minutes after stress compared to H-FSS mice. Moreover, the dopaminergic system was activated differentially in the medial prefrontal cortex and striatum of the two strains by acute stress. Thus, H-FSS mice showed increased basal noradrenaline tissue levels compatible with a fear phenotype or chronic stressed condition. Low corticosterone levels and the poor monoamine response to stress in H-FSS mice may point to mechanisms similar to those found in principal fear disorders or posttraumatic stress disorder. PMID:25117886

  18. Effect of acute swim stress on plasma corticosterone and brain monoamine levels in bidirectionally selected DxH recombinant inbred mouse strains differing in fear recall and extinction.

    PubMed

    Browne, Caroline A; Hanke, Joachim; Rose, Claudia; Walsh, Irene; Foley, Tara; Clarke, Gerard; Schwegler, Herbert; Cryan, John F; Yilmazer-Hanke, Deniz

    2014-12-01

    Stress-induced changes in plasma corticosterone and central monoamine levels were examined in mouse strains that differ in fear-related behaviors. Two DxH recombinant inbred mouse strains with a DBA/2J background, which were originally bred for a high (H-FSS) and low fear-sensitized acoustic startle reflex (L-FSS), were used. Levels of noradrenaline, dopamine, and serotonin and their metabolites 3,4-dihydroxyphenyacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were studied in the amygdala, hippocampus, medial prefrontal cortex, striatum, hypothalamus and brainstem. H-FSS mice exhibited increased fear levels and a deficit in fear extinction (within-session) in the auditory fear-conditioning test, and depressive-like behavior in the acute forced swim stress test. They had higher tissue noradrenaline and serotonin levels and lower dopamine and serotonin turnover under basal conditions, although they were largely insensitive to stress-induced changes in neurotransmitter metabolism. In contrast, acute swim stress increased monoamine levels but decreased turnover in the less fearful L-FSS mice. L-FSS mice also showed a trend toward higher basal and stress-induced corticosterone levels and an increase in noradrenaline and serotonin in the hypothalamus and brainstem 30 min after stress compared to H-FSS mice. Moreover, the dopaminergic system was activated differentially in the medial prefrontal cortex and striatum of the two strains by acute stress. Thus, H-FSS mice showed increased basal noradrenaline tissue levels compatible with a fear phenotype or chronic stressed condition. Low corticosterone levels and the poor monoamine response to stress in H-FSS mice may point to mechanisms similar to those found in principal fear disorders or post-traumatic stress disorder. PMID:25117886

  19. Molecular therapeutics in pancreas cancer

    PubMed Central

    Narayanan, Vignesh; Weekes, Colin D

    2016-01-01

    The emergence of the “precision-medicine” paradigm in oncology has ushered in tremendous improvements in patient outcomes in a wide variety of malignancies. However, pancreas ductal adenocarcinoma (PDAC) has remained an obstinate challenge to the oncology community and continues to be associated with a dismal prognosis with 5-year survival rates consistently less than 5%. Cytotoxic chemotherapy with gemcitabine-based regimens has been the cornerstone of treatment in PDAC especially because most patients present with inoperable disease. But in recent years remarkable basic science research has improved our understanding of the molecular and genetic basis of PDAC. Whole genomic analysis has exemplified the genetic heterogeneity of pancreas cancer and has led to ingenious efforts to target oncogenes and their downstream signaling cascades. Novel stromal depletion strategies have been devised based on our enhanced recognition of the complex architecture of the tumor stroma and the various mechanisms in the tumor microenvironment that sustain tumorigenesis. Immunotherapy using vaccines and immune checkpoint inhibitors has also risen to the forefront of therapeutic strategies against PDAC. Furthermore, adoptive T cell transfer and strategies to target epigenetic regulators are being explored with enthusiasm. This review will focus on the recent advances in molecularly targeted therapies in PDAC and offer future perspectives to tackle this lethal disease. PMID:27096032

  20. Molecular therapeutics in pancreas cancer.

    PubMed

    Narayanan, Vignesh; Weekes, Colin D

    2016-04-15

    The emergence of the "precision-medicine" paradigm in oncology has ushered in tremendous improvements in patient outcomes in a wide variety of malignancies. However, pancreas ductal adenocarcinoma (PDAC) has remained an obstinate challenge to the oncology community and continues to be associated with a dismal prognosis with 5-year survival rates consistently less than 5%. Cytotoxic chemotherapy with gemcitabine-based regimens has been the cornerstone of treatment in PDAC especially because most patients present with inoperable disease. But in recent years remarkable basic science research has improved our understanding of the molecular and genetic basis of PDAC. Whole genomic analysis has exemplified the genetic heterogeneity of pancreas cancer and has led to ingenious efforts to target oncogenes and their downstream signaling cascades. Novel stromal depletion strategies have been devised based on our enhanced recognition of the complex architecture of the tumor stroma and the various mechanisms in the tumor microenvironment that sustain tumorigenesis. Immunotherapy using vaccines and immune checkpoint inhibitors has also risen to the forefront of therapeutic strategies against PDAC. Furthermore, adoptive T cell transfer and strategies to target epigenetic regulators are being explored with enthusiasm. This review will focus on the recent advances in molecularly targeted therapies in PDAC and offer future perspectives to tackle this lethal disease. PMID:27096032

  1. Possible link between ectopic pancreas and holoprosencephaly

    PubMed Central

    Kin, Tatsuya; Korbutt, Gregory S.; Shapiro, A.M. James

    2012-01-01

    We report on the incidental observation of ectopic pancreas in a donor for islet cell transplantation. The donor’s clinical and imaging presentation was definitive for holoprosencephaly. This case report discusses a possible link between ectopic pancreas and holoprosencephaly. PMID:22688061

  2. Pancreas Transplantation: An Alarming Crisis in Confidence.

    PubMed

    Stratta, R J; Gruessner, A C; Odorico, J S; Fridell, J A; Gruessner, R W G

    2016-09-01

    In the past decade, the annual number of pancreas transplantations performed in the United States has steadily declined. From 2004 to 2011, the overall number of simultaneous pancreas-kidney (SPK) transplantations in the United States declined by 10%, whereas the decreases in pancreas after kidney (PAK) and pancreas transplant alone (PTA) procedures were 55% and 34%, respectively. Paradoxically, this has occurred in the setting of improvements in graft and patient survival outcomes and transplanting higher-risk patients. Only 11 centers in the United States currently perform ≥20 pancreas transplantations per year, and most centers perform <5 pancreas transplantations annually; many do not perform PAKs or PTAs. This national trend in decreasing numbers of pancreas transplantations is related to a number of factors including lack of a primary referral source, improvements in diabetes care and management, changing donor and recipient considerations, inadequate training opportunities, and increasing risk aversion because of regulatory scrutiny. A national initiative is needed to "reinvigorate" SPK and PAK procedures as preferred transplantation options for appropriately selected uremic patients taking insulin regardless of C-peptide levels or "type" of diabetes. Moreover, many patients may benefit from PTAs because all categories of pancreas transplantation are not only life enhancing but also life extending procedures. PMID:27232750

  3. Solitary fibrous tumor of the pancreas.

    PubMed

    Baxter, Andrew R; Newman, Elliot; Hajdu, Cristina H

    2015-01-01

    Solitary fibrous tumors (SFTs) are rare mesenchymal neoplasms of fibroblastic origin. Most commonly they affect the pleura but they been described in other viscera. SFT of the pancreas is extremely rare, and only eight cases have been reported to date. We perform a literature review and report a ninth case. The patient is a 54-year-old African-American female who presented with several months of abdominal pain. Abdominal radiography demonstrated a lesion in the head of the pancreas, and she underwent a Whipple operation. Pathology demonstrated SFT of the pancreas. She is alive and well 1 year post-operatively. SFT of the pancreas predominately affects middle-aged women. These tumors are difficult to distinguish radiologically from neuroendocrine tumors. While SFT of the pancreas tend to have an indolent course, there is the potential for malignancy. We recommend complete surgical excision. PMID:26628714

  4. Solitary fibrous tumor of the pancreas

    PubMed Central

    Baxter, Andrew R.; Newman, Elliot; Hajdu, Cristina H.

    2015-01-01

    Solitary fibrous tumors (SFTs) are rare mesenchymal neoplasms of fibroblastic origin. Most commonly they affect the pleura but they been described in other viscera. SFT of the pancreas is extremely rare, and only eight cases have been reported to date. We perform a literature review and report a ninth case. The patient is a 54-year-old African-American female who presented with several months of abdominal pain. Abdominal radiography demonstrated a lesion in the head of the pancreas, and she underwent a Whipple operation. Pathology demonstrated SFT of the pancreas. She is alive and well 1 year post-operatively. SFT of the pancreas predominately affects middle-aged women. These tumors are difficult to distinguish radiologically from neuroendocrine tumors. While SFT of the pancreas tend to have an indolent course, there is the potential for malignancy. We recommend complete surgical excision. PMID:26628714

  5. A mouse model of Townes-Brocks syndrome expressing a truncated mutant Sall1 protein is protected from acute kidney injury.

    PubMed

    Hirsch, Sara; El-Achkar, Tarek; Robbins, Lynn; Basta, Jeannine; Heitmeier, Monique; Nishinakamura, Ryuichi; Rauchman, Michael

    2015-11-15

    It has been postulated that developmental pathways are reutilized during repair and regeneration after injury, but functional analysis of many genes required for kidney formation has not been performed in the adult organ. Mutations in SALL1 cause Townes-Brocks syndrome (TBS) and nonsyndromic congenital anomalies of the kidney and urinary tract, both of which lead to childhood kidney failure. Sall1 is a transcriptional regulator that is expressed in renal progenitor cells and developing nephrons in the embryo. However, its role in the adult kidney has not been investigated. Using a mouse model of TBS (Sall1TBS), we investigated the role of Sall1 in response to acute kidney injury. Our studies revealed that Sall1 is expressed in terminally differentiated renal epithelia, including the S3 segment of the proximal tubule, in the mature kidney. Sall1TBS mice exhibited significant protection from ischemia-reperfusion injury and aristolochic acid-induced nephrotoxicity. This protection from acute injury is seen despite the presence of slowly progressive chronic kidney disease in Sall1TBS mice. Mice containing null alleles of Sall1 are not protected from acute kidney injury, indicating that expression of a truncated mutant protein from the Sall1TBS allele, while causative of congenital anomalies, protects the adult kidney from injury. Our studies further revealed that basal levels of the preconditioning factor heme oxygenase-1 are elevated in Sall1TBS kidneys, suggesting a mechanism for the relative resistance to injury in this model. Together, these studies establish a functional role for Sall1 in the response of the adult kidney to acute injury. PMID:26311113

  6. Glucagon in the Artificial Pancreas

    PubMed Central

    2014-01-01

    The use of glucagon, in conjunction with insulin, in a dual chamber pump (artificial pancreas, AP) is a working goal for multiple companies and researchers. However, capital investment to create, operate, and maintain facilities with sufficient scale to produce enough glucagon to treat millions of patients, at a level of profit that makes it feasible, will be substantial. It can be assumed that the marketplace will expect the daily cost of glucagon (to the consumer) to be similar to the daily cost of insulin. After one subtracts wholesaler and pharmacy markup, there may be very few dollars remaining for the drug company to cover profit, capital expenditures, marketing, burden, and other costs. Without the potential for adequate margins, manufacturers may not be willing to take the risk. Assuming that the projections discussed in this article are in the right ballpark, advance planning for the supply for glucagon needs to start today and not wait for the AP to come to market. PMID:25139825

  7. Robotic surgery of the pancreas

    PubMed Central

    Joyce, Daniel; Morris-Stiff, Gareth; Falk, Gavin A; El-Hayek, Kevin; Chalikonda, Sricharan; Walsh, R Matthew

    2014-01-01

    Pancreatic surgery is one of the most challenging and complex fields in general surgery. While minimally invasive surgery has become the standard of care for many intra-abdominal pathologies the overwhelming majority of pancreatic surgery is performed in an open fashion. This is attributed to the retroperitoneal location of the pancreas, its intimate relationship to major vasculature and the complexity of reconstruction in the case of pancreatoduodenectomy. Herein, we describe the application of robotic technology to minimally invasive pancreatic surgery. The unique capabilities of the robotic platform have made the minimally invasive approach feasible and safe with equivalent if not better outcomes (e.g., decreased length of stay, less surgical site infections) to conventional open surgery. However, it is unclear whether the robotic approach is truly superior to traditional laparoscopy; this is a key point given the substantial costs associated with procuring and maintaining robotic capabilities. PMID:25356035

  8. What You Need to Know about Cancer of the Pancreas

    MedlinePlus

    ... You Need To Know About™ Cancer of the Pancreas This booklet is about cancer of the pancreas, also called pancreatic cancer. There are two main ... care. This booklet covers: The anatomy of the pancreas and basics about cancer of the pancreas Treatments ...

  9. Contribution of Proteus mirabilis urease to persistence, urolithiasis, and acute pyelonephritis in a mouse model of ascending urinary tract infection.

    PubMed

    Johnson, D E; Russell, R G; Lockatell, C V; Zulty, J C; Warren, J W; Mobley, H L

    1993-07-01

    Proteus mirabilis, a significant cause of bacteriuria and acute pyelonephritis in humans, produces urease. This high-molecular-weight, multimeric, cytoplasmic enzyme hydrolyzes urea to ammonia and carbon dioxide. To assess the role of urease in colonization, urolithiasis, and acute pyelonephritis in an animal model of ascending urinary tract infection, we compared a uropathogenic strain of P. mirabilis with its isogenic urease-negative mutant, containing an insertion mutation within ureC, the gene encoding the large subunit of the enzyme. Mice challenged transurethrally with the parent strain developed significant bacteriuria and urinary stones. The urease-negative mutant had a 50% infective dose of 2.7 x 10(9) CFU, a value more than 1,000-fold greater than that of the parent strain (2.2 x 10(6) CFU). The urease-positive parent strain reached significantly higher concentrations and persisted significantly longer in the bladder and kidney than did the mutant. Indeed, in the kidney, the parent strain increased in concentration while the mutant concentration fell so that, by 1 week, the parent strain concentration was 10(6) times that of the mutant. Similarly, the urease-positive parent produced significantly more severe renal pathology than the mutant. The initial abnormalities were in and around the pelvis and consisted of acute inflammation and epithelial necrosis. By 1 week, pyelitis was more severe, crystals were seen in the pelvis, and acute pyelonephritis, with acute interstitial inflammation, tubular epithelial cell necrosis, and in some cases abscesses, had developed. By 2 weeks, more animals had renal abscesses and radial bands of fibrosis. We conclude that the urease of P. mirabilis is a critical virulence determinant for colonization, urolithiasis, and severe acute pyelonephritis. PMID:8514376

  10. An Advanced Preclinical Mouse Model for Acute Myeloid Leukemia Using Patients' Cells of Various Genetic Subgroups and In Vivo Bioluminescence Imaging

    PubMed Central

    Vick, Binje; Rothenberg, Maja; Sandhöfer, Nadine; Carlet, Michela; Finkenzeller, Cornelia; Krupka, Christina; Grunert, Michaela; Trumpp, Andreas; Corbacioglu, Selim; Ebinger, Martin; André, Maya C.; Hiddemann, Wolfgang; Schneider, Stephanie; Subklewe, Marion; Metzeler, Klaus H.; Spiekermann, Karsten; Jeremias, Irmela

    2015-01-01

    Acute myeloid leukemia (AML) is a clinically and molecularly heterogeneous disease with poor outcome. Adequate model systems are required for preclinical studies to improve understanding of AML biology and to develop novel, rational treatment approaches. Xenografts in immunodeficient mice allow performing functional studies on patient-derived AML cells. We have established an improved model system that integrates serial retransplantation of patient-derived xenograft (PDX) cells in mice, genetic manipulation by lentiviral transduction, and essential quality controls by immunophenotyping and targeted resequencing of driver genes. 17/29 samples showed primary engraftment, 10/17 samples could be retransplanted and some of them allowed virtually indefinite serial transplantation. 5/6 samples were successfully transduced using lentiviruses. Neither serial transplantation nor genetic engineering markedly altered sample characteristics analyzed. Transgene expression was stable in PDX AML cells. Example given, recombinant luciferase enabled bioluminescence in vivo imaging and highly sensitive and reliable disease monitoring; imaging visualized minimal disease at 1 PDX cell in 10000 mouse bone marrow cells and facilitated quantifying leukemia initiating cells. We conclude that serial expansion, genetic engineering and imaging represent valuable tools to improve the individualized xenograft mouse model of AML. Prospectively, these advancements enable repetitive, clinically relevant studies on AML biology and preclinical treatment trials on genetically defined and heterogeneous subgroups. PMID:25793878

  11. Live cell detection of chromosome 2 deletion and Sfpi1/PU1 loss in radiation-induced mouse acute myeloid leukaemia☆

    PubMed Central

    Olme, C.-H.; Finnon, R.; Brown, N.; Kabacik, S.; Bouffler, S.D.; Badie, C.

    2013-01-01

    The CBA/H mouse model of radiation-induced acute myeloid leukaemia (rAML) has been studied for decades to bring to light the molecular mechanisms associated with multistage carcinogenesis. A specific interstitial deletion of chromosome 2 found in a high proportion of rAML is recognised as the initiating event. The deletion leads to the loss of Sfpi, a gene essential for haematopoietic development. Its product, the transcription factor PU.1 acts as a tumour suppressor in this model. Although the deletion can be detected early following ionising radiation exposure by cytogenetic techniques, precise characterisation of the haematopoietic cells carrying the deletion and the study of their fate in vivo cannot be achieved. Here, using a genetically engineered C57BL/6 mouse model expressing the GFP fluorescent molecule under the control of the Sfpi1 promoter, which we have bred onto the rAML-susceptible CBA/H strain, we demonstrate that GFP expression did not interfere with X-ray induced leukaemia incidence and that GFP fluorescence in live leukaemic cells is a surrogate marker of radiation-induced chromosome 2 deletions with or without point mutations on the remaining allele of the Sfpi1 gene. This study presents the first experimental evidence for the detection of this leukaemia initiating event in live leukemic cells. PMID:23806234

  12. An advanced preclinical mouse model for acute myeloid leukemia using patients' cells of various genetic subgroups and in vivo bioluminescence imaging.

    PubMed

    Vick, Binje; Rothenberg, Maja; Sandhöfer, Nadine; Carlet, Michela; Finkenzeller, Cornelia; Krupka, Christina; Grunert, Michaela; Trumpp, Andreas; Corbacioglu, Selim; Ebinger, Martin; André, Maya C; Hiddemann, Wolfgang; Schneider, Stephanie; Subklewe, Marion; Metzeler, Klaus H; Spiekermann, Karsten; Jeremias, Irmela

    2015-01-01

    Acute myeloid leukemia (AML) is a clinically and molecularly heterogeneous disease with poor outcome. Adequate model systems are required for preclinical studies to improve understanding of AML biology and to develop novel, rational treatment approaches. Xenografts in immunodeficient mice allow performing functional studies on patient-derived AML cells. We have established an improved model system that integrates serial retransplantation of patient-derived xenograft (PDX) cells in mice, genetic manipulation by lentiviral transduction, and essential quality controls by immunophenotyping and targeted resequencing of driver genes. 17/29 samples showed primary engraftment, 10/17 samples could be retransplanted and some of them allowed virtually indefinite serial transplantation. 5/6 samples were successfully transduced using lentiviruses. Neither serial transplantation nor genetic engineering markedly altered sample characteristics analyzed. Transgene expression was stable in PDX AML cells. Example given, recombinant luciferase enabled bioluminescence in vivo imaging and highly sensitive and reliable disease monitoring; imaging visualized minimal disease at 1 PDX cell in 10000 mouse bone marrow cells and facilitated quantifying leukemia initiating cells. We conclude that serial expansion, genetic engineering and imaging represent valuable tools to improve the individualized xenograft mouse model of AML. Prospectively, these advancements enable repetitive, clinically relevant studies on AML biology and preclinical treatment trials on genetically defined and heterogeneous subgroups. PMID:25793878

  13. Effect of acute imipramine administration on the pattern of forced swim-induced c-Fos expression in the mouse brain.

    PubMed

    Yanagida, Satoru; Motomura, Keisuke; Ohashi, Ayako; Hiraoka, Kentaro; Miura, Tomofumi; Kanba, Shigenobu

    2016-08-26

    The forced swim test (FST) has been widely used for the preclinical evaluation of antidepressant drugs. Despite considerable differences in the protocol, equivalence of the FST for rats and mice has been rarely questioned. Previous research on the FST for rats revealed that repeated administration of antidepressant drugs attenuates the c-Fos response to swim stress in the hypothalamus and limbic regions. However, few studies have made similar investigations using the FST for mice. In the present study, we explored the mouse brain through immunohistochemistry staining for c-Fos after acute administration of imipramine or saline with or without a subsequent swim session. Imipramine enhanced the c-Fos density in regions of the central extended amygdala, while forced swim stress increased c-Fos expression in some hypothalamic (the ventrolateral preoptic nucleus and dorsomedial nucleus) and brain stem regions, which is consistent with previous reports. In contrast to previous literature with rats, swim stress brought a significant increase in c-Fos expression in the lateral septal nucleus and some other regions in the hypothalamus (the intermediate hypothalamic area, the paraventricular and arcuate nucleus) only in the imipramine-pretreated group, which has not been observed previously. In the arcuate nucleus, double immunostaining revealed that c-Fos was rarely co-expressed with proopiomelanocortin or tyrosine hydroxylase regardless of imipramine treatment. The present results suggest that the activation of several regions in the lateral septum and the hypothalamus underlies antidepressant-like effect in the mouse FST. PMID:27373591

  14. Apoptosis of hippocampal pyramidal neurons is virus independent in a mouse model of acute neurovirulent picornavirus infection.

    PubMed

    Buenz, Eric J; Sauer, Brian M; Lafrance-Corey, Reghann G; Deb, Chandra; Denic, Aleksandar; German, Christopher L; Howe, Charles L

    2009-08-01

    Many viruses, including picornaviruses, have the potential to infect the central nervous system (CNS) and stimulate a neuroinflammatory immune response, especially in infants and young children. Cognitive deficits associated with CNS picornavirus infection result from injury and death of neurons that may occur due to direct viral infection or during the immune responses to virus in the brain. Previous studies have concluded that apoptosis of hippocampal neurons during picornavirus infection is a cell-autonomous event triggered by direct neuronal infection. However, these studies assessed neuron death at time points late in infection and during infections that lead to either death of the host or persistent viral infection. In contrast, many neurovirulent picornavirus infections are acute and transient, with rapid clearance of virus from the host. We provide evidence of hippocampal pathology in mice acutely infected with the Theiler's murine encephalomyelitis picornavirus. We found that CA1 pyramidal neurons exhibited several hallmarks of apoptotic death, including caspase-3 activation, DNA fragmentation, and chromatin condensation within 72 hours of infection. Critically, we also found that many of the CA1 pyramidal neurons undergoing apoptosis were not infected with virus, indicating that neuronal cell death during acute picornavirus infection of the CNS occurs in a non-cell-autonomous manner. These observations suggest that therapeutic strategies other than antiviral interventions may be useful for neuroprotection during acute CNS picornavirus infection. PMID:19608874

  15. Recombinant expression of Bacillus anthracis lethal toxin components of Indian isolate in Escherichia coli and determination of its acute toxicity level in mouse model.

    PubMed

    Nagendra, Suryanarayana; Vanlalhmuaka; Verma, Sarika; Tuteja, Urmil; Thavachelvam, Kulanthaivel

    2015-12-15

    Bacillus anthracis lethal toxin (LeTx) is the principle factor responsible for toxaemia and anthrax related death. Lethal toxin consist of two proteins viz protective antigen (PA) and lethal factor which combines in a typical fashion similar to other toxins belonging to A-B toxin super family. The amount of LeTx required to kill a particular organism generally differs among strains owing to their geographical distributions and genetic variation. In the present study, we have cloned PA and LF genes from B. anthracis clinical isolate of Indian origin and expressed them in soluble form employing Escherichia coli expression system. Both the proteins were purified to near homogeneity level using Immobilized metal ion affinity chromatography (IMAC). Further we have used equal ratio of both the proteins to form LeTx and determined its acute toxicity level in Balb/c mice by graphical method of Miller and Tainter. The LD50 value of LeTx by intravenous (i.v) route was found to be 0.97 ± 0.634 mg kg(-1) Balb/c mice. This study highlights the expression of recombinant LeTx from E. coli and assessing its acute toxicity level in experimental mouse model. PMID:26472254

  16. Uric acid is released in the brain during seizure activity and increases severity of seizures in a mouse model for acute limbic seizures.

    PubMed

    Thyrion, Lisa; Raedt, Robrecht; Portelli, Jeanelle; Van Loo, Pieter; Wadman, Wytse J; Glorieux, Griet; Lambrecht, Bart N; Janssens, Sophie; Vonck, Kristl; Boon, Paul

    2016-03-01

    Recent evidence points at an important role of endogenous cell-damage induced pro-inflammatory molecules in the generation of epileptic seizures. Uric acid, under the form of monosodium urate crystals, has shown to have pro-inflammatory properties in the body, but less is known about its role in seizure generation. This study aimed to unravel the contribution of uric acid to seizure generation in a mouse model for acute limbic seizures. We measured extracellular levels of uric acid in the brain and modulated them using complementary pharmacological and genetic tools. Local extracellular uric acid levels increased three to four times during acute limbic seizures and peaked between 50 and 100 min after kainic acid infusion. Manipulating uric acid levels through administration of allopurinol or knock-out of urate oxidase significantly altered the number of generalized seizures, decreasing and increasing them by a twofold respectively. Taken together, our results consistently show that uric acid is released during limbic seizures and suggest that uric acid facilitates seizure generalization. PMID:26774005

  17. Imaging of Pancreas Transplantation and Its Complications.

    PubMed

    O'Malley, Ryan B; Moshiri, Mariam; Osman, Sherif; Menias, Christine O; Katz, Douglas S

    2016-03-01

    Whole pancreas transplantation is an effective treatment for obtaining euglycemic status in patients with insulin-dependent diabetes mellitus, and is usually performed concurrent with renal transplantation in the affected patient. This article discusses complex surgical anatomical details of pancreas transplantation including surgical options for endocrine and exocrine drainage pathways. It then describes several possible complications related to surgical factors in the immediate post operative period followed by other complications related to systemic issues, vasculature, and the pancreatic parenchyma. PMID:26896223

  18. Endothelium-derived essential signals involved in pancreas organogenesis

    PubMed Central

    Talavera-Adame, Dodanim; Dafoe, Donald C

    2015-01-01

    Endothelial cells (ECs) are essential for pancreas differentiation, endocrine specification, and endocrine function. They are also involved in the physiopathology of type 1 and type 2 diabetes. During embryogenesis, aortic ECs provide specific factors that maintain the expression of key genes for pancreas development such as pancreatic and duodenal homeobox-1. Other unknown factors are also important for pancreatic endocrine specification and formation of insulin-producing beta cells. Endocrine precursors proliferate interspersed with ductal cells and exocrine precursors and, at some point of development, these endocrine precursors migrate to pancreatic mesenchyme and start forming the islets of Langerhans. By the end of the gestation and close to birth, these islets contain immature beta cells with the capacity to express vascular endothelial growth factor and therefore to recruit ECs from the surrounding microenvironment. ECs in turn produce factors that are essential to maintain insulin secretion in pancreatic beta cells. Once assembled, a cross talk between endocrine cells and ECs maintain the integrity of islets toward an adequate function during the whole life of the adult individual. This review will focus in the EC role in the differentiation and maturation of pancreatic beta cells during embryogenesis as well as the current knowledge about the involvement of endothelium to derive pancreatic beta cells in vitro from mouse or human pluripotent stem cells. PMID:25992319

  19. Essential Contributions of Serotonin Transporter Inhibition to the Acute and Chronic Actions of Fluoxetine and Citalopram in the SERT Met172 Mouse.

    PubMed

    Nackenoff, Alex G; Moussa-Tooks, Alexandra B; McMeekin, Austin M; Veenstra-VanderWeele, Jeremy; Blakely, Randy D

    2016-06-01

    Depression is a common mental illness and a leading cause of disability. The most widely prescribed antidepressant medications are serotonin (5-HT) selective reuptake inhibitors (SSRIs). Although there is much support for 5-HT transporter (SERT) antagonism as a basis of antidepressant efficacy, this evidence is indirect and other targets and mechanisms have been proposed. In order to distinguish SERT-dependent and -independent effects of SSRIs, we developed a knock-in mouse model whereby high-affinity interactions of many antidepressants at SERT have been ablated via knock-in substitution (SERT Met172) without disrupting 5-HT recognition or uptake. Here we utilize the C57BL/6J SERT Met172 model to evaluate SERT dependence for the actions of two widely prescribed SSRIs, fluoxetine and citalopram, in tests sensitive to acute and chronic actions of antidepressants. In the tail suspension and forced swim tests, fluoxetine and citalopram fail to reduce immobility in SERT Met172 mice. In addition, SERT Met172 mice are insensitive to chronic fluoxetine and citalopram administration in the novelty induced hypophagia test (NIH) and fail to exhibit enhanced proliferation or survival of hippocampal stem cells. In both acute and chronic studies, SERT Met172 mice maintained sensitivity to paroxetine, an antidepressant that is unaffected by the Met172 mutation. Together, these studies provide definitive support for an essential role of SERT antagonism in the acute and chronic actions of two commonly used SSRIs in these tests, and reinforce the utility of the SERT Met172 model for isolating SERT/5-HT contributions of drug actions in vivo. PMID:26514584

  20. Bisphenol A down-regulates rate-limiting Cyp11a1 to acutely inhibit steroidogenesis in cultured mouse antral follicles

    SciTech Connect

    Peretz, Jackye; Flaws, Jodi A.

    2013-09-01

    Bisphenol A (BPA) is the backbone of polycarbonate plastic products and the epoxy resin lining of aluminum cans. Previous studies have shown that exposure to BPA decreases sex steroid hormone production in mouse antral follicles. The current study tests the hypothesis that BPA first decreases the expression levels of the steroidogenic enzyme cytochrome P450 side-chain cleavage (Cyp11a1) and steroidogenic acute regulatory protein (StAR) in mouse antral follicles, leading to a decrease in sex steroid hormone production in vitro. Further, the current study tests the hypothesis that these effects are acute and reversible after removal of BPA. Exposure to BPA (10 μg/mL and 100 μg/mL) significantly decreased expression of Cyp11a1 and StAR beginning at 18 h and 72 h, respectively, compared to controls. Exposure to BPA (10 μg/mL and 100 μg/mL) significantly decreased progesterone levels beginning at 24 h and decreased androstenedione, testosterone, and estradiol levels at 72 h and 96 h compared to controls. Further, after removing BPA from the culture media at 20 h, expression of Cyp11a1 and progesterone levels were restored to control levels by 48 h and 72 h, respectively. Additionally, expression of StAR and levels of androstenedione, testosterone, and estradiol never decreased compared to controls. These data suggest that BPA acutely decreases expression of Cyp11a1 as early as 18 h and this reduction in Cyp11a1 may lead to a decrease in progesterone production by 24 h, followed by a decrease in androstenedione, testosterone, and estradiol production and expression of StAR at 72 h. Therefore, BPA exposure likely targets Cyp11a1 and steroidogenesis, but these effects are reversible with removal of BPA exposure. - Highlights: • BPA may target Cyp11a1 to inhibit steroidogenesis in antral follicles. • BPA may decrease the expression of Cyp11a1 prior to inhibiting steroidogenesis. • The adverse effects of BPA on steroidogenesis in antral follicles are reversible.

  1. Cystic lesions of the pancreas

    PubMed Central

    Karoumpalis, Ioannis; Christodoulou, Dimitrios K.

    2016-01-01

    Different types of benign or malignant cystic lesions can be observed in the pancreas. Pancreatic cystic lesions are classified under pathology terms into simple retention cysts, pseudocysts and cystic neoplasms. Mucinous cystic neoplasm is a frequent type of cystic neoplasm and has a malignant potential. Serous cystadenoma follows in frequency and is usually benign. Intraductal papillary mucinous neoplasms are the most commonly resected cystic pancreatic neoplasms characterized by dilated segments of the main pancreatic duct and/or side branches, the wall of which is covered by mucus secreting cells. These neoplasms can occupy the pancreatic head or any part of the organ. Solid pseudopapillary tumor is rare, has a low tendency for malignancy, and is usually located in the pancreatic body or tail. Endoscopic ultrasound with the use of fine-needle aspiration and cytology permits discrimination of those lesions. In this review, the main characteristics of those lesions are presented, as well as recommendations regarding their follow up and management according to recent guidelines. PMID:27065727

  2. Cystic lesions of the pancreas.

    PubMed

    Karoumpalis, Ioannis; Christodoulou, Dimitrios K

    2016-01-01

    Different types of benign or malignant cystic lesions can be observed in the pancreas. Pancreatic cystic lesions are classified under pathology terms into simple retention cysts, pseudocysts and cystic neoplasms. Mucinous cystic neoplasm is a frequent type of cystic neoplasm and has a malignant potential. Serous cystadenoma follows in frequency and is usually benign. Intraductal papillary mucinous neoplasms are the most commonly resected cystic pancreatic neoplasms characterized by dilated segments of the main pancreatic duct and/or side branches, the wall of which is covered by mucus secreting cells. These neoplasms can occupy the pancreatic head or any part of the organ. Solid pseudopapillary tumor is rare, has a low tendency for malignancy, and is usually located in the pancreatic body or tail. Endoscopic ultrasound with the use of fine-needle aspiration and cytology permits discrimination of those lesions. In this review, the main characteristics of those lesions are presented, as well as recommendations regarding their follow up and management according to recent guidelines. PMID:27065727

  3. Pancreas Transplantation: Past, Present, Future.

    PubMed

    Dholakia, Shamik; Mittal, Shruti; Quiroga, Isabel; Gilbert, James; Sharples, Edward J; Ploeg, Rutger J; Friend, Peter J

    2016-07-01

    Diabetes is the pandemic disease of the modern era, with 10% of these patients having type 1 diabetes mellitus. Despite the prevalence, morbidities, and associated financial burden, treatment options have not changed since the introduction of injectable insulin. To date, over 40,000 pancreas transplants have been performed globally. It remains the only known method for restoring glycemic control and thus curing type 1 diabetes mellitus. The aim of this review is to bring pancreatic transplantation out of the specialist realm, informing practitioners about this important procedure, so that they feel better equipped to refer suitable patients for transplantation and manage, counsel, and support when encountering them within their own specialty. This study was a narrative review conducted in October 2015, with OVID interface searching EMBASE and MEDLINE databases, using Timeframe: Inception to October 2015. Articles were assessed for clinical relevance and most up-to-date content, with articles written in English as the only inclusion criterion. Other sources used included conference proceedings/presentations and unpublished data from our institution (Oxford Transplant Centre). Pancreatic transplantation is growing and has quickly become the gold standard of care for patients with type 1 diabetes mellitus and renal failure. Significant improvements in quality of life and life expectancy make pancreatic transplant a viable and economically feasible intervention. It remains the most effective method of establishing and maintaining euglycemia, halting and potentially reversing complications associated with diabetes. PMID:26965300

  4. Acetylcholinesterase activity in regions of mouse brain following acute and chronic treatment with a benzodiazepine inverse agonist.

    PubMed Central

    Appleyard, M. E.; Taylor, S. C.; Little, H. J.

    1990-01-01

    1. Chronic administration of the benzodiazepine inverse agonist FG 7142 has previously been shown to induce seizure activity in mice. In the present study we have investigated the effects of acute and chronic treatment with FG 7142 in mice on the levels of acetylcholinesterase activity in cortex, hippocampus, midbrain and striatum. We have also investigated the effects of acute and chronic stress in the form of handling (vehicle-injection) on acetylcholinesterase levels. 2. A single dose of FG 7142 produced a marked elevation of total acetylcholinesterase activities in the hippocampus and midbrain when compared with vehicle-injected control levels, but the levels were not different from those in unhandled animals. 3. Acute stress, in the form of vehicle-injection produced decreases in cortical and hippocampal soluble acetylcholinesterase activity but FG 7142 had no effect upon these stress-induced changes. 4. Total cortical and hippocampal acetylcholinesterase activities were increased by 56% and 16% respectively in the chronic FG 7142-treated mice that exhibited seizure activity (compared with vehicle-injected controls). 5. Soluble acetylcholinesterase activity in the midbrain was decreased to 82% of control levels only in animals that had undergone FG 7142-induced kindling. Smaller or no changes in acetylcholinesterase activity in the midbrain were observed in chronically FG 7142-treated animals that exhibited no seizure activity. 6. Mice that did not demonstrate seizure activity in response to chronic FG 7142 treatment showed alterations in the soluble acetylcholinesterase activities of the hippocampus and midbrain.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1963800

  5. Melatonin, endocrine pancreas and diabetes.

    PubMed

    Peschke, Elmar

    2008-01-01

    Melatonin influences insulin secretion both in vivo and in vitro. (i) The effects are MT(1)-and MT(2)-receptor-mediated. (ii) They are specific, high-affinity, pertussis-toxin-sensitive, G(i)-protein-coupled, leading to inhibition of the cAMP-pathway and decrease of insulin release. [Correction added after online publication 4 December 2007: in the preceding sentence, 'increase of insulin release' was changed to 'decrease of insulin release'.] Furthermore, melatonin inhibits the cGMP-pathway, possibly mediated by MT(2) receptors. In this way, melatonin likely inhibits insulin release. A third system, the IP(3)-pathway, is mediated by G(q)-proteins, phospholipase C and IP(3), which mobilize Ca(2+) from intracellular stores, with a resultant increase in insulin. (iii) Insulin secretion in vivo, as well as from isolated islets, exhibits a circadian rhythm. This rhythm, which is apparently generated within the islets, is influenced by melatonin, which induces a phase shift in insulin secretion. (iv) Observation of the circadian expression of clock genes in the pancreas could possibly be an indication of the generation of circadian rhythms in the pancreatic islets themselves. (v) Melatonin influences diabetes and associated metabolic disturbances. The diabetogens, alloxan and streptozotocin, lead to selective destruction of beta-cells through their accumulation in these cells, where they induce the generation of ROS. Beta-cells are very susceptible to oxidative stress because they possess only low-antioxidative capacity. Results suggest that melatonin in pharmacological doses provides protection against ROS. (vi) Finally, melatonin levels in plasma, as well as the arylalkylamine-N-acetyltransferase (AANAT) activity, are lower in diabetic than in nondiabetic rats and humans. In contrast, in the pineal gland, the AANAT mRNA is increased and the insulin receptor mRNA is decreased, which indicates a close interrelationship between insulin and melatonin. PMID:18078445

  6. In Vivo Acute on Chronic Ethanol Effects in Liver: A Mouse Model Exhibiting Exacerbated Injury, Altered Metabolic and Epigenetic Responses

    PubMed Central

    Shukla, Shivendra D.; Aroor, Annayya R.; Restrepo, Ricardo; Kharbanda, Kusum K.; Ibdah, Jamal A.

    2015-01-01

    Chronic alcoholics who also binge drink (i.e., acute on chronic) are prone to an exacerbated liver injury but its mechanism is not understood. We therefore investigated the in vivo effects of chronic and binge ethanol ingestion and compared to chronic ethanol followed by three repeat binge ethanol on the liver of male C57/BL6 mice fed ethanol in liquid diet (4%) for four weeks followed by binge ethanol (intragastric administration, 3.5 g/kg body weight, three doses, 12h apart). Chronic followed by binge ethanol exacerbated fat accumulation, necrosis, decrease in hepatic SAM and SAM:SAH ratio, increase in adenosine levels, and elevated CYP2E1 levels. Histone H3 lysine acetylation (H3AcK9), dually modified phosphoacetylated histone H3 (H3AcK9/PS10), and phosphorylated H2AX increased after binge whereas phosphorylation of histone H3 ser 10 (H3S10) and H3 ser 28 (H3S28) increased after chronic ethanol-binge. Histone H3 lysine 4 and 9 dimethylation increased with a marked dimethylation in H3K9 in chronic ethanol binge group. Trimethylated histone H3 levels did not change. Nuclear levels of histone acetyl transferase GCN5 and histone deacetylase HDAC3 were elevated whereas phospho-CREB decreased in a distinctive manner. Taken together, acute on chronic ethanol ingestion caused amplification of liver injury and elicited characteristic profiles of histone modifications, metabolic alterations, and changes in nuclear protein levels. These findings demonstrate that chronic ethanol exposure renders liver more susceptible to repeat acute/binge ethanol induced acceleration of alcoholic liver disease. PMID:26610587

  7. An enzyme-linked immuno focus assay for rapid detection and enumeration, and a newborn mouse model for human non-polio enteroviruses associated with acute diarrhea.

    PubMed

    Rao, C Durga; Reddy, Harikrishna; Naidu, Jagadish R; Raghavendra, A; Radhika, N S; Karande, Anjali

    2015-11-01

    We have recently reported significant association of non-polio enteroviruses (NPEVs) with acute and persistent diarrhea (18-21% of total diarrheal cases), and non-diarrheal Increased Frequency of Bowel Movements (IFoBM-ND) (about 29% of the NPEV infections) in children and that the NPEV-associated diarrhea was as significant as rotavirus diarrhea. However, their diarrhea-causing potential is yet to be demonstrated in an animal model system. Since the determination of virus titers by the traditional plaque assay takes 4-7 days, there is a need for development of a rapid method for virus titer determination to facilitate active clinical research on enterovirus-associated diarrhea. The goal of this study is to develop a cell-based rapid detection and enumeration method and to demonstrate the diarrhea-inducing potential of purified and characterized non-polio enteroviruses, which were isolated from diarrheic children. Here we describe generation of monoclonal and polyclonal antibodies against purified strains belonging to different serotypes, and development of an enzyme-linked immuno focus assay (ELIFA) for detection and enumeration of live NPEV particles in clinical and purified virus samples, and a newborn mouse model for NPEV diarrhea. Plaque-purified NPVEs, belonging to different serotypes, isolated from children with diarrhea, were grown in cell culture and purified by isopycnic CsCl density gradient centrifugation. By ELIFA, NPEVs could be detected and enumerated within 12h post-infection. Our results demonstrated that Coxsackievirus B1 (CVB1) and CVB5 strains, isolated from diarrheic children, induced severe diarrhea in orally-inoculated 9-12 day-old mouse pups, fulfilling Koch's postulates. The methods described here would facilitate studies on NPEV-associated gastrointestinal disease. PMID:26300372

  8. FLT3 and CDK4/6 inhibitors: signaling mechanisms and tumor burden in subcutaneous and orthotopic mouse models of acute myeloid leukemia.

    PubMed

    Zhang, Yaping; Hsu, Cheng-Pang; Lu, Jian-Feng; Kuchimanchi, Mita; Sun, Yu-Nien; Ma, Ji; Xu, Guifen; Zhang, Yilong; Xu, Yang; Weidner, Margaret; Huard, Justin; D'Argenio, David Z

    2014-12-01

    FLT3(ITD) subtype acute myeloid leukemia (AML) has a poor prognosis with currently available therapies. A number of small molecule inhibitors of FLT3 and/or CDK4/6 are currently under development. A more complete and quantitative understanding of the mechanisms of action of FLT3 and CDK4/6 inhibitors may better inform the development of current and future compounds that act on one or both of the molecular targets, and thus may lead to improved treatments for AML. In this study, we investigated in both subcutaneous and orthotopic AML mouse models, the mechanisms of action of three FLT3 and/or CDK4/6 inhibitors: AMG925 (Amgen), sorafenib (Bayer and Onyx), and quizartinib (Ambit Biosciences). A composite model was developed to integrate the plasma pharmacokinetics of these three compounds on their respective molecular targets, the coupling between the target pathways, as well as the resulting effects on tumor burden reduction in the subcutaneous xenograft model. A sequential modeling approach was used, wherein model structures and estimated parameters from upstream processes (e.g. PK, cellular signaling) were fixed for modeling subsequent downstream processes (cellular signaling, tumor burden). Pooled data analysis was employed for the plasma PK and cellular signaling modeling, while population modeling was applied to the tumor burden modeling. The resulting model allows the decomposition of the relative contributions of FLT3(ITD) and CDK4/6 inhibition on downstream signaling and tumor burden. In addition, the action of AMG925 on cellular signaling and tumor burden was further studied in an orthotopic tumor mouse model more closely representing the physiologically relevant environment for AML. PMID:25326874

  9. Toxicity assessment of perfluorooctane sulfonate using acute and subchronic male C57BL/6J mouse models.

    PubMed

    Xing, Jiali; Wang, Gang; Zhao, Jichun; Wang, Eryin; Yin, Boxing; Fang, Dongsheng; Zhao, Jianxin; Zhang, Hao; Chen, Yong Q; Chen, Wei

    2016-03-01

    Perfluorooctane sulfonate (PFOS) is a principal representative and the final degradation product of several commercially produced perfluorinated compounds. However, PFOS has a high bioaccumulation potential and therefore can exert toxicity on aquatic organisms, animals, and cells. Considering the widespread concern this phenomenon has attracted, we examined the acute and subchronic toxic effects of varying doses of PFOS on adult male C57BL/6 mice. The acute oral LD50 value of PFOS in male C57BL/6J mice was 0.579 g/kg body weight (BW). Exposure to the subchronic oral toxicity of PFOS at 2.5, 5, and 10 mg PFOS/kg BW/day for 30 days disrupted the homeostasis of antioxidative systems, induced hepatocellular apoptosis (as revealed by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay), triggered liver injury (as evidenced by the increased serum levels of aspartate aminotransferase, alanine amino transferase, alkaline phosphatase, and gamma-glutamyl transpeptidase and by the altered histology), and ultimately increased the liver size and relative weight of the mice. PFOS treatment caused liver damage but only slightly affected the kidneys and spleen of the mice. This study provided insights into the toxicological effects of PFOS. PMID:26807985

  10. Prostaglandin E2 Regulates Liver versus Pancreas Cell Fate Decisions and Endodermal Outgrowth

    PubMed Central

    Nissim, Sahar; Sherwood, Richard I.; Wucherpfennig, Julia; Saunders, Diane; Harris, James M.; Esain, Virginie; Carroll, Kelli J.; Frechette, Gregory M.; Kim, Andrew J.; Hwang, Katie L.; Cutting, Claire C.; Elledge, Susanna; North, Trista E.; Goessling, Wolfram

    2014-01-01

    SUMMARY The liver and pancreas arise from common endodermal progenitors. How these distinct cell fates are specified is poorly understood. Here, we describe prostaglandin E2 (PGE2) as a regulator of endodermal fate specification during development. Modulating PGE2 activity has opposing effects on liver-versus-pancreas specification in zebrafish embryos as well as mouse endodermal progenitors. The PGE2 synthetic enzyme cox2a and receptor ep2a are patterned such that cells closest to PGE2 synthesis acquire a liver fate whereas more distant cells acquire a pancreas fate. PGE2 interacts with the bmp2b pathway to regulate fate specification. At later stages of development, PGE2 acting via the ep4a receptor promotes outgrowth of both the liver and pancreas. PGE2 remains important for adult organ growth, as it modulates liver regeneration. This work provides in vivo evidence that PGE2 may act as a morphogen to regulate cell fate decisions and outgrowth of the embryonic endodermal anlagen. PMID:24530296

  11. The effect of matrix metalloproteinase-3 deficiency on pulmonary surfactant in a mouse model of acute lung injury.

    PubMed

    Yamashita, Cory M; Cybulskie, Candice; Milos, Scott; Zuo, Yi Y; McCaig, Lynda A; Veldhuizen, Ruud A W

    2016-06-01

    The acute respiratory distress syndrome (ARDS) is characterized by arterial hypoxemia accompanied by severe inflammation and alterations to the pulmonary surfactant system. Published data has demonstrated a protective effect of matrix metalloproteinase-3 (Mmp3) deficiency against the inflammatory response associated with ARDS; however, the effect of Mmp3 on physiologic parameters and alterations to surfactant have not been previously studied. It was hypothesized that Mmp3 deficient (Mmp3(-/-)) mice would be protected against lung dysfunction associated with ARDS and maintain a functional pulmonary surfactant system. Wild type (WT) and Mmp3(-/-) mice were subjected to acid-aspiration followed by mechanical ventilation. Mmp3(-/-) mice maintained higher arterial oxygenation compared with WT mice at the completion of ventilation. Significant increase in functional large aggregate surfactant forms were observed in Mmp3(-/-) mice compared with WT mice. These findings further support a role of Mmp3 as an attractive therapeutic target for drug development in the setting of ARDS. PMID:27096327

  12. Acute Reduction of Microglia Does Not Alter Axonal Injury in a Mouse Model of Repetitive Concussive Traumatic Brain Injury

    PubMed Central

    Bennett, Rachel E.

