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Yu X, Cao Y, Mao C, Tao C, Chen W. Association Between Genetically Proxied SLC12A2 Inhibition and Inflammatory Bowel Disease: A Mendelian Randomization Study. Biochem Genet 2025:10.1007/s10528-025-11037-y. [PMID: 39913044 DOI: 10.1007/s10528-025-11037-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 01/12/2025] [Indexed: 02/07/2025]
Abstract
The global rise in hypertension prompts the use of medications to manage blood pressure. However, selecting first-line drugs remains challenging as their efficacy often stems from blood pressure reduction rather than specific pharmacological actions. Evaluating interactions between antihypertensive drugs and common diseases can aid tailored treatment. Here, we assess the potential link between antihypertensives and inflammatory bowel disease (IBD). Summary-level coronary heart disease (CHD) data (184,305 individuals), systolic BP (SBP) data (757,601 individuals), ulcerative ileocolitis data (361,188 individuals), ulcerative colitis data (364,454 individuals), other ulcerative colitis data (361,619 individuals), and ulcerative proctitis data (361,700 individuals) were all from genome-wide association studies (GWASs), FinnGen or eQTL studies publicly accessible. The DrugBank10 and ChEMBL11 databases function to identify genes encoding protein products targeted by active constituents of BP-lowering drugs. Summary-data-based MR (SMR) estimated the associations between expressions of drug target genes and symptoms of IBD. A multivariable MR study was further conducted to examine if the observed association was direct association. Subsequently, we collected blood samples from IBD patients in the Gastroenterology Department of Gastroenterology, the First Affiliated Hospital of Anhui Medical University and blood from healthy individuals at the physical examination center. Real-time quantitative PCR was employed to detect the expression changes of drug target genes in the peripheral blood of patients with IBD. Furthermore, we used Caco2 cells to construct an in vitro model of IBD, examined the expression of the target molecules, and verified the potential of Bumetanide to improve IBD. SMR analysis revealed that enhanced SLC12A2 gene expression in blood (equivalent to a one standard deviation increase) was a risk factor for ulcerative ileocolitis (beta = 0.5861, se = 0.2972, p = 0.0486) and enhanced gene expression of ACE was a protective factor. Additionally, SCNN1D and SLC16A1 played protective roles of IBD, while NR3C1 was identified as a risk factor. However, among these genes, only SLC12A2 was considered to influence the progress of inflammatory bowel disease through systolic blood pressure based on Mendelian randomization analysis results. Other genes may be associated with IBD depending on the expression of their own proteins, independent of changes in blood pressure. In the peripheral blood of IBD patients and in vitro experiments, SCL12A2 has been shown to be highly expressed in IBD. In vitro experiments have confirmed that Bumetanide can inhibit SCL12A2 to improve tight junctions, reduce inflammation levels, and ameliorate IBD symptoms. Therapeutic inhibition of SCL12A2 may benefit patients with IBD. In the future, this study may contribute to the selection of more personalized antihypertensive medications for different subgroups of hypertensive patients.
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Affiliation(s)
- Xin Yu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Department of Urology, Anhui Provincial Children's Hospital, Hefei, Anhui, China
| | - Yongsheng Cao
- Department of Urology, Anhui Provincial Children's Hospital, Hefei, Anhui, China
| | - Changkun Mao
- Department of Urology, Anhui Provincial Children's Hospital, Hefei, Anhui, China
| | - Chengpin Tao
- Department of Urology, Anhui Provincial Children's Hospital, Hefei, Anhui, China
| | - Wei Chen
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
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Thangaiyan R, Sakwe AM, Hawkins AT, Washington MK, Ballard BR, Izban MG, Chirwa SS, Hildreth JEK, Shanker A, Blum DL, M'Koma AE. Functional characterization of novel anti-DEFA5 monoclonal antibody clones 1A8 and 4F5 in inflammatory bowel disease colitis tissues. Inflamm Res 2025; 74:30. [PMID: 39883179 PMCID: PMC11782311 DOI: 10.1007/s00011-024-01970-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 11/28/2024] [Accepted: 11/30/2024] [Indexed: 01/31/2025] Open
Abstract
BACKGROUND The aberrant expression of α defensin 5 (DEFA5) protein in colonic inflammatory bowel diseases (IBDs) underlies the distinct pathogenesis of Crohn's colitis (CC). It can serve as a biomarker for differentiating CC from Ulcerative colitis (UC), particularly in Indeterminate colitis (IC) cases into UC and CC. We evaluated the specificity of commercially available anti-DEFA5 antibodies, emphasizing the need to further validate their appropriateness for a given application and highlighting the necessity for novel antibodies. METHODS We established two mice monoclonal DEFA5 antibody clones, 1A8 and 4F5, by immunizing mice with purified recombinant protein. We validated the specificity, sensitivity, and cross-reactivity of these antibodies in recognizing both endogenous and recombinant DEFA5 protein, especially for use in Immunohistochemistry (IHC), Western blot (WB), Immunoprecipitation (IP), and enzyme-linked immunosorbent assay (ELISA). RESULTS Clones 1A8 and 4F5 effectively recognized the endogenous DEFA5 in active human colon tissue from patients with diverticulitis (DV), UC, CC, and IC disease samples, as well as in transiently transfected HEK293T cells expressing DEFA5 with minimal non-confounding cross reactivity. CONCLUSIONS The 1A8 and 4F5 clones are useful for a wide variety of immunoassays, including WB, IHC, IP/WB, and ELISA. Their specificity enhances their potential as valuable tools for research applications in IBD colitis.
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Affiliation(s)
- Rabi Thangaiyan
- Department of Biochemistry, Cancer Biology, Neuroscience, and Pharmacology, School of Medicine, Meharry Medical College, 1005 D.B. Todd Jr. Blvd, Nashville, TN, USA
| | - Amos M Sakwe
- Department of Biochemistry, Cancer Biology, Neuroscience, and Pharmacology, School of Medicine, Meharry Medical College, 1005 D.B. Todd Jr. Blvd, Nashville, TN, USA
| | - Alexander T Hawkins
- Section of Colon and Rectal Surgery, Division of General Surgery, School of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Mary K Washington
- Department of Pathology, Microbiology, and Immunology, School of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Billy R Ballard
- Department of Pathology, Anatomy and Cell Biology, School of Medicine, Meharry Medical College, Nashville, TN, USA
| | - Michael G Izban
- Department of Pathology, Anatomy and Cell Biology, School of Medicine, Meharry Medical College, Nashville, TN, USA
| | - Sanika S Chirwa
- Department of Biochemistry, Cancer Biology, Neuroscience, and Pharmacology, School of Medicine, Meharry Medical College, 1005 D.B. Todd Jr. Blvd, Nashville, TN, USA
| | - James E K Hildreth
- Department of Microbiology, Immunology, and Physiology, School of Medicine, Meharry Medical College, Nashville, TN, USA
| | - Anil Shanker
- Department of Biochemistry, Cancer Biology, Neuroscience, and Pharmacology, School of Medicine, Meharry Medical College, 1005 D.B. Todd Jr. Blvd, Nashville, TN, USA
| | - David L Blum
- Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, USA
| | - Amosy E M'Koma
- Department of Biochemistry, Cancer Biology, Neuroscience, and Pharmacology, School of Medicine, Meharry Medical College, 1005 D.B. Todd Jr. Blvd, Nashville, TN, USA.
- Section of Colon and Rectal Surgery, Division of General Surgery, School of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
- Department of Pathology, Anatomy and Cell Biology, School of Medicine, Meharry Medical College, Nashville, TN, USA.
