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Sample records for acute mouse pancreas

  1. Glucose-Stimulated Calcium Dynamics in Islets of Langerhans in Acute Mouse Pancreas Tissue Slices

    PubMed Central

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

    2013-01-01

    In endocrine cells within islets of Langerhans calcium ions couple cell stimulation to hormone secretion. Since the advent of modern fluorimetry, numerous in vitro studies employing primarily isolated mouse islets have investigated the effects of various secretagogues on cytoplasmic calcium, predominantly in insulin-secreting beta cells. Due to technical limitations, insights of these studies are inherently limited to a rather small subpopulation of outermost cells. The results also seem to depend on various factors, like culture conditions and duration, and are not always easily reconcilable with findings in vivo. The main controversies regard the types of calcium oscillations, presence of calcium waves, and the level of synchronized activity. Here, we set out to combine the in situ acute mouse pancreas tissue slice preparation with noninvasive fluorescent calcium labeling and subsequent confocal laser scanning microscopy to shed new light on the existing controversies utilizing an innovative approach enabling the characterization of responses in many cells from all layers of islets. Our experiments reproducibly showed stable fast calcium oscillations on a sustained plateau rather than slow oscillations as the predominant type of response in acute tissue slices, and that calcium waves are the mechanistic substrate for synchronization of oscillations. We also found indirect evidence that even a large amplitude calcium signal was not sufficient and that metabolic activation was necessary to ensure cell synchronization upon stimulation with glucose. Our novel method helped resolve existing controversies and showed the potential to help answer important physiological questions, making it one of the methods of choice for the foreseeable future. PMID:23358454

  2. RNA isolation from mouse pancreas: a ribonuclease-rich tissue.

    PubMed

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

    2014-08-02

    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.

  3. 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

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

    PubMed

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

    2014-07-19

    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.

  5. 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

  6. The Relationship between Membrane Potential and Calcium Dynamics in Glucose-Stimulated Beta Cell Syncytium in Acute Mouse Pancreas Tissue Slices

    PubMed Central

    Miller, Evan W.; Slak Rupnik, Marjan

    2013-01-01

    Oscillatory electrical activity is regarded as a hallmark of the pancreatic beta cell glucose-dependent excitability pattern. Electrophysiologically recorded membrane potential oscillations in beta cells are associated with in-phase oscillatory cytosolic calcium activity ([Ca2+]i) measured with fluorescent probes. Recent high spatial and temporal resolution confocal imaging revealed that glucose stimulation of beta cells in intact islets within acute tissue slices produces a [Ca2+]i change with initial transient phase followed by a plateau phase with highly synchronized [Ca2+]i oscillations. Here, we aimed to correlate the plateau [Ca2+]i oscillations with the oscillations of membrane potential using patch-clamp and for the first time high resolution voltage-sensitive dye based confocal imaging. Our results demonstrated that the glucose-evoked membrane potential oscillations spread over the islet in a wave-like manner, their durations and wave velocities being comparable to the ones for [Ca2+]i oscillations and waves. High temporal resolution simultaneous records of membrane potential and [Ca2+]i confirmed tight but nevertheless limited coupling of the two processes, with membrane depolarization preceding the [Ca2+]i increase. The potassium channel blocker tetraethylammonium increased the velocity at which oscillations advanced over the islet by several-fold while, at the same time, emphasized differences in kinetics of the membrane potential and the [Ca2+]i. The combination of both imaging techniques provides a powerful tool that will help us attain deeper knowledge of the beta cell network. PMID:24324777

  7. 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

  8. 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.

  9. Acute pancreatitis: pancreas divisum with ventral duct intraductal papillary mucinous neoplasms.

    PubMed

    Gurram, Krishna C; Czapla, Agata; Thakkar, Shyam

    2014-10-07

    Acute recurrent pancreatitis occurs rarely in individuals with pancreas divisum. A 39-year-old woman with no significant history presented with pancreatitis. CT scan and MRI suggested acute on chronic pancreatitis with calcifications and pancreatic divisum. An endoscopic ultrasound demonstrated complete pancreas divisum. A large calcification measuring 12 mm × 6 mm was seen in the head of the pancreas with associated dilation of the ventral pancreatic duct. Fine-needle aspiration of the dilated ventral pancreatic duct showed an amylase level of 36,923 U/L and a carcinoembryonic antigen of 194. A ventral duct intraductal papillary mucinous neoplasm was suspected and a pancreaticoduodenectomy procedure was recommended. After the procedure, pathology demonstrated an intraductal papillary lesion in the main duct with moderate dysplasia. A pancreatic intraepithelial neoplasia, grade 2 was also present. Margins of resection were clear. This case represents the importance of assessing for secondary causes of pancreatitis in pancreas divisum.

  10. Acute pancreatitis: pancreas divisum with ventral duct intraductal papillary mucinous neoplasms

    PubMed Central

    Gurram, Krishna C; Czapla, Agata; Thakkar, Shyam

    2014-01-01

    Acute recurrent pancreatitis occurs rarely in individuals with pancreas divisum. A 39-year-old woman with no significant history presented with pancreatitis. CT scan and MRI suggested acute on chronic pancreatitis with calcifications and pancreatic divisum. An endoscopic ultrasound demonstrated complete pancreas divisum. A large calcification measuring 12 mm × 6 mm was seen in the head of the pancreas with associated dilation of the ventral pancreatic duct. Fine-needle aspiration of the dilated ventral pancreatic duct showed an amylase level of 36 923 U/L and a carcinoembryonic antigen of 194. A ventral duct intraductal papillary mucinous neoplasm was suspected and a pancreaticoduodenectomy procedure was recommended. After the procedure, pathology demonstrated an intraductal papillary lesion in the main duct with moderate dysplasia. A pancreatic intraepithelial neoplasia, grade 2 was also present. Margins of resection were clear. This case represents the importance of assessing for secondary causes of pancreatitis in pancreas divisum. PMID:25293684

  11. p120 Catenin is required for normal tubulogenesis but not epithelial integrity in developing mouse pancreas.

    PubMed

    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

    2015-03-01

    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 p120(f/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.

  12. Acute non-traumatic pancreatitis in a patient with pancreas divisum: a case report.

    PubMed

    Anyfantakis, D; Partalis, N; Polimili, G; Kastanakis, S

    2013-09-15

    Pancreas divisum is a frequent congenital anatomical anomaly characterized by the failure of fusion of the ducts of Santorini and Wirsung during fetal development. Although the condition usually remains asymptomatic, it has been reported to be a predisposing factor of chronic and recurrent idiopathic pancreatitis. We report a case of acute non-traumatic pancreatitis in a 54-year-old Caucasian male with pancreas divisum. Diagnosis was established based on the findings from magnetic resonance imaging and magnetic resonance cholangiopancreatography. The patient was managed conservatively and was discharged home having an uneventful clinical course after five days of hospitalization. Although the role of the pancreas in the induction of acute pancreatitis is still a matter of debate, physicians have to be aware about this prevalent pancreatic anatomic abnormality. Timely detection may help in the prevention of potential recurrent pancreatic reaction.

  13. 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

  14. 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

  15. 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

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

    PubMed

    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.

  17. Recurrent Acute Pancreatitis Secondary to Graft Pancreas Divisum in a Patient with Modified Multi-Visceral Transplant

    PubMed Central

    Nawaz, Haq; Slivka, Adam

    2014-01-01

    A patient with modified multivisceral transplant developed recurrent acute pancreatitis (RAP) 1 year after transplant and was found to have graft pancreas divisum with otherwise negative work-up for identifying the etiology of RAP. Endoscopic retrograde cholangiopancreatography was performed with minor papilla sphincterotomy and pancreatic duct stent placement of the graft pancreas. The patient's symptoms resolved following endotherapy for a follow-up period of 2 years. This is a unique case of graft pancreatitis secondary to pancreas divisum. PMID:26157839

  18. 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

  19. [The function of the hydrokinetic and ekbolic pancreas after acute pancreatitis].

    PubMed

    Tympner, F; Domschke, W; Rösch, W; Koch, H; Demling, L

    1976-11-01

    Thirteen patients were investigated 3-4 weeks (I. examination) and 3-5 months (II. examination) after the ceasing of the signs symptoms of an acute pancreatitis concerning their hydrokinetic and ekbolic pancreas-functions. In addition, the pancreatic ducts were demonstrated by ERCP. Reduction of the secretion were shown in 31% at the I. examination and in 23% at the II. examination. There were significant differences in the outputs of bicarbonate, trypsine and chymotrypsine compared to healthy test persons at the I. examination. At the II. examination, however, no significant differences could be observed compared to healthy test persons. The exocrine function of the pancreas was getting worse during the interval between the I. and II. examination in 2 cases but it became normal in 5 cases. Pathological alterations at the pancreativ-duct-system were not demonstrable shown at all.

  20. [The function of the hydrokinetic and ekbolic pancreas after acute pancreatitis].

    PubMed

    Tympner, F; Domschke, W; Rösch, W; Koch, H; Demling, L

    1976-11-01

    Thirteen patients were investigated 3-4 weeks (I. examination) and 3-5 months (II. examination) after the ceasing of the signs symptoms of an acute pancreatitis concerning their hydrokinetic and ekbolic pancreas-functions. In addition, the pancreatic ducts were demonstrated by ERCP. Reduction of the secretion were shown in 31% at the I. examination and in 23% at the II. examination. There were significant differences in the outputs of bicarbonate, trypsine and chymotrypsine compared to healthy test persons at the I. examination. At the II. examination, however, no significant differences could be observed compared to healthy test persons. The exocrine function of the pancreas was getting worse during the interval between the I. and II. examination in 2 cases but it became normal in 5 cases. Pathological alterations at the pancreativ-duct-system were not demonstrable shown at all. PMID:1007339

  1. Acute pharmacokinetics of memantine in the mouse.

    PubMed

    Saab, Bechara J; Roder, John C

    2011-01-01

    The pharmacokinetics of memantine, a widely prescribed medication in the United States and the European Union for the treatment of moderate-to-severe Alzheimer's disease (AD), have not been well explored in the mouse. Memantine is a highly unspecific blocker of many channels and how memantine may be of benefit in AD remains a mystery. Therefore, the investigation of memantine in the mouse, the most commonly chosen subject for modeling AD, has strong potential to lead to better therapies. Here, we present an acute pharmacokinetic analysis of memantine in mouse brain tissue and blood serum for a variety of experimentally relevant doses. The data help shed light on the mechanism of memantine action in vivo, and demonstrate that subcutaneous doses above 10 mg/kg in the mouse are most likely not therapeutically relevant to the human.

  2. Expression and misexpression of members of the FGF and TGFbeta families of growth factors in the developing mouse pancreas.

    PubMed

    Dichmann, Darwin S; Miller, Christopher P; Jensen, Jan; Scott Heller, R; Serup, Palle

    2003-04-01

    We have performed a high-capacity, semiquantitative, reverse transcriptase-polymerase chain reaction screen for expression of fibroblast growth factor (FGF) and transforming growth factor beta (TGFbeta) family genes as well as their cognate receptors. By using cDNA prepared from embryonic day 12 to postnatal day 0 embryonic mouse pancreas, we have identified several factors potentially involved in the development of the endocrine pancreas. We find high-level early expression of TGFbeta-1 and -2, and constitutive expression of TGFbeta-3 and their receptors. Of the Inhibin/Activin members, we found exclusively Inhibin-alpha and Activin-betaB to be expressed, and the BMP family was represented by BMP4, BMP5, and BMP7. The predominant forms of the BMP and Activin type II receptors were ActR-IIB and BMPR-II and of the type I receptors, BMPR-1A and -1B were the highest expressed. FGF1, FGF7, FGF9, FGF10, FGF11, and FGF18 were also expressed in the pancreas at varying time points and levels, as well as FGF receptor forms FGFR1b, FGFR1c, FGFR2b, FGFR2c, FGFR3b, and FGFR4. To gain insight into the biological function, we misexpressed members of these families in the pancreas by using the early pancreas promoter Pdx1. Misexpression of FGF4 results in disruption of the pancreas morphology with epithelial structures interspersed in stroma tissue. The endocrine compartment was reduced to scattered single cells, and the exocrine consisted of unbranched ductal epithelia with acinar structures budding off. In contrast, misexpression of BMP-6 resulted in complete agenesis of the pancreas and reduced the size of the stomach and spleen dramatically and caused fusion of the liver and duodenum.

  3. Preliminary Study of MR Diffusion Tensor Imaging of Pancreas for the Diagnosis of Acute Pancreatitis

    PubMed Central

    Zhang, Xiaoming; Wang, Jian; Chen, Tianwu; Li, Liangjun; Aduah, Emmanuel Ajedichiga; Hu, Jiani

    2016-01-01

    Objectives To evaluate the feasibility of differentiating between acute pancreatitis (AP) and healthy pancreas using diffusion tensor imaging (DTI) and correlate apparent diffusion coefficient (ADC) /fractional anisotropy (FA) values with the severity of AP. Material and Methods 66 patients diagnosed with AP and 20 normal controls (NC) underwent DTI sequences and routine pancreatic MR sequences on a 3.0T MRI scanner. Average ADC and FA values of the pancreatic were measured. Differences of FA and ADC values between the AP group and the NC group with AP and healthy pancreas were compared by two-sample independent t-test. The severity of AP on MRI was classified into subgroups using MR severity index (MRSI), where the mean FA and ADC values were calculated. Relationship among the FA values, ADC values and MRSI were analyzed using Spearman's rank correlation coefficients. Results The pancreatic mean ADC value in the AP group (1.68 ± 0.45×10−3mm2/s) was significantly lower than in the NC group (2.09 ± 0.55×10−3mm2/s) (P = 0.02); the same as mean FA value (0.39 ± 0.23 vs 0.54 ± 0.12, P = 0.00). In the subgroup analysis, the pancreatic ADC and FA value of edema AP patients was significantly higher than necrosis AP patients with P = 0.000 and P = 0.001respectively. In addition, as severity of pancreatitis increased according to MRSI, lower pancreatic ADC (r = -0.635) and FA value (r = -0.654) were noted. Conclusion Both FA and ADC value from DTI can be used to differentiate AP patients from NC. Both ADC and FA value of pancreas have a negative correlation with the severity of AP. PMID:27584016

  4. 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.

  5. AMYLOID FORMATION IN HUMAN IAPP TRANSGENIC MOUSE ISLETS AND PANCREAS AND HUMAN PANCREAS IS NOT ASSOCIATED WITH ENDOPLASMIC RETICULUM STRESS

    PubMed Central

    Hull, R.L.; Zraika, S.; Udayasankar, J.; Aston-Mourney, K.; Subramanian, S.L.; Kahn, S.E.

    2009-01-01

    Hypothesis Supraphysiological levels of the amyloidogenic peptide human islet amyloid polypeptide (hIAPP) have been associated with beta cell endoplasmic reticulum (ER) stress. However, in human type 2 diabetes, levels of hIAPP are equivalent or decreased relative to matched controls. Thus, we sought to investigate whether ER stress is induced during amyloidogenesis at physiological levels of hIAPP. Methods Islets from hIAPP transgenic mice that develop amyloid, and non-transgenic mice that do not, were cultured for up to seven days in 11.1, 16.7 and 33.3 mmol/l glucose. Pancreata from hIAPP transgenic and non-transgenic mice and human subjects with or without type 2 diabetes were also evaluated. Amyloid formation was determined histologically. ER stress was determined in islets by quantifying mRNA levels of BiP, Atf4 and Chop, and alternate splicing of XBP-1 mRNA or in pancreata by immunostaining for BiP, CHOP and XBP-1. Results Amyloid formation in hIAPP transgenic islets was associated with reduced beta-cell area in a glucose- and time-dependent manner. However, amyloid formation was not associated with significant increases in expression of ER stress markers under any culture condition. Thapsigargin treatment, a positive control, did result in significant ER stress. Amyloid formation in vivo in pancreas samples from hIAPP transgenic mice or humans was not associated with upregulation of ER stress markers. Conclusions/interpretation Our data suggest that ER stress is not an obligatory pathway mediating the toxic effects of amyloid formation at physiological levels of hIAPP. PMID:19352619

  6. 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

  7. Adenoviral vector-mediated insulin gene transfer in the mouse pancreas corrects streptozotocin-induced hyperglycemia.

    PubMed

    Shifrin, A L; Auricchio, A; Yu, Q C; Wilson, J; Raper, S E

    2001-10-01

    Therapy for type 1 diabetes consists of tight blood glucose (BG) control to minimize complications. Current treatment relies on multiple insulin injections or an insulin pump placement, beta-cell or whole pancreas transplantation. All approaches have significant limitations and have led to the realization that novel treatment strategies are needed. Pancreatic acinar cells have features that make them a good target for insulin gene transfer. They are not subject to autoimmune attack, a problem with pancreas or islets transplantation, they are avidly transduced by recombinant adenoviral vectors, and capable of exporting a variety of peptides into the portal circulation. Recombinant adenoviral vectors were engineered to express either wild-type or furin-modified human insulin cDNA (AdCMVhInsM). Immunodeficient mice were made diabetic with streptozotocin and injected intrapancreatically with the vectors. BG and blood insulin levels have normalized after administration of AdCMVhInsM. Immunohistochemistry and electron microscopy showed the presence of insulin in acinar cells throughout the pancreas and localization of insulin molecules to acinar cell vesicles. The data clearly establish a relationship between intrapancreatic vector administration, decreased BG and elevated blood insulin levels. The findings support the use of pancreatic acinar cells to express and secrete insulin into the blood stream. PMID:11593361

  8. Establishment and Characterization of a Transgenic Mouse Model for In Vivo Imaging of Bmp4 Expression in the Pancreas

    PubMed Central

    Yasunaga, Mayu; Oumi, Nao; Osaki, Mitsuhiko; Kazuki, Yasuhiro; Nakanishi, Tomoko; Oshimura, Mitsuo; Sato, Kenzo

    2011-01-01

    Type-2 diabetes results from the development of insulin resistance and a concomitant impairment of insulin secretion. Bone morphogenetic protein 4 (Bmp4)-Bmp receptor 1A signaling in β cells has recently been reported to be required for insulin production and secretion. In addition, Bmp4 blocks the differentiation and promotes the expansion of endocrine progenitor cells. Bmp4 therefore regulates the maintenance of homeostasis in the pancreas. In this study, we constructed a reporter plasmid carrying 7-kb enhancer and promoter region of the Bmp4 gene upstream of the firefly luciferase gene. We used this construct to produce transgenic mice by pro-nuclear microinjection, for subsequent in vivo monitoring of Bmp4 expression. The bioluminescent signal was detected mainly in the pancreas in three independent lines of transgenic mice. Furthermore, the bioluminescent signal was enhanced in association with the autophagy response to 24-h fasting. These results suggest that pancreatic expression of Bmp4 is involved in responding to the physiological environment, including through autophagy. These mouse models represent useful tools for toxicological screening, and for investigating the mechanisms responsible for pancreatic Bmp4 functions in vivo, with relevance to improving our understanding of pancreatic diseases. PMID:21949805

  9. 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

  10. 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 ...

  11. 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

  12. Nkx2.2:Cre knock-in mouse line: a novel tool for pancreas- and CNS-specific gene deletion.

    PubMed

    Balderes, Dina A; Magnuson, Mark A; Sussel, Lori

    2013-12-01

    Nkx2.2 is a homeodomain-containing transcriptional regulator necessary for the appropriate differentiation of ventral neuronal populations in the spinal cord and hindbrain, and endocrine cell populations in the pancreas and intestine. In each tissue, Nkx2.2 inactivation leads to reciprocal cell fate alterations. To confirm the cell fate changes are due to respecification of Nkx2.2-expressing progenitors and to provide a novel tool for lineage tracing in the pancreas and CNS, we generated an Nkx2.2:Cre mouse line by knocking in a Cre-EGFP cassette into the Nkx2.2 genomic locus and inactivating endogenous Nkx2.2. The R26R-CAG-LSL-tdTomato reporter was used to monitor the specificity and efficiency of Nkx2.2:Cre activity; the tomato reporter faithfully recapitulated endogenous Nkx2.2 expression and could be detected as early as embryonic day (e) 9.25 in the developing CNS and was initiated shortly thereafter at e9.5 in the pancreas. Lineage analyses in the CNS confirmed the cell populations thought to be derived from Nkx2.2-expressing progenitor domains. Furthermore, lineage studies verified Nkx2.2 expression in the earliest pancreatic progenitors that give rise to all cell types of the pancreas; however they also revealed more robust Cre activity in the dorsal versus ventral pancreas. Thus, the Nkx2.2:Cre line provides a novel tool for gene manipulations in the CNS and pancreas.

  13. [The redox potentials and morphological features of the pancreas, small intestines and liver under early enteral nutrition via micro-jejunostomy in modeling of acute pancreatitis].

    PubMed

    Khatchapuridze, G; Leonov, V

    2014-01-01

    The article investigates morphological changes in pancreas, liver, and small intestine after early enteral nutrition in Vistar rats after modeling of acute pancreatitis and creation of jejunostomy. Morphological changes and redox potential measurements show that early enteral nutrition via micro-jejunostomy slows down the development of pathological processes in Vistar rats. PMID:24523337

  14. 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

    2015-08-07

    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.

  15. Pancreatic stellate cells and CX3CR1: occurrence in normal pancreas, acute and chronic pancreatitis and effect of their activation by a CX3CR1 agonist

    PubMed Central

    Uchida, Masahiko; Ito, Tetsuhide; Nakamura, Taichi; Hijioka, Masayuki; Igarashi, Hisato; Oono, Takamasa; Kato, Masaki; Nakamura, Kazuhiko; Suzuki, Koichi; Takayanagi, Ryoichi; Jensen, Robert T.

    2014-01-01

    Objectives Numerous studies suggest important roles of the chemokine, fractalkine (CX3CL1) in acute/chronic pancreatitis, however the possible mechanisms of the effects are unclear. Pancreatic stellate cells (PSCs) can play important roles in pancreatitis, secreting inflammatory cytokines/chemokines, as well as proliferation. Therefore, we investigated CX3CL1 receptor (CX3CR1) occurrence in normal pancreas and pancreatitis (acute/chronic) tissues, and the effects of CX3CL1 on activated-PSCs. Methods CX3CR1 expression/localization in normal pancreas and pancreatitis (acute/chronic) tissues were evaluated with immunohistochemical analysis. CX3CR1 expression and effects of CX3CL1 on activated-PSCs were examined with realtime-PCR, BrdU assays and Western Blotting. Results In normal pancreas, acinar cells expressed CX3CR1 within granule-like-formations in the cytoplasm, whereas in acute/chronic pancreatitis, acinar, ductal and activated-PSCs expressed CX3CR1 on cell membranes. With activation of normal PSCs, CX3CR1 is increased. CX3CL1 activated multiple signaling cascades in PSCs. CX3CL1, did not induce inflammatory-genes expression in activated-PSCs, but induced proliferation. Conclusions CX3CR1s are expressed in normal pancreas. Expression is increased in acute/chronic pancreatitis and the CX3CR1s are activated. CX3CL1 induces proliferation of activated-PSCs without increasing release of inflammatory-mediators. These results suggest that CX3CR1 activation of PSCs could be important in their effects in pancreatitis, especially to PSCs proliferation in pancreatitis where CX3CL1 levels are elevated. PMID:24681877

  16. 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

  17. 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.

  18. 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 ...

  19. Repeating regional acute pancreatitis in the head of the pancreas caused by intraductal papillary mucinous neoplasms in the tail: report of a case.

    PubMed

    Asari, Sadaki; Matsumoto, Ippei; Toyama, Hirochika; Shinzeki, Makoto; Goto, Tadahiro; Shirakawa, Sachiyo; Yamada, Isamu; Ajiki, Tetsuo; Fukumoto, Takumi; Ito, Tomoo; Ku, Yonson

    2012-04-01

    Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is a distinct entity characterized by papillary proliferations of mucin-producing epithelial cells with excessive mucin production and cystic dilatation of the pancreatic ducts. The clinical presentation often involves recurrent episodes of pancreatitis associated with the temporal obstruction of the main pancreatic duct caused by the hypersecretion of mucin. We herein describe a case in which the patient repeatedly experienced the occurrence of idiopathic acute pancreatitis in the head of the pancreas over a 9-year period, and who was ultimately was cured by distal pancreatectomy for IPMNs in the pancreatic tail. This case illustrates the potential pitfalls in the diagnosis of IPMNs owing to a discrepancy between the site of pancreatitis and that of the IPMN. The possible mechanisms linking acute pancreatitis with the formation of IPMNs are also reviewed.

  20. 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. ...

  1. 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

  2. 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.

  3. Failure of human and mouse leptin to affect insulin, glucagon and somatostatin secretion by the perfused rat pancreas at physiological glucose concentration.

    PubMed

    Leclercq-Meyer, V; Malaisse, W J

    1998-06-25

    In isolated perfused pancreas from normal rats, a rise in d-glucose concentration from 3.3 to 8.3 mM provoked a rapid phasic stimulation of both insulin and somatostatin secretion and rapid fall in glucagon output, these changes being reversed when the concentration of the hexose was brought back to its initial low level. In the presence of 8.3 mM d-glucose, the administration of either human or mouse leptin (10 nM in both cases) for 15 min failed to affect significantly the perfusion pressure and release of the three hormones. It is concluded that leptin does not exert any major immediate and direct effect upon pancreatic insulin, glucagon and somatostatin secretion, at least at the physiological concentration of d-glucose normally found in the plasma of fed rats. PMID:9723892

  4. 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 ...

  5. Pancreas transplant

    MedlinePlus

    ... evidence that the complications of diabetes, such as diabetic retinopathy, may not get worse and may even improve after a pancreas-kidney transplant. More than 95% of people survive ... of the donated pancreas and kidney for the rest of your life.

  6. 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

  7. Molecular Pathways Controlling Pancreas induction

    PubMed Central

    McCracken, Kyle W.; Wells, James M.

    2012-01-01

    Recent advances in generating pancreatic cell types from human pluripotent stem cells has depended on our knowledge of the developmental processes that regulate pancreas development in vivo. The developmental events between gastrulation and formation of the embryonic pancreatic primordia are both rapid and dynamic and studies in frog, fish, chick, and mouse have identified the molecular basis of how the pancreas develops from multipotent endoderm progenitors. Here, we review the current status of our understanding of molecular mechanisms that control endoderm formation, endoderm patterning, and pancreas specification and highlight how these discoveries have allowed for the development of robust methods to generate pancreatic cells from human pluripotent stem cells. PMID:22743233

  8. 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.

  9. 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 ...

  10. Precursor cells of mouse endocrine pancreas coexpress insulin, glucagon and the neuronal proteins tyrosine hydroxylase and neuropeptide Y, but not pancreatic polypeptide.

    PubMed

    Teitelman, G; Alpert, S; Polak, J M; Martinez, A; Hanahan, D

    1993-08-01

    The early progenitor cells to the pancreatic islets in the mouse have been characterized so as to re-examine their possible lineage relationships to the four islet cell types found in mature islets. Insulin and glucagon were both first expressed at embryonic day 9.5, and many cells coexpressed these two markers, as shown by light and electron microscopic analysis using double-label immunohistochemistry. Incubation of embryonic pancreas with 1% glutaraldehyde, a fixative commonly used by electron microscopists, abolished this reactivity, thereby explaining reported difficulties in detecting these precursor cells. Using antisera specific for neuropeptide Y (NPY) a peptide with considerable homology to pancreatic polypeptide (PP), we show that NPY first appears with insulin and glucagon immunoreactivity at E9.5, and is co-expressed with glucagon in a majority of adult alpha cells. As we have previously reported, PP itself is first detectable immunocytochemically at postnatal day 1 with PP-specific antibodies. However, antibodies raised against bovine PP are shown by dot blotting to recognize NPY with comparable avidity, indicating that a recent report of islet progenitor cells containing PP at E9.5 (Herrera, P. L., Huarte, J., Sanvito, F., Meda, P., Orci, L. and Vassalli, J. D. (1991) Development 113, 1257-1265), actually represents cross-reactivity to NPY. The data support a model in which early precursor cells to the endocrine pancreas co-activate and co-express a set of islet cell hormone and neural genes, whose expression is both selectively increased and extinguished as development proceeds, concomitant with a restriction to the patterns of expression characteristic of mature islet cell types.

  11. 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.

  12. 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

  13. 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

  14. 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.

  15. 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

  16. 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.

  17. 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

  18. 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

  19. 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.

  20. 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

  1. 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 ...

  2. 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...

  3. 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.

  4. Enlarged pancreas: not always a cancer.

    PubMed

    Calculli, Lucia; Festi, Davide; Pezzilli, Raffaele

    2015-02-01

    Pancreatic fat accumulation has been described with various terms including pancreatic lipomatosis, pancreatic steatosis, fatty replacement, fatty infiltration, fatty pancreas, lipomatous pseudohypertrophy and nonalcoholic fatty pancreas disease. It has been reported to be associated with type 2 diabetes mellitus, acute pancreatitis, pancreatic cancer and the formation of pancreatic fistula. The real incidence of this condition is still unknown. We report a case of pancreatic steatosis in a non-obese female patient initially diagnosed with a mass in the head of the pancreas. Magnetic resonance imaging (MRI) was carried out to define the characteristics of the pancreatic mass. MRI confirmed the diagnosis of fat pancreas. Enlarged pancreas is not always a cancer, but pancreatic steatosis is characterized by pancreatic enlargement. MRI could give a definite diagnosis of pancreatic steatosis or cancer.

  5. 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

  6. Notch signaling differentially regulates the cell fate of early endocrine precursor cells and their maturing descendants in the mouse pancreas and intestine.

    PubMed

    Li, Hui Joyce; Kapoor, Archana; Giel-Moloney, Maryann; Rindi, Guido; Leiter, Andrew B

    2012-11-15

    Notch signaling inhibits differentiation of endocrine cells in the pancreas and intestine. In a number of cases, the observed inhibition occurred with Notch activation in multipotential cells, prior to the initiation of endocrine differentiation. It has not been established how direct activation of Notch in endocrine precursor cells affects their subsequent cell fate. Using conditional activation of Notch in cells expressing Neurogenin3 or NeuroD1, we examined the effects of Notch in both organs, on cell fate of early endocrine precursors and maturing endocrine-restricted cells, respectively. Notch did not preclude the differentiation of a limited number of endocrine cells in either organ when activated in Ngn3(+) precursor cells. In addition, in the pancreas most Ngn3(+) cells adopted a duct but not acinar cell fate; whereas in intestinal Ngn3(+) cells, Notch favored enterocyte and goblet cell fates, while selecting against endocrine and Paneth cell differentiation. A small fraction of NeuroD1(+) cells in the pancreas retain plasticity to respond to Notch, giving rise to intraislet ductules as well as cells with no detectable pancreatic lineage markers that appear to have limited ultrastructural features of both endocrine and duct cells. These results suggest that Notch directly regulates cell fate decisions in multipotential early endocrine precursor cells. Some maturing endocrine-restricted NeuroD1(+) cells in the pancreas switch to the duct lineage in response to Notch, indicating previously unappreciated plasticity at such a late stage of endocrine differentiation.

  7. Acute phase serum proteins in syngeneic and allogeneic mouse pregnancy.

    PubMed Central

    Waites, G T; Bell, A M; Bell, S C

    1983-01-01

    The levels of two murine acute phase proteins, serum amyloid P component (SAP) and haptoglobin, have been measured in the serum of C57BL/10 female mice during syngeneic and allogeneic pregnancy. Both syngeneic and allogeneic pregnancy resulted in alterations in the levels of these proteins as compared to those observed in virgin females. Syngeneic mating resulted in an increase in concentration of both proteins during the final 3 days of pregnancy. During allogeneic pregnancy, SAP levels, after a transient increase on day 4, rose from days 6-8 and, after remaining relatively stable, increased from day 12 to reach maximum levels on day 18 of pregnancy. Levels fell dramatically during the immediate post-partum period. In contrast, although levels of haptoglobin also increased from days 6-8, for the remainder of pregnancy these increased levels remained stable. The implications of these findings are discussed in relation to the mechanisms of regulation of acute phase reactants and the immunological relationship between the mother and fetus. PMID:6409477

  8. Proteomic analysis of the soluble and the lysosomal+mitochondrial fractions from rat pancreas: Implications for cerulein-induced acute pancreatitis.

    PubMed

    García-Hernández, Violeta; Sánchez-Bernal, Carmen; Sarmiento, Nancy; Viana, Raúl A; Ferreira, Laura; Pérez, Nieves; Calvo, José J; Sánchez-Yagüe, Jesús

    2012-09-01

    Alterations in protein expression within the initiation phase of acute pancreatitis (AP) might play an important role in the development of this disease, lysosomes being involved in its pathophysiology. The use of pancreatic subcellular fractions in proteomic analysis, simplifies protein maps and helps in the identification of new protein changes and biomarkers characterizing tissue damage. The present study aims to determine the differentially expressed acidic proteins in the pancreatic soluble and lysosomal+mitochondrial (L+M) fractions from rats during the early phase of the experimental model of cerulein (Cer)-induced AP. Subcellular pancreatic extracts from diseased and control rats were analyzed by 2-DE (3-5.6 pH range) and MALDI-TOF/TOF MS. Comparative analysis afforded the conclusive identification of 13 (soluble fraction) and 7 (L+M fraction) proteins or protein fragments occuring in different amounts between diseased and control pancreas, some of them being newly described in AP. In the soluble fraction, we detected changes related to inflammation and apoptosis (α1-inhibitor-3, α-1 antitrypsin, α-1 macroglobulin, haptoglobin, STRAP), oxidative stress and stress response (peroxiredoxin-2, thioredoxin-like 1, GRP94/TRA1, heat shock cognate 71kDa protein), digestive proteases (elastase 3B), serine protease inhibition (serpins B6 and A3L) and translation processes (EF 1-δ). In the L+M fraction, we detected changes mainly related to energy generation or cellular metabolism (ATP synthase β subunit, chymotrypsinogen B, triacylglycerol lipase), cell redox homeostasis (iodothyronine 5´monodeiodinase) and digestive proteases (carboxypeptidase B1). The data should provide valuable information for unraveling the early pathophysiologic mechanisms of Cer-induced AP. PMID:22713802

  9. [Pancreas pseudocyst or metastasis?].

    PubMed

    Gyorffy, Hajnalka; Tihanyi, Tibor; Gyökeres, Tibor; Zsirka-Klein, Attila; Kádár, Péter; Kaszás, Ilona; Kovács, Margit

    2005-10-23

    The authors review a case of a 24-year-old male patient hospitalised for repeated acute abdominal symptoms. His medical history included no diseases worth of mentioning. By imaging techniques (abdominal US and CT scan) a cystic lesion, measuring 40 x 35 x 30 mm in diameter was found, and was diagnosed as pseudocyst in the region of the tail of the pancreas. Jejunal feeding was introduced. The lesion did not improve and the second CT scan suggested a suspicion of pancreatic cystadenoma. Three months after first presentation the surgical resection was performed. The tumour, however, was found independent of the pancreas (90 x 80 x 50 mm). Both histologically and immunohistochemically the lesion proved to be the metastasis of a germ cell (yolk-sac) tumour. Following the morphological diagnosis, detailed urological and medical check up was performed. A previously nonpalpable small tumour was found in the left testis which was radically resected. The testicular tumour measuring 9 x 9 x 5 mm in diameter was diagnosed as embryonal carcinoma. Later on the patient underwent chemotherapy. He has been undergoing close oncological followup. Clinically, he is disease free. Authors emphasize the importance of imaging techniques and fine needle aspiration cytology in the case of retroperitoneal masses in young males. The possibility of a metastasis, especially of germ cell origin, should be excluded (not only by physical examination, but by ultrasound of testis also) in case of retroperitoneal cystic tumours even with unusual morphology.

  10. Spontaneous acute tumor lysis syndrome in a DBA/1J mouse: a case report and review.

    PubMed

    Lovelace, Karen; vanGessel, Yvonne; Asher, Ludmila V; Vogel, Peter

    2003-01-01

    Spontaneous acute tumor lysis syndrome (ATLS) was diagnosed in a 10-month-old female DBA/1J sentinel mouse with leukemic lymphoma. The mouse was unable to maintain balance and died shortly after being observed rolling around in its cage. Disseminated neoplastic disease, including a large cranial mediastinal mass, enlarged lymph nodes and splenomegaly, was present at necropsy. Histopathologic examination revealed widespread massive necrosis of lymphoblastic tumor cells, and widely disseminated microemboli composed of nuclear and cytoplasmic cell debris. Although ATLS is widely recognized as an oncologic emergency in humans, acute lesions of ATLS have not been described. The mechanical obstruction of capillary beds by microemboli originating from disintegrating necrotic tumor cells was the likely cause of clinical signs and death in this mouse. We propose that similar microemboli may contribute to the pathogenesis of the acute renal failure and other clinical signs associated with ATLS in humans. Recognition of spontaneous ATLS in laboratory animals is especially important in studies that assess the efficacy and/or toxicity of anticancer treatments, where early deaths due to ATLS might mistakenly be attributed to a direct test article effect.

  11. 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 ...

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

    PubMed

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

    2015-10-01

    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.

  13. Resveratrol lacks protective activity against acute seizures in mouse models.

    PubMed

    Tomaciello, Francesca; Leclercq, Karine; Kaminski, Rafal M

    2016-10-01

    Resveratrol (3,4',5-stilbenetriol) is a natural product having diverse anti-inflammatory and antioxidant properties. The compound has a wide spectrum of pharmacological and metabolic activity, including cardioprotective, neuroprotective, anticarcinogenic and anti-aging effects reported in numerous studies. Some reports also suggest potential anticonvulsant properties of resveratrol. In the present study, we used in mice three different seizure models which are routinely applied in preclinical drug discovery. The protective effects of resveratrol were evaluated in the pentylenetetrazole (PTZ), maximal electroshock (MES) and 6-Hz electrical seizure models. Resveratrol (up to 300mg/kg) administered ip (5-60min pre-treatment time) remained without any protective activity against seizures induced in these models. There was only a trend towards a delay in seizure latency, which reached statistical significance after treatment with resveratrol (100mg/kg; 15min) in case of tonic convulsions induced by PTZ. Phenobarbital (PHB, ip, 45min), used as a reference compound, displayed a clear-cut and dose-dependent protection against seizures in all the models. The ED50 values obtained with PHB were as follows: 7.3mg/kg (PTZ model), 13.3mg/kg (MES model) and 29.7mg/kg (6-Hz model). The present data demonstrate that an acute treatment with resveratrol does not provide any significant protection in three seizure models which collectively are able to detect anticonvulsants with diverse mechanisms of action. However, it cannot be excluded that chronic treatment with resveratrol may offer some protection in these or other seizure models.

  14. Transcriptional control of mammalian pancreas organogenesis.

    PubMed

    Cano, David A; Soria, Bernat; Martín, Francisco; Rojas, Anabel

    2014-07-01

    The field of pancreas development has markedly expanded over the last decade, significantly advancing our understanding of the molecular mechanisms that control pancreas organogenesis. This growth has been fueled, in part, by the need to generate new therapeutic approaches for the treatment of diabetes. The creation of sophisticated genetic tools in mice has been instrumental in this progress. Genetic manipulation involving activation or inactivation of genes within specific cell types has allowed the identification of many transcription factors (TFs) that play critical roles in the organogenesis of the pancreas. Interestingly, many of these TFs act at multiple stages of pancreatic development, and adult organ function or repair. Interaction with other TFs, extrinsic signals, and epigenetic regulation are among the mechanisms by which TFs may play context-dependent roles during pancreas organogenesis. Many of the pancreatic TFs directly regulate each other and their own expression. These combinatorial interactions generate very specific gene regulatory networks that can define the different cell lineages and types in the developing pancreas. Here, we review recent progress made in understanding the role of pancreatic TFs in mouse pancreas formation. We also summarize our current knowledge of human pancreas development and discuss developmental pancreatic TFs that have been associated with human pancreatic diseases.

  15. 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 ...

  16. Pancreas transplantation: review.

    PubMed

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

    2015-01-01

    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.

  17. 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

  18. 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

  19. 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

  20. Xenopus pancreas development.

    PubMed

    Pearl, Esther J; Bilogan, Cassandra K; Mukhi, Sandeep; Brown, Donald D; Horb, Marko E

    2009-06-01

    Understanding how the pancreas develops is vital to finding new treatments for a range of pancreatic diseases, including diabetes and pancreatic cancer. Xenopus is a relatively new model organism for the elucidation of pancreas development, and has already made contributions to the field. Recent studies have shown benefits of using Xenopus for understanding both early patterning and lineage specification aspects of pancreas organogenesis. This review focuses specifically on Xenopus pancreas development, and covers events from the end of gastrulation, when regional specification of the endoderm is occurring, right through metamorphosis, when the mature pancreas is fully formed. We have attempted to cover pancreas development in Xenopus comprehensively enough to assist newcomers to the field and also to enable those studying pancreas development in other model organisms to better place the results from Xenopus research into the context of the field in general and their studies specifically. Developmental Dynamics 238:1271-1286, 2009. (c) 2009 Wiley-Liss, Inc.

  1. 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

  2. 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.

  3. 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

  4. Acute metabolic decompensation due to influenza in a mouse model of ornithine transcarbamylase deficiency

    PubMed Central

    McGuire, Peter J.; Tarasenko, Tatiana N.; Wang, Tony; Levy, Ezra; Zerfas, Patricia M.; Moran, Thomas; Lee, Hye Seung; Bequette, Brian J.; Diaz, George A.

    2014-01-01

    ABSTRACT The urea cycle functions to incorporate ammonia, generated by normal metabolism, into urea. Urea cycle disorders (UCDs) are caused by loss of function in any of the enzymes responsible for ureagenesis, and are characterized by life-threatening episodes of acute metabolic decompensation with hyperammonemia (HA). A prospective analysis of interim HA events in a cohort of individuals with ornithine transcarbamylase (OTC) deficiency, the most common UCD, revealed that intercurrent infection was the most common precipitant of acute HA and was associated with markers of increased morbidity when compared with other precipitants. To further understand these clinical observations, we developed a model system of metabolic decompensation with HA triggered by viral infection (PR8 influenza) using spf-ash mice, a model of OTC deficiency. Both wild-type (WT) and spf-ash mice displayed similar cytokine profiles and lung viral titers in response to PR8 influenza infection. During infection, spf-ash mice displayed an increase in liver transaminases, suggesting a hepatic sensitivity to the inflammatory response and an altered hepatic immune response. Despite having no visible pathological changes by histology, WT and spf-ash mice had reduced CPS1 and OTC enzyme activities, and, unlike WT, spf-ash mice failed to increase ureagenesis. Depression of urea cycle function was seen in liver amino acid analysis, with reductions seen in aspartate, ornithine and arginine during infection. In conclusion, we developed a model system of acute metabolic decompensation due to infection in a mouse model of a UCD. In addition, we have identified metabolic perturbations during infection in the spf-ash mice, including a reduction of urea cycle intermediates. This model of acute metabolic decompensation with HA due to infection in UCD serves as a platform for exploring biochemical perturbations and the efficacy of treatments, and could be adapted to explore acute decompensation in other types

  5. A genetic mouse model to investigate hyperoxic acute lung injury survival.

    PubMed

    Prows, Daniel R; Hafertepen, Amanda P; Gibbons, William J; Winterberg, Abby V; Nick, Todd G

    2007-08-20

    Acute lung injury (ALI) is a devastating disease that maintains a high mortality rate, despite decades of research. Hyperoxia, a universal treatment for ALI and other critically ill patients, can itself cause pulmonary damage, which drastically restricts its therapeutic potential. We stipulate that having the ability to use higher levels of supplemental O2 for longer periods would improve recovery rates. Toward this goal, a mouse model was sought to identify genes contributing to hyperoxic ALI (HALI) mortality. Eighteen inbred mouse strains were screened in continuous >95% O2. A significant survival difference was identified between sensitive C57BL/6J and resistant 129X1/SvJ strains. Although resistant, only one-fourth of 129X1/SvJ mice survived longer than any C57BL/6J mouse, demonstrating decreased penetrance of resistance. A survival time difference between reciprocal F1 mice implicated a parent-of-origin (imprinting) effect. To further evaluate imprinting and begin to delineate the genetic components of HALI survival, we generated and phenotyped offspring from all four possible intercrosses. Segregation analysis supported maternal inheritance of one or more genes but paternal inheritance of one or more contributor genes. A significant sex effect was demonstrated, with males more resistant than females for all F2 crosses. Survival time ranges and sensitive-to-resistant ratios of the different F2 crosses also supported imprinting and predicted that increased survival is due to dominant resistance alleles contributed by both the resistant and sensitive parental strains. HALI survival is multigenic with a complex mode of inheritance, which should be amenable to genetic dissection with this mouse model.

