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Fukui T, Kobayashi T, Jimbo E, Aida K, Shimada A, Oikawa Y, Mori Y, Fujii T, Koyama R, Kobayashi K, Takeshita A, Yagihashi S. Bi-glandular and persistent enterovirus infection and distinct changes of the pancreas in slowly progressive type 1 diabetes mellitus. Sci Rep 2023; 13:6977. [PMID: 37117225 PMCID: PMC10147722 DOI: 10.1038/s41598-023-33011-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 04/05/2023] [Indexed: 04/30/2023] Open
Abstract
In slowly progressive type 1 diabetes mellitus (SPIDDM), the pancreas shows sustained islet inflammation, pancreatitis, pancreatic acinar cell metaplasia/dysplasia (ADM), and intraepithelial neoplasia (PanIN), a precancerous lesion. The mechanisms underlying these changes remain unclear. The presence of enterovirus (EV) encoded-capsid protein 1 (VP1) and -2A protease (2Apro) and the innate immune responses of the pancreas were studied using immunohistochemistry and in situ hybridization in 12 SPIDDM and 19 non-diabetic control pancreases. VP1, 2Apro, and EV-RNA were detected in islets and the exocrine pancreas in all SPIDDM pancreases. Innate immune receptor, melanoma differentiation-associated gene 5 (MDA5), and interferon (IFN)-beta1 were intensified in the islets of SPIDDM patients with short disease duration. However, expressions of MDA5 and IFN-beta1were suppressed in those with longer disease duration. CD3+ T cell infiltration was observed in the VP1- and insulin-positive islets (insulitis) and exocrine acinar cells. CD11c+ dendritic cells (DCs) in islets were scarce in long-term SPIDDM. This study showed the consistent presence of EV, suggesting an association with inflammatory changes in the endocrine and exocrine pancreas in SPIDDM. Suppressed expressions of MDA5 and IFN-beta1, as well as decreased numbers of DCs in the host cells, may contribute to persistent EV infection and induction of ADM/PanIN lesions, which may potentially provide a scaffold for pancreatic neoplasms.
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Affiliation(s)
- Tomoyasu Fukui
- Division of Immunology and Molecular Medicine, Okinaka Memorial Institute for Medical Research, Tokyo, Japan
- Division of Diabetes, Metabolism and Endocrinology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Tetsuro Kobayashi
- Division of Immunology and Molecular Medicine, Okinaka Memorial Institute for Medical Research, Tokyo, Japan.
- Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan.
| | - Erika Jimbo
- Division of Immunology and Molecular Medicine, Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Kaoru Aida
- Department of Diabetes and Endocrinology, Kanoiwa Hospital, Yamanashi, Japan
| | - Akira Shimada
- Department of Endocrinology and Diabetes, Saitama Medical University, Saitama, Japan
| | - Yoichi Oikawa
- Department of Endocrinology and Diabetes, Saitama Medical University, Saitama, Japan
| | - Yasumichi Mori
- Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan
| | - Takeshi Fujii
- Department of Pathology, Toranomon Hospital, Tokyo, Japan
| | - Rikako Koyama
- Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan
| | - Kazuhiko Kobayashi
- Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Akira Takeshita
- Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan
| | - Soroku Yagihashi
- Department of Exploratory Medicine on Nature, Life, and Man, Toho University of Medicine, Chiba, Japan
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2
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A Monovalent Mt10-CVB3 Vaccine Prevents CVB4-Accelerated Type 1 Diabetes in NOD Mice. Vaccines (Basel) 2022; 11:vaccines11010076. [PMID: 36679922 PMCID: PMC9864234 DOI: 10.3390/vaccines11010076] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 12/27/2022] [Accepted: 12/27/2022] [Indexed: 12/30/2022] Open
Abstract
Enteroviruses, which include Coxsackieviruses, are a common cause of virus infections in humans, and multiple serotypes of the group B Coxsackievirus (CVB) can induce similar diseases. No vaccines are currently available to prevent CVB infections because developing serotype-specific vaccines is not practical. Thus, developing a vaccine that induces protective immune responses for multiple serotypes is desired. In that direction, we created a live-attenuated CVB3 vaccine virus, designated mutant (Mt)10, that offers protection against myocarditis and pancreatitis induced by CVB3 and CVB4 in disease-susceptible A/J mice. Here, we report that the Mt10 vaccine protected against CVB4-triggered type 1 diabetes (T1D) in non-obese diabetic (NOD) mice but the expected subsequent development of spontaneous T1D in these genetically predisposed NOD mice was not altered. We noted that Mt10 vaccine induced significant amounts of neutralizing antibodies, predominantly of the IgG2c isotype, and the virus was not detected in vaccine-challenged animals. Furthermore, monitoring blood glucose levels-and to a lesser extent, insulin antibodies-was found to be helpful in predicting vaccine responses. Taken together, our data suggest that the monovalent Mt10 vaccine has the potential to prevent infections caused by multiple CVB serotypes, as we have demonstrated in various pre-clinical models.