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Alnaqbi KA, Riaz A, Alaswad M. Paradoxical Inflammatory Bowel Disease Induced by Golimumab in a Patient With Ankylosing Spondylitis: A Case Report and Systematic Review. Cureus 2025; 17:e77363. [PMID: 39807347 PMCID: PMC11726622 DOI: 10.7759/cureus.77363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/12/2025] [Indexed: 01/16/2025] Open
Abstract
Paradoxical reactions (PRs) to biologic medications, such as psoriasis, arthritis, and inflammatory bowel disease (IBD), have been increasingly recognized. The aim of reporting this case is to establish an association between golimumab and exacerbation or new (de novo) IBD in patients with axial spondyloarthritis (SpA). Our case involves a young patient with juvenile-onset ankylosing spondylitis (AS) who developed de novo IBD following golimumab therapy for active spinal disease. The patient had no prior gastrointestinal (GI) symptoms, and AS symptoms significantly improved with golimumab. However, before the third dose, he experienced non-bloody diarrhea, mild abdominal cramping, and constitutional symptoms (fever, chills, and weight loss). Colonoscopy and biopsy confirmed unclassified IBD. The discontinuation of golimumab resulted in marked improvement in GI symptoms, but the recurrence of AS symptoms necessitated the initiation of infliximab, which resolved both AS and IBD symptoms. A comprehensive systematic literature review was conducted (from 2008 to October 2024) on Medical Literature Analysis and Retrieval System Online (MEDLINE) Complete/PubMed and Scopus databases using both Medical Subject Heading (MeSH) terms and keywords related to golimumab, SpA, and paradoxical IBD. Data from included cases were extracted by two researchers, and the quality assessment of case reports was performed using a standardized tool. Four cases of paradoxical IBD development following golimumab treatment in patients with pre-existing IBD were identified. This is the first reported case of de novo IBD development in a biologic-naïve patient with AS treated with golimumab. This case highlights the importance of prompt evaluation of gastrointestinal symptoms and early gastroenterology referral during biologic therapy.
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Affiliation(s)
- Khalid A Alnaqbi
- Department of Research, Emirates Medical Association, Dubai, ARE
- Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates (UAE) University, Al Ain, ARE
- Division of Rheumatology, Sheikh Tahnoon Medical City, Al Ain, ARE
- Division of Rheumatology, Tawam Hospital, Al Ain, ARE
| | - Amna Riaz
- Department of Internal Medicine, Sheikh Tahnoon Medical City, Al Ain, ARE
- Department of Internal Medicine, Tawam Hospital, Al Ain, ARE
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Prakash S, Tanaka T, Ashat D. A nationwide study of patients hospitalized with indeterminate colitis: a comparison with Crohn's disease and ulcerative colitis. Int J Colorectal Dis 2023; 38:223. [PMID: 37650980 DOI: 10.1007/s00384-023-04515-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/19/2023] [Indexed: 09/01/2023]
Abstract
PURPOSE Indeterminate colitis (IC) is subtype of colonic inflammatory bowel disease (IBD) that has features of both Crohn's disease (CD) and ulcerative colitis (UC). There have also been no studies to date examining patients hospitalized with IC in the United States (US). METHODS We examined the demographic and clinical characteristics of patients admitted with IC and compared them with patients admitted with CD and UC. We also analyzed trends in cost and length of stay (LOS). RESULTS Patients admitted with IC tended to be female (58%), Caucasian (72%), and younger [39 (SD: 23) years]. Patients with IC underwent lower endoscopy at higher rates (26%; CD: p < 0.001, UC: p = 0.08) but bowel surgery at lower rates compared to those with CD (11% vs. 16%; p = 0.04). Patients with IC were found to have a higher rate of bowel obstruction (4% vs. 0.7%, p = 0.004) than those with UC, but lower rates of abscess and obstruction compared to patients with CD (p < 0.001). When the analysis was confined to patients who underwent bowel surgery, IC patients still demonstrated higher rates of lower endoscopy (p = 0.03) but lower rates of abscess compared to CD patients (p = 0.049). Costs increased significantly over time for CD- and UC-related hospitalizations, but not for admissions related to IC. CONCLUSION This is the first nationwide US study illustrating the demographics and clinical characteristics of patients hospitalized with IC. We conclude that IC has notable differences in hospitalization characteristics compared to the main two IBD subtypes.
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Affiliation(s)
- Shahana Prakash
- Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA
- Iowa City Veterans Administration Medical Center, Iowa City, IA, USA
| | - Tomohiro Tanaka
- Iowa City Veterans Administration Medical Center, Iowa City, IA, USA
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, University of Iowa Carver College of Medicine, 4614 JCP, 200 Hawkins Drive, Iowa City, IA, 52242, USA
| | - Divya Ashat
- Iowa City Veterans Administration Medical Center, Iowa City, IA, USA.
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, University of Iowa Carver College of Medicine, 4614 JCP, 200 Hawkins Drive, Iowa City, IA, 52242, USA.
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Gao J, Zhang H, Zhang F. Research progress of TIPE2 in immune-related diseases. Int Immunopharmacol 2023; 121:110514. [PMID: 37348234 DOI: 10.1016/j.intimp.2023.110514] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 06/02/2023] [Accepted: 06/13/2023] [Indexed: 06/24/2023]
Abstract
The tumor necrosis factor α-induced protein 8 (TNFAIP8) family, which consists of TNFAIP8 (TIPE), TNFAIP8L1 (TIPE1), TNFAIP8L2 (TIPE2) and TNFAIP8L3 (TIPE3), has recently emerged as a regulatory factor involved in immune response and tumorigenesis. Among its members, TIPE2 acts as a negative regulator of both innate and adaptive immunity, playing a crucial role in maintaining immune homeostasis by negatively regulating T cell receptor (TCR) and toll-like receptor (TLR) signal transduction. Immune homeostasis is an indispensable characteristic of the immune system, which prevents harmful inflammatory reactions and ensures the proper functioning of the body. A large number of studies have shown that abnormal TIPE2 expression exists in a variety of inflammation-related diseases such as asthma, colitis, and systemic lupus erythematosus, highlighting the importance of comprehending its function for the prevention and treatment of immune-related conditions. This review aims to provide an overview of the in vivo distribution and expression of TIPE2, its regulatory role in central and peripheral immune-related diseases, and the underlying mechanisms that govern its function in the inflammatory response. By delving into these aspects, a deeper understanding of the role and functionality of TIPE2 in inflammatory responses can be achieved.
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Affiliation(s)
- Jie Gao
- Department of Pharmacology, Qingdao University School of Pharmacy, Qingdao 266000, China.
| | - Hanting Zhang
- Department of Pharmacology, Qingdao University School of Pharmacy, Qingdao 266000, China.
| | - Fang Zhang
- Department of Pharmacology, Qingdao University School of Pharmacy, Qingdao 266000, China.
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The Use of Endoscopic Ultrasonography in Inflammatory Bowel Disease: A Review of the Literature. Diagnostics (Basel) 2023; 13:diagnostics13030568. [PMID: 36766671 PMCID: PMC9914551 DOI: 10.3390/diagnostics13030568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Revised: 01/27/2023] [Accepted: 02/01/2023] [Indexed: 02/05/2023] Open
Abstract
The diagnosis of inflammatory bowel disease (IBD) can sometimes be challenging. By corroborating clinical, imaging and histological data, the two main entities of IBD, ulcerative colitis and Crohn's disease (CD), can be differentiated in most cases. However, there remains 10-20% of patients where the diagnosis cannot be accurately established, in which case the term "IBD unclassified" is used. The imaging techniques most used to evaluate patients with IBD include colonoscopy, ultrasonography and magnetic resonance imaging. Endoscopic ultrasonography is mainly recommended for the evaluation of perianal CD. Through this work, we aim to identify other uses of this method in the case of patients with IBD.
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Application of the capture–recapture method to ascertain the completeness of the Saxon pediatric IBD registry in Germany. J Public Health (Oxf) 2022. [DOI: 10.1007/s10389-022-01749-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022] Open
Abstract
Abstract
Aim
The incidence of inflammatory bowel disease (IBD) is increasing worldwide. The Saxon Pediatric IBD Registry was founded in 2000 to describe the epidemiology of pediatric IBD in Germany. The aim of this study was to determinate the completeness of this registry for children and adolescents younger than 15 years and to make this approach transparent. Results of this completeness update have broad implications for further scientific publications from the registry dataset.