  6. 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

  7. Diagnosis of early pancreas graft failure via antibody-mediated rejection: single-center experience with 256 pancreas transplantations.

    PubMed

    de Kort, H; Mallat, M J K; van Kooten, C; de Heer, E; Brand-Schaaf, S H; van der Wal, A M; Roufosse, C; Roelen, D L; Bruijn, J A; Claas, F H; de Fijter, J W; Bajema, I M

    2014-04-01

    Early pancreas graft loss is usually attributed to technical failure while the possibility of antibody-mediated rejection (AMR) is generally overlooked. To investigate the role of AMR in early pancreas graft loss, we retrospectively assessed 256 patients with simultaneous pancreas-kidney transplantation (SPK) between 1985 and 2010 at our institute. We included 33 SPK patients who lost their pancreas graft <1 year after transplantation. AMR was diagnosed based on donor-specific antibodies, C4d and histology in 7 cases, 8 cases were suspicious for AMR and 18 pancreas graft losses were not due to AMR. Acute AMR occurred >1 month after transplantation in 6/7 cases, whereas all other causes typically led to loss <1 month after transplantation. Thrombotic lesions occurred equally among the 33 cases. In 12/18 concurrent kidney specimens, the diagnostic results paralleled those of the pancreas graft. All patients with acute AMR of the pancreas graft lost their renal grafts <1 year after transplantation. In the setting of a thrombotic event, histopathological analysis of early pancreas graft loss is advisable to rule out the possibility of AMR, particularly because a diagnosis of acute AMR has important consequences for renal graft outcomes.

  8. [Exocrine function of the pancreas and pathological histology of the stomach in patients with stomach yin deficiency syndrome (SYDS) research on SYDS following abdominal operation or with severe acute abdominal diseases (Part 3)].

    PubMed

    Qi, Q H; Wu, X Z; Bai, J W

    1990-08-01

    Exocrine function of pancreas (BT-PABA test) in 13 patients with SYDS was examined and gastric membrane in 5 cases with SYDS other than gastric diseases was observed under light- and electro-microscopy. The results were as follows: urine rate of recovery of PABA in SYDS was 35. 42 +/- 14.33% and that in the control with same age was 64.70 +/- 10.55%. The rate in SYDS was decreased obviously (P less than 0.001). Under light microscopy gastric mucosa of patients with SYDS showed slight gland degenerative atrophy, smaller cytoplasm, eosinophilic decrease of parietal cells and infiltration of inflammatory cells in interstitial tissue. Under electro-microscopy, the main changes of the gastric mucosa with SYDS were severe mitochondria damage, inflating rough endoplasmic pools and large vacuole at which membrane major particles of ribosomes disappeared, degenerated secretory vessels and formation of myelin figure in parietal cells, decrease of secretory particles in main cells, degeneration in some degree and decrease of nervous secretory particles in G cells and damaged interstitial capillaries. The results in this study suggested that the exocrine function of pancreas in patients with SYDS after abdominal operation or with severe acute abdominal diseases was decreased and there were some damages in energy supply and protein manufacturing systems of the gastric mucosa and functional disturbances of main cells, parietal cells and G cells in patients with SYDS.

  9. 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

  10. 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

  11. 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.

  12. BIM mediates oncogene inactivation-induced apoptosis in multiple transgenic mouse models of acute lymphoblastic leukemia

    PubMed Central

    Li, Yulin; Deutzmann, Anja; Choi, Peter S.; Fan, Alice C.; Felsher, Dean W.

    2016-01-01

    Oncogene inactivation in both clinical targeted therapies and conditional transgenic mouse cancer models can induce significant tumor regression associated with the robust induction of apoptosis. Here we report that in MYC-, RAS-, and BCR-ABL-induced acute lymphoblastic leukemia (ALL), apoptosis upon oncogene inactivation is mediated by the same pro-apoptotic protein, BIM. The induction of BIMin the MYC- and RAS-driven leukemia is mediated by the downregulation of miR-17-92. Overexpression of miR-17-92 blocked the induction of apoptosis upon oncogene inactivation in the MYC and RAS-driven but not in the BCR-ABL-driven ALL leukemia. Hence, our results provide novel insight into the mechanism of apoptosis upon oncogene inactivation and suggest that induction of BIM-mediated apoptosis may be an important therapeutic approach for ALL. PMID:27095570

  13. 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.

  14. 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

  15. Homeostasis alteration within small intestinal mucosa after acute enteral refeeding in total parenteral nutrition mouse model.

    PubMed

    Feng, Yongjia; Barrett, Meredith; Hou, Yue; Yoon, Hong Keun; Ochi, Takanori; Teitelbaum, Daniel H

    2016-02-15

    Feeding strategies to care for patients who transition from enteral nutrient deprivation while on total parenteral nutrition (TPN) to enteral feedings generally proceed to full enteral nutrition once the gastrointestinal tract recovers; however, an increasing body of literature suggests that a subgroup of patients may actually develop an increased incidence of adverse events, including death. To examine this further, we studied the effects of acute refeeding in a mouse model of TPN. Interestingly, refeeding led to some beneficial effects, including prevention in the decline in intestinal epithelial cell (IEC) proliferation. However, refeeding led to a significant increase in mucosal expression of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), as well as an upregulation in Toll-like receptor 4 (TLR-4). Refeeding also failed to prevent TPN-associated increases in IEC apoptosis, loss of epithelial barrier function, and failure of the leucine-rich repeat-containing G protein-coupled receptor 5-positive stem cell expression. Transitioning from TPN to enteral feedings led to a partial restoration of the small bowel microbial population. In conclusion, while acute refeeding led to some restoration of normal gastrointestinal physiology, enteral refeeding led to a significant increase in mucosal inflammatory markers and may suggest alternative strategies to enteral refeeding should be considered.

  16. Isocitrate treatment of acute anemia of inflammation in a mouse model.

    PubMed

    Kim, Airie; Fung, Eileen; Parikh, Sona G; Gabayan, Victoria; Nemeth, Elizabeta; Ganz, Tomas

    2016-01-01

    Acute and severe anemia of inflammation (AI) is a common complication of various clinical syndromes, including fulminant infections, critical illness with multiorgan failure, and exacerbations of autoimmune diseases. Building on recent data showing beneficial results with isocitrate treatment for chronic low-grade AI in a rat model, we used a mouse model of acute and severe AI induced by intraperitoneal heat-killed Brucella abortus to determine if isocitrate would be effective in this more stringent application. Inflamed mice treated with isocitrate developed an early but transient improvement in hemoglobin compared to solvent-treated controls, with a robust improvement on day 7, and only a trend towards improvement by day 14. Reticulocyte counts were increased in treated mice transiently, with no significant difference by day 21. Serum erythropoietin (EPO) levels were similar in treated versus control mice, indicating that isocitrate increased sensitivity to EPO. Serum and tissue iron levels showed no significant differences between the treated and control mice, ruling out improved iron availability as the cause of the increased response to endogenous EPO. Compared to the milder rat model, much higher doses of isocitrate were required for a relatively modest benefit.

  17. 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.

  18. 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 ...

  19. National Pancreas Foundation

    MedlinePlus

    ... to NPF Contact Us Newsletter Sign Up Social Networking Button – Medium Search: Main menu Skip to primary ... 20814 1.866.726.2737 | Contact Us Social Networking Button – Medium © 2014 The National Pancreas Foundation | Health ...

  20. Partial annular pancreas

    PubMed Central

    Jindal, Gunjan; Mittal, Amit; Singal, Rikki; Singal, Samita

    2016-01-01

    Annular pancreas is a developmental anomaly that can be associated with other conditions such as Down syndrome, duodenal atresia, and Hirschsprung disease. A band of pancreatic tissue, in continuity with the pancreatic head, completely or incompletely encircles the descending duodenum, sometimes assuming a “crocodile jaw” configuration. We present the case of an adult who presented with epigastric pain and vomiting and was found to have annular pancreas. PMID:27695176

  1. [Mucinous cystadenocarcinoma of pancreas].

    PubMed

    Davies, Nestor R; Kasparian, Andres C; Viotto, Lucas E; Moreno, Walter A; Gramática, Luis

    2009-01-01

    Mucinous cystadenocarcinoma of the pancreas represents around 6-36% of mucinous cystic neoplasm. The lesions are usually found in the body and tail of the pancreas and are generally solitary with a size range of 6-36 cm. We present a clinical case of a 63 years old patient with abdominal pain and weight loss. We used radiographic imaging studies. It was treated with surgery by distal pancreatectomy with splenectomy and transverse colectomy. Patient was not post operative complications.

  2. Partial annular pancreas

    PubMed Central

    Jindal, Gunjan; Mittal, Amit; Singal, Rikki; Singal, Samita

    2016-01-01

    Annular pancreas is a developmental anomaly that can be associated with other conditions such as Down syndrome, duodenal atresia, and Hirschsprung disease. A band of pancreatic tissue, in continuity with the pancreatic head, completely or incompletely encircles the descending duodenum, sometimes assuming a “crocodile jaw” configuration. We present the case of an adult who presented with epigastric pain and vomiting and was found to have annular pancreas.

  3. 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.

  4. Selective depletion of mouse kidney proximal straight tubule cells causes acute kidney injury.

    PubMed

    Sekine, Michiko; Monkawa, Toshiaki; Morizane, Ryuji; Matsuoka, Kunie; Taya, Choji; Akita, Yoshiko; Joh, Kensuke; Itoh, Hiroshi; Hayashi, Matsuhiko; Kikkawa, Yoshiaki; Kohno, Kenji; Suzuki, Akemi; Yonekawa, Hiromichi

    2012-02-01

    The proximal straight tubule (S3 segment) of the kidney is highly susceptible to ischemia and toxic insults but has a remarkable capacity to repair its structure and function. In response to such injuries, complex processes take place to regenerate the epithelial cells of the S3 segment; however, the precise molecular mechanisms of this regeneration are still being investigated. By applying the "toxin receptor mediated cell knockout" method under the control of the S3 segment-specific promoter/enhancer, Gsl5, which drives core 2 β-1,6-N-acetylglucosaminyltransferase gene expression, we established a transgenic mouse line expressing the human diphtheria toxin (DT) receptor only in the S3 segment. The administration of DT to these transgenic mice caused the selective ablation of S3 segment cells in a dose-dependent manner, and transgenic mice exhibited polyuria containing serum albumin and subsequently developed oliguria. An increase in the concentration of blood urea nitrogen was also observed, and the peak BUN levels occurred 3-7 days after DT administration. Histological analysis revealed that the most severe injury occurred in the S3 segments of the proximal tubule, in which tubular cells were exfoliated into the tubular lumen. In addition, aquaporin 7, which is localized exclusively to the S3 segment, was diminished. These results indicate that this transgenic mouse can suffer acute kidney injury (AKI) caused by S3 segment-specific damage after DT administration. This transgenic line offers an excellent model to uncover the mechanisms of AKI and its rapid recovery.

  5. Influence of radiation quality on mouse chromosome 2 deletions in radiation-induced acute myeloid leukaemia.

    PubMed

    Brown, Natalie; Finnon, Rosemary; Manning, Grainne; Bouffler, Simon; Badie, Christophe

    2015-11-01

    Leukaemia is the prevailing neoplastic disorder of the hematopoietic system. Epidemiological analyses of the survivors of the Japanese atomic bombings show that exposure to ionising radiation (IR) can cause leukaemia. Although a clear association between radiation exposure and leukaemia development is acknowledged, the underlying mechanisms remain incompletely understood. A hemizygous deletion on mouse chromosome 2 (del2) is a common feature in several mouse strains susceptible to radiation-induced acute myeloid leukaemia (rAML). The deletion is an early event detectable 24h after exposure in bone marrow cells. Ultimately, 15-25% of exposed animals develop AML with 80-90% of cases carrying del2. Molecular mapping of leukaemic cell genomes identified a minimal deleted region (MDR) on chromosome 2 (chr2) in which a tumour suppressor gene, Sfpi1 is located, encoding the transcription factor PU.1, essential in haematopoiesis. The remaining copy of Sfpi1 has a point mutation in the coding sequence for the DNA-binding domain of the protein in 70% of rAML, which alters a single CpG sequence in the codon for arginine residue R235. In order to identify chr2 deletions and Sfpi.1/PU.1 loss, we performed array comparative genomic hybridization (aCGH) on a unique panel of 79rAMLs. Using a custom made CGH array specifically designed for mouse chr2, we analysed at unprecedentedly high resolution (1.4M array- 148bp resolution) the size of the MDR in low LET and high-LET induced rAMLs (32 X-ray- and 47 neutron-induced). Sequencing of Sfpi1/PU.1DNA binding domain identified the presence of R235 point mutations, showing no influence of radiation quality on R235 type or frequency. We identified for the first time rAML cases with complex del2 in a subset of neutron-induced AMLs. This study allowed us to re-define the MDR to a much smaller 5.5Mb region (still including Sfpi1/PU.1), identical regardless of radiation quality.

  6. MEK1/2 inhibitors reverse acute vascular occlusion in mouse models of sickle cell disease.

    PubMed

    Zhao, Yulin; Schwartz, Evan A; Palmer, Gregory M; Zennadi, Rahima

    2016-03-01

    In sickle cell disease (SCD), treatment of recurrent vasoocclusive episodes, leading to pain crises and organ damage, is still a therapeutic challenge. Vasoocclusion is caused primarily by adherence of homozygous for hemoglobin S (SS) red blood cells (SSRBCs) and leukocytes to the endothelium. We tested the therapeutic benefits of MEK1/2 inhibitors in reversing vasoocclusion in nude and humanized SCD mouse models of acute vasoocclusive episodes using intravital microscopy. Administration of 0.2, 0.3, 1, or 2 mg/kg MEK1/2 inhibitor to TNF-α-pretreated nude mice before human SSRBC infusion inhibited SSRBC adhesion in inflamed vessels, prevented the progression of vasoocclusion, and reduced SSRBC organ sequestration. By use of a more clinically relevant protocol, 0.3 or 1 mg/kg MEK1/2 inhibitor given to TNF-α-pretreated nude mice after human SSRBC infusion and onset of vasoocclusion reversed SSRBC adhesion and vasoocclusion and restored blood flow. In SCD mice, 0.025, 0.05, or 0.1 mg/kg MEK1/2 inhibitor also reversed leukocyte and erythrocyte adhesion after the inflammatory trigger of vasoocclusion and improved microcirculatory blood flow. Cell adhesion was reversed by shedding of endothelial E-selectin, P-selectin, and αvβ3 integrin, and leukocyte CD44 and β2 integrin. Thus, MEK1/2 inhibitors, by targeting the adhesive function of SSRBCs and leukocytes, could represent a valuable therapeutic intervention for acute sickle cell vasoocclusive crises.

  7. Differential effects of acute morphine administrations on polymorphonuclear cell metabolism in various mouse strains.

    PubMed

    Di Francesco, P; Tavazzi, B; Gaziano, R; Lazzarino, G; Casalinuovo, I A; Di Pierro, D; Garaci, E

    1998-01-01

    This paper shows that an acute morphine treatment dose-dependently alters the energetic and oxidative metabolism of polymorphonuclear leukocytes obtained from BALB/c and DBA/2 mice, while phagocytic cells from C57BL/6 were not affected. In sensitive mouse strains, i.e. BALB/c and DBA/2, morphine decreased both ATP concentration and energy charge potential. At the same time, ATP catabolic products, i.e. nucleosides (inosine+adenosine) and oxypurines (hypoxanthine+xanthine+uric acid), significantly increased, indicating an imbalance between energy production and consumption. Morphine treatment also induced malondialdehyde and superoxide anions production in leukocyte cells from sensitive mice. The opiate antagonist naloxone blocked morphine-induced modifications by the lower morphine dose. The same parameters in cells from C57BL/6 mice were not affected. These findings confirm that: i) the phagocytic cells are an important target for the in vivo effects of morphine, and ii) the genotype-dependent variation influences the immunological responsiveness to opiates.

  8. 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

  9. Genome-Wide Analysis of Acute Endurance Exercise-Induced Translational Regulation in Mouse Skeletal Muscle

    PubMed Central

    Sako, Hiroaki; Yada, Koichi; Suzuki, Katsuhiko

    2016-01-01

    Exercise dynamically changes skeletal muscle protein synthesis to respond and adapt to the external and internal stimuli. Many studies have focused on overall protein synthesis to understand how exercise regulates the muscular adaptation. However, despite the probability that each gene transcript may have its own unique translational characteristics and would be differentially regulated at translational level, little attention has been paid to how exercise affects translational regulation of individual genes at a genome-wide scale. Here, we conducted a genome-wide translational analysis using ribosome profiling to investigate the effect of a single bout of treadmill running (20 m/min for 60 min) on mouse gastrocnemius. Global translational profiles largely differed from those in transcription even at a basal resting condition as well as immediately after exercise. As for individual gene, Slc25a25 (Solute carrier family 25, member 25), localized in mitochondrial inner membrane and maintaining ATP homeostasis and endurance performance, showed significant up-regulation at translational level. However, multiple regression analysis suggests that Slc25a25 protein degradation may also have a role in mediating Slc25a25 protein abundance in the basal and early stages after acute endurance exercise. PMID:26845575

  10. 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.

  11. Metabolomic Analysis of Mouse Embryonic Fibroblast Cells in Response to Autophagy Induced by Acute Starvation

    PubMed Central

    Shen, Sensen; Weng, Rui; Li, Linnan; Xu, Xinyuan; Bai, Yu; Liu, Huwei

    2016-01-01

    Autophagy-related protein 7 (Atg7) is essential in the formation of the autophagophore and is indispensable for autophagy induction. Autophagy will exist in lower level or even be blocked in cells without Atg7. Even though the possible signaling pathways of Atg7 have been proposed, the metabolomic responses under acute starvation in cells with and without Atg7 have not been elucidated. This study therefore was designed and aimed to reveal the metabolomics of Atg7-dependent autophagy through metabolomic analysis of Atg7−/− mouse embryonic fibroblast cells (MEFs) and wild-type MEFs along with the starvation time. 30 significantly altered metabolites were identified in response to nutrient stress, which were mainly associated with amino acid, energy, carbohydrate, and lipid metabolism. For the wild-type MEFs, the induction of autophagy protected cell survival with some up-regulated lipids during the first two hours’ starvation, while the subsequent apoptosis resulted in the decrease of cell viability after four hours’ starvation. For the Atg7−/− MEFs, apoptosis perhaps led to the deactivation of tricarboxylic acid (TCA) cycle due to the lack of autophagy, which resulted in the immediate drop of cellular viability under starvation. These results contributed to the metabolomic study and provided new insights into the mechanism associated with Atg7-dependent autophagy. PMID:27703171

  12. 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

  13. Advances in pancreas transplantation.

    PubMed

    Dholakia, Shamik; Oskrochi, Youssof; Easton, Graham; Papalois, Vassilios

    2016-04-01

    The potential to reverse diabetes has to be balanced against the morbidity of long-term immunosuppression associated with transplantation. For a patient with renal failure, the treatment of choice is often a simultaneous transplant of the pancreas and kidney or pancreas after kidney. For a patient with glycaemic instability, choices between a solid organ or islet transplant have to be weighed against benefits and risks of remaining on insulin. Results of simultaneous transplant of the pancreas and kidney transplantation are comparable to other solid-organ transplants, and there is evidence of improved quality of life and life expectancy. There is some evidence of benefit with respect to the progression of secondary diabetic complications in patients with functioning transplants for several years.

  14. [Injuries of the pancreas].

    PubMed

    Vasiutkov, V Ia; Murasheva, Z M; Sukhov, D V; Burakov, M B

    1989-08-01

    Trauma of the pancreas was studied in 48 patients. It has a typical mechanisms and is characterized by intensity of the exerted force. Due to the last named circumstance, extensive retroperitoneal hematomas, ruptures of the parenchymatous organs, ligaments, veins, and large arteries often occur A severe condition of the patients with fall of arterial pressure and the development of shock is characteristic. It is difficult to establish the diagnosis of trauma of the pancreas before the operation. The most frequent complication is traumatic pancreatitis which is often attended by the development of cysts, fistulas, and peritonitis. The surgeon's tactics is determined by the character of the injury and is individual in each patient.

  15. Imaging pheromone sensing in a mouse vomeronasal acute tissue slice preparation.

    PubMed

    Brechbühl, Julien; Luyet, Gaëlle; Moine, Fabian; Rodriguez, Ivan; Broillet, Marie-Christine

    2011-01-01

    . Here, we present an acute tissue slice preparation of the mouse VNO for performing calcium imaging investigations. This physiological approach allows observations, in the natural environment of a living tissue, of general or individual subpopulations of VSNs previously loaded with Fura-2AM, a calcium dye. This method is also convenient for studying any GFP-tagged pheromone receptor and is adaptable for the use of other fluorescent calcium probes. As an example, we use here a VG mouse line, in which the translation of the pheromone V1rb2 receptor is linked to the expression of GFP by a polycistronic strategy.

  16. 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

  17. Glutathione Depletion and Recovery After Acute Ethanol Administration in the Aging Mouse

    PubMed Central

    Vogt, Barbara L.; Richie, John P.

    2007-01-01

    Glutathione (GSH) plays an important role in the detoxification of ethanol (EtOH) and acute EtOH administration leads to GSH depletion in the liver and other tissues. Aging is also associated with a progressive decline in GSH levels and impairment in GSH biosynthesis in many tissues. Thus, the present study was designed to examine the effects of aging on EtOH-induced depletion and recovery of GSH in different tissues of the C57Bl/6NNIA mouse. EtOH (2-5 g/kg) or saline was administered i.p. to mice of ages 6 mo (young), 12 mo (mature), and 24 mo (old); and GSH and cyst(e)ine concentrations were measured 0-24 hours thereafter. EtOH administration (5g/kg) depleted hepatic GSH levels >50% by 6 hr in all animals. By 24 hr, levels remained low in both young and old mice, but recovered to baseline levels in mature mice. At 6 hr, the decrease in hepatic GSH was dose-dependent up to 3 g/kg EtOH, but not at higher doses. The extent of depletion at the 3 g/kg dose was dependent upon age, with old mice demonstrating significantly lower GSH levels than mature mice (P<0.001). Altogether these results indicate that aging was associated with a greater degree of EtOH and fasting-induced GSH depletion and subsequent impaired recovery in liver. An impaired ability to recover was also observed in young animals. Further studies are required to determine if an inability to recover from GSH depletion by EtOH is associated with enhanced toxicity. PMID:17343832

  18. 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

  19. [Assessment and treatment of acute pancreatitis. Position document of the Catalan Society of Gastroenterology, Catalan Society of Surgery and Catalan Society of the Pancreas].

    PubMed

    Boadas, Jaume; Balsells, Joaquin; Busquets, Juli; Codina-B, Antoni; Darnell, Anna; Garcia-Borobia, Francisco; Ginés, Àngels; Gornals, Joan; Gruartmoner, Guillem; Ilzarbe, Lucas; Merino, Xavier; Oms, Lluís; Puig, Ignasi; Puig-Diví, Valentí; Vaquero, Eva; Vida, Francesc; Molero, Xavier

    2015-02-01

    The incidence of acute pancreatitis (AP) is increasing. AP is one of the gastrointestinal diseases that most frequently requires hospital admission in affected individuals. In the last few years, considerable scientific evidence has led to substantial changes in the medical and surgical treatment of this disease. New knowledge of the physiopathology of AP indicates that its severity is influenced by its systemic effects (organ failure), especially if the disease is persistent, and also by local complications (fluid collections or necrosis), especially if these become infected. Treatment should be personalized and depends on the patient's clinical status, the location of the necrosis, and disease stage.

  20. Generation and characterization of bioluminescent xenograft mouse models of MLL-related acute leukemias and in vivo evaluation of luciferase-targeting siRNA nanoparticles.

    PubMed

    Fazzina, Raffaella; Lombardini, Lorenza; Mezzanotte, Laura; Roda, Aldo; Hrelia, Patrizia; Pession, Andrea; Tonelli, Roberto

    2012-08-01

    Chromosomal translocations involving the MLL gene on 11q23 present frequent abnormalities in pediatric, adult and therapy-related acute leukemias, and are generally associated with aggressive disease and poor prognosis. Here, we report bioluminescent acute leukemia xenograft mouse models of the most frequent and aggressive MLL-related acute leukemias (infant and adult MLL-AF9, MLL-ENL, MLL-AF4). Four acute leukemia cell lines carrying MLL-related translocations were stably transduced with a firefly luciferase transgene and injected intravenously into NOD/SCID mice. Leukemia progression was monitored by in vivo bioluminescence imaging (BLI). All mice developed MLL-related acute leukemia. The four MLL-related acute leukemia models showed a different course of infant and adult MLL-AF9 acute myeloid leukemia, and a rapid aggressiveness of MLL-ENL acute lymphoblastic leukemia and MLL-AF4 acute biphenotypic leukemia. Tissue analysis and RT-PCR of bone marrow, spleen and liver from the mice confirmed the BL results. To validate BLI for the detection of a therapeutic response, systemic treatment with an anti-luciferase-targeting siRNA (siLuc) complexed with cationic nanoparticles was administered to mice with MLL-AF4 acute lymphoblastic leukemia. The BLI signal showed a reduction following treatment with siLuc compared to the control mice. These mouse models present MLL-related acute leukemia evolution similar to the human counterparts. Moreover, they are non-invasive, rapid and sensitive models, suitable for the in vivo study of MLL-related acute leukemias. Finally, BLI showed in vivo luminescence down modulation obtained by systemic treatment with luciferase-targeting siRNA nanoparticle complexes, confirming that these MLL-related leukemia mouse models are optimal for the evaluation and selection of delivery systems for siRNA and other new biotechnological pharmaceuticals.

  1. 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

  2. IL-33 Aggravates DSS-Induced Acute Colitis in Mouse Colon Lamina Propria by Enhancing Th2 Cell Responses.

    PubMed

    Zhu, Junfeng; Yang, Fangli; Sang, Lixuan; Zhai, Jingbo; Zhang, Xiaoqing; Yue, Dan; Li, Shengjun; Li, Yan; Lu, Changlong; Sun, Xun

    2015-01-01

    Interleukin- (IL-) 33, a member of the IL-1 cytokine family, is an important modulator of the immune system associated with several immune-mediated diseases. IL-33 was expressed in high level on epithelial cells of intestinal tract. It suggested that IL-33 plays a potential role in inflammatory bowel diseases (IBD). We investigated the role of interleukin- (IL-) 33 in dextran sulphate sodium- (DSS-) induced acute colitis in mice using recombinant mouse IL-33 protein (rIL-33). We found that DSS-induced acute colitis was aggravated by rIL-33 treatment. rIL-33-treated DSS mice showed markedly reduced levels of interferon- (IFN-)γ and IL-17A in their colon lamina propria lymphocytes (LPL), but the levels of Th2 cytokines, such as IL-5 and IL-13, in these cells were significantly increased, compared to DSS mice treated with PBS. Our results suggested that IL-33 stimulated CD4(+)T cells and caused the cell to adopt a Th2-type response but at the same time suppressed Th17 and Th1 cell responses. Therefore, IL-33 may be involved in pathogenesis of DSS-induced acute colitis by promoting Th2 cell response in intestinal mucosa of mice. Modulation of IL-33/ST2 signaling by monoclonal antibody (mAb) could be a novel biological therapy in DSS-induced acute colitis.

  3. GDNF is required for neural colonization of the pancreas.

    PubMed

    Muñoz-Bravo, José Luis; Hidalgo-Figueroa, María; Pascual, Alberto; López-Barneo, José; Leal-Cerro, Alfonso; Cano, David A

    2013-09-01

    The mammalian pancreas is densely innervated by both the sympathetic and parasympathetic nervous systems, which control exocrine and endocrine secretion. During embryonic development, neural crest cells migrating in a rostrocaudal direction populate the gut, giving rise to neural progenitor cells. Recent studies in mice have shown that neural crest cells enter the pancreatic epithelium at E11.5. However, the cues that guide the migration of neural progenitors into the pancreas are poorly defined. In this study we identify glial cell line-derived neurotrophic factor (GDNF) as a key player in this process. GDNF displays a dynamic expression pattern during embryonic development that parallels the chronology of migration and differentiation of neural crest derivatives in the pancreas. Conditional inactivation of Gdnf in the pancreatic epithelium results in a dramatic loss of neuronal and glial cells and in reduced parasympathetic innervation in the pancreas. Importantly, the innervation of other regions of the gut remains unaffected. Analysis of Gdnf mutant mouse embryos and ex vivo experiments indicate that GDNF produced in the pancreas acts as a neurotrophic factor for gut-resident neural progenitor cells. Our data further show that exogenous GDNF promotes the proliferation of pancreatic progenitor cells in organ culture. In summary, our results point to GDNF as crucial for the development of the intrinsic innervation of the pancreas.

  4. 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

  5. Successful treatment for graft-versus-host disease after pancreas transplantation.

    PubMed

    Chang, Jei wen; Sageshima, Junichiro; Ciancio, Gaetano; Mattiazzi, Adela; Chen, Linda; Tsai, Hsin-Lin; Ruiz, Phillip; Burke, George W

    2014-02-01

    Graft-versus-host disease (GVHD) after pancreas transplantation is a rare but serious complication: All previously reported cases were fatal. We herein report three cases of GVHD after pancreas transplantation with favorable outcomes. Patients with a history of kidney (and pancreas) transplantation subsequently received a pancreas (and kidney) transplantation (i.e., pancreas retransplantation or pancreas after kidney transplantation) and developed acute GVHD. All of them responded to increased immunosuppression (e.g., steroid bolus, antithymocyte globulin) and retained normal graft function. Because the clinical manifestations are non-specific, vigilance is necessary to make an accurate diagnosis. We underscored the importance of a biopsy of involved organs and the clinicopathologic correlation in the early diagnosis of GVHD. Augmented immunosuppression to prevent progression from a self-limited disease to life-threatening pancytopenia or sepsis may be most critical to improve outcome.

  6. Expression patterns of epiplakin1 in pancreas, pancreatic cancer and regenerating pancreas.

    PubMed

    Yoshida, Tetsu; Shiraki, Nobuaki; Baba, Hideo; Goto, Mizuki; Fujiwara, Sakuhei; Kume, Kazuhiko; Kume, Shoen

    2008-07-01

    Epiplakin1 (Eppk1) is a plakin family gene with its function remains largely unknown, although the plakin genes are known to function in interconnecting cytoskeletal filaments and anchoring them at plasma membrane-associated adhesive junction. Here we analyzed the expression patterns of Eppk1 in the developing and adult pancreas in the mice. In the embryonic pancreas, Eppk1+/Pdx1+ and Eppk1+/Sox9+ pancreatic progenitor cells were observed in early pancreatic epithelium. Since Pdx1 expression overlapped with that of Sox9 at this stage, these multipotent progenitor cells are Eppk1+/Pdx1+/Sox9+ cells. Then Eppk1 expression becomes confined to Ngn3+ or Sox9+ endocrine progenitor cells, and p48+ exocrine progenitor cells, and then restricted to the duct cells and a cells at birth. In the adult pancreas, Eppk1 is expressed in centroacinar cells (CACs) and in duct cells. Eppk1 is observed in pancreatic intraepithelial neoplasia (PanIN), previously identified as pancreatic ductal adenocarcinoma (PDAC) precursor lesions. In addition, the expansion of Eppk1-positive cells occurs in a caerulein-induced acute pancreatitis, an acinar cell regeneration model. Furthermore, in the partial pancreatectomy (Px) regeneration model using mice, Eppk1 is expressed in "ducts in foci", a tubular structure transiently induced. These results suggest that Eppk1 serves as a useful marker for detecting pancreatic progenitor cells in developing and regenerating pancreas.

  7. MR imaging of the pancreas.

    PubMed

    O'Neill, Erin; Hammond, Nancy; Miller, Frank H

    2014-07-01

    Magnetic resonance (MR) imaging of the pancreas is useful as both a problem-solving tool and an initial imaging examination of choice. With newer imaging sequences such as diffusion-weighted imaging, MR offers improved ability to detect and characterize lesions and identify and stage tumors and inflammation. MR cholangiopancreatography can be used to visualize the pancreatic and biliary ductal system. In this article, the use of MR to evaluate the pancreas, including recent advances, is reviewed and the normal appearance of the pancreas on different imaging sequences, as well as inflammatory diseases, congenital abnormalities, and neoplasms of the pancreas, are discussed.

  8. 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.

  9. 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

  10. [Prophylactic pancreas surgery].

    PubMed

    Langer, P; Rothmund, M; Bartsch, D K

    2006-01-01

    The goal of prophylactic surgery is to prevent malignant growth in patients with hereditary tumor predisposition. The pancreas presents as particularly challenging, due to the difficulty of operation and comparatively high risk of morbidity and even mortality. In addition, partial operative procedures and, more significantly, total resection lead to exocrine pancreas insufficiency and secondary diabetes, with grave consequences for the patient. Hereditary tumor predisposition syndromes that can result in pancreaticoduodenal endocrine tumors (PET) include multiple endocrine neoplasia type 1 syndrome and von Hippel-Lindau syndrome. As penetrance is maximally 70-80% and the 10-year survival rate over 80%, prophylactic pancreatic resection without evidence of a tumor is not indicated. However, prophylactic extension of a resection would be advised, should a PET be diagnosed. Patients predisposed to developing ductal pancreatic carcinoma (PC) are at risk of familial pancreatic cancer syndrome (FPC), hereditary pancreatitis, and other hereditary tumor predisposition syndromes such as Peutz-Jeghers syndrome and familial atypical multiple mole-melanoma syndrome. As the gene defect responsible for FPC has yet to be identified and the penetrance of PC in the other tumor predisposition syndromes is low or unknown, a prophylactic pancreatectomy based on today's knowledge is not indicated. Prophylactic extension of the resection is advisable should PC or high-grade PanIN lesions be diagnosed, as these patients often present with multifocal dysplasia and even carcinoma.

  11. 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 ...

  12. The acute phase response in parasite infection. Nippostrongylus brasiliensis in the mouse.

    PubMed Central

    Lamontagne, L R; Gauldie, J; Befus, A D; McAdam, K P; Baltz, M L; Pepys, M B

    1984-01-01

    Systemic inflammatory reactions are a prominent feature of many parasitic infections and the cellular and humoral components of the acute phase reaction may have an impact on the host-parasite relationship. We examined serum changes of four acute phase reactants: alpha 1-proteinase inhibition (alpha 1Pi); complement C3; serum amyloid A protein (SAA); and serum amyloid P component (SAP), in mice undergoing a primary infection with Nippostrongylus brasiliensis. SAA and SAP showed changes within the first 2 days of infection indicating the presence of an acute phase response associated with inflammation in the lung. Alpha 1Pi and C3 serum levels were not altered. However, all four acute phase reactants were synthesized in greater amounts by primary cultures of hepatocytes taken from infected animals at this time. Subsequently, as parasite-mediated inflammatory changes occur in the gut, both serum and hepatocyte cultures demonstrate an acute inflammatory response in all four reactants. It is proposed that the early reaction between parasites and macrophage/monocyte lead to the release of a mediator of inflammation which initiates the hepatocyte response. In this infection, at least one of the APR is shown to localize to the site of inflammation influencing the host-parasite relationship. Images Figure 2 Figure 3 PMID:6204934

  13. 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.

  14. 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

  15. 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

  16. 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.

  17. Chrysin, a natural flavonoid enhances steroidogenesis and steroidogenic acute regulatory protein gene expression in mouse Leydig cells.

    PubMed

    Jana, Kuladip; Yin, Xiangling; Schiffer, Randolph B; Chen, Jau-Jiin; Pandey, Akhilesh K; Stocco, Douglas M; Grammas, Paula; Wang, Xingjia

    2008-05-01

    During the aging process of males, testosterone biosynthesis declines in testicular Leydig cells resulting in decreases in various physiological functions. To explore the possibility of delaying the decline using food supplements, we have studied steroidogenic effects of a natural flavonoid, chrysin, in mouse Leydig cells. Chrysin dramatically increased cyclic AMP (cAMP)-induced steroidogenesis in MA-10 mouse Leydig tumor cells. This result was confirmed using Leydig cells isolated from mouse testes. The steroidogenic effect of chrysin is not associated with an increase in expression of the P450 side-chain cleavage enzyme, required for the conversion of cholesterol to pregnenolone. In addition, when 22(R)hydroxylcholesterol was used as a substrate, chrysin induced a non-significant increase in steroid hormone, suggesting that the majority of the observed increase in steroidogenesis was due to the increased supply of substrate cholesterol. These observations were corroborated by showing that chrysin induced a marked increase in the expression of steroidogenic acute regulatory (StAR) protein, the factor that controls mitochondrial cholesterol transfer. Also, chrysin significantly increased StAR promoter activity and StAR mRNA level. Further studies indicated that this compound depressed expression of DAX-1, a repressor in StAR gene transcription. In the absence of cAMP, chrysin did not increase steroidogenesis. However, when a sub-threshold level of cAMP was used, StAR protein and steroid hormone were increased by chrysin to the levels seen with maximal stimulation of cAMP. These results suggest that while chrysin itself is unable to induce StAR gene expression and steroidogenesis, it appears to function by increasing the sensitivity of Leydig cells to cAMP stimulation. PMID:18434361

  18. 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.

  19. 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

  20. 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

  1. Non-viral delivery of the porphobilinogen deaminase cDNA into a mouse model of acute intermittent porphyria.

    PubMed

    Johansson, Annika; Nowak, Grzegorz; Möller, Christer; Harper, Pauline

    2004-05-01

    Acute intermittent porphyria (AIP), an inborn error of metabolism, results from the deficient activity of the third enzyme in the heme biosynthetic pathway, porphobilinogen deaminase (PBGD). Clinical symptoms of this autosomal dominant hepatic porphyria include episodic acute attacks of abdominal pain, neuropathy, and psychiatric disturbances. Current therapy based on intravenous heme administration is palliative and there is no way to prevent the attacks. Thus, efforts are focused on methods to replace the deficient activity in the liver to prevent the acute attacks of this hepatic porphyria. Here we explore the efficiency of a non-viral gene delivery to obtain PBGD expression in the liver of AIP transgenic mice. Four vectors were evaluated: naked DNA and DNA complexed to liposomes, polyethylenimine (PEI), and PEI-galactose, using a luciferase construct as reporter gene. The vectors were administered intravenously or directly into the portal vein with transient blood flow blockage. After tail vein injection of the DNA complexes, the liposome vector had the highest luciferase expression in lung and less in liver. When injected into the portal vein, the naked DNA had considerably higher hepatic reporter gene expression; 100 microg of naked DNA had the highest hepatic luciferase expression 24h after portal vein injection. When these vectors were used to deliver the PBGD gene into the AIP mouse model no enhancement of the endogenous PBGD activity in liver was detectable, despite the presence of the PBGD-plasmids as verified by PCR. Thus, more efficient non-viral vectors are needed to express sufficient PBGD activity over the endogenous hepatic level (approximately 30% of normal) in this murine system.

  2. Correlative mRNA and protein expression of middle and inner ear inflammatory cytokines during mouse acute otitis media.

    PubMed

    Trune, Dennis R; Kempton, Beth; Hausman, Frances A; Larrain, Barbara E; MacArthur, Carol J

    2015-08-01

    Although the inner ear has long been reported to be susceptible to middle ear disease, little is known of the inflammatory mechanisms that might cause permanent sensorineural hearing loss. Recent studies have shown inner ear tissues are capable of expressing inflammatory cytokines during otitis media. However, little quantitative information is available concerning cytokine gene expression in the inner ear and the protein products that result. Therefore, this study was conducted of mouse middle and inner ear during acute otitis media to measure the relationship between inflammatory cytokine genes and their protein products with quantitative RT-PCR and ELISA, respectively. Balb/c mice were inoculated transtympanically with heat-killed Haemophilus influenzae and middle and inner ear tissues collected for either quantitative RT-PCR microarrays or ELISA multiplex arrays. mRNA for several cytokine genes was significantly increased in both the middle and inner ear at 6 h. In the inner ear, these included MIP-2 (448 fold), IL-6 (126 fold), IL-1β (7.8 fold), IL-10 (10.7 fold), TNFα (1.8 fold), and IL-1α (1.5 fold). The 24 h samples showed a similar pattern of gene expression, although generally at lower levels. In parallel, the ELISA showed the related cytokines were present in the inner ear at concentrations higher by 2-122 fold higher at 18 h, declining slightly from there at 24 h. Immunohistochemistry with antibodies to a number of these cytokines demonstrated they occurred in greater amounts in the inner ear tissues. These findings demonstrate considerable inflammatory gene expression and gene products in the inner ear following acute otitis media. These higher cytokine levels suggest one potential mechanism for the permanent hearing loss seen in some cases of acute and chronic otitis media.

  3. 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

  4. 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 ...

  5. Using pancreas tissue slices for in situ studies of islet of Langerhans and acinar cell biology.

    PubMed

    Marciniak, Anja; Cohrs, Christian M; Tsata, Vasiliki; Chouinard, Julie A; Selck, Claudia; Stertmann, Julia; Reichelt, Saskia; Rose, Tobias; Ehehalt, Florian; Weitz, Jürgen; Solimena, Michele; Slak Rupnik, Marjan; Speier, Stephan

    2014-12-01

    Studies on the cellular function of the pancreas are typically performed in vitro on its isolated functional units, the endocrine islets of Langerhans and the exocrine acini. However, these approaches are hampered by preparation-induced changes of cell physiology and the lack of an intact surrounding. We present here a detailed protocol for the preparation of pancreas tissue slices. This procedure is less damaging to the tissue and faster than alternative approaches, and it enables the in situ study of pancreatic endocrine and exocrine cell physiology in a conserved environment. Pancreas tissue slices facilitate the investigation of cellular mechanisms underlying the function, pathology and interaction of the endocrine and exocrine components of the pancreas. We provide examples for several experimental applications of pancreas tissue slices to study various aspects of pancreas cell biology. Furthermore, we describe the preparation of human and porcine pancreas tissue slices for the validation and translation of research findings obtained in the mouse model. Preparation of pancreas tissue slices according to the protocol described here takes less than 45 min from tissue preparation to receipt of the first slices.

  6. Pancreas transplantation in diabetic patients.

    PubMed

    Pozza, G; Di Carlo, V

    1989-01-01

    After a brief historical background on pancreas transplantation in the treatment of diabetes mellitus, this review deals with the major surgical, pharmacological and functional aspects of this approach. In the Authors' opinion pancreas transplantation should be proposed only when the end-stage renal failure (ESRF), due to diabetic nephropathy, needs kidney transplantation. By using injection of polymers (mainly neoprene) into the pancreatic ducts, or urinary diversion of pancreatic juice and appropriate immunosuppressive therapy (cyclosporin, corticosteroids and azathioprine), dramatic advantages have been achieved in the last years, so that a satisfactory segmental or total pancreas graft survival on one hand, and the early graft rejection recognition on the other have been presently obtained. A prompt and good functional activity of pancreas graft has also been demonstrated by the Authors in successfully transplanted patients. As far as chronic diabetic complications are concerned, no conclusive results have been reported up to now; it is noteworthy, however, that pancreas transplantation may preserve the transplanted kidney from a relapse of diabetic nephropathy. The combined pancreas-kidney transplantation may actually be considered as a correct solution to the problem of diabetic patients with ESRF. Moreover, careful selection of patients, appropriate surgical technique and experienced immunosuppressive treatment are the major prerequisites to achieve a satisfactory improvement of diabetic status in addition to that of renal failure.

