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Fu J, Zong X, Jin M, Min J, Wang F, Wang Y. Mechanisms and regulation of defensins in host defense. Signal Transduct Target Ther 2023; 8:300. [PMID: 37574471 PMCID: PMC10423725 DOI: 10.1038/s41392-023-01553-x] [Citation(s) in RCA: 71] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 04/11/2023] [Accepted: 06/26/2023] [Indexed: 08/15/2023] Open
Abstract
As a family of cationic host defense peptides, defensins are mainly synthesized by Paneth cells, neutrophils, and epithelial cells, contributing to host defense. Their biological functions in innate immunity, as well as their structure and activity relationships, along with their mechanisms of action and therapeutic potential, have been of great interest in recent years. To highlight the key research into the role of defensins in human and animal health, we first describe their research history, structural features, evolution, and antimicrobial mechanisms. Next, we cover the role of defensins in immune homeostasis, chemotaxis, mucosal barrier function, gut microbiota regulation, intestinal development and regulation of cell death. Further, we discuss their clinical relevance and therapeutic potential in various diseases, including infectious disease, inflammatory bowel disease, diabetes and obesity, chronic inflammatory lung disease, periodontitis and cancer. Finally, we summarize the current knowledge regarding the nutrient-dependent regulation of defensins, including fatty acids, amino acids, microelements, plant extracts, and probiotics, while considering the clinical application of such regulation. Together, the review summarizes the various biological functions, mechanism of actions and potential clinical significance of defensins, along with the challenges in developing defensins-based therapy, thus providing crucial insights into their biology and potential clinical utility.
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Affiliation(s)
- Jie Fu
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou, China
- Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, Hangzhou, Zhejiang Province, China
| | - Xin Zong
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou, China
- Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, Hangzhou, Zhejiang Province, China
| | - Mingliang Jin
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou, China
- Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, Hangzhou, Zhejiang Province, China
| | - Junxia Min
- The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Fudi Wang
- The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China.
- The First Affiliated Hospital, Basic Medical Sciences, School of Public Health, Hengyang Medical School, University of South China, Hengyang, China.
| | - Yizhen Wang
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou, China.
- Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, Hangzhou, Zhejiang Province, China.
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Brown G, Hoedt EC, Keely S, Shah A, Walker MM, Holtmann G, Talley NJ. Role of the duodenal microbiota in functional dyspepsia. Neurogastroenterol Motil 2022; 34:e14372. [PMID: 35403776 PMCID: PMC9786680 DOI: 10.1111/nmo.14372] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 02/04/2022] [Accepted: 03/14/2022] [Indexed: 12/30/2022]
Abstract
BACKGROUND Functional dyspepsia (FD) is a common and debilitating gastrointestinal disorder attributed to altered gut-brain interactions. While the etiology of FD remains unknown, emerging research suggests the mechanisms are likely multifactorial and heterogenous among patient subgroups. Small bowel motor disturbances, visceral hypersensitivity, chronic microinflammation, and increased intestinal tract permeability have all been linked to the pathogenesis of FD. Recently, alterations to the gut microbiome have also been implicated to play an important role in the disease. Changes to the duodenal microbiota may either trigger or be a consequence of immune and neuronal disturbances observed in the disease, but the mechanisms of influence of small intestinal flora on gastrointestinal function and symptomatology are unknown. PURPOSE This review summarizes and synthesizes the literature on the link between the microbiota, low-grade inflammatory changes in the duodenum and FD. This review is not intended to provide a complete overview of FD or the small intestinal microbiota, but instead outline some of the key conceptual advances in understanding the interactions between altered gastrointestinal bacterial communities; dietary factors; host immune activation; and stimulation of the gut-brain axes in patients with FD versus controls. Current and emerging treatment approaches such as dietary interventions and antibiotic or probiotic use that have demonstrated symptom benefits for patients are reviewed, and their role in modulating the host-microbiota is discussed. Finally, suggested opportunities for diagnostic and therapeutic improvements for patients with this condition are presented.