Method
The capture–recapture method with two data sources was used to ascertain completeness. A second data source was collected in 2019 for the observation period 2008–2014 from all pediatricians, gastroenterologists, and internists working in practices in a predefined region in Saxony, Germany.
Results
A total of 23 patients with IBD were reported who fulfilled the inclusion criteria. One of them was not recorded in the registry. Therefore, the completeness of the registry was estimated at 95.7% (95% CI 90.2–100). Initial analysis of the Saxon Pediatric IBD Registry over the 15-year period 2000–2014 includes 532 patients, 312 (58.6%) male and 220 (41.4%) female. The distribution of single IBD diseases in the registry was as follows: Crohn’s disease 338 patients (63.5%), ulcerative colitis 176 patients (33.1%), and unclassified IBD 18 patients (3.4%). Evaluations by sex and by disease in age groups and by age at onset were tabulated.
Conclusion
This study demonstrates that the completeness level of the Saxon Pediatric IBD Registry is high (95.7%), and thus the epidemiological data of the registry are reliable.
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M’Koma AE. Inflammatory Bowel Disease: Clinical Diagnosis and Surgical Treatment-Overview. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:567. [PMID: 35629984 PMCID: PMC9144337 DOI: 10.3390/medicina58050567] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/07/2022] [Accepted: 04/11/2022] [Indexed: 12/18/2022]
Abstract
This article is an overview of guidelines for the clinical diagnosis and surgical treatment of predominantly colonic inflammatory bowel diseases (IBD). This overview describes the systematically and comprehensively multidisciplinary recommendations based on the updated principles of evidence-based literature to promote the adoption of best surgical practices and research as well as patient and specialized healthcare provider education. Colonic IBD represents idiopathic, chronic, inflammatory disorders encompassing Crohn's colitis (CC) and ulcerative colitis (UC), the two unsolved medical subtypes of this condition, which present similarity in their clinical and histopathological characteristics. The standard state-of-the-art classification diagnostic steps are disease evaluation and assessment according to the Montreal classification to enable explicit communication with professionals. The signs and symptoms on first presentation are mainly connected with the anatomical localization and severity of the disease and less with the resulting diagnosis "CC" or "UC". This can clinically and histologically be non-definitive to interpret to establish criteria and is classified as indeterminate colitis (IC). Conservative surgical intervention varies depending on the disease phenotype and accessible avenues. The World Gastroenterology Organizations has, for this reason, recommended guidelines for clinical diagnosis and management. Surgical intervention is indicated when conservative treatment is ineffective (refractory), during intractable gastrointestinal hemorrhage, in obstructive gastrointestinal luminal stenosis (due to fibrotic scar tissue), or in the case of abscesses, peritonitis, or complicated fistula formation. The risk of colitis-associated colorectal cancer is realizable in IBD patients before and after restorative proctocolectomy with ileal pouch-anal anastomosis. Therefore, endoscopic surveillance strategies, aimed at the early detection of dysplasia, are recommended. During the COVID-19 pandemic, IBD patients continued to be admitted for IBD-related surgical interventions. Virtual and phone call follow-ups reinforcing the continuity of care are recommended. There is a need for special guidelines that explore solutions to the groundwork gap in terms of access limitations to IBD care in developing countries, and the irregular representation of socioeconomic stratification needs a strategic plan for how to address this serious emerging challenge in the global pandemic.
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Affiliation(s)
- Amosy Ephreim M’Koma
- Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, Meharry Medical College School of Medicine, Nashville, TN 37208-3500, USA; or ; Tel.: +1-615-327-6796; Fax: +1-615-327-6440
- Department of Pathology, Anatomy and Cell Biology, Meharry Medical College School of Medicine, Nashville General Hospital, Nashville, TN 37208-3599, USA
- Division of General Surgery, Section of Colon and Rectal Surgery, Vanderbilt University School of Medicine, Nashville, TN 37232-0260, USA
- The American Society of Colon and Rectal Surgeons (ASCRS), 2549 Waukegan Road, #210, Bannockburn, IL 600015, USA
- The American Gastroenterological Association (AGA), Bethesda, MD 20814, USA
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Liu T, Han L, Tilley M, Afzelius L, Maciejewski M, Jelinsky S, Tian C, McIntyre M, Bing N, Hung K, Altman RB. Distinct clinical phenotypes for Crohn's disease derived from patient surveys. BMC Gastroenterol 2021; 21:160. [PMID: 33836648 PMCID: PMC8034169 DOI: 10.1186/s12876-021-01740-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 03/25/2021] [Indexed: 11/14/2022] Open
Abstract
Background Defining clinical phenotypes provides opportunities for new diagnostics and may provide insights into early intervention and disease prevention. There is increasing evidence that patient-derived health data may contain information that complements traditional methods of clinical phenotyping. The utility of these data for defining meaningful phenotypic groups is of great interest because social media and online resources make it possible to query large cohorts of patients with health conditions. Methods We evaluated the degree to which patient-reported categorical data is useful for discovering subclinical phenotypes and evaluated its utility for discovering new measures of disease severity, treatment response and genetic architecture. Specifically, we examined the responses of 1961 patients with inflammatory bowel disease to questionnaires in search of sub-phenotypes. We applied machine learning methods to identify novel subtypes of Crohn’s disease and studied their associations with drug responses. Results Using the patients’ self-reported information, we identified two subpopulations of Crohn’s disease; these subpopulations differ in disease severity, associations with smoking, and genetic transmission patterns. We also identified distinct features of drug response for the two Crohn’s disease subtypes. These subtypes show a trend towards differential genotype signatures. Conclusion Our findings suggest that patient-defined data can have unplanned utility for defining disease subtypes and may be useful for guiding treatment approaches. Supplementary Information The online version contains supplementary material available at 10.1186/s12876-021-01740-6.
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Affiliation(s)
- Tianyun Liu
- Department of Bioengineering, Stanford University, Shriram Room 209, MC: 4245, 443 Via Ortega Drive, Stanford, CA, 94305-4145, USA
| | - Lichy Han
- Biomedical Informatics Training Program, Stanford University, Stanford, CA, USA
| | - Mera Tilley
- Inflammation and Immunology, Pfizer Inc., Cambridge, MA, USA
| | - Lovisa Afzelius
- Inflammation and Immunology, Pfizer Inc., Cambridge, MA, USA
| | | | - Scott Jelinsky
- Inflammation and Immunology, Pfizer Inc., Cambridge, MA, USA
| | - Chao Tian
- 23andMe Research Team, 23andMe Inc., Sunnyvale, CA, USA
| | | | | | - Nan Bing
- Inflammation and Immunology, Pfizer Inc., Cambridge, MA, USA
| | - Kenneth Hung
- Inflammation and Immunology, Pfizer Inc., Cambridge, MA, USA
| | - Russ B Altman
- Department of Bioengineering, Stanford University, Shriram Room 209, MC: 4245, 443 Via Ortega Drive, Stanford, CA, 94305-4145, USA.
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Sergi C, Villanacci V, Carroccio A. Non-celiac wheat sensitivity: rationality and irrationality of a gluten-free diet in individuals affected with non-celiac disease: a review. BMC Gastroenterol 2021; 21:5. [PMID: 33407153 PMCID: PMC7788993 DOI: 10.1186/s12876-020-01568-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Accepted: 12/03/2020] [Indexed: 02/08/2023] Open
Abstract
Non-celiac gluten or wheat sensitivity (NCWS) is a "clinical entity induced by the ingestion of wheat leading to intestinal and/or extraintestinal symptoms that improve once the wheat-containing foodstuff is removed from the diet, and celiac disease and wheat allergy have been excluded". This mostly accepted definition raises several points that remain controversial on this condition. In the present review, the authors summarize the most recent advances in the clinic and research on NCWS through an accurate analysis of different studies. We screened PubMed, Medline, Embase, and Scopus using the keywords "non-celiac gluten sensitivity", "non-celiac wheat sensitivity", and "diagnosis". We would like to emphasize two main points, including (A) the controversial clinical and etiological aspects in different trials and experiences with particular attention to the Salerno criteria for the diagnosis of NCWS and (B) the histological aspects. The etiology of NCWS remains controversial, and the relationship with irritable bowel syndrome is obscure. Histologically, the duodenal mucosa may show a variable pattern from unremarkable to a slight increase in the number of T lymphocytes in the superficial epithelium of villi. The endorsement of this disease is based on a positive response to a gluten-free diet for a limited period, followed by the reappearance of symptoms after gluten challenge. The Salerno expert criteria may help to diagnose NCWS accurately. Social media and inaccurate interpretation of websites may jeopardize the diagnostic process if individuals self-label as gluten intolerant.