  7. ACUTE ETHANOL MODULATES GLUTAMATERGIC AND SEROTONERGIC PHASE SHIFTS OF THE MOUSE CIRCADIAN LOCK IN VITRO

    PubMed Central

    Prosser, Rebecca A.; Mangrum, Charles A.; Glass, J. David

    2008-01-01

    Alcohol abuse is associated with sleep problems, which are often linked to circadian rhythm disturbances. However, there is no information on the direct effects of ethanol on the mammalian circadian clock. Acute ethanol inhibits glutamate signaling, which is the primary mechanism through which light resets the mammalian clock in the suprachiasmatic nucleus (SCN). Glutamate and light also inhibit circadian clock resetting induced by non-photic signals, including serotonin. Thus, we investigated the effects of acute ethanol on both glutamatergic and serotoninergic resetting of the SCN clock in vitro. We show that ethanol dose-dependently inhibits glutamate-induced phase shifts and enhances serotonergic phase shifts. The inhibition of glutamate-induced phase shifts is not affected by excess glutamate, glycine or D-serine, but is prevented by excess brain-derived neurotrophic factor (BDNF). BDNF is known to augment glutamate signaling in the SCN and to be necessary for glutamate/light-induced phase shifts. Thus, ethanol may inhibit glutamate-induced clock resetting at least in part by blocking BDNF enhancement of glutamate signaling. Ethanol enhancement of serotonergic phase shifts is mimicked by treatments that suppress glutamate signaling in the SCN, including antagonists of glutamate receptors, BDNF signaling and nitric oxide synthase. The combined effect of ethanol with these treatments is not additive, suggesting they act through a common pathway. Our data indicate further that the interaction between serotonin and glutamate in the SCN may occur downstream from nitric oxide synthase activation. Thus, acute ethanol disrupts normal circadian clock phase regulation, which could contribute to the physiological and psychological problems associated with alcohol abuse. PMID:18313227

  8. Acute Dietary Tryptophan Manipulation Differentially Alters Social Behavior, Brain Serotonin and Plasma Corticosterone in Three Inbred Mouse Strains

    PubMed Central

    Zhang, Wynne Q.; Smolik, Corey M.; Barba-Escobedo, Priscilla A.; Gamez, Monica; Sanchez, Jesus J.; Javors, Martin A.; Daws, Lynette C.; Gould, Georgianna G.

    2014-01-01

    Clinical evidence indicates brain serotonin (5-HT) stores and neurotransmission may be inadequate in subpopulations of individuals with autism, and this may contribute to characteristically impaired social behaviors. Findings that depletion of the 5-HT precursor tryptophan (TRP) worsens autism symptoms support this hypothesis. Yet dietetic studies show and parents report that many children with autism consume less TRP than peers. To measure the impact of dietary TRP content on social behavior, we administered either diets devoid of TRP, with standard TRP (0.2 gm%), or with 1% added TRP (1.2 gm%) overnight to three mouse strains. Of these, BTBRT+Itpr3tf/J and 129S1/SvImJ consistently exhibit low preference for social interaction relative to C57BL/6. We found that TRP depletion reduced C57BL/6 and 129S social interaction preference, while TRP enhancement improved BTBR sociability (p < 0.05; N= 8–10). Subsequent marble burying was similar regardless of grouping. After behavior tests, brain TRP levels and plasma corticosterone were higher in TRP enhanced C57BL/6 and BTBR, while 5-HT levels were reduced in all strains by TRP depletion (p <0.05; N= 4 −10). Relative hyperactivity of BTBR and hypoactivity of 129S, evident in self-grooming and chamber entries during sociability tests, were uninfluenced by dietary TRP. Our findings demonstrate mouse sociability and brain 5-HT turnover are reduced by acute TRP depletion, and can be enhanced by TRP supplementation. This outcome warrants further basic and/or clinical studies employing biomarker combinations such as TRP metabolism and 5-HT regulated hormones to characterize the conditions wherein TRP supplementation can best ameliorate sociability deficits. PMID:25445490

  9. 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.

  10. Acute stress increases neuropsin mRNA expression in the mouse hippocampus through the glucocorticoid pathway.

    PubMed

    Harada, Akiko; Shiosaka, Sadao; Ishikawa, Yasuyuki; Komai, Shoji

    2008-05-01

    Stress affects synaptic plasticity and may alter various types of behaviour, including anxiety or memory formation. In the present study, we examined the effects of acute stress (1 h restraint with or without tail-shock) on mRNA levels of a plasticity-related serine protease neuropsin (NP) in the hippocampus using semiquantitative RT-PCR and in situ hybridization. We found that NP mRNA expression was dramatically increased shortly after exposure to the acute restraint tail-shock stress and remained at high level for at least 24 h. The level of NP mRNA would be correlated to the elevated plasma concentration of the glucocorticoid corticosterone (CORT) and to the stress intensity. Application of CORT either onto primary cultured hippocampal neurons (5 nM) or in vivo to adrenalectomized (ADX) mice (10 mg/kg B.W., s.c.) mimicked the effect of stress and significantly elevated NP mRNA. These results suggest that the upregulation of NP mRNA after stress is CORT-dependent and point to a role for neuropsin in stress-induced neuronal plasticity.

  11. Enteric duplication cyst of the pancreas associated with chronic pancreatitis and pancreatic cancer.

    PubMed

    Chiu, Alexander S; Bluhm, David; Xiao, Shu-Yan; Waxman, Irving; Matthews, Jeffrey B

    2014-05-01

    Pancreas-associated enteric duplication cysts are rare developmental anomalies that communicate with the main pancreatic duct and may be associated with recurrent acute and chronic abdominal pain in children. In adults, these lesions may masquerade as pancreatic pseudocysts or pancreatic cystic neoplasms. An adult patient with a pancreas-associated enteric duplication is described which represents the first reported instance of association with both chronic calcific pancreatitis and pancreatic cancer. The clinical spectrum of pancreas-associated enteric duplication cyst, including diagnostic and therapeutic options, is reviewed.

  12. Pathogenesis of acute arthritis due to viable Chlamydia trachomatis (mouse pneumonitis agent) in C57Bl/6 mice.

    PubMed Central

    Hough, A. J.; Rank, R. G.

    1989-01-01

    The purpose of this investigation was to determine the natural history and pathogenesis of the acute arthritis induced by inoculation of a viable Chlamydia trachomatis biovar (mouse pneumonitis agent or MoPn) in C57Bl/6 mice. Immunologically naive (previously unsensitized) mice as well as mice immunized against Chlamydia (MoPn) by vaginal infection were employed. Both intravenous and intraarticular inoculations were employed. No arthritis developed after intravenous injections of MoPn although statistically significant antibody titers and splenic enlargement ensued. Intra-articular inoculation into knee joints produced a definite arthritis of 7 to 10 days duration marked by granulocyte and mononuclear cell infiltration of the joint and vacuolated synovial macrophages that stained heavily for chlamydial antigen by immunoperoxidase technique. Statistically significant increases in articular acute and chronic inflammation (P less than 0.02 were observed in previously sensitized, but not unsensitized, female mice at 2 but not 7 days after intra-articular chlamydial challenge. Chlamydiae were isolated from injected joints up to day 5, but not at day 10, after challenge. Chlamydial antigen disappeared rapidly from knee joints between day 10 and 15 after challenge. Electron micrographs demonstrated vacuolated synovial cells of the macrophage type, many of which contained degenerating chlamydial elementary bodies. Reticulate and intermediate bodies also were seen but were far less frequent than degenerating elementary bodies. Unaltered elementary bodies were difficult to identify beyond day 2 after articular inoculation. Thus, it appears likely that intra-articular chlamydial survival is shorter than the duration of the arthropathy. This may have important implications in attempts to identify chlamydiae in human joints in Reiter's Disease. Images Figure 1 Figure 3 Figure 4 Figure 5 Figure 6 Figure 8 Figure 9 Figure 10 Figure 11 PMID:2705510

  13. 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

  14. Transcriptome Profiling of the Newborn Mouse Lung Response to Acute Ozone Exposure

    PubMed Central

    Loader, Joan E.; White, Carl W.; Dakhama, Azzeddine

    2014-01-01

    Ozone pollution is associated with adverse effects on respiratory health in adults and children but its effects on the neonatal lung remain unknown. This study was carried out to define the effect of acute ozone exposure on the neonatal lung and to profile the transcriptome response. Newborn mice were exposed to ozone or filtered air for 3h. Total RNA was isolated from lung tissues at 6 and 24h after exposure and was subjected to microarray gene expression analysis. Compared to filtered air-exposed littermates, ozone-exposed newborn mice developed a small but significant neutrophilic airway response associated with increased CXCL1 and CXCL5 expression in the lung. Transcriptome analysis indicated that 455 genes were down-regulated and 166 genes were up-regulated by at least 1.5-fold at 6h post-ozone exposure (t-test, p < .05). At 24h, 543 genes were down-regulated and 323 genes were up-regulated in the lungs of ozone-exposed, compared to filtered air-exposed, newborn mice (t-test, p < .05). After controlling for false discovery rate, 50 genes were identified as significantly down-regulated and only a few (RORC, GRP, VREB3, and CYP2B6) were up-regulated at 24h post-ozone exposure (q < .05). Gene ontology enrichment analysis revealed that cell cycle-associated functions including cell division/proliferation were the most impacted pathways, which were negatively regulated by ozone exposure, an adverse effect that was associated with reduced bromo-deoxyuridine incorporation. These results demonstrate that acute ozone exposure alters cell proliferation in the developing neonatal lung through a global suppression of cell cycle function. PMID:24336422

  15. 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

  16. 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

  17. 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

  18. 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

  19. Ischemic tissue injury in the dorsal skinfold chamber of the mouse: a skin flap model to investigate acute persistent ischemia.

    PubMed

    Harder, Yves; Schmauss, Daniel; Wettstein, Reto; Egaña, José T; Weiss, Fabian; Weinzierl, Andrea; Schuldt, Anna; Machens, Hans-Günther; Menger, Michael D; Rezaeian, Farid

    2014-11-17

    Despite profound expertise and advanced surgical techniques, ischemia-induced complications ranging from wound breakdown to extensive tissue necrosis are still occurring, particularly in reconstructive flap surgery. Multiple experimental flap models have been developed to analyze underlying causes and mechanisms and to investigate treatment strategies to prevent ischemic complications. The limiting factor of most models is the lacking possibility to directly and repetitively visualize microvascular architecture and hemodynamics. The goal of the protocol was to present a well-established mouse model affiliating these before mentioned lacking elements. Harder et al. have developed a model of a musculocutaneous flap with a random perfusion pattern that undergoes acute persistent ischemia and results in ~50% necrosis after 10 days if kept untreated. With the aid of intravital epi-fluorescence microscopy, this chamber model allows repetitive visualization of morphology and hemodynamics in different regions of interest over time. Associated processes such as apoptosis, inflammation, microvascular leakage and angiogenesis can be investigated and correlated to immunohistochemical and molecular protein assays. To date, the model has proven feasibility and reproducibility in several published experimental studies investigating the effect of pre-, peri- and postconditioning of ischemically challenged tissue.

  20. 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

  1. An acute dose of gamma-hydroxybutyric acid alters gene expression in multiple mouse brain regions.

    PubMed

    Schnackenberg, B J; Saini, U T; Robinson, B L; Ali, S F; Patterson, T A

    2010-10-13

    Gamma-hydroxybutyric acid (GHB) is normally found in the brain in low concentrations and may function as a neurotransmitter, although the mechanism of action has not been completely elucidated. GHB has been used as a general anesthetic and is currently used to treat narcolepsy and alcoholism. Recreational use of GHB is primarily as a "club drug" and a "date rape drug," due to its amnesic effects. For this study, the hypothesis was that behavioral and neurochemical alterations may parallel gene expression changes in the brain after GHB administration. Adult male C57/B6N mice (n=5/group) were administered a single dose of 500 mg/kg GHB (i.p.) and were sacrificed 1, 2 and 4 h after treatment. Control mice were administered saline. Brains were removed and regionally dissected on ice. Total RNA from the hippocampus, cortex and striatum was extracted, amplified and labeled. Gene expression was evaluated using Agilent whole mouse genome 4x44K oligonucleotide microarrays. Microarray data were analyzed by ArrayTrack and differentially expressed genes (DEGs) were identified using P < or = 0.01 and a fold change > or = 1.7 as the criteria for significance. Principal component analysis (PCA) and Hierarchical Cluster Analysis (HCA) showed that samples from each time point clustered into distinct treatment groups with respect to sacrifice time. Ingenuity pathways analysis (IPA) was used to identify involved pathways. The results show that GHB induces gene expression alterations in hundreds of genes in the hippocampus, cortex and striatum, and the number of affected genes increases throughout a 4-h time course. Many of these DEGs are involved in neurological disease, apoptosis, and oxidative stress.

  2. 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

  3. Primary and secondary genetic responses after folic acid-induced acute renal injury in the mouse.

    PubMed

    Calvet, J P; Chadwick, L J

    1994-12-01

    Folic acid-induced acute renal injury results in dramatic changes in gene expression. Among the genes affected by folic acid treatment are the primary response genes, c-fos and c-myc, which are thought to function to initiate cell cycle events. In this report, changes in the expression of three other genes in response to folic acid injury have been investigated: ornithine decarboxylase, epidermal growth factor (EGF), and sulfated glycoprotein-2 (SGP-2). Renal injury was found to cause a rapid decrease in EGF mRNA, which remained absent for several days after the initial injury, gradually returning to normal levels over an approximately 3-wk regeneration and recovery period. Ornithine decarboxylase mRNA showed a similar decrease. In contrast, folic acid caused a rapid increase in SGP-2 mRNA, which peaked several days after treatment, decreasing to normal levels over the 3-wk period. The mRNAs for the primary response genes were superinduced in the injured kidneys in the presence of the protein synthesis inhibitor cycloheximide. In contrast, the changes in EGF and SGP-2 mRNA levels were blocked by cycloheximide, indicating that these responses required new protein synthesis during the first few hours after folic acid injury. The opposite but parallel responses in the expression of the EGF and SGP-2 genes suggest that their regulation is coupled to the initial injury-induced dedifferentiation and subsequent return to the fully differentiated state.

  4. Protective effect of Jolkinolide B on LPS-induced mouse acute lung injury.

    PubMed

    Yang, Hailing; Li, Yan; Huo, Pengfei; Li, Xiao-Ou; Kong, Daliang; Mu, Wei; Fang, Wei; Li, Lingxia; Liu, Ning; Fang, Ling; Li, Hongjun; He, Chengyan

    2015-05-01

    Jolkinolide B (JB), an ent-abietane diterpenoid, isolated from the dried root of Euphorbia fischeriana, has been reported to have potent anti-tumor and anti-inflammatory activities. However, the effects of JB on acute lung injury (ALI) and underlying molecular mechanisms have not been investigated. The present study aimed to investigate the effect of JB on lipopolysaccharide (LPS)-induced ALI. Male C57BL/6 mice were pretreated with dexamethasone or JB 1h before intranasal instillation of LPS. The results showed that JB markedly attenuated LPS-induced histological alterations, lung edema, inflammatory cell infiltration, myeloperoxidase (MPO) activity as well as the production of TNF-α, IL-6 and IL-1β. Furthermore, JB also significantly inhibited LPS-induced the degradation of IκBα and phosphorylation of NF-κB p65 and MAPK. Therefore, our study provides the first line of evidence that pretreatment of JB has a protective effect on LPS-induced ALI in mice. The anti-inflammatory mechanism of JB may be attributed to its suppression of NF-κB and MAPK activation.

  5. Changes in Gene Expression and Estrogen Receptor Cistrome in Mouse Liver Upon Acute E2 Treatment.

    PubMed

    Palierne, Gaëlle; Fabre, Aurélie; Solinhac, Romain; Le Péron, Christine; Avner, Stéphane; Lenfant, Françoise; Fontaine, Coralie; Salbert, Gilles; Flouriot, Gilles; Arnal, Jean-François; Métivier, Raphaël

    2016-07-01

    Transcriptional regulation by the estrogen receptor-α (ER) has been investigated mainly in breast cancer cell lines, but estrogens such as 17β-estradiol (E2) exert numerous extrareproductive effects, particularly in the liver, where E2 exhibits both protective metabolic and deleterious thrombotic actions. To analyze the direct and early transcriptional effects of estrogens in the liver, we determined the E2-sensitive transcriptome and ER cistrome in mice after acute administration of E2 or placebo. These analyses revealed the early induction of genes involved in lipid metabolism, which fits with the crucial role of ER in the prevention of liver steatosis. Characterization of the chromatin state of ER binding sites (BSs) in mice expressing or not ER demonstrated that ER is not required per se for the establishment and/or maintenance of chromatin modifications at the majority of its BSs. This is presumably a consequence of a strong overlap between ER and hepatocyte nuclear factor 4α BSs. In contrast, 40% of the BSs of the pioneer factor forkhead box protein a (Foxa2) were dependent upon ER expression, and ER expression also affected the distribution of nucleosomes harboring dimethylated lysine 4 of Histone H3 around Foxa2 BSs. We finally show that, in addition to a network of liver-specific transcription factors including CCAAT/enhancer-binding protein and hepatocyte nuclear factor 4α, ER might be required for proper Foxa2 function in this tissue.

  6. 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

  7. Acute effects of Helicobacter pylori extracts on gastric mucosal blood flow in the mouse

    PubMed Central

    Henriksnäs, Johanna; Atuma, Christer; Phillipson, Mia; Sandler, Stellan; Engstrand, Lars; Holm, Lena

    2009-01-01

    AIM: To investigate the mechanisms underlying the reduction in gastric blood flow induced by a luminal water extract of Helicobacter pylori (HPE). METHODS: The stomachs of isoflurane-anesthetized mice were exteriorized, and the mucosal surface exposed. Blood flow was measured with the laser-Doppler technique, and systemic arterial blood pressure monitored. C57BL/6 mice were exposed to water extract produced from H pylori strain 88-23. To investigate the role of a nerve- or iNOS-mediated pathway, we used intraluminal lidocaine and iNOS-/- mice. Blood flow response to the endogenous nitric oxide synthase inhibitor asymmetric dimethyl arginine (ADMA) was also assessed. RESULTS: In wild-type mice, HPE decreased mucosal blood flow by approximately 30%. This reduction was abolished in iNOS-deficient mice, and by pre-treatment with lidocaine. Luminally applied ADMA resulted in reduction in blood flow similar to that observed in wild-type mice exposed to HPE. CONCLUSION: A H pylori water extract reduces gastric mucosal blood flow acutely through iNOS- and nerve-mediated pathways. PMID:19132773

  8. 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.

  9. 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

  10. 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

  11. Antithrombin therapy in pancreas retransplantation and pancreas-after-kidney/pancreas-transplantation-alone patients.

    PubMed

    Fertmann, Jan M; Arbogast, Helmut P; Illner, Wolf-Dieter; Tarabichi, Anwar; Dieterle, Christoph; Land, Walter; Jauch, Karl-Walter; Hoffmann, Johannes N

    2011-01-01

    Antithrombin (AT) is a coagulatory inhibitor with pleiotropic activities. AT reduces ischemia/reperfusion injury and has been successfully used in patients with simultaneous pancreas kidney transplantation. This study retrospectively analyzes prophylactic high-dose AT application in patients with solitary pancreas transplantation traditionally related to suboptimal results. In our center, 31 patients received solitary pancreas transplantation between 7/1994 and 7/2005 (pancreas retransplantation, PAK/PTA). The perioperative treatment protocol was modified in 5/2002 now including application of 3000 IU. AT was given intravenously before pancreatic reperfusion (AT, n = 18). Patients receiving standard therapy served as controls (n = 13). Daily blood sampling was performed during five postoperative days. Standard coagulatory parameters and number of transfused red blood cell units were not altered by AT. In AT patients serum amylase (p < 0.01) and lipase (p < 0.01) on postoperative days 1, 2 and 3 were significantly reduced. Our actual perioperative management protocol including high dose AT application in human solitary pancreas transplantation reduced postoperative liberation of pancreatic enzymes in this pilot study. Prophylactic AT application should deserve further clinical testing in a randomized controlled trial. PMID:21999781

  12. Collection protocol for human pancreas.

    PubMed

    Campbell-Thompson, Martha L; Montgomery, Emily L; Foss, Robin M; Kolheffer, Kerwin M; Phipps, Gerald; Schneider, Lynda; Atkinson, Mark A

    2012-05-23

    This dissection and sampling procedure was developed for the Network for Pancreatic Organ Donors with Diabetes (nPOD) program to standardize preparation of pancreas recovered from cadaveric organ donors. The pancreas is divided into 3 main regions (head, body, tail) followed by serial transverse sections throughout the medial to lateral axis. Alternating sections are used for fixed paraffin and fresh frozen blocks and remnant samples are minced for snap frozen sample preparations, either with or without RNAse inhibitors, for DNA, RNA, or protein isolation. The overall goal of the pancreas dissection procedure is to sample the entire pancreas while maintaining anatomical orientation. Endocrine cell heterogeneity in terms of islet composition, size, and numbers is reported for human islets compared to rodent islets. The majority of human islets from the pancreas head, body and tail regions are composed of insulin-containing β-cells followed by lower proportions of glucagon-containing α-cells and somatostatin-containing δ-cells. Pancreatic polypeptide-containing PP cells and ghrelin-containing epsilon cells are also present but in small numbers. In contrast, the uncinate region contains islets that are primarily composed of pancreatic polypeptide-containing PP cells. These regional islet variations arise from developmental differences. The pancreas develops from the ventral and dorsal pancreatic buds in the foregut and after rotation of the stomach and duodenum, the ventral lobe moves and fuses with the dorsal. The ventral lobe forms the posterior portion of the head including the uncinate process while the dorsal lobe gives rise to the rest of the organ. Regional pancreatic variation is also reported with the tail region having higher islet density compared to other regions and the dorsal lobe-derived components undergoing selective atrophy in type 1 diabetes. Additional organs and tissues are often recovered from the organ donors and include pancreatic lymph

  13. 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

  14. Nodular Elastosis of the Pancreas

    PubMed Central

    Wedel, Whitney; Talmon, Geoffrey; Sasson, Aaron

    2015-01-01

    Elastofibromatous change is a benign process that has been increasingly recognized in the tubular gastrointestinal tract. These changes can present as a colonic polyp or be seen in conjunction with inflammatory changes. Similar lesions have been noted in the liver, apparently associated with vascular injury. We describe a case in which multiple circumscribed nodules of elastofibromatous change within the pancreas had a similar morphology to nodular elastosis of the liver. To our knowledge, this is the first description of such a finding occurring within the pancreas. PMID:26346767

  15. The economics of pancreas surgery.

    PubMed

    Vollmer, Charles M

    2013-06-01

    Pancreas surgery is a paradigm for high-acuity surgical specialization. Given the current intrigue over containing health care expenditures, pancreas surgery provides an ideal model to investigate the cost of care. This article explores the economics of this field from literature accrued over the last 2 decades. The cost of performing a pancreatic resection is established and then embellished with a discussion of the effects of clinical care paths. Then the influence of complications on costs is explored. Next, cost is investigated as an emerging outcome metric regarding variations in pancreatic surgical care. Finally, the societal-level fiscal impact is considered.

  16. Collection Protocol for Human Pancreas

    PubMed Central

    Campbell-Thompson, Martha L.; Montgomery, Emily L.; Foss, Robin M.; Kolheffer, Kerwin M.; Phipps, Gerald; Schneider, Lynda; Atkinson, Mark A.

    2012-01-01

    This dissection and sampling procedure was developed for the Network for Pancreatic Organ Donors with Diabetes (nPOD) program to standardize preparation of pancreas recovered from cadaveric organ donors. The pancreas is divided into 3 main regions (head, body, tail) followed by serial transverse sections throughout the medial to lateral axis. Alternating sections are used for fixed paraffin and fresh frozen blocks and remnant samples are minced for snap frozen sample preparations, either with or without RNAse inhibitors, for DNA, RNA, or protein isolation. The overall goal of the pancreas dissection procedure is to sample the entire pancreas while maintaining anatomical orientation. Endocrine cell heterogeneity in terms of islet composition, size, and numbers is reported for human islets compared to rodent islets 1. The majority of human islets from the pancreas head, body and tail regions are composed of insulin-containing β-cells followed by lower proportions of glucagon-containing α-cells and somatostatin-containing δ-cells. Pancreatic polypeptide-containing PP cells and ghrelin-containing epsilon cells are also present but in small numbers. In contrast, the uncinate region contains islets that are primarily composed of pancreatic polypeptide-containing PP cells 2. These regional islet variations arise from developmental differences. The pancreas develops from the ventral and dorsal pancreatic buds in the foregut and after rotation of the stomach and duodenum, the ventral lobe moves and fuses with the dorsal 3. The ventral lobe forms the posterior portion of the head including the uncinate process while the dorsal lobe gives rise to the rest of the organ. Regional pancreatic variation is also reported with the tail region having higher islet density compared to other regions and the dorsal lobe-derived components undergoing selective atrophy in type 1 diabetes4,5. Additional organs and tissues are often recovered from the organ donors and include pancreatic

  17. IL-35 inhibits acute graft-versus-host disease in a mouse model.

    PubMed

    Zhang, Xiao-Hui; Zhou, Yi; Zhang, Jia-Min; Zhou, Shi-Yuan; Wang, Min; Feng, Ru; Feng, Fer-Er; Wang, Qian-Ming; Zhu, Xiao-Lu; Zhao, Xiao-Su; Lv, Meng; Kong, Yuan; Chang, Ying-Jun; Huang, Xiao-Jun

    2015-12-01

    Acute graft-versus-host disease (aGVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our previous study found that the novel anti-inflammatory cytokine IL-35 could suppress aGVHD in patients after allo-HSCT. In this study, we used C57BL/6 (B6, H-2b) mice as donors and (B6×DBA/2) F1 (BDF1, H-2b×d) mice as recipients to create a model of aGVHD and explore the relationship between IL-35 and aGVHD. The mice receiving IL-35 survived longer than did the control mice. We observed that treatment with IL-35 and RAPA could reduce the incidence of aGVHD. Additionally, this treatment inhibited intestinal and thymic epithelial cell apoptosis and liver infiltration by the donor T-cells, thereby ameliorating the enteropathy and liver injury caused by aGVHD. We found that IL-35 and RAPA also markedly suppressed TNF-α and IL-17A expression and enhanced IFN-γ expression in the intestine and liver. We measured Tregs in spleen and found that IL-35 and RAPA treatment expanded the number of Tregs in spleen. We found that the phosphorylation of STAT1 and STAT4 were inhibited in mice with aGVHD. In contrast, STAT1 and STAT4 were phosphorylated when the mice were treated with IL-35. IL-35 may have therapeutic potential in the treatment of aGVHD after allo-HSCT. PMID:26507167

  18. IL-35 inhibits acute graft-versus-host disease in a mouse model.

    PubMed

    Zhang, Xiao-Hui; Zhou, Yi; Zhang, Jia-Min; Zhou, Shi-Yuan; Wang, Min; Feng, Ru; Feng, Fer-Er; Wang, Qian-Ming; Zhu, Xiao-Lu; Zhao, Xiao-Su; Lv, Meng; Kong, Yuan; Chang, Ying-Jun; Huang, Xiao-Jun

    2015-12-01

    Acute graft-versus-host disease (aGVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our previous study found that the novel anti-inflammatory cytokine IL-35 could suppress aGVHD in patients after allo-HSCT. In this study, we used C57BL/6 (B6, H-2b) mice as donors and (B6×DBA/2) F1 (BDF1, H-2b×d) mice as recipients to create a model of aGVHD and explore the relationship between IL-35 and aGVHD. The mice receiving IL-35 survived longer than did the control mice. We observed that treatment with IL-35 and RAPA could reduce the incidence of aGVHD. Additionally, this treatment inhibited intestinal and thymic epithelial cell apoptosis and liver infiltration by the donor T-cells, thereby ameliorating the enteropathy and liver injury caused by aGVHD. We found that IL-35 and RAPA also markedly suppressed TNF-α and IL-17A expression and enhanced IFN-γ expression in the intestine and liver. We measured Tregs in spleen and found that IL-35 and RAPA treatment expanded the number of Tregs in spleen. We found that the phosphorylation of STAT1 and STAT4 were inhibited in mice with aGVHD. In contrast, STAT1 and STAT4 were phosphorylated when the mice were treated with IL-35. IL-35 may have therapeutic potential in the treatment of aGVHD after allo-HSCT.

  19. 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

  20. Protective effects of luteolin against acetaminophen-induced acute liver failure in mouse.

    PubMed

    Tai, Minghui; Zhang, Jingyao; Song, Sidong; Miao, RunChen; Liu, Sushun; Pang, Qing; Wu, Qifei; Liu, Chang

    2015-07-01

    Acetaminophen (APAP) is widely used as a safety analgesic and antipyretic agent. Although considered safe at therapeutic doses, overdose of APAP can cause acute liver injury that is sometimes fatal, requiring efficient pharmacological intervention. Luteolin is a naturally occurring flavonoid which is abundant in plants. The objective of this study was to investigate corresponding anti-oxidative and anti-inflammatory activities of luteolin, using acetaminophen-treated mice as a model system. Male C57BL/C mice were randomly divided into three groups (n=6 each). The control group was given phosphate buffered saline (PBS) orally. The APAP group was given APAP by intraperitoneal injection (i.p) at 300 mg/kg suspended in PBS. The luteolin-treated group was given APAP and luteolin (0-100 mg/kg/day, 1 or 3 days before APAP administration) suspended in PBS orally. 16 h after APAP administration, the liver and serum were collected to determine the liver injury. Luteolin administration significantly decreased acetaminophen-induced serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), malondialdehyde (MDA) levels, as well as glutathione (GSH) depletion and decrease of superoxide dismutase (SOD). Luteolin restored SOD, GSH and GSH-px activities and depressed the expression of pro-inflammatory factors, such as inducible nitric oxide synthase (i-NOS), TNF-α, nuclear factor kappa B (NF-κB), and IL-6, respectively. Moreover, luteolin down-regulated acetaminophen-induced nitrotyrosine (NT) formation and endoplasmic reticulum (ER) stress. These results suggest the presence of anti-oxidative, anti-inflammatory and anti-ER stress properties of luteolin in response to acetaminophen-induced liver injury in mice.

  1. 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.

  2. Exploring the metabolic syndrome: Nonalcoholic fatty pancreas disease

    PubMed Central

    Catanzaro, Roberto; Cuffari, Biagio; Italia, Angelo; Marotta, Francesco

    2016-01-01

    After the first description of fatty pancreas in 1933, the effects of pancreatic steatosis have been poorly investigated, compared with that of the liver. However, the interest of research is increasing. Fat accumulation, associated with obesity and the metabolic syndrome (MetS), has been defined as “fatty infiltration” or “nonalcoholic fatty pancreas disease” (NAFPD). The term “fatty replacement” describes a distinct phenomenon characterized by death of acinar cells and replacement by adipose tissue. Risk factors for developing NAFPD include obesity, increasing age, male sex, hypertension, dyslipidemia, alcohol and hyperferritinemia. Increasing evidence support the role of pancreatic fat in the development of type 2 diabetes mellitus, MetS, atherosclerosis, severe acute pancreatitis and even pancreatic cancer. Evidence exists that fatty pancreas could be used as the initial indicator of “ectopic fat deposition”, which is a key element of nonalcoholic fatty liver disease and/or MetS. Moreover, in patients with fatty pancreas, pancreaticoduodenectomy is associated with an increased risk of intraoperative blood loss and post-operative pancreatic fistula. PMID:27678349

  3. Exploring the metabolic syndrome: Nonalcoholic fatty pancreas disease.

    PubMed

    Catanzaro, Roberto; Cuffari, Biagio; Italia, Angelo; Marotta, Francesco

    2016-09-14

    After the first description of fatty pancreas in 1933, the effects of pancreatic steatosis have been poorly investigated, compared with that of the liver. However, the interest of research is increasing. Fat accumulation, associated with obesity and the metabolic syndrome (MetS), has been defined as "fatty infiltration" or "nonalcoholic fatty pancreas disease" (NAFPD). The term "fatty replacement" describes a distinct phenomenon characterized by death of acinar cells and replacement by adipose tissue. Risk factors for developing NAFPD include obesity, increasing age, male sex, hypertension, dyslipidemia, alcohol and hyperferritinemia. Increasing evidence support the role of pancreatic fat in the development of type 2 diabetes mellitus, MetS, atherosclerosis, severe acute pancreatitis and even pancreatic cancer. Evidence exists that fatty pancreas could be used as the initial indicator of "ectopic fat deposition", which is a key element of nonalcoholic fatty liver disease and/or MetS. Moreover, in patients with fatty pancreas, pancreaticoduodenectomy is associated with an increased risk of intraoperative blood loss and post-operative pancreatic fistula.

  4. Exploring the metabolic syndrome: Nonalcoholic fatty pancreas disease.

    PubMed

    Catanzaro, Roberto; Cuffari, Biagio; Italia, Angelo; Marotta, Francesco

    2016-09-14

    After the first description of fatty pancreas in 1933, the effects of pancreatic steatosis have been poorly investigated, compared with that of the liver. However, the interest of research is increasing. Fat accumulation, associated with obesity and the metabolic syndrome (MetS), has been defined as "fatty infiltration" or "nonalcoholic fatty pancreas disease" (NAFPD). The term "fatty replacement" describes a distinct phenomenon characterized by death of acinar cells and replacement by adipose tissue. Risk factors for developing NAFPD include obesity, increasing age, male sex, hypertension, dyslipidemia, alcohol and hyperferritinemia. Increasing evidence support the role of pancreatic fat in the development of type 2 diabetes mellitus, MetS, atherosclerosis, severe acute pancreatitis and even pancreatic cancer. Evidence exists that fatty pancreas could be used as the initial indicator of "ectopic fat deposition", which is a key element of nonalcoholic fatty liver disease and/or MetS. Moreover, in patients with fatty pancreas, pancreaticoduodenectomy is associated with an increased risk of intraoperative blood loss and post-operative pancreatic fistula. PMID:27678349

  5. Exploring the metabolic syndrome: Nonalcoholic fatty pancreas disease

    PubMed Central

    Catanzaro, Roberto; Cuffari, Biagio; Italia, Angelo; Marotta, Francesco

    2016-01-01

    After the first description of fatty pancreas in 1933, the effects of pancreatic steatosis have been poorly investigated, compared with that of the liver. However, the interest of research is increasing. Fat accumulation, associated with obesity and the metabolic syndrome (MetS), has been defined as “fatty infiltration” or “nonalcoholic fatty pancreas disease” (NAFPD). The term “fatty replacement” describes a distinct phenomenon characterized by death of acinar cells and replacement by adipose tissue. Risk factors for developing NAFPD include obesity, increasing age, male sex, hypertension, dyslipidemia, alcohol and hyperferritinemia. Increasing evidence support the role of pancreatic fat in the development of type 2 diabetes mellitus, MetS, atherosclerosis, severe acute pancreatitis and even pancreatic cancer. Evidence exists that fatty pancreas could be used as the initial indicator of “ectopic fat deposition”, which is a key element of nonalcoholic fatty liver disease and/or MetS. Moreover, in patients with fatty pancreas, pancreaticoduodenectomy is associated with an increased risk of intraoperative blood loss and post-operative pancreatic fistula.

  6. 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

  7. Ventilation defects observed with hyperpolarized 3He magnetic resonance imaging in a mouse model of acute lung injury.

    PubMed

    Thomas, Abe C; Nouls, John C; Driehuys, Bastiaan; Voltz, James W; Fubara, Boma; Foley, Julie; Bradbury, J Alyce; Zeldin, Darryl C

    2011-05-01

    Regions of diminished ventilation are often evident during functional pulmonary imaging studies, including hyperpolarized gas magnetic resonance imaging (MRI), positron emission tomography, and computed tomography (CT). The objective of this study was to characterize the hypointense regions observed via (3)He MRI in a murine model of acute lung injury. LPS at doses ranging from 15-50 μg was intratracheally administered to C57BL/6 mice under anesthesia. Four hours after exposure to either LPS or saline vehicle, mice were imaged via hyperpolarized (3)He MRI. All images were evaluated to identify regions of hypointense signals. Lungs were then characterized by conventional histology, or used to obtain tissue samples from regions of normal and hypointense (3)He signals and analyzed for cytokine content. The characterization of (3)He MRI images identified three distinct types of hypointense patterns: persistent defects, atelectatic defects, and dorsal lucencies. Persistent defects were associated with the administration of LPS. The number of persistent defects depended on the dose of LPS, with a significant increase in mean number of defects in 30-50-μg LPS-dosed mice versus saline-treated control mice. Atelectatic defects predominated in LPS-dosed mice under conditions of low-volume ventilation, and could be reversed with deep inspiration. Dorsal lucencies were present in nearly all mice studied, regardless of the experimental conditions, including control animals that did not receive LPS. A comparison of (3)He MRI with histopathology did not identify tissue abnormalities in regions of low (3)He signal, with the exception of a single region of atelectasis in one mouse. Furthermore, no statistically significant differences were evident in concentrations of IL-1β, IL-6, macrophage inflammatory protein (MIP)-1α, MIP-2, chemokine (C-X-C motif) ligand 1 (KC), TNFα, and monocyte chemotactic protein (MCP)-1 between hypointense and normally ventilated lung regions in LPS

  8. Pancreas transplant for diabetes mellitus.

    PubMed

    Kerr, Hannah R; Hatipoglu, Betul; Krishnamurthi, Venkatesh

    2015-11-01

    Pancreas transplant is an option for patients with type 1 diabetes and for some patients with type 2 diabetes and advanced diabetic kidney disease. The procedure has a high success rate, and performing it earlier in the course of diabetes could help prevent or reverse the long-term complications of diabetes.

  9. Prepubertal mouse testis growth and maturation and androgen production are acutely sensitive to di-n-butyl phthalate.

    PubMed

    Moody, Sarah; Goh, Hoey; Bielanowicz, Amanda; Rippon, Paul; Loveland, Kate L; Itman, Catherine

    2013-09-01

    Phthalates are plasticizers with widespread industrial, domestic, and medical applications. Epidemiological data indicating increased incidence of testicular dysgenesis in boys exposed to phthalates in utero are reinforced by studies demonstrating that phthalates impair fetal rodent testis development. Because humans are exposed to phthalates continuously from gestation through adulthood, it is imperative to understand what threat phthalates pose at other life stages. To determine the impact during prepuberty, we assessed the consequences of oral administration of 1 to 500 mg di-n-butyl phthalate (DBP)/kg/d in corn oil to wild-type (C57BL/6J) male mice from 4 to 14 days of age. Dose-dependent effects on testis growth correlated with reduced Sertoli cell proliferation. Histological and immunohistochemical analyses identified delayed spermatogenesis and impaired Sertoli cell maturation after exposure to 10 to 500 mg DBP/kg/d. Interference with the hypothalamic-pituitary-gonadal axis was indicated in mice fed 500 mg DBP/kg/d, which had elevated circulating inhibin but no change in serum FSH. Increased immunohistochemical staining for inhibin-α was apparent at doses of 10 to 500 mg DBP/kg/d. Serum testosterone and testicular androgen activity were lower in the 500 mg DBP/kg/d group; however, reduced anogenital distance in all DBP-treated mice suggested impaired androgen action at earlier time points. Long-term effects were evident, with smaller anogenital distance and indications of disrupted spermatogenesis in adult mice exposed prepubertally to doses from 1 mg DBP/kg/d. These data demonstrate the acute sensitivity of the prepubertal mouse testis to DBP at doses 50- to 500-fold lower than those used in rat and identify the upregulation of inhibin as a potential mechanism of DBP action.

  10. 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.

  11. 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

  12. 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

  13. Pathophysiology of the pancreas after oral infection of genetically diverse mice with coxsackievirus B4-E2.

    PubMed

    Precechtelova, Jana; Borsanyiova, Maria; Stipalova, Darina; Sarmirova, Sona; Gomolcak, Pavol; Berakova, Katarina; Bopegamage, Shubhada

    2015-01-01

    Coxsackievirus B4 strain E2 (CVB4-E2) and its association with type 1 diabetes (T1D) have been studied in experimental in vitro and in vivo murine models. CVB4-E2, known to be pancreotropic and diabetogenic in nature, is associated with acute pancreatitis in mice but shows differences in the induction of glycemia after intraperitoneal (i.p.) infection. Therefore, the aim of this work was to study the outcome of oral infection with CVB4-E2 in five mouse strains with different genetic backgrounds: two outbred (Swiss albino, CD1), two inbred (SJL, NOD) and one transgenic (NOD.SCID). Survival rates, fasting blood glucose, histopathology, viral titres and persistence were studied in selected organs and stool samples. Viral protein (VP1), proinflammatory cytokines, and interferon alpha (IFN-α) were analyzed by immunohistochemistry. We observed mortality only in infected NOD and NOD.SCID mice, with differing survival rates implying initial innate protection in the NOD.SCID mice and low virus clearance with replicating virus titres in the studied organs and stool up to day 40 post infection (p.i.). Independent of the mouse strain hyperglycemia, proinflammatory cytokines and histopathological changes were absent in the endocrine pancreas of infected mice. Only the pancreata of the dead NOD.SCID mice showed inflammation even in presence of IFN-α. Host-dependent viral RNA persistence was observed in all outbred mice. In conclusion, oral infection with CVB4-E2, despite the known affinity of this strain towards the pancreatic tissue and the presence of replicating virus, conferred total protection to the endocrine pancreas in all mice and failed to induce the proinflammatory cytokines studied by us.

  14. Integrative Metabolome and Transcriptome Profiling Reveals Discordant Energetic Stress between Mouse Strains with Differential Sensitivity to Acrolein-Induced Acute Lung Injury

    PubMed Central

    Fabisiak, James P.; Medvedovic, Mario; Alexander, Danny C.; McDunn, Jonathan E.; Concel, Vincent J.; Bein, Kiflai; Jang, An Soo; Brendt, Annerose; Vuga, Louis J.; Brant, Kelly A.; Pope-Varsalona, Hannah; Dopico, Richard A.; Ganguly, Koustav; Upadhyay, Swapna; Li, Qian; Hu, Zhen; Kaminski, Naftali; Leikauf, George D.

    2012-01-01

    A respiratory irritant, acrolein is generated by overheating cooking oils or by domestic cooking using biomass fuels, and is in tobacco smoke, an occupational health hazard in the restaurant workplace. To better understand the metabolic role of the lung and to generate insights into the pathogenesis of acrolein-induced acute lung injury, SM/J (sensitive) and 129×1/SvJ (resistant) inbred mouse strains were exposed and the lung metabolome was integrated with the transcriptome profile. A total of 280 small molecules were identified and mean values (log 2 >0.58 or <−0.58, .p<0.05) were considered different for between-strain comparisons or within-strain responses to acrolein treatment. At baseline, 24 small molecules increased and 33 small molecules decreased in the SM/J mouse lung as compared to 129×1/SvJ mouse lung. Notable among the increased compounds was malonyl carnitine. Following acrolein exposure, several compounds indicative of glycolysis and branched chain amino acid metabolism increased similarly in both strains, whereas SM/J mice were less effective in generating metabolites related to fatty acid β-oxidation. These findings suggest management of energetic stress varies between these strains, and that the ability to evoke auxiliary energy generating pathways rapidly and effectively may be critical in enhancing survival during acute lung injury in mice. PMID:21823223

  15. [Pancreas and biliary tract: recent developments].

    PubMed

    de-Madaria, Enrique

    2014-09-01

    Acute pancreatitis (AP) is a common disease that is associated with significant morbidity and considerable mortality. In this article, developments relating to this disease that were presented in DDW 2014 are reviewed. Pancreatic steatosis could be a cause of recurrent AP. Patients with DM have an increased incidence of AP and pancreatic cancer. The use of anti-TNF drugs in inflammatory bowel disease may protect against the occurrence of AP. The presence of pancreas divisum protects against acute biliary pancreatitis. The PANCODE system for describing local complications of AP has good interobserver agreement, when the new definitions of the revised Atlanta classification are applied. The use of prophylactic antibiotics in early-stage AP predisposes the development of intra-abdominal fungal infections. Fluid sequestration in AP is linked with young age, alcoholism and indicators of systemic inflammatory response syndrome. The most common cause of mortality in AP is early onset of multiple organ failure, not pancreatic necrosis infection. Patients with AP and vitamin D deficiency could benefit from taking vitamin D supplements. Moderate fluid administration in emergencies (500-1000 mL) could be associated with better AP development.