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Affiliation(s)
- Georgia Brown
- School of Medicine and Public HealthUniversity of NewcastleNewcastleNew South WalesAustralia,AGIRA (Australian Gastrointestinal Research Alliance)NewcastleNew South WalesAustralia,NHMRC Centre of Research Excellence in Digestive HealthNewcastleNew South WalesAustralia
| | - Emily C. Hoedt
- AGIRA (Australian Gastrointestinal Research Alliance)NewcastleNew South WalesAustralia,NHMRC Centre of Research Excellence in Digestive HealthNewcastleNew South WalesAustralia,School of Biomedical Sciences and PharmacyUniversity of NewcastleNewcastleNew South WalesAustralia,Hunter Medical Research InstituteNew Lambton HeightsNewcastleNew South WalesAustralia
| | - Simon Keely
- AGIRA (Australian Gastrointestinal Research Alliance)NewcastleNew South WalesAustralia,NHMRC Centre of Research Excellence in Digestive HealthNewcastleNew South WalesAustralia,School of Biomedical Sciences and PharmacyUniversity of NewcastleNewcastleNew South WalesAustralia,Hunter Medical Research InstituteNew Lambton HeightsNewcastleNew South WalesAustralia
| | - Ayesha Shah
- AGIRA (Australian Gastrointestinal Research Alliance)NewcastleNew South WalesAustralia,NHMRC Centre of Research Excellence in Digestive HealthNewcastleNew South WalesAustralia,Faculty of Medicine and Faculty of Health and Behavioural SciencesThe University of QueenslandSt. LuciaQueenslandAustralia
| | - Marjorie M. Walker
- School of Medicine and Public HealthUniversity of NewcastleNewcastleNew South WalesAustralia,AGIRA (Australian Gastrointestinal Research Alliance)NewcastleNew South WalesAustralia,NHMRC Centre of Research Excellence in Digestive HealthNewcastleNew South WalesAustralia
| | - Gerald Holtmann
- AGIRA (Australian Gastrointestinal Research Alliance)NewcastleNew South WalesAustralia,NHMRC Centre of Research Excellence in Digestive HealthNewcastleNew South WalesAustralia,Faculty of Medicine and Faculty of Health and Behavioural SciencesThe University of QueenslandSt. LuciaQueenslandAustralia,Department of Gastroenterology & HepatologyPrincess Alexandra HospitalWoolloongabbaQueenslandAustralia
| | - Nicholas J. Talley
- School of Medicine and Public HealthUniversity of NewcastleNewcastleNew South WalesAustralia,AGIRA (Australian Gastrointestinal Research Alliance)NewcastleNew South WalesAustralia,NHMRC Centre of Research Excellence in Digestive HealthNewcastleNew South WalesAustralia,Hunter Medical Research InstituteNew Lambton HeightsNewcastleNew South WalesAustralia
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Burns G, Pryor J, Holtmann G, Walker MM, Talley NJ, Keely S. Immune Activation in Functional Gastrointestinal Disorders. Gastroenterol Hepatol (N Y) 2019; 15:539-548. [PMID: 31802978 PMCID: PMC6883739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
There is growing appreciation that functional gastrointestinal disorders (FGIDs) such as functional dyspepsia and irritable bowel syndrome are heterogeneous conditions linked by subtle inflammation within the gastrointestinal (GI) tract. The literature suggests that while the symptoms of these diseases may manifest with similar clinical presentations, there are significant differences in triggers and disease severity among patients classified into the same subtype. It is hypothesized that the subtle inflammation observed in these patients is related to an imbalance in GI homeostasis. Disruption of the delicate homeostatic balance within the GI tract can result from any number or combination of factors, including dysbiosis, loss of barrier integrity, genetic predisposition, or immune responses to dietary or luminal antigens. This article discusses the interplay between the immune system, microbiota, and luminal environment in FGIDs. In addition, the article proposes emerging immune pathways, including those involving T-helper type 17 response and innate lymphoid cells, as potential regulators of the subtle inflammation characteristic of FGIDs that warrant investigation in future studies.
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Affiliation(s)
- Grace Burns
- Ms Burns is a PhD graduate student, Ms Pryor is an undergraduate research student
- Dr Walker is a professor of anatomical pathology
- Dr Talley is a laureate professor
- Dr Keely is an associate professor in the Priority Research Centre for Digestive Health and Neurogastroenterology in the Faculty of Health and Medicine at the University of Newcastle in Callaghan, New South Wales, Australia, as well as in the Hunter Medical Research Institute in New Lambton Heights, New South Wales, Australia
- Dr Holtmann is director of gastroenterology and hepatology at the Princess Alexandra Hospital in Brisbane, Queensland, Australia and a professor in the Faculty of Medicine at the University of Queensland in Woolloongabba, Queensland, Australia
| | - Jennifer Pryor
- Ms Burns is a PhD graduate student, Ms Pryor is an undergraduate research student
- Dr Walker is a professor of anatomical pathology
- Dr Talley is a laureate professor
- Dr Keely is an associate professor in the Priority Research Centre for Digestive Health and Neurogastroenterology in the Faculty of Health and Medicine at the University of Newcastle in Callaghan, New South Wales, Australia, as well as in the Hunter Medical Research Institute in New Lambton Heights, New South Wales, Australia
- Dr Holtmann is director of gastroenterology and hepatology at the Princess Alexandra Hospital in Brisbane, Queensland, Australia and a professor in the Faculty of Medicine at the University of Queensland in Woolloongabba, Queensland, Australia
| | - Gerald Holtmann
- Ms Burns is a PhD graduate student, Ms Pryor is an undergraduate research student
- Dr Walker is a professor of anatomical pathology
- Dr Talley is a laureate professor
- Dr Keely is an associate professor in the Priority Research Centre for Digestive Health and Neurogastroenterology in the Faculty of Health and Medicine at the University of Newcastle in Callaghan, New South Wales, Australia, as well as in the Hunter Medical Research Institute in New Lambton Heights, New South Wales, Australia
- Dr Holtmann is director of gastroenterology and hepatology at the Princess Alexandra Hospital in Brisbane, Queensland, Australia and a professor in the Faculty of Medicine at the University of Queensland in Woolloongabba, Queensland, Australia