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Affiliation(s)
- Consolato Sergi
- Department of Laboratory Medicine and Pathology, Stollery Children's Hospital, University of Alberta, 8440 112 St., Edmonton, AB, T6G 2B7, Canada.
| | | | - Antonio Carroccio
- Internal Medicine Unit, "V Cervello Hospital", Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90129, Palermo, Italy
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Venkateswaran N, Weismiller S, Clarke K. Indeterminate Colitis - Update on Treatment Options. J Inflamm Res 2021; 14:6383-6395. [PMID: 34876831 PMCID: PMC8643196 DOI: 10.2147/jir.s268262] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 11/17/2021] [Indexed: 12/30/2022] Open
Abstract
Indeterminate colitis (IC) is described in approximately 5-15% of patients with inflammatory bowel disease (IBD). It usually reflects a difficulty or lack of clarity in distinguishing between ulcerative colitis (UC) and Crohn's disease (CD) on biopsy or colectomy specimens. The diagnostic difficulty may explain the variability in the reported prevalence and incidence of IC. Clinically, most IC patients tend to evolve over time to a definite diagnosis of either UC or CD. IC has also been interchangeably described as inflammatory bowel disease unclassified (IBDU). This review offers an overview of the available limited literature on the conventional medical and surgical treatments for IC. In contrast to the numerous studies on the medical management of UC and CD, there are very few data from dedicated controlled trials on the treatment of IC. The natural evolution of IC more closely mimics UC. Regarding medical options for treatment, most patients diagnosed with IC are treated similarly to UC, and treatment choices are based on disease severity. Others are managed similarly to CD if there are features suggestive of CD, including fissures, skin tags, or rectal sparing. In medically refractory IC, surgical treatment options are limited and include total proctocolectomy (TPC) and ileal pouch-anal anastomosis (IPAA), with its associated risk factors and complications. Post-surgical complications and pouch failure rates were historically thought to be more common in IC patients, but recent meta-analyses reveal similar rates between UC and IC patients. Future therapies in IBD are focused on known mechanisms in the disease pathways of UC and CD. Owing to the lack of IC-specific studies, clinicians have traditionally and historically extrapolated the data to IC patients based on their symptomatology, clinical course, and endoscopic findings.
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Affiliation(s)
- Niranjani Venkateswaran
- Division of General Internal Medicine, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Scott Weismiller
- Division of General Internal Medicine, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Kofi Clarke
- Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA, USA
- Correspondence: Kofi Clarke Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA, 17033, USATel +1 717-531-8741Fax +1 717-531-6770 Email
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Ning L, Shan G, Sun Z, Zhang F, Xu C, Lou X, Li S, Du H, Chen H, Xu G. Quantitative Proteomic Analysis Reveals the Deregulation of Nicotinamide Adenine Dinucleotide Metabolism and CD38 in Inflammatory Bowel Disease. BIOMED RESEARCH INTERNATIONAL 2019; 2019:3950628. [PMID: 31179321 PMCID: PMC6507272 DOI: 10.1155/2019/3950628] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 03/25/2019] [Accepted: 04/02/2019] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel disease (IBD) has become a major health challenge worldwide. However, the precise etiological and pathophysiological factors involved in IBD remain unclear. Proteomics can be used for large-scale protein identification analysis. In the current study, using tandem mass tag- (TMT-) based shotgun proteomics, proteomic differences between intestinal tissue from health controls, patients with Crohn's disease (CD), and patients with ulcerative colitis (UC) were compared. Proteins with fold change >2 or <0.5 and P value < 0.05 between groups were considered differentially expressed. ProteinAtlas was used to analyze the tissue specificity of differentially expressed proteins (DEPs). Reactome pathway analysis was applied to cluster functional pathways. A total of 4786 proteins were identified, with 59 proteins showing higher levels and 43 showing lower levels in patients with IBD than in controls. Seventeen proteins, including angiotensin converting enzyme 2 (ACE2) and angiotensin converting enzyme 1 (ACE), showed higher levels in CD than in UC. Several novel proteins such as CD38, chitinase 3-like 1 (CHI3L1), olfactomedin 4 (OLFM4), and intelectin 1 were screened out between patients with IBD and controls. When proteins with fold change >1.2 or <0.84 and P value < 0.05 between groups were considered differentially expressed, the expression of 10 proteins, including CD38, involved in the nicotinamide adenine dinucleotide (NAD) metabolism and signaling pathway showed significant changes in IBD. Using the NCBI GEO database, we confirmed increased CD38 mRNA expression in patients with UC and in mouse colitis models. Protein CD38 expression was higher in CD and UC than in normal controls. CD38 expression was higher in inflamed tissues than in noninflamed tissues, and CD38 was located in F4/80-positive cells. Our study may provide novel insights into the molecular pathogenesis of IBD. Further studies are required on the role of NAD metabolism and CD38 in intestinal inflammation.
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Affiliation(s)
- LongGui Ning
- Department of Gastroenterology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Guodong Shan
- Department of Gastroenterology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zeyu Sun
- Proteomics & Metabolomics Platform, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Hangzhou, China
| | - Fenming Zhang
- Department of Gastroenterology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chengfu Xu
- Department of Gastroenterology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xinhe Lou
- Department of Gastroenterology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Sha Li
- Department of Gastroenterology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haojie Du
- Department of Gastroenterology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hongtan Chen
- Department of Gastroenterology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Guoqiang Xu
- Department of Gastroenterology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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13
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M'Koma AE. The Multifactorial Etiopathogeneses Interplay of Inflammatory Bowel Disease: An Overview. GASTROINTESTINAL DISORDERS 2019; 1:75-105. [PMID: 37577036 PMCID: PMC10416806 DOI: 10.3390/gidisord1010007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The gastrointestinal system where inflammatory bowel disease occurs is central to the immune system where the innate and the adaptive/acquired immune systems are balanced in interactions with gut microbes under homeostasis conditions. This article overviews the high-throughput research screening on multifactorial interplay between genetic risk factors, the intestinal microbiota, urbanization, modernization, Westernization, the environmental influences and immune responses in the etiopathogenesis of inflammatory bowel disease in humans. Inflammatory bowel disease is an expensive multifactorial debilitating disease that affects thousands new people annually worldwide with no known etiology or cure. The conservative therapeutics focus on the established pathology where the immune dysfunction and gut injury have already happened but do not preclude or delay the progression. Inflammatory bowel disease is evolving globally and has become a global emergence disease. It is largely known to be a disease in industrial-urbanized societies attributed to modernization and Westernized lifestyle associated with environmental factors to genetically susceptible individuals with determined failure to process certain commensal antigens. In the developing nations, increasing incidence and prevalence of inflammatory bowel disease (IBD) has been associated with rapid urbanization, modernization and Westernization of the population. In summary, there are identified multiple associations to host exposures potentiating the landscape risk hazards of inflammatory bowel disease trigger, that include: Western life-style and diet, host genetics, altered innate and/or acquired/adaptive host immune responses, early-life microbiota exposure, change in microbiome symbiotic relationship (dysbiosis/dysbacteriosis), pollution, changing hygiene status, socioeconomic status and several other environmental factors have long-standing effects/influence tolerance. The ongoing multipronged robotic studies on gut microbiota composition disparate patterns between the rural vs. urban locations may help elucidate and better understand the contribution of microbiome disciplines/ecology and evolutionary biology in potentially protecting against the development of inflammatory bowel disease.