  16. [Pancreas and biliary tract: recent developments].

    PubMed

    de-Madaria, Enrique

    2014-09-01

    Acute pancreatitis (AP) is a common disease that is associated with significant morbidity and considerable mortality. In this article, developments relating to this disease that were presented in DDW 2014 are reviewed. Pancreatic steatosis could be a cause of recurrent AP. Patients with DM have an increased incidence of AP and pancreatic cancer. The use of anti-TNF drugs in inflammatory bowel disease may protect against the occurrence of AP. The presence of pancreas divisum protects against acute biliary pancreatitis. The PANCODE system for describing local complications of AP has good interobserver agreement, when the new definitions of the revised Atlanta classification are applied. The use of prophylactic antibiotics in early-stage AP predisposes the development of intra-abdominal fungal infections. Fluid sequestration in AP is linked with young age, alcoholism and indicators of systemic inflammatory response syndrome. The most common cause of mortality in AP is early onset of multiple organ failure, not pancreatic necrosis infection. Patients with AP and vitamin D deficiency could benefit from taking vitamin D supplements. Moderate fluid administration in emergencies (500-1000 mL) could be associated with better AP development. PMID:25294273

  17. Pancreaticoduodenectomy for pancreas carcinoma occurring in the annular pancreas: report of a case.

    PubMed

    Kawaida, Hiromichi; Kono, Hiroshi; Watanabe, Mitsuaki; Maki, Akira; Amemiya, Hidetake; Matsuda, Masanori; Fujii, Hideki; Fukasawa, Mitsuharu; Takahashi, Ei; Sano, Katsuhiro; Inoue, Tomohiro

    2015-08-01

    The annular pancreas is a rare congenital anomaly in which a ring of the pancreas parenchyma surrounds the second part of the duodenum. Malignant tumors are extremely rare in patients with an annular pancreas. A 64-year-old man presented with appetite loss and vomiting. Abdominal contrast-enhanced computed tomography (CT) indicated pancreas parenchyma surrounding the second part of the duodenum, and a hypovascular area occupying lesion in the annular pancreas. Subtotal stomach-preserving pancreaticoduodenectomy was performed. Histopathology showed pancreatic carcinoma occurring in the complete annular pancreas.

  18. 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

  19. Endocrine pancreas development in zebrafish.

    PubMed

    Tehrani, Zahra; Lin, Shuo

    2011-10-15

    Type 1 diabetes results from the autoimmune destruction of insulin-producing pancreatic β cells. Current efforts to cure diabetes are aimed at replenishing damaged cells by generating a new supply of β cells in vitro. The most promising strategy for achieving this goal is to differentiate embryonic stem (ES) cells by sequentially exposing them to signaling molecules that they would normally encounter in vivo. This approach requires a thorough understanding of the temporal sequence of the signaling events underlying pancreatic β-cell induction during embryonic development. The zebrafish system has emerged as a powerful tool in the study of pancreas development. In this review, we provide a temporal summary of pancreas development in zebrafish with a special focus on the formation of pancreatic β cells.

  20. Lymphoepithelial cyst of the pancreas.

    PubMed

    Domen, Hiromitsu; Ohara, Masanori; Kimura, Noriko; Takahashi, Mizuna; Yamabuki, Takumi; Komuro, Kazuteru; Iwashiro, Nozomu; Ishizaka, Masanori

    2012-09-01

    Cystic lesions of the pancreas can be divided into true cysts, pseudocysts, and cystic neoplasms. Lymphoepithelial cysts (LECs) are a type of true cyst that can mimic pseudocysts and cystic neoplasms. LECs are rare lesions; fewer than 90 cases have been reported in the English language literature. The case of a 60-year-old man with an LEC of the pancreas is reported. He was admitted with upper abdominal discomfort. Computed tomography showed a 64 × 39 mm cystic mass in the retroperitoneum behind the duodenum and inferior caval vein. Magnetic resonance imaging revealed a right-sided mass on T1-weighted imaging, with a clear boundary between the mass and its surroundings, except for the pancreas. The mass had an inhomogeneous intensity on T2-weighted imaging. Within the mass, small floating nodules with low intensity were seen. Endoscopic ultrasound showed many high-echoic nodules and smaller grains scattered everywhere in the mass. Fine needle aspiration and cytologic examination were performed. Characteristic chylaceous fluid was obtained in which anucleate squamous cells were found. There were also a few atypical large cells with irregularly shaped marked nucleoli and degenerative cytoplasm. Cytologic diagnosis was suspicious for malignancy. The lesion was diagnosed as a retroperitoneal cyst, probably of pancreatic origin. Since a neoplastic lesion could not be ruled out, surgery was performed. The lesion was palpable on the dorsal side of the second portion of the duodenum. The mass was completely resected. Macroscopically, the lesion was a multilocular cyst with a thin septal wall. The cyst was filled with cottage cheese-like substance. Microscopically, the cyst wall was composed of stratified squamous epithelium and dense subepithelial lymphatic tissue with developed lymph follicles. The epithelial cells had no atypia. The histopathologic diagnosis was LEC of the pancreas. The patient's postoperative course was good.

  1. 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

  2. [Functional distinction of secreting pools of the pancreas and participation of the pancreatic ductal system in the development of the pancreatic secret properties].

    PubMed

    Korot'ko, G F; Voskanian, S E; Gladkiĭ, E Iu; Makarova, T M; Bulgakov, V A

    2002-08-01

    Acute experiments on dogs with separate secretion of the pancreatic enzymes, either stimulated or inhibited, from two lobes of pancreas, and investigation into the character of kinetics of the secretion from 5-7 ductal pools of the pancreas showed the functional specifics, with the device of ductal valves and microdepot of a secret of the pancreas ductal system playing an important role. The conclusion is made that the final secret of pancreas removed to the duodenum is a product of a secret-motor activation of non-equipotentional microregions of the gland, being the components of an intervisceral dynamical mosaic.

  3. Stromal reengineering to treat pancreas cancer.

    PubMed

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

    2014-07-01

    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

  4. Pancreas Transplantation in the Modern Era.

    PubMed

    Redfield, Robert R; Rickels, Michael R; Naji, Ali; Odorico, Jon S

    2016-03-01

    The field of pancreas transplantation has evolved from an experimental procedure in the 1980s to become a routine transplant in the modern era. With short- and long-term outcomes continuing to improve and the significant mortality, quality-of-life, and end-organ disease benefits, pancreas transplantation should be offered to more patients. In this article, we review current indications, patient selection, surgical considerations, complications, and outcomes in the modern era of pancreas transplantation.

  5. 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.

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

    PubMed Central

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

    2015-01-01

    Background & Aims Sustained activation of the cytosolic calcium concentration induces injury to pancreatic acinar cells and necrosis. The calcium release–activated calcium modulator ORAI1 is the most abundant Ca2+ entry channel in pancreatic acinar cells; it sustains calcium overload in mice exposed to toxins that induce pancreatitis. We investigated the roles of ORAI1 in pancreatic acinar cell injury and the development of acute pancreatitis in mice. Methods Mouse and human acinar cells, as well as HEK 293 cells transfected to express human ORAI1 with human stromal interaction molecule 1, were hyperstimulated or incubated with human bile acid, thapsigargin, or cyclopiazonic acid to induce calcium entry. GSK-7975A or CM_128 were added to some cells, which were analyzed by confocal and video microscopy and patch clamp recordings. Acute pancreatitis was induced in C57BL/6J mice by ductal injection of taurolithocholic acid 3-sulfate or intravenous' administration of cerulein or ethanol and palmitoleic acid. Some mice then were given GSK-7975A or CM_128, which inhibit ORAI1, at different time points to assess local and systemic effects. Results GSK-7975A and CM_128 each separately inhibited toxin-induced activation of ORAI1 and/or activation of Ca2+ currents after Ca2+ release, in a concentration-dependent manner, in mouse and human pancreatic acinar cells (inhibition >90% of the levels observed in control cells). The ORAI1 inhibitors also prevented activation of the necrotic cell death pathway in mouse and human pancreatic acinar cells. GSK-7975A and CM_128 each inhibited all local and systemic features of acute pancreatitis in all 3 models, in dose- and time-dependent manners. The agents were significantly more effective, in a range of parameters, when given at 1 vs 6 hours after induction of pancreatitis. Conclusions Cytosolic calcium overload, mediated via ORAI1, contributes to the pathogenesis of acute pancreatitis. ORAI1 inhibitors might be developed

  7. 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.

  8. Asymptomatic leukemic-cell infiltration of the pancreas: US findings.

    PubMed

    Collado, Laura; Dardanelli, Esteban; Sierre, Sergio; Moguillansky, Silvia; Lipsich, José

    2011-06-01

    Pancreatic infiltration of leukemic cells is a very rare manifestation at the onset of acute lymphoblastic leukemia (ALL) in childhood. Pancreatic enlargement in this situation is unusual and pancreatic involvement is often associated with biliary obstruction, cholestasis and pancreatitis. We report a 3-month-old girl who presented with asymptomatic leukemic infiltration of the pancreas, demonstrated by US with heterogeneous pancreatic enlargement associated with multiple hypoechogenic lesions, without cholestasis. Although these manifestations are rare, ALL should be considered a cause of pancreatic enlargement.

  9. [Differential sonographic diagnosis. Pancreas (pseudo) cyst--choledochus cyst].

    PubMed

    Brockmann, W P; Klapdor, R; Kremer, B

    1984-10-01

    The case of a woman patient with an extended prepapillary choledochal cyst and pancreaticobiliary reflux shows that it is necessary to consider the possibility of a choledochal cyst on detecting a cystic structure in the head of the pancreas (condition after acute pancreatitis); besides this, differential diagnosis will have to consider a pancreatic pseudocyst, hydrops of the gallbladder, a retroperitoneal cyst or even vascular aneurysm. If necessary, the physician should take suitable diagnostic measures before performing any percutaneous cyst drainage which he may have planned, since this may entail the risk of biliary peritonitis.

  10. Priming of long-term potentiation in mouse hippocampus by corticotropin-releasing factor and acute stress: implications for hippocampus-dependent learning.

    PubMed

    Blank, Thomas; Nijholt, Ingrid; Eckart, Klaus; Spiess, Joachim

    2002-05-01

    In the present experiments, we characterized the action of human/rat corticotropin-releasing factor (h/rCRF) and acute stress (1 hr of immobilization) on hippocampus-dependent learning and on synaptic plasticity in the mouse hippocampus. We first showed that h/rCRF application and acute stress facilitated (primed) long-term potentiation of population spikes (PS-LTP) in the mouse hippocampus and enhanced context-dependent fear conditioning. Both the priming of PS-LTP and the improvement of context-dependent fear conditioning were prevented by the CRF receptor antagonist [Glu(11,16)]astressin. PS-LTP priming and improved learning were also reduced by the protein kinase C inhibitor bisindolylmaleimide I. Acute stress induced the activation of Ca2+/calmodulin-dependent kinase II (CaMKII) 2 hr after the end of the stress session. The CaMKII inhibitor KN-62 antagonized the stress-mediated learning enhancement, however, with no effect on PS-LTP persistence. Thus, long-lasting increased neuronal excitability as reflected in PS-LTP priming appeared to be essential for the enhancement of learning in view of the observation that inhibition of PS-LTP priming was associated with impaired learning. Conversely, it was demonstrated that inhibition of CaMKII activity reduced contextual fear conditioning without affecting PS-LTP priming. This observation suggests that priming of PS-LTP and activation of CaMKII represent two essential mechanisms that may contribute independently to long-term memory.

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

    PubMed

    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 (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.

  12. 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.

  13. 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

  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. 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

  16. 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

  17. Lymphoepithelial cyst of the pancreas.

    PubMed

    Truong, L D; Rangdaeng, S; Jordan, P H

    1987-11-01

    A rare cystic lesion of the pancreas is reported. Morphologically, this unilocular cyst was filled with keratin material and lined by mature, keratinizing squamous epithelium; it was surrounded by lymphoid tissue and also focally by pancreatic tissue. Clinically, the lesion was associated with diarrhea and abdominal pain, both of which promptly disappeared after its removal. Although the histogenesis of this lesion is not known, it can be histologically differentiated from other pancreatic and retroperitoneal cysts. We propose the name "lymphoepithelial cyst" for this lesion and note that only one similar case has been described previously.

  18. 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

  19. Mucinous Cystic Neoplasms of Pancreas

    PubMed Central

    Naveed, Shah; Qari, Hasina; Banday, Tanveer; Altaf, Asma; Para, Mah

    2014-01-01

    The purpose of this study was to investigate the actual management of mucinous cystic neoplasm (MCN) of the pancreas. A systematic review was performed in December 2009 by consulting PubMed MEDLINE for publications and matching the key words “pancreatic mucinous cystic neoplasm”, “pancreatic mucinous cystic tumor”, “pancreatic mucinous cystic mass”, “pancreatic cyst” and “pancreatic cystic neoplasm” to identify English language articles describing the diagnosis and treatment of the MCN of the pancreas. In total, 16,322 references ranging from January 1969 to December 2009 were analyzed and 77 articles were identified. No articles published before 1996 were selected because MCNs were not previously considered to be a completely autonomous disease. Definition, epidemiology, anatomopathological findings, clinical presentation, preoperative evaluation, treatment and prognosis were reviewed. MCNs are pancreatic mucin-producing cysts with a distinctive ovarian-type stroma localized in the body-tail of the gland and occurring in middle-aged females. The majority of MCNs are slow growing and asymptomatic. The prevalence of invasive carcinoma varies between 6% and 55%. Preoperative diagnosis depends on a combination of clinical features, tumor markers, computed tomography (CT), magnetic resonance imaging, endoscopic ultrasound with cyst fluid analysis and positron emission tomography-CT. Surgery is indicated for all MCNs.

  20. 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

  1. Distinct enhancers of ptf1a mediate specification and expansion of ventral pancreas in zebrafish.

    PubMed

    Pashos, Evanthia; Park, Joon Tae; Leach, Steven; Fisher, Shannon

    2013-09-15

    Development of the pancreas and cerebellum require Pancreas-specific transcription factor-1a (Ptf1a), which encodes a subunit of the transcription factor complex PTF1. Ptf1a is required in succession for specification of the pancreas, proper allocation of pancreatic progenitors to endocrine and exocrine fates, and the production of digestive enzymes from the exocrine acini. In several neuronal structures, including the cerebellum, hindbrain, retina and spinal cord, Ptf1a is transiently expressed and promotes inhibitory neuron fates at the expense of excitatory fates. Transcription of Ptf1a in mouse is maintained in part by PTF1 acting on an upstream autoregulatory enhancer. However, the transcription factors and enhancers that initially activate Ptf1a expression in the pancreas and in certain structures of the nervous system have not yet been identified. Here we describe a zebrafish autoregulatory element, conserved among teleosts, with activity similar to that described in mouse. In addition, we performed a comprehensive survey of all non-coding sequences in a 67kb interval encompassing zebrafish ptf1a, and identified several neuronal enhancers, and an enhancer active in the ventral pancreas prior to activation of the autoregulatory enhancer. To test the requirement for autoregulatory control during pancreatic development, we restored ptf1a function through BAC transgenesis in ptf1a morphants, either with an intact BAC or one lacking the autoregulatory enhancer. We find that ptf1a autoregulation is required for development of the exocrine pancreas and full rescue of the ptf1a morphant phenotype. Similarly, we demonstrate that a ptf1a locus lacking the early enhancer region is also capable of rescue, but only supports formation of a hypoplastic exocrine pancreas. Through our dissection of the complex regulatory control of ptf1a, we identified separate cis-regulatory elements that underlie different aspects of its expression and function, and further demonstrated

  2. 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.

  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. 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

  5. Estrogen Receptor α Regulates β-Cell Formation During Pancreas Development and Following Injury.

    PubMed

    Yuchi, Yixing; Cai, Ying; Legein, Bart; De Groef, Sofie; Leuckx, Gunter; Coppens, Violette; Van Overmeire, Eva; Staels, Willem; De Leu, Nico; Martens, Geert; Van Ginderachter, Jo A; Heimberg, Harry; Van de Casteele, Mark

    2015-09-01

    Identifying pathways for β-cell generation is essential for cell therapy in diabetes. We investigated the potential of 17β-estradiol (E2) and estrogen receptor (ER) signaling for stimulating β-cell generation during embryonic development and in the severely injured adult pancreas. E2 concentration, ER activity, and number of ERα transcripts were enhanced in the pancreas injured by partial duct ligation (PDL) along with nuclear localization of ERα in β-cells. PDL-induced proliferation of β-cells depended on aromatase activity. The activation of Neurogenin3 (Ngn3) gene expression and β-cell growth in PDL pancreas were impaired when ERα was turned off chemically or genetically (ERα(-/-)), whereas in situ delivery of E2 promoted β-cell formation. In the embryonic pancreas, β-cell replication, number of Ngn3(+) progenitor cells, and expression of key transcription factors of the endocrine lineage were decreased by ERα inactivation. The current study reveals that E2 and ERα signaling can drive β-cell replication and formation in mouse pancreas.

  6. Pancreatic pseudocyst or a cystic tumor of the pancreas?

    PubMed Central

    Rabie, Mohammad Ezzedien; El Hakeem, Ismail; Al Skaini, Mohammad Saad; El Hadad, Ahmad; Jamil, Salim; Tahir Shah, Mian; Obaid, Mahmoud

    2014-01-01

    Pancreatic pseudocysts are the most common cystic lesions of the pancreas and may complicate acute pancreatitis, chronic pancreatitis, or pancreatic trauma. While the majority of acute pseudocysts resolve spontaneously, few may require drainage. On the other hand, pancreatic cystic tumors, which usually require extirpation, may disguise as pseudocysts. Hence, the distinction between the two entities is crucial for a successful outcome. We conducted this study to highlight the fundamental differences between pancreatic pseudocysts and cystic tumors so that relevant management plans can be devised. We reviewed the data of patients with pancreatic cystic lesions that underwent intervention between June 2007 and December 2010 in our hospital. We identified 9 patients (5 males and 4 females) with a median age of 40 years (range, 30–70 years). Five patients had pseudocysts, 2 had cystic tumors, and 2 had diseases of undetermined pathology. Pancreatic pseudocysts were treated by pseudocystogastrostomy in 2 cases and percutaneous drainage in 3 cases. One case recurred after percutaneous drainage and required pseudocystogastrostomy. The true pancreatic cysts were serous cystadenoma, which was treated by distal pancreatectomy, and mucinous cystadenocarcinoma, which was initially treated by drainage, like a pseudocyst, and then by distal pancreatectomy when its true nature was revealed. We conclude that every effort should be exerted to distinguish between pancreatic pseudocysts and cystic tumors of the pancreas to avoid the serious misjudgement of draining rather than extirpating a pancreatic cystic tumor. Additionally, percutaneous drainage of a pancreatic pseudocyst is a useful adjunct that may substitute for surgical drainage. PMID:23958054

  7. [Study of the Effect of Cholecystokinin-Induced Acute Pancreatitis on the Free-Running Rhythm of Mouse].

    PubMed

    Li, Yonghong; Yang, Xiaoping; Guo, Panpan; Liu, Yanyou; Yan, Hongli; Li, Shuaizhen; Guan, Junwen

    2016-02-01

    The present paper reports the effect of pancreatitis induced by cholecystokinin (CCK) on free-running rhythm of locomotor activity of the ICR mice, and analyzes the interaction of inflammatory diseases and acute pancreatitis with circadian rhythm system. In the study, the mice were modeled under different phases of acute pancreatitis in DD status (Double Dark, constant dark condition). By comparing of the inflammatory status and the indicators of rhythm before and after modeling of the running wheel activity group and the rest group, it was observed that the rest group showed more possibility of inflammation than the activity group did in ICR mice model of acute pancreatitis. In the rest phase model, the extension of the period is particularly longer. The results presented indicated that CCK-induced acute pancreatitis impacted free activity rhythm of ICR mice. Also in a free running model under different phase, the inflammation severity was proved significantly different. This study provides possible clues for the research of the pathogenesis of acute pancreatitis severe tendency.

  8. Pancreas transplant imaging: how I do it.

    PubMed

    Tolat, Parag P; Foley, W Dennis; Johnson, Christopher; Hohenwalter, Mark D; Quiroz, Francisco A

    2015-04-01

    Pancreas transplantation aims to restore physiologic normoglycemia in diabetic patients with glomerulopathy and avoid or delay the onset of diabetic retinopathy and arteriopathy. Simultaneous pancreas-kidney transplant is the most common approach, using a cadaveric pancreas donation in conjunction with either cadaveric or live donor renal transplant. Alternative techniques include pancreas after kidney transplant, in which the pancreas transplant is performed some years after renal transplant. Pancreas transplant alone is utilized rarely in diabetic patients with compensated renal function. Pancreas grafts have vascular and enteric connections that vary in their anatomic approach, and understanding of this is critical for imaging with ultrasonography, computed tomography, or magnetic resonance imaging. Imaging techniques are directed to display the pancreatic transplant arterial and venous vasculature, parenchyma, and intestinal drainage pathway. Critical vascular information includes venous thrombosis (partial or complete), arterial occlusion, or aneurysm. Parenchymal abnormalities are nonspecific and occur in pancreatitis, graft rejection, and subsequent graft ischemia. Peripancreatic fluid collections include hematoma/seroma, pseudocyst, and abscess. The latter two are related to pancreatitis, duct disruption, or leak from the duodenojejunostomy. An understanding of transplant anatomy and complications will lead to appropriate use of imaging techniques to diagnose or exclude important complications.

  9. 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

  10. 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

  11. 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

  12. Macrophage dynamics are regulated by local macrophage proliferation and monocyte recruitment in injured pancreas.

    PubMed

    Van Gassen, Naomi; Van Overmeire, Eva; Leuckx, Gunter; Heremans, Yves; De Groef, Sofie; Cai, Ying; Elkrim, Yvon; Gysemans, Conny; Stijlemans, Benoît; Van de Casteele, Mark; De Baetselier, Patrick; De Leu, Nico; Heimberg, Harry; Van Ginderachter, Jo A

    2015-05-01

    Pancreas injury by partial duct ligation (PDL) activates a healing response, encompassing β-cell neogenesis and proliferation. Macrophages (MΦs) were recently shown to promote β-cell proliferation after PDL, but they remain poorly characterized. We assessed myeloid cell diversity and the factors driving myeloid cell dynamics following acute pancreas injury by PDL. In naive and sham-operated pancreas, the myeloid cell compartment consisted mainly of two distinct tissue-resident MΦ types, designated MHC-II(lo) and MHC-II(hi) MΦs, the latter being predominant. MHC-II(lo) and MHC-II(hi) pancreas MΦs differed at the molecular level, with MHC-II(lo) MΦs being more M2-activated. After PDL, there was an early surge of Ly6C(hi) monocyte infiltration in the pancreas, followed by a transient MHC-II(lo) MΦ peak and ultimately a restoration of the MHC-II(hi) MΦ-dominated steady-state equilibrium. These intricate MΦ dynamics in PDL pancreas depended on monocyte recruitment by C-C chemokine receptor 2 and macrophage-colony stimulating factor receptor as well as on macrophage-colony stimulating factor receptor-dependent local MΦ proliferation. Functionally, MHC-II(lo) MΦs were more angiogenic. We further demonstrated that, at least in C-C chemokine receptor 2-KO mice, tissue MΦs, rather than Ly6C(hi) monocyte-derived MΦs, contributed to β-cell proliferation. Together, our study fully characterizes the MΦ subsets in the pancreas and clarifies the complex dynamics of MΦs after PDL injury.

  13. 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 ...

  14. Apoptosis of Hippocampal Pyramidal Neurons Is Virus Independent in a Mouse Model of Acute Neurovirulent Picornavirus Infection

    PubMed Central

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

    2009-01-01

    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. 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

  16. 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.

  17. 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

  18. New mouse model of acute adult T-cell leukemia generated by transplantation of AKT, BCLxL, and HBZ-transduced T cells.

    PubMed

    Kasugai, Yumiko; Yoshida, Noriaki; Ohshima, Koichi; Matsuo, Keitaro; Seto, Masao; Tsuzuki, Shinobu

    2016-08-01

    Adult T-cell leukemia/lymphoma (ATL) develops in human T-cell leukemia virus type 1 (HTLV-1) carriers. Although the HTLV-1-encoded HBZ gene is critically involved, HBZ alone is insufficient and additional, cooperative "hits" are required for the development of ATL. Candidate cooperative hits are being defined, but methods to rapidly explore their roles in ATL development in collaboration with HBZ are lacking. Here, we present a new mouse model of acute type ATL that can be generated rapidly by transplanting in vitro-induced T cells that have been retrovirally transduced with HBZ and two cooperative genes, BCLxL and AKT, into mice. Co-transduction of HBZ and BCLxL/AKT allowed these T cells to grow in vitro in the absence of cytokines (Flt3-ligand and interleukin-7), which did not occur with any two-gene combination. Although transplanted T cells were a mixture of cells transduced with different combinations of the genes, tumors that developed in mice were composed of HBZ/BCLxL/AKT triply transduced T cells, showing the synergistic effect of the three genes. The genetic/epigenetic landscape of ATL has only recently been elucidated, and the roles of additional "hits" in ATL pathogenesis remain to be explored. Our model provides a versatile tool to examine the roles of these hits, in collaboration with HBZ, in the development of acute ATL. PMID:27223899

  19. Effects of chronic and acute methylphenidate hydrochloride (Ritalin) administration on locomotor activity, ultrasonic vocalizations, and neuromotor development in 3- to 11-day-old CD-1 mouse pups.

    PubMed

    Penner, M R; McFadyen, M P; Carrey, N; Brown, R E

    2001-11-01

    The present study examined the effects of chronic and acute treatment with methylphenidate hydrochloride (Ritalin) on isolation-induced ultrasonic vocalizations, spontaneous locomotor activity, and neuromotor coordination in 3- to 11-day-old CD-1 mouse pups. In Experiment 1, 3- to 11-day-old pups received daily injections of saline, 5 mg/kg or 20 mg/kg of methylphenidate hydrochloride, or no injection and were tested on postnatal Days 3, 5, 7, 9, and 11. Both doses of methylphenidate resulted in significant increases in locomotor activity at all ages, but had no significant effect on body weight, neuromotor development, or emission of ultrasonic vocalizations. In Experiment 2, pups were given a single dose of methylphenidate (5 or 20 mg/kg), saline, or no injection on one of postnatal Days 5, 7, 9, or 11. This acute methylphenidate treatment increased locomotor activity, but had no significant effects on ultrasonic vocalizations or neuromotor coordination. These results indicate that short-term, chronic methylphenidate treatment elevates locomotor responses, but has no immediate effects on anxietylike responses or on the development of neuromotor behavior of CD-1 mice in the first 11 days of life.

  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. Acute allergic skin response as a new tool to evaluate the allergenicity of whey hydrolysates in a mouse model of orally induced cow's milk allergy.

    PubMed

    van Esch, Betty C A M; Schouten, Bastiaan; Hofman, Gerard A; van Baalen, Ton; Nijkamp, Frans P; Knippels, Léon M J; Willemsen, Linette E M; Garssen, Johan

    2010-06-01

    Hypoallergenic milk formulae are used for cow's milk allergic infants and may be a good option for infants at risk. Clinical studies have shown that the protein source or the hydrolysis methodology used may influence the effectiveness in infants stressing the importance of adequate pre-clinical testing of hypoallergenic formulae in an in vivo model of orally induced cow's milk allergy. This study was undertaken to introduce a new read-out system to measure the residual allergenicity of whey hydrolysates on both the sensitization and challenge phase of orally induced cow's milk allergy in mice. Mice were sensitized orally to whey or a partial whey hydrolysate (pWH) to measure the residual sensitizing capacity. To predict the residual allergenicity of hydrolysates, whey allergic mice were challenged in the ear with pWH, extensive whey hydrolysate or an amino acid-based formula. An acute allergic skin response (ear swelling at 1 h), whey-specific serum antibodies, and local MCP-1 concentrations were measured. In contrast to whey, oral sensitization with pWH did not result in the induction of whey-specific antibodies, although a minor residual skin response to whey was observed after challenge. Skin exposure to whey hydrolysates showed a hydrolysation dependent reduction of the acute allergic skin response in whey allergic mice. In contrast to whey, skin exposure to pWH did not enhance tissue MCP-1 levels. The acute allergic skin response in mice orally sensitized to cow's milk proteins reveals a new pre-clinical tool which might provide information about the residual sensitizing capacity of hydrolysates supporting the discussion on the use of hypoallergenic formulae in high risk children. This mouse model might be a relevant model for the screening of new hypoallergenic formulae aimed to prevent or treat cow's milk allergy.

  2. Expression of genes involved in mouse lung cell differentiation/regulation after acute exposure to photons and protons with or without low-dose preirradiation.

    PubMed

    Tian, Jian; Zhao, WeiLing; Tian, Sisi; Slater, James M; Deng, Zhiyong; Gridley, Daila S

    2011-11-01

    The goal of this study was to compare the effects of acute 2 Gy irradiation with photons (0.8 Gy/min) or protons (0.9 Gy/min), both with and without pre-exposure to low-dose/low-dose-rate γ rays (0.01 Gy at 0.03 cGy/h), on 84 genes involved in stem cell differentiation or regulation in mouse lungs on days 21 and 56. Genes with a ≥1.5-fold difference in expression and P < 0.05 compared to 0 Gy controls are emphasized. Two proteins specific for lung stem cells/progenitors responsible for local tissue repair were also compared. Overall, striking differences were present between protons and photons in modulating the genes. More genes were affected by protons than by photons (22 compared to 2 and 6 compared to 2 on day 21 and day 56, respectively) compared to 0 Gy. Preirradiation with low-dose-rate γ rays enhanced the acute photon-induced gene modulation on day 21 (11 compared to 2), and all 11 genes were significantly downregulated on day 56. On day 21, seven genes (aldh2, bmp2, cdc2a, col1a1, dll1, foxa2 and notch1) were upregulated in response to most of the radiation regimens. Immunoreactivity of Clara cell secretory protein was enhanced by all radiation regimens. The number of alveolar type 2 cells positive for prosurfactant protein C in irradiated groups was higher on day 56 (12.4-14.6 cells/100) than on day 21 (8.5-11.2 cells/100) (P < 0.05). Taken together, these results showed that acute photons and protons induced different gene expression profiles in the lungs and that pre-exposure to low-dose-rate γ rays sometimes had modulatory effects. In addition, proteins associated with lung-specific stem cells/progenitors were highly sensitive to radiation.

  3. Endotherapy in symptomatic pancreas divisum: a systematic review.

    PubMed

    Kanth, Rajan; Samji, N Swetha; Inaganti, Anupama; Komanapalli, Sarah D; Rivera, Ramon; Antillon, Mainor R; Roy, Praveen K

    2014-01-01

    Pancreas divisum (PD) is the most common congenital variant of the pancreas and has been implicated as a cause of pancreatitis; however, endoscopic treatment is controversial. Our objective was to examine patient response to endotherapy for treatment of symptomatic PD in adult patients in a systematic review of the literature. A systematic review of all case series and case-control studies with ten or more patients undergoing endotherapy for treatment of symptomatic PD indicated by acute recurrent pancreatitis (ARP), chronic pancreatitis (CP), or chronic abdominal pain (CAP) was performed. PubMed, Embase, and Web of Science databases were searched from inception through February 2013 using [pancreas divisum] AND [endoscopic retrograde cholangiopancreatography (ERCP)] OR [endotherapy] OR [endoscopy] as search terms. Importantly, the majority of studies were retrospective in nature, significantly limiting analysis capacity. Main outcomes measures included endotherapy response rate in patients with PD and ARP, CP, or CAP. Twenty-two studies were included in the review, with a total of 838 patients. Response to endoscopy was seen in 528 patients, but response rate varied by clinical presentation. Patients with ARP had a response rate ranging from 43% to 100% (median 76%). Reported response rates were lower in the other two groups, ranging from 21% to 80% (median 42%) for patients with CP and 11%-55% (median 33%) for patients with CAP. Complications reported included perforation, post-endoscopic retrograde cholangiopancreatography pancreatitis, bleeding, and clogged stents. Endotherapy appears to offer an effective treatment option for patients with symptomatic PD, with the best results in patients presenting with ARP.

  4. 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

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

    PubMed

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

    2015-11-20

    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.

  6. 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.

  7. Group X secretory phospholipase A2 regulates the expression of steroidogenic acute regulatory protein (StAR) in mouse adrenal glands.

    PubMed

    Shridas, Preetha; Bailey, William M; Boyanovsky, Boris B; Oslund, Rob C; Gelb, Michael H; Webb, Nancy R

    2010-06-25

    We developed C57BL/6 mice with targeted deletion of group X secretory phospholipase A(2) (GX KO). These mice have approximately 80% higher plasma corticosterone concentrations compared with wild-type (WT) mice under both basal and adrenocorticotropic hormone (ACTH)-induced stress conditions. This increased corticosterone level was not associated with increased circulating ACTH or a defect in the hypothalamic-pituitary axis as evidenced by a normal response to dexamethasone challenge. Primary cultures of adrenal cells from GX KO mice exhibited significantly increased corticosteroid secretion compared with WT cells. Conversely, overexpression of GX secretory phospholipase A(2) (sPLA(2)), but not a catalytically inactive mutant form of GX sPLA(2), significantly reduced steroid production 30-40% in Y1 mouse adrenal cell line. This effect was reversed by the sPLA(2) inhibitor, indoxam. Silencing of endogenous M-type receptor expression did not restore steroid production in GX sPLA(2)-overexpressing Y1 cells, ruling out a role for this sPLA(2) receptor in this regulatory process. Expression of steroidogenic acute regulatory protein (StAR), the rate-limiting protein in corticosteroid production, was approximately 2-fold higher in adrenal glands of GX KO mice compared with WT mice, whereas StAR expression was suppressed in Y1 cells overexpressing GX sPLA(2). Results from StAR-promoter luciferase reporter gene assays indicated that GX sPLA(2) antagonizes StAR promoter activity and liver X receptor-mediated StAR promoter activation. In summary, GX sPLA(2) is expressed in mouse adrenal glands and functions to negatively regulate corticosteroid synthesis, most likely by negatively regulating StAR expression.

  8. Group X Secretory Phospholipase A2 Regulates the Expression of Steroidogenic Acute Regulatory Protein (StAR) in Mouse Adrenal Glands*

    PubMed Central

    Shridas, Preetha; Bailey, William M.; Boyanovsky, Boris B.; Oslund, Rob C.; Gelb, Michael H.; Webb, Nancy R.

    2010-01-01

    We developed C57BL/6 mice with targeted deletion of group X secretory phospholipase A2 (GX KO). These mice have ∼80% higher plasma corticosterone concentrations compared with wild-type (WT) mice under both basal and adrenocorticotropic hormone (ACTH)-induced stress conditions. This increased corticosterone level was not associated with increased circulating ACTH or a defect in the hypothalamic-pituitary axis as evidenced by a normal response to dexamethasone challenge. Primary cultures of adrenal cells from GX KO mice exhibited significantly increased corticosteroid secretion compared with WT cells. Conversely, overexpression of GX secretory phospholipase A2 (sPLA2), but not a catalytically inactive mutant form of GX sPLA2, significantly reduced steroid production 30–40% in Y1 mouse adrenal cell line. This effect was reversed by the sPLA2 inhibitor, indoxam. Silencing of endogenous M-type receptor expression did not restore steroid production in GX sPLA2-overexpressing Y1 cells, ruling out a role for this sPLA2 receptor in this regulatory process. Expression of steroidogenic acute regulatory protein (StAR), the rate-limiting protein in corticosteroid production, was ∼2-fold higher in adrenal glands of GX KO mice compared with WT mice, whereas StAR expression was suppressed in Y1 cells overexpressing GX sPLA2. Results from StAR-promoter luciferase reporter gene assays indicated that GX sPLA2 antagonizes StAR promoter activity and liver X receptor-mediated StAR promoter activation. In summary, GX sPLA2 is expressed in mouse adrenal glands and functions to negatively regulate corticosteroid synthesis, most likely by negatively regulating StAR expression. PMID:20421306

  9. Mechanisms of action of hormone-sensitive lipase in mouse Leydig cells: its role in the regulation of the steroidogenic acute regulatory protein.

    PubMed

    Manna, Pulak R; Cohen-Tannoudji, Joëlle; Counis, Raymond; Garner, Charles W; Huhtaniemi, Ilpo; Kraemer, Fredric B; Stocco, Douglas M

    2013-03-22

    Hormone-sensitive lipase (HSL) catalyzes the hydrolysis of cholesteryl esters in steroidogenic tissues and, thus, facilitates cholesterol availability for steroidogenesis. The steroidogenic acute regulatory protein (StAR) controls the rate-limiting step in steroid biosynthesis. However, the modes of action of HSL in the regulation of StAR expression remain obscure. We demonstrate in MA-10 mouse Leydig cells that activation of the protein kinase A (PKA) pathway, by a cAMP analog Bt2cAMP, enhanced expression of HSL and its phosphorylation (P) at Ser-660 and Ser-563, but not at Ser-565, concomitant with increased HSL activity. Phosphorylation and activation of HSL coincided with increases in StAR, P-StAR (Ser-194), and progesterone levels. Inhibition of HSL activity by CAY10499 effectively suppressed Bt2cAMP-induced StAR expression and progesterone synthesis. Targeted silencing of endogenous HSL, with siRNAs, resulted in increased cholesteryl ester levels and decreased cholesterol content in MA-10 cells. Depletion of HSL affected lipoprotein-derived cellular cholesterol influx, diminished the supply of cholesterol to the mitochondria, and resulted in the repression of StAR and P-StAR levels. Cells overexpressing HSL increased the efficacy of liver X receptor (LXR) ligands on StAR expression and steroid synthesis, suggesting HSL-mediated steroidogenesis entails enhanced oxysterol production. Conversely, cells deficient in LXRs exhibited decreased HSL responsiveness. Furthermore, an increase in HSL was correlated with the LXR target genes, steroid receptor element-binding protein 1c and ATP binding cassette transporter A1, demonstrating HSL-dependent regulation of steroidogenesis predominantly involves LXR signaling. LXRs interact/cooperate with RXRs and result in the activation of StAR gene transcription. These findings provide novel insight and demonstrate the molecular events by which HSL acts to drive cAMP/PKA-mediated regulation of StAR expression and

  10. Acute effects of guarana (Paullinia cupana Mart.) on mouse behaviour in forced swimming and open field tests.

    PubMed

    Campos, A R; Barros, A I S; Albuquerque, F A A; M Leal, L K A; Rao, V S N

    2005-05-01

    Guarana, a herbal extract from the seeds of Paullinia cupana Mart. has been evaluated in comparison with caffeine on mouse behaviour in forced swimming and open field tests. Guarana (25 and 50 mg/kg, p.o.) and caffeine (10 and 20 mg/kg, p.o.) each significantly reduced the duration of immobility in the forced swimming test suggesting an antidepressant-like effect in mice. At these doses, neither substance affected ambulation in the open field test. However, a high dose of guarana (100 mg/kg) and caffeine (30 mg/kg) significantly enhanced the locomotor activity in the open field test. Caffeine, but not guarana, could effectively block an adenosine agonist, cyclopentyl adenosine (CPA)-induced increase in swimming immobility suggesting that mechanism(s) other than the adenosinergic mechanism are involved in the antidepressant-like activity of guarana.

  11. A key role for EZH2 and associated genes in mouse and human adult T-cell acute leukemia.

    PubMed

    Simon, Camille; Chagraoui, Jalila; Krosl, Jana; Gendron, Patrick; Wilhelm, Brian; Lemieux, Sébastien; Boucher, Geneviève; Chagnon, Pierre; Drouin, Simon; Lambert, Raphaëlle; Rondeau, Claude; Bilodeau, Annie; Lavallée, Sylvie; Sauvageau, Martin; Hébert, Josée; Sauvageau, Guy

    2012-04-01

    In this study, we show the high frequency of spontaneous γδ T-cell leukemia (T-ALL) occurrence in mice with biallelic deletion of enhancer of zeste homolog 2 (Ezh2). Tumor cells show little residual H3K27 trimethylation marks compared with controls. EZH2 is a component of the PRC2 Polycomb group protein complex, which is associated with DNA methyltransferases. Using next-generation sequencing, we identify alteration in gene expression levels of EZH2 and acquired mutations in PRC2-associated genes (DNMT3A and JARID2) in human adult T-ALL. Together, these studies document that deregulation of EZH2 and associated genes leads to the development of mouse, and likely human, T-ALL.

  12. Inflammation, regeneration, and transformation in the pancreas: results of the Collaborative Research Center 518 (SFB 518) at the University of Ulm.

    PubMed

    Giehl, Klaudia; Bachem, Max; Beil, Michael; Böhm, Bernhard O; Ellenrieder, Volker; Fulda, Simone; Gress, Thomas M; Holzmann, Karlheinz; Kestler, Hans A; Kornmann, Marko; Menke, Andre; Möller, Peter; Oswald, Franz; Schmid, Roland M; Schmidt, Volker; Schirmbeck, Reinhold; Seufferlein, Thomas; von Wichert, Götz; Wagner, Martin; Walther, Paul; Wirth, Thomas; Adler, Guido

    2011-05-01

    The primary diseases of the pancreas include diabetes mellitus, acute and chronic pancreatitis, as well as pancreatic carcinoma. This review presents findings and emerging questions on the diseases of the pancreas obtained by the consortium of the Collaborative Research Center 518 (SFB 518), "Inflammation, Regeneration, and Transformation in the Pancreas" at the University of Ulm. During the last 12 years, the SFB 518 contributed considerably to the understanding of the cellular and molecular basis of pancreatic diseases and established the basis for the development of new strategies for prevention and causal therapy for diabetes, pancreatitis, and pancreatic cancer.