| | - Marjorie M Walker
- Ms Burns is a PhD graduate student, Ms Pryor is an undergraduate research student
- Dr Walker is a professor of anatomical pathology
- Dr Talley is a laureate professor
- Dr Keely is an associate professor in the Priority Research Centre for Digestive Health and Neurogastroenterology in the Faculty of Health and Medicine at the University of Newcastle in Callaghan, New South Wales, Australia, as well as in the Hunter Medical Research Institute in New Lambton Heights, New South Wales, Australia
- Dr Holtmann is director of gastroenterology and hepatology at the Princess Alexandra Hospital in Brisbane, Queensland, Australia and a professor in the Faculty of Medicine at the University of Queensland in Woolloongabba, Queensland, Australia
| | - Nicholas J Talley
- Ms Burns is a PhD graduate student, Ms Pryor is an undergraduate research student
- Dr Walker is a professor of anatomical pathology
- Dr Talley is a laureate professor
- Dr Keely is an associate professor in the Priority Research Centre for Digestive Health and Neurogastroenterology in the Faculty of Health and Medicine at the University of Newcastle in Callaghan, New South Wales, Australia, as well as in the Hunter Medical Research Institute in New Lambton Heights, New South Wales, Australia
- Dr Holtmann is director of gastroenterology and hepatology at the Princess Alexandra Hospital in Brisbane, Queensland, Australia and a professor in the Faculty of Medicine at the University of Queensland in Woolloongabba, Queensland, Australia
| | - Simon Keely
- Ms Burns is a PhD graduate student, Ms Pryor is an undergraduate research student
- Dr Walker is a professor of anatomical pathology
- Dr Talley is a laureate professor
- Dr Keely is an associate professor in the Priority Research Centre for Digestive Health and Neurogastroenterology in the Faculty of Health and Medicine at the University of Newcastle in Callaghan, New South Wales, Australia, as well as in the Hunter Medical Research Institute in New Lambton Heights, New South Wales, Australia
- Dr Holtmann is director of gastroenterology and hepatology at the Princess Alexandra Hospital in Brisbane, Queensland, Australia and a professor in the Faculty of Medicine at the University of Queensland in Woolloongabba, Queensland, Australia
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Kabeerdoss J, Sandhya P, Danda D. Gut inflammation and microbiome in spondyloarthritis. Rheumatol Int 2015; 36:457-68. [PMID: 26719306 DOI: 10.1007/s00296-015-3414-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2015] [Accepted: 12/21/2015] [Indexed: 12/16/2022]
Abstract
Spondyloarthritis (SpA) is chronic inflammatory disease involving joints and the spine. Bowel inflammation is common in SpA, which may be classified as acute or chronic. Chronic gut inflammation is most common in SpA patients with axial involvement as compared to those presenting with peripheral involvement alone. The pathogenesis of gut inflammation in SpA could be explained by two factors-over-activation of immunological cells and altered gut microbiome. This is exemplified by SpA animal models, namely HLA-B27-expressing transgenic animals and SKG mice models. Immunological mechanisms include homing of activated T cells from gut into synovium, excess pro-inflammatory cytokines secretion by immune cells such as IL-23 and genetic variations in immunological genes. The evidence for role of gut microbiome in SpA is gradually emerging. Recently, metagenomic study of gut microbiome by sequencing of microbial nucleic acids has enabled identification of new microbial taxa and their functions in gut of patients with SpA. In SpA, the gut microbiome could emerge as diagnostic and prognostic marker of disease. Modulation of gut microbiome is slated to have therapeutic potential as well.
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Affiliation(s)
- Jayakanthan Kabeerdoss
- Department of Clinical Immunology and Rheumatology, Christian Medical College, Vellore, Tamil Nadu, 632004, India
| | - Pulukool Sandhya
- Department of Clinical Immunology and Rheumatology, Christian Medical College, Vellore, Tamil Nadu, 632004, India
| | - Debashish Danda
- Department of Clinical Immunology and Rheumatology, Christian Medical College, Vellore, Tamil Nadu, 632004, India.
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Däbritz J, Musci J, Foell D. Diagnostic utility of faecal biomarkers in patients with irritable bowel syndrome. World J Gastroenterol 2014; 20:363-375. [PMID: 24574706 PMCID: PMC3923012 DOI: 10.3748/wjg.v20.i2.363] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Revised: 11/12/2013] [Accepted: 11/30/2013] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a common functional gastrointestinal (GI) disorder characterized by unspecific symptoms. In clinical practice it is crucial to distinguish between non-inflammatory functional problems and inflammatory, malignant or infectious diseases of the GI tract. Differentiation between these involves the use of clinical, radiological, endoscopic, histological and serological techniques, which are invasive, expensive, time-consuming and/or hindered by inaccuracies arising from subjective components. A range of faecal markers now appears to have the potential to greatly assist in the differentiation of inflammatory bowel disease (IBD) and IBS. Faecal markers of neutrophil influx into the mucosa are reliable indicators of intestinal inflammation and their role has been mainly studied in discriminating IBD from non-IBD conditions (including IBS) rather than organic from non-organic diseases. Phagocyte-specific proteins of the S100 family (S100A12, calprotectin) are amongst the most promising faecal biomarkers of inflammation. Faecal leukocyte degranulation markers (lactoferrin, polymorphonuclear elastase and myeloperoxidase) have also been suggested as diagnostic tools for the differentiation of IBD and IBS. More recently, additional proteins, including granins, defensins and matrix-metalloproteases, have been discussed as differential diagnostic markers in IBD and IBS. In this review, some of the most promising faecal markers, which have the potential to differentiate IBD and IBS and to advance diagnostic practices, will be discussed.