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Fewel CE, Weiss JR, Harrington JC. OUP accepted manuscript. J Surg Case Rep 2022; 2022:rjac074. [PMID: 35300287 PMCID: PMC8923371 DOI: 10.1093/jscr/rjac074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 02/15/2022] [Indexed: 11/17/2022] Open
Abstract
A 41-year-old female presented with an 8-month history of right upper quadrant pain, exacerbated by ingestion of saturated fats. The patient was positive for antibodies to Coxsackievirus serotype B4, established by an investigation incited by an acute episode of pleurodynia 8 months before the current presentation. Imaging studies including a hepatobiliary iminodiacetic acid scan showed no gallbladder structural or functional abnormalities. Laboratory studies indicated pancreatic enzyme insufficiency associated with below-normal lipase and amylase levels. Patient symptomology was consistent with cholecystitis with positive Murphy’s sign, so cholecystectomy was recommended. Post-surgery pathological report confirmed chronic acalculous cholecystitis. Patient demonstrated full recovery, indicated by return of normal pancreatic enzymes levels and resolution of abdominal pain.
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Affiliation(s)
- Connor E Fewel
- Department of Microbiology, Immunology and Pharmacology School of Medicine, St. George's University, Grenada, West Indies
| | - Joshua R Weiss
- Department of Microbiology, Immunology and Pharmacology School of Medicine, St. George's University, Grenada, West Indies
| | - Jane C Harrington
- Correspondence address. Department of Microbiology, Immunology and Pharmacology Science Hall, Floor 1 St. George, Grenada, West Indies. Tel: 1-473-444-4175; Fax: 1-473-439-1845;
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Pandanaboyana S, Moir J, Leeds JS, Oppong K, Kanwar A, Marzouk A, Belgaumkar A, Gupta A, Siriwardena AK, Haque AR, Awan A, Balakrishnan A, Rawashdeh A, Ivanov B, Parmar C, M Halloran C, Caruana C, Borg CM, Gomez D, Damaskos D, Karavias D, Finch G, Ebied H, K Pine J, R A Skipworth J, Milburn J, Latif J, Ratnam Apollos J, El Kafsi J, Windsor JA, Roberts K, Wang K, Ravi K, V Coats M, Hollyman M, Phillips M, Okocha M, Sj Wilson M, A Ameer N, Kumar N, Shah N, Lapolla P, Magee C, Al-Sarireh B, Lunevicius R, Benhmida R, Singhal R, Balachandra S, Demirli Atıcı S, Jaunoo S, Dwerryhouse S, Boyce T, Charalampakis V, Kanakala V, Abbas Z, Nayar M. SARS-CoV-2 infection in acute pancreatitis increases disease severity and 30-day mortality: COVID PAN collaborative study. Gut 2021; 70:1061-1069. [PMID: 33547182 PMCID: PMC7871229 DOI: 10.1136/gutjnl-2020-323364] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 01/04/2021] [Accepted: 01/11/2021] [Indexed: 02/07/2023]
Abstract
OBJECTIVE There is emerging evidence that the pancreas may be a target organ of SARS-CoV-2 infection. This aim of this study was to investigate the outcome of patients with acute pancreatitis (AP) and coexistent SARS-CoV-2 infection. DESIGN A prospective international multicentre cohort study including consecutive patients admitted with AP during the current pandemic was undertaken. Primary outcome measure was severity of AP. Secondary outcome measures were aetiology of AP, intensive care unit (ICU) admission, length of hospital stay, local complications, acute respiratory distress syndrome (ARDS), persistent organ failure and 30-day mortality. Multilevel logistic regression was used to compare the two groups. RESULTS 1777 patients with AP were included during the study period from 1 March to 23 July 2020. 149 patients (8.3%) had concomitant SARS-CoV-2 infection. Overall, SARS-CoV-2-positive patients were older male patients and more likely to develop severe AP and ARDS (p<0.001). Unadjusted analysis showed that SARS-CoV-2-positive patients with AP were more likely to require ICU admission (OR 5.21, p<0.001), local complications (OR 2.91, p<0.001), persistent organ failure (OR 7.32, p<0.001), prolonged hospital stay (OR 1.89, p<0.001) and a higher 30-day mortality (OR 6.56, p<0.001). Adjusted analysis showed length of stay (OR 1.32, p<0.001), persistent organ failure (OR 2.77, p<0.003) and 30-day mortality (OR 2.41, p<0.04) were significantly higher in SARS-CoV-2 co-infection. CONCLUSION Patients with AP and coexistent SARS-CoV-2 infection are at increased risk of severe AP, worse clinical outcomes, prolonged length of hospital stay and high 30-day mortality.