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Affiliation(s)
- Amosy E M'Koma
- Meharry Medical College School of Medicine, Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, Nashville, TN 37208, USA
- Vanderbilt University School of Medicine, Department of Surgery, Colon and Rectal Surgery, Nashville, TN 37232, USA
- The American Society of Colon and Rectal Surgeons (ASCRS), Arlington Heights, IL 60005, USA
- The American Gastroenterological Association (AGA), Bethesda, MD 20814, USA
- Vanderbilt-Ingram Cancer Center (VICC), Vanderbilt University Medical Center, Nashville, TN 37232, USA
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14
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Chandradevan R, Hofmekler T, Mondal K, Harun N, Venkateswaran S, Somineni HK, Ballengee CR, Kim MO, Griffiths A, Noe JD, Crandall WV, Snapper S, Rabizadeh S, Rosh JR, Walters TD, Bertha M, Dubinsky MC, Denson LA, Sauer CG, Markowitz JF, LeLeiko NS, Hyams JS, Kugathasan S. Evolution of Pediatric Inflammatory Bowel Disease Unclassified (IBD-U): Incorporated With Serological and Gene Expression Profiles. Inflamm Bowel Dis 2018; 24:2285-2290. [PMID: 29860529 DOI: 10.1093/ibd/izy136] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) mainly consists of Crohn's disease (CD) and ulcerative colitis (UC). About 10%-15% of patients with IBD cannot be firmly diagnosed with CD or UC; hence, they are initially diagnosed as inflammatory bowel disease unclassified (IBD-U). Having a firm diagnosis is clearly preferred to guide treatment choices, and better understanding of the nature of IBD-U is required. METHODS We performed an analysis of a subset of pediatric subjects from an inception IBD cohort of patients initially enrolled in a prospective multicenter study (the RISK study). Initial diagnosis and 2-year follow-up data from the subjects diagnosed with IBD-U were analyzed. An expert panel verified final diagnosis using predefined criteria as a guide. Serological and disease-relevant ileal and rectal tissue gene expression profiles were investigated. The use and the time to initiate anti-TNFα treatment was analyzed among the outcome groups. RESULTS A total of 1411 subjects were enrolled with initial diagnosis of IBD, and among them, 136 subjects were initially diagnosed as IBD-U at enrollment. And 26% were reclassified as UC and 14% as CD within 2 years of diagnosis, while 60% remained as IBD-U. Of those who were reclassified, there was a 2:1 ratio, UC (n = 35) to CD (n = 19). The molecular and serological features of IBD-U at the end of follow-up were very similar to UC and very different from CD. There was less likelihood of receiving anti-TNFα agents if the diagnosis was IBD-U compared with CD (P < 0.0001). CONCLUSIONS In our cohort, 60% of the IBD-U subjects remained as unclassified at 2 years; of those subsequently classified, a higher percentage followed a course more similar to UC. Most of the IBD-U subjects at diagnosis had serological and molecular signatures that are very similar to UC. Although the atypical presentations made the clinician to make an interim diagnosis of IBD-U, results of the molecular and serological factors performed at the time of diagnosis suggests that they were very similar to UC. However, long-term studies are needed to better understand the natural history and molecular characterization of pediatric onset IBD-U. 10.1093/ibd/izy136_video1Video 1.Video 1. Watch now at https://academic.oup.com/ibd/article-lookup/doi/10.1093/ibd/izy136izy136.video15791389938001.
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Affiliation(s)
- Raguraj Chandradevan
- Division of Pediatric Gastroenterology, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Tatyana Hofmekler
- Division of Pediatric Gastroenterology, Emory University School of Medicine, Atlanta, Georgia, USA.,Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Kajari Mondal
- Division of Pediatric Gastroenterology, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Nusrat Harun
- Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA
| | - Suresh Venkateswaran
- Division of Pediatric Gastroenterology, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Hari K Somineni
- Division of Pediatric Gastroenterology, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Cortney R Ballengee
- Division of Pediatric Gastroenterology, Emory University School of Medicine, Atlanta, Georgia, USA.,Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Mi-Ok Kim
- Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA
| | - Anne Griffiths
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Joshua D Noe
- Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Wallace V Crandall
- Department of Pediatric Gastroenterology, Nationwide Children's Hospital, Ohio State University College of Medicine, Columbus, Ohio, USA
| | - Scott Snapper
- Department of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Shervin Rabizadeh
- Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Joel R Rosh
- Department of Pediatrics, Goryeb Children's Hospital, Morristown, New Jersey, USA
| | - Thomas D Walters
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Madeline Bertha
- Division of Pediatric Gastroenterology, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Marla C Dubinsky
- Department of Pediatrics, Mount Sinai Hospital, New York, New York, USA
| | - Lee A Denson
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Cary G Sauer
- Division of Pediatric Gastroenterology, Emory University School of Medicine, Atlanta, Georgia, USA.,Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | | | - Neal S LeLeiko
- Division of Pediatric Gastroenterology, Nutrition and Liver Disease, Hasbro Children Hospital, Brown Medical School, Providence, Rhode Island, USA
| | - Jeffrey S Hyams
- Division of Digestive Diseases, Hepatology, and Nutrition Connecticut Children's Medical Center, Hartford, Connecticut, USA
| | - Subra Kugathasan
- Division of Pediatric Gastroenterology, Emory University School of Medicine, Atlanta, Georgia, USA.,Children's Healthcare of Atlanta, Atlanta, Georgia, USA
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15
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Hirono H, Watanabe K, Hasegawa K, Honma T, Ajioka Y, Ohkoshi S. A Case of Right-Sided Ulcerative Colitis with Mesalamine-Induced Hypersensitivity Reactions. AMERICAN JOURNAL OF CASE REPORTS 2018; 19:623-629. [PMID: 29849018 PMCID: PMC6005098 DOI: 10.12659/ajcr.909644] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 03/16/2018] [Indexed: 12/30/2022]
Abstract
BACKGROUND Ulcerative colitis (UC) is a chronic inflammatory bowel disease, affecting the colon continuously from the rectum proximally. However, a clinical type with right-sided colitis sparing the anal side of the colon is also known. Mesalamine, which is generally used to treat UC, can rarely aggravate the disease. CASE REPORT A 56-year-old woman with no history of colonic diseases visited our hospital because of a positive fecal occult blood test. The first colonoscopy showed inflamed and edematous mucosa extending from the ascending colon to the right-half of the transverse colon. Colonic biopsy specimens demonstrated infiltrations of chronic inflammatory cells in the mucosa and crypt abscesses, but no epithelioid granulomas, compatible with UC. She was highly positive for PR3-ANCA, confirming the diagnosis of UC. After starting mesalamine, she had hypersensitivity reactions and aggravations of UC, which were confirmed endoscopically. CONCLUSIONS Right-sided colitis may be a subgroup of UC, and this is the first report of this type of disease complicated by aggravation due to mesalamine hypersensitivity.