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Paschoal PO, Chamberlin W. Review of the 1st Annual World Congress of Immunodiseases and Therapeutics. Expert Rev Clin Immunol 2014; 6:757-9. [DOI: 10.1586/eci.10.54] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Langhorst J, Choi KE. The role of human defensins in gastrointestinal diseases. Expert Rev Clin Immunol 2012; 7:779-87. [PMID: 22014019 DOI: 10.1586/eci.11.62] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In clarifying the pathogenesis of inflammatory bowel diseases, a dysregulation of the adaptive immune function was the main focus of research in the last decade. With increasing knowledge of antimicrobial peptides, a primary disturbed barrier function and the system of innate immunity has recently received increasing attention. Contrary to the common understanding of irritable bowel syndrome as a functional disorder, there is first evidence for an involvement of innate immunity for this condition. Peptides with high relevance seem to be the class of human defensins. This article will thus discuss current advances in immunologic research of inflammatory bowel disease and irritable bowel syndrome, focusing on defensins and their possible role as biomarkers of these diseases.
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Affiliation(s)
- Jost Langhorst
- Integrative Gastroenterology, Department of Integrative and Internal Medicine, Kliniken Essen-Mitte, University of Duisburg-Essen, Knappschafts Krankenhaus, Am Deimelsberg 34a, 45276 Essen, Germany.
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Parkes GC, Rayment NB, Hudspith BN, Petrovska L, Lomer MC, Brostoff J, Whelan K, Sanderson JD. Distinct microbial populations exist in the mucosa-associated microbiota of sub-groups of irritable bowel syndrome. Neurogastroenterol Motil 2012; 24:31-9. [PMID: 22070725 DOI: 10.1111/j.1365-2982.2011.01803.x] [Citation(s) in RCA: 145] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND There is increasing evidence to support a role for the gastrointestinal microbiota in the etiology of irritable bowel syndrome (IBS). Given the evidence of an inflammatory component to IBS, the mucosa-associated microbiota potentially play a key role in its pathogenesis. The objectives were to compare the mucosa-associated microbiota between patients with diarrhea predominant IBS (IBS-D), constipation predominant IBS (IBS-C) and controls using fluorescent in situ hybridization and to correlate specific bacteria groups with individual IBS symptoms. METHODS Forty-seven patients with IBS (27 IBS-D and 20 IBS-C) and 26 healthy controls were recruited to the study. Snap-frozen rectal biopsies were taken at colonoscopy and bacterial quantification performed by hybridizing frozen sections with bacterial-group specific oligonucleotide probes. KEY RESULTS Patients with IBS had significantly greater numbers of total mucosa-associated bacteria per mm of rectal epithelium than controls [median 218 (IQR - 209) vs 128 (121) P = 0.007], and this was chiefly comprised of bacteroides IBS [69 (67) vs 14 (41) P = 0.001] and Eubacterium rectale-Clostridium coccoides [52 (58) vs 25 (35) P = 0.03]. Analysis of IBS sub-groups demonstrated that bifidobacteria were lower in the IBS-D group than in the IBS-C group and controls [24 (32) vs 54 (88) vs 32 (35) P = 0.011]. Finally, amongst patients with IBS, the maximum number of stools per day negatively correlated with the number of mucosa-associated bifidobacteria (P < 0.001) and lactobacilli (P = 0.002). CONCLUSIONS & INFERENCES The mucosa-associated microbiota in patients with IBS is significantly different from healthy controls with increases in bacteroides and clostridia and a reduction in bifidobacteria in patients with IBS-D.
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Affiliation(s)
- G C Parkes
- Diet and Gastrointestinal Health, Nutritional Sciences Division, King's College London, London, UK.
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Antimicrobial peptides in the duodenum at the acute and convalescent stages in patients with diarrhea due to Vibrio cholerae O1 or enterotoxigenic Escherichia coli infection. Microbes Infect 2011; 13:1111-20. [PMID: 21782033 DOI: 10.1016/j.micinf.2011.06.014] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2011] [Revised: 06/27/2011] [Accepted: 06/29/2011] [Indexed: 01/29/2023]
Abstract
Patients with acute watery diarrhea caused by Vibrio cholerae O1 or enterotoxigenic Escherichia coli (ETEC) were analyzed for innate immune factors produced by the epithelium during the disease process. Duodenal biopsies were obtained from study participants at the acute (day 2) and convalescent (day 21) stages of disease. Levels of α-defensin (HD-5 and -6), β-defensin (hBD-1-4), and cathelicidin (LL-37) mRNAs were determined by real-time qRT-PCR. hBD-2, HD-5, LL-37 peptides were analyzed in duodenal epithelium by immunomorphometry. Concentration of hBD-2 in stool was determined by ELISA. Specimens from healthy controls were also analyzed. hBD-2 mRNA levels were significantly increased at acute stage of diarrhea; hBD-2 peptide was detected in fecal specimens but barely in duodenal epithelium at acute stage. Immunomorphometry analysis showed that Paneth cells contain significantly higher amounts of HD-5 pre/propeptide at convalescence (P<0.01) and in healthy controls (P<0.001) compared to acute stage, LL-37 peptide levels also decreased at acute stage while mRNA levels remained unchanged. mRNA expression levels of the other antimicrobial peptides remained unchanged with higher levels of α-defensins than β-defensins. V. cholerae induced an innate immune response at the acute stage of disease characterized by increased expression of hBD-2, and continued expression of hBD-1, HD-5-6, and LL-37.