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Affiliation(s)
- Sanjay Pandanaboyana
- HPB Unit, Freeman Hospital, Newcastle upon Tyne, UK
- Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - John Moir
- HPB Unit, Freeman Hospital, Newcastle upon Tyne, UK
| | - John S Leeds
- HPB Unit, Freeman Hospital, Newcastle upon Tyne, UK
- Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Kofi Oppong
- HPB Unit, Freeman Hospital, Newcastle upon Tyne, UK
- Translational and Clinical Research Institute, University of Newcastle upon Tyne, Newcastle upon Tyne, UK
| | - Aditya Kanwar
- University Hospitals Plymouth NHS Trust, Plymouth, UK
| | | | | | - Ajay Gupta
- South Bristol Community hospital, Bristol, UK
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - Guy Finch
- Northampton General Hospital, Northampton, UK
| | | | | | | | | | | | | | | | | | | | - Kelvin Wang
- Wrightington, Wigan and Leigh NHS Foundation Trust, Wigan, UK
| | - Krish Ravi
- Chesterfield Royal Hospital NHS Trust, Chesterfield, UK
| | | | | | | | | | | | - Nadeem A Ameer
- University Hospital of Coventry and Warwickshire, Coventry, UK
| | | | - Nehal Shah
- Northern General Hospital, Sheffield, UK
| | | | | | | | | | | | - Rishi Singhal
- University Hospital Birmingham NHS Foundation Trust, Birmingham, UK
| | | | - Semra Demirli Atıcı
- University of Health Sciences Tepecik Training and Research Hospital, Department of General Surgery, İzmir, Turkey
| | - Shameen Jaunoo
- Brighton and Sussex University Hospitals NHS Trust, Brighton, UK
| | | | | | | | | | - Zaigham Abbas
- Dr Ziauddin University Hospital, Clifton Karachi, Pakistan
| | - Manu Nayar
- HPB Unit, Freeman Hospital, Newcastle upon Tyne, UK
- Translational and Clinical Research Institute, University of Newcastle upon Tyne, Newcastle upon Tyne, UK
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Taylor DJ, Hamid SM, Andres AM, Saadaeijahromi H, Piplani H, Germano JF, Song Y, Sawaged S, Feuer R, Pandol SJ, Sin J. Antiviral Effects of Menthol on Coxsackievirus B. Viruses 2020; 12:E373. [PMID: 32231022 PMCID: PMC7232514 DOI: 10.3390/v12040373] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 03/24/2020] [Accepted: 03/25/2020] [Indexed: 12/20/2022] Open
Abstract
Coxsackievirus B (CVB) is a common human enterovirus that causes systemic infection but specifically replicates to high titers in the pancreas. It was reported that certain viruses induce mitochondrial fission to support infection. We documented that CVB triggers mitochondrial fission and blocking mitochondrial fission limits infection. The transient receptor potential channels have been implicated in regulating mitochondrial dynamics; namely, the heat and capsaicin receptor transient receptor potential cation channel subfamily V member 1 (TRPV1) contributes to mitochondrial depolarization and fission. When we transiently warmed HeLa cells to 39 °C prior to CVB exposure, infection was heightened, whereas cooling cells to 25 °C reduced infection. Inducing "cold" by stimulating transient receptor potential cation channel subfamily M member 8 (TRPM8) with menthol led to reduced infection and also resulted in lower levels of mitochondrial fission during infection. Additionally, menthol stabilized levels of mitochondrial antiviral signaling (MAVS) which is known to be tied to mitochondrial dynamics. Taken together, this highlights a novel pathway wherein CVB relies on TRPV1 to initiate proviral mitochondrial fission, which may contribute to the disruption of antiviral immunity. TRPM8 has been shown to antagonize TRPV1, and thus we hypothesize that stimulating TRPM8 blocks TRPV1-mediated mitochondrial fragmentation following CVB exposure and attenuates infection.
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Affiliation(s)
- David J.R. Taylor
- The Smidt Heart Institute and the Barbra Streisand Women’s Heart Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA (S.M.H.); (A.M.A.); (H.S.); (H.P.); (J.F.G.); (Y.S.); (S.S.)
| | - Syed M. Hamid
- The Smidt Heart Institute and the Barbra Streisand Women’s Heart Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA (S.M.H.); (A.M.A.); (H.S.); (H.P.); (J.F.G.); (Y.S.); (S.S.)
| | - Allen M. Andres
- The Smidt Heart Institute and the Barbra Streisand Women’s Heart Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA (S.M.H.); (A.M.A.); (H.S.); (H.P.); (J.F.G.); (Y.S.); (S.S.)
| | - Hannaneh Saadaeijahromi
- The Smidt Heart Institute and the Barbra Streisand Women’s Heart Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA (S.M.H.); (A.M.A.); (H.S.); (H.P.); (J.F.G.); (Y.S.); (S.S.)
| | - Honit Piplani
- The Smidt Heart Institute and the Barbra Streisand Women’s Heart Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA (S.M.H.); (A.M.A.); (H.S.); (H.P.); (J.F.G.); (Y.S.); (S.S.)
| | - Juliana F. Germano
- The Smidt Heart Institute and the Barbra Streisand Women’s Heart Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA (S.M.H.); (A.M.A.); (H.S.); (H.P.); (J.F.G.); (Y.S.); (S.S.)
| | - Yang Song
- The Smidt Heart Institute and the Barbra Streisand Women’s Heart Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA (S.M.H.); (A.M.A.); (H.S.); (H.P.); (J.F.G.); (Y.S.); (S.S.)
| | - Savannah Sawaged
- The Smidt Heart Institute and the Barbra Streisand Women’s Heart Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA (S.M.H.); (A.M.A.); (H.S.); (H.P.); (J.F.G.); (Y.S.); (S.S.)
| | - Ralph Feuer
- The Integrated Regenerative Research Institute (IRRI) at San Diego State University, San Diego State University, San Diego, CA 92182, USA;
| | - Stephen J. Pandol
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA;
| | - Jon Sin
- The Smidt Heart Institute and the Barbra Streisand Women’s Heart Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA (S.M.H.); (A.M.A.); (H.S.); (H.P.); (J.F.G.); (Y.S.); (S.S.)