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Affiliation(s)
- Haruka Hirono
- Department of Internal Medicine, Nippon Dental University School of Life Dentistry at Niigata, Chuo-ku, Niigata, Japan
| | - Kazuhiko Watanabe
- Department of Internal Medicine, Nippon Dental University School of Life Dentistry at Niigata, Chuo-ku, Niigata, Japan
| | - Katsuhiko Hasegawa
- Department of Internal Medicine, Nippon Dental University School of Life Dentistry at Niigata, Chuo-ku, Niigata, Japan
| | - Terasu Honma
- Department of Gastroenterology and Hepatology, Saiseikai Niigata Daini Hospital, Teraji, Niigata, Japan
| | - Yoichi Ajioka
- Division of Molecular and Diagnostic Pathology, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata, Japan
| | - Shogo Ohkoshi
- Department of Internal Medicine, Nippon Dental University School of Life Dentistry at Niigata, Chuo-ku, Niigata, Japan
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16
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Netz U, Carter J, Eichenberger MR, Feagins K, Galbraith NJ, Dryden GW, Pan J, Rai SN, Galandiuk S. Plasma microRNA Profile Differentiates Crohn's Colitis From Ulcerative Colitis. Inflamm Bowel Dis 2018; 24:159-165. [PMID: 29272478 PMCID: PMC5858028 DOI: 10.1093/ibd/izx009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is commonly divided into 2 entities: Crohn's disease (CD) and ulcerative colitis (UC). Differentiating between these entities when dealing with IBD confined to the colon is important, especially when planning surgical treatment. Due to ambiguous histological or endoscopic findings, accurate diagnosis is not possible in up to 15% of cases. The aim of this study was to determine whether plasma microRNAs (miRNAs) can help differentiate Crohn's colitis (CC) from ulcerative colitis. METHODS Patients with isolated CC and with UC were enrolled in our study from January 2010 to May 2016. Peripheral blood was collected, and total RNA was isolated from plasma. Screening was performed for 380 common miRNAs. miRNAs that were differentially expressed between these 2 groups were chosen, and their differential expression was confirmed using single miRNA assays in a larger sample size. A predictive model was generated using these data. Significantly differentially expressed miRNAs were then validated utilizing the predictive model to assess blinded data from the single assays. RESULTS Screening was performed on 8 patients from each group. Seven differentially expressed miRNAs were chosen for single assay confirmation. Two miRNAs (miR-598, miR-642) were consistently different between the patient groups (P = 0.013, P = 0.005). Using blinded data, these 2 miRNAs were validated using the predictive model, achieving an overall accuracy of 75% (95% confidence interval, 40.7-92.9). CONCLUSIONS We identified 2 plasma miRNAs that differentiated CC from UC. Our data indicate the promise and feasibility of a plasma miRNA-based assay to distinguish between these 2 conditions.
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Affiliation(s)
- Uri Netz
- Price Institute of Surgical Research, The Hiram C. Polk Jr., MD Department of
Surgery, University of Louisville, Louisville, Kentucky,Department of Surgery A, Soroka University Medical Center, Beer Sheva,
Israel,Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva,
Israel
| | - Jane Carter
- Price Institute of Surgical Research, The Hiram C. Polk Jr., MD Department of
Surgery, University of Louisville, Louisville, Kentucky
| | - M Robert Eichenberger
- Price Institute of Surgical Research, The Hiram C. Polk Jr., MD Department of
Surgery, University of Louisville, Louisville, Kentucky
| | - Kayla Feagins
- Price Institute of Surgical Research, The Hiram C. Polk Jr., MD Department of
Surgery, University of Louisville, Louisville, Kentucky
| | - Norman J Galbraith
- Price Institute of Surgical Research, The Hiram C. Polk Jr., MD Department of
Surgery, University of Louisville, Louisville, Kentucky
| | - Gerald W Dryden
- Department of Medicine, Division of Gastroenterology, Hepatology, and
Nutrition University of Louisville School of Medicine Louisville, Kentucky
| | - Jianmin Pan
- Department of Bioinformatics and Biostatistics, University of Louisville
School of Public Health and Information Sciences, Louisville, Kentucky
| | - Shesh N Rai
- Department of Bioinformatics and Biostatistics, University of Louisville
School of Public Health and Information Sciences, Louisville, Kentucky
| | - Susan Galandiuk
- Price Institute of Surgical Research, The Hiram C. Polk Jr., MD Department of
Surgery, University of Louisville, Louisville, Kentucky,Address correspondence to: Susan Galandiuk, MD, FACG, AGAF, The Hiram C.
Polk Jr, MD Department of Surgery, 550 South Jackson Street, Louisville, KY 40202 (e-mail:
)
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17
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Rinawi F, Assa A, Eliakim R, Mozer-Glassberg Y, Nachmias Friedler V, Niv Y, Rosenbach Y, Silbermintz A, Zevit N, Shamir R. The natural history of pediatric-onset IBD-unclassified and prediction of Crohn's disease reclassification: a 27-year study. Scand J Gastroenterol 2017; 52:558-563. [PMID: 28128677 DOI: 10.1080/00365521.2017.1282008] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES A definitive diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) in patients who were initially diagnosed as inflammatory bowel disease-unclassified (IBDU) remains challenging. Our aims were to describe the natural history of pediatric-onset IBDU patients during prolonged period of follow up and to identify associated predictors for CD reclassification among them. MATERIALS AND METHODS In this retrospective single center study, out of 723 patients with pediatric onset IBD, we identified 53 patients (7.3%) diagnosed with IBDU at the Schneider Children's Medical Center of Israel between 1986 and 2013. Potential predictors for CD reclassification including age at diagnosis, gender, clinical manifestations, disease extent and laboratory findings were assessed. RESULTS The median follow-up was 6.8 (± 6.7) years. Reclassification to CD was observed in 24/53 (45%) of patients. The median interval from diagnosis to CD reclassification was 9.4 years. In 58% of these patients, CD reclassification occurred within 5 years from diagnosis. Multivariate Cox models showed that familial history of CD and hypoalbuminemia at diagnosis were significantly associated with CD reclassification (HR 11.3, p = .02 and HR 5.3, p = .03, respectively). All other assessed clinical, laboratory and endoscopic parameters did not serve as predictors for CD reclassification later on. CONCLUSIONS In our cohort, a substantial high proportion of pediatric onset IBDU patients were later re-diagnosed as CD. Only a family history of CD and hypoalbuminemia could predict reclassification among IBDU patients.
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Affiliation(s)
- Firas Rinawi
- a Institute of Gastroenterology, Nutrition and Liver Diseases , Schneider Children's Medical Center of Israel , Petach Tikva , Israel
| | - Amit Assa
- a Institute of Gastroenterology, Nutrition and Liver Diseases , Schneider Children's Medical Center of Israel , Petach Tikva , Israel.,b Sackler Faculty of Medicine , Tel-Aviv University , Tel Aviv , Israel
| | - Rami Eliakim
- b Sackler Faculty of Medicine , Tel-Aviv University , Tel Aviv , Israel.,c Department of Gastroenterology , Sheba Medical Center -Tel Hashomer , Tel Aviv , Israel
| | - Yael Mozer-Glassberg
- a Institute of Gastroenterology, Nutrition and Liver Diseases , Schneider Children's Medical Center of Israel , Petach Tikva , Israel.,b Sackler Faculty of Medicine , Tel-Aviv University , Tel Aviv , Israel
| | - Vered Nachmias Friedler
- a Institute of Gastroenterology, Nutrition and Liver Diseases , Schneider Children's Medical Center of Israel , Petach Tikva , Israel
| | - Yaron Niv
- b Sackler Faculty of Medicine , Tel-Aviv University , Tel Aviv , Israel.,d Department of Gastroenterology , Rabin Medical Center , Petach Tikva , Israel
| | - Yoram Rosenbach
- a Institute of Gastroenterology, Nutrition and Liver Diseases , Schneider Children's Medical Center of Israel , Petach Tikva , Israel
| | - Ari Silbermintz
- a Institute of Gastroenterology, Nutrition and Liver Diseases , Schneider Children's Medical Center of Israel , Petach Tikva , Israel
| | - Noam Zevit
- a Institute of Gastroenterology, Nutrition and Liver Diseases , Schneider Children's Medical Center of Israel , Petach Tikva , Israel.,b Sackler Faculty of Medicine , Tel-Aviv University , Tel Aviv , Israel
| | - Raanan Shamir
- a Institute of Gastroenterology, Nutrition and Liver Diseases , Schneider Children's Medical Center of Israel , Petach Tikva , Israel.,b Sackler Faculty of Medicine , Tel-Aviv University , Tel Aviv , Israel
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18
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Soubières AA, Poullis A. Emerging role of novel biomarkers in the diagnosis of inflammatory bowel disease. World J Gastrointest Pharmacol Ther 2016; 7:41-50. [PMID: 26855811 PMCID: PMC4734953 DOI: 10.4292/wjgpt.v7.i1.41] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 10/06/2015] [Accepted: 11/11/2015] [Indexed: 02/06/2023] Open
Abstract
There is currently no gold standard test for the diagnosis of inflammatory bowel disease (IBD). Physicians must rely on a number of diagnostic tools including clinical and endoscopic evaluation as well as histologic, serologic and radiologic assessment. The real difficulty for physicians in both primary and secondary care is differentiating between patients suffering from functional symptoms and those with true underlying IBD. Alongside this, there is always concern regarding the possibility of a missed, or delayed diagnosis of ulcerative colitis (UC) or Crohn’s disease. Even once the diagnosis of IBD has been made, there is often uncertainty in distinguishing between cases of UC or Crohn’s. As a consequence, in cases of incorrect diagnosis, optimal treatment and management may be adversely affected. Endoscopic evaluation can be uncomfortable and inconvenient for patients. It carries significant risks including perforation and in terms of monetary cost, is expensive. The use of biomarkers to help in the diagnosis and differentiation of IBD has been increasing over time. However, there is not yet one biomarker, which is sensitive of specific enough to be used alone in diagnosing IBD. Current serum testing includes C-reactive protein and erythrocyte sedimentation rate, which are cheap, reliable but non-specific and thus not ideal. Stool based testing such as faecal calprotectin is a much more specific tool and is currently in widespread clinical use. Non-invasive sampling is of the greatest clinical value and with the recent advances in metabolomics, genetics and proteomics, there are now more tools available to develop sensitive and specific biomarkers to diagnose and differentiate between IBD. Many of these new advances are only in early stages of development but show great promise for future clinical use.
