Serum Immune Responses Predict Rapid Disease Progression among Children with Crohn’s Disease: Immune Responses Predict Disease Progression

PubMed Central

Dubinsky, Marla C.; Lin, Ying-Chao; Dutridge, Debra; Picornell, Yoana; Landers, Carol J.; Farrior, Sharmayne; Wrobel, Iwona; Quiros, Antonio; Vasiliauskas, Eric A.; Grill, Bruce; Israel, David; Bahar, Ron; Christie, Dennis; Wahbeh, Ghassan; Silber, Gary; Dallazadeh, Saied; Shah, Praful; Thomas, Danny; Kelts, Drew; Hershberg, Robert M.; Elson, Charles O.; Targan, Stephan R.; Taylor, Kent D.; Rotter, Jerome I.; Yang, Huiying

2007-01-01

BACKGROUND AND AIM Crohn’s disease (CD) is a heterogeneous disorder characterized by diverse clinical phenotypes. Childhood-onset CD has been described as a more aggressive phenotype. Genetic and immune factors may influence disease phenotype and clinical course. We examined the association of immune responses to microbial antigens with disease behavior and prospectively determined the influence of immune reactivity on disease progression in pediatric CD patients. METHODS Sera were collected from 196 pediatric CD cases and tested for immune responses: anti-I2, anti-outer membrane protein C (anti-OmpC), anti-CBir1 flagellin (anti-CBir1), and anti-Saccharomyces-cerevisiae (ASCA) using ELISA. Associations between immune responses and clinical phenotype were evaluated. RESULTS Fifty-eight patients (28%) developed internal penetrating and/or stricturing (IP/S) disease after a median follow-up of 18 months. Both anti-OmpC (p < 0.0006) and anti-I2 (p < 0.003) were associated with IP/S disease. The frequency of IP/S disease increased with increasing number of immune responses (p trend = 0.002). The odds of developing IP/S disease were highest in patients positive for all four immune responses (OR (95% CI): 11 (1.5–80.4); p = 0.03). Pediatric CD patients positive for ≥1 immune response progressed to IP/S disease sooner after diagnosis as compared to those negative for all immune responses (p < 0.03). CONCLUSIONS The presence and magnitude of immune responses to microbial antigens are significantly associated with more aggressive disease phenotypes among children with CD. This is the first study to prospectively demonstrate that the time to develop a disease complication in children is significantly faster in the presence of immune reactivity, thereby predicting disease progression to more aggressive disease phenotypes among pediatric CD patients. PMID:16454844

Functional characterization of mouse spinal cord infiltrating CD8+ lymphocytes

PubMed Central

Deb, Chandra; Howe, Charles L

2011-01-01

Understanding the immunopathogenesis of neuroimmunological diseases of the CNS requires a robust method for isolating and characterizing the immune effector cells that infiltrate the spinal cord in animal models. We have developed a simple and rapid isolation method that produces high yields of spinal cord infiltrating leukocytes from a single demyelinated spinal cord and which maintains high surface expression of key immunophenotyping antigens. Using this method and the Theiler’s virus model of chronic demyelination, we report the presence of spinal cord infiltrating acute effector CD8+ lymphocytes that are CD45hiCD44loCD62L− and a population of spinal cord infiltrating target effector memory CD8+ lymphocytes that are CD45hiCD44hiCD62L−. These cells respond robustly to ex vivo stimulation by producing interferon γ but do not exhibit specificity for Theiler’s virus in a cytotoxicity assay. We conclude that target-derived lymphocytes in a mouse model of chronic spinal cord demyelination may have unique functional specificities. PMID:19596449

Quantification of cardiovascular disease biomarkers via functionalized magnetic beads and on-demand detachable quantum dots

NASA Astrophysics Data System (ADS)

Park, Hoyoung; Lee, Jong-Wook; Hwang, Mintai P.; Lee, Kwan Hyi

2013-08-01

Cardiovascular disease (CVD) is a potent cause of mortality in both advanced and developing countries. While soluble CD40L (sCD40L) has been implicated as a correlative factor among CVD patients, methods to quantify sCD40L are not yet well-established. In this paper, we present an ability to separate and quantify sCD40L via a simple immunomagnetic assay. Composed of functionalized magnetic beads conferred with directionality and on-demand detachable quantum dots for subsequent optical analysis, our system utilizes the competitive nature of imidazole and nickel ions for histidine. In essence, we demonstrate the capacity to effectively separate and detect sCD40L within a clinically relevant range that contains the cut-off value for acute coronary disease. While sCD40L was used to conduct this study, we envision the use of our system for the separation and quantification of other biomarkers.

Pediatric medical complexity algorithm: a new method to stratify children by medical complexity.

PubMed

Simon, Tamara D; Cawthon, Mary Lawrence; Stanford, Susan; Popalisky, Jean; Lyons, Dorothy; Woodcox, Peter; Hood, Margaret; Chen, Alex Y; Mangione-Smith, Rita

2014-06-01

The goal of this study was to develop an algorithm based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM), codes for classifying children with chronic disease (CD) according to level of medical complexity and to assess the algorithm's sensitivity and specificity. A retrospective observational study was conducted among 700 children insured by Washington State Medicaid with ≥1 Seattle Children's Hospital emergency department and/or inpatient encounter in 2010. The gold standard population included 350 children with complex chronic disease (C-CD), 100 with noncomplex chronic disease (NC-CD), and 250 without CD. An existing ICD-9-CM-based algorithm called the Chronic Disability Payment System was modified to develop a new algorithm called the Pediatric Medical Complexity Algorithm (PMCA). The sensitivity and specificity of PMCA were assessed. Using hospital discharge data, PMCA's sensitivity for correctly classifying children was 84% for C-CD, 41% for NC-CD, and 96% for those without CD. Using Medicaid claims data, PMCA's sensitivity was 89% for C-CD, 45% for NC-CD, and 80% for those without CD. Specificity was 90% to 92% in hospital discharge data and 85% to 91% in Medicaid claims data for all 3 groups. PMCA identified children with C-CD (who have accessed tertiary hospital care) with good sensitivity and good to excellent specificity when applied to hospital discharge or Medicaid claims data. PMCA may be useful for targeting resources such as care coordination to children with C-CD. Copyright © 2014 by the American Academy of Pediatrics.

Improving Gene Therapy Efficiency through the Enrichment of Human Hematopoietic Stem Cells.

PubMed

Masiuk, Katelyn E; Brown, Devin; Laborada, Jennifer; Hollis, Roger P; Urbinati, Fabrizia; Kohn, Donald B

2017-09-06

Lentiviral vector (LV)-based hematopoietic stem cell (HSC) gene therapy is becoming a promising clinical strategy for the treatment of genetic blood diseases. However, the current approach of modifying 1 × 10 8 to 1 × 10 9 CD34 + cells per patient requires large amounts of LV, which is expensive and technically challenging to produce at clinical scale. Modification of bulk CD34 + cells uses LV inefficiently, because the majority of CD34 + cells are short-term progenitors with a limited post-transplant lifespan. Here, we utilized a clinically relevant, immunomagnetic bead (IB)-based method to purify CD34 + CD38 - cells from human bone marrow (BM) and mobilized peripheral blood (mPB). IB purification of CD34 + CD38 - cells enriched severe combined immune deficiency (SCID) repopulating cell (SRC) frequency an additional 12-fold beyond standard CD34 + purification and did not affect gene marking of long-term HSCs. Transplant of purified CD34 + CD38 - cells led to delayed myeloid reconstitution, which could be rescued by the addition of non-transduced CD38 + cells. Importantly, LV modification and transplantation of IB-purified CD34 + CD38 - cells/non-modified CD38 + cells into immune-deficient mice achieved long-term gene-marked engraftment comparable with modification of bulk CD34 + cells, while utilizing ∼7-fold less LV. Thus, we demonstrate a translatable method to improve the clinical and commercial viability of gene therapy for genetic blood cell diseases. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Cushing's disease: pathobiology, diagnosis, and management.

PubMed

Lonser, Russell R; Nieman, Lynnette; Oldfield, Edward H

2017-02-01

Cushing's disease (CD) is the result of excess secretion of adrenocorticotropic hormone (ACTH) by a benign monoclonal pituitary adenoma. The excessive secretion of ACTH stimulates secretion of cortisol by the adrenal glands, resulting in supraphysiological levels of circulating cortisol. The pathophysiological levels of cortisol are associated with hypertension, diabetes, obesity, and early death. Successful resection of the CD-associated ACTH-secreting pituitary adenoma is the treatment of choice and results in immediate biochemical remission with preservation of pituitary function. Accurate and early identification of CD is critical for effective surgical management and optimal prognosis. The authors review the current pathophysiological principles, diagnostic methods, and management of CD.

Capsule endoscopy in Crohn’s disease: Are we seeing any better?

PubMed Central

Hudesman, David; Mazurek, Jonathan; Swaminath, Arun

2014-01-01

Crohn’s disease (CD) is a complex, immune-mediated disorder that often requires a multi-modality approach for optimal diagnosis and management. While traditional methods include ileocolonoscopy and radiologic modalities, increasingly, capsule endoscopy (CE) has been incorporated into the algorithm for both the diagnosis and monitoring of CD. Multiple studies have examined the utility of this emerging technology in the management of CD, and have compared it to other available modalities. CE offers a noninvasive approach to evaluate areas of the small bowel that are difficult to reach with traditional endoscopy. Furthermore, CE maybe favored in specific sub segments of patients with inflammatory bowel disease (IBD), such as those with IBD unclassified (IBD-U), pediatric patients and patients with CD who have previously undergone surgery. PMID:25278698

High Frequency of Haplotype HLA-DQ7 in Celiac Disease Patients from South Italy: Retrospective Evaluation of 5,535 Subjects at Risk of Celiac Disease

PubMed Central

Tinto, Nadia; Cola, Arturo; Piscopo, Chiara; Capuano, Marina; Galatola, Martina; Greco, Luigi; Sacchetti, Lucia

2015-01-01

Background Celiac disease (CD) has a strong genetic component mainly due to HLA DQ2/DQ8 encoding genes. However, a minority of CD patients are DQ2/DQ8-negative. To address this issue, we retrospectively characterized HLA haplotypes in 5,535 subjects at risk of CD (either relatives of CD patients or subjects with CD-like symptoms) referred to our center during a 10-year period. Methods We identified loci DQA1/DQB1/DRB1 by sequence-specific oligonucleotide-PCR and sequence-specific primer-PCR; anti-transglutaminase IgA/IgG and anti-endomysium IgA by ELISA and indirect immunofluorescence, respectively. Results We diagnosed CD in 666/5,535 individuals, 4.2% of whom were DQ2/DQ8-negative. Interestingly, DQ7 was one of the most abundant haplotypes in all CD patients and significantly more frequent in DQ2/DQ8-negative (38%) than in DQ2/DQ8-positive CD patients (24%) (p<0.05). Conclusion Our data lend support to the concept that DQ7 represents an additive or independent CD risk haplotype with respect to DQ2/DQ8 haplotypes but this finding should be verified in other large CD populations. PMID:26398634

Does haemochromatosis predispose to coeliac disease? A study of 29,096 coeliac disease patients

PubMed Central

Ludvigsson, Jonas F; Murray, Joseph A; Adams, Paul C; Elmberg, Maria

2013-01-01

Background and aim Case reports suggest an association between hereditary haemochromatosis (HH) and coeliac disease (CD), but estimates of association are lacking. We estimated the association between HH and CD in a population-based study. Materials and methods Case-control study. We identified 29,096 individuals with biopsy-verified CD (equal to villous atrophy, Marsh stage III) through biopsy reports from all 28 pathology departments in Sweden. We then investigated the risk of a clinical diagnosis of HH in CD and in 144,522 controls matched for age, sex, county and calendar year. Conditional logistic regression was used to calculate odds ratios (ORs) for CD in patients with HH. Results HH was seen in 30 patients with CD and in 60 matched controls. HH was hence associated with an increased risk of CD (OR=2.30; 95%CI=1.53–3.25). Restricting HH to individuals with at least 2 records of HH, the OR for CD was 2.54 (95%CI=1.57–4.11), with a similar risk estimate when we only looked at HH diagnosed before CD (and matched date in controls) (OR=2.64; 95%CI=1.24–5.60). Conclusion HH seems to be associated with an increased risk of CD. PMID:23256862

A method for the generation of ectromelia virus (ECTV) recombinants: in vivo analysis of ECTV vCD30 deletion mutants.

PubMed

Alejo, Ali; Saraiva, Margarida; Ruiz-Argüello, Maria Begoña; Viejo-Borbolla, Abel; de Marco, Mar Fernández; Salguero, Francisco Javier; Alcami, Antonio

2009-01-01

Ectromelia virus (ECTV) is the causative agent of mousepox, a lethal disease of mice with similarities to human smallpox. Mousepox progression involves replication at the initial site of infection, usually the skin, followed by a rapid spread to the secondary replicative organs, spleen and liver, and finally a dissemination to the skin, where the typical rash associated with this and other orthopoxviral induced diseases appears. Case fatality rate is genetically determined and reaches up to 100% in susceptible mice strains. Like other poxviruses, ECTV encodes a number of proteins with immunomodulatory potential, whose role in mousepox progression remains largely undescribed. Amongst these is a secreted homologue of the cellular tumour necrosis factor receptor superfamily member CD30 which has been proposed to modulate a Th1 immune response in vivo. To evaluate the contribution of viral CD30 (vCD30) to virus pathogenesis in the infected host, we have adapted a novel transient dominant method for the selection of recombinant ECTVs. Using this method, we have generated an ECTV vCD30 deletion mutant, its corresponding revertant control virus as well as a virus encoding the extracellular domain of murine CD30. These viruses contain no exogenous marker DNA sequences in their genomes, as opposed to other ECTVs reported up to date. We show that the vCD30 is expressed as a secreted disulfide linked trimer and that the absence of vCD30 does not impair mousepox induced fatality in vivo. Replacement of vCD30 by a secreted version of mouse CD30 caused limited attenuation of ECTV. The recombinant viruses generated may be of use in the study of the role of the cellular CD30-CD30L interaction in the development of the immune response. The method developed might be useful for the construction of ECTV mutants for the study of additional genes.

Investigation of Crohn’s Disease Risk Loci in Ulcerative Colitis Further Defines Their Molecular Relationship

PubMed Central

ANDERSON, CARL A.; MASSEY, DUNECAN C. O.; BARRETT, JEFFREY C.; PRESCOTT, NATALIE J.; TREMELLING, MARK; FISHER, SHEILA A.; GWILLIAM, RHIAN; JACOB, JEMIMA; NIMMO, ELAINE R.; DRUMMOND, HAZEL; LEES, CHARLIE W.; ONNIE, CLIVE M.; HANSON, CATHERINE; BLASZCZYK, KATARZYNA; RAVINDRARAJAH, RADHI; HUNT, SARAH; VARMA, DHIRAJ; HAMMOND, NAOMI; LEWIS, GREGORY; ATTLESEY, HEATHER; WATKINS, NICK; OUWEHAND, WILLEM; STRACHAN, DAVID; MCARDLE, WENDY; LEWIS, CATHRYN M.; LOBO, ALAN; SANDERSON, JEREMY; JEWELL, DEREK P.; DELOUKAS, PANOS; MANSFIELD, JOHN C.; MATHEW, CHRISTOPHER G.; SATSANGI, JACK; PARKES, MILES

2009-01-01

Background & Aims Identifying shared and disease-specific susceptibility loci for Crohn’s disease (CD) and ulcerative colitis (UC) would help define the biologic relationship between the inflammatory bowel diseases. More than 30 CD susceptibility loci have been identified. These represent important candidate susceptibility loci for UC. Loci discovered by the index genome scans in CD have previously been tested for association with UC, but those identified in the recent meta-analysis await such investigation. Furthermore, the recently identified UC locus at ECM1 requires formal testing for association with CD. Methods We analyzed 45 single nucleotide polymorphisms, tagging 29 of the loci recently associated with CD in 2527 UC cases and 4070 population controls. We also genotyped the UC-associated ECM1 variant rs11205387 in 1560 CD patients and 3028 controls. Results Nine regions showed association with UC at a threshold corrected for the 29 loci tested (P < .0017). The strongest association (P = 4.13 × 10-8; odds ratio = 1.27) was identified with a 170-kilobase region on chromosome 1q32 that contains 3 genes. We also found association with JAK2 and replicated a recently reported association with STAT3, further implicating the role of this signaling pathway in inflammatory bowel disease. Additional novel UC susceptibility genes were LYRM4 and CDKAL1. Twenty of the loci were not associated with UC, and several appear to be specific to CD. ECM1 variation was not associated with CD. Conclusions Collectively, these data help define the genetic relationship between CD and UC and characterize common, as well as disease-specific mechanisms of pathogenesis. PMID:19068216

Evaluation of 22 genetic variants with Crohn's Disease risk in the Ashkenazi Jewish population: a case-control study

PubMed Central

2011-01-01

Background Crohn's disease (CD) has the highest prevalence among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Caucasian populations (NJ). We evaluated a set of well-established CD-susceptibility variants to determine if they can explain the increased CD risk in the AJ population. Methods We recruited 369 AJ CD patients and 503 AJ controls, genotyped 22 single nucleotide polymorphisms (SNPs) at or near 10 CD-associated genes, NOD2, IL23R, IRGM, ATG16L1, PTGER4, NKX2-3, IL12B, PTPN2, TNFSF15 and STAT3, and assessed their association with CD status. We generated genetic scores based on the risk allele count alone and the risk allele count weighed by the effect size, and evaluated their predictive value. Results Three NOD2 SNPs, two IL23R SNPs, and one SNP each at IRGM and PTGER4 were independently associated with CD risk. Carriage of 7 or more copies of these risk alleles or the weighted genetic risk score of 7 or greater correctly classified 92% (allelic count score) and 83% (weighted score) of the controls; however, only 29% and 47% of the cases were identified as having the disease, respectively. This cutoff was associated with a >4-fold increased disease risk (p < 10e-16). Conclusions CD-associated genetic risks were similar to those reported in NJ population and are unlikely to explain the excess prevalence of the disease in AJ individuals. These results support the existence of novel, yet unidentified, genetic variants unique to this population. Understanding of ethnic and racial differences in disease susceptibility may help unravel the pathogenesis of CD leading to new personalized diagnostic and therapeutic approaches. PMID:21548950

Scenarios, personas and user stories from design ethnography: Evidence-based design representations of communicable disease investigations

PubMed Central

Turner, Anne M; Reeder, Blaine; Ramey, Judith

2014-01-01

Purpose Despite years of effort and millions of dollars spent to create a unified electronic communicable disease reporting systems, the goal remains elusive. A major barrier has been a lack of understanding by system designers of communicable disease (CD) work and the public health workers who perform this work. This study reports on the application of User Center Design representations, traditionally used for improving interface design, to translate the complex CD work identified through ethnographic studies to guide designers and developers of CD systems. The purpose of this work is to: (1) better understand public health practitioners and their information workflow with respect to communicable disease (CD) monitoring and control at a local health department, and (2) to develop evidence-based design representations that model this CD work to inform the design of future disease surveillance systems. Methods We performed extensive onsite semi-structured interviews, targeted work shadowing and a focus group to characterize local health department communicable disease workflow. Informed by principles of design ethnography and user-centered design (UCD) we created persona, scenarios and user stories to accurately represent the user to system designers. Results We sought to convey to designers the key findings from ethnographic studies: 1) that public health CD work is mobile and episodic, in contrast to current CD reporting systems, which are stationary and fixed 2) health department efforts are focused on CD investigation and response rather than reporting and 3) current CD information systems must conform to PH workflow to ensure their usefulness. In an effort to illustrate our findings to designers, we developed three contemporary design-support representations: persona, scenario, and user story. Conclusions Through application of user centered design principles, we were able to create design representations that illustrate complex public health communicable disease workflow and key user characteristics to inform the design of CD information systems for public health. PMID:23618996

Serum Analysis of Tryptophan Catabolism Pathway: Correlation with Crohn’s Disease Activity

PubMed Central

Gupta, Nitin K; Thaker, Ameet I; Kanuri, Navya; Riehl, Terrence E; Rowley, Christopher W; Stenson, William F; Ciorba, Matthew A

2011-01-01

BACKGROUND Indoleamine 2,3 dioxygenase 1 (IDO1) is a tryptophan catabolizing enzyme with immunotolerance promoting functions. We sought to determine if increased gut expression of IDO1 in Crohn’s disease (CD) would result in detectable changes in serum levels of tryptophan and the initial IDO1 pathway catabolite, kynurenine. METHODS Individuals were prospectively enrolled through the Washington University Digestive Diseases Research Center. Montreal classification was used for disease phenotyping. Disease severity was categorized by physician’s global assessment. Serum tryptophan and kynurenine were measured by high pressure liquid chromatography. IDO1 immunohistochemical staining was performed on formalin-fixed tissue blocks. RESULTS 25 CD patients and 11 controls were enrolled. 8 CD patients had serum collected at two different time points and levels of disease activity. Strong IDO1 expression exists in both the lamina propria and epithelium during active CD compared to controls. Suppressed serum tryptophan levels and an elevated kynurenine/tryptophan (K/T) ratio were found in individuals with active CD as compared to those in remission or the control population. K/T ratios correlated positively with disease activity as well as with C-reactive protein and erythrocyte sedimentation rate. In the subgroup of CD patients with two serum measurements, tryptophan levels elevated while kynurenine levels and the K/T ratio lowered as the disease activity lessened. CONCLUSIONS IDO1 expression in Crohn’s disease is associated with lower serum tryptophan and an elevated K/T ratio. These levels may serve a reasonable objective marker of gut mucosal immune activation and surrogate for Crohn’s Disease activity. PMID:21823214

The CTLA4/CD28 gene region on chromosome 2q33 confers susceptibility to celiac disease in a way possibly distinct from that of type 1 diabetes and other chronic inflammatory disorders.

PubMed

Naluai, A T; Nilsson, S; Samuelsson, L; Gudjónsdóttir, A H; Ascher, H; Ek, J; Hallberg, B; Kristiansson, B; Martinsson, T; Nerman, O; Sollid, L M; Wahlström, J

2000-10-01

The effect of the gene region on chromosome 2q33 containing the CD28 and the cytotoxic T-lymphocyte associated (CTLA4) genes has been investigated in several diseases with chronic inflammatory nature. In addition to celiac disease (CD), type I diabetes, Grave's disease, rheumatoid arthritis and multiple sclerosis have all demonstrated associations to the A/G single nucleotide polymorphism (SNP) in exon 1, position +49 of the CTLA4 gene. The purpose of this study was to investigate this gene region in a genetically homogeneous population consisting of 107 Swedish and Norwegian families with CD using genetic association and linkage methods. We found a significant association with preferential transmission of the A-allele of the exon 1 +49 polymorphism by using the transmission disequilibrium test (TDT). Suggestive linkage of this region to CD was moreover demonstrated by non-parametric linkage (NPL) analysis giving a NPL-score of 2.1. These data strongly indicates that the CTLA4 region is a susceptibility region in CD. Interestingly, of the several chronic inflammatory diseases that exhibit associations to the CTLA4 +49 A/G dimorphism, CD appears to be the only disease associated to the A allele. This suggests that the +49 alleles of the CTLA4 gene are in linkage disequilibrium with two distinct disease predisposing alleles with separate effects. The peculiar association found in the gut disorder CD may possibly relate to the fact that the gastrointestinal immune system, in contrast to the rest of the immune system, aims to establish tolerance to foreign proteins.

B Lymphocyte intestinal homing in inflammatory bowel disease

PubMed Central

2011-01-01

Background Inflammatory bowel disease (IBD) is thought to be due to an abnormal interaction between the host immune system and commensal microflora. Within the intestinal immune system, B cells produce physiologically natural antibodies but pathologically atypical anti-neutrophil antibodies (xANCAs) are frequently observed in patients with IBD. The objective is to investigate the localisation of immunoglobulin-producing cells (IPCs) in samples of inflamed intestinal tissue taken from patients with IBD, and their possible relationship with clinical features. Methods The IPCs in small intestinal, colonic and rectal biopsy specimens of patients with IBD were analysed by means of immunofluorescence using polyclonal rabbit anti-human Ig and goat anti-human IgM. The B cell phenotype of the IPC-positive samples was assessed using monoclonal antibodies specific for CD79, CD20, CD23, CD21, CD5, λ and κ chains. Statistical correlations were sought between the histological findings and clinical expression. Results The study involved 96 patients (64 with ulcerative colitis and 32 with Crohn's disease). Two different patterns of B lymphocyte infiltrates were found in the intestinal tissue: one was characterised by a strong to moderate stromal localisation of small IgM+/CD79+/CD20-/CD21-/CD23-/CD5± IPCs (42.7% of cases); in the other (57.3%) no such small IPCs were detected in stromal or epithelial tissues. IPCs were significantly less frequent in the patients with Crohn's disease than in those with ulcerative colitis (p = 0.004). Conclusion Our findings suggest that different immunopathogenetic pathways underlie chronic intestinal inflammation with different clinical expressions. The presence of small B lymphocytes resembling B-1 cells also seemed to be negatively associated with Crohn's disease. It can therefore be inferred that the gut contains an alternative population of B cells that have a regulatory function. PMID:22208453

Disease duration and age influence CARD15 expression in Crohn's disease.

PubMed

Poniewierka, Elżbieta; Neubauer, Katarzyna; Kempiński, Radosław; Sadakierska-Chudy, Anna

2016-01-05

One of the susceptibility genes in Crohn's disease (CD) is CARD15. Our study examined the relationship between peripheral CARD15 expression and phenotype and duration of CD, treatment methods and inflammatory indices. Sixty patients with CD and 30 healthy volunteers as controls were enrolled in the study. Total RNA was isolated from peripheral blood mononuclear cells (PBMCs) with E.Z.N.A. Total RNA Kit (Omega Bio-tek) then quantitative real-time PCR was performed on the ABI Prism 7900 HT Real-Time PCR System. CARD15 gene expression in PBMCs in CD was significantly higher than in the control group. The highest level of gene expression was found in CD patients in the fourth decade of life. The mRNA level of the CARD15 gene was higher in patients with disease duration between 12 and 60 months. A positive correlation was found between erythrocyte sedimentation rate (ESR) and gene expression level. Gene expression increased with increasing level of C-reactive protein and ESR, but it was not statistically significant. CARD15 expression significantly decreased in CD patients treated with anti-TNFα agents compared to azathioprine or steroid treatment groups. Expression of the CARD15 gene in Crohn›s disease is higher than in healthy individuals. Disease duration and age of patients seem to be the most important factors influencing CARD15 expression.

A microchip CD4 counting method for HIV monitoring in resource-poor settings.

PubMed

Rodriguez, William R; Christodoulides, Nicolaos; Floriano, Pierre N; Graham, Susan; Mohanty, Sanghamitra; Dixon, Meredith; Hsiang, Mina; Peter, Trevor; Zavahir, Shabnam; Thior, Ibou; Romanovicz, Dwight; Bernard, Bruce; Goodey, Adrian P; Walker, Bruce D; McDevitt, John T

2005-07-01

More than 35 million people in developing countries are living with HIV infection. An enormous global effort is now underway to bring antiretroviral treatment to at least 3 million of those infected. While drug prices have dropped considerably, the cost and technical complexity of laboratory tests essential for the management of HIV disease, such as CD4 cell counts, remain prohibitive. New, simple, and affordable methods for measuring CD4 cells that can be implemented in resource-scarce settings are urgently needed. Here we describe the development of a prototype for a simple, rapid, and affordable method for counting CD4 lymphocytes. Microliter volumes of blood without further sample preparation are stained with fluorescent antibodies, captured on a membrane within a miniaturized flow cell and imaged through microscope optics with the type of charge-coupled device developed for digital camera technology. An associated computer algorithm converts the raw digital image into absolute CD4 counts and CD4 percentages in real time. The accuracy of this prototype system was validated through testing in the United States and Botswana, and showed close agreement with standard flow cytometry (r = 0.95) over a range of absolute CD4 counts, and the ability to discriminate clinically relevant CD4 count thresholds with high sensitivity and specificity. Advances in the adaptation of new technologies to biomedical detection systems, such as the one described here, promise to make complex diagnostics for HIV and other infectious diseases a practical global reality.

Patient Perception of Treatment Burden is High in Celiac Disease Compared to Other Common Conditions

PubMed Central

Shah, Sveta; Akbari, Mona; Vanga, Rohini; Kelly, Ciaran P.; Hansen, Joshua; Theethira, Thimmaiah; Tariq, Sohaib; Dennis, Melinda; Leffler, Daniel A.

2014-01-01

Introduction The only treatment for celiac disease (CD) is life-long adherence to a gluten-free diet (GFD). Noncompliance is associated with signs and symptoms of celiac disease, yet long-term adherence rates are poor. It is not known how the burden of the GFD compares to other medical treatments, and there are limited data on the socio-economic factors influencing treatment adherence. In this study we compared treatment burden and health state in CD compared with other chronic illnesses and evaluated the relationship between treatment burden and adherence. Methods A survey was mailed to participants with: CD, gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), hypertension (HTN), diabetes mellitus (DM), congestive heart failure (CHF), and end stage renal disease on dialysis (ESRD). Surveys included demographic information and visual analog scales measuring treatment burden, importance of treatment, disease-specific and overall health status. Results We collected surveys from 341 celiac and 368 non-celiac participants. Celiac participants reported high treatment burden, greater than participants with GERD or HTN and comparable to ESRD. Conversely, patients with CD reported the highest health state of all groups. Factors associated with high treatment burden in CD included poor adherence, concern regarding food cost, eating outside the home, higher income, lack of college education and time limitations in preparing food. Poor adherence in CD was associated with increased symptoms, income, and low perceived importance of treatment. Discussion Participants with CD have high treatment burden but also excellent overall health status in comparison with other chronic medical conditions. The significant burden of dietary therapy for celiac disease argues for the need for safe adjuvant treatment as well as interventions designed to lower the perceived burden of the GFD. PMID:24980880

Prevalence of Chagas Disease in the Latin American–born Population of Los Angeles

PubMed Central

Forsyth, Colin J.; Soverow, Jonathan; Hernandez, Salvador; Sanchez, Daniel; Montgomery, Susan P.; Traina, Mahmoud

2017-01-01

Abstract Background. According to an estimate from the Centers for Disease Control and Prevention (CDC), Chagas disease (CD) may affect 1.31% of Latin American immigrants in the United States, with >300 000 cases. However, there is a lack of real-world data to support this estimate. Little is known about the actual prevalence of this neglected tropical disease in the United States, and the bulk of those infected are undiagnosed. Methods. From April 2008 to May 2014, we screened 4,755 Latin American–born residents of Los Angeles County. Blood samples were tested for serologic evidence of CD. We collected demographic data and assessed the impact of established risk factors on CD diagnosis, including sex, country of origin, housing materials, family history of CD, and awareness of CD. Results. There were 59 cases of CD, for an overall prevalence of 1.24%. Prevalence was highest among Salvadorans (3.45%). Of the 3,182 Mexican respondents, those from Oaxaca (4.65%) and Zacatecas (2.2%) had the highest CD prevalence. Salvadoran origin (aOR = 6.2; 95% CI = 2.8–13.5; P < .001), prior knowledge of CD (aOR = 2.4; 95% CI = 1.0–5.8; P = .047), and exposure to all 3 at-risk housing types (adobe, mud, and thatched roof) (aOR = 2.5; 95% CI = 1.0–6.4; P = .048) were associated with positive diagnosis. Conclusions. In the largest screening of CD in the United States to date outside of blood banks, we found a CD prevalence of 1.24%. This implies >30 000 people infected in Los Angeles County alone, making CD an important public health concern. Efficient, targeted surveillance of CD may accelerate diagnosis and identify candidates for early treatment. PMID:28329123

Pediatric Cushing disease: disparities in disease severity and outcomes in the Hispanic and African-American populations.

PubMed

Gkourogianni, Alexandra; Sinaii, Ninet; Jackson, Sharon H; Karageorgiadis, Alexander S; Lyssikatos, Charalampos; Belyavskaya, Elena; Keil, Margaret F; Zilbermint, Mihail; Chittiboina, Prashant; Stratakis, Constantine A; Lodish, Maya B

2017-08-01

BackgroundLittle is known about the contribution of racial and socioeconomic disparities to severity and outcomes in children with Cushing disease (CD).MethodsA total of 129 children with CD, 45 Hispanic/Latino or African-American (HI/AA) and 84 non-Hispanic White (non-HW), were included in this study. A 10-point index for rating severity (CD severity) incorporated the degree of hypercortisolemia, glucose tolerance, hypertension, anthropomorphic measurements, disease duration, and tumor characteristics. Race, ethnicity, age, gender, local obesity prevalence, estimated median income, and access to care were assessed in regression analyses of CD severity.ResultsThe mean CD severity in the HI/AA group was worse than that in the non-HW group (4.9±2.0 vs. 4.1±1.9, P=0.023); driving factors included higher cortisol levels and larger tumor size. Multiple regression models confirmed that race (P=0.027) and older age (P=0.014) were the most important predictors of worse CD severity. When followed up a median of 2.3 years after surgery, the relative risk for persistent CD combined with recurrence was 2.8 times higher in the HI/AA group compared with that in the non-HW group (95% confidence interval: 1.2-6.5).ConclusionOur data show that the driving forces for the discrepancy in severity of CD are older age and race/ethnicity. Importantly, the risk for persistent and recurrent CD was higher in minority children.

Sensorineural hearing loss and celiac disease: A coincidental finding

PubMed Central

Volta, Umberto; Ferri, Gian Gaetano; De Giorgio, Roberto; Fabbri, Angela; Parisi, Claudia; Sciajno, Laura; Castellari, Alessandra; Fiorini, Erica; Piscaglia, Maria; Barbara, Giovanni; Granito, Alessandro; Pirodda, Antonio

2009-01-01

BACKGROUND Celiac disease (CD) can be associated with a variety of extraintestinal manifestations, including neurological diseases. A new neurological correlation has been found between CD and sensorineural hearing loss (SNHL). OBJECTIVE To verify the association between SNHL and CD, and to establish whether the neurological hearing impairment in CD is related to nonorgan-specific and antineuronal antibodies, as well as the presence of autoimmune disorders. METHODS A sample of 59 consecutive biopsy- and serologically proven CD patients were studied. Among CD patients, 11 were newly diagnosed and 48 were on a gluten-free diet. Hearing function was assessed by audiometric analysis in all CD patients as well as in 59 age- and sex-matched controls. Patients were tested for a panel of immune markers including nonorgan-specific autoantibodies and antineuronal antibodies. RESULTS SNHL was detected in five CD patients (8.5%) and in two controls (3.4%). In one patient, the SNHL was bilateral, whereas the remaining four had a monolateral impairment. The prevalence of SNHL was not significantly different between CD patients and controls. At least one of the antibodies tested for was positive in two of the five CD patients with SNHL and in 12 of the 54 CD patients without SNHL. Antineuronal antibodies to central nervous system antigens were consistently negative in the five CD patients with SNHL. Only one of the five CD patients with SNHL had Hashimoto thyroiditis. CONCLUSIONS SNHL and CD occur coincidentally. Hearing function should be assessed only in CD patients with clinical signs of hearing deficiency. PMID:19668795

Elevated Expression of Immunoreceptor Tyrosine-Based Inhibitory Motif (TIGIT) on T Lymphocytes is Correlated with Disease Activity in Rheumatoid Arthritis.

PubMed

Luo, Qing; Deng, Zhen; Xu, Chuxin; Zeng, Lulu; Ye, Jianqing; Li, Xue; Guo, Yang; Huang, Zikun; Li, Junming

2017-03-10

BACKGROUND It is well known that lymphocytes play an important role in rheumatoid arthritis (RA). T cell immunoreceptors with immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitory motif (TIGIT) have immunosuppressive co-stimulatory molecules that mediate inhibitory effects, but their roles in RA are poorly understood. MATERIAL AND METHODS Were recruited 76 patients with RA and 33 healthy controls (HC). Clinical manifestations, laboratory measurements, physical examination, and medical history of RA patients were recorded. The expression of TIGIT on CD3+ T lymphocytes, B lymphocytes, monocytes, neutrophils, CD3+CD4+ T lymphocytes, and CD3+CD8+ T lymphocytes was determined using flow cytometry. The expression of TIGIT on T lymphocytes in patients with RA was further analyzed to investigate its correlations with markers of autoimmune response, inflammation, and disease activity in RA. RESULTS Compared with HC, the expression levels of TIGIT on CD3+CD4+ T lymphocytes and CD3+CD8+ T lymphocytes were significantly increased in patients with RA (P < 0.01). The frequency of TIGIT-expressing CD3+CD4+ T lymphocytes was positively correlated with RF, increased ACPA, ESR, and CRP levels. The frequency of TIGIT-expressing CD3+CD8+ T lymphocytes was positively correlated with RF and ESR levels. Furthermore, the expression level of TIGIT on CD3+CD4+ T lymphocytes was positively correlated with the DAS28 score in RA. CONCLUSIONS The expression levels of TIGIT on T lymphocytes were elevated and correlated with disease activity in RA.

Mucosal CCR1 gene expression as a marker of molecular activity in Crohn's disease: preliminary data.

PubMed

Dobre, Maria; Mănuc, Teodora Ecaterina; Milanesi, Elena; Pleşea, Iancu Emil; Ţieranu, Eugen Nicolae; Popa, Caterina; Mănuc, Mircea; Preda, Carmen Monica; Ţieranu, Ioana; Diculescu, Mihai Mircea; Ionescu, Elena Mirela; Becheanu, Gabriel

2017-01-01

A series of mechanisms of immune response, inflammation and apoptosis have been demonstrated to contribute to the appearance and evolution of Crohn's disease (CD) through the overexpression of several cytokines and chemokines in a susceptible host. The aim of this study was to identify the differences in gene expression profiles analyzing a panel of candidate genes in the mucosa from patients with active CD (CD-A), patients in remission (CD-R), and normal controls. Nine individuals were enrolled in the study: six CD patients (three with active lesions, three with mucosal healing) and three controls without inflammatory bowel disease (IBD) seen on endoscopy. All the individuals underwent mucosal biopsy during colonoscopy. Gene expression levels of 84 genes previously associated with CD were evaluated by polymerase chain reaction (PCR) array. Ten genes out of 84 were found significantly differentially expressed in CD-A (CCL11, CCL25, DEFA5, GCG, IL17A, LCN2, REG1A, STAT3, MUC1, CCR1) and eight genes in CD-R (CASP1, IL23A, STAT1, STAT3, TNF, CCR1, CCL5, and HSP90B1) when compared to controls. A quantitative gene expression analysis revealed that CCR1 gene was more expressed in CD-A than in CD-R. Our data suggest that CCR1 gene may be a putative marker of molecular activity of Crohn's disease. Following these preliminary data, a confirmation in larger cohort studies could represent a useful method in order to identify new therapeutic targets.

Small bowel video capsule endoscopy in Crohn's disease: What have we learned in the last ten years?

PubMed

Lucendo, Alfredo J; Guagnozzi, Danila

2011-02-16

Since its introduction in 2001, capsule endoscopy (CE) has become the most important advance in the study of small bowel disease, including Crohn's disease (CD). This technique has been demonstrated to be superior to all other current forms of radiological investigation in detecting mucosal abnormalities of small bowel nonstricturing CD. CE has proven to be extremely useful in diagnosing CD in patients with inconclusive findings from ileocolonoscopy and x-ray-based studies. Almost half of all patients with CD involving the ileum also present lesions in proximal intestinal segments, with the small bowel being exclusively involved in up to 30% of all CD cases. Despite the widespread use of CE, several questions concerning the utility of this technique remain unanswered. The lack of commonly agreed diagnostic criteria for defining CD lesions with the aid of CE may have had an influence on the variation in diagnostic results for CE reported in the literature. The utility of CE in monitoring CD and in guiding therapy has also been proposed. Furthermore, CE could be a useful second-line technique for patients with an established diagnosis of CD and unexplained symptoms. Finally, as no threshold for CD diagnosis has been agreed upon, a severity scale of mucosal disease activity has not been universally followed. None of the available activity indexes based on CE findings has been independently validated. This article discusses several cutting-edge aspects of the usefulness of CE in CD 10 years after its introduction as a sensible method to study the small intestine.

Small bowel video capsule endoscopy in Crohn’s disease: What have we learned in the last ten years?

PubMed Central

Lucendo, Alfredo J; Guagnozzi, Danila

2011-01-01

Since its introduction in 2001, capsule endoscopy (CE) has become the most important advance in the study of small bowel disease, including Crohn’s disease (CD). This technique has been demonstrated to be superior to all other current forms of radiological investigation in detecting mucosal abnormalities of small bowel nonstricturing CD. CE has proven to be extremely useful in diagnosing CD in patients with inconclusive findings from ileocolonoscopy and x-ray-based studies. Almost half of all patients with CD involving the ileum also present lesions in proximal intestinal segments, with the small bowel being exclusively involved in up to 30% of all CD cases. Despite the widespread use of CE, several questions concerning the utility of this technique remain unanswered. The lack of commonly agreed diagnostic criteria for defining CD lesions with the aid of CE may have had an influence on the variation in diagnostic results for CE reported in the literature. The utility of CE in monitoring CD and in guiding therapy has also been proposed. Furthermore, CE could be a useful second-line technique for patients with an established diagnosis of CD and unexplained symptoms. Finally, as no threshold for CD diagnosis has been agreed upon, a severity scale of mucosal disease activity has not been universally followed. None of the available activity indexes based on CE findings has been independently validated. This article discusses several cutting-edge aspects of the usefulness of CE in CD 10 years after its introduction as a sensible method to study the small intestine. PMID:21403813

The Value of Ensari’s Proposal in Evaluating the Mucosal Pathology of Childhood Celiac Disease: Old Classification versus New Version

PubMed Central

Güreşci, Servet; Hızlı, Şamil; Şimşek, Gülçin Güler

2012-01-01

Objective: Small intestinal biopsy remains the gold standard in diagnosing celiac disease (CD); however, the wide spectrum of histopathological states and differential diagnosis of CD is still a diagnostic problem for pathologists. Recently, Ensari reviewed the literature and proposed an update of the histopathological diagnosis and classification for CD. Materials and Methods: In this study, the histopathological materials of 54 children in whom CD was diagnosed at our hospital were reviewed to compare the previous Marsh and Modified Marsh-Oberhuber classifications with this new proposal. Results: In this study, we show that the Ensari classification is as accurate as the Marsh and Modified Marsh classifications in describing the consecutive states of mucosal damage seen in CD. Conclusions: Ensari’s classification is simple, practical and facilitative in diagnosing and subtyping of mucosal pathology of CD. PMID:25207015

Similar risk of Depression and Anxiety following surgery or hospitalization for Crohn’s disease and Ulcerative colitis

PubMed Central

Ananthakrishnan, Ashwin N.; Gainer, Vivian S.; Cai, Tianxi; Perez, Raul Guzman; Cheng, Su-Chun; Savova, Guergana; Chen, Pei; Szolovits, Peter; Xia, Zongqi; De Jager, Philip L; Shaw, Stanley; Churchill, Susanne; Karlson, Elizabeth W.; Kohane, Isaac; Perlis, Roy H; Plenge, Robert M.; Murphy, Shawn N.; Liao, Katherine P.

2013-01-01

Introduction Psychiatric co-morbidity is common in Crohn’s disease (CD) and ulcerative colitis (UC). IBD-related surgery or hospitalizations represent major events in the natural history of disease. Whether there is a difference in risk of psychiatric co-morbidity following surgery in CD and UC has not been examined previously. Methods We used a multi-institution cohort of IBD patients without a diagnosis code for anxiety or depression preceding their IBD-related surgery or hospitalization. Demographic, disease, and treatment related variables were retrieved. Multivariate logistic regression analysis was performed to individually identify risk factors for depression and anxiety. Results Our study included a total of 707 CD and 530 UC patients who underwent bowel resection surgery and did not have depression prior to surgery. The risk of depression 5 years after surgery was 16% and 11% in CD and UC respectively. We found no difference in the risk of depression following surgery in CD and UC patients (adjusted OR 1.11, 95%CI 0.84 – 1.47). Female gender, co-morbidity, immunosuppressant use, perianal disease, stoma surgery, and early surgery within 3 years of care predicted depression after CD-surgery; only female gender and co-morbidity predicted depression in UC. Only 12% of the CD cohort had ≥ 4 risk factors for depression, but among them nearly 44% were subsequently received a diagnosis code for depression. Conclusion IBD-related surgery or hospitalization is associated with a significant risk for depression and anxiety with a similar magnitude of risk in both diseases. PMID:23337479

Chagas disease in bone marrow transplantation: an approach to preemptive therapy.

PubMed

Altclas, J; Sinagra, A; Dictar, M; Luna, C; Verón, M T; De Rissio, A M; García, M M; Salgueira, C; Riarte, A

2005-07-01

The efficacy of preemptive therapy was evaluated in bone marrow transplantation (BMT) recipients associated with Chagas disease (CD). The criterion to include patients in the protocol was the serological reactivity for CD in recipients and/or donors before transplant. After BMT, the monitoring was performed using the direct Strout method (SM), which detects clinical levels of Trypanosome cruzi parasitemia, and CD conventional serological tests. Monitoring took place during 60 days in ABMT and throughout the immunosuppressive period in allogeneic BMT. Reactivation of CD was diagnosed by detecting T. cruzi parasites in blood or tissues. In primary T. cruzi infection, an additional diagnostic criterion was the serological conversion. A total of 25 CD-BMT patients were included. Two ABMT and four allogeneic BMT recipients showed CD recurrences diagnosed by SM. One patient also showed skin lesions with T. cruzi amastigotes. Benznidazole treatment (Roche Lab), an antiparasitic drug, was prescribed at a dose of 5 mg/kg/day during 4-8 weeks with recovery of patients. Primary T. cruzi infection was not observed. This report proves the relevance of monitoring CD in BMT patients and demonstrates that preemptive therapy was able to abrogate the development of clinical and systemic disease.

Mapping of HLA- DQ haplotypes in a group of Danish patients with celiac disease.

PubMed

Lund, Flemming; Hermansen, Mette N; Pedersen, Merete F; Hillig, Thore; Toft-Hansen, Henrik; Sölétormos, György

2015-10-01

A cost-effective identification of HLA- DQ risk haplotypes using the single nucleotide polymorphism (SNP) technique has recently been applied in the diagnosis of celiac disease (CD) in four European populations. The objective of the study was to map risk HLA- DQ haplotypes in a group of Danish CD patients using the SNP technique. Cohort A: Among 65 patients with gastrointestinal symptoms we compared the HLA- DQ2 and HLA- DQ8 risk haplotypes obtained by the SNP technique (method 1) with results based on a sequence specific primer amplification technique (method 2) and a technique used in an assay from BioDiagene (method 3). Cohort B: 128 patients with histologically verified CD were tested for CD risk haplotypes (method 1). Patients with negative results were further tested for sub-haplotypes of HLA- DQ2 (methods 2 and 3). Cohort A: The three applied methods provided the same HLA- DQ2 and HLA- DQ8 results among 61 patients. Four patients were negative for the HLA- DQ2 and HLA- DQ8 haplotypes (method 1) but were positive for the HLA- DQ2.5-trans and HLA- DQ2.2 haplotypes (methods 2 and 3). Cohort B: A total of 120 patients were positive for the HLA- DQ2.5-cis and HLA- DQ8 haplotypes (method 1). The remaining seven patients were positive for HLA- DQ2.5-trans or HLA- DQ2.2 haplotypes (methods 2 and 3). One patient was negative with all three HLA methods. The HLA- DQ risk haplotypes were detected in 93.8% of the CD patients using the SNP technique (method 1). The sensitivity increased to 99.2% by combining methods 1 - 3.

Role of CD81 and CD58 in minimal residual disease detection in pediatric B lymphoblastic leukemia.

PubMed

Tsitsikov, E; Harris, M H; Silverman, L B; Sallan, S E; Weinberg, O K

2018-06-01

Minimal residual disease (MRD) in B lymphoblastic leukemia has been demonstrated to be a powerful predictor of clinical outcome in numerous studies in both children and adults. In this study, we evaluated 86 pediatric patients with both diagnostic and remission flow cytometry studies and compared expression of CD81, CD58, CD19, CD34, CD20, and CD38 in the detection of MRD. We evaluated 86 patients with B lymphoblastic leukemia who had both diagnostic studies and remission studies for the presence of MRD using multicolor flow cytometry. We established our detection limit for identifying abnormal lymphoblasts using serial dilutions. We also compared flow cytometry findings with molecular MRD detection in a subset of patients. We found that we can resolve differences between hematogones and lymphoblasts in 85 of 86 cases using a combination of CD45, CD19, CD34, CD10, CD20, CD38, CD58, and CD81. Our detection limit using flow cytometry is 0.002% for detecting a population of abnormal B lymphoblasts. Comparison with MRD assessment by molecular methods showed a high concordance rate with flow cytometry findings. Our study highlights importance of using multiple markers to detect MRD in B lymphoblastic leukemia. Our findings indicate that including both CD58 and CD81 markers in addition to CD19, CD34, CD20, CD38, and CD10 are helpful in MRD detection by flow cytometry. © 2018 John Wiley & Sons Ltd.

Paradoxical arthritis occurring during anti-TNF in patients with inflammatory bowel disease: histological and immunological features of a complex synovitis

PubMed Central

Alivernini, Stefano; Pugliese, Daniela; Tolusso, Barbara; Bui, Laura; Petricca, Luca; Guidi, Luisa; Mirone, Luisa; Rapaccini, Gian Ludovico; Federico, Francesco; Ferraccioli, Gianfranco; Armuzzi, Alessandro; Gremese, Elisa

2018-01-01

Objective Paradoxical arthritis under tumour necrosis factor inhibitor (TNF-i) for inflammatory bowel disease (IBD) has been described. This study aims to evaluate the histological features of paired synovial tissue (ST) and colonic mucosa (CM) tissue in patients with IBD developing paradoxical arthritis under TNF-i. Methods Patients with IBD without history of coexisting joint involvement who developed arthritis under TNF-i were enrolled. Each patient underwent ST biopsy and ileocolonoscopy with CM biopsies. ST and CM paired samples were stained through immunohistochemistry (IHC) for CD68, CD21, CD20, CD3 and CD117. Clinical and immunological parameters (anticitrullinated peptides antibodies (ACPA)-immunoglobulin (Ig)M/IgA rheumatoid factor (RF)) were collected. Psoriatic arthritis (PsA) and ACPA/IgM-RF/IgA-RF negative rheumatoid arthritis (RA) were enrolled as comparison. Results 10 patients with IBD (age 46.0±9.7 years, 13.2±9.9 years of disease duration, 2.5±1.6 years of TNF-i exposure, six with Crohn’s disease and four with ulcerative colitis, respectively) were studied. At ST level, IHC revealed that patients with IBD with paradoxical arthritis showed more similar histological findings in terms of synovial CD68+, CD21+, CD20+, CD3+ and CD117+ cells compared with PsA than ACPA/IgM-RF/IgA-RF negative RA. Analysing the CM specimens, patients with IBD showed the presence of CD68+, CD3+, CD117+ and CD20+ cells in 100%, 70%, 60% and 50% of cases, respectively, despite endoscopic remission. Finally, addition of conventional disease-modifying antirheumatic drugs and switch to ustekinumab were more effective than swapping into different TNF-i in patients with IBD with paradoxical arthritis. Conclusion Patients with IBD may develop histologically proven synovitis during TNF-i, comparable to PsA. The inhibition of inflammatory pathways alternative to TNF (IL12/1L23) may be an effective therapeutic option for severe paradoxical articular manifestations. PMID:29657833

Direct Isolation, Culture and Transplant of Mouse Skeletal Muscle Derived Endothelial Cells with Angiogenic Potential

PubMed Central

Ieronimakis, Nicholas; Balasundaram, Gayathri; Reyes, Morayma

2008-01-01

Background Although diseases associated with microvascular endothelial dysfunction are among the most prevalent illnesses to date, currently no method exists to isolate pure endothelial cells (EC) from skeletal muscle for in vivo or in vitro study. Methodology By utilizing multicolor fluorescent-activated cell sorting (FACS), we have isolated a distinct population of Sca-1+, CD31+, CD34dim and CD45− cells from skeletal muscles of C57BL6 mice. Characterization of this population revealed these cells are functional EC that can be expanded several times in culture without losing their phenotype or capabilities to uptake acetylated low-density lipoprotein (ac-LDL), produce nitric oxide (NO) and form vascular tubes. When transplanted subcutaneously or intramuscularly into the tibialis anterior muscle, EC formed microvessels and integrated with existing vasculature. Conclusion This method, which is highly reproducible, can be used to study the biology and role of EC in diseases such as peripheral vascular disease. In addition this method allows us to isolate large quantities of skeletal muscle derived EC with potential for therapeutic angiogenic applications. PMID:18335025

Capsule endoscopy in the evaluation and management of inflammatory bowel disease: a future perspective.

PubMed

Saruta, Masayuki; Papadakis, Konstantinos A

2009-01-01

Wireless capsule endoscopy (WCE) has emerged as an important diagnostic tool for the evaluation of patients with suspected small intestinal (SI) disease, including obscure gastrointestinal bleeding, Crohn's disease (CD), malabsorptive disorders and SI tumors. Since a great number of patients with CD have small-bowel (SB) involvement, it is important for newly diagnosed patients to undergo an evaluation of the SB, which has traditionally been performed using a radiographic study such as a SB follow-through. The greatest utility of WCE in the evaluation of SB CD has been observed in cases of suspected CD, where the initial evaluation with upper and lower endoscopy as well as traditional radiographic techniques have failed to establish the diagnosis. WCE can detect SB involvement in CD, particularly early lesions that can be overlooked by traditional radiological studies. The sensitivity of diagnosing SB CD by WCE is superior to other endoscopic or radiological methods such as push enteroscopy, computed tomography or magnetic resonance enteroclysis. The utility of WCE in patients with known CD, indeterminate colitis and a select group of patients with ulcerative colitis can help to better define the diagnosis and extent of the disease, and assist in the management of patients with persistent symptoms. A disadvantage of WCE is that the device may be retained in a strictured area of the SB, which may often be present in patients with CD, in addition to a lower specificity. WCE may replace classical studies and become the gold standard for diagnosing SB involvement in patients with suspected, or known CD, in the absence of strictures and fistulae.

Health utility of patients with Crohn's disease and ulcerative colitis: a systematic review and meta-analysis.

PubMed

Malinowski, Krzysztof Piotr; Kawalec, Paweł

2016-08-01

The aim of this systematic review was to collect and summarize the current data on the utilities of patients with Crohn's disease (CD) and ulcerative colitis (UC). A meta-analysis of the obtained utilities was performed using a random-effects model and meta-regression by the disease type and severity. A bootstrap analysis was performed as it does not require assumption on distribution of the data. The highest utility among patients with CD and UC was observed when the diseases were in remission. The meta-regression analysis showed that both disease severity and an instrument/method/questionnaire used to obtain utilities were significant predictors of utility. Utility was the lowest for severe disease and the highest for disease in remission, the association was more notable in patients with CD compared with UC. Expert commentary: The issue of patients' utility is important for healthcare decision makers but it has not been fully investigated and requires further study.

Phenotypic variability within the JAK2 V617F-positive MPD: The roles of progenitor cell and neutrophil allele burdens

PubMed Central

Moliterno, Alison R.; Williams, Donna M.; Rogers, Ophelia; Isaacs, Mary Ann; Spivak, Jerry L.

2008-01-01

(1) Objective The myeloproliferative disorders (MPD), polycythemia vera (PV), essential thrombocytosis (ET) and primary myelofibrosis (PMF) differ phenotypically but share the same JAK2V617F mutation. We examined the relationship of the quantitative JAK2V617F allele burden to MPD disease phenotype among the three MPD classes and within PV. (2) Methods We measured the JAK2V617F allele percentage in genomic DNA from neutrophils, CD34+ cells, and cloned progenitors in 212 JAK2V617F –positive MPD patients and correlated the allele burdens to both disease class and disease features. (3) Results In ET and PV, the mean CD34+ cell JAK2V617F allele burdens were lower than the corresponding neutrophil allele burdens, but these were equivalent in PMF. JAK2WT progenitors were present in ET and PV when the CD34+ JAK2V617F allele burden was lower than the neutrophil allele burden, but not in PV and PMF subjects in whom the CD34+ cell and neutrophil allele burdens were similar. CD34+ cell JAK2V617F clonal dominance, defined as coherence between the CD34+ cell and neutrophil JAK2V617F allele burdens, was present in 24% of ET, 56% of PV and 93% of PMF patients, and was independent of the CD34+ cell JAK2V617F genotype. Clonally-dominant PV patients had significantly longer disease durations, higher white cell counts and larger spleens than nondominant PV patients. (4) Conclusions We conclude that the extent of JAK2V617F CD34+ cell clonal dominance is associated with disease phenotype within the MPD, and in PV, is associated with extramedullary disease, leukocytosis and disease duration. PMID:18723264

A comprehensive questionnaire for the assessment of health-related quality of life in coeliac disease (CDQL).

PubMed

Skjerning, Halfdan; Hourihane, Jonathan; Husby, Steffen; DunnGalvin, Audrey

2017-10-01

Coeliac disease (CD) is a chronic immune-mediated disease in genetically susceptible individuals, induced by ingested gluten. The treatment for CD is a lifelong gluten-free diet (GFD). The GFD involves restrictions in diet that may impact on a person's Health-Related Quality of Life (HRQoL). The aim of the present study was to develop the Coeliac Disease Quality of Life questionnaire (CDQL): a comprehensive CD-specific HRQoL measure that can be completed by children, adolescents, and adults or by proxy. The questionnaire was developed in three phases. In phase 1, focus group methods and qualitative analysis of verbatim transcripts generated CD-specific items for a prototype instrument to sensitively captured patient concerns. In phase 2, CD patients completed the prototype CDQL. The questionnaire was refined through analysis of data and cognitive interviewing. In phase 3, the final version of the CDQL was answered by Danish respondents. The psychometric properties of the CDQL were assessed, and the HRQoL data were analyzed. The CDQL was completed by 422 respondents. The CDQL has 12 patient background items, 2 generic HRQoL items, and 30 CD-specific HRQoL item. The CD-specific HRQoL items were distributed on eight scales with acceptable to excellent reliability. Comprehensiveness and understandability was shown by feedback from cognitive interviewing from children, adolescents, and adults. Content validity was ensured by involving patients and clinicians in the development of the questionnaire. Sensitivity of the questionnaire was demonstrated in differences found between children, adolescents, and adult's perception of their HRQoL in relation to having CD. The CDQL comprehensively measures HRQoL in CD, and is psychometrically robust. The questionnaire may prove useful in tracking HRQoL in CD across age groups.