    2014-01-01

    Abstract The pathological processes that lead to long-term consequences of multiple concussions are unclear. Primary mechanical damage to axons during concussion is likely to contribute to dysfunction. Secondary damage has been hypothesized to be induced or exacerbated by inflammation. The main inflammatory cells in the brain are microglia, a type of macrophage. This research sought to determine the contribution of microglia to axon degeneration after repetitive closed-skull traumatic brain injury (rcTBI) using CD11b-TK (thymidine kinase) mice, a valganciclovir-inducible model of macrophage depletion. Low-dose (1 mg/mL) valganciclovir was found to reduce the microglial population in the corpus callosum and external capsule by 35% after rcTBI in CD11b-TK mice. At both acute (7 days) and subacute (21 days) time points after rcTBI, reduction of the microglial population did not alter the extent of axon injury as visualized by silver staining. Further reduction of the microglial population by 56%, using an intermediate dose (10 mg/mL), also did not alter the extent of silver staining, amyloid precursor protein accumulation, neurofilament labeling, or axon injury evident by electron microscopy at 7 days postinjury. Longer treatment of CD11b-TK mice with intermediate dose and treatment for 14 days with high-dose (50 mg/mL) valganciclovir were both found to be toxic in this injury model. Altogether, these data are most consistent with the idea that microglia do not contribute to acute axon degeneration after multiple concussive injuries. The possibility of longer-term effects on axon structure or function cannot be ruled out. Nonetheless, alternative strategies directly targeting injury to axons may be a more beneficial approach to concussion treatment than targeting secondary processes of microglial-driven inflammation. PMID:24797413

  13. Multipotent pancreas progenitors: Inconclusive but pivotal topic.

    PubMed

    Jiang, Fang-Xu; Morahan, Grant

    2015-12-26

    The establishment of multipotent pancreas progenitors (MPP) should have a significant impact not only on the ontology of the pancreas, but also for the translational research of glucose-responding endocrine β-cells. Deficiency of the latter may lead to the pandemic type 1 or type 2 diabetes mellitus, a metabolic disorder. An ideal treatment of which would potentially be the replacement of destroyed or failed β-cells, by restoring function of endogenous pancreatic endocrine cells or by transplantation of donor islets or in vitro generated insulin-secreting cells. Thus, considerable research efforts have been devoted to identify MPP candidates in the pre- and post-natal pancreas for the endogenous neogenesis or regeneration of endocrine insulin-secreting cells. In order to advance this inconclusive but critical field, we here review the emerging concepts, recent literature and newest developments of potential MPP and propose measures that would assist its forward progression. PMID:26730269

  14. Three-dimensional pancreas organogenesis models.

    PubMed

    Grapin-Botton, A

    2016-09-01

    A rediscovery of three-dimensional culture has led to the development of organ biogenesis, homeostasis and disease models applicable to human tissues. The so-called organoids that have recently flourished serve as valuable models bridging between cell lines or primary cells grown on the bottom of culture plates and experiments performed in vivo. Though not recapitulating all aspects of organ physiology, the miniature organs generated in a dish are useful models emerging for the pancreas, starting from embryonic progenitors, adult cells, tumour cells and stem cells. This review focusses on the currently available systems and their relevance to the study of the pancreas, of β-cells and of several pancreatic diseases including diabetes. We discuss the expected future developments for studying human pancreas development and function, for developing diabetes models and for producing therapeutic cells. PMID:27615129

  15. Intraductal Oncocytic Papillary Neoplasms of the Pancreas.

    PubMed

    Kallen, Michael E; Naini, Bita V

    2016-09-01

    Intraductal oncocytic papillary neoplasms (IOPNs) are cystic neoplasms with intraductal growth and complex papillae composed of oncocytic cells. IOPNs have been reported both in the pancreas and biliary tree, and are most likely closely related in these 2 locations. In the pancreas, these rare tumors are now considered 1 of the 4 histologic subtypes of intraductal papillary mucinous neoplasm (IPMN). Significant differences in histology, immunophenotype, and molecular genetics have been reported between IOPNs and other IPMN subtypes. However, there are limited data regarding the clinical behavior and prognosis of IOPNs in comparison to other subtypes of IPMN. We review features of pancreatic IOPNs and discuss the differential diagnosis of other intraductal lesions in the pancreas. PMID:27575268

  16. Multipotent pancreas progenitors: Inconclusive but pivotal topic

    PubMed Central

    Jiang, Fang-Xu; Morahan, Grant

    2015-01-01

    The establishment of multipotent pancreas progenitors (MPP) should have a significant impact not only on the ontology of the pancreas, but also for the translational research of glucose-responding endocrine β-cells. Deficiency of the latter may lead to the pandemic type 1 or type 2 diabetes mellitus, a metabolic disorder. An ideal treatment of which would potentially be the replacement of destroyed or failed β-cells, by restoring function of endogenous pancreatic endocrine cells or by transplantation of donor islets or in vitro generated insulin-secreting cells. Thus, considerable research efforts have been devoted to identify MPP candidates in the pre- and post-natal pancreas for the endogenous neogenesis or regeneration of endocrine insulin-secreting cells. In order to advance this inconclusive but critical field, we here review the emerging concepts, recent literature and newest developments of potential MPP and propose measures that would assist its forward progression. PMID:26730269

  17. Progenitor cells in the adult pancreas.

    PubMed

    Holland, Andrew M; Góñez, L Jorge; Harrison, Leonard C

    2004-01-01

    The beta-cell mass in the adult pancreas possesses the ability to undergo limited regeneration following injury. Identifying the progenitor cells involved in this process and understanding the mechanisms leading to their maturation will open new avenues for the treatment of type 1 diabetes. However, despite steady advances in determining the molecular basis of early pancreatic development, the identification of pancreatic stem cells or beta-cell progenitors and the molecular mechanisms underlying beta-cell regeneration remain unclear. Recent advances in the directed differentiation of embryonic and adult stem cells has heightened interest in the possible application of stem cell therapy in the treatment of type 1 diabetes. Drawing on the expanding knowledge of pancreas development, beta-cell regeneration and stem cell research, this review focuses on progenitor cells in the adult pancreas as a potential source of beta-cells. PMID:14737742

  18. Conservative Pancreas Graft Preservation at the Extreme.

    PubMed

    Laurence, Jerome Martin; Sapisochin, Gonzalo; Selzner, Markus; Norgate, Andrea; Kumar, Deepali; McGilvary, Ian D; Preig, Paul D; Schiff, Jeffrey; Cattral, Mark S

    2016-01-01

    Because of the value some patients place in remaining insulin-independent after pancreas transplantation, they may be reluctant to undergo graft pancreatectomy, even in the face of extreme complications, such as graft thrombosis and duodenal segment leak. Partly, for this reason, a variety of complex salvage techniques have been described to save the graft in such circumstances. We report a case of a series of extreme complications related to a leak from the duodenal segment after a simultaneous pancreas and kidney transplant. These included infected thrombosis of the inferior vena cava associated with a graft venous thrombosis and a retroperitoneal fistula. The patient retained graft function with insulin independence and repeatedly declined graft pancreatectomy against the advice of the transplant team. Conservative treatment with percutaneous drainage, antibiotics, and anticoagulation was eventually successful. This outcome is unique in our experience and may be instructive to teams caring for pancreas transplant recipients. PMID:27500244

  19. Acute and long-term transcriptional responses in sulfur mustard-exposed SKH-1 hairless mouse skin.

    PubMed

    Vallet, V; Poyot, T; Cléry-Barraud, C; Coulon, D; Sentenac, C; Peinnequin, A; Boudry, I

    2012-03-01

    Sulfur mustard (HD) ranks among the alkylating chemical warfare agents. Skin contact with HD produces an inflammatory response that evolves into separation at the epidermal-dermal junction conducting to blistering and epidermis necrosis. Up to now, current treatment strategies of HD burns have solely consisted in symptomatic management of skin damage. Therapeutic efficacy studies are still being conducted; classically using appropriate animal skin toxicity models. In order to substantiate the use of SKH-1 hairless mouse as an appropriate model for HD-induced skin lesions, we investigate the time-dependent quantitative gene expression of various selected transcripts associated to the dorsal skin exposure to HD saturated vapors. Using quantitative real time polymerase chain reaction (RT-qPCR), the expression of interleukins (IL-1β and IL-6), tumor necrosis factor (TNF)-α, macrophage inflammatory proteins (MIP)-2α (also called Cxcl2) and MIP-1αR (also called Ccr1), matrix metalloproteases (MMP-9 and MMP-2), laminin γ2 monomer (Lamc2) and keratin (K)1 was determined up to 21 days after HD challenge in order to allow enough time for wound repair to begin. Specific transcript RT-qPCR analysis demonstrated that IL-6, IL-1β, Ccr1, Cxcl2 mRNA levels increased as early as 6 h in HD-exposed skins and remained up-regulated over a 14-day period. Topical application of HD also significantly up-regulated MMP-9, TNF-α, and Lamc2 expression at specific time points. In contrast, MMP-2 mRNA levels remained unaffected by HD over the time-period considered, whereas that long-term study revealed that K1 mRNA level significantly increased only 21 days after HD challenge. Our study hereby provides first-hand evidence to substantiate a long period variation expression in the inflammatory cytokine, MMPs and structural components following cutaneous HD exposure in hairless mouse SKH-1. Our data credit the use of SKH-1 for investigating mechanisms of HD-induced skin toxicity and for

  20. Atg5-dependent autophagy contributes to the development of acute myeloid leukemia in an MLL-AF9-driven mouse model.

    PubMed

    Liu, Qiang; Chen, Longgui; Atkinson, Jennifer M; Claxton, David F; Wang, Hong-Gang

    2016-01-01

    Acute myeloid leukemia (AML) is a hierarchical hematopoietic malignancy originating from leukemic stem cells (LSCs). Autophagy is a lysosomal degradation pathway that is hypothesized to be important for the maintenance of AML as well as contribute to chemotherapy response. Here we employ a mouse model of AML expressing the fusion oncogene MLL-AF9 and explore the effects of Atg5 deletion, a key autophagy protein, on the malignant transformation and progression of AML. Consistent with a transient decrease in colony-forming potential in vitro, the in vivo deletion of Atg5 in MLL-AF9-transduced bone marrow cells during primary transplantation prolonged the survival of recipient mice, suggesting that autophagy has a role in MLL-AF9-driven leukemia initiation. In contrast, deletion of Atg5 in malignant AML cells during secondary transplantation did not influence the survival or chemotherapeutic response of leukemic mice. Interestingly, autophagy was found to be involved in the survival of differentiated myeloid cells originating from MLL-AF9-driven LSCs. Taken together, our data suggest that Atg5-dependent autophagy may contribute to the development but not chemotherapy sensitivity of murine AML induced by MLL-AF9. PMID:27607576

  1. The Polycomb complex PRC2 supports aberrant self-renewal in a mouse model of MLL-AF9;NrasG12D acute myeloid leukemia

    PubMed Central

    Shi, Junwei; Wang, Eric; Zuber, Johannes; Rappaport, Amy; Taylor, Meredith; Johns, Christopher

    2014-01-01

    The Trithorax and Polycomb groups of chromatin regulators are critical for cell-lineage specification during normal development; functions that often become deregulated during tumorigenesis. As an example, oncogenic fusions of the Trithorax-related protein MLL can initiate aggressive leukemias by altering the transcriptional circuitry governing hematopoietic cell differentiation, a process that is known to require additional epigenetic pathways to implement. Here we used shRNA screening to identify chromatin regulators uniquely required in a mouse model of MLL-fusion acute myeloid leukemia, which revealed a role for the Polycomb Repressive Complex 2 (PRC2) in maintenance of this disease. shRNA-mediated suppression of PRC2 subunits Eed, Suz12, or Ezh1/Ezh2 led to proliferation-arrest and differentiation of leukemia cells, with a minimal impact on growth of several non-transformed hematopoietic cell lines. The requirement for PRC2 in leukemia is partly due to its role in direct transcriptional repression of genes that limit the self-renewal potential of hematopoietic cells, including Cdkn2a. In addition to implicating a role for PRC2 in the pathogenesis of MLL-fusion leukemia, our results suggest, more generally, that Trithorax and Polycomb group proteins can cooperate with one another to maintain aberrant lineage programs in cancer. PMID:22469984

  2. Necrotizing Enterocolitis in a mouse model leads to widespread renal inflammation, acute kidney injury and disruption of renal tight junction proteins

    PubMed Central

    Garg, Parvesh M; Tatum, Rodney; Ravisankar, Srikanth; Shekhawat, Prem S; Chen, Yan-Hua

    2015-01-01

    BACKGROUND Necrotizing enterocolitis (NEC) is a devastating condition affecting premature infants and leads to high mortality and chronic morbidity. Severe form of NEC is associated with acute renal failure, fluid imbalance, hyponatremia and acidosis. We investigated the effect of NEC on tight junction (TJ) proteins in kidneys using a NEC mouse model to investigate the basis for the observed renal dysfunction. METHODS NEC was induced in C57BL/6 mice by formula feeding and subjecting them to periods of hypoxia and cold stress. NEC was confirmed by gross and histological examination. We studied various markers of inflammation in kidneys and investigated changes in expression of several TJ proteins and AQP2 using immunofluorecent staining and Western blotting. RESULTS We found markedly increased expression of NFκB, TGFβ and ERK1/2 along with claudin-1, -2, -3, -4, -8 and AQP-2 in NEC kidneys. The membrane localization of claudin-2 was altered in the NEC kidneys and its immunostaining signal at TJ was disrupted. CONCLUSION NEC led to a severe inflammatory response not only in the gut but also the kidneys. NEC increased expression of several TJ proteins and caused disruption of claudin-2 in renal tubules. These observed changes can help explain some of the clinical findings observed in NEC. PMID:26270572

  3. Resveratrol given intraperitoneally does not inhibit the growth of high-risk t(4;11) acute lymphoblastic leukemia cells in a NOD/SCID mouse model

    PubMed Central

    ZUNINO, SUSAN J.; STORMS, DAVID H.; NEWMAN, JOHN W.; PEDERSEN, THERESA L.; KEEN, CARL L.; DUCORE, JONATHAN M.

    2012-01-01

    The efficacy of resveratrol as a preventive agent against the growth of t(4;11) acute lymphoblastic leukemia (ALL) was evaluated in NOD.CB17-Prkdcscid/J mice engrafted with the human t(4;11) ALL SEM cell line. SEM cells were injected into the tail vein and engraftment was monitored by flow cytometry. Once engraftment was observed, mice were injected intraperitoneally with resveratrol (10 mg/kg body weight) dissolved in dimethylsulfoxide (DMSO) or DMSO alone (control) every other day, or vincristine (0.5 mg/kg body weight) 3 times per week for 4 weeks (n=16 per group). Comparisons of the percent of human leukemia cells in blood and survival curves showed resveratrol did not inhibit progression of the disease. Liquid chromatography-tandem mass spectrometry analyses of mouse sera showed resveratrol was rapidly metabolized to glucuronidated and sulfated forms 1 h post-injection, with low to no resveratrol or metabolites observed in sera by 24–48 h. These data indicate that in contrast to findings in in vitro models, parenterally administered resveratrol does not have potential as a preventive agent against high risk t(4;11) ALL. PMID:22200740

  4. Skin pathology induced by snake venom metalloproteinase: acute damage, revascularization, and re-epithelization in a mouse ear model.

    PubMed

    Jiménez, Natalia; Escalante, Teresa; Gutiérrez, José María; Rucavado, Alexandra

    2008-10-01

    Viperid snakebite envenomation induces blistering and dermonecrosis. The pathological alterations induced by a snake venom metalloproteinase in the skin were investigated in a mouse ear model. Metalloproteinase BaP1, from Bothrops asper, induced rapid edema, hemorrhage, and blistering; the latter two effects were abrogated by preincubation with the metalloproteinase inhibitor batimastat. Neutrophils did not play a role in the pathology, as depletion of these cells resulted in a similar histological picture. Blisters are likely to result from the direct proteolytic activity of BaP1 of proteins at the dermal-epidermal junction, probably at the lamina lucida, as revealed by immunostaining for type IV collagen and laminin. Widespread apoptosis of keratinocytes was detected by the TUNEL assay, whereas no apoptosis of capillary endothelial cells was observed. BaP1 induced a drastic reduction in the microvessel density, revealed by immunostaining for the endothelial marker vascular endothelial growth factor receptor-2. This was followed by a rapid angiogenic response, leading to a partial revascularization. Skin damage was followed by inflammation and granulation tissue formation. Then, a successful re-epithelization process occurred, and the skin of the ear regained its normal structure by 2 weeks. Venom metalloproteinase-induced skin damage reproduces the pathological changes described in snakebitten patients. PMID:18449209

  5. Novel Inhibitors of Neurotropic Alphavirus Replication That Improve Host Survival in a Mouse Model of Acute Viral Encephalitis

    PubMed Central

    Sindac, Janice; Yestrepsky, Bryan D.; Barraza, Scott J.; Bolduc, Kyle L.; Blakely, Pennelope K.; Keep, Richard F.; Irani, David N.; Miller, David J.; Larsen, Scott D.

    2012-01-01

    Arboviral encephalitis is a potentially devastating human disease with no approved therapies that target virus replication. We previously discovered a novel class of thieno[3,2-b]pyrrole-based inhibitors active against neurotropic alphaviruses such as western equine encephalitis virus (WEEV) in cultured cells. In this report we describe initial development of these novel antiviral compounds, including bioisosteric replacement of the 4H-thieno[3,2-b]pyrrole core with indole to improve metabolic stability and the introduction of chirality to assess target enantioselectivity. Selected modifications enhanced antiviral activity while maintaining low cytotoxicity, increased stability to microsomal metabolism, and also revealed striking enantiospecific activity in cultured cells. Furthermore, we demonstrate improved outcomes (both symptoms and survival) following treatment with indole analog 9h (CCG-203926) in an in vivo mouse model of alphaviral encephalitis that closely correlate with the enantiospecific in vitro antiviral activity. These results represent a substantial advancement in the early preclinical development of a promising class of novel antiviral drugs against virulent neurotropic alphaviruses. PMID:22428985

  6. [Ectopic pancreas imitating gastric neoplasm -- a case report].

    PubMed

    Buczek, Tomasz; Puzdrowski, Witold; Lenekowski, Radosław; Kruszewski, Wiesław Janusz

    2013-01-01

    Ectopic pancreas is a rare developmental disorder. Usually is asymptomatic. Most frequently is diagnosed in its gastric location accidentally during endoscopy. A patient with ectopic pancreas was described manifesting as a gastric tumor arousing oncological concern. PMID:24455840

  7. Progress of artificial pancreas devices toward clinical use: the first outpatient studies

    PubMed Central

    Russell, Steven J.

    2015-01-01

    Purpose of review This article describes recent progress in the automated control of glycemia in type 1 diabetes with artificial pancreas devices that combine continuous glucose monitoring with automated decision-making and insulin delivery. Recent findings After a gestation period of closely supervised feasibility studies in research centers, the last 2 years have seen publication of studies testing these devices in outpatient environments, and many more such studies are ongoing. The most basic form of automation, suspension of insulin delivery for actual or predicted hypoglycemia, has been shown to be effective and well tolerated, and a first-generation device has actually reached the market. Artificial pancreas devices that actively dose insulin fall into two categories, those that dose insulin alone and those that also use glucagon to prevent and treat hypoglycemia (bihormonal artificial pancreas). Initial outpatient clinical trials have shown that both strategies can improve glycemic management in comparison with patient-controlled insulin pump therapy, but only the bihormonal strategy has been tested without restrictions on exercise. Summary Artificial pancreas technology has the potential to reduce acute and chronic complications of diabetes and mitigate the burden of diabetes self-management. Successful outpatient studies bring these technologies one step closer to availability for patients. PMID:25692927

  8. Studies on the absence of photodynamic mechanism in the normal pancreas

    NASA Astrophysics Data System (ADS)

    Mang, Thomas S.; Wieman, Thomas J.; Crean, David H.

    1991-06-01

    Extraction procedures to quantitate porfimer sodium concentration in tissues were correlated with fluorescence measurements made in vivo, on hamster and rat normal pancreas and intra-pancreatic tumors. The uptake of photosensitizer has been shown to be high in both normal and malignant pancreatic tissues, in both animal models studied. Photobleaching of the drug, as evidenced by both techniques within the pancreatic tumor, occurs in a typical manner during PDT, with resultant tissue destruction. In contrast, when the normal pancreas is exposed to PDT, a negligible photobleaching effect, as well as a lack of tissue response, is observed. The lack of observable response is corroborated by a lack of measurable physiological response. Both serum amylase and serum glucose show acute changes up to 12 hours post treatment but quickly return to normal. HPLC analysis shows that the drug extracted from both the normal pancreas and intrapancreatic tumor is essentially the same as that extracted from other tissues and similar to that which has been injected into the animal. Fluorescence microscopy has shown that at time points between 12-120 hours the drug is associated with lymphatic channels. This would not, however, necessarily preclude normal tissue destruction. Similar results have been found with other photosensitizers. Understanding the lack of response in the pancreas may lead to a deeper understanding of the diseased state which is normally refractory to all therapy as well as understanding the fundamental concepts of the mechanisms of PDT.

  9. CXCR4 inhibitors selectively eliminate CXCR4-expressing human acute myeloid leukemia cells in NOG mouse model

    PubMed Central

    Zhang, Y; Patel, S; Abdelouahab, H; Wittner, M; Willekens, C; Shen, S; Betems, A; Joulin, V; Opolon, P; Bawa, O; Pasquier, F; Ito, M; Fujii, N; Gonin, P; Solary, E; Vainchenker, W; Coppo, P; De Botton, S; Louache, F

    2012-01-01

    The chemokine receptor CXCR4 favors the interaction of acute myeloid leukemia (AML) cells with their niche but the extent to which it participates in pathogenesis is unclear. Here, we show that CXCR4 expression at the surface of leukemic cells allowed distinguishing CXCR4high from CXCR4neg/low AML patients. When high levels of CXCR4 are expressed at the surface of AML cells, blocking the receptor function with small molecule inhibitors could promote leukemic cell death and reduce NOD/Shi-scid/IL-2Rγnull (NOG) leukemia-initiating cells (LICs). Conversely, these drugs had no efficacy when AML cells do not express CXCR4 or when they do not respond to chemokine CXC motif ligand 12 (CXCL12). Functional analysis showed a greater mobilization of leukemic cells and LICs in response to drugs, suggesting that they target the interaction between leukemic cells and their supportive bone marrow microenvironment. In addition, increased apoptosis of leukemic cells in vitro and in vivo was observed. CXCR4 expression level on AML blast cells and their migratory response to CXCL12 are therefore predictive of the response to the inhibitors and could be used as biomarkers to select patients that could potentially benefit from the drugs. PMID:23034331

  10. Acute exposure to waterpipe tobacco smoke induces changes in the oxidative and inflammatory markers in mouse lung

    PubMed Central

    Khabour, Omar F.; Alzoubi, Karem H.; Bani-Ahmad, Mohammed; Dodin, Arwa; Eissenberg, Thomas; Shihadeh, Alan

    2013-01-01

    Context Tobacco smoking represents a global public health threat, claiming approximately 5 million lives a year. Waterpipe tobacco use has become popular particularly among youth in the past decade, buttressed by the perception that the waterpipe “filters” the smoke, rendering it less harmful than cigarette smoke. Objective In this study, we examined the acute exposure of waterpipe smoking on lung inflammation and oxidative stress in mice, and compared that to cigarette smoking. Materials and methods Mice were divided into three groups; fresh air control, cigarette and waterpipe. Animals were exposed to fresh air, cigarette, or waterpipe smoke using whole body exposure system one hour daily for 7 days. Results Both cigarette and waterpipe smoke exposure resulted in elevation of total white blood cell count, as well as absolute count of neutrophils, macrophages, and lymphocytes (P < 0.01). Both exposures also elevated proinflammatory markers such as TNF-α and IL-6 in BALF (P < 0.05), and oxidative stress markers including GPx activity in lungs (P < 0.05). Moreover, waterpipe smoke increased catalase activity in the lung (P < 0.05). However, none of the treatments altered IL-10 levels. Discussion and conclusion Results of cigarette smoking confirmed previous finding. Waterpipe results indicate that, similar to cigarettes, exposure to waterpipe tobacco smoke is harmful to the lungs. PMID:22906173

  11. Hormone-Dependent Expression of a Steroidogenic Acute Regulatory Protein Natural Antisense Transcript in MA-10 Mouse Tumor Leydig Cells

    PubMed Central

    Castillo, Ana Fernanda; Fan, Jinjiang; Papadopoulos, Vassilios; Podestá, Ernesto J.

    2011-01-01

    Cholesterol transport is essential for many physiological processes, including steroidogenesis. In steroidogenic cells hormone-induced cholesterol transport is controlled by a protein complex that includes steroidogenic acute regulatory protein (StAR). Star is expressed as 3.5-, 2.8-, and 1.6-kb transcripts that differ only in their 3′-untranslated regions. Because these transcripts share the same promoter, mRNA stability may be involved in their differential regulation and expression. Recently, the identification of natural antisense transcripts (NATs) has added another level of regulation to eukaryotic gene expression. Here we identified a new NAT that is complementary to the spliced Star mRNA sequence. Using 5′ and 3′ RACE, strand-specific RT-PCR, and ribonuclease protection assays, we demonstrated that Star NAT is expressed in MA-10 Leydig cells and steroidogenic murine tissues. Furthermore, we established that human chorionic gonadotropin stimulates Star NAT expression via cAMP. Our results show that sense-antisense Star RNAs may be coordinately regulated since they are co-expressed in MA-10 cells. Overexpression of Star NAT had a differential effect on the expression of the different Star sense transcripts following cAMP stimulation. Meanwhile, the levels of StAR protein and progesterone production were downregulated in the presence of Star NAT. Our data identify antisense transcription as an additional mechanism involved in the regulation of steroid biosynthesis. PMID:21829656

  12. Mouse Models of Acute Respiratory Distress Syndrome: A Review of Analytical Approaches, Pathologic Features, and Common Measurements.

    PubMed

    Aeffner, Famke; Bolon, Brad; Davis, Ian C

    2015-12-01

    Acute respiratory distress syndrome (ARDS) is a severe pulmonary reaction requiring hospitalization, which is incited by many causes, including bacterial and viral pneumonia as well as near drowning, aspiration of gastric contents, pancreatitis, intravenous drug use, and abdominal trauma. In humans, ARDS is very well defined by a list of clinical parameters. However, until recently no consensus was available regarding the criteria of ARDS that should be evident in an experimental animal model. This lack was rectified by a 2011 workshop report by the American Thoracic Society, which defined the main features proposed to delineate the presence of ARDS in laboratory animals. These should include histological changes in parenchymal tissue, altered integrity of the alveolar capillary barrier, inflammation, and abnormal pulmonary function. Murine ARDS models typically are defined by such features as pulmonary edema and leukocyte infiltration in cytological preparations of bronchoalveolar lavage fluid and/or lung sections. Common pathophysiological indicators of ARDS in mice include impaired pulmonary gas exchange and histological evidence of inflammatory infiltrates into the lung. Thus, morphological endpoints remain a vital component of data sets assembled from animal ARDS models. PMID:26296628

  13. Pancreas Recovery Following Caerulein-induced Pancreatitis is Impaired in Plasminogen Deficient Mice

    PubMed Central

    Lugea, Aurelia; Nan, Li; French, Samuel W.; Bezerra, Jorge A.; Gukovskaya, Anna S; Pandol, Stephen J.

    2006-01-01

    Background & Aims: The plasminogen (plg) system participates in tissue repair in several organs, but its role in pancreas repair remains poorly characterized. To better understand the role of plg in pancreas recovery following injury, we examined the course of caerulein-induced pancreatitis in plg deficient and sufficient mice. Methods: Pancreatitis was induced by caerulein administration (50 μg/kg, 7 ip injections). Mice were sacrificed either at the acute phase (7 hours after the first caerulein injection) or during recovery (at 2, 4 and 7 days). In pancreatic sections we examined: pancreatic morphology, trypsin activation, inflammatory cell infiltration, acinar cell death, cell proliferation, extracellular matrix (ECM) deposition, activation of stellate cells (PSCs), and components of the plg and metalloproteinase systems. Results: In plg sufficient mice, pancreatic plg levels and plasmin activity increased during the acute phase and remained elevated during recovery. Pancreatitis resolved in plg sufficient mice within 7 days. Pancreas recovery involved reorganization of the parenchyma structure, removal of necrotic debris, cell proliferation, transient activation of PSCs and moderate deposition of ECM proteins. Acute pancreatitis (7-h) was indistinguishable between plg deficient and sufficient mice. In contrast, pancreas recovery was impaired in plg deficient mice. Plg deficiency led to disorganized parenchyma, extensive acinar cell loss, poor removal of necrotic debris, reduced cell proliferation and fibrosis. Fibrosis was characterized by deposition of collagens and fibronectin, persistent activation of PSCs and upregulation of pancreatic TGF-β1. Conclusions: Plg/plasmin deficiency leads to features similar to those found in chronic pancreatitis such as parenchymal atrophy and fibrosis. PMID:16952557

  14. OPTN/SRTR 2013 Annual Data Report: pancreas.

    PubMed

    Kandaswamy, R; Skeans, M A; Gustafson, S K; Carrico, R J; Tyler, K H; Israni, A K; Snyder, J J; Kasiske, B L

    2015-01-01

    Pancreas listings and transplants decreased during the past decade, most notably pancreas after kidney transplants. Center-reported outcomes of pancreas transplant across all groups, short-term and long-term, improved during the same period. Changes to the pancreas allocation system creating an efficient, uniform national system will be implemented in late 2014. Pancreas-alone and simultaneous pancreas-kidney (SPK) candidates will form a single match-run list with priority to most SPK candidates ahead of kidney-alone candidates to decrease waiting times for SPK candidates, given their higher waitlist mortality compared with nondiabetic kidney transplant candidates. The changes are expected to eliminate local variability, providing more consistent pancreas allocation nationwide. Outcomes after pancreas transplant are challenging to interpret due to lack of a uniform definition of graft failure. Consequently, SRTR has not published data on pancreas graft failure for the past 2 years. The Organ Procurement and Transplantation Network Pancreas Transplantation Committee is working on a definition that could provide greater validity for future outcomes analyses. Challenges in pancreas transplantation include high risk of technical failures, rejection (early and late), and surgical complications. Continued outcome improvement and innovation has never been more critical, as alternatives such as islet transplant and artificial pancreas move closer to clinical application. PMID:25626343

  15. Pancreas-Specific Delivery of β-Cell Proliferating Small Molecules.

    PubMed

    Hao, Xueshi; Jin, Qihui; Va, Porino; Li, Chun; Shen, Weijun; Laffitte, Bryan; Wu, Tom Y-H

    2016-06-01

    Our research groups recently described a series of small-molecule inducers of β-cell proliferation that could be used to increase β-cell mass. To mitigate the risk of nonspecific proliferation of other cell types, we devised a delivery strategy built on the tissue specificity observed in the experimental β-cell imaging agent (+)-dihydrotetrabenazine (DTBZ). The β-cell proliferator agent aminopyrazine (AP) was covalently linked with (+)-DTBZ to afford conjugates that retain both the proliferation activity and binding affinity for vesicular monoamine transporter-2 (VMAT2). In vivo mouse tissue distribution studies of a prototypical AP-DTBZ conjugate showed 15-fold pancreas exposure over plasma. Tissue-to-plasma ratios in liver and kidneys were two- and five-fold, respectively. This work is the first demonstration of enhanced delivery of β-cell-proliferating molecules to the pancreas by leveraging the intrinsic tissue specificity of a β-cell imaging agent. PMID:27095073

  16. Malignant Fibrous Histiocytoma of The Pancreas

    PubMed Central

    Garvey, J. F. W.; Ng, A.; England, J. F.

    1989-01-01

    A case of fibrous histiocytoma of low grade malignancy arising from the uncinate lobe of the pancreas is reported. This is an unusual site for these extremely rare tumours. Survival up to 4 years has been achieved in our patient following surgical resection. PMID:2562132

  17. CARCINOMA OF THE EXOCRINE PANCREAS IN MEDAKA

    EPA Science Inventory

    Eight cases of acinar cell carcinoma of the exocrine pancreas were diagnosed in Japanese medaka (Oryzias latipes) from a pool of approximately 10,000 specimens used in a variety of carcinogenesis bioassays. hree cases occurred in specimens from control groups and one case in a sp...

  18. Optimizing Mouse Surgery with Online Rectal Temperature Monitoring and Preoperative Heat Supply. Effects on Post-Ischemic Acute Kidney Injury

    PubMed Central

    Holderied, Alexander; Anders, Hans-Joachim

    2016-01-01

    Body temperature affects outcomes of tissue injury. We hypothesized that online body core temperature recording and selective interventions help to standardize peri-interventional temperature control and the reliability of outcomes in experimental renal ischemia reperfusion injury (IRI). We recorded core temperature in up to seven mice in parallel using a Thermes USB recorder and ret-3-iso rectal probes with three different protocols. Setup A: Heating pad during ischemia time; Setup B: Heating pad from incision to wound closure; Setup C: A ventilated heating chamber before surgery and during ischemia time with surgeries performed on a heating pad. Temperature profile recording displayed significant declines upon installing anesthesia. The profile of the baseline experimental setup A revealed that <1% of the temperature readings were within the target range of 36.5 to 38.5°C. Setup B and C increased the target range readings to 34.6 ± 28.0% and 99.3 ± 1.5%, respectively. Setup C significantly increased S3 tubular necrosis, neutrophil influx, and mRNA expression of kidney injury markers. In addition, using setup C different ischemia times generated a linear correlation with acute tubular necrosis parameters at a low variability, which further correlated with the degree of kidney atrophy 5 weeks after surgery. Changing temperature control setup A to C was equivalent to 10 minutes more ischemia time. We conclude that body temperature drops quickly in mice upon initiating anesthesia. Immediate heat supply, e.g. in a ventilated heating chamber, and online core temperature monitoring can help to standardize and optimize experimental outcomes. PMID:26890071

  19. Targeted disruption of the mouse gene encoding steroidogenic acute regulatory protein provides insights into congenital lipoid adrenal hyperplasia

    PubMed Central

    Caron, Kathleen M.; Soo, Shiu-Ching; Wetsel, William C.; Stocco, Douglas M.; Clark, Barbara J.; Parker, Keith L.

    1997-01-01

    An essential component of regulated steroidogenesis is the translocation of cholesterol from the cytoplasm to the inner mitochondrial membrane where the cholesterol side-chain cleavage enzyme carries out the first committed step in steroidogenesis. Recent studies showed that a 30-kDa mitochondrial phosphoprotein, designated steroidogenic acute regulatory protein (StAR), is essential for this translocation. To allow us to explore the roles of StAR in a system amenable to experimental manipulation and to develop an animal model for the human disorder lipoid congenital adrenal hyperplasia (lipoid CAH), we used targeted gene disruption to produce StAR knockout mice. These StAR knockout mice were indistinguishable initially from wild-type littermates, except that males and females had female external genitalia. After birth, they failed to grow normally and died from adrenocortical insufficiency. Hormone assays confirmed severe defects in adrenal steroids—with loss of negative feedback regulation at hypothalamic–pituitary levels—whereas hormones constituting the gonadal axis did not differ significantly from levels in wild-type littermates. Histologically, the adrenal cortex of StAR knockout mice contained florid lipid deposits, with lesser deposits in the steroidogenic compartment of the testis and none in the ovary. The sex-specific differences in gonadal involvement support a two-stage model of the pathogenesis of StAR deficiency, with trophic hormone stimulation inducing progressive accumulation of lipids within the steroidogenic cells and ultimately causing their death. These StAR knockout mice provide a useful model system in which to determine the mechanisms of StAR’s essential roles in adrenocortical and gonadal steroidogenesis. PMID:9326645

  20. Concussive Brain Trauma in the Mouse Results in Acute Cognitive Deficits and Sustained Impairment of Axonal Function

    PubMed Central

    Creed, Jennifer A.; DiLeonardi, Ann Mae; Fox, Douglas P.; Tessler, Alan R.

    2011-01-01

    Abstract Concussive brain injury (CBI) accounts for approximately 75% of all brain-injured people in the United States each year and is particularly prevalent in contact sports. Concussion is the mildest form of diffuse traumatic brain injury (TBI) and results in transient cognitive dysfunction, the neuropathologic basis for which is traumatic axonal injury (TAI). To evaluate the structural and functional changes associated with concussion-induced cognitive deficits, adult mice were subjected to an impact on the intact skull over the midline suture that resulted in a brief apneic period and loss of the righting reflex. Closed head injury also resulted in an increase in the wet weight:dry weight ratio in the cortex suggestive of edema in the first 24 h, and the appearance of Fluoro-Jade-B-labeled degenerating neurons in the cortex and dentate gyrus of the hippocampus within the first 3 days post-injury. Compared to sham-injured mice, brain-injured mice exhibited significant deficits in spatial acquisition and working memory as measured using the Morris water maze over the first 3 days (p<0.001), but not after the fourth day post-injury. At 1 and 3 days post-injury, intra-axonal accumulation of amyloid precursor protein in the corpus callosum and cingulum was accompanied by neurofilament dephosphorylation, impaired transport of Fluoro-Gold and synaptophysin, and deficits in axonal conductance. Importantly, deficits in retrograde transport and in action potential of myelinated axons continued to be observed until 14 days post-injury, at which time axonal degeneration was apparent. These data suggest that despite recovery from acute cognitive deficits, concussive brain trauma leads to axonal degeneration and a sustained perturbation of axonal function. PMID:21299360

  1. Pancreas After Islet Transplantation: A First Report of the International Pancreas Transplant Registry.

    PubMed

    Gruessner, R W G; Gruessner, A C

    2016-02-01

    Pancreas after islet (PAI) transplantation is a treatment option for patients seeking insulin independence through a whole-organ transplant after a failed cellular transplant. This report from the International Pancreas Transplant Registry (IPTR) and the United Network for Organ Sharing (UNOS) studied PAI transplant outcomes over a 10-year time period. Forty recipients of a failed alloislet transplant subsequently underwent pancreas transplant alone (50%), pancreas after previous kidney transplant (22.5%), or simultaneous pancreas and kidney (SPK) transplant (27.5%). Graft and patient survival rates were not statistically significantly different compared with matched primary pancreas transplants. Regardless of the recipient category, overall 1- and 5-year PAI patient survival rates for all 40 cases were 97% and 83%, respectively; graft survival rates were 84% and 65%, respectively. A failed previous islet transplant had no negative impact on kidney graft survival in the SPK category: It was the same as for primary SPK transplants. According to this IPTR/UNOS analysis, a PAI transplant is a safe procedure with low recipient mortality, high graft-function rates in both the short and long term and excellent kidney graft outcomes. Patients with a failed islet transplant should know about this alternative in their quest for insulin independence through transplantation. PMID:26436323

  2. [Acute pancreas necrosis with biliary peritonitis in cesarean section].

    PubMed

    Zoldos, L; Hincová, M

    1986-01-01

    The authors describe the case of a hemorrhagic pancreatitis with non-perforating biliary peritonitis. The abdomen symptomatology was hidden by the beginning contractions and due to the dystocia the delivery was finished by caesarean section. The presence of choleperitoneum required a surgical revision of the abdominal cavity which enabled to make the right diagnosis. This thesis deals with aetiology and mechanism of choleperitoneum inception during hemorrhagic pancreatitis. PMID:3788337

  3. Effect of siRNA against NF-κB on sepsis‑induced acute lung injury in a mouse model.

    PubMed

    Jin, Li-Yan; Li, Cong-Feng; Zhu, Guang-Fa; Wu, Chun-Ting; Wang, Jun; Yan, Shu-Feng

    2014-08-01

    The aim of the present study was to explore the protective effect of small interfering RNA (siRNA) against nuclear factor κB (NF-κB) p65 on sepsis-induced acute lung injury (ALI) in mice. In total, 70 male Kunming mice were randomly divided into a healthy control group, a sepsis group, a specific interfering group and a scrambled control group (Sc), and the latter three groups were divided into post-operational 6 and 12 h subgroups, each of which consisted of 10 mice. The mice were administered with NF-κB siRNA, scrambled siRNA and normal saline via tail vein injection. Following 1 h, a mouse model of septic ALI was produced by cecal ligation and puncture (CLP) in the two siRNA groups and the sepsis control group. At 6 and 12 h post‑operation, the experimental mice were sacrificed and the lung tissue samples were collected. Histopathological changes, wet/dry ratio of lung weight, NF-κB protein and NF-κB p65 mRNA levels, matrix metalloproteinase-9 (MMP-9) mRNA and protein activity were detected. Compared with the sepsis group and the Sc at the corresponding time, the expression levels of NF-κB p65 mRNA, the lung injury of experimental mice, the wet/dry ratio and the levels of MMP-9 mRNA and protein activity decreased, and significant differences were observed at 6 h post-operation (P<0.05). RNA interference against NF-κB p65 was able to decrease the expression of NF-κB and further inhibit the early phasic excessive inflammatory reaction in sepsis, which may alleviate ALI. PMID:24913772

  4. Mitochondrial alterations and oxidative stress in an acute transient mouse model of muscle degeneration: implications for muscular dystrophy and related muscle pathologies.

    PubMed

    Ramadasan-Nair, Renjini; Gayathri, Narayanappa; Mishra, Sudha; Sunitha, Balaraju; Mythri, Rajeswara Babu; Nalini, Atchayaram; Subbannayya, Yashwanth; Harsha, Hindalahalli Chandregowda; Kolthur-Seetharam, Ullas; Srinivas Bharath, Muchukunte Mukunda

    2014-01-01

    Muscular dystrophies (MDs) and inflammatory myopathies (IMs) are debilitating skeletal muscle disorders characterized by common pathological events including myodegeneration and inflammation. However, an experimental model representing both muscle pathologies and displaying most of the distinctive markers has not been characterized. We investigated the cardiotoxin (CTX)-mediated transient acute mouse model of muscle degeneration and compared the cardinal features with human MDs and IMs. The CTX model displayed degeneration, apoptosis, inflammation, loss of sarcolemmal complexes, sarcolemmal disruption, and ultrastructural changes characteristic of human MDs and IMs. Cell death caused by CTX involved calcium influx and mitochondrial damage both in murine C2C12 muscle cells and in mice. Mitochondrial proteomic analysis at the initial phase of degeneration in the model detected lowered expression of 80 mitochondrial proteins including subunits of respiratory complexes, ATP machinery, fatty acid metabolism, and Krebs cycle, which further decreased in expression during the peak degenerative phase. The mass spectrometry (MS) data were supported by enzyme assays, Western blot, and histochemistry. The CTX model also displayed markers of oxidative stress and a lowered glutathione reduced/oxidized ratio (GSH/GSSG) similar to MDs, human myopathies, and neurogenic atrophies. MS analysis identified 6 unique oxidized proteins from Duchenne muscular dystrophy samples (n = 6) (versus controls; n = 6), including two mitochondrial proteins. Interestingly, these mitochondrial proteins were down-regulated in the CTX model thereby linking oxidative stress and mitochondrial dysfunction. We conclude that mitochondrial alterations and oxidative damage significantly contribute to CTX-mediated muscle pathology with implications for human muscle diseases. PMID:24220031

  5. Experimental ablation of the pancreas with high intensity focused ultrasound (HIFU) in a porcine model

    PubMed Central

    Xie, Biao; Li, Yu-Yuan; Jia, Lin; Nie, Yu-Qiang; Du, Hong; Jiang, Shu-Man

    2011-01-01

    The aim of this study was to determine the feasibility and safety of high intensity focused ultrasound's (HIFU) in pancreatic diseases. Twelve pigs were divided into three groups. The pancreases of pigs in Group A were ablated directly with HIFU, but those in Group B and C ablated by extracorporeal HIFU. The pigs in Group C were sacrificed at day 7 after HIFU. Serological parameters were determined pre-operation and post-operation. The entire pancreas was removed for histological examination. Each animal tolerate the HIFU ablation well. The complete necrosis was observed in targeted regions. The margins of the necrotic regions were clearly delineated from the surrounding normal tissues. Infiltration of inflammatory cells and phorocytosis on the boundary were found in group C. Blood and urine amylase levels were relatively steady after HIFU. No acute pancreatitis or severe complications occurred. In conclusion, HIFU ablation on the pancreas was safe and effective in experimental pigs. PMID:21197259

  6. Demonstration of murine pancreas elastase and its interstrain variation by isoelectric focusing.

    PubMed

    von Deimling, O H; Gaa, A; Hameister, H

    1991-06-01

    Isoelectric focusing between pH 9 and 11 was used for separation of murine pancreas proteases. One of these proteases is characterized by its preference for N-acetyl-L-alanine-alpha-naphthylester as substrate and by its genetic linkage to bt, a coat color marker of chromosome 15. This protease was identified as elastase, and is probably elastase-1 (ELA-1). Because of the simple procedure and the excellent reproducibility of the focusing pattern, ELA-1 is recommended as a useful marker for mouse chromosome 15. PMID:1889396

  7. Diazepam binding inhibitor and the endocrine pancreas.

    PubMed

    Ostenson, C G; Ahrén, B; Johansson, O; Karlsson, S; Hilliges, M; Efendic, S

    1991-12-01

    Regulation of blood glucose homeostasis is complex. Its major hormonal regulators include insulin, glucagon and somatostatin from the endocrine pancreas. Secretion of these hormones is controlled predominantly by the supply of nutrients in the circulation but also by nerve signals and other peptides. Thus, it is likely that peptides, released from cells of the gut or endocrine pancreas or from peptidergic nerves, affect glucose homeostasis by modulating the secretion of insulin, glucagon and somatostatin. When searching for novel gut peptides with such effects, diazepam binding inhibitor (DBI) was isolated from the porcine small intestine. By immunocytochemistry, DBI has been demonstrated to occur not only in the gut but also in endocrine cells of the pancreatic islets, namely in the somatostatin-producing D-cells in pig and man, and in the glucagon-producing A-cells in rat. Porcine DBI (pDBI; 10(-8)-10(-7) M) has been shown to suppress glucose-stimulated release of insulin from both isolated islets and perfused pancreas of the rat. Furthermore, secretion of insulin stimulated by either the sulfonylurea glibenclamide or the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), was inhibited by the peptide. In contrast, arginine-induced release of insulin was unaffected by pDBI. Moreover, pDBI decreased arginine-induced release of glucagon from the perfused rat pancreas, whereas release of somatostatin was unchanged. Notably, rat DBI, structurally identical with rat acyl-CoA-binding protein, has also been demonstrated to inhibit glucose-stimulated release of insulin in the rat, both in vivo and in vitro. Long-term exposure of cultured fetal rat islets to pDBI (10(-8) M) significantly decreased the synthesis of DNA in islet cells.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1780037

  8. Imaging of the pancreas: Recent advances

    PubMed Central

    Chaudhary, Vikas; Bano, Shahina

    2011-01-01

    A wide spectrum of anomalies of pancreas and the pancreatic duct system are commonly encountered at radiological evaluation. Diagnosing pancreatic lesions generally requires a multimodality approach. This review highlights the new advances in pancreatic imaging and their applications in the diagnosis and management of pancreatic pathologies. The mainstay techniques include computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasound (EUS), radionuclide imaging (RNI) and optical coherence tomography (OCT). PMID:21847450

  9. Bringing the Artificial Pancreas Home: Telemedicine Aspects

    PubMed Central

    Lanzola, Giordano; Capozzi, Davide; Serina, Nadia; Magni, Lalo; Bellazzi, Riccardo

    2011-01-01

    The design and implementation of telemedicine systems able to support the artificial pancreas need careful choices to cope with technological requirements while preserving performance and decision support capabilities. This article addresses the issue of designing a general architecture for the telemedicine components of an artificial pancreas and illustrates a viable solution that is able to deal with different use cases and is amenable to support mobile-health implementations. The goal is to enforce interoperability among the components of the architecture and guarantee maximum flexibility for the ensuing implementations. Thus, the design stresses modularity and separation of concerns along with adoption of clearly defined protocols for interconnecting the necessary components. This accounts for the implementation of integrated telemedicine systems suitable as short-term monitoring devices for supporting validation of closed-loop algorithms as well as devices meant to provide a lifelong tighter control on the patient state once the artificial pancreas has become the preferred treatment for patients with diabetes. PMID:22226255

  10. Differential ability of Ptf1a and Ptf1a-VP16 to convert stomach, duodenum and liver to pancreas

    PubMed Central

    Jarikji, Zeina H.; Vanamala, Sandeep; Beck, Caroline W.; Wright, Chris V.E.; Leach, Steven D.; Horb, Marko E.