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Cromer WE, Mathis JM, Granger DN, Chaitanya GV, Alexander JS. Role of the endothelium in inflammatory bowel diseases. World J Gastroenterol 2011; 17:578-93. [PMID: 21350707 PMCID: PMC3040330 DOI: 10.3748/wjg.v17.i5.578] [Citation(s) in RCA: 136] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2010] [Revised: 06/29/2010] [Accepted: 07/06/2010] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBD) are a complex group of diseases involving alterations in mucosal immunity and gastrointestinal physiology during both initiation and progressive phases of the disease. At the core of these alterations are endothelial cells, whose continual adjustments in structure and function coordinate vascular supply, immune cell emigration, and regulation of the tissue environment. Expansion of the endothelium in IBD (angiogenesis), mediated by inflammatory growth factors, cytokines and chemokines, is a hallmark of active gut disease and is closely related to disease severity. The endothelium in newly formed or inflamed vessels differs from that in normal vessels in the production of and response to inflammatory cytokines, growth factors, and adhesion molecules, altering coagulant capacity, barrier function and blood cell recruitment in injury. This review examines the roles of the endothelium in the initiation and propagation of IBD pathology and distinctive features of the intestinal endothelium contributing to these conditions.
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Brint EK, MacSharry J, Fanning A, Shanahan F, Quigley EMM. Differential expression of toll-like receptors in patients with irritable bowel syndrome. Am J Gastroenterol 2011; 106:329-36. [PMID: 21102570 DOI: 10.1038/ajg.2010.438] [Citation(s) in RCA: 158] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The pathogenesis of irritable bowel syndrome (IBS) is poorly understood. One contributory factor may be low-grade mucosal inflammation, perhaps initiated by the microbiota. Toll-like receptors (TLRs) are a family of pathogen-recognition receptors of the innate immune system. The aim of this study was to evaluate the potential involvement of TLRs in IBS to further understand the involvement of the innate immune system in this complex disorder. METHODS The expression of TLRs was investigated in colonic biopsy samples obtained from 26 IBS patients and compared with 19 healthy controls. Protein expression of TLR4, TLR7, and TLR8 was confirmed by immunofluorescence and alterations in the TLR4 protein were confirmed by western blot. RESULTS Quantitative reverse transcriptase-PCR showed increased levels of TLR4 (P≤0.001) and TLR5 (P=0.0013) and decreased levels of TLR7 (P≤0.001) and TLR8 (P=0.0019) in IBS patients. CONCLUSIONS Our results support the presence of an immune engagement between the microbiota and the host in IBS; an interaction that involves innate immunity and could generate a low-grade inflammatory response. These findings could also offer an additional biomarker of the disease or a disease subset.
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Affiliation(s)
- Elizabeth K Brint
- Department of Pathology, University College Cork, National University of Ireland, and Alimentary Pharmabiotic Centre, Cork University Hospital, Cork, Ireland.
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Seo ES, Blaum BS, Vargues T, De Cecco M, Deakin JA, Lyon M, Barran PE, Campopiano DJ, Uhrín D. Interaction of human β-defensin 2 (HBD2) with glycosaminoglycans. Biochemistry 2010; 49:10486-95. [PMID: 21062008 DOI: 10.1021/bi1011749] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Human β-defensin 2 (HBD2) is a member of the defensin family of antimicrobial peptides that plays important roles in the innate and adaptive immune system of both vertebrates and invertebrates. In addition to their direct bactericidal action, defensins are also involved in chemotaxis and Toll-like receptor activation. In analogy to chemokine/glycosaminoglycan (GAG) interactions, GAG-defensin complexes are likely to play an important role in chemotaxis and in presenting defensins to their receptors. Using a gel mobility shift assay, we found that HBD2 bound to a range of GAGs including heparin/heparan sulfate (HS), dermatan sulfate (DS), and chondroitin sulfate. We used NMR spectroscopy of (15)N-labeled HBD2 to map the binding sites for two GAG model compounds, a heparin/HS pentasaccharide (fondaparinux sodium; FX) and enzymatically prepared DS hexasaccharide (DSdp6). We identified a number of basic amino acids that form a common ligand binding site, which indicated that these interactions are predominantly electrostatic. The dissociation constant of the [DSdp6-HBD2] complex was determined by NMR spectroscopy to be 5 ± 5 μM. Binding of FX could not be quantified because of slow exchange on the NMR chemical shift time scale. FX was found to induce HBD2 dimerization as evidenced by the analysis of diffusion coefficients, (15)N relaxation, and nESI-MS measurements. The formation of FX-bridged HBD2 dimers exhibited features of a cooperative binding mechanism. In contrast, the complex with DSdp6 was found to be mostly monomeric.