A complementary role of multiparameter flow cytometry and high-throughput sequencing for minimal residual disease detection in chronic lymphocytic leukemia: an European Research Initiative on CLL study.

PubMed

Rawstron, A C; Fazi, C; Agathangelidis, A; Villamor, N; Letestu, R; Nomdedeu, J; Palacio, C; Stehlikova, O; Kreuzer, K-A; Liptrot, S; O'Brien, D; de Tute, R M; Marinov, I; Hauwel, M; Spacek, M; Dobber, J; Kater, A P; Gambell, P; Soosapilla, A; Lozanski, G; Brachtl, G; Lin, K; Boysen, J; Hanson, C; Jorgensen, J L; Stetler-Stevenson, M; Yuan, C; Broome, H E; Rassenti, L; Craig, F; Delgado, J; Moreno, C; Bosch, F; Egle, A; Doubek, M; Pospisilova, S; Mulligan, S; Westerman, D; Sanders, C M; Emerson, R; Robins, H S; Kirsch, I; Shanafelt, T; Pettitt, A; Kipps, T J; Wierda, W G; Cymbalista, F; Hallek, M; Hillmen, P; Montserrat, E; Ghia, P

2016-04-01

In chronic lymphocytic leukemia (CLL) the level of minimal residual disease (MRD) after therapy is an independent predictor of outcome. Given the increasing number of new agents being explored for CLL therapy, using MRD as a surrogate could greatly reduce the time necessary to assess their efficacy. In this European Research Initiative on CLL (ERIC) project we have identified and validated a flow-cytometric approach to reliably quantitate CLL cells to the level of 0.0010% (10(-5)). The assay comprises a core panel of six markers (i.e. CD19, CD20, CD5, CD43, CD79b and CD81) with a component specification independent of instrument and reagents, which can be locally re-validated using normal peripheral blood. This method is directly comparable to previous ERIC-designed assays and also provides a backbone for investigation of new markers. A parallel analysis of high-throughput sequencing using the ClonoSEQ assay showed good concordance with flow cytometry results at the 0.010% (10(-4)) level, the MRD threshold defined in the 2008 International Workshop on CLL guidelines, but it also provides good linearity to a detection limit of 1 in a million (10(-6)). The combination of both technologies would permit a highly sensitive approach to MRD detection while providing a reproducible and broadly accessible method to quantify residual disease and optimize treatment in CLL.

One-step immunochromatographic visual assay for anti-transglutaminase detection in organ culture system: An easy and prompt method to simplify the in vitro diagnosis of celiac disease.

PubMed

Di Tola, Marco; Marino, Mariacatia; Casale, Rossella; Borghini, Raffaele; Tiberti, Antonio; Donato, Giuseppe; Occhiuzzi, Umberto; Picarelli, Antonio

2018-01-01

Anti-tissue transglutaminase (anti-tTG) and endomysium antibodies (EMA) are detectable in duodenal culture media of celiac disease (CD) patients. To improve the management of this organ culture system, we evaluated the anti-tTG occurrence by immunochromatographic assay (ICA). A total of 103 CD patients and 41 disease controls underwent duodenal biopsy for the organ culture. In culture supernatants, IgA anti-tTG were tested by both enzyme-linked immunosorbent assay (ELISA) and ICA, IgA EMA were searched by indirect immunofluorescence analysis (iIFA). Endomysium antibodies and anti-tTG measured by ELISA were positive in culture media of all CD patients, while anti-tTG detected by ICA were positive in culture media of 87/103 CD patients. Anti-tTG ICA scores significantly correlated with anti-tTG ELISA values (r=.71, P<.0001). Sensitivity, specificity and diagnostic accuracy of anti-tTG detected by ICA were 84.5%, 100% and 88.9%, respectively. Using ICA, anti-tTG are detectable in duodenal culture media of most CD patients and the intensity of indicative lines depends on the anti-tTG concentration. Sensitivity and diagnostic accuracy achieved with ICA are lower than those obtained with ELISA but, given that the first is a more easy and prompt method, data suggest the possibility of utilizing it in the in vitro diagnosis of CD. © 2017 Wiley Periodicals, Inc.

Treatment inferred disease severity in Crohn's disease: evidence for a European gradient of disease course.

PubMed

Wolters, Frank L; Joling, Catelijne; Russel, Maurice G; Sijbrandij, Jildou; De Bruin, Marion; Odes, Selwyn; Riis, Lene; Munkholm, Pia; Bodini, Paolo; Ryan, Barbara; O'Morain, Colm; Mouzas, Ioannis A; Tsianos, Epameinondas; Vermeire, Severine; Monteiro, Estela; Limonard, Charles; Vatn, Morten; Fornaciari, Giovanni; Rodriguez, Dolores; Groot, Wim; Moum, Bjørn; Stockbrügger, Reinhold W

2007-03-01

Geographic differences in disease course of Crohn's disease (CD) might possibly be related to differences in genetic and environmental factors encountered in different parts of the world. The aim of this study was to assess differences in treatment regimens within a European cohort of CD patients as a reflection of disease course, and to identify associated phenotypic risk factors at diagnosis. A prospective European population-based inception cohort of 380 CD patients was studied. The patients were classified for phenotype according to the Vienna classification. Differences between Northern and Southern European centres in treatment over the first 10 years of disease were analysed using a competing risks survival analysis method. Patients in the North were more likely to have had surgery (p<0.01), whereas patients in the South were more likely to have been treated medically (p<0.01). Phenotype at diagnosis was not predictive of differences in treatment regimens between North and South. In this study, a difference in management of CD was observed between Northern and Southern European centres. This suggests that there may be a North-South disease severity gradient across Europe. Phenotypic differences between patients in the North and South did not explain this observed difference.

Risk factors for gallstones and kidney stones in a cohort of patients with inflammatory bowel diseases

PubMed Central

Rossel, Jean-Benoît; Biedermann, Luc; Frei, Pascal; Zeitz, Jonas; Spalinger, Marianne; Battegay, Edouard; Zimmerli, Lukas; Vavricka, Stephan R.; Rogler, Gerhard

2017-01-01

Background Gallstones and kidney stones are known complications of inflammatory bowel diseases (IBD). Risk factors have been insufficiently studied and explanatory studies date back up to 30 years. It remains unclear, whether improved treatment options also influenced risk factors for these complications. Objectives Identifying risk factors for gallstones and kidney stones in IBD patients. Methods Using data from the Swiss Inflammatory Bowel Disease Cohort Study we assessed associations of diseases characteristics with gallstones and kidney stones in univariate and multivariate logistic regression analyses. Results Out of 2323 IBD patients, 104 (7.8%) Crohn’s disease (CD) and 38 (3.8%) ulcerative colitis (UC) patients were diagnosed with gallstones. Significant risk factors for gallstones were diagnosis of CD, age at diagnosis, disease activity and duration, NSAID intake, extra-intestinal manifestations and intestinal surgery. Kidney stones were described in 61 (4.6%) CD and 30 (3.0%) UC patients. Male gender, disease activity, intestinal surgery, NSAID usage and reduced physical activity were significant risk factors. Hospitalization was associated with gallstones and kidney stones. The presence of gallstones increased the risk for kidney stones (OR 4.87, p<0.001). Conclusion The diagnosis of CD, intestinal surgery, prolonged NSAID use, disease activity and duration and bowel stenosis were significantly associated with cholecystonephrolithiasis in IBD. PMID:29023532

Infliximab Combined with Enteral Nutrition for Managing Crohn's Disease Complicated with Intestinal Fistulas

PubMed Central

Wu, Xiao-Li; Tao, Li-Ping; Wu, Jian-Sheng; Chen, Xiang-Rong

2016-01-01

Aim. This study was performed to evaluate the additional enteral nutrition (EN) in the efficacy of infliximab (IFX) compared with the conventional therapy in managing Crohn's disease (CD) complicated with intestinal fistulas. Methods. A total of 42 CD with intestinal fistulas were randomly divided into infliximab treatment group (n = 20) and conventional therapy group (n = 22). We evaluated the laboratory indexes, Crohn's disease activity index (CDAI), Crohn's disease simplified endoscopic score (SES-CD), and healing of fistula in the two groups before treatment, at 14 weeks, and at 30 weeks, respectively. Results. In the IFX treatment group, the CDAI score, the SES-CD, erythrocyte sedimentation rate, and C-reactive protein levels were significantly decreased during treatment compared with those before treatment. The body mass index and albumin levels were increased in both groups. Moreover, in the IFX treatment group, fistula healing was found in 8 at the 14th week and 18 at the 30th week, respectively, which was greater than that in the conventional therapy group. Conclusion. Our study suggested that infliximab combined with EN is an effective treatment for CD patients complicated with intestinal fistulas. PMID:27738427

Carbohydrate Intake in the Etiology of Crohn's Disease and Ulcerative Colitis

PubMed Central

Luben, Robert; van Schaik, Fiona; Oldenburg, Bas; Bueno-de-Mesquita, H. Bas; Hallmans, Göran; Karling, Pontus; Lindgren, Stefan; Grip, Olof; Key, Timothy; Crowe, Francesca L.; Bergmann, Manuela M.; Overvad, Kim; Palli, Domenico; Masala, Giovanna; Khaw, Kay-Tee; Racine, Antoine; Carbonnel, Franck; Boutron-Ruault, Marie-Christine; Olsen, Anja; Tjonneland, Anne; Kaaks, Rudolf; Tumino, Rosario; Trichopoulou, Antonia; Hart, Andrew R.

2014-01-01

Background: Diet may have a role in the etiology of inflammatory bowel disease. In previous studies, the associations between increased intakes of carbohydrates, sugar, starch, and inflammatory bowel disease are inconsistent. However, few prospective studies have investigated the associations between these macronutrients and incident Crohn's disease (CD) or ulcerative colitis (UC). Methods: A total of 401,326 men and women were recruited between 1991 and 1998. At recruitment, dietary intakes of carbohydrate, sugar, and starch were measured using validated food frequency questionnaires. The cohort was monitored identifying participants who developed incident CD or UC. Cases were matched with 4 controls, and odds ratios were calculated for quintiles of total carbohydrate, sugar, and starch intakes adjusted for total energy intake, body mass index, and smoking. Results: One hundred ten participants developed CD, and 244 participants developed UC during follow-up. The adjusted odds ratio for the highest versus the lowest quintiles of total carbohydrate intake for CD was 0.87, 95% CI = 0.24 to 3.12 and for UC 1.46, 95% CI = 0.62 to 3.46, with no significant trends across quintiles for either (CD, Ptrend = 0.70; UC, Ptrend = 0.41). Similarly, no associations were observed with intakes of total sugar (CD, Ptrend = 0.50; UC, Ptrend = 0.71) or starch (CD, Ptrend = 0.69; UC, Ptrend = 0.17). Conclusions: The lack of associations with these nutrients is in agreement with many case–control studies that have not identified associations with CD or UC. As there is biological plausibility for how specific carbohydrates could have an etiological role in inflammatory bowel disease, future epidemiological work should assess individual carbohydrates, although there does not seem to be a macronutrient effect. PMID:25265262

Increased Prevalence of Luminal Narrowing and Stricturing Identified by Enterography in Pediatric Crohn Disease Patients with Elevated Granulocyte-Macrophage Colony Stimulating Factor Auto-antibodies

PubMed Central

Dykes, Dana M.H.; Towbin, Alexander J.; Bonkowski, Erin; Chalk, Claudia; Bezold, Ramona; Lake, Kathleen; Kim, Mi-Ok; Heubi, James E.; Trapnell, Bruce C.; Podberesky, Daniel J.; Denson, Lee A.

2013-01-01

Background Crohn disease (CD) patients with elevated Granulocyte-Macrophage Colony-Stimulating Factor auto-antibodies (GM-CSF Ab) are more likely to develop stricturing behavior requiring surgery. Computed Tomography or Magnetic Resonance Enterography (CTE or MRE) may detect luminal narrowing (LN) prior to stricture development. Objective To determine whether CD patients with elevated GM-CSF Ab (≥ 1.6 mcg/mL) have a higher prevalence of LN and stricturing on CTE or MRE. Methods A single center, cross-sectional study of 153 pediatric CD patients and controls undergoing CTE or MRE. A novel scoring system evaluated for disease activity, presence of LN, stricture, intra-abdominal abscess, or fistulae Ouutcomes were compared with respect to antibody status using Fisher's exact test, logistic regression, and the unpaired t-test. Results GM-CSF Ab were elevated in CD patients (n=114) with a median (IQR) GM-CSF Ab level of 2.3 mcg/mL (0.5, 6.6) compared with healthy and disease controls, p=0.001. Ileal disease location was more common in CD patients with high GM-CSF Ab, p<0.001. Luminal narrowing increased from 39% in CD patients with low GM-CSF Ab to 71% in those with high levels (p=0.004). High GM-CSF Ab remained significantly associated with LN in a multivariate logistic model. Stricturing increased from 4% in CD patients with low GM-CSF Ab to 19% in those with high GM-CSF Ab (p=0.03). Conclusions Pediatric CD patients with high GM-CSF Ab levels have a higher prevalence of LN on CTE or MRE. Further study will be needed to determine whether medical therapy will reduce progression to stricturing behavior in these patients. PMID:23893081

Comparison between handgrip strength, subjective global assessment, anthropometry, and biochemical markers in assessing nutritional status of patients with Crohn's disease in clinical remission.

PubMed

Bin, Céres Maltz; Flores, Cristina; Alvares-da-Silva, Mário Reis; Francesconi, Carlos Fernando Magalhães

2010-01-01

Crohn's disease (CD) may lead to protein and calorie malnutrition (PCM) secondary to impaired digestive and absorptive functions of the small intestine and sometimes to the influence of diet taboos. The earlier the PCM is diagnosed, the higher are the odds of reversal. The objective of this study was to compare different methods of nutritional assessment in patients with CD and correlate them with the disease characteristics. The sample comprised 75 patients with CD from the Gastroenterology Service at the Hospital de Clínicas de Porto Alegre; 37 were male, with a mean age of 38.2 years old (SD = 13.3). All patients had been in clinical remission (CDAI <150) for over 3 months. They were not receiving enteral or parenteral nutrition. The nutritional assessment was considered: body mass index (BMI), triceps skin fold (TSF), arm circumference (MAC), arm muscle circumference (MAMC), subjective global assessment (SGA), non-dominating handgrip strength (HGS) and food intake inquiries. When comparing the different nutritional assessment methods, 26.7% of the patients were malnourished according to the MAC, 29.3% according to the MAMC, 18.7% according to the SGA, 6.7% according to the BMI, 37.3% according to the TSF and 73.3% according to the HGS. No statistically significant associations were found for disease location, its behavior, drugs utilized, ESR, CRP, age of patients and disease time with the nutritional state verified by HGS, TSF, MAMC and SGA. The prevalence of malnutrition is significant in patients with CD, even in clinical remission. The BMI should not be used as reference in this population. The HGS detected a high prevalence of nutritional risk in patients with CD in remission. Studies are required that correlate it with more sensitive methods, for the patients' effective nutritional state assessment.

Ileal Crohn disease: mural microvascularity quantified with contrast-enhanced US correlates with disease activity.

PubMed

De Franco, Antonio; Di Veronica, Alessandra; Armuzzi, Alessandro; Roberto, Italia; Marzo, Manuela; De Pascalis, Barbara; De Vitis, Italo; Papa, Alfredo; Bock, Enrico; Danza, Francesco M; Bonomo, Lorenzo; Guidi, Luisa

2012-02-01

To quantitatively assess microvascular activation in the thickened ileal walls of patients with Crohn disease (CD) by using contrast-enhanced ultrasonography (US) and evaluate its correlation with widely used indexes of CD activity. This prospective study was approved by the ethics committee, and written informed consent was obtained from all patients. The authors examined 54 consecutively enrolled patients (mean age, 35.29 years; age range, 18-69 years; 39 men, 15 women) with endoscopically confirmed CD of the terminal ileum. Ileal wall segments thicker than 3 mm were examined with low-mechanical-index contrast-enhanced US and a second-generation US contrast agent. The authors analyzed software-plotted time-enhancement intensity curves to determine the maximum peak intensity (MPI) and wash-in slope coefficient (β) and evaluated their correlation with (a) the composite index of CD activity (CICDA), (b) the CD activity index (CDAI), and (c) the simplified endoscopic score for CD (SES-CD, evaluated in 37 patients) for the terminal ileum. Statistical analysis was performed with the Mann-Whitney test, Spearman rank test, and receiver operating characteristic (ROC) analysis. MPI and β coefficients were significantly increased in the 36 patients with a CICDA indicative of active disease (P<.0001 for both), the 33 patients with a CDAI of at least 150 (P<.032 and P<.0074, respectively), and the 26 patients with an SES-CD of at least 1 (P<.0001 and P<.002, respectively). ROC analysis revealed accurate identification (compared with CICDA) of active CD with an MPI threshold of 24 video intensity (VI) (sensitivity, 97%; specificity, 83%) and a β coefficient of 4.5 VI/sec (sensitivity, 86%; specificity, 83%). Contrast-enhanced US of the ileal wall is a promising method for objective, reproducible assessment of disease activity in patients with ileal CD. © RSNA, 2011

Growth hormone impaired secretion and antipituitary antibodies in patients with coeliac disease and poor catch-up growth after a long gluten-free diet period: a causal association?

PubMed

Iughetti, Lorenzo; De Bellis, Annamaria; Predieri, Barbara; Bizzarro, Antonio; De Simone, Michele; Balli, Fiorella; Bellastella, Antonio; Bernasconi, Sergio

2006-12-01

Coeliac disease (CD) is usually associated with impaired growth in children. A gluten-free diet (GFD) induces a catch-up growth with the recovery of height in about 2 years. AIM AND DISCUSSION: The lack of the height improvement has been related to growth hormone (GH) secretion impairment. CD is an autoimmune disease often associated with other endocrine and non-endocrine autoimmune disease. The aim of this study was to evaluate antipituitary autoantibodies (APA) and antihypothalamus autoantibodies in CD children with poor clinical response to a GFD and growth hormone deficiency (GHD). We diagnosed CD on the basis of specific antibodies and endoscopic biopsies in 130 patients aged 1-15 years. Seven CD children, without catch-up growth after at least 12-months GFD, were tested for GH secretion and, in five out of seven patients, the diagnosis of GHD was made in the absence of metabolic and systemic diseases. APA and antihypothalamus antibodies were detected by the indirect immunofluorescence method in the seven CD children without catch-up growth factor and in 25 CD children without growth impairment matched for sex and age, and in 58 healthy children as control groups. APA resulted positive at high titres in four out of five CD-GHD patients and were also positive at low titres (<1:8) in three of only CD children and in two out of 58 controls. Hypothalamic-pituitary magnetic resonance imaging (MRI) was normal in all patients except in one with cystic pineal. APA have been previously detected not only in adults with GHD, but also in idiopathic GHD children, suggesting the occurrence of an autoimmune hypophysitis in these patients. In our study, the presence of APA in CD children without catch-up growth after GFD seems to be able to identify an autoimmune form of hypophysitis involving the somatotrophs cells.

Low expression of CD39+/CD45RA+ on regulatory T cells (Treg) cells in type 1 diabetic children in contrast to high expression of CD101+/CD129+ on Treg cells in children with coeliac disease

PubMed Central

Åkesson, K; Tompa, A; Rydén, A; Faresjö, M

2015-01-01

Type 1 diabetes (T1D) and coeliac disease are both characterized by an autoimmune feature. As T1D and coeliac disease share the same risk genes, patients risk subsequently developing the other disease. This study aimed to investigate the expression of T helper (Th), T cytotoxic (Tc) and regulatory T cells (Treg) in T1D and/or coeliac disease children in comparison to healthy children. Subgroups of T cells (Th : CD4+ or Tc : CD8+); naive (CD27+CD28+CD45RA+CCR7+), central memory (CD27+CD28+CD45RA−CCR7+), effector memory (early differentiated; CD27+CD28+CD45RA−CCR7− and late differentiated; CD27−CD28−CD45RA−CCR7−), terminally differentiated effector cells (TEMRA; CD27−CD28−CD45RA+CCR7−) and Treg (CD4+CD25+FOXP3+CD127−) cells, and their expression of CD39, CD45RA, CD101 and CD129, were studied by flow cytometry in T1D and/or coeliac disease children or without any of these diseases (reference group). Children diagnosed with both T1D and coeliac disease showed a higher percentage of TEMRA CD4+ cells (P < 0·05), but lower percentages of both early and late effector memory CD8+ cells (P < 0·05) compared to references. Children with exclusively T1D had lower median fluorescence intensity (MFI) of forkhead box protein 3 (FoxP3) (P < 0·05) and also a lower percentage of CD39+ and CD45RA+ within the Treg population (CD4+CD25+FOXP3+CD127−) (P < 0·05). Children with exclusively coeliac disease had a higher MFI of CD101 (P < 0·01), as well as a higher percentage of CD129+ (P < 0·05), in the CD4+CD25hi lymphocyte population, compared to references. In conclusion, children with combined T1D and coeliac disease have a higher percentage of differentiated CD4+ cells compared to CD8+ cells. T1D children show signs of low CD39+/CD45RA+ Treg cells that may indicate loss of suppressive function. Conversely, children with coeliac disease show signs of CD101+/CD129+ Treg cells that may indicate suppressor activity. PMID:25421756

[Characteristics of Crohn's disease under 
double balloon enteroscopy].

PubMed

Jia, Jia; Liu, Rui; Liu, Xiangjie; Shen, Shourong; Guo, Qin

2018-05-28

To observe ulcer characteristics of Crohn's disease under double balloon enteroscopy, and to evaluate the correlation between endoscopic severity and clinical manifestations.
 Methods: A prospective, observational study from July 2015 to December 2016 in the Third Xiangya Hospital, Central South University, we selected 45 patients with positive double-balloon enteroscopy (DBE) and confirmed Crohn's disease. Two digestive internal physician observed the ulcer characteristics of Crohn's disease under double balloon enteroscopy, and gave a simple endoscopic score for CD (SES-CD). We analyzed the correlation between SES-CD and Crohn's disease activity index (CDAI).
 Results: DBE indicated 24 patient ulcers (53.33%) locating at the end of the ileum, 5 (11.11%) locating at ileocolon, 16 (35.56%) locating at upper gatrointestinal tract and they did not affect the end of the ileum. Among them, 8 cases (17.78%) affected only jejunum. Thirty-two patients with longitudinal ulcers in Crohn's disease, accounting for 71.11%. There was no correlation between SES-CD score and CDAI score (r=0.237, P=0.136).
 Conclusion: The ulcerative appearance in Crohn's disease were diverse under double balloon enteroscopy. Crohn's disease could only affect the upper gastrointestinal tract or jejunum. The unwounded ileum and ileocecal valve couldn't be a sign to exclude Crohn's disease. CDAI score couldn't fully assess the prognosis of Crohn's disease.

Whole Genome Gene Expression Meta-Analysis of Inflammatory Bowel Disease Colon Mucosa Demonstrates Lack of Major Differences between Crohn's Disease and Ulcerative Colitis

PubMed Central

Østvik, Ann E.; Drozdov, Ignat; Gustafsson, Bjørn I.; Kidd, Mark; Beisvag, Vidar; Torp, Sverre H.; Waldum, Helge L.; Martinsen, Tom Christian; Damås, Jan Kristian; Espevik, Terje; Sandvik, Arne K.

2013-01-01

Background In inflammatory bowel disease (IBD), genetic susceptibility together with environmental factors disturbs gut homeostasis producing chronic inflammation. The two main IBD subtypes are Ulcerative colitis (UC) and Crohn’s disease (CD). We present the to-date largest microarray gene expression study on IBD encompassing both inflamed and un-inflamed colonic tissue. A meta-analysis including all available, comparable data was used to explore important aspects of IBD inflammation, thereby validating consistent gene expression patterns. Methods Colon pinch biopsies from IBD patients were analysed using Illumina whole genome gene expression technology. Differential expression (DE) was identified using LIMMA linear model in the R statistical computing environment. Results were enriched for gene ontology (GO) categories. Sets of genes encoding antimicrobial proteins (AMP) and proteins involved in T helper (Th) cell differentiation were used in the interpretation of the results. All available data sets were analysed using the same methods, and results were compared on a global and focused level as t-scores. Results Gene expression in inflamed mucosa from UC and CD are remarkably similar. The meta-analysis confirmed this. The patterns of AMP and Th cell-related gene expression were also very similar, except for IL23A which was consistently higher expressed in UC than in CD. Un-inflamed tissue from patients demonstrated minimal differences from healthy controls. Conclusions There is no difference in the Th subgroup involvement between UC and CD. Th1/Th17 related expression, with little Th2 differentiation, dominated both diseases. The different IL23A expression between UC and CD suggests an IBD subtype specific role. AMPs, previously little studied, are strongly overexpressed in IBD. The presented meta-analysis provides a sound background for further research on IBD pathobiology. PMID:23468882

Detection of paroxysmal nocturnal hemoglobinuria clones in patients with myelodysplastic syndromes and related bone marrow diseases, with emphasis on diagnostic pitfalls and caveats

PubMed Central

Wang, Sa A.; Pozdnyakova, Olga; Jorgensen, Jeffrey L.; Medeiros, L. Jeffrey; Stachurski, Dariusz; Anderson, Mary; Raza, Azra; Woda, Bruce A.

2009-01-01

Background The presence of paroxysmal nocturnal hemoglobinuria clones in the setting of aplastic anemia or myelodysplastic syndrome has been shown to have prognostic and therapeutic implications. However, the status of paroxysmal nocturnal hemoglobinuria clones in various categories of myelodysplastic syndrome and in other bone marrow disorders is not well-studied. Design and Methods By using multiparameter flow cytometry immunophenotypic analysis with antibodies specific for four glycosylphosphatidylinositol-anchored proteins (CD55, CD59, CD16, CD66b) and performing an aerolysin lysis confirmatory test in representative cases, we assessed the paroxysmal nocturnal hemoglobinuria-phenotype granulocytes in 110 patients with myelodysplastic syndrome, 15 with myelodysplastic/myeloproliferative disease, 5 with idiopathic myelofibrosis and 6 with acute myeloid leukemia. Results Paroxysmal nocturnal hemoglobinuria-phenotype granulocytes were detected in nine patients with low grade myelodysplastic syndrome who showed clinicopathological features of bone marrow failure, similar to aplastic anemia. All paroxysmal nocturnal hemoglobinuria-positive cases demonstrated loss of the four glycosylphosphatidylinositol-anchored proteins, with CD16−CD66b− clones being larger than those of CD55−CD59− (p<0.05). Altered glycosylphosphatidylinositol-anchored protein expression secondary to granulocytic hypogranulation, immaturity, and/or immunophenotypic abnormalities was present in a substantial number of cases and diagnostically challenging. Conclusions These results show that routine screening for paroxysmal nocturnal hemoglobinuria clones in patients with an intrinsic bone marrow disease who show no clinical evidence of hemolysis has an appreciable yield in patients with low grade myelodysplastic syndromes. The recognition of diagnostic caveats and pitfalls associated with the underlying intrinsic bone marrow disease is essential in interpreting paroxysmal nocturnal hemoglobinuria testing correctly. In our experience, the CD16/CD66b antibody combination is superior to CD55/CD59 in screening for subclinical paroxysmal nocturnal hemoglobinuria because it detects a large clone size and is less subject to analytical interference. PMID:19001281

Alterations of the Subgingival Microbiota in Pediatric Crohn's Disease Studied Longitudinally in Discovery and Validation Cohorts

PubMed Central

Kelsen, Judith; Bittinger, Kyle; Pauly-Hubbard, Helen; Posivak, Leah; Grunberg, Stephanie; Baldassano, Robert; Lewis, James D; Wu, Gary D; Bushman, Frederic D

2016-01-01

Background Oral manifestations are common in Crohn's disease (CD). Here we characterized the subgingival microbiota in pediatric CD patients initiating therapy and after 8 weeks to identify microbial community features associated with CD and therapy. Methods Pediatric CD patients were recruited from The Children's Hospital of Pennsylvania. Healthy control subjects were recruited from primary care or orthopedics clinic. Subgingival plaque samples were collected at initiation of therapy and after 8 weeks. Treatment exposures included 5-ASAs, immunomodualtors, steroids, and infliximab. The microbiota was characterized by 16S rRNA gene sequencing. The study was repeated in separate discovery (35 CD, 43 healthy) and validation cohorts (43 CD, 31 healthy). Results A majority of subjects in both cohorts demonstrated clinical response after 8 weeks of therapy (discovery cohort 88%, validation cohort 79%). At week 0, both antibiotic exposure and disease state were associated with differences in bacterial community composition. Seventeen genera were identified in the discovery cohort as candidate biomarkers, of which 11 were confirmed in the validation cohort. Capnocytophaga, Rothia, and TM7 were more abundant in CD relative to healthy controls. Other bacteria were reduced in abundance with antibiotic exposure among CD subjects. CD-associated genera were not enriched compared to healthy controls after 8 weeks of therapy. Conclusions Subgingival microbial community structure differed with CD and antibiotic use. Results in the discovery cohort were replicated in a separate validation cohort. Several potentially pathogenic bacterial lineages were associated with CD but were not diminished in abundance by antibiotic treatment, suggesting targets for additional surveillance. PMID:26288001

Accurate and robust genomic prediction of celiac disease using statistical learning.

PubMed

Abraham, Gad; Tye-Din, Jason A; Bhalala, Oneil G; Kowalczyk, Adam; Zobel, Justin; Inouye, Michael

2014-02-01

Practical application of genomic-based risk stratification to clinical diagnosis is appealing yet performance varies widely depending on the disease and genomic risk score (GRS) method. Celiac disease (CD), a common immune-mediated illness, is strongly genetically determined and requires specific HLA haplotypes. HLA testing can exclude diagnosis but has low specificity, providing little information suitable for clinical risk stratification. Using six European cohorts, we provide a proof-of-concept that statistical learning approaches which simultaneously model all SNPs can generate robust and highly accurate predictive models of CD based on genome-wide SNP profiles. The high predictive capacity replicated both in cross-validation within each cohort (AUC of 0.87-0.89) and in independent replication across cohorts (AUC of 0.86-0.9), despite differences in ethnicity. The models explained 30-35% of disease variance and up to ∼43% of heritability. The GRS's utility was assessed in different clinically relevant settings. Comparable to HLA typing, the GRS can be used to identify individuals without CD with ≥99.6% negative predictive value however, unlike HLA typing, fine-scale stratification of individuals into categories of higher-risk for CD can identify those that would benefit from more invasive and costly definitive testing. The GRS is flexible and its performance can be adapted to the clinical situation by adjusting the threshold cut-off. Despite explaining a minority of disease heritability, our findings indicate a genomic risk score provides clinically relevant information to improve upon current diagnostic pathways for CD and support further studies evaluating the clinical utility of this approach in CD and other complex diseases.

Developing in vitro expanded CD45RA+ regulatory T cells as an adoptive cell therapy for Crohn's disease

PubMed Central

Canavan, James B; Scottà, Cristiano; Vossenkämper, Anna; Goldberg, Rimma; Elder, Matthew J; Shoval, Irit; Marks, Ellen; Stolarczyk, Emilie; Lo, Jonathan W; Powell, Nick; Fazekasova, Henrieta; Irving, Peter M; Sanderson, Jeremy D; Howard, Jane K; Yagel, Simcha; Afzali, Behdad; MacDonald, Thomas T; Hernandez-Fuentes, Maria P; Shpigel, Nahum Y; Lombardi, Giovanna; Lord, Graham M

2016-01-01

Background and aim Thymus-derived regulatory T cells (Tregs) mediate dominant peripheral tolerance and treat experimental colitis. Tregs can be expanded from patient blood and were safely used in recent phase 1 studies in graft versus host disease and type 1 diabetes. Treg cell therapy is also conceptually attractive for Crohn's disease (CD). However, barriers exist to this approach. The stability of Tregs expanded from Crohn's blood is unknown. The potential for adoptively transferred Tregs to express interleukin-17 and exacerbate Crohn's lesions is of concern. Mucosal T cells are resistant to Treg-mediated suppression in active CD. The capacity for expanded Tregs to home to gut and lymphoid tissue is unknown. Methods To define the optimum population for Treg cell therapy in CD, CD4+CD25+CD127loCD45RA+ and CD4+CD25+CD127loCD45RA− Treg subsets were isolated from patients’ blood and expanded in vitro using a workflow that can be readily transferred to a good manufacturing practice background. Results Tregs can be expanded from the blood of patients with CD to potential target dose within 22–24 days. Expanded CD45RA+ Tregs have an epigenetically stable FOXP3 locus and do not convert to a Th17 phenotype in vitro, in contrast to CD45RA− Tregs. CD45RA+ Tregs highly express α4β7 integrin, CD62L and CC motif receptor 7 (CCR7). CD45RA+ Tregs also home to human small bowel in a C.B-17 severe combined immune deficiency (SCID) xenotransplant model. Importantly, in vitro expansion enhances the suppressive ability of CD45RA+ Tregs. These cells also suppress activation of lamina propria and mesenteric lymph node lymphocytes isolated from inflamed Crohn's mucosa. Conclusions CD4+CD25+CD127loCD45RA+ Tregs may be the most appropriate population from which to expand Tregs for autologous Treg therapy for CD, paving the way for future clinical trials. PMID:25715355

CD28-Negative CD4+ and CD8+ T Cells in Antiretroviral Therapy–Naive HIV-Infected Adults Enrolled in Adult Clinical Trials Group Studies

PubMed Central

Tassiopoulos, Katherine; Landay, Alan; Collier, Ann C.; Connick, Elizabeth; Deeks, Steven G.; Hunt, Peter; Lewis, Dorothy E.; Wilson, Cara; Bosch, Ronald

2012-01-01

Background Individuals infected with human immunodeficiency virus (HIV) have higher risk than HIV-negative individuals for diseases associated with aging. T-cell senescence, characterized by expansion of cells lacking the costimulatory molecule CD28, has been hypothesized to mediate these risks. Methods We measured the percentage of CD28−CD4+ and CD8+ T cells from HIV-infected treatment-naive adults from 5 Adult Clinical Trials Group (ACTG) antiretroviral therapy (ART) studies and the ALLRT (ACTG Longitudinal Linked Randomized Trials) cohort, and from 48 HIV-negative adults. Pretreatment and 96-week posttreatment %CD28− cells were assessed using linear regression for associations with age, sex, race/ethnicity, CD4 count, HIV RNA, ART regimen, and hepatitis C virus (HCV) infection. Results In total, 1291 chronically HIV-infected adults were studied. Pretreatment, lower CD4 count was associated with higher %CD28−CD4+ and %CD28−CD8+ cells. For CD8+ cells, younger age and HCV infection were associated with a lower %CD28−. ART reduced %CD28− levels at week 96 among virally suppressed individuals. Older age was strongly predictive of higher %CD28−CD8+. Compared to HIV-uninfected individuals, HIV-infected individuals maintained significantly higher %CD28−. Conclusions Effective ART reduced the proportion of CD28− T cells. However, levels remained abnormally high and closer to levels in older HIV-uninfected individuals. This finding may inform future research of increased rates of age-associated disease in HIV-infected adults. PMID:22448010

Advanced imaging techniques for small bowel Crohn's disease: what does the future hold?

PubMed

Pita, Inês; Magro, Fernando

2018-01-01

Treatment of Crohn's disease (CD) is intrinsically reliant on imaging techniques, due to the preponderance of small bowel disease and its transmural pattern of inflammation. Ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI) are the most widely employed imaging methods and have excellent diagnostic accuracy in most instances. Some limitations persist, perhaps the most clinically relevant being the distinction between inflammatory and fibrotic strictures. In this regard, several methodologies have recently been tested in animal models and human patients, namely US strain elastography, shear wave elastography, contrast-enhanced US, magnetization transfer MRI and contrast dynamics in standard MRI. Technical advances in each of the imaging methods may expand their indications. The addition of oral contrast to abdominal US appears to substantially improve its diagnostic capabilities compared to standard US. Ionizing dose-reduction methods in CT can decrease concern about cumulative radiation exposure in CD patients and diffusion-weighted MRI may reduce the need for gadolinium contrast. Clinical indexes of disease activity and severity are also increasingly relying on imaging scores, such as the recently developed Lémann Index. In this review we summarize some of the recent advances in small bowel CD imaging and how they might affect clinical practice in the near future.

An evaluation of health care expenditures in Crohn's disease using the United States Medical Expenditure Panel Survey from 2003 to 2013.

PubMed

Bounthavong, Mark; Li, Meng; Watanabe, Jonathan H

Previous estimates of the economic burden of Crohn's disease (CD) varied widely from $2.0 to $18.2 billion per year (adjusted to 2015 $US). However, these estimates do not reflect recent changes in pharmaceutical treatment options and guidelines. The goal of this study was to update cost estimates of Crohn's disease based on a representative sample of the US population from the most recent 11 years (2003-2013) of the Medical Expenditure Panel Survey (MEPS). A secondary aim described expenditure trends in respondents with and without Crohn's disease pre-post FDA approvals of new biologics and the American College of Gastroenterology Crohn's disease treatment guidelines. Average annual expenditures (total, prescription, inpatient, and outpatient) were evaluated using a pooled cross-sectional design. Respondent data from the most recent 11 years (2003-2013) of MEPS were analyzed. Two-part generalized linear models with power-link were used to estimate the average annual expenditures per patient adjusted to multiple covariates. Confidence intervals (CI) were estimated using bootstrap methods. Difference-in-differences estimations were performed to compare the changes in health care expenditures pre-post FDA approvals of new biologics and the American College of Gastroenterology Crohn's disease treatment guidelines. The annual aggregate economic burden of CD was $6.3 billion in the US. Respondents with CD had higher total (+$6442; 95% CI: $4864 to $8297), prescription (+$3283; 95% CI: $2289 to $4445), inpatient (+$1764; 95% CI: $748 to $3551), and outpatient (+$1191; 95% CI: $592 to $2160) expenditures compared to respondents without CD. In the difference-in-differences estimation, respondents with CD had significantly higher total (P = 0.001) and prescription (P < 0.001) expenditures compared with respondents without CD. Although inpatient and outpatient expenditures were higher in respondents with CD, they were not statistically significant. Respondents with CD diagnosis had higher expenditures compared to respondents without CD diagnosis from 2003 to 2013. This study captured the most recent availability of new treatment options and changes to treatment guidelines, while providing updated estimates of the economic burden of CD in the US. However, this research was unable to study the causes of these increased health care expenditures in respondents with CD. Future investigations will need to determine the causal factors for increased expenditures in CD. Copyright © 2016 Elsevier Inc. All rights reserved.

Prevalence of inflammatory bowel disease in two districts of Sri Lanka: a hospital based survey

PubMed Central

2010-01-01

Background Inflammatory bowel disease (IBD) is being increasingly diagnosed in Asia. However there are few epidemiological data from the region. Methods To determine prevalence and clinical characteristics of IBD, a hospital-based survey was performed in the Colombo and Gampaha districts (combined population 4.5 million) in Sri Lanka. Patients with established ulcerative colitis (UC) and Crohn's disease (CD), who were permanent residents of these adjoining districts, were recruited from hospital registries and out-patient clinics. Clinical information was obtained from medical records and patient interviews. Results There were 295 cases of IBD (UC = 240, CD = 55), of which 34 (UC = 30, CD = 4) were newly diagnosed during the study year. The prevalence rate for UC was 5.3/100,000 (95% CI 5.0-5.6/100,000), and CD was 1.2/100,000 (95% CI 1.0-1.4/100,000). The incidence rates were 0.69/100,000 (95% CI 0.44-0.94/100,000) for UC and 0.09/100,000 (95% CI 0.002-0.18/100,000) for CD. Female:male ratios were 1.5 for UC and 1.0 for CD. Mean age at diagnosis was (males and females) 36.6 and 38.1y for UC and 33.4 and 36.2y for CD. Among UC patients, 51.1% had proctitis and at presentation 58.4% had mild disease. 80% of CD patients had only large bowel involvement. Few patients had undergone surgery. Conclusions The prevalence of IBD in this population was low compared to Western populations, but similar to some in Asia. There was a female preponderance for UC. UC was mainly mild, distal or left-sided, while CD mainly involved the large bowel. PMID:20302651

Immune phenotype in children with therapy-naïve remitted and relapsed Crohn’s disease

PubMed Central

Cseh, Aron; Vasarhelyi, Barna; Molnar, Kriszta; Szalay, Balazs; Svec, Peter; Treszl, Andras; Dezsofi, Antal; Lakatos, Peter Laszlo; Arato, Andras; Tulassay, Tivadar; Veres, Gabor

2010-01-01

AIM: To characterize the prevalence of subpopulations of CD4+ cells along with that of major inhibitor or stimulator cell types in therapy-naïve childhood Crohn’s disease (CD) and to test whether abnormalities of immune phenotype are normalized with the improvement of clinical signs and symptoms of disease. METHODS: We enrolled 26 pediatric patients with CD. 14 therapy-naïve CD children; of those, 10 children remitted on conventional therapy and formed the remission group. We also tested another group of 12 children who relapsed with conventional therapy and were given infliximab; and 15 healthy children who served as controls. The prevalence of Th1 and Th2, naïve and memory, activated and regulatory T cells, along with the members of innate immunity such as natural killer (NK), NK-T, myeloid and plasmocytoid dendritic cells (DCs), monocytes and Toll-like receptor (TLR)-2 and TLR-4 expression were determined in peripheral blood samples. RESULTS: Children with therapy-naïve CD and those in relapse showed a decrease in Th1 cell prevalence. Simultaneously, an increased prevalence of memory and activated lymphocytes along with that of DCs and monocytes was observed. In addition, the ratio of myeloid /plasmocytoid DCs and the prevalence of TLR-2 or TLR-4 positive DCs and monocytes were also higher in therapy-naïve CD than in controls. The majority of alterations diminished in remitted CD irrespective of whether remission was obtained by conventional or biological therapy. CONCLUSION: The finding that immune phenotype is normalized in remission suggests a link between immune phenotype and disease activity in childhood CD. Our observations support the involvement of members of the adaptive and innate immune systems in childhood CD. PMID:21157977

Evolution of disease phenotype in adult and pediatric onset Crohn’s disease in a population-based cohort

PubMed Central

Lovasz, Barbara Dorottya; Lakatos, Laszlo; Horvath, Agnes; Szita, Istvan; Pandur, Tunde; Mandel, Michael; Vegh, Zsuzsanna; Golovics, Petra Anna; Mester, Gabor; Balogh, Mihaly; Molnar, Csaba; Komaromi, Erzsebet; Kiss, Lajos Sandor; Lakatos, Peter Laszlo

2013-01-01

AIM: To investigate the evolution of disease phenotype in adult and pediatric onset Crohn’s disease (CD) populations, diagnosed between 1977 and 2008. METHODS: Data of 506 incident CD patients were analyzed (age at diagnosis: 28.5 years, interquartile range: 22-38 years). Both in- and outpatient records were collected prospectively with a complete clinical follow-up and comprehensively reviewed in the population-based Veszprem province database, which included incident patients diagnosed between January 1, 1977 and December 31, 2008 in adult and pediatric onset CD populations. Disease phenotype according to the Montreal classification and long-term disease course was analysed according to the age at onset in time-dependent univariate and multivariate analysis. RESULTS: Among this population-based cohort, seventy-four (12.8%) pediatric-onset CD patients were identified (diagnosed ≤ 17 years of age). There was no significant difference in the distribution of disease behavior between pediatric (B1: 62%, B2: 15%, B3: 23%) and adult-onset CD patients (B1: 56%, B2: 21%, B3: 23%) at diagnosis, or during follow-up. Overall, the probability of developing complicated disease behaviour was 49.7% and 61.3% in the pediatric and 55.1% and 62.4% in the adult onset patients after 5- and 10-years of follow-up. Similarly, time to change in disease behaviour from non stricturing, non penetrating (B1) to complicated, stricturing or penetrating (B2/B3) disease was not significantly different between pediatric and adult onset CD in a Kaplan-Meier analysis. Calendar year of diagnosis (P = 0.04), ileal location (P < 0.001), perianal disease (P < 0.001), smoking (P = 0.038) and need for steroids (P < 0.001) were associated with presence of, or progression to, complicated disease behavior at diagnosis and during follow-up. A change in disease location was observed in 8.9% of patients and it was associated with smoking status (P = 0.01), but not with age at diagnosis. CONCLUSION: Long-term evolution of disease behavior was not different in pediatric- and adult-onset CD patients in this population-based cohort but was associated to location, perianal disease and smoking status. PMID:23599648

Associations of hormonal contraceptive use with measures of HIV disease progression and antiretroviral therapy effectiveness.

PubMed

Whiteman, Maura K; Jeng, Gary; Samarina, Anna; Akatova, Natalia; Martirosyan, Margarita; Kissin, Dmitry M; Curtis, Kathryn M; Marchbanks, Polly A; Hillis, Susan D; Mandel, Michele G; Jamieson, Denise J

2016-01-01

To examine the associations between hormonal contraceptive use and measures of HIV disease progression and antiretroviral treatment (ART) effectiveness. A prospective cohort study of women with prevalent HIV infection in St. Petersburg, Russia, was conducted. After contraceptive counseling, participants chose to use combined oral contraceptives (COCs), depot-medroxyprogesterone acetate (DMPA), a copper intrauterine device (IUD) or male condoms for pregnancy prevention. Among participants not using ART at enrollment, we used multivariate Cox regression to assess the association between current (time-varying) contraceptive use and disease progression, measured by the primary composite outcome of CD4 decline to <350 cells/mm(3), ART initiation or death. Among participants using ART at enrollment, we used linear mixed models to estimate the predicted mean CD4 change at select time points by contraceptive method. During a total of 5233 months follow-up among participants not using ART with enrollment CD4 ≥350 cells/mm(3) (n=315), 97 experienced disease progression. Neither current use of COCs [adjusted hazard ratio (aHR) 0.91, 95% confidence interval (CI) 0.56-1.48] nor DMPA (aHR 1.28, 95% CI 0.71-2.31) was associated with a statistically significant increased risk for disease progression compared with use of nonhormonal methods (IUD or condoms). Among participants using ART at enrollment (n=77), we found no statistically significant differences in the predicted mean changes in CD4 cell count comparing current use of COCs (p=.1) or DMPA (p=.3) with nonhormonal methods. Hormonal contraceptive use was not significantly associated with measures of HIV disease progression or ART effectiveness among women with prevalent HIV infection. Hormonal contraceptive use was not significantly associated with measures of HIV disease progression or ART effectiveness among women with prevalent HIV infection. Published by Elsevier Inc.

Targeting CD4+ T cells for the treatment of sarcoidosis: a promising strategy?

PubMed Central

Celada, Lindsay J; Drake, Wonder P

2017-01-01

Sarcoidois is an inflammatory disease of unknown origin characterized by the abnormal accumulation of noncaseating granulomas at sites of disease activity in multiple organs throughout the body with a predilection for the lungs. Because the exact trigger that leads to disease activity is still under investigation, current treatment options are contingent on the organ or organs affected. Corticosteroids are the therapy of choice, but antimalarials and TNF-α antagonists are also commonly prescribed. Recent findings provide evidence for the use of CD20 B-cell-depleting therapy as an alternative method of choice. However, because sarcoidosis is predominantly a T-helper cell-driven disorder, an overwhelming amount of compelling evidence exists for the use of CD4+ T-cell targeted therapy. PMID:25572480

Toward the Clonotype Analysis of Alopecia Areata-Specific, Intralesional Human CD8+ T Lymphocytes.

PubMed

Bertolini, Marta; Uchida, Youhei; Paus, Ralf

2015-11-01

Alopecia areata (AA) is an organ-restricted autoimmune disease that mainly affects the hair follicle (HF). Several findings support a key primary effector role of CD8+ T cells in the disease pathogenesis. Autoreactive CD8+ T cells are not only present in the characteristic peribulbar inflammatory cell infiltrate of lesional AA HFs but are also found to be infiltrating in lesional HF epithelium where they are thought to recognize major histocompatibility complex class I-presented (auto-)antigens. However, the latter still remain unidentified. Therefore, one key aim in AA research is to identify the clonotypes of autoaggressive, intralesional CD8+ T cells. Therapeutically, this is important (a) so that these lymphocytes can be selectively eliminated or inhibited, (b) to identify the-as yet elusive-key (auto-)antigens in AA, and/or (c) to induce peripheral tolerance against the latter. Therefore, we have recently embarked on a National Alopecia Areata Foundation-supported project that attempts to isolate disease-specific, intralesional CD8+ T cells from AA skin in order to determine their TCR clonotype, using two complementary strategies. The first method is based on the enzymatic skin digestion from lesional AA skin, followed by either MACS technology and single-cell picking or FACS cell sorting, while the second method on laser microdissection. The identification of disease-specific TCRs can serve as a basis for specific AA immunotherapy along the lines sketched above and may possibly also provide prognostic biomarkers. If successful, this research strategy promises to permit, at long last, the causal therapy of AA.

Variable outcome in infantile-onset inflammatory bowel disease in an Asian cohort

PubMed Central

Lee, Way Seah; Ng, Ruey Terng; Chan, Koon-Wing; Lau, Yu-Lung

2016-01-01

AIM Infantile-onset inflammatory bowel disease (IO-IBD) with the onset of disease before 12 mo of age, is a different disease entity from childhood IBD. We aimed to describe the clinical features, outcome and role of mutation in interleukin-10 (IL-10) and interleukin-10 receptors (IL-10R) in Asian children with IO-IBD. METHODS All cases of IO-IBD, defined as onset of disease before 12 mo of age, seen at University Malaya Medical Center, Malaysia were reviewed. We performed mutational analysis for IL10 and IL10R genes in patients with presenting clinical features of Crohn’s disease (CD). RESULTS Six [13%; CD = 3, ulcerative colitis (UC) = 2, IBD-unclassified (IBD-U) = 1] of the 48 children (CD = 25; UC = 23) with IBD have IO-IBD. At final review [median (range) duration of follow-up: 6.5 (3.0-20) years], three patients were in remission without immunosuppression [one each for post-colostomy (IBD-U), after standard immunosuppression (CD), and after total colectomy (UC)]. Three patients were on immunosuppression: one (UC) was in remission while two (both CD) had persistent disease. As compared with later-onset disease, IO-IBD were more likely to present with bloody diarrhea (100% vs 55%, P = 0.039) but were similar in terms of an associated autoimmune liver disease (0% vs 19%, P = 0.31), requiring biologics therapy (50% vs 36%, P = 0.40), surgery (50% vs 29%, P = 0.27), or achieving remission (50% vs 64%, P = 0.40). No mutations in either IL10 or IL10R in the three patients with CD and the only patient with IBD-U were identified. CONCLUSION The clinical features of IO-IBD in this Asian cohort of children who were negative for IL-10 or IL-10R mutations were variable. As compared to childhood IBD with onset of disease after 12 mo of age, IO-IBD achieved remission at a similar rate. PMID:28082818

Increased peripheral blood CD4+ T cell responses to deamidated but not to native gliadin in children with coeliac disease

PubMed Central

Lammi, A; Arikoski, P; Vaarala, O; Kinnunen, T; Ilonen, J

2012-01-01

T cell recognition of gliadin from dietary gluten is essential for the pathogenesis of coeliac disease (CD). The aim of the present study was to analyse whether gliadin-specific T cells are detectable in the circulation of children with newly diagnosed coeliac disease by using a sensitive carboxfluorescein diacetate succinimidyl ester (CFSE) dilution method. Peripheral blood CD4+ T cell responses were analysed in 20 children at diagnosis of CD and compared to those in 64 healthy control children carrying the CD-associated human leucocyte antigen (HLA)-DQ2 or -DQ8 alleles. Deamidated gliadin (gTG)-specific T cells were detectable in the peripheral blood of more than half the children with CD (11 of 20, 55%) compared to 15 of 64 (23·4%) of the control children (P = 0·008). Proliferative responses to gTG were also significantly stronger in children with CD than in controls (P = 0·01). In contrast, T cells specific to native gliadin were detectable at comparable frequencies in children with CD (two of 19, 10·5%) and controls (13 of 64, 20·3%). gTG-specific T cells had a memory phenotype more often than those specific to native gliadin in children with CD (P = 0·02), whereas controls had similar percentages of memory cells in both stimulations. Finally, gTG-specific CD4+ T cells had a higher expression of the gut-homing molecule β7 integrin than those specific to the control antigen tetanus toxoid. Collectively, our current results demonstrate that the frequency of circulating memory CD4+ T cells specific to gTG but not native gliadin is increased in children with newly diagnosed CD. PMID:22471282

Increased peripheral blood CD4+ T cell responses to deamidated but not to native gliadin in children with coeliac disease.

PubMed

Lammi, A; Arikoski, P; Vaarala, O; Kinnunen, T; Ilonen, J

2012-05-01

T cell recognition of gliadin from dietary gluten is essential for the pathogenesis of coeliac disease (CD). The aim of the present study was to analyse whether gliadin-specific T cells are detectable in the circulation of children with newly diagnosed coeliac disease by using a sensitive carboxfluorescein diacetate succinimidyl ester (CFSE) dilution method. Peripheral blood CD4(+) T cell responses were analysed in 20 children at diagnosis of CD and compared to those in 64 healthy control children carrying the CD-associated human leucocyte antigen (HLA)-DQ2 or -DQ8 alleles. Deamidated gliadin (gTG)-specific T cells were detectable in the peripheral blood of more than half the children with CD (11 of 20, 55%) compared to 15 of 64 (23.4%) of the control children (P = 0.008). Proliferative responses to gTG were also significantly stronger in children with CD than in controls (P = 0.01). In contrast, T cells specific to native gliadin were detectable at comparable frequencies in children with CD (two of 19, 10.5%) and controls (13 of 64, 20.3%). gTG-specific T cells had a memory phenotype more often than those specific to native gliadin in children with CD (P = 0.02), whereas controls had similar percentages of memory cells in both stimulations. Finally, gTG-specific CD4(+) T cells had a higher expression of the gut-homing molecule β7 integrin than those specific to the control antigen tetanus toxoid. Collectively, our current results demonstrate that the frequency of circulating memory CD4(+) T cells specific to gTG but not native gliadin is increased in children with newly diagnosed CD. © 2012 The Authors;Clinical and Experimental Immunology © 2012 British Society for Immunology.

Diagnostic sensitivity and specificity of a participatory disease surveillance method for highly pathogenic avian influenza in household chicken flocks in Indonesia.

PubMed

Robyn, M; Priyono, W B; Kim, L M; Brum, E

2012-06-01

A study was conducted to assess the diagnostic sensitivity and specificity of a disease surveillance method for diagnosis of highly pathogenic avian influenza (HPAI) outbreaks in household chicken flocks used by participatory disease surveillance (PDS) teams in Yogyakarta Province, Indonesia. The Government of Indonesia, in partnership with the Food and Agriculture Organization of the United Nations, has implemented a PDS method for the detection of HPAI outbreaks in poultry since 2006. The PDS method in Indonesia utilizes both a clinical case definition (CD) and the result of a commercial rapid antigen test kit Yogyakarta 55611, to diagnose HPAI outbreaks, primarily in backyard chicken flocks. The following diagnostic sensitivities and specificities were obtained relative to real-time reverse transcription-PCR as the gold standard diagnostic test: 1) 89% sensitivity (CI95: 75%-97%) and 96% specificity (CI95: 89%-99%) for the PDS CD alone; 2) 86% sensitivity (CI95: 71%-95%) and 99% specificity (CI95: 94%-100%) for the rapid antigen test alone; and 3) 84% sensitivity (CI95: 68%-94%) and 100% specificity (CI95: 96%-100%) for the PDS CD result combined with the rapid antigen test result. Based on these results, HPAI outbreaks in extensively raised household chickens can be diagnosed with sufficient sensitivity and specificity using the PDS method as implemented in Indonesia. Subject to further field evaluation, data from this study suggest that the diagnostic sensitivity of the PDS method may be improved by expanding the PDS CD to include more possible clinical presentations of HPAI and by increasing the number of rapid antigen tests to three different birds with HPAI-compatible signs of same flock.

Soluble CD40 ligand in prediction of acute severe pancreatitis

PubMed Central

Frossard, Jean Louis; Morel, Philippe; Kwak, Brenda; Pastor, Catherine; Berney, Thierry; Buhler, Léo; Von Laufen, Alain; Demulder, Sandrine; Mach, Francois

2006-01-01

AIM: To assess the early predictability of the soluble CD40L (sCD40L) in pancreatitis severity. METHODS: Between February 2000 and February 2003, 279 consecutive patients with acute pancreatitis were prospectively enrolled in our study. In this report, 40 patients with mild and 40 patients with severe pancreatitis were randomly studied. sCD40L concentrations were measured 48 hours after admission. RESULTS: sCD40L levels were significantly higher 48 hours after admission in severe pancreatitis than in mild pancreatitis. Using a cutoff of 1 000 pg/L, the sensitivity and specificity of sCD40L to detect a severe course of the disease were 78% and 62% respectively compared to 72% and 81% for CRP. Logistic regression analysis found that CRP was the only statistically significant marker able to detect a severe course of the disease. CONCLUSION: These findings indicate that CRP remains a valuable marker to determine the severity and prognosis of acute pancreatitis whereas sCD40L levels should be assessed in further studies. PMID:16570356

Genome-wide association study for Crohn's disease in the Quebec Founder Population identifies multiple validated disease loci.