    2014-01-01

    Summary Determining the functional attributes of pancreatic transcription factors is essential to understand how the pancreas is specified distinct from other endodermal organs, such as liver, stomach and duodenum, and to direct the differentiation of other cell types into pancreas. Previously, we demonstrated that Pdx1-VP16 was sufficient to convert liver to pancreas. In this paper we characterize the functional ability of another pancreatic transcription factor, Ptf1a, in promoting ectopic pancreatic fates at early stages throughout the endoderm and later in during organogenesis. Using the transthyretin promoter to drive expression in the early liver region/bud of transgenic Xenopus tadpoles, we find that Ptf1a-VP16 is able to convert liver to pancreas. Overexpression of the unmodified Ptf1a on the other hand, has no effect in liver, but is able to convert stomach and duodenum to pancreas. When overexpressed at earlier embryonic stages throughout the endoderm, Ptf1a activity is similarly limited, whereas Ptf1a-VP16 has increased activity. Interestingly, in all instances we find that Ptf1a-VP16 is only capable of promoting acinar cell fates, whereas Ptf1a promotes both acinar and endocrine fates. Lastly, we demonstrate that, similar to mouse and zebrafish, Xenopus Ptf1a is essential for the initial specification of both endocrine and exocrine cells during normal pancreas development. PMID:17320068

  11. Stem cells to replace or regenerate the diabetic pancreas: Huge potential & existing hurdles.

    PubMed

    Bhartiya, Deepa

    2016-03-01

    Various stem cell sources are being explored to treat diabetes since the proof-of-concept for cell therapy was laid down by transplanting cadaveric islets as a part of Edmonton protocol in 2000. Human embryonic stem (hES) cells derived pancreatic progenitors have got US-FDA approval to be used in clinical trials to treat type 1 diabetes mellitus (T1DM). However, these progenitors more closely resemble their foetal counterparts and thus whether they will provide long-term regeneration of adult human pancreas remains to be demonstrated. In addition to lifestyle changes and administration of insulin sensitizers, regeneration of islets from endogenous pancreatic stem cells may benefit T2DM patients. The true identity of pancreatic stem cells, whether these exist or not, whether regeneration involves reduplication of existing islets or ductal epithelial cells transdifferentiate, remains a highly controversial area. We have recently demonstrated that a novel population of very small embryonic-like stem cells (VSELs) is involved during regeneration of adult mouse pancreas after partial-pancreatectomy. VSELs (pluripotent stem cells in adult organs) should be appreciated as an alternative for regenerative medicine as these are autologous (thus immune rejection issues do not exist) with no associated risk of teratoma formation. T2DM is a result of VSELs dysfunction with age and uncontrolled proliferation of VSELs possibly results in pancreatic cancer. Extensive brainstorming and financial support are required to exploit the potential of endogenous VSELs to regenerate the pancreas in a patient with diabetes. PMID:27241638

  12. Stem cells to replace or regenerate the diabetic pancreas: Huge potential & existing hurdles

    PubMed Central

    Bhartiya, Deepa

    2016-01-01

    Various stem cell sources are being explored to treat diabetes since the proof-of-concept for cell therapy was laid down by transplanting cadaveric islets as a part of Edmonton protocol in 2000. Human embryonic stem (hES) cells derived pancreatic progenitors have got US-FDA approval to be used in clinical trials to treat type 1 diabetes mellitus (T1DM). However, these progenitors more closely resemble their foetal counterparts and thus whether they will provide long-term regeneration of adult human pancreas remains to be demonstrated. In addition to lifestyle changes and administration of insulin sensitizers, regeneration of islets from endogenous pancreatic stem cells may benefit T2DM patients. The true identity of pancreatic stem cells, whether these exist or not, whether regeneration involves reduplication of existing islets or ductal epithelial cells transdifferentiate, remains a highly controversial area. We have recently demonstrated that a novel population of very small embryonic-like stem cells (VSELs) is involved during regeneration of adult mouse pancreas after partial-pancreatectomy. VSELs (pluripotent stem cells in adult organs) should be appreciated as an alternative for regenerative medicine as these are autologous (thus immune rejection issues do not exist) with no associated risk of teratoma formation. T2DM is a result of VSELs dysfunction with age and uncontrolled proliferation of VSELs possibly results in pancreatic cancer. Extensive brainstorming and financial support are required to exploit the potential of endogenous VSELs to regenerate the pancreas in a patient with diabetes. PMID:27241638

  13. In Vivo Senescence in the Sbds-Deficient Murine Pancreas: Cell-Type Specific Consequences of Translation Insufficiency.

    PubMed

    Tourlakis, Marina E; Zhang, Siyi; Ball, Heather L; Gandhi, Rikesh; Liu, Hongrui; Zhong, Jian; Yuan, Julie S; Guidos, Cynthia J; Durie, Peter R; Rommens, Johanna M

    2015-06-01

    Genetic models of ribosome dysfunction show selective organ failure, highlighting a gap in our understanding of cell-type specific responses to translation insufficiency. Translation defects underlie a growing list of inherited and acquired cancer-predisposition syndromes referred to as ribosomopathies. We sought to identify molecular mechanisms underlying organ failure in a recessive ribosomopathy, with particular emphasis on the pancreas, an organ with a high and reiterative requirement for protein synthesis. Biallelic loss of function mutations in SBDS are associated with the ribosomopathy Shwachman-Diamond syndrome, which is typified by pancreatic dysfunction, bone marrow failure, skeletal abnormalities and neurological phenotypes. Targeted disruption of Sbds in the murine pancreas resulted in p53 stabilization early in the postnatal period, specifically in acinar cells. Decreased Myc expression was observed and atrophy of the adult SDS pancreas could be explained by the senescence of acinar cells, characterized by induction of Tgfβ, p15(Ink4b) and components of the senescence-associated secretory program. This is the first report of senescence, a tumour suppression mechanism, in association with SDS or in response to a ribosomopathy. Genetic ablation of p53 largely resolved digestive enzyme synthesis and acinar compartment hypoplasia, but resulted in decreased cell size, a hallmark of decreased translation capacity. Moreover, p53 ablation resulted in expression of acinar dedifferentiation markers and extensive apoptosis. Our findings indicate a protective role for p53 and senescence in response to Sbds ablation in the pancreas. In contrast to the pancreas, the Tgfβ molecular signature was not detected in fetal bone marrow, liver or brain of mouse models with constitutive Sbds ablation. Nevertheless, as observed with the adult pancreas phenotype, disease phenotypes of embryonic tissues, including marked neuronal cell death due to apoptosis, were determined to

  14. In Vivo Senescence in the Sbds-Deficient Murine Pancreas: Cell-Type Specific Consequences of Translation Insufficiency

    PubMed Central

    Tourlakis, Marina E.; Zhang, Siyi; Ball, Heather L.; Gandhi, Rikesh; Liu, Hongrui; Zhong, Jian; Yuan, Julie S.; Guidos, Cynthia J.; Durie, Peter R.; Rommens, Johanna M.

    2015-01-01

    Genetic models of ribosome dysfunction show selective organ failure, highlighting a gap in our understanding of cell-type specific responses to translation insufficiency. Translation defects underlie a growing list of inherited and acquired cancer-predisposition syndromes referred to as ribosomopathies. We sought to identify molecular mechanisms underlying organ failure in a recessive ribosomopathy, with particular emphasis on the pancreas, an organ with a high and reiterative requirement for protein synthesis. Biallelic loss of function mutations in SBDS are associated with the ribosomopathy Shwachman-Diamond syndrome, which is typified by pancreatic dysfunction, bone marrow failure, skeletal abnormalities and neurological phenotypes. Targeted disruption of Sbds in the murine pancreas resulted in p53 stabilization early in the postnatal period, specifically in acinar cells. Decreased Myc expression was observed and atrophy of the adult SDS pancreas could be explained by the senescence of acinar cells, characterized by induction of Tgfβ, p15Ink4b and components of the senescence-associated secretory program. This is the first report of senescence, a tumour suppression mechanism, in association with SDS or in response to a ribosomopathy. Genetic ablation of p53 largely resolved digestive enzyme synthesis and acinar compartment hypoplasia, but resulted in decreased cell size, a hallmark of decreased translation capacity. Moreover, p53 ablation resulted in expression of acinar dedifferentiation markers and extensive apoptosis. Our findings indicate a protective role for p53 and senescence in response to Sbds ablation in the pancreas. In contrast to the pancreas, the Tgfβ molecular signature was not detected in fetal bone marrow, liver or brain of mouse models with constitutive Sbds ablation. Nevertheless, as observed with the adult pancreas phenotype, disease phenotypes of embryonic tissues, including marked neuronal cell death due to apoptosis, were determined to

  15. Metastatic Renal Cell Carcinoma to the Pancreas: A Review.

    PubMed

    Cheng, Shaun Kian Hong; Chuah, Khoon Leong

    2016-06-01

    The pancreas is an unusual site for tumor metastasis, accounting for only 2% to 5% of all malignancies affecting the pancreas. The more common metastases affecting the pancreas include renal cell carcinomas, melanomas, colorectal carcinomas, breast carcinomas, and sarcomas. Although pancreatic involvement by nonrenal malignancies indicates widespread systemic disease, metastatic renal cell carcinoma to the pancreas often represents an isolated event and is thus amenable to surgical resection, which is associated with long-term survival. As such, it is important to accurately diagnose pancreatic involvement by metastatic renal cell carcinoma on histology, especially given that renal cell carcinoma metastasis may manifest more than a decade after its initial presentation and diagnosis. In this review, we discuss the clinicopathologic findings of isolated renal cell carcinoma metastases of the pancreas, with special emphasis on separating metastatic renal cell carcinoma and its various differential diagnoses in the pancreas. PMID:27232353

  16. Early Gastric Cancer Just above a Heterotopic Pancreas

    PubMed Central

    Murabayashi, Toji; Kawaguchi, Shinya; Okuda, Naoko; Oyamada, Jun; Yabana, Tadashi

    2016-01-01

    We report the first case of early gastric cancer just above a heterotopic pancreas for which the differential diagnosis was carcinoma arising from heterotopic pancreas. Routine upper gastrointestinal endoscopy in an 83-year-old man with sigmoid colon cancer revealed a gastric cancer in the lesser curvature of the antrum. Endoscopic ultrasonography (EUS) for evaluating the depth of tumor invasion revealed a hypoechoic mass in the submucosal layer. The depth of tumor invasion was diagnosed as muscularis propria. Distal gastrectomy and sigmoidectomy were performed. Histologically, the resected specimen of the stomach unexpectedly revealed a heterotopic pancreas just below the gastric cancer. They were not linked, and the heterotopic pancreas had no dysplasia. The gastric cancer had slightly invaded the submucosa. The hypoechoic mass on EUS was not the invasive tumor but the heterotopic pancreas. The preoperative staging of the gastric cancer on EUS was confounded by the presence of the heterotopic pancreas just below the gastric cancer. PMID:27482189

  17. Assessment of Islet Function Following Islet and Pancreas Transplantation

    PubMed Central

    Dy, Emily C.; Harlan, David M.; Rother, Kristina I.

    2014-01-01

    Pancreas and islet transplant recipients are monitored using various metabolic and imaging methods. The inaccessibility of the transplanted whole pancreas and of the isolated islets poses specific problems (eg, all assessment techniques are indirect). Although successful pancreas transplantation typically restores normal glucose homeostasis, islet transplantation into the liver does not completely normalize islet hormone secretion and glucose metabolism. Development of better testing strategies, such as direct islet imaging, will significantly advance the field. PMID:16879785

  18. Pancreaticoduodenectomy for metastasis of uterine leiomyosarcoma to the pancreas.

    PubMed

    Hernández, Sara; Martín-Fernández, José; Lasa, Inmaculada; Busteros, Ignacio; García-Moreno, Francisca

    2010-09-01

    Metastasis of uterine leiomyosarcoma to the pancreas is rare. A 46-year-old woman was diagnosed with uterine leiomyosarcoma and underwent surgery. Thereafter, recurrences in the lung and subsequently in the pancreas were diagnosed. These lesions were resected and diagnosed as metastasis of uterine leiomyosarcoma. We report a rare case of uterine leiomyosarcoma with metastasis to the lung and pancreas, both of which were resected using aggressive surgery. PMID:20851807

  19. OPTN/SRTR 2012 Annual Data Report: pancreas.

    PubMed

    Israni, A K; Skeans, M A; Gustafson, S K; Schnitzler, M A; Wainright, J L; Carrico, R J; Tyler, K H; Kades, L A; Kandaswamy, R; Snyder, J J; Kasiske, B L

    2014-01-01

    The number of pancreas transplants has decreased over the past decade, most notably numbers of pancreas after kidney (pak) and pancreas transplant alone (pta) procedures. This decrease may be mitigated in the future when changes to national pancreas allocation policy approved by the Organ Procurement and Transplantation Network Board of Directors in 2010 are implemented. The new policy will combine waiting lists for pak, pta, and simultaneous pancreas-kidney (spk) transplants), and give equal priority to candidates for all three procedures. This policy change may also eliminate geographic variation in waiting times caused by geographic differences in allocation policy. Deceased donor pancreas donation rates have been declining since 2005, and the donation rate remains low. The outcomes of pancreas grafts are difficult to describe due to lack of a uniform definition of graft failure in the transplant community. However long-term survival is better for spk versus pak and pta transplants. This may represent the difficulty of detecting rejection in the absence of a simultaneously transplanted kidney. The challenges of pancreas transplant are reflected in high rates of rehospitalization, most occurring within the first 6 months posttransplant. Pancreas transplant is associated with higher incidence of rejection compared with kidney transplant. PMID:24373167

  20. Portal annular pancreas: the pancreatic duct ring sign on MRCP.

    PubMed

    Lath, Chinar O; Agrawal, Dilpesh S; Timins, Michael E; Wein, Melissa M

    2015-12-01

    Portal annular pancreas is a rare pancreatic variant in which the uncinate process of the pancreas extends and fuses to the dorsal surface of the body of the pancreas by surrounding the portal vein. It is asymptomatic, but it can be mistaken for a pancreatic head mass on imaging and could also have serious consequences during pancreatic surgery, if unrecognized. We report this case of a 53-year-old female patient who was diagnosed to have portal annular pancreas on the basis of an unusual course (ring appearance) of the main pancreatic duct on magnetic resonance cholangiopancreatography, not described earlier in the radiology literature. PMID:26649117

  1. Cystic lesions of the pancreas: challenging issues in clinical practice.

    PubMed

    Oh, Hyoung-Chul; Kim, Myung-Hwan; Hwang, Chang Yun; Lee, Tae Yoon; Lee, Sang Soo; Seo, Dong-Wan; Lee, Sung Koo

    2008-01-01

    Cystic lesions of the pancreas are being recognized with increasing frequency and have become a common finding in clinical practice. Cystic lesions of the pancreas display a wide spectrum of histopathology and biologic behavior. Differentiating among lesions and choosing an optimal therapy is challenging, and evidence-based guidelines for diagnosis, management, and follow-up for cystic lesions of the pancreas are needed. This review describes the epidemiology and typical features of cystic lesions of the pancreas, including a summary of commonly used descriptive terms, as well as the primary issues in the differential diagnosis and management of these lesions. PMID:18076739

  2. Portal annular pancreas: the pancreatic duct ring sign on MRCP

    PubMed Central

    Lath, Chinar O.; Agrawal, Dilpesh S.; Timins, Michael E.; Wein, Melissa M.

    2015-01-01

    Portal annular pancreas is a rare pancreatic variant in which the uncinate process of the pancreas extends and fuses to the dorsal surface of the body of the pancreas by surrounding the portal vein. It is asymptomatic, but it can be mistaken for a pancreatic head mass on imaging and could also have serious consequences during pancreatic surgery, if unrecognized. We report this case of a 53-year-old female patient who was diagnosed to have portal annular pancreas on the basis of an unusual course (ring appearance) of the main pancreatic duct on magnetic resonance cholangiopancreatography, not described earlier in the radiology literature. PMID:26649117

  3. Hemorrhagic Pseudocyst of Pancreas Treated with Coil Embolization of Gastroduodenal Artery: A Case Report and Review of Literature

    PubMed Central

    Jain, Sudhir Kumar; Rajendran, Vishnuraja; Jain, Maneesh K.; Kori, Ronal

    2015-01-01

    Hemorrhage into pseudocyst of pancreas can rarely present as life threatening massive UGI bleeding. We present a case of 21-year-old male, admitted to our department, who was a known case of posttraumatic acute pancreatitis and who developed massive upper GI bleeding. CT angiography of abdomen showed aneurysm of gastroduodenal artery. Patient was successfully treated with coil embolization of gastroduodenal artery. PMID:26819796

  4. Endovascular Method for Transplantation of Insulin-Producing Cells to the Pancreas Parenchyma in Swine

    PubMed Central

    Lundberg, J; Stone-Elander, S; Zhang, X-M; Korsgren, O; Jonsson, S; Holmin, S

    2014-01-01

    Insulin-producing cells are transplanted by portal vein injection as an alternative to pancreas transplantation in both clinical and preclinical trials. Two of the main limitations of portal vein transplantation are the prompt activation of the innate immunity and concomitant loss of islets and a small but significant risk of portal vein thrombosis. Furthermore, to mimic physiological release, the insulin-producing cells should instead be located in the pancreas. The trans-vessel wall approach is an endovascular method for penetrating the vessel wall from the inside. In essence, a working channel is established to the parenchyma of organs that are difficult to access by percutaneous technique. In this experiment, we accessed the extra-vascular pancreatic parenchyma in swine by microendovascular technique and injected methylene blue, contrast fluids and insulin-producing cells without acute adverse events. Further, we evaluated the procedure itself by a 1-year angiographical follow-up, without adverse events. This study shows that the novel approach utilizing endovascular minimal invasiveness coupled to accurate trans-vessel wall placement of an injection in the pancreatic parenchyma with insulin-producing cells is possible. In clinical practice, the potential benefits compared to portal vein cell transplantation should significantly improve endocrine function of the graft and potentially reduce adverse events. This study presents one-year follow-up safety data on the microendovascular trans-vessel wall technique and shows that the technique can be used to transplant insulin-producing cells to the swine pancreas parenchyma. PMID:24517268

  5. Early findings of prospective anti-HLA donor specific antibodies monitoring study in pancreas transplantation: Indiana University Health Experience.

    PubMed

    Mujtaba, Muhammad A; Fridell, Jonathan A; Higgins, Nancy; Sharfuddin, Asif A; Yaqub, Muhammad S; Kandula, Praveen; Chen, Jeanne; Mishler, Dennis P; Lobashevsky, Andrew; Book, Benita; Powelson, John; Taber, Tim E

    2012-01-01

    The significance of donor-specific antibodies (DSA) is not well known in the setting of pancreas transplantation. Since December 2009, we prospectively followed pancreas transplant patients with single-antigen-luminex-bead testing at one, two, three, six, and then every six months for the first two yr. Thirty-five of the 92 patients that underwent pancreas transplantation (13 pancreas-alone [PTA], 20 with a kidney [SPK], and two after a kidney [PAK]) agreed to participate in study. Median age at transplant was 45 yr and follow-up was 23 months. Majority were Caucasian (n = 33) and male (n = 18). Rabbit anti-thymocyte globulin induction was used. Median HLA-mismatch was 4.2 ± 1.1. Eight patients (7SPK, 1PAK) developed post-transplant DSA at median follow-up of 76 d (26-119), 1 SPK had pre-formed DSA. Seven patients had both class I and class II DSA, one with class I and one with class II only. Mean peak class I DSA-MFI was 3529 (±1456); class II DSA-MFI was 5734 (±3204) whereas cumulative DSA MFI (CI + CII) was 9264 (±4233). No difference was observed in the patient and donor demographics among patients with and without DSA. One patient in non-DSA group developed acute cellular rejection of pancreas. From our data it appears that post-transplant DSA in pancreas allograft recipients may not impact the early-pancreatic allograft outcomes. The utility of prospective DSA monitoring in pancreatic transplant patients needs further evaluation and long-term follow-up. PMID:22938159

  6. Cyclosporine pharmacokinetics in pancreas transplant recipients.

    PubMed

    Munda, R; Schroeder, T J; Pedersen, S A; Clardy, C W; Wadhwa, N K; Myre, S A; Stephens, G W; Pesce, A J; Alexander, J W; First, M R

    1988-04-01

    Ten CsA pharmacokinetic studies were performed on five pancreas transplant recipients to determine proper doses and dosing intervals. These cadaver pancreas transplants were performed with exocrine ductal drainage into the urinary tract through a bladder anastomosis in four cases and into the bowel in one case. Four CsA pharmacokinetic studies were performed on diabetic renal transplant recipients and an additional six studies were performed while with pancreas transplant patients taking metoclopramide in an effort to enhance absorption of CsA. Mean CsA dose was 3.7 mg/kg/dose (range 2.1 to 7.5 mg/kg/dose). All patients but one were on twice daily dosing intervals yielding an average daily dose of 7.4 mg/kg/d. Noncompartmental pharmacokinetic analyses were used. The adequacy of a 1-, 2-, or 3-exponential model was determined by breakpoint analysis of the log concentration v time curve using the F statistic. The terminal rate constant was calculated by nonlinear regression analysis. The AUC and AUMC were calculated by the trapezoidal method with exponential extrapolation and these were used to calculate the MRT and Vdss. The unknown fractional absorption, F, was used to correct the oral data. The average CsA concentration maximum (Cmax) was 528 ng/mL with an average time to maximum concentration (Tmax) of 4.7 hours, a mean residence time of 7.75 hours, with a Vdss/%F of 9.61 L/kg in the pancreas transplant recipients. Additional studies of six patients receiving metoclopramide with CsA revealed an average Cmax of 723 ng/mL, an average Tmax of 2.3 hours, an average MRT of 6.08 hours, and an average Vdss/%F of 5.7% L/kg. These results indicate that coexistent gastroparesis in diabetic recipients of either pancreatic or renal transplants may result in reduced bioavailability of CsA. PMID:3284095

  7. Cystic Neoplasms of the Exocrine Pancreas

    PubMed Central

    Ribaux, C.; Schnyder, P.

    1990-01-01

    Cystic neoplasms of the pancreas are rare and their diagnosis and treatment can be difficult. This report details 7 patients who had histologically proven serous cystadenoma4, mucinous cystadenoma2 and cystadeno carcinoma1. Computed tomography and sonography allowed excellent preoperative assessment but to attempt a distinction between the histological variants may be hazardous. Two tumours were only autopsy findings and 5 patients underwent laparotomy. It is confirmed that potentially malignant mucinous cystadenomas and cytadenocarcinomas should be resected whenever possible; serous cystadenomas are always benign and should therefore be resected only when the diagnosis is doubtful or if they cause symptoms. PMID:2278913

  8. Susceptibility of the pancreas to ischemic injury in shock.

    PubMed Central

    Warshaw, A L; O'Hara, P J

    1978-01-01

    The pancreas, like the kidney, is highly vulnerable to ischemic necrosis. This form of pancreatic injury may express itself as prolonged hyperamylasemia with only minimal signs or symptoms of inflammation, or may produce severe pancreatitis followed by abscesses and death. Autopsy examination of patients dying after oligemic shock showed a 9% incidence of major pancreatic injury if there was not concomitant acute renal tubular necrosis (ATN), but a 50% incidence in those with ATN. Similarly, among patients dying after non-oligemic shock, 12% of those without ATN had major pancreatic injury but 35% with ATN also had pancreatic ischemic injury. Among 13 selected patients examined prospectively after being in shock, pancreatic injury was indicated by hyperamylasemia, hyperlipasemia, elevated amylase/creatinine clearance ratio, and elevated circulating isoamylases specifically of pancreatic origin. Four of the 13 had clinical manifestations of pancreatitis. Not only must shock be added to this list of causes of pancreatitis, but pancreatic ischemia due to hypoperfusion may also be the critical factor which causes the progression from edema to necrosis in other forms of pancreatitis, including those associated with alcohol and biliary disease. PMID:686887

  9. Cystathionine-gamma-lyase gene silencing with siRNA in monocytes/macrophages protects mice against acute pancreatitis.

    PubMed

    Badiei, A; Chambers, S T; Gaddam, R R; Fraser, R; Bhatia, M

    2016-01-01

    Hydrogen sulphide (H2S) is an endogenous inflammatory mediator produced by cystathionine-γ-lyase (CSE) in monocytes/macrophages. To determine the role of H2S and macrophages in inflammation, we used small interference RNA (siRNA) to target the CSE gene and investigated its effect in a mouse model of acute pancreatitis. Acute pancreatitis is characterised by increased levels of plasma amylase, myeloperoxidase (MPO) activity and pro-inflammatory cytokines and chemokines in the pancreas and lung. SiRNA treatment attenuated inflammation in the pancreas and lungs of mice following caerulein-induced acute pancreatitis. MPO activity increased in caerulein-induced acute pancreatitis (16.21 ± 3.571 SD fold increase over control) and treatment with siRNA significantly reduced this (mean 3.555 ± 2.522 SD fold increase over control) (p < 0.0001). Similarly, lung MPO activity increased following treatment with caerulein (3.56 ± 0.941 SD fold increase over control) while siRNA treatment significantly reduced MPO activity (0.8243 ± 0.4353 SD fold increase over control) (p < 0.0001). Caerulein treatment increased plasma amylase activity (7094 ± 207 U/l) and this significantly decreased following siRNA administration (5895 ± 115 U/l) (p < 0.0001). Cytokine and chemokine levels in caerulein-induced acute pancreatitis reduced following treatment with siRNA. For example, siRNA treatment significantly decreased pancreatic and lung monocyte chemoattractant protein (MCP)-1 (169.8 ± 59.75 SD; 90.01 ± 46.97 SD pg/ml, respectively) compared to caerulein-treated mice (324.7 ± 103.9 SD; 222.8 ± 85.37 SD pg/ml, pancreas and lun,g respectively) (p < 0.0001). These findings show a crucial pro-inflammatory role for H2S synthesised by CSE in macrophages in acute pancreatitis and suggest CSE gene silencing with siRNA as a potential therapeutic approach for this condition. PMID:26411454

  10. Artificial Pancreas Project at Cambridge 2013.

    PubMed

    Hovorka, R

    2015-08-01

    The development and clinical testing of closed-loop systems (the artificial pancreas) is underpinned by advances in continuous glucose monitoring and benefits from concerted academic and industry collaborative efforts. This review describes the progress of the Artificial Pancreas Project at the University of Cambridge from 2006 to 2014. Initial studies under controlled laboratory conditions, designed to collect representative safety and performance data, were followed by short to medium free-living unsupervised outpatient studies demonstrating the safety and efficacy of closed-loop insulin delivery using a model predictive control algorithm. Accompanying investigations included assessment of the psychosocial impact and key factors affecting glucose control such as insulin kinetics and glucose absorption. Translation to other disease conditions such as critical illness and Type 2 diabetes took place. It is concluded that innovation of iteratively enhanced closed-loop systems will provide tangible means to improve outcomes and quality of life in people with Type 1 diabetes and their families in the next decade. PMID:25819473

  11. Design Considerations for Artificial Pancreas Pivotal Studies.

    PubMed

    Russell, Steven J; Beck, Roy W

    2016-07-01

    The development of artificial pancreas systems has evolved to the point that pivotal studies designed to assess efficacy and safety are in progress or soon to be initiated. These pivotal studies are intended to provide the necessary data to gain clearance from the U.S. Food and Drug Administration, coverage by payers, and adoption by patients and clinicians. Although there will not be one design that is appropriate for every system, there are certain aspects of protocol design that will be considerations in all pivotal studies designed to assess efficacy and safety. One key aspect of study design is the intervention to be used by the control group. A case can be made that the control group should use the currently available best technology, which is sensor-augmented pump therapy. However, an equally, if not more, compelling case can be made that the control intervention should be usual care. In this Perspective, we elaborate on this issue and provide a pragmatic approach to the design of clinical trials of artificial pancreas systems. PMID:27330125

  12. SOLID PSEUDOPAPILLARY NEOPLASM OF THE PANCREAS

    PubMed Central

    CARLOTTO, Jorge Roberto Marcante; TORREZ, Franz Robert Apodaca; GONZALEZ, Adriano Miziara; LINHARES, Marcelo Moura; TRIVIÑO, Tarcisio; HERANI-FILHO, Benedito; GOLDENBERG, Alberto; LOPES-FILHO, Gaspar de Jesus; LOBO, Edson José

    2016-01-01

    ABSTRACT Background: The solid pseudopapillary neoplasm is a rare tumor of the pancreas. However, it´s etiology still maintain discussions. Aim: To analyze it´s clinical data, diagnosis and treatment. Methods: A retrospective study of medical records of all patients treated from January 1997 until July 2015. Results: Were identified 17 cases. Most patients were women (94.11%) and the average age was 32.88 years. The main complaint was abdominal mass (47.05%). The most frequent location was in the body/tail of the pancreas (72.22%) and the most frequently performed surgery was distal pancreatectomy with splenectomy (64.70%). No patient had metastases at diagnosis. Conservative surgery for pancreatic parenchyma was performed in only three cases. The rate of complications in the postoperative period was 35.29% and the main complication was pancreatic fistula (29.41%). No patient underwent adjuvant treatment. Conclusions: The treatment is surgical and the most common clinical presentation is abdominal mass. Distal pancreatectomy with splenectomy was the most frequently performed surgery for its treatment. PMID:27438034

  13. Ectopic Pancreas in the Wall of the Small Intestine.

    PubMed

    Serrano, Jose Salvador; Stauffer, John A

    2016-07-01

    Ectopic pancreas is an uncommon and benign finding. However, these lesions can cause symptoms including abdominal pain and often require removal. We present the case of a 27-year-old patient with long-standing vague abdominal symptoms eventually found to have ectopic pancreas tissue in the proximal jejunum. PMID:26892166

  14. Squamous Cell Carcinoma of Pancreas: Mystery and Facts.

    PubMed

    Raghavapuram, Saikiran; Vaid, Arjun; Rego, Rayburn F

    2015-08-01

    Squamous cell carcinoma of the pancreas is very rare as pancreas does not have any squamous cells. Only a few cases have been reported in the literature so far. We describe such a case where in the patient presented with painless jaundice. CT and EUS confirmed the pancreatic mass biopsy of which showed squamous cell cancer. PMID:26376556

  15. Successful Pancreatic Duct Stent Placement for Recurrent Pancreatitis in a Patient with Polysplenia with Agenesis of the Dorsal Pancreas and Peutz-Jeghers Syndrome.

    PubMed

    Kawasaki, Shintaro; Itoi, Takao; Iwasaki, Eisuke; Hosoe, Naoki; Ogata, Haruhiko; Kanai, Takanori

    2016-01-01

    A 52-year-old woman presented with relapsing acute pancreatitis. A contrast CT scan revealed polysplenia, agenesis of the dorsal pancreas, preduodenal portal vein, inferior vena cava with persistent continuity of the azygos vein, abnormal lung lobation with bilateral left bronchial morphology, and intestinal malrotation (non-rotation type). To the best of our knowledge, this is the first report in which successful pancreatic duct stent placement for the treatment of recurrent pancreatitis was performed in a polysplenia patient with agenesis of the dorsal pancreas, separate bile and pancreatic ducts and Peutz-Jeghers syndrome. PMID:27374675

  16. Islet Insulin Secretion Measurements in the Mouse.

    PubMed

    Hugill, Alison; Shimomura, Kenju; Cox, Roger D

    2016-01-01

    This article describes detailed protocols for in vitro measurements of insulin function and secretion in isolated mouse islets for the analysis of glucose homeostasis. We specify a method of enzyme digestion and hand picking to isolate and release the greatest number of high quality islets from the pancreas of the mouse. We describe an effective method for generating dynamic measurements of insulin secretion using a perifusion assay including a detailed protocol for constructing a peristaltic pump and tubing assembly. In addition we describe an alternative and simple technique for measuring insulin secretion using static incubation of isolated islets. © 2016 by John Wiley & Sons, Inc. PMID:27584553

  17. Subtotal resection of the head of the pancreas combined with ductal obliteration of the distal pancreas in chronic pancreatitis.

    PubMed Central

    Kerremans, R P; Penninckx, F M; De Groote, J; Fevery, J

    1987-01-01

    Subtotal resection of the head of the pancreas combined with duct obliteration of the distal pancreas by prolamine was performed in 12 selected patients who had chronic alcohol-induced pancreatitis with most destruction in the proximal pancreas. The main indication for operation was intractable pain. There was no postoperative mortality but morbidity was high when no pancreaticojejunostomy was constructed. After a follow-up period of 32 months, lasting pain relief was obtained in 10 patients; pseudocyst formation occurred in three patients; calcification of the distal pancreas, absent before operation, was demonstrated in four of six patients; six of 11 nondiabetic patients became hyperglycemic either abruptly (1 patient) or progressively (5 patients); quality of life improved in most patients. This procedure preserves the stomach, duodenum, spleen, distal pancreas and common bile duct if possible. However, pancreatic ductal obliteration with prolamine does not prevent relapses of chronic pancreatitis. PMID:3827358

  18. TLR4-mediated NF-κB signaling pathway mediates HMGB1-induced pancreatic injury in mice with severe acute pancreatitis

    PubMed Central

    LI, GANG; WU, XUEJUN; YANG, LE; HE, YUXIANG; LIU, YANG; JIN, XING; YUAN, HAI

    2016-01-01

    Severe acute pancreatitis (SAP) is an extremely dangerous acute abdominal disorder which causes multiple complications and has a high mortality rate. Previous research has suggested that high-mobility group box 1 (HMGB1) plays an important role in the pathogenesis of SAP; however, the mechanisms underlying this strong correlation remain unclear. In this study, to further investigate whether HMGB1 acts as a stimulating factor, and whether Toll-like receptor 4 (TLR4) acts as its major mediator in the development of pancreatic injury during SAP, recombinant human HMGB1 (rhHMGB1) and TLR4-deficient mice were used. We found that HMGB1 and TLR4 were highly expressed, and nuclear factor-κB (NF-κB) was activated in our mouse model of SAP. We noted that the rhHMGB1 pancreas-targeted injection activated the TLR4-mediated NF-κB signaling pathway and induced pancreatic injury in wild-type mice. In TLR4-deficient mice, the rhHMGB1-induced activation of NF-κB and pathological changes in the pancreas were less evident than in wild-type mice. Therefore, this study provides evidence that HMGB1 promotes the pathogenesis of pancreatitis, and its downstream TLR4-mediated NF-κB signaling pathway is a potential important mediator in the development of this form of pancreatic injury. PMID:26719855

  19. Regeneration and Repair of the Exocrine Pancreas

    PubMed Central

    Murtaugh, L. Charles; Keefe, Matthew

    2015-01-01

    Pancreatitis is caused by inflammatory injury to the exocrine pancreas, from which both humans and animal models appear to recover via regeneration of digestive enzyme-producing acinar cells. This regenerative process involves transient phases of inflammation, metaplasia and redifferentiation, driven by cell-cell interactions between acinar cells, leukocytes and resident fibroblasts. The NFκB signaling pathway is a critical determinant of pancreatic inflammation and metaplasia, whereas a number of developmental signals and transcription factors are devoted to promoting acinar redifferentiation after injury. Imbalances between these pro-inflammatory and pro-differentiation pathways contribute to chronic pancreatitis, characterized by persistent inflammation, fibrosis and acinar dedifferentiation. Loss of acinar cell differentiation also drives pancreatic cancer initiation, providing a mechanistic link between pancreatitis and cancer risk. Unraveling the molecular bases of exocrine regeneration may identify new therapeutic targets for treatment and prevention of both of these deadly diseases. PMID:25386992

  20. Cystadenomas and Cystadenocarcinomas of the Pancreas

    PubMed Central

    Le Borgne, Joël; de Calan, Loïc; Partensky, Christian

    1999-01-01

    Objective To review the features of patients with benign and malignant cystadenomas of the pancreas, focusing on preoperative diagnostic accuracy and long-term outcome, especially for nonoperated serous cystadenomas and resected cystadenocarcinomas. Summary Background Data Serous cystadenomas (SCAs) are benign tumors. Mucinous cystic neoplasms should be resected because of the risk of malignant progression. A correct preoperative diagnosis of tumor type is based on morphologic criteria. Despite the high quality of recent imaging procedures, the diagnosis frequently remains uncertain. Invasive investigations such as endosonography and diagnostic aspiration of cystic fluid may be helpful, but their assessment is limited to small series. The management of typical SCA may require resection or observation. Survival after pancreatic resection seems better for cystadenocarcinomas (MCACs) than for ductal adenocarcinomas of the pancreas. Methods Three hundred ninety-eight cases of cystadenomas of the pancreas were collected between 1984 and 1996 in 73 institutions of the French Surgical Association. Clinical presentation, radiologic evaluation, and surgical procedures were analyzed for 144 operated SCAs, 150 mucinous cystadenomas (MCAs), and 78 MCACs. The outcome of 372 operated patients and 26 nonoperated patients with SCA was analyzed. Results Cystadenomas represented 76% of all primary pancreatic cystic tumors (398/522). An asymptomatic tumor was discovered in 32% of patients with SCA, 26% of those with MCA, and 13% of those with MCAC. The tumor was located in the head or uncinate process of the pancreas in 38% of those with SCA, 27% of those with MCA, and 49% of those with MCAC. A communication between the cyst and pancreatic duct was discovered in 0.6% of those with SCA, 6% of those with MCA, and 10% of those with MCAC. The main investigations were ultrasonography and computed tomography (94% for SCA, MCA, and MCAC), endosonography (34%, 28%, and 22% for SCA, MCA, and

  1. Regeneration and repair of the exocrine pancreas.

    PubMed

    Murtaugh, L Charles; Keefe, Matthew D

    2015-01-01

    Pancreatitis is caused by inflammatory injury to the exocrine pancreas, from which both humans and animal models appear to recover via regeneration of digestive enzyme-producing acinar cells. This regenerative process involves transient phases of inflammation, metaplasia, and redifferentiation, driven by cell-cell interactions between acinar cells, leukocytes, and resident fibroblasts. The NFκB signaling pathway is a critical determinant of pancreatic inflammation and metaplasia, whereas a number of developmental signals and transcription factors are devoted to promoting acinar redifferentiation after injury. Imbalances between these proinflammatory and prodifferentiation pathways contribute to chronic pancreatitis, characterized by persistent inflammation, fibrosis, and acinar dedifferentiation. Loss of acinar cell differentiation also drives pancreatic cancer initiation, providing a mechanistic link between pancreatitis and cancer risk. Unraveling the molecular bases of exocrine regeneration may identify new therapeutic targets for treatment and prevention of both of these deadly diseases. PMID:25386992

  2. Premalignant cystic neoplasms of the pancreas.

    PubMed

    Dudeja, Vikas; Allen, Peter J

    2015-02-01

    Due to increasing utilization of cross-sectional imaging, asymptomatic pancreatic cysts are frequently being diagnosed. Many of these cysts have premalignant potential and offer a unique opportunity for cancer prevention. Mucinous cystic neoplasm and intraductal papillary mucinous neoplasm are the major premalignant cystic neoplasms of pancreas. The prediction of the risk of malignancy (incidental and future risk of malignant transformation) and balancing the risks of watchful waiting with that of operative management with associated mortality and morbidity is the key to the management of these lesions. We review the literature that has contributed to the development of our approach to the management of these cystic neoplasms. We provide an overview of the key features used in diagnosis and in predicting malignancy. Particular attention is given to the natural history and management decision making. PMID:25726053

  3. MD-Logic Artificial Pancreas System

    PubMed Central

    Atlas, Eran; Nimri, Revital; Miller, Shahar; Grunberg, Eli A.; Phillip, Moshe

    2010-01-01

    OBJECTIVE Current state-of-the-art artificial pancreas systems are either based on traditional linear control theory or rely on mathematical models of glucose-insulin dynamics. Blood glucose control using these methods is limited due to the complexity of the biological system. The aim of this study was to describe the principles and clinical performance of the novel MD-Logic Artificial Pancreas (MDLAP) System. RESEARCH DESIGN AND METHODS The MDLAP applies fuzzy logic theory to imitate lines of reasoning of diabetes caregivers. It uses a combination of control-to-range and control-to-target strategies to automatically regulate individual glucose levels. Feasibility clinical studies were conducted in seven adults with type 1 diabetes (aged 19–30 years, mean diabetes duration 10 ± 4 years, mean A1C 6.6 ± 0.7%). All underwent 14 full, closed-loop control sessions of 8 h (fasting and meal challenge conditions) and 24 h. RESULTS The mean peak postprandial (overall sessions) glucose level was 224 ± 22 mg/dl. Postprandial glucose levels returned to <180 mg/dl within 2.6 ± 0.6 h and remained stable in the normal range for at least 1 h. During 24-h closed-loop control, 73% of the sensor values ranged between 70 and 180 mg/dl, 27% were >180 mg/dl, and none were <70 mg/dl. There were no events of symptomatic hypoglycemia during any of the trials. CONCLUSIONS The MDLAP system is a promising tool for individualized glucose control in patients with type 1 diabetes. It is designed to minimize high glucose peaks while preventing hypoglycemia. Further studies are planned in the broad population under daily-life conditions. PMID:20150292

  4. Exocrine Pancreas in Cats With Diabetes Mellitus.

    PubMed

    Zini, E; Ferro, S; Lunardi, F; Zanetti, R; Heller, R S; Coppola, L M; Guscetti, F; Osto, M; Lutz, T A; Cavicchioli, L; Reusch, C E

    2016-01-01

    Pancreatitis has been described in cats with diabetes mellitus, although the number of studies currently available is very limited. In addition, ketoacidosis has been hypothesized to be associated with pancreatitis in diabetic cats. The aims of the present study were to investigate whether diabetic cats have pancreatitis and to determine if pancreatitis is more frequent with ketoacidosis. Samples of pancreas were collected postmortem from 37 diabetic cats, including 15 with ketoacidosis, and 20 control cats matched for age, sex, breed, and body weight. Sections were stained with hematoxylin and eosin, double-labeled for insulin/CD3, insulin/CD20, insulin/myeloperoxidase, insulin/PCNA, and glucagon/Ki67, and single-labeled for Iba1. A previously proposed semiquantitative score was used to characterize pancreatitis, along with counts of inflammatory cells. Scores of pancreatitis and the number of neutrophils, macrophages, and lymphocytes in the exocrine pancreas did not differ between diabetic and control cats or between diabetic cats with and without ketoacidosis. Of note, PCNA-positive acinar cells were increased (P = .002) in diabetic cats, particularly near islets (P < .001). Ki67-positive acinar cells were increased only near islets (P = .038). Ketoacidosis was not linked to proliferation. The results suggest that histopathologic evidence of pancreatitis may not be more frequent in diabetic cats and that ketoacidosis may not be associated with it at the time of death. Augmented PCNA-positive acinar cells might indicate increased proliferation due to chronic pancreatitis. The reason behind the prevalent proliferation of acinar cells surrounding pancreatic islets deserves further investigation. PMID:26319779

  5. A morphometric study of human pancreas in Nepalese people.

    PubMed

    Basnet, K S; Thapa, T P; Upreti, R P; Dangol, P M S; Shrestha, R N; Dhungel, S

    2011-06-01

    Considering the seriousness of pancreatic diseases and the utmost importance of its correct diagnosis and treatment, a morphometric study of pancreas among Nepalese population has emerged as a demand of present time. This study was carried out to establish a normal dimension of pancreas which could be a guideline for the correct diagnosis, treatment and research on various diseases related to it. Thus, a descriptive type of study was done within a period of eight years of time (2004-2011) on 40 pancreases of both sexes and different age groups, collected from embalmed cadavers from four medical colleges of Kathmandu, Nepal. The obtained specimens of pancreas were classified according to the age and sex. Simultaneously, the weight and length were measured. The data was statistically analyzed and compared, which revealed that the mean size of pancreas was significantly larger in below forty years of age group. Although, there was no significant difference in the size of pancreas between male and female, the pancreas of male subjects was found larger. Thus, the result of the present study not only provides standard dimension of pancreas in Nepalese peoples but also reveals that it is larger in younger people and males. PMID:22364088

  6. Endoscopic ultrasound in the diagnosis and management of carcinoma pancreas

    PubMed Central

    Puri, Rajesh; Manrai, Manish; Thandassery, Ragesh Babu; Alfadda, Abdulrahman A

    2016-01-01

    Endoscopic ultrasound (EUS) has become an important component in the diagnosis and treatment of carcinoma pancreas. With the advent of advanced imaging techniques and tissue acquisition methods the role of EUS is becoming increasingly important. Small pancreatic tumors can be reliably diagnosed with EUS. EUS guided fine needle aspiration establishes diagnosis in some cases. EUS plays an important role in staging of carcinoma pancreas and in some important therapeutic methods that include celiac plexus neurolysis, EUS guided biliary drainage and drug delivery. In this review we attempt to review the role of EUS in diagnosis and management of carcinoma pancreas. PMID:26839647

  7. Acute Exercise Induced Mitochondrial H2O2 Production in Mouse Skeletal Muscle: Association with p66Shc and FOXO3a Signaling and Antioxidant Enzymes

    PubMed Central

    Wang, Ping; Qi, Zhengtang; Cui, Di; Ding, Shuzhe

    2015-01-01

    Exercise induced skeletal muscle phenotype change involves a complex interplay between signaling pathways and downstream regulators. This study aims to investigate the effect of acute exercise on mitochondrial H2O2 production and its association with p66Shc, FOXO3a, and antioxidant enzymes. Male ICR/CD-1 mice were subjected to an acute exercise. Muscle tissues (gastrocnemius and quadriceps femoris) were taken after exercise to measure mitochondrial H2O2 content, expression of p66Shc and FOXO3a, and the activity of antioxidant enzymes. The results showed that acute exercise significantly increased mitochondrial H2O2 content and expressions of p66Shc and FOXO3a in a time-dependent manner, with a linear correlation between the increase in H2O2 content and p66Shc or FOXO3a expression. The activity of mitochondrial catalase was slightly reduced in the 90 min exercise group, but it was significantly higher in groups with 120 and 150 min exercise compared to that of 90 min exercise group. The activity of SOD was not significantly affected. The results indicate that acute exercise increases mitochondrial H2O2 production in the skeletal muscle, which is associated with the upregulation of p66Shc and FOXO3a. The association of p66Shc and FOXO3a signaling with exercise induced H2O2 generation may play a role in regulating cellular oxidative stress during acute exercise. PMID:25874020

  8. Identification of the interaction of VP1 with GM130 which may implicate in the pathogenesis of CVB3-induced acute pancreatitis

    PubMed Central

    Li, Xiuzhen; Xia, Yanhua; Huang, Shengping; Liu, Fadi; Ying, Ying; Xu, Qiufang; Liu, Xin; Jin, Guili; Papasian, Christopher J.; Chen, Jack; Fu, Mingui; Huang, Xiaotian

    2015-01-01

    Coxsackievirus B3 (CVB3) is a causative agent of viral myocarditis, pancreatitis, and meningitis in humans. Although the susceptibility of CVB3-induced acute pancreatitis is age-dependent, the underlying mechanisms remain unclear. Here we identified the host factor Golgi matrix protein 130 (GM130) as a novel target of CVB3 during CVB3-induced acute pancreatitis. The viral protein VP1 interacted with GM130, disrupted GM130-GRASP65 complexes, and caused GM130 degradation, which may lead to disruption of the Golgi ribbon and development of acute pancreatitis in mice. Interestingly, the expression level of GM130 in mouse pancreas was age-dependent, which was nicely correlated with the age-associated susceptibility of CVB3-induced acute pancreatitis. Furthermore, interference RNA-mediated knockdown of GM130 significantly reduced CVB3 replication in HeLa cells. Taken together, the study identified GM130 as a novel target of CVB3, which may implicate in the pathogenesis of CVB3-induced acute pancreatitis. PMID:26314804

  9. Experimental analysis of the mechanical behavior of the viscoelastic porcine pancreas and preliminary case study on the human pancreas.

    PubMed

    Wex, C; Fröhlich, M; Brandstädter, K; Bruns, C; Stoll, A

    2015-01-01

    The aim of this article is to study the mechanical properties of the pancreas. Up to now, the mechanical properties of the pancreas are not sufficiently characterized. The possibility of intraoperative mechanical testing of pathological pancreata will allow the classification of pancreatic diseases in the future. The application of mechanical parameters instead of the intraoperative frozen section analysis shortens waiting times in the operating room. This study proves the general applicability of shear rheology for the determination of the mechanical properties of pancreas and the assessment of graft quality for transplantation. Porcine and human pancreas samples were examined ex vivo and a nonlinear viscoelastic behavior was observed. Pancreas was found to be more viscous than liver but both abdominal organs showed a similar flow behavior. The shear deformation dependence of healthy human pancreas was similar to porcine pancreas. An increase in the post-mortem time led to an increase in the complex modulus for a post-mortem time up to 8.5 days. Histological investigations showed that an increased amount of collagen coincides with the stiffening of the pancreatic tissue. PMID:25460416

  10. Partial characterization of specific cantharidin binding sites in mouse tissues

    SciTech Connect

    Graziano, M.J.; Pessah, I.N.; Matsuzawa, M.; Casida, J.E.

    1988-06-01

    The mode of action of cantharidin, the natural vesicant of blister beetles, is examined by radioligand binding studies with mouse tissues. (3H)Cantharidin undergoes specific and saturable binding with the liver cytosol, which is characterized as follows: Kd and Bmax values of 30 nM and 1.8 pmol/mg of protein, respectively; linearity with respect to protein concentration; pH optimum of 6.5 to 7.5; association and dissociation half-times of 20 min and 12 hr, respectively; and 50% inhibition by Mg2+ at 70 microM, Ca2+ at 224 microM, pyrophosphate at 27 microM, and nucleotide triphosphates at 52-81 microM. The binding site undergoes a loss of activity at 45 degrees or higher. The toxicological relevance of this specific (3H)cantharidin binding site of mouse liver cytosol is established in three ways. First, the potency of 15 active cantharidin analogs for inhibiting (3H)cantharidin binding is correlated with their acute toxicity to mice (r = 0.829). Second, 26 related compounds that are inactive in inhibiting (3H)cantharidin binding are also of little or no toxicity to mice. Finally, the binding of (3H) cantharidin to liver cytosol from mice poisoned with increasing amounts of unlabeled cantharidin is inhibited in a dose-dependent manner. (3H)Cantharidin also specifically binds to cytosol fractions of blood, brain, heart, kidney, lung, pancreas, skin, spleen, and stomach. The characteristics of the specific binding site in brain are very similar to those determined in liver with respect to Kd, Bmax, association/dissociation kinetics, and sensitivity to inhibitors. It therefore appears that the toxicity of cantharidin and related oxabicycloheptanes, including the herbicide endothal, is attributable to binding at a specific site in liver and possibly other tissues.