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Affiliation(s)
- Emily S Seo
- EastChem, School of Chemistry, The University of Edinburgh, King's Buildings, West Mains Road, Edinburgh EH9 3JJ, UK
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Larauche M, Kiank C, Tache Y. Corticotropin releasing factor signaling in colon and ileum: regulation by stress and pathophysiological implications. JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY : AN OFFICIAL JOURNAL OF THE POLISH PHYSIOLOGICAL SOCIETY 2009; 60 Suppl 7:33-46. [PMID: 20388944 PMCID: PMC3295842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/15/2009] [Accepted: 12/11/2009] [Indexed: 05/29/2023]
Abstract
It is well established that central corticotropin releasing factor (CRF) signaling mediates the gastrointestinal responses to stress. However, as shown in the brain, both CRF receptors and ligands are also widely expressed in the colon and the ileum of humans and rodents, and stress modulates their expression. Several functional studies documented that peripheral injection of CRF or urocortin stimulates colonic transit, motility, Fos expression in myenteric neurons, and defecation through activation of CRF(1) receptors, whereas it decreases ileal contractility via CRF(2) receptors. Additionally, intraperitoneal administration of CRF induces colonic mast cells degranulation via both CRF(1) and CRF(2) receptors and increases ion secretion and mucosal permeability to macromolecules, which can in turn promote intestinal inflammation and alter visceral sensitivity. Most peripheral CRF-induced alterations of colonic and ileal functions mimic effects which are observed after stress exposure, and CRF receptor antagonists given peripherally prevent stress-induced GI dysfunction. Furthermore, CRF peptides can reproduce secretomotor and mucosal alterations in vitro. Therefore, accumulated clinical and preclinical evidence supports in addition to the brain, a role for peripheral CRF signaling in mediating stress-induced effects on gastrointestinal sensorimotor, mucosal and immune functions, that may be components of underlying mechanisms involved in stress-related impact on inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS).
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Affiliation(s)
- M Larauche
- CURE, Digestive Diseases Research Center and Center for Neurobiology of Stress; Digestive Diseases Division, Department of Medicine, David Geffen School of Medicine UCLA and VA Greater Los Angeles Healthcare System, Angeles, California, USA.
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Ohman L, Isaksson S, Lindmark AC, Posserud I, Stotzer PO, Strid H, Sjövall H, Simrén M. T-cell activation in patients with irritable bowel syndrome. Am J Gastroenterol 2009; 104:1205-12. [PMID: 19367268 DOI: 10.1038/ajg.2009.116] [Citation(s) in RCA: 121] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
OBJECTIVES Irritable bowel syndrome (IBS) has been found to be associated with low-grade immune activation in a subset of patients. We therefore investigated blood and colonic T-cell activity in IBS patients. METHODS Blood samples were initially obtained from 74 IBS patients and 30 controls. Supplementary blood samples, to confirm data, were taken from another cohort (26 patients and 14 controls). In addition, colonic biopsies were taken from a third cohort (11 patients and 10 controls). Peripheral blood and colonic mononuclear cells were stimulated with anti-CD3/CD28 antibodies. Proliferation, cytokine secretion, and T-cell phenotype were investigated. IBS symptom severity was assessed. RESULTS IBS patients displayed an activated phenotype with increased frequencies of blood T cells expressing CD69 and integrin beta7/HLA-DR. Anti-CD3/CD28-stimulated blood and colonic T cells from IBS patients proliferated less than T cells from controls. IBS patients had an increased polyclonally stimulated T-cell secretion of IL-1beta, which also weakly correlated with increased bowel habit dissatisfaction. Furthermore, despite normal frequencies of CD25high T cells in the blood of IBS patients, lower blood CD25high T-cell frequencies were modestly correlated with more bowel habit dissatisfaction and increased total IBS symptom severity. CONCLUSIONS IBS patients have an increased frequency of activated T cells, demonstrated by the expression of activation markers and reduced proliferation in response to restimulation in vitro. The increased level of T-cell activation is consistent with the hypothesis of low-grade immune activation in IBS and may also be involved in symptom generation in IBS.
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Affiliation(s)
- Lena Ohman
- Department of Internal Medicine, Institute of Medicine, The Sahlgren's Academy, University of Gothenburg, Gothenburg, Sweden.
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Al-Khatib K, Lin HC. Immune activation and gut microbes in irritable bowel syndrome. Gut Liver 2009; 3:14-9. [PMID: 20479895 DOI: 10.5009/gnl.2009.3.1.14] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2008] [Accepted: 02/06/2009] [Indexed: 12/23/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a highly prevalent disorder that is characterized by chronic abdominal pain and altered bowel habit. The diagnosis of IBS has traditionally been made by matching the complaints of the patient with established clinical criteria, since the underlying pathophysiology was not known. Various new findings have recently been reported in IBS patients that challenge our concept of IBS as a syndrome with no explanation. While the florid inflammation characteristic of inflammatory bowel disease is absent in IBS, changes suggesting immune activation are present in nearly all IBS patients. Is IBS an autoimmune disease, or is the immune activation responding to a trigger? In this review we present evidence that points to a state of immune activation in IBS and show data that suggest that small intestinal bacterial overgrowth triggers immune activation in IBS.