PubMed

Raelson, John V; Little, Randall D; Ruether, Andreas; Fournier, Hélène; Paquin, Bruno; Van Eerdewegh, Paul; Bradley, W E C; Croteau, Pascal; Nguyen-Huu, Quynh; Segal, Jonathan; Debrus, Sophie; Allard, René; Rosenstiel, Philip; Franke, Andre; Jacobs, Gunnar; Nikolaus, Susanna; Vidal, Jean-Michel; Szego, Peter; Laplante, Nathalie; Clark, Hilary F; Paulussen, René J; Hooper, John W; Keith, Tim P; Belouchi, Abdelmajid; Schreiber, Stefan

2007-09-11

Genome-wide association (GWA) studies offer a powerful unbiased method for the identification of multiple susceptibility genes for complex diseases. Here we report the results of a GWA study for Crohn's disease (CD) using family trios from the Quebec Founder Population (QFP). Haplotype-based association analyses identified multiple regions associated with the disease that met the criteria for genome-wide significance, with many containing a gene whose function appears relevant to CD. A proportion of these were replicated in two independent German Caucasian samples, including the established CD loci NOD2 and IBD5. The recently described IL23R locus was also identified and replicated. For this region, multiple individuals with all major haplotypes in the QFP were sequenced and extensive fine mapping performed to identify risk and protective alleles. Several additional loci, including a region on 3p21 containing several plausible candidate genes, a region near JAKMIP1 on 4p16.1, and two larger regions on chromosome 17 were replicated. Together with previously published loci, the spectrum of CD genes identified to date involves biochemical networks that affect epithelial defense mechanisms, innate and adaptive immune response, and the repair or remodeling of tissue.

Presence of DQ2.2 Associated with DQ2.5 Increases the Risk for Celiac Disease

PubMed Central

Almeida, Lucas Malta; Gandolfi, Lenora; Pratesi, Riccardo; Uenishi, Rosa Harumi; de Almeida, Fernanda Coutinho; Selleski, Nicole

2016-01-01

Background. Celiac disease (CD) is a genetically determined immune-mediated disorder in which gluten immunogenic peptides are presented to CD4 T cells by HLA-DQ2.5, DQ8, DQ2.2, and their combinations. Our aim is to establish a risk gradient for celiac disease based on HLA-DQ profile in a brazilian representative population and the relevance of DQ2.2 in celiac disease development. Materials and Methods. 237 celiac patients and 237 controls (both groups with 164 females and 73 males) were included. All samples were tested for the presence of predisposing HLA-DQ alleles using the PCR-SSP method. Results were considered significant when p < 0.05. Disease risk was expressed as 1 : N for each HLA-DQ category described at this study. Results. DQ2.5 and/or DQ8 were detected in 224 celiac patients (94.5%) and 84 controls (35.4%). Eight celiac patients (3.4%) and 38 controls (16%) disclosed only DQ2.2. Even though DQ2.2 (β2/β2 or β2/x) showed a low CD risk of 1 : 251 and 1 : 550, respectively, the genotype DQ2.5/DQ2.2 (β2/β2) showed high CD risk of 1 : 10 (p < 0.0001). The disease risk gradient ranged from 1 : 3014 to 1 : 7. Conclusion. Our study allowed the determination of a risk gradient for celiac disease development in at-risk population, showing that DQ2.2 variant was relevant when associated with DQ2.5. PMID:28042478

Effector T-cells are expanded in systemic lupus erythematosus patients with high disease activity and damage indexes.

PubMed

Piantoni, S; Regola, F; Zanola, A; Andreoli, L; Dall'Ara, F; Tincani, A; Airo', P

2018-01-01

Background and objectives T-cell activation may be one of the pathogenic mechanisms of systemic lupus erythematosus (SLE). After repeated antigenic stimulation, T-cells undergo different modifications, leading to the differentiation into effector memory T-cells (CCR7-CD45RA-) and terminally differentiated effector memory (TDEM) T-cells (CCR7-CD45RA+). Similarly, down-modulation of CD28 may lead to the expansion of the CD28- T-cells, a subpopulation with peculiar effector activities. The aim of this study was the characterization of T-cell phenotype in a cohort of patients with SLE according to disease activity and damage index. Materials and methods Phenotypic analysis of peripheral blood T lymphocytes of 51 SLE patients and 21 healthy controls was done by flow-cytometry. SLE disease activity was evaluated by SLE Disease Activity Index-2000 (SLEDAI-2K) and damage by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index (SDI). The variations between different groups were evaluated by Mann-Whitney test. Bonferroni correction was applied to adjust for multiple comparisons ( p adj ). Spearman rank test was used to evaluate the correlations between quantitative variables. Results CD4+ lymphopenia was found among SLE patients. Patients showed a trend for a higher percentage of TDEM among the CD4+ T-cell subpopulation in comparison with healthy controls ( p = .04). SLE patients were divided into two groups according to disease activity: patients with SLEDAI-2K ≥ 6 ( n = 13) had a higher percentage of circulating CD4+ T-cells with CD28- phenotype ( p adj  = .005) as well as those with an effector memory ( p adj  = .004) and TDEM ( p adj  = .002) phenotype and a trend of decrease of regulatory T-cells (TREGs) ( p = .02), in comparison with patients with low disease activity ( n = 38). Patients with damage (SDI ≥ 1) tended to show an expansion of TDEM among CD4+ T-cells as compared with patients with no damage ( p = .01). In SLE patients an inverse correlation was found between the percentages of TREGs and those of TDEM ( p < .01) or CD4 + CD28- ( p < .01) T-cells. Conclusions CD4+ T-cell subpopulations displaying phenotype characteristics of effector lymphocytes are proportionally expanded in patients with active SLE and a higher damage index. These findings may suggest a role of effector T-cells in the pathogenesis of the disease and in the mechanisms of damage in SLE.

IL-23 Receptor (IL-23R) Gene Protects Against Pediatric Crohn’s Disease

PubMed Central

Dubinsky, Marla C.; Wang, Dai; Picornell, Yoana; Wrobel, Iwona; Katzir, Lirona; Quiros, Antonio; Dutridge, Debra; Wahbeh, Ghassan; Silber, Gary; Bahar, Ron; Mengesha, Emebet; Targan, Stephan R.; Taylor, Kent D.; Rotter, Jerome I.

2007-01-01

Background The IL-23 receptor (IL-23R) has been found to be associated with small bowel Crohn’s disease (CD) in a whole genome association study. Specifically, the rare allele of the R381Q single nucleotide polymorphism (SNP) conferred protection against CD. It is unknown whether IL-23R is associated with IBD in children. The aim was to examine the association of IL-23R with susceptibility to IBD in pediatric patients. Methods DNA was collected from 609 subjects (151 CD and 52 ulcerative colitis [UC] trios). Trios were genotyped for the R381Q SNP of the IL-23R gene and SNP8, SNP12, SNP13, of the CARD15 gene using Taqman. The transmission disequilibrium test (TDT) was used for association to disease using GENEHUNTER 2.0. Results The rare allele of R381Q SNP was present in 2.7% of CD and 2.9% UC probands. The CARD15 frequency was 31.5% (CD) and 18% (UC). The IL-23R allele was negatively associated with inflammatory bowel disease (IBD): the R381Q SNP was undertransmitted in children with IBD (8 transmitted [T] versus 27 untransmitted [UT]; P = 0.001). This association was significant for all CD patients (6 T versus 19 UT; P = 0.009), especially for non-Jewish CD patients (2 T versus 17 UT; P = 0.0006). TDT showed a borderline association for UC (2 T versus 8 UT; P = 0.06). As expected, CARD15 was associated with CD in children by the TDT (58 T versus 22 UT P = 0.00006), but not with UC. Conclusions The protective IL-23R R381Q variant was particularly associated with CD in non-Jewish children. Thus, the initial whole genome association study based on ileal CD in adults has been extended to the pediatric population and beyond small bowel CD. PMID:17309073

Polymorphisms in the Toll-Like Receptor and the IL-23/IL-17 Pathways Were Associated with Susceptibility to Inflammatory Bowel Disease in a Danish Cohort

PubMed Central

Bank, Steffen; Andersen, Paal Skytt; Burisch, Johan; Pedersen, Natalia; Roug, Stine; Galsgaard, Julied; Ydegaard Turino, Stine; Broder Brodersen, Jacob; Rashid, Shaista; Kaiser Rasmussen, Britt; Avlund, Sara; Bastholm Olesen, Thomas; Hoffmann, Hans Jürgen; Andersen Nexø, Bjørn; Sode, Jacob; Vogel, Ulla; Andersen, Vibeke

2015-01-01

Background The inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC), result from the combined effects of susceptibility genes and environmental factors. Previous studies have shown that polymorphisms in the Toll-like receptor (TLR), the apoptosis, the IL-23/IL-17 and the interferon gamma (IFNG) pathways are associated with risk of both CD and UC. Methods Using a candidate gene approach, 21 functional single nucleotide polymorphisms (SNPs) in 15 genes were assessed in a clinical homogeneous group of severely diseased ethnic Danish patients consisting of 624 patients with CD, 411 patients with UC and 795 controls. The results were analysed using logistic regression. Results The polymorphisms TLR5 (rs5744174) and IL12B (rs6887695) were associated with risk of CD, and TLR1 (rs4833095) and IL18 (rs187238) were associated with risk of both CD and UC (p<0.05). After Bonferroni correction for multiple testing, the homozygous variant genotype of TLR1 743 T>C (rs4833095) was associated with increased risk CD (OR: 3.15, 95% CI: 1.59–6.26, p = 0.02) and CD and UC combined (OR: 2.96, 95% CI: 1.64–5.32, p = 0.005). Conclusion Our results suggest that genetically determined high activity of TLR1 and TLR5 was associated with increased risk of both CD and UC and CD, respectively. This supports that the host microbial composition or environmental factors in the gut are involved in risk of IBD. Furthermore, genetically determined high activity of the IL-23/IL-17 pathway was associated with increased risk of CD and UC. Overall, our results support that genetically determined high inflammatory response was associated with increased risk of both CD and UC. PMID:26698117

Evaluation of CD44 and CD133 as markers of liver cancer stem cells in Egyptian patients with HCV-induced chronic liver diseases versus hepatocellular carcinoma

PubMed Central

Rozeik, Mohammed Saeed; Hammam, Olfat Ali; Ali, Ali Ibrahim; Magdy, Mona; Khalil, Heba; Anas, Amgad; Abo el Hassan, Ahmed Abdelaleem; Rahim, Ali Abdel; El-Shabasy, Ahmed Ibrahim

2017-01-01

Background Cancer stem cells (CSCs) play a critical role in tumor development, progression, metastasis and recurrence. Aim To evaluate hepatic expression of CD44 and CD133 in Egyptian patients with HCV-induced chronic liver diseases and hepatocellular carcinomas (HCCs), and to assess its correlation with inflammatory activity scores, stages of fibrosis (in chronic hepatitis with or without cirrhosis) and grades of HCC. Methods This prospective case-control study was conducted on eighty subjects who attended the Tropical Diseases Department, Al-Azhar University Hospital, and in collaboration with Theodor Bilharz Research Institute (2014–2016). They were divided as follows: A) Control healthy group: Ten individuals with serologically negative HCV-Ab and HBsAg, and histopathologically normal liver, B) Seventy patients subdivided into 3 groups; Twenty subjects each, as: HCV-Ab+ non-cirrhotic, HCV-Ab+ cirrhotic and HCC. Necroinflammatory activity and fibrosis in non-neoplastic liver biopsies were scored according to the METAVIR scoring system. CD44 and CD133 immunostaining was evaluated in all groups semi-quantitatively using H score. Statistical analysis was performed by SPSS version 22, using independent-samples t-test. Results Our study showed a significant increase of mean CD44 & CD133 expression values with disease progression among the groups (p<0.05). Their expressions increased significantly with the inflammatory activity scores and stages of fibrosis, reaching the highest values in A3F4 score compared to A1F1 (p<0.05). Moreover, there was a significant increase of their expressions across HCC grades (p<0.05), however with no significant correlation with focal lesions size. Conclusion CSCs clusters exhibiting CD133+ and/or CD44+ profiles were identified in chronic hepatitis, liver cirrhosis and HCC. CD133 and CD44 expressions significantly corresponded to the increased inflammatory activity, fibrosis stages and higher tumor grades. Therefore, evaluation of CD44 and CD133 expression profiles as CSCs markers in non-neoplastic liver and HCCs can help in development of novel therapeutic agents for HCC targeting and prevention. PMID:28894525

Vitamin D increases programmed death receptor-1 expression in Crohn’s disease

PubMed Central

Bendix, Mia; Greisen, Stinne; Dige, Anders; Hvas, Christian L.; Bak, Nina; Jørgensen, Søren P.; Dahlerup, Jens F.; Deleuran, Bent; Agnholt, Jørgen

2017-01-01

Background: Vitamin D modulates inflammation in Crohns disease (CD). Programmed death (PD)-1 receptor contributes to the maintenance of immune tolerance. Vitamin D might modulate PD-1 signalling in CD. Aim: To investigate PD-1 expression on T cell subsets in CD patients treated with vitamin D or placebo. Methods: We included 40 CD patients who received 1200 IU vitamin D3 for 26 weeks or placebo and eight healthy controls. Peripheral blood mononuclear cells (PBMCs) and plasma were isolated at baseline and week 26. The expressions of PD-1, PD-L1, and surface activation markers were analysed by flow cytometry. Soluble PD-1 plasma levels were measured by ELISA. Results: PD-1 expression upon T cell stimulation was increased in CD4+CD25+int T cells in vitamin D treated CD patients from 19% (range 10 39%) to 29% (11 79%)(p = 0.03) compared with placebo-treated patients. Vitamin D treatment, but not placebo, decreased the expression of the T cell activation marker CD69 from 42% (31 62%) to 33% (19 - 54%)(p = 0.01). Soluble PD-1 levels were not influenced by vitamin D treatment. Conclusions: Vitamin D treatment increases CD4+CD25+int T cells ability to up-regulate PD-1 in response to activation and reduces the CD69 expression in CD patients. PMID:28412753

GFP Labeling and Hepatic Differentiation Potential of Human Placenta-Derived Mesenchymal Stem Cells.

PubMed

Yu, Jiong; Su, Xiaoru; Zhu, Chengxing; Pan, Qiaoling; Yang, Jinfeng; Ma, Jing; Shen, Leyao; Cao, Hongcui; Li, Lanjuan

2015-01-01

Stem cell-based therapy in liver diseases has received increasing interest over the past decade, but direct evidence of the homing and implantation of transplanted cells is conflicting. Reliable labeling and tracking techniques are essential but lacking. The purpose of this study was to establish human placenta-derived mesenchymal stem cells (hPMSCs) expressing green fluorescent protein (GFP) and to assay their hepatic functional differentiation in vitro. The GFP gene was transduced into hPMSCs using a lentivirus to establish GFP(+) hPMSCs. GFP(+) hPMSCs were analyzed for their phenotypic profile, viability and adipogenic, osteogenic and hepatic differentiation. The derived GFP(+) hepatocyte-like cells were evaluated for their metabolic, synthetic and secretory functions, respectively. GFP(+) hPMSCs expressed high levels of HLA I, CD13, CD105, CD73, CD90, CD44 and CD29, but were negative for HLA II, CD45, CD31, CD34, CD133, CD271 and CD79. They possessed adipogenic, osteogenic and hepatic differentiation potential. Hepatocyte-like cells derived from GFP(+) hPMSCs showed typical hepatic phenotypes. GFP gene transduction has no adverse influences on the cellular or biochemical properties of hPMSCs or markers. GFP gene transduction using lentiviral vectors is a reliable labeling and tracking method. GFP(+) hPMSCs can therefore serve as a tool to investigate the mechanisms of MSC-based therapy, including hepatic disease therapy. © 2015 S. Karger AG, Basel.

Potential Linkage Between Cerebrovascular Diseases and Metabolic Syndrome.

PubMed

Jabir, Nasimudeen R; Firoz, Chelapram Kandy; Khan, Mohd Shahnawaz; Zaidi, Syed Kashif; Ashraf, Ghulam Md; Shakil, Shazi; Kamal, Mohammad Amjad; Tabrez, Shams

2017-01-01

Cerebrovascular disease (CD) and metabolic syndrome (MetS) are two devastating health dilemma that continues to be a potential contributor to disability and mortality in human population all across the world. Scientific data clearly shows several mechanistic similarities between these two co-existing and interlinked conditions. The linkage exacerbates ongoing patho-physiological condition towards more lethal events. In view of the presence of modifiable risk factors in both CD and MetS, their management holds potential therapeutic value. Hence, developing common treatment strategies for these diseases could involve common molecular agents. In this communication, we have summarized some of the common pathological conditions viz. abdominal obesity, insulin resistance, dyslipidemia, hypertension, and endothelial dysfunction that further deteriorate existing homeostasis in CD and MetS. Based on our article, it is advocated that substantial improvements in novel multi-targeted drug discovery could provide the effective treatment methods in order to avoid the fatal complications related with CD and MetS. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Evolution of Costs of Inflammatory Bowel Disease over Two Years of Follow-Up

PubMed Central

van der Valk, Mirthe E.; Mangen, Marie-Josée J.; Severs, Mirjam; van der Have, Mike; Dijkstra, Gerard; van Bodegraven, Ad A.; Fidder, Herma H.; de Jong, Dirk J.; van der Woude, C. Janneke; Romberg-Camps, Mariëlle J. L.; Clemens, Cees H. M.; Jansen, Jeroen M.; van de Meeberg, Paul C.; Mahmmod, Nofel; van der Meulen-de Jong, Andrea E.; Ponsioen, Cyriel Y.; Bolwerk, Clemens; Vermeijden, J. Reinoud; Siersema, Peter D.; Leenders, Max; Oldenburg, Bas

2016-01-01

Background With the increasing use of anti-TNF therapy in inflammatory bowel disease (IBD), a shift of costs has been observed with medication costs replacing hospitalization and surgery as major cost driver. We aimed to explore the evolution of IBD-related costs over two years of follow-up. Methods and Findings In total 1,307 Crohn's disease (CD) patients and 915 ulcerative colitis (UC) patients were prospectively followed for two years by three-monthly web-based questionnaires. Changes of healthcare costs, productivity costs and out-of-pocket costs over time were assessed using mixed model analysis. Multivariable logistic regression analysis was used to identify costs drivers. In total 737 CD patients and 566 UC were included. Total costs were stable over two years of follow-up, with annual total costs of €7,835 in CD and €3,600 in UC. However, within healthcare costs, the proportion of anti-TNF therapy-related costs increased from 64% to 72% in CD (p<0.01) and from 31% to 39% in UC (p < 0.01). In contrast, the proportion of hospitalization costs decreased from 19% to 13% in CD (p<0.01), and 22% to 15% in UC (p < 0.01). Penetrating disease course predicted an increase of healthcare costs (adjusted odds ratio (adj. OR) 1.95 (95% CI 1.02–3.37) in CD and age <40 years in UC (adj. OR 4.72 (95% CI 1.61–13.86)). Conclusions BD-related costs remained stable over two years. However, the proportion of anti-TNF-related healthcare costs increased, while hospitalization costs decreased. Factors associated with increased costs were penetrating disease course in CD and age <40 in UC. PMID:27099937

Clinical correlations of infliximab trough levels and antibodies to infliximab in South Korean patients with Crohn’s disease

PubMed Central

Oh, Eun Hye; Ko, Dae-Hyun; Seo, Hyungil; Chang, Kiju; Kim, Gwang-Un; Song, Eun Mi; Seo, Myeongsook; Lee, Ho-Su; Hwang, Sung Wook; Yang, Dong-Hoon; Ye, Byong Duk; Byeon, Jeong-Sik; Myung, Seung-Jae; Yang, Suk-Kyun; Park, Sang Hyoung

2017-01-01

AIM To investigate the clinical implications of infliximab trough levels (IFX-TLs) and antibodies to infliximab (ATI) levels in Crohn’s disease (CD) patients in Asian countries. METHODS IFX-TL and ATI level were measured using prospectively collected samples obtained with informed consent from CD patients being treated at Asan Medical Center, South Korea. We analyzed the correlations between IFX-TLs/ATI levels and the clinical activity of CD (quiescent vs active disease) based on the CD activity index, C-reactive protein level, and physician’s judgment of patients’ clinical status at enrollment. The impact of concomitant immunomodulators was also investigated. RESULTS This study enrolled 138 patients with CD (84 with quiescent and 54 with active disease). In patients with quiescent and active diseases, the median IFX-TLs were 1.423 μg/mL and 0.163 μg/mL, respectively (P < 0.001) and the median ATI levels were 8.064 AU/mL and 11.209 AU/mL, respectively (P < 0.001). In the ATI-negative and -positive groups, the median IFX-TLs were 1.415 μg/mL and 0.141 μg/mL, respectively (P < 0.001). In patients with and without concomitant immunomodulator use, there were no differences in IFX-TLs (0.632 μg/mL and 1.150 μg/mL, respectively; P = 0.274) or ATI levels (8.655 AU/mL and 9.017 AU/mL, respectively; P = 0.083). CONCLUSION IFX-TL/ATI levels were well correlated with the clinical activity in South Korean CD patients. Our findings support the usefulness of IFX-TLs/ATI levels in treating CD patients receiving IFX in clinical practice. PMID:28293096

Prognostic Indications of Elevated MCT4 and CD147 across Cancer Types: A Meta-Analysis

PubMed Central

Bovenzi, Cory D.; Hamilton, James; Tassone, Patrick; Johnson, Jennifer; Cognetti, David M.; Luginbuhl, Adam; Keane, William M.; Zhan, Tingting; Tuluc, Madalina; Bar-Ad, Voichita; Martinez-Outschoorn, Ubaldo; Curry, Joseph M.

2015-01-01

Background. Metabolism in the tumor microenvironment can play a critical role in tumorigenesis and tumor aggression. Metabolic coupling may occur between tumor compartments; this phenomenon can be prognostically significant and may be conserved across tumor types. Monocarboxylate transporters (MCTs) play an integral role in cellular metabolism via lactate transport and have been implicated in metabolic synergy in tumors. The transporters MCT1 and MCT4 are regulated via expression of their chaperone, CD147. Methods. We conducted a meta-analysis of existing publications on the relationship between MCT1, MCT4, and CD147 expression and overall survival and disease-free survival in cancer, using hazard ratios derived via multivariate Cox regression analyses. Results. Increased MCT4 expressions in the tumor microenvironment, cancer cells, or stromal cells were all associated with decreased overall survival and decreased disease-free survival (p < 0.001 for all analyses). Increased CD147 expression in cancer cells was associated with decreased overall survival and disease-free survival (p < 0.0001 for both analyses). Few studies were available on MCT1 expression; MCT1 expression was not clearly associated with overall or disease-free survival. Conclusion. MCT4 and CD147 expression correlate with worse prognosis across many cancer types. These results warrant further investigation of these associations. PMID:26779534

Screening for celiac disease in the general population and in high-risk groups

PubMed Central

Card, Timothy R; Kaukinen, Katri; Bai, Julio; Zingone, Fabiana; Sanders, David S; Murray, Joseph A

2015-01-01

Background Celiac disease (CD) occurs in approximately 1% of the Western population. It is a lifelong disorder that is associated with impaired quality of life (QOL) and an excessive risk of comorbidity and death. Objectives To review the literature on screening for CD in relation to the current World Health Organization (WHO) criteria for mass screening. Methods We performed a PubMed search to identify indexed papers on CD screening with a publication date from 1900 until 1 June 2014. When we deemed an abstract relevant, we read the corresponding paper in detail. Results CD fulfills several WHO criteria for mass screening (high prevalence, available treatment and difficult clinical detection), but it has not yet been established that treatment of asymptomatic CD may reduce the excessive risk of severe complications, leading to higher QOL nor that it is cost-effective. Conclusions Current evidence is not sufficient to support mass screening for CD, but active case-finding may be appropriate, as we recognize that most patients with CD will still be missed by this strategy. Although proof of benefit is still lacking, screening for CD may be appropriate in high-risk groups. PMID:25922671

Single Insulin-Specific CD8+ T Cells Show Characteristic Gene Expression Profiles in Human Type 1 Diabetes

PubMed Central

Luce, Sandrine; Lemonnier, François; Briand, Jean-Paul; Coste, Joel; Lahlou, Najiba; Muller, Sylviane; Larger, Etienne; Rocha, Benedita; Mallone, Roberto; Boitard, Christian

2011-01-01

OBJECTIVE Both the early steps and the high recurrence of autoimmunity once the disease is established are unexplained in human type 1 diabetes. Because CD8+ T cells are central and insulin is a key autoantigen in the disease process, our objective was to characterize HLA class I–restricted autoreactive CD8+ T cells specific for preproinsulin (PPI) in recent-onset and long-standing type 1 diabetic patients and healthy control subjects. RESEARCH DESIGN AND METHODS We used HLA-A*02:01 tetramers complexed to PPI peptides to enumerate circulating PPI-specific CD8+ T cells in patients and characterize them using membrane markers and single-cell PCR. RESULTS Most autoreactive CD8+ T cells detected in recent-onset type 1 diabetic patients are specific for leader sequence peptides, notably PPI6–14, whereas CD8+ T cells in long-standing patients recognize the B-chain peptide PPI33–42 (B9–18). Both CD8+ T-cell specificities are predominantly naïve, central, and effector memory cells, and their gene expression profile differs from cytomegalovirus-specific CD8+ T cells. PPI6–14–specific CD8+ T cells detected in one healthy control displayed Il-10 mRNA expression, which was not observed in diabetic patients. CONCLUSIONS PPI-specific CD8+ T cells in type 1 diabetic patients include central memory and target different epitopes in new-onset versus long-standing disease. Our data support the hypothesis that insulin therapy may contribute to the expansion of autoreactive CD8+ T cells in the long term. PMID:21998398

Salivary microbiota and metabolome associated with celiac disease.

PubMed

Francavilla, Ruggiero; Ercolini, Danilo; Piccolo, Maria; Vannini, Lucia; Siragusa, Sonya; De Filippis, Francesca; De Pasquale, Ilaria; Di Cagno, Raffaella; Di Toma, Michele; Gozzi, Giorgia; Serrazanetti, Diana I; De Angelis, Maria; Gobbetti, Marco

2014-06-01

This study aimed to investigate the salivary microbiota and metabolome of 13 children with celiac disease (CD) under a gluten-free diet (treated celiac disease [T-CD]). The same number of healthy children (HC) was used as controls. The salivary microbiota was analyzed by an integrated approach using culture-dependent and -independent methods. Metabolome analysis was carried out by gas chromatography-mass spectrometry-solid-phase microextraction. Compared to HC, the number of some cultivable bacterial groups (e.g., total anaerobes) significantly (P < 0.05) differed in the saliva samples of the T-CD children. As shown by community-level catabolic profiles, the highest Shannon's diversity and substrate richness were found in HC. Pyrosequencing data showed the highest richness estimator and diversity index values for HC. Levels of Lachnospiraceae, Gemellaceae, and Streptococcus sanguinis were highest for the T-CD children. Streptococcus thermophilus levels were markedly decreased in T-CD children. The saliva of T-CD children showed the largest amount of Bacteroidetes (e.g., Porphyromonas sp., Porphyromonas endodontalis, and Prevotella nanceiensis), together with the smallest amount of Actinobacteria. T-CD children were also characterized by decreased levels of some Actinomyces species, Atopobium species, and Corynebacterium durum. Rothia mucilaginosa was the only Actinobacteria species found at the highest level in T-CD children. As shown by multivariate statistical analyses, the levels of organic volatile compounds markedly differentiated T-CD children. Some compounds (e.g., ethyl-acetate, nonanal, and 2-hexanone) were found to be associated with T-CD children. Correlations (false discovery rate [FDR], <0.05) were found between the relative abundances of bacteria and some volatile organic compounds (VOCs). The findings of this study indicated that CD is associated with oral dysbiosis that could affect the oral metabolome.

Salivary Microbiota and Metabolome Associated with Celiac Disease

PubMed Central

Francavilla, Ruggiero; Ercolini, Danilo; Piccolo, Maria; Vannini, Lucia; Siragusa, Sonya; De Filippis, Francesca; De Pasquale, Ilaria; Di Cagno, Raffaella; Di Toma, Michele; Gozzi, Giorgia; Serrazanetti, Diana I.; Gobbetti, Marco

2014-01-01

This study aimed to investigate the salivary microbiota and metabolome of 13 children with celiac disease (CD) under a gluten-free diet (treated celiac disease [T-CD]). The same number of healthy children (HC) was used as controls. The salivary microbiota was analyzed by an integrated approach using culture-dependent and -independent methods. Metabolome analysis was carried out by gas chromatography-mass spectrometry–solid-phase microextraction. Compared to HC, the number of some cultivable bacterial groups (e.g., total anaerobes) significantly (P < 0.05) differed in the saliva samples of the T-CD children. As shown by community-level catabolic profiles, the highest Shannon's diversity and substrate richness were found in HC. Pyrosequencing data showed the highest richness estimator and diversity index values for HC. Levels of Lachnospiraceae, Gemellaceae, and Streptococcus sanguinis were highest for the T-CD children. Streptococcus thermophilus levels were markedly decreased in T-CD children. The saliva of T-CD children showed the largest amount of Bacteroidetes (e.g., Porphyromonas sp., Porphyromonas endodontalis, and Prevotella nanceiensis), together with the smallest amount of Actinobacteria. T-CD children were also characterized by decreased levels of some Actinomyces species, Atopobium species, and Corynebacterium durum. Rothia mucilaginosa was the only Actinobacteria species found at the highest level in T-CD children. As shown by multivariate statistical analyses, the levels of organic volatile compounds markedly differentiated T-CD children. Some compounds (e.g., ethyl-acetate, nonanal, and 2-hexanone) were found to be associated with T-CD children. Correlations (false discovery rate [FDR], <0.05) were found between the relative abundances of bacteria and some volatile organic compounds (VOCs). The findings of this study indicated that CD is associated with oral dysbiosis that could affect the oral metabolome. PMID:24657864

Season of Birth in a Nationwide Cohort of Coeliac Disease Patients

PubMed Central

Lebwohl, Benjamin; Green, Peter HR; Murray, Joseph A.; Ludvigsson, Jonas F.

2013-01-01

Background and objective Genetic factors alone cannot explain the risk of developing coeliac disease (CD). Children born in summer months are likely to be weaned and introduced to gluten during winter when viral infections are more frequent. Earlier studies on birth season and CD are limited in sample size and results are contradictory. Method Case-control study. We used biopsy reports from all 28 Swedish pathology departments to identify individuals with CD, defined as small intestinal villous atrophy (n=29,096). The government agency Statistics Sweden then identified 144,522 controls matched for gender, age, calendar year and county. Through conditional logistic regression we examined the association between summer birth (March-August) and later CD diagnosis (outcome measure). Results Some 54.10% of individuals with CD vs. 52.75% of controls were born in the summer months. Summer birth was hence associated with a small increased risk of later CD (Odds ratio: 1.06; 95%CI=1.03–1.08; p<0.0001). Stratifying CD patients according to age at diagnosis, we found the highest OR in those diagnosed before age 2 years (OR=1.17; 95%CI=1.10–1.26), while summer birth was not associated with a CD diagnosis in later childhood (age 2–18 years: OR=1.02; 95%CI=0.97–1.08), but had a marginal effect on the risk of CD in adulthood (age ≥18years: OR=1.04; 95%CI=1.01–1.07). Conclusions In this study, summer birth was associated with an increased risk of later CD, but the excess risk was small, and general infectious disease exposure early in life is unlikely to be a major cause of CD. PMID:23172784

CD4+ CD25+ CD127low Regulatory T Cells as Indicator of Rheumatoid Arthritis Disease Activity.

PubMed

Khattab, Sahar S; El-Saied, Amany M; Mohammed, Rehab A; Mohamed, Eman E

2016-06-01

Rheumatoid arthritis (RA) is an autoimmune disease characterized by disturbed immune regulation, inducing a progressive cartilage and bone destruction. Despite enrichment of T regulatory cell (T-regs) in synovial fluid, conflicting results are reported concerning T-regs in peripheral blood (PB) of RA patients. To determine possible correlation between the frequency of PB CD4+ CD25+CD127low (T-regs) with RA disease activity. Forty females with RA, classified according to the Disease Activity Score 28 (DAS-28), as highly active, mild-moderate or low disease activity; and 20 age and sex matched healthy controls, were enrolled to study CD4+ CD25+ CD127low T- regs in PB by flow cytometry. Active RA patients had lower frequency of the CD4+ CD25+ CD127low T- regs compared to those with mild-moderate or low disease activity (P <0.001). The frequencies of the T- regs showed negative correlation with the DAS-28 (P<0.01). In conclusion, CD4+ CD25+ CD127low T-regs is significantly lower in highly active RA patients compared to patients with lower activity or controls. Copyright© by the Egyptian Association of Immunologists.

A pilot study examining the relationship among Crohn disease activity, glucagon-like peptide-2 signalling and intestinal function in pediatric patients

PubMed Central

Sigalet, David L; Kravarusic, Dragan; Butzner, Decker; Hartmann, Bolette; Holst, Jens J; Meddings, Jon

2013-01-01

BACKGROUND/OBJECTIVES: The relationship between the enteroendocrine hormone glucagon-like peptide 2 (GLP-2) and intestinal inflammation is unclear. GLP-2 promotes mucosal growth, decreases permeability and reduces inflammation in the intestine; physiological stimulation of GLP-2 release is triggered by nutrient contact. The authors hypothesized that ileal Crohn disease (CD) affects GLP-2 release. METHODS: With ethics board approval, pediatric patients hospitalized with CD were studied; controls were recruited from local schools. Inclusion criteria were endoscopy-confirmed CD (primarily of the small intestine) with a disease activity index >150. Fasting and post-prandial GLP-2 levels and quantitative urinary recovery of orally administered 3-O-methyl-glucose (active transport) and lactulose/mannitol (passive) were quantified during the acute and remission phases. RESULTS: Seven patients (mean [± SD] age 15.3±1.3 years) and 10 controls (10.3±1.6 years) were studied. In patients with active disease, fasting levels of GLP-2 remained stable but postprandial levels were reduced. Patients with active disease exhibited reduced glucose absorption and increased lactulose/mannitol recovery; all normalized with disease remission. The change in the lactulose/mannitol ratio was due to both reduced lactulose and increased mannitol absorption. CONCLUSIONS: These findings suggest that pediatric patients with acute ileal CD have decreased postprandial GLP-2 release, reduced glucose absorption and increased intestinal permeability. Healing of CD resulted in normalization of postprandial GLP-2 release and mucosal functioning (nutrient absorption and permeability), the latter due to an increase in mucosal surface area. These findings have implications for the use of GLP-2 and feeding strategies as a therapy in CD patients; further studies of the effects of inflammation and the GLP-2 axis are recommended. PMID:24106731

Crohn's disease: increased mortality 10 years after diagnosis in a Europe‐wide population based cohort

PubMed Central

Wolters, F L; Russel, M G; Sijbrandij, J; Schouten, L J; Odes, S; Riis, L; Munkholm, P; Bodini, P; O'Morain, C; Mouzas, I A; Tsianos, E; Vermeire, S; Monteiro, E; Limonard, C; Vatn, M; Fornaciari, G; Pereira, S; Moum, B; Stockbrügger, R W

2006-01-01

Background No previous correlation between phenotype at diagnosis of Crohn's disease (CD) and mortality has been performed. We assessed the predictive value of phenotype at diagnosis on overall and disease related mortality in a European cohort of CD patients. Methods Overall and disease related mortality were recorded 10 years after diagnosis in a prospectively assembled, uniformly diagnosed European population based inception cohort of 380 CD patients diagnosed between 1991 and 1993. Standardised mortality ratios (SMRs) were calculated for geographic and phenotypic subgroups at diagnosis. Results Thirty seven deaths were observed in the entire cohort whereas 21.5 deaths were expected (SMR 1.85 (95% CI 1.30–2.55)). Mortality risk was significantly increased in both females (SMR 1.93 (95% CI 1.10–3.14)) and males (SMR 1.79 (95% CI 1.11–2.73)). Patients from northern European centres had a significant overall increased mortality risk (SMR 2.04 (95% CI 1.32–3.01)) whereas a tendency towards increased overall mortality risk was also observed in the south (SMR 1.55 (95% CI 0.80–2.70)). Mortality risk was increased in patients with colonic disease location and with inflammatory disease behaviour at diagnosis. Mortality risk was also increased in the age group above 40 years at diagnosis for both total and CD related causes. Excess mortality was mainly due to gastrointestinal causes that were related to CD. Conclusions This European multinational population based study revealed an increased overall mortality risk in CD patients 10 years after diagnosis, and age above 40 years at diagnosis was found to be the sole factor associated with increased mortality risk. PMID:16150857

Risk of Idiopathic Dilated Cardiomyopathy in 29 000 Patients With Celiac Disease

PubMed Central

Emilsson, Louise; Andersson, Bert; Elfström, Peter; Green, Peter H.R.; Ludvigsson, Jonas F.

2012-01-01

Background Dilated cardiomyopathy (DCM) is a rare disease of largely unknown origin. Previous studies have suggested an increased prevalence of celiac disease (CD) in patients with DCM. These studies, however, were based on a maximum of 5 patients with both CD and DCM. In the present large Swedish population-based cohort study, we examined the risk of idiopathic DCM in patients with CD determined by small-intestinal histopathology. Methods and Results From 2006 to 2008, we collected duodenal/jejunal biopsy data on CD (equal to villous atrophy, Marsh stage 3, n=29 071 unique individuals) from (all) 28 pathology departments in Sweden. These individuals were compared with 144 429 reference individuals matched for age, sex, calendar year, and county. Data on DCM were obtained through the National Patient Register and confirmed by patient charts and echocardiography data. During follow-up, 17 patients with CD and 52 reference individuals developed idiopathic DCM. Thus, patients with CD were at an increased risk of idiopathic DCM (hazard ratio, 1.73; 95% confidence interval, 1.00 to 3.00), although the risk estimate failed to attain statistical significance (P=0.052). Conclusion This nationwide study found a moderately but not statistically significantly increased risk of idiopathic DCM in patients with biopsy-verified CD. (J Am Heart Assoc. 2012;1:e001594 doi: 10.1161/JAHA.112.001594.) PMID:23130142

Fistulizing pattern in Crohn's disease and pancolitis in ulcerative colitis are independent risk factors for cancer: a single-center cohort study.

PubMed

Biancone, Livia; Zuzzi, Sara; Ranieri, Micaela; Petruzziello, Carmelina; Calabrese, Emma; Onali, Sara; Ascolani, Marta; Zorzi, Francesca; Condino, Giovanna; Iacobelli, Simona; Pallone, Francesco

2012-06-01

The combined role of immunomodulators (IMM) and clinical characteristics of Inflammatory Bowel Disease (IBD) in determining the cancer risk is undefined. The aim was to assess whether clinical characteristics of IBD are independent risk factors for cancer, when considering thiopurines and anti-TNFs use. In a single-center cohort study, clinical characteristics of IBD patients with IBD duration ≥1 year and ≥2 visits from 2000 to 2009 were considered. Tests for crude rates and survival analysis methods were used to assess differences of incidence of cancer between groups. The methods were adjusted for the time interval between diagnosis and immunomodulatory treatments. IBD population included 1222 patients :615 Crohn's disease (CD), 607 ulcerative colitis (UC). Cancer was diagnosed in 51 patients (34 CD,17 UC), with an incidence rate of 4.3/1000 pt/year. The incidence rate of cancer was comparable between CD and UC (4.6/1000 pt/year vs 2.9/1000 pt/year ;p=n.s.). Cancer most frequently involved the breast, the GI tract, the skin. Lymphoma was diagnosed in CD (1HL, 1NHL,0 HSTCL). Risk factors for cancer included older age at diagnosis of IBD (CD: HR 1.25;95%CI 1.08-1.45; UC:HR 1.33;95%CI 1.15-1.55 for an increase by 5 years; p=0.0023; p=0.0002), fistulizing pattern in CD (HR 2.55; 95%CI 1.11-5.86,p=0.0275), pancolitis in UC (HR 2.79;95%CI 1.05-7.40 p=0.0396 vs distal). IMM and anti-TNFs did not increase the cancer risk in CD, neither IMM in UC (anti-TNFs risk in UC not feasible as no cases observed). Fistulizing pattern in CD, pancolitis in UC and older age at diagnosis of IBD are independent risk factors for cancer. Copyright © 2011 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

Synovial features of patients with rheumatoid arthritis and psoriatic arthritis in clinical and ultrasound remission differ under anti-TNF therapy: a clue to interpret different chances of relapse after clinical remission?

PubMed Central

Alivernini, Stefano; Tolusso, Barbara; Petricca, Luca; Bui, Laura; Di Sante, Gabriele; Peluso, Giusy; Benvenuto, Roberta; Fedele, Anna Laura; Federico, Franco; Ferraccioli, Gianfranco; Gremese, Elisa

2017-01-01

Objective To define the synovial characteristics of patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) in clinical and ultrasound remission achieved by combination therapy with methotrexate (MTX) and tumour necrosis factor (TNF) blockers. Methods Patients with RA in remission (n=25) (disease activity score (DAS)<1.6 for at least 6 months), patients with RA in low disease activity (LDA) (n=10) (1.6

Effect of Concomitant Medications on the Safety and Efficacy of Extended-Release Carbidopa-Levodopa (IPX066) in Patients With Advanced Parkinson Disease: A Post Hoc Analysis

PubMed Central

LeWitt, Peter A.; Verhagen Metman, Leo; Rubens, Robert; Khanna, Sarita; Kell, Sherron; Gupta, Suneel

2018-01-01

Objectives Extended-release (ER) carbidopa-levodopa (CD-LD) (IPX066/RYTARY/NUMIENT) produces improvements in “off” time, “on” time without troublesome dyskinesia, and Unified Parkinson Disease Rating Scale scores compared with immediate-release (IR) CD-LD or IR CD-LD plus entacapone (CLE). Post hoc analyses of 2 ER CD-LD phase 3 trials evaluated whether the efficacy and safety of ER CD-LD relative to the respective active comparators were altered by concomitant medications (dopaminergic agonists, monoamine oxidase B [MAO-B] inhibitors, or amantadine). Methods ADVANCE-PD (n = 393) assessed safety and efficacy of ER CD-LD versus IR CD-LD. ASCEND-PD (n = 91) evaluated ER CD-LD versus CLE. In both studies, IR- and CLE-experienced patients underwent a 6-week, open-label dose-conversion period to ER CD-LD prior to randomization. For analysis, the randomized population was divided into 3 subgroups: dopaminergic agonists, rasagiline or selegiline, and amantadine. For each subgroup, changes from baseline in PD diary measures (“off” time and “on” time with and without troublesome dyskinesia), Unified Parkinson Disease Rating Scale Parts II + III scores, and adverse events were analyzed, comparing ER CD-LD with the active comparator. Results and Conclusions Concomitant dopaminergic agonist or MAO-B inhibitor use did not diminish the efficacy (improvement in “off” time and “on” time without troublesome dyskinesia) of ER CD-LD compared with IR CD-LD or CLE, whereas the improvement with concomitant amantadine failed to reach significance. Safety and tolerability were similar among the subgroups, and ER CD-LD did not increase troublesome dyskinesia. For patients on oral LD regimens and taking a dopaminergic agonist, and/or a MAO-B inhibitor, changing from an IR to an ER CD-LD formulation provides approximately an additional hour of “good” on time. PMID:29432286

Fecal Gluten Peptides Reveal Limitations of Serological Tests and Food Questionnaires for Monitoring Gluten-Free Diet in Celiac Disease Patients

PubMed Central

Comino, Isabel; Fernández-Bañares, Fernando; Esteve, María; Ortigosa, Luís; Castillejo, Gemma; Fambuena, Blanca; Ribes-Koninckx, Carmen; Sierra, Carlos; Rodríguez-Herrera, Alfonso; Salazar, José Carlos; Caunedo, Ángel; Marugán-Miguelsanz, J M; Garrote, José Antonio; Vivas, Santiago; lo Iacono, Oreste; Nuñez, Alejandro; Vaquero, Luis; Vegas, Ana María; Crespo, Laura; Fernández-Salazar, Luis; Arranz, Eduardo; Jiménez-García, Victoria Alejandra; Antonio Montes-Cano, Marco; Espín, Beatriz; Galera, Ana; Valverde, Justo; Girón, Francisco José; Bolonio, Miguel; Millán, Antonio; Cerezo, Francesc Martínez; Guajardo, César; Alberto, José Ramón; Rosinach, Mercé; Segura, Verónica; León, Francisco; Marinich, Jorge; Muñoz-Suano, Alba; Romero-Gómez, Manuel; Cebolla, Ángel; Sousa, Carolina

2016-01-01

Objectives: Treatment for celiac disease (CD) is a lifelong strict gluten-free diet (GFD). Patients should be followed-up with dietary interviews and serology as CD markers to ensure adherence to the diet. However, none of these methods offer an accurate measure of dietary compliance. Our aim was to evaluate the measurement of gluten immunogenic peptides (GIP) in stools as a marker of GFD adherence in CD patients and compare it with traditional methods of GFD monitoring. Methods: We performed a prospective, nonrandomized, multicenter study including 188 CD patients on GFD and 84 healthy controls. Subjects were given a dietary questionnaire and fecal GIP quantified by enzyme-linked immunosorbent assay (ELISA). Serological anti-tissue transglutaminase (anti-tTG) IgA and anti-deamidated gliadin peptide (anti-DGP) IgA antibodies were measured simultaneously. Results: Of the 188 celiac patients, 56 (29.8%) had detectable GIP levels in stools. There was significant association between age and GIP in stools that revealed increasing dietary transgressions with advancing age (39.2% in subjects ≥13 years old) and with gender in certain age groups (60% in men ≥13 years old). No association was found between fecal GIP and dietary questionnaire or anti-tTG antibodies. However, association was detected between GIP and anti-DGP antibodies, although 46 of the 53 GIP stool-positive patients were negative for anti-DGP. Conclusions: Detection of gluten peptides in stools reveals limitations of traditional methods for monitoring GFD in celiac patients. The GIP ELISA enables direct and quantitative assessment of gluten exposure early after ingestion and could aid in the diagnosis and clinical management of nonresponsive CD and refractory CD. Trial registration number NCT02711397. PMID:27644734

A supervised learning approach for Crohn's disease detection using higher-order image statistics and a novel shape asymmetry measure.

PubMed

Mahapatra, Dwarikanath; Schueffler, Peter; Tielbeek, Jeroen A W; Buhmann, Joachim M; Vos, Franciscus M

2013-10-01

Increasing incidence of Crohn's disease (CD) in the Western world has made its accurate diagnosis an important medical challenge. The current reference standard for diagnosis, colonoscopy, is time-consuming and invasive while magnetic resonance imaging (MRI) has emerged as the preferred noninvasive procedure over colonoscopy. Current MRI approaches assess rate of contrast enhancement and bowel wall thickness, and rely on extensive manual segmentation for accurate analysis. We propose a supervised learning method for the identification and localization of regions in abdominal magnetic resonance images that have been affected by CD. Low-level features like intensity and texture are used with shape asymmetry information to distinguish between diseased and normal regions. Particular emphasis is laid on a novel entropy-based shape asymmetry method and higher-order statistics like skewness and kurtosis. Multi-scale feature extraction renders the method robust. Experiments on real patient data show that our features achieve a high level of accuracy and perform better than two competing methods.

Bronchoalveolar Lavage Fluid Characteristics of Patients With Sarcoidosis and Nonsarcoidosis Interstitial Lung Diseases: Ten-Year Experience of a Single Center in Turkey

PubMed Central

Tanriverdi, Hakan; Erboy, Fatma; Altinsoy, Bulent; Uygur, Firat; Arasli, Mehmet; Ozel Tekin, Ishak; Tor, Muge Meltem; Atalay, Figen

2015-01-01

Background: Bronchoalveolar lavage (BAL) is a noninvasive and useful technique for evaluating interstitial lung diseases (ILDs). Flow cytometric analysis of BAL fluid reveals specific diagnostic information in some unusual ILDs, and helps to narrow down the possible causes of interstitial diseases in most patients with more common disorders. A high BAL CD4/CD8 ratio is highly specific for sarcoidosis but can also be seen in other ILDs. Objectives: In this retrospective, descriptive, cross-sectional study, we compared BAL fluid characteristics and clinical variables in patients with sarcoidosis and non-sarcoidosis ILDs in a large cohort. Patients and Methods: The study was conducted in a tertiary university hospital in Zonguldak, the biggest city of the western Black Sea region of Turkey. Between 2004 and 2014, all patients who underwent both fiberoptic bronchoscopy and BAL with a suspicion of ILD were included in the study, retrospectively. Patients were divided into two main groups: sarcoidosis and non-sarcoidosis ILDs. Non-sarcoidosis ILDs were further divided into subgroups: pneumoconiosis, tuberculosis (TB), collagen vascular diseases, idiopathic interstitial pneumonias, malignancies, and unclassified ILDs. The clinical data of patients, including age, gender, smoking status, pulmonary function tests, and BAL flow cytometric analysis results, were compared among groups. Results: In total, 261 patients (119 sarcoidosis and 142 non-sarcoidosis ILDs) were enrolled. The median (interquartile range) BAL CD4/CD8 ratio and lymphocyte fraction were significantly higher in sarcoidosis than in non-sarcoidosis ILDs: 3.88 (3.76) versus 0.88 (1.01), respectively, and 20.6 (28.3) versus 6.0 (13.7), respectively. T cell receptor γ delta, CD16+56+, CD103+, CD8+103+, and CD3+16+56+ cells were significantly lower in sarcoidosis than in non-sarcoidosis ILDs. The median BAL CD4/CD8 ratios were significantly higher in patients with TB (1.87, P = 0.01) and malignancies (1.69, P = 0.03) than in other non-sarcoidosis ILDs. Conclusions: Among BAL fluid flow cytometric parameters, CD4/CD8 and lymphocyte fraction may be helpful for distinguishing sarcoidosis from other ILDs, but they are neither specific nor diagnostic for any lung disease. Thus, a multidisciplinary diagnostic discussion is required to differentiate various ILDs. PMID:26566455

Microparticles (CD146) and Arterial Stiffness Versus Carotid Intima Media Thickness as an Early Predictors of Vascular Affection in Systemic Lupus Patients.

PubMed

Nassef, Sahar; El Guindey, Hala; Fawzy, Mary; Nasser, Amal; Reffai, Rasha; Shemiy, Doa

2016-03-01

This study aims to evaluate cluster of differentiation 146 (CD146) and pulse wave velocity (PWV) as non-invasive methods for prediction of early vascular affection in systemic lupus erythematosus (SLE) patients without symptoms of vascular disease, to detect the outcome and reproducibility of these methods, and to correlate CD146 and PWV with lipid profile, intima media thickness (IMT), and ankle brachial index. Thirty female SLE patients (mean age 26.6±6.6 years; range 15 to 35 years) fulfilling the American College of Rheumatology 1997 revised criteria for SLE classification, and 15 age and sex matched healthy controls were included. All participants were performed full clinical assessments including measurement of Systemic Lupus Erythematosus Disease Activity Index, lipid profile, CD146, carotid IMT, PWV, and rise time as an indication of how fast the waveform rises. Cluster of differentiation 146 levels were elevated in patients with SLE compared to controls (p<0.001). There was a statistically significant difference between patients and controls in the femoral, lower thigh, and ankle rise time. There was a statistically significant correlation between IMT and ages of patients, Systemic Lupus Erythematosus Disease Activity Index, and brachial-below knee PWV, while there was no correlation between IMT and disease duration, lipid profile, brachial-femoral PWV, and brachial-ankle PWV. There was statistically significant correlations between brachial-femoral PWV and serum cholesterol level, and between brachial-ankle PWV and low density lipoprotein cholesterol. Our results showed that SLE vascular affection is more pronounced in small arteries. Also, elevated CD146 and brachial-femoral PWV are useful early markers of vascular affection in SLE as well as rise time may be a marker for arterial stiffness.

Medical and surgical treatment of haemorrhoids and anal fissure in Crohn’s disease: a critical appraisal

PubMed Central

2013-01-01

Background The principle to avoid surgery for haemorrhoids and/or anal fissure in Crohn’s disease (CD) patients is still currently valid despite advances in medical and surgical treatments. In this study we report our prospectively recorded data on medical and surgical treatment of haemorrhoids and anal fissures in CD patients over a period of 8 years. Methods Clinical data of patients affected by perianal disease were routinely and prospectively inserted in a database between October 2003 and October 2011 at the Department of Surgery, Tor Vergata University Hospital, Rome. We reviewed and divided in two groups records on CD patients treated either medically or surgically according to the diagnosis of haemorrhoids or anal fissures. Moreover, we compared in each group the outcome in patients with prior diagnosis of CD and in patients diagnosed with CD only after perianal main treatment. Results Eighty-six CD patients were included in the study; 45 were treated for haemorrhoids and 41 presented with anal fissure. Conservative approach was initially adopted for all patients; in case of medical treatment failure, the presence of stable intestinal disease made them eligible for surgery. Fifteen patients underwent haemorrhoidectomy (open 11; closed 3; stapled 1), and two rubber band ligation. Fourteen patients required surgery for anal fissure (Botox ± fissurectomy 8; LIS 6). In both groups we observed high complication rate, 41.2% for haemorrhoids and 57.1% for anal fissure. Patients who underwent haemorrhoidectomy without certain diagnosis of CD had significantly higher risk of complications. Conclusions Conservative treatment of proctologic diseases in CD patients has been advocated given the high risk of complications and the evidence that spontaneous healing may also occur. From these preliminary results a role of surgery is conceivable in high selected patients, but definitve conclusions can’t be made. Further randomized trials are needed to establish the efficacy of the surgical approach, giving therapeutic recommendations and guidelines. PMID:23496835

HIV-1 disease progression in immune-competent HIV-1-infected and breastfeeding mothers participating in the ANRS 12174 clinical trial in Burkina Faso, South Africa, Uganda and Zambia: a cohort study

PubMed Central

Engebretsen, Ingunn M S; Nagot, Nicolas; Meda, Nicolas Yelbomkan; Vallo, Roselyne; Kankasa, Chipepo; Tumwine, James K; Singata-Madliki, Mandisa; Harper, Kim; Hofmeyr, G Justus; Van de Perre, Philippe; Tylleskär, Thorkild

2018-01-01

Objective We have assessed HIV-1 disease progression among HIV-1-positive mothers in relation to duration of any or exclusive breast feeding in the context of ANRS 12174 trial. Methods The analysis was completed on 203, 212, 272 and 529 HIV-1-positive and lactating mothers with CD4 count >350 cells/µL from Burkina Faso, South Africa, Uganda and Zambia, respectively. The trial compared lamivudine and lopinavir/ritonavir as a peri-exposure prophylaxis during a 50-week follow-up time. A multiple logistic regression model was run with the mothers’ weight, CD4 count and HIV-1 viral load as separate dependent variables, then combined into a dependent composite endpoint called HIV-1 disease progression where HIV-1 viral load was replaced by the HIV-1 clinical stage. Exclusive or predominant breast feeding (EPBF) and any breastfeeding duration were the key explanatory variables. Results In the adjusted model, the associations between EPBF duration and weight change, CD4 cell count and the HIV-1 viral load were consistently insignificant. The CD4 cell count was associated with a significantly higher mothers’ body mass index (BMI; a mean increase of 4.9 (95% CI 2.1 to 7.7) CD4 cells/µL per each additional kilogram per square metre of BMI) and haemoglobin concentration (19.4 (95% CI 11.4 to 27.4) CD4 cells/µL per each additional gram per decilitre of haemoglobin concentration). There was no significant association between EPBF duration and HIV-1 disease progression. A higher education level was a factor associated with a slower HIV-1 disease progression. Conclusion Breast feeding was not a risk factor for a faster progression of HIV-1 disease in mothers of this cohort with a baseline CD4 cell count >350 cells/µL. Trial registration number NCT0064026; Post-results. PMID:29626043

Clinical Features and Extraintestinal Manifestations of Crohn Disease in Children

PubMed Central

Lee, Young Ah; Chun, Peter; Hwang, Eun Ha; Mun, Sang Wook; Lee, Yeoun Joo

2016-01-01

Purpose The aim of this study was to investigate the clinical features and extraintestinal manifestations (EIMs) of Crohn disease (CD) in Korean pediatric patients. Methods The medical records of 73 children diagnosed with CD were retrospectively reviewed. Data regarding baseline demographic and clinical characteristics, including CD phenotype at diagnosis based on the Montreal classification, and clinical features and course of EIMs were investigated. Results Fifty-two (71.2%) of the patients were males. The mean age of the patients was 12.5 years. The mean follow-up period was 3.4 years. The disease location was ileal in 3 (4.1%) of the patients, colonic in 13 (17.8%), ileocolonic in 56 (76.7%). The clinical behavior was inflammatory in 62 (84.9%) of the patients, stricturing in 8 (11.0%), and penetrating in 3 (4.1%). Perianal abscesses or fistulas were found in 37 (50.7%) of the patients. EIMs observed during the study period were anal skin tag in 25 patients (34.2%), hypertransaminasemia in 20 (27.4%), peripheral arthritis in 2 (2.7%), erythema nodosum in 2 (2.7%), vulvitis in 1 (1.4%), uveitis in 1 (1.4%), and pulmonary thromboembolism in 1 (1.4%). Conclusion Perianal diseases and manifestations were present in more than half of Korean pediatric CD patients at diagnosis. Inspection of the anus should be mandatory in Korean children with suspicious CD, as perianal fistulas, abscesses, and anal skin tags may be the first clue to the diagnosis of CD. PMID:28090468

Real-Time PCR in HIV/Trypanosoma cruzi Coinfection with and without Chagas Disease Reactivation: Association with HIV Viral Load and CD4+ Level

PubMed Central

de Freitas, Vera Lúcia Teixeira; da Silva, Sheila Cristina Vicente; Sartori, Ana Marli; Bezerra, Rita Cristina; Westphalen, Elizabeth Visone Nunes; Molina, Tatiane Decaris; Teixeira, Antonio R. L.; Ibrahim, Karim Yaqub; Shikanai-Yasuda, Maria Aparecida

2011-01-01

Background Reactivation of chronic Chagas disease, which occurs in approximately 20% of patients coinfected with HIV/Trypanosoma cruzi (T. cruzi), is commonly characterized by severe meningoencephalitis and myocarditis. The use of quantitative molecular tests to monitor Chagas disease reactivation was analyzed. Methodology Polymerase chain reaction (PCR) of kDNA sequences, competitive (C-) PCR and real-time quantitative (q) PCR were compared with blood cultures and xenodiagnosis in samples from 91 patients (57 patients with chronic Chagas disease and 34 with HIV/T. cruzi coinfection), of whom 5 had reactivation of Chagas disease and 29 did not. Principal Findings qRT-PCR showed significant differences between groups; the highest parasitemia was observed in patients infected with HIV/T. cruzi with Chagas disease reactivation (median 1428.90 T. cruzi/mL), followed by patients with HIV/T. cruzi infection without reactivation (median 1.57 T. cruzi/mL) and patients with Chagas disease without HIV (median 0.00 T. cruzi/mL). Spearman's correlation coefficient showed that xenodiagnosis was correlated with blood culture, C-PCR and qRT-PCR. A stronger Spearman correlation index was found between C-PCR and qRT-PCR, the number of parasites and the HIV viral load, expressed as the number of CD4+ cells or the CD4+/CD8+ ratio. Conclusions qRT-PCR distinguished the groups of HIV/T. cruzi coinfected patients with and without reactivation. Therefore, this new method of qRT-PCR is proposed as a tool for prospective studies to analyze the importance of parasitemia (persistent and/or increased) as a criterion for recommending pre-emptive therapy in patients with chronic Chagas disease with HIV infection or immunosuppression. As seen in this study, an increase in HIV viral load and decreases in the number of CD4+ cells/mm3 and the CD4+/CD8+ ratio were identified as cofactors for increased parasitemia that can be used to target the introduction of early, pre-emptive therapy. PMID:21912712

CD19 CAR–T cells of defined CD4+:CD8+ composition in adult B cell ALL patients

PubMed Central

Turtle, Cameron J.; Hanafi, Laïla-Aïcha; Berger, Carolina; Gooley, Theodore A.; Cherian, Sindhu; Hudecek, Michael; Sommermeyer, Daniel; Melville, Katherine; Pender, Barbara; Budiarto, Tanya M.; Robinson, Emily; Steevens, Natalia N.; Chaney, Colette; Soma, Lorinda; Chen, Xueyan; Li, Daniel; Cao, Jianhong; Heimfeld, Shelly; Jensen, Michael C.; Riddell, Stanley R.; Maloney, David G.