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19
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Gene Expression-Genotype Analysis Implicates GSDMA, GSDMB, and LRRC3C as Contributors to Inflammatory Bowel Disease Susceptibility. BIOMED RESEARCH INTERNATIONAL 2015; 2015:834805. [PMID: 26484354 PMCID: PMC4592899 DOI: 10.1155/2015/834805] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Accepted: 09/06/2015] [Indexed: 02/07/2023]
Abstract
To investigate the biological foundation of the inflammatory bowel disease (IBD), ulcerative colitis and Crohn's disease, susceptibility locus rs2872507, we have investigated the expression of 13 genes using ileal and colonic biopsies from patients with IBD (inflamed and noninflamed mucosa) or from individuals without IBD (noninflamed mucosa). The susceptibility allele was consistently associated with reduced expression of GSDMB (P = 4.1 × 10−3–7.2 × 10−10). The susceptibility allele was also associated with the increased expression of GSDMA (P = 1.6 × 10−4) and LRRC3C (P = 7.8 × 10−6) in colon tissue from individuals without IBD and with the reduced expression of PGAP3 (IBD; P = 2.0 × 10−3) and ZPBP2 (Crohn's disease; P = 7.7 × 10−4) in noninflamed ileum. Inflammation resulted in the reduced colonic expression of ERBB2, GRB7, MIEN1, and PGAP3 (P = 1.0 × 10−4–1.0 × 10−9) and the increased colonic expression of IKZF3 and CSF3 (P = 2.4 × 10−7–3.5 × 10−8). Based on our results and published findings on GSDMA, GSDMB, LRRC3C, and related proteins, we propose that this locus in part affects IBD susceptibility via effects on apoptosis and cell proliferation and believe this hypothesis warrants further experimental investigation.
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20
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Ballard BR, M’Koma AE. Gastrointestinal endoscopy biopsy derived proteomic patterns predict indeterminate colitis into ulcerative colitis and Crohn's colitis. World J Gastrointest Endosc 2015; 7:670-674. [PMID: 26140094 PMCID: PMC4482826 DOI: 10.4253/wjge.v7.i7.670] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2015] [Revised: 04/24/2015] [Accepted: 05/08/2015] [Indexed: 02/05/2023] Open
Abstract
Patients with indeterminate colitis (IC) are significantly younger at diagnosis with onset of symptoms before the age of 18 years with significant morbidity in the interim. The successful care of IC is based on microscopic visual predict precision of eventual ulcerative colitis (UC) or Crohn's colitis (CC) which is not offered in 15%-30% of inflammatory bowel disease (IBD) patients even after a combined state-of-the-art classification system of clinical, visual endoscopic, radiologic and histologic examination. These figures have not changed over the past 3 decades despite the introduction of newer diagnostic modalities. The patient outcomes after restorative proctocolectomy and ileal pouch-anal anastomosis may be painstaking if IC turns into CC. Our approach is aiming at developing a single sensitive and absolute accurate diagnostic test tool during the first clinic visit through endoscopic biopsy derived proteomic patterns. Matrix-assisted-laser desorption/ionization mass spectrometry (MS) and/or imaging MS technologies permit a histology-directed cellular test of endoscopy biopsy which identifies phenotype specific proteins, as biomarker that would assist clinicians more accurately delineate IC as being either a UC or CC or a non-IBD condition. These novel studies are underway on larger cohorts and are highly innovative with significances in differentiating a UC from CC in patients with IC and could lend mechanistic insights into IBD pathogenesis.
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21
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Korolkova OY, Myers JN, Pellom ST, Wang L, M’Koma AE. Characterization of Serum Cytokine Profile in Predominantly Colonic Inflammatory Bowel Disease to Delineate Ulcerative and Crohn's Colitides. CLINICAL MEDICINE INSIGHTS. GASTROENTEROLOGY 2015; 8:29-44. [PMID: 26078592 PMCID: PMC4459555 DOI: 10.4137/cgast.s20612] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/28/2014] [Revised: 11/23/2014] [Accepted: 11/23/2014] [Indexed: 02/05/2023]
Abstract
BACKGROUND As accessible diagnostic approaches fail to differentiate between ulcerative colitis (UC) and Crohn's colitis (CC) in one-third of patients with predominantly colonic inflammatory bowel disease (IBD), leading to inappropriate therapy, we aim to investigate the serum cytokine levels in these patients in search of molecular biometric markers delineating UC from CC. METHODS We measured 38 cytokines, chemokines, and growth factors using magnetic-bead-based multiplex immunoassay in 25 UC patients, 28 CC patients, and 30 controls. Our results are compared with those from a review of current literature regarding advances in serum cytokine profiles and associated challenges preventing their use for diagnostic/prognostic purposes. RESULTS Univariate analysis showed statistically significant increases of eotaxin, GRO, and TNF-α in UC patients compared to controls (Ctrl); interferon γ, interleukin (IL)-6, and IL-7 in CC group compared to Ctrl; and IL-8 in both UC and CC versus Ctrl. No cytokines were found to be different between UC and CC. A generalized linear model identified combinations of cytokines, allowing the identification of UC and CC patients, with area under the curve (AUC) = 0.936, as determined with receiver operating characteristic (ROC) analysis. CONCLUSIONS The current knowledge available about circulating cytokines in IBD is often contradictory. The development of an evidence-based tool using cytokines for diagnostic accuracy is still preliminary.