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Affiliation(s)
- Khaldun Al-Khatib
- Gastroenterology Section, New Mexico VA Health Care System, Albuquerque, NM, and Department of Medicine, University of New Mexico, Albuquerque, NM, USA
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Möndel M, Schroeder BO, Zimmermann K, Huber H, Nuding S, Beisner J, Fellermann K, Stange EF, Wehkamp J. Probiotic E. coli treatment mediates antimicrobial human beta-defensin synthesis and fecal excretion in humans. Mucosal Immunol 2009; 2:166-72. [PMID: 19129752 PMCID: PMC10026704 DOI: 10.1038/mi.2008.77] [Citation(s) in RCA: 116] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Inducible epithelial human beta-defensins (hBD) play an important role in intestinal barrier function. In vitro studies showed that clinically effective probiotics induce antimicrobial hBD-2. Here, we aimed to assess the in vivo effect in healthy volunteers and also addressed how defensins affect probiotic survival. Symbioflor 2 containing one strain of several viable genotypes of Escherichia coli was administered to 23 healthy individuals. After 3 weeks, fecal hBD-2 peptide was increased in 78% (mean 3.7-fold; P<0.0001). Interestingly, the fecal hBD-2 peptide was still elevated 9 weeks after treatment (P=0.008). In vitro studies revealed that this effect was mediated by only one out of three tested E. coli genotypes and comparable to probiotic E. coli Nissle 1917 (10- to 15-fold). Functional assays showed that all tested bacteria were similarly killed by defensins allowing to speculate about a suicidal character of this effect. Defensin induction seems to be a common and important mechanism of probiotic treatment.
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Affiliation(s)
- M Möndel
- Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology and University of Tübingen, Stuttgart, Germany
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17
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Elevated human beta-defensin-2 levels indicate an activation of the innate immune system in patients with irritable bowel syndrome. Am J Gastroenterol 2009; 104:404-10. [PMID: 19174795 DOI: 10.1038/ajg.2008.86] [Citation(s) in RCA: 121] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Irritable bowel syndrome (IBS) is a highly prevalent functional disorder. According to the Rome criteria, macroscopic and histological inflammation is a crucial exclusion criterion for IBS. Human defensins appear to be part of the innate immune system in the gastrointestinal tract. Human beta-defensin-2 (HBD-2) was the first inducible human antimicrobial protein discovered. The expression is induced by probiotic microorganisms and proinflammatory cytokines. Recent results imply that HBD-2 is expressed in active intestinal inflammation, especially in ulcerative colitis (UC). Our aim was to evaluate fecal measurements of HBD-2 in patients with active UC and IBS, and in healthy controls (HCs). METHODS Fecal specimens were collected from a total of 100 participants (30 with active UC, 46 IBS, and 24 HCs). Exclusion criteria were the current use of probiotics and antibiotics. Furthermore, IBS patients with elevated C-reactive protein or leukocytes, a history of bacterial overgrowth or infectious gastrointestinal disease over the last 6 month were excluded. Disease status was addressed in all participating subjects by medical history and current symptoms. In addition, each IBS and UC patient underwent ileocolonoscopy with histopathology. Fecal inflammation markers lactoferrin (Lf) and calprotectin (Cal) were measured by enzyme-linked immunosorbent assay (ELISA) and reported as microg/g. Fecal HBD-2 was measured by ELISA and reported as ng/g feces. In addition, immunoblots were performed for fecal HBD-2. Paraffin-embedded tissue from colonic biopsies was tested for HBD-2 peptides by immunohistochemistry. RESULTS Lf as well as Cal was elevated in active UC (mean: 152.1+/-s.d. 374.7 microg/g; 103.5+/-87.1 microg/g), compared with IBS (8.3+/-19.4 microg/g; 18.6+/-23.3 microg/g), and HCs (0.4+/-0.5 microg/g; 7.1+/-7.9 microg/g). Scheffe post hoc tests revealed significant differences (P=0.006; P<0.001) between active UC vs. IBS and HC. In contrast, HBD-2 levels were highest in active UC (mean: 106.9+/-s.d. 91.5 ng/g), almost as high in IBS (pts 76.0+/-67.9 ng/g), and lowest for HCs (29.9+/-16.1 ng/g). Scheffe post hoc tests revealed significant differences (P<0.001) between the groups of patients (UC and IBS) vs. HCs. Immunohistochemical investigation was consistent with fecal secretion data and demonstrated the presence of beta-defensin 2 peptides in colonic epithelial enterocytes in UC as well as IBS patients with elevated fecal HBD-2. CONCLUSIONS The results indicate significantly elevated levels of HBD-2 in patients with IBS compared with HCs and similar to those with active UC. The results support an activation of the mucosal innate defense system toward a proinflammatory response in IBS patients in the absence of macroscopic signs of inflammation.