2016-01-01

BACKGROUND. T cells that have been modified to express a CD19-specific chimeric antigen receptor (CAR) have antitumor activity in B cell malignancies; however, identification of the factors that determine toxicity and efficacy of these T cells has been challenging in prior studies in which phenotypically heterogeneous CAR–T cell products were prepared from unselected T cells. METHODS. We conducted a clinical trial to evaluate CD19 CAR–T cells that were manufactured from defined CD4+ and CD8+ T cell subsets and administered in a defined CD4+:CD8+ composition to adults with B cell acute lymphoblastic leukemia after lymphodepletion chemotherapy. RESULTS. The defined composition product was remarkably potent, as 27 of 29 patients (93%) achieved BM remission, as determined by flow cytometry. We established that high CAR–T cell doses and tumor burden increase the risks of severe cytokine release syndrome and neurotoxicity. Moreover, we identified serum biomarkers that allow testing of early intervention strategies in patients at the highest risk of toxicity. Risk-stratified CAR–T cell dosing based on BM disease burden decreased toxicity. CD8+ T cell–mediated anti-CAR transgene product immune responses developed after CAR–T cell infusion in some patients, limited CAR–T cell persistence, and increased relapse risk. Addition of fludarabine to the lymphodepletion regimen improved CAR–T cell persistence and disease-free survival. CONCLUSION. Immunotherapy with a CAR–T cell product of defined composition enabled identification of factors that correlated with CAR–T cell expansion, persistence, and toxicity and facilitated design of lymphodepletion and CAR–T cell dosing strategies that mitigated toxicity and improved disease-free survival. TRIAL REGISTRATION. ClinicalTrials.gov NCT01865617. FUNDING. R01-CA136551; Life Science Development Fund; Juno Therapeutics; Bezos Family Foundation. PMID:27111235

Coeliac disease screening is suboptimal in a tertiary gastroenterology setting.

PubMed

Iskandar, Heba; Gray, Darrell M; Vu, Hongha; Mirza, Faiz; Rude, Mary Katherine; Regan, Kara; Abdalla, Adil; Gaddam, Srinivas; Almaskeen, Sami; Mello, Michael; Marquez, Evelyn; Meyer, Claire; Bolkhir, Ahmed; Kanuri, Navya; Sayuk, Gregory; Gyawali, C Prakash

2017-08-01

Coeliac disease (CD) is widely prevalent in North America, but case-finding techniques currently used may not be adequate for patient identification. We aimed to determine the adequacy of CD screening in an academic gastroenterology (GI) practice. Consecutive initial visits to a tertiary academic GI practice were surveyed over a 3-month period as a fellow-initiated quality improvement project. All electronic records were reviewed to look for indications for CD screening according to published guidelines. The timing of screening was noted (before or after referral), as well as the screening method (serology or biopsy). Data were analysed to compare CD screening practices across subspecialty clinics. 616 consecutive patients (49±0.6 years, range 16-87 years, 58.5% females, 94% Caucasian) fulfilled inclusion criteria. CD testing was indicated in 336 (54.5%), but performed in only 145 (43.2%). The need for CD screening was highest in luminal GI and inflammatory bowel disease clinics, followed by biliary and hepatology clinics (p<0.0001); CD screening rate was highest in the luminal GI clinic (p=0.002). Of 145 patients screened, 4 patients (2.4%) had serology consistent with CD, of which 2 were proven by duodenal biopsy. Using this proportion, an additional 5 patients might have been diagnosed in 191 untested patients with indications for CD screening. More than 50% of patients in a tertiary GI clinic have indications for CD screening, but <50% of indicated cases are screened. Case-finding techniques therefore are suboptimal, constituting a gap in patient care and an important target for future quality improvement initiatives. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Bromelain exerts anti-inflammatory effects in an ovalbumin-induced murine model of allergic airway disease ☆

PubMed Central

Secor, Eric R.; Carson, William F.; Cloutier, Michelle M.; Guernsey, Linda A.; Schramm, Craig M.; Wu, Carol A.; Thrall, Roger S.

2008-01-01

Objective Bromelain, a clinically used pineapple extract and natural product, has reported anti-inflammatory and immunomodulatory activities. The purpose of this study was to determine the effect of bromelain treatment in an ovalbumin (OVA)-induced murine model of allergic airway disease (AAD). Methods To establish AAD, mice were sensitized with intraperitoneal (i.p.) OVA/alum and challenged with daily OVA aerosols. Mice were treated i.p. with either saline, 2 or 6 mg/kg bromelain, twice daily for four consecutive days. Bronchoalveolar lavage leukocytes and cytokines, lung histology, airway hyperresponsiveness, and lymphocyte populations via flow cytometry were compared between groups. Results Bromelain treatment of AAD mice resulted in reduced total BAL leukocytes, eosinophils, CD4+ and CD8+ T lymphocytes, CD4+/CD8+ T cell ratio, and IL-13. Conclusion Bromelain attenuated development of AAD while altering CD4+ to CD8+ T lymphocyte populations. The reduction in AAD outcomes suggests that bromelain may have similar effects in the treatment of human asthma and hypersensitivity disorders. PMID:16337164

Cross-sectional, descriptive study of Chagas disease among citizens of Bolivian origin living in Munich, Germany

PubMed Central

Navarro, Miriam; Berens-Riha, Nicole; Hohnerlein, Stefan; Seiringer, Peter; von Saldern, Charlotte; Garcia, Sarah; Blasco-Hernández, Teresa; Navaza, Bárbara; Shock, Jonathan; Bretzel, Gisela; Hoelscher, Michael; Löscher, Thomas; Albajar-Viñas, Pedro; Pritsch, Michael

2017-01-01

Purpose Chagas disease (CD) has become a global health issue mainly due to migration. Germany lacks surveillance data and is home to a large Latin American immigrant population. Recognising that Bolivia is the country with the highest CD prevalence in Latin America, this cross-sectional, descriptive pilot study investigated CD and associated factors among citizens of Bolivian origin living in Munich, Germany. Methods Participants completed a questionnaire in order to collect socioeconomic and health-related data. In addition, serology was performed. In case of positive serological tests, PCR diagnostic and clinical staging together with disease management was initiated. Qualitative research was conducted to identify personal and community barriers as well as strategies to increase CD awareness among the population at risk. Results Between June 2013 and June 2014, 43 people from Bolivia (or descendants) were enrolled. A total of 9.3% (4/43), of whom two women were of childbearing age, tested seropositive (ELISA and IFAT), and one also by PCR. For 2/4 positive participants, clinical evaluation was performed and the indeterminate form of CD was diagnosed. Knowledge about CD symptoms and ways of transmission were completely absent among 55.8% (24/43, 2/4 with CD) and 30.2% (13/43, 1/4 with CD) of participants, respectively. A total of 27.9% (12/43, 0/4 with CD) of participants had donated blood prior to the study, whereas 62.8% (27/43, 3/4 with CD) were motivated to donate blood in the future. The qualitative research identified lack of knowledge as well as stigma and fears related to CD. Conclusions Despite the small number of participants, the prevalence of CD as well as the potential risk of non-vectorial transmission was alarming. Campaigns adapted for Latin American migrants as well as control strategies should be developed and put in place in order to prevent non-vectorial transmission and actively detect cases of CD in Germany. PMID:28093440

The Expenditures for Academic Inpatient Care of Inflammatory Bowel Disease Patients Are Almost Double Compared with Average Academic Gastroenterology and Hepatology Cases and Not Fully Recovered by Diagnosis-Related Group (DRG) Proceeds

PubMed Central

Baumgart, Daniel C.; le Claire, Marie

2016-01-01

Background Crohn’s disease (CD) and ulcerative colitis (UC) challenge economies worldwide. Detailed health economic data of DRG based academic inpatient care for inflammatory bowel disease (IBD) patients in Europe is unavailable. Methods IBD was identified through ICD-10 K50 and K51 code groups. We took an actual costing approach, compared expenditures to G-DRG and non-DRG proceeds and performed detailed cost center and type accounting to identify coverage determinants. Results Of all 3093 hospitalized cases at our department, 164 were CD and 157 UC inpatients in 2012. On average, they were 44.1 (CD 44.9 UC 43.3 all 58) years old, stayed 10.1 (CD 11.8 UC 8.4 vs. all 8) days, carried 5.8 (CD 6.4 UC 5.2 vs. all 6.8) secondary diagnoses, received 7.4 (CD 7.7 UC 7 vs. all 6.2) procedures, had a higher cost weight (CD 2.8 UC 2.4 vs. all 1.6) and required more intense nursing. Their care was more costly (means: total cost IBD 8477€ CD 9051€ UC 7903€ vs. all 5078€). However, expenditures were not fully recovered by DRG proceeds (means: IBD 7413€, CD 8441€, UC 6384€ vs all 4758€). We discovered substantial disease specific mismatches in cost centers and types and identified the medical ward personnel and materials budgets to be most imbalanced. Non-DRG proceeds were almost double (IBD 16.1% vs. all 8.2%), but did not balance deficits at total coverage analysis, that found medications (antimicrobials, biologics and blood products), medical materials (mostly endoscopy items) to contribute most to the deficit. Conclusions DRGs challenge sophisticated IBD care. PMID:26784027

Serum Proteome Profiles in Stricturing Crohn’s Disease: A pilot study.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Townsend, Peter; Zhang, Qibin; Shapiro, Jason

Background: Crohn’s disease (CD) is a form of inflammatory bowel disease (IBD) with different described behaviors, including stricture. At present, there are no laboratory studies that can differentiate stricturing CD from other phenotypes of IBD. We performed a pilot study to examine differences in the proteome among patients with stricturing Crohn’s disease, non-stricturing Crohn’s disease, and ulcerative colitis (UC). Methods: Serum samples were selected from the Ocean State Crohn’s and Colitis Area Registry (OSCCAR), an established cohort of patients with IBD. Crohn’s disease patients with surgically-resected stricture were matched with similar patients with Crohn’s disease without known stricture, and withmore » UC. Serum samples from each patient were digested and analyzed using liquid chromatography-mass spectrometry to characterize the proteome. Statistical analyses were performed to identify peptides and proteins that can differentiate CD with stricture. Results: Samples from 9 patients in each group (27 total patients) were analyzed. Baseline demographic characteristics were similar among the three groups. We quantified 7668 peptides and 897 proteins for analysis. ROC analysis identified a subset of peptides with an area under the curve greater than 0.9, indicating greater separation potential. Partial least squares discriminant analysis was able to distinguish among the three groups with up to 70% accuracy by peptides, and up to 80% accuracy by proteins. We identified the significantly different proteins and peptides, and determined their function based on previously published literature. Conclusions: The serum of patients with stricturing CD, non-stricturing CD, and UC are distinguishable via proteomic analysis. Some of the proteins that differentiate the stricturing phenotype have been implicated in complement activation, fibrinolytic pathways, and lymphocyte adhesion.« less

The Effects of an Oral Supplement Enriched With Fish Oil, Prebiotics, and Antioxidants on Nutrition Status in Crohn’s Disease Patients

PubMed Central

Wiese, Dawn M.; Lashner, Bret A.; Lerner, Edith; DeMichele, Stephen J.; Seidner, Douglas L.

2015-01-01

Background Research in the treatment of Crohn’s disease (CD) supports anti-inflammatory benefits of n-3 fatty acids from fish oil, prebiotics, and antioxidants. A nutritionally balanced inflammatory bowel disease nutrition formula (IBDNF) enriched with these compounds has the potential to improve nutrition status and disease activity in CD. Methods This is an open-label pilot study investigating the effects of IBDNF on nutrition status in CD patients. Twenty-eight patients with active CD on stable medication were asked to consume 16 oz of IBDNF/d for 4 months. Nutrition status was assessed with dual-energy X-ray absorptiometry scans and serum micronutrient levels. Disease activity and quality of life were measured using the Crohn’s Disease Activity Index (CDAI) and the Inflammatory Bowel Disease Questionnaire (IBDQ). Results Twenty patients completed the final visit. After 4 months, there was a significant decrease in plasma phospholipid levels of arachidonic acid with increases in eicosapentaenoic acid (EPA) and docosahexaenoic acid. Ten patients had a final EPA concentration of >2%. There was improvement in fat-free and fat mass in patients with final EPA >2% (P = .014 and P = .05). Vitamin D (25-OH) levels improved in all patients (18.5–25.9 ng/mL, P < .001). Those with EPA >2% had significantly lower CDAI (116 ± 94.5 vs 261.8 ± 86.5; P = .005) and higher IBDQ (179.1 ± 26.6 vs 114.6 ± 35.9, P < .001) compared to those with EPA <2%. Conclusions IBDNF has the potential to deposit fat-free and fat mass, improve vitamin D status, and improve quality of life in CD patients. PMID:21775642

Increased numbers of Foxp3-positive regulatory T cells in gastritis, peptic ulcer and gastric adenocarcinoma

PubMed Central

Cheng, Hsin-Hung; Tseng, Guan-Ying; Yang, Hsiao-Bai; Wang, Hung-Jung; Lin, Hwai-Jeng; Wang, Wen-Ching

2012-01-01

AIM: To determine the number of regulatory T cells (Tregs) in gastric mucosa of patients with gastritis, peptic ulcers and gastric cancer. METHODS: This study was a retrospective analysis of gastric antrum biopsy specimens from healthy controls (n = 22) and patients with gastritis (n = 30), peptic ulcer (n = 83), or gastric cancer (n = 32). Expression of CD4, CD25 and Foxp3 was determined by immunohistochemistry in three consecutive sections per sample. RESULTS: Compared with healthy controls, there was an increased number of CD25+ and Foxp3+ cells in patients with gastritis (P = 0.004 and P = 0.008), peptic ulcer (P < 0.001 and P < 0.001), and gastric cancer (P < 0.001 and P < 0.001). The ratio of CD25+/CD4+ or Foxp3+/CD4+ cells was also significantly higher in all disease groups (P < 0.001, respectively). The number of CD4+, CD25+, and Foxp3+ cells, and the ratio of CD25+/CD4+ and Foxp3+/CD4+ cells, were associated with the histological grade of the specimens, including acute inflammation, chronic inflammation, lymphoid follicle number, and Helicobacter pylori infection. The number of CD4+, CD25+ and Foxp3+ cells, and the ratio of CD25+/CD4+ and Foxp3+/CD4+ cells, were negatively associated with intestinal metaplasia among gastritis (P < 0.001, P < 0.001, P < 0.001, P = 0.002 and P = 0.002) and peptic ulcer groups (P = 0.013, P = 0.004, P < 0.001, P = 0.040 and P = 0.003). CONCLUSION: Tregs are positively associated with endoscopic findings of gastroduodenal diseases and histological grade but negatively associated with intestinal metaplasia in gastritis and peptic ulcer groups. PMID:22228968

Assessing Health Status in Inflammatory Bowel Disease using a Novel Single-Item Numeric Rating Scale

PubMed Central

Surti, Bijal; Spiegel, Brennan; Ippoliti, Andrew; Vasiliauskas, Eric; Simpson, Peter; Shih, David; Targan, Stephan; McGovern, Dermot; Melmed, Gil Y.

2014-01-01

Background Current instruments used to measure disease activity and health-related quality of life (HRQOL) in patients with Crohn’s disease (CD) and ulcerative colitis (UC) are often cumbersome, time-consuming, and expensive; although used in clinical trials, they are not convenient for clinical practice. A numeric rating scale (NRS) is a quick, inexpensive, and convenient patient-reported outcome (PRO) that can capture the patient’s overall perception of health. Aims To assess the validity, reliability, and responsiveness of an NRS and evaluate its use in clinical practice in patients with CD and UC. Methods We prospectively evaluated patient-reported NRS scores and measured correlations between NRS and a range of severity measures, including physician-reported NRS, Crohn’s disease activity index (CDAI), Harvey-Bradshaw index (HBI), inflammatory bowel disease questionnaire (IBDQ), and C-reactive protein (CRP) in patients with CD. Subsequently, we evaluated the correlation between the NRS and standard measures of health status (HBI or simple colitis clinical activity index [SCCAI]) and laboratory tests (sedimentation rate [ESR], CRP, and fecal calprotectin) in patients with CD and UC. Results The patient-reported NRS showed excellent correlation with CDAI (R2=0.59, p<0.0001), IBDQ (R2=0.66, p<0.0001), and HBI (R2=0.32, p<0.0001) in patients with CD. The NRS showed poor, but statistically significant correlation with SCCAI (R2=0.25, p<0.0001) in patients with UC. The NRS did not correlate with CRP, ESR, or calprotectin. The NRS was reliable and responsive to change. Conclusions The NRS is a valid, reliable, and responsive measure that may be useful to evaluate patients with CD and possibly UC. PMID:23250673

A Low Peripheral Blood CD4/CD8 Ratio Is Associated with Pulmonary Emphysema in HIV

PubMed Central

Attia, Engi F.; Akgün, Kathleen M.; Soo Hoo, Guy W.; Freiberg, Matthew S.; Butt, Adeel A.; Wongtrakool, Cherry; Goetz, Matthew Bidwell; Brown, Sheldon T.; Graber, Christopher J.; Huang, Laurence; Crothers, Kristina

2017-01-01

Objectives The prevalence of emphysema is higher among HIV-infected (HIV+) individuals compared to HIV-uninfected persons. While greater tobacco use contributes, HIV-related effects on immunity likely confer additional risk. Low peripheral blood CD4+ to CD8+ T-lymphocyte (CD4/CD8) ratio may reflect chronic inflammation in HIV and may be a marker of chronic lung disease in this population. Therefore, we sought to determine whether the CD4/CD8 ratio was associated with chronic obstructive pulmonary disease (COPD), particularly the emphysema subtype, in a cohort of HIV+ subjects. Methods We performed a cross-sectional analysis of 190 HIV+ subjects enrolled in the Examinations of HIV Associated Lung Emphysema (EXHALE) study. Subjects underwent baseline laboratory assessments, pulmonary function testing and chest computed tomography (CT) analyzed for emphysema severity and distribution. We determined the association between CD4/CD8 ratio and emphysema, and the association between CD4/CD8 ratio and pulmonary function markers of COPD. Results Mild or greater emphysema (>10% lung involvement) was present in 31% of subjects. Low CD4/CD8 ratio was associated with >10% emphysema in multivariable models, adjusting for risk factors including smoking, current and nadir CD4 count and HIV RNA level. Those with CD4/CD8 ratio <0.4 had 6.3 (1.1–39) times the odds of >10% emphysema compared to those with a ratio >1.0 in fully adjusted models. A low CD4/CD8 ratio was also associated with reduced diffusion capacity (DLCO). Conclusions A low CD4/CD8 ratio was associated with emphysema and low DLCO in HIV+ subjects, independent of other risk factors and clinical markers of HIV. The CD4/CD8 ratio may be a useful, clinically available, marker for risk of emphysema in HIV+ subjects in the antiretroviral therapy (ART) era. PMID:28122034

Universal monitoring of minimal residual disease in acute myeloid leukemia.

PubMed

Coustan-Smith, Elaine; Song, Guangchun; Shurtleff, Sheila; Yeoh, Allen Eng-Juh; Chng, Wee Joo; Chen, Siew Peng; Rubnitz, Jeffrey E; Pui, Ching-Hon; Downing, James R; Campana, Dario

2018-05-03

Optimal management of acute myeloid leukemia (AML) requires monitoring of treatment response, but minimal residual disease (MRD) may escape detection. We sought to identify distinctive features of AML cells for universal MRD monitoring. We compared genome-wide gene expression of AML cells from 157 patients with that of normal myeloblasts. Markers encoded by aberrantly expressed genes, including some previously associated with leukemia stem cells, were studied by flow cytometry in 240 patients with AML and in nonleukemic myeloblasts from 63 bone marrow samples. Twenty-two (CD9, CD18, CD25, CD32, CD44, CD47, CD52, CD54, CD59, CD64, CD68, CD86, CD93, CD96, CD97, CD99, CD123, CD200, CD300a/c, CD366, CD371, and CX3CR1) markers were aberrantly expressed in AML. Leukemia-associated profiles defined by these markers extended to immature CD34+CD38- AML cells; expression remained stable during treatment. The markers yielded MRD measurements matching those of standard methods in 208 samples from 52 patients undergoing chemotherapy and revealed otherwise undetectable MRD. They allowed MRD monitoring in 129 consecutive patients, yielding prognostically significant results. Using a machine-learning algorithm to reduce high-dimensional data sets to 2-dimensional data, the markers allowed a clear visualization of MRD and could detect 1 leukemic cell among more than 100,000 normal cells. The markers uncovered in this study allow universal and sensitive monitoring of MRD in AML. In combination with contemporary analytical tools, the markers improve the discrimination between leukemic and normal cells, thus facilitating data interpretation and, hence, the reliability of MRD results. National Cancer Institute (CA60419 and CA21765); American Lebanese Syrian Associated Charities; National Medical Research Council of Singapore (1299/2011); Viva Foundation for Children with Cancer, Children's Cancer Foundation, Tote Board & Turf Club, and Lee Foundation of Singapore.

RAGE gene three polymorphisms with Crohn's disease susceptibility in Chinese Han population.

PubMed

Wang, Zheng-Ting; Hu, Jia-Jia; Fan, Rong; Zhou, Jie; Zhong, Jie

2014-03-07

To investigate the association of three polymorphisms in the receptor for advanced glycation end product (RAGE) gene with Crohn's disease (CD) risk in a Chinese population. A hospital-based case-control association study involving 312 CD patients and 479 healthy controls was conducted. Peripheral blood samples were collected from 791 study subjects, and genomic DNA was extracted. Genotyping was performed using polymerase chain reaction-ligase detection reaction method. The association between polymorphic genotype and CD predisposition was determined using odds ratio and 95% confidence interval (CI). Data were analyzed using Haplo.stats program. Significant differences were observed between patients and controls in allele/genotype distributions of rs1800624 (P(allele)=0.012; P(genotype)=0.005) and in allele distributions of rs2070600 (P=0.02). The risk for CD associated with the rs1800624-A mutant allele decreased by 36% (95%CI: 0.47-0.88, P = 0.005) under the additive model and by 35% (95%CI: 0.46-0.91, P=0.013) under the dominant model. Carriers of rs2070600-A mutant allele showed a 37% (95%CI: 1.02-1.83, P=0.036) increased risk of developing CD relative to the GG genotype carriers. In haplotype analysis, haplotype T-A-G (in the order rs1800625, rs1800624, and rs2070600) decreased the odds of CD by 33% (95%CI: 0.49-0.94, P=0.018). CD is an immune-related disease with genetic predisposition. Genetic defects in the RAGE gene are strongly associated with CD in Chinese population.

A pleiotropic missense variant in SLC39A8 is associated with Crohn’s disease and human gut microbiome composition

PubMed Central

Li, Dalin; Achkar, Jean-Paul; Haritunians, Talin; Jacobs, Jonathan P; Hui, Ken Y; D’Amato, Mauro; Brand, Stephan; Radford-Smith, Graham; Halfvarson, Jonas; Niess, Jan-Hendrik; Kugathasan, Subra; Büning, Carsten; Schumm, L Philip; Klei, Lambertus; Ananthakrishnan, Ashwin; Aumais, Guy; Baidoo, Leonard; Dubinsky, Marla; Fiocchi, Claudio; Glas, Jürgen; Milgrom, Raquel; Proctor, Deborah D; Regueiro, Miguel; Simms, Lisa A; Stempak, Joanne M; Targan, Stephan R.; Törkvist, Leif; Sharma, Yashoda; Devlin, Bernie; Borneman, James; Hakonarson, Hakon; Xavier, Ramnik J; Daly, Mark; Brant, Steven R; Rioux, John D; Silverberg, Mark S; Cho, Judy H; Braun, Jonathan; McGovern, Dermot PB; Duerr, Richard H

2016-01-01

BACKGROUND & AIMS Genome-wide association studies (GWAS) have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn’s disease (CD) and ulcerative colitis (UC) remains incompletely defined. Here we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip. METHODS Genotyping was performed in 10,523 IBD cases and 5,726 non-IBD controls. 91,713 functional single nucleotide polymorphism (SNP) loci in coding regions were analyzed. A novel identified association was further replicated in two independent cohorts. We further examined the association of the identified SNP with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface (MLI) cohort measured using 16S sequencing. RESULTS We identified an association between CD and a missense variant encoding alanine (Ala) or threonine (Thr) at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 Ala391Thr, rs13107325) and replicated the association with CD in two replication cohorts (combined meta-analysis p=5.55×10−13). This variant has previously been associated with distinct phenotypes including obesity, lipid levels, blood pressure and schizophrenia. We subsequently determined that the CD-risk allele was associated with altered colonic mucosal microbiome composition in both healthy controls (p=0.009) and CD cases (p=0.0009). Moreover, microbes depleted in healthy carriers strongly overlap with those reduced in CD patients (p=9.24×10−16) and overweight individuals (p=6.73×10−16). CONCLUSIONS Our results suggest that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases including CD. PMID:27492617

A Herpes Simplex Virus Type 1 Human Asymptomatic CD8+ T-Cell Epitopes-Based Vaccine Protects Against Ocular Herpes in a “Humanized” HLA Transgenic Rabbit Model

PubMed Central

Srivastava, Ruchi; Khan, Arif A.; Huang, Jiawei; Nesburn, Anthony B.; Wechsler, Steven L.; BenMohamed, Lbachir

2015-01-01

Purpose. A clinical vaccine that protects from ocular herpes simplex virus type 1 (HSV-1) infection and disease still is lacking. In the present study, preclinical vaccine trials of nine asymptomatic (ASYMP) peptides, selected from HSV-1 glycoproteins B (gB), and tegument proteins VP11/12 and VP13/14, were performed in the “humanized” HLA–transgenic rabbit (HLA-Tg rabbit) model of ocular herpes. We recently reported that these peptides are highly recognized by CD8+ T cells from “naturally” protected HSV-1–seropositive healthy ASYMP individuals (who have never had clinical herpes disease). Methods. Mixtures of three ASYMP CD8+ T-cell peptides derived from either HSV-1 gB, VP11/12, or VP13/14 were delivered subcutaneously to different groups of HLA-Tg rabbits (n = 10) in incomplete Freund's adjuvant, twice at 15-day intervals. The frequency and function of HSV-1 epitope-specific CD8+ T cells induced by these peptides and their protective efficacy, in terms of survival, virus replication in the eye, and ocular herpetic disease were assessed after an ocular challenge with HSV-1 (strain McKrae). Results. All mixtures elicited strong and polyfunctional IFN-γ– and TNF-α–producing CD107+CD8+ cytotoxic T cells, associated with a significant reduction in death, ocular herpes infection, and disease (P < 0.015). Conclusions. The results of this preclinical trial support the screening strategy used to select the HSV-1 ASYMP CD8+ T-cell epitopes, emphasize their valuable immunogenic and protective efficacy against ocular herpes, and provide a prototype vaccine formulation that may be highly efficacious for preventing ocular herpes in humans. PMID:26098469

Psychological stress and coeliac disease in childhood: a cohort study

PubMed Central

2010-01-01

Background Psychological stress has previously been associated with several immunological diseases, e.g. inflammatory bowel disease. Through questionnaire data from the ABIS study (All Babies In southeast Sweden) we examined the association between psychological stress in the family and biopsy-proven coeliac disease (CD) in the child. Methods We used serious life event, parenting stress, and parental worries as measures of psychological stress. Data were collected when the child was 1 and 2.5 years old in some 11,000 and 8,800 children, respectively. CD was confirmed through small intestinal biopsy (with villous atrophy), and the diagnosis was validated through patient chart data. Results Serious life event in the family in the child's first 1 or 2.5 years after childbirth was not associated with future CD in the child (Odds Ratio (OR) = 0.45; 95% Confidence Interval (CI) = 0.01-2.65; P = 0.72; and OR = 1.21; 95% CI = 0.43-3.05; P = 0.64, respectively). Neither did we see any association between CD and parenting stress at age 1 year and at 2.5 years (OR = 0.40; 95% CI = 0.01-2.38; P = 0.73 and OR = 0.74; 95% CI = 0.01-4.56; P = 1.00, respectively). Among children exposed to parental worries at 2.5 years, no child had a diagnosis of CD before end of follow-up, compared to 25/8082 (0.3%) among non-exposed children (OR = 0.00; 95% CI = 0.00-2.34; P = 0.64). There was no association between the combined measures of stress and CD. Conclusion This study found no association between psychological stress and later development of CD in Swedish children. However, we cannot rule out that the lack of such an association is due to limited statistical power. PMID:20840747

Ethnic and socio-cultural specificities in Tunisia have no impact on the prevalence of anti-Saccharomyces cerevisiae antibodies in Crohn's disease patients, their relatives or associated clinical factors.

PubMed

Hadrich, Ines; Vandewalle, Peggy; Cheikhrouhou, Fatma; Makni, Fattouma; Krichen, Mohamed Salah; Sendid, Boualem; Standaert-Vitse, Annie; Ayadi, Ali; Poulain, Daniel

2007-06-01

In Western Europe and the USA, the presence of anti-Saccharomyces cerevisiae antibodies (ASCAs) in Crohn's disease (CD) patients and their healthy relatives suggests that ASCAs may be influenced by genetic and/or environmental factors. To assess the prevalence of ASCAs in Tunisian patients with CD or ulcerative colitis (UC), and unaffected family members, in relation to clinical phenotype. Patients and methods. Seventy-seven patients (39 CD, 38 UC), 66 healthy relatives of CD patients, 16 relatives of UC patients and 70 healthy controls were studied. ASCAs were quantified with a new isotype-specific ELISA test involving an antigenic extract from S. cerevisiae strain W303 and by the original test which detects total immunoglobulins against S. cerevisiae Su1 mannan. The specificity of the two tests was identical (91%). The isotype-specific ASCA W303 test was more sensitive than the ASCA Su1 test for immunoglobulin detection, but some CD patients were positive only with this latter test. A high percentage of patients with CD (72%) and their unaffected family members (35%) were ASCA-positive in contrast to UC patients (16%) and their relatives (0%) and controls (8.6%). ASCAs were shown to be independent of rural or urban living, disease activity, but were associated with ileal location. The antigen of S. cerevisiae strain W303 discriminated patients depending on age at onset or location of the disease. This study confirms the antigenic heterogeneity of S. cerevisiae strains in their ability to detect ASCA. It suggests that ASCAs are markers of immunoregulatory disturbance in CD, independently of ethnic/cultural differences between Europe, the USA and North Africa.

Accuracy of 99mTc (V)-Dimercaptosuccinic Acid Scintigraphy and Fecal Calprotectin Compared with Colonoscopy in Localizing Active Lesions in Inflammatory Bowel Disease

PubMed Central

Basirat, Vahid; Azizi, Zahra; Javid Anbardan, Sanam; Taghizadeh Asl, Mina; Farbod, Yasaman; Teimouri, Azam; Ebrahimi Daryani, Nasser

2016-01-01

INTRODUCTION Due to limitation of colonoscopy in assessing the entire bowel and patients’ intolerance in inflammatory bowel disease (IBD), in the current study, we aimed to prospectively compare the accuracy of 99mTc(V)-dimercaptosuccinic acid (DMSA) and fecal calprotectin with ileocolonoscopy as new methods for localizing inflammations. METHODS Current prospective study conducted between 2012 and 2014 on 30 patients with IBD attending Gastroenterology Clinic of Tehran University of Medical Sciences. Fecal calprotectin and disease activity were measured for all participants and all of them underwent 99mTc (V)-DMSA scintigraphy and colonoscopy. The accuracy of 99mTc (V)-DMSA scintigraphy and calprotectin in localizing bowel lesions were calculated. RESULTS A total of 22 patients with ulcerative colitis (UC) and 8 patients with Crohn’s disease (CD) were evaluated in our study. Sensitivity, positive likelihood ratio (PLR), and positive predictive value (PPV) of scintigraphy and calprotectin over colonoscopy in localization of UC lesions were 86.36%, 0.86%, 100.00% and 90.91%, 0.91, and 100.00%, respectively. Meanwhile, it showed 66.67% sensitivity and 81.25% specificity with PLR=3.56, negative likelihood ratio (NLR)=0.41, PPV=84.21%, and negative predictive value (NPV)= 61.90% in localizing lesions in patients with CD. The calprotectin level had sensitivity, PLR, and PPV of 90.00%, 0.90, and 100.00% in detecting active disease over colonoscopy, respectively. CONCLUSION The 99mTc (V)-DMSA scintigraphy would be an accurate method for detecting active inflammation in follow-up of patients with IBD and assessing response to treatment as a non-invasive and complementary method beside colonoscopy for more accurate diagnosis of CD or UC. PMID:27698971

Reintervention Rate Following Emergency Surgery for Crohn Disease.

PubMed

Slavu, Iulian; Alecu, Lucian; Tulin, Adrian; Mihaila, Daniela; Braga, Vlad; Voiosu, Theodor; Tomescu, Luminiţa; Constantinoiu, Silviu

2018-01-01

Backround/Objective: To assess the impact of emergency surgery and postoperative recurrence in Crohn's disease (CD) and to evaluate the disease course while observing different factors that may influence it. Methods: Information on 37 consecutive patients which were diagnosed and operated in emergency for CD complications and the the relapse rate (regarded as a second surgery) were retrospectively evaluated. Results: The risk of relapse and second surgery was increased in males under 50 years and in those who benefited from an anastomosis during the first invervention while stomy seemed to reduce the rate of surgical relapse. The median duration until relapse was 2,3 years while a percentage of 33% required reintervention. Conclusions: The majority of patients with CD will undergo at least one surgical intervention during their lifetime and one third of them will relapse requiring a second intervention. Although medical treatment has seen great advancements, surgery requirements have remained unchanged as the mainstay treatment in emergent complications of CD. The age of the patients, smoking status and the postoperative medication influence the rate of postoperative recurrence. Celsius.

Incomplete gastric metaplasia in children with insulin-dependent diabetes mellitus and celiac disease. An ultrastructural study

PubMed Central

Bertini, Marina; Sbarbati, Andrea; Valletta, Enrico; Pinelli, Leonardo; Tatò, Luciano

2001-01-01

Background The association of insulin-dependent diabetes mellitus (IDDM) and celiac disease (CD) has been widely reported in children but the relationship between the two conditions is incompletely understood. Moreover, specific studies on intestinal biopsies of patients with the association of the two diseases are still lacking. Methods We studied the ultrastructure of the duodenal mucosa in 12 patients with both IDDM and CD. Results All patients had either total or partial atrophy of duodenal mucosa. In seven subjects, an accumulation of electrondense granules in the apical cytoplasm of groups of enterocytes was found. In four of them, a double population of granules existed (mean diameter: 400-800 nm and 100-200 nm respectively) showing a biphasic pattern. In the other three patients, only smaller granules (100- 200 nm) were found in the enterocytes. Conclusions The present work suggests that patients with IDDM/CD may represent a subgroup in the context of the CD population. Intestinal biopsies of such individuals often show accumulation of electrondense granules in the apical cytoplasm of enterocytes that can be interpreted as incomplete gastric metaplasia. PMID:11466133

Predictors of Clinical Progression in HIV-1-Infected Adults Initiating Combination Antiretroviral Therapy with Advanced Disease in the Asia-Pacific Region: Results from the TREAT Asia HIV Observational Database

PubMed Central

Byakwaga, H.; Petoumenos, K.; Ananworanich, J.; Zhang, F.; Boyd, M. A.; Sirisanthana, T.; Li, P. C. K.; Lee, C.; Mean, C. V.; Saphonn, V.; Omar, S. F. S.; Pujari, S.; Phanuphak, P.; Lim, P. L.; Kumarasamy, N.; Chen, Y. M. A.; Merati, T. P.; Sungkanuparph, S.; Ditangco, R.; Oka, S.; Tau, G.; Zhou, J.; Law, M. G.; Emery, S.

2013-01-01

The majority of HIV-infected patients in developing countries commences combination antiretroviral therapy (cART) with advanced disease. We examined predictors of disease progression in patients initiating cART with CD4 count ≤200 cells/mm3 in the TREAT Asia HIV Observational Database. The main outcome measure was progression to either an AIDS-defining illness or death occurring 6 months after initiation of cART. We used survival analysis methods. A total of 1255 patients contributed 2696 person years of follow-up; 73 were diagnosed with AIDS and 9 died. The rate of progression to the combined end point was 3.0 per 100 person years. The factors significantly associated with a higher risk of disease progression were Indian ethnicity, infection through intravenous drug use, lower CD4 count, and hemoglobin ≤130 g/dL at 6 months. In conclusion, measurements of CD4 count and hemoglobin at month 6 may be useful for early identification of disease progression in resource-limited settings. PMID:23422741

Enhancement of soluble CD28 levels in the serum of Graves' disease.

PubMed

Sun, Zhongwen; Yi, Lixian; Tao, Hong; Huang, Jingfang; Jin, Zhenghong; Xiao, Yang; Feng, Caiyun; Sun, Jing

2014-01-01

Graves' disease is an autoimmune disease of the thyroid gland mediated by T cells. CD28, a member of costimulatory molecules, plays a pivotal role in regulating T-cell responses. Plasma-soluble CD28 is one form of CD28 in peripheral blood. To investigate the concentrations of soluble CD28 in patients with Graves' disease, we used a sensitive dual monoclonal antibody sandwich enzyme-linked immunosorbent assay (ELISA) to detect the soluble form of CD28. Our results suggested that mean concentrations of soluble CD28 in plasma of patients with Graves' disease were 1.79 ±1.52 ng/ml, and levels of soluble CD28 in healthy subjects were only 0.83 ±1.35 ng/ml. Concentrations of soluble CD28 detected in patients with Graves' disease were significantly higher than those of healthy subjects (p < 0.01). Moreover, there was a significant positive correlation between the concentrations of soluble CD28 in plasma and levels of FT3 (r = 0.663), FT4 (r = 0.624) and TRAb (r = 0.728) in serum, but a negative correlation was found between sCD28 levels and TSH (r = -0.726). Through in vitro experiments we observed that engagement of soluble CD28 protein and B7-1/B7-2 molecules expressed on dendritic cells could exert the secretion of cytokine IL-6, which may promote the production of autoantibody and aggravate Graves' disease. Therefore, aberrant elevation of plasma-soluble CD28 in patients with Graves' disease may reflect the dysregulation of immune system, and may serve as a useful biomarker in Graves' disease diagnosis.

Blocking of CD1d Decreases Trypanosoma cruzi-Induced Activation of CD4-CD8- T Cells and Modulates the Inflammatory Response in Patients With Chagas Heart Disease.

PubMed

Passos, Lívia Silva Araújo; Villani, Fernanda Nobre Amaral; Magalhães, Luísa Mourão Dias; Gollob, Kenneth J; Antonelli, Lis Ribeiro do Vale; Nunes, Maria Carmo Pereira; Dutra, Walderez Ornelas

2016-09-15

The control of inflammatory responses to prevent the deadly cardiac pathology in human Chagas disease is a desirable and currently unattained goal. Double-negative (DN) T cells are important sources of inflammatory and antiinflammatory cytokines in patients with Chagas heart disease and those with the indeterminate clinical form of Chagas disease, respectively. Given the importance of DN T cells in immunoregulatory processes and their potential as targets for controlling inflammation-induced pathology, we studied the involvement of CD1 molecules in the activation and functional profile of Trypanosoma cruzi-specific DN T cells. We observed that parasite stimulation significantly increased the expression of CD1a, CD1b, CD1c, and CD1d by CD14(+) cells from patients with Chagas disease. Importantly, among the analyzed molecules, only CD1d expression showed an association with the activation of DN T cells, as well as with worse ventricular function in patients with Chagas disease. Blocking of CD1d-mediated antigen presentation led to a clear reduction of DN T-cell activation and a decrease in the expression of interferon γ (IFN-γ) by DN T cells. Thus, our results showed that antigen presentation via CD1d is associated with activation of DN T cells in Chagas disease and that CD1d blocking leads to downregulation of IFN-γ by DN T cells from patients with Chagas heart disease, which may be a potential target for preventing progression of inflammation-mediated dilated cardiomyopathy. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Artificial intelligence techniques applied to the development of a decision–support system for diagnosing celiac disease

PubMed Central

Tenório, Josceli Maria; Hummel, Anderson Diniz; Cohrs, Frederico Molina; Sdepanian, Vera Lucia; Pisa, Ivan Torres; de Fátima Marin, Heimar

2013-01-01

Background Celiac disease (CD) is a difficult-to-diagnose condition because of its multiple clinical presentations and symptoms shared with other diseases. Gold-standard diagnostic confirmation of suspected CD is achieved by biopsying the small intestine. Objective To develop a clinical decision–support system (CDSS) integrated with an automated classifier to recognize CD cases, by selecting from experimental models developed using intelligence artificial techniques. Methods A web-based system was designed for constructing a retrospective database that included 178 clinical cases for training. Tests were run on 270 automated classifiers available in Weka 3.6.1 using five artificial intelligence techniques, namely decision trees, Bayesian inference, k-nearest neighbor algorithm, support vector machines and artificial neural networks. The parameters evaluated were accuracy, sensitivity, specificity and area under the ROC curve (AUC). AUC was used as a criterion for selecting the CDSS algorithm. A testing database was constructed including 38 clinical CD cases for CDSS evaluation. The diagnoses suggested by CDSS were compared with those made by physicians during patient consultations. Results The most accurate method during the training phase was the averaged one-dependence estimator (AODE) algorithm (a Bayesian classifier), which showed accuracy 80.0%, sensitivity 0.78, specificity 0.80 and AUC 0.84. This classifier was integrated into the web-based decision–support system. The gold-standard validation of CDSS achieved accuracy of 84.2% and k = 0.68 (p < 0.0001) with good agreement. The same accuracy was achieved in the comparison between the physician’s diagnostic impression and the gold standard k = 0. 64 (p < 0.0001). There was moderate agreement between the physician’s diagnostic impression and CDSS k = 0.46 (p = 0.0008). Conclusions The study results suggest that CDSS could be used to help in diagnosing CD, since the algorithm tested achieved excellent accuracy in differentiating possible positive from negative CD diagnoses. This study may contribute towards developing of a computer-assisted environment to support CD diagnosis. PMID:21917512

Diet adherence and gluten exposure in coeliac disease and self-reported non-coeliac gluten sensitivity.

PubMed

Løvik, A; Skodje, G; Bratlie, J; Brottveit, M; Lundin, K E A

2017-02-01

Adherence to gluten-free diet in self reported non-coeliac gluten sensitive subjects is scarcely researched. Objectives of the study were to compare dietary adherence in coeliac disease (CD) subjects and in non-coeliac gluten sensitive (NCGS) subjects, and to estimate gluten exposure based on weighed food records and analysis of gluten content in selected food items. Twenty-three subjects with biopsy verified CD on a gluten-free diet and 34 HLA-DQ2 + NCGS subjects on a self-instituted gluten-free diet were enrolled. The latter group was under investigation of CD. Dietary adherence was assessed by frequency questionnaire and structured forms supplied by weighed food records. For the analyses of food samples, the sandwich R5-ELISA, Ridascreen ® Gliadin competitive method was used. There was no difference in dietary adherence between CD and NCGS subjects (83% vs 68%, p = 0.21). NCGS subjects were mainly self-educated in gluten-free diet compared to CD subjects (91% and 39%, respectively, p < 0.001). In non-adherent subjects, there was no difference in gluten exposure between CD and NCGS (10 vs 138 mg/day, p = 0.83). There was no difference in BMR-factor between CD and NCGS subjects, or between adherent and non-adherent subjects. Both CD and NCGS subjects were largely adherent, and adherence did not differ between the groups. Gluten exposure varied greatly, and some CD and NCGS subjects reached gluten intake above 500 mg/day, which might have considerable health effects on the individual, especially in case of coeliac disease. Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Cigarette smoke induces β2-integrin-dependent neutrophil migration across human endothelium

PubMed Central

2011-01-01

Background Cigarette smoking induces peripheral inflammatory responses in all smokers and is the major risk factor for neutrophilic lung disease such as chronic obstructive pulmonary disease. The aim of this study was to investigate the effect of cigarette smoke on neutrophil migration and on β2-integrin activation and function in neutrophilic transmigration through endothelium. Methods and results Utilizing freshly isolated human PMNs, the effect of cigarette smoke on migration and β2-integrin activation and function in neutrophilic transmigration was studied. In this report, we demonstrated that cigarette smoke extract (CSE) dose dependently induced migration of neutrophils in vitro. Moreover, CSE promoted neutrophil adherence to fibrinogen. Using functional blocking antibodies against CD11b and CD18, it was demonstrated that Mac-1 (CD11b/CD18) is responsible for the cigarette smoke-induced firm adhesion of neutrophils to fibrinogen. Furthermore, neutrophils transmigrated through endothelium by cigarette smoke due to the activation of β2-integrins, since pre-incubation of neutrophils with functional blocking antibodies against CD11b and CD18 attenuated this transmigration. Conclusion This is the first study to describe that cigarette smoke extract induces a direct migratory effect on neutrophils and that CSE is an activator of β2-integrins on the cell surface. Blocking this activation of β2-integrins might be an important target in cigarette smoke induced neutrophilic diseases. PMID:21651795

[Celiac disease - disease of children and adults: symptoms, disease complications, risk groups and comorbidities].

PubMed

Majsiak, Emilia; Cichoż-Lach, Halina; Gubska, Olena; Cukrowska, Bożena

2018-01-23

About 1% of human population suffers from celiac disease (CD) and it is one of the most commonly diagnosed autoimmune disorders. Until recently it was believed that CD affects mainly children, but as the newest studies show, up to 60% recently diagnosed patients are adults, often over the age of 60. CD's medical signs are nonspecific. Atypical course of the disease with extraintestinal symptoms is being increasingly observed. The disease may also be asymptomatic over many years. The studies show that the average diagnosis of CD takes more than 10 years since the first symptoms appear. Nonspecific medical signs cause undiagnosed patients suffering from CD to visit gastroenterologists, endocrinologists, allergists, gynaecologists and other medical specialists. However, most frequently general practitioners have the first encounter with patients suffering from CD, therefore they are able to recognize symptoms of the disease at the earliest and refer the patient to a gastroenterologist. Early diagnosis and beginning of the treatment reduce complications of untreated CD. The aim of this paper is to show general practitioners symptoms, disease complications, risk groups and comorbidities of CD.

Assessing the educational needs of Canadian gastroenterologists and gastroenterology nurses: Challenges to optimal care in Crohn’s disease

PubMed Central

Dupuis, Martin; Marshall, John K; Hayes, Sean M; Cytryn, Kayla; Murray, Suzanne

2009-01-01

OBJECTIVE: A national needs assessment of Canadian gastroenterologists and gastroenterology nurses was undertaken to determine the perceived and unperceived educational and performance barriers to caring for patients with Crohn’s disease (CD). METHODS: A triangulated, mixed-method approach (qualitative and quantitative) was used to determine the nature and extent of knowledge gaps and barriers in the care of patients with CD. RESULTS: Qualitative interviews were conducted with nine gastroenterologists, four gastroenterology nurses and nine patients with CD. Based on this exploratory research, a survey was designed and launched nationally (37 gastroenterologists, 36 gastroenterology nurses). Findings indicated that Canadian gastroenterologists and gastroenterology nurses lacked clarity regarding their roles and responsibilities across the continuum of CD care, and face communication gaps within the health care team, undermining their effectiveness. Gastroenterologists identified challenges in optimal diagnosis due to unclear testing and diagnostic criteria. They recognized knowledge gaps when treating patient subgroups and in prescribing biological therapies. Furthermore, gastroenterologists self-identified gaps in skill, knowledge, and confidence in monitoring disease progression and effectively assessing response to therapy. When managing patients with CD, gastroenterologists expressed challenges with patient issues outside their domain of medical expertise, particularly with the skills needed to facilitate effective patient communication and education that would enhance adherence to recommended treatments. CONCLUSIONS: Educational initiatives should address diagnostic and treatment guidelines, as well as enhancement of clinical performance gaps in health care team processes and the patient-professional therapeutic relationship. To impact care and patient outcomes, these initiatives must be relevant to clinical practice settings and applicable to the practice context. PMID:20011732

Fluorescence turn-on sensing of trace cadmium ions based on EDTA-etched CdTe@CdS quantum dot.

PubMed

Wang, Si-Nan; Zhu, Jian; Li, Xin; Li, Jian-Jun; Zhao, Jun-Wu

2018-05-01

Cadmium-caused environmental pollution and diseases have always been worldwide problems. Thus it is extremely urgent to establish a cheap, rapid, simple and selective detection method for trace cadmium in drinking water. In this study, a fluorescence "turn-on" method based on ethylene diamine tetraacetic acid (EDTA)-etched CdTe@CdS quantum dots (QDs) was designed to detect Cd 2+ . High resolution transmission electron microscopy (HRTEM) and X-ray photoelectron spectroscopy (XPS) were utilized for chemical and structural characterization of the as-prepared QDs. Based on chemical etching of EDTA on the surface of CdTe@CdS QDs, specific Cd 2+ recognition sites were produced, and then results in fluorescence quenching. The introduction of Cd 2+ could identify these sites and restore the fluorescence of the EDTA-QDs system. Under the optimum conditions, the nanoprobe shows a linear response range from 0.05 to 9 μM with a very low detection limit of 0.032 μM. In addition, the reported fluorescence probe in this work displays a good selectivity for trace Cd 2+ over other metal ions and an admirable practicability in real water samples. Copyright © 2018 Elsevier B.V. All rights reserved.

Cost and efficiency of a hybrid mobile multi-disease testing approach with high HIV testing coverage in East Africa

PubMed Central

Chang, Wei; Chamie, Gabriel; Mwai, Daniel; Clark, Tamara D.; Thirumurthy, Harsha; Charlebois, Edwin D.; Petersen, Maya; Kabami, Jane; Ssemmondo, Emmanuel; Kadede, Kevin; Kwarisiima, Dalsone; Sang, Norton; Bukusi, Elizabeth A.; Cohen, Craig R.; Kamya, Moses; Havlir, Diane V.; Kahn, James G.

2016-01-01

Background In 2013-14, we achieved 89% adult HIV testing coverage using a hybrid testing approach in 32 communities in Uganda and Kenya (SEARCH: NCT01864603). To inform scalability, we sought to determine: 1) overall cost and efficiency of this approach; and 2) costs associated with point-of-care (POC) CD4 testing, multi-disease services, and community mobilization. Methods We applied micro-costing methods to estimate costs of population-wide HIV testing in 12 SEARCH Trial communities. Main intervention components of the hybrid approach are census, multi-disease community health campaigns (CHC), and home-based testing (HBT) for CHC non-attendees. POC CD4 tests were provided for all HIV-infected participants. Data were extracted from expenditure records, activity registers, staff interviews, and time and motion logs. Results The mean cost per adult tested for HIV was $20.5 (range: $17.1 - $32.1) [2014 US$], including a POC CD4 test at $16 per HIV+ person identified. Cost per adult tested for HIV was $13.8 at CHC vs. $31.7 via HBT. The cost per HIV+ adult identified was $231 ($87 - $1,245), with variability due mainly to HIV prevalence among persons tested (i.e., HIV positivity rate). The marginal costs of multi-disease testing at CHCs were $1.16/person for hypertension and diabetes, and $0.90 for malaria. Community mobilization constituted 15.3% of total costs. Conclusions The hybrid testing approach achieved very high HIV testing coverage, with POC CD4, at costs similar to previously reported mobile, home-based, or venue-based HIV testing approaches in sub-Saharan Africa. By leveraging HIV infrastructure, multi-disease services were offered at low marginal costs. PMID:27741031

Internalizing the threat of risk-a qualitative study about adolescents’ experience living with screening-detected celiac disease 5 years after diagnosis

PubMed Central

2014-01-01

Background Mass screening could identify those with unrecognized celiac disease (CD), but the experience of being detected through screening and living with screening-detected CD should be explored before considering this as acceptable intervention. For this study we invited screening-detected adolescents to describe their experience living with screening-detected CD five years after diagnosis with the aim to explore how their perceptions, practices, and beliefs evolved. Methods Adolescents who were diagnosed through a population-based CD screening were invited to write narratives after being diagnosed. Of 153 adolescents who were eventually diagnosed through the screening, 91 wrote narratives one year after diagnosis and 72 five years after diagnosis. A qualitative content analysis resulted in a theme and categories that describe the experience living with screening-detected CD five years after diagnosis. Results The overall theme – Internalizing the threat of risk – illustrates that being detected through screening and the internalized threat of future health complications have impacted how these adolescents felt about the diagnosis, coped with the gluten-free diet (GFD), and thought about CD screening. This theme is supported by four categories: maintaining an imposed disease identity describes how they continued to define their diagnosis in relation to the screening. They also expressed moving from forced food changes to adapted diet routines by describing habits, routines, coping strategies, and the financial burden of the GFD. They had enduring beliefs of being spared negative consequences, however, even after five years, some doubted they had CD and worried that being detected and eating a GFD might not be beneficial, i.e. continuing to fear it is “all in vain”. Conclusions There was maintenance and evolution in the perceptions, practices, and beliefs of the adolescents after five years. Some have adjusted to the disease and adapted new habits and coping strategies to deal with the GFD, while others still doubt they have CD or that being detected was beneficial. The transition to adapting to the disease and GFD is ongoing, illustrating the importance of providing ongoing support for those with screening-detected CD as they adjust to this chronic disease and the GFD. PMID:24915870

Impact of benznidazole treatment on the functional response of Trypanosoma cruzi antigen-specific CD4+CD8+ T cells in chronic Chagas disease patients.

PubMed

Pérez-Antón, Elena; Egui, Adriana; Thomas, M Carmen; Puerta, Concepción J; González, John Mario; Cuéllar, Adriana; Segovia, Manuel; López, Manuel Carlos

2018-05-11

Chagas disease is caused by Trypanosoma cruzi. The persistence of the parasite is associated with the disease chronicity and the impairment of the cellular immune response. It has been reported that the CD4+CD8+ T cell population expands in chronic Chagas disease patients. Few studies have focused on this subset of cells, and very little is known about the impact of antiparasitic treatment on this population. Thirty-eight chronic Chagas disease patients (20 asymptomatic and 18 symptomatic) and twelve healthy controls were enrolled in this study. Peripheral blood mononuclear cells were stimulated with soluble T. cruzi antigens to analyze the production of cytokines and cytotoxic molecules by CD4+CD8+ T cells before and after benznidazole treatment. Additionally, expression and co-expression of five inhibitory receptors in these patients after treatment were studied using a multiparameter flow cytometry technique. The frequency of CD4+CD8+ T cells was higher in chronic Chagas disease patients compared with healthy donors. Furthermore, a higher ratio of CD4+CD8low/CD4+CD8high subpopulations was observed in chronic Chagas disease patients than in healthy donors. Additionally, CD4+CD8+ T cells from these patients expressed and co-expressed higher levels of inhibitory receptors in direct proportion to the severity of the pathology. Benznidazole treatment reduced the frequency of CD4+CD8+ T cells and decreased the ratio of CD4+CD8low/CD4+CD8high subpopulations. The co-expression level of the inhibitory receptor was reduced after treatment simultaneously with the enhancement of the multifunctional capacity of CD4+CD8+ T cells. After treatment, an increase in the frequency of T. cruzi antigen-specific CD4+CD8+ T cells expressing IL-2 and TNF-α was also observed. CD4+CD8+ T cells could play an important role in the control of T. cruzi infection since they were able to produce effector molecules for parasite control. Benznidazole treatment partially reversed the exhaustion process caused by T. cruzi infection in these cells with an improvement in the functional response of the T. cruzi antigen-specific CD4+CD8+ T cells.