  13. Is a fatty pancreas a banal lesion?

    PubMed

    Smereczyński, Andrzej; Kołaczyk, Katarzyna

    2016-09-01

    So far, a fatty pancreas has been related to obesity and the ageing processes in the body. The current list of pathogenetic factors of the condition is clearly extended with genetically conditioned diseases (cystic fibrosis, Shwachman-Diamond syndrome and Johanson-Blizzard syndrome), pancreatitis, especially hereditary and obstructive, metabolic and hormonal disorders (hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia and hypercortisolemia), alcohol overuse, taking some medicines (especially adrenal cortex hormones), disease of the liver and visceral adiposis. As regards lipomatosis of that organ resulting mainly from dyslipidemia and hyperglycemia, the term "nonalcoholic fatty pancreas disease" was introduced. Experimental studies on animals and histological preparations of the pancreatic fragments show that the lipotoxicity of the collected adipocytes collected ion the organ release a cascade of proinflammatory phenomena, and even induces the processes of carcinogenesis. Pancreas adiposis is best defined in Computed Tomography and Magnetic Resonance Imaging. However, a series of works proved the usefulness in the diagnostics of that pathology of transabdominal and endoscopic ultrasonography. In that method, the degree of adiposis was based on the comparison of echogenicity of the pancreas and the liver, renal parenchyma, spleen and/or retroperitoneal adipose. Recently, the evaluation was expanded by the evaluation of the degree of pancreatic adipose with the pancreas-to-liver index, utilizing to that end a special computer program. According to our experience, the simplest solution is the method utilized by us. On one crosssection of the body of the pancreas, its echogenicity is assessed in comparison to retroperitoneal adipose and the visibility of the splenic vein, pancreatic duct and the major retroperitoneal vessels. Depending on the visualization of these structures, it is possible to determine the degree of pancreas adiposis. Such a study applies

  14. Is a fatty pancreas a banal lesion?

    PubMed Central

    Kołaczyk, Katarzyna

    2016-01-01

    So far, a fatty pancreas has been related to obesity and the ageing processes in the body. The current list of pathogenetic factors of the condition is clearly extended with genetically conditioned diseases (cystic fibrosis, Shwachman-Diamond syndrome and Johanson-Blizzard syndrome), pancreatitis, especially hereditary and obstructive, metabolic and hormonal disorders (hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia and hypercortisolemia), alcohol overuse, taking some medicines (especially adrenal cortex hormones), disease of the liver and visceral adiposis. As regards lipomatosis of that organ resulting mainly from dyslipidemia and hyperglycemia, the term “nonalcoholic fatty pancreas disease” was introduced. Experimental studies on animals and histological preparations of the pancreatic fragments show that the lipotoxicity of the collected adipocytes collected ion the organ release a cascade of proinflammatory phenomena, and even induces the processes of carcinogenesis. Pancreas adiposis is best defined in Computed Tomography and Magnetic Resonance Imaging. However, a series of works proved the usefulness in the diagnostics of that pathology of transabdominal and endoscopic ultrasonography. In that method, the degree of adiposis was based on the comparison of echogenicity of the pancreas and the liver, renal parenchyma, spleen and/or retroperitoneal adipose. Recently, the evaluation was expanded by the evaluation of the degree of pancreatic adipose with the pancreas-to-liver index, utilizing to that end a special computer program. According to our experience, the simplest solution is the method utilized by us. On one crosssection of the body of the pancreas, its echogenicity is assessed in comparison to retroperitoneal adipose and the visibility of the splenic vein, pancreatic duct and the major retroperitoneal vessels. Depending on the visualization of these structures, it is possible to determine the degree of pancreas adiposis. Such a study

  15. Is a fatty pancreas a banal lesion?

    PubMed Central

    Kołaczyk, Katarzyna

    2016-01-01

    So far, a fatty pancreas has been related to obesity and the ageing processes in the body. The current list of pathogenetic factors of the condition is clearly extended with genetically conditioned diseases (cystic fibrosis, Shwachman-Diamond syndrome and Johanson-Blizzard syndrome), pancreatitis, especially hereditary and obstructive, metabolic and hormonal disorders (hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia and hypercortisolemia), alcohol overuse, taking some medicines (especially adrenal cortex hormones), disease of the liver and visceral adiposis. As regards lipomatosis of that organ resulting mainly from dyslipidemia and hyperglycemia, the term “nonalcoholic fatty pancreas disease” was introduced. Experimental studies on animals and histological preparations of the pancreatic fragments show that the lipotoxicity of the collected adipocytes collected ion the organ release a cascade of proinflammatory phenomena, and even induces the processes of carcinogenesis. Pancreas adiposis is best defined in Computed Tomography and Magnetic Resonance Imaging. However, a series of works proved the usefulness in the diagnostics of that pathology of transabdominal and endoscopic ultrasonography. In that method, the degree of adiposis was based on the comparison of echogenicity of the pancreas and the liver, renal parenchyma, spleen and/or retroperitoneal adipose. Recently, the evaluation was expanded by the evaluation of the degree of pancreatic adipose with the pancreas-to-liver index, utilizing to that end a special computer program. According to our experience, the simplest solution is the method utilized by us. On one crosssection of the body of the pancreas, its echogenicity is assessed in comparison to retroperitoneal adipose and the visibility of the splenic vein, pancreatic duct and the major retroperitoneal vessels. Depending on the visualization of these structures, it is possible to determine the degree of pancreas adiposis. Such a study

  16. 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

  17. Nonalcoholic fatty pancreas disease1

    PubMed Central

    Mathur, Abhishek; Marine, Megan; Lu, Debao; Swartz-Basile, Deborah A.; Saxena, Romil; Zyromski, Nicholas J.

    2007-01-01

    Background. Obesity leads to fat infiltration of multiple organs including the heart, kidneys, and liver. Under conditions of oxidative stress, fat-derived cytokines are released locally and result in an inflammatory process and organ dysfunction. In the liver, fat infiltration has been termed nonalcoholic fatty liver disease, which may lead to nonalcoholic steatohepatitis. No data are available, however, on the influence of obesity on pancreatic fat and cytokines, and nonalcoholic fatty pancreas disease (NAFPD) has not been described. Therefore, we designed a study to determine whether obesity is associated with increased pancreatic fat and cytokines. Materials and methods. Thirty C57BL/6J lean control and 30 leptin-deficient obese female mice were fed a 15% fat diet for 4 weeks. At 12 weeks of age all animals underwent total pancreatectomy. Pancreata from each strain were pooled for measurement of a) wet and dry weight, b) histologic presence of fat, c) triglycerides, free fatty acids (FFAs), cholesterol, phospholipids, and total fat, and d) interleukin (IL)-1β and tumor necrosis factor-alpha (TNF-α). Data were analyzed by Student's t test and Fisher's exact test. Results. Pancreata from obese mice were heavier (p<0.05) and had more fat histologically (p<0.05). Pancreata from obese mice had more triglycerides, FFAs, cholesterol, and total fat (p<0.05). Triglycerides represented 11% of pancreatic fat in lean mice compared with 67% of pancreatic fat in obese mice (p<0.01). Cytokines IL-1β and TNF-α also were elevated in the pancreata of obese mice (p<0.05). Conclusions. These data suggest that obese mice have 1) heavier pancreata, 2) more pancreatic fat, especially triglycerides and FFAs, and 3) increased cytokines. We conclude that obesity leads to nonalcoholic fatty pancreatic disease. PMID:18345311

  18. Editor's Highlight: Neonatal Activation of the Xenobiotic-Sensors PXR and CAR Results in Acute and Persistent Down-regulation of PPARα-Signaling in Mouse Liver.

    PubMed

    Li, Cindy Yanfei; Cheng, Sunny Lihua; Bammler, Theo K; Cui, Julia Yue

    2016-10-01

    Safety concerns have emerged regarding the potential long-lasting effects due to developmental exposure to xenobiotics. The pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are critical xenobiotic-sensing nuclear receptors that are highly expressed in liver. The goal of this study was to test our hypothesis that neonatal exposure to PXR- or CAR-activators not only acutely but also persistently regulates the expression of drug-processing genes (DPGs). A single dose of the PXR-ligand PCN (75 mg/kg), CAR-ligand TCPOBOP (3 mg/kg), or vehicle (corn oil) was administered intraperitoneally to 3-day-old neonatal wild-type mice. Livers were collected 24 h post-dose or from adult mice at 60 days of age, and global gene expression of these mice was determined using Affymetrix Mouse Transcriptome Assay 1.0. In neonatal liver, PCN up-regulated 464 and down-regulated 449 genes, whereas TCPOBOP up-regulated 308 and down-regulated 112 genes. In adult liver, there were 15 persistently up-regulated and 22 persistently down-regulated genes following neonatal exposure to PCN, as well as 130 persistently up-regulated and 18 persistently down-regulated genes following neonatal exposure to TCPOBOP. Neonatal exposure to both PCN and TCPOBOP persistently down-regulated multiple Cyp4a members, which are prototypical-target genes of the lipid-sensor PPARα, and this correlated with decreased PPARα-binding to the Cyp4a gene loci. RT-qPCR, western blotting, and enzyme activity assays in livers of wild-type, PXR-null, and CAR-null mice confirmed that the persistent down-regulation of Cyp4a was PXR and CAR dependent. In conclusion, neonatal exposure to PXR- and CAR-activators both acutely and persistently regulates critical genes involved in xenobiotic and lipid metabolism in liver. PMID:27413110

  19. Editor's Highlight: Neonatal Activation of the Xenobiotic-Sensors PXR and CAR Results in Acute and Persistent Down-regulation of PPARα-Signaling in Mouse Liver.

    PubMed

    Li, Cindy Yanfei; Cheng, Sunny Lihua; Bammler, Theo K; Cui, Julia Yue

    2016-10-01

    Safety concerns have emerged regarding the potential long-lasting effects due to developmental exposure to xenobiotics. The pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are critical xenobiotic-sensing nuclear receptors that are highly expressed in liver. The goal of this study was to test our hypothesis that neonatal exposure to PXR- or CAR-activators not only acutely but also persistently regulates the expression of drug-processing genes (DPGs). A single dose of the PXR-ligand PCN (75 mg/kg), CAR-ligand TCPOBOP (3 mg/kg), or vehicle (corn oil) was administered intraperitoneally to 3-day-old neonatal wild-type mice. Livers were collected 24 h post-dose or from adult mice at 60 days of age, and global gene expression of these mice was determined using Affymetrix Mouse Transcriptome Assay 1.0. In neonatal liver, PCN up-regulated 464 and down-regulated 449 genes, whereas TCPOBOP up-regulated 308 and down-regulated 112 genes. In adult liver, there were 15 persistently up-regulated and 22 persistently down-regulated genes following neonatal exposure to PCN, as well as 130 persistently up-regulated and 18 persistently down-regulated genes following neonatal exposure to TCPOBOP. Neonatal exposure to both PCN and TCPOBOP persistently down-regulated multiple Cyp4a members, which are prototypical-target genes of the lipid-sensor PPARα, and this correlated with decreased PPARα-binding to the Cyp4a gene loci. RT-qPCR, western blotting, and enzyme activity assays in livers of wild-type, PXR-null, and CAR-null mice confirmed that the persistent down-regulation of Cyp4a was PXR and CAR dependent. In conclusion, neonatal exposure to PXR- and CAR-activators both acutely and persistently regulates critical genes involved in xenobiotic and lipid metabolism in liver.

  20. Giant gastric ulcer penetrating into the pancreas.

    PubMed

    Fujihara, Shintaro; Mori, Hirohito; Nishiyama, Noriko; Kobara, Hideki; Masaki, Tsutomu

    2012-09-01

    A 57-year-old man developed haematemesis and was referred to our institution. His discomfort had begun 3 weeks earlier and localised to the upper abdomen. Abdominal CT showed a defect of gastric mucosa and gastric wall thickening. Oesophagogastroduodenoscopy showed that he had an active gastric ulcer, 40 mm in diameter, on the lesser curvature in the upper third of the corpus and the presence of a pancreatic body at the ulcer base, penetration to the pancreas. Open gastrectomy was performed with a preoperative diagnosis of localised peritonitis caused by penetration of the stomach into the pancreas. Histopathology of resected specimens showed a benign peptic ulcer, 40×40 mm in size, was found on the lesser curvature in the antrum, and this had penetrated through the pancreas. The most serious complications of PUD include haemorrhage, perforation, penetration, and gastric outlet obstruction. Approximately 7% of patients experience perforation, which occurs when an ulcer erodes through the wall and leaks air and digestive contents into the peritoneal cavity. Antral and duodenal ulcers can penetrate into the pancreas. We report a case of gastric ulcer penetrating into the pancreas.

  1. Renal progenitors derived from human iPSCs engraft and restore function in a mouse model of acute kidney injury

    PubMed Central

    Imberti, Barbara; Tomasoni, Susanna; Ciampi, Osele; Pezzotta, Anna; Derosas, Manuela; Xinaris, Christodoulos; Rizzo, Paola; Papadimou, Evangelia; Novelli, Rubina; Benigni, Ariela; Remuzzi, Giuseppe; Morigi, Marina

    2015-01-01

    Acute kidney injury (AKI) is one of the most relevant health issues, leading to millions of deaths. The magnitude of the phenomenon remarks the urgent need for innovative and effective therapeutic approaches. Cell-based therapy with renal progenitor cells (RPCs) has been proposed as a possible strategy. Studies have shown the feasibility of directing embryonic stem cells or induced Pluripotent Stem Cells (iPSCs) towards nephrogenic intermediate mesoderm and metanephric mesenchyme (MM). However, the functional activity of iPSC-derived RPCs has not been tested in animal models of kidney disease. Here, through an efficient inductive protocol, we directed human iPSCs towards RPCs that robustly engrafted into damaged tubuli and restored renal function and structure in cisplatin-mice with AKI. These results demonstrate that iPSCs are a valuable source of engraftable cells with regenerative activity for kidney disease and create the basis for future applications in stem cell-based therapy. PMID:25744951

  2. 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.

  3. Downstream signaling pathways in mouse adipose tissues following acute in vivo administration of fibroblast growth factor 21.

    PubMed

    Muise, Eric S; Souza, Sandra; Chi, An; Tan, Yejun; Zhao, Xuemei; Liu, Franklin; Dallas-Yang, Qing; Wu, Margaret; Sarr, Tim; Zhu, Lan; Guo, Hongbo; Li, Zhihua; Li, Wenyu; Hu, Weiwen; Jiang, Guoqiang; Paweletz, Cloud P; Hendrickson, Ronald C; Thompson, John R; Mu, James; Berger, Joel P; Mehmet, Huseyin

    2013-01-01

    FGF21 is a novel secreted protein with robust anti-diabetic, anti-obesity, and anti-atherogenic activities in preclinical species. In the current study, we investigated the signal transduction pathways downstream of FGF21 following acute administration of the growth factor to mice. Focusing on adipose tissues, we identified FGF21-mediated downstream signaling events and target engagement biomarkers. Specifically, RNA profiling of adipose tissues and phosphoproteomic profiling of adipocytes, following FGF21 treatment revealed several specific changes in gene expression and post-translational modifications, specifically phosphorylation, in several relevant proteins. Affymetrix microarray analysis of white adipose tissues isolated from both C57BL/6 (fed either regular chow or HFD) and db/db mice identified over 150 robust potential RNA transcripts and over 50 potential secreted proteins that were changed greater than 1.5 fold by FGF21 acutely. Phosphoprofiling analysis identified over 130 phosphoproteins that were modulated greater than 1.5 fold by FGF21 in 3T3-L1 adipocytes. Bioinformatic analysis of the combined gene and phosphoprotein profiling data identified a number of known metabolic pathways such as glucose uptake, insulin receptor signaling, Erk/Mapk signaling cascades, and lipid metabolism. Moreover, a number of novel events with hitherto unknown links to FGF21 signaling were observed at both the transcription and protein phosphorylation levels following treatment. We conclude that such a combined "omics" approach can be used not only to identify robust biomarkers for novel therapeutics but can also enhance our understanding of downstream signaling pathways; in the example presented here, novel FGF21-mediated signaling events in adipose tissue have been revealed that warrant further investigation.

  4. Downstream Signaling Pathways in Mouse Adipose Tissues Following Acute In Vivo Administration of Fibroblast Growth Factor 21

    PubMed Central

    Chi, An; Tan, Yejun; Zhao, Xuemei; Liu, Franklin; Dallas-yang, Qing; Wu, Margaret; Sarr, Tim; Zhu, Lan; Guo, Hongbo; Li, Zhihua; Li, Wenyu; Hu, Weiwen; Jiang, Guoqiang; Paweletz, Cloud P.; Hendrickson, Ronald C.; Thompson, John R.; Mu, James; Berger, Joel P.; Mehmet, Huseyin

    2013-01-01

    FGF21 is a novel secreted protein with robust anti-diabetic, anti-obesity, and anti-atherogenic activities in preclinical species. In the current study, we investigated the signal transduction pathways downstream of FGF21 following acute administration of the growth factor to mice. Focusing on adipose tissues, we identified FGF21-mediated downstream signaling events and target engagement biomarkers. Specifically, RNA profiling of adipose tissues and phosphoproteomic profiling of adipocytes, following FGF21 treatment revealed several specific changes in gene expression and post-translational modifications, specifically phosphorylation, in several relevant proteins. Affymetrix microarray analysis of white adipose tissues isolated from both C57BL/6 (fed either regular chow or HFD) and db/db mice identified over 150 robust potential RNA transcripts and over 50 potential secreted proteins that were changed greater than 1.5 fold by FGF21 acutely. Phosphoprofiling analysis identified over 130 phosphoproteins that were modulated greater than 1.5 fold by FGF21 in 3T3-L1 adipocytes. Bioinformatic analysis of the combined gene and phosphoprotein profiling data identified a number of known metabolic pathways such as glucose uptake, insulin receptor signaling, Erk/Mapk signaling cascades, and lipid metabolism. Moreover, a number of novel events with hitherto unknown links to FGF21 signaling were observed at both the transcription and protein phosphorylation levels following treatment. We conclude that such a combined "omics" approach can be used not only to identify robust biomarkers for novel therapeutics but can also enhance our understanding of downstream signaling pathways; in the example presented here, novel FGF21-mediated signaling events in adipose tissue have been revealed that warrant further investigation. PMID:24039848

  5. N-acetyl cysteine improves the effects of corticosteroids in a mouse model of chlorine-induced acute lung injury.

    PubMed

    Wigenstam, Elisabeth; Koch, Bo; Bucht, Anders; Jonasson, Sofia

    2015-02-01

    Chlorine (Cl2) causes tissue damage and a neutrophilic inflammatory response in the airways manifested by pronounced airway hyperreactivity (AHR). The importance of early anti-inflammatory treatment has previously been addressed. In the previous study, both high-dose and low-dose of dexamethasone (DEX) decreased the risk of developing delayed effects, such as persistent lung injuries, while only high-dose treatment could significantly counteract acute-phase effects. One aim of this study was to evaluate whether a low-dose of DEX in combination with the antioxidant N-acetyl cysteine (NAC) and if different treatments (Triptolide, Reparixin and Rolipram) administered 1h after Cl2-exposure could improve protection against acute lung injury in Cl2-exposed mice. BALB/c mice were exposed to 300 ppm Cl2 during 15 min. Assessment of AHR and inflammatory cells in bronchoalveolar lavage was analyzed 24h post exposure. Neither of DEX nor NAC reduced the AHR and displayed only minor effects on inflammatory cell influx when given as separate treatments. When given in combination, a protective effect on AHR and a significant reduction in inflammatory cells (neutrophils) was observed. Neither of triptolide, Reparixin nor Rolipram had an effect on AHR but Triptolide had major effect on the inflammatory cell influx. Treatments did not reduce the concentration of either fibrinogen or plasminogen activator inhibitor-1 in serum, thereby supporting the theory that the inflammatory response is not solely limited to the lung. These results provide a foundation for future studies aimed at identifying new concepts for treatment of chemical-induced lung injury. Studies addressing combination of anti-inflammatory and antioxidant treatment are highly motivated.

  6. Histopathologic changes induced by cellophane wrapping of the pancreas are unaffected by cigarette smoke exposure in hamsters.

    PubMed

    Kim, Anthony W; Patel, Dhaval; Liu, Qiang; Gattuso, Paolo; Djuricin, Goldie; Kelly, Holly M; Girard, Scott; Cambria, Robert A; Freischlag, Julie A; Prinz, Richard A

    2002-01-01

    This study tests whether exposure to cigarette smoke alone or combined with cellophane wrapping of the pancreas increases the development of microscopic abnormalities in the pancreas of Syrian golden hamsters. Ninety hamsters were randomly divided into 4 groups. Thirty-five hamsters were exposed to 3 continuous hours of cigarette smoke daily for 3 months following celiotomy to cellophane wrap the gastric lobe of the pancreas (group 1). Thirty-two hamsters were not exposed to continuous cigarette smoke and had the wrap surgery alone (group 2). Twelve hamsters were exposed to cigarette smoke and had no surgery (group 3). Eleven hamsters had no exposure to cigarette smoke and no surgery (group 4). All of the hamsters were sacrificed after 3 months. The gastric (wrapped) and splenic (unwrapped) lobes of the pancreas were reviewed grossly and histologically. In all 4 groups, there were no gross abnormalities in either lobe of the pancreas. Histopathologic evaluation of the gastric lobes from group 1 showed that 13 of 35 lobes (37%) had pancreatitis (11 chronic, 1 acute, and 1 both). In group 2, 12 of 32 (38%) gastric lobes had pancreatitis (10 chronic, 2 acute). The incidence of pancreatitis in groups 1 and 2 was significantly higher than in groups 3 (0/12; p < 0.04) and 4 (0/11; p < 0.03), respectively. A significantly lower incidence of pancreatitis was found in the splenic lobes of all 4 groups when compared to gastric lobes in groups 1 and 2. Three of the 67 cellophane-wrapped glands had ductal hyperplasia. The effects of cellophane wrapping of the pancreas, both in the wrapped and unwrapped areas, induced changes of pancreatitis and hyperplasia that may be preneoplastic. Cigarette smoking, alone or combined with cellophane wrapping, did not cause these changes. Longer exposure to cigarette smoke may be needed to cause premalignant changes in the hamster pancreas.

  7. In-depth Physiological Analysis of Defined Cell Populations in Acute Tissue Slices of the Mouse Vomeronasal Organ.

    PubMed

    Ackels, Tobias; Drose, Daniela R; Spehr, Marc

    2016-01-01

    In most mammals, the vomeronasal organ (VNO) is a chemosensory structure that detects both hetero- and conspecific social cues. Vomeronasal sensory neurons (VSNs) express a specific type of G protein-coupled receptor (GPCR) from at least three different chemoreceptor gene families allowing sensitive and specific detection of chemosensory cues. These families comprise the V1r and V2r gene families as well as the formyl peptide receptor (FPR)-related sequence (Fpr-rs) family of putative chemoreceptor genes. In order to understand the physiology of vomeronasal receptor-ligand interactions and downstream signaling, it is essential to identify the biophysical properties inherent to each specific class of VSNs. The physiological approach described here allows identification and in-depth analysis of a defined population of sensory neurons using a transgenic mouse line (Fpr-rs3-i-Venus). The use of this protocol, however, is not restricted to this specific line and thus can easily be extended to other genetically modified lines or wild type animals. PMID:27684435

  8. 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

  9. 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

  10. 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

  11. CAMKII-conditional deletion of histone deacetylase 2 potentiates acute methamphetamine-induced expression of immediate early genes in the mouse nucleus accumbens.

    PubMed

    Torres, Oscar V; McCoy, Michael T; Ladenheim, Bruce; Jayanthi, Subramaniam; Brannock, Christie; Tulloch, Ingrid; Krasnova, Irina N; Cadet, Jean Lud

    2015-08-24

    Methamphetamine (METH) produces increases in the expression of immediate early genes (IEGs) and of histone deacetylase 2 (HDAC2) in the rat nucleus accumbens (NAc). Here, we tested whether HDAC2 deletion influenced the effects of METH on IEG expression in the NAc. Microarray analyses showed no baseline differences in IEG expression between wild-type (WT) and HDAC2 knockout (KO) mice. Quantitative-PCR analysis shows that an acute METH injection produced time-dependent increases in mRNA levels of several IEGs in both genotypes. Interestingly, HDAC2KO mice displayed greater METH-induced increases in Egr1 and Egr2 mRNA levels measured at one hour post-injection. The levels of Fosb, Fra2, Egr1, and Egr3 mRNAs stayed elevated in the HDAC2KO mice 2 hours after the METH injection whereas these mRNAs had normalized in the WT mice. In WT mice, METH caused increased HDAC2 recruitment to the promoters some IEGs at 2 hours post injection. METH-induced prolonged increases in Fosb, Fra2, Egr1, and Egr3 mRNA levels in HDAC2KO mice were associated with increased enrichment of phosphorylated CREB (pCREB) on the promoters of these genes. Based on our observations, we hypothesize that HDAC2 may regulate the expression of these genes, in part, by prolonging the actions of pCREB in the mouse NAc.

  12. Stromal cell-derived factor-1 (SDF1)-dependent recruitment of bone marrow-derived renal endothelium-like cells in a mouse model of acute kidney injury

    PubMed Central

    OHNISHI, Hiroyuki; MIZUNO, Shinya; MIZUNO-HORIKAWA, Yoko; KATO, Takashi

    2015-01-01

    Ischemic acute kidney injury (AKI) is the most key pathological event for accelerating progression to chronic kidney disease through vascular endothelial injury or dysfunction. Thus, it is critical to elucidate the molecular mechanism of endothelial protection and regeneration. Emerging evidence indicates that bone marrow-derived cells (BMCs) contribute to tissue reconstitution in several types of organs post-injury, but little is known whether and how BMCs contribute to renal endothelial reconstitution, especially in an early-stage of AKI. Using a mouse model of ischemic AKI, we provide evidence that incorporation of BMCs in vascular components (such as endothelial and smooth muscle cells) becomes evident within four days after renal ischemia and reperfusion, associated with an increase in stromal cell-derived factor-1 (SDF1) in endothelium and that in CXCR4/SDF1-receptor in BMCs. Notably, anti-CXCR4 antibody decreased the numbers of infiltrated BMCs and BMC-derived endothelium-like cells, but not of BMC-derived smooth muscle cell-like cells. These results suggest that reconstitution of renal endothelium post-ischemia partially depends on a paracrine loop of SDF1-CXCR4 between resident endothelium and BMCs. Such a chemokine ligand-receptor system may be attributable for selecting a cellular lineage (s), required for renal vascular protection, repair and homeostasis, even in an earlier phase of AKI. PMID:25833353

  13. CAMKII-conditional deletion of histone deacetylase 2 potentiates acute methamphetamine-induced expression of immediate early genes in the mouse nucleus accumbens

    PubMed Central

    Torres, Oscar V.; McCoy, Michael T.; Ladenheim, Bruce; Jayanthi, Subramaniam; Brannock, Christie; Tulloch, Ingrid; Krasnova, Irina N.; Cadet, Jean Lud

    2015-01-01

    Methamphetamine (METH) produces increases in the expression of immediate early genes (IEGs) and of histone deacetylase 2 (HDAC2) in the rat nucleus accumbens (NAc). Here, we tested whether HDAC2 deletion influenced the effects of METH on IEG expression in the NAc. Microarray analyses showed no baseline differences in IEG expression between wild-type (WT) and HDAC2 knockout (KO) mice. Quantitative-PCR analysis shows that an acute METH injection produced time-dependent increases in mRNA levels of several IEGs in both genotypes. Interestingly, HDAC2KO mice displayed greater METH-induced increases in Egr1 and Egr2 mRNA levels measured at one hour post-injection. The levels of Fosb, Fra2, Egr1, and Egr3 mRNAs stayed elevated in the HDAC2KO mice 2 hours after the METH injection whereas these mRNAs had normalized in the WT mice. In WT mice, METH caused increased HDAC2 recruitment to the promoters some IEGs at 2 hours post injection. METH-induced prolonged increases in Fosb, Fra2, Egr1, and Egr3 mRNA levels in HDAC2KO mice were associated with increased enrichment of phosphorylated CREB (pCREB) on the promoters of these genes. Based on our observations, we hypothesize that HDAC2 may regulate the expression of these genes, in part, by prolonging the actions of pCREB in the mouse NAc. PMID:26300473

  14. Survival, Differentiation, and Migration of High-Purity Mouse Embryonic Stem Cell-derived Progenitor Motor Neurons in Fibrin Scaffolds after Sub-Acute Spinal Cord Injury.

    PubMed

    McCreedy, D A; Wilems, T S; Xu, H; Butts, J C; Brown, C R; Smith, A W; Sakiyama-Elbert, S E

    2014-11-01

    Embryonic stem (ES) cells can be differentiated into many neural cell types that hold great potential as cell replacement therapies following spinal cord injury (SCI). Coupling stem cell transplantation with biomaterial scaffolds can produce a unified combination therapy with several potential advantages including enhanced cell survival, greater transplant retention, reduced scarring, and improved integration at the transplant/host interface. Undesired cell types, however, are commonly present in ES-cell derived cultures due to the limited efficiency of most ES cell induction protocols. Heterogeneous cell populations can confound the interaction between the biomaterial and specific neural populations leading to undesired outcomes. In particular, biomaterials scaffolds may enhance tumor formation by promoting survival and proliferation of undifferentiated ES cells that can persist after induction. Methods for purification of specific ES cell-derived neural populations are necessary to recognize the full potential of combination therapies involving biomaterials and ES cell-derived neural populations. We previously developed a method for enriching ES cell-derived progenitor motor neurons (pMNs) induced from mouse ES cells via antibiotic selection and showed that the enriched cell populations are depleted of pluripotent stem cells. In this study, we demonstrate the survival and differentiation of enriched pMNs within three dimensional (3D) fibrin scaffolds in vitro and when transplanted into a sub-acute dorsal hemisection model of SCI into neurons, oligodendrocytes and astrocytes. PMID:25346848

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

    PubMed Central

    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

  16. QUILT-2.014: Gemcitabine and AMG 479 in Metastatic Adenocarcinoma of the Pancreas

    ClinicalTrials.gov

    2016-10-26

    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

  17. 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

  18. 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

  19. 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

  20. 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

  1. 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.

  2. Hormone-dependent expression of a steroidogenic acute regulatory protein natural antisense transcript in MA-10 mouse tumor Leydig cells.

    PubMed

    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.

  3. Circumportal pancreas with retroportal main pancreatic duct.

    PubMed

    Hashimoto, Yasushi; Ross, Andrew S; Traverso, L William

    2009-08-01

    There have been 6 cases of circumportal pancreas reported, and 2 of them had the main pancreatic duct in a retroportal dorsal portion. This extremely uncommon anomaly is asymptomatic and therefore incidentally discovered. For the surgeon, it is important to discover this during pancreatic resection so the pancreatic duct can be closed and fistula is avoided. We describe the third case where a circumportal pancreas had its main pancreatic duct passing under the portal vein. The duct was identified and ligated. A fistula did not occur.

  4. The first simultaneous kidney-adrenal gland-pancreas transplantation: outcome at 1 year.

    PubMed

    Vouillarmet, J; Buron, F; Houzard, C; Carlier, M C; Chauvet, C; Brunet, M; Thivolet, C; Morelon, E; Badet, L

    2013-07-01

    Adrenal insufficiency is a rare but life-threatening disease. Replacement therapy sometimes fails to prevent an acute adrenal crisis and most often does not lead to restoration of well-being. We report here the 1-year outcome of the first simultaneous kidney-adrenal gland-pancreas transplantation in a 33-year-old patient with type 1 diabetes and concomitant autoimmune adrenal insufficiency. En bloc left adrenal gland and kidney grafts were anastomosed on the left iliac vessels in normal vascular conditions and the pancreas graft was anastomosed on the right iliac vessels. The immunosuppressive regimen was not modified by the addition of the adrenal gland. We observed no additional morbidity due to the adrenal gland transplantation, as there were no surgical complications. One-year kidney and pancreas graft functions were satisfactory (estimated glomerular filtration rate: 55 mL/min/1.73 m(2) and HbA1c: 4.8%). The adrenal graft functioned well at 12 months with a normalization of cortisol and aldosterone baseline levels. Functional imaging at 3 months showed good uptake of [(123) I]-metaiodobenzylguanidine by the adrenal graft. Transplantation of the adrenal gland en bloc with the left kidney appears to be a good therapeutic option in patients with adrenal insufficiency awaiting kidney or kidney-pancreas transplantation.

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

    PubMed

    Caron, K M; Soo, S C; Wetsel, W C; Stocco, D M; Clark, B J; Parker, K L

    1997-10-14

    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.

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

    PubMed

    Marschner, Julian A; Schäfer, Hannah; 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.

  7. 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.

  8. [Endoscopic ultrasonography in diagnosis of surgical treatment of pancreas].

    PubMed

    Starkov, Iu G; Solodinina, E N; Shishin, K V; Plotnikova, L S

    2008-01-01

    Results of endoscopic ultrasonography at 137 patients suspected for pancreas pathology are analyzed. Methodology of endoscopic ultrasonography, semiotics of pancreas surgical diseases, advantages over other diagnostic methods are described. Endosonography is informative method for final diagnosis of different disease of pancreas. Diagnostic value of method and area of its clinical application are described.

  9. Spatiotemporal proteomic analyses during pancreas cancer progression identifies serine/threonine stress kinase 4 (STK4) as a novel candidate biomarker for early stage disease.

    PubMed

    Mirus, Justin E; Zhang, Yuzheng; Hollingsworth, Michael A; Solan, Joell L; Lampe, Paul D; Hingorani, Sunil R

    2014-12-01

    Pancreas cancer, or pancreatic ductal adenocarcinoma, is the deadliest of solid tumors, with a five-year survival rate of <5%. Detection of resectable disease improves survival rates, but access to tissue and other biospecimens that could be used to develop early detection markers is confounded by the insidious nature of pancreas cancer. Mouse models that accurately recapitulate the human condition allow disease tracking from inception to invasion and can therefore be useful for studying early disease stages in which surgical resection is possible. Using a highly faithful mouse model of pancreas cancer in conjunction with a high-density antibody microarray containing ∼2500 antibodies, we interrogated the pancreatic tissue proteome at preinvasive and invasive stages of disease. The goal was to discover early stage tissue markers of pancreas cancer and follow them through histologically defined stages of disease using cohorts of mice lacking overt clinical signs and symptoms and those with end-stage metastatic disease, respectively. A panel of seven up-regulated proteins distinguishing pancreas cancer from normal pancreas was validated, and their levels were assessed in tissues collected at preinvasive, early invasive, and moribund stages of disease. Six of the seven markers also differentiated pancreas cancer from an experimental model of chronic pancreatitis. The levels of serine/threonine stress kinase 4 (STK4) increased between preinvasive and invasive stages, suggesting its potential as a tissue biomarker, and perhaps its involvement in progression from precursor pancreatic intraepithelial neoplasia to pancreatic ductal adenocarcinoma. Immunohistochemistry of STK4 at different stages of disease revealed a dynamic expression pattern further implicating it in early tumorigenic events. Immunohistochemistry of a panel of human pancreas cancers confirmed that STK4 levels were increased in tumor epithelia relative to normal tissue. Overall, this integrated approach

  10. Cytotoxic Capacity of IL-15-Stimulated Cytokine-Induced Killer Cells Against Human Acute Myeloid Leukemia and Rhabdomyosarcoma in Humanized Preclinical Mouse Models

    PubMed Central

    Rettinger, Eva; Meyer, Vida; Kreyenberg, Hermann; Volk, Andreas; Kuçi, Selim; Willasch, Andre; Koscielniak, Ewa; Fulda, Simone; Wels, Winfried S.; Boenig, Halvard; Klingebiel, Thomas; Bader, Peter

    2012-01-01

    Allogeneic stem cell transplantation (allo-SCT) has become an important treatment modality for patients with high-risk acute myeloid leukemia (AML) and is also under investigation for soft tissue sarcomas. The therapeutic success is still limited by minimal residual disease (MRD) status ultimately leading to patients’ relapse. Adoptive donor lymphocyte infusions based on MRD status using IL-15-expanded cytokine-induced killer (CIK) cells may prevent relapse without causing graft-versus-host-disease (GvHD). To generate preclinical data we developed mouse models to study anti-leukemic- and anti-tumor-potential of CIK cells in vivo. Immunodeficient mice (NOD/SCID/IL-2Rγc−, NSG) were injected intravenously with human leukemic cell lines THP-1, SH-2 and with human rhabdomyosarcoma (RMS) cell lines RH41 and RH30 at minimal doses required for leukemia or tumor engraftment. Mice transplanted with THP-1 or RH41 cells were randomly assigned for analysis of CIK cell treatment. Organs of mice were analyzed by flow cytometry as well as quantitative polymerase chain reaction for engraftment of malignant cells and CIK cells. Potential of CIK cells to induce GvHD was determined by histological analysis. Tissues of the highest degree of THP-1 cell expansion included bone marrow followed by liver, lung, spleen, peripheral blood (PB), and brain. RH30 and RH41 engraftment mainly took place in liver and lung, but was also detectable in spleen and PB. In spite of delayed CIK cell expansion compared with malignant cells, CIK cells injected at equal amounts were sufficient for significant reduction of RH41 cells, whereas against fast-expanding THP-1 cells 250 times more CIK than THP-1 cells were needed to achieve comparable results. Our preclinical in vivo mouse models showed a reliable 100% engraftment of malignant cells which is essential for analysis of anti-cancer therapy. Furthermore our data demonstrated that IL-15-activated CIK cells have potent cytotoxic capacity against AML

  11. New variant for whole pancreas grafting

    SciTech Connect

    Kootstra, G.; van Hooff, J.P.; Joerning, P.J.L.; Leunissen, K.M.; van der Linden, C.J.; Beukers, E.; Buurman, W.A.

    1987-02-01

    A new variant for whole pancreas grafting is described in which a segment of the duodenum and the spleen is included in the graft. The graft is placed extraperitoneally as in kidney transplantation. The exocrine drainage is with side-to-side anastomosis between duodenum and bladder. The spleen is irradiated to prevent the occurrence of GVHD, as is reported in splenic transplantation.

  12. [Sonographic topography of the pancreas (author's transl)].

    PubMed

    Triller, J

    1978-07-01

    Vascular abdominal structures can be demonstrated by the gray-scale-B-scan-technique. These vascular anatomical structures are important to differentiate pathological lesions from normal structures and to evaluate the localisation of space occupying lesions within the pancreas, liver and retroperitoneal space.

  13. 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.

  14. No influence of acute RF exposure (GSM-900, GSM-1800, and UMTS) on mouse retinal ganglion cell responses under constant temperature conditions.

    PubMed

    Ahlers, Malte T; Ammermüller, Josef

    2014-01-01

    Possible non-thermal effects of radio frequency electromagnetic fields (RF-EMF) on retinal ganglion cells were studied in vitro under conditions of constant temperature. Isolated mouse retinae were exposed to GSM-900, GSM-1800, and universal mobile telecommunication system (UMTS) RF-EMF applying specific absorption rates (SAR) of 0 (sham), 0.02, 0.2, 2, and 20 W/kg. Temperature was kept constant within ±0.5 to 1 °C for GSM-900 and ±0.5 °C for GSM-1800 and UMTS. Responses of retinal ganglion cells to light stimuli of three intensities (0.5, 16, and 445 lx) were recorded before, during, and up to 35 min after exposure. Experiments were performed under double-blind conditions. Changes in light responses during and after exposure were determined for each condition (RF-EMF; SAR value; light intensity) with respect to the responses before exposure, respectively. Changes were calculated using the Euclidian distance of the n-dimensional response vectors, respectively. Some changes already occurred during sham (0 W/kg) exposure, reflecting the intrinsic variability in retinal ganglion cell responses. Comparison of the distance values from sham exposure with those from actual exposure yielded no significant differences. In addition, linear regression analysis of the distance values versus SAR values yielded no consistent dependence of light response changes. From these results we conclude that RF-EMF exposure at three mobile phone frequencies (GSM-900, GSM-1800, UMTS) and SARs up to 20 W/kg has no acute effects on retinal ganglion cell responses under constant temperature conditions.

  15. Formation of Collateral Veins in a Graft Pancreas After a Simultaneous Pancreas and Kidney Transplantation: A Case Report.

    PubMed

    Choi, B H; Lee, H Y; Park, Y M; Yang, K H; Ryu, J H; Chu, C W

    2015-09-01

    A graft vein thrombosis is the main cause of early graft failure after pancreas transplantation. We report a case of formation of collateral veins in a graft pancreas after transplant. A 30-year-old woman underwent simultaneous pancreas and kidney transplantation. She was discharged 16 days after the operation with good pancreas and kidney function. A total occlusion of the portal vein was discovered on computed tomography (CT) performed at an outpatient clinic. She had no symptoms or signs of hyperglycemia. Venography was attempted for vein thrombectomy but failed. After 2 weeks of heparinization therapy, the edema disappeared and perfusion of the graft pancreas improved. However, the thrombotic occlusion was not resolved on CT. Arteriography of the Y-graft revealed collateral veins. She was discharged with warfarin. She is currently doing well without any symptoms or signs. This is the first reported case of collateral vein formation in a grafted pancreas after pancreas transplantation.

  16. Solitary fibrous tumor of the pancreas.

    PubMed

    Sugawara, Yoshifumi; Sakai, Shinya; Aono, Shoji; Takahashi, Tadaaki; Inoue, Takeshi; Ohta, Koji; Tanada, Minoru; Teramoto, Norihiro

    2010-07-01

    A solitary fibrous tumor (SFT) originating in the pancreas is rare. We report a 55-year-old woman with an asymptomatic pancreatic mass incidentally discovered on abdominal ultrasonography. Contrast-enhanced computed tomography (CT) showed a well-demarcated exophytic mass in the pancreatic head with prolonged and delayed enhancement. The mass showed hypointensity on T1-weighted images and heterogeneous hypointensity with spotty hyperintensity foci on T2-weighted images. Fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT showed no significant FDG uptake. The resected mass was composed of spindle cells that were positive for CD34; and hemangiopericytomatous vessels were focally detected. The mass was finally diagnosed as an SFT of the pancreas.

  17. Pancreas transplants: Evaluation using perfusion scintigraphy

    SciTech Connect

    Kuni, C.C.; du Cret, R.P.; Boudreau, R.J.

    1989-07-01

    To determine the value of scintigraphic perfusion studies in evaluating pancreas transplant patients, we reviewed 56 of these studies in 22 patients who had 27 transplants. Seventeen patients underwent two or more studies. The perfusion studies were performed with 20 mCi (740 MBq) of 99mTc-DTPA injected as a bolus followed by eight to 16 serial 2-sec images and a 500,000-count immediate static image. Images were evaluated for (1) the time and intensity of pancreatic peak radioactivity relative to the time and intensity of the iliac arterial peak; (2) relative pancreatic to iliac arterial intensity on the static image; and (3) size, homogeneity, and definition of the pancreas. Clinical diagnoses at the time of scintigraphy of normal function (n = 36), rejection (n = 13), pancreatitis (n = 6), or arterial thrombosis (n = 1) were based on insulin requirement, urine amylase, serum glucose, serum amylase, response to therapy, cultures, CT, MR, sonography, scintigraphy with 67Ga or 111In-WBCs, percutaneous drainage results, angiography, surgery, and pathologic examination of resected transplants. Three 99mTc-DTPA perfusion studies showed no pancreatic perfusion, four showed decreasing perfusion on serial studies, and five showed progressive loss of definition of the pancreas on serial studies. Of the three patients with no detectable perfusion, one had a normally functioning transplant, one had arterial thrombosis with transplant infarction, and one had severe rejection with minimal function. Decreasing perfusion was associated with rejection in three patients and pancreatitis in one. Decreasing definition was seen in four patients with rejection and one with pancreatitis. We conclude that perfusion scintigraphy is useful, primarily when performed serially, although nonspecific for evaluating pancreas transplants.