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6
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Ramsingh AI, Manley K, Rong Y, Reilly A, Messer A. Transcriptional dysregulation of inflammatory/immune pathways after active vaccination against Huntington's disease. Hum Mol Genet 2015; 24:6186-97. [PMID: 26307082 PMCID: PMC4599676 DOI: 10.1093/hmg/ddv335] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Revised: 08/04/2015] [Accepted: 08/10/2015] [Indexed: 01/01/2023] Open
Abstract
Immunotherapy, both active and passive, is increasingly recognized as a powerful approach to a wide range of diseases, including Alzheimer's and Parkinson's. Huntington's disease (HD), an autosomal dominant disorder triggered by misfolding of huntingtin (HTT) protein with an expanded polyglutamine tract, could also benefit from this approach. Individuals can be identified genetically at the earliest stages of disease, and there may be particular benefits to a therapy that can target peripheral tissues in addition to brain. In this active vaccination study, we first examined safety and immunogenicity for a broad series of peptide, protein and DNA plasmid immunization protocols, using fragment (R6/1), and knock-in (zQ175) models. No safety issues were found. The strongest and most uniform immune response was to a combination of three non-overlapping HTT Exon1 coded peptides, conjugated to KLH, delivered with alum adjuvant. An N586-82Q plasmid, delivered via gene gun, also showed ELISA responses, mainly in the zQ175 strain, but with more variability, and less robust responses in HD compared with wild-type controls. Transcriptome profiling of spleens from the triple peptide-immunized cohort showed substantial HD-specific differences including differential activation of genes associated with innate immune responses, absence of negative feedback control of gene expression by regulators, a temporal dysregulation of innate immune responses and transcriptional repression of genes associated with memory T cell responses. These studies highlight critical issues for immunotherapy and HD disease management in general.
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Affiliation(s)
- Arlene I Ramsingh
- New York State Department of Health, Wadsworth Center, Albany, NY, USA and
| | - Kevin Manley
- New York State Department of Health, Wadsworth Center, Albany, NY, USA and
| | - Yinghui Rong
- New York State Department of Health, Wadsworth Center, Albany, NY, USA and
| | - Andrew Reilly
- New York State Department of Health, Wadsworth Center, Albany, NY, USA and
| | - Anne Messer
- New York State Department of Health, Wadsworth Center, Albany, NY, USA and Neural Stem Cell Institute, Regenerative Research Foundation, Rensselaer, NY, USA
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7
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Echovirus 7 associated with hand, foot, and mouth disease in mainland China has undergone a recombination event. Arch Virol 2015; 160:1291-5. [PMID: 25680567 PMCID: PMC4412592 DOI: 10.1007/s00705-015-2350-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2014] [Accepted: 01/24/2015] [Indexed: 02/06/2023]
Abstract
To investigate the evolution of echovirus 7 (Echo7) strains and the relationship between Echo7 strains and the prototype strain Wallace, phylogenetic analysis of Echo7 strains prevailing in mainland China was performed. The Echo7 strain, DH22G/JS/2012 was isolated from a 32-month-old boy who was clinically diagnosed with HFMD. The complete genome sequence of this isolate was determined after the virus was propagated in cell culture. Phylogenetic analysis showed that the subgroups B1 and C1 prevailed in mainland China from 1998 to 2012 and that the subgroup B2 began to circulate in mainland China in 2009. The result of Simplot analysis showed that the Echo7 strain DH22G/JS/2012 is a recombinant coxsackievirus B4 (CVB4) that circulated in mainland China in 2010.
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8
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Khan J, Nordback I, Seppänen H, Lappalainen-Lehto R, Järvinen S, Oikarinen S, Tauriainen S, Räty S, Hyöty H, Sand J. Is alcoholic pancreatitis associated with enteroviral infection? World J Gastroenterol 2013; 19:3819-23. [PMID: 23840120 PMCID: PMC3699032 DOI: 10.3748/wjg.v19.i24.3819] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2012] [Revised: 09/29/2012] [Accepted: 10/30/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate whether enteroviral infection might trigger acute pancreatitis in patients made susceptible due to high alcohol consumption.
METHODS: Patients with alcohol-induced acute pancreatitis were analyzed for signs of simultaneous or preceding enteroviral infection. We studied the serum samples of 40 patients hospitalized for alcohol-induced acute pancreatitis and 40 controls recruited from an alcohol detoxification center. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect enterovirus RNA and diagnose acute viremia. Immunoglobulin G (IgG), immunoglobulin A (IgA) and immunoglobulin M (IgM) enteroviral antibodies were measured using enzyme immunoassay to detect subacute and previous infections. The samples were considered positive when the antibody titers were ≥ 15 IU. Furthermore, using RT-PCR, we studied pancreatic biopsy samples obtained during surgery from nine patients with chronic pancreatitis, one patient with acute pancreatitis and ten control patients with pancreatic carcinoma for evidence of persisting enteroviral RNA in the pancreatic tissue.
RESULTS: No enterovirus RNA indicating acute viremia was detected by RT-PCR in the serum samples of any patient or control. A high incidence of positive antibody titers was observed in both study groups: IgM antibodies had positive titers in 5/40 (13%) vs 4/40 (10%), P = 0.723; IgG in 15/40 (38%) vs 19/40 (48%), P = 0.366; and IgA in 25/40 (63%) vs 33/40 (83%), P = 0.045, patients and controls, respectively. Ten (25%) patients had severe pancreatitis and two (5%) required treatment in intensive care. The median length of hospitalization was 7 d (range: 3-47 d). The severity of acute pancreatitis or the length of hospitalization was not associated with enteroviral IgM, IgG or IgA antibodies. Five pancreatic biopsy samples tested positive with RT-PCR, three (8%) in the control group and two (5%) in the patient group (P = 0.64).