Impact of benznidazole treatment on the functional response of Trypanosoma cruzi antigen-specific CD4+CD8+ T cells in chronic Chagas disease patients

PubMed Central

Pérez-Antón, Elena; Egui, Adriana; Thomas, M. Carmen; Puerta, Concepción J.; González, John Mario; Cuéllar, Adriana; Segovia, Manuel

2018-01-01

Background Chagas disease is caused by Trypanosoma cruzi. The persistence of the parasite is associated with the disease chronicity and the impairment of the cellular immune response. It has been reported that the CD4+CD8+ T cell population expands in chronic Chagas disease patients. Few studies have focused on this subset of cells, and very little is known about the impact of antiparasitic treatment on this population. Methodology Thirty-eight chronic Chagas disease patients (20 asymptomatic and 18 symptomatic) and twelve healthy controls were enrolled in this study. Peripheral blood mononuclear cells were stimulated with soluble T. cruzi antigens to analyze the production of cytokines and cytotoxic molecules by CD4+CD8+ T cells before and after benznidazole treatment. Additionally, expression and co-expression of five inhibitory receptors in these patients after treatment were studied using a multiparameter flow cytometry technique. Principal findings The frequency of CD4+CD8+ T cells was higher in chronic Chagas disease patients compared with healthy donors. Furthermore, a higher ratio of CD4+CD8low/CD4+CD8high subpopulations was observed in chronic Chagas disease patients than in healthy donors. Additionally, CD4+CD8+ T cells from these patients expressed and co-expressed higher levels of inhibitory receptors in direct proportion to the severity of the pathology. Benznidazole treatment reduced the frequency of CD4+CD8+ T cells and decreased the ratio of CD4+CD8low/CD4+CD8high subpopulations. The co-expression level of the inhibitory receptor was reduced after treatment simultaneously with the enhancement of the multifunctional capacity of CD4+CD8+ T cells. After treatment, an increase in the frequency of T. cruzi antigen-specific CD4+CD8+ T cells expressing IL-2 and TNF-α was also observed. Conclusions CD4+CD8+ T cells could play an important role in the control of T. cruzi infection since they were able to produce effector molecules for parasite control. Benznidazole treatment partially reversed the exhaustion process caused by T. cruzi infection in these cells with an improvement in the functional response of the T. cruzi antigen-specific CD4+CD8+ T cells. PMID:29750791

CD4+ Foxp3+ T cells promote aberrant immunoglobulin G production and maintain CD8+ T-cell suppression during chronic liver disease.

PubMed

Tedesco, Dana; Thapa, Manoj; Gumber, Sanjeev; Elrod, Elizabeth J; Rahman, Khalidur; Ibegbu, Chris C; Magliocca, Joseph F; Adams, Andrew B; Anania, Frank; Grakoui, Arash

2017-02-01

Persistent hepatotropic viral infections are a common etiologic agent of chronic liver disease. Unresolved infection can be attributed to nonfunctional intrahepatic CD8+ T-cell responses. In light of dampened CD8 + T-cell responses, liver disease often manifests systemically as immunoglobulin (Ig)-related syndromes due to aberrant B-cell functions. These two opposing yet coexisting phenomena implicate the potential of altered CD4 + T-cell help. Elevated CD4 + forkhead box P3-positive (Foxp3+) T cells were evident in both human liver disease and a mouse model of chemically induced liver injury despite marked activation and spontaneous IgG production by intrahepatic B cells. While this population suppressed CD8 + T-cell responses, aberrant B-cell activities were maintained due to expression of CD40 ligand on a subset of CD4 + Foxp3+ T cells. In vivo blockade of CD40 ligand attenuated B-cell abnormalities in a mouse model of liver injury. A phenotypically similar population of CD4 + Foxp3+, CD40 ligand-positive T cells was found in diseased livers explanted from patients with chronic hepatitis C infection. This population was absent in nondiseased liver tissues and peripheral blood. Liver disease elicits alterations in the intrahepatic CD4 + T-cell compartment that suppress T-cell immunity while concomitantly promoting aberrant IgG mediated manifestations. (Hepatology 2017;65:661-677). © 2016 by the American Association for the Study of Liver Diseases.

Low CD1c + myeloid dendritic cell counts correlated with a high risk of rapid disease progression during early HIV-1 infection.

PubMed

Diao, Yingying; Geng, Wenqing; Fan, Xuejie; Cui, Hualu; Sun, Hong; Jiang, Yongjun; Wang, Yanan; Sun, Amy; Shang, Hong

2015-08-19

During early HIV-1 infection (EHI), the interaction between the immune response and the virus determines disease progression. Although CD1c + myeloid dendritic cells (mDCs) can trigger the immune response, the relationship between CD1c + mDC alteration and disease progression has not yet been defined. EHI changes in CD1c + mDC counts, surface marker (CD40, CD86, CD83) expression, and IL-12 secretion were assessed by flow cytometry in 29 patients. When compared with the normal controls, patients with EHI displayed significantly lower CD1c + mDC counts and IL-12 secretion and increased surface markers. CD1c + mDC counts were positively correlated with CD4+ T cell counts and inversely associated with viral loads. IL-12 secretion was only positively associated with CD4+ T cell counts. Rapid progressors had lower counts, CD86 expression, and IL-12 secretion of CD1c + mDCs comparing with typical progressors. Kaplan-Meier analysis and Cox regression models suggested patients with low CD1c + mDC counts (<10 cells/μL) had a 4-fold higher risk of rapid disease progression than those with high CD1c + mDC counts. However, no relationship was found between surface markers or IL-12 secretion and disease progression. During EHI, patients with low CD1c + mDC counts were more likely to experience rapid disease progression than those with high CD1c + mDC counts.

Chronic exposure to water pollutant trichloroethylene increased epigenetic drift in CD4+ T cells

PubMed Central

Gilbert, Kathleen M; Blossom, Sarah J; Erickson, Stephen W; Reisfeld, Brad; Zurlinden, Todd J; Broadfoot, Brannon; West, Kirk; Bai, Shasha; Cooney, Craig A

2016-01-01

Aim: Autoimmune disease and CD4+ T-cell alterations are induced in mice exposed to the water pollutant trichloroethylene (TCE). We examined here whether TCE altered gene-specific DNA methylation in CD4+ T cells as a possible mechanism of immunotoxicity. Materials & methods: Naive and effector/memory CD4+ T cells from mice exposed to TCE (0.5 mg/ml in drinking water) for 40 weeks were examined by bisulfite next-generation DNA sequencing. Results: A probabilistic model calculated from multiple genes showed that TCE decreased methylation control in CD4+ T cells. Data from individual genes fitted to a quadratic regression model showed that TCE increased gene-specific methylation variance in both CD4 subsets. Conclusion: TCE increased epigenetic drift of specific CpG sites in CD4+ T cells. PMID:27092578

OSI-027 modulates acute graft-versus-host disease after liver transplantation in a rat model.

PubMed

Zhi, Xiao; Xue, Fei; Chen, Wei; Liang, Chao; Liu, Hao; Ma, Tao; Xia, Xuefeng; Hu, Liqiang; Bai, Xueli; Liang, Tingbo

2017-09-01

Despite its rarity (1%-2%), acute graft-versus-host disease after liver transplantation (LT-aGVHD) has a high mortality rate (85%). A gradual decrease in regulatory T cells (Tregs) correlates with disease progression in a rat LT-GVHD model, and treatments which increase Tregs exert therapeutic effects on LT-aGVHD. In this study, LT-aGVHD model rats were treated with rapamycin (RAPA), OSI-027, or an equal quantity of vehicle. Rats treated with OSI-027 survived longer (>100 days) than those in the RAPA (70 ± 8 days) or control (24 ± 3 days) groups. Flow cytometric analysis showed that the Treg ratios in peripheral blood mononuclear cells in the OSI-027 group were higher than those in the RAPA or control groups. The proportions of donor-derived lymphocytes in the OSI-027 group were lower than those in the RAPA or control groups. Hematoxylin-eosin staining of skin tissue demonstrated less severe lymphocyte infiltration in the OSI-027 group than that in the RAPA or control groups. In vitro, OSI-027 induced differentiation of CD4 + CD25 - T cells into CD4 + CD25 + forkhead box P3 + Tregs. Furthermore, injection of OSI-027-induced donor-derived CD4 + CD25 + T cells into the peripheral blood of LT-aGVHD model rats prevented LT-aGVHD. Thus, OSI-027 is implicated as a novel method for the treatment of LT-aGVHD. Liver Transplantation 23 1186-1198 2017 AASLD. © 2017 by the American Association for the Study of Liver Diseases.

Impact of Two Measures of Micrometastatic Disease on Clinical Outcomes in Patients with Newly Diagnosed Ewing Sarcoma: A Report from the Children’s Oncology Group

PubMed Central

Vo, Kieuhoa T.; Edwards, Jeremy V.; Epling, C. Lorrie; Sinclair, Elizabeth; Hawkins, Douglas S.; Grier, Holcombe E.; Janeway, Katherine A.; Barnette, Phillip; McIlvaine, Elizabeth; Krailo, Mark D.; Barkauskas, Donald A.; Matthay, Katherine K.; Womer, Richard B.; Gorlick, Richard G.; Lessnick, Stephen L.; Mackall, Crystal L.; DuBois, Steven G.

2016-01-01

Purpose Flow cytometry and RT-PCR can detect occult Ewing sarcoma (ES) cells in the blood and bone marrow (BM). These techniques were used to evaluate the prognostic significance of micrometastatic disease in ES. Experimental Design Newly diagnosed patients with ES were enrolled on two prospective multi-center studies. In the flow cytometry cohort, patients were defined as “positive” for BM micrometastatic disease if their CD99+/CD45− values were above the upper limit in 22 control patients. In the PCR cohort, RT-PCR on blood or BM samples classified the patients as “positive” or “negative” for EWSR1/FLI1 translocations. The association between micrometastatic disease burden with clinical features and outcome was assessed. Co-expression of IGF-1R on detected tumor cells was performed in a subset of flow cytometry samples. Results The median total BM CD99+CD45− percent was 0.0012% (range 0–1.10%) in the flow cytometry cohort, with 14/109 (12.8%) of ES patients defined as “positive.” In the PCR cohort, 19.6% (44/225) patients were “positive” for any EWSR1/FLI1 translocation in blood or BM. There were no differences in baseline clinical features or event-free or overall survival between patients classified as “positive” vs. “negative” by either method. CD99+CD45− cells had significantly higher IGF-1R expression compared to CD45+ hematopoietic cells (mean geometric mean fluorescence intensity 982.7 vs. 190.9; p<0.001). Conclusion The detection of micrometastatic disease at initial diagnosis by flow cytometry or RT-PCR is not associated with outcome in newly diagnosed patients with ES. Flow cytometry provides a tool to characterize occult micrometastatic tumor cells for proteins of interest. PMID:26861456

Inflammatory bowel disease in Bahrain: single-center experience

PubMed Central

Abdulla, Maheeba; Al Saeed, Mahmood; Fardan, Rawdha Hameed; Alalwan, Hawra Faisal; Ali Almosawi, Zahra S; Almahroos, Amal Fuad; Al Qamish, Jehad

2017-01-01

Purpose The number of newly diagnosed inflammatory bowel disease (IBD) cases such as ulcerative colitis (UC), Crohn’s disease (CD), and indeterminate colitis (IC) is rapidly increasing in Gulf countries and Saudi Arabia. The aim of this study was to investigate the incidence and prevalence of IBD in patients who have attended the Salmaniya Medical Complex, Bahrain, between the years 1984 and 2014. Patients and methods All patients who had attended the Salmaniya Medical Complex, Bahrain, and had been diagnosed with UC, CD, or IC, between the years 1984 and 2014, were included in the analysis. Data collected were: patient demographics, symptoms, clinical signs, complications, surgical interventions, extent of disease, endoscopic findings, histopathology, and lab measurements. Results A total of 187 cases were included; 61 had CD, 123 had UC, and a further 3 cases presented with IC. A clear increase in the incidence and prevalence of IBD can be seen in this cohort. The prevalence of IBD was calculated to be 26.25/105 cases. The average number of IBD cases increased from 3 cases (average for the years 1984–2001) to 12 cases (average for the years 2002–2014). A number of factors correlate positively or negatively with CD and UC. In the current study, a link between gastrointestinal complications in CD cases and the use of steroids as a treatment was noted (p-value −0.02). Age also had a significant influence on the need for surgery in CD cases (p-value −0.04), and a family history of UC was statistically linked to surgical intervention (p-value −0.05). Conclusions IBD can no longer be considered a rare disease in Bahrain. The incidence of both UC and CD is steadily increasing. There is a need for increasing awareness of the Bahraini public to IBD in order for proper medical care to be given. PMID:28765713

Fecal Gluten Peptides Reveal Limitations of Serological Tests and Food Questionnaires for Monitoring Gluten-Free Diet in Celiac Disease Patients.

PubMed

Comino, Isabel; Fernández-Bañares, Fernando; Esteve, María; Ortigosa, Luís; Castillejo, Gemma; Fambuena, Blanca; Ribes-Koninckx, Carmen; Sierra, Carlos; Rodríguez-Herrera, Alfonso; Salazar, José Carlos; Caunedo, Ángel; Marugán-Miguelsanz, J M; Garrote, José Antonio; Vivas, Santiago; Lo Iacono, Oreste; Nuñez, Alejandro; Vaquero, Luis; Vegas, Ana María; Crespo, Laura; Fernández-Salazar, Luis; Arranz, Eduardo; Jiménez-García, Victoria Alejandra; Antonio Montes-Cano, Marco; Espín, Beatriz; Galera, Ana; Valverde, Justo; Girón, Francisco José; Bolonio, Miguel; Millán, Antonio; Cerezo, Francesc Martínez; Guajardo, César; Alberto, José Ramón; Rosinach, Mercé; Segura, Verónica; León, Francisco; Marinich, Jorge; Muñoz-Suano, Alba; Romero-Gómez, Manuel; Cebolla, Ángel; Sousa, Carolina

2016-10-01

Treatment for celiac disease (CD) is a lifelong strict gluten-free diet (GFD). Patients should be followed-up with dietary interviews and serology as CD markers to ensure adherence to the diet. However, none of these methods offer an accurate measure of dietary compliance. Our aim was to evaluate the measurement of gluten immunogenic peptides (GIP) in stools as a marker of GFD adherence in CD patients and compare it with traditional methods of GFD monitoring. We performed a prospective, nonrandomized, multicenter study including 188 CD patients on GFD and 84 healthy controls. Subjects were given a dietary questionnaire and fecal GIP quantified by enzyme-linked immunosorbent assay (ELISA). Serological anti-tissue transglutaminase (anti-tTG) IgA and anti-deamidated gliadin peptide (anti-DGP) IgA antibodies were measured simultaneously. Of the 188 celiac patients, 56 (29.8%) had detectable GIP levels in stools. There was significant association between age and GIP in stools that revealed increasing dietary transgressions with advancing age (39.2% in subjects ≥13 years old) and with gender in certain age groups (60% in men ≥13 years old). No association was found between fecal GIP and dietary questionnaire or anti-tTG antibodies. However, association was detected between GIP and anti-DGP antibodies, although 46 of the 53 GIP stool-positive patients were negative for anti-DGP. Detection of gluten peptides in stools reveals limitations of traditional methods for monitoring GFD in celiac patients. The GIP ELISA enables direct and quantitative assessment of gluten exposure early after ingestion and could aid in the diagnosis and clinical management of nonresponsive CD and refractory CD. Trial registration number NCT02711397.

Patients with inflammatory bowel disease have increased risk of autoimmune and inflammatory diseases

PubMed Central

Halling, Morten L; Kjeldsen, Jens; Knudsen, Torben; Nielsen, Jan; Hansen, Lars Koch

2017-01-01

AIM To investigate whether immune mediated diseases (IMD) are more frequent in patients with inflammatory bowel disease (IBD). METHODS In this population based registry study, a total of 47325 patients with IBD were alive and registered in the Danish National Patient Registry on December 16, 2013. Controls were randomly selected from the Danish Civil Registration System (CRS) and matched for sex, age, and municipality. We used ICD 10 codes to identify the diagnoses of the included patients. The IBD population was divided into three subgroups: Ulcerative colitis (UC), Crohn’s disease (CD) and Both the latter referring to those registered with both diagnoses. Subsequently, odds-ratios (OR) and 95%CI were obtained separately for each group and their respective controls. The use of Bonferoni post-test correction adjusted the significance level to P < 0.00125. P-values were estimated using Fisher’s exact test. RESULTS There were significantly more women than men in the registry, and a greater percentage of comorbidity in the IBD groups (P < 0.05). Twenty different IMDs were all significantly more frequent in the IBD group. Sixteen were associated with UC versus twelve with CD. In both UC and CD ORs were significantly increased (P < 0.00125) for primary sclerosing cholangitis (PSC), celiac disease, type 1 diabetes (T1D), sarcoidosis, asthma, iridocyclitis, psoriasis, pyoderma gangrenosum, rheumatoid arthritis, and ankylosing spondylitis. Restricted to UC (P < 0.00125) were autoimmune hepatitis, primary biliary cholangitis, Grave’s disease, polymyalgia rheumatica, temporal arteritis , and atrophic gastritis. Restricted to CD (P < 0.00125) were psoriatic arthritis and episcleritis. Restricted to women with UC (P < 0.00125) were atrophic gastritis, rheumatoid arthritis, temporal arteritis, and polymyalgia rheumatica. Restricted to women with CD were episcleritis, rheumatoid arthritis, and psoriatic arthritis. The only disease restricted to men (P < 0.00125) was sarcoidosis. CONCLUSION Immune mediated diseases were significantly more frequent in patients with IBD. Our results strengthen the hypothesis that some IMDs and IBD may have overlapping pathogenic pathways. PMID:28970729

Differentiated all-trans retinoic acid response of naive CD4+CD25– cells isolated from rats with collagen-induced arthritis and healthy ones under in vitro conditions

PubMed Central

Żyromska, Edyta; Piasecki, Tomasz; Rossowska, Joanna; Kędzierska, Anna; Nowak, Marcin; Żyromski, Marcin; Chełmońska-Soyta, Anna

2017-01-01

Aim o the study To compare the potential of CD4+CD25– cells, isolated from both healthy rats and rats with CIA (Collagen-Induced Arthritis), for differentiation into regulatory T cells in the presence of all-trans retinoic acid in order to learn more about the activation mechanisms and therapeutic potential of regulatory T cells. Material and methods Sorted CD4+CD25– cells were cultured in vitro with/without ATRA, and then the frequency of regulatory T cells and their ability to secrete IL-10 by CD4+ FOXP3+ cells was examined. Gene expression of the foxp3, rarα, rarβ, rxrβ, and ppar β/δ and protein expression of the Rarα, Rarβ, and Rxrβ in cells after stimulation with ATRA were also investigated. Results CD4+CD25– cells isolated from healthy animals or from animals with CIA are characterised by different potential of the differentiation into CD4+CD25+ FOXP3+ cells. Retinoic acid receptor Rxrβ is present in the CD4+CD25– cells isolated from rats with CIA. Conclusions We showed that although ATRA did not increase the frequency of Treg in culture, it significantly increased expression of rarβ and rxrβ only in lymphocytes taken from diseased animals and foxp3 expression only in healthy animals. Moreover, after ATRA stimulation, the frequency of Treg-produced IL-10 tended to be lower in diseased animals than in the healthy group. The results imply that the potential of naïve cell CD4 lymphocytes to differentiate into Tregs and their putative suppressive function is dependent on the donor’s health status. PMID:28680330

Association of the expression of Th cytokines with peripheral CD4 and CD8 lymphocyte subsets after vaccination with FMD vaccine in Holstein young sires.

PubMed

Yang, Ling; Liu, Zhichao; Li, Jianbin; He, Kaili; Kong, Lingna; Guo, Runqing; Liu, Wenjiao; Gao, Yundong; Zhong, Jifeng

2018-05-25

High immune response (HIR) cows have a balanced and robust host defense and lower disease incidence, and immune response is more important to consider for selecting young sires than for selecting cows. The protective immune response against foot-and-mouth disease (FMD) virus infection is T-cell-independent in an animal experimental model. However, there is no convenient method to select young sires with a HIR to FMD virus. In this study, 39 healthy Holstein young sires were vaccinated with the trivalent (A, O and Asia 1) FMD vaccine, and T-lymphocyte subsets in peripheral blood lymphocytes (PBLs) were detected using flow cytometric analysis before and after vaccination. The expression of interferon-gamma (IFN-γ), interleukin-2 (IL-2), IL-4, and IL-6 mRNA in PBLs was analyzed after stimulation by lipopolysaccharide (LPS) or Concanavalin A (ConA) after vaccination. According to the percentage of CD4 + lymphocyte and CD4/CD8 ratio after vaccination for selecting the HIR young sires, the results showed that the percentages of CD3 + , CD4 + , CD3 + CD4 + lymphocytes and the CD4/CD8 ratio in the HIR group were higher compared to those in the medium immune response (MIR) and low immune response (LIR) groups before vaccination. Additionally, the percentage of CD4 + lymphocytes and the CD4/CD8 ratio after vaccination were positively associated with the expression level of IFN-γ mRNA in the PBLs after stimulation by LPS. In conclusion, the in vitro expression level of IFN-γ mRNA in the PBLs stimulated by LPS may serve as a parameter for selecting young sires with a HIR to FMD virus. Copyright © 2018 Elsevier Ltd. All rights reserved.

Immaturity associated antigens are lost during induction for T cell lymphoblastic leukemia: implications for minimal residual disease detection

PubMed Central

Roshal, Mikhail; Fromm, Jonathan R; Winter, Stuart; Dunsmore, Kimberly; Wood, Brent

2011-01-01

Background Induction chemotherapy for acute leukemia often leads to antigenic shifts in residual abnormal blast populations. Studies in precursor B cell ALL (B-ALL) and AML have demonstrated that chemotherapy commonly results in the loss of antigens associated with immaturity, limiting their utility for minimal residual disease (MRD) detection. Little information is available about the stability of these antigens in precursor T cell ALL (T-ALL) though it is presumed that CD99 and TdT are highly informative based on limited studies. Methods In a longitudinal investigation, we explored patterns of lineage specific and immaturity associated antigens in T-ALL in a large cohort of patients treated under the multicenter Children's Oncology Group (COG) protocol. All samples were analyzed using multicolor flow cytometry in a standardized fashion at a single institution. Results We report that markers of immaturity particularly, TdT and CD99 dramatically decline on leukemic blasts during therapy. CD34 and CD10 expression is confined to a minority of pre-treatment samples and is also not stable. In contrast, lineage associated markers including CD2, CD3, CD4, CD5, CD7 and CD8 failed to show significant trends. Conclusions Our study strongly argues for expansion of immunophenotyping panels for T-ALL MRD to decrease reliance on immature antigens. This study represents the first demonstration of consistent immunophenotypic shifts in T-ALL. PMID:20155852

CdS/TiO2-fluorescein isothiocyanate nanoparticles as fluorescence resonance energy transfer probe for the determination of trace alkaline phosphatase based on affinity adsorption assay.

PubMed

Liu, Jia-Ming; Lin, Li-ping; Jiao, Li; Cui, Ma-Lin; Wang, Xin-Xing; Zhang, Li-Hong; Zheng, Zhi-Yong

2012-08-30

The CdS/TiO(2)-fluorescein isothiocyanate (FITC) luminescent nanoparticles (CdS/TiO(2)-FITC) with the particle size of 20 nm have been synthesized by sol-gel method. CdS/TiO(2)-FITC could emit the fluorescence of both FITC and CdS/TiO(2). The fluorescence resonance energy transfer (FRET) occurred between the donor CdS/TiO(2) and the acceptor FITC in the CdS/TiO(2)-FITC. Taking advantages of the excellent characteristics of FRET, a new CdS/TiO(2)-FITC FRET labeling reagent and a CdS/TiO(2)-FITC-wheat germ agglutinin (CdS/TiO(2)-FITC-WGA) fluorescent probe have been developed. The FRET occurring between the donor CdS/TiO(2) and the acceptor FITC in the labelled product CdS/TiO(2)-FITC-WGA-AP, formed in the affinity adsorption reaction between the WGA in this CdS/TiO(2)-FITC-WGA fluorescent probe and alkaline phosphatase (AP), sharply enhanced the fluorescence signal of FITC and quench the fluorescence signal of CdS/TiO(2). Moreover, the ΔF (the change of the fluorescence signal) of FITC and CdS/TiO(2) were proportional to the content of AP, respectively. Thus, a new method that CdS/TiO(2)-fluorescein isothiocyanate nanoparticles for the determination of trace AP based on FRET-affinity adsorption assay has been established. The limit of quantification (LOQ) of the method was 1.3×10(-17) g AP mL(-1) for CdS/TiO(2) and 1.1×10(-17) g AP mL(-1) for FITC, respectively. This sensitive, rapid, high selective and precise method has been applied to the determination of AP in human serum and the prediction of human disease with the results agreed well with enzyme-linked immunosorbent assay (ELISA) in Zhangzhou Municipal Hospital of Fujian Province. Simultaneously, the reaction mechanism for the determination of AP was also discussed. Copyright © 2012 Elsevier B.V. All rights reserved.

Prevalence and predictors of hospitalization in Crohn’s disease in a prospective population-based inception cohort from 2000-2012

PubMed Central

Golovics, Petra A; Lakatos, Laszlo; Mandel, Michael D; Lovasz, Barbara D; Vegh, Zsuzsanna; Kurti, Zsuzsanna; Szita, Istvan; Kiss, Lajos S; Pandur, Tunde; Lakatos, Peter L

2015-01-01

AIM: To analyze the prevalence, length and predictors of hospitalization in the biological era in the population-based inception cohort from Veszprem province. METHODS: Data of 331 incident Crohn’s disease (CD) patients diagnosed between January 1, 2000 and December 31, 2010 were analyzed (median age at diagnosis: 28; IQR: 21-40 years). Both in- and outpatient records were collected and comprehensively reviewed. RESULTS: Probabilities of first CD-related hospitalization and re-hospitalization were 32.3%, 45.5%, 53.7% and 13.6%, 23.9%, 29.8%, respectively after one, three and five years of follow-up in Kaplan-Meier analysis. First-year hospitalizations were related to diagnostic procedures (37%), surgery or disease activity (27% and 21%). Non-inflammatory disease behavior at diagnosis (HR = 1.32, P = 0.001) and perianal disease (HR = 1.47, P = 0.04) were associated with time to first CD-related hospitalization, while disease behavior change (HR = 2.38, P = 0.002) and need for steroids (HR = 3.14, P = 0.003) were associated with time to first re-hospitalization in multivariate analyses. Early CD-related hospitalization (within the year of diagnosis) was independently associated with need for immunosuppressives (OR = 2.08, P = 0.001) and need for surgeries (OR = 7.25, P < 0.001) during the disease course. CONCLUSION: Hospitalization and re-hospitalization rates are still high in this cohort, especially during the first-year after the diagnosis. Non-inflammatory disease behavior at diagnosis was identified as the pivotal predictive factor of both hospitalization and re-hospitalization. PMID:26109815

Detection of gluten immunogenic peptides in the urine of patients with coeliac disease reveals transgressions in the gluten-free diet and incomplete mucosal healing

PubMed Central

Moreno, María de Lourdes; Cebolla, Ángel; Muñoz-Suano, Alba; Carrillo-Carrion, Carolina; Comino, Isabel; Pizarro, Ángeles; León, Francisco; Rodríguez-Herrera, Alfonso; Sousa, Carolina

2017-01-01

Objective Gluten-free diet (GFD) is the only management for coeliac disease (CD). Available methods to assess GFD compliance are insufficiently sensitive to detect occasional dietary transgressions that may cause gut mucosal damage. We aimed to develop a method to determine gluten intake and monitor GFD compliance in patients with CD and to evaluate its correlation with mucosal damage. Design Urine samples of 76 healthy subjects and 58 patients with CD subjected to different gluten dietary conditions were collected. A lateral flow test (LFT) with the highly sensitive and specific G12 monoclonal antibody for the most dominant gluten immunogenic peptides (GIP) and a LFT reader were used to quantify GIP in solid-phase extracted urines. Results GIP were detectable in concentrated urines from healthy individuals previously subjected to GFD as early as 4–6 h after single gluten intake, and remained detectable for 1–2 days. The urine assay revealed infringement of the GFD in about 50% of the patients. Analysis of duodenal biopsies revealed that most of patients with CD (89%) with no villous atrophy had no detectable GIP in urine, while all patients with quantifiable GIP in urine showed incomplete intestinal mucosa recovery. Conclusion GIP are detected in urine after gluten consumption, enabling a new and non-invasive method to monitor GFD compliance and transgressions. The method was sensitive, specific and simple enough to be convenient for clinical monitoring of patients with CD as well as for basic and clinical research applications including drug development. Trial registration number NCT02344758. PMID:26608460

Detection of gluten immunogenic peptides in the urine of patients with coeliac disease reveals transgressions in the gluten-free diet and incomplete mucosal healing.

PubMed

Moreno, María de Lourdes; Cebolla, Ángel; Muñoz-Suano, Alba; Carrillo-Carrion, Carolina; Comino, Isabel; Pizarro, Ángeles; León, Francisco; Rodríguez-Herrera, Alfonso; Sousa, Carolina

2017-02-01

Gluten-free diet (GFD) is the only management for coeliac disease (CD). Available methods to assess GFD compliance are insufficiently sensitive to detect occasional dietary transgressions that may cause gut mucosal damage. We aimed to develop a method to determine gluten intake and monitor GFD compliance in patients with CD and to evaluate its correlation with mucosal damage. Urine samples of 76 healthy subjects and 58 patients with CD subjected to different gluten dietary conditions were collected. A lateral flow test (LFT) with the highly sensitive and specific G12 monoclonal antibody for the most dominant gluten immunogenic peptides (GIP) and a LFT reader were used to quantify GIP in solid-phase extracted urines. GIP were detectable in concentrated urines from healthy individuals previously subjected to GFD as early as 4-6 h after single gluten intake, and remained detectable for 1-2 days. The urine assay revealed infringement of the GFD in about 50% of the patients. Analysis of duodenal biopsies revealed that most of patients with CD (89%) with no villous atrophy had no detectable GIP in urine, while all patients with quantifiable GIP in urine showed incomplete intestinal mucosa recovery. GIP are detected in urine after gluten consumption, enabling a new and non-invasive method to monitor GFD compliance and transgressions. The method was sensitive, specific and simple enough to be convenient for clinical monitoring of patients with CD as well as for basic and clinical research applications including drug development. NCT02344758. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Diagnostic Delay in Romanian Patients with Inflammatory Bowel Disease: Risk Factors and Impact on the Disease Course and Need for Surgery

PubMed Central

Zaharie, Roxana; Zaharie, Florin; Tantau, Marcel; Gheorghe, Liana; Gheorghe, Cristian; Gologan, Serban; Cijevschi, Cristina; Trifan, Anca; Dobru, Daniela; Goldis, Adrian; Constantinescu, Gabriel; Iacob, Razvan; Diculescu, Mircea

2016-01-01

Background: The epidemiology of inflammatory bowel disease [IBD] in Eastern Europe is poorly understood, particularly with regard to diagnostic delay. Here we investigated the factors leading to delayed diagnosis and the effect of the delay on several disease progression and outcome measures. Methods: A total of 1196 IBD cases [682 ulcerative colitis [UC], 478 Crohn’s disease [CD], 36 indeterminate colitis] from the Romanian national registry IBDPROSPECT were reviewed. Standard clinical and demographic factors were evaluated as predictors of a long diagnostic delay in both CD and UC. Diagnostic delay was subsequently evaluated as a potential risk factor for bowel stenoses, bowel fistulas, perianal fistulas, perianal surgery, and intestinal surgery in CD patients. Results: The median diagnostic delay was significantly longer in CD [5 months] than in UC [1 month] patients [p < 0.001]. Compared with 5 months for UC patients, 75% of CD patients were diagnosed within 18 months of symptom onset. In CD patients, extra-ileal location was a protective factor (odds ratio [OR], 0.5; p = 0.03), whereas being an active smoker [OR, 2.09; p = 0.01] and symptom onset during summer [OR, 3.35; p < 0.001] were independent risk factors for a long diagnostic delay [> 18 months]. In UC patients, an age > 40 years was a protective factor [OR, 0.68; p = 0.04] for a long delay. Regarding outcomes, a long diagnostic delay in CD patients positively correlated with bowel stenoses [OR, 3.38; p < 0.01] and any IBD-related surgery [OR, 1.95; p = 0.03] and had a positive trend for intestinal fistulas [OR, 2.64; p = 0.08] and perianal fistulas [OR, 2.9; p = 0.07]. Disease duration since diagnosis positively correlated with bowel stenoses [OR, 1.04; p = 0.04], any IBD-related surgery [OR, 1.04; p = 0.02], and intestinal surgery [OR, 1.07; p < 0.01]. Conclusions: A long diagnostic delay in IBD correlates with an increased frequency of bowel stenoses and need for IBD-related surgery. PMID:26589956

Platelets Play Differential Role During the Initiation and Progression of Autoimmune Neuroinflammation

PubMed Central

Starossom, Sarah C.; Veremeyko, Tatyana; Yung, Amanda W. Y.; Dukhinova, Marina; Au, Cheryl; Lau, Alexander Y.; Weiner, Howard L.; Ponomarev, Eugene D.

2015-01-01

Rationale Platelets are known to participate in vascular pathologies; however, their role in neuroinflammatory diseases such as multiples sclerosis (MS) is unknown. Autoimmune CD4 T cells have been the main focus of studies of MS, although the factors that regulate T cell differentiation towards pathogenic Th1/Th17 phenotypes are not completely understood. Objectives We investigated the role of platelets in the modulation of CD4 T cell functions in MS patients and in mice with experimental autoimmune encephalitis (EAE), an animal model for MS. Methods and Results We found that early in MS and EAE platelets degranulated and produced a number of soluble factors serotonin (5HT), PF4 and PAF, which specifically stimulated differentiation of T cells towards pathogenic Th1, Th17 and IFN-γ/IL-17-producing CD4 T cells. At the later stages of MS and EAE platelets became exhausted in their ability to produce proinflammatory factors and stimulate CD4 T cells, but substantially increased their ability to form aggregates with CD4 T cells. Formation of platelet-CD4 T cell aggregates involved interaction of CD62P on activated platelets with adhesion molecule CD166 on activated CD4 T cells, contributing to downmodulation of CD4 T cell activation, proliferation and production of IFN-γ. Blocking of formation of platelet-CD4 T cell aggregates during progression of EAE substantially enhanced proliferation of CD4 T cell in the CNS and the periphery leading to exacerbation of the disease. Conclusion Our study indicates differential roles for platelets in the regulation of functions of pathogenic CD4 T cells during initiation and progression of CNS autoimmune inflammation. PMID:26294656

Microbiota Separation and C-reactive protein Elevation in Treatment Naïve Pediatric Granulomatous Crohn Disease

PubMed Central

Kellermayer, Richard; Mir, Sabina A. V.; Nagy-Szakal, Dorottya; Cox, Stephen B.; Dowd, Scot E.; Kaplan, Jess L.; Sun, Yan; Reddy, Sahna; Bronsky, Jiri; Winter, Harland S.

2012-01-01

Objectives In patients with inflammatory bowel diseases (IBD), the presence of non-caseating mucosal granuloma is sufficient for diagnosing Crohn disease (CD) and may represent a specific immune response or microbial-host interaction. The cause of granulomas in CD is unknown and their association with the intestinal microbiota has not been addressed with high-throughput methodologies. Methods The mucosal microbiota from three different pediatric centers was studied with 454 pyrosequencing of the bacterial 16S rRNA gene and the fungal small subunit (SSU) ribosomal region in transverse colonic biopsy specimens from 26 controls and 15 treatment naïve pediatric CD cases. Mycobacterium avium subspecies paratuberculosis (MAP) was tested with real-time PCR. The correlation of granulomatous inflammation with C-reactive protein (CRP) was expanded to 86 treatment naïve CD cases. Results The CD microbiota separated from controls by distance based redundancy analysis (dbRDA; p=0.035). Mucosal granulomata found in any portion of the intestinal tract associated with an augmented colonic bacterial microbiota divergence (p=0.013). The granuloma based microbiota separation persisted even when research center bias was eliminated (p=0.04). Decreased Roseburia and Ruminococcus in granulomatous CD were important in this separation. However, principal coordinates analysis (PCoA) did not reveal partitioning of the groups. CRP levels above 1mg/dl predicted the presence of mucosal granulomata (OR: 28 [6–134.32]; 73% sensitivity, 91% specificity). Conclusions Granulomatous CD associates with microbiota separation and CRP elevation in treatment naïve children. However, overall dysbiosis in pediatric CD appears rather limited. Geographical/center bias should be accounted for in future multi-center microbiota studies. PMID:22699834

Clinical features of Crohn disease concomitant with ankylosing spondylitis

PubMed Central

Liu, Song; Ding, Jie; Wang, Meng; Zhou, Wanqing; Feng, Min; Guan, Wenxian

2016-01-01

Abstract Extraintestinal manifestations (EIMs) cause increased morbidity and decreased quality of life in Crohn disease (CD). Ankylosing spondylitis (AS) belongs to EIMs. Very little is known on the clinical features of CD concomitant with AS. This study is to investigate the clinical features of CD patients with AS. We retrospectively collected all CD patients with AS in our hospital, and established a comparison group (CD without AS) with age, sex, and duration of Crohn disease matched. Clinical information was retrieved for comparison. Eight CD + AS patients were identified from 195 CD patients. Sixteen CD patients were randomly selected into comparison group. All CD + AS patients were male, HLA-B27 (+), and rheumatoid factor (−) with an average age of 40.8 ± 4.52 years. Significant correlation between disease activity of CD and AS was revealed (r = 0.857, P = 0.011). Significant correlation between disease activity of CD and functional limitation associated with AS was identified (r = 0.881, P < 0.01). C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and globulin were positively correlated to Crohn disease activity index (CDAI), Bath AS disease activity index, and Bath AS functional index(BASFI) scores (r = 0.73–0.93, P < 0.05). Albumin was negatively associated with CDAI and BASFI (r = −0.73 to −0.91, P < 0.05). The ratio of albumin to globulin (Alb/Glo) was significantly related to all 3 scores (r = −0.81 to −0.91, P < 0.05). Male predominance with a 4.12% concomitant incidence of AS is observed in CD patients. Disease activity of CD correlates with disease activity of AS and functional limitation caused by AS. CRP, ESR, and Alb/Glo may serve as biomarkers for disease activity and functional limitation in CD patients concomitant with AS, although future studies are expected. PMID:27428240

Clinical features of Crohn disease concomitant with ankylosing spondylitis: A preliminary single-center study.

PubMed

Liu, Song; Ding, Jie; Wang, Meng; Zhou, Wanqing; Feng, Min; Guan, Wenxian

2016-07-01

Extraintestinal manifestations (EIMs) cause increased morbidity and decreased quality of life in Crohn disease (CD). Ankylosing spondylitis (AS) belongs to EIMs. Very little is known on the clinical features of CD concomitant with AS. This study is to investigate the clinical features of CD patients with AS.We retrospectively collected all CD patients with AS in our hospital, and established a comparison group (CD without AS) with age, sex, and duration of Crohn disease matched. Clinical information was retrieved for comparison.Eight CD + AS patients were identified from 195 CD patients. Sixteen CD patients were randomly selected into comparison group. All CD + AS patients were male, HLA-B27 (+), and rheumatoid factor (-) with an average age of 40.8 ± 4.52 years. Significant correlation between disease activity of CD and AS was revealed (r = 0.857, P = 0.011). Significant correlation between disease activity of CD and functional limitation associated with AS was identified (r = 0.881, P < 0.01). C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and globulin were positively correlated to Crohn disease activity index (CDAI), Bath AS disease activity index, and Bath AS functional index(BASFI) scores (r = 0.73-0.93, P < 0.05). Albumin was negatively associated with CDAI and BASFI (r = -0.73 to -0.91, P < 0.05). The ratio of albumin to globulin (Alb/Glo) was significantly related to all 3 scores (r = -0.81 to -0.91, P < 0.05).Male predominance with a 4.12% concomitant incidence of AS is observed in CD patients. Disease activity of CD correlates with disease activity of AS and functional limitation caused by AS. CRP, ESR, and Alb/Glo may serve as biomarkers for disease activity and functional limitation in CD patients concomitant with AS, although future studies are expected.

Intestinal DMBT1 Expression Is Modulated by Crohn’s Disease-Associated IL23R Variants and by a DMBT1 Variant Which Influences Binding of the Transcription Factors CREB1 and ATF-2

PubMed Central

Le Bras, Emmanuelle; Zimmermann, Eva; Olszak, Torsten; Bedynek, Andrea; Göke, Burkhard; Franke, Andre

2013-01-01

Objectives DMBT is an antibacterial pattern recognition and scavenger receptor. In this study, we analyzed the role of DMBT1 single nucleotide polymorphisms (SNPs) regarding inflammatory bowel disease (IBD) susceptibility and examined their functional impact on transcription factor binding and downstream gene expression. Methods Seven SNPs in the DMBT1 gene region were analyzed in 2073 individuals including 818 Crohn’s disease (CD) patients and 972 healthy controls in two independent case-control panels. Comprehensive epistasis analyses for the known CD susceptibility genes NOD2, IL23R and IL27 were performed. The influence of IL23R variants on DMBT1 expression was analyzed. Functional analysis included siRNA transfection, quantitative PCR, western blot, electrophoretic mobility shift and luciferase assays. Results IL-22 induces DMBT1 protein expression in intestinal epithelial cells dependent on STAT3, ATF-2 and CREB1. IL-22 expression-modulating, CD risk-associated IL23R variants influence DMBT1 expression in CD patients and DMBT1 levels are increased in the inflamed intestinal mucosa of CD patients. Several DMBT1 SNPs were associated with CD susceptibility. SNP rs2981804 was most strongly associated with CD in the combined panel (p = 3.0×10−7, OR 1.42; 95% CI 1.24–1.63). All haplotype groups tested showed highly significant associations with CD (including omnibus P-values as low as 6.1×10−18). The most strongly CD risk-associated, non-coding DMBT1 SNP rs2981804 modifies the DNA binding sites for the transcription factors CREB1 and ATF-2 and the respective genomic region comprising rs2981804 is able to act as a transcriptional regulator in vitro. Intestinal DMBT1 expression is decreased in CD patients carrying the rs2981804 CD risk allele. Conclusion We identified novel associations of DMBT1 variants with CD susceptibility and discovered a novel functional role of rs2981804 in regulating DMBT1 expression. Our data suggest an important role of DMBT1 in CD pathogenesis. PMID:24223725

Assessment of selected psychological factors in patients with inflammatory bowel disease

PubMed Central

Kaczówka, Anna; Jeżewska, Maria

2015-01-01

Introduction In the majority of patients with inflammatory bowel diseases (IBD) mental health problems are demonstrated in the form of excessive anxiety and unstable emotional reactions. Emotional instability affects the wellbeing of these patients, and also their attitude towards the disease and the course of treatment. Aim The objective of the study is to evaluate psychological factors in patients with IBD, and to compare patients with ulcerative colitis (UC) and patients suffering from Crohn's disease (CD) with respect to intensity of these factors. Material and methods The study included 108 patients with IBD. NEO-FFI and type-D Scale were used to evaluate personality traits. Anxiety level was measured with STAI. CECS was used to measure the patients’ tendency to suppress negative emotions. Results In the patients with CD 45% of subjects presented type D personality. In the group of patients with UC, type D personality was found in 38%. The higher levels of neuroticism and extraversion were observed in patients with UC, whereas the patients with CD exhibited a higher level of openness to experience and agreeableness. In patients with CD the levels of state anxiety were elevated, whereas in patients with UC higher scores were both for state and trait anxiety. Conclusions There were no statistically significant differences in terms of personality factors in a group of patients with CD and UC. It was found that the majority of patients with IBD suffer elevated or high sense of anxiety. PMID:27110311

Donor Cell Composition and Reactivity Predict Risk of Acute Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation.

PubMed

Sairafi, Darius; Stikvoort, Arwen; Gertow, Jens; Mattsson, Jonas; Uhlin, Michael

2016-01-01

Background . Graft-versus-host disease (GVHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). We designed a functional assay for assessment of individual risk for acute GVHD. Study Design and Methods . Blood samples were collected from patients and donors before HSCT. Two groups of seven patients each were selected, one in which individuals developed acute GVHD grades II-IV and one in which none showed any clinical signs of GVHD. Peripheral blood mononuclear cells (PBMCs) isolated from donors were incubated in mixed lymphocyte cultures (MLCs) with recipient PBMCs. The cells were characterized by flow cytometry before and after MLC. Results . Samples from donors in the GVHD group contained significantly lower frequencies of naïve γδ T-cells and T-cells expressing NK-cell markers CD56 and CD94. Donor samples in this group also exhibited lower frequencies of naïve CD95 + T-cells compared to controls. After MLC, there were dissimilarities in the CD4/CD8 T-cell ratio and frequency of CD69 + T-cells between the two patient groups, with the non-GVHD group showing higher frequencies of CD8 + and CD69 + T-cells. Conclusion . We conclude that a thorough flow cytometric analysis of donor cells for phenotype and allogeneic reactivity may be of value when assessing pretransplant risk for severe acute GVHD.

TRAIL Death Receptor-4, Decoy Receptor-1 and Decoy Receptor-2 Expression on CD8+ T Cells Correlate with the Disease Severity in Patients with Rheumatoid Arthritis

PubMed Central

2010-01-01

Background Rheumatoid Arthritis (RA) is a chronic autoimmune inflammatory disorder. Although the pathogenesis of disease is unclear, it is well known that T cells play a major role in both development and perpetuation of RA through activating macrophages and B cells. Since the lack of TNF-Related Apoptosis Inducing Ligand (TRAIL) expression resulted in defective thymocyte apoptosis leading to an autoimmune disease, we explored evidence for alterations in TRAIL/TRAIL receptor expression on peripheral T lymphocytes in the molecular mechanism of RA development. Methods The expression of TRAIL/TRAIL receptors on T cells in 20 RA patients and 12 control individuals were analyzed using flow cytometry. The correlation of TRAIL and its receptor expression profile was compared with clinical RA parameters (RA activity scored as per DAS28) using Spearman Rho Analysis. Results While no change was detected in the ratio of CD4+ to CD8+ T cells between controls and RA patient groups, upregulation of TRAIL and its receptors (both death and decoy) was detected on both CD4+ and CD8+ T cells in RA patients compared to control individuals. Death Receptor-4 (DR4) and the decoy receptors DcR1 and DcR2 on CD8+ T cells, but not on CD4+ T cells, were positively correlated with patients' DAS scores. Conclusions Our data suggest that TRAIL/TRAIL receptor expression profiles on T cells might be important in revelation of RA pathogenesis. PMID:20799941

Personality and HIV Disease Progression: Role of NEO-PI-R Openness, Extraversion, and Profiles of Engagement

PubMed Central

O'Cleirigh, Conall; Schneiderman, Neil; Weiss, Alexander; Costa, Paul T.

2008-01-01

Objective To examine the role of the big five personality domains (Neuroticism, Extraversion, Openness, Agreeableness, Conscientiousness) and their respective facets and profiles on change in CD4 and log HIV-RNA copies/ml (VL) over 4 years. The examination of psychosocial predictors of disease progression in human immunodeficiency virus (HIV) has focused primarily on depression, coping, and stress, with little attention paid to stable individual differences. Methods A diverse sample of HIV-seropositive patients (n = 104) completed personality assessment (NEO-PI-R), underwent comprehensive psychological assessment and blood samples every 6 months for 4 years. Linear rates of change for CD4 cells and VL were modeled using Hierarchical Linear Modeling controlling for antiretrovirals (time dependent covariate), initial disease status, age, gender, ethnicity, and education. Results Domains that were significantly associated with slower disease progression over 4 years included Openness (CD4, VL), Extraversion (CD4, VL), and Conscientiousness (VL). Facets of the above domains that were significantly related to slower disease progression were assertiveness, positive emotions, and gregariousness (Extraversion); ideas, esthetics (Openness); achievement striving and order (Conscientiousness). In addition, profile analyses suggested personality styles which seem to underscore the importance of remaining engaged (e.g., Creative Interactors (E+O+), Upbeat Optimists (N−E+), Welcomers (E+A+), Go Getters (C+E+), and Directed (N−C+)) had slower disease progression, whereas the “homebody” profile (Low Extraversion-Low Openness) was significantly associated with faster disease progression. Conclusions These results provide good initial evidence of the relationship between personality and disease progression in HIV and suggest protective aspects of profiles of engagement. These finding may help identify those individuals at risk for poorer disease course and specify targets for psychosocial interventions. PMID:18256349

The clinical relevance of plasma CD147/basigin in biopsy-proven kidney diseases.

PubMed

Mori, Yoshiko; Masuda, Tomohiro; Kosugi, Tomoki; Yoshioka, Tomoki; Hori, Mayuko; Nagaya, Hiroshi; Maeda, Kayaho; Sato, Yuka; Kojima, Hiroshi; Kato, Noritoshi; Ishimoto, Takuji; Katsuno, Takayuki; Yuzawa, Yukio; Kadomatsu, Kenji; Maruyama, Shoichi

2017-12-12

Precise understanding of kidney disease activity is needed to design therapeutic strategies. CD147/basigin is involved in the pathogenesis of acute kidney injury and renal fibrosis through inflammatory cell infiltration. The present study examined the clinical relevance of CD147 in biopsy-proven kidney diseases that lead to the progression of chronic kidney disease. Kidney biopsy specimens and plasma and urine samples were obtained from patients with kidney diseases, including IgA nephropathy (IgAN), Henoch-Schönlein purpura nephritis (HSPN), diabetic kidney disease (DKD), focal segmental glomerulosclerosis (FSGS), and membranous nephropathy (MN), who underwent renal biopsy between 2011 and 2014. Plasma and urinary CD147 levels were measured and evaluated for their ability to reflect histological features. Disease activity of IgAN tissues was evaluated according to the Oxford classification and the Japanese histological grading system. In biopsy tissues, CD147 induction was detected in injured lesions representing renal inflammation. Plasma CD147 values correlated with eGFR in patients with inflammation-related kidney diseases such as IgAN, HSPN, and DKD. Particularly in IgAN patients, plasma CD147 levels were correlated with injured regions comprising more than 50% of glomeruli or with tubular atrophy/interstitial injury in biopsy tissues. Proteinuria showed a closer correlation with urinary values of CD147 and L-FABP. Of note, plasma and urinary CD147 levels showed a strong correlation with eGFR or proteinuria, respectively, only in DKD patients. Evaluation of plasma and urinary CD147 levels might provide key insights for the understanding of the activity of various kidney diseases.

Abnormal costimulatory phenotype and function of dendritic cells before and after the onset of severe murine lupus

PubMed Central

Colonna, Lucrezia; Dinnall, Joudy-Ann; Shivers, Debra K; Frisoni, Lorenza; Caricchio, Roberto; Gallucci, Stefania

2006-01-01

We analyzed the activation and function of dendritic cells (DCs) in the spleens of diseased, lupus-prone NZM2410 and NZB-W/F1 mice and age-matched BALB/c and C57BL/6 control mice. Lupus DCs showed an altered ex vivo costimulatory profile, with a significant increase in the expression of CD40, decreased expression of CD80 and CD54, and normal expression of CD86. DCs from young lupus-prone NZM2410 mice, before the development of the disease, expressed normal levels of CD80 and CD86 but already overexpressed CD40. The increase in CD40-positive cells was specific for DCs and involved the subset of myeloid and CD8α+ DCs before disease onset, with a small involvement of plasmacytoid DCs in diseased mice. In vitro data from bone marrow-derived DCs and splenic myeloid DCs suggest that the overexpression of CD40 is not due to a primary alteration of CD40 regulation in DCs but rather to an extrinsic stimulus. Our analyses suggest that the defect of CD80 in NZM2410 and NZB-W/F1 mice, which closely resembles the costimulatory defect found in DCs from humans with systemic lupus erythematosus, is linked to the autoimmune disease. The increase in CD40 may instead participate in disease pathogenesis, being present months before any sign of autoimmunity, and its downregulation should be explored as an alternative to treatment with anti-CD40 ligand in lupus. PMID:16507174

Circulating gluten-specific FOXP3+CD39+ regulatory T cells have impaired suppressive function in patients with celiac disease.

PubMed

Cook, Laura; Munier, C Mee Ling; Seddiki, Nabila; van Bockel, David; Ontiveros, Noé; Hardy, Melinda Y; Gillies, Jana K; Levings, Megan K; Reid, Hugh H; Petersen, Jan; Rossjohn, Jamie; Anderson, Robert P; Zaunders, John J; Tye-Din, Jason A; Kelleher, Anthony D

2017-12-01

Celiac disease is a chronic immune-mediated inflammatory disorder of the gut triggered by dietary gluten. Although the effector T-cell response in patients with celiac disease has been well characterized, the role of regulatory T (Treg) cells in the loss of tolerance to gluten remains poorly understood. We sought to define whether patients with celiac disease have a dysfunction or lack of gluten-specific forkhead box protein 3 (FOXP3) + Treg cells. Treated patients with celiac disease underwent oral wheat challenge to stimulate recirculation of gluten-specific T cells. Peripheral blood was collected before and after challenge. To comprehensively measure the gluten-specific CD4 + T-cell response, we paired traditional IFN-γ ELISpot with an assay to detect antigen-specific CD4 + T cells that does not rely on tetramers, antigen-stimulated cytokine production, or proliferation but rather on antigen-induced coexpression of CD25 and OX40 (CD134). Numbers of circulating gluten-specific Treg cells and effector T cells both increased significantly after oral wheat challenge, peaking at day 6. Surprisingly, we found that approximately 80% of the ex vivo circulating gluten-specific CD4 + T cells were FOXP3 + CD39 + Treg cells, which reside within the pool of memory CD4 + CD25 + CD127 low CD45RO + Treg cells. Although we observed normal suppressive function in peripheral polyclonal Treg cells from patients with celiac disease, after a short in vitro expansion, the gluten-specific FOXP3 + CD39 + Treg cells exhibited significantly reduced suppressive function compared with polyclonal Treg cells. This study provides the first estimation of FOXP3 + CD39 + Treg cell frequency within circulating gluten-specific CD4 + T cells after oral gluten challenge of patients with celiac disease. FOXP3 + CD39 + Treg cells comprised a major proportion of all circulating gluten-specific CD4 + T cells but had impaired suppressive function, indicating that Treg cell dysfunction might be a key contributor to disease pathogenesis. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

CD4 and CD8 T-Cell Responses to Mycobacterial Antigens in African Children

PubMed Central

Tena-Coki, Nontobeko G.; Scriba, Thomas J.; Peteni, Nomathemba; Eley, Brian; Wilkinson, Robert J.; Andersen, Peter; Hanekom, Willem A.; Kampmann, Beate

2010-01-01

Rationale: The current tuberculosis (TB) vaccine, bacille Calmette-Guérin (BCG), does not provide adequate protection against TB disease in children. Furthermore, more efficacious TB vaccines are needed for children with immunodeficiencies such as HIV infection, who are at highest risk of disease. Objectives: To characterize mycobacteria-specific T cells in children who might benefit from vaccination against TB, focusing on responses to antigens contained in novel TB vaccines. Methods: Whole blood was collected from three groups of BCG-vaccinated children: HIV-seronegative children receiving TB treatment (n = 30), HIV-infected children (n = 30), and HIV-unexposed healthy children (n = 30). Blood was stimulated with Ag85B and TB10.4, or purified protein derivative, and T-cell cytokine production by CD4 and CD8 was determined by flow cytometry. The memory phenotype of antigen-specific CD4 and CD8 T cells was also determined. Measurements and Main Results: Mycobacteria-specific CD4 and CD8 T-cell responses were detectable in all three groups of children. Children receiving TB treatment had significantly higher frequencies of antigen-specific CD4 T cells compared with HIV-infected children (P = 0.0176). No significant differences in magnitude, function, or phenotype of specific T cells were observed in HIV-infected children compared with healthy control subjects. CD4 T cells expressing IFN-γ, IL-2, or both expressed a CD45RA−CCR7−CD27+/− effector memory phenotype. Mycobacteria-specific CD8 T cells expressed mostly IFN-γ in all groups of children; these cells expressed CD45RA−CCR7−CD27+/− or CD45RA+CCR7−CD27+/− effector memory phenotypes. Conclusions: Mycobacteria-specific T-cell responses could be demonstrated in all groups of children, suggesting that the responses could be boosted by new TB vaccines currently in clinical trials. PMID:20224065

Phenotypically non-suppressive cells predominate among FoxP3-positive cells in oral lichen planus.

PubMed

Schreurs, Olav; Karatsaidis, Andreas; Schenck, Karl

2016-11-01

Oral lichen planus (OLP) is a common T-cell-dominated oral chronic inflammatory disease occurring in periods of remission, quiescence, activity with pronounced inflammation, and acute ulceration. Cell infiltrates in OLP contain varying numbers of CD4 + T cells expressing the transcription factor FoxP3. FoxP3 + CD4 + T cells are, however, a heterogeneous cell population containing suppressive and non-suppressive cells, and their distribution in infiltrates from OLP is unknown. Biopsies were taken from normal oral mucosa (n = 8) and OLP lesions (n = 19), and a set of in situ methods for the determination of the functional phenotype of FoxP3 + CD4 + T cells was applied. Numbers of FoxP3 + CD4 + T cells were highest in the atrophic form of the disease, yet low in the ulcerative form. The main FoxP3 + CD4 + T-cell population observed was FoxP3 + CD45RA - CD25 + CD45RO + and CD15s - , a phenotype delineating a non-suppressive subset. Numbers of cells with an actively suppressing phenotype (FoxP3 + CD45RA - CD25 + CD45RO + and CD15s + ) were, however, about twice as high in reticular lesions as compared with the atrophic form. Many FoxP3 + CD4 + T cells expressed T-bet, the hallmark transcription factor for IFN-γ-producing T cells, indicating that they may enhance immune and inflammatory responses rather than suppress them. The absence of actively suppressing FoxP3 + CD4 + T cells may in part explain why OLP is a remarkably persisting condition, in spite of the presence of substantially high numbers of FoxP3 + CD4 + T cells. The findings emphasize that it is crucial to examine not only numbers but also functional phenotype of FoxP3 + CD4 + T cells in human tissues. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Electrochemical magneto-actuated biosensor for CD4 count in AIDS diagnosis and monitoring.