  18. 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

  19. Pancreas sparing duodenectomy as an emergency procedure

    PubMed Central

    Paluszkiewicz, Piotr; Dudek, Wojciech; Lowery, Kathryn; Hart, Colin A

    2009-01-01

    Background The operative techniques to close extensive wounds to the duodenum are well described. However, postoperative morbidity is common and includes suture line leak and the formation of fistulae. The aim of this case series is to present pancreas sparing duodenectomy as a safe and viable alternative procedure in the emergency milieu. Methods Five patients underwent emergency pancreas sparing duodenal excisions. Re-implantation of the papilla of Vater or the papilla with a surrounding mucosal patch was performed in two patients. In one, the procedure was further supplemented with a duodenocholangiostomy, stapled pyloric exclusion and enterogastrostomy to defunction the pylorus. In another three patients, distal duodenal excisions were done. Results In four patients, an uneventful recovery was made. One patient died following a myocardial infarction. The surgery lasted meanly 160 minutes with average blood loss of approximately 500 milliliters. The mean hospital stay was 12 days. Enteral nutrition was introduced within the 20 hours after the surgery. Long term follow-up of all surviving patients confirmed a good outcome and normal nutritional status. Conclusion Based on the presented series of patients, we suggest that pancreas-sparing duodenectomy can be considered in selected patients with laceration of the duodenum deemed unsuitable for surgical reconstruction. PMID:19445694

  20. Stereological analyses of the whole human pancreas

    PubMed Central

    Poudel, Ananta; Fowler, Jonas L.; Zielinski, Mark C.; Kilimnik, German; Hara, Manami

    2016-01-01

    The large size of human tissues requires a practical stereological approach to perform a comprehensive analysis of the whole organ. We have developed a method to quantitatively analyze the whole human pancreas, as one of the challenging organs to study, in which endocrine cells form various sizes of islets that are scattered unevenly throughout the exocrine pancreas. Furthermore, the human pancreas possesses intrinsic characteristics of intra-individual variability, i.e. regional differences in endocrine cell/islet distribution, and marked inter-individual heterogeneity regardless of age, sex and disease conditions including obesity and diabetes. The method is built based on large-scale image capture, computer-assisted unbiased image analysis and quantification, and further mathematical analyses, using widely-used software such as Fiji/ImageJ and MATLAB. The present study includes detailed protocols of every procedure as well as all the custom-written computer scripts, which can be modified according to specific experimental plans and specimens of interest. PMID:27658965

  1. 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

  2. Pancreas Transplantation: Solid Organ and Islet

    PubMed Central

    Mittal, Shruti; Johnson, Paul; Friend, Peter

    2014-01-01

    Transplantation of the pancreas, either as a solid organ or as isolated islets of Langerhans, is indicated in a small proportion of patients with insulin-dependent diabetes in whom severe complications develop, particularly severe glycemic instability and progressive secondary complications (usually renal failure). The potential to reverse diabetes has to be balanced against the morbidity of long-term immunosuppression. For a patient with renal failure, the treatment of choice is often a simultaneous transplant of the pancreas and kidney (SPK), whereas for a patient with glycemic instability, specifically hypoglycemic unawareness, the choice between a solid organ and an islet transplant has to be individual to the patient. Results of SPK transplantation are comparable to other solid-organ transplants (kidney, liver, heart) and there is evidence of improved quality of life and life expectancy, but the results of solitary pancreas transplantation and islets are inferior with respect to graft survival. There is some evidence of benefit with respect to the progression of secondary diabetic complications in patients with functioning transplants for several years. PMID:24616200

  3. An Integrated Multivariable Artificial Pancreas Control System

    PubMed Central

    Turksoy, Kamuran; Quinn, Lauretta T.; Littlejohn, Elizabeth

    2014-01-01

    The objective was to develop a closed-loop (CL) artificial pancreas (AP) control system that uses continuous measurements of glucose concentration and physiological variables, integrated with a hypoglycemia early alarm module to regulate glucose concentration and prevent hypoglycemia. Eleven open-loop (OL) and 9 CL experiments were performed. A multivariable adaptive artificial pancreas (MAAP) system was used for the first 6 CL experiments. An integrated multivariable adaptive artificial pancreas (IMAAP) system consisting of MAAP augmented with a hypoglycemia early alarm system was used during the last 3 CL experiments. Glucose values and physical activity information were measured and transferred to the controller every 10 minutes and insulin suggestions were entered to the pump manually. All experiments were designed to be close to real-life conditions. Severe hypoglycemic episodes were seen several times during the OL experiments. With the MAAP system, the occurrence of severe hypoglycemia was decreased significantly (P < .01). No hypoglycemia was seen with the IMAAP system. There was also a significant difference (P < .01) between OL and CL experiments with regard to percentage of glucose concentration (54% vs 58%) that remained within target range (70-180 mg/dl). Integration of an adaptive control and hypoglycemia early alarm system was able to keep glucose concentration values in target range in patients with type 1 diabetes. Postprandial hypoglycemia and exercise-induced hypoglycemia did not occur when this system was used. Physical activity information improved estimation of the blood glucose concentration and effectiveness of the control system. PMID:24876613

  4. An integrated multivariable artificial pancreas control system.

    PubMed

    Turksoy, Kamuran; Quinn, Lauretta T; Littlejohn, Elizabeth; Cinar, Ali

    2014-05-01

    The objective was to develop a closed-loop (CL) artificial pancreas (AP) control system that uses continuous measurements of glucose concentration and physiological variables, integrated with a hypoglycemia early alarm module to regulate glucose concentration and prevent hypoglycemia. Eleven open-loop (OL) and 9 CL experiments were performed. A multivariable adaptive artificial pancreas (MAAP) system was used for the first 6 CL experiments. An integrated multivariable adaptive artificial pancreas (IMAAP) system consisting of MAAP augmented with a hypoglycemia early alarm system was used during the last 3 CL experiments. Glucose values and physical activity information were measured and transferred to the controller every 10 minutes and insulin suggestions were entered to the pump manually. All experiments were designed to be close to real-life conditions. Severe hypoglycemic episodes were seen several times during the OL experiments. With the MAAP system, the occurrence of severe hypoglycemia was decreased significantly (P < .01). No hypoglycemia was seen with the IMAAP system. There was also a significant difference (P < .01) between OL and CL experiments with regard to percentage of glucose concentration (54% vs 58%) that remained within target range (70-180 mg/dl). Integration of an adaptive control and hypoglycemia early alarm system was able to keep glucose concentration values in target range in patients with type 1 diabetes. Postprandial hypoglycemia and exercise-induced hypoglycemia did not occur when this system was used. Physical activity information improved estimation of the blood glucose concentration and effectiveness of the control system.

  5. [Tomodensitometry of severe acute pancreatitis].

    PubMed

    Frija, J; Abanou, A; Viandier, A; Laval-Jeantet, M

    1983-01-01

    90 computed tomographic examinations were performed to 57 patients referred at Hospital Saint-Louis for an acute pancreatitis. 32 patients were operated or autopsied. Among these 32 patients, 19 patients had 21 examinations before surgery or autopsy; the other 13 patients had their computed tomographic examinations after one or more surgical procedures. During a severe acute pancreatitis the pancreas is always large either locally or diffusely. A pancreatic reaction is visible around and possibly at distance of the pancreas. When extraluminal gas is visible (3/5) it signifies gangrenous pancreatitis but it is necessary to eliminate a digestive fistulous tract and/or a communication between a pseudocyst and the digestive tract. Except gangrenous it is not possible to precise the nature of pancreatic reaction. The diagnosis of pseudocyst was easy 9/10, difficult 1/10; we did a false positive diagnosis of pseudocyst. Computed tomography and ultrasounds were compared in ten patients for the search of gallbladder lithiasis. Computed tomography can show large and small (2/4) biliary calculus in the gallbladder that cannot be shown by ultrasounds. A normal pancreas in a normal retroperitoneal space exclude the diagnosis of a severe acute pancreatitis. CT aspects of acute pancreatitis must be considered as a good diagnostic test of an acute pancreatitis.

  6. 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

  7. 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

  8. GPRC6A Mediates Responses to Osteocalcin in β-Cells In Vitro and Pancreas In Vivo

    PubMed Central

    Pi, Min; Wu, Yunpeng; Quarles, L Darryl

    2016-01-01

    A bone-pancreas endocrine loop has been identified recently that involves insulin secreted from β-cells in the pancreas stimulating insulin receptors in osteoblasts, leading to osteoblastic differentiation and increased secretion of osteocalcin (Ocn), a bone-derived hormone that regulates insulin secretion in β-cells. The identity of the Ocn-sensing receptor in β-cells is a missing component of this endocrine loop. The abnormalities in glucose homeostasis in Gprc6a null mice suggests that this pertussis toxin–sensitive G protein– coupled receptor is a candidate for mediating the effects of Ocn on insulin secretion in the pancreas. In support of this possibility, we found that transfection of non-Gprc6a-expressing HEK-293 cells with a full-length Gprc6a cDNA imparted a dose-dependent response to Ocn (5 to 60 ng/mL), as measured by PKD1 and ERK phosphorylation. In addition, Gprc6a is highly expressed in mouse pancreatic tissue and in the mouse TC-6 pancreatic β-cell line. Ocn also stimulated ERK activity in TC-6 pancreatic β-cells. Finally, intraperitoneal injection of Ocn stimulated ERK activity in the pancreas and increased serum insulin levels in wild-type mice, but these responses were markedly attenuated in Gprc6a−/− mice. These findings suggest that GPRC6A is a candidate for mediating the response to Ocn in the bone-pancreas endocrine loop regulating insulin signaling. PMID:21425331

  9. 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

  10. 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

  11. 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

  12. 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

  13. Human pancreas scintigraphy using iodine-123-labeled HIPDM and SPECT

    SciTech Connect

    Yamamoto, K.; Shibata, T.; Saji, H.; Kubo, S.; Aoki, E.; Fujita, T.; Yonekura, Y.; Konishi, J.; Yokoyama, A. )

    1990-06-01

    The pancreatic affinity of iodine-123-labeled HIPDM (N,N,N'-trimethyl-N'-(2-hydroxy-3-methyl-5-iodobenzyl)-1,3-propane diamine) (({sup 123}I)HIPDM) was studied in 18 cases (5 normal volunteers, 7 cases with pancreas cancer, and 6 with chronic pancreatitis). In the normal cases, the pancreas was visualized in the planar images as early as 3 hr, and again at 20 hr postinjection. Single-photon emission computed tomography (SPECT) performed following 3-hr planar scintigraphy, provided excellent pancreas images without an overlap of activity in the liver or spleen. The mean pancreas-to-liver (P/L) ratio was 1.26 +/- 0.22 in normal controls. With the exception of one case of massive calcification in the pancreas, the entire pancreas could be observed in the cases with chronic pancreatitis, but the P/L ratio was 0.74 +/- 0.15, significantly lower than that of normal cases. Defective areas of the distal portion of the pancreas were clearly seen in those with cancer of the pancreas. The results of our study indicate that ({sup 123}I) HIPDM may have clinical potential as a human pancreas imaging agent.

  14. 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

  15. Role of early systemic inflammatory response in simultaneous pancreas-kidney transplantation.

    PubMed

    Piros, L; Fazakas, J; Smudla, A; Földes, K; Langer, R M

    2012-09-01

    Pancreas grafts are susceptible to surgical complications mostly related to exocrine secretions and the low microcirculatory blood flow through the gland. During simultaneous kidney-pancreas transplantation, the systemic response depends on reperfusion of two organs acute graft pancreatitis, immunotherapy, coagulopathy, bleeding, and other factors. We performed a retrospective review of 10 adult simultaneous pancreas-kidney transplant patients to evaluate progression of early postoperative inflammation in the absence of infection. All patients were treated with four-drug therapy. We performed analyses of procalcitonin (PCT), C-reactive protein, serum creatinine, amylase, and lipase levels over the first 5 postoperative days. Relatively high peak PCT levels (maximum 130 ng/mL) were reached within 24 to 48 hours postoperatively followed by a moderate decrease. Consistent with this observation, the serum creatinine, amylase, and lipase levels decreased continuously to normal concentrations within the first week. The increased PCT levels seemed depend upon the surgical procedure and intraoperative events. PCT was superior to C-reactive protein to discriminate infection from inflammation in this setting. The dynamics of PCT levels, rather than absolute values, seemed to be important. Lack of a decrease in PCT levels after the peak, suggested an infectious complication or the development of sepsis. Monitoring and assessment of PCT levels may help in early recognition of infection and institution of therapy.

  16. 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

  17. Endoscopic Stenting and Sphincterotomy of the Minor Papilla in Symptomatic Pancreas Divisum: Results and Complications

    PubMed Central

    Cohen, Seth A.; Rutkovsky, Frederick D.; Kasmin, Franklin E.

    1995-01-01

    Pancreas divisum has been postulated as a cause of acute pancreatitis and a chronic pain syndrome in a small subgroup of patients and can be treated with endoscopic dorsal pancreatic duct stent placement and minor papilla sphincterotomy. Twenty patients (9 with at least one attack of idiopathic pancreatitis, and 11 with severe pancreatic-type pain) were treated endoscopically. Dorsal duct stents were placed in 19 patients with subsequent needle knife sphincterotomy of the minor papilla over the stent. Clinical response was judged by comparison of symptoms (using a 0-to-l0 scale and the patient's overall assessment). The symptom score improved from 9.3 to 5.1 in the pancreatitis group and from 9.3 to 5.7 in the pain group. A good clinical response was observed in 3 of 7 patients in the pancreatitis group and in 6 of 11 in the pain group at a mean follow-up of 22 months. Complications of sphincterotomy were limited to pancreatitis in 6 patients (29%), 5 mild and 1 moderate according to published criteria. No patient required more than 4 days hospitalization. Two of 39 stents migrated into the pancreas, and another stent fractured and remained lodged in the pancreas. Eight of 9 patients evaluated demonstrated new morphologic duct changes on follow-up pancreatograms. Endoscopic stenting and sphincterotomy of the minor papilla are feasible and may be effective in some patients with pancreas divisum but carries a significant complication rate. The subjective improvement in patients with chronic pain warrants further controlled study. PMID:18493355

  18. 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

  19. Isolation of the murine ribonuclease gene Rib-1: structure and tissue specific expression in pancreas and parotid gland.

    PubMed Central

    Samuelson, L C; Wiebauer, K; Howard, G; Schmid, R M; Koeplin, D; Meisler, M H

    1991-01-01

    The mouse pancreatic ribonuclease gene Rib-1 was isolated from a library of mouse genomic DNA and sequenced. This small gene contains a nontranslated exon of 52 base pairs, an intron of 791 base pairs, and a coding exon of 741 base pairs. Rib-1 transcripts were detected in parotid gland as well as in pancreas. The abundance of the transcripts were approximately 200-fold greater in pancreatic RNA than in parotid RNA. The sites of transcription initiation were mapped by primer extension and ribonuclease protection assays. One major initiation site and several minor initiation sites were identified in pancreatic RNA. Transcription in parotid appears to be initiated from the same sites. Parotid-specific transcripts were not detected. The data suggest that Rib-1 is transcribed in pancreas and parotid from the same promoter. This is in contrast with the mechanism for production of amylase in pancreas and parotid, which is accomplished by tissue specific expression of different gene copies. Images PMID:1840677

  20. Malignant Solitary Fibrous Tumor of the Pancreas.

    PubMed

    Estrella, Jeannelyn S; Wang, Huamin; Bhosale, Priya R; Evans, Harry L; Abraham, Susan C

    2015-08-01

    Solitary fibrous tumor (SFT) arising in the pancreas is exceedingly rare, with only 11 cases reported in the English literature. All cases described thus far have exhibited benign histology. We report the first case of malignant SFT of the pancreas. The patient was a 52-year-old woman who presented with obstructive jaundice and a 15-cm pancreatic head mass. The mass showed areas with typical histologic features for SFT including small fibroblastlike cells arranged in the well-characterized "patternless pattern" of architecture, hemangiopericytomalike vessels, areas with dense collagen and infrequent mitoses (0-2 per 10 high-power fields [HPFs]). In addition, multiple areas with an overtly sarcomatous morphology were present, containing large spindle and epithelioid cells with nuclear pleomorphism, marked cellularity, up to17 mitoses per 10 HPFs, and necrosis. Immunohistochemical stains were positive for CD34 and B-cell CLL/lymphoma 2 (Bcl-2) in both benign and malignant components and showed strong, diffuse p53 and p16 staining in the malignant component. At last follow-up (40 months), the patient was alive and well without evidence of disease. However, given that the presence of a malignant component in extrapancreatic SFT has been associated with recurrence/metastasis and death, complete surgical resection and close long-term follow-up is required.

  1. 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.

  2. Malignant Solitary Fibrous Tumor of the Pancreas.

    PubMed

    Estrella, Jeannelyn S; Wang, Huamin; Bhosale, Priya R; Evans, Harry L; Abraham, Susan C

    2015-08-01

    Solitary fibrous tumor (SFT) arising in the pancreas is exceedingly rare, with only 11 cases reported in the English literature. All cases described thus far have exhibited benign histology. We report the first case of malignant SFT of the pancreas. The patient was a 52-year-old woman who presented with obstructive jaundice and a 15-cm pancreatic head mass. The mass showed areas with typical histologic features for SFT including small fibroblastlike cells arranged in the well-characterized "patternless pattern" of architecture, hemangiopericytomalike vessels, areas with dense collagen and infrequent mitoses (0-2 per 10 high-power fields [HPFs]). In addition, multiple areas with an overtly sarcomatous morphology were present, containing large spindle and epithelioid cells with nuclear pleomorphism, marked cellularity, up to17 mitoses per 10 HPFs, and necrosis. Immunohistochemical stains were positive for CD34 and B-cell CLL/lymphoma 2 (Bcl-2) in both benign and malignant components and showed strong, diffuse p53 and p16 staining in the malignant component. At last follow-up (40 months), the patient was alive and well without evidence of disease. However, given that the presence of a malignant component in extrapancreatic SFT has been associated with recurrence/metastasis and death, complete surgical resection and close long-term follow-up is required. PMID:26166470

  3. 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

  4. Purinergic signalling in the pancreas in health and disease.

    PubMed

    Burnstock, G; Novak, I

    2012-05-01

    Pancreatic cells contain specialised stores for ATP. Purinergic receptors (P2 and P1) and ecto-nucleotidases are expressed in both endocrine and exocrine calls, as well as in stromal cells. The pancreas, especially the endocrine cells, were an early target for the actions of ATP. After the historical perspective of purinergic signalling in the pancreas, the focus of this review will be the physiological functions of purinergic signalling in the regulation of both endocrine and exocrine pancreas. Next, we will consider possible interaction between purinergic signalling and other regulatory systems and their relation to nutrient homeostasis and cell survival. The pancreas is an organ exhibiting several serious diseases - cystic fibrosis, pancreatitis, pancreatic cancer and diabetes - and some are associated with changes in life-style and are increasing in incidence. There is upcoming evidence for the role of purinergic signalling in the pathophysiology of the pancreas, and the new challenge is to understand how it is integrated with other pathological processes.

  5. [Acute pancreatitis in the sequestration phase].

    PubMed

    Filin, V I; Spassakaia, M G; Chumak, P Ia

    1975-07-01

    Pathoanatomical, pathogenetic and clinical characteristics of acute pancreatitis in a sequestration phase are given. Under observation were 95 patients with purulentputrid sequestration of the pancreas and retroperitoneal cellular tissue and 20 patients with postnecrotic pancreatic cysts. Some features of the operative treatment in different kinds of sequestration are described.

  6. Effects of the GLP-1 Receptor Agonist Dulaglutide on the Structure of the Exocrine Pancreas of Cynomolgus Monkeys.

    PubMed

    Vahle, John L; Byrd, Richard A; Blackbourne, Jamie L; Martin, Jennifer A; Sorden, Steven D; Ryan, Thomas; Pienkowski, Thomas; Rosol, Thomas J; Snyder, Paul W; Klöppel, Günter

    2015-10-01

    Clinical and nonclinical studies have implicated glucagon-like peptide-1 (GLP-1) receptor agonist therapy as a risk factor for acute pancreatitis in patients with type 2 diabetes. Therefore, it is critical to understand the effect that dulaglutide, an approved GLP-1 receptor agonist, has on the exocrine pancreas. Dulaglutide 8.15 mg/kg (approximately 500 times the maximum recommended human dose based on plasma exposure) was administered twice weekly for 12 months to cynomolgus monkeys. Serum amylase and lipase activities were measured and 6 sections of each pancreas were examined microscopically. Ductal epithelial cell proliferation was estimated using Ki67 labeling. Dulaglutide administration did not alter serum amylase or lipase activities measured at the end of treatment compared to control values. An extensive histologic evaluation of the pancreas revealed no changes in the acinar or endocrine portions and no evidence of pancreatitis, necrosis, or pancreatic intraepithelial neoplasia. An increase in goblet cells noted in 4 of the 19 treated monkeys was considered an effect of dulaglutide but was not associated with dilation, blockage, or accumulation of mucin in the pancreatic duct. There was no difference in cell proliferation in ductal epithelium between control and dulaglutide-treated monkeys. These data reveal that chronic dosing of nondiabetic primates with dulaglutide does not induce inflammatory or preneoplastic changes in exocrine pancreas.

  7. [Effect of oxygen free radicals on the rat pancreas in vivo].

    PubMed

    Tamura, K; Manabe, T; Tobe, T

    1991-09-01

    Many reports concerning the involvement of active oxygen free radicals in the pathogenesis and progression of acute pancreatitis have been published. In this study, the direct toxic effect of active oxygen free radicals on the rat pancreas was evaluated in vivo. Superoxide anions, generated via the xanthine/xanthine oxidase (X/XO) system, and hydrogen peroxide (H2O2) were used. After continuous arterial injection of X/XO into the celiac artery hemorrhage and extensive edema developed. However, additional continuous injection of superoxide dismutase (SOD) into the external jugular vein completely suppressed the hemorrhage and relieved the edema. When hydrogen peroxide (100 microM/Kg/hour) was injected continuously through the celiac artery made hemorrhage and edema were recognized in the pancreas, both of which were suppressed by continuous injection of catalase (10 mg/Kg/hour) or gabexate mesilate (10 mg/Kg/hour) into the external jugular vein. The amylase and lipase levels in the intraperitoneal fluid rose to more than 10 times the preoperative values 5 hours after drug administration. These levels were lowered to 2 times the preoperative values by the continuous venous injection of SOD or catalase (which are specific scavengers of superoxide anions or hydrogen peroxide, respectively) or by gabexate mesilate. On the other hand, serum amylase and lipase levels remained almost constant throughout the entire experiment. Thus, the administration of active oxygen free radicals caused acute pancreatitis, which was suppressed by the systemic administration of specific scavengers for each free radical. Active oxygen free radicals were shown to have a direct, toxic effect on the pancreas.

  8. Beneficial effects of trypsin inhibitors derived from a spider venom peptide in L-arginine-induced severe acute pancreatitis in mice.

    PubMed

    Ning, Weiwen; Wang, Yongjun; Zhang, Fan; Wang, Hengyun; Wang, Fan; Wang, Xiaojuan; Tang, Huaxin; Liang, Songping; Shi, Xiaoliu; Liu, Zhonghua

    2013-01-01

    HWTI is a 55-residue protein isolated from the venom of the spider Ornithoctonus huwena. It is a potent trypsin inhibitor and a moderate voltage-gated potassium channel blocker. Here, we designed and expressed two HWTI mutants, HWTI-mut1 and HWTI-mut2, in which the potassium channel inhibitory activity was reduced while the trypsin inhibitory activity of the wild type form (approximately 5 EPU/mg) was retained. Animal studies showed that these mutants were less toxic than HWTI. The effects of HWTI and HWTI-mut1 were examined in a mouse model of acute pancreatitis induced by intraperitoneal injection of a large dose of L-arginine (4 mg/kg, twice). Serum amylase and serum lipase activities were assessed, and pathological sections of the pancreas were examined. Treatment with HWTI and HWTI-mut1 significantly reduced serum amylase and lipase levels in a dose dependent manner. Compared with the control group, at 4 mg/kg, HWTI significantly reduced serum amylase level by 47% and serum lipase level by 73%, while HWTI-mut1 significantly reduced serum amylase level by 59% and serum lipase level by 72%. Moreover, HWTI and HWTI-mut1 effectively protected the pancreas from acinar cell damage and inflammatory cell infiltration. The trypsin inhibitory potency and lower neurotoxicity of HWTI-mut1 suggest that it could potentially be developed as a drug for the treatment of acute pancreatitis with few side effects. PMID:23613780

  9. 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

  10. A newly discovered role of transcription factors involved in pancreas development and the pathogenesis of diabetes mellitus.

    PubMed

    Habener, J F; Stoffers, D A

    1998-01-01

    The prevalence of diabetes mellitus is increasing worldwide, averaging 5% to 15% in various population groups. Diabetes predisposes to premature morbidity and death. The underlying metabolic cause of diabetes is a failure of the beta-cells of the pancreas to provide insulin in amounts sufficient to meet the body's needs, leading to hyperglycemia. Juvenile (type 1) diabetes results from immune destruction of the beta-cells. Adult onset (type 2) diabetes, which accounts for 90% of all forms of diabetes, is a complex polygenic disease manifested in a dysregulation of insulin secretion. Environmental influences and complex genetic traits contribute to the pathogenesis of both types of diabetes. However, a subpopulation of type 2 diabetes is monogenic and due to inactivating mutations in genes that are critical for normal beta-cell function. Heterozygous carriers of the mutant genes develop early-onset diabetes known as MODY (mature onset diabetes of the young). Notably, three MODY genes encode transcription factors implicated in the regulation of insulin gene transcription: hepatocyte nuclear factors 1 alpha and 4 alpha, and islet duodenum homeobox-1 (IDX-1, also known as IPF-1). The fourth gene encodes glucokinase, the rate-limiting enzyme required for glucose metabolism in beta-cells. Further, an individual born without a pancreas (agenesis) is homozygous for an inactivating mutation of the IDX-1 gene, recapitulating the phenotype of the IDX-1 knockout mouse and demonstrating that expression of IDX-1 is critical for pancreas development. Recently, mouse knockouts of the transcription factors Pax4, Pax6, beta 2/neuroD, and Isl-1 result in severe anomalies in the development of the endocrine pancreas. Gene mutations for these factors are possible candidates for additional MODY genes. PMID:9460079

  11. Microcirculatory detection of Toll-like receptor 4 in rat pancreas and intestine.

    PubMed

    Li, Yuan; Zhou, Zong-Guang; Zhang, Jie; Chen, You-Dai; Li, Hong-Guang; Gao, Hong-Kai; Wang, Rong; Hu, Ting-Ze

    2006-01-01

    This paper was aimed to detect Toll-like receptor 4 (TLR4) microcirculatory expression and localization in rat pancreas and intestine. Acute pancreatitis (AP) was induced by twice injections of cerulein (20 mug in total) and acute necrotizing pancreatitis (ANP) was induced by intraductal injection of 5% taurocholate (1 ml/kg.bw). Reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) were used to detect and localize TLR4 in the pancreas and intestine. Results showed that RT-PCR of RNA isolated from pancreatic and intestinal tissue yielded the predicted amplicon for TLR4; IHC analysis localized TLR4 expression to the endothelium of pancreatic arteriole, venule, acinar capillary network and sinusoidal capillary of endocrine islet; TLR4 expression in intestine was principally in the microvascular endothelium and leucocytes within the mucosa lamina propria. TLR4 staining in intestine was more intense in taurocholate-induced pancreatitis (TIP) than that in cerulein-induced pancreatitis (CIP). In conclusion, TLR4 could be detected in the pancreatic and intestinal microcirculation, suggesting TLR4 involved in the microcirculatory impairment in AP; the more intense intestinal TLR4 expression in TIP suggests a potential risk for secondary infection.

  12. Lipase turbidimetric assay and acute pancreatitis.

    PubMed

    Orda, R; Orda, S; Baron, J; Wiznitzer, T

    1984-04-01

    The simplified turbidimetric assay for lipase activity was used for the differential diagnosis of acute pancreatitis. Serum lipase levels were found to be increased in a group of 17 patients in whom acute pancreatitis was clinically suspected and confirmed by a high ACCR and decreased uptake of the radionuclide in the pancreas scan. The lipase levels were within normal limits in a control group of 14 patients suffering from diseases other than acute pancreatitis. The turbidimetric test was helpful for rapid quantitative determination of serum lipase and thus for the early and accurate diagnosis of acute pancreatitis. PMID:6200277

  13. Proteomic profiling in incubation medium of mouse, rat and human precision-cut liver slices for biomarker detection regarding acute drug-induced liver injury.

    PubMed

    van Swelm, Rachel P L; Hadi, Mackenzie; Laarakkers, Coby M M; Masereeuw, Rosalinde; Groothuis, Geny M M; Russel, Frans G M

    2014-09-01

    Drug-induced liver injury is one of the leading causes of drug withdrawal from the market. In this study, we investigated the applicability of protein profiling of the incubation medium of human, mouse and rat precision-cut liver slices (PCLS) exposed to liver injury-inducing drugs for biomarker identification, using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. PCLS were incubated with acetaminophen (APAP), 3-acetamidophenol, diclofenac and lipopolysaccharide for 24-48 h. PCLS medium from all species treated with APAP demonstrated similar changes in protein profiles, as previously found in mouse urine after APAP-induced liver injury, including the same key proteins: superoxide dismutase 1, carbonic anhydrase 3 and calmodulin. Further analysis showed that the concentration of hepcidin, a hepatic iron-regulating hormone peptide, was reduced in PCLS medium after APAP treatment, resembling the decreased mouse plasma concentrations of hepcidin observed after APAP treatment. Interestingly, comparable results were obtained after 3-acetamidophenol incubation in rat and human, but not mouse PCLS. Incubation with diclofenac, but not with lipopolysaccharide, resulted in the same toxicity parameters as observed for APAP, albeit to a lesser extent. In conclusion, proteomics can be applied to identify potential translational biomarkers using the PCLS system.

  14. Treatment of pancreatitis associated with pancreas divisum by dorsal duct sphincterotomy alone.

    PubMed

    Keith, R G; Shapero, T F; Saibil, F G

    1982-11-01

    Of 480 patients seen with pancreatitis at the Sunnybrook Medical Centre, Toronto, in the past 5 years, 5 had pancreas divisum, demonstrated by pancreatography. Clinical presentations included recurrent acute pancreatitis, chronic pancreatitis and recurrent subcutaneous fat necrosis with steatorrhea. Pancreatography demonstrated dorsal pancreatic drainage through the duct of Santorini in all cases. The luminal diameter at the orifice of the duct of Santorini, assessed at operation, was inadequate to provide normal drainage from the gland. Sphincterotomy of the duct of Santorini alone, without surgery to the duct of Wirsung or sphincter of Oddi, was performed in four patients. This relieved the pain of chronic pancreatitis, eliminated recurrent attacks of acute pancreatitis and curtailed recurrence of subcutaneous fat necrosis and steatorrhea during follow-up periods of 51, 27, 17 and 28 months respectively. One patient who refused operation continued to have recurrent pancreatitis 41 months after diagnosis.

  15. Human ductal adenocarcinomas of the pancreas express extracellular matrix proteins.

    PubMed Central

    Löhr, M.; Trautmann, B.; Göttler, M.; Peters, S.; Zauner, I.; Maillet, B.; Klöppel, G.

    1994-01-01

    Pancreatic ductal adenocarcinomas are characterised by a dense connective tissue reaction. To test the hypothesis that stroma components are synthesised and produced by the tumour cells themselves, eight cell lines as well as six xenografted tumours from human ductal adenocarcinomas of the pancreas were examined for the expression of extracellular matrix proteins (ECM), using cDNA probes and antibodies to collagen types I, III and IV, vitronectin, fibronectin, undulin and laminin. All tumour cell lines (CAPAN-1, CAPAN-2, AsPC-1, BxPC-3, PANC-1, PaCa-2, PaCa-3, PaCa-44) and xenografted human pancreatic tumours expressed at least one of the examined ECM at the RNA (collagen type IV > laminin = fibronectin = vitronectin > collagen type III > undulin > collagen type I) or protein level (collagen type IV = collagen type III > vitronectin > laminin > collagen type I = fibronectin > undulin). In nude mouse tumours expression of laminin and collagen I was most pronounced in well-differentiated carcinomas. In a few tumours, collagen type III, vitronectin and undulin were expressed on the luminal side of the neoplastic glands, suggesting loss of normal polar differentiation. Incubation with fetal calf serum modulated ECM RNA levels to a varying extent in all but one cell line (AsPC-1). The results suggest that human pancreatic ductal adenocarcinomas cells are capable of synthesising and producing extracellular matrix proteins in vitro and in vivo, but that the extent and pattern of ECM expression differs between the various tumours and conditions tested. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:8286197

  16. 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.

  17. [Function of pancreas transplants in increased metabolic stress].

    PubMed

    Teuscher, A U; Seaquist, E R; Barrou, Z; Kendall, D M; Robertson, R P

    1995-01-01

    Patients undergoing successful pancreas transplantation have normal glucose levels in the fasting and fed states and normal levels of hemoglobin A1c without use of exogenous inulin or any other medications for diabetes. In some of these patients, these measures have remained stable for more than 10 years. Additionally pancreas transplant recipients recover from short-term hypoglycemia produced by an intravenous pulse of insulin. However, metabolic success has been determined by relatively routine, unsophisticated tests such as oral and intravenous glucose tolerance tests or stimulation with intravenous arginine. These tests may not provide measures of the functional reserve of the pancreas, which is called on during periods of maximal stress. Consequently, we designed studies to ascertain beta and alpha cell performance in recipients of whole pancreas transplants and recipients of a segment of a living related donor. All recipients were recruited from the University of Minnesota Transplant Registry, Minneapolis, Minnesota. Successfully transplanted recipients were subjected to prolonged hyperglycemia to assess insulin secretory reserve using the method of glucose potentiation of arginine induced insulin secretion and to prolonged hypoglycemia to assess glucagon responsiveness and hepatic glucose production using the technique of the hyperinsulinemic hypoglycemic clamp. Our studies show that pancreas transplant recipients have markedly diminished insulin secretory reserve, a defect not evident with conventional tests of beta-cell function. No difference was found between the whole graft and segmental graft recipients. Pancreas transplantation restores the defective glucagon secretory response and enhances hepatic glucose production during prolonged hypoglycemia in subjects with type I diabetes. We conclude that pancreas transplantation does not completely restore beta-cell secretory reserve. This defect might be probably caused in part by cyclosporine and by the

  18. The Association between Nonalcoholic Fatty Pancreas Disease and Diabetes

    PubMed Central

    Yang, Yi-Ching; Chen, Ming-Fong; Chang, Chih-Jen

    2013-01-01

    Background Fatty infiltration of the pancreas has been shown to interfere with insulin secretion. Both insulin sensitivity and secretion are important in the pathogenesis of diabetes and prediabetes. However, the relationship between diabetes, prediabetes, and fatty pancreas remains unknown. We aim to investigate the relationships that fatty pancreas and nonalcoholic fatty liver disease (NAFLD) have with prediabetes and diabetes in a Chinese population. Patients and Methods This was a cross-sectional study. A total of 7,464 subjects were recruited. NAFLD and fatty pancreas were assessed by sonography. Clinico-metabolic parameters were compared among subjects with normoglycemia, prediabetes, and diabetes. Multinomial logistic regression was used to evaluate the relationship between fatty pancreas and NAFLD and diabetes or prediabetes with adjustment for cardiometabolic risk factors. Results With an increase in glycemia, a significantly greater proportion of subjects had NAFLD and fatty pancreas (test for trend p<0.05). Similar trends were also found for hypertension, general and central obesity, low-HDL cholesterol, and hypertriglyceridemia. In the logistic regression analysis, age, hypertension, male gender, hypertriglyceridemia, and central obesity were significantly associated with prediabetes and diabetes. Furthermore, the ORs of prediabetes and diabetes for NAFLD were 1.798 (95% CI 1.544–2.094) and 2.578 (95% CI 2.024–3.284), respectively. In addition, fatty pancreas was independently related to diabetes (OR, 1.379; 95% CI, 1.047–1.816) and prediabetes (OR, 1.222; 95% CI, 1.002–1.491) in male subjects. Conclusions Both NAFLD and fatty pancreas were associated with diabetes independent of age, gender, adiposity, and other cardiometabolic risk factors. Fatty pancreas was also related to prediabetes in males. PMID:23671610

  19. Incomplete Annular Pancreas with Ectopic Opening of the Pancreatic and Bile Ducts into the Pyloric Ring: First Report of a Rare Anomaly

    PubMed Central

    Kobayashi, Shinjiro; Hoshino, Horoyuki; Segami, Kouhei; Koizumi, Satoshi; Ooike, Nobuyuki; Otsubo, Takehito

    2016-01-01

    The patient was a 56-year-old woman who had experienced epigastralgia and dorsal pain several times over the last 20 years. She was admitted for a diagnosis of acute cholecystitis, and severe intra- and extrahepatic bile duct dilatation with inner air density was noted. No papilla of Vater was present in the descending duodenum, and 2 small holes were present in the pyloric ring. Bile excretion from one of the small holes was observed under forward-viewing endoscope. It was considered that the pancreatic and bile ducts separately opened into the pyloric ring. Based on these findings, malformation of the pancreaticobiliary duct was diagnosed. She did not wish treatment, but the obstruction associated with duodenal stenosis was noted after 2 years. Pancreatoduodenectomy was performed as curative treatment for duodenal stenosis and retrograde biliary infection through the bile duct opening in the pyloric ring. The ventral pancreas encompassed almost the entire circumference of the pyloric ring, suggesting a subtype of annular pancreas. Generally, lesions are present in the descending part of the duodenum in an annular pancreas, and the pancreatic and bile ducts join in the papillary region. However, in this patient, (1) the pancreas encompassed the pyloric ring, (2) the pancreatic and bile ducts opened separately, and (3) the openings of the pancreatic and bile ducts were present in the pyloric ring. The pancreas and biliary tract develop through a complex process, which may cause various types of malformation of the pancreaticobiliary system, but no similar case report was found on a literature search. This case was very rare and could not be classified in any type of congenital anomaly of the pancreas. We would classify it as a subtype of annular pancreas with separate ectopic opening of the pancreatic and bile ducts into the pyloric ring. PMID:27721721

  20. Obstructing pseudocyst of the duct of Santorini in pancreas divisum.

    PubMed

    Browder, W; Gravois, E; Vega, P; Ertan, A

    1987-03-01

    Pancreas divisum is a pancreatic duct anomaly that occurs due to failure of fusion of the dorsal and ventral ducts. While recognition of this anomaly is increasing due to more aggressive endoscopic retrograde cholangiopancreatography, its significance remains unclear. A patient with chronic pancreatitis and a history of alcohol abuse was noted to have pancreas divisum. At surgical exploration, intraoperative pancreatography revealed an obstructing pseudocyst of the duct of Santorini. Extended sphincteroplasty and cystduodenostomy as well as Roux-en-Y pancreatojejunostomy were necessary to insure adequate accessory duct drainage. Surgical therapy of pancreas divisum in chronic pancreatitis should be designed to correct existing pancreatic duct obstruction.

  1. 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

  2. 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.

  3. Acute effects of AMPA-type glutamate receptor antagonists on intermale social behavior in two mouse lines bidirectionally selected for offensive aggression.

    PubMed

    Vekovischeva, O Yu; Aitta-aho, T; Verbitskaya, E; Sandnabba, K; Korpi, E R

    2007-01-01

    Involvement of AMPA-type glutamate receptors in the regulation of social behavior has been suggested by experiments with mice deficient for the GluR-A subunit-containing AMPA receptors showing reduced intermale aggression. In the present study, effects of AMPA receptor antagonists on mouse social behavior towards unfamiliar Swiss-Webster males on a neutral territory were tested using male subjects from the Turku Aggressive (TA) and Turku Non-Aggressive (TNA) mouse lines bidirectionally selected for high and low levels of offensive aggression. The drugs were the competitive antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX), and the non-competitive antagonist 4-(8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-5-yl)-benzenamine (GYKI 52466). In TA mice, CNQX and NBQX decreased the biting component of aggressive structure, while GYKI 52466 suppressed all aggressive manifestations. All drugs increased anxiety-like behavior towards the partner. In TNA mice, NBQX activated mouse social behavior and ambivalent aggression, while CNQX and GYKI 52466 only increased anxiety. Thus, AMPA receptor antagonists affect aggressive behaviors in TA mice supporting the idea that AMPA receptors are involved in the modulation of agonistic impulsive behavioral pattern. GYKI 52466 appeared to be the most selective and efficacious in suppressing the aggression.

  4. 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.

  5. The secretagogue effect of the poison from Centruroides limpidus limpidus on the pancreas of mice and the antagonistic action of the Bouvardia ternifolia extract.

    PubMed

    Jiménez-Ferrer, E; Reynosa-Zapata, I; Pérez-Torres, Y; Tortoriello, J

    2005-01-01

    In Mexican traditional medicine the plant species Bouvardia ternifolia is used as remedy to treat patients who have been stung by scorpions. In the preceding study, the methanol extract from the roots of this plant was capable of reducing the poisonous effect of Centruroides limpidus limpidus on mice. The poisoning from scorpion C. limpidus limpidus includes manifestations associated with the pancreatitis. This study evaluated the effect produced by the hexane and methanol extract from the root of B. ternifolia upon the acutely inflamed pancreas induced by the venom of C. limpidus limpidus on rats, and the release of amylase in the isolated pancreas of mice. The intravenous administration of venom induced the extravasation of labelled albumin, in a dose dependant manner. The pre-administration of both extracts of Bouvardia ternifolia reduced significantly (p < 0.05) the extravasation by 60%. Upon measuring the secretagogue effect of the venom in the isolated pancreas of mice, the EC50 of the venom was 3.76 x 10(-3) mg ml(-1), whilst in the presence of the methanol and hexane extracts, this EC50 was 9.13 x 10(-3) mg ml(-1) and 0.01629 mg ml(-1). In conclusion, the C. limpidus limpidus venom possesses a secretagogue effect of amylase on the pancreas of mice and produces an inflamed pancreas which is effectively antagonised by the hexane and methanol extracts from the roots of B. ternifolia.

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

    PubMed

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

    2015-03-01

    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.

  7. 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 ...

  8. ROLE OF THE MATERNAL ACUTE PHASE RESPONSE AND TUMOR NECROSIS FACTOR ALPHA IN THE DEVELOPMENTAL TOXICITY OF LIPOPOLYSACCHARIDE IN THE CD-1 MOUSE

    EPA Science Inventory

    ABSTRACT
    The acute phase response (APR) functions to reset metabolic homeostasis following infectious, toxic or traumatic insult. TNF- , a putative mediator of the APR, has been associated with fetal death in rodents and preterm labor and delivery in humans. We hypothesized...

  9. 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.

  10. 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.

  11. 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.

  12. Occupational exposure and cancer of the pancreas: a review.

    PubMed Central

    Pietri, F; Clavel, F

    1991-01-01

    Many hypotheses have been proposed about the aetiology of cancer of the pancreas, especially concerning the effects of tobacco, coffee, alcohol, diet, and pancreatic pathology. Results of numerous epidemiological studies are, however, inconsistent. Chemical carcinogens have been implicated as possible risk factors. Animal studies have been carried out to determine the role of these chemical factors but, except for nitrosamines and their derivatives (components of tobacco), chemicals have not been proved carcinogenic for the pancreas. Many studies have also been conducted among occupational groups. Several of them showed an excess risk of cancer of the pancreas, especially in the chemical and petroleum industries. The lack of accuracy about the nature of products used, however, does not permit a definitive conclusion as to their carcinogenic role. This paper is a review of publications about occupational exposures and cancer of the pancreas. PMID:1911399

  13. Pancreas procurement and preservation for islet transplantation: personal considerations.

    PubMed

    Noguchi, Hirofumi

    2011-01-01

    Pancreatic islet transplantation is a promising option for the treatment of type 1 diabetic patients. After the successful demonstration of the Edmonton protocol, islet transplantation has advanced significantly on several fronts, including improved pancreas procurement and preservation systems. Since we frequently use pancreata from donors after cardiac death in Japan,we have applied the in situ regional organ cooling system for pancreas procurement to reduce the warm ischemic time. To reduce the apoptosis of pancreatic tissue during cold preservation, we have applied the ductal injection of preservation solution. For pancreas preservation, we use modified Kyoto solution, which is advantageous at trypsin inhibition and less collagenase inhibition. In this paper, we show pancreas procurement and preservation in our group for islet transplantation.

  14. One compound of saponins from Disocorea zingiberensis protected against experimental acute pancreatitis by preventing mitochondria-mediated necrosis

    PubMed Central

    Zhang, Rui; Wen, Li; Shen, Yan; Shi, Na; Xing, Zhihua; Xia, Qing; Niu, Hai; Huang, Wen

    2016-01-01

    Acute pancreatitis (AP) is a painful inflammatory disorder of the exocrine pancreas, ranking as the most common gastrointestinal reasons for hospitalization with no specific therapy currently. Diosgenyl saponins extracted from natural products and diosgenin or its derivatives have been shown to exert anti-inflammatory effects in various diseases. However, the therapeutic effects of diosgenyl saponins from Dioscorea zingiberensis C. H. Wright in AP have not yet been determined. Five compounds were extracted and screened for taurocholate-induced necrosis in mouse pancreatic acinar cells. Particularly, 26-O-β-d-glucopyranosyl-3β, 22α, 26-trihydroxy-25(R)-furosta-5-en-3-O-[α-L-rhamnopyranosyl-(1 → 4)]-β-d-glucopyranoside (compound 1) exhibited the best protective effects with no toxicity observed. Next, we showed compound 1 concentration-dependently inhibited necrotic cell death pathway activation and 2.5 mM compound 1 also prevented the loss of mitochondrial membrane potential, adenosine triphosphate production, and reactive oxygen species generation in mouse pancreatic acinar cells. Finally, we showed compound 1 protected against three clinically representative murine models of AP and significantly improved pancreatitis-associated acute lung injury. These data provide in vitro and in vivo evidence that one compound of diosgenyl saponins can be potential treatment for AP. This study suggests natural saponins may serve as fruitful sources for exploring/identifying potential therapies for inflammatory diseases. PMID:27779235

  15. 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.