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Affiliation(s)
- Olga Y Korolkova
- Laboratory of Inflammatory Bowel Disease Research, Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, Tennessee
| | - Jeremy N Myers
- Laboratory of Inflammatory Bowel Disease Research, Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, Tennessee
| | - Samuel T Pellom
- Laboratory of Inflammatory Bowel Disease Research, Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, Tennessee
| | - Li Wang
- Department of Statistics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Amosy E M’Koma
- Laboratory of Inflammatory Bowel Disease Research, Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, Tennessee
- Department of General Surgery, Colon and Rectal Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee
- Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
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22
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Odze RD. A contemporary and critical appraisal of 'indeterminate colitis'. Mod Pathol 2015; 28 Suppl 1:S30-46. [PMID: 25560598 DOI: 10.1038/modpathol.2014.131] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Revised: 07/29/2014] [Accepted: 07/30/2014] [Indexed: 02/06/2023]
Abstract
Distinguishing ulcerative colitis (UC) from Crohn's disease (CD) is normally based on evaluation of a variety of clinical, radiologic, serologic and pathologic findings, the latter in biopsy and/or resection specimens. Unfortunately, some patients with IBD show overlapping pathologic features of UC and CD, which makes definite distinction between these two disorders difficult or even impossible. In most instances of uncertainty, the patient shows clinical and pathologic features of UC, but in addition, the patient's colon resection specimen reveals one or more CD-like features. In this setting, a diagnosis of indeterminate colitis (IC) is often rendered. IC is not a distinct disease entity, and, thus, it has no diagnostic criteria. The most common causes of uncertainty in IBD pathology that may lead to a diagnosis of IC in a colon resection specimen includes the presence of fulminant (severe and toxic) colitis, insufficient radiologic, endoscopic, or pathologic information (including analysis of prior biopsies) on the patient, failure to utilize major diagnostic criteria as hard evidence in favor of CD, failure to recognize unusual variants of UC and CD that may mimic each other, failure to recognize non-IBD mimics and other superimposed diseases that cause unusual pathologic features in a resection specimen, an attempt to distinguish UC from CD in mucosal biopsies of the colon and ileum, or an attempt to change the patients diagnosis (of UC or CD) based on pouch or diversion-related complications. Details of each of these causes of uncertainty are discussed, in detail, in this review article. A diagnosis of IC should never be made clinically or by pathologists based on evaluation of pre-resection colonic mucosal biopsies. Ultimately, the majority of indeterminate cases represent UC, and, thus, most of these patient can be treated safely with a colectomy combined with an ileal pouch anal anastomosis procedure.
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Affiliation(s)
- Robert D Odze
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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23
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M'Koma AE. Diagnosis of inflammatory bowel disease: Potential role of molecular biometrics. World J Gastrointest Surg 2014. [PMID: 25429322 DOI: 10.4240/wjgs.v6.i11.20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Accurate diagnosis of predominantly colonic inflammatory bowel disease (IBD) is not possible in 30% of patients. For decades, scientists have worked to find a solution to improve diagnostic accuracy for IBD, encompassing Crohn's colitis and ulcerative colitis. Evaluating protein patterns in surgical pathology colectomy specimens of colonic mucosal and submucosal compartments, individually, has potential for diagnostic medicine by identifying integrally independent, phenotype-specific cellular and molecular characteristics. Mass spectrometry (MS) and imaging (I) MS are analytical technologies that directly measure molecular species in clinical specimens, contributing to the in-depth understanding of biological molecules. The biometric-system complexity and functional diversity is well suited to proteomic and diagnostic studies. The direct analysis of cells and tissues by Matrix-Assisted-Laser Desorption/Ionization (MALDI) MS/IMS has relevant medical diagnostic potential. MALDI-MS/IMS detection generates molecular signatures obtained from specific cell types within tissue sections. Herein discussed is a perspective on the use of MALDI-MS/IMS and bioinformatics technologies for detection of molecular-biometric patterns and identification of differentiating proteins. I also discuss a perspective on the global challenge of transferring technologies to clinical laboratories dealing with IBD issues. The significance of serologic-immunometric advances is also discussed.
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Affiliation(s)
- Amosy E M'Koma
- Amosy E M'Koma, Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, TN 37208-3599, United States
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24
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M’Koma AE. Diagnosis of inflammatory bowel disease: Potential role of molecular biometrics. World J Gastrointest Surg 2014; 6:208-219. [PMID: 25429322 PMCID: PMC4241488 DOI: 10.4240/wjgs.v6.i11.208] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Revised: 10/16/2014] [Accepted: 10/23/2014] [Indexed: 02/06/2023] Open
Abstract
Accurate diagnosis of predominantly colonic inflammatory bowel disease (IBD) is not possible in 30% of patients. For decades, scientists have worked to find a solution to improve diagnostic accuracy for IBD, encompassing Crohn's colitis and ulcerative colitis. Evaluating protein patterns in surgical pathology colectomy specimens of colonic mucosal and submucosal compartments, individually, has potential for diagnostic medicine by identifying integrally independent, phenotype-specific cellular and molecular characteristics. Mass spectrometry (MS) and imaging (I) MS are analytical technologies that directly measure molecular species in clinical specimens, contributing to the in-depth understanding of biological molecules. The biometric-system complexity and functional diversity is well suited to proteomic and diagnostic studies. The direct analysis of cells and tissues by Matrix-Assisted-Laser Desorption/Ionization (MALDI) MS/IMS has relevant medical diagnostic potential. MALDI-MS/IMS detection generates molecular signatures obtained from specific cell types within tissue sections. Herein discussed is a perspective on the use of MALDI-MS/IMS and bioinformatics technologies for detection of molecular-biometric patterns and identification of differentiating proteins. I also discuss a perspective on the global challenge of transferring technologies to clinical laboratories dealing with IBD issues. The significance of serologic-immunometric advances is also discussed.
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25
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An Esophagogastroduodenal Crohn's-Like Disease in a Long-Standing Pan-Ulcerative Colitis Patient. Case Rep Gastrointest Med 2014; 2014:464139. [PMID: 25295198 PMCID: PMC4176905 DOI: 10.1155/2014/464139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Accepted: 08/29/2014] [Indexed: 11/17/2022] Open
Abstract
Inflammatory bowel disease (IBD) comprises the principal subtypes Crohn's disease (CD) and ulcerative colitis (UC), with a fraction remaining as IBD unclassified (IBDU). Given the complexity of IBD manifestations in a patient over time and our increasing understanding of IBD biology, a modification in subtype diagnosis can also occur. Herein is a case of a 27-year-old female with well-controlled and long-standing pan-UC, who developed Crohn's-like esophagogastroduodenitis. The difficulty in classifying IBD into a single traditional subtype, and the debated presentation of a coexistent IBD will be discussed.
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Bjerrum JT, Nyberg C, Olsen J, Nielsen OH. Assessment of the validity of a multigene analysis in the diagnostics of inflammatory bowel disease. J Intern Med 2014; 275:484-93. [PMID: 24206446 DOI: 10.1111/joim.12160] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVES The findings of a previous multigene study indicated that the expression of a panel of seven specific genes had strong differential power regarding inflammatory bowel disease (IBD) versus non-IBD, as well as ulcerative colitis (UC) versus Crohn's disease (CD). This prospective confirmatory study based on an independent patient cohort from a national Danish IBD centre was conducted in an attempt to verify these earlier observations. DESIGN, SETTING AND PARTICIPANTS A total of 119 patients were included in the study (CD, UC and controls). Three mucosal biopsies were retrieved from the left side of the colon of each patient. RNA was extracted, and RT-PCR was performed to retain expression profiles from the seven selected genes. Expression data from the training set (18 CD, 20 UC and 20 controls) were used to build a classification model, using quadratic discriminant analysis, and data from the test set (20 CD, 21 UC and 20 controls) were used to test the validity of the model. RESULTS The present investigation did not confirm the previous observation that a panel of seven specific genes is able to distinguish between patients with CD and UC, whereas the discriminative power for IBD versus control subjects was substantiated. CONCLUSION Our results fail to demonstrate that the previously identified seven-gene classification model is able to discriminate between CD and UC but suggest that the gene panel merely discriminates between inflamed and noninflamed colonic tissue. Thus, a reliable and simple diagnostic tool is still warranted for optimal diagnosis and treatment of patients with IBD, especially the subgroup with unclassified disease.
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Affiliation(s)
- J T Bjerrum
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Cellular & Molecular Medicine, The Panum Institute, University of Copenhagen, Copenhagen, Denmark
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27
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Lawrance IC. The importance of validating proposed genetic profiles in IBD. J Intern Med 2014; 275:481-3. [PMID: 24344969 DOI: 10.1111/joim.12180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- I C Lawrance
- Fremantle Hospital, Centre for Inflammatory Bowel Disease, Fremantle, WA, Australia
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