CONCLUSION: The rate of enteroviral infection is not increased in patients with alcohol-induced acute pancreatitis when compared to alcoholics with similar high alcohol use.
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9
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Sesti-Costa R, Silva GK, Proença-Módena JL, Carlos D, Silva ML, Alves-Filho JC, Arruda E, Liew FY, Silva JS. The IL-33/ST2 pathway controls coxsackievirus B5-induced experimental pancreatitis. THE JOURNAL OF IMMUNOLOGY 2013; 191:283-92. [PMID: 23733876 DOI: 10.4049/jimmunol.1202806] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Coxsackievirus B (CVB) is a common cause of acute and chronic infectious myocarditis and pancreatitis. Th1 cells producing IFN-γ and TNF-α are important for CVB clearance, but they are also associated with the pathogenesis of inflammatory lesions, suggesting that the modulation of Th1 and Th2 balance is likely important in controlling CVB-induced pancreatitis. We investigated the role of IL-33, which is an important recently discovered cytokine for induction of Th2-associated responses, in experimental CVB5 infection. We found that mice deficient in IL-33R, T1/ST2, significantly developed more severe pancreatitis, had greater weight loss, and contained higher viral load compared with wild-type (WT) mice when infected with CVB5. Conversely, WT mice treated with rIL-33 developed significantly lower viral titers, and pancreatitis was attenuated. Mechanistic studies demonstrated that IL-33 enhances the degranulation and production of IFN-γ and TNF-α by CD8(+) T and NK cells, which is associated with viral clearance. Furthermore, IL-33 triggers the production of IL-4 from mast cells, which results in enhanced differentiation of M2 macrophages and regulatory T cells, leading to the attenuation of inflammatory pancreatitis. Adoptively transferred mast cells or M2 macrophages reversed the heightened pancreatitis in the T1/ST2(-/-) mice. In contrast, inhibition of regulatory T cells exacerbated the disease in WT mice. Together, our findings reveal an unrecognized IL-33/ST2 functional pathway and a key mechanism for CVB5-induced pancreatitis. These data further suggest a novel approach in treating virus-induced pancreatitis, which is a major medical condition with unmet clinical needs.
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Affiliation(s)
- Renata Sesti-Costa
- Department of Biochemistry and Immunology, University of São Paulo-Ribeirão Preto School of Medicine, Monte Alegre, Ribeirão Preto, São Paulo, Brazil
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10
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Lerch MM, Gorelick FS. Models of acute and chronic pancreatitis. Gastroenterology 2013; 144:1180-93. [PMID: 23622127 DOI: 10.1053/j.gastro.2012.12.043] [Citation(s) in RCA: 313] [Impact Index Per Article: 26.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2012] [Revised: 12/06/2012] [Accepted: 12/13/2012] [Indexed: 12/16/2022]
Abstract
Animal models of acute and chronic pancreatitis have been created to examine mechanisms of pathogenesis, test therapeutic interventions, and study the influence of inflammation on the development of pancreatic cancer. In vitro models can be used to study early stage, short-term processes that involve acinar cell responses. Rodent models reproducibly develop mild or severe disease. One of the most commonly used pancreatitis models is created by administration of supraphysiologic concentrations of caerulein, an ortholog of cholecystokinin. Induction of chronic pancreatitis with factors thought to have a role in human disease, such as combinations of lipopolysaccharide and chronic ethanol feeding, might be relevant to human disease. Models of autoimmune chronic pancreatitis have also been developed. Most models, particularly of chronic pancreatitis, require further characterization to determine which features of human disease they include.
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Affiliation(s)
- Markus M Lerch
- Department of Medicine A, University Medicine Greifswald, Ferdinand-Sauerbruch-Strasse, Greifswald, Germany.
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11
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Spleen-derived interleukin-10 downregulates the severity of high-fat diet-induced non-alcoholic fatty pancreas disease. PLoS One 2012; 7:e53154. [PMID: 23285260 PMCID: PMC3532347 DOI: 10.1371/journal.pone.0053154] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2012] [Accepted: 11/26/2012] [Indexed: 02/07/2023] Open
Abstract
Obesity is associated with systemic low-grade inflammation and is a risk factor for non-alcoholic fatty pancreas disease (NAFPD), but the molecular mechanisms of these associations are not clear. Interleukin (IL)-10, a potent anti-inflammatory cytokine, is released during acute pancreatitis and is known to limit inflammatory responses by downregulating the release of proinflammatory mediators. The origin of IL-10 that suppresses pancreatitis has not been investigated. Since obesity is known to reduce expression of proinflammatory cytokines in the spleen, we examined whether spleen-derived IL-10 regulates NAFPD caused by high-fat (HF) diet-induced obesity. The following investigations were performed: 1) IL-10 induction from spleen was examined in male mice fed a HF diet; 2) triglyceride content, expression of pro- and anti-inflammatory cytokines and infiltration of M1 and M2 macrophages were determined to evaluate ectopic fat accumulation and inflammatory responses in the pancreas of splenectomy (SPX)-treated mice fed HF diet; 3) exogenous IL-10 was systemically administered to SPX-treated obese mice and the resulting pathogenesis caused by SPX was assessed; and 4) IL-10 knockout (IL-10KO) mice were treated with SPX and ectopic fat deposition and inflammatory conditions in the pancreas were investigated. Obesity impaired the ability of the spleen to synthesize cytokines, including IL-10. SPX aggravated fat accumulation and inflammatory responses in the pancreas of HF diet-induced obese mice and these effects were inhibited by systemic administration of IL-10. Moreover, SPX had little effect on fat deposition and inflammatory responses in the pancreas of IL-10KO mice. Our findings indicate that obesity reduces IL-10 production by the spleen and that spleen-derived IL-10 may protect against the development of NAFPD.