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Ramasundara M, Leach ST, Lemberg DA, Day AS. Defensins and inflammation: the role of defensins in inflammatory bowel disease. J Gastroenterol Hepatol 2009; 24:202-208. [PMID: 19215333 DOI: 10.1111/j.1440-1746.2008.05772.x] [Citation(s) in RCA: 125] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Defensins are antimicrobial peptides produced at a variety of epithelial surfaces. In the intestinal tract, they contribute to host immunity and assist in maintaining the balance between protection from pathogens and tolerance to normal flora. However, attenuated expression of defensins compromises host immunity and hence may alter the balance toward inflammation. Altered defensin production is suggested to be an integral element in the pathogenesis of inflammatory bowel disease (IBD). Evidence for this is shown in Crohn's disease where reduced alpha-defensin levels are seen in patients with ileal disease and reduced beta-defensin levels in those with colonic involvement. Further evidence is provided by research linking nucleotide oligomerization domain 2 (NOD2) mutations and deficient defensin expression. However, alternate studies suggest that NOD2 status and defensin expression are independent, and that defensin deficiency is due to mucosal surface destruction as a result of inflammatory changes, indicating that reduced defensin expression is a symptom of the disease and not the cause. Although it is clear that defensin expression is altered in IBD, it is less clear whether defensin deficiency is implicated in the pathogenesis of IBD or is a consequence of the disease process. The aim of this article is to review the current knowledge of defensins in IBD and discuss their potential role in IBD pathogenesis.
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Affiliation(s)
- Malith Ramasundara
- School of Women's and Children's Health, University of New South Wales, New South Wales, Australia
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Abstract
Defensins, endogenous antibiotic peptides, are part of the intestinal epithelial barrier. In this pilot study we analyzed the possibility of measuring fecal beta-defensin-2 (HBD2) in comparing inflammatory and noninflammatory conditions. In samples from healthy control individuals, low levels of HBD2 were detectable, which markedly rose under inflammatory conditions (P = 0.0002 vs normal control individuals), the highest levels being observed in patients with ulcerative colitis (median 356 ng/g, range 40-527). Despite frank inflammation, Crohn disease patients with colitis had significantly lower, albeit enhanced, HBD2 levels than did ulcerative colitis patients. These data confirm the possibility of quantifying HBD2 in feces and indicate that colitis in Crohn disease and colitis in ulcerative colitis differ from each other with respect to their ability to secrete HBD2.
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Parkes GC, Brostoff J, Whelan K, Sanderson JD. Gastrointestinal microbiota in irritable bowel syndrome: their role in its pathogenesis and treatment. Am J Gastroenterol 2008; 103:1557-67. [PMID: 18513268 DOI: 10.1111/j.1572-0241.2008.01869.x] [Citation(s) in RCA: 113] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Irritable bowel syndrome (IBS) is a chronic disorder characterized by abdominal pain, change in bowel habit, and bloating. It has traditionally been viewed as a disorder of visceral hypersensitivity heavily influenced by stress, and therefore therapeutic strategies to date have largely reflected this. However, more recently, there is good evidence for a role of the gastrointestinal (GI) microbiota in its pathogenesis. Changes in fecal microbiota, the use of probiotics, the phenomenon of postinfectious IBS, and the recognition of an upregulated host immune system response suggest that an interaction between the host and GI microbiota may be important in the pathogenesis of IBS. This article explores the role of the GI microbiota in IBS and how their modification might lead to therapeutic benefit.
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Affiliation(s)
- Gareth C Parkes
- Diet and Gastrointestinal Health, Nutritional Sciences Division, King's College London, London, United Kingdom
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Musial F, Häuser W, Langhorst J, Dobos G, Enck P. Psychophysiology of visceral pain in IBS and health. J Psychosom Res 2008; 64:589-97. [PMID: 18501259 DOI: 10.1016/j.jpsychores.2008.02.024] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2007] [Revised: 02/05/2008] [Accepted: 02/07/2008] [Indexed: 12/14/2022]
Abstract
The psychophysiology of visceral pain as it relates to gastrointestinal motility, visceral sensitivity, and putative mechanisms of the processing of visceral stimuli by the central and peripheral nervous systems are discussed. Peripheral mechanisms may include low-grade mucosal inflammation, and it is likely that central nervous mechanisms such as neuronal plasticity at the level of the spinal cord and attentional bias at the cortical level are relevant for the chronification of visceral pain. From a psychophysiological perspective, visceral pain therefore remains a complex symptom because behavioral variables, such as the way an individual deals with stress, may be as important for the etiology of visceral pain as, for example, a history of inflammation.
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Affiliation(s)
- Frauke Musial
- Complementary and Integrative Medicine, University of Duisburg-Essen, Department of Internal Medicine, Kliniken Essen-Mitte, Germany.
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Lochs H. A question of survival? Interaction between probiotics and the gastrointestinal tract. Wien Klin Wochenschr 2007; 119:441-3. [PMID: 17721762 DOI: 10.1007/s00508-007-0854-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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