  11. Hnf1b controls pancreas morphogenesis and the generation of Ngn3+ endocrine progenitors

    PubMed Central

    De Vas, Matias G.; Kopp, Janel L.; Heliot, Claire; Sander, Maike; Cereghini, Silvia; Haumaitre, Cécile

    2015-01-01

    Heterozygous mutations in the human HNF1B gene are associated with maturity-onset diabetes of the young type 5 (MODY5) and pancreas hypoplasia. In mouse, Hnf1b heterozygous mutants do not exhibit any phenotype, whereas the homozygous deletion in the entire epiblast leads to pancreas agenesis associated with abnormal gut regionalization. Here, we examine the specific role of Hnf1b during pancreas development, using constitutive and inducible conditional inactivation approaches at key developmental stages. Hnf1b early deletion leads to a reduced pool of pancreatic multipotent progenitor cells (MPCs) due to decreased proliferation and increased apoptosis. Lack of Hnf1b either during the first or the secondary transitions is associated with cystic ducts. Ductal cells exhibit aberrant polarity and decreased expression of several cystic disease genes, some of which we identified as novel Hnf1b targets. Notably, we show that Glis3, a transcription factor involved in duct morphogenesis and endocrine cell development, is downstream Hnf1b. In addition, a loss and abnormal differentiation of acinar cells are observed. Strikingly, inactivation of Hnf1b at different time points results in the absence of Ngn3+ endocrine precursors throughout embryogenesis. We further show that Hnf1b occupies novel Ngn3 putative regulatory sequences in vivo. Thus, Hnf1b plays a crucial role in the regulatory networks that control pancreatic MPC expansion, acinar cell identity, duct morphogenesis and generation of endocrine precursors. Our results uncover an unappreciated requirement of Hnf1b in endocrine cell specification and suggest a mechanistic explanation of diabetes onset in individuals with MODY5. PMID:25715395

  12. A study of MRI-guided diffuse fluorescence molecular tomography for monitoring PDT effects in pancreas cancer

    NASA Astrophysics Data System (ADS)

    Samkoe, Kimberley S.; Davis, Scott C.; Srinivasan, Subhadra; O'Hara, Julia A.; Hasan, Tayyaba; Pogue, Brian W.

    2009-06-01

    Over the last several decades little progress has been made in the therapy and treatment monitoring of pancreas adenocarcinoma, a devastating and aggressive form of cancer that has a 5-year patient survival rate of 3%. Currently, investigations for the use of interstitial Verteporfin photodynamic therapy (PDT) are being undertaken in both orthotopic xenograft mouse models and in human clinical trials. In the mouse models, magnetic resonance (MR) imaging has been used as a measure of surrogate response to Verteporfin PDT; however, MR imaging alone lacks the molecular information required to assess the metabolic function and growth rates of the tumor immediately after treatment. We propose the implementation of MR-guided fluorescence tomography in conjunction with a fluorescently labeled (IR-Dye 800 CW, LI-COR) epidermal growth factor (EGF) as a molecular measure of surrogate response. To demonstrate the effectiveness of MR-guided diffuse fluorescence tomography for molecular imaging, we have used the AsPC-1 (+EGFR) human pancreatic adenocarcinoma in an orthotopic mouse model. EGF IRDye 800CW was injected 48 hours prior to imaging. MR image sequences were collected simultaneously with the fluorescence data using a MR-coupled diffuse optical tomography system. Image reconstruction was performed multiple times with varying abdominal organ segmentation in order to obtain a optimal tomographic image. It is shown that diffuse fluorescence tomography of the orthotopic pancreas model is feasible, with consideration of confounding fluorescence signals from the multiple organs and tissues surrounding the pancreas. MR-guided diffuse fluorescence tomography will be used to monitor EGF response after photodynamic therapy. Additionally, it provide the opportunity to individualize subsequent therapies based on response to PDT as well as to evaluate the success of combination therapies, such as PDT with chemotherapy, antibody therapy or even radiation.

  13. Testosterone biotransformation by the isolated perfused canine pancreas

    SciTech Connect

    Fernandez-del Castillo, C.; Diaz-Sanchez, V.; Varela-Fascinetto, G.; Altamirano, A.; Odor-Morales, A.; Lopez-Medrano, R.M.; Robles-Diaz, G. )

    1991-01-01

    There is strong evidence indicating that the pancreas is under the influence of sex steroid hormones, and that it may even participate in their biosynthesis and metabolism. In the present study, (3H)testosterone was perfused into the isolated canine pancreas, and measured in the effluent with several of its metabolites (5 alpha-dihydrotestosterone, androstenedione, and estradiol). Results show that testosterone is readily transformed by the canine pancreas. The main product found in the effluent is androstenedione. The testis and spleen were also perfused with (3H)testosterone and used as controls. In both cases, this hormone appeared mostly unchanged in the effluent as compared to the pancreatic perfusion (p less than 0.0001). From our data, we conclude that the canine pancreas has the capacity to transform sex steroid hormones, and could be considered an extragonadal site of sex steroid biosynthesis.

  14. Proteomic analysis of pancreas derived from adult cloned pig

    SciTech Connect

    Chae, Jung-Il; Cho, Young Keun; Cho, Seong-Keun; Kim, Jin-Hoi; Han, Yong-Mahn; Koo, Deog-Bon Lee, Kyung-Kwang

    2008-02-08

    The potential medical applications of animal cloning include xenotransplantation, but the complex molecular cascades that control porcine organ development are not fully understood. Still, it has become apparent that organs derived from cloned pigs may be suitable for transplantation into humans. In this study, we examined the pancreas of an adult cloned pig developed through somatic cell nuclear transfer (SCNT) using two-dimensional electrophoresis (2-DE) and Western blotting. Proteomic analysis revealed 69 differentially regulated proteins, including such apoptosis-related species as annexins, lamins, and heat shock proteins, which were unanimously upregulated in the SCNT sample. Among the downregulated proteins in SCNT pancreas were peroxiredoxins and catalase. Western blot results indicate that several antioxidant enzymes and the anti-apoptotic protein were downregulated in SCNT pancreas, whereas several caspases were upregulated. Together, these data suggest that the accumulation of reactive oxygen species (ROS) in the pancreas of an adult cloned pig leads to apoptosis.

  15. Heterotopic Pancreas: A Rare Cause of Ileo-Ileal Intussusception

    PubMed Central

    Monier, Ahmed; Awad, Ahmed; Szmigielski, Wojciech; Muneer, Mohamed; Alrashid, Amal; Darweesh, Adham; Hassan, Heba

    2014-01-01

    Background Heterotopic pancreas is a rare developmental anomaly defined as pancreatic tissue found on ectopic sites without contiguity with the main pancreas. An isolated heterotopic pancreas as a cause of bowel intussusception is extremely rare. Case Report A case of 47-year old male with multiple episodes of melena, constipation and abdominal pain for one year duration is presented. CT eneterography revealed a large circumferential lesion involving the terminal ileum that acted as a leading point to an ileo-ileal intussusception. The resection of the lesion and related bowel segment was carried out. The histopathological examination confirmed the excised lesion as a heterotopic pancreatic tissue. Conclusions Though a rare entity, heterotopic pancreas should be considered in the differential diagnosis of bowel intussusception. PMID:25302087

  16. GENETIC MAPPING OF VOCALIZATION TO A SERIES OF INCREASING ACUTE FOOTSHOCKS USING B6.A CONSOMIC AND B6.D2 CONGENIC MOUSE STRAINS

    SciTech Connect

    Matthews, Douglas B; Chesler, Elissa J; Cook, Melloni N.; Cockroft, Judy; Philip, Vivek M; Goldowitz, Daniel

    2008-01-01

    Footshock response is used to study biological functions in mammals. However, the genetics underlying variability in footshock sensitivity are not well understood. In the current studies, a panel of B6.A consomic mouse strains, two B6.D2 congenic mouse strains and the progenitor strains were screened for footshock sensitivity as measured by audible vocalization. It was found that A/J (A) mice and C57BL/6J (B6) mice with an A Chromosome 1 (Chr 1) were less sensitive to footshock compared to B6 animals. Furthermore, the offspring of Chr 1 consomic mice crossed with B6 mice had vocalization levels that were intermediate to A/J and B6 animals. A F2 mapping panel revealed two significant QTLs for footshock vocalization centered around D1Mit490 and D1Mit206 on Chr 1. The role of these Chr 1 loci in footshock sensitivity was confirmed in B6.D2 congenic mice. These data identify genetic regions involved in footshock sensitivity and establish additional mouse resources for use in investigating complex behaviors.

  17. Resveratrol given intraperitoneally does not inhibit growth of high-risk t(4;11) acute lymphoblastic leukemia cells in NOD/SCID mouse model

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The efficacy of the phytochemical resveratrol as a preventive agent against the growth of t(4;11) acute lymphoblastic leukemia (ALL) was evaluated in NOD.CB17-Prkdcscid/J mice engrafted with the human t(4;11) ALL line SEM. SEM cells were injected into the tail vein and engraftment was monitored by ...

  18. Stem cells versus plasticity in liver and pancreas regeneration.

    PubMed

    Kopp, Janel L; Grompe, Markus; Sander, Maike

    2016-03-01

    Cell replacement in adult organs can be achieved through stem cell differentiation or the replication or transdifferentiation of existing cells. In the adult liver and pancreas, stem cells have been proposed to replace tissue cells, particularly following injury. Here we review how specialized cell types are produced in the adult liver and pancreas. Based on current evidence, we propose that the plasticity of differentiated cells, rather than stem cells, accounts for tissue repair in both organs. PMID:26911907

  19. Automatic segmentation of abdominal vessels for improved pancreas localization

    NASA Astrophysics Data System (ADS)

    Farag, Amal; Liu, Jiamin; Summers, Ronald M.

    2014-03-01

    Accurate automatic detection and segmentation of abdominal organs from CT images is important for quantitative and qualitative organ tissue analysis as well as computer-aided diagnosis. The large variability of organ locations, the spatial interaction between organs that appear similar in medical scans and orientation and size variations are among the major challenges making the task very difficult. The pancreas poses these challenges in addition to its flexibility which allows for the shape of the tissue to vastly change. Due to the close proximity of the pancreas to numerous surrounding organs within the abdominal cavity the organ shifts according to the conditions of the organs within the abdomen, as such the pancreas is constantly changing. Combining these challenges with typically found patient-to-patient variations and scanning conditions the pancreas becomes harder to localize. In this paper we focus on three abdominal vessels that almost always abut the pancreas tissue and as such useful landmarks to identify the relative location of the pancreas. The splenic and portal veins extend from the hila of the spleen and liver, respectively, travel through the abdominal cavity and join at a position close to the head of the pancreas known as the portal confluence. A third vein, the superior mesenteric vein, anastomoses with the other two veins at the portal confluence. An automatic segmentation framework for obtaining the splenic vein, portal confluence and superior mesenteric vein is proposed using 17 contrast enhanced computed-tomography datasets. The proposed method uses outputs from the multi-organ multi-atlas label fusion and Frangi vesselness filter to obtain automatic seed points for vessel tracking and generation of statistical models of the desired vessels. The approach shows ability to identify the vessels and improve localization of the pancreas within the abdomen.

  20. Cell Cycle–Dependent Differentiation Dynamics Balances Growth and Endocrine Differentiation in the Pancreas

    PubMed Central

    Kim, Yung Hae; Larsen, Hjalte List; Rué, Pau; Lemaire, Laurence A.; Ferrer, Jorge; Grapin-Botton, Anne

    2015-01-01

    Organogenesis relies on the spatiotemporal balancing of differentiation and proliferation driven by an expanding pool of progenitor cells. In the mouse pancreas, lineage tracing at the population level has shown that the expanding pancreas progenitors can initially give rise to all endocrine, ductal, and acinar cells but become bipotent by embryonic day 13.5, giving rise to endocrine cells and ductal cells. However, the dynamics of individual progenitors balancing self-renewal and lineage-specific differentiation has never been described. Using three-dimensional live imaging and in vivo clonal analysis, we reveal the contribution of individual cells to the global behaviour and demonstrate three modes of progenitor divisions: symmetric renewing, symmetric endocrinogenic, and asymmetric generating a progenitor and an endocrine progenitor. Quantitative analysis shows that the endocrine differentiation process is consistent with a simple model of cell cycle–dependent stochastic priming of progenitors to endocrine fate. The findings provide insights to define control parameters to optimize the generation of β-cells in vitro. PMID:25786211

  1. Cell cycle-dependent differentiation dynamics balances growth and endocrine differentiation in the pancreas.

    PubMed

    Kim, Yung Hae; Larsen, Hjalte List; Rué, Pau; Lemaire, Laurence A; Ferrer, Jorge; Grapin-Botton, Anne

    2015-03-01

    Organogenesis relies on the spatiotemporal balancing of differentiation and proliferation driven by an expanding pool of progenitor cells. In the mouse pancreas, lineage tracing at the population level has shown that the expanding pancreas progenitors can initially give rise to all endocrine, ductal, and acinar cells but become bipotent by embryonic day 13.5, giving rise to endocrine cells and ductal cells. However, the dynamics of individual progenitors balancing self-renewal and lineage-specific differentiation has never been described. Using three-dimensional live imaging and in vivo clonal analysis, we reveal the contribution of individual cells to the global behaviour and demonstrate three modes of progenitor divisions: symmetric renewing, symmetric endocrinogenic, and asymmetric generating a progenitor and an endocrine progenitor. Quantitative analysis shows that the endocrine differentiation process is consistent with a simple model of cell cycle-dependent stochastic priming of progenitors to endocrine fate. The findings provide insights to define control parameters to optimize the generation of β-cells in vitro. PMID:25786211

  2. EGF targeted fluorescence molecular tomography as a predictor of PDT outcomes in pancreas cancer models

    NASA Astrophysics Data System (ADS)

    Samkoe, Kimberley S.; Davis, Scott C.; Srinivasan, Subhadra; Isabelle, Martin E.; O'Hara, Julia; Hasan, Tayyaba; Pogue, Brian W.

    2010-02-01

    Verteporfin photodynamic therapy (PDT) is a promising adjuvant therapy for pancreas cancer and investigations for its use are currently underway in both orthotopic xenograft mouse models and in human clinical trials. The mouse models have been studied extensively using magnetic resonance (MR) imaging as a measure of surrogate response to verteporfin PDT and it was found that tumor lines with different levels of aggression respond with varying levels to PDT. MR imaging was successful in determining the necrotic volume caused by PDT but there was difficultly in distinguishing inflamed tissues and regions of surviving tumor. In order to understand the molecular changes within the tumor immediately post-PDT we propose the implementation of MR-guided fluorescence molecular tomography (FMT) in conjunction with an exogenously administered fluorescently labeled epidermal growth factor (EGF-IRDye800CW, LI-COR Biosciences). We have previously shown that MR-guided FMT is feasible in the mouse abdomen when multiple regions of fluorescence are considered from contributing internal organs. In this case the highly aggressive AsPC-1 (+EGFR) orthotopic tumor was implanted in SCID mice, interstitial verteporfin PDT (1mg/kg, 20J/cm) was performed when the tumor reached ~60mm3 and both tumor volume and EGF binding were followed with MR-guided FMT.

  3. Epidemiology of pancreas cancer in Los Angeles

    SciTech Connect

    Mack, T.M.; Paganini-Hill, A.

    1981-03-15

    The characteristics of the 3614 Los Angeles County residents in whom cancer of the exocrine pancreas was diagnosed during the period 1972-1977 were compared with those of all county residents and patients in whom any cancer was diagnosed during the same period. Seventy-nine percent of the diagnoses had been pathologically verified. This disease still preferentially afflicts the old, the black, and men, although the differences in risk with factors other than age are modest. The disease is not evenly distributed by social class, or over time, although it is not clear that the observed differences reflect etiology. The distributions with respect to important categories of occupation and industry, religion, marital status, geography of residence, and birthplace were rather uniform. Although there is no obvious explanation for any of several unexpected minor inequities in the pattern of incidence, there is no compelling evidence to support any specific environmental cause. There is substantial evidence which is inconsistent with those environmental hypotheses that have been proposed previously.

  4. Endocrine Cell Clustering During Human Pancreas Development

    PubMed Central

    Jeon, Jongmin; Correa-Medina, Mayrin; Ricordi, Camillo; Edlund, Helena; Diez, Juan A.

    2009-01-01

    The development of efficient, reproducible protocols for directed in vitro differentiation of human embryonic stem (hES) cells into insulin-producing β cells will benefit greatly from increased knowledge regarding the spatiotemporal expression profile of key instructive factors involved in human endocrine cell generation. Human fetal pancreases 7 to 21 weeks of gestational age, were collected following consent immediately after pregnancy termination and processed for immunostaining, in situ hybridization, and real-time RT-PCR expression analyses. Islet-like structures appear from approximately week 12 and, unlike the mixed architecture observed in adult islets, fetal islets are initially formed predominantly by aggregated insulin- or glucagon-expressing cells. The period studied (7–22 weeks) coincides with a decrease in the proliferation and an increase in the differentiation of the progenitor cells, the initiation of NGN3 expression, and the appearance of differentiated endocrine cells. The present study provides a detailed characterization of islet formation and expression profiles of key intrinsic and extrinsic factors during human pancreas development. This information is beneficial for the development of efficient protocols that will allow guided in vitro differentiation of hES cells into insulin-producing cells. (J Histochem Cytochem 57:811–824, 2009) PMID:19365093

  5. High precision innovative micropump for artificial pancreas

    NASA Astrophysics Data System (ADS)

    Chappel, E.; Mefti, S.; Lettieri, G.-L.; Proennecke, S.; Conan, C.

    2014-03-01

    The concept of artificial pancreas, which comprises an insulin pump, a continuous glucose meter and a control algorithm, is a major step forward in managing patient with type 1 diabetes mellitus. The stability of the control algorithm is based on short-term precision micropump to deliver rapid-acting insulin and to specific integrated sensors able to monitor any failure leading to a loss of accuracy. Debiotech's MEMS micropump, based on the membrane pump principle, is made of a stack of 3 silicon wafers. The pumping chamber comprises a pillar check-valve at the inlet, a pumping membrane which is actuated against stop limiters by a piezo cantilever, an anti-free-flow outlet valve and a pressure sensor. The micropump inlet is tightly connected to the insulin reservoir while the outlet is in direct communication with the patient skin via a cannula. To meet the requirement of a pump dedicated to closed-loop application for diabetes care, in addition to the well-controlled displacement of the pumping membrane, the high precision of the micropump is based on specific actuation profiles that balance effect of pump elasticity in low-consumption push-pull mode.

  6. Microendoscopes for imaging of the pancreas

    NASA Astrophysics Data System (ADS)

    Kano, Angelique L.; Rouse, Andrew R.; Kroto, Shona M.; Gmitro, Arthur F.

    2004-07-01

    Patients diagnosed with pancreatic cancer have a 5-year survival rate of only 3%. Endoscopic imaging of the pancreas is limited by the small size of the pancreatic duct, which has an average size of 3 mm. To improve imaging capabilities for the pancreatic duct, two small catheter-based imaging systems have been developed that will fit through the therapeutic channel of a clinical endoscope and into the pancreatic duct. One is a miniature endoscope designed to provide macro-imaging of tissue with both white light reflectance and fluorescence imaging modes. The 1.75 mm diameter catheter consists of separate illumination and imaging channels. At a nominal focal distance of 10 mm, the field of view of the system is ~ 10 mm, and the corresponding in-plane resolution is 60 microns. To complement the broadfield view of the tissue, a confocal microendoscope with 2 micron lateral resolution over a field of view of 450 microns and 25 micron axial resolution has been developed. With an outer diameter of 3 mm, the catheter in this system will also fit through the therapeutic channel and into the pancreatic duct. Images of tissue with both the miniature endoscope and confocal microendoscope are presented.

  7. A BDNF loop-domain mimetic acutely reverses spontaneous apneas and respiratory abnormalities during behavioral arousal in a mouse model of Rett syndrome

    PubMed Central

    Kron, Miriam; Lang, Min; Adams, Ian T.; Sceniak, Michael; Longo, Frank; Katz, David M.

    2014-01-01

    Reduced levels of brain-derived neurotrophic factor (BDNF) are thought to contribute to the pathophysiology of Rett syndrome (RTT), a severe neurodevelopmental disorder caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). In Mecp2 mutant mice, BDNF deficits have been associated with breathing abnormalities, a core feature of RTT, as well as with synaptic hyperexcitability within the brainstem respiratory network. Application of BDNF can reverse hyperexcitability in acute brainstem slices from Mecp2-null mice, suggesting that therapies targeting BDNF or its receptor, TrkB, could be effective at acute reversal of respiratory abnormalities in RTT. Therefore, we examined the ability of LM22A-4, a small-molecule BDNF loop-domain mimetic and TrkB partial agonist, to modulate synaptic excitability within respiratory cell groups in the brainstem nucleus tractus solitarius (nTS) and to acutely reverse abnormalities in breathing at rest and during behavioral arousal in Mecp2 mutants. Patch-clamp recordings in Mecp2-null brainstem slices demonstrated that LM22A-4 decreases excitability at primary afferent synapses in the nTS by reducing the amplitude of evoked excitatory postsynaptic currents and the frequency of spontaneous and miniature excitatory postsynaptic currents. In vivo, acute treatment of Mecp2-null and -heterozygous mutants with LM22A-4 completely eliminated spontaneous apneas in resting animals, without sedation. Moreover, we demonstrate that respiratory dysregulation during behavioral arousal, a feature of human RTT, is also reversed in Mecp2 mutants by acute treatment with LM22A-4. Together, these data support the hypothesis that reduced BDNF signaling and respiratory dysfunction in RTT are linked, and establish the proof-of-concept that treatment with a small-molecule structural mimetic of a BDNF loop domain and a TrkB partial agonist can acutely reverse abnormal breathing at rest and in response to behavioral arousal

  8. Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis

    PubMed Central

    Huch, Meritxell; Bonfanti, Paola; Boj, Sylvia F; Sato, Toshiro; Loomans, Cindy J M; van de Wetering, Marc; Sojoodi, Mozhdeh; Li, Vivian S W; Schuijers, Jurian; Gracanin, Ana; Ringnalda, Femke; Begthel, Harry; Hamer, Karien; Mulder, Joyce; van Es, Johan H; de Koning, Eelco; Vries, Robert G J; Heimberg, Harry; Clevers, Hans

    2013-01-01

    Lgr5 marks adult stem cells in multiple adult organs and is a receptor for the Wnt-agonistic R-spondins (RSPOs). Intestinal, stomach and liver Lgr5+ stem cells grow in 3D cultures to form ever-expanding organoids, which resemble the tissues of origin. Wnt signalling is inactive and Lgr5 is not expressed under physiological conditions in the adult pancreas. However, we now report that the Wnt pathway is robustly activated upon injury by partial duct ligation (PDL), concomitant with the appearance of Lgr5 expression in regenerating pancreatic ducts. In vitro, duct fragments from mouse pancreas initiate Lgr5 expression in RSPO1-based cultures, and develop into budding cyst-like structures (organoids) that expand five-fold weekly for >40 weeks. Single isolated duct cells can also be cultured into pancreatic organoids, containing Lgr5 stem/progenitor cells that can be clonally expanded. Clonal pancreas organoids can be induced to differentiate into duct as well as endocrine cells upon transplantation, thus proving their bi-potentiality. PMID:24045232

  9. Acute relaxation of mouse duodenum [correction of duodenun] by estrogens. Evidence for an estrogen receptor-independent modulation of muscle excitability.

    PubMed

    Díaz, Mario; Ramírez, Cristina M; Marin, Raquel; Marrero-Alonso, Jorge; Gómez, Tomás; Alonso, Rafael

    2004-10-01

    17-beta-Estradiol, the stereoisomer 17-alpha-estradiol and the synthetic estrogen diethylstilbestrol (DES), all caused a rapid (<3 min) dose-dependent reversible relaxation of mouse duodenal spontaneous activity, reduced basal tone and depressed the responses to CaCl(2) and KCl. The steroidal antiestrogen 7alpha-[9-[(4,4,5,5,5,-pentafluoropenty)sulphinyl]nonyl]-estra-1,3,5(19)-triene-3,17beta-diol (ICI182,780) failed to either mimic or prevent the effect of 17-beta-estradiol. The effect of estrogens was unrelated to activation of nitric oxide (NO), mitogen-activated protein kinase (MAPK), protein kinase A (PKA), protein kinase G (PKG) or protein kinase C (PKC). Estrogen-induced relaxation was partially reversed by 1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-pyridine-3-carboxilic acid methyl ester (BAY-K8644), depolarization, or by application of tetraethylammonium or 4-aminopyridine, but not by glibenclamide, apamin, charybdotoxin, paxilline or verruculogen. The effects of BAY-K8644 and K(+) channel blockers were synergistic, and allowed relaxed tissues to recover spontaneous activity and basal tone. We hypothesize that the rapid non-genomic spasmolytic effect of estrogens on mouse duodenal muscle might be triggered by an estrogen-receptor-independent mechanism likely involving activation of tetraethylamonium- and 4-aminopyridine-sensitive K(+) channels and inhibition of L-type Ca2(+) channels on the smooth muscle cells. PMID:15464075

  10. Functional up-regulation of endopeptidase neurolysin during post-acute and early recovery phases of experimental stroke in mouse brain.

    PubMed

    Rashid, Mamoon; Wangler, Naomi J; Yang, Li; Shah, Kaushik; Arumugam, Thiruma V; Abbruscato, Thomas J; Karamyan, Vardan T

    2014-04-01

    In this study, we provide evidence for the first time that membrane-bound endopeptidase neurolysin is up-regulated in different parts of mouse brain affected by focal ischemia-reperfusion in a middle cerebral artery occlusion model of stroke. Radioligand binding, enzymatic and immunoblotting experiments in membrane preparations of frontoparietal cortex, striatum, and hippocampus isolated from the ischemic hemisphere of mouse brain 24 h after reperfusion revealed statistically significant increase (≥ twofold) in quantity and activity of neurolysin compared with sham-operated controls. Cerebellar membranes isolated from the ischemic hemisphere served as negative control supporting the observations that up-regulation of neurolysin occurs in post-ischemic brain regions. This study also documents sustained functional up-regulation of neurolysin in frontoparietal cortical membranes for at least 7 days after stroke, which appears not to be transcriptionally or translationally regulated, but rather depends on translocation of cytosolic neurolysin to the membranes and mitochondria. Considering diversity of endogenous neurolysin substrates (neurotensin, bradykinin, angiotensins I/II, substance P, hemopressin, dynorphin A(1-8), metorphamide, somatostatin) and the well-documented role of these peptidergic systems in pathogenesis of stroke, resistance to ischemic injury and/or post-stroke brain recovery, our findings suggest that neurolysin may play a role in processes modulating the brain's response to stroke and its recovery after stroke. PMID:24164478

  11. Monitoring of canine pancreas allograft function with measurements of urinary amylase.

    PubMed

    Ekberg, H; Deane, S A; Allen, R D; Hawthorne, W J; Williamson, P; Grierson, J M; Stewart, G J; Little, J M

    1988-07-01

    A canine model of whole pancreas transplantation with pancreaticocystostomy was studied for predictability of graft rejection using urinary amylase (UA) monitoring. Six pancreatectomized dogs were transplanted without immunosuppression and with acute rejection occurring at a median of 9.5 days (range 7-12 days). A differential loss of allograft exocrine and endocrine function was demonstrated, with a gradual decrease in UA after transplantation but maintenance of fasting blood glucose levels (FBGL) till the day before complete loss of graft structure. Another 13 dogs treated with cyclosporin (25 mg/kg per day) had prolonged graft survival (P less than 0.01) with an actuarial median survival of 91 days (range 8-159 days). Five allografts were lost because of rejection and eight dogs died with functioning grafts. Fasting spot levels of UA less than 5000 iu/l or less than 10,000 iu/l had a positive predictivity of graft failure of 71% or 31%, respectively. Falls of UA levels of greater than 75% in 24 h and 48 h were seen equally in both rejecting and functioning allografts. This study confirmed the role of UA as an earlier marker of rejection than FBGL. The clinical role of UA will be important, but its use as a predictor of pancreas rejection may be dependent on a fall to a predetermined level rather than the rate of fall. PMID:2473736

  12. Distinct patterns of peritumoral histological findings in subtypes of intraductal papillary mucinous neoplasms of the pancreas.

    PubMed

    Saito, Michihiro; Imada, Hiroki; Suzuki, Tsukasa; Sata, Naohiro; Yasuda, Yoshikazu; Maetani, Iruru; Fukushima, Noriyoshi

    2015-10-01

    Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are primary pancreatic neoplasms that can act as precursors to invasive adenocarcinoma of the pancreas. The peritumoral stroma has been increasingly recognized to play an important role in many types of tumors. Therefore, to investigate the clinicopathological significance of the peritumoral stroma in IPMNs, we examined the histological features of the peritumoral stroma in each subtype and histological grade of IPMNs. Eighty-two patients with IPMN, who underwent surgical resection, were reviewed clinicopathologically. Intraductal papillary mucinous neoplasms (86 lesions in total) were histologically subclassified into gastric (n = 51), intestinal (n = 22), pancreatobiliary (n = 11), and oncocytic (n = 2) subtypes. Peritumoral histological features between the gastric and intestinal subtypes were evaluated by each histological grade. The results showed that subepithelial edema and inflammatory cell infiltration were more commonly observed in the gastric subtype (74% and 79%, respectively) than in the intestinal subtype (12% and 25%, respectively) of low-grade IPMNs. On the other hand, mucus lakes were more commonly observed in the intestinal subtype (100%) than in the gastric subtype (0%) of high-grade IPMNs. In addition, pancreatobiliary subtype IPMNs tended to exhibit acute inflammation such as neutrophil predominance. This study showed that peritumoral histological features differed among subtypes of IPMNs from low-grade tumors. These differences suggest the possibility that each subtype of IPMNs has a distinct mechanism from an early stage of tumor progression, which is reflected in the properties of the peritumoral stroma. PMID:26265194

  13. Application of Rotating Wall Vessel (RWV) Cell Culture for Pancreas Islet Cell Transplantation

    NASA Technical Reports Server (NTRS)

    Rutzky, Lynne P.

    1998-01-01

    Type I insulin-dependent diabetes mellitus (IDDM) remains a major cause of morbidity and mortality in both pediatric and adult populations, despite significant advances in medical management. While insulin therapy treats symptoms of acute diabetes, it fails to prevent chronic complications such as microvascular disease, blindness, neuropathy, and chronic renal failure. Strict control of blood glucose concentrations delays but does not prevent the onset and progression of secondary complications. Although, whole pancreas transplantation restores physiological blood glucose levels, a continuous process of allograft rejection causes vascular and exocrine-related complications. Recent advances in methods for isolation and purification of pancreatic islets make transplantation of islet allografts an attractive alternative to whole pancreas transplantation. However, immunosuppressive drugs are necessary to prevent rejection of islet allografts and many of these drugs are known to be toxic to the islets. Since auto-transplants of isolated islets following total pancreatectomy survive and function in vivo, it is apparent that a major obstacle to successful clinical islet transplantation is the immunogenicity of the islet allografts.

  14. Methylation profile and amplification of proto-oncogenes in rat pancreas induced with phytoestrogens

    SciTech Connect

    Lyn-Cook, B.D.; Blann, E.; Bo, J.

    1995-01-01

    Specific gene hypermethylation has been shown in DNA from neonatal rats exposed to the phytoestrogens, coumestrol, and equol. The pancreas is an organ in which estrogen receptors have been shown to be present. Studies have correlated the development of acute pancreatitis with rising levels of human estrogen binding proteins. Neonatal rats were dosed with 10 or 100 {mu}g of coumestrol or equol on postnatal day (PND) 1-10. The animals were sacrificed at Day 15. The pancreas was excised and pancreatic acinar cells isolated for molecular analysis. DNA was isolated from the cells by lysis in TEN-9 buffer supplemented with proteinase K and 0.1% SDS. High molecular weight (HMW) DNA was digested with the methylated DNA specific restriction enzymes, Hpa II and Msp I, for determination of methylation profiles. Both coumestrol and equol at high doses caused hypermethylation of the c-H-ras proto-oncogene. No hypermethylation or hypomethylation was observed in the proto-oncogenes, c-myc or c-fos. Methylation is thought to be an epigenetic mechanism involved in the activation (hypomethylation) or inactivation (hypermethylation) of cellular genes which are known to play a role in carcinogenesis. Epidemiology studies have shown that equol may have anti-carcinogenic effects on some hormone-dependent cancers. Additional studies are needed to further understand the role of phytoestrogens and methylation in relation to pancreatic disorders. 15 refs., 4 figs.

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

    PubMed Central

    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

  16. Pancreas Transplantation—Registry Report and a Commentary

    PubMed Central

    Sutherland, David E. R.; Kendall, David M.

    1985-01-01

    From December 1966 through December 1984, there were 561 pancreas transplants reported to the American College of Surgeons/National Institutes of Health Organ Transplant Registry, including 60 from 1966 through June 1977, 206 from July 1977 through December 1982 and 295 from January 1983 through December 1984. One-year graft function-survival rates (insulin-independent) in each of the three periods were 3%, 20% and 40%, and the corresponding patient survival rates were 40%, 72% and 77%. Currently 140 patients have functioning grafts, 76 for more than one year. Of the transplants since July 1977, one-year graft survival rates according to technique are 41% for enteric drainage (N = 155), 30% for polymer injection (N = 260) and 29% for urinary drainage (N = 47). Pancreas graft survival rates at one year according to whether or not the recipients have had a kidney transplant were 35% for recipients of simultaneous grafts (N = 281), 28% in recipients of a pancreas after a kidney (N = 112) and 26% in recipients of a pancreas only who did not have uremia (N = 106); corresponding patient survival rates were 69%, 83% and 83%. Overall, one-year pancreas graft survival rates according to whether the patients did or did not have end-stage diabetic nephropathy were 33% versus 25% and the corresponding patient survival rates were 73% versus 84% (P < .01). Patient survival rates were significantly higher in those without than in those with end-stage diabetic nephropathy. An analysis of technically successful grafts according to principal immunosuppressant showed one-year function rates of 46% in 258 cyclosporine-treated recipients and 26% in 143 azathioprine-treated recipients. Pancreas graft survival rates have progressively improved and the procedure has become safer with advances in surgical technique and immunosuppression. Pancreas transplantation is currently applicable to patients with diabetes mellitus whose complications are, or predictably will be, more serious than the

  17. Ectopic Ptf1a expression in murine ESCs potentiates endocrine differentiation and models pancreas development in vitro

    PubMed Central

    Nair, Gopika; Vincent, Robert K.; Odorico, Jon S.

    2014-01-01

    Besides its role in exocrine differentiation, pancreas-specific transcription factor 1a (PTF1a) is required for pancreas specification from the foregut endoderm and ultimately for endocrine cell formation. Examining the early role of PTF1a in pancreas development has been challenging due to limiting amounts of embryonic tissue material for study. Embryonic stem cells (ESCs) which can be differentiated in vitro, and without limit to the amount of experimental material, can serve as a model system to study these early developmental events. To this end, we derived and characterized a mouse ESC line with tetracycline-inducible expression of PTF1a (tet-Ptf1a mESCs). We found that transient ectopic expression of PTF1a initiated the pancreatic program in differentiating ESCs causing cells to activate PDX1 expression in bud-like structures resembling pancreatic primordia in vivo. These bud-like structures also expressed progenitor markers characteristic of a developing pancreatic epithelium. The epithelium differentiated to generate a wave of NGN3+ endocrine progenitors, and further formed cells of all three pancreatic lineages. Notably, the insulin+ cells in the cultures were monohormonal, and expressed PDX1 and NKX6.1. PTF1a-induced cultures differentiated into significantly more endocrine and exocrine cells and the ratio of endocrine-to-exocrine cell differentiation could be regulated by retinoic acid and nicotinamide signaling. Moreover, induced cultures treated with RA and Nic exhibited a modest glucose response. Thus, this tet-Ptf1a ESC-based in vitro system is a valuable new tool for interrogating the role of PTF1a in pancreas development and in directing differentiation of ESCs to endocrine cells. PMID:24375815

  18. Repurposed biological scaffolds: kidney to pancreas

    PubMed Central

    Willenberg, Bradley J; Oca-Cossio, Jose; Cai, Yunqing; Brown, Alicia R; Clapp, William L; Abrahamson, Dale R; Terada, Naohiro; Ellison, Gary W; Mathews, Clayton E; Batich, Christopher D; Ross, Edward A

    2015-01-01

    ABSTRACT. Advances in organ regeneration have been facilitated by gentle decellularization protocols that maintain distinct tissue compartments, and thereby allow seeding of blood vessels with endothelial lineages separate from populations of the parenchyma with tissue-specific cells. We hypothesized that a reconstituted vasculature could serve as a novel platform for perfusing cells derived from a different organ: thus discordance of origin between the vascular and functional cells, leading to a hybrid repurposed organ. The need for a highly vascular bed is highlighted by tissue engineering approaches that involve transplantation of just cells, as attempted for insulin production to treat human diabetes. Those pancreatic islet cells present unique challenges since large numbers are needed to allow the cell-to-cell signaling required for viability and proper function; however, increasing their number is limited by inadequate perfusion and hypoxia. As proof of principle of the repurposed organ methodology we harnessed the vasculature of a kidney scaffold while seeding the collecting system with insulin-producing cells. Pig kidneys were decellularized by sequential detergent, enzymatic and rinsing steps. Maintenance of distinct vascular and collecting system compartments was demonstrated by both fluorescent 10 micron polystyrene microspheres and cell distributions in tissue sections. Sterilized acellular scaffolds underwent seeding separately via the artery (fibroblasts or endothelioma cells) and retrograde (murine βTC-tet cells) up the ureter. After three-day bioreactor incubation, histology confirmed separation of cells in the vasculature from those in the collecting system. βTC-tet clusters survived in tubules, glomerular Bowman's space, demonstrated insulin immunolabeling, and thereby supported the feasibility of kidney-to-pancreas repurposing. PMID:26252820

  19. Endocrine Pancreas in Cats With Diabetes Mellitus.

    PubMed

    Zini, E; Lunardi, F; Zanetti, R; Heller, R S; Coppola, L M; Ferro, S; Guscetti, F; Osto, M; Lutz, T A; Reusch, C E; Cavicchioli, L

    2016-01-01

    Pancreatic amyloidosis and loss of α and β cells have been shown to occur in cats with diabetes mellitus, although the number of studies currently available is very limited. Furthermore, it is not known whether pancreatic islet inflammation is a common feature. The aims of the present study were to characterize islet lesions and to investigate whether diabetic cats have inflammation of the pancreatic islets. Samples of pancreas were collected postmortem from 37 diabetic and 20 control cats matched for age, sex, breed, and body weight. Histologic sections were stained with hematoxylin and eosin and Congo red; double labeled for insulin/CD3, insulin/CD20, insulin/myeloperoxidase, insulin/proliferating cell nuclear antigen, and glucagon/Ki67; and single labeled for amylin and Iba1. Mean insulin-positive cross-sectional area was approximately 65% lower in diabetic than control cats (P = .009), while that of amylin and glucagon was similar. Surprisingly, amyloid deposition was similar between groups (P = .408). Proliferation of insulin- and glucagon-positive cells and the number of neutrophils, macrophages, and T (CD3) and B (CD20) lymphocytes in the islets did not differ. The presence of T and B lymphocytes combined tended to be more frequent in diabetic cats (n = 8 of 37; 21.6%) than control cats (n = 1 of 20; 5.0%). The results confirm previous observations that loss of β cells but not α cells occurs in diabetic cats. Islet amyloidosis was present in diabetic cats but was not greater than in controls. A subset of diabetic cats had lymphocytic infiltration of the islets, which might be associated with β-cell loss. PMID:26113611

  20. Effects of different concentration and duration time of isoflurane on acute and long-term neurocognitve function of young adult C57BL/6 mouse

    PubMed Central

    Liu, Jianhui; Wang, Peijun; Zhang, Xiaoqing; Zhang, Wei; Gu, Guojun

    2014-01-01

    Postoperative cognitive dysfunction (POCD) is a decline in cognitive performance after a surgery with anaesthesia. The exact reasons of surgery and/or anaesthesia resulting in POCD are unclear. The aim of this study is to investigate the effects of different concentration and duration time of isoflurane anaesthesia on cognitive performance and cellular mechanisms involved in learning and memory function. In present work, young adult male C57BL/6 mice (age: 8 weeks) were anaesthetized by different concentration isoflurane in 100% oxygen for different duration time (Mice in group I1 received 0.7% isoflurane 0.5 h, mice in I2 received 0.7% isoflurane 2 h, mice in I3 received 1.4% isoflurane 2 h, and mice in I4 received 1.4% isoflurane 4 h). Non-anaesthetized mice served as control group (I0). Spatial learning was assessed at 10 days post-anesthesia in Morris water maze (MWM). Hippocampal protein expressions of activated caspase 3, NMDA receptor subunit NR2B, and extracellular-signal regulated kinase (ERK) 1/2 were evaluated 24 hours and 2 weeks post anesthesia. Protein expression of activated caspase3 was detected acute elevated in I3 (24 h post-anesthesia) and acute and long-term elevated in I4 (24 hours and 2 weeks post-anesthesia). There was no significant difference between I1, I2 and control group. Protein expressions of NR2B showed an acute and long-term increasement in I1 and I2, decreasement in I4, and an acute decline, then returned to normal in I3 compared to control group. The ratio of phosopho-ERK1/2 to total-ERK showed an acute increasement in I1 and I2, then came to normal 2 weeks post anesthesia compared to control group, meanwhile, we detected an acute and long-term decline in I3 and I4. In MWM test, mice in I1 and I2 showed cognitive improvement, mice in I3 showed similar to control group, while mice in I4 demonstrated cognitive impairment, which were approximately corresponding to the changes of protein expression of NR2B and activation of ERK1

  1. Acute and chronic cocaine differentially alter the subcellular distribution of AMPA GluR1 subunits in region-specific neurons within the mouse ventral tegmental area

    PubMed Central

    Lane, D.A.; Jaferi, A.; Kreek, M.J.; Pickel, V.M.

    2010-01-01

    Cocaine administration increases AMPA GluR1 expression and receptor-mediated activation of the ventral tegmental area (VTA). Functionality is determined, however, by surface availability of these receptors in transmitter- and VTA-region-specific neurons, which may also be affected by cocaine. To test this hypothesis, we used electron microscopic immunolabeling of AMPA GluR1 subunits and tyrosine hydroxylase (TH; the enzyme needed for dopamine synthesis), in the cortical-associated parabrachial (PB) and in the limbic-associated paranigral (PN) VTA of adult male C57BL/6 mice receiving either a single injection (acute) or repeated escalating-doses for 14 days (chronic) of cocaine. Acute cocaine resulted in opposing VTA-region-specific changes in TH-containing dopaminergic dendrites. TH-labeled dendrites within the PB VTA showed increased cytoplasmic GluR1 immunogold particle density consistent with decreased AMPA receptor-mediated glutamatergic transmission. Conversely, TH-labeled dendrites within the PN VTA showed greater surface expression of GluR1 with increases in both synaptic and plasmalemmal GluR1 immunogold density after a single injection of cocaine. These changes diminished in both VTA subregions after chronic cocaine administration. In contrast, non-TH-containing (presumably GABAergic) dendrites showed VTA-region-specific changes only after repeated cocaine administration such that synaptic GluR1 decreased in the PB, but increased in the PN VTA. Taken together, these findings provide ultrastructural evidence suggesting that chronic cocaine not only reverses the respective depression and facilitation of mesocortical (PB) and mesolimbic (PN) dopaminergic neurons elicited by acute cocaine, but also differentially affects synaptic availability of these receptors in non-dopaminergic neurons of each region. These adaptations may contribute to increased cocaine seeking/relapse and decreased reward that is reported with chronic cocaine use. PMID:20553819

  2. Acute pancreatitis: clinical vs. CT findings

    SciTech Connect

    Hill, M.C.; Barkin, J.; Isikoff, M.B.; Silver stein, W.; Kalser, M.

    1982-08-01

    In a prospective study of 91 patients with acute pancreatitis, computed tomographic (CT) findings were correlated with the clinical type of acute pancreatitis. In acute edematous pancreatitis (63 patients; 16 with repeat CT), CT was normal (28%) or showed inflammation limited to the pancreas (61%). Phlegmonous changes were present in 11%, including one patient with focal pancreatic hemorrhage, indicating that clinically unsuspected hemorrhagic pancreatitis can occur. In acute necrotizing (hemorrhagic, suppurative) pancreatitis (nine patients; eight with repeat CT), no patient had a normal CT scan and 89% had phlegmonous changes. One patient had hemorrhagic pancreatitis and three had abscesses. In acute exacerbation of chronic pancreatitis (10 patients; three with repeat CT), there were pancreatic calcifications (70%), a focal mass (40%), and pancreatic ductal dilation (30%). On follow-up CT, the findings of acute pancreatitis did not always disappear with resolution of the clinical symptons. This was especialy true of phlegmonous pancreatitis, where the CT findings could persist for months.

  3. Solid-pseudopapillary neoplasm (SPN) of the pancreas: case series and literature review on an enigmatic entity.

    PubMed

    Vassos, Nikolaos; Agaimy, Abbas; Klein, Peter; Hohenberger, Werner; Croner, Roland S

    2013-01-01

    Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare tumor which typically affects young women without significant clinical symptoms. SPN usually shows an indolent behavior and only rare cases recur and/or metastasize after complete resection. We report our experience with four cases of SPN of the pancreas. All four patients were female with an age range of 15-42 years (mean age: 24.5 years). Two patients presented with abdominal pain, one with abdominal mass and one with acute abdominal signs following blunt trauma. Tumor's size ranged from 1 to 16 cm (mean size: 5.5 cm). Two tumors were diagnosed preoperatively through percutaneous core needle biopsy and two underwent surgery without preoperative diagnosis because of high suspicion of SPN based on clinical and radiological findings. By immunohistochemistry, all cases stained strongly for vimentin, progesterone-receptor and beta-catenin (nuclear) and variably with pankeratin and neuroendocrine markers. The proliferation index (Ki-67) was <2% in all cases. After a median follow-up of 40 months (range: 24-57 months), all patients were alive with no evidence of recurrence or metastatic disease. In conclusion, SPN of the pancreas should be considered in the differential diagnosis of any solid and partly cystic pancreatic or upper abdominal mass, particularly in young females. SPN possesses a low malignant potential and complete surgical resection with clear margins is the treatment of choice. Following R0 resection, SPN has an excellent prognosis. PMID:23696922

  4. Elastography for the pancreas: Current status and future perspective

    PubMed Central

    Kawada, Natsuko; Tanaka, Sachiko

    2016-01-01

    Elastography for the pancreas can be performed by either ultrasound or endoscopic ultrasound (EUS). There are two types of pancreatic elastographies based on different principles, which are strain elastography and shear wave elastography. The stiffness of tissue is estimated by measuring the grade of strain generated by external pressure in the former, whereas it is estimated by measuring propagation speed of shear wave, the transverse wave, generated by acoustic radiation impulse (ARFI) in the latter. Strain elastography is difficult to perform when the probe, the pancreas and the aorta are not located in line. Accordingly, a fine elastogram can be easily obtained in the pancreatic body but not in the pancreatic head and tail. In contrast, shear wave elastography can be easily performed in the entire pancreas because ARFI can be emitted to wherever desired. However, shear wave elastography cannot be performed by EUS to date. Recently, clinical guidelines for elastography specialized in the pancreas were published from Japanese Society of Medical Ultrasonics. The guidelines show us technical knacks of performing elastography for the pancreas. PMID:27076756

  5. Pancreatic GIST with pancreas divisum: A new entity

    PubMed Central

    Soufi, Mehdi; Bouziane, Mohammed; Massrouri, Rahal; Chad, Bouziane

    2012-01-01

    INTRODUCTION Gastrointestinal stromal tumours (GISTs) are uncommon intra-abdominal tumours. These tumours tend to arise with a higher frequency in the stomach and the small bowel. In fewer than 5% of cases, they originate primarily from extra-gastrointestinal tumours (EGISTs). Gastrointestinal stromal tumour of the pancreas is very rare. Only few cases have been published. We report the first case of stromal tumour of the pancreas with concomitant pancreas divisum. PRESENTATION OF CASE A 39-year-old male who presented with constipation and abdominal pain. A computerized tomography demonstrated a 9 cm pancreatic mass, without liver lesions. A Whipple procedure with segmental colectomy was performed with success. After 24 months follow up, the patient is doing well and disease-free. DISCUSSION Mesenchymal tumours of the pancreas are extremely rare, accounting for less than 1% of all pancreatic tumours. The endoscopic ultrasound is helpful for diagnosis. Surgical resection with negative pathologic margins remains the treatment of choice. CONCLUSION in our knowledge, this is the first case of pancreatic GIST with pancreas divisum. Although pancreatic GISTs are uncommon tumours, they must be considered in the differential diagnosis of solid pancreatic lesions. Even though the tumour can be evaluated as high risk, treatment must be aggressive in order to improve survival rate. PMID:23123418

  6. Ectopic Pancreas Imitating Gastrointestinal Stromal Tumor (GIST) In The Stomach.

    PubMed

    Zińczuk, Justyna; Bandurski, Roman; Pryczynicz, Anna; Konarzewska-Duchnowska, Emilia; Kemona, Andrzej; Kędra, Bogusław

    2015-05-01

    Ectopic pancreas is a rare congenital disorder defined as pancreatic tissue lacking vascular or anatomic communication with the normal body of the pancreas. Most cases of ectopic pancreas are asymptomatic, but it may become clinically evident depending on the size, location and the pathological changes similar to those observed in case of the normal pancreas. It is often an incidental finding and can be located at different sites in the gastrointestinal tract. The most common locations are: the stomach, duodenum or the proximal part of small intestine. The risk of malignancy, bleeding and occlusion are the most serious complications. Despite the development in diagnostics, it still remains a challenge for the clinician to differentiate it from neoplasm. In this report, we described a case of 28-years old woman who presented recurrent epigastric pain. The upper gastrointestinal endoscopy revealed gastrointestinal stromal tumor on the border of the body and antrum of the back wall of great curvature of the stomach. The histopathological examination after surgery showed heterotopic pancreatic tissue. Ectopic pancreas should be considered in the differential diagnosis of gastric mass lesions. PMID:26172167

  7. Mouse model of human RPE65 P25L hypomorph resembles wild type under normal light rearing but is fully resistant to acute light damage.