  16. Imaging spectrum after pancreas transplantation with enteric drainage.

    PubMed

    Chen, Jian-Ling; Lee, Rheun-Chuan; Shyr, Yi-Ming; Wang, Sing-E; Tseng, Hsiuo-Shan; Wang, Hsin-Kai; Huang, Shan-Su; Chang, Cheng-Yen

    2014-01-01

    Since the introduction of pancreas transplantation more than 40 years ago, surgical techniques and immunosuppressive regiments have improved and both have contributed to increase the number and success rate of this procedure. However, graft survival corresponds to early diagnosis of organ-related complications. Thus, knowledge of the transplantation procedure and postoperative image anatomy are basic requirements for radiologists. In this article, we demonstrate the imaging spectrum of pancreas transplantation with enteric exocrine drainage.

  17. 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.

  18. Anaplastic Carcinoma Possibly Arising from a Heterotopic Pancreas.

    PubMed

    Adachi, Yasushi; Mita, Hiroaki; Takahashi, Hideaki; Akino, Kimishige; Kikuchi, Takefumi; Ishii, Yoshifumi; Endo, Takao

    2015-01-01

    Anaplastic carcinoma is a rare pancreatic cancer, and the malignant transformation of a heterotopic pancreas is also rare. We herein report a case of an elderly woman with a mass of unknown origin in the abdominal cavity. Computed tomography identified the extent of the tumor but not the organ of origin. The abdominal tumor eventually metastasized to the liver and lung. An autopsy and immunohistochemical examination revealed an anaplastic carcinoma possibly originating in an ectopic pancreas.

  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. 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

  1. Spontaneous hemorrhage due to pseudocysts of the pancreas.

    PubMed

    Wu, T K; Zaman, S N; Gullick, H D; Powers, S R

    1977-09-01

    Spontaneous hemorrhage caused by erosion of major arteries by a pseudocyst of the pancreas is a rare condition. We have encountered three cases, one involving the abdominal aorta and two the superior pancreaticoduodenal artery. It is important to keep in mind that pseudocyst of the pancreas may cause massive gastrointestinal or intraabdominal bleeding. Operative treatment offers a better chance of survival than more conservative management.

  2. Has the gap between pancreas and islet transplantation closed?

    PubMed

    Niclauss, Nadja; Morel, Philippe; Berney, Thierry

    2014-09-27

    Both pancreas and islet transplantations are therapeutic options for complicated type 1 diabetes. Until recent years, outcomes of islet transplantation have been significantly inferior to those of whole pancreas. Islet transplantation is primarily performed alone in patients with severe hypoglycemia, and recent registry reports have suggested that results of islet transplantation alone in this indication may be about to match those of pancreas transplant alone in insulin independence. Figures of 50% insulin independence at 5 years for either procedure have been cited. In this article, we address the question whether islet transplantation has indeed bridged the gap with whole pancreas. Looking at the evidence to answer this question, we propose that although pancreas may still be more efficient in taking recipients off insulin than islets, there are in fact numerous "gaps" separating both procedures that must be taken into the equation. These "gaps" relate to organ utilization, organ allocation, indication for transplantation, and morbidity. In-depth analysis reveals that islet transplantation, in fact, has an edge on whole pancreas in some of these aspects. Accordingly, attempts should be made to bridge these gaps from both sides to achieve the same level of success with either procedure. More realistically, it is likely that some of these gaps will remain and that both procedures will coexist and complement each other, to ensure that β cell replacement can be successfully implemented in the greatest possible number of patients with type 1 diabetes.

  3. 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.

  4. A historical perspective on the discovery of the accessory duct of the pancreas, the ampulla 'of Vater' and pancreas divisum.

    PubMed

    Stern, C D

    1986-02-01

    The discovery of the accessory duct of the pancreas is usually ascribed to Giovanni Domenico Santorini (1681-1737), after whom this structure is named. The papilla duodeni (ampulla 'of Vater', or papilla 'of Santorini') is named after Abraham Vater (1684-1751) or after GD Santorini. Pancreas divisum, a persistence through non-fusion of the embryonic dorsal and ventral pancreas is a relatively common clinical condition, the discovery of which is usually ascribed to Joseph Hyrtl (1810-1894). In this review I report that pancreas divisum, the accessory duct and the papilla duodeni (ampulla 'of Vater') had all been observed and the observations published during the 17th century by at least seven anatomists before Santorini, Vater, and Hyrtl. I further suggest, in the light of frequent anatomical misattributions in common usage, that anatomical structures be referred to only by their proper anatomical names.

  5. Inflammatory mediators in acute pancreatitis.

    PubMed

    Bhatia, M; Brady, M; Shokuhi, S; Christmas, S; Neoptolemos, J P; Slavin, J

    2000-02-01

    Inflammatory mediators play a key role in acute pancreatitis and the resultant multiple organ dysfunction syndrome, which is the primary cause of death in this condition. Recent studies have confirmed the critical role played by inflammatory mediators such as TNF-alpha, IL-1beta, IL-6, IL-8, PAF, IL-10, C5a, ICAM-1, and substance P. The systemic effects of acute pancreatitis have many similarities to those of other conditions such as septicaemia, severe burns, and trauma. The delay between the onset of inflammation in the pancreas and the development of the systemic response makes acute pancreatitis an ideal experimental and clinical model with which to study the role of inflammatory mediators and to test novel therapies. Elucidation of the key mediators involved in the pathogenesis of acute pancreatitis will facilitate the development of clinically effective anti-inflammatory therapy.

  6. 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

  7. 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.

  8. 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.

  9. 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.

  10. [Peroperative ultrasound scanning of the pancreas].

    PubMed

    Alexandre, J H; Hernigou, A; Billebaud, T; Bouillot, J L; Plainfosse, M C

    1985-01-01

    Intraoperative realtime high resolution ultrasound scanning of the pancreas seems to be a new and promising procedure. We have performed it in 28 patients: the normal ultrasound picture of pancreatic ducts and parenchyma was defined in 9 patients without pancreatic disease; in 19 patients with pancreatic disease, intraoperative ultrasound was compared with preoperative ultrasound examination. Seven of 8 patients with pancreatic carcinoma and 4 of 6 with calcifying chronic pancreatitis had positive findings, respectively. In 3 cancer patients, intraoperative ultrasound investigation avoided a long and unavailing dissection of the tumor by revealing extensive spread. In selected cases, intraoperative sonography allowed to characterize and to localize pancreatic carcinoma: portal vein invasion, relationship of the tumor to the duct of Wirsung and small hepatic metastases. In chronic pancreatitis, intraoperative ultrasound information concerning the dimensions of the pancreatic duct, the structure and the localization of pseudocysts was comparable to that obtained by radiological opacification. Furthermore, intraoperative ultrasound exploration guided proper incision and evacuation of pancreatic pseudocysts in two patients. Operative ultrasound seems to us to be mandatory during pancreatic surgery. Further experience with this technique is needed in a larger number of patients. However, we believe that it could replace intraoperative cholangiography and pancreaticography in the assessment of extension and complications of pancreatic disease.

  11. 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

  12. 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

  13. Frey operation for chronic pancreatitis associated with pancreas divisum: case report and review of the literature

    PubMed Central

    Skórzewska, Magdalena; Romanowicz, Tomasz; Mielko, Jerzy; Kurylcio, Andrzej; Pertkiewicz, Jan; Zymon, Robert

    2014-01-01

    Pancreas divisum (PD) is the most common congenital anomaly of the pancreas, which increases susceptibility to recurrent pancreatitis. Usually, after failure of initial endoscopic therapies, surgical treatment combining pancreatic resection or drainage is used. The Frey procedure is used for chronic pancreatitis, but it has not been reported to be applied in an adult patient with PD-associated pancreatitis. The purpose of the paper was to describe effective treatment of this rare condition by the Frey procedure after failure of interventional endoscopic treatment. A 39-year-old female patient was initially treated for recurrent acute pancreatitis. After endoscopic diagnosis of PD, the minor duodenal papilla was incised and a plastic stent was inserted into the dorsal pancreatic duct. During the following 36 months, the patient was hospitalised several times because of recurrent episodes of pancreatitis. Thereafter, local resection of the pancreatic head combined with lateral pancreaticojejunostomy was performed with no complications. After 54 months of follow-up, the patient demonstrates abnormal glucose metabolism, with a need for enzyme supplementation, and she is free of pain. Local resection of the pancreatic head combined with lateral pancreaticojejunostomy (Frey procedure) offers a favourable outcome after failure of endoscopic papillotomy and duct stenting for pancreatitis associated with PD. PMID:25097717

  14. 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.

  15. 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.

  16. Topical Application of a Platelet Activating Factor Receptor Agonist Suppresses Phorbol Ester-Induced Acute and Chronic Inflammation and Has Cancer Chemopreventive Activity in Mouse Skin

    PubMed Central

    Ocana, Jesus A.; DaSilva-Arnold, Sonia C.; Bradish, Joshua R.; Richey, Justin D.; Warren, Simon J.; Rashid, Badri; Travers, Jeffrey B.; Konger, Raymond L.

    2014-01-01

    Platelet activating factor (PAF) has long been associated with acute edema and inflammatory responses. PAF acts by binding to a specific G-protein coupled receptor (PAF-R, Ptafr). However, the role of chronic PAF-R activation on sustained inflammatory responses has been largely ignored. We recently demonstrated that mice lacking the PAF-R (Ptafr-/- mice) exhibit increased cutaneous tumorigenesis in response to a two-stage chemical carcinogenesis protocol. Ptafr-/- mice also exhibited increased chronic inflammation in response to phorbol ester application. In this present study, we demonstrate that topical application of the non-hydrolysable PAF mimetic (carbamoyl-PAF (CPAF)), exerts a potent, dose-dependent, and short-lived edema response in WT mice, but not Ptafr -/- mice or mice deficient in c-Kit (c-KitW-sh/W-sh mice). Using an ear inflammation model, co-administration of topical CPAF treatment resulted in a paradoxical decrease in both acute ear thickness changes associated with a single PMA application, as well as the sustained inflammation associated with chronic repetitive PMA applications. Moreover, mice treated topically with CPAF also exhibited a significant reduction in chemical carcinogenesis. The ability of CPAF to suppress acute and chronic inflammatory changes in response to PMA application(s) was PAF-R dependent, as CPAF had no effect on basal or PMA-induced inflammation in Ptafr-/- mice. Moreover, c-Kit appears to be necessary for the anti-inflammatory effects of CPAF, as CPAF had no observable effect in c-KitW-sh/W-sh mice. These data provide additional evidence that PAF-R activation exerts complex immunomodulatory effects in a model of chronic inflammation that is relevant to neoplastic development. PMID:25375862

  17. Ectopic Ptf1a expression in murine ESCs potentiates endocrine differentiation and models pancreas development in vitro.

    PubMed

    Nair, Gopika G; Vincent, Robert K; Odorico, Jon S

    2014-05-01

    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 (RA) and nicotinamide (Nic) 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.

  18. 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

  19. Temperature profiles of different cooling methods in porcine pancreas procurement.

    PubMed

    Weegman, Bradley P; Suszynski, Thomas M; Scott, William E; Ferrer Fábrega, Joana; Avgoustiniatos, Efstathios S; Anazawa, Takayuki; O'Brien, Timothy D; Rizzari, Michael D; Karatzas, Theodore; Jie, Tun; Sutherland, David E R; Hering, Bernhard J; Papas, Klearchos K

    2014-01-01

    Porcine islet xenotransplantation is a promising alternative to human islet allotransplantation. Porcine pancreas cooling needs to be optimized to reduce the warm ischemia time (WIT) following donation after cardiac death, which is associated with poorer islet isolation outcomes. This study examines the effect of four different cooling Methods on core porcine pancreas temperature (n = 24) and histopathology (n = 16). All Methods involved surface cooling with crushed ice and chilled irrigation. Method A, which is the standard for porcine pancreas procurement, used only surface cooling. Method B involved an intravascular flush with cold solution through the pancreas arterial system. Method C involved an intraductal infusion with cold solution through the major pancreatic duct, and Method D combined all three cooling Methods. Surface cooling alone (Method A) gradually decreased core pancreas temperature to <10 °C after 30 min. Using an intravascular flush (Method B) improved cooling during the entire duration of procurement, but incorporating an intraductal infusion (Method C) rapidly reduced core temperature 15-20 °C within the first 2 min of cooling. Combining all methods (Method D) was the most effective at rapidly reducing temperature and providing sustained cooling throughout the duration of procurement, although the recorded WIT was not different between Methods (P = 0.36). Histological scores were different between the cooling Methods (P = 0.02) and the worst with Method A. There were differences in histological scores between Methods A and C (P = 0.02) and Methods A and D (P = 0.02), but not between Methods C and D (P = 0.95), which may highlight the importance of early cooling using an intraductal infusion. In conclusion, surface cooling alone cannot rapidly cool large (porcine or human) pancreata. Additional cooling with an intravascular flush and intraductal infusion results in improved core porcine pancreas temperature profiles during procurement and

  20. 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.

  1. Histology of Type 1 Diabetes Pancreas.

    PubMed

    Willcox, Abby; Gillespie, Kathleen M

    2016-01-01

    The islets of Langerhans play a critical role in glucose homeostasis. Islets are predominantly composed of insulin-secreting beta cells and glucagon-secreting alpha cells. In type 1 diabetes, the beta cells are destroyed by autoimmune destruction of insulin producing beta cells resulting in hyperglycemia. This is a gradual process, taking from several months to decades. Much of the beta cell destruction takes place during a silent, asymptomatic phase. Type 1 diabetes becomes clinically evident upon destruction of approximately 70-80 % of beta cell mass. Studying the decline in beta cell mass and the cells which are responsible for their demise is difficult as pancreatic biopsies are not feasible in patients with type 1 diabetes. The relative size of islets and their dispersed location throughout the pancreas means in vivo imaging of human islets is currently not manageable. At present, there are no validated biomarkers which accurately track the decline in beta cell mass in individuals who are at risk of developing, or have already developed, type 1 diabetes. Therefore, studies of pancreatic tissue retrieved at autopsy from donors with type 1 diabetes, or donors with high risk markers of type 1 diabetes such as circulating islet-associated autoantibodies, is currently the best method for studying beta cells and the associated inflammatory milieu in situ. In recent years, concerted efforts have been made to source such tissues for histological studies, enabling great insights to be made into the relationship between islets and the inflammatory insult to which they are subjected. This article describes in detail, a robust immunohistochemical method which can be utilized to study both recent, and archival human pancreatic tissue, in order to examine islet endocrine cells and the surrounding immune cells. PMID:26801316

  2. 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

  3. The Neuraminidase Inhibitor Oseltamivir Is Effective Against A/Anhui/1/2013 (H7N9) Influenza Virus in a Mouse Model of Acute Respiratory Distress Syndrome

    PubMed Central

    Baranovich, Tatiana; Burnham, Andrew J.; Marathe, Bindumadhav M.; Armstrong, Jianling; Guan, Yi; Shu, Yuelong; Peiris, Joseph Malik Sriyal; Webby, Richard J.; Webster, Robert G.; Govorkova, Elena A.

    2014-01-01

    Background. High mortality and uncertainty about the effectiveness of neuraminidase inhibitors (NAIs) in humans infected with influenza A(H7N9) viruses are public health concerns. Methods. Susceptibility of N9 viruses to NAIs was determined in a fluorescence-based assay. The NAI oseltamivir (5, 20, or 80 mg/kg/day) was administered to BALB/c mice twice daily starting 24, 48, or 72 hours after A/Anhui/1/2013 (H7N9) virus challenge. Results. All 12 avian N9 and 3 human H7N9 influenza viruses tested were susceptible to NAIs. Without prior adaptation, A/Anhui/1/2013 (H7N9) caused lethal infection in mice that was restricted to the respiratory tract and resulted in pulmonary edema and acute lung injury with hyaline membrane formation, leading to decreased oxygenation, all characteristics of human acute respiratory distress syndrome. Oseltamivir at 20 and 80 mg/kg protected 80% and 88% of mice when initiated after 24 hours, and the efficacy decreased to 70% and 60%, respectively, when treatment was delayed by 48 hours. Emergence of oseltamivir-resistant variants was not detected. Conclusions. H7N9 viruses are comparable to currently circulating influenza A viruses in susceptibility to NAIs. Based on these animal studies, early treatment is associated with improved outcomes. PMID:24133191

  4. 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

  5. Elevated blood interleukin-10 levels and undiminished systemic interleukin-10 production rate prevail throughout acute protein-energy malnutrition in the weanling mouse.

    PubMed

    Monk, Jennifer M; Woodward, Bill

    2009-08-01

    The objectives were to determine if blood IL-10 levels rise during the early stages of acute (wasting) pre-pubescent malnutrition in metabolically distinct murine models known to depress inflammatory immune competence and whether systemic IL-10 production is affected in these pathologies. Weanling C57BL/6J mice were assigned to dietary protocols that elicited wasting pathologies mimicking the human diseases of marasmus (restricted-intake group) or incipient kwashiorkor (low-protein group). An age-matched control group also was included. Serum IL-10 bioactivities were assessed in the early (day 3) and advanced (day 14) stages of weight loss, and net systemic IL-10 production was assessed at the same stages of pathology by in vivo cytokine capture. Blood IL-10 levels were elevated in both malnourished groups relative to controls at days 3 and 14 (range of P values: 0.03-0.0001). Further, despite a limited supply of energy and nitrogenous substrates, the systemic IL-10 production rate was at least sustained in the malnourished groups and, in fact, was elevated in the marasmic group (P=0.05) throughout the progression of weight loss. IL-10 emerges as an anti-inflammatory mediator positioned to participate in initiating and upholding the depressed immune competence that accompanies acute pre-pubescent deficits of protein and energy.

  6. 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.

  7. Functioning pancreas graft with thromboses of splenic and superior mesenteric arteries after simultaneous pancreas-kidney transplantation: a case report.

    PubMed

    Matsumoto, I; Shinzeki, M; Asari, S; Goto, T; Shirakawa, S; Ajiki, T; Fukumoto, T; Ku, Y

    2014-04-01

    Graft thrombosis is the most common cause of early graft loss after pancreas transplantation. The grafted pancreas is difficult to salvage after complete thrombosis, especially arterial thrombosis, and graft pancreatectomy is required. We describe a patient presenting with a functioning pancreas graft with thromboses of the splenic artery (SA) and superior mesenteric artery (SMA) after simultaneous pancreas-kidney transplantation (SPK). A 37-year-old woman with a 20-year history of type 1 diabetes mellitus underwent SPK. The pancreaticoduodenal graft was implanted in the right iliac fossa with enteric drainage. A Carrel patch was anastomosed to the recipient's right common iliac artery, and the graft gastroduodenal artery was anastomosed to the common hepatic artery using an arterial I-graft. The donor portal vein was anastomosed to the recipient's inferior vena cava. Four days after surgery, graft thromboses were detected by Doppler ultrasound without increases in the serum amylase and blood glucose levels. Contrast enhanced computed tomography revealed thromboses in the SA, splenic vein and SMA. Selective angiography showed that blood flow was interrupted in the SA and SMA. However, pancreatic graft perfusion was maintained by the I-graft in the head of the pancreas and the transverse pancreatic artery in the body and tail of the pancreas. We performed percutaneous direct thrombolysis and adjuvant thrombolytic therapy. However, we had to stop the thrombolytic therapy because of gastrointestinal hemorrhage. Thereafter, the postoperative course was uneventful and the pancreas graft was functioning with a fasting blood glucose level of 75 mg/dL, HbA1c of 5.1%, and serum C-peptide level of 1.9 ng/mL at 30 months post-transplantation.

  8. Pancreas Development Ex Vivo: Culturing Embryonic Pancreas Explants on Permeable Culture Inserts, with Fibronectin-Coated Glass Microwells, or Embedded in Three-Dimensional Matrigel™

    PubMed Central

    Shih, Hung Ping; Sander, Maike

    2015-01-01

    Pancreas development is a complex and dynamic process orchestrated by cellular and molecular events, including morphogenesis and cell differentiation. As a result of recent explorations into possible cell-therapy-based treatments for diabetes, researchers have made significant progress in deciphering the developmental program of pancreas formation. In vitro pancreas organ culture systems provide a valuable tool for exploring the mechanisms of gene regulation, cellular behaviors, and cell differentiation. In this chapter, we review three common techniques for culturing embryonic pancreas explants. Each technique is suitable for different applications. Specifically, culturing embryonic pancreas on culture inserts provides an excellent platform to test the effects of chemical compounds. Conversely, when the embryonic pancreas is cultured in fibronectin-coated glass microwells, the system provides unique culture conditions to monitor organ growth and cellular dynamic events. Lastly, when the embryonic pancreas is embedded in Matrigel, organogenesis can be studied in a three-dimensional environment instead of limiting the analysis to one plane. PMID:25173172

  9. Portal annular pancreas: a systematic review of a clinical challenge.

    PubMed

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

    2014-10-01

    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.

  10. 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.

  11. Restoration of glucose metabolism in leptin-resistant mouse hearts after acute myocardial infarction through the activation of survival kinase pathways.

    PubMed

    Witham, William; Yester, Keith; O'Donnell, Christopher P; McGaffin, Kenneth R

    2012-07-01

    In the normal heart, leptin modulates cardiac metabolism. It is unknown, however, what effect leptin has on cardiac metabolism and outcomes in acute myocardial infarction (MI). This study was performed to test the hypothesis that leptin signaling increases glucose metabolism and attenuates injury in the acutely infarcted heart. Mice with (ObR(+/+)) and without (ObR(-/-)) cardiomyocyte specific expression of leptin receptor (ObR) were randomly assigned to experimental MI or sham procedure, and studied 3 days later. ObR(+/+) and ObR(-/-) sham mice were not significantly different in any measured outcome. However, after MI, ObR(-/-) mice had greater cardiac dysfunction, left ventricular dilation, and levels of oxidative stress. These worse indices of cardiac injury in ObR(-/-) mice were associated with attenuated signal transducer and activator of transcription (STAT) 3, phosphatidylinositol-3-kinase (PI3K), and Akt signaling, decreased malonyl CoA content, and reduced mitochondrial pyruvate dehydrogenase and electron transport Complex I, II and IV activities. Furthermore, ObR(-/-) mice maintained high rates of cardiac fatty acid oxidation after MI, whereas ObR(+/+) mice demonstrated a switch away from fatty acid oxidation to glucose metabolism. Restoration of cardiac STAT3, PI3K and Akt activity and mitochondrial function in ObR(-/-) mice post-MI was accomplished by ciliary neurotrophic factor (CNTF), an established STAT3 activator, administered immediately after MI. Moreover, CNTF therapy resulted in mitigation of cardiac structural and functional injury, attenuated levels of oxidative stress, and rescued glucose metabolism in the infarcted ObR(-/-) heart. These data demonstrate that impaired cardiac leptin signaling results in metabolic inflexibility for glucose utilization in the face of cardiac stress, and greater morbidity after MI. Further, these studies show that cardiac glucose metabolism can be restored in leptin-resistant hearts by CNTF-mediated activation

  12. 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

  13. An in vitro iron superoxide dismutase inhibitor decreases the parasitemia levels of Trypanosoma cruzi in BALB/c mouse model during acute phase.

    PubMed

    Olmo, Francisco; Urbanová, Kristína; Rosales, Maria Jose; Martín-Escolano, Ruben; Sánchez-Moreno, Manuel; Marín, Clotilde

    2015-12-01

    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 (1)H 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

  14. MRL/lpr-->severe combined immunodeficiency mouse allografts produce autoantibodies, acute graft-versus-host disease or a wasting syndrome depending on the source of cells.

    PubMed Central

    Ashany, D; Hines, J J; Gharavi, A E; Mouradian, J; Drappa, J; Elkon, K B

    1992-01-01

    MRL/lpr (lpr) mice spontaneously develop a lupus-like illness as well as massive lymphadenopathy. Attempts to transfer autoimmunity by adoptive transfer or radiation bone marrow chimeras have been unsuccessful. Since severe combined immunodeficiency (SCID) mice have been engrafted with human and rat xenografts without apparent graft-versus-host disease (GVHD), we subjected SCID mice to low-dose irradiation and reconstituted the mice with spleen cells from young or old lpr mice or with lpr bone marrow. Fourteen out of twenty (70%) of SCID mice engrafted with spleen cells from old lpr mice produced autoantibodies (anti-DNA and anti-Sm) without evidence of the severe lymphoid atrophy previously described for lpr spleen-->+/+ chimeras. SCID mice engrafted with spleen cells from young lpr mice developed acute GVHD and 5/6 (83%) died within 4 weeks post-transfer. Although 8/11 (73%) of lpr-->SCID bone marrow allografts survived for at least 4 months, these mice developed a wasting disease characterized by lymphoid atrophy and fibrosis without the production of autoantibodies. None of the lpr-->SCID grafts resulted in the transfer of double negative T cells or the lymphoproliferative syndrome characteristic of MRL/lpr mice. These findings indicate that SCID mice can be engrafted with splenocytes from old MRL/lpr mice and that B cells continue to secrete autoantibodies for several months in the SCID recipients. This study also demonstrates that, unlike i.p. transplant of xenogeneic cells, acute GVHD is a consistent feature of i.p. transplants of normal allogeneic mononuclear cells into SCID mice. Images Fig. 5 Fig. 7 Fig. 7 PMID:1458684

  15. 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

  16. 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.

  17. 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

  18. IL-17 contributes to neutrophil recruitment but not to control of viral replication during acute mouse adenovirus type 1 respiratory infection.

    PubMed

    McCarthy, Mary K; Zhu, Lingqiao; Procario, Megan C; Weinberg, Jason B

    2014-05-01

    IL-17-producing CD4(+) helper T cells (Th17 cells) promote inflammatory responses to many pathogens. We used mouse adenovirus type 1 (MAV-1) to determine contributions of IL-17 to adenovirus pathogenesis. MAV-1 infection of C57BL/6 mice upregulated lung expression of IL-17 and the Th17-associated factors IL-23 and RORγt. Only CD4(+)T cells were associated with virus-specific IL-17 production. Fewer neutrophils were recruited to airways of IL-17(-/-) mice following MAV-1 infection, but there were no other differences in pulmonary inflammation between IL-17(+/+) and IL-17(-/-) mice. Mice depleted of neutrophils using anti-Gr-1 antibody had greater lung viral loads than controls. Despite impaired neutrophil recruitment, there were no differences between IL-17(+/+) and IL-17(-/-) mice in peak lung viral loads, clearance of virus from the lungs, or establishment of protective immunity. We demonstrate robust Th17 responses during MAV-1 respiratory infection, but these responses are not essential for control of virus infection or for virus-induced pulmonary inflammation. PMID:24889245

  19. 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

  20. 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

  1. Multiple metastatic renal cell carcinoma isolated to pancreas.

    PubMed

    Comunoğlu, Cem; Altaca, Gülüm; Demiralay, Ebru; Moray, Gökhan

    2012-06-01

    Renal cell carcinoma (RCC) metastases to the pancreas are reported to be rare. Isolated multiple pancreatic metastases are even rarer. We report a 68-year-old asymptomatic male patient who presented with multiple metastatic nodular lesions in the pancreas demonstrated by computerized tomography 3.5 years after radical nephrectomy performed for clear cell RCC. Spleen-preserving total pancreatectomy was performed. Gross examination revealed five well-demarcated tumoral nodules in the head, body and tail of the pancreas. Histopathological examination revealed clusters of epithelial clear cells, immunohistochemically positive for CD10 and vimentin, and negative for CK19 and chromogranin, supporting a diagnosis of metastatic RCC. The patient has remained well at 29 months post-resection, in agreement with recent experience that radical resection for multiple isolated metastatic nodular lesions can achieve improved survival and better quality of life.

  2. 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

  3. 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

  4. Acute pancreatitis

    MedlinePlus

    ... rate Lab tests that show the release of pancreatic enzymes will be done. These include: Increased blood amylase level Increased serum blood lipase level Increased urine amylase ... swelling of the pancreas include: CT scan of the abdomen MRI of ...

  5. 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 ...

  6. The Artificial Pancreas: How Sweet Engineering Will Solve Bitter Problems

    PubMed Central

    Klonoff, David C.

    2007-01-01

    An artificial pancreas is a closed-loop system containing only synthetic materials which substitutes for an endocrine pancreas. No artificial pancreas system is currently approved; however, devices that could become components of such a system are now becoming commercially available. An artificial pancreas will consist of functionally integrated components that will continuously sense glucose levels, determine appropriate insulin dosages, and deliver the insulin. Any proposed closed loop system will be closely scrutinized for its safety, efficacy, and economic impact. Closed loop control utilizes models of glucose homeostasis which account for the influences of feeding, stress, insulin, exercise, and other factors on blood glucose levels. Models are necessary for understanding the relationship between blood glucose levels and insulin dosing; developing algorithms to control insulin dosing; and customizing each user's system based on individual responses to factors that influence glycemia. Components of an artificial pancreas are now being developed, including continuous glucose sensors; insulin pumps for parenteral delivery; and control software, all linked through wireless communication systems. Although a closed-loop system providing glucagon has not been reported in 40 years, the use of glucagon to prevent hypoglycemia is physiologically attractive and future devices might utilize this hormone. No demonstration of long-term closed loop control of glucose in a free-living human with diabetes has been reported to date, but many centers around the world are working on closed loop control systems. It is expected that many types of artificial pancreas systems will eventually be available, and they will greatly benefit patients with diabetes. PMID:19888383

  7. Under Utilization of Pancreas Transplants in Cystic Fibrosis Recipients in the United Network Organ Sharing (UNOS) Data 1987-2014.

    PubMed

    Usatin, D J; Perito, E R; Posselt, A M; Rosenthal, P

    2016-05-01

    Despite a high prevalence of pancreatic endocrine and exocrine insufficiency in cystic fibrosis (CF), pancreas transplantation is rarely reported. United Network for Organ Sharing (UNOS) data were used to examine utilization of pancreas transplant and posttransplant outcomes in CF patients. Between 1987-2014, CF patients (N = 4600) underwent 17 liver-pancreas, three lung-pancreas, one liver-lung pancreas, four kidney-pancreas, and three pancreas-only transplants. Of the 303 CF patients who received liver transplantation, 20% had CF-related diabetes (CFRD) before transplantation, and nine of those received a liver-pancreas transplant. Of 4241 CF patients who underwent lung transplantation, 33% had CFRD before transplantation, and three of those received a pancreas transplant. Of 49 CF patients who received a liver-lung transplant, 57% had CFRD before transplantation and one received a pancreas transplant. Posttransplantation diabetes developed in 7% of CF pancreas transplant recipients versus 24% of CF liver and 29% of CF lung recipients. UNOS has no data on pancreas exocrine insufficiency. Two-year posttransplantation survival was 88% after liver-pancreas transplant, 33% after lung-pancreas transplant, and 100% after pancreas-kidney and pancreas-only transplants. Diabetes is common pretransplantation and posttransplantation in CF solid organ transplant recipients, but pancreas transplantation remains rare. Further consideration of pancreas transplant in CF patients undergoing other solid organ transplant may be warranted.

  8. Giant mucinous cystic adenoma with pancreatic atrophy mimicking dorsal agenesis of the pancreas

    PubMed Central

    Gagnière, Johan; Dupré, Aurélien; Ines, David Da; Tixier, Lucie; Pezet, Denis; Buc, Emmanuel

    2014-01-01

    Mucinous cystic adenoma (MCA) of the pancreas is a rare benign cystic tumor with ovarian-like stroma and lack of communication with the pancreatic ductal system. The ovarian tissue is incorporated from the left gonad within the dorsal pancreas during embryogenesis. Consequently, congenital dorsal agenesis of the pancreas (DAP) cannot be associated with MCA. We report the case of a giant MCA associated with atrophy of the dorsal pancreas mimicking complete DAP. Pancreato-magnetic resonance imaging failed to identify the dorsal pancreas but the absence of diabetes mellitus and compression of the splenic vein with major tributaries rectified the diagnosis of secondary atrophy of the distal pancreas. Unusual proximal location of the cyst in the pancreas may have induced chronic obstruction of both the dorsal pancreatic duct and the splenic vein, with secondary atrophy of the distal pancreas. PMID:24672649

  9. [Solitary fibrous tumor of the pancreas. A case report].

    PubMed

    Chatti, Kais; Nouira, Kais; Ben Reguigua, Meher; Bedioui, Haykel; Oueslati, Saddik; Laabidi, Besma; Alaya, Mohamed; Ben Abdallah, Nejmeddine

    2006-02-01

    Solitary fibrous tumour (SFT), a rare mesenchymal neoplasm usually arising from the pleura, may also occur in many other extra pleural sites. It has exceptionally been described in the pancreas. This report describes the case of a benign SFT of the pancreas occurring in a 41-year-old man who presented with a solid epigastric mass. Pathological and immunohistochemical findings are presented. Imaging features on ultrasonography, CT, MRI, and arteriography are widely detailed. Surgical resection of the tumour was performed, and the patient died from postoperative complications.

  10. 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

  11. 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.

  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.

  13. 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

  14. Cutting edge: retrobulbar inflammation, adipogenesis, and acute orbital congestion in a preclinical female mouse model of Graves' orbitopathy induced by thyrotropin receptor plasmid-in vivo electroporation.

    PubMed

    Moshkelgosha, Sajad; So, Po-Wah; Deasy, Neil; Diaz-Cano, Salvador; Banga, J Paul

    2013-09-01

    Graves' orbitopathy (GO) is a complication in Graves' disease (GD) but mechanistic insights into pathogenesis remain unresolved, hampered by lack of animal model. The TSH receptor (TSHR) and perhaps IGF-1 receptor (IGF-1R) are considered relevant antigens. We show that genetic immunization of human TSHR (hTSHR) A-subunit plasmid leads to extensive remodeling of orbital tissue, recapitulating GO. Female BALB/c mice immunized with hTSHR A-subunit or control plasmids by in vivo muscle electroporation were evaluated for orbital remodeling by histopathology and magnetic resonance imaging (MRI). Antibodies to TSHR and IGF-1R were present in animals challenged with hTSHR A-subunit plasmid, with predominantly TSH blocking antibodies and were profoundly hypothyroid. Orbital pathology was characterized by interstitial inflammation of extraocular muscles with CD3+ T cells, F4/80+ macrophages, and mast cells, accompanied by glycosaminoglycan deposition with resultant separation of individual muscle fibers. Some animals showed heterogeneity in orbital pathology with 1) large infiltrate surrounding the optic nerve or 2) extensive adipogenesis with expansion of retrobulbar adipose tissue. A striking finding that underpins the new model were the in vivo MRI scans of mouse orbital region that provided clear and quantifiable evidence of orbital muscle hypertrophy with protrusion (proptosis) of the eye. Additionally, eyelid manifestations of chemosis, including dilated and congested orbital blood vessels, were visually apparent. Immunization with control plasmids failed to show any orbital pathology. Overall, these findings support TSHR as the pathogenic antigen in GO. Development of a new preclinical model will facilitate molecular investigations on GO and evaluation of new therapeutic interventions.

  15. 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.

  16. 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

  17. Pili play an important role in enhancing the bacterial clearance from the middle ear in a mouse model of acute otitis media with Moraxella catarrhalis.

    PubMed

    Kawano, Toshiaki; Hirano, Takashi; Kodama, Satoru; Mitsui, Marcelo Takahiro; Ahmed, Kamruddin; Nishizono, Akira; Suzuki, Masashi

    2013-03-01

    Moraxella catarrhalis is a Gram-negative aerobic diplococcus that is currently the third most frequent cause of bacterial acute otitis media (AOM) in children. In this study, we developed an experimental murine AOM model by inoculating M. catarrhalis in the middle ear bulla and studied the local response to this inoculation, and modulation of its course by the pili of M. catarrhalis. The pili-positive and pili-negative M. catarrhalis showed differences in bacterial clearance and infiltration of inflammatory cells in the middle ear. Pili-negative M. catarrhalis induced a more delayed and prolonged immune response in the middle ear than that of pili-positive M. catarrhalis. TLR2, -4, -5 and -9 mRNA expression was upregulated in neutrophils that infiltrated the middle ear cavity during AOM caused by both pili-positive and pili-negative bacteria. TLR5 mRNA expression and TLR5 protein in the neutrophils were induced more robustly by pili-positive M. catarrhalis. This immune response is likely to be related to neutrophil function such as toll-like 5-dependent phagocytosis. Our results show that mice may provide a useful AOM model for studying the role of M. catarrhalis. Furthermore, we show that pili play an important role in enhancing M. catarrhalis clearance from the middle ear that is probably mediated through neutrophil-dependent TLR5 signaling.

  18. Acute blockage of voltage-gated K⁺ currents by 17β-estradiol in mouse neuroblastoma N2A cells.

    PubMed

    Li, Xiaoqing; Hao, Xuran; Cheng, Bo; Li, Xiantao

    2014-05-28

    In this study, whole-cell recording was carried out to explore the effects of 17β-estradiol on voltage-gated K⁺ (Kv) currents in N2A cells. The acute exposure to 17β-estradiol, in a concentration-dependent manner, significantly inhibited the peak and steady-state currents through Kv channels, showing IC50 values of 3.6 and 3.8 μM, respectively. The reduction in both the amplitude and the decay rate of Kv currents, with an increase in depolarization, suggested that it was a voltage-dependent block. The activation and inactivation experiments were conducted to determine the exact causes of the inhibitory effects. The half-maximum activation potential (V₁/₂) was +8.1 mV in control and remained stable after exposure to 10 μM 17β-estradiol. For steady-state inactivation, the half-maximum inactivation potential (V₁/₂) was -45.0 mV and shifted right to -39.7 mV without a statistical difference, and the time constants of recovery from inactivation were not altered by 17β-estradiol, suggesting that the depression was not correlated with the inactivation gate. PMID:24784585

  19. Growing new endocrine pancreas in situ.

    PubMed

    Hammerman, Marc R

    2006-03-01

    Type 1 diabetes mellitus is a major cause of endstage renal disease in young adults. Maintenance of normoglycemia in type 1 diabetics using exogenous insulin is difficult under the best of circumstances. Transplantation therapies are limited by the scarcity of human donor organs, rendering a priority the identification of an alternative source for replacing insulin-secreting cells. Embryonic pancreatic primordia transplanted into diabetic animal hosts undergo selective endocrine differentiation in situ and normalize glucose tolerance. Pancreatic primordia can be transplanted across isogeneic, allogeneic, and both concordant (rat-to-mouse) and highly disparate (pig-to-rodent) xenogeneic barriers. Successful transplantation of pancreatic primordia depends on obtaining them at defined windows during embryonic development within which the risk of teratogenicity is eliminated, growth potential is maximized, and immunogenicity is reduced. Here we review studies exploring the potential for pancreatic organogenesis post-transplantation of embryonic primordia as a therapy for type 1 diabetes.

  20. Current topics in glycemic control by wearable artificial pancreas or bedside artificial pancreas with closed-loop system.

    PubMed

    Hanazaki, Kazuhiro; Munekage, Masaya; Kitagawa, Hiroyuki; Yatabe, Tomoaki; Munekage, Eri; Shiga, Mai; Maeda, Hiromichi; Namikawa, Tsutomu

    2016-09-01

    The incidence of diabetes is increasing at an unprecedented pace and has become a serious health concern worldwide during the last two decades. Despite this, adequate glycemic control using an artificial pancreas has not been established, although the 21st century has seen rapid developments in this area. Herein, we review current topics in glycemic control for both the wearable artificial pancreas for type 1 and type 2 diabetic patients and the bedside artificial pancreas for surgical diabetic patients. In type 1 diabetic patients, nocturnal hypoglycemia associated with insulin therapy remains a serious problem that could be addressed by the recent development of a wearable artificial pancreas. This smart phone-like device, comprising a real-time, continuous glucose monitoring system and insulin pump system, could potentially significantly reduce nocturnal hypoglycemia compared with conventional glycemic control. Of particular interest in this space are the recent inventions of a low-glucose suspend feature in the portable systems that automatically stops insulin delivery 2 h following a glucose sensor value <70 mg/dL and a bio-hormonal pump system consisting of insulin and glucagon pumps. Perioperative tight glycemic control using a bedside artificial pancreas with the closed-loop system has also proved safe and effective for not only avoiding hypoglycemia, but also for reducing blood glucose level variability resulting in good surgical outcomes. We hope that a more sophisticated artificial pancreas with closed-loop system will now be taken up for routine use worldwide, providing enormous relief for patients suffering from uncontrolled hyperglycemia, hypoglycemia, and/or variability in blood glucose concentrations. PMID:27142278

  1. Current topics in glycemic control by wearable artificial pancreas or bedside artificial pancreas with closed-loop system.

    PubMed

    Hanazaki, Kazuhiro; Munekage, Masaya; Kitagawa, Hiroyuki; Yatabe, Tomoaki; Munekage, Eri; Shiga, Mai; Maeda, Hiromichi; Namikawa, Tsutomu

    2016-09-01

    The incidence of diabetes is increasing at an unprecedented pace and has become a serious health concern worldwide during the last two decades. Despite this, adequate glycemic control using an artificial pancreas has not been established, although the 21st century has seen rapid developments in this area. Herein, we review current topics in glycemic control for both the wearable artificial pancreas for type 1 and type 2 diabetic patients and the bedside artificial pancreas for surgical diabetic patients. In type 1 diabetic patients, nocturnal hypoglycemia associated with insulin therapy remains a serious problem that could be addressed by the recent development of a wearable artificial pancreas. This smart phone-like device, comprising a real-time, continuous glucose monitoring system and insulin pump system, could potentially significantly reduce nocturnal hypoglycemia compared with conventional glycemic control. Of particular interest in this space are the recent inventions of a low-glucose suspend feature in the portable systems that automatically stops insulin delivery 2 h following a glucose sensor value <70 mg/dL and a bio-hormonal pump system consisting of insulin and glucagon pumps. Perioperative tight glycemic control using a bedside artificial pancreas with the closed-loop system has also proved safe and effective for not only avoiding hypoglycemia, but also for reducing blood glucose level variability resulting in good surgical outcomes. We hope that a more sophisticated artificial pancreas with closed-loop system will now be taken up for routine use worldwide, providing enormous relief for patients suffering from uncontrolled hyperglycemia, hypoglycemia, and/or variability in blood glucose concentrations.

  2. ESPEN Guidelines on Enteral Nutrition: Pancreas.

    PubMed

    Meier, R; Ockenga, J; Pertkiewicz, M; Pap, A; Milinic, N; Macfie, J; Löser, C; Keim, V

    2006-04-01

    The two major forms of inflammatory pancreatic diseases, acute and chronic pancreatitis, require different approaches in nutritional management, which are presented in the present guideline. This clinical practice guideline gives evidence-based recommendations for the use of ONS and TF in these patients. It was developed by an interdisciplinary expert group in accordance with officially accepted standards and is based on all relevant publications since 1985. The guideline was discussed and accepted in a consensus conference. In mild acute pancreatitis enteral nutrition (EN) has no positive impact on the course of disease and is only recommended in patients who cannot consume normal food after 5-7 days. In severe necrotising pancreatitis EN is indicated and should be supplemented by parenteral nutrition if needed. In the majority of patients continuous TF with peptide-based formulae is possible. The jejunal route is recommended if gastric feeding is not tolerated. In chronic pancreatitis more than 80% of patients can be treated adequately with normal food supplemented by pancreatic enzymes. 10-15% of all patients require nutritional supplements, and in approximately 5% tube feeding is indicated.

  3. 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.