PubMed

Carinelli, S; Xufré Ballesteros, C; Martí, M; Alegret, S; Pividori, M I

2015-12-15

The counting of CD4(+) T lymphocytes is a clinical parameter used for AIDS diagnosis and follow-up. As this disease is particularly prevalent in developing countries, simple and affordable CD4 cell counting methods are urgently needed in resource-limited settings. This paper describes an electrochemical magneto-actuated biosensor for CD4 count in whole blood. The CD4(+) T lymphocytes were isolated, preconcentrated and labeled from 100 μL of whole blood by immunomagnetic separation with magnetic particles modified with antiCD3 antibodies. The captured cells were labeled with a biotinylated antiCD4 antibody, followed by the reaction with the electrochemical reporter streptavidin-peroxidase conjugate. The limit of detection for the CD4 counting magneto-actuated biosensor in whole blood was as low as 44 cells μL(-1) while the logistic range was found to be from 89 to 912 cells μL(-1), which spans the whole medical interest range for CD4 counts in AIDS patients. The electrochemical detection together with the immunomagnetic separation confers high sensitivity, resulting in a rapid, inexpensive, robust, user-friendly method for CD4 counting. This approach is a promising alternative for the costly standard flow cytometry and suitable as diagnostic tool at decentralized practitioner sites in low resource settings, especially in less developed countries. Copyright © 2015 Elsevier B.V. All rights reserved.

Hippocampal and cerebellar atrophy in patients with Cushing's disease.

PubMed

Burkhardt, Till; Lüdecke, Daniel; Spies, Lothar; Wittmann, Linus; Westphal, Manfred; Flitsch, Jörg

2015-11-01

OBJECT Cushing's disease (CD) may cause atrophy of different regions of the human brain, mostly affecting the hippocampus and the cerebellum. This study evaluates the use of 3-T MRI of newly diagnosed patients with CD to detect atrophic degeneration with voxel-based volumetry. METHODS Subjects with newly diagnosed, untreated CD were included and underwent 3-T MRI. Images were analyzed using a voxelwise statistical test to detect reduction of brain parenchyma. In addition, an atlas-based volumetric study for regions likely to be affected by CD was performed. RESULTS Nineteen patients with a mean disease duration of 24 months were included. Tumor markers included adrenocorticotropic hormone (median 17.5 pmol/L), cortisol (949.4 nmol/L), and dehydroepiandrosterone sulfate (5.4 μmol/L). The following values are expressed as the mean ± SD. The voxelwise statistical test revealed clusters of significantly reduced gray matter in the hippocampus and cerebellum, with volumes of 2.90 ± 0.26 ml (right hippocampus), 2.89 ± 0.28 ml (left hippocampus), 41.95 ± 4.67 ml (right cerebellar hemisphere), and 42.11 ± 4.59 ml (left cerebellar hemisphere). Healthy control volunteers showed volumes of 3.22 ± 0.25 ml for the right hippocampus, 3.23 ± 0.25 ml for the left hippocampus, 50.87 ± 4.23 ml for the right cerebellar hemisphere, and 50.42 ± 3.97 ml for the left cerebellar hemisphere. CONCLUSIONS Patients with untreated CD show significant reduction of gray matter in the cerebellum and hippocampus. These changes can be analyzed and objectified with the quantitative voxel-based method described in this study.

Preclinical characterization of DUOC-01, a cell therapy product derived from banked umbilical cord blood for use as an adjuvant to umbilical cord blood transplantation for treatment of inherited metabolic diseases

PubMed Central

KURTZBERG, JOANNE; BUNTZ, SUSAN; GENTRY, TRACY; NOELDNER, PAMELA; OZAMIZ, APRIL; RUSCHE, BENJAMIN; STORMS, ROBERT W.; WOLLISH, AMY; WENGER, DAVID A.; BALBER, ANDREW E.

2016-01-01

Background aims Cord blood (CB) transplantation slows neurodegeneration during certain inherited metabolic diseases. However, the number of donor cells in the brain of patients does not appear to be sufficient to provide benefit until several months after transplant. We developed the cell product DUOC-01 to provide therapeutic effects in the early post-transplant period. Methods DUOC-01 cultures initiated from banked CB units were characterized by use of time-lapse photomicroscopy during the 21-day manufacturing process. Antigen expression was measured by means of flow cytometry and immunocytochemistry; transcripts for cytokines and enzymes by quantitative real-time polymerase chain reaction; activities of lysosomal enzymes by direct biochemical analysis; alloreactivity of DUOC-01 and of peripheral blood (PB) mononuclear cells (MNC) to DUOC-01 by mixed lymphocyte culture methods; and cytokine secretion by Bioplex assays. Results DUOC-01 cultures contained highly active, attached, motile, slowly proliferating cells that expressed common (cluster of differentiation [CD]11b, CD14 and Iba1), M1 type (CD16, inducible nitric oxide synthase), and M2-type (CD163, CD206) macrophage or microglia markers. Activities of 11 disease-relevant lysosomal enzymes in DUOC-01 products were similar to those of normal PB cells. All DUOC-01 products secreted interleukin (IL)-6 and IL-10. Accumulation of transforming growth factor-β, IL-1β, interferon-γ and TNF-α in supernatants was variable. IL-12, IL-2, IL-4, IL-5 and IL-13 were not detected at significant concentrations. Galactocerebrosidase, transforming growth factor-β and IL-10 transcripts were specifically enriched in DUOC-01 relative to CB cells. PB MNCs proliferated and released cytokines in response to DUOC-01. DUOC-01 did not proliferate in response to mismatched MNC. Conclusions DUOC-01 has potential as an adjunctive cell therapy to myeloablative CB transplant for treatment of inherited metabolic diseases. PMID:25770677

Colonic Crohn's Disease Is Associated with Less Aggressive Disease Course Than Ileal or Ileocolonic Disease.

PubMed

Arora, Umang; Kedia, Saurabh; Garg, Prerna; Bopanna, Sawan; Jain, Saransh; Yadav, Dawesh P; Goyal, Sandeep; Gupta, Vipin; Sahni, Peush; Pal, Sujoy; Dash, Nihar Ranjan; Madhusudhan, Kumble Seetharama; Sharma, Raju; Makharia, Govind; Ahuja, Vineet

2018-06-01

The literature on disease characteristics of colonic Crohn's disease (CD) is sparse, especially from Asia, where the burden of inflammatory bowel disease is on the rise. The present study aims to describe the disease characteristics of colonic CD, and compare it with that of ileal/ileocolonic disease. This retrospective study included adult patients of CD (diagnosed by standard criteria, follow-up duration > 6 months) on follow-up between August 2004 and January 2016. The disease location was classified by Montreal classification. The data were recorded on demographic characteristics, smoking status, disease phenotype, disease course, treatment received, hospitalization and surgeries. Of 406 CD patients, 123 had colonic [mean age (at onset) 30.4 ± 13.2 years, 59.3% males] and 265 had ileal/ileocolonic disease [mean age (at onset) 32.9 ± 13.8 years, 61.5% males] while 18 patients had isolated upper GI disease. The frequency of inflammatory behavior (B1 phenotype; 61.8 vs. 46.4%, p = 0.003), perianal disease (23.6 vs. 4.5%, p < 0.001), and extra-intestinal manifestation (42.3 vs. 30.2%, p = 0.019) was higher in colonic than ileal/ileocolonic CD. Though not statistically significant, requirement of atleast one course of steroid was lower in colonic CD (72.7 vs. 84.2%, p = 0.098). Although there was no difference in the frequency of hospitalization (30.1 vs. 27.1%, p = 0.45), the overall requirement for surgery was significantly lower in colonic CD (17.1 vs. 26.1%, p = 0.032) and patients with colonic disease had a lower cumulative probability of first surgery in the first 10 years of follow-up [Hazard ratio 0.556 (95% CI 0.313-0.985), p = 0.045]. Colonic CD was associated with less aggressive disease behavior and lower requirement of surgery as compared to ileal/ileocolonic CD.

Significant CD4, CD8, and CD19 lymphopenia in peripheral blood of sarcoidosis patients correlates with severe disease manifestations.

PubMed

Sweiss, Nadera J; Salloum, Rafah; Gandhi, Seema; Ghandi, Seema; Alegre, Maria-Luisa; Sawaqed, Ray; Badaracco, Maria; Pursell, Kenneth; Pitrak, David; Baughman, Robert P; Moller, David R; Garcia, Joe G N; Niewold, Timothy B

2010-02-05

Sarcoidosis is a poorly understood chronic inflammatory condition. Infiltration of affected organs by lymphocytes is characteristic of sarcoidosis, however previous reports suggest that circulating lymphocyte counts are low in some patients with the disease. The goal of this study was to evaluate lymphocyte subsets in peripheral blood in a cohort of sarcoidosis patients to determine the prevalence, severity, and clinical features associated with lymphopenia in major lymphocyte subsets. Lymphocyte subsets in 28 sarcoid patients were analyzed using flow cytometry to determine the percentage of CD4, CD8, and CD19 positive cells. Greater than 50% of patients had abnormally low CD4, CD8, or CD19 counts (p<4x10(-10)). Lymphopenia was profound in some cases, and five of the patients had absolute CD4 counts below 200. CD4, CD8, and CD19 lymphocyte subset counts were significantly correlated (Spearman's rho 0.57, p = 0.0017), and 10 patients had low counts in all three subsets. Patients with severe organ system involvement including neurologic, cardiac, ocular, and advanced pulmonary disease had lower lymphocyte subset counts as a group than those patients with less severe manifestations (CD4 p = 0.0043, CD8 p = 0.026, CD19 p = 0.033). No significant relationships were observed between various medical therapies and lymphocyte counts, and lymphopenia was present in patients who were not receiving any medical therapy. Significant lymphopenia involving CD4, CD8, and CD19 positive cells was common in sarcoidosis patients and correlated with disease severity. Our findings suggest that lymphopenia relates more to disease pathology than medical treatment.

Significant CD4, CD8, and CD19 Lymphopenia in Peripheral Blood of Sarcoidosis Patients Correlates with Severe Disease Manifestations

PubMed Central

Sweiss, Nadera J.; Salloum, Rafah; Ghandi, Seema; Alegre, Maria-Luisa; Sawaqed, Ray; Badaracco, Maria; Pursell, Kenneth; Pitrak, David; Baughman, Robert P.; Moller, David R.; Garcia, Joe G. N.; Niewold, Timothy B.

2010-01-01

Background Sarcoidosis is a poorly understood chronic inflammatory condition. Infiltration of affected organs by lymphocytes is characteristic of sarcoidosis, however previous reports suggest that circulating lymphocyte counts are low in some patients with the disease. The goal of this study was to evaluate lymphocyte subsets in peripheral blood in a cohort of sarcoidosis patients to determine the prevalence, severity, and clinical features associated with lymphopenia in major lymphocyte subsets. Methodology/Principal Findings Lymphocyte subsets in 28 sarcoid patients were analyzed using flow cytometry to determine the percentage of CD4, CD8, and CD19 positive cells. Greater than 50% of patients had abnormally low CD4, CD8, or CD19 counts (p<4×10−10). Lymphopenia was profound in some cases, and five of the patients had absolute CD4 counts below 200. CD4, CD8, and CD19 lymphocyte subset counts were significantly correlated (Spearman's rho 0.57, p = 0.0017), and 10 patients had low counts in all three subsets. Patients with severe organ system involvement including neurologic, cardiac, ocular, and advanced pulmonary disease had lower lymphocyte subset counts as a group than those patients with less severe manifestations (CD4 p = 0.0043, CD8 p = 0.026, CD19 p = 0.033). No significant relationships were observed between various medical therapies and lymphocyte counts, and lymphopenia was present in patients who were not receiving any medical therapy. Conclusions/Significance Significant lymphopenia involving CD4, CD8, and CD19 positive cells was common in sarcoidosis patients and correlated with disease severity. Our findings suggest that lymphopenia relates more to disease pathology than medical treatment. PMID:20140091

Resource Use and Costs Associated with Coeliac Disease before and after Diagnosis in 3,646 Cases: Results of a UK Primary Care Database Analysis

PubMed Central

Violato, Mara; Gray, Alastair; Papanicolas, Irini; Ouellet, Melissa

2012-01-01

Background Despite the considerable health impact of coeliac disease (CD), reliable estimates of the impact of diagnosis on health care use and costs are lacking. Aims To quantify the volume, type and costs, in a United Kingdom primary care setting, of healthcare resources used by individuals diagnosed with CD up to ten years before and after diagnosis, and to estimate medical costs associated with CD. Methods A cohort of 3,646 CD cases and a parallel cohort of 32,973 matched controls, extracted from the General Practice Research Database (GPRD) over the period 1987–2005 were used i) to evaluate the impact of diagnosis on the average resource use and costs of cases; ii) to assess direct healthcare costs due to CD by comparing average resource use and costs incurred by cases vs. controls. Results Average annual healthcare costs per patient increased by £310 (95% CI £299, £320) after diagnosis. CD cases experienced higher healthcare costs than controls both before diagnosis (mean difference £91; 95% CI: £86, £97) and after diagnosis (mean difference £354; 95% CI: £347, £361). These differences were driven mainly by higher test and referral costs before diagnosis, and by increased prescription costs after diagnosis. Conclusions This study shows significant additional primary care costs associated with coeliac disease. It provides novel evidence that will assist researchers evaluating interventions in this area, and will challenge policymakers, clinicians, researchers and the public to develop strategies that maximise the health benefits of the resources associated with this disease. PMID:22815991

Canine distemper of vaccine origin in European mink, Mustela lutreola--a case report.

PubMed

Ek-Kommonen, C; Rudbäck, E; Anttila, M; Aho, M; Huovilainen, A

2003-04-02

Cases of canine distemper (CD) related to vaccination of exotic carnivores extend over three decades and have been described in at least nine different species. Our report describes a case of acute CD in a European mink, Mustela lutreola, vaccinated with live attenuated CD vaccine licensed for use in fur-farmed mink. The male mink died of an acute grey matter disease with an unusually long incubation period. A female vaccinated at the same time showed no obvious signs of illness. The diagnosis was confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) and by subsequent sequencing of the PCR products. The sequenced products of the virus isolated from the mink and of the vaccine batch showed 100% identity. This is the first report in which molecular methods were used to confirm that the disease was caused by the vaccine strain. Based on our findings, it is clearly evident that current CD vaccines cannot be safely used in exotic species.

Cardiac Magnetic Resonance-Verified Myocardial Fibrosis in Chagas Disease: Clinical Correlates and Risk Stratification

PubMed Central

Uellendahl, Marly; de Siqueira, Maria Eduarda Menezes; Calado, Eveline Barros; Kalil-Filho, Roberto; Sobral, Dário; Ribeiro, Clébia; Oliveira, Wilson; Martins, Silvia; Narula, Jagat; Rochitte, Carlos Eduardo

2016-01-01

Background Chagas disease (CD) is an important cause of heart failure and mortality, mainly in Latin America. This study evaluated the morphological and functional characteristics of the heart as well the extent of myocardial fibrosis (MF) in patients with CD by cardiac magnetic resonance (CMR). The prognostic value of MF evaluated by myocardial-delayed enhancement (MDE) was compared with that via Rassi score. Methods This study assessed 39 patients divided into 2 groups: 28 asymptomatic patients as indeterminate form group (IND); and symptomatic patients as Chagas Heart Disease (CHD) group. All patients underwent CMR using the techniques of cine-MRI and MDE, and the amount of MF was compared with the Rassi score. Results Regarding the morphological and functional analysis, significant differences were observed between both groups (p < 0.001). Furthermore, there was a strong correlation between the extent of MF and the Rassi score (r = 0.76). Conclusions CMR is an important technique for evaluating patients with CD, stressing morphological and functional differences in all clinical presentations. The strong correlation with the Rassi score and the extent of MF detected by CMR emphasizes its role in the prognostic stratification of patients with CD. PMID:27982271

Prevalence of transfusion-transmitted Chagas disease among multitransfused patients in Brazil

PubMed Central

De Paula, Erich V; Goncales, Neiva SL; Xueref, Serge; Addas-Carvalho, Marcelo; Gilli, Simone CO; Angerami, Rodrigo N; Goncales, Fernando L

2008-01-01

Background Blood transfusion has always been an important route for Chagas Disease (CD) transmission. The high prevalence of CD in Latin America and its lifelong asymptomatic clinical picture pose a threat for the safety of the blood supply. The outcome of measures designed to improve transfusion safety can be assessed by evaluating the prevalence of CD among multitransfused patients Methods In order to assess the impact of CD control measures on the safety of the blood supply, an observational cross-sectional study was designed to determine the prevalence of CD in 351 highly transfused patients, in which vectorial transmission was excluded. This study compared patients that received transfusion products before (n = 230) and after (n = 121) 1997, when measures to control transfusion-transmitted CD were fully implemented in Brazil. Results The study group consisted of 351 patients exposed to high numbers of blood products during their lifetime (median number of units transfused = 51, range 10–2086). A higher prevalence of transfusion-transmitted CD (1.30%) was observed among multitransfused patients that received their first transfusion before 1997, compared with no cases of transfusion-transmitted CD among multitransfused patients transfused after that year. The magnitude of the exposure to blood products was similar among both groups (mean number of units transfused per year of exposure = 25.00 ± 26.46 and 23.99 ± 30.58 respectively; P = 0.75, Mann-Whitney test). Conclusion Multiple initiatives aimed to control vector and parental transmission of CD can significantly decrease transfusion-transmitted CD in Brazil. Our data suggest that mandatory donor screening for CD represents the most important measure to interrupt transmission of CD by blood transfusions. PMID:18199334

[Inflammatory bowel diseases: an immunological approach].

PubMed

Sepúlveda, Sofía E; Beltrán, Caroll J; Peralta, Alexis; Rivas, Paola; Rojas, Néstor; Figueroa, Carolina; Quera, Rodrigo; Hermoso, Marcela A

2008-03-01

Inflammatory bowel diseases (IBD) are inflammatory diseases with a multifactorial component that involve the intestinal tract. The two relevant IBD syndromes are Crohn's disease (CD) and ulcerative colitis (UC). One factor involved in IBD development is a genetic predisposition, associated to NOD2/CARD15 and Toll-like receptor 4 (TLR4) polymorphisms that might favor infectious enterocolitis that is possibly associated to the development of IBD. The identification of specific immunologic alterations in IBD and their relationship to the etiology of the disease is a relevant research topic. The role of intra and extracellular molecules, such as transcription factors and cytokines that are involved in the inflammatory response, needs to be understood. The relevance of immunologic molecules that might drive the immune response to a T helper (Th) 1, Th 2 or the recently described Th 17 phenotype, has been demonstrated in animal models and clinical studies with IBD patients. CD and UC predominantly behave with a Th 1 and Th 2 immune phenotype, respectively. Recently, an association between CD and Th 17 has been reported. The knowledge acquired from immunologic and molecular research will help to develop accurate diagnostic methods and efficient therapies.

β-Cyclodextrin hydrogels for the ocular release of antibacterial thiosemicarbazones.

PubMed

Glisoni, Romina J; García-Fernández, María J; Pino, Marylú; Gutkind, Gabriel; Moglioni, Albertina G; Alvarez-Lorenzo, Carmen; Concheiro, Angel; Sosnik, Alejandro

2013-04-02

Two types of hydrophilic networks with conjugated beta-cyclodextrin (β-CD) were developed with the aim of engineering useful platforms for the localized release of an antimicrobial 5,6-dimethoxy-1-indanone N4-allyl thiosemicarbazone (TSC) in the eye and its potential application in ophthalmic diseases. Poly(2-hydroxyethyl methacrylate) soft contact lenses (SCLs) displaying β-CD, namely pHEMA-co-β-CD, and super-hydrophilic hydrogels (SHHs) of directly cross-linked hydroxypropyl-β-CD were synthesized and characterized regarding their structure (ATR/FT-IR), drug loading capacity, swelling and in vitro release in artificial lacrimal fluid. Incorporation of TSC to the networks was carried out both during polymerization (DP method) and after synthesis (PP method). The first method led to similar drug loads in all the hydrogels, with minor drug loss during the washing steps to remove unreacted monomers, while the second method evidenced the influence of structural parameters on the loading efficiency (proportion of CD units, mesh size, swelling degree). Both systems provided a controlled TSC release for at least two weeks, TSC concentrations (up to 4000μg/g dry hydrogel) being within an optimal therapeutic window for the antimicrobial ocular treatment. Microbiological tests against P. aeruginosa and S. aureus confirmed the ability of TSC-loaded pHEMA-co-β-CD network to inhibit bacterial growth. Copyright © 2012 Elsevier Ltd. All rights reserved.

Soluble CD163 is increased in patients with acute pancreatitis independent of disease severity.

PubMed

Karrasch, Thomas; Brünnler, Tanja; Hamer, Okka W; Schmid, Karin; Voelk, Markus; Herfarth, Hans; Buechler, Christa

2015-10-01

Macrophages are crucially involved in the pathophysiology of acute pancreatitis. Soluble CD163 (sCD163) is specifically released from macrophages and systemic levels are increased in inflammatory diseases. Here, sCD163 was measured in serum of 50 patients with acute pancreatitis to find out possible associations with disease activity. Admission levels of systemic sCD163 were nearly three-fold higher in patients with acute pancreatitis compared to controls. In patients sCD163 did not correlate with C-reactive protein and leukocyte count as established markers of inflammation. Levels were not associated with disease severity assessed by the Schroeder score, Balthazar score, Acute Physiology, Age, and Chronic Health Evaluation (Apache) II score and peripancreatic necrosis score. Soluble CD163 was not related to complications of acute pancreatitis. These data show that serum sCD163 is increased in acute pancreatitis indicating activation of macrophages but is not associated with disease severity and outcome. Copyright © 2015 Elsevier Inc. All rights reserved.

The effect of regulatory T-cell depletion on the spectrum of organ-specific autoimmune diseases in nonobese diabetic mice at different ages.

PubMed

Nakahara, Mami; Nagayama, Yuji; Ichikawa, Tatsuki; Yu, Liping; Eisenbarth, George S; Abiru, Norio

2011-09-01

The nonobese diabetic (NOD) mouse spontaneously develops several autoimmune diseases, including type 1 diabetes and to a lesser extent thyroiditis and sialitis. Imbalance between effector T cells (Teffs) and regulatory T cells (Tregs) has recently been proposed as a mechanism for the disease pathogenesis in NOD mice, but previous studies have shown the various outcomes by different timing and methods of Treg-depletion. This study was, therefore, designed to compare the consequences of Treg-depletion by the same method (anti-CD25 antibody) on the spectrum of organ-specific autoimmune diseases in NOD mice of different ages. Treg-depletion by anti-CD25 antibody at 10 days of age accelerated development of all three diseases we examined (insulitis/diabetes, thyroiditis, and sialitis); Treg-depletion at 4 weeks of age accelerated only diabetes but not thyroiditis or sialitis; and Treg-depletion at 12 weeks of age hastened only development of thyroiditis and exhibited little influence on diabetes or sialitis. Increased levels of insulin autoantibodies (IAA) were, however, observed in mice depleted of Tregs at 10 days of age, not in those at 4 weeks. Thus, the consequences of Treg-depletion on the spectrum of organ-specific autoimmune diseases depend on the timing of anti-CD25 antibody injection in NOD mice. Aging gradually tips balance between Teffs and Tregs toward Teff-dominance for diabetes, but this balance for thyroiditis and sialitis likely alters more intricately. Our data also suggest that the levels of IAA are not necessarily correlated with diabetes development.

Relation of body mass index to risk of developing inflammatory bowel disease amongst women in the Danish National Birth Cohort

PubMed Central

Harpsøe, Maria Christina; Kumar, Devinder; Andersson, Mikael; Jess, Tine

2018-01-01

Background Crohn’s disease (CD) has traditionally been associated with weight loss and low BMI, yet paradoxically obesity has recently been suggested as a risk factor for CD, but not for ulcerative colitis (UC). We therefore hypothesized that the relation between BMI and CD is U shaped. Aim To conduct a large population-based prospective cohort study of BMI and later risk of IBD, taking age at IBD diagnosis into account. Methods A cohort of 74,512 women from the Danish National Birth Cohort, with BMI measured pre-pregnancy and 18 months after delivery, was followed for 1,022,250 person-years for development of IBD, according to the Danish National Patient Register. Associations were tested by Cox regression. Results Overweight subjects (25≤BMI<30 kg/m2) had the lowest risk of CD, whereas obesity (BMI≥30kg/m2) increased the risk of CD at all ages, and low BMI (BMI<18.5kg/m2) associated with CD diagnosed at age 18-<40 years. Hence, using normal weight subjects as the reference, adjusted HRs for risk of developing CD (at age 18-<40 years) were 1.8(95%CI, 0.9–3.7) for underweight, 0.6(0.3–1.2) for overweight, and 1.5(0.8–2.7) for obese individuals (pre-pregnancy BMI). HRs were greater for BMI determined 18 months after delivery. Splines for CD risk according to waist:height ratio confirmed a U-shaped relationship with CD occurring <40 years, and a linear relationship with CD diagnosed at age 40+. There was no relationship between BMI and risk of UC. Conclusion For the first time, we demonstrate that both high BMI and low BMI are risk factors for CD. Underweight may be a pre-clinical manifestation of disease being present many years before onset with obesity being a true risk factor. This raises the question as to whether there may be two distinct forms of CD. PMID:29364914

Mucosal barrier in ulcerative colitis and Crohn's disease.

PubMed

Dorofeyev, A E; Vasilenko, I V; Rassokhina, O A; Kondratiuk, R B

2013-01-01

Background. The mucus layer in the gastrointestinal tract plays important role in host innate defense, regulation of secretion, and absorption processes, maintaining colonization resistance, which composes the integrity of protective mucus barrier in the large intestine. Investigations of mucin expression in the colon mucosa can improve the understanding of protective function of mucosal barrier in ulcerative colitis (UC) and Crohn's disease (CD). Materials and Methods. 77 patients with UC and CD were examined. Histological analysis of colon mucosa was done by standard method (haematoxylin-eosin, alcian blue at pH 1.0 and 2.5 to determine sulfated and nonsulfated glycosaminoglycans and glycoproteins, and goblet cells). To characterize the mucus production the PAS-reaction was performed. Immunohistochemistry was performed using monoclonal mouse antibodies raised against MUC2, MUC3, MUC4, and TFF3 (USBiological, USA). Results. The moderate expression of MUC2 and MUC3 (50.0% and 32.1%, P = 0.03) and high expression of MUC4 and TFF3 in the colon mucosa were observed in all patients with CD. The intensive labeling of MUC4 and TFF3 occurred more often (42.9% and 57.1%, P = 0.03) in patients with CD. The level of expression of secretory MUC2 and transmembrane MUC3 and MUC4 in all patients with UC was low, up to its complete absence (59.2% and 53.1% cases, P = 0.05). TFF3 expression had high and medium staining intensity in patients with UC. Conclusions. Different types of mucins synthesis, secretion, and expression were found in patients with UC and CD. The expression of mucin MUC2, MUC3, MUC4, and TFF3 correlated with the activity of disease and the extent of the inflammatory process in the large intestine. The most pronounced alteration of mucins expression was observed in patients with severe UC and CD.

Fexinidazole: A Potential New Drug Candidate for Chagas Disease

PubMed Central

Bahia, Maria Terezinha; de Andrade, Isabel Mayer; Martins, Tassiane Assíria Fontes; do Nascimento, Álvaro Fernando da Silva; Diniz, Lívia de Figueiredo; Caldas, Ivo Santana; Talvani, André; Trunz, Bernadette Bourdin; Torreele, Els; Ribeiro, Isabela

2012-01-01

Background New safe and effective treatments for Chagas disease (CD) are urgently needed. Current chemotherapy options for CD have significant limitations, including failure to uniformly achieve parasitological cure or prevent the chronic phase of CD, and safety and tolerability concerns. Fexinidazole, a 2-subsituted 5-nitroimidazole drug candidate rediscovered following extensive compound mining by the Drugs for Neglected Diseases initiative and currently in Phase I clinical study for the treatment of human African trypanosomiasis, was evaluated in experimental models of acute and chronic CD caused by different strains of Trypanosoma cruzi. Methods and Findings We investigated the in vivo activity of fexinidazole against T. cruzi, using mice as hosts. The T. cruzi strains used in the study were previously characterized in murine models as susceptible (CL strain), partially resistant (Y strain), and resistant (Colombian and VL-10 strains) to the drugs currently in clinical use, benznidazole and nifurtimox. Our results demonstrated that fexinidazole was effective in suppressing parasitemia and preventing death in infected animals for all strains tested. In addition, assessment of definitive parasite clearance (cure) through parasitological, PCR, and serological methods showed cure rates of 80.0% against CL and Y strains, 88.9% against VL-10 strain, and 77.8% against Colombian strain among animals treated during acute phase, and 70% (VL-10 strain) in those treated in chronic phase. Benznidazole had a similar effect against susceptible and partially resistant T. cruzi strains. Fexinidazole treatment was also shown to reduce myocarditis in all animals infected with VL-10 or Colombian resistant T. cruzi strains, although parasite eradication was not achieved in all treated animals at the tested doses. Conclusions Fexinidazole is an effective oral treatment of acute and chronic experimental CD caused by benznidazole-susceptible, partially resistant, and resistant T. cruzi. These findings illustrate the potential of fexinidazole as a drug candidate for the treatment of human CD. PMID:23133682

Immunological role of CD4+CD28null T lymphocytes, natural killer cells, and interferon-gamma in pediatric patients with sickle cell disease: relation to disease severity and response to therapy.

PubMed

ElAlfy, Mohsen Saleh; Adly, Amira Abdel Moneam; Ebeid, Fatma Soliman ElSayed; Eissa, Deena Samir; Ismail, Eman Abdel Rahman; Mohammed, Yasser Hassan; Ahmed, Manar Elsayed; Saad, Aya Sayed

2018-06-20

Sickle cell disease (SCD) is associated with alterations in immune phenotypes. CD4 + CD28 null T lymphocytes have pro-inflammatory functions and are linked to vascular diseases. To assess the percentage of CD4 + CD28 null T lymphocytes, natural killer cells (NK), and IFN-gamma levels, we compared 40 children and adolescents with SCD with 40 healthy controls and evaluated their relation to disease severity and response to therapy. Patients with SCD steady state were studied, focusing on history of frequent vaso-occlusive crisis, hydroxyurea therapy, and IFN-gamma levels. Analysis of CD4 + CD28 null T lymphocytes and NK cells was done by flow cytometry. Liver and cardiac iron overload were assessed. CD4 + CD28 null T lymphocytes, NK cells, and IFN-gamma levels were significantly higher in patients than controls. Patients with history of frequent vaso-occlusive crisis and those with vascular complications had higher percentage of CD4 + CD28 null T lymphocytes and IFN-gamma while levels were significantly lower among hydroxyurea-treated patients. CD4 + CD28 null T lymphocytes were positively correlated to transfusional iron input while these cells and IFN-gamma were negatively correlated to cardiac T2* and duration of hydroxyurea therapy. NK cells were correlated to HbS and indirect bilirubin. Increased expression of CD4 + CD28 null T lymphocytes highlights their role in immune dysfunction and pathophysiology of SCD complications.

Clinical spectrum of Castleman disease-associated neuropathy.

PubMed

Naddaf, Elie; Dispenzieri, Angela; Mandrekar, Jay; Mauermann, Michelle L

2016-12-06

To define the peripheral neuropathy phenotypes associated with Castleman disease. We conducted a retrospective chart review for patients with biopsy-proven Castleman disease evaluated between January 2003 and December 2014. Patients with associated peripheral neuropathy were identified and divided into 2 groups: those with Castleman disease without POEMS syndrome (CD-PN) and those with Castleman disease with POEMS syndrome (CD-POEMS). We used a cohort of patients with POEMS as controls. Clinical, electrodiagnostic, and laboratory characteristics were collected and compared among patient subgroups. There were 7 patients with CD-PN, 20 with CD-POEMS, and 122 with POEMS. Patients with CD-PN had the mildest neuropathy characterized by predominant sensory symptoms with no pain and mild distal sensory deficits (median Neuropathy Impairment Score of 7 points). Although both patients with CD-POEMS and patients with POEMS had a severe sensory and motor neuropathy, patients with CD-POEMS were less affected (median Neuropathy Impairment Score of 33 and 66 points, respectively). The degree of severity was also reflected on electrodiagnostic testing in which patients with CD-PN demonstrated a mild degree of axonal loss, followed by patients with CD-POEMS and then those with POEMS. Demyelinating features, defined by European Federation of Neurologic Societies/Peripheral Nerve Society criteria, were present in 43% of the CD-PN, 78% of the CD-POEMS, and 86% of the POEMS group. There is a spectrum of demyelinating peripheral neuropathies associated with Castleman disease. CD-PN is sensory predominant and is the mildest phenotype, whereas CD-POEMS is a more severe sensory and motor neuropathy. Compared to the POEMS cohort, those with CD-POEMS neuropathy have a similar but less severe phenotype. Whether these patients respond differently to treatment deserves further study. © 2016 American Academy of Neurology.

Shared and unique common genetic determinants between pediatric and adult celiac disease.

PubMed

Senapati, Sabyasachi; Sood, Ajit; Midha, Vandana; Sood, Neena; Sharma, Suresh; Kumar, Lalit; Thelma, B K

2016-07-22

Based on age of presentation, celiac disease (CD) is categorised as pediatric CD and adult CD. It however remains unclear if these are genetically and/or phenotypically distinct disorders or just different spectrum of the same disease. We therefore explored the common genetic components underlying pediatric and adult CD in a well characterized north Indian cohort. A retrospective analysis of children (n = 531) and adult (n = 871) patients with CD between January 2001 and December 2010 was done. The database included basic demographic characteristics, clinical presentations, associated diseases and complications, if any. The genotype dataset was acquired for children (n = 217) and adult CD patients (n = 340) and controls (n = 736) using Immunochip. Association analysis was performed using logistic regression model to identify susceptibility genetic variants. The predominant form of CD was classical CD in both pediatric and adult CD groups. There was remarkable similarity between pediatric and adult CD except for quantitative differences between the two groups such as female preponderance, non-classical presentation, co-occurrence of other autoimmune diseases being more common amongst adult CD. Notably, same HLA-DQ2 and -DQ8 haplotypes were established as the major risk factors in both types of CD. In addition, a few suggestively associated (p < 5 × 10(-4)) non-HLA markers were identified of which only ANK3 (rs4948256-A; rs10994257-T) was found to be shared and explain risk for ~45 % of CD patients with HLA allele. Overall phenotypic similarity between pediatric and adult CD groups can be explained by contribution of same HLA risk alleles. Different non-HLA genes/loci with minor risk seem to play crucial role in disease onset and extra intestinal manifestation of CD. None of the non-HLA risk variants reached genome-wide significance, however most of them were shown to have functional implication to disease pathogenesis. Functional relevance of our findings needs to be investigated to address clinical heterogeneity of CD. This present study is the first comparative study based on common genetic markers to suggest that CD in pediatric age group and in adults are the spectrum of the same disease with novel and shared genetic risk determinants. Follow-up fine mapping studies with larger study cohorts are warranted for further genetic investigation.

Vedolizumab Effectiveness and Safety Over the First Year of Use in an IBD Clinical Practice

PubMed Central

Vivio, Emily E.; Kanuri, Navya; Gilbertsen, Joanna J.; Monroe, Kelly; Dey, Neelendu; Chen, Chien-Huan; Gutierrez, Alexandra M.

2016-01-01

Background and aims: Vedolizumab inhibits leucocyte vascular adhesion and migration into the gastrointestinal tract through α4β7 integrin blockade. This agent became available in mid-2014 for the treatment of moderate to severe Crohn’s disease (CD) and UC (UC). The aim of this study was to assess the patterns of use, effectiveness and safety of vedolizumab in an inflammatory bowel disease (IBD) clinical practice. Methods: Patients beginning vedolizumab were enrolled with informed consent. A prospective cohort was followed with laboratory, disease activity and quality-of-life assessments made during infusion visits up to week 14. Duration of vedolizumab use, mucosal healing and safety were analysed retrospectively for all patients not captured in the prospective component of this study. Results: One hundred and two patients started vedolizumab, with 51 patients (30 CD, 21 UC) followed prospectively. The CD patients exhibited a significant decrease in Crohn’s Disease Activity Index (p = 0.04) and Harvey–Bradshaw index (p < 0.01) by week 14. The UC patients demonstrated improved partial Mayo scores at weeks 6 (p < 0.01) and 14 (p < 0.001). Ninety percent of all CD and UC patients remained on vedolizumab up to week 14. IBD-related quality of life was improved by week 6 in CD and UC cohorts (p = 0.02 and p < 0.01 respectively). Colectomy for lack of response and systemic histoplamosis were notable reasons for early discontinuation of vedolizumab, which was otherwise well tolerated. Conclusions: Vedolizumab was efficacious and a high percentage of patients continued this therapy beyond induction dosing. Observed safety signals may be attributed to the refractory IBD disease state of this early-adopting clinical cohort. PMID:26681763

Whole genome gene expression meta-analysis of inflammatory bowel disease colon mucosa demonstrates lack of major differences between Crohn's disease and ulcerative colitis.

PubMed

Granlund, Atle van Beelen; Flatberg, Arnar; Østvik, Ann E; Drozdov, Ignat; Gustafsson, Bjørn I; Kidd, Mark; Beisvag, Vidar; Torp, Sverre H; Waldum, Helge L; Martinsen, Tom Christian; Damås, Jan Kristian; Espevik, Terje; Sandvik, Arne K

2013-01-01

In inflammatory bowel disease (IBD), genetic susceptibility together with environmental factors disturbs gut homeostasis producing chronic inflammation. The two main IBD subtypes are Ulcerative colitis (UC) and Crohn's disease (CD). We present the to-date largest microarray gene expression study on IBD encompassing both inflamed and un-inflamed colonic tissue. A meta-analysis including all available, comparable data was used to explore important aspects of IBD inflammation, thereby validating consistent gene expression patterns. Colon pinch biopsies from IBD patients were analysed using Illumina whole genome gene expression technology. Differential expression (DE) was identified using LIMMA linear model in the R statistical computing environment. Results were enriched for gene ontology (GO) categories. Sets of genes encoding antimicrobial proteins (AMP) and proteins involved in T helper (Th) cell differentiation were used in the interpretation of the results. All available data sets were analysed using the same methods, and results were compared on a global and focused level as t-scores. Gene expression in inflamed mucosa from UC and CD are remarkably similar. The meta-analysis confirmed this. The patterns of AMP and Th cell-related gene expression were also very similar, except for IL23A which was consistently higher expressed in UC than in CD. Un-inflamed tissue from patients demonstrated minimal differences from healthy controls. There is no difference in the Th subgroup involvement between UC and CD. Th1/Th17 related expression, with little Th2 differentiation, dominated both diseases. The different IL23A expression between UC and CD suggests an IBD subtype specific role. AMPs, previously little studied, are strongly overexpressed in IBD. The presented meta-analysis provides a sound background for further research on IBD pathobiology.

Significance of the genetic polymorphism of CYP2D6 and NAT2 in patients with inflammatory bowel diseases.

PubMed

Dudarewicz, Michał; Rychlik-Sych, Mariola; Barańska, Małgorzata; Wojtczak, Anna; Trzciński, Radzisław; Dziki, Adam; Skrętkowicz, Jadwiga

2014-08-01

The main types of inflammatory bowel diseases (IBD) are ulcerative colitis (UC) and Crohn's disease (CD). There is evidence that, in addition to immunological and environmental factors, genetic factors also play an important role in the pathogenesis of IBD. Determination of polymorphism of CYP2D6 and NAT2 genes encoding I and II phase enzymes of xenobiotic biotransformation may have clinical value as an indicator of individual predisposition to diseases, and also contribute to effective and safe pharmacotherapy. The aim of this study was to investigate the association between genetic polymorphism of CYP2D6 and NAT2 and the incidence of IBD, including UC and CD, among inhabitants of central Poland. The study was performed in 258 individuals from central Poland (115 patients with IBD, including 65 patients with UC and 50 with CD; and in 143 healthy controls). The CYP2D6 genotypes of oxidation and NAT2 genotypes of acetylation were analyzed using the PCR-RFLP method. There were no statistically significant differences in the frequency of the CYP2D6 genotypes and alleles in patients with IBD, UC and CD in comparison with the control group. The relative risk (OR) of IBD, UC and CD was higher in carriers of the allele NAT2*7 and was OR=3.49 (p=0.0019), OR=3.86 (p=0.0019), and OR=3.02 (p=0.0247), respectively. Polymorphism of the gene encoding CYP2D6 does not affect the incidence of inflammatory bowel diseases. The carriers of the NAT2*7 allele which determines slow acetylation may be more predisposed to inflammatory bowel diseases, including ulcerative colitis and Crohn's disease. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Eliciting Epitope-Specific CD8+ T Cell Response by Immunization with Microbial Protein Antigens Formulated with α-Galactosylceramide: Theory, Practice, and Protocols.

PubMed

Gilchuk, Pavlo; Knight, Frances C; Wilson, John T; Joyce, Sebastian

2017-01-01

CD8+ cytotoxic T lymphocytes confer protection against infectious diseases caused by viruses, bacteria, and parasites. Hence, significant efforts have been invested into devising ways to generate CD8+ T cell-targeted vaccines. Generation of microbe-free protein subunit vaccines requires a thorough knowledge of protective target antigens. Such antigens are proteolytically processed peptides presented by MHC class I molecules. To induce a robust antigen-specific CD8+ T cell response through vaccination, it is essential to formulate the antigen with an effective adjuvant. Here, we describe a versatile method for generating high-frequency antigen-specific CD8+ T cells through immunization of mice using the invariant natural killer T cell agonist α-galactosylceramide as the adjuvant.

Trends in and correlates of CD4+ cell count at antiretroviral therapy initiation after changes in national ART guidelines in Rwanda

PubMed Central

Mutimura, Eugene; Addison, Diane; Anastos, Kathryn; Hoover, Donald; Dusingize, Jean Claude; Karenzie, Ben; Izimukwiye, Isabelle; Mutesa, Leo; Nsanzimana, Sabin; Nashi, Denis

2015-01-01

Background Initiation of antiretroviral therapy (ART) in the advanced stages of HIV infection remains a major challenge in sub-Saharan Africa. This study was conducted to better understand barriers and enablers to timely ART initiation in Rwanda where ART coverage is high and national ART eligibility guidelines first expanded in 2007–2008. Methods Using data on 6326 patients (≥15 years) at five Rwandan clinics, we assessed trends and correlates of CD4+ cell count at ART initiation and the proportion initiating ART with advanced HIV disease (CD4+ <200 cells/µl or WHO stage IV). Results Out of 6326 patients, 4486 enrolling in HIV care initiated ART with median CD4+ cell count of 211 cells/µl [interquartile range: 131–300]. Median CD4+ cell counts at ART initiation increased from 183 cells/µl in 2007 to 293 cells/µl in 2011–2012, and the proportion with advanced HIV disease decreased from 66.2 to 29.4%. Factors associated with a higher odds of advanced HIV disease at ART initiation were male sex [adjusted odds ratios (AOR) = 1.7; 95% confidence interval (CI): 1.3–2.1] and older age (AOR46–55+ vs. <25 = 2.3; 95% CI: 1.2–4.3). Among those initiating ART more than 1 year after enrollment in care, those who had a gap in care of 12 or more months prior to ART initiation had higher odds of advanced HIV disease (AOR = 5.2; 95% CI: 1.2–21.1). Conclusion Marked improvements in the median CD4+ cell count at ART initiation and proportion initiating ART with advanced HIV disease were observed following the expansion of ART eligibility criteria in Rwanda. However, sex disparities in late treatment initiation persisted through 2011–2012, and appeared to be driven by later diagnosis and/or delayed linkage to care among men. PMID:25562492

Body Mass Index Is Associated with Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis

PubMed Central

Tang, Yuchen; Xu, Fei; Yu, Chaohui; Li, Youming; Pankaj, Prasoon; Dai, Ning

2015-01-01

Background Prior work suggested that patients with inflammatory bowel diseases (IBD) have lower body mass index (BMI) than controls and patients with lower BMI have more serious complications. Goal The study was aimed to find relationship between BMI in patients with and without IBD, investigate effects of medicine therapy and disease stages on patients’ BMI. Methods Potentially eligible studies were identified through searching PubMed, Cochrane and Embase databases. Outcome measurements of mean BMI and the number of patients from each study were pooled by a random-effect model. Publication bias test, sensitivity analysis and subgroup analysis were conducted. Results A total of 24 studies containing 1442 patients and 2059 controls were included. Main results were as follows: (1) BMI in Crohn’s disease (CD) patients was lower than that in health controls (-1.88, 95% CI -2.77 to -1.00, P< 0.001); (2) Medical therapy significantly improved BMI of CD patients (with therapy: -1.58, -3.33 to 0.16; without: -2.09, 95% CI -3.21 to -0.98) while on the contrary not significantly improving BMI of UC patients (with therapy: -0.24, 95% CI -3.68 to 3.20; without: -1.34, 95% CI -2.87 to 0.20, P = 0.57); (3) Both CD and UC patients in active phase showed significantly greater BMI difference compared with controls than those in remission (CD patients: remission: -2.25, 95% CI -3.38 to -1.11; active phase: -4.25, 95% CI -5.58 to -2.92, P = 0.03; UC patients: remission: 0.4, 95% CI -2.05 to 2.84; active phase: -5.38, -6.78 to -3.97, P = 0.001). Conclusions BMI is lower in CD patients; medical therapy couldn’t improve BMI of IBD patients; the state of disease affects BMI of CD patients and UC patients. PMID:26658675

Systematic Review with Meta-analysis: Recurrence of Crohn's disease after Total Colectomy with Permanent Ileostomy

PubMed Central

Fumery, Mathurin; Dulai, Parambir S.; Meirick, Paul; Farrell, Ann M.; Ramamoorthy, Sonia; Sandborn, William J.; Singh, Siddharth

2016-01-01

Background Subtotal or total colectomy or proctocolectomy with permanent ileostomy (TC-PI) may be a treatment option for medically refractory colonic Crohn's disease (CD). Aim To perform a systematic review and meta-analysis to evaluate the rate, risk factors and outcomes of CD recurrence after TC-PI. Methods In a systematic review ending March 31, 2016, we identified 18 cohort studies (1438 adults) who underwent TC-PI for colonic CD (median follow-up, 7.4 years; interquartile range, 5.3-9.0). We estimated pooled rates (with 95% confidence interval [CI]) of clinical and surgical recurrence, and risk factors for disease recurrence. Results On meta-analysis, the risk of clinical recurrence after TC-PI was 28.0% (95% CI, 21.7-35.3; 14 studies, 260/1004 patients), with a 5- and 10-year median cumulative rate of 23.5% (range, 7-35) and 40% (range, 11-60), respectively. The risk of surgical recurrence was 16.0% (95% CI, 11.1-22.7; 10 studies; 183/1092 patients), with a 5- and 10-year median cumulative rate of 10% (range, 3-29) and 18.5% (range, 14-34), respectively. The risk of clinical and surgical recurrence in patients without ileal disease at baseline was 11.5% (95% CI, 7.7-16.8) and 10.4% (95% CI, 4.5-22.5), respectively. History of ileal disease was associated with 3.2 times higher risk of disease recurrence (RR, 3.2; 95% CI, 1.8-5.6). Other inconsistent risk factors for disease recurrence were penetrating disease and young age at disease onset. Conclusions Small bowel clinical recurrence occurs in about 28% of patients after TC-PI for colonic CD. Disease recurrence risk is 3.2 times higher in patients with history of ileal disease, and continued medical therapy may be advisable in this population. In patients without ileal inflammation at surgery, continued endoscopic surveillance may identify asymptomatic disease recurrence to guide therapy. PMID:27928830

Validation of the "German Inflammatory Bowel Disease Activity Index (GIBDI)": An Instrument for Patient-Based Disease Activity Assessment in Crohn's Disease and Ulcerative Colitis.

PubMed

Hüppe, Angelika; Langbrandtner, Jana; Häuser, Winfried; Raspe, Heiner; Bokemeyer, Bernd

2018-05-09

 Assessment of disease activity in Crohn's disease (CD) and ulcerative colitis (UC) is usually based on the physician's evaluation of clinical symptoms, endoscopic findings, and biomarker analysis. The German Inflammatory Bowel Disease Activity Index for CD (GIBDI CD ) and UC (GIBDI UC ) uses data from patient-reported questionnaires. It is unclear to what extent the GIBDI agrees with the physicians' documented activity indices.  Data from 2 studies were reanalyzed. In both, gastroenterologists had documented disease activity in UC with the partial Mayo Score (pMS) and in CD with the Harvey Bradshaw Index (HBI). Patient-completed GIBDI questionnaires had also been assessed. The analysis sample consisted of 151 UC and 150 CD patients. Kappa coefficients were determined as agreement measurements.  Rank correlations were 0.56 (pMS, GIBDI UC ) and 0.57 (HBI, GIBDI CD ), with p < 0.001. The absolute agreement for 2 categories of disease activity (remission yes/no) was 74.2 % (UC) and 76.6 % (CD), and for 4 categories (none/mild/moderate/severe) 60.3 % (UC) and 61.9 % (CD). The kappa values ranged between 0.47 for UC (2 categories) and 0.58 for CD (4 categories).  There is satisfactory agreement of GIBDI with the physician-documented disease activity indices. GIBDI can be used in health care research without access to assessments of medical practitioners. In clinical practice, the index offers a supplementary source of information. © Georg Thieme Verlag KG Stuttgart · New York.

A two-step non-flowcytometry-based naïve B cell isolation method and its application in Staphylococcal enterotoxin B (SEB) presentation.

PubMed

Chokeshai-u-saha, Kaj; Buranapraditkun, Supranee; Jacquet, Alain; Nguyen, Catherine; Ruxrungtham, Kiat

2012-09-01

To study the role of human naïve B cells in antigen presentation and stimulation to naïve CD4+ T cell, a suitable method to reproducibly isolate sufficient naïve B cells is required. To improve the purity of isolated naive B cells obtained from a conventional one-step magnetic bead method, we added a rosetting step to enrich total B cell isolates from human whole blood samples prior to negative cell sorting by magnetic beads. The acquired naïve B cells were analyzed for phenotypes and for their role in Staphylococcal enterotoxin B (SEB) presentation to naïve CD4+ T cells. The mean (SD) naïve B cell (CD19+/CD27-) purity obtained from this two-step method compared with the one-step method was 97% (1.0) versus 90% (1.2), respectively. This two-step method can be used with a sample of whole blood as small as 10 ml. The isolated naive B cells were phenotypically at a resting state and were able to prime naïve CD4+ T cell activation by Staphylococcal enterotoxin B (SEB) presentation. This two-step non-flow cytometry-based approach improved the purity of isolated naïve B cells compared with conventional one-step magnetic bead method. It also worked well with a small blood volume. In addition, this study showed that the isolated naïve B cells can present a super-antigen "SEB" to activate naïve CD4 cells. These methods may thus be useful for further in vitro characterization of human naïve B cells and their roles as antigen presenting cells in various diseases.

Function of CD147 in atherosclerosis and atherothrombosis

PubMed Central

Wang, Cuiping; Jin, Rong; Zhu, Xiaolei; Yan, Jinchuan; Guohong, Li

2015-01-01

CD147, a member of the immunoglobulin super family, is a well-known potent inducer of extracellular matrix metalloproteinases. Studies show that CD147 is upregulated in inflammatory diseases. Atherosclerosis is a chronic inflammatory disease of the artery wall. Further understanding of the functions of CD147 in atherosclerosis and atherothrombosis may provide a new strategy for preventing and treating cardiovascular disease. In this review, we discuss how CD147 contributes to atherosclerosis and atherothrombosis. PMID:25604960

Incidence and Prevalence of Celiac Disease and Dermatitis Herpetiformis in the UK Over Two Decades: Population-Based Study

PubMed Central

West, Joe; Fleming, Kate M; Tata, Laila J; Card, Timothy R; Crooks, Colin J

2014-01-01

OBJECTIVES: Few studies have quantified the incidence and prevalence of celiac disease (CD) and dermatitis herpetiformis (DH) nationally and regionally by time and age groups. Understanding this epidemiology is crucial for hypothesizing about causes and quantifying the burden of disease. METHODS: Patients with CD or DH were identified in the Clinical Practice Research Datalink between 1990 and 2011. Incidence rates and prevalence were calculated by age, sex, year, and region of residence. Incidence rate ratios (IRR) adjusted for age, sex, and region were calculated with Poisson regression. RESULTS: A total of 9,087 incident cases of CD and 809 incident cases of DH were identified. Between 1990 and 2011, the incidence rate of CD increased from 5.2 per 100,000 (95% confidence interval (CI), 3.8–6.8) to 19.1 per 100,000 person-years (95% CI, 17.8–20.5; IRR, 3.6; 95% CI, 2.7–4.8). The incidence of DH decreased over the same time period from 1.8 per 100,000 to 0.8 per 100,000 person-years (average annual IRR, 0.96; 95% CI, 0.94–0.97). The absolute incidence of CD per 100,000 person-years ranged from 22.3 in Northern Ireland to 10 in London. There were large regional variations in prevalence for CD but not DH. CONCLUSIONS: We found a fourfold increase in the incidence of CD in the United Kingdom over 22 years, with large regional variations in prevalence. This contrasted with a 4% annual decrease in the incidence of DH, with minimal regional variations in prevalence. These contrasts could reflect differences in diagnosis between CD (serological diagnosis and case finding) and DH (symptomatic presentation) or the possibility that diagnosing and treating CD prevents the development of DH. PMID:24667576

The Impact of Ostomy on Quality of Life and Functional Status of Crohn’s Disease Patients within CCFA Partners

PubMed Central

Abdalla, Maisa I.; Sandler, Robert S.; Kappelman, Michael D.; Martin, Christopher F.; Chen, Wenli; Anton, Kristen; Long, Millie D.

2016-01-01

Background The potential need for an ostomy is a main concern for patients with inflammatory bowel disease. We performed this study to evaluate the impact of a long term ostomy (≥ 6 months duration) on the functional status and specific patient-reported outcomes (PRO) in a population of patients with Crohn’s disease (CD). Methods We performed a cross-sectional analysis within the CCFA Partners cohort Study. Bivariate analyses and logistic regression models were used to investigate associations between ostomy and various demographic, disease factors, and PROs for health related quality of life (HRQOL). Results A total of 402 CD patients with ostomy for a minimum duration of 6 months were compared to 4331 CD patients with no ostomy. Patients with ostomy were more likely to be in clinical remission compared to those without ostomy, 48.5% vs. 31.3%, respectively. Having an ostomy did not impact overall HRQOL and was not associated with anxiety, depression, sleep disturbances, or reduced sexual interest and satisfaction. However, the presence of ostomy was associated with reduced social role satisfaction in patients both with controlled and active disease. Additionally, in the subset of patients who did not achieve clinical remission, those with ostomy experienced greater pain interference (OR 1.63, 95% CI 1.12–2.35) and fatigue (OR 1.66 95% CI 1.15–2.39). Conclusion Ostomy is well-tolerated in CD patients, particularly when clinical remission is achieved. PMID:27661669

Development and Validation of an Inflammatory Bowel Diseases Monitoring Index for Use With Mobile Health Technologies.

PubMed

Van Deen, Welmoed K; van der Meulen-de Jong, Andrea E; Parekh, Nimisha K; Kane, Ellen; Zand, Aria; DiNicola, Courtney A; Hall, Laurin; Inserra, Elizabeth K; Choi, Jennifer M; Ha, Christina Y; Esrailian, Eric; van Oijen, Martijn G H; Hommes, Daniel W

2016-12-01

Mobile health technologies are advancing rapidly as smartphone use increases. Patients with inflammatory bowel disease (IBD) might be managed remotely through smartphone applications, but no tools are yet available. We tested the ability of an IBD monitoring tool, which can be used with mobile technologies, to assess disease activity in patients with Crohn's disease (CD) or ulcerative colitis (UC). We performed a prospective observational study to develop and validate a mobile health index for CD and UC, which monitors IBD disease activity using patient-reported outcomes. We collected data from disease-specific questionnaires completed by 110 patients with CD and 109 with UC who visited the University of California, Los Angeles, Center for IBD from May 2013 through January 2014. Patient-reported outcomes were compared with clinical disease activity index scores to identify factors associated with disease activity. Index scores were validated in 301 patients with CD and 265 with UC who visited 3 tertiary IBD referral centers (in California or Europe) from April 2014 through March 2015. We assessed activity of CD based on liquid stool frequency, abdominal pain, patient well-being, and patient-assessed disease control, and activity of UC based on stool frequency, abdominal pain, rectal bleeding, and patient-assessed disease control. The indices identified clinical disease activity with area under the receiver operating characteristic curve values of 0.90 in patients with CD and 0.91 in patients with UC. They identified endoscopic activity with area under the receiver operating characteristic values of 0.63 in patients with CD and 0.82 in patients with UC. Both scoring systems responded to changes in disease activity (P < .003). The intraclass correlation coefficient for test-retest reliability was 0.94 for CD and for UC. We developed and validated a scoring system to monitor disease activity in patients with CD and UC that can be used with mobile technologies. The indices identified clinical disease activity with area under the receiver operating characteristic curve values of 0.9 or higher in patients with CD or UC, and endoscopic activity in patients with UC but not CD. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

Mobilization Characteristics and Strategies to Improve Hematopoietic Progenitor Cell Mobilization and Collection in Patients with Chronic Granulomatous Disease and Severe Combined Immunodeficiency

PubMed Central

Panch, Sandhya R.; Yau, Yu Ying; Kang, Elizabeth M.; De Ravin, Suk See; Malech, Harry L.; Leitman, Susan F.

2014-01-01

Background G-CSF mobilized autologous hematopoietic progenitor cells (HPC) may be collected by apheresis of patients with chronic granulomatous disease (CGD) and severe combined immunodeficiency (SCID) for use in gene therapy trials. CD34+ cell mobilization has not been well characterized in such patients. Study Design and Methods We retrospectively evaluated CD34+ cell mobilization and collection in 73 consecutive CGD and SCID patients and in 99 age, weight and G-CSF dose-matched healthy allogeneic controls. Results In subjects aged ≤20 years, day 5 pre-apheresis circulating CD34+ counts were significantly lower in CGD and SCID than in controls; mean peak CD34+ cells 58, 64, and 87/uL, respectively, p=0.01. The SCIDs had lower CD34+ collection efficiency than CGDs and controls; mean efficiency 40%, 63% and 57%, respectively, p=0.003. In subjects >20 years, the CGDs had significantly lower CD34+ cell mobilization than controls; mean peak CD34+ cells 41 and 113/uL, respectively, p<0.0001. In a multivariate analysis, lower sedimentation rate (ESR) at mobilization was significantly correlated with better CD34+ cell mobilization, p=0.007. In SCIDs, CD34 collection efficiency was positively correlated with higher red cell indices (MCV: R2=0.77; MCH: R2=0.94; MCHC: R2=0.7, p<0.007) but not hemoglobin. Conclusions CGD and SCID populations are characterized by significantly less robust CD34+ HPC mobilization than healthy controls. The presence of active inflammation/infection as suggested by an elevated ESR may negatively impact mobilization. Among SCIDs, markedly reduced CD34 collection efficiencies were related to iron deficiency, wherein decreased red cell size and density may impair apheresis cell separation mechanics. PMID:25143186

Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease.