    PubMed

    Li, Yan; Yu, Shirley; Duncan, Todd; Li, Yichao; Liu, Pinghu; Gene, Erelda; Cortes-Pena, Yoel; Qian, Haohua; Dong, Lijin; Redmond, T Michael

    2015-08-01

    Human RPE65 mutations cause a spectrum of blinding retinal dystrophies from severe early-onset disease to milder manifestations. The RPE65 P25L missense mutation, though having <10% of wild-type (WT) activity, causes relatively mild retinal degeneration. To better understand these mild forms of RPE65-related retinal degeneration, and their effect on cone photoreceptor survival, we generated an Rpe65/P25L knock-in (KI/KI) mouse model. We found that, when subject to the low-light regime (∼100 lux) of regular mouse housing, homozygous Rpe65/P25L KI/KI mice are morphologically and functionally very similar to WT siblings. While mutant protein expression is decreased by over 80%, KI/KI mice retinae retain comparable 11-cis-retinal levels with WT. Consistently, the scotopic and photopic electroretinographic (ERG) responses to single-flash stimuli also show no difference between KI/KI and WT mice. However, the recovery of a-wave response following moderate visual pigment bleach is delayed in KI/KI mice. Importantly, KI/KI mice show significantly increased resistance to high-intensity (20 000 lux for 30 min) light-induced retinal damage (LIRD) as compared with WT, indicating impaired rhodopsin regeneration in KI/KI. Taken together, the Rpe65/P25L mutant produces sufficient chromophore under normal conditions to keep opsins replete and thus manifests a minimal phenotype. Only when exposed to intensive light is this hypomorphic mutation manifested physiologically, as its reduced expression and catalytic activity protects against the successive cycles of opsin regeneration underlying LIRD. These data also help define minimal requirements of chromophore for photoreceptor survival in vivo and may be useful in assessing a beneficial therapeutic dose for RPE65 gene therapy in humans. PMID:25972377

  8. Neuroprotective and Antiapoptotic Activity of Lineage-Negative Bone Marrow Cells after Intravitreal Injection in a Mouse Model of Acute Retinal Injury

    PubMed Central

    Machalińska, Anna; Pius-Sadowska, Ewa; Kawa, Miłosz P.; Paczkowska, Edyta; Rudnicki, Michał; Lejkowska, Renata; Baumert, Bartłomiej; Wiszniewska, Barbara; Machaliński, Bogusław

    2015-01-01

    We investigated effects of bone marrow-derived, lineage-negative cell (Lin−BMC) transplantation in acute retinal injury. Lin−BMCs were intravitreally injected into murine eyes at 24 h after NaIO3-induced injury. Morphology, function, and expression of apoptosis-related genes, including brain-derived neurotrophic factor (BDNF) and its receptor, were assessed in retinas at 7 days, 28 days, and 3 months after transplantation. Moreover, global gene expression at day 7 was analyzed by RNA arrays. We observed that Lin−BMCs integrated into outer retinal layers improving morphological retinal structure and induced molecular changes such as downregulation of proapoptotic caspase-3 gene, a decrease in BAX/BCL-2 gene ratio, and significant elevation of BDNF expression. Furthermore, transplanted Lin−BMCs differentiated locally into cells with a macrophage-like phenotype. Finally, Lin−BMCs treatment was associated with generation of two distinct transcriptomic patterns. The first relates to downregulated genes associated with regulation of neuron cell death and apoptosis, response to oxidative stress/hypoxia and external stimuli, and negative regulation of cell proliferation. The second relates to upregulated genes associated with neurological system processes and sensory perception. Collectively, our data demonstrate that transplanted Lin−BMCs exert neuroprotective function against acute retinal injury and this effect may be associated with their antiapoptotic properties and ability to express neurotrophic factors. PMID:25810725

  9. Knock-in of a FLT3/ITD mutation cooperates with a NUP98-HOXD13 fusion to generate acute myeloid leukemia in a mouse model

    PubMed Central

    Greenblatt, Sarah; Li, Li; Slape, Christopher; Nguyen, Bao; Novak, Rachel; Duffield, Amy; Huso, David; Desiderio, Stephen; Borowitz, Michael J.; Aplan, Peter

    2012-01-01

    Constitutive activation of FLT3 by internal tandem duplication (ITD) is one of the most common molecular alterations in acute myeloid leukemia (AML). FLT3/ITD mutations have also been observed in myelodysplastic syndrome patients both before and during progression to AML. Previous work has shown that insertion of an FLT3/ITD mutation into the murine Flt3 gene induces a myeloproliferative neoplasm, but not progression to acute leukemia, suggesting that additional cooperating events are required. We therefore combined the FLT3/ITD mutation with a model of myelodysplastic syndrome involving transgenic expression of the Nup98-HoxD13 (NHD13) fusion gene. Mice expressing both the FLT3/ITD and NHD13 transgene developed AML with 100% penetrance and short latency. These leukemias were driven by mutant FLT3 expression and were susceptible to treatment with FLT3 tyrosine kinase inhibitors. We also observed a spontaneous loss of the wild-type Flt3 allele in these AMLs, further modeling the loss of the heterozygosity phenomenon that is seen in human AML with FLT3-activating mutations. Because resistance to FLT3 inhibitors remains an important clinical issue, this model may help identify new molecular targets in collaborative signaling pathways. PMID:22323452

  10. Neuroprotective and antiapoptotic activity of lineage-negative bone marrow cells after intravitreal injection in a mouse model of acute retinal injury.

    PubMed

    Machalińska, Anna; Rogińska, Dorota; Pius-Sadowska, Ewa; Kawa, Miłosz P; Paczkowska, Edyta; Rudnicki, Michał; Lejkowska, Renata; Baumert, Bartłomiej; Wiszniewska, Barbara; Machaliński, Bogusław

    2015-01-01

    We investigated effects of bone marrow-derived, lineage-negative cell (Lin(-)BMC) transplantation in acute retinal injury. Lin(-)BMCs were intravitreally injected into murine eyes at 24 h after NaIO3-induced injury. Morphology, function, and expression of apoptosis-related genes, including brain-derived neurotrophic factor (BDNF) and its receptor, were assessed in retinas at 7 days, 28 days, and 3 months after transplantation. Moreover, global gene expression at day 7 was analyzed by RNA arrays. We observed that Lin(-)BMCs integrated into outer retinal layers improving morphological retinal structure and induced molecular changes such as downregulation of proapoptotic caspase-3 gene, a decrease in BAX/BCL-2 gene ratio, and significant elevation of BDNF expression. Furthermore, transplanted Lin(-)BMCs differentiated locally into cells with a macrophage-like phenotype. Finally, Lin(-)BMCs treatment was associated with generation of two distinct transcriptomic patterns. The first relates to downregulated genes associated with regulation of neuron cell death and apoptosis, response to oxidative stress/hypoxia and external stimuli, and negative regulation of cell proliferation. The second relates to upregulated genes associated with neurological system processes and sensory perception. Collectively, our data demonstrate that transplanted Lin(-)BMCs exert neuroprotective function against acute retinal injury and this effect may be associated with their antiapoptotic properties and ability to express neurotrophic factors. PMID:25810725

  11. Reversible immortalization of Nestin-positive precursor cells from pancreas and differentiation into insulin-secreting cells

    SciTech Connect

    Wei, Pei; Li, Li; Qi, Hui; Zhou, Han-xin; Deng, Chun-yan; Li, Fu-rong

    2012-02-10

    Highlights: Black-Right-Pointing-Pointer The NPPCs from mouse pancreas were isolated. Black-Right-Pointing-Pointer Tet-on system for SV40 large in NPPCs was used to get RINPPCs. Black-Right-Pointing-Pointer The RINPPCs can undergo at least 80 population doublings without senescence. Black-Right-Pointing-Pointer The RINPPCs can be induced to differentiate into insulin-producing cells. Black-Right-Pointing-Pointer The combination of GLP-1 and sodium butyrate promoted the differentiation process. -- Abstract: Pancreatic stem cells or progenitor cells posses the ability of directed differentiation into pancreatic {beta} cells. However, these cells usually have limited proliferative capacity and finite lifespan in vitro. In the present study, Nestin-positive progenitor cells (NPPCs) from mouse pancreas that expressed the pancreatic stem cells or progenitor cell marker Nestin were isolated to obtain a sufficient number of differentiated pancreatic {beta} cells. Tet-on system for SV40 large T-antigen expression in NPPCs was used to achieve reversible immortalization. The reversible immortal Nestin-positive progenitor cells (RINPPCs) can undergo at least 80 population doublings without senescence in vitro while maintaining their biological and genetic characteristics. RINPPCs can be efficiently induced to differentiate into insulin-producing cells that contain a combination of glucagon-like peptide-1 (GLP-1) and sodium butyrate. The results of the present study can be used to explore transplantation therapy of type I diabetes mellitus.

  12. Oral or parenteral administration of curcumin does not prevent the growth of high-risk t(4;11) acute lymphoblastic leukemia cells engrafted into a NOD/SCID mouse model

    PubMed Central

    ZUNINO, SUSAN J.; STORMS, DAVID H.; NEWMAN, JOHN W.; PEDERSEN, THERESA L.; KEEN, CARL L.; DUCORE, JONATHAN M.

    2013-01-01

    In this study, the efficacy of orally and parenter-ally administered curcumin was evaluated in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice (NOD.CB17-Prkdcscid/J mice) engrafted with the human t(4;11) acute lymphoblastic leukemia line, SEM. SEM cells were injected into the tail vein and engraftment was monitored by flow cytometry. Once engraftment was observed, the chemotherapeutic potential was examined by injecting mice intraperitoneally with curcumin (5 mg/kg body weight) dissolved in dimethylsulfoxide (DMSO) or DMSO alone (control) every other day, or vincristine (0.5 mg/kg body weight) 3 times per week for 4 weeks (n=16 per group). The intraperitoneal administration of curcumin did not inhibit the growth of the leukemia cells. To determine the efficacy of oral curcumin, mice were fed a control diet or a diet containing 0.5% w/w curcumin 3 weeks prior to the injection of the leukemia cells and throughout the experimental period (n=16 per group). To determine whether dietary curcumin can enhance the efficacy of a conventional chemotherapeutic agent, vincristine was injected intraperitoneally into leukemic mice fed the different diets. Dietary curcumin did not delay the engraftment or growth of leukemia cells, or sensitize the cells to vincristine. Liquid chromatography-tandem mass spectrometry analyses of mouse sera showed that curcumin rapidly metabolized to glucuronidated and sulfated forms within 1 h post-injection and these were the major curcumin metabolites found in the sera of the mice fed the curcumin diet. In contrast to the findings in previous in vitro models, the current data indicate that orally or parenterally administered curcumin is not a potent preventive agent against high-risk t(4;11) acute lymphoblastic leukemia. PMID:23232667

  13. Tissue-specific deletion of c-Jun in the pancreas has limited effects on pancreas formation

    SciTech Connect

    Yamamoto, Kaoru; Miyatsuka, Takeshi; Tanaka, Ayako; Toyoda, Shuichi; Kato, Ken; Shiraiwa, Toshihiko; Fujitani, Yoshio; Yamasaki, Yoshimitsu; Hori, Masatsugu; Matsuhisa, Munehide; Matsuoka, Taka-aki; Kaneto, Hideaki

    2007-11-30

    It is well known that activating protein-1 (AP-1) is involved in a variety of cellular functions such as proliferation, differentiation, apoptosis, and oncogenesis. AP-1 is a dimer complex consisting of different subunits, and c-Jun is known to be one of its major components. In addition, it has been shown that mice lacking c-Jun are embryonic lethal and that c-Jun is essential for liver and heart development. However, the role of c-Jun in the pancreas is not well known. The aim of this study was to examine the possible role of c-Jun in the pancreas. First, c-Jun was strongly expressed in pancreatic duct-like structures at an embryonic stage, while a lower level of expression was observed in some part of the adult pancreas, implying that c-Jun might play a role during pancreas development. Second, to address this point, we generated pancreas-specific c-Jun knock-out mice (Ptf1a-Cre; c-Jun{sup flox/flox} mice) by crossing Ptf1a-Cre knock-in mice with c-Jun floxed mice. Ptf1a is a pancreatic transcription factor and its expression is confined to pancreatic stem/progenitor cells, which give rise to all three types of pancreatic tissue: endocrine, exocrine, and duct. Contrary to our expectation, however, there was no morphological difference in the pancreas between Ptf1a-Cre; c-Jun{sup flox/flox} and control mice. In addition, there was no difference in body weight, pancreas weight, and the expression of various pancreas-related factors (insulin, glucagon, cytokeratin, and amylase) between the two groups. Furthermore, there was no difference in glucose tolerance between Ptf1a-Cre; c-Jun{sup flox/flox} and control mice. Taken together, although we cannot exclude the possibility that c-Jun ablation is compensated by some unknown factors, c-Jun appears to be dispensable for pancreas development at least after ptf1a gene promoter is activated.

  14. Solid pseudopapillary tumor of the pancreas: emphasis on differential diagnosis from aggressive tumors of the pancreas.

    PubMed

    Aydiner, Fatma; Erinanç, Hilal; Savaş, Berna; Erden, Esra; Karayalçin, Kaan

    2006-09-01

    Solid pseudopapillary tumor is an unusual primary tumor of the pancreas with a low potential for malignancy and unknown cell origin, seen mostly in young women. Although it is discussed among pancreatic epithelial tumors, many cases do not express cytokeratin but show neuroendocrine differentiation. Three cases (2 female, 1 male, aged 24, 45 and 50 years, respectively) of solid pseudopapillary tumor localized in the pancreas are presented. All cases displayed a well-circumscribed tumor, with an average diameter of 6 cm and a red-brown colored, hemorrhagic, cystic cut surface. Microscopically they were encapsulated with large areas composed of thin papillary formations and solid areas focally. Tumor cells were dyscohesive with small, round- to-oval, central nuclei, and vacuolated, clear or eosinophilic cytoplasm without mitotic activity. NSE, vimentin, synaptophysin, ER, PR, Ki-67, S-100, Pan CK, a1-antitrypsin, a2-antichymotrypsin, and antibodies were used in the immunohistochemical study. Vimentin, synaptophysin, NSE, PR, and a1-antitrypsin showed expression in all cases, while Pan-CK was expressed in two cases. Ki-67 expression was below 1% in all cases. Morphologic features of solid pseudopapillary tumor may be confused with pancreatic endocrine neoplasm and ductal adenocarcinoma. All cases showed features of histiocytic and neuroendocrine differentiation. Epithelial differentiation was identified in two cases. We conclude that immunohistochemistry is incapable of giving additional information for the diagnosis of solid pseudopapillary tumor due to different lines of differentiation of tumor cells. We believe that macroscopic and microscopic features (using hematoxylin and eosin stain) are more important for the diagnosis and differential diagnosis of this tumor. PMID:16941259

  15. Intraductal Papillary Mucinous Neoplasm of Pancreas

    PubMed Central

    Machado, Norman Oneil; al Qadhi, Hani; al Wahibi, Khalifa

    2015-01-01

    Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are neoplasms that are characterized by ductal dilation, intraductal papillary growth, and thick mucus secretion. This relatively recently defined pathology is evolving in terms of its etiopathogenesis, clinical features, diagnosis, management, and treatment guidelines. A PubMed database search was performed. All the relevant abstracts in English language were reviewed and the articles in which cases of IPMN could be identified were further scrutinized. Information of IPMN was derived, and duplication of information in several articles and those with areas of persisting uncertainties were excluded. The recent consensus guidelines were examined. The reported incidence of malignancy varies from 57% to 92% in the main duct-IPMN (MD-IPMN) and from 6% to 46% in the branch duct-IPMN (BD-IPMN). The features of high-risk malignant lesions that raise concern include obstructive jaundice in a patient with a cystic lesion in the pancreatic head, the findings on radiological imaging of a mass lesion of >30 mm, enhanced solid component, and the main pancreatic duct (MPD) of size ≥10 mm; while duct size 5-9 mm and cyst size <3 mm are considered as “worrisome features.” Magnetic resonance imaging (MRI) and endoscopic ultrasound (EUS) are primary investigations in diagnosing and following up on these patients. The role of pancreatoscopy and the analysis of aspirated cystic fluid for cytology and DNA analysis is still to be established. In general, resection is recommended for most MD-IPMN, mixed variant, and symptomatic BD-IPMN. The 5-year survival of patients after surgical resection for noninvasive IPMN is reported to be at 77-100%, while for those with invasive carcinoma, it is significantly lower at 27-60%. The follow-up of these patients could vary from 6 months to 1 year and would depend on the risk stratification for invasive malignancy and the pathology of the resected specimen. The understanding of

  16. Pancreas procurement from multiorgan donors for islet trasplantation

    PubMed Central

    Ricordi, C.; Mazzeferro, V.; Casavilla, A.; Scotti, C.; Pinna, A.; Tzakis, A.; Starzl, T.E.

    2010-01-01

    The outcome of human islet isolation procedures can be significantly effected by the technique used for pancreas procurement. In fact, the final step of islet purification using discontinuous density gradients requires a significant difference between the density of the islets and the density of the non-endocrine component of the gland. Therefore, any procedure during multi-organ procurement that will result in edema or degranulation of the acinar tissue will result in failure of the islet purification step. In this report a technique for combined harvesting of liver and pancreas is presented. The use of this procedure can be of assistance to avoid damage to the pancreas that could result in a compromised islet purification for improper handling of the gland even before it arrives to the isolation facility. PMID:21572947

  17. Pancreas procurement from multiorgan donors for islet trasplantation.

    PubMed

    Ricordi, C; Mazzeferro, V; Casavilla, A; Scotti, C; Pinna, A; Tzakis, A; Starzl, T E

    1992-01-01

    The outcome of human islet isolation procedures can be significantly effected by the technique used for pancreas procurement. In fact, the final step of islet purification using discontinuous density gradients requires a significant difference between the density of the islets and the density of the non-endocrine component of the gland. Therefore, any procedure during multi-organ procurement that will result in edema or degranulation of the acinar tissue will result in failure of the islet purification step. In this report a technique for combined harvesting of liver and pancreas is presented. The use of this procedure can be of assistance to avoid damage to the pancreas that could result in a compromised islet purification for improper handling of the gland even before it arrives to the isolation facility. PMID:21572947

  18. The evolution of diabetic chronic complications after pancreas transplantation.

    PubMed

    de Sá, João R; Monteagudo, Patricia T; Rangel, Erika B; Melaragno, Cláudio S; Gonzalez, Adriano M; Linhares, Marcelo M; Salzedas, Alcides; Neves, Maria-Deolinda F; Stela, Camila; Medina-Pestana, José O

    2009-01-01

    Pancreas transplantation is an invasive procedure that can restore and maintain normoglycemic level very successfully and for a prolonged period in DM1 patients. The procedure elevates the morbimortality rates in the first few months following the surgery if compared to kidney transplants with living donors, but it offers a better quality of life to patients.Although controversial, several studies have shown the stabilization or the improvement of some of the chronic complications related to diabetes, as well as the extra number of years of life that patients submitted to a double pancreas-kidney transplantation may gain.Recent studies have demonstrated clashing outcomes regarding isolated pancreas transplantations, a fact which reinforces the need for a more discerning selection of patients for this procedure. PMID:19825148

  19. En-bloc liver-pancreas transplant in Iran.

    PubMed

    Nikeghbalian, Saman; Mehdi, Seyed Haider; Aliakbarian, Mohsen; Kazemi, Kourosh; Shamsaeefar, Alireza; Bahreini, Amin; Gholami, Siavash; Malekhosseini, Seyed Ali

    2014-09-01

    Liver transplant can be challenging in cirrhotic patients with diabetes mellitus. In chronic liver disease, the glucose metabolism is altered; uncontrolled diabetes negatively influences the outcome of liver transplantation and poses difficulty in the management of immediate post transplantation period. Simultaneous liver-pancreas transplantation is an option to prevent early complications due to diabetes and also to improve the quality of life after transplantation in patients with Insulin-Dependent Diabetes Mellitus (IDDM) and chronic liver disease. We report the first en-bloc liver-pancreas transplant done in the transplant history of Iran. We describe the technical details of the procedure as well as the short term outcome after transplantation. In this case report, we also discuss in some details, the surgical, medical and immunological advantages of combined liver-pancreas transplantation as opposed to separate implantation of both organs. PMID:25204483

  20. Turnover of pancreas phospholipids in rats fed inadequate dietary protein.

    PubMed

    Bhutani, V; Kumar, V; Misra, U K

    1986-01-01

    Effect of feeding rice diets with and without lysine and threonine supplementation has been studied on phospholipid turnover of rat pancreas and compared to rats fed casein diet at 20% protein level. Rice diet without amino acid supplementation significantly reduced the levels of pancreas PC, PE, PI, PS and Sph and increased that of total cholesterol and TG. Incorporation of palmitate-1-14C, labelled choline, labelled methionine and NaH2(32)PO4 into PC and of palmitate-1-14C into TG was significantly reduced in rats fed unsupplemented rice diet. Incorporation of NaH2(32)PO4 into pancreas PI, DPI, TPI, PA, LPA and into IP, IP2', IP3 and GPI was significantly reduced in rats fed unsupplemented rice diet. PMID:3781752

  1. Acute cholecystitis

    MedlinePlus

    ... that forms in the wall of the gallbladder) Pancreatitis (inflamed pancreas) Persistent bile duct blockage Inflammation of ... draining the liver (may occur after gallbladder surgery) Pancreatitis Perforation Peritonitis (inflammation of the lining of the ...

  2. Kynurenine–3–monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis

    PubMed Central

    Mole, Damian J; Webster, Scott P; Uings, Iain; Zheng, Xiaozhong; Binnie, Margaret; Wilson, Kris; Hutchinson, Jonathan P; Mirguet, Olivier; Walker, Ann; Beaufils, Benjamin; Ancellin, Nicolas; Trottet, Lionel; Bénéton, Véronique; Mowat, Christopher G; Wilkinson, Martin; Rowland, Paul; Haslam, Carl; McBride, Andrew; Homer, Natalie ZM; Baily, James E; Sharp, Matthew GF; Garden, O James; Hughes, Jeremy; Howie, Sarah EM; Holmes, Duncan S; Liddle, John; Iredale, John P

    2015-01-01

    Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death1,2 Acute mortality from AP-MODS exceeds 20%3 and for those who survive the initial episode, their lifespan is typically shorter than the general population4. There are no specific therapies available that protect individuals against AP-MODS. Here, we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism5, is central to the pathogenesis of AP-MODS. We created a mouse strain deficient for Kmo with a robust biochemical phenotype that protected against extrapancreatic tissue injury to lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 Å resolution. Treatment with GSK180 resulted in rapid changes in levels of kynurenine pathway metabolites in vivo and afforded therapeutic protection against AP-MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS and open up a new area for drug discovery in critical illness. PMID:26752518

  3. Kynurenine-3-monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis.

    PubMed

    Mole, Damian J; Webster, Scott P; Uings, Iain; Zheng, Xiaozhong; Binnie, Margaret; Wilson, Kris; Hutchinson, Jonathan P; Mirguet, Olivier; Walker, Ann; Beaufils, Benjamin; Ancellin, Nicolas; Trottet, Lionel; Bénéton, Véronique; Mowat, Christopher G; Wilkinson, Martin; Rowland, Paul; Haslam, Carl; McBride, Andrew; Homer, Natalie Z M; Baily, James E; Sharp, Matthew G F; Garden, O James; Hughes, Jeremy; Howie, Sarah E M; Holmes, Duncan S; Liddle, John; Iredale, John P

    2016-02-01

    Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death. Acute mortality from AP-MODS exceeds 20% (ref. 3), and the lifespans of those who survive the initial episode are typically shorter than those of the general population. There are no specific therapies available to protect individuals from AP-MODS. Here we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism, is central to the pathogenesis of AP-MODS. We created a mouse strain that is deficient for Kmo (encoding KMO) and that has a robust biochemical phenotype that protects against extrapancreatic tissue injury to the lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of the oxazolidinone GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 Å resolution. Treatment with GSK180 resulted in rapid changes in the levels of kynurenine pathway metabolites in vivo, and it afforded therapeutic protection against MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS, and they open up a new area for drug discovery in critical illness. PMID:26752518

  4. Proteomic profiling of a mouse model of acute intestinal Apc deletion leads to identification of potential novel biomarkers of human colorectal cancer (CRC).

    PubMed

    Hammoudi, Abeer; Song, Fei; Reed, Karen R; Jenkins, Rosalind E; Meniel, Valerie S; Watson, Alastair J M; Pritchard, D Mark; Clarke, Alan R; Jenkins, John R

    2013-10-25

    Colorectal cancer (CRC) is the fourth most common cause of cancer-related death worldwide. Accurate non-invasive screening for CRC would greatly enhance a population's health. Adenomatous polyposis coli (Apc) gene mutations commonly occur in human colorectal adenomas and carcinomas, leading to Wnt signalling pathway activation. Acute conditional transgenic deletion of Apc in murine intestinal epithelium (AhCre(+)Apc(fl)(/)(fl)) causes phenotypic changes similar to those found during colorectal tumourigenesis. This study comprised a proteomic analysis of murine small intestinal epithelial cells following acute Apc deletion to identify proteins that show altered expression during human colorectal carcinogenesis, thus identifying proteins that may prove clinically useful as blood/serum biomarkers of colorectal neoplasia. Eighty-one proteins showed significantly increased expression following iTRAQ analysis, and validation of nine of these by Ingenuity Pathaway Analysis showed they could be detected in blood or serum. Expression was assessed in AhCre(+)Apc(fl)(/)(fl) small intestinal epithelium by immunohistochemistry, western blot and quantitative real-time PCR; increased nucelolin concentrations were also detected in the serum of AhCre(+)Apc(fl)(/)(fl) and Apc(Min)(/)(+) mice by ELISA. Six proteins; heat shock 60kDa protein 1, Nucleolin, Prohibitin, Cytokeratin 18, Ribosomal protein L6 and DEAD (Asp-Glu-Ala-Asp) box polypeptide 5,were selected for further investigation. Increased expression of 4 of these was confirmed in human CRC by qPCR. In conclusion, several novel candidate biomarkers have been identified from analysis of transgenic mice in which the Apc gene was deleted in the intestinal epithelium that also showed increased expression in human CRC. Some of these warrant further investigation as potential serum-based biomarkers of human CRC. PMID:23998936

  5. An in vitro iron superoxide dismutase inhibitor decreases the parasitemia levels of Trypanosoma cruzi in BALB/c mouse model during acute phase

    PubMed Central

    Olmo, Francisco; Urbanová, Kristína; Rosales, Maria Jose; Martín-Escolano, Ruben; Sánchez-Moreno, Manuel; Marín, Clotilde

    2015-01-01

    In order to identify new compounds to treat Chagas disease during the acute phase with higher activity and lower toxicity than the reference drug benznidazole (Bz), two hydroxyphthalazine derivative compounds were prepared and their trypanocidal effects against Trypanosoma cruzi were evaluated by light microscopy through the determination of IC50 values. Cytotoxicity was determined by flow cytometry assays against Vero cells. In vivo assays were performed in BALB/c mice, in which the parasitemia levels were quantified by fresh blood examination; the assignment of a cure was determined by reactivation of blood parasitemia levels after immunosuppression. The mechanism of action was elucidated at metabolic and ultra-structural levels, by 1H NMR and TEM studies. Finally, as these compounds are potentially capable of causing oxidative damage in the parasites, the study was completed, by assessing their activity as potential iron superoxide dismutase (Fe-SOD) inhibitors. High-selectivity indices observed in vitro were the basis of promoting one of the tested compounds to in vivo assays. The tests on the murine model for the acute phase of Chagas disease showed better parasitemia inhibition values than those found for Bz. Compound 2 induced a remarkable decrease in the reactivation of parasitemia after immunosuppression. Compound 2 turned out to be a great inhibitor of Fe-SOD. The high antiparasitic activity and low toxicity together with the modest costs for the starting materials render this compound an appropriate molecule for the development of an affordable anti-Chagas agent. PMID:26236582

  6. Effects of particle size and coating on toxicologic parameters, fecal elimination kinetics and tissue distribution of acutely ingested silver nanoparticles in a mouse model.

    PubMed

    Bergin, Ingrid L; Wilding, Laura A; Morishita, Masako; Walacavage, Kim; Ault, Andrew P; Axson, Jessica L; Stark, Diana I; Hashway, Sara A; Capracotta, Sonja S; Leroueil, Pascale R; Maynard, Andrew D; Philbert, Martin A

    2016-01-01

    Consumer exposure to silver nanoparticles (AgNP) via ingestion can occur due to incorporation of AgNP into products such as food containers and dietary supplements. AgNP variations in size and coating may affect toxicity, elimination kinetics or tissue distribution. Here, we directly compared acute administration of AgNP of two differing coatings and sizes to mice, using doses of 0.1, 1 and 10 mg/kg body weight/day administered by oral gavage for 3 days. The maximal dose is equivalent to 2000× the EPA oral reference dose. Silver acetate at the same doses was used as ionic silver control. We found no toxicity and no significant tissue accumulation. Additionally, no toxicity was seen when AgNP were dosed concurrently with a broad-spectrum antibiotic. Between 70.5% and 98.6% of the administered silver dose was recovered in feces and particle size and coating differences did not significantly influence fecal silver. Peak fecal silver was detected between 6- and 9-h post-administration and <0.5% of the administered dose was cumulatively detected in liver, spleen, intestines or urine at 48 h. Although particle size and coating did not affect tissue accumulation, silver was detected in liver, spleen and kidney of mice administered ionic silver at marginally higher levels than those administered AgNP, suggesting that silver ion may be more bioavailable. Our results suggest that, irrespective of particle size and coating, acute oral exposure to AgNP at doses relevant to potential human exposure is associated with predominantly fecal elimination and is not associated with accumulation in tissue or toxicity. PMID:26305411

  7. Pancreas tumor model in rabbit imaged by perfusion CT scans

    NASA Astrophysics Data System (ADS)

    Gunn, Jason; Tichauer, Kenneth; Moodie, Karen; Kane, Susan; Hoopes, Jack; Stewart, Errol E.; Hadway, Jennifer; Lee, Ting-Yim; Pereira, Stephen P.; Pogue, Brian W.

    2013-03-01

    The goal of this work was to develop and validate a pancreas tumor animal model to investigate the relationship between photodynamic therapy (PDT) effectiveness and photosensitizer drug delivery. More specifically, this work lays the foundation for investigating the utility of dynamic contrast enhanced blood perfusion imaging to be used to inform subsequent PDT. A VX2 carcinoma rabbit cell line was grown in the tail of the pancreas of three New Zealand White rabbits and approximately 3-4 weeks after implantation the rabbits were imaged on a CT scanner using a contrast enhanced perfusion protocol, providing parametric maps of blood flow, blood volume, mean transit time, and vascular permeability surface area product.

  8. Multidisciplinary approach to tumors of the pancreas and biliary tree.

    PubMed

    Brown, Kimberly M

    2009-02-01

    Tumors of the pancreas and biliary tree remain formidable challenges to patients and clinicians. These tumors elude early detection, rapidly spread locally and systemically, and frequently recur despite apparently complete resection. Cystic tumors of the pancreas, however, may represent a subset of patients who do not uniformly require aggressive resection, and a thoughtful, evidence-based approach to work-up allows for the rational application of surgical therapy. Increasing evidence supports treating patients who have pancreaticobiliary disease in a multidisciplinary setting. PMID:19186234

  9. Attempted suicide by insulin injection treated with artificial pancreas.

    PubMed Central

    Gin, H; Larnaudie, B; Aubertin, J

    1983-01-01

    An elderly woman with longstanding insulin dependent diabetes tried to commit suicide by injecting 400 units of insulin subcutaneously (usual total daily dose 56 units). She was admitted to hospital within the hour and treated with the aid of an artificial pancreas. This avoided the usual difficulty of the physician having to cope with rapid and substantial fluctuations in blood glucose concentrations and 67 hours after the overdose insulin was reinstituted. Using an artificial pancreas in insulin overdose is an important advance in management and may avoid the need for surgical intervention such as excising the site of injection. Images p250-a PMID:6409269

  10. Aging and sleep deprivation induce the unfolded protein response in the pancreas: implications for metabolism

    PubMed Central

    Naidoo, Nirinjini; Davis, James G; Zhu, Jingxu; Yabumoto, Maya; Singletary, Kristan; Brown, Marishka; Galante, Raymond; Agarwal, Beamon; Baur, Joseph A

    2014-01-01

    Sleep disruption has detrimental effects on glucose metabolism through pathways that remain poorly defined. Although numerous studies have examined the consequences of sleep deprivation (SD) in the brain, few have directly tested its effects on peripheral organs. We examined several tissues in mice for induction of the unfolded protein response (UPR) following acute SD. In young animals, we found a robust induction of BiP in the pancreas, indicating an active UPR. At baseline, pancreata from aged animals exhibited a marked increase in a pro-apoptotic transcription factor, CHOP, that was amplified by SD, whereas BiP induction was not observed, suggesting a maladaptive response to cellular stress with age. Acute SD increased plasma glucose levels in both young and old animals. However, this change was not overtly related to stress in the pancreatic beta cells, as plasma insulin levels were not lower following acute SD. Accordingly, animals subjected to acute SD remained tolerant to a glucose challenge. In a chronic SD experiment, young mice were found to be sensitized to insulin and have improved glycemic control, whereas aged animals became hyperglycemic and failed to maintain appropriate plasma insulin concentrations. Our results show that both age and SD cooperate to induce the UPR in pancreatic tissue. While changes in insulin secretion are unlikely to play a major role in the acute effects of SD, CHOP induction in pancreatic tissues suggests that chronic SD may contribute to the loss or dysfunction of endocrine cells and that these effects may be exacerbated by normal aging. PMID:24102714

  11. ULTRASTRUCTURE OF NORMAL AND NEOPLASTIC EXOCRINE PANCREAS IN THE MUMMICHOG, FUNDULUS HETEROLCLITUS

    EPA Science Inventory

    The ultrastructure of normal exocrine pancreas and exocrine pancreatic neoplasms in Fundulus heteroclitus from a creosote-contaminated environment in the Elizabeth River, Virginia, is described. he normal exocrine pancreas in this species was an anastomosing tubular rather than a...

  12. [Change in pancreatic exocrine function in acute appendicitis].

    PubMed

    Ivanov, Iu A

    1979-10-01

    In order to study changes in the functional state of the pancreas 1572 investigations of the blood and urine amylase, atoxylresistant lipase of the blood serum before operation were performed in different postoperative periods in 131 patients with acute appendicitis. The enzyme activity was established to increase, especially in destructive forms of appendicitis and in elderly patients. PMID:505800

  13. MicroRNA-674-5p/5-LO axis involved in autoimmune reaction of Concanavalin A-induced acute mouse liver injury.

    PubMed

    Su, Kunkai; Wang, Qi; Qi, Luoyang; Hua, Dasong; Tao, Jingjing; Mangan, Connor J; Lou, Yijia; Li, Lanjuan

    2016-09-01

    Autoimmune hepatitis is characterized, in part, by the pathways involving cysteinyl-leukotriene metabolites of arachidonic acid, the dynamics of which remain unclear. Here, we explored post-transcriptional regulation in the 5-lipoxygenase (5-LO) pathway of arachidonic acid in a Concanavalin A (Con A) induced mouse model. We found that Con A administration lead to 5-LO overexpression and cysteinyl-leukotriene release in early hepatic injury, which was attenuated by cyclosporin A pretreatment. Subsequent microarray and qRT-PCR analysis further showed that microRNA-674-5p (miR-674-5p) displayed a significant decrease in expression in Con A-damaged liver. Noting that miR-674-5p harbors a potential binding region for 5-LO, we further transfected hepatic cell lines with overexpressing miR-674-5p mimic and discovered a negative regulating effect of miR-674-5p on 5-LO expression in the presence of IL-6 or TNF-α. These findings suggest that miR-674-5p might be a negative regulator in 5-LO mediated autoimmune liver injury, representing a compelling avenue towards future therapeutic interventions. PMID:27313091

  14. p19ARF is a critical mediator of both cellular senescence and an innate immune response associated with MYC inactivation in mouse model of acute leukemia

    PubMed Central

    Yetil, Alper; Anchang, Benedict; Gouw, Arvin M.; Adam, Stacey J.; Zabuawala, Tahera; Parameswaran, Ramya; van Riggelen, Jan; Plevritis, Sylvia; Felsher, Dean W.

    2015-01-01

    MYC-induced T-ALL exhibit oncogene addiction. Addiction to MYC is a consequence of both cell-autonomous mechanisms, such as proliferative arrest, cellular senescence, and apoptosis, as well as non-cell autonomous mechanisms, such as shutdown of angiogenesis, and recruitment of immune effectors. Here, we show, using transgenic mouse models of MYC-induced T-ALL, that the loss of either p19ARF or p53 abrogates the ability of MYC inactivation to induce sustained tumor regression. Loss of p53 or p19ARF, influenced the ability of MYC inactivation to elicit the shutdown of angiogenesis; however the loss of p19ARF, but not p53, impeded cellular senescence, as measured by SA-beta-galactosidase staining, increased expression of p16INK4A, and specific histone modifications. Moreover, comparative gene expression analysis suggested that a multitude of genes involved in the innate immune response were expressed in p19ARF wild-type, but not null, tumors upon MYC inactivation. Indeed, the loss of p19ARF, but not p53, impeded the in situ recruitment of macrophages to the tumor microenvironment. Finally, p19ARF null-associated gene signature prognosticated relapse-free survival in human patients with ALL. Therefore, p19ARF appears to be important to regulating cellular senescence and innate immune response that may contribute to the therapeutic response of ALL. PMID:25784651

  15. Effects of reproductive status on behavioral and endocrine responses to acute stress in a biparental rodent, the California mouse (Peromyscus californicus)

    PubMed Central

    Chauke, Miyetani; Malisch, Jessica L.; Robinson, Cymphonee; de Jong, Trynke R.; Saltzman, Wendy

    2014-01-01

    In several mammalian species, lactating females show blunted neural, hormonal, and behavioral responses to stressors. It is not known whether new fathers also show stress hyporesponsiveness in species in which males provide infant care. To test this possibility, we determined the effects of male and female reproductive status on stress responsiveness in the biparental, monogamous California mouse (Peromyscus californicus).Breeding (N=8 females, 8 males), nonbreeding (N=10 females, 10 males) and virgin mice (N=12 females, 9 males) were exposed to a 5-min predator-urine stressor at two time points, corresponding to the early postpartum (5–7 days postpartum) and mid/late postpartum (19–21 days postpartum) phases, and blood samples were collected immediately afterwards. Baseline blood samples were obtained 2 days prior to each stress test. Baseline plasma corticosterone (CORT) concentrations did not differ among male or female groups. CORT responses to the stressor did not differ among female reproductive groups, and all three groups showed distinct behavioral responses to predator urine. Virgin males tended to increase their CORT response from the first to the second stress test, while breeding and nonbreeding males did not. Moreover, virgin and nonbreeding males showed significant behavioral changes in response to predator urine, whereas breeding males did not. These results suggest that adrenocortical responses to a repeated stressor in male California mice may be modulated by cohabitation with a female, whereas behavioral responses to stress may be blunted by parental status. PMID:21557946

  16. [Galvanic current in the conservative treatment of acute pancreatitis].

    PubMed

    Alekseenko, A V; Iftodiĭ, A G; Stoliar, V F

    1990-10-01

    Experiments were conducted on 42 adult dogs with a model of acute pancreatitis to study the degree of antibiotic storage in the pancreatic tissue in different variants of intralesional+ electrophoresis. Optimum concentration of the antibiotic was produced in transverse galvanization of the zone of the pancreas. Clinical observations over 63 patients with various forms of acute pancreatitis bear evidence that the method raises the efficacy of nonoperative treatment in the oedematous stage of the process and reduces the duration of treatment. PMID:2283730

  17. Ampullary carcinoma in a patient with agenesis of the dorsal pancreas: a case report.

    PubMed

    Mistry, Jitendra H; Yadav, Amitabh; Nundy, Samiran

    2015-04-01

    The most common congenital anomaly of the pancreas is pancreatic divisum (Tadokoro et al. in Anat Res Int 2011:1-7, 2011). Agenesis of the dorsal pancreas is extremely rare (Schnedl et al. in World J Gastroenterol 15(3):376-377, 2009). We are reporting a case of agenesis of dorsal pancreas presented with ampullary carcinoma. PMID:25972636

  18. Functional expression of P2X family receptors in macrophages is affected by microenvironment in mouse T cell acute lymphoblastic leukemia

    SciTech Connect

    Chen, Shayan; Feng, Wenli; Yang, Xiao; Yang, Wanzhu; Ru, Yongxin; Liao, Jinfeng; Wang, Lina; Lin, Yongmin; Ren, Qian; Zheng, Guoguang

    2014-04-18

    Highlights: • We study the impact of leukemic microenvironment on P2X family receptors in Mφs. • Bone marrow and spleen Mφs are studied in Notch1-induced mouse leukemia model. • Increased expression of P2X7R is found in Mφs during the development of leukemia. • Elevated P2X7R-mediated calcium response is found in Mφs at late stage of leukemia. • More apoptotic Mφs are found in bone marrow and spleen at late stage of leukemia. - Abstract: Nucleotides are important players in intercellular signaling communication network. P2X family receptors (P2XRs) are ATP-gated plasma membrane ion channels with diverse biological functions. Macrophages are important components in the microenvironment of hematopoiesis participating in both physiological and pathological processes. However, the role of P2XRs in macrophages in leukemia has not been established. Here we investigated expression pattern and functions of P2XRs in macrophages from bone marrow (BM) and spleen of Notch1-induced T-ALL mice. Real-time PCR showed that P2XRs except P2X5R were expressed in BM and spleen macrophages. Furthermore, with the development of leukemia, the expression of P2X7R increased in both BM and spleen macrophages whereas expression of P2X1R increased in spleen macrophages. Live cell imaging recoding the Ca{sup 2+} response demonstrated that P2X7R expressed in macrophages was functional. TUNEL and electron microscopy analysis found that apoptotic macrophages were frequently observed in BM and spleen at late stage of leukemia, which was partly contributed by the activation of overexpressed P2X7R. Our results suggested that the intercellular communication mediated by nucleotides might orchestrate in the pathological process of leukemia and could be a potential target for the treatment of leukemia.

  19. Acute administration of L-dopa induces changes in methylation metabolites, reduced protein phosphatase 2A methylation and hyperphosphorylation of Tau protein in mouse brain

    PubMed Central

    Bottiglieri, Teodoro; Arning, Erland; Wasek, Brandi; Nunbhakdi-Craig, Viyada; Sontag, Jean-Marie; Sontag, Estelle

    2012-01-01

    Folate deficiency and hypomethylation have been implicated in a number of age-related neurodegenerative disorders including dementia and Parkinson’s disease (PD). Levodopa (L-dopa) therapy in PD patients has been shown to cause an increase in plasma total homocysteine (tHcy) as well as depleting cellular concentrations of the methyl donor, S-adenosylmethionine (SAM), and increasing the demethylated product S-adenosylhomocysteine (SAH). Modulation of the cellular SAM/SAH ratio can influence activity of methyltransferase enzymes including leucine carboxyl methyltransferase (LCMT1), that specifically methylates Ser/Thr protein phosphatase 2A (PP2A), a major Tau phosphatase. Here we show in human SH-SY5Y cells and dopaminergic neurons, and in wild type mice that L-dopa results in a reduced SAM/SAH ratio that is associated with hypomethylation of PP2A and increased phosphorylation of Tau (p-Tau) at the Alzheimer disease-like PHF-1 phosphoepitope. The effect of L-dopa on PP2A and p-Tau was exacerbated in cells exposed to folate deficiency. In the folate deficient mouse model, L-dopa resulted in a marked depletion of SAM and increase in SAH in various brain regions with parallel down regulation of PP2A methylation and increased Tau phosphorylation. L-dopa also enhanced demethylated PP2A amounts in the liver. These findings reveal a novel mechanism involving methylation-dependent pathways in which L-dopa induces PP2A hypomethylation and increases Tau phosphorylation, which may be potentially detrimental to neuronal cells. PMID:22764226

  20. Impact of de novo donor-specific anti-HLA antibodies on grafts outcomes in simultaneous pancreas-kidney transplantation.

    PubMed

    Malheiro, Jorge; Martins, La Salete; Tafulo, Sandra; Dias, Leonídio; Fonseca, Isabel; Beirão, Idalina; Castro-Henriques, António; Cabrita, António

    2016-02-01

    De novo donor-specific antibodies (dDSA) relevance in simultaneous pancreas-kidney (SPK) transplantation has been scarcely investigated. We analyzed dDSA relationship with grafts outcomes in a long-term follow-up SPK-transplanted cohort. In 150 patients that received SPK transplant between 2000 and 2013, post-transplant anti-human leukocyte antigen (HLA) antibodies were screened and identified using Luminex-based assays in sera collected at 3, 6, and 12 months, then yearly. dDSA were detected in 22 (14.7%) patients at a median 3.1 years after transplant. Pretransplant anti-HLA sensitization (OR = 4.64), full HLA-DR mismatch (OR = 4.38), and previous acute cellular rejection (OR = 9.45) were significant risk factors for dDSA. dDSA were significantly associated with kidney (in association with acute rejection) and pancreas graft failure. In dDSA+ patients, those with at least one graft failure presented more frequently dDSA against class II or I + II (P = 0.011) and locusDQ (P = 0.043) and had a higher median dDSA number (P = 0.014) and strength (P = 0.030). Median time between dDSA emergence and pancreas and kidney graft failure was 5 and 12 months, respectively. Emergence of dDSA increased the risk of grafts failure in SPK-transplanted patients. Full HLA-DR mismatch was associated with dDSA emergence. dDSA characteristics might help identify patients at a higher risk of graft failure. PMID:26404891

  1. Bile acids acutely stimulate insulin secretion of mouse β-cells via farnesoid X receptor activation and K(ATP) channel inhibition.

    PubMed

    Düfer, Martina; Hörth, Katrin; Wagner, Rebecca; Schittenhelm, Björn; Prowald, Susanne; Wagner, Thomas F J; Oberwinkler, Johannes; Lukowski, Robert; Gonzalez, Frank J; Krippeit-Drews, Peter; Drews, Gisela

    2012-06-01

    Type 2 diabetes mellitus is associated with alterations in bile acid (BA) signaling. The aim of our study was to test whether pancreatic β-cells contribute to BA-dependent regulation of glucose homeostasis. Experiments were performed with islets from wild-type, farnesoid X receptor (FXR) knockout (KO), and β-cell ATP-dependent K(+) (K(ATP)) channel gene SUR1 (ABCC8) KO mice, respectively. Sodium taurochenodeoxycholate (TCDC) increased glucose-induced insulin secretion. This effect was mimicked by the FXR agonist GW4064 and suppressed by the FXR antagonist guggulsterone. TCDC and GW4064 stimulated the electrical activity of β-cells and enhanced cytosolic Ca(2+) concentration ([Ca(2+)](c)). These effects were blunted by guggulsterone. Sodium ursodeoxycholate, which has a much lower affinity to FXR than TCDC, had no effect on [Ca(2+)](c) and insulin secretion. FXR activation by TCDC is suggested to inhibit K(ATP) current. The decline in K(ATP) channel activity by TCDC was only observed in β-cells with intact metabolism and was reversed by guggulsterone. TCDC did not alter insulin secretion in islets of SUR1-KO or FXR-KO mice. TCDC did not change islet cell apoptosis. This is the first study showing an acute action of BA on β-cell function. The effect is mediated by FXR by nongenomic elements, suggesting a novel link between FXR activation and K(ATP) channel inhibition. PMID:22492528

  2. Therapeutic efficacy of cord blood-derived mesenchymal stromal cells for the prevention of acute graft-versus-host disease in a xenogenic mouse model.

    PubMed

    Gregoire-Gauthier, Joëlle; Selleri, Silvia; Fontaine, François; Dieng, Mame Massar; Patey, Natalie; Despars, Geneviève; Beauséjour, Christian M; Haddad, Elie

    2012-07-01

    Human mesenchymal stromal cells (MSCs) have been successfully utilized for the treatment of refractory graft-versus-host disease (GvHD). Despite the large number of in vitro and in vivo models developed for clarifying their immunomodulatory properties, the mechanism of action of MSCs remains elusive and their efficacy controversial. Here, we tested the ability of cord blood-derived MSCs to alleviate the symptoms of GvHD induced by the injection of human peripheral blood mononuclear cells into NOD/SCID/γc(-) mice. In this in vivo xeno-GvHD model, we demonstrate that a single MSC injection is able to inhibit GvHD in terms of clinical signs and related mortality. We also show that in this model MSCs act by both immunomodulating T-cells and fostering recovery after irradiation. The translational impact of these findings could provide a reliable preclinical model for studying the efficacy, dosage, and time of administration of human MSCs for the prevention of acute GvHD. PMID:21910645

  3. Inhibition of Notch Signaling Ameliorates Acute Kidney Failure and Downregulates Platelet-Derived Growth Factor Receptor β in the Mouse Model.