  4. Pathophysiology of gene-targeted mouse models for cystic fibrosis.

    PubMed

    Grubb, B R; Boucher, R C

    1999-01-01

    Pathophysiology of Gene-Targeted Mouse Models for Cystic Fibrosis. Physiol. Rev. 79, Suppl.: S193-S214, 1999. - Mutations in the gene causing the fatal disease cystic fibrosis (CF) result in abnormal transport of several ions across a number of epithelial tissues. In just 3 years after this gene was cloned, the first CF mouse models were generated. The CF mouse models generated to date have provided a wealth of information on the pathophysiology of the disease in a variety of organs. Heterogeneity of disease in the mouse models is due to the variety of gene-targeting strategies used in the generation of the CF mouse models as well as the diversity of the murine genetic background. This paper reviews the pathophysiology in the tissues and organs (gastrointestinal, airway, hepatobiliary, pancreas, reproductive, and salivary tissue) involved in the disease in the various CF mouse models. Marked similarities to and differences from the human disease have been observed in the various murine models. Some of the CF mouse models accurately reflect the ion-transport abnormalities and disease phenotype seen in human CF patients, especially in gastrointestinal tissue. However, alterations in airway ion transport, which lead to the devastating lung disease in CF patients, appear to be largely absent in the CF mouse models. Reasons for these unexpected findings are discussed. This paper also reviews pharmacotherapeutic and gene therapeutic studies in the various mouse models. PMID:9922382

  5. Progression of alcoholic acute to chronic pancreatitis.

    PubMed Central

    Ammann, R W; Muellhaupt, B

    1994-01-01

    Alcoholic chronic pancreatitis usually progresses from acute attacks to chronic pancreatitis within one to 19 years. The factors responsible for the appreciable variability in progression are unclear. In this study the relation between progression and the incidence and severity of acute episodes in a large cohort of patients with alcoholic chronic pancreatitis was analysed. All patients with at least one documented episode of acute pancreatitis have been studied prospectively over the past 30 years according to our protocol. Patients were classified according to their long term course into (a) calcific (n = 185), (b) non-calcific (n = 30), and (c) non-progressive (n = 39) chronic pancreatitis groups. The yearly incidence of acute attacks of pancreatitis was significantly higher in groups (a) and (b) than in group (c). Furthermore, the progression rate to advanced chronic pancreatitis (groups (a) and (b)) correlated with the incidence of severe pancreatitis (associated with pseudocysts in more than 55%). Pseudocysts were located primarily in the cephalic pancreas in groups (a) and (b) (58-71%) and in the pancreatic tail in group (c) (61%). In conclusion, these data suggest that the progression of acute to chronic pancreatitis is closely related to the incidence and severity of acute attacks. This finding and the primary location of pseudocysts in the cephalic pancreas (groups (a) plus (b)) are compatible with the 'necrosis-fibrosis' pathogenetic hypothesis. PMID:8174996

  6. 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

  7. 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

  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. Pancreas β cell regeneration and type 1 diabetes (Review)

    PubMed Central

    WU, JINXIAO; YANG, XIYAN; CHEN, BIN; XU, XIUPING

    2015-01-01

    Diabetes mellitus, which may cause hyperglycemia and a number of complications, mostly results from a deficiency of β cell mass (type 1 diabetes) or a limitation of β cell function (type 2 diabetes). Currently, enhancing β cell regeneration and increasing cell proliferation have not only been described in experimental diabetes models, but have also been proven to improve outcomes for patients with diabetes. Therefore, understanding the mechanisms controlling the development and regeneration of β cells in the human pancreas may be helpful for the treatment of β cell-deficient disease. In this review, we first introduce the various cell types in the adult pancreas and thereby clarify their functions and origins. Then, the known mechanisms of β cell development and expansion in the normal human pancreas are described. The potential mechanisms of β cell regeneration, including β cell self-replication, neogenesis from non-β cell precursors and transdifferentiation from α cells, are discussed in the next part. Finally, the ability of the pancreas to regenerate mature β cells is explored in pathological conditions, including type 1 diabetes, chronic pancreatitis and persistent hyperinsulinemic hypoglycemia of infancy. PMID:25667609

  10. Stimulus-secretion coupling in the developing exocrine pancreas

    SciTech Connect

    Chang, A.Y.S.

    1986-01-01

    Acinar cells of the embryonic pancreas are filled with zymogen granules containing, among others, the secretory protein, cholecystokinin (CCK) ..cap alpha..-amylase, the rate of amylase secretion from pancreatic lobules incubated in vitro was not increased in response to CCK. In contrast, the rate of CCK-stimulated amylase discharge from the neonatal pancreas was increased 4- to 8-fold above that seen in the embryonic gland. The postnatal amplification of secretory responsiveness was not associated with an increase in the level of /sup 125/I-CCK octapeptide specifically bound/cell equivalent or a change in the affinity of binding. Light microscopic autoradiography revealed a similar /sup 125/I-CCK-33 labeling pattern in pancreatic lobules from both ages with autoradiographic grains specifically localized at the periphery of acinar cells. In order to determine whether CCK binding is coupled to a rise in the cytosolic Ca/sup + +/concentration, (Ca/sup + +/)c, in the embryonic pancreas, /sup 45/Ca/sup + +/ efflux from tracer-loaded lobules was measured. Efflux of /sup 45/Ca/sup + +/ from both embryonic and neonatal pancreas was comparably increased in the presence of CCK.

  11. The surgical anatomy of the lymphatic system of the pancreas.

    PubMed

    Cesmebasi, Alper; Malefant, Jason; Patel, Swetal D; Du Plessis, Maira; Renna, Sarah; Tubbs, R Shane; Loukas, Marios

    2015-05-01

    The lymphatic system of the pancreas is a complex, intricate network of lymphatic vessels and nodes responsible for the drainage of the head, neck, body, and tail of the pancreas. Its anatomical divisions and embryological development have been well described in the literature with emphasis on its clinical relevance in regards to pancreatic pathologies. A thorough knowledge and understanding of the lymphatic system surrounding the pancreas is critical for physicians in providing diagnostic and treatment strategies for patients with pancreatic cancer and pancreatitis. Pancreatic cancer has an extremely poor prognosis and is a notable cause of morbidity and mortality worldwide. Although a surgeon may try to predict the routes for metastasis for pancreatic cancer, the complexity of this system presents difficulty due to variable drainage patterns. Pancreatitis also presents as another severe disease which has been shown to have an association with the lymphatics. The aim of this article is to review the literature on the lymphatics of the pancreas, pancreatic pathologies, and the available imaging methodologies used to study the pancreatic lymphatics.

  12. FDA Approves 1st 'Artificial Pancreas' for Type 1 Diabetes

    MedlinePlus

    ... Juvenile Diabetes Research Foundation), said until there's a cure for type 1 diabetes, "I know that the artificial pancreas will change ... welcome step forward for people with type 1 diabetes," he added. "It will be many years for a biologic cure or prevention, and it is exciting to know ...

  13. 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

  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. Pancreatic autoantibodies after pancreas-kidney transplantation - do they matter?

    PubMed

    Martins, La Salete; Henriques, Antonio C; Fonseca, Isabel M; Rodrigues, Anabela S; Oliverira, José C; Dores, Jorge M; Dias, Leonidio S; Cabrita, Antonio M; Silva, José D; Noronha, Irene L

    2014-04-01

    Type 1 diabetes recurrence has been documented in simultaneous pancreas-kidney transplants (SPKT), but this diagnosis may be underestimated. Antibody monitoring is the most simple, noninvasive, screening test for pancreas autoimmune activity. However, the impact of the positive autoimmune markers on pancreas graft function remains controversial. In our cohort of 105 SPKT, we studied the cases with positive pancreatic autoantibodies. They were immunosuppressed with antithymocyte globulin, tacrolimus, mycophenolate, and steroids. The persistence or reappearance of these autoantibodies after SPKT and factors associated with their evolution and with graft outcome were analyzed. Pancreatic autoantibodies were prospectively monitored. Serum samples were collected before transplantation and at least once per year thereafter. At the end of the follow-up (maximum 138 months), 43.8% of patients were positive (from pre-transplant or after recurrence) for at least one autoantibody - the positive group. Antiglutamic acid decarboxylase was the most prevalent (31.4%), followed by anti-insulin (8.6%) and anti-islet cell autoantibodies (3.8%). Bivariate analysis showed that the positive group had higher fasting glucose, higher glycated hemoglobin (HbA1c), lower C-peptide levels, and a higher number of HLA-matches. Analyzing the sample divided into four groups according to pre-/post-transplant autoantibodies profile, the negative/positive group tended to present the higher HbA1c values. Multivariate analysis confirmed the significant association between pancreas autoimmunity and HbA1c and C-peptide levels. Positivity for these autoantibodies pre-transplantation did not influence pancreas survival. The unfavorable glycemic profile observed in the autoantibody-positive SPKT is a matter of concern, which deserves further attention.

  16. Pancreatic stellate cells--multi-functional cells in the pancreas.

    PubMed

    Masamune, Atsushi; Shimosegawa, Tooru

    2013-01-01

    There is accumulating evidence that activated pancreatic stellate cells (PSCs) play a pivotal role in pancreatic fibrosis in chronic pancreatitis and pancreatic cancer. In addition, we have seen great progress in our understanding of the cell biology of PSCs and the interactions between PSCs and other cell types in the pancreas. In response to pancreatic injury or inflammation, quiescent PSCs are activated to myofibroblast-like cells. Recent studies have shown that the activation of intracellular signaling pathways such as mitogen-activated protein kinases plays a role in the activation of PSCs. microRNAs might also play a role, because the microRNA expression profiles are dramatically altered in the process of activation. In addition to producing extracellular matrix components such as type I collagen, PSCs have a wide variety of cell functions related to local immunity, inflammation, angiogenesis, and exocrine and endocrine functions in the pancreas. From this point of view, the interactions between PSCs and other cell types such as pancreatic exocrine cells, endocrine cells, and cancer cells have attracted increasing attention of researchers. PSCs might regulate exocrine functions in the pancreas through the cholecystokinin-induced release of acetylcholine. PSCs induce apoptosis and decrease insulin expression in β-cells, suggesting a novel mechanism of diabetes in diseased pancreas. PSCs promote the progression of pancreatic cancer by multiple mechanisms. Recent studies have shown that PSCs induce epithelial-mesenchymal transition and enhance the stem-cell like features of pancreatic cancer cells. In conclusion, PSCs should now be recognized as not only profibrogenic cells but as multi-functional cells in the pancreas.

  17. Cystitis - acute

    MedlinePlus

    Uncomplicated urinary tract infection; UTI - acute; Acute bladder infection; Acute bacterial cystitis ... International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 ...

  18. Comparative study of protective activities of Neospora caninum bradyzoite antigens, NcBAG1, NcBSR4, NcMAG1, and NcSAG4, in a mouse model of acute parasitic infection.

    PubMed

    Uchida, Masaki; Nagashima, Kotomi; Akatsuka, Yui; Murakami, Takashi; Ito, Akira; Imai, Soichi; Ike, Kazunori

    2013-02-01

    Neospora caninum is an obligate intracellular protozoan parasite that causes severe neuromuscular diseases, repeated abortion, stillbirth, and congenital infection in livestock and companion animals. The development of an effective vaccine against neosporosis in cattle is an important issue due to the significant worldwide economic impact of this disease. We evaluated the immunogenicity of four bradyzoite antigens, NcBAG1 (first described in this study), NcBSR4, NcMAG1, and NcSAG4, using an acute infection mouse model to determine synergistic effects with the tachyzoite antigen as a candidate for vaccine production. Mice were inoculated with the recombinant vaccines (r-)NcBAG1, rNcBSR4, rNcMAG1, rNcSAG4, or phosphate-buffered saline (PBS) (adjuvant control group) in an oil-in-water emulsion with bitter gourd extract, a Th1 immune stimulator, or PBS alone as the infection control group. Mice inoculated with each vaccine developed antigen-specific IgG1 and IgG2a antibodies and isolated splenocytes from mice produced high levels of interferon-γ when infected with the N. caninum tachyzoite. The mice inoculated with rNcBAG1, rNcMAG1, or rNcSAG4 developed slight to moderate clinical symptoms but did not succumb to infection. In contrast, rNcBSR4 and both control groups developed severe disease and some mice required euthanasia. The parasitic burden in the brain tissues of vaccinated mice was assessed by N. caninum-specific real-time PCR at 5 weeks after infection. The parasite load in rNcBAG1-, rNcMAG1-, and rNcSAG4-inoculated mice was significantly lower than that in adjuvant and infection control mice. Therefore, these antigens may be useful for the production of a N. caninum-specific vaccination protocol.

  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. Consensus guidelines on severe acute pancreatitis.

    PubMed

    Pezzilli, Raffaele; Zerbi, Alessandro; Campra, Donata; Capurso, Gabriele; Golfieri, Rita; Arcidiacono, Paolo G; Billi, Paola; Butturini, Giovanni; Calculli, Lucia; Cannizzaro, Renato; Carrara, Silvia; Crippa, Stefano; De Gaudio, Raffaele; De Rai, Paolo; Frulloni, Luca; Mazza, Ernesto; Mutignani, Massimiliano; Pagano, Nico; Rabitti, Piergiorgio; Balzano, Gianpaolo

    2015-07-01

    This Position Paper contains clinically oriented guidelines by the Italian Association for the Study of the Pancreas (AISP) for the diagnosis and treatment of severe acute pancreatitis. The statements were formulated by three working groups of experts who searched and analysed the most recent literature; a consensus process was then performed using a modified Delphi procedure. The statements provide recommendations on the most appropriate definition of the complications of severe acute pancreatitis, the diagnostic approach and the timing of conservative as well as interventional endoscopic, radiological and surgical treatments.

  1. Agenesis of the dorsal pancreas and its association with pancreatic tumors.

    PubMed

    Sakpal, Sujit Vijay; Sexcius, Lucretia; Babel, Nitin; Chamberlain, Ronald Scott

    2009-05-01

    Morphogenesis of the pancreas is a complex process; nevertheless, congenital anomalies are rare. At embryogenesis, the pancreas develops from the endoderm-lined dorsal and ventral buds of the duodenum. The ventral bud gives rise to the lower head and uncinate process of the pancreas; whereas, the dorsal bud gives rise to the upper head, isthmus, body, and tail of the pancreas. Rarely, developmental failure of the dorsal pancreatic bud at embryogenesis results in the agenesis of the dorsal pancreas--neck, body, and tail. Even rarer is the association of pancreatic tumors with agenesis of the dorsal pancreas. In addition to citing our case, we provide a comprehensive review on agenesis of the dorsal pancreas and its association with pancreatic tumors.

  2. ESPEN Guidelines on Parenteral Nutrition: pancreas.

    PubMed

    Gianotti, L; Meier, R; Lobo, D N; Bassi, C; Dejong, C H C; Ockenga, J; Irtun, O; MacFie, J

    2009-08-01

    Assessment of the severity of acute pancreatitis (AP), together with the patient's nutritional status is crucial in the decision making process that determines the need for artificial nutrition. Both should be done on admission and at frequent intervals thereafter. The indication for nutritional support in AP is actual or anticipated inadequate oral intake for 5-7 days. This period may be shorter in those with pre-existing malnutrition. Substrate metabolism in severe AP is similar to that in severe sepsis or trauma. Parenteral amino acids, glucose and lipid infusion do not affect pancreatic secretion and function. If lipids are administered, serum triglycerides must be monitored regularly. The use of intravenous lipids as part of parenteral nutrition (PN) is safe and feasible when hypertriglyceridemia is avoided. PN is indicated only in those patients who are unable to tolerate targeted requirements by the enteral route. As rates of EN tolerance increase then volumes of PN should be decreased. When PN is administered, particular attention should be given to avoid overfeeding. When PN is indicated, a parenteral glutamine supplementation should be considered. In chronic pancreatitis PN may, on rare occasions, be indicated in patients with gastric outlet obstruction secondary to duodenal stenosis or those with complex fistulation, and in occasional malnourished patients prior to surgery.

  3. Surgical treatment of hydatid cysts of the pancreas.

    PubMed

    Ismail, K; Haluk, G I; Necati, O

    1991-01-01

    This series consists of seven patients with hydatid cysts of the pancreas; five females and two males, with an average age of 31 years. In a follow-up extending up to 33 years, about a 50% rate of correct preoperative diagnosis was recorded. The most sensitive and effective diagnostic modalities such as latex agglutination, ultrasonic, radionuclide, computerized tomographic and magnetic resonance imaging techniques were not available till the late seventies and therefore were only used during diagnosis of the latter 3 cases. Four patients had cysts located in the head of the pancreas. Three cysts were situated in the body and tail. Two distal pancreatectomies, two cystectomies and three marsupialization and external drainage procedures were performed for the surgical management of these cases. Two of the marsupialized and externally drained patients had fistulas which eventually dried up within a month leading to a total morbidity of 29% and a mortality rate of nil. PMID:1938210

  4. Immunosuppression in pancreas transplantation: the Euro SPK trials and beyond.

    PubMed

    Malaise, J; De Roover, A; Squifflet, J P; Land, W; Neuhaus, P; Pratschke, J; Kahl, A; Pascher, A; Boas-Knoop, S; Arbogast, H; Hoffmann, J; Illner, W D; Seissler; Schlamp; Viebahn; Wunsch; Hajt; Klar, E; Scharek, W; Hopt; Pisarski, P; Drognitz, O; Thurow, C; Dette, K; Bechstein, W O; Woeste, G; Klempnauer, J; Becker, T; Lück; Neipp; Königsrainer, A; Steurer, W; Margreiter, R; Mark; Bonatti; Saudek, F; Boucek, P; Adamec, M; Havrdova, T; Koznarova, R; Vanrenterghem, Y; Pirenne, J; Maes, B; Kuypers, D; Coosemans, W; Evenepoel, P; van Ophem, D; Marcelis, V; van Vlem; Peeters; de Hemptinne; de Roose; Fernandez-Cruz, L; Ricart, M J; Nakache, R; Morel, P; Berney, T; Demuylder, S

    2008-01-01

    The Immunosuppression in Pancreas Transplantation was historically based on the fact that the pancreas is an extremely immunogenic organ. Quadruple drug therapy with polyclonal or monoclonal antibodies induction was the mainstay therapy since the introduction of Cyclosporine A. In the modern era of Immunosuppression, Mycophenolate Mofetil replaced Azathioprine while Tacrolimus-another potent calcineurin inhibitor-had-and still has-a difficult challenge to replaced Cyclosporine A, due to its potential diabetogenic effect. Thanks to the first two EuroSPK studies which prospectively tried to answer several questions in that field. But, the future challenge will be in understanding the impact of innate immunity and ischemic reperfusion injuries on the long-term graft function. Hopefully, new drugs will be available and tested to block unspecific deleterious reactions to attenuate the proinflammatory response. It will be the aim of the third Euro SPK Study.

  5. 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

  6. A novel strategy for long-term implantable artificial pancreas.

    PubMed

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

    2011-01-01

    Technology has recently changed type 1 diabetes treatment by introducing several advancements able to improve patients' quality of life. However, despite of several decades of research efforts, the dream of a fully-automated implanted artificial pancreas is quite far from its realization. The need for periodically restoring the implanted battery charge and refilling the implanted insulin reservoir are the main issues, for which invasive surgery, transcutaneous catheters or external portable devices are presently the only solutions. In this paper we propose a novel approach to these issues, describing a totally implanted closed-loop artificial pancreas with a wireless battery charger and a non-invasive strategy for insulin refilling, based on sensorized swallowable "insulin carrier" capsules. Such system has the potential to represent a final solution for diabetes treatment, by fully restoring patients' quality of life.

  7. Minor papilla cannulation and dorsal ductography in pancreas divisum.

    PubMed

    Benage, D; McHenry, R; Hawes, R H; O'Connor, K W; Lehman, G A

    1990-01-01

    Until recently, pancreas divisum represented a major technical barrier to a complete evaluation of pancreatic ductal anatomy. Technical refinements have now made it possible to achieve minor papilla cannulation and dorsal ductography in more than 90% of attempts. In 120 consecutive dorsal ductograms, structural pathology was demonstrated in 36 subjects (30%): chronic pancreatitis in 23, pancreatic stones in 10, pseudocyst(s) in 4, ductal "cut-off" in 7, pancreatic cancer in 3, and partial agenesis in 1 (some patients had more than one finding). For patients in whom alcohol abuse was excluded, ductal pathology was present in 25%. Abnormal ventral ductograms were present in only 8% of cases, demonstrating that dorsal ductography has an appreciable additional diagnostic yield. When the clinical situation indicates the need for pancreatography, minor papilla cannulation should be performed if major papilla cannulation fails or reveals only the ventral pancreatogram of pancreas divisum.

  8. PDX-1 functions as a master factor in the pancreas.

    PubMed

    Kaneto, Hideaki; Matsuoka, Taka-aki; Miyatsuka, Takeshi; Kawamori, Dan; Katakami, Naoto; Yamasaki, Yoshimitsu; Matsuhisa, Munehide

    2008-05-01

    Various pancreatic transcription factors are involved in pancreas development and beta-cell differentiation. Among them, pancreatic and duodenal homeobox factor-1 (PDX-1) plays a crucial role in pancreas development and beta-cell differentiation, and maintaining mature beta-cell function. MafA is a recently isolated beta-cell-specific transcription factor and functions as a potent activator of insulin gene transcription. These pancreatic transcription factors also play a crucial role in inducing surrogate beta-cells from non-beta-cells and thus could be therapeutic targets for diabetes. On the other hand, under diabetic conditions, expression and/or activities of PDX-1 and MafA in beta-cells are reduced, which leads to suppression of insulin biosynthesis and secretion. Thus, it is likely that alteration of such transcription factors explains, at least in part, the molecular mechanism for beta-cell glucose toxicity found in diabetes.

  9. 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

  10. 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

  11. 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

  12. 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

  13. Imaging of acute pancreatitis and its complications. Part 1: acute pancreatitis.

    PubMed

    Türkvatan, A; Erden, A; Türkoğlu, M A; Seçil, M; Yener, Ö

    2015-02-01

    Acute pancreatitis is an acute inflammatory disease of the pancreas that may also involve surrounding tissues or remote organs. The Atlanta classification of acute pancreatitis was introduced in 1992 and divides patients into mild and severe groups based on clinical and biochemical criteria. Recently, the terminology and classification scheme proposed at the initial Atlanta Symposium have been reviewed and a new consensus statement has been proposed by the Acute Pancreatitis Classification Working Group. Generally, imaging is recommended to confirm the clinical diagnosis, investigate the etiology, and grade the extend and severity of the acute pancreatitis. Ultrasound is the first-line imaging modality in most centers for the confirmation of the diagnosis of acute pancreatitis and the ruling out of other causes of acute abdomen, but it has limitations in the acute clinical setting. Computed tomography not only establishes the diagnosis of acute pancreatitis, but also enables to stage severity of the disease. Magnetic resonance imaging has earned an ever more important role in the diagnosis of acute pancreatitis. It is especially useful for imaging of patients with iodine allergies, characterizing collections and assessment of an abnormal or disconnected pancreatic duct. The purpose of this review article is to present an overview of the acute pancreatitis, clarify confusing terminology, underline the role of ultrasound, computed tomography and magnetic resonance imaging according to the proper clinical context and compare the advantages and limitations of each modality.

  14. 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

  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. Autoimmune diabetes recurrence should be routinely monitored after pancreas transplantation

    PubMed Central

    Martins, La Salete

    2014-01-01

    Autoimmune type 1 diabetes recurrence in pancreas grafts was first described 30 years ago, but it is not yet completely understood. In fact, the number of transplants affected and possibly lost due to this disease may be falsely low. There may be insufficient awareness to this entity by clinicians, leading to underdiagnosis. Some authors estimate that half of the immunological losses in pancreas transplantation are due to autoimmunity. Pancreas biopsy is the gold standard for the definitive diagnosis. However, as an invasive procedure, it is not the ideal approach to screen the disease. Pancreatic autoantibodies which may be detected early before graft dysfunction, when searched for, are probably the best initial tool to establish the diagnosis. The purpose of this review is to revisit the autoimmune aspects of type 1 diabetes and to analyse data about the identified autoantibodies, as serological markers of the disease. Therapeutic strategies used to control the disease, though with unsatisfactory results, are also addressed. In addition, the author’s own experience with the prospective monitoring of pancreatic autoantibodies after transplantation and its correlation with graft outcome will be discussed. PMID:25346891

  17. 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

  18. Composite pheochromocytoma masquerading as solid-pseudopapillary neoplasm of pancreas

    PubMed Central

    Gupta, Geetanjali; Saran, Ravindra Kumar; Godhi, Satyajit; Srivastava, Siddharth; Saluja, Sundeep Singh; Mishra, Pramod Kumar

    2015-01-01

    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

  19. [Symptomatic cyst of the pancreas and asymptomatic bilateral phaeochromocytoma

    PubMed

    Karvar, S; Breidert, M; Nagel, M; Kirsch, C; Pinkert, J; Ehninger, G

    2001-01-01

    Symptomatic cyst of the pancreas and asymptomatic bilateral phaeochromocytoma. HISTORY AND CLINICAL FINDINGS: A 39-year-old woman was admitted to our department of gastroenterology with recurrent epigastrical pain. Ten years previously the diagnosis of von Hippel-Lindau (VHL)-syndrome has been established. Two years before a germ line mutation in exon 3 of the VHL-tumour suppressor gene has been detected. The patient has a healthy son with a normal VHL-gene and four healthy siblings who had refused a genetic blood test. INVESTIGATIONS: At abdominal ultrasound at the head of the pancreas three 4 2 cm large cysts and in the region of the left adrenal gland a 2,9 2,7 cm large tumor were visible. MRI of the abdomen revealed in addition a 2,2 1,5 cm large tumour of the right adrenal gland. An asymptomatic biadrenal phaeochromocytoma was detected by elevated urine catecholamines and 123I-MIBG-scintigraphy. TREATMENT AND COURSE: The cysts of the pancreas were punctured under endosonographical control and analysis of the cyst fluid was not suspicious of a malignant cystic tumour. The patient had no further abdominal complaints. After oral treatment with the alpha-blocker phentolamine the biadrenal phaeochromocytoma was treated by retroperitoneal laparoscopic surgery in an organ-sparing fashion. Postoperatively ACTH-stimulating test revealed a normal cortisol response. CONCLUSION: Adrenocortical function can be preserved by la-paroscopic adrenal-sparing surgery in bilateral phaeochromocytoma.

  20. Ganglionar nervous cells and telocytes in the pancreas of Octodon degus: extra and intrapancreatic ganglionar cells and telocytes in the degus.

    PubMed

    Bosco, Cleofina; Díaz, Eugenia; Gutiérrez, Rodrigo; González, Jaime; Pérez, Johanna

    2013-10-01

    This study shows for the first time the presence of intra and extrapancreatic ganglionar neurons and telocytes in Octodon degus such as those described in human and guinea pig pancreas. Pancreatic ganglionar neurons were identified by their histological characteristics as well as their positive immunostaining with mouse anti-human neuron specific enolase (NSE) antibody. Somatostatin secreting delta cells (D cells) in the islets of Langerhans were identified by positive immunostaining with rabbit antihuman polyclonal somatostatin antibody. Electron microscopy evidenced the presence of some unmyelinated axons in the interlobular spaces or septa, usually located adjacent to blood vessels and the exocrine epithelial ducts. The presence of telocytes with at least 2 telopodes was observed in the interlobular space, frequently in close spatial relationship with blood vessels and nerve endings. Telocytes were often observed in the vicinity or even in close proximity with both secretory acini and exocrine epithelial ducts and regulatory nerves and blood vessel apparatuses. A possible framework has been put forward within which such structures might contribute to elicit physiological responses in the pancreas. Further studies of synaptic interactions within and between pancreatic neuron cells are needed to help clarify the morphological results reported here. A broad overview of the field of neurogastroenterology with focus on the pancreas of O. degus related to the enteric nervous system (ENS) is provided in order to help design future studies on the connections of specific neurons forming pancreatic pathways, their neurotransmission processes and how disruption of these pathways may contribute to pancreatic disease.

  1. 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...

  2. Antizyme inhibitor 2 hypomorphic mice. New patterns of expression in pancreas and adrenal glands suggest a role in secretory processes.

    PubMed

    López-Garcia, Carlos; Ramos-Molina, Bruno; Lambertos, Ana; López-Contreras, Andrés J; Cremades, Asunción; Peñafiel, Rafael

    2013-01-01

    The intracellular levels of polyamines, polycations implicated in proliferation, differentiation and cell survival, are regulated by controlling their biosynthesis, catabolism and transport. Antizymes and antizyme inhibitors are key regulatory proteins of polyamine levels by affecting ornithine decarboxylase, the rate-limiting biosynthetic enzyme, and polyamine uptake. We recently described the molecular function of a novel antizyme inhibitor (AZIN2). However, the physiological function of AZIN2 in mammals is mostly unknown. To gain insight on the tissue expression profile of AZIN2 and to find its possible physiological role, we have generated, transgenic mice with severe Azin2 hypomorphism. This mouse model expresses transgenic bacterial β-D-galactosidase as a reporter gene, under the control of the Azin2 endogenous promoter, what allows a very sensitive and specific detection of the expression of the gene in the different tissues of transgenic mice. The biochemical and histochemical analyses of β-D-galactosidase together with the quantification of Azin2 mRNA levels, corroborated that AZIN2 is mainly expressed in testis and brain, and showed for the first time that AZIN2 is also expressed in the adrenal glands and pancreas. In these tissues, AZIN2 was not expressed in all type of cells, but rather in specific type of cells. Thus, AZIN2 was mainly found in the haploid germinal cells of the testis and in different brain regions such as hippocampus and cerebellum, particularly in specific type of neurons. In the adrenal glands and pancreas, the expression was restricted to the adrenal medulla and to the Langerhans islets, respectively. Interestingly, plasma insulin levels were significantly reduced in the transgenic mice. These results support the idea that AZIN2 may have a role in the modulation of reproductory and secretory functions and that this mouse model might be an interesting tool for the progress of our understanding on the role of AZIN2 and polyamines in

  3. Zinc-associated acute pancreatitis in a dog.

    PubMed

    Mikszewski, J S; Saunders, H M; Hess, R S

    2003-04-01

    Zinc-induced haemolytic anaemia is a common phenomenon in dogs in the USA following the ingestion of pennies minted after 1982. A case of acute pancreatitis secondary to zinc toxicosis in a dog is described. Acute pancreatitis has been reported in humans, following the ingestion of liquid zinc chloride, but zinc-associated pancreatitis has not been reported previously in the dog. The mechanism of toxicity is unknown, although the pathophysiology may relate to the role of the pancreas in zinc excretion. Acute pancreatitis as a sequela to zinc toxicosis in the dog represents a complication that may prolong hospitalisation and worsen the prognosis.

  4. 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

  5. Characterization of Antibodies to Products of Proinsulin Processing Using Immunofluorescence Staining of Pancreas in Multiple Species.

    PubMed

    Asadi, Ali; Bruin, Jennifer E; Kieffer, Timothy J

    2015-08-01

    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.

  6. Acute Bronchitis

    MedlinePlus

    ... tightness. There are two main types of bronchitis: acute and chronic. Most cases of acute bronchitis get better within several days. But your ... that cause colds and the flu often cause acute bronchitis. These viruses spread through the air when ...

  7. 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

  8. [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

  9. 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

  10. A Modified Perfusion Method to Improve the Quality of Procured Donor Pancreas in Rats

    PubMed Central

    Du, Fu Tian; Lin, Hong Feng; Ding, Wei

    2012-01-01

    Background In this animal study, we evaluated a modified pancreas perfusion method to improve the quality of harvested pancreas in rats. In this model, the portal vein was used as the outflow route during the pancreas perfusion. Methods Forty-eight male Wistar rats were randomly divided into study group and control group, with 24 rats in each group. In the study group, the portal vein was used as outflow of perfusion. While in the control group, the post-hepatic vein (right artrium) was used as perfusion outflow. UW solution was used as perfusion and preservation solution. Pancreas tissue samples were collected at 6, 10, and 14 hours after perfusion and cold preserved for histology and immunohistochemistry examination, P-selection (PS) and ICAM-1 were determined. Pancreas samples were also examined using electronic microscope for ultra-structures. Results Compared with the study group, in the pancreas of control group there were significant pathological impairments and cellular ultra-structural alterations observed by immunohistochemistry and electronic microscope, and these impairments aggravated with time. There were mild histological alterations in the pancreas of study group. Conclusions During the donor pancreas perfusion, the early opening of portal vein as the outflow is better than the opening of the post-hepatic vein for the preservation of donor graft pancreas and the reduction of tissue impairments.

  11. 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

  12. 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

  13. Reg-II Is an Exocrine Pancreas Injury-Response Product That Is Up-Regulated by Keratin Absence or Mutation

    PubMed Central

    Zhong, Bihui; Strnad, Pavel; Toivola, Diana M.; Tao, Guo-Zhong; Ji, Xuhuai; Greenberg, Harry B.

    2007-01-01

    The major keratins in the pancreas and liver are keratins 8 and 18 (K8/K18), but their function seemingly differs in that liver K8/K18 are essential cytoprotective proteins, whereas pancreatic K8/K18 are dispensable. This functional dichotomy raises the hypothesis that K8-null pancreata may undergo compensatory cytoprotective gene expression. We tested this hypothesis by comparing the gene expression profile in pancreata of wild-type and K8-null mice. Most prominent among the up-regulated genes in K8-null pancreas was mRNA for regenerating islet-derived (Reg)-II, which was confirmed by quantitative reverse transcription-polymerase chain reaction and by an anti-Reg-II peptide antibody we generated. Both K8-null and wild-type mice express Reg-II predominantly in acinar cells as determined by in situ hybridization and immunostaining. Analysis of Reg-II expression in various keratin-related transgenic mouse models showed that its induction also occurs in response to keratin cytoplasmic filament collapse, absence, or ablation of K18 Ser52 but not Ser33 phosphorylation via Ser-to-Ala mutation, which represent situations associated with predisposition to liver but not pancreatic injury. In wild-type mice, Reg-II is markedly up-regulated in two established pancreatitis models in response to injury and during the recovery phase. Thus, Reg-II is a likely mouse exocrine pancreas cytoprotective candidate protein whose expression is regulated by keratin filament organization and phosphorylation. PMID:17898082

  14. Recurrent acute pancreatitis and persistent hyperamylasemia as a presentation of pancreatic osteoclastic giant cell tumor: an unusual presentation of a rare tumor.

    PubMed

    Rustagi, Tarun; Rampurwala, Murtuza; Rai, Mridula; Golioto, Michael

    2011-01-01

    Giant cell tumors of the pancreas are rare neoplasms divided into three forms: osteoclastic, pleomorphic, and mixed. We report an unusual case of a 62-year-old male presenting with recurrent acute pancreatitis and found to have a mass in the head of the pancreas on routine imaging. Endoscopic retrograde cholangiopancreatography showed a main pancreatic duct stricture, with brush cytology revealing the diagnosis of osteoclastic giant cell tumor of the pancreas. Whipple's procedure was successfully performed for resection of this tumor. and IAP.

  15. Robot-Assisted Subtotal Pancreas-Preserving Duodenectomy

    PubMed Central

    Gheza, Federico; Raimondi, Paolo; D'Ugo, Stefano; Calatayud, David; Giulianotti, Pier C.

    2012-01-01

    Background: Angiodysplasia of the duodenum is a rare disorder, often requiring surgical resection. Technical difficulties have made the use of the minimally invasive approach uncommon. Herein, we present a subtotal pancreas-preserving duodenectomy using robotic assistance. Methods: The patient is a 60-y-old female with a long medical history including chronic gastrointestinal bleeding due to angiodysplasia with intermittent melena, and requiring multiples blood transfusions. A capsule endoscopy and double-balloon upper endoscopy showed angiectasis, which appeared to be limited to the third and fourth portion of the duodenum and the proximal loops of the jejunum. Despite multiple endoscopic cauterizations, the patient continued to require blood transfusion for several years. The patient underwent a robot-assisted subtotal pancreas-preserving duodenectomy. Results: The operation lasted 420 min with minimal blood loss. The postoperative course was uneventful. The pathology report showed multiple small bowel mucosal and submucosal distorted and dilated vasculature, consistent with angiodysplasia. At 2-mo follow-up, the patient was totally asymptomatic. A barium swallow study showed contrast passed antegrade through the duodenojejunostomy with no evidence of obstruction, stricture, or leakage. Conclusion: The use of robotic assistance to perform a subtotal pancreas-preserving duodenectomy for the treatment of benign duodenal disease, such as angiodysplasia, is feasible and safe. The technical advantages include a high degree of freedom offered by the robotic instruments, as well as enhanced visualization, which allows for precise microdissection and microsuture, thereby preserving the benefits of minimally invasive surgery. The use of robotic technology allows for a wider range of indications for minimally invasive surgery. PMID:23484581

  16. Strategy to differentiate autoimmune pancreatitis from pancreas cancer

    PubMed Central

    Takuma, Kensuke; Kamisawa, Terumi; Gopalakrishna, Rajesh; Hara, Seiichi; Tabata, Taku; Inaba, Yoshihiko; Egawa, Naoto; Igarashi, Yoshinori

    2012-01-01

    Autoimmune pancreatitis (AIP) is a newly described entity of pancreatitis in which the pathogenesis appears to involve autoimmune mechanisms. Based on histological and immunohistochemical examinations of various organs of AIP patients, AIP appears to be a pancreatic lesion reflecting a systemic “IgG4-related sclerosing disease”. Clinically, AIP patients and patients with pancreatic cancer share many features, such as preponderance of elderly males, frequent initial symptom of painless jaundice, development of new-onset diabetes mellitus, and elevated levels of serum tumor markers. It is of uppermost importance not to misdiagnose AIP as pancreatic cancer. Since there is currently no diagnostic serological marker for AIP, and approach to the pancreas for histological examination is generally difficult, AIP is diagnosed using a combination of clinical, serological, morphological, and histopathological features. Findings suggesting AIP rather than pancreatic cancer include: fluctuating obstructive jaundice; elevated serum IgG4 levels; diffuse enlargement of the pancreas; delayed enhancement of the enlarged pancreas and presence of a capsule-like rim on dynamic computed tomography; low apparent diffusion coefficient values on diffusion-weighted magnetic resonance image; irregular narrowing of the main pancreatic duct on endoscopic retrograde cholangiopancreatography; less upstream dilatation of the main pancreatic duct on magnetic resonance cholangiopancreatography, presence of other organ involvement such as bilateral salivary gland swelling, retroperitoneal fibrosis and hilar or intrahepatic sclerosing cholangitis; negative work-up for malignancy including endoscopic ultrasound-guided fine needle aspiration; and steroid responsiveness. Since AIP responds dramatically to steroid therapy, accurate diagnosis of AIP can avoid unnecessary laparotomy or pancreatic resection. PMID:22416175

  17. Effects of prolonged ethanol intake and malnutrition on rat pancreas.

    PubMed Central

    López, J M; Bombi, J A; Valderrama, R; Giménez, A; Parés, A; Caballería, J; Imperial, S; Navarro, S

    1996-01-01

    Nutritional factors, especially the protein and fat content of the diet, may change pancreatic morphology after ethanol induced injury. This study was performed to delineate the combined effects of a low fat diet and longterm ethanol ingestion on the rat pancreas. Male Sprague-Dawley rats were maintained with five different diets for 12 weeks and the pancreas removed on the day they were killed. Rats fed a very low fat diet without ethanol (5% of total calories as lipid) developed malnutrition, pancreatic steatosis, and reduction in zymogen granules content. Animals fed a 35% lipid diet with ethanol also developed pancreatic steatosis but changes in zymogen granules content were not detected. Both malnutrition and longterm ethanol consumption increased pancreatic cholesterol ester content, and their effects were additive. Pancreatic steatosis was accompanied with hypercholesterolaemia. Amylase, lipase, and cholesterol esterase content were reduced in malnourished rats; but longterm ethanol ingestion, regardless of the nutritional state, increased lipase content and decreased amylase. It is suggested that high serum cholesterol concentrations and increased pancreatic lipase activity could cause accumulation of cholesterol esters in acinar cells. Fat accumulation in the pancreas has been reported as the earliest histopathological feature in alcoholic patients and may be responsible for cytotoxic effects on the acinar cells at the level of the cell membrane. Although it is difficult to extrapolate results in this animal study to the human situation, the results presented in this work might explain the higher incidence of pancreatitis is malnourished populations as well as in alcoholic subjects that is reported in dietary surveys. Images Figure 3 Figure 4 Figure 6 Figure 7 Figure 8 PMID:8801213

  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. Plasticity and dedifferentiation within the pancreas: development, homeostasis, and disease.

    PubMed

    Puri, Sapna; Folias, Alexandra E; Hebrok, Matthias

    2015-01-01

    Cellular identity is established by genetic, epigenetic, and environmental factors that regulate organogenesis and tissue homeostasis. Although some flexibility in fate potential is beneficial to overall organ health, dramatic changes in cellular identity can have disastrous consequences. Emerging data within the field of pancreas biology are revising current beliefs about how cellular identity is shaped by developmental and environmental cues under homeostasis and stress conditions. Here, we discuss the changes occurring in cellular states upon fate modulation and address how our understanding of the nature of this fluidity is shaping therapeutic approaches to pancreatic disorders such as diabetes and cancer.

  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.

  1. 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.

  2. 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

  3. 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

  4. 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.

  5. 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.

  6. The human pancreas proteome defined by transcriptomics and antibody-based profiling.

    PubMed

    Danielsson, Angelika; Pontén, Fredrik; Fagerberg, Linn; Hallström, Björn M; Schwenk, Jochen M; Uhlén, Mathias; Korsgren, Olle; Lindskog, Cecilia

    2014-01-01

    The pancreas is composed of both exocrine glands and intermingled endocrine cells to execute its diverse functions, including enzyme production for digestion of nutrients and hormone secretion for regulation of blood glucose levels. To define the molecular constituents with elevated expression in the human pancreas, we employed a genome-wide RNA sequencing analysis of the human transcriptome to identify genes with elevated expression in the human pancreas. This quantitative transcriptomics data was combined with immunohistochemistry-based protein profiling to allow mapping of the corresponding proteins to different compartments and specific cell types within the pancreas down to the single cell level. Analysis of whole pancreas identified 146 genes with elevated expression levels, of which 47 revealed a particular higher expression as compared to the other analyzed tissue types, thus termed pancreas enriched. Extended analysis of in vitro isolated endocrine islets identified an additional set of 42 genes with elevated expression in these specialized cells. Although only 0.7% of all genes showed an elevated expression level in the pancreas, this fraction of transcripts, in most cases encoding secreted proteins, constituted 68% of the total mRNA in pancreas. This demonstrates the extreme specialization of the pancreas for production of secreted proteins. Among the elevated expression profiles, several previously not described proteins were identified, both in endocrine cells (CFC1, FAM159B, RBPJL and RGS9) and exocrine glandular cells (AQP12A, DPEP1, GATM and ERP27). In summary, we provide a global analysis of the pancreas transcriptome and proteome with a comprehensive list of genes and proteins with elevated expression in pancreas. This list represents an important starting point for further studies of the molecular repertoire of pancreatic cells and their relation to disease states or treatment effects.

  7. Redox signaling in acute pancreatitis.

    PubMed

    Pérez, Salvador; Pereda, Javier; Sabater, Luis; Sastre, Juan

    2015-08-01

    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.

  8. 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

  9. Influence of bile flow interruption on acute experimental pancreatitis.

    PubMed

    Sarli, L; Gafà, M; Lupi, M; Peracchia, A

    1984-01-01

    The influence of bile flow interruption on the pathogenesis of acute pancreatitis has been evaluated in the rat. The pancreatitis was induced by Pfeffer's technique and the severity of the disease was assessed by a macroscopic examination of the pancreatic damage and the calculation of amylase-to-creatinine clearance ratio (ACCR) as well. The results showed that the bile reflux into the pancreas made the pancreatic lesions caused by stasis in the gland associated with hyperstimulation of exocrine secretion more severe. On the other hand the bile reflux had no influence when the pancreatitis was due to flowing back of duodenal contents into the pancreas (closed duodenal loop). It was concluded that the bile effect is probably consistent with a pressure mechanism. In addition the reliability of ACCR in the diagnosis of acute pancreatitis was confirmed, and the test was effective in detecting even milder pancreatic damages. PMID:6206023

  10. 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.

  11. Squamous Cell Carcinoma of the Pancreas: A Case Report and Review of Literature

    PubMed Central

    Brijbassie, Alan; Stelow, Edward; Shami, Vanessa M

    2014-01-01

    Primary squamous cell carcinoma (SCC) of the pancreas is an extremely rare tumor with the normal pancreas being entirely devoid of squamous cells. It, however, has been noted that during inflammatory episodes, squamous metaplasia of ductal columnar cells has been observed; however, transformation to SCC is rare. We herein describe a case of pancreatic SCC and provide a review of existing literature.

  12. 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 understan