PubMed

Hui, Ken Y; Fernandez-Hernandez, Heriberto; Hu, Jianzhong; Schaffner, Adam; Pankratz, Nathan; Hsu, Nai-Yun; Chuang, Ling-Shiang; Carmi, Shai; Villaverde, Nicole; Li, Xianting; Rivas, Manual; Levine, Adam P; Bao, Xiuliang; Labrias, Philippe R; Haritunians, Talin; Ruane, Darren; Gettler, Kyle; Chen, Ernie; Li, Dalin; Schiff, Elena R; Pontikos, Nikolas; Barzilai, Nir; Brant, Steven R; Bressman, Susan; Cheifetz, Adam S; Clark, Lorraine N; Daly, Mark J; Desnick, Robert J; Duerr, Richard H; Katz, Seymour; Lencz, Todd; Myers, Richard H; Ostrer, Harry; Ozelius, Laurie; Payami, Haydeh; Peter, Yakov; Rioux, John D; Segal, Anthony W; Scott, William K; Silverberg, Mark S; Vance, Jeffery M; Ubarretxena-Belandia, Iban; Foroud, Tatiana; Atzmon, Gil; Pe'er, Itsik; Ioannou, Yiannis; McGovern, Dermot P B; Yue, Zhenyu; Schadt, Eric E; Cho, Judy H; Peter, Inga

2018-01-10

Crohn's disease (CD), a form of inflammatory bowel disease, has a higher prevalence in Ashkenazi Jewish than in non-Jewish European populations. To define the role of nonsynonymous mutations, we performed exome sequencing of Ashkenazi Jewish patients with CD, followed by array-based genotyping and association analysis in 2066 CD cases and 3633 healthy controls. We detected association signals in the LRRK2 gene that conferred risk for CD (N2081D variant, P = 9.5 × 10 -10 ) or protection from CD (N551K variant, tagging R1398H-associated haplotype, P = 3.3 × 10 -8 ). These variants affected CD age of onset, disease location, LRRK2 activity, and autophagy. Bayesian network analysis of CD patient intestinal tissue further implicated LRRK2 in CD pathogenesis. Analysis of the extended LRRK2 locus in 24,570 CD cases, patients with Parkinson's disease (PD), and healthy controls revealed extensive pleiotropy, with shared genetic effects between CD and PD in both Ashkenazi Jewish and non-Jewish cohorts. The LRRK2 N2081D CD risk allele is located in the same kinase domain as G2019S, a mutation that is the major genetic cause of familial and sporadic PD. Like the G2019S mutation, the N2081D variant was associated with increased kinase activity, whereas neither N551K nor R1398H variants on the protective haplotype altered kinase activity. We also confirmed that R1398H, but not N551K, increased guanosine triphosphate binding and hydrolyzing enzyme (GTPase) activity, thereby deactivating LRRK2. The presence of shared LRRK2 alleles in CD and PD provides refined insight into disease mechanisms and may have major implications for the treatment of these two seemingly unrelated diseases. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Hybridomas using athymic nude mouse injected with Crohn's disease (CD) tissue filtrate. Immunoreactivity of the hybridomas with CD sera.

PubMed Central

Das, K. M.; Vecchi, M.; Novikoff, A.; Mazumdar, S.; Novikoff, P. M.

1990-01-01

Injections of Crohn's disease (CD) tissue filtrates produce lymphoma and hyperplastic lymph nodes from plasma cell hyperplasia (PCH) in athymic nude (nu/nu) mice; these lymphoid tissue contain an antigen(s) recognized by CD serum/gamma G immunoglobulin (IgG). To immortalize the "CD-reactive antigen(s)," the authors fused the lymphoid cells from a CD tissue filtrate primed nu/nu mouse with nonsecretory mouse myeloma cells. Hybrids were screened and selected based on their reactivity with CD serum IgG, but not with control serum IgG in an indirect immunofluorescence assay (IF). Two CD-positive hybridomas were examined by IF with sera from 47 CD, 38 ulcerative colitis (UC), 13 controls with other gastrointestinal diseases, 19 with autoimmune diseases, and 21 normal subjects. Sera from 16 CD patients (34%) reacted with the two hybridomas, but only one of 38 UC sera and none of the 53 other disease or normal control sera reacted. The immunoreactivity of CD sera was significantly higher than UC sera (P less than 0.01) and each of the other groups (P less than 0.007). Using immunoperoxidase techniques at light and electron microscopic levels, the authors localized CD-associated antigen(s) in the plasma membrane of the two hybridomas. Further characterization of these hybridomas and the immunoreactive protein(s) may provide an important probe(s) for the diagnosis and the understanding of the pathogenesis of CD. Images Figure 2 Figure 3 PMID:2192559

Hodgkin's disease and CD30-positive anaplastic large cell lymphomas--a continuous spectrum of malignant disorders. A quantitative morphometric and immunohistologic study.

PubMed Central

Leoncini, L.; Del Vecchio, M. T.; Kraft, R.; Megha, T.; Barbini, P.; Cevenini, G.; Poggi, S.; Pileri, S.; Tosi, P.; Cottier, H.

1990-01-01

The authors have examined cellular areas of lymphoma tissue in 28 cases of Hodgkin's disease (HD) or anaplastic large cell lymphoma (ALCL, 'Ki-1 cell lymphoma') to evaluate the boundaries between the two entities. Methods applied included conventional histology; test point analysis; semiautomated morphometry of nuclear profile features of Reed-Sternberg and other atypical large cells (RSALCs); and immunohistochemistry of these elements on all paraffin sections and, in 15 cases, on frozen sections. Mean nuclear profile morphotypes of RSALCs per case varied independently of immunophenotype and histologic diagnosis. Conversely, immunohistochemistry demonstrated significant, although not consistent, preferential positivities of these CD30+ elements for CD15 in HD, and for epithelial membrane antigen (EMA) and CD43 in ALCLs. In the latter, RSALCs also exhibited a tendency for CD45 and CD45RO positivity and for the expression of T-cell-associated antigens. However, there were considerable overlaps. This continuous spectrum of RSALC nuclear profile morphotypes and immunophenotypes, ranging from HD over questionable cases, intermediate between HD and ALCL, to ALCLs, was paralleled by differences in the reactive component of lymphomas. Lymphocytes and granulocytes were significantly deficient in ALCLs. Images Figure 1 PMID:2173409

Adalimumab Treatment in Biologically Naïve Crohn's Disease: Relationship with Ectopic MUC5AC Expression and Endoscopic Improvement

PubMed Central

Mizoshita, Tsutomu; Tanida, Satoshi; Tsukamoto, Hironobu; Ozeki, Keiji; Katano, Takahito; Nishiwaki, Hirotaka; Ebi, Masahide; Mori, Yoshinori; Kubota, Eiji; Kataoka, Hiromi; Kamiya, Takeshi; Joh, Takashi

2014-01-01

Background. Adalimumab (ADA) is effective for patients with Crohn's disease (CD). However, there have been few reports on ADA therapy with respect to its relationship with pathologic findings and drug efficacy in biologically naïve CD cases. Methods. Fifteen patients with active biologically naïve CD were treated with ADA. We examined them clinically and pathologically with ectopic MUC5AC expression in the lesions before and after 12 and 52 weeks of ADA therapy, retrospectively. Results. Both mean CD activity index scores and serum C-reactive protein values were significantly lower after ADA therapy (P < 0.001). In the MUC5AC negative group, all cases exhibited clinical remission (CR) and endoscopic improvement at 52 weeks. In MUC5AC positive groups, loss of MUC5AC expression was detected in cases having CR and endoscopic improvement at 52 weeks, while remnant ectopic MUC5AC expression was observed in those exhibiting no endoscopic improvement and flare up after 52 weeks. Conclusions. ADA leads to CR and endoscopic improvement in biologically naïve CD cases. In addition, ectopic MUC5AC expression may be a predictive marker of flare up and endoscopic improvement in the intestines of CD patients. PMID:24829572

Voxel-based comparison of brain glucose metabolism between patients with Cushing's disease and healthy subjects.

PubMed

Liu, Shuai; Wang, Yinyan; Xu, Kaibin; Ping, Fan; Li, Fang; Wang, Renzhi; Cheng, Xin

2018-01-01

Cognitive impairment and psychiatric symptoms are common in patients with Cushing's disease (CD) owing to elevated levels of glucocorticoids. Molecular neuroimaging methods may help to detect changes in the brain of patients with CD. The aim of this study was to investigate the characteristics of brain metabolism and its association with serum cortisol level in CD. We compared brain metabolism, as measured using [ 18 F]-fluorodeoxyglucose positron emission tomography (FDG PET), between 92 patients with CD and 118 normal subjects on a voxel-wise basis. Pearson correlation was performed to evaluate the association between cerebral FDG uptake and serum cortisol level in patients with CD. We demonstrated that certain brain regions in patients with CD showed significantly increased FDG uptake, including the basal ganglia, anteromedial temporal lobe, thalamus, precentral cortex, and cerebellum. The clusters that demonstrated significantly decreased uptake were mainly located in the medial and lateral frontal cortex, superior and inferior parietal lobule, medial occipital cortex, and insular cortex. The metabolic rate of the majority of these regions was found to be significantly correlated with the serum cortisol level. Our findings may help to explain the underlying mechanisms of cognitive impairment and psychiatric symptoms in patients exposed to excessive glucocorticoids and evaluate the efficacy of treatments during follow-up.

Immunomodulatory effects of two different physical therapy modalities in patients with chronic obstructive pulmonary disease.

PubMed

Mehani, Sherin Hassan M

2017-09-01

[Purpose] Counteracting the systemic cytokine release and its inflammatory effects by improving respiratory muscle strength and controlling lung inflammation may be important for improving immune system in patients with chronic obstructive pulmonary disease, So the aim of the present study was to evaluate the effect of low level laser therapy and inspiratory muscle training on interleukin-6 (IL-6) as a marker of inflammation and CD4+/CD8+ ratio as a marker for T Lymphocytes in these patients. [Subjects and Methods] Forty male patients with stable COPD participated in the study, their ages ranged between 55-65 years. They were randomly divided into group (A) who received inspiratory muscle training and group (B) who received low level laser (LLL) acupuncture stimulation for about 8 week. [Results] There was a reduction in the concentration of plasma IL-6 associated with an increase in CD4+/CD8+ ratio in both groups, but laser was superior to inspiratory muscle training. IL-6 and CD4+/CD8+ were negatively correlated. [Conclusion] Both inspiratory muscle training and low level laser therapy are effective physical therapy modalities in promoting immune disturbances. The results also supported the superior role of LLLT over IMT in managing immune disturbances.

Perianal disease, small bowel disease, smoking, prior steroid or early azathioprine/biological therapy are predictors of disease behavior change in patients with Crohn’s disease

PubMed Central

Lakatos, Peter Laszlo; Czegledi, Zsofia; Szamosi, Tamas; Banai, Janos; David, Gyula; Zsigmond, Ferenc; Pandur, Tunde; Erdelyi, Zsuzsanna; Gemela, Orsolya; Papp, Janos; Lakatos, Laszlo

2009-01-01

AIM: To assess the combined effect of disease phenotype, smoking and medical therapy [steroid, azathioprine (AZA), AZA/biological therapy] on the probability of disease behavior change in a Caucasian cohort of patients with Crohn’s disease (CD). METHODS: Three hundred and forty well-characterized, unrelated, consecutive CD patients were analyzed (M/F: 155/185, duration: 9.4 ± 7.5 years) with a complete clinical follow-up. Medical records including disease phenotype according to the Montreal classification, extraintestinal manifestations, use of medications and surgical events were analyzed retrospectively. Patients were interviewed on their smoking habits at the time of diagnosis and during the regular follow-up visits. RESULTS: A change in disease behavior was observed in 30.8% of patients with an initially non-stricturing, non-penetrating disease behavior after a mean disease duration of 9.0 ± 7.2 years. In a logistic regression analysis corrected for disease duration, perianal disease, smoking, steroid use, early AZA or AZA/biological therapy use were independent predictors of disease behavior change. In a subsequent Kaplan-Meier survival analysis and a proportional Cox regression analysis, disease location (P = 0.001), presence of perianal disease (P < 0.001), prior steroid use (P = 0.006), early AZA (P = 0.005) or AZA/biological therapy (P = 0.002), or smoking (P = 0.032) were independent predictors of disease behavior change. CONCLUSION: Our data suggest that perianal disease, small bowel disease, smoking, prior steroid use, early AZA or AZA/biological therapy are all predictors of disease behavior change in CD patients. PMID:19630105

CD8+ T Cells Provide an Immunologic Signature of Tuberculosis in Young Children

PubMed Central

Nyendak, Melissa; Kiguli, Sarah; Zalwango, Sarah; Mori, Tomi; Mayanja-Kizza, Harriet; Balyejusa, Stephen; Null, Megan; Baseke, Joy; Mulindwa, Deo; Byrd, Laura; Swarbrick, Gwendolyn; Scott, Christine; Johnson, Denise F.; Malone, LaShaunda; Mudido-Musoke, Philipa; Boom, W. Henry; Lewinsohn, David M.; Lewinsohn, Deborah A.

2012-01-01

Rationale: The immunologic events surrounding primary Mycobacterium tuberculosis infection and development of tuberculosis remain controversial. Young children who develop tuberculosis do so quickly after first exposure, thus permitting study of immune response to primary infection and disease. We hypothesized that M. tuberculosis–specific CD8+ T cells are generated in response to high bacillary loads occurring during tuberculosis. Objectives: To determine if M. tuberculosis–specific T cells are generated among healthy children exposed to M. tuberculosis and children with tuberculosis. Methods: Enzyme-linked immunosorbent spot assays were used to measure IFN-γ production in response to M. tuberculosis–specific proteins ESAT-6/CFP-10 by peripheral blood mononuclear cells and CD8+ T cells isolated from Ugandan children hospitalized with tuberculosis (n = 96) or healthy tuberculosis contacts (n = 62). Measurements and Main Results: The proportion of positive CD8+ T-cell assays and magnitude of CD8+ T-cell responses were significantly greater among young (<5 yr) tuberculosis cases compared with young contacts (P = 0.02, Fisher exact test, P = 0.01, Wilcoxon rank-sum, respectively). M. tuberculosis–specific T-cell responses measured in peripheral blood mononuclear cells were equivalent between groups. Conclusions: Among young children, M. tuberculosis–specific CD8+ T cells develop in response to high bacillary loads, as occurs during tuberculosis, and are unlikely to be found after M. tuberculosis exposure. T-cell responses measured in peripheral blood mononuclear cells are generated after M. tuberculosis exposure alone, and thus cannot distinguish exposure from disease. In young children, IFN-γ–producing M. tuberculosis–specific CD8+ T cells provide an immunologic signature of primary M. tuberculosis infection resulting in disease. PMID:22071329

Factors Associated with Timing of Initiation of Antiretroviral Therapy among HIV-1 Infected Adults in the Niger Delta Region of Nigeria

PubMed Central

Ogoina, Dimie

2015-01-01

Introduction Based on growing evidence mainly from countries outside Sub-Saharan Africa, the World Health Organisation (WHO) now recommends initiation of antiretroviral therapy (ART) in HIV-infected individuals in developing countries when CD4 cell count (CD4+) is ≤ 500cells/ul. Nigeria accounts for about 14% of the estimated HIV/AIDS burden in Sub-Saharan Africa. We evaluated the factors associated with timing of initiation of ART among treatment-ineligible HIV-infected adults from Nigeria. Methods We retrospectively reviewed the hospital records of ART ineligible HIV-infected adults who enrolled into HIV care between January 2008 and December 2012 at two major tertiary hospitals in Bayelsa State, South-South Nigeria. Demographic, clinical and laboratories data were obtained at presentation, at each subsequent visit at 6 monthly intervals and at time of initiation of ART. Cox proportional regression and Kaplan-Meier survival analysis were used to evaluate independent predictors of time to initiation of ART. Results Amongst the 280 study participants, 70.6% were females, 62.6% had CD4+ ≥500cells/ul, 48.4% had WHO HIV Stage 1 disease and 34.3% were lost to follow up. In a cohort of 180 participants followed up for ≥3months, participants with CD4+ of 351-500cells/ul and stage 2 disease were more likely to start ART earlier than those with CD4+ > 500cells/ul (Hazard ratio [HR]-1.7, 95% confidence interval [CI] of 1.0-2.9) and stage 1 disease (HR-2.3 (95% CI-1.3-4.2) respectively. HIV-infected adults with faster CD4+ decay required earlier ART initiation, especially in the first year of follow up. Conclusion ART-ineligible HIV-infected adults on follow up in South-South Nigeria are more likely to require earlier initiation of ART if they have stage 2 HIV disease or CD4+ ≤500cells/ul at presentation. Our findings suggest faster progression of HIV-disease in these groups of individuals and corroborate the growing evidence in support for earlier initiation of ART. PMID:25933356

Quality of life in cervical dystonia after treatment with botulinum toxin A: a 24-week prospective study

PubMed Central

Kongsaengdao, Subsai; Maneeton, Benchalak; Maneeton, Narong

2017-01-01

Objective This study aimed to identify possible improvements in disease-specific health-related quality of life (HRQoL) after multiple injections of botulinum toxin A over 24 weeks in Thai cervical dystonia (CD) patients. Materials and methods A 24-week prospective study comparing HRQoL of Thai CD patients before and after multiple injections of botulinum toxin A at 3-month intervals was performed. Disease-specific HRQoL was assessed by using the Cervical Dystonia Impact Profile-58 questionnaire (CDIP-58) and the Craniocervical Dystonia Questionnaire-24 (CDQ-24). General HRQoL was assessed by using the Medical Outcomes’ 36-Item Short Form Health Survey (SF-36) and the EuroQoL 5-dimension questionnaire (EQ-5D). All the assessments were performed before and after the 24-week treatment period. Results A total of 20 CD patients were enrolled in this study from April to December 2011. CDIP-58 and CDQ-24 scores, which assess disease-specific HRQoL, showed a significant improvement after 24 weeks of treatment by botulinum toxin A (P<0.001). However, EQ-5D and SF-36 scores, which assess general HRQoL, showed no significant improvement after the treatment (P>0.05). Conclusion CD patients’ disease-specific HRQoL improved after being treated with multiple botulinum toxin A injections. However, general HRQoL was not improved. PMID:28138245

Formulation of Newcastle disease virus coupled calcium phosphate nanoparticles: an effective strategy for oculonasal delivery to chicken.

PubMed

Viswanathan, Kaliyaperumal; Gopinath, Vadivel Ponnuswamy; Raj, Gopal Dhinakar

2014-04-01

In this report, calcium phosphate (CaP) nanoparticles were synthesized by continuous flow method using β-cyclodextrin (β-CD) as a medium and functionalized with amino propyl triethoxy silane (APTES). The blood biocompatibility of the nanoparticles was assessed using the whole blood haemolysis, erythrocytes haemolysis and erythrocyte aggregation tests. Based on the results, we found that the synthesized β-CD-CaP nanoparticles did not cause any remarkable toxic effect. The 5-dimethylthiazol-2-yl-2, 5-diphenyltetrazolium bromide (MTT) assay of chicken peripheral blood mononucleated cells (PBMCs) incubated with these nanoparticles indicated that these particles did not exert any significant cytotoxicity. The aminosilane functional group modified β-CD-CaP was used as tool for coupling of Newcastle disease virus (NDV). The NDV conjugated nanoparticles were confirmed by using Fourier transformed infrared spectroscopy, X-ray diffraction patterns, Raman spectroscopy differential scanning calorimetry and energy-dispersive X-ray spectroscopy. Immunogenicity trials in chickens proved that β-CD-CaP-NDV used as a vaccine was better than the commercial vaccine when given oculonasally during the first 2 weeks post vaccination. The birds vaccinated with the above nano-NDV vaccine were completely protected against virulent NDV challenge. This study confirms that the oculonasal β-CD-CaP-NDV delivery of vaccines is a potential method for enhancing the immune responses of existing commercial vaccines. Copyright © 2013 Elsevier B.V. All rights reserved.

Marek's disease is a natural model for lymphomas overexpressing Hodgkin's disease antigen (CD30)

PubMed Central

Burgess, S. C.; Young, J. R.; Baaten, B. J. G.; Hunt, L.; Ross, L. N. J.; Parcells, M. S.; Kumar, P. M.; Tregaskes, C. A.; Lee, L. F.; Davison, T. F.

2004-01-01

Animal models are essential for elucidating the molecular mechanisms of carcinogenesis. Hodgkin's and many diverse non-Hodgkin's lymphomas overexpress the Hodgkin's disease antigen CD30 (CD30hi), a tumor necrosis factor receptor II family member. Here we show that chicken Marek's disease (MD) lymphoma cells are also CD30hi and are a unique natural model for CD30hi lymphoma. Chicken CD30 resembles an ancestral form, and we identify a previously undescribed potential cytoplasmic signaling domain conserved in chicken, human, and mouse CD30. Our phylogeneic analysis defines a relationship between the structures of human and mouse CD30 and confirms that mouse CD30 represents the ancestral mammalian gene structure. CD30 expression by MD virus (MDV)-transformed lymphocytes correlates with expression of the MDV Meq putative oncogene (a c-Jun homologue) in vivo. The chicken CD30 promoter has 15 predicted high-stringency Meq-binding transcription factor recognition motifs, and Meq enhances transcription from the CD30 promoter in vitro. Plasma proteomics identified a soluble form of CD30. CD30 overexpression is evolutionarily conserved and defines one class of neoplastic transformation events, regardless of etiology. We propose that CD30 is a component of a critical intracellular signaling pathway perturbed in neoplastic transformation. Specific anti-CD30 Igs occurred after infection of genetically MD-resistant chickens with oncogenic MDV, suggesting immunity to CD30 could play a role in MD lymphoma regression. PMID:15356338

Circulating follicular helper T cells in Crohn's disease (CD) and CD-associated colorectal cancer.

PubMed

Wang, Zhenlong; Wang, Zhiming; Diao, Yanqing; Qian, Xiaoli; Zhu, Nan; Dong, Wen

2014-09-01

Follicular helper T cells (Tfh) represent a distinct subset of CD4+ T cells specialized in providing help to B lymphocytes. Studies have indicated that Tfh in circulating blood can act as a prognostic marker for diseases. In the current study, we investigated the percentages of circulating Tfh (CTfh) in Crohn's disease (CD) and CD-associated colorectal cancer (CRC). CTfh and it subtypes were determined by measuring CD3, CD4, CXCR5, CXCR3, and CCR6 using flow cytometry in 32 healthy controls and 78 CD patients, which included 16 CD-associated CRC. Data showed that proportion of CTfh in CD4+ T cells was significantly increased in CD patients (9.8 %) than in controls (5.1 %) (p < 0.01). Further analysis revealed that the upregulation of CTfh was contributed by CTfh-Th1 subtype and CTfh-Th17 subtype. Investigating the behavior of the patients demonstrated that prevalence of CTfh was significantly elevated in penetrating CD (20.9 %) than inflammatory CD (8.2 %) or stricturing CD (7.5 %). In addition, we analyzed CTfh in CD-associated CRC, and identified that patients with CRC had 1.59-fold higher percentage of CTfh than patients without CRC (p < 0.01). Furthermore, the distribution of CTfh subsets was significantly altered in patients with the cancer. This study suggests the involvement of CTfh in CD and CD-associated CRC, in which the effect of CTfh is partially different between these two diseases.

Psychophysical assessment of low visual function in patients with retinal degenerative diseases (RDDs) with the Diagnosys full-field stimulus threshold (D-FST).

PubMed

Klein, M; Birch, D G

2009-12-01

To determine whether the Diagnosys full-field stimulus threshold (D-FST) is a valid, sensitive and repeatable psychophysical method of measuring and following visual function in low-vision subjects. Fifty-three affected eyes of 42 subjects with severe retinal degenerative diseases (RDDs) were tested with achromatic stimuli on the D-FST. Included were subjects who were either unable to perform a static perimetric field or had non-detectable or sub-microvolt electroretinograms (ERGs). A subset of 21 eyes of 17 subjects was tested on both the D-FST and the FST2, a previous established full-field threshold test. Seven eyes of 7 normal control subjects were tested on both the D-FST and the FST2. Results for the two methods were compared with the Bland-Altman test. On the D-FST, a threshold could successfully be determined for 13 of 14 eyes with light perception (LP) only (median 0.9 +/- 1.4 log cd/m2), and all eyes determined to be counting fingers (CF; median 0.3 +/- 1.8 log cd/m2). The median full-field threshold for the normal controls was -4.3 +/- 0.6 log cd/m2 on the D-FST and -4.8 +/- 0.9 log cd/m2 on the FST2. The D-FST offers a commercially available method with a robust psychophysical algorithm and is a useful tool for following visual function in low vision subjects.

Gluten and celiac disease--an immunological perspective.

PubMed

Rallabhandi, Prasad

2012-01-01

Gluten, a complex protein group in wheat, rye, and barley, causes celiac disease (CD), an autoimmune enteropathy of the small intestine, in genetically susceptible individuals. CD affects about 1% of the general population and causes significant health problems. Adverse inflammatory reactions to gluten are mediated by inappropriate T-cell activation leading to severe damage of the gastrointestinal mucosa, causing atrophy of absorptive surface villi. Gluten peptides bind to the chemokine receptor, CXCR3, and induce release of zonulin, which mediates tight-junction disassembly and subsequent increase in intestinal permeability. Proinflammatory cytokine IL-15 also contributes to the pathology of CD, by driving the expansion of intra-epithelial lymphocytes that damage the epithelium and promote the onset of T-cell lymphomas. There is no cure or treatment for CD, except for avoiding dietary gluten. Current gluten thresholds for food labeling have been established based on the available analytical methods, which show variation in gluten detection and quantification. Also, the clinical heterogeneity of celiac patients poses difficulty in defining clinically acceptable gluten thresholds in gluten-free foods. Presently, there is no bioassay available to measure gluten-induced immunobiological responses. This review focuses on various aspects of CD, and the importance of gluten thresholds and reference material from an immunological perspective.

A multicenter study confirms CD226 gene association with systemic sclerosis-related pulmonary fibrosis

PubMed Central

2012-01-01

Introduction CD226 genetic variants have been associated with a number of autoimmune diseases and recently with systemic sclerosis (SSc). The aim of this study was to test the influence of CD226 loci in SSc susceptibility, clinical phenotypes and autoantibody status in a large multicenter European population. Methods A total of seven European populations of Caucasian ancestry were included, comprising 2,131 patients with SSc and 3,966 healthy controls. Three CD226 single nucleotide polymorphisms (SNPs), rs763361, rs3479968 and rs727088, were genotyped using Taqman 5'allelic discrimination assays. Results Pooled analyses showed no evidence of association of the three SNPs, neither with the global disease nor with the analyzed subphenotypes. However, haplotype block analysis revealed a significant association for the TCG haplotype (SNP order: rs763361, rs34794968, rs727088) with lung fibrosis positive patients (PBonf = 3.18E-02 OR 1.27 (1.05 to 1.54)). Conclusion Our data suggest that the tested genetic variants do not individually influence SSc susceptibility but a CD226 three-variant haplotype is related with genetic predisposition to SSc-related pulmonary fibrosis. PMID:22531499

Small-bowel capsule endoscopy in patients with suspected Crohn's disease-diagnostic value and complications.

PubMed

Figueiredo, Pedro; Almeida, Nuno; Lopes, Sandra; Duque, Gabriela; Freire, Paulo; Lérias, Clotilde; Gouveia, Hermano; Sofia, Carlos

2010-01-01

The aim of this work was to assess the value of capsule enteroscopy in the diagnosis of patients with suspected Crohn's Disease (CD). Methods. This was a retrospective study in a single tertiary care centre involving patients undergoing capsule enteroscopy for suspected CD. Patients taking nonsteroidal anti inflammatory drugs during the thirty preceding days or with a follow-up period of less than six months were excluded. Results. Seventy eight patients were included. The endoscopic findings included mucosal breaks in 50%, ulcerated stenosis in 5%, and villous atrophy in 4%. The diagnosis of CD was established in 31 patients. The sensitivity, specificity, positive and negative predictive value of the endoscopic findings were 93%, 80%, 77%, and 94%, respectively. Capsule retention occurred in four patients (5%). The presence of ulcerated stenosis was significantly more frequent in patients with positive inflammatory markers. The diagnostic yield of capsule enteroscopy in patients with negative ileoscopy was 56%, with a diagnostic acuity of 93%. Small bowel capsule endoscopy is a safe and valid technique for assessing patients with suspected CD. Capsule retention is more frequent in patients with positive inflammatory markers. Patients with negative ileoscopy and suspected CD should be submitted to capsule enteroscopy.

Flow-cytometric monitoring of disease-associated expression of 9-O-acetylated sialoglycoproteins in combination with known CD antigens, as an index for MRD in children with acute lymphoblastic leukaemia: a two-year longitudinal follow-up study

PubMed Central

Chowdhury, Suchandra; Bandyopadhyay, Suman; Mandal, Chandan; Chandra, Sarmila; Mandal, Chitra

2008-01-01

Background Over expression of 9-O-acetylated sialoglycoproteins (Neu5,9Ac2-GPs, abbreviated as OAcSGP) has been demonstrated as a disease-associated antigen on the lymphoblasts of childhood acute lymphoblastic leukaemia (ALL). Achatinin-H, a lectin, has selective affinity towards terminal 9-O-acetylated sialic acids-α2-6-Nacetylated galactosamine. Exploring this affinity, enhanced expression of OAcSGP was observed, at the onset of disease, followed by its decrease with chemotherapy and reappearance with relapse. In spite of treatment, patients retain the diseased cells referred to as minimal residual disease (MRD) responsible for relapse. Our aim was to select a suitable template by using the differential expression of OAcSGP along with other known CD antigens to monitor MRD in peripheral blood (PB) and bone marrow (BM) of Indian patients with B- or T-ALL during treatment and correlate it with the disease status. Methods A two-year longitudinal follow-up study was done with 109 patients from the onset of the disease till the end of chemotherapy, treated under MCP841protocol. Paired samples of PB (n = 1667) and BM (n = 999) were monitored by flow cytometry. Three templates selected for this investigation were OAcSGP+CD10+CD19+ or OAcSGP+CD34+CD19+ for B-ALL and OAcSGP+CD7+CD3+ for T-ALL. Results Using each template the level of MRD detection reached 0.01% for a patient in clinical remission (CR). 81.65% of the patients were in CR during these two years while the remaining relapsed. Failure in early clearance of lymphoblasts, as indicated by higher MRD, implied an elevated risk of relapse. Soaring MRD during the chemotherapeutic regimen predicted clinical relapse, at least a month before medical manifestation. Irrespective of B- or T-lineage ALL, the MRD in PB and BM correlated well. Conclusion A range of MRD values can be predicted for the patients in CR, irrespective of their lineage, being 0.03 ± 0.01% (PB) and 0.05 ± 0.015% (BM). These patients may not be stated as normal with respect to the presence of MRD. Hence, MRD study beyond two-years follow-up is necessary to investigate further reduction in MRD, thereby ensuring their disease-free survival. Therefore, we suggest use of these templates for MRD detection, during and post-chemotherapy for proper patient management strategies, thereby helping in personalizing the treatment. PMID:18241334

Interleukin 27 is up-regulated in patients with active inflammatory bowel disease.

PubMed

Furuzawa Carballeda, Janette; Fonseca Camarillo, Gabriela; Yamamoto-Furusho, Jesús K

2016-08-01

The aim of the study was to characterize and quantify tissue gene and protein expression of IL-27 in ulcerative colitis (UC) and Crohn's disease (CD) patients. This is an observational and cross-sectional study. Fifty-four patients with IBD were studied: 27 active UC, 12 inactive UC, 10 active CD, and 5 inactive CD. All patients belonged to the Inflammatory Bowel Disease Clinic at the Instituto Nacional de Ciencias Médicas y Nutrición. We found that IL-27 gene expression was significantly higher in active UC versus inactive UC group (P = 0.015). The IL-27 mRNA expression was increased in patients with active CD compared with inactive CD disease (P = 0.035). The percentage of IL-27 immunoreactive cells was higher in active UC versus active CD patients and non-inflamed tissue controls. The IL-27 was significantly elevated in active UC and CD patients, and it was associated with disease severity.

Label-free haemogram using wavelength modulated Raman spectroscopy for identifying immune-cell subset

NASA Astrophysics Data System (ADS)

Ashok, Praveen C.; Praveen, Bavishna B.; Campbell, Elaine C.; Dholakia, Kishan; Powis, Simon J.

2014-03-01

Leucocytes in the blood of mammals form a powerful protective system against a wide range of dangerous pathogens. There are several types of immune cells that has specific role in the whole immune system. The number and type of immune cells alter in the disease state and identifying the type of immune cell provides information about a person's state of health. There are several immune cell subsets that are essentially morphologically identical and require external labeling to enable discrimination. Here we demonstrate the feasibility of using Wavelength Modulated Raman Spectroscopy (WMRS) with suitable machine learning algorithms as a label-free method to distinguish between different closely lying immune cell subset. Principal Component Analysis (PCA) was performed on WMRS data from single cells, obtained using confocal Raman microscopy for feature reduction, followed by Support Vector Machine (SVM) for binary discrimination of various cell subset, which yielded an accuracy >85%. The method was successful in discriminating between untouched and unfixed purified populations of CD4+CD3+ and CD8+CD3+ T lymphocyte subsets, and CD56+CD3- natural killer cells with a high degree of specificity. It was also proved sensitive enough to identify unique Raman signatures that allow clear discrimination between dendritic cell subsets, comprising CD303+CD45+ plasmacytoid and CD1c+CD141+ myeloid dendritic cells. The results of this study clearly show that WMRS is highly sensitive and can distinguish between cell types that are morphologically identical.

Prenatal Exposure to Arsenic and Cadmium Impacts Infectious Disease-Related Genes within the Glucocorticoid Receptor Signal Transduction Pathway

PubMed Central

Rager, Julia E.; Yosim, Andrew; Fry, Rebecca C.

2014-01-01

There is increasing evidence that environmental agents mediate susceptibility to infectious disease. Studies support the impact of prenatal/early life exposure to the environmental metals inorganic arsenic (iAs) and cadmium (Cd) on increased risk for susceptibility to infection. The specific biological mechanisms that underlie such exposure-mediated effects remain understudied. This research aimed to identify key genes/signal transduction pathways that associate prenatal exposure to these toxic metals with changes in infectious disease susceptibility using a Comparative Genomic Enrichment Method (CGEM). Using CGEM an infectious disease gene (IDG) database was developed comprising 1085 genes with known roles in viral, bacterial, and parasitic disease pathways. Subsequently, datasets collected from human pregnancy cohorts exposed to iAs or Cd were examined in relationship to the IDGs, specifically focusing on data representing epigenetic modifications (5-methyl cytosine), genomic perturbations (mRNA expression), and proteomic shifts (protein expression). A set of 82 infection and exposure-related genes was identified and found to be enriched for their role in the glucocorticoid receptor signal transduction pathway. Given their common identification across numerous human cohorts and their known toxicological role in disease, the identified genes within the glucocorticoid signal transduction pathway may underlie altered infectious disease susceptibility associated with prenatal exposures to the toxic metals iAs and Cd in humans. PMID:25479081

Review article: moving towards common therapeutic goals in Crohn's disease and rheumatoid arthritis.

PubMed

Allen, P B; Olivera, P; Emery, P; Moulin, D; Jouzeau, J-Y; Netter, P; Danese, S; Feagan, B; Sandborn, W J; Peyrin-Biroulet, L

2017-04-01

Crohn's disease (CD) and rheumatoid arthritis are chronic, progressive and disabling conditions that frequently lead to structural tissue damage. Based on strategies originally developed for rheumatoid arthritis, the treatment goal for CD has recently moved from exclusively controlling symptoms to both clinical remission and complete mucosal healing (deep remission), with the final aim of preventing bowel damage and disability. To review the similarities and differences in treatment goals between CD and rheumatoid arthritis. This review examined manuscripts from 1982 to 2016 that discussed and/or proposed therapeutic goals with their supportive evidence in CD and rheumatoid arthritis. Proposed therapeutic strategies to improve outcomes in both rheumatoid arthritis and CD include: (i) evaluation of musculoskeletal or organ damage and disability, (ii) tight control, (iii) treat-to-target, (iv) early intervention and (v) disease modification. In contrast to rheumatoid arthritis, there is a paucity of disease-modification trials in CD. Novel therapeutic strategies in CD based on tight control of objective signs of inflammation are expected to change disease course and patients' lives by halting progression or, ideally, preventing the occurrence of bowel damage. Most of these strategies require validation in prospective studies, whereas several disease-modification trials have addressed these issues in rheumatoid arthritis over the last decade. The recent approval of new drugs in CD such as vedolizumab and ustekinumab should facilitate initiation of disease-modification trials in CD in the near future. © 2017 John Wiley & Sons Ltd.

Prevalence, significance and predictive value of antiphospholipid antibodies in Crohn’s disease

PubMed Central

Sipeki, Nora; Davida, Laszlo; Palyu, Eszter; Altorjay, Istvan; Harsfalvi, Jolan; Antal Szalmas, Peter; Szabo, Zoltan; Veres, Gabor; Shums, Zakera; Norman, Gary L; Lakatos, Peter L; Papp, Maria

2015-01-01

AIM: To assess the prevalence and stability of different antiphospholipid antibodies (APLAs) and their association with disease phenotype and progression in inflammatory bowel diseases (IBD) patients. METHODS: About 458 consecutive patients [Crohn’s disease (CD): 271 and ulcerative colitis (UC): 187] were enrolled into a follow-up cohort study in a tertiary IBD referral center in Hungary. Detailed clinical phenotypes were determined at enrollment by reviewing the patients’ medical charts. Disease activity, medical treatment and data about evolvement of complications or surgical interventions were determined prospectively during the follow-up. Disease course (development f complicated disease phenotype and need for surgery), occurrence of thrombotic events, actual state of disease activity according to clinical, laboratory and endoscopic scores and accurate treatment regime were recorded during the follow-up, (median, 57.4 and 61.6 mo for CD and UC). Sera of IBD patients and 103 healthy controls (HC) were tested on individual anti-β2-Glycoprotein-I (anti-β2-GPI IgA/M/G), anti-cardiolipin (ACA IgA/M/G) and anti-phosphatidylserine/prothrombin (anti-PS/PT IgA/M/G) antibodies and also anti-Saccharomyces cerevisiae antibodies (ASCA IgA/G) by enzyme-linked immunosorbent assay (ELISA). In a subgroup of CD (n = 198) and UC patients (n = 103), obtaining consecutive samples over various arbitrary time-points during the disease course, we evaluated the intraindividual stability of the APLA status. Additionally, we provide an overview of studies, performed so far, in which significance of APLAs in IBD were assessed. RESULTS: Patients with CD had significantly higher prevalence of both ACA (23.4%) and anti-PS/PT (20.4%) antibodies than UC (4.8%, P < 0.0001 and 10.2%, P = 0.004) and HC (2.9%, P < 0.0001 and 15.5%, P = NS). No difference was found for the prevalence of anti-β2-GPI between different groups (7.2%-9.7%). In CD, no association was found between APLA and ASCA status of the patients. Occurrence of anti-β2-GPI, ACA and anti-PS/PT was not different between the group of patients with active vs inactive disease state according to appropriate clinical, laboratory and endoscopic scores in CD as well as in UC patients. All subtypes of anti-β2-GPI and ACA IgM status were found to be very stable over time, in contrast ACA IgG and even more ACA IgA status showed significant intraindividual changes. Changes in antibody status were more remarkable in CD than UC (ACA IgA: 49.9% vs 23.3% and ACA IgG: 21.2% vs 5.8%). Interestingly, 59.1% and 30.1% of CD patients who received anti-TNF therapy showed significant negative to positive changes in ACA IgA and IgG antibody status respectively. APLA status was not associated with the clinical phenotype at diagnosis or during follow-up, medical therapy, or thrombotic events and it was not associated with the probability of developing complicated disease phenotype or surgery in a Kaplan-Meier analysis. CONCLUSION: The present study demonstrated enhanced formation of APLAs in CD patients. However, presence of different APLAs were not associated with the clinical phenotype or disease course. PMID:26078573

Effects of Periconception Cadmium and Mercury Co-Administration to Mice on Indices of Chronic Diseases in Male Offspring at Maturity

PubMed Central

Camsari, Cagri; Folger, Joseph K.; McGee, Devin; Bursian, Steven J.; Wang, Hongbing; Knott, Jason G.; Smith, George W.

2016-01-01

Background: Long-term exposure to the heavy metals cadmium (Cd) and mercury (Hg) is known to increase the risk of chronic diseases. However, to our knowledge, exposure to Cd and Hg beginning at the periconception period has not been studied to date. Objective: We examined the effect of Cd and Hg that were co-administered during early development on indices of chronic diseases in adult male mice. Methods: Adult female CD1 mice were subcutaneously administered a combination of cadmium chloride (CdCl2) and methylmercury (II) chloride (CH3HgCl) (0, 0.125, 0.5, or 2.0 mg/kg body weight each) 4 days before and 4 days after conception (8 days total). Indices of anxiety-like behavior, glucose homeostasis, endocrine and molecular markers of insulin resistance, and organ weights were examined in adult male offspring. Results: Increased anxiety-like behavior, impaired glucose homeostasis, and higher body weight and abdominal adipose tissue weight were observed in male offspring of treated females compared with controls. Significantly increased serum leptin and insulin concentrations and impaired insulin tolerance in the male offspring of dams treated with 2.0 mg/kg body weight of Cd and Hg suggested insulin resistance. Altered mRNA abundance for genes associated with glucose and lipid homeostasis (GLUT4, IRS1, FASN, ACACA, FATP2, CD36, and G6PC) in liver and abdominal adipose tissues as well as increased IRS1 phosphorylation in liver (Ser 307) provided further evidence of insulin resistance. Conclusions: Results suggest that the co-administration of Cd and Hg to female mice during the early development of their offspring (the periconception period) was associated with anxiety-like behavior, altered glucose metabolism, and insulin resistance in male offspring at adulthood. Citation: Camsari C, Folger JK, McGee D, Bursian SJ, Wang H, Knott JG, Smith GW. 2017. Effects of periconception cadmium and mercury co-administration to mice on indices of chronic diseases in male offspring at maturity. Environ Health Perspect 125:643–650; http://dx.doi.org/10.1289/EHP481 PMID:27814245

The Role of T cell PPAR γ in mice with experimental inflammatory bowel disease

PubMed Central

2010-01-01

Background Peroxisome proliferator-activated receptor γ (PPAR γ) is a nuclear receptor whose activation has been shown to modulate macrophage and T cell-mediated inflammation. The objective of this study was to investigate the mechanisms by which the deletion of PPAR γ in T cells modulates immune cell distribution and colonic gene expression and the severity of experimental IBD. Methods PPAR γ flfl; CD4 Cre+ (CD4cre) or Cre- (WT) mice were challenged with 2.5% dextran sodium sulfate in their drinking water for 0, 2, or 7 days. Mice were scored on disease severity both clinically and histopathologically. Flow cytometry was used to assess lymphocyte and macrophage populations in the blood, spleen, and mesenteric lymph nodes (MLN). Global gene expression in colonic mucosa was profiled using Affymetrix microarrays. Results The deficiency of PPAR γ in T cells accelerated the onset of disease and body weight loss. Examination of colon histopathology revealed significantly greater epithelial erosion, leukocyte infiltration, and mucosal thickening in the CD4cre mice on day 7. CD4cre mice had more CD8+ T cells than WT mice and fewer CD4+FoxP3+ regulatory T cells (Treg) and IL10+CD4+ T cells in blood and MLN, respectively. Transcriptomic profiling revealed around 3000 genes being transcriptionally altered as a result of DSS challenge in CD4cre mice. These included up-regulated mRNA expression of adhesion molecules, proinflammatory cytokines interleukin-6 (IL-6) and IL-1β, and suppressor of cytokine signaling 3 (SOCS-3) on day 7. Gene set enrichment analysis (GSEA) showed that the ribosome and Krebs cycle pathways were downregulated while the apoptosis pathway was upregulated in colons of mice lacking PPAR γ in T cells. Conclusions The expression of PPAR γ in T cells is involved in preventing gut inflammation by regulating colonic expression of adhesion molecules and inflammatory mediators at later stages of disease while favoring the recruitment of Treg to the mucosal inductive sites. PMID:20537136

Interrelation secretory activity of stomach and immunes changes of peripheral blood when ulcerogenesis stomach.

PubMed

Matveeva, L V; Mosina, L M

2016-01-01

Incidence of gastric ulcer is high in almost all countries of the world. On the development and course of the disease affect the state acid- and enzymes production stomach, immune status. The purpose was to determine the presence and power of correlative links secretory activity of the stomach and immune changes in the peripheral blood during exacerbation of ulcer disease stomach. Surveyed in obtaining informed consent 42 patients with gastric ulcer in the acute phase prior to the eradication and antisecretory therapy and 40 healthy volunteers. On the state of function acid- and enzymes production of the gastric mucosa judged by the results of a 2-hour intragastric pH-metry and serum concentration pepsinogen, gastrin before the start of active treatment. Immunophenotype lymphocytes on CD-antigens (CD3, CD4, CD8, CD16, CD19, CD45, CD56) was measured by immunofluorescence, levels immunoglobulin isotype M, G, A, E - ELISA method. When short-term intragastric pH-metry of the stomach hyperacidity patients recorded 6.7 times more likely than healthy, normacidity - 12.3 times less. Reduction of acid production was observed up to 8.6 times more, indicating the development of mucosal atrophy. Basal pH in the antrum was lower by 54.5% than in the control group, with stimulation increased by 33.6%, but remained lower than the values of healthy individuals by 48.7%. When ELISA amount pepsinogen patients showed significant increase in serum levels of PG-I relative to the control group at 33.4%, PG-II - 52%. In assessing the immune status of patients were identified changes in system phagocytes, cellular and humoral links, most pronounced for severe current peptic ulcer disease. The results indicate the presence of positive and negative correlative links mild to moderate force between indicators of secretory activity of gastric mucosal innate and adaptive immunity in patients with acute exacerbation of peptic ulcer disease. The presence and nature of these relationships should be taken into account when appointing antisecretory drugs.

Healthcare professionals' views of the experiences of individuals living with Crohn's Disease in Spain. A qualitative study.

PubMed

García-Sanjuán, Sofía; Lillo-Crespo, Manuel; Richart-Martínez, Miguel; Sanjuán-Quiles, Ángela

2018-01-01

Crohn's Disease (CD) in Spain lacks of a unified National Clinical Pathway and not even any early detection program and professional follow-up outpatient attention once it has been diagnosed. Little is known about the Spanish health professionals' views of the experiences of individuals living with Crohn's Disease nationwide and also about how the Spanish Health System faces this situation. A qualitative research method was conducted to explore this topic through in-depth interviews with eleven healthcare professionals, who represented different clinics treating people with CD from the province of Alicante (Spain). Three topics and seven sub-topics were derived from the analysis of the content emerging from the interviews. The three main topics were: the healthcare system as a hindrance for ongoing treatment of CD, the impact of the disease, support networks. The knowledge of CD gained by healthcare professionals, in the contexts studied here within, with regards to the psychosocial aspects and the experience of those living with the disease and their immediate circles, is poor, if not null on an academic level, becoming experiential on their incorporation into the professional field. Additionally, a priori, they lack the tools to address the doubts and concerns of patients from the moment of diagnosis through the ongoing care of the patient. Organizational hindrances, such as the lack of time and consensual guidelines for adequately monitoring CD patients in Alicante (Spain), further restrict the patient-professional relationship. Due to the consensus established by the National Agency regulating the contents of the Health Professions' Education and Training across the country, we are assuming that the phenomenon highlighted may be similar in other parts of Spain. Therefore, it can be said that healthcare professionals have a limited understanding of the impact of CD on the day-to-day life of those affected, not being considered a part of the CD patients' formal support network. Nonetheless, they are conscious of this limitation and advocate for multidisciplinary teams as the best means of attending to people living with CD. Our study outcomes may represent the first step onto identifying strategies and best practices for establishing an effective therapeutic relationship, as well as any hindering factors.

Analysis of PD-1 and Tim-3 expression on CD4+ T cells of patients with rheumatoid arthritis; negative association with DAS28.

PubMed

Koohini, Zohreh; Hossein-Nataj, Hadi; Mobini, Maryam; Hosseinian-Amiri, Aref; Rafiei, Alireza; Asgarian-Omran, Hossein

2018-04-07

Expression of T cell immunoglobulin and mucin-domain containing-3 (Tim-3) and programmed cell death-1 (PD-1) was studied on CD4 + T cells of patients with rheumatoid arthritis (RA). Association of Tim-3 and PD-1 expression with disease activity of RA patients was also addressed. A total of 37 RA patients and 31 sex- and age-matched healthy controls were included in this study. Disease activity of RA patients was determined by Disease Activity Score of 28 joints scoring system (DAS28). A three-color flow cytometry method was applied to determine the frequency of Tim-3 + /PD-1 + /CD4 + T cells. To measure the cytokine production, peripheral blood mononuclear cells (PBMCs) were stimulated with PMA/ionomycin. Concentrations of IL-17, IL-10, IFN-γ, and TNF-α were measured in culture supernatants by ELISA. The frequency of PD-1 + /CD4 + and Tim-3 + /PD-1 + /CD4 + T cells was significantly higher in patients with RA compared to that in controls (p = 0.0013 and p = 0.050, respectively). The percentage of Tim-3 + /CD4 + T cells was similar in patients and controls (p = 0.4498). The RA patients have produced significant higher levels of TNF-α, IL-17, and IFN-γ than those of healthy controls (p = 0.0121, p = 0.0417, and p = 0.0478, respectively). Interestingly, an inverse correlation was found between the frequency of Tim-3 + /CD4 + cells and DAS28 of RA patients (r = - 0.4696, p = 0.0493). Similarly, the percentage of Tim-3 + /PD-1 + /CD4 + T cells was also revealed an inverse correlation with DAS28 (r = - 0.5268, p = 0.0493). Moreover, significant positive correlations were detected between the concentrations of TNF-α (r = 0.6418, p = 0.0023) and IL-17 (r = 0.4683, p = 0.0373) with disease activity of RA patients. Our results indicate that Tim-3 and PD-1 are involved in immune dysregulation mechanisms of rheumatoid arthritis and could be considered as useful biomarkers for determination of disease activity and progression.

Healthcare professionals’ views of the experiences of individuals living with Crohn’s Disease in Spain. A qualitative study

PubMed Central

Richart-Martínez, Miguel; Sanjuán-Quiles, Ángela

2018-01-01

Crohn’s Disease (CD) in Spain lacks of a unified National Clinical Pathway and not even any early detection program and professional follow-up outpatient attention once it has been diagnosed. Little is known about the Spanish health professionals’ views of the experiences of individuals living with Crohn’s Disease nationwide and also about how the Spanish Health System faces this situation. A qualitative research method was conducted to explore this topic through in-depth interviews with eleven healthcare professionals, who represented different clinics treating people with CD from the province of Alicante (Spain). Three topics and seven sub-topics were derived from the analysis of the content emerging from the interviews. The three main topics were: the healthcare system as a hindrance for ongoing treatment of CD, the impact of the disease, support networks. The knowledge of CD gained by healthcare professionals, in the contexts studied here within, with regards to the psychosocial aspects and the experience of those living with the disease and their immediate circles, is poor, if not null on an academic level, becoming experiential on their incorporation into the professional field. Additionally, a priori, they lack the tools to address the doubts and concerns of patients from the moment of diagnosis through the ongoing care of the patient. Organizational hindrances, such as the lack of time and consensual guidelines for adequately monitoring CD patients in Alicante (Spain), further restrict the patient-professional relationship. Due to the consensus established by the National Agency regulating the contents of the Health Professions’ Education and Training across the country, we are assuming that the phenomenon highlighted may be similar in other parts of Spain. Therefore, it can be said that healthcare professionals have a limited understanding of the impact of CD on the day-to-day life of those affected, not being considered a part of the CD patients’ formal support network. Nonetheless, they are conscious of this limitation and advocate for multidisciplinary teams as the best means of attending to people living with CD. Our study outcomes may represent the first step onto identifying strategies and best practices for establishing an effective therapeutic relationship, as well as any hindering factors. PMID:29360881

Mycobiome of the bat white nose syndrome affected caves and mines reveals diversity of fungi and local adaptation by the fungal pathogen Pseudogymnoascus (Geomyces) destructans.

PubMed

Zhang, Tao; Victor, Tanya R; Rajkumar, Sunanda S; Li, Xiaojiang; Okoniewski, Joseph C; Hicks, Alan C; Davis, April D; Broussard, Kelly; LaDeau, Shannon L; Chaturvedi, Sudha; Chaturvedi, Vishnu

2014-01-01

Current investigations of bat White Nose Syndrome (WNS) and the causative fungus Pseudogymnoascus (Geomyces) destructans (Pd) are intensely focused on the reasons for the appearance of the disease in the Northeast and its rapid spread in the US and Canada. Urgent steps are still needed for the mitigation or control of Pd to save bats. We hypothesized that a focus on fungal community would advance the understanding of ecology and ecosystem processes that are crucial in the disease transmission cycle. This study was conducted in 2010-2011 in New York and Vermont using 90 samples from four mines and two caves situated within the epicenter of WNS. We used culture-dependent (CD) and culture-independent (CI) methods to catalogue all fungi ('mycobiome'). CD methods included fungal isolations followed by phenotypic and molecular identifications. CI methods included amplification of DNA extracted from environmental samples with universal fungal primers followed by cloning and sequencing. CD methods yielded 675 fungal isolates and CI method yielded 594 fungal environmental nucleic acid sequences (FENAS). The core mycobiome of WNS comprised of 136 operational taxonomic units (OTUs) recovered in culture and 248 OTUs recovered in clone libraries. The fungal community was diverse across the sites, although a subgroup of dominant cosmopolitan fungi was present. The frequent recovery of Pd (18% of samples positive by culture) even in the presence of dominant, cosmopolitan fungal genera suggests some level of local adaptation in WNS-afflicted habitats, while the extensive distribution of Pd (48% of samples positive by real-time PCR) suggests an active reservoir of the pathogen at these sites. These findings underscore the need for integrated disease control measures that target both bats and Pd in the hibernacula for the control of WNS.

Differential expression of NK receptors CD94 and NKG2A by T cells in rheumatoid arthritis patients in remission compared to active disease.

PubMed

Walsh, Ceara E; Ryan, Elizabeth J; O'Farrelly, Cliona; Golden-Mason, Lucy; FitzGerald, Oliver; Veale, Douglas J; Bresnihan, Barry; Fearon, Ursula

2011-01-01

TNF inhibitors (TNFi) have revolutionised the treatment of rheumatoid arthritis (RA). Natural killer (NK) cells and Natural Killer Cell Receptor+ T (NKT) cells comprise important effector lymphocytes whose activity is tightly regulated through surface NK receptors (NKRs). Dysregulation of NKRs in patients with autoimmune diseases has been shown, however little is known regarding NKRs expression in patients with TNFi-induced remission and in those who maintain remission vs disease flare following TNFi withdrawal. Patients with RA were recruited for this study, (i) RA patients in clinical remission following a minimum of one year of TNFi therapy (n = -15); (2) Active RA patients, not currently or ever receiving TNFi (n = 18); and healthy control volunteers (n = 15). Patients in remission were divided into two groups: those who were maintained on TNFi and those who withdrew from TNFi and maintained on DMARDS. All patients underwent full clinical assessment. Peripheral blood mononuclear cells were isolated and NKR (CD94, NKG2A, CD161, CD69, CD57, CD158a, CD158b) expression on T-(CD3+CD56-), NK-(CD3-CD56+) and NKT-(CD3+CD56+) cells was determined by flow cytometry. Following TNFi withdrawal, percentages and numbers of circulating T cells, NK cells or NKT cell populations were unchanged in patients in remission versus active RA or HCs. Expression of the NKRs CD161, CD57, CD94 and NKG2A was significantly increased on CD3+CD56-T cells from patients in remission compared to active RA (p<0.05). CD3+CD56-T cell expression of CD94 and NKG2A was significantly increased in patients who remained in remission compared with patients whose disease flared (p<0.05), with no differences observed for CD161 and CD57. CD3+CD56- cell expression of NKG2A was inversely related to DAS28 (r = -0.612, p<0.005). High CD94/NKG2A expression by T cells was demonstrated in remission patients following TNFi therapy compared to active RA, while low CD94/NKG2A were associated with disease flare following withdrawal of therapy.

To screen or not to screen? Celiac antibodies in liver diseases

PubMed Central

Narciso-Schiavon, Janaína Luz; Schiavon, Leonardo Lucca

2017-01-01

Celiac disease (CD) is a systemic immune-mediated disorder triggered by dietary gluten in genetically predisposed individuals. The typical symptoms are anemia, diarrhea, fatigue, weight loss, and abdominal pain. CD has been reported in patients with primary sclerosing cholangitis, primary biliary cholangitis, autoimmune hepatitis, aminotransferase elevations, nonalcoholic fatty liver disease, hepatitis B, hepatitis C, portal hypertension and liver cirrhosis. We evaluate recommendations for active screening for CD in patients with liver diseases, and the effect of a gluten-free diet in these different settings. Active screening for CD is recommended in patients with liver diseases, particularly in those with autoimmune disorders, steatosis in the absence of metabolic syndrome, noncirrhotic intrahepatic portal hypertension, cryptogenic cirrhosis, and in the context of liver transplantation. In hepatitis C, diagnosis of CD can be important as a relative contraindication to interferon use. Gluten-free diet ameliorates the symptoms associated with CD; however, the associated liver disease may improve, remain the same, or progress. PMID:28223722

Altered CD19/CD22 balance in Egyptian children and adolescents with systemic lupus erythematosus.