    PubMed

    Kramer, Jan; Schwanbeck, Ralf; Pagel, Horst; Cakiroglu, Figen; Rohwedel, Jürgen; Just, Ursula

    2016-01-01

    Ischemic acute kidney injury (AKI) is associated with high morbidity and frequent complications. Repeated episodes of AKI may lead to end-stage renal failure. The pathobiology of regeneration in AKI is not well understood and there is no effective clinical therapy that improves regeneration. The Notch signaling pathway plays an essential role in kidney development and has been implicated in tissue repair in the adult kidney. Here, we found that kidneys after experimental AKI in mice showed increased expression of Notch receptors, specifically Notch1-3, of the Notch ligands Jagged-1 (Jag1), Jag2 and Delta-like-4 (Dll4) and of the Notch target genes Hes1, Hey2, HeyL, Sox9 and platelet-derived growth factor receptor β (Pdgfrb). Treatment of ischemic mice with the x03B3;-secretase inhibitor DBZ blocked Notch signaling and specifically downregulated the expression of Notch3 and the Notch target genes Hes1, Hey2, HeyL and Pdgfrb. After DBZ treatment, the mice developed less interstitial edema and displayed altered interstitial inflammation patterns. Furthermore, serum urea and creatinine levels were significantly decreased from 6 h onwards when compared to control mice treated with DMSO only. Our data are consistent with an amelioration of the severity of kidney injury by blocking Notch activation following AKI, and suggest an involvement of Notch-regulated Pdgfrb in AKI pathogenesis. PMID:26939110

  4. Autophagy-Modulated Human Bone Marrow-Derived Mesenchymal Stem Cells Accelerate Liver Restoration in Mouse Models of Acute Liver Failure

    PubMed Central

    Amiri, Fatemeh; Molaei, Sedigheh; Bahadori, Marzie; Nasiri, Fatemeh; Deyhim, Mohammad Reza; Jalili, Mohammad Ali; Nourani, Mohammad Reza; Habibi Roudkenar, Mehryar

    2016-01-01

    Background: Mesenchymal stem cells (MSCs) have been recently received increasing attention for cell-based therapy, especially in regenerative medicine. However, the low survival rate of these cells restricts their therapeutic applications. It is hypothesized that autophagy might play an important role in cellular homeostasis and survival. This study aims to investigate the regenerative potentials of autophagy-modulated MSCs for the treatment of acute liver failure (ALF) in mice. Methods: ALF was induced in mice by intraperitoneal injection of 1.5 ml/kg carbon tetrachloride. Mice were intravenously infused with MSCs, which were suppressed in their autophagy pathway. Blood and liver samples were collected at different intervals (24, 48 and 72 h) after the transplantation of MSCs. Both the liver enzymes and tissue necrosis levels were evaluated using biochemical and histopathological assessments. The survival rate of the transplanted mice was also recorded during one week. Results: Biochemical and pathological results indicated that 1.5 ml/kg carbon tetrachloride induces ALF in mice. A significant reduction of liver enzymes and necrosis score were observed in autophagy-modulated MSC-transplanted mice compared to sham (with no cell therapy) after 24 h. After 72 h, liver enzymes reached their normal levels in mice transplanted with autophagy-suppressed MSCs. Interestingly, normal histology without necrosis was also observed. Conclusion: Autophagy suppression in MSCs ameliorates their liver regeneration potentials due to paracrine effects and might be suggested as a new strategy for the improvement of cell therapy in ALF. PMID:26899739

  5. [Acute pancreatitis with hypertriglyceridemia--an underestimated disease?].

    PubMed

    Wild, Wolfgang; Tajjiou, Morad; Ferschke, Melanie; Bormann, Fabian; Dörr, Pius; Schwarzbach, Matthias

    2016-01-01

    Hypertriglyceridemia is a rare, but since a long time well known etiology for acute pancreatitis. It could occure alone or coactive with other triggers like alcohlic excess. Nevertheless it found no approach to the current classifications and parameters of prognosis of the acute pancreatitis. We refer about two patients with hypertriglyceridemia and acute pancreatitis, whose initial disease was limited on the tail of the pancreas with just a circumscripted or--in the other case--no necrosis. However, in both cases and although a consequent treatment started immediately, a serious process developed including a life-threatening acute respiratory distress syndrome in one case, which necessitated an extracorporal membrane oxygenation. PMID:26710203

  6. [New model of acute pancreatitis].

    PubMed

    Cherkezova-Kinova, E; Lateva, E

    1981-01-01

    The authors propose a new model of acute pancreatitis by infusing duodenal content, obtained both from animals with experimental pancreatitis and from patients with pancreatitis, hepatitis and cholecystitis, into the duodenum of experimental animals without pressure for a period of several days. Pancreatitis was established functionally and histomorphologically. The control group of animals did not reveal deviations from the norm after infusion of duodenal content. The authors suggested the presence of pathogenic substances in the duodenal content of animals and sick persons, and these components damaged the pancreas, liver and kidneys by means of blood and lymph ways. PMID:7227280

  7. Multifocal Insulinoma in Pancreas and Effect of Intraoperative Ultrasonography

    PubMed Central

    Borazan, Ersin; Aytekin, Alper; Yilmaz, Latif; Elci, Muhsin; Karaca, Mehmet Salih; Kervancioglu, Selim; Balik, Ahmet Abdulhalik

    2015-01-01

    Insulinoma is the most frequently seen functional pancreatic neuroendocrine tumor. The incidence of multifocal insulinoma is lower than 10%. Its treatment is direct or laparoscopic excision. The present case was examined with the findings of hypoglycemia and hypercalcemia, and as there was high insulin and C-peptide levels the initial diagnosis was insulinoma. The case was investigated in terms of MEN 1. During preoperative screening for localization, there was one focus in the head of the pancreas in the abdominal tomography and two foci in endoscopic ultrasonography. No other focus was detected through intraoperative visual or manual palpation. However, five foci were detected during operation by intraoperative ultrasonography. The relation of masses with the main pancreatic canal was evaluated and they were excised by enucleation method. There was no recurrence during the postoperative 18-month follow-up of the patient. As a result, during treatment for insulinoma, it should be kept in mind that there might be multifocal foci. In all insulinomas, the whole pancreas should be evaluated with intraoperative ultrasonography because none of the current preoperative diagnostic methods are as sensitive as manual palpation of pancreas and intraoperative ultrasonography. The intraoperative detection of synchronous five foci in pancreas is quite a rare condition. PMID:26295000

  8. Neurogenin 3 Expressing Cells in the Human Exocrine Pancreas Have the Capacity for Endocrine Cell Fate

    PubMed Central

    Gomez, Danielle L.; O’Driscoll, Marci; Sheets, Timothy P.; Hruban, Ralph H.; Oberholzer, Jose; McGarrigle, James J.; Shamblott, Michael J.

    2015-01-01

    Neurogenin 3 (NGN3) is necessary and sufficient for endocrine differentiation during pancreatic development and is expressed by a population of progenitor cells that give rise exclusively to hormone-secreting cells within islets. NGN3 protein can be detected in the adult rodent pancreas only following certain types of injury, when it is transiently expressed by exocrine cells undergoing reprogramming to an endocrine cell fate. Here, NGN3 protein can be detected in 2% of acinar and duct cells in living biopsies of histologically normal adult human pancreata and 10% in cadaveric biopsies of organ donor pancreata. The percentage and total number of NGN3+ cells increase during culture without evidence of proliferation or selective cell death. Isolation of highly purified and viable NGN3+ cell populations can be achieved based on coexpression of the cell surface glycoprotein CD133. Transcriptome and targeted expression analyses of isolated CD133+ / NGN3+ cells indicate that they are distinct from surrounding exocrine tissue with respect to expression phenotype and Notch signaling activity, but retain high level mRNA expression of genes indicative of acinar and duct cell function. NGN3+ cells have an mRNA expression profile that resembles that of mouse early endocrine progenitor cells. During in vitro differentiation, NGN3+ cells express genes in a pattern characteristic of endocrine development and result in cells that resemble beta cells on the basis of coexpression of insulin C-peptide, chromogranin A and pancreatic and duodenal homeobox 1. NGN3 expression in the adult human exocrine pancreas marks a dedifferentiating cell population with the capacity to take on an endocrine cell fate. These cells represent a potential source for the treatment of diabetes either through ex vivo manipulation, or in vivo by targeting mechanisms controlling their population size and endocrine cell fate commitment. PMID:26288179

  9. [Effects of atovaquone and astragalus combination on the treatment and IL-2, IL-12, IFN-γ levels on mouse models of acute toxoplasmosis].

    PubMed

    Sönmez, Neşe; Büyükbaba Boral, Ozden; Kaşali, Kamber; Tekeli, Fatma

    2014-10-01

    Bioscience, Austria). The mean number of trophozoites in Ato + Astra group was found significantly lower than the number of trophozoites in the other three groups (p< 0.05). The number of trophozoites in the atovaquone and astragalus groups were found significantly lower than the number of trophozoites in the control group (p< 0.05). There was a significant increase in IL-2 levels of astragalus group compared with the other three groups, in addition when IL-2 levels of Ato + Astra group were compared with ones in other three groups, a significant decrease was noticed (p< 0.05). There was a definite increase in IL-12 levels of atovaquone, astragalus and the control groups compared to those in Ato + Astra group (p< 0.05). A significant increase was found in IFN-γ levels in atovaquone and Ato + Astra groups compared with those in the control group (p< 0.05). Within the reach of our literature survey, this study was the first research in which the effectiveness of the combination of atovaquone and AmE was investigated in the treatment of acute toxoplasmosis. The results of our study suggested that there might be a synergy between atovaquone and AmE in the treatment of acute toxoplasmosis. In case these results are supported by further studies, atovaquone and AmE combination may have a potential to be used for therapy in immunocompromized patients such as AIDS patients who have a risk for toxoplasmosis. PMID:25492659

  10. Acute and chronic stress differentially regulate cyclin-dependent kinase 5 in mouse brain: implications to glucocorticoid actions and major depression

    PubMed Central

    Papadopoulou, A; Siamatras, T; Delgado-Morales, R; Amin, N D; Shukla, V; Zheng, Y-L; Pant, H C; Almeida, O F X; Kino, T

    2015-01-01

    Stress activates the hypothalamic–pituitary–adrenal axis, which in turn increases circulating glucocorticoid concentrations and stimulates the glucocorticoid receptor (GR). Chronically elevated glucocorticoids by repetitive exposure to stress are implicated in major depression and anxiety disorders. Cyclin-dependent kinase 5 (CDK5), a molecule essential for nervous system development, function and pathogenesis of neurodegenerative disorders, can modulate GR activity through phosphorylation. We examined potential contribution of CDK5 to stress response and pathophysiology of major depression. In mice, acute immobilized stress (AS) caused a biphasic effect on CDK5 activity, initially reducing but increasing afterwards in prefrontal cortex (PFC) and hippocampus (HIPPO), whereas chronic unpredictable stress (CS) strongly increased it in these brain areas, indicating that AS and CS differentially regulate this kinase activity in a brain region-specific fashion. GR phosphorylation contemporaneously followed the observed changes of CDK5 activity after AS, thus CDK5 may in part alter GR phosphorylation upon this stress. In the postmortem brains of subjects with major depression, CDK5 activity was elevated in Brodmann's area 25, but not in entire PFC and HIPPO. Messenger RNA expression of glucocorticoid-regulated/stress-related genes showed distinct expression profiles in several brain areas of these stressed mice or depressive subjects in which CDK5-mediated changes in GR phosphorylation may have some regulatory roles. Taken together, these results indicate that CDK5 is an integral component of stress response and major depression with regulatory means specific to different stressors, brain areas and diseases in part through changing phosphorylation of GR. PMID:26057048

  11. Serum Neutrophil Gelatinase Associated Lipocalin (NGAL) Outperforms Serum Creatinine in Detecting Sepsis-Induced Acute Kidney Injury, Experiments on Bilateral Nephrectomy and Bilateral Ureter Obstruction Mouse Models.

    PubMed

    Leelahavanichkul, Asada; Somparn, Poorichaya; Issara-Amphorn, Jiraphorn; Eiam-Ong, Somchai; Avihingsanon, Yingyos; Hirankarn, Nattiya; Srisawat, Nattachai

    2016-05-01

    Serum neutrophil gelatinase associated lipocalin (sNGAL), a promising acute kidney injury (AKI) biomarker produced by renal and non-renal tissues, might be affected by sepsis. We evaluated sNGAL in zero glomerular filtration rate models [bilateral ureter obstruction (BUO) and bilateral nephrectomy (BiNx)] with subsequent cecal ligation and puncture (CLP)-induced sepsis in 6 to 8-week-old ICR mice. We found that sNGAL increased earlier than serum creatinine (Scr) in BiNx/BUO with and without CLP. The earliest time-point of increased sNGAL in BiNx+CLP was 1 h after surgery. Scr, but not sNGAL, was lower at 18 h after BiNx/BUO+CLP compared with BiNx/BUO alone. Compared with BUO, BiNx had higher, and equal sNGAL at 1 to 18 h and 36 h, respectively. Additionally, similar NGAL expression in internal organs (heart, lung, liver, and spleen) and survival rates indicated the comparable severity of BiNx and BUO. Serum interleukin (IL)-6 was increased and correlated with sNGAL in BiNx/BUO with and without sepsis. In summary, we demonstrated: sNGAL is an early AKI biomarker, which is not affected by sepsis; sNGAL is mainly produced by extrarenal sources as demonstrated by the comparable sNGAL in BiNx and BUO; the saturation of renal NGAL re-absorption in BUO is demonstrated by lower sNGAL in BUO at 1 to 18 h, but not at 36 h when compared with BiNx; and a correlation of sNGAL and IL-6 implied sNGAL is a good sepsis prognostic biomarker. Therefore, sNGAL is a more beneficial sepsis-AKI biomarker than Scr. PMID:26863120

  12. Roles of ASIC3, TRPV1, and NaV1.8 in the transition from acute to chronic pain in a mouse model of fibromyalgia

    PubMed Central

    2014-01-01

    Background Tissue acidosis is effective in causing chronic muscle pain. However, how muscle nociceptors contribute to the transition from acute to chronic pain is largely unknown. Results Here we showed that a single intramuscular acid injection induced a priming effect on muscle nociceptors of mice. The primed muscle nociceptors were plastic and permitted the development of long-lasting chronic hyperalgesia induced by a second acid insult. The plastic changes of muscle nociceptors were modality-specific and required the activation of acid-sensing ion channel 3 (ASIC3) or transient receptor potential cation channel V1 (TRPV1). Activation of ASIC3 was associated with increased activity of tetrodotoxin (TTX)-sensitive voltage-gated sodium channels but not protein kinase Cϵ (PKCϵ) in isolectin B4 (IB4)-negative muscle nociceptors. In contrast, increased activity of TTX-resistant voltage-gated sodium channels with ASIC3 or TRPV1 activation in NaV1.8-positive muscle nociceptors was required for the development of chronic hyperalgesia. Accordingly, compared to wild type mice, NaV1.8-null mice showed briefer acid-induced hyperalgesia (5 days vs. >27 days). Conclusion ASIC3 activation may manifest a new type of nociceptor priming in IB4-negative muscle nociceptors. The activation of ASIC3 and TRPV1 as well as enhanced NaV1.8 activity are essential for the development of long-lasting hyperalgesia in acid-induced, chronic, widespread muscle pain. PMID:24957987

  13. Sex differences in the acute in vivo effects of different human SP-A variants on the mouse alveolar macrophage proteome

    PubMed Central

    Phelps, David S.; Umstead, Todd M.; Floros, Joanna

    2014-01-01

    Surfactant protein A (SP-A) is involved in lung innate immunity. Humans have two SP-A genes, SFTPA1 and SFTPA2, each with several variants. We examined the in vivo effects of treatment with specific SP-A variants on the alveolar macrophage (AM) proteome from SP-A knockout (KO) mice. KO mice received either SP-A1, SP-A2, or both. AM were collected and their proteomes examined with 2D-DIGE. We identified 90 proteins and categorized them as related to actin/cytoskeleton, oxidative stress, protease balance/chaperones, regulation of inflammation, and regulatory/developmental processes. SP-A1 and SP-A2 had different effects on the AM proteome and these effects differed between sexes. In males more changes occurred in the oxidative stress, protease/chaperones, and inflammation groups with SP-A2 treatment than with SP-A1. In females most SP-A1-induced changes were in the actin/cytoskeletal and oxidative stress groups. We conclude that after acute SP-A1 and SP-A2 treatment, sex-specific differences were observed in the AM proteomes from KO mice, and that these sex differences differ in response to SP-A1 and SP-A2. Females are more responsive to SP-A1, whereas the gene-specific differences in males were minimal. These observations not only demonstrate the therapeutic potential of exogenous SP-A, but also illustrate sex- and gene-specific differences in the response to it. PMID:24954098

  14. Deep convolutional networks for pancreas segmentation in CT imaging

    NASA Astrophysics Data System (ADS)

    Roth, Holger R.; Farag, Amal; Lu, Le; Turkbey, Evrim B.; Summers, Ronald M.

    2015-03-01

    Automatic organ segmentation is an important prerequisite for many computer-aided diagnosis systems. The high anatomical variability of organs in the abdomen, such as the pancreas, prevents many segmentation methods from achieving high accuracies when compared to state-of-the-art segmentation of organs like the liver, heart or kidneys. Recently, the availability of large annotated training sets and the accessibility of affordable parallel computing resources via GPUs have made it feasible for "deep learning" methods such as convolutional networks (ConvNets) to succeed in image classification tasks. These methods have the advantage that used classification features are trained directly from the imaging data. We present a fully-automated bottom-up method for pancreas segmentation in computed tomography (CT) images of the abdomen. The method is based on hierarchical coarse-to-fine classification of local image regions (superpixels). Superpixels are extracted from the abdominal region using Simple Linear Iterative Clustering (SLIC). An initial probability response map is generated, using patch-level confidences and a two-level cascade of random forest classifiers, from which superpixel regions with probabilities larger 0.5 are retained. These retained superpixels serve as a highly sensitive initial input of the pancreas and its surroundings to a ConvNet that samples a bounding box around each superpixel at different scales (and random non-rigid deformations at training time) in order to assign a more distinct probability of each superpixel region being pancreas or not. We evaluate our method on CT images of 82 patients (60 for training, 2 for validation, and 20 for testing). Using ConvNets we achieve maximum Dice scores of an average 68% +/- 10% (range, 43-80%) in testing. This shows promise for accurate pancreas segmentation, using a deep learning approach and compares favorably to state-of-the-art methods.

  15. Feasibility of automated pancreas segmentation based on dynamic MRI

    PubMed Central

    Gou, S; Wu, J; Liu, F; Lee, P; Rapacchi, S; Hu, P

    2014-01-01

    Objective: MRI-guided radiotherapy is particularly attractive for abdominal targets with low CT contrast. To fully utilize this modality for pancreas tracking, automated segmentation tools are needed. A hybrid gradient, region growth and shape constraint (hGReS) method to segment two-dimensional (2D) upper abdominal dynamic MRI (dMRI) is developed for this purpose. Methods: 2D coronal dynamic MR images of two healthy volunteers were acquired with a frame rate of 5 frames per second. The regions of interest (ROIs) included the liver, pancreas and stomach. The first frame was used as the source where the centres of the ROIs were manually annotated. These centre locations were propagated to the next dMRI frame. Four-neighborhood region transfer growth was performed from these initial seeds before refinement using shape constraints. Results from hGReS and two other automated segmentation methods using integrated edge detection and region growth (IER) and level set, respectively, were compared with manual contours using Dice's index (DI). Results: For the first patient, the hGReS resulted in the organ segmentation accuracy as a measure by the DI (0.77) for the pancreas, superior to the level set method (0.72) and IER (0.71). The hGReS was shown to be reproducible on the second subject, achieving a DI of 0.82, 0.92 and 0.93 for the pancreas, stomach and liver, respectively. Motion trajectories derived from the hGReS were highly correlated to respiratory motion. Conclusion: We have shown the feasibility of automated segmentation of the pancreas anatomy on dMRI. Advances in knowledge: Using the hybrid method improves segmentation robustness of low-contrast images. PMID:25270713

  16. A stubborn anemia caused by ectopic pancreas bleeding in the jejunum revealed by capsule endoscopy

    PubMed Central

    Wang, Qun-Ying; Yang, Xiao-Yun

    2015-01-01

    Ectopic pancreas is extremely rare in clinical setting. Meanwhile, a stubborn anemia without obvious dark bloody stool due to ectopic pancreas diagnosed by capsule endoscopy has not been reported. We reported a case of an ectopic pancreas inducing obscure gastrointestinal bleeding in a 70-year-old woman presenting as stubborn anemia, which was diagnosed by capsule endoscopy. The patient recovered well after resection the lesion. Diagnosis of ectopic pancreas is extremely difficult with conventional techniques. Endoscopists should pay more attention to the ectopic pancreas as a rare differential consideration for occult intestinal bleeding. PMID:26682148

  17. Challenges in detecting pre-malignant pancreatic lesions during acute pancreatitis using a serum microRNA assay: a study based on KrasG12D transgenic mice

    PubMed Central

    Hong, Xiafei; Zhang, Jie; Wu, Qiao; Wang, Wenze; Ye, Adam Yongxin; Song, Wei; Dai, Hongmei; Wang, Xianze; Wu, Fan; You, Lei; Wu, Wenming; Zhao, Yupei

    2016-01-01

    Caerulein-induced acute pancreatitis accelerates the progression of pancreatic intraepithelial neoplasia (PanIN) lesions in a pancreas-specific KrasG12D mouse model. The purpose of this study was to explore whether serum microRNAs (miRNAs) can serve as sensitive biomarkers to detect occult PanIN in the setting of acute pancreatitis. Serum miRNA profiles were quantified by an array-based method and normalized by both Variance Stabilization Normalization (VSN) and invariant methods. Individual miRNAs were validated by TaqMan real-time PCR with synthetic spike-in C. elegans miRNAs as external controls. Serum miRNA profiles distinguished KrasG12D mice with pancreatitis from wild-type mice without pancreatitis, but failed to differentiate KrasG12D mice with pancreatitis from wild-type mice with pancreatitis. Most individual miRNAs that increased in KrasG12D mice with pancreatitis were not significantly different between KrasG12D mice without pancreatitis and wild-type mice without pancreatitis. Mechanistically, Gene Set Enrichment Analysis (GSEA) of the mRNA array data and immunohistochemical assays showed that caerulein-induced acute pancreatitis involved acinar cell loss and immune cell infiltration, which might contribute to serum miRNA profile changes. This study highlighted the challenges in using sensitive serum miRNA biomarker screening for the early detection of pancreatic malignancies during acute pancreatitis. PMID:27009811

  18. Type IV collagen is a tumour stroma-derived biomarker for pancreas cancer

    PubMed Central

    Öhlund, D; Lundin, C; Ardnor, B; Öman, M; Naredi, P; Sund, M

    2009-01-01

    Background: Pancreas cancer is a dreaded disease with high mortality, despite progress in surgical and oncological treatments in recent years. The field is hampered by a lack of good prognostic and predictive tumour biomarkers to be used during follow-up of patients. Methods: The circulating level of type IV collagen was measured by ELISA in pancreas cancer patients and controls. The expression pattern of type IV collagen in normal pancreas, pancreas cancer tissue and in pancreas cancer cell lines was studied by immunofluorescence and Western blot techniques. Results: Patients with pancreas cancer have significantly increased circulating levels of type IV collagen. In pancreas cancer tissue high levels of type IV collagen expression was found in close proximity to cancer cells in the tumour stroma. Furthermore, pancreas cancer cells were found to produce and secrete type IV collagen in vitro, which in part can explain the high type IV collagen expression observed in pancreas cancer tissue, and the increased circulating levels in pancreas cancer patients. Of clinical importance, our results show that the circulating level of type IV collagen after surgery is strongly related to prognosis in patients treated for pancreas cancer by pancreatico-duodenectomy with curative intent. Persisting high levels of circulating type IV collagen after surgery indicates a quick relapse in disease and poor survival. Conclusion: Our results most importantly show that stroma related substances can be evaluated as potential cancer biomarkers, and thereby underline the importance of the tumour microenvironment also in this context. PMID:19491897

  19. Use of the Electronic Medical Record to Assess Pancreas Size in Type 1 Diabetes

    PubMed Central

    Virostko, John; Hilmes, Melissa; Eitel, Kelsey; Moore, Daniel J.; Powers, Alvin C.

    2016-01-01

    Aims This study harnessed the electronic medical record to assess pancreas volume in patients with type 1 diabetes (T1D) and matched controls to determine whether pancreas volume is altered in T1D and identify covariates that influence pancreas volume. Methods This study included 25 patients with T1D and 25 age-, sex-, and weight-matched controls from the Vanderbilt University Medical Center enterprise data warehouse. Measurements of pancreas volume were made from medical imaging studies using magnetic resonance imaging (MRI) or computed tomography (CT). Results Patients with T1D had a pancreas volume 47% smaller than matched controls (41.16 ml vs. 77.77 ml, P < 0.0001) as well as pancreas volume normalized by subject body weight, body mass index, or body surface area (all P < 0.0001). Pancreatic volume was smaller with a longer duration of T1D across the patient population (N = 25, P = 0.04). Additionally, four individual patients receiving multiple imaging scans displayed progressive declines in pancreas volume over time (~ 6% of volume/year), whereas five controls scanned a year apart did not exhibit a decline in pancreas size (P = 0.03). The pancreas was uniformly smaller on the right and left side of the abdomen. Conclusions Pancreas volume declines with disease duration in patients with T1D, suggesting a protracted pathological process that may include the exocrine pancreas. PMID:27391588

  20. Elevated Erythropoietin and Multicystic Neoplasm of the Pancreas

    PubMed Central

    Nai, Qiang; Regeti, Kalyani; Arshed, Sabrina; Hossain, Mohammed Amzad; Zhang, Ping; Luo, Hongxiu; Singh, Shilpi; Mathew, Teena; Islam, Mohammed; Sen, Shuvendu; Yousif, Abdalla M.; Duhl, Jozsef

    2015-01-01

    Cystic lesions of the pancreas are more frequently recognized due to the widespread use of improved imaging techniques. There are a variety of pancreatic cystic lesions with different clinical presentations and malignant potentials, and their management depends on the type of the cysts. Although the early recognition of a cystic neoplasm with malignant potential provides an opportunity of early surgical treatment, the precise diagnosis of the cystic neoplasm can be a challenge, largely due to the lack of reliable biomarkers of malignant transformation. We report a case of a large, multicystic neoplasm within the body and tail of the pancreas complicated by elevated erythropoietin, which is likely related to the malignant transformation of the pancreatic neoplasm. PMID:25873882

  1. Elevated erythropoietin and multicystic neoplasm of the pancreas.

    PubMed

    Nai, Qiang; Regeti, Kalyani; Arshed, Sabrina; Hossain, Mohammed Amzad; Zhang, Ping; Luo, Hongxiu; Singh, Shilpi; Mathew, Teena; Islam, Mohammed; Sen, Shuvendu; Yousif, Abdalla M; Duhl, Jozsef

    2015-01-01

    Cystic lesions of the pancreas are more frequently recognized due to the widespread use of improved imaging techniques. There are a variety of pancreatic cystic lesions with different clinical presentations and malignant potentials, and their management depends on the type of the cysts. Although the early recognition of a cystic neoplasm with malignant potential provides an opportunity of early surgical treatment, the precise diagnosis of the cystic neoplasm can be a challenge, largely due to the lack of reliable biomarkers of malignant transformation. We report a case of a large, multicystic neoplasm within the body and tail of the pancreas complicated by elevated erythropoietin, which is likely related to the malignant transformation of the pancreatic neoplasm. PMID:25873882

  2. Computed tomography of cystadenoma and cystadenocarcinoma of the pancreas

    SciTech Connect

    Itai, Y.; Moss, A.A.; Ohtomo, K.

    1982-11-01

    Ten cases of cystadenoma or cystadenocarcinoma of the pancreas were examined by computed tomography (CT). All but one showed characteristic findings consisting of both cystic and solid components. Innumerable small cysts producing a honeycomb appearance were noticed in serous cystadenomas. A well-defined multilocular cystic mass containing thin, straight, and/or curvilinear septa or a unilocular cystic tumor with a papillary projection and locally thickened wall was present in mucinous cystadenomas. The CT findings in cystadenocarcinomas varied depending on the relative size of the cystic and solid portions and the grade of malignancy. CT was useful in detecting and diagnosing cystic neoplasms of the pancreas and differentiating benign serous cystadenomas from potentially malignant cystadenomas in typical cases. However, aspiration biopsy is recommended when findings are equivocal.

  3. Implication of epigenetics in pancreas development and disease.

    PubMed

    Quilichini, Evans; Haumaitre, Cécile

    2015-12-01

    Pancreas development is controlled by a complex interaction of signaling pathways and transcription factor networks that determine pancreatic specification and differentiation of exocrine and endocrine cells. Epigenetics adds a new layer of gene regulation. DNA methylation, histone modifications and non-coding RNAs recently appeared as important epigenetic factors regulating pancreas development. In this review, we report recent findings obtained by analyses in model organisms as well as genome-wide approaches that demonstrate the role of these epigenetic regulators in the control of exocrine and endocrine cell differentiation, identity, function, proliferation and regeneration. We also highlight how altered epigenetic processes contribute to pancreatic disorders: diabetes and pancreatic cancer. Uncovering these epigenetic events can help to better understand these diseases, provide novel therapeutical targets for their treatment, and improve cell-based therapies for diabetes. PMID:26696517

  4. An immunohistochemical study of the endocrine pancreas in raptors.

    PubMed

    Palmieri, C; Shivaprasad, H L

    2014-12-01

    The cytoarchitecture of the endocrine pancreas of 10 raptors (golden eagles, peregrine falcons, Saker falcon, turkey vultures, red-tailed hawk and unspecified falcon) was examined by immunohistochemistry. Three islet types were identified: type A mixed islets composed mainly by glucagon (A)-secreting cells, type B mixed islets with predominantly insulin (B)-secreting cell component and type M mixed islets (type M) consisting of variable number of glucagon-, insulin- and somatostatin (D)-secreting cells. The latter were further characterized into Type I, II or III according to the cell distribution of the three cell types. A and D cells were also randomly scattered within the exocrine pancreas. The results of this study suggest that the classical concept in birds of a segregation of A and B cells in well-defined and distinct islets is not applicable in raptors, reflecting an evolutionary adaptation to different dietary habits and variation in developmental mechanisms. PMID:25468799

  5. Endoscopic Ultrasound Elastography: Current Clinical Use in Pancreas.

    PubMed

    Mondal, Utpal; Henkes, Nichole; Patel, Sandeep; Rosenkranz, Laura

    2016-08-01

    Elastography is a newer technique for the assessment of tissue elasticity using ultrasound. Cancerous tissue is known to be stiffer (hence, less elastic) than corresponding healthy tissue, and as a result, could be identified in an elasticity-based imaging. Ultrasound elastography has been used in the breast, thyroid, and cervix to differentiate malignant from benign neoplasms and to guide or avoid unnecessary biopsies. In the liver, elastography has enabled a noninvasive and reliable estimate of fibrosis. Endoscopic ultrasound has become a robust diagnostic and therapeutic tool for the management of pancreatic diseases. The addition of elastography to endoscopic ultrasound enabled further characterization of pancreas lesions, and several European and Asian studies have reported encouraging results. The current clinical role of endoscopic ultrasound elastography in the management of pancreas disorders and related literature are reviewed. PMID:26825864

  6. Heterotopic Pancreas Presented as Duodenal Tumor with Obstruction.

    PubMed

    Kim, Sung Heun; Nam, So Hyun

    2015-12-01

    Heterotopic pancreas (HP) is defined as pancreatic tissue lacking anatomic and vascular continuity with the main body of the pancreas. Most are asymptomatic, but can cause ulcer, bleeding, intussusception, and mechanical obstruction. Herein, we presented one case of HP presented as duodenal tumor causing duodenal obstruction. A 7-year-old girl visited the emergency room for abdominal pain with vomiting for 24 hours. Computed tomography and upper gastrointestinal series revealed a polypoid mass with short stalk in the 2nd portion of duodenum. We attempted an endoscopic removal. However, the lumen was nearly obstructed by the mass and the stalk was too broad and hard to excise. The mass was surgically removed via duodenotomy. It was confirmed as a HP with ductal and acini components (type 2 by Heinrich classification). Postoperatively, the patient has been well without any complication and recurrence. PMID:26770904

  7. Outcome Measures for Artificial Pancreas Clinical Trials: A Consensus Report.

    PubMed

    Maahs, David M; Buckingham, Bruce A; Castle, Jessica R; Cinar, Ali; Damiano, Edward R; Dassau, Eyal; DeVries, J Hans; Doyle, Francis J; Griffen, Steven C; Haidar, Ahmad; Heinemann, Lutz; Hovorka, Roman; Jones, Timothy W; Kollman, Craig; Kovatchev, Boris; Levy, Brian L; Nimri, Revital; O'Neal, David N; Philip, Moshe; Renard, Eric; Russell, Steven J; Weinzimer, Stuart A; Zisser, Howard; Lum, John W

    2016-07-01

    Research on and commercial development of the artificial pancreas (AP) continue to progress rapidly, and the AP promises to become a part of clinical care. In this report, members of the JDRF Artificial Pancreas Project Consortium in collaboration with the wider AP community 1) advocate for the use of continuous glucose monitoring glucose metrics as outcome measures in AP trials, in addition to HbA1c, and 2) identify a short set of basic, easily interpreted outcome measures to be reported in AP studies whenever feasible. Consensus on a broader range of measures remains challenging; therefore, reporting of additional metrics is encouraged as appropriate for individual AP studies or study groups. Greater consistency in reporting of basic outcome measures may facilitate the interpretation of study results by investigators, regulatory bodies, health care providers, payers, and patients themselves, thereby accelerating the widespread adoption of AP technology to improve the lives of people with type 1 diabetes. PMID:27330126

  8. Notochord repression of endodermal Sonic hedgehog permits pancreas development

    PubMed Central

    Hebrok, Matthias; Kim, Seung K.; Melton, Douglas A.

    1998-01-01

    Notochord signals to the endoderm are required for development of the chick dorsal pancreas. Sonic hedgehog (SHH) is normally absent from pancreatic endoderm, and we provide evidence that notochord, in contrast to its effects on adjacent neuroectoderm where SHH expression is induced, represses SHH expression in adjacent nascent pancreatic endoderm. We identify activin-βB and FGF2 as notochord factors that can repress endodermal SHH and thereby permit expression of pancreas genes including Pdx1 and insulin. Endoderm treatment with antibodies that block hedgehog activity also results in pancreatic gene expression. Prevention of SHH expression in prepancreatic dorsal endoderm by intercellular signals, like activin and FGF, may be critical for permitting early steps of chick pancreatic development. PMID:9620856

  9. Accumulation of Extracellular Matrix and Developmental Dysregulation in the Pancreas by Transgenic Production of Transforming Growth Factor-β1

    PubMed Central

    Lee, Myung-Shik; Gu, Danling; Feng, Lili; Curriden, Scott; Arnush, Marc; Krahl, Troy; Gurushanthaiah, Deepak; Wilson, Curtis; Loskutoff, David L.; Fox, Howard; Sarvetnick, Nora

    1995-01-01

    Transgenic mice expressing transforming growth factor-β1 (TGF-β1) in the pancreatic β-islet cells directed by human insulin promoter were produced to study in vivo effects of TGF-β1. Fibroblast proliferation and abnormal deposition of extracellular matrix were observed from birth onward, finally replacing almost all the exocrine pancreas. Cellular infiltrates comprising macrophages and neutrophils were also observed. Plasminogen activator inhibitor was induced in the transgenic pancreas as well as fibronectin and laminin, partly explaining accumulation of extracellular matrix. TGF-β1 inhibited proliferation of acinar cells in vivo as evidenced by decreased bromodeoxyuridine incorporation. Development of pancreatic islets was dysregulated, resulting in small islet cell clusters without formation of normal adult islets; however, the overall islet cell mass was not signfifcantly diminished. Additional transgenic lines with less pronounced phenotypes had less expression of TGF-β1 transgene. These findings suggest that TGF-β1 might be a mediator of diseases associated with extracellular matrix deposition such as chronic pancreatitis, and this mouse model will be useful for further analysis of the in vivo effects of TGF-β1, including its potential for immunosuppression. Imagesp43-aFigure 2Figure 3Figure 4Figure 5Figure 6 PMID:7604884

  10. Protective Effect of Tetrandrine on Sodium Taurocholate-Induced Severe Acute Pancreatitis

    PubMed Central

    Wu, Xian-lin; Li, Jie-xing; Li, Zhen-dong; Liu, Da-sheng; Lu, Su-hong; Liu, Kang-li; Duan, Hong-yan; Luo, Yu-hong

    2015-01-01

    Tet is a type of alkaloid extracted from Stephania tetrandra, and it has recently been demonstrated that Tet can protect against inflammation and free radical injury and inhibit the release of inflammatory mediators. The present study was designed to observe the protective effect of Tet on sodium taurocholate-induced severe acute pancreatitis (SAP). The rat model of SAP was induced by retrograde bile duct injection of sodium taurocholate and then treated with Verapamil and Tet. The results showed that Tet can reduce NF-κB activation in pancreas issue, inhibit the SAP cascade, and improve SAP through inducing pancreas acinar cell apoptosis and stabilizing intracellular calcium in the pancreas, thus mitigating the damage to the pancreas. Our study revealed that Tet may reduce systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndromes (MODS) to protect against damage, and these roles may be mediated through the NF-κB pathway to improve the proinflammatory/anti-inflammatory imbalance. PMID:26557854

  11. Protective Effect of Tetrandrine on Sodium Taurocholate-Induced Severe Acute Pancreatitis.

    PubMed

    Wu, Xian-Lin; Li, Jie-Xing; Li, Zhen-Dong; Liu, Da-Sheng; Lu, Su-Hong; Liu, Kang-Li; Duan, Hong-Yan; Luo, Yu-Hong

    2015-01-01

    Tet is a type of alkaloid extracted from Stephania tetrandra, and it has recently been demonstrated that Tet can protect against inflammation and free radical injury and inhibit the release of inflammatory mediators. The present study was designed to observe the protective effect of Tet on sodium taurocholate-induced severe acute pancreatitis (SAP). The rat model of SAP was induced by retrograde bile duct injection of sodium taurocholate and then treated with Verapamil and Tet. The results showed that Tet can reduce NF-κB activation in pancreas issue, inhibit the SAP cascade, and improve SAP through inducing pancreas acinar cell apoptosis and stabilizing intracellular calcium in the pancreas, thus mitigating the damage to the pancreas. Our study revealed that Tet may reduce systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndromes (MODS) to protect against damage, and these roles may be mediated through the NF-κB pathway to improve the proinflammatory/anti-inflammatory imbalance. PMID:26557854

  12. Cryosurgery: ultrastructural changes in pancreas tissue after low temperature exposure.

    PubMed

    Korpan, N N

    2007-04-01

    A number of theoretical and experimental studies, both in vitro and in vivo, have been performed to explain the action of low temperatures on tissue. It is now evident that the thermal parameters used in the past for freezing during cryosurgery were not precise; this may have resulted in the failure of treatment. For the first time, this report describes the early ultrastructural features of pancreatic parenchyma after low temperature exposure, i.e., cryosurgery, in vivo. We demonstrate the effect of freeze-thawing processes using temperatures of various intensities. The cryosurgical response of pancreas parenchyma, i.e., ultrastructural cellular changes in pancreas tissue, was investigated. The electronic microscopic analysis showed that, after local cryodestruction at temperatures of -80 degrees C and -180 degrees C, similar processes occurred within the pancreas tissue in the early postcryosurgical phase -- immediately and up to 24 hours after low temperature exposure on tissue. The exocrine pancreatic cells in the center of the cryozone changed upon thawing. Ultrastructural changes in the exocrine pancreatic cells, where the first signs of dystrophic processes had been noticed, were increased. These ultrastructural changes in the pancreatic cells provide a platform to better understand the mechanisms of damage and the pathogenesis of frostbite after cryosurgery. The properties of the pancreas parenchyma response after low temperature exposure provide important insights into the mechanisms of damage and the cryogenic lesion immediately after thawing in cryosurgery. Our new insights prove on the cell level that suddenly and progressively damaged pancreatic cells in the postcryosurgical zone lead to aseptic cryonecrosis and then to aseptic cryoapoptosis of vital normal tissue. The vascular capillary changes and circulatory stagnation demonstrate the anti-angiogenesis mechanism, which, together with cryoaponecrosis and cryoapoptosis, are some of the main mechanisms

  13. Dynamic development of the pancreas from birth to adulthood

    PubMed Central

    Aguayo-Mazzucato, Cristina; Weir, Gordon C.

    2016-01-01

    After birth the endocrine pancreas continues its development, a complex process that involves both the maturation of islet cells and a marked expansion of their numbers. New beta cells are formed both by duplication of pre-existing cells and by new differentiation (neogenesis) across the first postnatal weeks, with the result of beta cells of different stages of maturation even after weaning. Improving our understanding of this period of beta cell expansion could provide valuable therapeutic insights. PMID:26998806

  14. Dynamic development of the pancreas from birth to adulthood.

    PubMed

    Bonner-Weir, Susan; Aguayo-Mazzucato, Cristina; Weir, Gordon C

    2016-05-01

    After birth the endocrine pancreas continues its development, a complex process that involves both the maturation of islet cells and a marked expansion of their numbers. New beta cells are formed both by duplication of pre-existing cells and by new differentiation (neogenesis) across the first postnatal weeks, with the result of beta cells of different stages of maturation even after weaning. Improving our understanding of this period of beta cell expansion could provide valuable therapeutic insights. PMID:26998806

  15. Monitoring Artificial Pancreas Trials Through Agent-based Technologies

    PubMed Central

    Scarpellini, Stefania; Di Palma, Federico; Toffanin, Chiara; Del Favero, Simone; Magni, Lalo; Bellazzi, Riccardo

    2014-01-01

    The increase in the availability and reliability of network connections lets envision systems supporting a continuous remote monitoring of clinical parameters useful either for overseeing chronic diseases or for following clinical trials involving outpatients. We report here the results achieved by a telemedicine infrastructure that has been linked to an artificial pancreas platform and used during a trial of the AP@home project, funded by the European Union. The telemedicine infrastructure is based on a multiagent paradigm and is able to deliver to the clinic any information concerning the patient status and the operation of the artificial pancreas. A web application has also been developed, so that the clinic staff and the researchers involved in the design of the blood glucose control algorithms are able to follow the ongoing experiments. Albeit the duration of the experiments in the trial discussed in the article was limited to only 2 days, the system proved to be successful for monitoring patients, in particular overnight when the patients are sleeping. Based on that outcome we can conclude that the infrastructure is suitable for the purpose of accomplishing an intelligent monitoring of an artificial pancreas either during longer trials or whenever that system will be used as a routine treatment. PMID:24876570

  16. Mallotus roxburghianus modulates antioxidant responses in pancreas of diabetic rats.

    PubMed

    Roy, V K; Chenkual, L; Gurusubramanian, G

    2016-03-01

    Mallotus roxburghianus has long been used by Mizo tribal people for the treatment of diabetes. Scientific validation at known doses may provide information about its safety and efficacy. Methanolic leaf extract of M. roxburghianus (MRME 100 and 400mg/kg) was tested in comparison with normal and alloxan diabetic rats for 28 days p.o. in terms of body and pancreatic weight, blood glucose level, antioxidant enzymes, expression of visfatin and PCNA, histopathology and histomorphometric measurements of pancreas. The results were evaluated statistically using ANOVA, correlation and regression and Principal component analysis (PCO). MRME (100 and 400mg/kg) treatment significantly (p<0.0001) decreased the body weight, blood glucose level, improved the mass and size of pancreas, elevated the levels of antioxidant enzymes and up regulate the expression of visfatin and PCNA. PCO analysis was good to fitness and prediction distinguishes the therapeutic effects of M. roxburghianus from the alloxan induced diabetic rats. MRME has significant role in protecting animals from alloxan-induced diabetic oxidative stress in pancreas and exhibited promising antihyperglycaemic and antioxidant activities along with significant reversal of disturbed antioxidant status and lipid peroxidative damage. Pancreatic architecture and physiology under diabetic oxidative stress have been significantly modulated by MRME and validated as a drug candidate for antidiabetic treatment. M. roxburghianus treatment restores the antioxidant enzyme system and rejuvenates the islets mass in alloxanized rat by accelerating visfatin and PCNA expression in pancreatic tissue. PMID:26764087

  17. Composite pheochromocytoma masquerading as solid-pseudopapillary neoplasm of pancreas.

    PubMed

    Gupta, Geetanjali; Saran, Ravindra Kumar; Godhi, Satyajit; Srivastava, Siddharth; Saluja, Sundeep Singh; Mishra, Pramod Kumar

    2015-05-16

    Pheochromocytoma and ganglioneuroma form rare composite tumours of the adrenal medulla comprising less than 3% of all sympathoadrenal tumours. We present a case of intraoperatively detected adrenal medullary tumour of composite pheochromocytoma and ganglioneuroma diagnosed on histopathology, in a normotensive patient. A 50-year-old male with a past history of chronic obstructive pulmonary disease presented with abdominal pain and significant weight loss since one month. Ultrasound and contrast-enhanced computed tomography abdomen revealed a large lobulated lesion in the distal body and tail of pancreas suggestive of solid and papillary neoplasm of body and tail of pancreas. Intra-operatively, a 15 cm × 10 cm solid lesion with cystic areas was seen arising from the left lower pole of the adrenal gland pushing the pancreas which appeared unremarkable. In our case, exploratory laparotomy with tumour excision was done. Extensive sectioning and microscopic examination of this adrenal tumour confirmed a diagnosis of composite Pheochromocytoma with Ganglioneuroma on histopathology. Immunophenotyping with S-100 further supported the diagnosis. The goal of this report is to increase the awareness of this rare disease and to further identify its variable presentation. PMID:25984524

  18. Making β(-like)-cells from exocrine pancreas.

    PubMed

    Staels, W; De Groef, S; Bussche, L; Leuckx, G; Van de Casteele, M; De Leu, N; Baeyens, L; Heremans, Y; Heimberg, H

    2016-09-01

    Creating an abundant source of β(-like)-cells has been a major goal in diabetes research for many decades. The concept of cell plasticity has inspired many strategies towards regenerative medicine, but its successes have been limited until very recently. Today, most cell types in the pancreas are considered candidates for the generation of β(-like)-cells through transdifferentiation. While β(-like)-cells that are in vitro differentiated from human embryonic stem cells are already being grafted in patients, β(-like)-cells generated by transdifferentiation are not yet ready for clinical application. These cells would however offer several advantages over the current β(-like)-cells generated by directed differentiation, especially concerning safety issues. In addition, perfect control of the transdifferentiation efficiency would through targeted drug delivery support a non-invasive cell therapy for diabetes. Lastly, focusing on the exocrine pancreas as prime candidate makes sense in view of their abundance and high plasticity. Keeping these hopeful perspectives in mind, it is worth to continue focused research on the mechanisms that control transdifferentiation from pancreas exocrine to β-cells. PMID:27615144

  19. Designing an artificial pancreas architecture: the AP@home experience.

    PubMed

    Lanzola, Giordano; Toffanin, Chiara; Di Palma, Federico; Del Favero, Simone; Magni, Lalo; Bellazzi, Riccardo

    2015-12-01

    The latest achievements in sensor technologies for blood glucose level monitoring, pump miniaturization for insulin delivery, and the availability of portable computing devices are paving the way toward the artificial pancreas as a treatment for diabetes patients. This device encompasses a controller unit that oversees the administration of insulin micro-boluses and continuously drives the pump based on blood glucose readings acquired in real time. In order to foster the research on the artificial pancreas and prepare for its adoption as a therapy, the European Union in 2010 funded the AP@home project, following a series of efforts already ongoing in the USA. This paper, authored by members of the AP@home consortium, reports on the technical issues concerning the design and implementation of an architecture supporting the exploitation of an artificial pancreas platform. First a PC-based platform was developed by the authors to prove the effectiveness and reliability of the algorithms responsible for insulin administration. A mobile-based one was then adopted to improve the comfort for the patients. Both platforms were tested on real patients, and a description of the goals, the achievements, and the major shortcomings that emerged during those trials is also reported in the paper. PMID:25430423

  20. [A case of chronic pancreatitis occurring in gastric aberrant pancreas poorly distinguishable from gastric aberrant pancreas ductal carcinoma].