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Dynamics of molecular responses to coxsackievirus B4 infection differentiate between resolution and progression of acute pancreatitis. Virology 2012; 427:135-43. [PMID: 22414343 DOI: 10.1016/j.virol.2012.02.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2011] [Revised: 12/23/2011] [Accepted: 02/13/2012] [Indexed: 02/06/2023]
Abstract
A coxsackievirus B4 induces acute pancreatitis with different outcomes. The study utilized a systems biology approach to identify molecular immune responses that differentiate between disease resolution and disease progression. The data establish a temporal pattern of host responses that differentiate the resolution of acute pancreatitis from the progression to chronic pancreatitis. A group of twenty-five genes exhibited characteristic expression profiles that were observed during the development of chronic pancreatitis but not during the resolution of disease. We postulate that the temporal dynamics of the twenty-five genes influence the development of pathogenic immune responses associated with chronic pancreatitis. Furthermore, a subset of eleven genes exhibited increased expression as viral titers waned. Of the eleven gene products, five are secreted molecules, TNF-α, IFN-γ, CXCL10, IL-10, and IL-22b, and represent novel potential therapeutic targets since they can be readily modulated with antibodies against the specific cytokine/chemokine or with antibodies against the corresponding receptors.
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Gu R, Shampang A, Nashar T, Patil M, Fuller DH, Ramsingh AI. Oral immunization with a live coxsackievirus/HIV recombinant induces gag p24-specific T cell responses. PLoS One 2010; 5. [PMID: 20824074 PMCID: PMC2932689 DOI: 10.1371/journal.pone.0012499] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2010] [Accepted: 08/06/2010] [Indexed: 11/18/2022] Open
Abstract
Background The development of an HIV/AIDS vaccine has proven to be elusive. Because human vaccine trials have not yet demonstrated efficacy, new vaccine strategies are needed for the HIV vaccine pipeline. We have been developing a new HIV vaccine platform using a live enterovirus, coxsackievirus B4 (CVB4) vector. Enteroviruses are ideal candidates for development as a vaccine vector for oral delivery, because these viruses normally enter the body via the oral route and survive the acidic environment of the stomach. Methodology/Principal Findings We constructed a live coxsackievirus B4 recombinant, CVB4/p24(733), that expresses seventy-three amino acids of the gag p24 sequence (HXB2) and assessed T cell responses after immunization of mice. The CVB4 recombinant was physically stable, replication-competent, and genetically stable. Oral or intraperitoneal immunization with the recombinant resulted in strong systemic gag p24-specific T cell responses as determined by the IFN-γ ELISPOT assay and by multiparameter flow cytometry. Oral immunization with CVB4/p24(733) resulted in a short-lived, localized infection of the gut without systemic spread. Because coxsackieviruses are ubiquitous in the human population, we also evaluated whether the recombinant was able to induce gag p24-specific T cell responses in mice pre-immunized with the CVB4 vector. We showed that oral immunization with CVB4/p24(733) induced gag p24-specific immune responses in vector-immune mice. Conclusions/Significance The CVB4/p24(733) recombinant retained the physical and biological characteristics of the parental CVB4 vector. Oral immunization with the CVB4 recombinant was safe and resulted in the induction of systemic HIV-specific T cell responses. Furthermore, pre-existing vector immunity did not preclude the development of gag p24-specific T cell responses. As the search continues for new vaccine strategies, the present study suggests that live CVB4/HIV recombinants are potential new vaccine candidates for HIV.
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Affiliation(s)
- Rui Gu
- Division of Infectious Diseases, Wadsworth Center, New York State Department of Health, Albany, New York, United States of America
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Gu R, Shampang A, Reilly A, Fisher D, Glass W, Ramsingh AI. IL-10 is pathogenic during the development of coxsackievirus B4-induced chronic pancreatitis. Virology 2009; 395:77-86. [PMID: 19800092 DOI: 10.1016/j.virol.2009.09.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2009] [Revised: 08/31/2009] [Accepted: 09/08/2009] [Indexed: 12/13/2022]
Abstract
Using a mouse model of coxsackievirus B4 (CVB4-V)-induced chronic pancreatitis, we investigated whether cytokines are involved in the progression of acute disease to chronic inflammatory disease. We show that IL-10 contributed to the development of chronic pancreatitis since acute disease resolved when IL-10 was absent or when IL-10 signaling was disrupted. We explored the underlying mechanisms by which IL-10 affected disease progression, using a novel approach to assess immunological events occurring in situ. Multiple markers that define functional innate immune responses and functional T cell responses were monitored over the course of CVB4-V infection of wild-type and IL-10 knockout mice, using a multiplex transcriptional profiling approach. We show that high levels of IL-10 early during infection were associated with delayed innate and T cell responses. Furthermore, high IL-10 production correlated with altered kinetics of T regulatory responses indicating a disruption in the balance between effector and regulatory T cell responses.