    PubMed

    Ogawa, Sayaka; Miyaoka, Youichi; Fujiwara, Aya; Tsukano, Kousuke; Kotani, Satoshi; Yamanouchi, Satoshi; Kusunoki, Ryusaku; Ito, Satoko; Fujishiro, Hirofumi; Kohge, Nariaki; Onuma, Hideyuki

    2015-11-01

    A man in his 40s was referred to our hospital with abdominal pain. A gastric submucosal tumor (SMT) was diagnosed nine years previously, but the patient was lost to follow-up. Upon our evaluation, the SMT had enlarged, as demonstrated by esophagogastroduodenoscopy and abdominal computed tomography. Endoscopic ultrasonography revealed a hypoechoic and isoechoic mosaic mass, which primarily occupied the third and fourth layers of the gastric wall. Aspiration cytodiagnosis was performed, the results of which led to a suspicion of adenocarcinoma arising from gastric ectopic pancreas. Next, we conducted segmental gastrectomy. Pathological examination showed adiponecrosis, a pancreatic stone, chronic inflammatory cell infiltration, and fibrosis. Thus, the patient was diagnosed with chronic pancreatitis occurring in a gastric aberrant pancreas. PMID:26537325

  1. A Revised Classification System and Recommendations From the Baltimore Consensus Meeting for Neoplastic Precursor Lesions in the Pancreas.

    PubMed

    Basturk, Olca; Hong, Seung-Mo; Wood, Laura D; Adsay, N Volkan; Albores-Saavedra, Jorge; Biankin, Andrew V; Brosens, Lodewijk A A; Fukushima, Noriyoshi; Goggins, Michael; Hruban, Ralph H; Kato, Yo; Klimstra, David S; Klöppel, Günter; Krasinskas, Alyssa; Longnecker, Daniel S; Matthaei, Hanno; Offerhaus, G Johan A; Shimizu, Michio; Takaori, Kyoichi; Terris, Benoit; Yachida, Shinichi; Esposito, Irene; Furukawa, Toru

    2015-12-01

    distinguish them from IPMN. (7) Human lesions resembling the acinar to ductal metaplasia and atypical flat lesions of genetically engineered mouse models exist and may reflect an alternate pathway of carcinogenesis; however, their biological significance requires further study. These revised recommendations are expected to improve our management and understanding of precursor lesions in the pancreas. PMID:26559377

  2. The fetal/neonatal mouse liver exhibits transcriptional features of the adult pancreas.

    EPA Science Inventory

    Metabolic homeostasis of the organism is maintained by the liver’s ability to detoxify and eliminate xenobiotics through the expression of xenobiotic metabolism enxymes (XME). The fetus and neonate have been hypothesized to exhibit increased sensitivity to xenobiotic toxicity. T...

  3. Streptozotocin induces endoplasmic reticulum stress and apoptosis via disruption of calcium homeostasis in mouse pancreas.

    PubMed

    Ahn, Changhwan; An, Beum-Soo; Jeung, Eui-Bae

    2015-09-01

    Calcium homeostasis refers to the regulation of calcium ion concentration in the body. This concentration is tightly controlled by a stabilizing system consisting of calcium channels and calcium buffering proteins. Calcium homeostasis is crucial for cell survival. Various forms of cell death (e.g., necrosis and apoptosis) also share calcium signaling pathways and molecular effectors. Calcium acts not only as a ubiquitous second messenger involved in apoptosis along with various cell death inducers but also a regulator for the synthesis of enzymes/hormones such as insulin. We hypothesized that streptozotocin disrupts calcium homeostasis and the altered intracellular calcium levels may induce cell death. After streptozotocin administration, blood glucose level was increased while insulin levels decreased. The expression of insulin response markers also decreased relative to the vehicle group. L-type voltage-gated calcium channel expression and sarcoplasmic reticulum Ca(2+) ATPase were increased by streptozotocin. Calcium buffering protein calbindin-D9k and calmodulin family members were also increased. The expression of genes involved in transporting calcium ions to the endoplasmic reticulum (ER) was decrease while the expression of those affecting the removal of calcium from the ER was increased. Depletion of calcium from the ER leads to ER-stress and can induce apoptosis. In the streptozotocin-treatment group, apoptosis markers were increased. Taken together, these results imply that the disruption of calcium homeostasis by streptozotocin induces ER-stress and leads to the apoptosis of pancreatic cells. Additionally, findings from this study suggest that imbalances in calcium homeostasis could promote pancreatic beta cell death and result in type I diabetes. PMID:26003140

  4. Constitutively active Akt1 expression in mouse pancreas requires S6 kinase 1 for insulinoma formation

    PubMed Central

    Alliouachene, Samira; Tuttle, Robyn L.; Boumard, Stephanie; Lapointe, Thomas; Berissi, Sophie; Germain, Stephane; Jaubert, Francis; Tosh, David; Birnbaum, Morris J.; Pende, Mario

    2008-01-01

    Factors that promote pancreatic β cell growth and function are potential therapeutic targets for diabetes mellitus. In mice, genetic experiments suggest that signaling cascades initiated by insulin and IGFs positively regulate β cell mass and insulin secretion. Akt and S6 kinase (S6K) family members are activated as part of these signaling cascades, but how the interplay between these proteins controls β cell growth and function has not been determined. Here, we found that although transgenic mice overexpressing the constitutively active form of Akt1 under the rat insulin promoter (RIP-MyrAkt1 mice) had enlarged β cells and high plasma insulin levels, leading to improved glucose tolerance, a substantial proportion of the mice developed insulinomas later in life, which caused decreased viability. This oncogenic transformation tightly correlated with nuclear exclusion of the tumor suppressor PTEN. To address the role of the mammalian target of rapamycin (mTOR) substrate S6K1 in the MyrAkt1-mediated phenotype, we crossed RIP-MyrAkt1 and S6K1-deficient mice. The resulting mice displayed reduced insulinemia and glycemia compared with RIP-MyrAkt1 mice due to a combined effect of improved insulin secretion and insulin sensitivity. Importantly, although the increase in β cell size in RIP-MyrAkt1 mice was not affected by S6K1 deficiency, the hyperplastic transformation required S6K1. Our results therefore identify S6K1 as a critical element for MyrAkt1-induced tumor formation and suggest that it may represent a useful target for anticancer therapy downstream of mTOR. PMID:18846252

  5. Acute Bronchitis

    MedlinePlus

    ... or though physical contact (for example, on unwashed hands). Being exposed to tobacco smoke, air pollution, dusts, vapors, and fumes can also cause acute bronchitis. Less often, bacteria can also cause acute bronchitis. To diagnose acute ...

  6. Cystitis - acute

    MedlinePlus

    Uncomplicated urinary tract infection; UTI - acute; Acute bladder infection; Acute bacterial cystitis ... control. Menopause also increases the risk for a urinary tract infection. The following also increase your chances of having ...

  7. Characterization of Antibodies to Products of Proinsulin Processing Using Immunofluorescence Staining of Pancreas in Multiple Species

    PubMed Central

    Asadi, Ali; Bruin, Jennifer E.

    2015-01-01

    The efficient processing of proinsulin into mature insulin and C-peptide is often compromised under conditions of beta cell stress, including diabetes. Impaired proinsulin processing has been challenging to examine by immunofluorescence staining in pancreas tissue because the characterization of antibodies specific for proinsulin, proinsulin intermediates, processed insulin and C-peptide has been limited. This study aimed to identify and characterize antibodies that can be used to detect products of proinsulin processing by immunofluorescence staining in pancreata from different species (mice, rats, dog, pig and human). We took advantage of several knockout mouse lines that lack either an enzyme involved in proinsulin processing or an insulin gene. Briefly, we report antibodies that are specific for several proinsulin processing products, including: a) insulin or proinsulin that has been appropriately processed at the B-C junction; b) proinsulin with a non-processed B-C junction; c) proinsulin with a non-processed A-C junction; d) rodent-specific C-peptide 1; e) rodent-specific C-peptide 2; and f) human-specific C-peptide or proinsulin. In addition, we also describe two ‘pan-insulin’ antibodies that react with all forms of insulin and proinsulin intermediates, regardless of the species. These antibodies are valuable tools for studying proinsulin processing by immunofluorescence staining and distinguishing between proinsulin products in different species. PMID:26216140

  8. A case of MUC5AC-positive intraductal neoplasm of the pancreas classified as an intraductal tubulopapillary neoplasm?

    PubMed

    Muraki, Takashi; Uehara, Takeshi; Sano, Kenji; Oota, Hiroyoshi; Yoshizawa, Akihiko; Asaka, Shiho; Tateishi, Ayako; Otsuki, Toshiaki; Shingu, Kunihiko; Matoba, Hisanori; Kobayashi, Shota; Ichimata, Shojiro; Watanabe, Takayuki; Itou, Tetsuya; Tanaka, Eiji

    2015-12-01

    This report describes a unique case of intraductal tubulopapillary neoplasm (ITPN) of the pancreas in order to clarify its oncogenesis and more precisely classify pancreatic intraductal neoplasms. A 74-year-old man visited our institution for follow-up of acute pancreatitis. Imaging examinations revealed a hypovascular intraductal mass in the head of the pancreas with progressive dilation of the pancreatic duct, atrophy of the pancreatic parenchyma, and a non-mucinous appearance. A pancreatoduodenectomy was performed to identify this pancreatic intraductal neoplasm. Macroscopically, the tumor was a solid nodular mass with no visibly secreted mucin obstructing the dilated ducts. Histologically, it had a homogeneous appearance with nodules of back-to-back tubular glands and occasional papillary elements, and there were no apparent transitions to areas with less marked cytoarchitectural atypia. Although the intraductal neoplastic growth corresponded to an ITPN, immunohistochemical staining revealed partial positivity for MUC5AC, for which ITPNs are characteristically negative. Somatic mutations in KRAS, GNAS, BRAF, and PIK3CA were not detected. A loss of MUC5AC expression and mutations in KRAS and GNAS are key elements in the diagnosis of ITPN. Thus, it was difficult to distinguish the present case as a pancreatobiliary-type (PB-type) intraductal papillary mucinous neoplasm (IPMN) or a phenotypic variant of ITPN. As it is possible that some cases of PB-type IPMN and ITPN overlap, the precise classification of these rare lesions may require re-evaluation. PMID:26586167

  9. [Tertiary syphilis of the pancreas and liver in 82-year-old patient: case study].

    PubMed

    Denisova, T L; Tiul'tiaeva, L A; Lipatova, T E; Bakulev, A L; Alipova, L N; Apanasevich, A V; Bezrodnaia, L A; Borisova, E A

    2013-01-01

    It has been described a clinical case of late diagnosis of syphilis of the pancreas and liver of elderly patients. Two years before that it was wrongly diagnosed with cancer of the pancreas with liver metastases, and the patient was operated on with the imposition of cholecystostomy. It was conducted appropriate therapy and reconstructive surgery after verification of the diagnosis of syphilis of the pancreas and liver. PMID:24772875

  10. Intracellular Hmgb1 Inhibits Inflammatory Nucleosome Release and Limits Acute Pancreatitis in Mice

    PubMed Central

    Kang, Rui; Zhang, Qiuhong; Hou, Wen; Yan, Zhenwen; Chen, Ruochan; Bonaroti, Jillian; Bansal, Preeti; Billiar, Timothy R.; Tsung, Allan; Wang, Qingde; Bartlett, David L.; Whitcomb, David C; Chang, Eugene B.; Zhu, Xiaorong; Wang, Haichao; Lu, Ben; Tracey, Kevin J.; Cao, Lizhi; Fan, Xue-Gong; Lotze, Michael T.; Zeh, Herbert J.; Tang, Daolin

    2014-01-01

    BACKGROUND & AIMS: High mobility group box 1 (HMGB1) is an abundant protein that regulates chromosome architecture and also functions as a damage-associated molecular pattern molecule. Little is known about its intracellular roles in response to tissue injury or during subsequent local and systemic inflammatory responses. We investigated the function of Hmgb1 in mice following induction of acute pancreatitis. METHODS: We utilized a Cre/LoxP system to create mice with pancreas-specific disruption in Hmbg1 (Pdx1-Cre; HMGB1flox/flox mice). Acute pancreatitis was induced in these mice (HMGB1flox/flox mice served as controls) following injection of L-arginine or cerulein. Pancreatic tissues and acinar cells were collected and analyzed by histologic, immunoblot, and immunohistochemical analyses. RESULTS: Following injection of L-arginine or cerulein, Pdx1-Cre; HMGB1flox/flox mice developed acute pancreatitis more rapidly than controls, with increased mortality. Pancreatic tissues of these mice also had higher levels of serum amylase, acinar cell death, leukocyte infiltration, and interstitial edema than controls. Pancreatic tissues and acinar cells collected from the Pdx1-Cre; HMGB1flox/flox mice following L-arginine- or cerulein injection demonstrated nuclear catastrophe with greater nucleosome release when compared with controls, along with increased phosphorylation/activation of RELA Nfκb, degradation of Iκb, and phosphorylation of Mapk. Inhibitors of reactive oxygen species (N-acetyl-L-cysteine) blocked L-arginine–induced DNA damage, necrosis, apoptosis, release of nucleosomes, and activation of Nfκb in pancreatic tissues and acinar cells from Pdx1-Cre; HMGB1flox/flox and control mice. Exogenous genomic DNA and recombinant histone H3 proteins significantly induced release of HMGB1 from mouse macrophages; administration of antibodies against H3 to mice reduced serum levels of HMGB1 and increased survival following L-arginine injection. CONCLUSIONS: In 2 mouse

  11. An artificial pancreas for automated blood glucose control in patients with Type 1 diabetes.

    PubMed

    Schmidt, Signe; Boiroux, Dimitri; Ranjan, Ajenthen; Jørgensen, John Bagterp; Madsen, Henrik; Nørgaard, Kirsten

    2015-01-01

    Automated glucose control in patients with Type 1 diabetes is much-coveted by patients, relatives and healthcare professionals. It is the expectation that a system for automated control, also know as an artificial pancreas, will improve glucose control, reduce the risk of diabetes complications and markedly improve patient quality of life. An artificial pancreas consists of portable devices for glucose sensing and insulin delivery which are controlled by an algorithm residing on a computer. The technology is still under development and currently no artificial pancreas is commercially available. This review gives an introduction to recent progress, challenges and future prospects within the field of artificial pancreas research. PMID:26001176

  12. Solid Serous Adenoma of the Pancreas: A Case Report and Review of the Literature.

    PubMed

    Katsourakis, Anastasios; Dimitriou, Ioannis; Noussios, Georgios; Chatzis, Iosiph; Chatzitheoclitos, Efthimios

    2016-01-01

    Herein, we report a case of a solid-type serous cystadenoma of the pancreas which is the 16th case reported worldwide and the first ever reported in Greece. Magnetic resonance imaging showed a hypervascular mass in the tail of the pancreas of a 72-year-old female who presented with mild abdominal pain. Distal pancreatectomy was performed by laparotomy and histological and immunohistochemical examination revealed a solid-type serous cystadenoma of the pancreas. Preoperative diagnosis of a solid-type serous cystadenoma of the pancreas is difficult, and, due to its benign nature, simple excision of the tumor is the recommended treatment. PMID:27525151

  13. Solid Serous Adenoma of the Pancreas: A Case Report and Review of the Literature

    PubMed Central

    Noussios, Georgios

    2016-01-01

    Herein, we report a case of a solid-type serous cystadenoma of the pancreas which is the 16th case reported worldwide and the first ever reported in Greece. Magnetic resonance imaging showed a hypervascular mass in the tail of the pancreas of a 72-year-old female who presented with mild abdominal pain. Distal pancreatectomy was performed by laparotomy and histological and immunohistochemical examination revealed a solid-type serous cystadenoma of the pancreas. Preoperative diagnosis of a solid-type serous cystadenoma of the pancreas is difficult, and, due to its benign nature, simple excision of the tumor is the recommended treatment. PMID:27525151

  14. TRPV1 and TRPA1 antagonists prevent the transition of acute to chronic inflammation and pain in chronic pancreatitis

    PubMed Central

    Schwartz, Erica S.; La, Jun-Ho; Scheff, Nicole N.; Davis, Brian M.; Albers, Kathryn M.; Gebhart, G.F.

    2013-01-01

    Visceral afferents expressing transient receptor potential channels TRPV1 and TRPA1 are thought to be required for neurogenic inflammation and development of inflammatory hyperalgesia. In a mouse model of chronic pancreatitis (CP) produced by repeated episodes (twice/wk) of caerulein-induced acute pancreatitis (AP), we studied involvement of these TRP channels in pancreatic inflammation and pain-related behaviors. Antagonists of the two TRP channels were administered at different times to block the neurogenic component of AP. Six bouts of AP (over 3 wks) increased pancreatic inflammation and pain-related behaviors, produced fibrosis, sprouting of pancreatic nerve fibers and increased TRPA1 and TRPV1 gene transcripts and a nociceptive marker, pERK, in pancreas afferent somata. Treatment with TRP antagonists, when initiated prior to week 3, decreased pancreatic inflammation and pain-related behaviors and also blocked development of histopathological changes in the pancreas and upregulation of TRPV1, TRPA1 and pERK in pancreatic afferents. Continued treatment with TRP antagonists blocked development of CP and pain behaviors even when mice were challenged with seven more weeks of twice/wk caerulein. When started after week 3, however, treatment with TRP antagonists was ineffective in blocking the transition from AP to CP and the emergence of pain behaviors. These results suggest 1) an important role for neurogenic inflammation in pancreatitis and pain-related behaviors, 2) there is transition from AP to CP, after which TRP channel antagonism is ineffective, and thus 3) that early intervention with TRP channel antagonists may effectively attenuate the transition to and development of CP. PMID:23536075

  15. Acute selective ablation of rat insulin promoter-expressing (RIPHER) neurons defines their orexigenic nature

    PubMed Central

    Rother, Eva; Belgardt, Bengt F.; Tsaousidou, Eva; Hampel, Brigitte; Waisman, Ari; Myers, Martin G.; Brüning, Jens C.

    2012-01-01

    Rat insulin promoter (RIP)-expressing neurons in the hypothalamus control body weight and energy homeostasis. However, genetic approaches to study the role of these neurons have been limited by the fact that RIP expression is predominantly found in pancreatic β-cells, which impedes selective targeting of neurons. To define the function of hypothalamic RIP-expressing neurons, we set out to acutely and selectively eliminate them via diphtheria toxin-mediated ablation. Therefore, the diphtheria toxin receptor transgene was specifically expressed upon RIP-specific Cre recombination using a RIP-Cre line first described by Herrera (RIPHER-Cre) [Herrera PL (2000) Development 127:2317–2322]. Using proopiomelanocortin–expressing cells located in the arcuate nucleus of the hypothalamus and in the pituitary gland as a model, we established a unique protocol of intracerebroventricular application of diphtheria toxin to efficiently ablate hypothalamic cells with no concomitant effect on pituitary proopiomelanocortin–expressing corticotrophs in the mouse. Using this approach to ablate RIPHER neurons in the brain, but not in the pancreas, resulted in decreased food intake and loss of body weight and fat mass. In addition, ablation of RIPHER neurons caused increased c-Fos immunoreactivity of neurons in the paraventricular nucleus (PVN) of the hypothalamus. Moreover, transsynaptic tracing of RIPHER neurons revealed labeling of neurons located in the PVN and dorsomedial hypothalamic nucleus. Thus, our experiments indicate that RIPHER neurons inhibit anorexigenic neurons in the PVN, revealing a basic orexigenic nature of these cells. PMID:23064638

  16. US Findings in Patients at Risk for Pancreas Transplant Failure.

    PubMed

    Morgan, Tara A; Smith-Bindman, Rebecca; Harbell, Jack; Kornak, John; Stock, Peter G; Feldstein, Vickie A

    2016-07-01

    Purpose To determine if ultrasonographic (US) findings, including Doppler US findings, are associated with subsequent pancreas transplant failure. Materials and Methods A cohort of adult patients who underwent pancreas transplantation at a tertiary institution over the course of 10 years (from 2003 to 2012) was retrospectively evaluated for failure, which was defined as return to insulin therapy or surgical graft removal. The institutional review board provided a waiver of informed consent. All US images obtained within the 1st postoperative year were reviewed for three findings: arterial flow (presence or absence of intraparenchymal forward diastole flow), splenic vein thrombus, and edema. These findings were correlated with pancreas graft failure within 1-year after surgery by using Cox proportional hazards models and hazard ratios. Results A total of 228 transplants were included (mean patient age, 41.6 years; range, 19-57 years; 122 men, 106 women). Absent or reversed arterial diastolic flow was identified in nine of 20 failed transplants (sensitivity, 45%; 95% confidence interval [CI]: 23, 68) and in 15 of 208 transplants that survived (specificity, 93% [193 of 208]; 95% CI: 89, 96). The Cox proportional hazard ratio was 6.2 (95% CI: 3.1, 12.4). Splenic vein thrombus was identified in 10 of 20 failed transplants (sensitivity, 50%; 95% CI: 27, 73) and in 25 of 208 transplants that survived (specificity, 88% [183 of 208]; 95% CI: 83, 92). The Cox proportional hazard ratio was 4.2 (95% CI: 2.4, 7.4). Edema had the lowest specificity (Cox proportional hazard ratio, 2.0; 95% CI: 1.3, 2.9). In the multivariate analysis, only absent or reversed arterial diastolic flow remained significantly associated with transplant failure (adjusted hazard ratio, 3.6; 95% CI: 1.0, 12.8; P = .045). Conclusion Absent or reversed diastolic arterial Doppler flow has a stronger association with transplant failure than does splenic vein thrombus or edema. (©) RSNA, 2016. PMID:26807892

  17. Sclerosing mesenteritis involving the pancreas: A mimicker of pancreatic cancer

    PubMed Central

    Scudiere, Jennifer R.; Shi, Chanjuan; Hruban, Ralph H.; Herman, Joseph; Fishman, Elliot K.; Schulick, Richard D.; Wolfgang, Christopher L.; Makary, Martin A.; Thornton, Katherine; Montgomery, Elizabeth; Horton, Karen M.

    2010-01-01

    Sclerosing mesenteritis (SM), also known as mesenteric lipodystrophy, rarely involves the parenchyma of the pancreas. When sclerosing mesenteritis does involve the pancreas, it can mimic pancreatic carcinoma both clinically and radiographically with pain, obstructive jaundice, a mass lesion and even the appearance of vascular invasion. We report 6 patients with sclerosing mesenteritis involving the pancreas (mean age 43.2 years, 5 female), and review their clinical presentation, radiographic findings, pathology, and outcome. Five of these 6 patients were originally thought to have a primary pancreatic neoplasm. Initial presenting clinical information was available for each patient: all 6 reported abdominal or epigastric pain, 3 reported weight loss, and 2 reported one or more of the following: back pain, fever, abdominal bloating/distention, nausea with/without vomiting, and anorexia. The lesions formed masses with an infiltrative pattern, and all had three key histologic features: fibrosis, chronic inflammation, and fat necrosis—without a known etiology. The inflammatory infiltrate was composed of a mixture of lymphocytes, plasma cells, and scattered eosinophils. Of the five patients with post-treatment clinical information available, four had at least a partial response to treatment with steroids, tamoxifen, azathioprine, resection, or a combination of these, and 1 did not respond. A dramatic response to immunosuppressive therapy is illustrated by the case of a 46-year-old woman who presented with the presumptive diagnosis of an unresectable pancreatic cancer. Distinguishing sclerosing mesenteritis from pancreatic carcinoma is crucial to appropriate management, as patients with sclerosing mesenteritis may benefit from immunosuppressive therapy. PMID:20351487

  18. Automatic Data Processing to Achieve a Safe Telemedical Artificial Pancreas

    PubMed Central

    Hernando, M. Elena; García-Sáez, Gema; Martínez-Sarriegui, Iñaki; Rodríguez-Herrero, Agustín; Pérez-Gandía, Carmen; Rigla, Mercedes; de Leiva, Alberto; Capel, Ismael; Pons, Belén; Gómez, Enrique J.

    2009-01-01

    Background The use of telemedicine for diabetes care has evolved over time, proving that it contributes to patient self-monitoring, improves glycemic control, and provides analysis tools for decision support. The timely development of a safe and robust ambulatory artificial pancreas should rely on a telemedicine architecture complemented with automatic data analysis tools able to manage all the possible high-risk situations and to guarantee the patient's safety. Methods The Intelligent Control Assistant system (INCA) telemedical artificial pancreas architecture is based on a mobile personal assistant integrated into a telemedicine system. The INCA supports four control strategies and implements an automatic data processing system for risk management (ADP-RM) providing short-term and medium-term risk analyses. The system validation comprises data from 10 type 1 pump-treated diabetic patients who participated in two randomized crossover studies, and it also includes in silico simulation and retrospective data analysis. Results The ADP-RM short-term risk analysis prevents hypoglycemic events by interrupting insulin infusion. The pump interruption has been implemented in silico and tested for a closed-loop simulation over 30 hours. For medium-term risk management, analysis of capillary blood glucose notified the physician with a total of 62 alarms during a clinical experiment (56% for hyperglycemic events). The ADP-RM system is able to filter anomalous continuous glucose records and to detect abnormal administration of insulin doses with the pump. Conclusions Automatic data analysis procedures have been tested as an essential tool to achieve a safe ambulatory telemedical artificial pancreas, showing their ability to manage short-term and medium-term risk situations. PMID:20144417

  19. [A case of acute pancreatitis and acute hepatitis caused by ingestion of Ceramium kondoi].

    PubMed

    Kim, Da-bin; Cho, Yoo-Kyung; Song, Hyun Joo; Song, Byung-Cheol

    2013-11-01

    In Korea, the use of herbal remedies is a common cause of drug-induced liver injury. However, the occurrence of both acute pancreatitis and acute hepatitis after taking herbal remedies has rarely been reported. Herein, we report a case of concurrent acute pancreatitis and acute hepatitis associated with Ceramium kondoi ingestion. A 58-year-old woman was diagnosed with advanced gastric cancer 7 months ago. Total gastrectomy and adjuvant chemotherapy was performed without complications. The patient had been well until recently, when she presented with severe abdominal pain after ingestion of Ceramium kondoifor 4 weeks. The laboratory findings demonstrated elevated liver enzymes and lipase, and abdominal computed tomography revealed pancreas swelling with fat infiltration. The diagnosis was made based on the diagnostic criteria for drug induced pancreatitis and the Russel Uclaf Causality Assessment Method scale for drug-induced liver injury. After cessation of Ceramium kondoi, she showed clinical and biochemical improvement. PMID:24262598

  20. Agent-based model of macrophage action on endocrine pancreas.

    PubMed

    Martínez, Ignacio V; Gómez, Enrique J; Hernando, M Elena; Villares, Ricardo; Mellado, Mario

    2012-01-01

    This paper proposes an agent-based model of the action of macrophages on the beta cells of the endocrine pancreas. The aim of this model is to simulate the processes of beta cell proliferation and apoptosis and also the process of phagocytosis of cell debris by macrophages, all of which are related to the onset of the autoimmune response in type 1 diabetes. We have used data from the scientific literature to design the model. The results show that the model obtains good approximations to real processes and could be used to shed light on some open questions concerning such processes. PMID:23155767

  1. Solid and papillary epithelial neoplasm of the pancreas

    SciTech Connect

    Friedman, A.C.; Lichtenstein, J.E.; Fishman, E.K.; Oertel, J.E.; Dachman, A.H.; Siegelman, S.S.

    1985-02-01

    Solid and papillary epithelial neoplasm of the pancreas is an uncommon low grade malignant tumor histologically distinct from the usual ductal adenocarcinoma and amenable to cure by surgical excision. It tends to occur in black women in their second or third decade of life and has often been misclassified as nonfunctional islet cell tumor or as cystadenoma or cystadenocarcinoma. Twelve cases were reviewed. Sonography and CT of solid and pipillary epithelial neoplasms depict a well-demarcated mass that can be solid, mixed cystic and solid, or largely cystic. The radiologic appearance is dependent on the maintenance of the integrity of the neoplasm versus the extent of retrogressive changes that have occurred.

  2. Extragastric manifestations of Helicobacter pylori infection: Possible role of bacterium in liver and pancreas diseases.

    PubMed

    Rabelo-Gonçalves, Elizabeth Ma; Roesler, Bruna M; Zeitune, José Mr

    2015-12-28

    Helicobacter pylori (H. pylori) is an ancient microorganism that has co-evolved with humans for over 60000 years. This bacterium typically colonizes the human stomach and it is currently recognized as the most common infectious pathogen of the gastroduodenal tract. Although its chronic infection is associated with gastritis, peptic ulcer, dysplasia, neoplasia, MALT lymphoma and gastric adenocarcinoma, it has been suggested the possible association of H. pylori infection with several extragastric effects including hepatobiliary and pancreatic diseases. Since a microorganism resembling H. pylori was detected in samples from patients with hepatobiliary disorders, several reports have been discussed the possible role of bacteria in hepatic diseases as hepatocellular carcinoma, cirrhosis and hepatic encephalopathy, nonalcoholic fatty liver disease and fibrosis. Additionally, studies have reported the possible association between H. pylori infection and pancreatic diseases, especially because it has been suggested that this infection could change the pancreatic physiology. Some of them have related a possible association between the microorganism and pancreatic cancer. H. pylori infection has also been suggested to play a role in the acute and chronic pancreatitis pathogenesis, autoimmune pancreatitis, diabetes mellitus and metabolic syndrome. Considering that association of H. pylori to liver and pancreas diseases needs further clarification, our work offers a review about the results of some investigations related to the potential pathogenicity of H. pylori in these extragastric diseases. PMID:26730276

  3. Outcomes of Cardiac Surgery in Patients With Previous Solid Organ Transplantation (Kidney, Liver, and Pancreas).

    PubMed

    Vargo, Patrick R; Schiltz, Nicholas K; Johnston, Douglas R; Smedira, Nicholas G; Moazami, Nader; Blackstone, Eugene H; Soltesz, Edward G

    2015-12-15

    A growing number of solid organ transplant survivors require surgery for cardiac disease. We examined the effect of having a previous transplant on outcomes after cardiac surgery in these patients from a population-based perspective. Of 1,709,735 patients who underwent coronary artery bypass grafting, valve, or thoracic aorta surgery from 2004 to 2008 in the Nationwide Inpatient Sample, 3,535 patients (0.21%) had a previous organ transplant (2,712 kidney, 738 liver, 300 pancreas). Multivariate logistic regression analysis and propensity score matching were used to determine the effect of a previous solid organ transplant on outcomes. In-hospital mortality rate was 7% for patients who underwent transplantation versus 4% for patients who did not undergo transplantation (odds ratio [OR] 1.66, 95% confidence interval [CI] 1.16 to 2.38). Patients who underwent transplantation were at an increased risk for acute renal failure (OR 1.62, CI 1.36 to 1.94) and blood transfusions (OR 1.63, CI 1.36 to 1.95). Median length of stay was longer (10 vs 9 days), with greater median total charges ($111,362 vs $102,221; both p <0.001). Occurrence of stroke, gastrointestinal complication, infection, and pneumonia was similar between groups. In conclusion, previous solid organ transplantation is an incremental risk factor for postoperative mortality after cardiac surgery. Renal protective strategies and bleeding control should be stressed to mitigate complications. PMID:26520471

  4. Radiofrequency ablation of the pancreas: protective effect of local cooling techniques.

    PubMed

    Geranios, Angelos; Pikoulis, Emmanouil; Papalois, Apostolos; Kontos, Michael; Agrogiannis, George; Petrou, Athanasios; Pavlakis, Emmanuel; Felekouras, Evangelos

    2015-05-01

    Pancreatic carcinoma is one of the commonest malignant diseases today and the majority of patients are suitable for palliative treatment only. Radiofrequency ablation (RFA) has been used extensively for the treatment of solid organ tumors but little is known on the efficacy and safety of pancreatic ablation. To further investigate the safety of pancreatic RFA, 18 pigs had RFA of the pancreas, close to superior mesenteric vein and duodenum. Group A (nine animals) was protected with peripancreatic cool perfusion and Group B (nine animals) with portal vein (PV) intravenous injection of cool saline. Biochemical and histological evidence suggested lateral thermal injury of the duodenal wall and superior mesenteric vein and acute pancreatitis in most animals. However, clinically and at autopsy, Group B animals fared much better. PV thrombosis, hepatic abscess, duodenal perforation, ascites, and extensive pancreatic necrosis were observed in Group A but not in Group B. The present study suggests that PV cool saline perfusion can prevent major complications caused by pancreatic RFA and may be used in combination with other protective techniques in the clinical setting to reduce RFA-associated morbidity. PMID:25975333

  5. Extragastric manifestations of Helicobacter pylori infection: Possible role of bacterium in liver and pancreas diseases

    PubMed Central

    Rabelo-Gonçalves, Elizabeth MA; Roesler, Bruna M; Zeitune, José MR

    2015-01-01

    Helicobacter pylori (H. pylori) is an ancient microorganism that has co-evolved with humans for over 60000 years. This bacterium typically colonizes the human stomach and it is currently recognized as the most common infectious pathogen of the gastroduodenal tract. Although its chronic infection is associated with gastritis, peptic ulcer, dysplasia, neoplasia, MALT lymphoma and gastric adenocarcinoma, it has been suggested the possible association of H. pylori infection with several extragastric effects including hepatobiliary and pancreatic diseases. Since a microorganism resembling H. pylori was detected in samples from patients with hepatobiliary disorders, several reports have been discussed the possible role of bacteria in hepatic diseases as hepatocellular carcinoma, cirrhosis and hepatic encephalopathy, nonalcoholic fatty liver disease and fibrosis. Additionally, studies have reported the possible association between H. pylori infection and pancreatic diseases, especially because it has been suggested that this infection could change the pancreatic physiology. Some of them have related a possible association between the microorganism and pancreatic cancer. H. pylori infection has also been suggested to play a role in the acute and chronic pancreatitis pathogenesis, autoimmune pancreatitis, diabetes mellitus and metabolic syndrome. Considering that association of H. pylori to liver and pancreas diseases needs further clarification, our work offers a review about the results of some investigations related to the potential pathogenicity of H. pylori in these extragastric diseases. PMID:26730276

  6. Role of histone deacetylases in pancreas: Implications for pathogenesis and therapy

    PubMed Central

    Klieser, Eckhard; Swierczynski, Stefan; Mayr, Christian; Schmidt, Johanna; Neureiter, Daniel; Kiesslich, Tobias; Illig, Romana

    2015-01-01

    In the last years, our knowledge of the pathogenesis in acute and chronic pancreatitis (AP/CP) as well as in pancreatic cancerogenesis has significantly diversified. Nevertheless, the medicinal therapeutic options are still limited and therapeutic success and patient outcome are poor. Epigenetic deregulation of gene expression is known to contribute to development and progression of AP and CP as well as of pancreatic cancer. Therefore, the selective inhibition of aberrantly active epigenetic regulators can be an effective option for future therapies. Histone deacetylases (HDACs) are enzymes that remove an acetyl group from histone tails, thereby causing chromatin compaction and repression of transcription. In this review we present an overview of the currently available literature addressing the role of HDACs in the pancreas and in pancreatic diseases. In pancreatic cancerogenesis, HDACs play a role in the important process of epithelial-mesenchymal-transition, ubiquitin-proteasome pathway and, hypoxia-inducible-factor-1-angiogenesis. Finally, we focus on HDACs as potential therapeutic targets by summarizing currently available histone deacetylase inhibitors. PMID:26691388

  7. Charcot neuroarthropathy after simultaneous pancreas-kidney transplantation: risk factors, prevalence, and outcome.

    PubMed

    García Barrado, Fernando; Kuypers, Dirk R; Matricali, Giovanni A

    2015-08-01

    We retrospectively analyzed outcome and risk factors of developing Charcot foot (CF) in 100 patients with type 1 diabetes mellitus who underwent a simultaneous pancreas-kidney (SPK) transplantation. Patients who developed CF after SPK transplantation had significantly higher mortality (56% vs. 18%) and more frequently graft failure (44% vs. 13%). Recipients with CF also experienced acute rejections more frequently (78% vs. 41%). They furthermore had higher pre-transplant values of HbA1c , received cyclosporine and azathioprine more often, and had significantly higher cumulative corticosteroid use. Patients transplanted in an earlier era (1992-1998) received cyclosporine and azathioprine more often and had a significantly higher cumulative corticosteroid use with the higher prevalence of CF. Conversely, patients with diabetes transplanted more recently (1999-2012) received lower doses of corticosteroids as part of their tacrolimus-based immunosuppressive therapy, resulting in fewer CF attacks. In conclusion, development of CF after SPK is associated with poor patient and graft outcome. Poor pre-transplant diabetic control and the use of high-dose corticosteroids are risk factors for the development of CF. We recommend reduction in or even total avoidance of corticosteroids after SPK transplantation. Given the importance of the diagnosis of CF on outcome, a systematic examination of SPK patients' feet is recommended. PMID:26033225

  8. Redox signaling in acute pancreatitis

    PubMed Central

    Pérez, Salvador; Pereda, Javier; Sabater, Luis; Sastre, Juan

    2015-01-01

    Acute pancreatitis is an inflammatory process of the pancreatic gland that eventually may lead to a severe systemic inflammatory response. A key event in pancreatic damage is the intracellular activation of NF-κB and zymogens, involving also calcium, cathepsins, pH disorders, autophagy, and cell death, particularly necrosis. This review focuses on the new role of redox signaling in acute pancreatitis. Oxidative stress and redox status are involved in the onset of acute pancreatitis and also in the development of the systemic inflammatory response, being glutathione depletion, xanthine oxidase activation, and thiol oxidation in proteins critical features of the disease in the pancreas. On the other hand, the release of extracellular hemoglobin into the circulation from the ascitic fluid in severe necrotizing pancreatitis enhances lipid peroxidation in plasma and the inflammatory infiltrate into the lung and up-regulates the HIF–VEGF pathway, contributing to the systemic inflammatory response. Therefore, redox signaling and oxidative stress contribute to the local and systemic inflammatory response during acute pancreatitis. PMID:25778551

  9. [Severe acute pancreatitis and infection by influenza A (H1N1) virus in a child: case report].

    PubMed

    Rodríguez Schulz, Diego; Martínez, Agustina; Guzmán, María Belén; Robledo, Hugo; Capocasa, Patricia; Martínez, Luz; Garnero, Analía

    2015-08-01

    Acute pancreatitis is an inflammatory disease of the pancreas, characterized by abdominal pain and high level of pancreatic enzymes. Pancreatitis is the most common disease of pancreas in children and adults. For the diagnosis we need 2 of 3 characteristics: abdominal pain characteristic of acute pancreatitis, amylase and/or lipase 3 times higher than the normal upper limit and characteristic findings in images. The etiologies are multiple: trauma, metabolic disease and infections: mixovirus, HIV, measles, coxsackie, hepatitis B, C, cytomegalovirus, varicella, herpes simplex. Three cases of PA associated with H1N1 Influenza virus were reported, only one in a child with uncomplicated features. PMID:26172021

  10. Roles of Commensal Microbiota in Pancreas Homeostasis and Pancreatic Pathologies

    PubMed Central

    Leal-Lopes, Camila; Velloso, Fernando J.; Campopiano, Julia C.; Sogayar, Mari C.; Correa, Ricardo G.

    2015-01-01

    The pancreas plays a central role in metabolism, allowing ingested food to be converted and used as fuel by the cells throughout the body. On the other hand, the pancreas may be affected by devastating diseases, such as pancreatitis, pancreatic adenocarcinoma (PAC), and diabetes mellitus (DM), which generally results in a wide metabolic imbalance. The causes for the development and progression of these diseases are still controversial; therefore it is essential to better understand the underlying mechanisms which compromise the pancreatic homeostasis. The interest in the study of the commensal microbiome increased extensively in recent years, when many discoveries have illustrated its central role in both human physiology and maintenance of homeostasis. Further understanding of the involvement of the microbiome during the development of pathological conditions is critical for the improvement of new diagnostic and therapeutic approaches. In the present review, we discuss recent findings on the behavior and functions played by the microbiota in major pancreatic diseases and provide further insights into its potential roles in the maintenance of pancreatic steady-state activities. PMID:26347203

  11. Postnatal development of the exocrine pancreas in suckling goat kids.

    PubMed

    Lopez, V; Martínez-Victoria, E; Yago, M D; Lupiani, M J; Mañas, M

    1997-04-01

    A total of 25 preruminant Granadina breed goats were used. They were bottle-fed goat milk ad libitum from postnatal day 3 to 28. Until the age of 3 d, kids were fed colostrum. Body weight, pancreas weight, total protein concentration, enzyme activities in pancreatic tissue and hormone concentrations (cortisol, gastrin, T3 and T4) were determined at 3, 7, 14, 21 and 28 d of age. Our results show that the rates of pancreatic synthesis and secretion of chymotrypsin are well developed at birth in the kid, and may compensate for possible deficiencies in gastric and/or enterocytes intracellular proteolysis. In week 4, there was a marked increase in amylase activity, change that can be attributed to the beginning of the transitional period known as weaning. The significant increase in circulating concentration of cortisol during week 4 suggests the involvement of corticosteroid as a mediator of pancreatic development at weaning. Changes in blood levels of this hormone are believed to be important in the expression of amylase in the neonatal period. However, T3-T4 blood levels remained unchanged from d 3 to 28, suggesting that, in the kid, these hormones appear to have no clear influence upon the postnatal development of the exocrine pancreas. PMID:9255407

  12. Role of Connexins and Pannexins in the Pancreas.

    PubMed

    Cigliola, Valentina; Allagnat, Florent; Berchtold, Lukas Adrian; Lamprianou, Smaragda; Haefliger, Jacques-Antoine; Meda, Paolo

    2015-11-01

    The pancreas produces enzymes with a digestive function and hormones with a metabolic function, which are produced by distinct cell types of acini and islets, respectively. Within these units, secretory cells coordinate their functioning by exchanging information via signals that flow in the intercellular spaces and are generated either at distance (several neural and hormonal inputs) or nearby the pancreatic cells themselves (inputs mediated by membrane ionic-specific channels and by ionic- and metabolite-permeant pannexin channels and connexin "hemichannels"). Pancreatic secretory cells further interact via the extracellular matrix of the pancreas (inputs mediated by integrins) and directly with neighboring cells, by mechanisms that do not require extracellular mediators (inputs mediated by gap and tight junction channels). Here, we review the expression and function of the connexins and pannexins that are expressed by the main secretory cells of the exocrine and endocrine pancreatic cells. Available data show that the patterns of expression of these proteins differ in acini and islets, supporting distinct functions in the physiological secretion of pancreatic enzymes and hormones. Circumstantial evidence further suggests that alterations in the signaling provided by these proteins are involved in pancreatic diseases. PMID:26465951

  13. Dorothy Hodgkin Lecture 2013: Artificial Pancreas Project at Cambridge 2013

    PubMed Central

    Hovorka, R.

    2015-01-01

    The development and clinical testing of closed-loop systems (the artificial pancreas) is underpinned by advances in continuous glucose monitoring and benefits from concerted academic and industry collaborative efforts. This review describes the progress of the Artificial Pancreas Project at the University of Cambridge from 2006 to 2014. Initial studies under controlled laboratory conditions, designed to collect representative safety and performance data, were followed by short to medium free-living unsupervised outpatient studies demonstrating the safety and efficacy of closed-loop insulin delivery using a model predictive control algorithm. Accompanying investigations included assessment of the psychosocial impact and key factors affecting glucose control such as insulin kinetics and glucose absorption. Translation to other disease conditions such as critical illness and Type 2 diabetes took place. It is concluded that innovation of iteratively enhanced closed-loop systems will provide tangible means to improve outcomes and quality of life in people with Type 1 diabetes and their families in the next decade. PMID:25819473

  14. Preclinical fluorescent mouse models of pancreatic cancer

    NASA Astrophysics Data System (ADS)

    Bouvet, Michael; Hoffman, Robert M.

    2007-02-01

    Here we describe our cumulative experience with the development and preclinical application of several highly fluorescent, clinically-relevant, metastatic orthotopic mouse models of pancreatic cancer. These models utilize the human pancreatic cancer cell lines which have been genetically engineered to selectively express high levels of the bioluminescent green fluorescent (GFP) or red fluorescent protein (RFP). Fluorescent tumors are established subcutaneously in nude mice, and tumor fragments are then surgically transplanted onto the pancreas. Locoregional tumor growth and distant metastasis of these orthotopic implants occurs spontaneously and rapidly throughout the abdomen in a manner consistent with clinical human disease. Highly specific, high-resolution, real-time visualization of tumor growth and metastasis may be achieved in vivo without the need for contrast agents, invasive techniques, or expensive imaging equipment. We have shown a high correlation between florescent optical imaging and magnetic resonance imaging in these models. Alternatively, transplantation of RFP-expressing tumor fragments onto the pancreas of GFP-expressing transgenic mice may be used to facilitate visualization of tumor-host interaction between the pancreatic tumor fragments and host-derived stroma and vasculature. Such in vivo models have enabled us to serially visualize and acquire images of the progression of pancreatic cancer in the live animal, and to demonstrate the real-time antitumor and antimetastatic effects of several novel therapeutic strategies on pancreatic malignancy. These fluorescent models are therefore powerful and reliable tools with which to investigate human pancreatic cancer and therapeutic strategies directed against it.

  15. Pazopanib-Induced Severe Acute Pancreatitis.

    PubMed

    Kawakubo, Kazumichi; Hata, Hiroo; Kawakami, Hiroshi; Kuwatani, Masaki; Kawahata, Shuhei; Kubo, Kimitoshi; Imafuku, Keisuke; Kitamura, Shinya; Sakamoto, Naoya

    2015-01-01

    Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptors, platelet-derived growth factor receptors, and c-Kit approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Nonselective kinase inhibitors, such as sunitinib and sorafenib, are known to be associated with acute pancreatitis. There are few case reports of severe acute pancreatitis induced by pazopanib treatment. We present a case of severe acute pancreatitis caused by pazopanib treatment for cutaneous angiosarcoma. The patient was an 82-year-old female diagnosed with cutaneous angiosarcoma. She had been refractory to docetaxel treatment and began pazopanib therapy. Three months after pazopanib treatment, CT imaging of the abdomen showed the swelling of the pancreas and surrounding soft tissue inflammation without abdominal pain. After she continued pazopanib treatment for 2 months, she presented with nausea and appetite loss. Abdominal CT showed the worsening of the surrounding soft tissue inflammation of the pancreas. Serum amylase and lipase levels were 296 and 177 IU/l, respectively. She was diagnosed with acute pancreatitis induced by pazopanib treatment and was managed conservatively with discontinuation of pazopanib, but the symptoms did not improve. Subsequently, an abdominal CT scan demonstrated the appearance of a pancreatic pseudocyst. She underwent endoscopic ultrasound-guided pseudocyst drainage using a flared-end fully covered self-expandable metallic stent. Then, the symptoms resolved without recurrence. Due to the remarkable progress of molecular targeted therapy, the oncologist should know that acute pancreatitis was recognized as a potential adverse event of pazopanib treatment and could proceed to severe acute pancreatitis. PMID:26464570

  16. [Incretin-based antidiabetic treatment and diseases of the pancreas (pancreatitis, pancreas carcinoma)].

    PubMed

    Jermendy, György

    2016-04-01

    In the last couple of years incretin-based antidiabetic drugs became increasingly popular and widely used for treating patients with type 2 diabetes. Immediately after launching, case reports and small case series were published on the potential side effects of the new drugs, with special attention to pancreatic disorders such as acute pancreatitis or pancreatic cancer. As clinical observations accumulated, these side-effects were noted with nearly all drugs of this class. Although these side-effects proved to be rare, an intensive debate evolved in the literature. Opinion of diabetes specialists and representatives of pharmaceutical industry as well as position statements of different international scientific boards and health authorities were published. In addition, results of randomized clinical trials with incretin-based therapy and meta-analyses became available. Importantly, in everyday clinical practice, the label of the given drug should be followed. With regards to incretins, physicians should be cautious if pancreatitis in the patients' past medical history is documented. Early differential diagnosis of any abdominal pain during treatment of incretin-based therapy should be made and the drug should be discontinued if pancreatitis is verified. Continuous post-marketing surveillance and side-effect analysis are still justified with incretin-based antidiabetic treatment in patients with type 2 diabetes. PMID:27017851

  17. Exercise increases mitochondrial glutamate oxidation in the mouse cerebral cortex.

    PubMed

    Herbst, Eric A F; Holloway, Graham P

    2016-07-01

    The present study investigated the impact of acute exercise on stimulating mitochondrial respiratory function in mouse cerebral cortex. Where pyruvate-stimulated respiration was not affected by acute exercise, glutamate respiration was enhanced following the exercise bout. Additional assessment revealed that this affect was dependent on the presence of malate and did not occur when substituting glutamine for glutamate. As such, our results suggest that glutamate oxidation is enhanced with acute exercise through activation of the malate-aspartate shuttle. PMID:27184881

  18. Pancreas and Diabetes Mellitus: The Relationship between the Organ and the Disease.

    PubMed

    Menon, Saumya; Rajesh, Gopalakrishna; Balakrishnan, Vallath

    2015-10-01

    Diabetes mellitus has been a fascinating disease from the dawn of medical history. The first breakthrough in its treatment came in 1922, with the discovery of insulin which was extracted from the pancreas of a dog. Even earlier, a relationship between pancreas and diabetes mellitus had been suspected by medical scientists. However, the study of diabetes mellitus is much more than its relationship with the pancreas. On the other hand the pancreas has been known to be a very reclusive organ that is hidden away from physicians and surgeons for centuries. In recent times, it has become more accessible and has yielded some of its secrets. The relationship between the pancreas and diabetes mellitus is a story full of complexities and surprises. This article attempts to reveal some of the important events and persons in the story and the controversies surrounding them. PMID:27608692

  19. Analyses of pancreas development by generation of gfp transgenic zebrafish using an exocrine pancreas-specific elastaseA gene promoter

    SciTech Connect

    Wan Haiyan; Korzh, Svitlana; Li Zhen; Mudumana, Sudha Puttur; Korzh, Vladimir; Jiang Yunjin; Lin Shuo; Gong Zhiyuan . E-mail: dbsgzy@nus.edu.sg

    2006-05-15

    In contrast to what we know on development of endocrine pancreas, the formation of exocrine pancreas remains poorly understood. To create an animal model that allows observation of exocrine cell differentiation, proliferation, and morphogenesis in living animals, we used the zebrafish elastaseA (elaA) regulatory sequence to develop transgenic zebrafish that display highly specific exocrine pancreas expression of GFP in both larvae and adult. By following GFP expression, we found that the pancreas in early development was a relatively compact organ and later extended posterior along the intestine. By transferring the elaA:gfp transgene into slow muscle omitted mutant that is deficient in receiving Hedgehog signals, we further showed that Hedgehog signaling is required for exocrine morphogenesis but not for cell differentiation. We also applied the morpholino knockdown and toxin-mediated cell ablation approaches to this transgenic line. We showed that the development of exocrine pancreas is Islet-1 dependent. Injection of the diphtheria toxin A (DTA) construct under the elastaseA promoter resulted in selective ablation of exocrine cells while the endocrine cells and other endodermal derivatives (liver and intestine) were not affected. Thus, our works demonstrated the new transgenic line provided a useful experimental tool in analyzing exocrine pancreas development.