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Affiliation(s)
- Rui Gu
- Wadsworth Center, New York State Department of Health, 120 New Scotland Avenue, Albany, NY 12208, USA
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Reding T, Wagner U, Silva AB, Sun LK, Bain M, Kim SY, Bimmler D, Graf R. Inflammation-dependent expression of SPARC during development of chronic pancreatitis in WBN/Kob rats and a microarray gene expression analysis. Physiol Genomics 2009; 38:196-204. [PMID: 19435834 DOI: 10.1152/physiolgenomics.00028.2009] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The pathophysiology of human chronic pancreatitis is not well understood and difficult to follow on a molecular basis. Therefore, we used a rat model [Wistar-Bonn/Kobori (WBN/Kob)] that exhibits spontaneous chronic inflammation and fibrosis in the pancreas. Using microarrays we compared gene expression patterns in the pancreas during development of inflammation and fibrosis of WBN/Kob rats with age-matched healthy Wistar rats. The extracellular matrix protein SPARC (secreted protein, acidic, and rich in cysteines) and other transcripts of inflammatory genes were quantified by real-time PCR, and some were localized by immunohistochemistry. When pancreatic inflammation becomes obvious at the age of 16 wk, several hundred genes are increased between 3- and 50-fold in WBN/Kob rats compared with healthy Wistar rats. Proteins produced by acinar cells and characteristic for inflammation, e.g., pancreatitis-associated protein, are highly upregulated. Other proteins, derived from infiltrating inflammatory cells and from activated stellate cells (fibrosis) such as collagens and fibronectins are also significantly upregulated. SPARC was localized to acinar cells where it increased in the vicinity of inflammatory foci. However, acinar expression of SPARC was lost during destruction of acinar cells. In human pancreatic specimens with chronic pancreatitis, SPARC exhibited a similar expression profile. During chronic inflammation and fibrosis in the WBN/Kob rat, inflammatory genes, growth factors, and structural genes exhibit a high increase of expression. A temporal profile including pre- and postinflammatory phases indicates a concurrent activation of inflammatory and fibrotic changes. Inflammation dependent expression of SPARC appears to be lost during acinar-to-duct metaplasia both in rat and human pancreas.
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Affiliation(s)
- T Reding
- Swiss-HBP (Hepato-Pancreato-Biliary) Center, Department of Visceral and Transplantation Surgery, University Hospital Zurich, Zürich, Switzerland
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De Palma AM, Thibaut HJ, Li S, Van Aelst I, Dillen C, Swinnen M, Verbeken E, Neyts J, Opdenakker G. Inflammatory rather than infectious insults play a role in exocrine tissue damage in a mouse model for coxsackievirus B4-induced pancreatitis. J Pathol 2008; 217:633-41. [DOI: 10.1002/path.2501] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Frisk P, Tallkvist J, Gadhasson IL, Blomberg J, Friman G, Ilbäck NG. Coxsackievirus B3 infection affects metal-binding/transporting proteins and trace elements in the pancreas in mice. Pancreas 2007; 35:e37-44. [PMID: 17895834 DOI: 10.1097/mpa.0b013e3180986e84] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVE The trigger of juvenile diabetes has been suggested to be an interaction between a virus and trace elements, where enteroviruses, including coxsackievirus B3 (CVB3), have been discussed as potential initiators. The aim of this study was to investigate the effects in the pancreas on gene expressions of metallothionein 1 (MT1), divalent metal transporter 1 (DMT1), and zinc transporter 5 (ZnT-5) and concomitant changes in iron (Fe), copper (Cu), and zinc (Zn) in serum and pancreas of Balb/c mice on days 3, 6, and 9 of CVB3 infection. METHODS Trace elements were measured through inductively coupled plasma-mass spectrometry, and CVB3, MT1, DMT1, and ZnT-5 were measured by reverse transcription-polymerase chain reaction. RESULTS Virus was found in the pancreas on all days, with a peak on day 3. Infection tended to increase Fe in both serum and the pancreas. The Cu/Zn ratio in the pancreas increased early in the infection because of a great decrease in Zn. In serum, the Cu/Zn ratio was not increased until day 9 of the disease. In the pancreas, MT1 decreased, whereas DMT1 tended to increase on day 6, and ZnT-5 increased progressively during the course of the disease. CONCLUSIONS Virus-induced changes in trace elements, MT1, DMT1, and ZnT-5 in the pancreas may reflect early stages of the development of pancreatitis and prestages of diabetic disease.
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Affiliation(s)
- Peter Frisk
- Research in Metal Biology, Rudbeck Laboratory, Uppsala University, Sweden.
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Jerrells TR, Vidlak D, Strachota JM. Alcoholic pancreatitis: mechanisms of viral infections as cofactors in the development of acute and chronic pancreatitis and fibrosis. J Leukoc Biol 2006; 81:430-9. [PMID: 17095612 DOI: 10.1189/jlb.1004622] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Acute and chronic pancreatitis is associated with alcohol abuse, but symptomatic pancreatitis develops in only a small proportion of persons (10-20%) who abuse alcohol. This apparent paradox has led to the notion that additional cofactors are involved in the development of alcoholic pancreatitis. Potential cofactors, such as diet and smoking, have been suggested, but there are no compelling epidemiologic data to support this idea. A number of viruses and some bacteria have been shown to infect the pancreas and produce pancreatitis. One important mediator of pancreatitis in persons with a compromised immune system is a viral infection. The increased susceptibility of immunocompromised persons to viral pancreatitis led to the hypothesis, described in this paper, that the well-known immunosuppression associated with alcohol abuse would result in a more severe viral pancreatitis in mice, which are provided ethanol, than in control animals. To test this hypothesis, C57BL/6 mice were infected with a virulent strain of coxsackievirus B3, which preferentially induces pancreatitis, or with a strain that is naturally avirulent. The study findings presented in this paper show that ethanol consumption alone does not produce pancreas damage but results in a more severe and prolonged pancreatitis after infection with a virulent virus and interestingly, after infection with the avirulent strain of virus. This was associated with an increased number of viruses in the pancreas and spleen, which correlated with decreased humoral immune responses to the virus.
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Affiliation(s)
- Thomas R Jerrells
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-6495, USA.
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Abstract
PURPOSE OF REVIEW As in our previous reviews, we endeavor to review important new observations in chronic pancreatitis made in the past year. Topics recently reviewed were truncated to accommodate a surge in publications on clinical aspects of chronic pancreatitis, which contained new observations or insights into new or old concepts. RECENT FINDINGS Cystic fibrosis carriers have been found to be at increased risk of pancreatitis. Autoimmune pancreatitis may belong to a multiorgan immunoglobulin G4-related autoimmune disease, and the natural history of chronic pancreatitis differs among the etiologies. Diffusion-weighted magnetic resonance imaging improves upon previous methodologies for diagnosing reduced pancreatic exocrine secretion, and fecal elastase-1 has been found to be a poor test for diagnosing pancreatic malabsorption. Visceral hyperalgesia or heightened central pain perception may contribute to pain in chronic pancreatitis. Instruments are evolving to assess quality of life in chronic pancreatitis, and fibrolytic agents have been found to have therapeutic promise. SUMMARY Researchers this past year have further characterized genetic, molecular and clinical aspects of chronic pancreatitis. Advancing the understanding of fibrogenesis, mechanisms of exocrine insufficiency, calcification, and pain and continuing development/modification of diagnostic tests should lead to improved prevention, detection and treatment of the condition. More accurate quantification of outcomes is critical for translating potential therapies from bench to bedside.
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Affiliation(s)
- Matthew J DiMagno
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
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Abstract
PURPOSE OF REVIEW As in our previous reviews, we endeavor to review important new observations in chronic pancreatitis made in the past year. We included articles, including review articles, only if they contained new observations or readdressed old questions and provided new insights into old and new concepts. RECENT FINDINGS Important observations include the following: (1) Strong association between cystic fibrosis transmembrane regulator dysfunction/mutations and 'recurrent acute pancreatitis', particularly in patients with pancreas divisum (2) Pancreas divisum may be incidental finding in recurrent acute pancreatitis (3) Smoking increases risk of chronic pancreatitis (4) Coxsackie B virus may increase severity of alcoholic chronic pancreatitis (5) CD4+ T cells and an immune reaction against amylase may play a role in pathogenesis of autoimmune pancreatitis (6) 2-(18F)-Fluro-2-deoxy-D-glucose positron emission tomography might be useful to detect pancreatic cancer in chronic pancreatitis patients at risk for developing pancreatic cancer, but contrast-enhanced Doppler ultrasound or endosonography may be as sensitive and better than contrast enhanced computed tomography (7) Superiority of surgery vs endotherapy for long term pain relief and weight gain in painful chronic pancreatitis (8) Early treatment of pain and malabsorption may improve life quality (9) Antifibrogenesis and fibrolytic agents as potential therapies. SUMMARY Ongoing basic and clinical research this past year has further characterized genetic, molecular and clinical aspects of chronic pancreatitis. The advent of predictable and lasting treatments of chronic pancreatitis is most likely to appear on the wings of carefully conducted studies targeting genetic and molecular mechanisms of chronic pancreatitis, particularly pancreatic fibrogenesis.
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Affiliation(s)
- Matthew J DiMagno
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109-0362, USA.
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Abstract
In humans, infections with the group B coxsackieviruses (CVBs) range from asymptomatic infections to chronic, debilitating diseases. The CVBs are associated with chronic inflammatory diseases of the pancreas, heart, and central nervous system. A major focus in CVB pathogenesis is to understand the mechanisms by which these viruses cause acute diseases that resolve or acute diseases that progress to chronic diseases. The present review explores CVB infections in the development of acute and chronic pancreatitis. Mouse models of CVB-induced pancreatitis share many features with the human diseases and are providing insight into the multi-faceted processes of pancreatic tissue repair and irreversible tissue destruction. The development and progression of CVB-induced pancreatic inflammatory disease is an extremely complex process, involving both viral and host factors. The review examines the roles of the virus and host in contributing to the disease process. Recent studies of global gene expression during CVB-induced pancreatitis have increased our understanding of host factors that influence the outcome of infection and have highlighted interrelationships among complex biological programs. As we unravel the complexity of the disease process, the information gained will lead to the design of therapeutics that not only prevent the progression of chronic inflammatory disease, but that also restore functionality of affected tissues and organs.
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Affiliation(s)
- Sally Huber
- Department of Pathology, University of Vermont, Bington, Vermont, USA
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