  20. Identification of the bHLH Factor Math6 as a Novel Component of the Embryonic Pancreas Transcriptional Network

    PubMed Central

    Lynn, Francis C.; Sanchez, Lidia; Gomis, Ramon; German, Michael S.; Gasa, Rosa

    2008-01-01

    Background Basic helix-loop-helix (bHLH) transcription factors play important roles in differentiation processes during embryonic development of vertebrates. In the pancreas, the atonal-related bHLH gene Neurogenin3 (Neurog3) controls endocrine cell fate specification in uncommitted progenitor cells. Therefore, it is likely that Neurog3-regulated factors will have important functions during pancreatic endocrine cell differentiation. The gene for the atonal-related bHLH factor Math6 was recognized as a potential target of Neurog3 in a genomic scale profiling during endocrine differentiation. Herein we have explored the role of Math6 during endocrine pancreas development. Results We demonstrate that the Math6 gene is a direct target of Neurog3 in vitro and that, during mouse development, Math6 is expressed in both endocrine and exocrine pancreatic precursor cells. We have investigated the role of Math6 in endocrine differentiation by over-expressing this factor in pancreatic duct cells. Math6 possesses intrinsic transcriptional repressor activity and, in contrast to Neurog3 it does not induce the endocrine differentiation program; however, it can modulate some of the pro-endocrine functions of Neurog3 in this system. In addition, we show that Math6 is broadly expressed in mouse embryonic tissues and its expression is induced by tissue-specific bHLH genes other than Neurog3. Furthermore, inactivation of the Math6 gene in the mouse results in early embryonic lethality demonstrating an essential role of this factor in organismal development. Conclusions These data demonstrate that Math6 is a novel component of the pancreatic transcriptional network during embryonic development and suggest a potential role for Math6 as a modulator of the differentiation program initiated by the pro-endocrine factor Neurog3. Furthermore, our results demonstrate that Math6 is indispensable for early embryonic development and indicate a more widespread function for this factor in tissue

  1. Mouse models of myasthenia gravis.

    PubMed

    Ban, Joanne; Phillips, William D

    2015-01-01

    Myasthenia gravis is a muscle weakness disease characterized by autoantibodies that target components of the neuromuscular junction, impairing synaptic transmission. The most common form of myasthenia gravis involves antibodies that bind the nicotinic acetylcholine receptors in the postsynaptic membrane. Many of the remaining cases are due to antibodies against muscle specific tyrosine kinase (MuSK). Recently, autoantibodies against LRP4 (another component of the MuSK signaling complex in the postsynaptic membrane) were identified as the likely cause of myasthenia gravis in some patients. Fatiguing weakness is the common symptom in all forms of myasthenia gravis, but muscles of the body are differentially affected, for reasons that are not fully understood. Much of what we have learnt about the immunological and neurobiological aspects of the pathogenesis derives from mouse models. The most widely used mouse models involve either passive transfer of autoantibodies, or active immunization of the mouse with acetylcholine receptors or MuSK protein. These models can provide a robust replication of many of the features of the human disease. Depending upon the protocol, acute fatiguing weakness develops 2 - 14 days after the start of autoantibody injections (passive transfer) or might require repeated immunizations over several weeks (active models). Here we review mouse models of myasthenia gravis, including what they have contributed to current understanding of the pathogenic mechanisms and their current application to the testing of therapeutics. PMID:25777761

  2. SU-E-J-65: Motion Difference Between the Pancreas and Nearby Veins for Pancreas Motion Monitoring Using Ultrasound During Radiation Therapy

    SciTech Connect

    Omari, E; Erickson, B; Li, X; Zhang, J

    2015-06-15

    Purpose: As it is generally difficult to outline the pancreas on an ultrasound b-mode image, visualized structures such as the portal or the splenic veins are assumed to have the same motion as the pancreas. These structures can be used as a surrogate for monitoring pancreas motion during radiation therapy (RT) delivery using ultrasound. To verify this assumption, we studied the motion difference between the head of the pancreas, the portal vein, the tail of the pancreas, and splenic vein. Methods: 4DCT data acquired during RT simulation were analyzed for a total of 5 randomly selected patients with pancreatic cancer. The data was sorted into 10 respiratory phases from 0% to 90% (0%: end of the inspiration, 50%: end of expiration) . The head of the pancreas (HP), tail of the pancreas (TP), portal vein (PV), and splenic vein (SV) were contoured on all 10 phases. The volume change and motion were measured in the left-right (LR), anterior-superior (AP), and superior-inferior (SI) directions. Results: The volume change for all patients/phases were: 1.2 ± 3% for HP, 0.78 ± 1.6% for PV, 2.5 ± 2.9% for TP, and 0.53 ± 2.1% for SV. Motion for each structure was estimated from the centroid displacements due to the uniformity of the structures and the small volume change. The measured motion between HP and PV was: LR: 0.1 ± 0.17 mm, AP: 0.04 ± 0.1 mm, SI: 0.17 ± 0.16 mm and between TP and the PV was: LR: 0.05 ± 0.3 mm, AP: 0.1 ± 0.4 mm, SI: 0.01 ± 0.022 mm. Conclusion: There are small motion differences between the portal vein and the head of the pancreas, and the splenic vein and the tail of the pancreas. This suggests the feasibility of utilizing these features for monitoring the pancreas motion during radiation therapy.

  3. Revisiting the immunocytochemical detection of Neurogenin 3 expression in mouse and man.

    PubMed

    Honoré, C; Rescan, C; Hald, J; McGrath, P S; Petersen, M B K; Hansson, M; Klein, T; Østergaard, S; Wells, J M; Madsen, O D

    2016-09-01

    During embryonic development, endocrine cells of the pancreas are specified from multipotent progenitors. The transcription factor Neurogenin 3 (NEUROG3) is critical for this development and it has been shown that all endocrine cells of the pancreas arise from endocrine progenitors expressing NEUROG3. A thorough understanding of the role of NEUROG3 during development, directed differentiation of pluripotent stem cells and in models of cellular reprogramming, will guide future efforts directed at finding novel sources of β-cells for cell replacement therapies. In this article, we review the expression and function of NEUROG3 in both mouse and human and present the further characterization of a monoclonal antibody directed against NEUROG3. This antibody has been previously been used for detection of both mouse and human NEUROG3. However, our results suggest that the epitope recognized by this antibody is specific to mouse NEUROG3. Thus, we have also generated a monoclonal antibody specifically recognizing human NEUROG3 and present the characterization of this antibody here. Together, these antibodies will provide useful tools for future studies of NEUROG3 expression, and the data presented in this article suggest that recently described expression patterns of NEUROG3 in human foetal and adult pancreas should be re-examined. PMID:27615127

  4. Acute Bronchitis

    MedlinePlus

    Bronchitis is an inflammation of the bronchial tubes, the airways that carry air to your lungs. It ... chest tightness. There are two main types of bronchitis: acute and chronic. Most cases of acute bronchitis ...

  5. Development of the endocrine pancreas and novel strategies for β-cell mass restoration and diabetes therapy

    PubMed Central

    Márquez-Aguirre, A.L.; Canales-Aguirre, A.A.; Padilla-Camberos, E.; Esquivel-Solis, H.; Díaz-Martínez, N.E.

    2015-01-01

    Diabetes mellitus represents a serious public health problem owing to its global prevalence in the last decade. The causes of this metabolic disease include dysfunction and/or insufficient number of β cells. Existing diabetes mellitus treatments do not reverse or control the disease. Therefore, β-cell mass restoration might be a promising treatment. Several restoration approaches have been developed: inducing the proliferation of remaining insulin-producing cells, de novo islet formation from pancreatic progenitor cells (neogenesis), and converting non-β cells within the pancreas to β cells (transdifferentiation) are the most direct, simple, and least invasive ways to increase β-cell mass. However, their clinical significance is yet to be determined. Hypothetically, β cells or islet transplantation methods might be curative strategies for diabetes mellitus; however, the scarcity of donors limits the clinical application of these approaches. Thus, alternative cell sources for β-cell replacement could include embryonic stem cells, induced pluripotent stem cells, and mesenchymal stem cells. However, most differentiated cells obtained using these techniques are functionally immature and show poor glucose-stimulated insulin secretion compared with native β cells. Currently, their clinical use is still hampered by ethical issues and the risk of tumor development post transplantation. In this review, we briefly summarize the current knowledge of mouse pancreas organogenesis, morphogenesis, and maturation, including the molecular mechanisms involved. We then discuss two possible approaches of β-cell mass restoration for diabetes mellitus therapy: β-cell regeneration and β-cell replacement. We critically analyze each strategy with respect to the accessibility of the cells, potential risk to patients, and possible clinical outcomes. PMID:26176316

  6. In Vitro Colony Assays for Characterizing Tri-potent Progenitor Cells Isolated from the Adult Murine Pancreas.

    PubMed

    Tremblay, Jacob R; LeBon, Jeanne M; Luo, Angela; Quijano, Janine C; Wedeken, Lena; Jou, Kevin; Riggs, Arthur D; Tirrell, David A; Ku, H Teresa

    2016-01-01

    Stem and progenitor cells from the adult pancreas could be a potential source of therapeutic beta-like cells for treating patients with type 1 diabetes. However, it is still unknown whether stem and progenitor cells exist in the adult pancreas. Research strategies using cre-lox lineage-tracing in adult mice have yielded results that either support or refute the idea that beta cells can be generated from the ducts, the presumed location where adult pancreatic progenitors may reside. These in vivo cre-lox lineage-tracing methods, however, cannot answer the questions of self-renewal and multi-lineage differentiation-two criteria necessary to define a stem cell. To begin addressing this technical gap, we devised 3-dimensional colony assays for pancreatic progenitors. Soon after our initial publication, other laboratories independently developed a similar, but not identical, method called the organoid assay. Compared to the organoid assay, our method employs methylcellulose, which forms viscous solutions that allow the inclusion of extracellular matrix proteins at low concentrations. The methylcellulose-containing assays permit easier detection and analyses of progenitor cells at the single-cell level, which are critical when progenitors constitute a small sub-population, as is the case for many adult organ stem cells. Together, results from several laboratories demonstrate in vitro self-renewal and multi-lineage differentiation of pancreatic progenitor-like cells from mice. The current protocols describe two methylcellulose-based colony assays to characterize mouse pancreatic progenitors; one contains a commercial preparation of murine extracellular matrix proteins and the other an artificial extracellular matrix protein known as a laminin hydrogel. The techniques shown here are 1) dissociation of the pancreas and sorting of CD133(+)Sox9/EGFP(+) ductal cells from adult mice, 2) single cell manipulation of the sorted cells, 3) single colony analyses using microfluidic q

  7. AAVP displaying octreotide for ligand-directed therapeutic transgene delivery in neuroendocrine tumors of the pancreas

    PubMed Central

    Smith, Tracey L.; Yuan, Ziqiang; Cardó-Vila, Marina; Sanchez Claros, Carmen; Adem, Asha; Cui, Min-Hui; Branch, Craig A.; Gelovani, Juri G.; Libutti, Steven K.; Sidman, Richard L.; Pasqualini, Renata; Arap, Wadih

    2016-01-01

    Patients with inoperable or unresectable pancreatic neuroendocrine tumors (NETs) have limited treatment options. These rare human tumors often express somatostatin receptors (SSTRs) and thus are clinically responsive to certain relatively stable somatostatin analogs, such as octreotide. Unfortunately, however, this tumor response is generally short-lived. Here we designed a hybrid adeno-associated virus and phage (AAVP) vector displaying biologically active octreotide on the viral surface for ligand-directed delivery, cell internalization, and transduction of an apoptosis-promoting tumor necrosis factor (TNF) transgene specifically to NETs. These functional attributes of AAVP-TNF particles displaying the octreotide peptide motif (termed Oct-AAVP-TNF) were confirmed in vitro, in SSTR type 2-expressing NET cells, and in vivo using cohorts of pancreatic NET-bearing Men1 tumor-suppressor gene KO mice, a transgenic model of functioning (i.e., insulin-secreting) tumors that genetically and clinically recapitulates the human disease. Finally, preclinical imaging and therapeutic experiments with pancreatic NET-bearing mice demonstrated that Oct-AAVP-TNF lowered tumor metabolism and insulin secretion, reduced tumor size, and improved mouse survival. Taken together, these proof-of-concept results establish Oct-AAVP-TNF as a strong therapeutic candidate for patients with NETs of the pancreas. More broadly, the demonstration that a known, short, biologically active motif can direct tumor targeting and receptor-mediated internalization of AAVP particles may streamline the potential utility of myriad other short peptide motifs and provide a blueprint for therapeutic applications in a variety of cancers and perhaps many nonmalignant diseases as well. PMID:26884209

  8. AAVP displaying octreotide for ligand-directed therapeutic transgene delivery in neuroendocrine tumors of the pancreas.

    PubMed

    Smith, Tracey L; Yuan, Ziqiang; Cardó-Vila, Marina; Sanchez Claros, Carmen; Adem, Asha; Cui, Min-Hui; Branch, Craig A; Gelovani, Juri G; Libutti, Steven K; Sidman, Richard L; Pasqualini, Renata; Arap, Wadih

    2016-03-01

    Patients with inoperable or unresectable pancreatic neuroendocrine tumors (NETs) have limited treatment options. These rare human tumors often express somatostatin receptors (SSTRs) and thus are clinically responsive to certain relatively stable somatostatin analogs, such as octreotide. Unfortunately, however, this tumor response is generally short-lived. Here we designed a hybrid adeno-associated virus and phage (AAVP) vector displaying biologically active octreotide on the viral surface for ligand-directed delivery, cell internalization, and transduction of an apoptosis-promoting tumor necrosis factor (TNF) transgene specifically to NETs. These functional attributes of AAVP-TNF particles displaying the octreotide peptide motif (termed Oct-AAVP-TNF) were confirmed in vitro, in SSTR type 2-expressing NET cells, and in vivo using cohorts of pancreatic NET-bearing Men1 tumor-suppressor gene KO mice, a transgenic model of functioning (i.e., insulin-secreting) tumors that genetically and clinically recapitulates the human disease. Finally, preclinical imaging and therapeutic experiments with pancreatic NET-bearing mice demonstrated that Oct-AAVP-TNF lowered tumor metabolism and insulin secretion, reduced tumor size, and improved mouse survival. Taken together, these proof-of-concept results establish Oct-AAVP-TNF as a strong therapeutic candidate for patients with NETs of the pancreas. More broadly, the demonstration that a known, short, biologically active motif can direct tumor targeting and receptor-mediated internalization of AAVP particles may streamline the potential utility of myriad other short peptide motifs and provide a blueprint for therapeutic applications in a variety of cancers and perhaps many nonmalignant diseases as well. PMID:26884209

  9. Abnormalities of the Exocrine Pancreas in Type 1 Diabetes.

    PubMed

    Campbell-Thompson, Martha; Rodriguez-Calvo, Teresa; Battaglia, Manuela

    2015-10-01

    Type 1 diabetes (T1D) is considered a pancreatic beta cell-specific disease that results in absolute insulin deficiency. Nevertheless, clinical studies from 1940 onwards showed that patients with T1D had an abnormal exocrine pancreas due to the presence of subclinical exocrine insufficiency and acinar atrophy. Exocrine abnormalities are an important, and mostly neglected, characteristic associated with T1D. It is however still unclear whether the exocrine dysfunction in T1D is a primary damage caused by the same pathogenic event that led to beta cell destruction or secondary to beta cell loss. In this review, we collect evidence supporting the hypothesis that T1D is a combined endocrine-exocrine disease in which the loss of functional beta cell mass is most clinically apparent. PMID:26318606

  10. 17 beta-hydroxysteroid dehydrogenase activity in canine pancreas

    SciTech Connect

    Mendoza-Hernandez, G.; Lopez-Solache, I.; Rendon, J.L.; Diaz-Sanchez, V.; Diaz-Zagoya, J.C.

    1988-04-15

    The mitochondrial fraction of the dog pancreas showed NAD(H)-dependent enzyme activity of 17 beta-hydroxysteroid dehydrogenase. The enzyme catalyzes oxidoreduction between androstenedione and testosterone. The apparent Km value of the enzyme for androstenedione was 9.5 +/- 0.9 microM, the apparent Vmax was determined as 0.4 nmol mg-1 min-1, and the optimal pH was 6.5. In phosphate buffer, pH 7.0, maximal rate of androstenedione reduction was observed at 37 degrees C. The oxidation of testosterone by the enzyme proceeded at the same rate as the reduction of the androstenedione at a pH of 6.8-7.0. The apparent Km value and the optimal pH of the enzyme for testosterone were 3.5 +/- 0.5 microM and 7.5, respectively.

  11. The Human Endocrine Pancreas: New Insights on Replacement and Regeneration.

    PubMed

    Domínguez-Bendala, Juan; Lanzoni, Giacomo; Klein, Dagmar; Álvarez-Cubela, Silvia; Pastori, Ricardo L

    2016-03-01

    Islet transplantation is an effective cell therapy for type 1 diabetes (T1D) but its clinical application is limited due to shortage of donors. After a decade-long period of exploration of potential alternative cell sources, the field has only recently zeroed in on two of them as the most likely to replace islets. These are pluripotent stem cells (PSCs) (through directed differentiation) and pancreatic non-endocrine cells (through directed differentiation or reprogramming). Here we review progress in both areas, including the initiation of Phase I/II clinical trials using human embryonic stem cell (hESc)-derived progenitors, advances in hESc differentiation in vitro, novel insights on the developmental plasticity of the pancreas, and groundbreaking new approaches to induce β cell conversion from the non-endocrine compartment without genetic manipulation. PMID:26774512

  12. Arteriovenous malformation of the pancreas: a case report.

    PubMed

    Abe, Tsuyoshi; Suzuki, Nobuyasu; Haga, Junichirou; Azami, Ayaka; Todate, Yukitoshi; Waragai, Mitsuru; Sato, Atai; Takano, Yoshinao; Kawakura, Kenji; Imai, Shigeki; Sakuma, Hideo; Teranishi, Yasushi

    2016-12-01

    Arteriovenous malformation (AVM) of the pancreas is uncommon in the gastrointestinal tract. We present a case of AVM of the pancreatic head in a 59-year-old male. He was admitted to a hospital with hematemesis and tarry stool and referred to our hospital in March 2014 on the diagnosis of pancreatic artery pseudoaneurysm. A computed tomography scan showed the presence of irregular dilated and/or stenotic vessels with meandering in the pancreatic head. Magnetic resonance imaging showed strong enhancement of the conglomeration in the pancreatic head. Selective angiography showed the proliferation of a vascular network in the pancreatic head and an early visualization of the portal vein at the arterial phase. The patient qualified for surgery with a preoperative diagnosis of AVM of the pancreatic head. We performed pylorus-preserving pancreaticoduodenectomy. The histological results confirmed the presence of irregular dilated tortuous arteries and veins in the pancreatic head. Surgical treatment may represent definitive management of symptomatic AVM. PMID:26943682

  13. Glucagon in the artificial pancreas: supply and marketing challenges.

    PubMed

    Rylander, Dick

    2015-01-01

    The use of glucagon, in conjunction with insulin, in a dual chamber pump (artificial pancreas, AP) is a working goal for multiple companies and researchers. However, capital investment to create, operate, and maintain facilities with sufficient scale to produce enough glucagon to treat millions of patients, at a level of profit that makes it feasible, will be substantial. It can be assumed that the marketplace will expect the daily cost of glucagon (to the consumer) to be similar to the daily cost of insulin. After one subtracts wholesaler and pharmacy markup, there may be very few dollars remaining for the drug company to cover profit, capital expenditures, marketing, burden, and other costs. Without the potential for adequate margins, manufacturers may not be willing to take the risk. Assuming that the projections discussed in this article are in the right ballpark, advance planning for the supply for glucagon needs to start today and not wait for the AP to come to market. PMID:25139825

  14. Characteristics and Outcomes of Adenosquamous Carcinoma of the Pancreas

    PubMed Central

    Simone, Christine G.; Zuluaga Toro, Tania; Chan, Ellie; Feely, Michael M.; Trevino, Jose G.

    2013-01-01

    ABSTRACT BACKGROUND: Adenosquamous carcinoma of the pancreas (ASCAP) is a rare histologic type of pancreatic carcinoma that constitutes 1% to 4% of all pancreatic exocrine malignancies. It has a clinical presentation similar to that of adenocarcinoma of the pancreas (ACP), but may have a worse overall prognosis, with most patients surviving for less than 2 years. METHODS: This was an institutional, retrospective, cohort analysis of 237 patients who underwent resection of pancreatic cancer with curative intent. RESULTS: Of the 237 cases examined, we identified 7 (2.9%) with histologically confirmed ASCAP. Demographics, comorbidities, risk factors, presenting symptoms, survival data, tumor characteristics, and types of treatment for each patient were included in the analysis. Risk factors for development of ASCAP were not conclusive. Although human papilloma virus (HPV) has been implicated in other squamous cell cancers, in our cohort, its involvement in ASCAP was 0%. Presurgical fine-needle aspiration failed to identify the invasive squamous cell component in all cases. In this cohort analysis, overall survival ranged from 3 to 25 months, with 2 patients surviving more than 20 months after surgical resection. With a median follow-up of 2.9 years, our data demonstrate a trend to worse median overall survival for ASCAP than for ACP (8.2 vs. 20.4 months; P = .23), with a limited number of long-term survivors. CONCLUSIONS: Although recommended, adjuvant treatment was inconsistently provided for patients in this ASCAP cohort. Published data show variability in overall survival, but our findings support that surgical resection is one of the few options for control of this rare, poorly understood pancreatic malignancy. Further research is necessary to define risk factors and adjuvant and neoadjuvant treatments, to help improve patient outcomes. PMID:23936547

  15. Purinergic receptors in the endocrine and exocrine pancreas

    PubMed Central

    2007-01-01

    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, these processes have been viewed separately. In β cells, stimulation of P2Y1 receptors amplifies secretion of insulin in the presence of glucose. Nucleotides released from secretory granules could also contribute to autocrine/paracrine regulation in pancreatic islets. In addition to P2Y1 receptors, there is also evidence for other P2 and adenosine receptors in β cells (P2Y2, P2Y4, P2Y6, P2X subtypes and A1 receptors) and in glucagon-secreting α cells (P2X7, A2 receptors). In the exocrine pancreas, acini release ATP and ATP-hydrolysing and ATP-generating enzymes. P2 receptors are prominent in pancreatic ducts, and several studies indicate that P2Y2, P2Y4, P2Y11, P2X4 and P2X7 receptors could regulate secretion, primarily by affecting Cl− and K+ channels and intracellular Ca2+ signalling. In order to understand the physiology of the whole organ, it is necessary to consider the full complement of purinergic receptors on different cells as well as the structural and functional relation between various cells within the whole organ. In addition to the possible physiological function of purinergic receptors, this review analyses whether the receptors could be potential therapeutic targets for drug design aimed at treatment of pancreatic diseases. PMID:18368520

  16. Maternal obesity alters endoplasmic reticulum homeostasis in offspring pancreas.

    PubMed

    Soeda, Jumpei; Mouralidarane, Angelina; Cordero, Paul; Li, Jiawei; Nguyen, Vi; Carter, Rebeca; Kapur, Sabrina R; Pombo, Joaquim; Poston, Lucilla; Taylor, Paul D; Vinciguerra, Manlio; Oben, Jude A

    2016-06-01

    The prevalence of non-alcoholic fatty pancreas disease (NAFPD) is increasing in parallel with obesity rates. Stress-related alterations in endoplasmic reticulum (ER), such as the unfolded protein response (UPR), are associated with obesity. The aim of this study was to investigate ER imbalance in the pancreas of a mice model of adult and perinatal diet-induced obesity. Twenty female C57BL/6J mice were assigned to control (Con) or obesogenic (Ob) diets prior to and during pregnancy and lactation. Their offspring were weaned onto Con or Ob diets up to 6 months post-partum. Then, after sacrifice, plasma biochemical analyses, gene expression, and protein concentrations were measured in pancreata. Offspring of Ob-fed mice had significantly increased body weight (p < 0.001) and plasma leptin (p < 0.001) and decreased insulin (p < 0.01) levels. Maternal obesogenic diet decreased the total and phosphorylated Eif2α and increased spliced X-box binding protein 1 (XBP1). Pancreatic gene expression of downstream regulators of UPR (EDEM, homocysteine-responsive endoplasmic reticulum-resident (HERP), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP)) and autophagy-related proteins (LC3BI/LC3BII) were differently disrupted by obesogenic feeding in both mothers and offspring (from p < 0.1 to p < 0.001). Maternal obesity and Ob feeding in their offspring alter UPR in NAFPD, with involvement of proapoptotic and autophagy-related markers. Upstream and downstream regulators of PERK, IRE1α, and ATF6 pathways were affected differently following the obesogenic insults. PMID:26979740

  17. CLINICAL PROGRAMS OF STEM CELL THERAPIES FOR LIVER AND PANCREAS

    PubMed Central

    Lanzoni, Giacomo; Oikawa, Tsunekazu; Wang, Yunfang; Cui, Cai-Bin; Carpino, Guido; Cardinale, Vincenzo; Gerber, David; Gabriel, Mara; Dominguez-Bendala, Juan; Furth, Mark E.; Gaudio, Eugenio; Alvaro, Domenico; Inverardi, Luca; Reid, Lola M.

    2013-01-01

    Regenerative medicine is transitioning into clinical programs utilizing stem/progenitor cell therapies for repair of damaged organs. We summarize those for liver and pancreas, organs that share endodermal stem cell populations, biliary tree stem cells (hBTSCs), located in peribiliary glands: they are precursors to hepatic stem/progenitors in canals of Hering and to committed progenitors in pancreatic duct glands. They give rise to maturational lineages along a radial axis within bile duct walls and a proximal-to-distal axis starting at the duodenum and ending with mature cells in the liver or pancreas. Clinical trials have been ongoing for years assessing effects of fetal-liver-derived hepatic stem/progenitors transplanted into the hepatic artery of patients with various liver diseases. Immunosuppression was not required. Control subjects, those given standard of care for a given condition, all died within a year or deteriorated in their liver functions. Subjects transplanted with 100–150 million hepatic stem/progenitor cells had improved liver functions and survival extending for several years. Full evaluations of safety and efficacy of transplants are still in progress. Determined stem cell therapies for diabetes utilizing hBTSCs remain to be explored but are likely to occur following ongoing preclinical studies. In addition, mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) are being used for patients with chronic liver conditions or with diabetes. MSCs have demonstrated significant effects through paracrine signaling of trophic and immune-modulatory factors, and there is limited evidence for inefficient lineage restriction into mature parenchymal or islet cells. HSCs’ effects are primarily via modulation of immune mechanisms. PMID:23873634

  18. Histidine-tryptophan-ketoglutarate for pancreas allograft preservation: the Indiana University experience.

    PubMed

    Fridell, J A; Mangus, R S; Powelson, J A

    2010-05-01

    Histidine-tryptophan-ketoglutarate solution (HTK) has been scrutinized for use in pancreas transplantation. A recent case series and a United Network for Organ Sharing data base review have suggested an increased incidence of allograft pancreatitis and graft loss with HTK compared to the University of Wisconsin solution (UW). Conversely, a recent randomized, controlled study failed to show any significant difference between HTK and UW for pancreas allograft preservation. This study was a retrospective review of all pancreas transplants performed at Indiana University between 2003 and 2009 comparing preservation with HTK or UW. Data included recipient and donor demographics, 7-day, 90-day and 1-year graft survival, peak 30-day serum amylase and lipase, HbA1c and C-peptide levels. Of the 308 pancreas transplants, 84% used HTK and 16% UW. There were more SPK compared to pancreas after kidney and pancreas transplant alone in the HTK group. Donor and recipient demographics were similar. There was no significant difference in 7-day, 90-day or 1-year graft survival, 30-day peak serum amylase and lipase, HbA1c or C-peptide. No clinically significant difference between HTK and UW for pancreas allograft preservation was identified. Specifically, in the context of low-to-moderate flush volume and short cold ischemia time (

  19. Pancreas-specific lipase concentrations and amylase and lipase activities in the peritoneal fluid of dogs with suspected pancreatitis.

    PubMed

    Chartier, Marie A; Hill, Steve L; Sunico, Sarena; Suchodolski, Jan S; Robertson, Jane E; Steiner, Joerg M

    2014-09-01

    Diagnosing acute pancreatitis in the dog can be challenging. The aim of this study was to determine the concentrations of pancreas-specific lipase immunoreactivity (cPLI), and the activities of amylase and lipase, in the peritoneal fluid from a population of dogs diagnosed with acute pancreatitis based on clinical signs, ultrasonographic findings and serum cPLI concentrations. In a prospective study, cPLI concentrations, and amylase and lipase activities, were measured in the peritoneal fluid of 14 dogs with pancreatitis and 19 dogs with non-pancreatic disease. The sensitivity and specificity of peritoneal fluid cPLI concentration (cut-off value 500 µg/L) were 100.0% (95% confidence interval, CI, 80.7-100.0%) and 94.7% (95% CI 76.7-99.7%), respectively. The sensitivity and specificity of peritoneal fluid amylase (cut-off value 1050 U/L) and lipase activities (cut-off value 500 U/L) were 71.4% (95% CI 44.5-90.2%) and 84.2% (95% CI 62.8-95.8%) for amylase activity, and 92.9% (95% CI 69.5-99.6%) and 94.7% (95% CI 76.7-99.7%) for lipase activity, respectively. In conclusion, peritoneal fluid cPLI concentration was highly sensitive as a complementary diagnostic tool in a group of dogs with suspected acute pancreatitis. Peritoneal fluid lipase activity was not as sensitive as cPLI concentration, but may also support a diagnosis of acute pancreatitis in dogs. PMID:25106805

  20. Evaluating an etiologically relevant platform for therapy development for temporal lobe epilepsy: effects of carbamazepine and valproic acid on acute seizures and chronic behavioral comorbidities in the Theiler's murine encephalomyelitis virus mouse model.

    PubMed

    Barker-Haliski, Melissa L; Dahle, E Jill; Heck, Taylor D; Pruess, Timothy H; Vanegas, Fabiola; Wilcox, Karen S; White, H Steve

    2015-05-01

    Central nervous system infections can underlie the development of epilepsy, and Theiler's murine encephalomyelitis virus (TMEV) infection in C57BL/6J mice provides a novel model of infection-induced epilepsy. Approximately 50-65% of infected mice develop acute, handling-induced seizures during the infection. Brains display acute neuropathology, and a high number of mice develop spontaneous, recurrent seizures and behavioral comorbidities weeks later. This study characterized the utility of this model for drug testing by assessing whether antiseizure drug treatment during the acute infection period attenuates handling-induced seizures, and whether such treatment modifies associated comorbidities. Male C57BL/6J mice infected with TMEV received twice-daily valproic acid (VPA; 200 mg/kg), carbamazepine (CBZ; 20 mg/kg), or vehicle during the infection (days 0-7). Mice were assessed twice daily during the infection period for handling-induced seizures. Relative to vehicle-treated mice, more CBZ-treated mice presented with acute seizures; VPA conferred no change. In mice displaying seizures, VPA, but not CBZ, reduced seizure burden. Animals were then randomly assigned to acute and long-term follow-up. VPA was associated with significant elevations in acute (day 8) glial fibrillary acidic protein (astrocytes) immunoreactivity, but did not affect NeuN (neurons) immunoreactivity. Additionally, VPA-treated mice showed improved motor performance 15 days postinfection (DPI). At 36 DPI, CBZ-treated mice traveled significantly less distance through the center of an open field, indicative of anxiety-like behavior. CBZ-treated mice also presented with significant astrogliosis 36 DPI. Neither CBZ nor VPA prevented long-term reductions in NeuN immunoreactivity. The TMEV model thus provides an etiologically relevant platform to evaluate potential treatments for acute seizures and disease modification. PMID:25755209

  1. Histopathological effects of intraoperative radiotherapy on pancreas and adjacent tissues: a postmortem analysis

    SciTech Connect

    Hoekstra, H.J.; Restrepo, C.; Kinsella, T.J.; Sindelar, W.F.

    1988-02-01

    Intraoperative radiotherapy (IORT) has been utilized in the treatment of resectable and unresectable pancreatic carcinoma at the National Cancer Institute. Detailed autopsy analyses of the radiation effects on the pancreas and adjacent tissues were performed on 13 patients dying at various times following therapy. IORT can induce a progressive retroperitoneal fibrosis and fibrosis of the porta hepatis in patients with resectable pancreatic carcinoma. In unresectable pancreatic carcinoma, the major expression of intraoperative irradiation with external beam irradiation is a progressive fibrosis of the pancreas with vascular sclerosis, nerve degeneration, atrophy of acinar cells, and atypical changes in the ducts of the pancreas, as well as degenerative changes of the pancreatic tumor.

  2. Cytology Specimen Management, Triage and Standardized Reporting of Fine Needle Aspiration Biopsies of the Pancreas

    PubMed Central

    Yoon, Won Jae; Bishop Pitman, Martha

    2015-01-01

    The recent advances in pancreas cytology specimen sampling methods have enabled a specific cytologic diagnosis in most cases. Proper triage and processing of the cytologic specimen is pivotal in making a diagnosis due to the need for ancillary testing in addition to cytological evaluation, which is especially true in the diagnosis of pancreatic cysts. Newly proposed terminology for pancreaticobiliary cytology offers a standardized language for reporting that aims to improve communication among patient caregivers and provide for increased flexibility in patient management. This review focuses on these updates in pancreas cytology for the optimal evaluation of solid and cystic lesions of the pancreas. PMID:26265683

  3. Serous Microcystic Adenocarcinoma of Pancreas Infiltrating Into Spleen: A Case Report

    PubMed Central

    Ramu, Sathyalakshmi; Mishra, Nidhi; Adaikalam, Mary Lilly Susai; Venkatesan, Ramya

    2015-01-01

    Cystic tumours of pancreas account for 5-10% of all pancreatic neoplasms and serous tumours represent 1% among those tumours. Most of the serous tumours are benign and very rarely they infiltrate adjacent organs like liver and spleen. Herewith we present a rare case report of serous cystadenocarcinoma of pancreas in a 65-year-old woman. The tumour involved the body and tail of pancreas and contiguously invaded the spleen. The histopathology of tumour was similar to serous cystadenoma with mild nuclear hyperchromasia and atypia. The spleen showed tumour infiltration as microcysts diffusely infitrating the red pulp. PMID:26500911

  4. The pattern of the arterial supply of the pancreas in anthropoid apes, catarrhine monkeys and platyrrhine monkeys.

    PubMed

    Shawuti, Alimujiang; Miyaki, Takayoshi; Saito, Toshiyuki; Itoh, Masahiro

    2009-11-01

    To get the full understanding of the arterial distribution to the pancreas, the analysis of the distribution of the variety of monkey species would be helpful. In this study, we studied the layout of the pancreatic artery in anthropoids (1 gorilla, 3 chimpanzees and 2 white-handed gibbons), in catarrhine monkeys (1 hamadryas baboon, 2 anubid baboons, 10 savannah monkeys) and in platyrrhine monkeys (6 squirrel monkeys). The pancreas of the monkeys was supplied by the arteries originating from the celiac trunk and/or superior mesenteric artery. There were three patterns in the arterial distribution; (1) the celiac artery supplied the major area of the pancreas. (2) the superior mesenteric artery supplied the major area of the pancreas. (3) the celiac artery supplied the whole pancreas. The pattern of the arterial distribution to the monkey pancreas had a wide variety. The result would be helpful for the elucidation of the development of the vascular distribution in the pancreas. PMID:20166548

  5. Clinicoradiological appraisal of ‘paraduodenal pancreatitis’: Pancreatitis outside the pancreas!

    PubMed Central

    Arora, Ankur; Rajesh, S; Mukund, Amar; Patidar, Yashwant; Thapar, Shalini; Arora, Asit; Bhatia, Vikram

    2015-01-01

    Purpose: Paraduodenal pancreatitis (PP) is a unique form of focal chronic pancreatitis that selectively involves the duodenum and aberrant pancreatic tissue located near the minor papilla (beyond the pancreas proper). The pseudotumoral nature of the disease often generates considerable clinical quandary and patient apprehension, and therefore merits a better understanding. The present study appraises the clinicoradiological manifestations of PP in 33 patients. Materials and Methods: Clinical, laboratory, and radiological manifestations of 33 patients of PP treated in gastroenterology/hepatology and hepato-pancreatico-biliary surgery units during June 2010-August 2014 were retrospectively reviewed. Results: All patients were young to middle-aged men (100%) with history of alcohol abuse (93.9%) and/or smoking (42.4%), who presented either with acute or gradually worsening abdominal pain (90.9%). Pancreatic enzymes and serum tumor markers remained normal or were mildly/transiently elevated. Cystic variant was detected in 57.6% (solid in 42.4%); the disease remained confined to the groove/duodenum (pure form) in 45.4%. Medial duodenal wall thickening with increased enhancement was seen in 87.87 and 81.81%, respectively, and duodenal/paraduodenal cysts were seen in 78.78%. Pancreatic calcifications and biliary stricture were seen 27.3% patients. Peripancreatic arteries were neither infiltrated nor encased. Conclusion: PP has a discrete predilection for middle-aged men with history of longstanding alcohol abuse and/or smoking. Distinguishing imaging findings include thickening of the pancreatic side of duodenum exhibiting increased enhancement with intramural/paraduodenal cysts. This may be accompanied by plate-like scar tissue in the groove region, which may simulate groove pancreatic carcinoma. However, as opposed to carcinoma, the peripancreatic arteries are neither infiltrated nor encased, rather are medially displaced. PMID:26288527

  6. CdSe/ZnS Quantum Dots-Labeled Mesenchymal Stem Cells for Targeted Fluorescence Imaging of Pancreas Tissues and Therapy of Type 1 Diabetic Rats

    NASA Astrophysics Data System (ADS)

    Liu, Haoqi; Tang, Wei; Li, Chao; Lv, Pinlei; Wang, Zheng; Liu, Yanlei; Zhang, Cunlei; Bao, Yi; Chen, Haiyan; Meng, Xiangying; Song, Yan; Xia, Xiaoling; Pan, Fei; Cui, Daxiang; Shi, Yongquan

    2015-06-01

    Mesenchymal stem cells (MSCs) have been used for therapy of type 1 diabetes mellitus. However, the in vivo distribution and therapeutic effects of transplanted MSCs are not clarified well. Herein, we reported that CdSe/ZnS quantum dots-labeled MSCs were prepared for targeted fluorescence imaging and therapy of pancreas tissues in rat models with type 1 diabetes. CdSe/ZnS quantum dots were synthesized, their biocompatibility was evaluated, and then, the appropriate concentration of quantum dots was selected to label MSCs. CdSe/ZnS quantum dots-labeled MSCs were injected into mouse models with type 1 diabetes via tail vessel and then were observed by using the Bruker In-Vivo F PRO system, and the blood glucose levels were monitored for 8 weeks. Results showed that prepared CdSe/ZnS quantum dots owned good biocompatibility. Significant differences existed in distribution of quantum dots-labeled MSCs between normal control rats and diabetic rats ( p < 0.05). The ratios of the fluorescence intensity (RFI) analysis showed an accumulation rate of MSCs in the pancreas of rats in the diabetes group, and was about 32 %, while that in the normal control group rats was about 18 %. The blood glucose levels were also monitored for 8 weeks after quantum dots-labeled MSC injection. Statistical differences existed between the blood glucose levels of the diabetic rat control group and MSC-injected diabetic rat group ( p < 0.01), and the MSC-injected diabetic rat group displayed lower blood glucose levels. In conclusion, CdSe/ZnS-labeled MSCs can target in vivo pancreas tissues in diabetic rats, and significantly reduce the blood glucose levels in diabetic rats, and own potential application in therapy of diabetic patients in the near future.

  7. CdSe/ZnS Quantum Dots-Labeled Mesenchymal Stem Cells for Targeted Fluorescence Imaging of Pancreas Tissues and Therapy of Type 1 Diabetic Rats.

    PubMed

    Liu, Haoqi; Tang, Wei; Li, Chao; Lv, Pinlei; Wang, Zheng; Liu, Yanlei; Zhang, Cunlei; Bao, Yi; Chen, Haiyan; Meng, Xiangying; Song, Yan; Xia, Xiaoling; Pan, Fei; Cui, Daxiang; Shi, Yongquan

    2015-12-01

    Mesenchymal stem cells (MSCs) have been used for therapy of type 1 diabetes mellitus. However, the in vivo distribution and therapeutic effects of transplanted MSCs are not clarified well. Herein, we reported that CdSe/ZnS quantum dots-labeled MSCs were prepared for targeted fluorescence imaging and therapy of pancreas tissues in rat models with type 1 diabetes. CdSe/ZnS quantum dots were synthesized, their biocompatibility was evaluated, and then, the appropriate concentration of quantum dots was selected to label MSCs. CdSe/ZnS quantum dots-labeled MSCs were injected into mouse models with type 1 diabetes via tail vessel and then were observed by using the Bruker In-Vivo F PRO system, and the blood glucose levels were monitored for 8 weeks. Results showed that prepared CdSe/ZnS quantum dots owned good biocompatibility. Significant differences existed in distribution of quantum dots-labeled MSCs between normal control rats and diabetic rats (p < 0.05). The ratios of the fluorescence intensity (RFI) analysis showed an accumulation rate of MSCs in the pancreas of rats in the diabetes group which was about 32 %, while that in the normal control group rats was about 18 %. The blood glucose levels were also monitored for 8 weeks after quantum dots-labeled MSC injection. Statistical differences existed between the blood glucose levels of the diabetic rat control group and MSC-injected diabetic rat group (p < 0.01), and the MSC-injected diabetic rat group displayed lower blood glucose levels. In conclusion, CdSe/ZnS-labeled MSCs can target in vivo pancreas tissues in diabetic rats, and significantly reduce the blood glucose levels in diabetic rats, and own potential application in therapy of diabetic patients in the near future. PMID:26078050

  8. Drug-Induced Acute Pancreatitis: A Review

    PubMed Central

    Jones, Mark R.; Hall, Oliver Morgan; Kaye, Adam M.; Kaye, Alan David

    2015-01-01

    Background The majority of drug-induced pancreatitis cases are mild to moderate in severity, but severe and even fatal cases can occur. Management of drug-induced pancreatitis requires withdrawal of the offending agent and supportive care. Methods This review focuses on differential diagnosis, clinical presentation, drug-mediated effects, treatments, and mechanisms of pancreatitis, with an emphasis on drug-induced pancreatitis. Results Although only a minority of cases associated with acute pancreatitis are linked to drugs, clinical presentation and mechanisms of injury to the pancreas are not well understood by clinicians in terms of individual drug effects in the mediation or modulation of injury to the pancreas. In recent years, a large number of commonly prescribed medications has been linked to drug-induced pancreatitis pathogenesis. Although mechanisms are proposed, the exact cause of injury is either not well understood or controversial. Conclusion Future investigation into the mechanisms of pancreatitis and an appreciation by clinicians of the drugs commonly linked to the condition will help establish earlier diagnosis and quicker cessation of offending drugs in the treatment of drug-induced acute pancreatitis. PMID:25829880

  9. Reporter islets in the eye reveal the plasticity of the endocrine pancreas

    PubMed Central

    Ilegems, Erwin; Dicker, Andrea; Speier, Stephan; Sharma, Aarti; Bahow, Alan; Edlund, Patrick Karlsson; Leibiger, Ingo B.; Berggren, Per-Olof

    2013-01-01

    The islets of Langerhans constitute the endocrine part of the pancreas and are responsible for maintenance of blood glucose homeostasis. They are deeply embedded in the exocrine pancreas, limiting their accessibility for functional studies. Understanding regulation of function and survival and assessing the clinical outcomes of individual treatment strategies for diabetes requires a monitoring system that continuously reports on the endocrine pancreas. We describe the application of a natural body window that successfully reports on the properties of in situ pancreatic islets. As proof of principle, we transplanted “reporter islets” into the anterior chamber of the eye of leptin-deficient mice. These islets displayed obesity-induced growth and vascularization patterns that were reversed by leptin treatment. Hence, reporter islets serve as optically accessible indicators of islet function in the pancreas, and also reflect the efficacy of specific treatment regimens aimed at regulating islet plasticity in vivo. PMID:24248353

  10. A 3D map of the islet routes throughout the healthy human pancreas

    PubMed Central

    Ionescu-Tirgoviste, Constantin; Gagniuc, Paul A.; Gubceac, Elvira; Mardare, Liliana; Popescu, Irinel; Dima, Simona; Militaru, Manuella

    2015-01-01

    Islets of Langerhans are fundamental in understanding diabetes. A healthy human pancreas from a donor has been used to asses various islet parameters and their three-dimensional distribution. Here we show that islets are spread gradually from the head up to the tail section of the pancreas in the form of contracted or dilated islet routes. We also report a particular anatomical structure, namely the cluster of islets. Our observations revealed a total of 11 islet clusters which comprise of small islets that surround large blood vessels. Additional observations in the peripancreatic adipose tissue have shown lymphoid-like nodes and blood vessels captured in a local inflammatory process. Our observations are based on regional slice maps of the pancreas, comprising of 5,423 islets. We also devised an index of sphericity which briefly indicates various islet shapes that are dominant throughout the pancreas. PMID:26417671

  11. Simultaneous Extensive Intraductal Papillary Neoplasm of the Bile Duct and Pancreas: A Very Rare Entity

    PubMed Central

    Luvira, Vor; Pugkhem, Ake; Tipwaratorn, Theerawee; Chamgramol, Yaovalux; Pairojkul, Chawalit; Bhudhisawasdi, Vajarabhongsa

    2016-01-01

    Intraductal papillary neoplasm of the bile duct (IPNB) is a specific type of bile duct tumor. It has been proposed that it could be the biliary counterpart of the intraductal papillary neoplasm of the pancreas (IPMN-P). This hypothesis is supported by the presence of simultaneous intraductal tumors of both the bile duct and pancreas. There have been five reports of patients with simultaneous IPNB and IPMN-P. In all of these cases, biliary involvement was limited to the intrahepatic and perihilar bile duct, which had characteristics similar to IPMN-P and usually had slow progression in nature. Herein, we present the first case of extensive intraductal neoplasm involving the extrahepatic bile duct, intrahepatic bile duct, and entire length of the pancreas with a poor outcome, even after being treated aggressively with radical surgery and adjuvant chemotherapy. Additionally, we summarize previous case reports of simultaneous intraductal lesions of the bile duct and pancreas. PMID:26925284

  12. On the diabetic menu: Zebrafish as a model for pancreas development and function

    PubMed Central

    Kinkel, Mary D.; Prince, Victoria E.

    2009-01-01

    Summary Development of the vertebrate pancreas is a complex stepwise process comprising regionalization, cell differentiation, and morphogenesis. Studies in zebrafish are contributing to an emerging picture of pancreas development in which extrinsic signaling molecules influence intrinsic transcriptional programs to allow ultimate differentiation of specific pancreatic cell types. Zebrafish experiments have revealed roles for several signaling molecules in aspects of this process; for example our own work has shown that Retinoic Acid signals specify the pre-pancreatic endoderm. Time-lapse imaging of live zebrafish embryos has started to provide detailed information about early pancreas morphogenesis. In addition to modeling embryonic development, the zebrafish has recently begun to be used as a model for pancreas regeneration studies. Here we review the significant progress in these areas and consider the future potential of zebrafish as a diabetes research model. PMID:19204986

  13. Shear mechanical properties of the porcine pancreas: experiment and analytical modelling.

    PubMed

    Nicolle, S; Noguer, L; Palierne, J-F

    2013-10-01

    We provide the first account of the shear mechanical properties of porcine pancreas using a rheometer both in linear oscillatory tests and in constant strain-rate tests reaching the non-linear sub-failure regime. Our results show that pancreas has a low and weakly frequency-dependent dynamic modulus and experiences a noticeable strain-hardening beyond 20% strain. In both linear and non-linear regime, the viscoelastic behaviour of porcine pancreas follows a four-parameter bi-power model that has been validated on kidney, liver and spleen. Among the four solid organs of the abdomen, pancreas proves to be the most compliant and the most viscous one. PMID:23820244

  14. A 3D map of the islet routes throughout the healthy human pancreas.

    PubMed