PubMed

El-Sayed, Zeinab A; Ragab, Seham M; Khalifa, Khaled A; El Ashmawy, Ramy A

2009-01-01

B cells from systemic lupus erythematosus (SLE) patients display signalling defects that may underlie disease pathogenesis activity.CD19 and CD22 play a major role as regulators of B-cell response. The aim of this study was to clarify the relationship between B cell surface markers namely CD19, CD20 and CD22 expression and clinical and laboratory indices of SLE activity. The study included 33 SLE patients and 20 healthy children and adolescents as controls. Flowcytometric assay of dual markers, CD19/CD20, and CD20/CD22 was done. SLE disease activity was assessed by SLEDAI score. CD22% was significantly higher while CD20% was significantly lower in the study compared to the control group. No significant difference was observed in both groups with respect to CD19% or CD19/CD22% ratio. The level of CD22 expression was significantly lower in high and very high active cases than in mild and moderate cases and negatively correlated with SLDEAI score and ESR. Results obtained showed that, B cell surface receptors CD20 and CD22 are significantly affected in patients with SLE, pointing to their possible involvement in the aetiopathogenesis of the disease and in the regulatory mechanisms in response to the immune disturbance.

CD4 decline is associated with increased risk of cardiovascular disease, cancer, and death in virally suppressed patients with HIV.

PubMed

Helleberg, Marie; Kronborg, Gitte; Larsen, Carsten S; Pedersen, Gitte; Pedersen, Court; Obel, Niels; Gerstoft, Jan

2013-07-01

The clinical implications of a considerable CD4 decline despite antiretroviral treatment and viral suppression are unknown. We aimed to test the hypothesis that a major CD4 decline could be a marker of cardiovascular disease or undiagnosed cancer. Patients with human immunodeficiency virus (HIV) were followed in the Danish nationwide, population-based cohort study in the period 1995-2010 with quarterly CD4 measurements. Associations between a CD4 decline of ≥30% and cardiovascular disease, cancer, and death were analyzed using Poisson regression with date of CD4 decline as a time-updated variable. We followed 2584 virally suppressed HIV patients for 13 369 person-years (PY; median observation time, 4.7 years). Fifty-six patients developed CD4 decline (incidence rate, 4.2/1000 PY [95% confidence interval {CI}, 3.2-5.4]). CD4 counts dropped from a median of 492 cells/µL to 240 cells/µL. CD8, CD3, and total lymphocyte counts dropped concomitantly. No HIV-related factors, apart from treatment with didanosine, were associated with CD4 decline. The risk of cardiovascular disease, cancer, and death increased markedly ≤6 months after CD4 decline (incidence rate ratio, 11.7 [95% CI, 3.6-37.4] and 13.7 [95% CI, 4.3-43.6], respectively, and mortality rate ratio 4.3 [95% CI, 1.1-17.6]). A major decline in CD4 count is associated with a marked increased risk of cardiovascular disease, cancer, and death among virally suppressed HIV patients.

Matrix Expansion and Syncytial Aggregation of Syndecan-1+ Cells Underpin Villous Atrophy in Coeliac Disease

PubMed Central

Salvestrini, Camilla; Lucas, Mark; Lionetti, Paolo; Torrente, Franco; James, Sean; Phillips, Alan D.; Murch, Simon H.

2014-01-01

Background We studied the expression of sulphated glycosaminoglycans (GAGs) in coeliac disease (CD) mucosa, as they are critical determinants of tissue volume, which increases in active disease. We also examined mucosal expression of IL-6, which stimulates excess GAG synthesis in disorders such as Grave's ophthalmopathy. Methods We stained archival jejunal biopsies from 5 children with CD at diagnosis, on gluten-free diet and challenge for sulphated GAGs. We then examined duodenal biopsies from 9 children with CD compared to 9 histological normal controls, staining for sulphated GAGs, heparan sulphate proteoglycans (HSPG), short-chain HSPG (Δ-HSPG) and the proteoglycan syndecan-1 (CD138), which is expressed on epithelium and plasma cells. We confirmed findings with a second monoclonal in another 12 coeliac children. We determined mucosal IL-6 expression by immunohistochemistry and PCR in 9 further cases and controls, and used quantitative real time PCR for other Th17 pathway cytokines in an additional 10 cases and controls. Results In CD, HSPG expression was lost in the epithelial compartment but contrastingly maintained within an expanded lamina propria. Within the upper lamina propria, clusters of syndecan-1+ plasma cells formed extensive syncytial sheets, comprising adherent plasma cells, lysed cells with punctate cytoplasmic staining and shed syndecan ectodomains. A dense infiltrate of IL-6+ mononuclear cells was detected in active coeliac disease, also localised to the upper lamina propria, with significantly increased mRNA expression of IL-6 and IL-17A but not IL-23 p19. Conclusions Matrix expansion, through syndecan-1+ cell recruitment and lamina propria GAG increase, underpins villous atrophy in coeliac disease. The syndecan-1+ cell syncytia and excess GAG production recapitulate elements of the invertebrate encapsulation reaction, itself dependent on insect transglutaminase and glutaminated early response proteins. As in other matrix expansion disorders, IL-6 is upregulated and represents a logical target for immunotherapy in patients with coeliac disease refractory to gluten-free diet. PMID:25198673

Crohn's disease-associated interstitial lung disease mimicking sarcoidosis: a case report and review of the literature.

PubMed

Thao, Choua; Lagstein, Amir; Allen, Tadashi; Dincer, Huseyin Erhan; Kim, Hyun Joo

2016-10-07

Respiratory involvement in Crohn's disease (CD) is a rare manifestation known to involve the large and small airways, lung parenchyma, and pleura. The clinical presentation is nonspecific, and diagnostic tests can mimic other pulmonary diseases, posing a diagnostic challenge and delay in treatment. We report a case of a 60-year-old female with a history of CD and psoriatic arthritis who presented with dyspnea, fever, and cough with abnormal radiological findings. Diagnostic testing revealed an elevated CD4:CD8 ratio in the bronchoalveolar lavage fluid, and cryoprobe lung biopsy results showed non-necrotizing granulomatous inflammation. We describe here the second reported case of pulmonary involvement mimicking sarcoidosis in Crohn's disease and a review of the literature on the approaches to making a diagnosis of CD-associated interstitial lung disease.

Preventing Collateral Damage in Crohn’s Disease: The Lémann Index

PubMed Central

Fiorino, Gionata; Bonifacio, Cristiana; Peyrin-Biroulet, Laurent

2016-01-01

Crohn’s disease [CD] is a chronic progressive and destructive condition. Half of all CD patients will develop bowel damage at 10 years. As in rheumatic diseases, preventing the organ damage consequent to CD complications [fistula, abscess, and/or stricture] is emerging as a new therapeutic goal for these patients in clinical practice. This might be the only way to alter disease course, as surgery is often required for disease complications. Similar to the joint damage in rheumatoid arthritis, bowel damage has also emerged as a new endpoint in disease-modification trials such as the REACT trial. Recently, the Lemann Index [LI] has been developed to measure CD-related bowel damage, and to assess damage progression over time, in order to evaluate the impact of therapeutic strategies in terms of preventing bowel damage. While validation is pending, recent reports suggested that bowel damage is reversible by anti-tumour necrosis factor [TNF] therapy. The Lémann index may play a key role in CD management, and should be implemented in all upcoming disease-modification trials in CD. PMID:26744441

Crohn’s disease incidence evolution in North-western Greece is not associated with alteration of NOD2/CARD15 variants

PubMed Central

Economou, Michael; Filis, Grigoris; Tsianou, Zoi; Alamanos, John; Kogevinas, Antonios; Masalas, Kostas; Petrou, Anna; Tsianos, Epameinondas V

2007-01-01

AIM: To assess the trends in the incidence of inflammatory bowel disease (IBD) over 23 years in the same area and to identify genetic factors related to incidence evolution. METHODS: Patients with IBD arising from North-western Greece were systematically recorded through the 1983-2005 period. Trends in disease incidence and genetic patterns related to CARD15 variants were documented and correlated. RESULTS: A total of 447 patients with IBD were recorded (23.5% Crohn’s disease, 72.7% Ulcerative colitis and 3.8% indeterminate colitis). Mean annual incidence rates of CD and UC were 0.9/100 000 (95% CI 0.1-1.7) and 2.7/100 000 (95% CI 1.7-4.1) inhabitants, respectively. There was a statistically significant increase of CD incidence (P < 0.01) during the study period, in contrast to the UC incidence. There were no statistical differences in CARD15 variants over the study period. CONCLUSION: The incidence of CD in North-western Greece has risen disproportionately to that of UC in the 21st century. This is not related to alterations of genetic background though. PMID:17876878

Blastic plasmacytoid dendritic cell neoplasm in an elderly woman.

PubMed

Foong, H B B; Chong, M; Taylor, E M; Carlson, J A; Petrella, T

2013-04-01

Blastic plasmacytoid dendritic cell neoplasm (a.k.a. NK cell lymphoma, CD4+CD56+ haematodermic neoplasm) is a rare aggressive tumour that arises from plasmacytoid dendritic cell precursors. We report the first case from Malaysia of a 79-year-old Chinese woman who presented with purpuric plaques and nodules produced by pleomorphic CD4+, CD56+, CD68+, CD123+ and CD303+, but CD2APmononuclear cell infiltrates. Leukemic dissemination occurred and she succumbed to disease without treatment 4 weeks after diagnosis and 9 months after onset of cutaneous disease.

Increased risk of esophageal eosinophilia and eosinophilic esophagitis in patients with active celiac disease on biopsy

PubMed Central

Jensen, Elizabeth T.; Eluri, Swathi; Lebwohl, Benjamin; Genta, Robert M.; Dellon, Evan S.

2015-01-01

Background and Aims The possible association between eosinophilic esophagitis (EoE) and celiac disease (CD) is controversial as prior results have been contradictory. We aimed to determine the relationship between EoE and CD among patients with concomitant esophageal and duodenal biopsies. Methods We conducted a cross-sectional study in a U.S. national pathology database, using data from January 2009 and June 2012. Our primary case definition was defined by the presence of esophageal eosinophilia with ≥ 15 eosinophils per high-power field. The crude and adjusted (for age and sex) odds of esophageal eosinophilia for patients with active CD were compared to those without CD. Sensitivity analyses were performed using more stringent case definitions and by estimating the associations between CD and reflux esophagitis, and CD and Barrett's esophagus (BE). Results Of 292,621 patients in the source population, 88,517 with both esophageal and duodenal biopsies were studied. 4,101 (4.6%) met criteria for EoE and 1,203 (1.4%) met criteria for CD. Odds of EoE were 26% higher in patients with CD than patients without CD (aOR: 1.26, 95% confidence interval [CI]: 0.98 – 1.60). The magnitude of association varied according to EoE case definition (Table 3), but all definitions showed a weak, positive association between the two conditions. There was no association between CD and reflux esophagitis (aOR 0.95, 95% CI: 0.85 – 1.07) or BE (aOR 0.89, 95% CI: 0.69 – 1.14) and CD. Conclusions There is a weak increase in EoE in patients with CD. This association strengthened with increasingly stringent definitions of EoE, and was not observed for other esophageal conditions. In patients with CD, concomitant EoE should be considered in the correct clinical setting. PMID:25724709

A Novel Epitope from CD22 Regulates Th1 and Th17 Cell Function in Systemic Lupus Erythematosus

PubMed Central

Chen, Xiao; Zhang, Li-Hua; Song, You; Cheng, Xiang; Zhou, Zi-Hua; Wang, Min; Guo, He-Ping; Du, Rong; Liao, Yu-Hua

2013-01-01

The published antibodies (Abs) against CD22 on B cells including Epratuzumab could inhibit B cell activation mainly through binding to C2-set Ig domain of CD22, but they are rarely reported to modulate the pathogenic CD4+ T cell function in systemic lupus erythematosus (SLE). Recently, it was proved that the extracellular amino-terminal V-set Ig domain of CD22 might mediate the interaction of B and T cells, but for now the exact effect of this domain on CD4+ T cell biology have not been identified. Thus, in this study, we screened out a peptide termed B2285 from this V-set Ig domain, developed the novel specific anti-B2285 Abs in rabbits, and investigated their effects in MRL/lpr mice with spontaneous SLE. The results showed that anti-B2285 Abs could ameliorate the disease severity obviously in spontaneous SLE mice with the decreased differentiations of Th1 and Th17 cells and no changes of Th2 and Treg cells. In co-cultured B cells and CD4+ T cells, this specific anti-CD22 Abs was observed to inhibit the anti-dsDNA Abs production, CD4+ T cells proliferation, the protein levels of T-bet and RORγt, and the mRNA levels of TNF-α, IFN-γ, IL-6 and IL-17 in CD4+ T cells. Moreover, the expression of CD45RO on CD4+ T cells could be also apparently diminished by this novel Abs. The data suggested that anti-B2285 Abs could slow SLE progression significantly by regulating Th1 and Th17 cells function via B-T cell interaction and the cytokine network regulation. The treatment against V-set Ig domain of CD22 would be a valuable therapeutic method for SLE and other autoimmune diseases. PMID:23704998

A novel epitope from CD22 regulates Th1 and Th17 cell function in systemic lupus erythematosus.

PubMed

Yuan, Jing; Yu, Miao; Cao, Ai-Lin; Chen, Xiao; Zhang, Li-Hua; Song, You; Cheng, Xiang; Zhou, Zi-Hua; Wang, Min; Guo, He-Ping; Du, Rong; Liao, Yu-Hua

2013-01-01

The published antibodies (Abs) against CD22 on B cells including Epratuzumab could inhibit B cell activation mainly through binding to C2-set Ig domain of CD22, but they are rarely reported to modulate the pathogenic CD4(+) T cell function in systemic lupus erythematosus (SLE). Recently, it was proved that the extracellular amino-terminal V-set Ig domain of CD22 might mediate the interaction of B and T cells, but for now the exact effect of this domain on CD4(+) T cell biology have not been identified. Thus, in this study, we screened out a peptide termed B2285 from this V-set Ig domain, developed the novel specific anti-B2285 Abs in rabbits, and investigated their effects in MRL/lpr mice with spontaneous SLE. The results showed that anti-B2285 Abs could ameliorate the disease severity obviously in spontaneous SLE mice with the decreased differentiations of Th1 and Th17 cells and no changes of Th2 and Treg cells. In co-cultured B cells and CD4(+) T cells, this specific anti-CD22 Abs was observed to inhibit the anti-dsDNA Abs production, CD4(+) T cells proliferation, the protein levels of T-bet and RORγt, and the mRNA levels of TNF-α, IFN-γ, IL-6 and IL-17 in CD4(+) T cells. Moreover, the expression of CD45RO on CD4(+) T cells could be also apparently diminished by this novel Abs. The data suggested that anti-B2285 Abs could slow SLE progression significantly by regulating Th1 and Th17 cells function via B-T cell interaction and the cytokine network regulation. The treatment against V-set Ig domain of CD22 would be a valuable therapeutic method for SLE and other autoimmune diseases.

Treatment of inflammatory bowel disease: A review of medical therapy

PubMed Central

Kozuch, Patricia L; Hanauer, Stephen B

2008-01-01

Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the gastrointestinal tract. While a cure remains elusive, both can be treated with medications that induce and maintain remission. With the recent advent of therapies that inhibit tumor necrosis factor (TNF) alpha the overlap in medical therapies for UC and CD has become greater. Although 5-ASA agents have been a mainstay in the treatment of both CD and UC, the data for their efficacy in patients with CD, particularly as maintenance therapy, are equivocal. Antibiotics may have a limited role in the treatment of colonic CD. Steroids continue to be the first choice to treat active disease not responsive to other more conservative therapy; non-systemic steroids such as oral and rectal budesonide for ileal and right-sided CD and distal UC respectively are also effective in mild-moderate disease. 6-mercaptopurine (6-MP) and its prodrug azathioprine are steroid-sparing immunomodulators effective in the maintenance of remission of both CD and UC, while methotrexate may be used in both induction and maintenance of CD. Infliximab and adalimumab are anti-TNF agents approved in the US and Europe for the treatment of Crohn's disease, and infliximab is also approved for the treatment of UC. PMID:18200659

Interferon-γ production by tubulointerstitial human CD56bright natural killer cells contributes to renal fibrosis and chronic kidney disease progression.

PubMed

Law, Becker M P; Wilkinson, Ray; Wang, Xiangju; Kildey, Katrina; Lindner, Mae; Rist, Melissa J; Beagley, Kenneth; Healy, Helen; Kassianos, Andrew J

2017-07-01

Natural killer (NK) cells are a population of lymphoid cells that play a significant role in mediating innate immune responses. Studies in mice suggest a pathological role for NK cells in models of kidney disease. In this study, we characterized the NK cell subsets present in native kidneys of patients with tubulointerstitial fibrosis, the pathological hallmark of chronic kidney disease. Significantly higher numbers of total NK cells (CD3 - CD56 + ) were detected in renal biopsies with tubulointerstitial fibrosis compared with diseased biopsies without fibrosis and healthy kidney tissue using multi-color flow cytometry. At a subset level, both the CD56 dim NK cell subset and particularly the CD56 bright NK cell subset were elevated in fibrotic kidney tissue. However, only CD56 bright NK cells significantly correlated with the loss of kidney function. Expression of the tissue-retention and -activation molecule CD69 on CD56 bright NK cells was significantly increased in fibrotic biopsy specimens compared with non-fibrotic kidney tissue, indicative of a pathogenic phenotype. Further flow cytometric phenotyping revealed selective co-expression of activating receptor CD335 (NKp46) and differentiation marker CD117 (c-kit) on CD56 bright NK cells. Multi-color immunofluorescent staining of fibrotic kidney tissue localized the accumulation of NK cells within the tubulointerstitium, with CD56 bright NK cells (NKp46 + CD117 + ) identified as the source of pro-inflammatory cytokine interferon-γ within the NK cell compartment. Thus, activated interferon-γ-producing CD56 bright NK cells are positioned to play a key role in the fibrotic process and progression to chronic kidney disease. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

Association of extraintestinal manifestations and anaemia with disease outcomes in patients with inflammatory bowel disease.

PubMed

Vegh, Zsuzsanna; Kurti, Zsuzsanna; Gonczi, Lorant; Golovics, Petra Anna; Lovasz, Barbara Dorottya; Szita, Istvan; Balogh, Mihaly; Pandur, Tunde; Vavricka, Stephan R; Rogler, Gerhard; Lakatos, Laszlo; Lakatos, Peter Laszlo

2016-07-01

The association between extraintestinal manifestations (EIMs) and disease activity suggest a common pathogenetic link with inflammatory bowel disease (IBD). We report on the association of EIMs and anaemia with long-term disease outcomes, including treatment steps, hospitalization, and surgery in the prospective population-based IBD inception cohort from Veszprem province. Data of 678 incident IBD patients (Crohn's disease/ulcerative colitis(CD/UC): 331/347) diagnosed from 1st January 2000 to 31st December 2012 were analyzed (CD: m/f: 176/155, median age at diagnosis: 28, IQR: 21-40 years, disease duration: 6, IQR: 2-9 years; UC: m/f: 200/147, median age at diagnosis: 36, IQR: 26-50 years, duration: 7, IQR: 4-10 years). EIMs were present in 30% of the CD and 17.3% of the UC patients. In CD, female gender (p = 0.02) need for steroid (p  < 0.001) and azathioprine (AZA) (p = 0.02), while in UC, young age at onset (p = 0.03), extensive disease (p = 0.003), female gender (p = 0.07), need for steroids (p < 0.001) and AZA (p = 0.004) and need for IBD-related hospitalization (p = 0.01) were associated with the presence of EIMs. Anaemia was present in 56.7% of the CD and 30.2% of the UC patients. In both CD and UC anaemia was associated with age at onset (pCD = 0.001, pUC = 0.04), disease location/extent (pCD = 0.02, pUC < 0.001), steroid and AZA use (for both pCD,UC < 0.001), need for surgery/colectomy (pCD < 0.001, pUC = 0.002) and hospitalization (pCD = 0.004, pUC < 0.001) and in CD, it was associated with anti TNF therapy(p = 0.002). The presence of EIMs was associated with disease phenotype in UC and with treatment strategy in both CD and UC. Additionally, anaemia was associated with hospitalization and surgery in both CD and UC, suggesting that EIMs and anaemia may be helpful in stratifying disease severity in IBD.

Small intestinal bacterial overgrowth in inactive Crohn’s disease: Influence of thiopurine and biological treatment

PubMed Central

Sánchez-Montes, Cristina; Ortiz, Vicente; Bastida, Guillermo; Rodríguez, Ester; Yago, María; Beltrán, Belén; Aguas, Mariam; Iborra, Marisa; Garrigues, Vicente; Ponce, Julio; Nos, Pilar

2014-01-01

AIM: To investigate the influence of thiopurines and biological drugs on the presence of small intestinal bacterial overgrowth (SIBO) in patients with inactive Crohn’s disease (CD). METHODS: This was a prospective study in patients with CD in remission and without corticosteroid treatment, included consecutively from 2004 to 2010. SIBO was investigated using the hydrogen glucose breath test. RESULTS: One hundred and seven patients with CD in remission were included. Almost 58% of patients used maintenance immunosuppressant therapy and 19.6% used biological therapy. The prevalence of SIBO was 16.8%. No association was observed between SIBO and the use of thiopurine Immunosuppressant (12/62 patients), administration of biological drugs (2/21 patients), or with double treatment with an anti-tumor necrosis factor drugs plus thiopurine (1/13 patients). Half of the patients had symptoms that were suggestive of SIBO, though meteorism was the only symptom that was significantly associated with the presence of SIBO on univariate analysis (P < 0.05). Multivariate analysis revealed that the presence of meteorism and a fistulizing pattern were associated with the presence of SIBO (P < 0.05). CONCLUSION: Immunosuppressants and/or biological drugs do not induce SIBO in inactive CD. Fistulizing disease pattern and meteorism are associated with SIBO. PMID:25320539

Treatment Perspectives in Crohn's Disease.

PubMed

Vetter, Marcel; Neurath, Markus F

2018-06-05

Crohn's disease (CD) is a chronic immune-mediated disorder of the gastrointestinal tract. The pathophysiological understanding of this disease is limited and no curative therapy is available so far. Therefore, most patients require long-lasting or even life-long immunosuppressive therapies for the suppression of symptoms to improve quality of life and reduction of long-term risks. However, in a relevant subgroup of patients, these therapeutic goals cannot be sufficiently attained. Clinically established therapies in active CD comprise corticosteroids and immunosuppressants such as azathioprine. After the introduction of anti-TNFα (Tumor necrosis factor alpha) antibodies, other biologicals (e.g., vedolizumab and ustekinumab) have also been approved. New drugs in the pipeline like filgotinib, upadacitinib, risankizumab or rifaximin could improve the therapy of CD in the near future. Thus, an individualized therapy management, based on optimal selection of therapeutic agents will become more important. Additionally, the local application of mesenchymal stem cells might be helpful in the management of fistulas. Key Messages: The targeted biological therapeutic agents (anti-TNFα antibodies, vedolizumab, ustekinumab) are well established for therapy in CD. There are several new substances in the pipeline with promising results in phase II trials (filgotinib, rifaximin, risankizumab, upadacitinib). The upcoming extension of the therapeutic arsenal will require methods for an optimized selection of substances, thus enabling a more individualized therapy. © 2018 S. Karger AG, Basel.

Ex-vivo characterization of regulatory T cells in pulmonary tuberculosis patients, latently infected persons, and healthy endemic controls

PubMed Central

Zewdie, Martha; Howe, Rawleigh; Hoff, Søren T.; Doherty, T. Mark; Getachew, Nahom; Tarekegne, Azeb; Tessema, Bamlak; Yamuah, Lawrence; Aseffa, Abraham; Abebe, Markos

2016-01-01

SUMMARY Background Regulatory T cells (Treg) are an essential arm of adaptive immunity not only in tolerance and autoimmunity but also in infectious diseases. In Tuberculosis (TB), it has been suggested that the frequency of Tregs is higher in the blood of TB patients when compared to healthy controls with subsequent decline after treatment. However, with the discovery that FOXP3, the hallmark marker of Tregs, is not exclusive to Tregs and the lack of specific markers for Tregs, it has been a challenge to fully understand the role of Tregs in TB. Method We isolated PBMC from smear positive TB patients (TB, N = 13) before and after treatment, latent TB infected participants (LTBI, N = 8), and healthy endemic controls (EC, N = 9) and evaluated the frequency of different populations of Tregs and expression of FOXP3 by flowcytometry using six markers. Results The findings in this study showed that the association of Treg frequency with TB disease depends on the phenotypic markers used. While the frequency of CD4+CD25+/hi T cells was higher in TB patients compared to LTBI individuals, there was no difference in the frequency of CD4+CD25+FOXP3+CD127lo Treg among TB, LTBI, or EC. However, delineation of Tregs into active and naïve subsets revealed a significant increase in FOXP3 expression in active primed Tregs (CD4+CD25+FOXP3+CD127loCD45RO+Ki-67+) of TB patients compared to LTBI and EC; and a significantly higher frequency of resting primed (CD45RO+Ki-67−) Treg in QuantiFERON negative EC compared to TB patients. After treatment completion, there was a significant decline in the frequency of active primed Treg, median (IQR) from 12.4% (9.5–21.9) of Tregs to 9.3% (7.0–12.2); P = 0.003 Wilcoxon signed rank test. We conclude that Treg subsets may be differentially regulated and expressed in TB disease, cure, and infection. PMID:27553411

NOD2 mutations and anti-Saccharomyces cerevisiae antibodies are risk factors for Crohn’s disease in African Americans

PubMed Central

Dassopoulos, Themistocles; Nguyen, Geoffrey C.; Talor, Monica Vladut; Datta, Lisa Wu; Isaacs, Kim L.; Lewis, James D.; Gold, Michael S.; Valentine, John F.; Smoot, Duane T.; Harris, Mary L.; Oliva-Hemker, Maria; Bayless, Theodore M.; Burek, C. Lynne; Brant, Steven R.

2012-01-01

Background NOD2 mutations and anti-Saccharomyces cerevisiae antibodies (ASCA) are associated with Crohn’s disease (CD), ileal involvement and complicated disease behavior in whites. ASCA and the three common NOD2 mutations have not been assessed in African American (AA) adults with CD. Methods AA patients with CD and controls were recruited by the Mid-Atlantic African American IBD Study (Johns Hopkins Hospital and satellite centers at Howard University, University of Florida, University of North Carolina, University of Pennsylvania, and the Washington Hospital Center, Washington, DC) as part of the NIDDK IBD Genetics Consortium. Genotyping for the three common CD associated NOD2 mutations (Leu1007fsinsC, G908R/2722g>c, and R702W/2104c>t) and ASCA ELISA assays were performed in 183 AA CD patients and 143 controls. Positive ASCA was based on either IgA or IgG above threshold. CD phenotyping was performed using the NIDDK IBD Genetics Consortium guidelines. Logistic regression was used to calculate adjusted odds ratios (OR) for the association between ASCA and disease phenotype. Results ASCA sensitivity and specificity in this AA population were 70.5% and 70.4% respectively. On univariate analysis, ASCA was associated with younger mean age at diagnosis (25.0±11.8 vs. 32.1±14.2 yrs, p<0.001), ileal involvement (73.0% vs. 48.0%, p=0.002), and complicated (stricturing/ penetrating) behavior (60.3% vs. 41.7%, p=0.03). On multivariate analysis, ASCA titer (/25U) was associated with ileal involvement (OR 1.18, 95% CI 1.04-1.34), complicated behavior (OR 1.13, 95% CI 1.01-1.28) and surgery (hazard ratio 1.11, 95% CI 1.02-1.21). Risks for surgery also included smoking (hazard ratio 1.50, 95% CI 1.14-1.99) and CD family history (hazard ratio 2.39, 95% CI 1.11-5.14). NOD2 carriers (all heterozygotes) were more common among CD cases than controls (8.2 vs. 2.1%; OR 4.17, 95% CI: 1.18 - 14.69). NOD2 mutation population attributable risk was 6.2%. Conclusions In comparison to whites, ASCA in AAs has a similar sensitivity but a lower specificity for CD. ASCA is associated with ileal involvement, complicated behavior and surgery in AAs with CD. NOD2 is a risk gene for AA CD, although mutation frequency and population attributable risk are much lower than in whites. PMID:19826411

Recurrence rate of clostridium difficile infection in hospitalized pediatric patients with inflammatory bowel disease.

PubMed

Kelsen, Judith R; Kim, Jason; Latta, Dan; Smathers, Sarah; McGowan, Karin L; Zaoutis, Theodore; Mamula, Petar; Baldassano, Robert N

2011-01-01

The incidence and associated morbidity of Clostridium difficile (CD) infection has been increasing at an alarming rate in North America. Clostridium difficile-associated diarrhea (CDAD) is the leading cause of nosocomial diarrhea in the USA. Patients with CDAD have longer average hospital admissions and additional hospital costs. Evidence has demonstrated that patients with inflammatory bowel disease (IBD) have a higher incidence of CD in comparison to the general population. The aim of this study was to compare the rate of recurrence of CD in hospitalized pediatric patients with IBD compared to hospitalized controls. The secondary aim was to evaluate whether infection with CD resulted in a more severe disease course of IBD. This was a nested case control retrospective study of hospitalized pediatric patients. Diagnosis of CD was confirmed with stool Toxin A and B analysis. The following data were obtained from the medical records: demographic information, classification of IBD including location of disease, IBD therapy, and prior surgeries. In addition, prior hospital admissions within 1 year and antibiotic exposure were recorded. The same information was recorded following CD infection. Cases were patients with IBD and CD; two control populations were also studied: patients with CD but without IBD, and patients with IBD but without CD. For aim 1, a total of 111 eligible patients with IBD and CD infection and 77 eligible control patients with CD infection were included. The rate of recurrence of CD in the IBD population was 34% compared to 7.5% in the control population (P < 0.0001). In evaluating the effect of CD infection on IBD disease severity, we compared the 111 IBD patients with CD to a second control population of 127 IBD patients without CD. 57% of IBD-CD patients were readmitted with an exacerbation of disease within 6 months of infection with CD and 67% required escalation of therapy following CD infection, compared to 30% of IBD patients without CD (P < 0.001). Of the patients with IBD and CD, 44% of the cases were new-onset IBD, 63% were on immunosuppression therapy, and 33% were on gastric acid suppression prior to infection. In comparing the IBD-CD and control CD populations, there was no significant difference in antibiotic exposure: 33% of IBD patients and 26% of control patients were on antibiotics (P < 0.2). With regard to prior hospitalization, 10% of patients with IBD were hospitalized in the 30 days prior to infection in comparison to 27% of the control CD patients (P < 0.002). CD infection in patients with IBD results in a higher rate of recurrence and is associated with higher morbidity than the general population. Patients with IBD often required hospitalization and escalation of therapy following infection with CD, suggesting that CD resulted in increased severity of IBD disease. In addition, IBD patients were more likely develop community-acquired CD, while the control patients developed nosocomial infections, indicating a higher susceptibility to CD infection in patients with IBD. Copyright © 2010 Crohn's & Crohn's & Colitis Foundation of America, Inc.

Pathologic Markers Determining Prognosis in Patients with Treated or Healing Giant Cell Arteritis.

PubMed

Sultan, Harris; Smith, Stacy V; Lee, Andrew G; Chévez-Barrios, Patricia

2018-06-08

To provide quantitative evidence linking the Cluster of Differentiation-68 (CD68)+ macrophage-marker found on temporal artery biopsies (TABs) with disease prognosis. Retrospective, cross-sectional study METHODS: We examined 42 consecutive patients who had undergone unilateral TABs at a single hospital in 2015. Clinical data, laboratory data, and histopathologic features of TABs were recorded. clinical diagnosis of giant cell arteritis (GCA) with TAB performed at the same center. CD68 immunohistochemistry was used to label macrophages in the TABs. multiple logistic regression and bivariate comparisons to measure the association between CD68+ cells per histologic section with placement on immunomodulatory therapy (IMT). Twenty seven patients were females (64%), with a mean age of 72 (standard deviation [S.D.] ±7.7). Eleven patients (26%) were placed on IMT, 17 (40%) had disease recurrence during steroid taper, and 25 (60%) were referred to rheumatology. Of 42 biopsies, 35 underwent staining with CD68 to confirm active inflammation in suspicious, but not diagnostic, specimens. Patients eventually placed on IMT had increased CD68+ cells/slice compared to those not on IMT (median 5.00 [25-75 th quartile 2.00-7.15] vs 1.21 [0.38-2.57], p=0.031, respectively). A receiver operating characteristics (ROC) curve demonstrates that 2.17 CD68+ cells/slice predicts placement on IMT with an odds ratio of 1.54 (95% C.I. 1.02-2.33, p=0.038). Patients refractory to initial steroid tapers and those eventually placed on IMT had increased CD68 cells/section. CD68+ macrophages and their location on the internal elastic lamina may predict disease severity in patients with presumed GCA. Our results suggest that this marker may expedite patient triaging to alternate treatment to the usual steroid therapy. Copyright © 2018 Elsevier Inc. All rights reserved.

Pregnancy and HIV Disease Progression in an Early Infection Cohort from Five African Countries

PubMed Central

Rida, Wasima; Haddad, Lisa B.; Kamali, Anatoli; Karita, Etienne; Lakhi, Shabir; Kilembe, William; Allen, Susan; Inambao, Mubiana; Yang, Annie H.; Latka, Mary H.; Anzala, Omu; Sanders, Eduard J.; Bekker, Linda-Gail; Edward, Vinodh A.; Price, Matt A.

2017-01-01

Background: Understanding associations between pregnancy and HIV disease progression is critical to provide appropriate counseling and care to HIV-positive women. Methods: From 2006 to 2011, women less than age 40 with incident HIV infection were enrolled in an early HIV infection cohort in Kenya, Rwanda, South Africa, Uganda, and Zambia. Time-dependent Cox models evaluated associations between pregnancy and HIV disease progression. Clinical progression was defined as a single CD4 measurement <200 cells/μl, percent CD4 <14%, or category C event, with censoring at antiretroviral (ART) initiation for reasons other than prevention of mother-to-child transmission (PMTCT). Immunologic progression was defined as two consecutive CD4s ≤350 cells/μl or a single CD4 ≤350 cells/μl followed by non-PMTCT ART initiation. Generalized estimating equations assessed changes in CD4 before and after pregnancy. Results: Among 222 women, 63 experienced clinical progression during 783.5 person-years at risk (8.0/100). Among 205 women, 87 experienced immunologic progression during 680.1 person-years at risk (12.8/100). The association between pregnancy and clinical progression was adjusted hazard ratio [aHR] = 0.7; 95% confidence interval (CI): 0.2, 1.8. The association between pregnancy and immunologic progression was aHR = 1.7; 95% CI: 0.9, 3.3. Models controlled for age; human leukocyte antigen alleles A*03:01, B*45, B*57; CD4 set point; and HIV-1 subtype. CD4 measurements before versus after pregnancies were not different. Conclusions: In this cohort, pregnancy was not associated with increased clinical or immunologic HIV progression. Similarly, we did not observe meaningful deleterious associations of pregnancy with CD4s. Our findings suggest that HIV-positive women may become pregnant without harmful health effects occurring during the pregnancy. Evaluation of longer-term impact of pregnancy on progression is warranted. PMID:27893488

RSV Vaccine-Enhanced Disease Is Orchestrated by the Combined Actions of Distinct CD4 T Cell Subsets

PubMed Central

Knudson, Cory J.; Hartwig, Stacey M.; Meyerholz, David K.; Varga, Steven M.

2015-01-01

There is no currently licensed vaccine for respiratory syncytial virus (RSV) despite being the leading cause of lower respiratory tract infections in children. Children previously immunized with a formalin-inactivated RSV (FI-RSV) vaccine exhibited enhanced respiratory disease following natural RSV infection. Subsequent studies in animal models have implicated roles for CD4 T cells, eosinophils and non-neutralizing antibodies in mediating enhanced respiratory disease. However, the underlying immunological mechanisms responsible for the enhanced respiratory disease and other disease manifestations associated with FI-RSV vaccine-enhanced disease remain unclear. We demonstrate for the first time that while CD4 T cells mediate all aspects of vaccine-enhanced disease, distinct CD4 T cell subsets orchestrate discrete and specific disease parameters. A Th2-biased immune response, but not eosinophils specifically, was required for airway hyperreactivity and mucus hypersecretion. In contrast, the Th1-associated cytokine TNF-α was necessary to mediate airway obstruction and weight loss. Our data demonstrate that individual disease manifestations associated with FI-RSV vaccine-enhanced disease are mediated by distinct subsets of CD4 T cells. PMID:25769044

Th40 cells (CD4+CD40+ Tcells) drive a more severe form of Experimental Autoimmune Encephalomyelitis than conventional CD4 T cells

PubMed Central

Vaitaitis, Gisela M.; Yussman, Martin G.; Waid, Dan M.; Wagner, David H.

2017-01-01

CD40-CD154 interaction is critically involved in autoimmune diseases, and CD4 T cells play a dominant role in the Experimental Autoimmune Encephalomyelitis (EAE) model of Multiple Sclerosis (MS). CD4 T cells expressing CD40 (Th40) are pathogenic in type I diabetes but have not been evaluated in EAE. We demonstrate here that Th40 cells drive a rapid, more severe EAE disease course than conventional CD4 T cells. Adoptively transferred Th40 cells are present in lesions in the CNS and are associated with wide spread demyelination. Primary Th40 cells from EAE-induced donors adoptively transfer EAE without further in-vitro expansion and without requiring the administration of the EAE induction regimen to the recipient animals. This has not been accomplished with primary, non-TCR-transgenic donor cells previously. If co-injection of Th40 donor cells with Freund’s adjuvant (CFA) in the recipient animals is done, the disease course is more severe. The CFA component of the EAE induction regimen causes generalized inflammation, promoting expansion of Th40 cells and infiltration of the CNS, while MOG-antigen shapes the antigen-specific TCR repertoire. Those events are both necessary to precipitate disease. In MS, viral infections or trauma may induce generalized inflammation in susceptible individuals with subsequent disease onset. It will be important to further understand the events leading up to disease onset and to elucidate the contributions of the Th40 T cell subset. Also, evaluating Th40 levels as predictors of disease onset would be highly useful because if either the generalized inflammation event or the TCR-honing can be interrupted, disease onset may be prevented. PMID:28192476

Autologous hematopoietic stem cells for refractory Crohn's disease.

PubMed

DiNicola, C A; Zand, A; Hommes, D W

2017-05-01

Autologous hematopoietic stem cells are gaining ground as an effective and safe treatment for treating severe refractory Crohn's disease (CD). Autologous hematopoietic stem cell therapy (AHSCT) induces resetting of the immune system by de novo regeneration of T-cell repertoire and repopulation of epithelial cells by bone-marrow derived cells to help patients achieve clinical and endoscopic remission. Areas covered: Herein, the authors discuss the use of AHSCT in treating patients with CD. Improvements in disease activity have been seen in patients with severe autoimmune disease and patients with severe CD who underwent AHSCT for a concomitant malignant hematological disease. Clinical and endoscopic remission has been achieved in patients treated with AHSCT for CD. The only randomized trial published to date, the ASTIC Trial, did not support further use of AHSCT to treat CD. Yet, critics of this trial have deemed AHSCT as a promising treatment for severe refractory CD. Expert opinion: Even with the promising evidence presented for HSCT for refractory CD, protocols need to be refined through the collaboration of GI and hemato-oncology professionals. The goal is to incorporate safe AHSCT and restore tolerance by delivering an effective immune 'cease fire' as a treatment option for severe refractory CD.

Regulatory T cell subsets in children with systemic lupus erythematosus.

PubMed

Eltayeb, Azza A; Sayed, Douaa M; Afifi, Noha A; Ibrahim, Maggie A; Sheref, Tahra M

2014-08-01

The aim of this work was to quantify CD4(+)CD25(+)Foxp3(+) T cells (Tregs) in Egyptian children with SLE and to correlate these findings with their disease activity scores and drug therapy. We enrolled 37 Egyptian children with active SLE. Disease activity was assessed by measuring serum levels of anti-dsDNA antibody and by the SLEDAI scores. Twenty healthy children were also enrolled as normal controls. The CD4+CD25+, CD4+CD25(bright), and CD4+CD25(dim) cells in patients were significantly increased in comparison to controls. There was no significant difference in the Foxp3 gated on CD4+CD25(bright) and CD4+CD25(dim), but there was a significant increase when gated on CD4+CD25- and whole CD4+ cells in patients than controls. There was no significant difference among patients with different degrees of activity on different lines of treatments and their outcomes as regards all studied values. There was no significant correlation between SLEDAI score and any of the studied parameters except for a significant negative correlation with gated lymphocytes. There is increased expression of Foxp3 in CD4+ T cells mostly CD25- in Egyptian children with active SLE under corticosteroid treatment regardless of disease activity.

Respiratory Syncytial Virus (RSV) Infects CD4+ T Cells: Frequency of Circulating CD4+ RSV+ T Cells as a Marker of Disease Severity in Young Children.

PubMed

Raiden, Silvina; Sananez, Inés; Remes-Lenicov, Federico; Pandolfi, Julieta; Romero, Cecilia; De Lillo, Leonardo; Ceballos, Ana; Geffner, Jorge; Arruvito, Lourdes

2017-04-01

Although human airway epithelial cells are the main target of respiratory syncytial virus (RSV), it also infects immune cells, such as macrophages and B cells. Whether T cells are permissive to RSV infection is unknown. We sought to analyze the permissiveness of CD4+ T cells to RSV infection. CD4+ and CD8+ T cells from cord blood, healthy young children, and adults were challenged by RSV or cocultured with infected HEp-2 cells. Infection, phenotype, and cytokine production by T cells were analyzed by flow cytometry or enzyme-linked immunosorbent assay. Expression of RSV antigens by circulating CD4+ T cells from infected children was analyzed by flow cytometry, and disease severity was defined by standard criteria. CD4+ and CD8+ T cells were productively infected by RSV. Infection decreased interleukin 2 and interferon γ production as well as the expression of CD25 and Ki-67 by activated CD4+ T cells. Respiratory syncytial virus antigens were detected in circulating CD4+ and CD8+ T cells during severe RSV infection of young children. Interestingly, the frequency of CD4+ RSV+ T cells positively correlated with disease severity. Respiratory syncytial virus infects CD4+ and CD8+ T cells and compromises T-cell function. The frequency of circulating CD4+ RSV+ T cells might represent a novel marker of severe infection. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Early evolution of HLA-associated escape mutations in variable Gag proteins predicts CD4+ decline in HIV-1 subtype C infected women

PubMed Central

Chopera, Denis R.; Ntale, Roman; Ndabambi, Nonkululeko; Garrett, Nigel; Gray, Clive M.; Matten, David; Karim, Quarraisha Abdool; Karim, Salim Abdool; Williamson, Carolyn

2016-01-01

Objective HIV-1 escape from cytotoxic T-lymphocytes (CTL) results in the accumulation of HLA-associated mutations in the viral genome. To understand the contribution of early escape to disease progression, this study investigated the evolution and pathogenic implications of CTL escape in a cohort followed from infection for five years. Methods Viral loads and CD4+ counts were monitored in 78 subtype C infected individuals from onset of infection until CD4+ decline to <350 cells/μl or five years post-infection. The gag gene was sequenced and HLA-associated changes between enrolment and 12 months post-infection were mapped. Results HLA-associated escape mutations were identified in 48 (62%) of the participants and were associated with CD4+ decline to <350 copies/ml (p=0.05). Escape mutations in variable Gag proteins (p17 and p7p6) had a greater impact on disease progression than escape in more conserved regions (p24) (p=0.03). The association between HLA-associated escape mutations and CD4+ decline was independent of protective HLA allele (B*57, B*58:01, B*81) expression. Conclusion The high frequency of escape contributed to rapid disease progression in this cohort. While HLA-adaption in both conserved and variable Gag domains in the first year of infection was detrimental to long term clinical outcome, escape in variable domains had greater impact. PMID:27755110

Development and validation of sensitive LC-MS/MS assays for quantification of HP-β-CD in human plasma and CSF

PubMed Central

Jiang, Hui; Sidhu, Rohini; Fujiwara, Hideji; De Meulder, Marc; de Vries, Ronald; Gong, Yong; Kao, Mark; Porter, Forbes D.; Yanjanin, Nicole M.; Carillo-Carasco, Nuria; Xu, Xin; Ottinger, Elizabeth; Woolery, Myra; Ory, Daniel S.; Jiang, Xuntian

2014-01-01

2-Hydroxypropyl-β-cyclodextrin (HP-β-CD), a widely used excipient for drug formulation, has emerged as an investigational new drug for the treatment of Niemann-Pick type C1 (NPC1) disease, a neurodegenerative cholesterol storage disorder. Development of a sensitive quantitative LC-MS/MS assay to monitor the pharmacokinetics (PKs) of HP-β-CD required for clinical trials has been challenging owing to the dispersity of the HP-β-CD. To support a phase 1 clinical trial for ICV delivery of HP-β-CD in NPC1 patients, novel methods for quantification of HP-β-CD in human plasma and cerebrospinal fluid (CSF) using LC-MS/MS were developed and validated: a 2D-LC-in-source fragmentation-MS/MS (2D-LC-IF-MS/MS) assay and a reversed phase ultra performance LC-MS/MS (RP-UPLC-MS/MS) assay. In both assays, protein precipitation and “dilute and shoot” procedures were used to process plasma and CSF, respectively. The assays were fully validated and in close agreement, and allowed determination of PK parameters for HP-β-CD. The LC-MS/MS methods are ∼100-fold more sensitive than the current HPLC assay, and were successfully employed to analyze HP-β-CD in human plasma and CSF samples to support the phase 1 clinical trial of HP-β-CD in NPC1 patients. PMID:24868096

Development and validation of sensitive LC-MS/MS assays for quantification of HP-β-CD in human plasma and CSF.

PubMed

Jiang, Hui; Sidhu, Rohini; Fujiwara, Hideji; De Meulder, Marc; de Vries, Ronald; Gong, Yong; Kao, Mark; Porter, Forbes D; Yanjanin, Nicole M; Carillo-Carasco, Nuria; Xu, Xin; Ottinger, Elizabeth; Woolery, Myra; Ory, Daniel S; Jiang, Xuntian

2014-07-01

2-Hydroxypropyl-β-cyclodextrin (HP-β-CD), a widely used excipient for drug formulation, has emerged as an investigational new drug for the treatment of Niemann-Pick type C1 (NPC1) disease, a neurodegenerative cholesterol storage disorder. Development of a sensitive quantitative LC-MS/MS assay to monitor the pharmacokinetics (PKs) of HP-β-CD required for clinical trials has been challenging owing to the dispersity of the HP-β-CD. To support a phase 1 clinical trial for ICV delivery of HP-β-CD in NPC1 patients, novel methods for quantification of HP-β-CD in human plasma and cerebrospinal fluid (CSF) using LC-MS/MS were developed and validated: a 2D-LC-in-source fragmentation-MS/MS (2D-LC-IF-MS/MS) assay and a reversed phase ultra performance LC-MS/MS (RP-UPLC-MS/MS) assay. In both assays, protein precipitation and "dilute and shoot" procedures were used to process plasma and CSF, respectively. The assays were fully validated and in close agreement, and allowed determination of PK parameters for HP-β-CD. The LC-MS/MS methods are ∼100-fold more sensitive than the current HPLC assay, and were successfully employed to analyze HP-β-CD in human plasma and CSF samples to support the phase 1 clinical trial of HP-β-CD in NPC1 patients. Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.

[Different patterns of 123I-BMIPP myocardial accumulation in patients with type I and II CD36 deficiency].

PubMed

Watanabe, K; Toba, K; Ogawa, Y; Aizawa, Y; Tanabe, N; Miyajima, S; Kusano, Y; Nagatomo, T; Hirokawa, Y

1997-12-01

The CD36 molecule is a multifunctional membrane type receptor glycoprotein that reacts with thrombospondin, collagen, oxidized LDL and long-chain fatty acids (LCFA). LCFA are one of the major cardiac energy substrates, hence LCFA metabolism may have an important role in cardiac diseases. In this study, we analyzed CD36 expression in 200 patients with heart diseases [44 patients with hypertrophic cardiomyopathy (HCM), 16 with dilated cardiomyopathy (DCM), 26 with old myocardial infarction (OMI), 55 with angina pectoris (AP) and 59 with other miscellaneous heart diseases] using a flow cytometer. 123I-beta-methyl-p-iodophenylpentadecanoic acid (BMIPP) myocardial accumulation was also examined in some patients. Eight patients (2 with HCM, 1 with DCM, 2 with OMI, and 3 with AP) were diagnosed as having type I CD36 deficiency (neither platelets nor monocytes expressed CD36). Sixteen patients (3 with HCM, 1 with DCM, 1 with OMI, 8 with AP, and 3 with other heart diseases) showed type II CD36 deficiency (monocytes expressed CD36 but platelets did not). In all 8 patients with type I CD36 deficiency, there was no BMIPP accumulation in the heart. However, in 13 patients with type II CD36 deficiency, focally reduced BMIPP accumulation was observed, but there were no patients without BMIPP accumulation. CD36 deficiency was observed in a higher proportion (12%) of patients with heart disease in this study than in a reported control study. Type I CD36 deficiency is associated with absence of BMIPP accumulation in the heart, hence it may have an important role in LCFA metabolic disorders and some types of cardiac hypertrophy as well as other heart diseases.

Association Study of ITGAM, ITGAX, and CD58 Autoimmune Risk Loci in Systemic Sclerosis: Results from 2 Large European Caucasian Cohorts

PubMed Central

COUSTET, BAPTISTE; AGARWAL, SANDEEP K.; GOURH, PRAVITT; GUEDJ, MICKAEL; MAYES, MAUREEN D.; DIEUDE, PHILIPPE; WIPFF, JULIEN; AVOUAC, JEROME; HACHULLA, ERIC; DIOT, ELISABETH; CRACOWSKI, JEAN LUC; TIEV, KIET; SIBILIA, JEAN; MOUTHON, LUC; FRANCES, CAMILLE; AMOURA, ZAHIR; CARPENTIER, PATRICK; MEYER, OLIVIER; KAHAN, ANDRE; BOILEAU, CATHERINE; ARNETT, FRANK C.; ALLANORE, YANNICK

2012-01-01

Objective Accumulating evidence shows that shared autoimmunity is critical for the pathogenesis of many autoimmune diseases. Systemic sclerosis (SSc) belongs to the connective tissue disorders, and recent data have highlighted strong associations with autoimmunity genes shared with other autoimmune diseases. To determine whether novel risk loci associated with systemic lupus erythematosus or multiple sclerosis may confer susceptibility to SSc, we tested single-nucleotide polymorphisms (SNP) from ITGAM, ITGAX, and CD58 for associations. Methods SNP harboring associations with autoimmune diseases, ITGAM rs9937837, ITGAX rs11574637, and CD58 rs12044852, were genotyped in 2 independent cohorts of European Caucasian ancestry: 1031 SSc patients and 1014 controls from France and 1038 SSc patients and 691 controls from the USA, providing a combined study population of 3774 individuals. ITGAM rs1143679 was additionally genotyped in the French cohort. Results The 4 polymorphisms were in Hardy-Weinberg equilibrium in the 2 control populations, and allelic frequencies were similar to those expected in European Caucasian populations. Allelic and genotypic frequencies for these 3 SNP were found to be statistically similar in SSc patients and controls. Subphenotype analyses for subgroups having diffuse cutaneous subtype disease, specific autoantibodies, or fibrosing alveolitis did not reveal any difference between SSc patients and controls. Conclusion These results obtained through 2 large cohorts of SSc patients of European Caucasian ancestry do not support the implication of ITGAM, ITGAX, and CD58 genes in the genetic susceptibility of SSc, although they were recently identified as autoimmune disease risk genes. PMID:21362770

Inflammatory models drastically alter tumor growth and the immune microenvironment in hepatocellular carcinoma.

PubMed

Markowitz, Geoffrey J; Michelotti, Gregory A; Diehl, Anna Mae; Wang, Xiao-Fan

2015-04-01

Initiation and progression of hepatocellular carcinoma (HCC) is intimately associated with a chronically diseased liver tissue. This diseased liver tissue background is a drastically different microenvironment from the healthy liver, especially with regard to immune cell prevalence and presence of mediators of immune function. To better understand the consequences of liver disease on tumor growth and the interplay with its microenvironment, we utilized two standard methods of fibrosis induction and orthotopic implantation of tumors into the inflamed and fibrotic liver to mimic the liver condition in human HCC patients. Compared to non-diseased controls, tumor growth was significantly enhanced under fibrotic conditions. The immune cells that infiltrated the tumors were also drastically different, with decreased numbers of natural killer cells but greatly increased numbers of immune-suppressive CD11b + Gr1 hi myeloid cells in both models of fibrosis. In addition, there were model-specific differences: Increased numbers of CD11b + myeloid cells and CD4 + CD25 + T cells were found in tumors in the bile duct ligation model but not in the carbon tetrachloride model. Induction of fibrosis altered the cytokine production of implanted tumor cells, which could have farreaching consequences on the immune infiltrate and its functionality. Taken together, this work demonstrates that the combination of fibrosis induction with orthotopic tumor implantation results in a markedly different tumor microenvironment and tumor growth kinetics, emphasizing the necessity for more accurate modeling of HCC progression in mice, which takes into account the drastic changes in the tissue caused by chronic liver disease.

Lectin Staining Shows no Evidence of Involvement of Glycocalyx/Mucous Layer Carbohydrate Structures in Development of Celiac Disease

PubMed Central

Toft-Hansen, Henrik; Nielsen, Christian; Biagini, Matteo; Husby, Steffen; Lillevang, Søren T.

2013-01-01

The presence of unique carbohydrate structures in the glycocalyx/mucous layer of the intestine may be involved in a susceptibility to celiac disease (CD) by serving as attachment sites for bacteria. This host-microbiota interaction may influence the development of CD and possibly other diseases with autoimmune components. We examined duodenal biopsies from a total of 30 children, of which 10 had both celiac disease (CD) and type 1 diabetes (T1D); 10 had CD alone; and 10 were suspected of having gastrointestinal disease, but had normal duodenal histology (non-CD controls). Patients with both CD and T1D were examined before and after remission following a gluten-free diet. We performed lectin histochemistry using peanut agglutinin (PNA) and Ulex europaeus agglutinin (UEA) staining for Gal-β(1,3)-GalNAc and Fucα1-2Gal-R, respectively, of the glycocalyx/mucous layer. The staining was scored based on dissemination of stained structures on a scale from 0 to 3. Evaluation of the scores revealed no difference between biopsies obtained before and after remission in the group of children with both CD and T1D. A comparison of this pre-remission group with the children who had CD alone or the non-CD controls also showed no significant differences. Based on our material, we found no indication that the presence of Gal-β(1,3)-GalNAc or Fucα1-2Gal-R is involved in the susceptibility to CD, or that the disease process affects the expression of these carbohydrates. PMID:24253051

Predictors of CD4 count over time among HIV patients initiated ART in Felege Hiwot Referral Hospital, northwest Ethiopia: multilevel analysis.

PubMed

Gezie, Lemma Derseh

2016-07-30

The response of HIV patients to antiretroviral therapy could be measured by its strong predictor, the CD4+ T cell (CD4) count for the initiation of antiretroviral therapy and proper management of disease progress. However, in addition to HIV, there are other factors which can influence the CD4 cell count. Patient's socio-economic, demographic, and behavioral variables, accessibility, duration of treatment etc., can be used to predict CD4 count. A retrospective cohort study was conducted to examine the predictors of CD4 count among ART users enrolled in the first 6 months of 2010 and followed upto mid 2014. The covariance components model was employed to determine the predictors of CD4 count over time. A total of 1196 ART attendants were used to analyze their data descriptively. Eight hundred sixty-one of the attendants had two or more CD4 count measurements and were used in modeling their data using the linear mixed method. Thus, the mean rates of incensement of CD4 counts for patients with ambulatory/bedridden and working baseline functional status were 17.4 and 30.6 cells/mm(3) per year, respectively. After adjusting for other variables, for each additional baseline CD4 count, the gain in CD4 count during treatment was 0.818 cells/mm(3) (p value <0.001). Patient's age and baseline functional status were also statistically significantly associated with CD4 count. In this study, higher baseline CD4 count, younger age, working functional status, and time in treatment contributed positively to the increment of the CD4 count. However, the observed increment at 4 year was unsatisfactory as the proportion of ART users who reached the normal range of CD4 count was very low. To see their long term treatment outcome, it requires further research with a sufficiently longer follow up data. In line with this, the local CD4 count for HIV negative persons should also be investigated for better comparison and proper disease management.

Fecal Calprotectin in Ileal Crohn's Disease: Relationship with Magnetic Resonance Enterography and a Pathology Score.

PubMed

Cerrillo, Elena; Beltrán, Belén; Pous, Salvador; Echarri, Ana; Gallego, Jose Carlos; Iborra, Marisa; Pamies, Jose; Nos, Pilar

2015-07-01

Magnetic resonance enterography (MRE) is an effective method of assessing small bowel Crohn's disease (CD). Fecal calprotectin (FC) correlates well with endoscopic disease activity. We aimed to evaluate the correlation between FC and disease activity according to MRE and surgical pathology in small bowel CD. One hundred twenty consecutive patients with ileal CD who underwent MRE assessment were included. Clinical data, C-reactive protein and FC, radiological and histological variables were obtained. Clinical activity was evaluated by the Harvey-Bradshaw Index and FC by enzyme-linked immunosorbent assay. MRE activity was assessed by means of the Magnetic Resonance Index of Activity score. Chiorean's score was used to grade pathological inflammation in surgical specimens. Seventy-five patients (62.5%) were in clinical remission (Harvey-Bradshaw Index < 5) and 45 (37.5%) had active disease (Harvey-Bradshaw Index ≥ 5). The Magnetic Resonance Index of Activity score was significantly associated with FC levels (P < 0.01), with a moderate overall correlation (Spearman's r = 0.56, P < 0.001). FC reflected MRE inflammatory activity with an area under the receiver operating characteristic curve of 0.914 (confidence interval, 0.849-0.958; P < 0.001). A cutoff value of 166.50 μg/g had 90% sensitivity, 74% specificity, 89% positive predictive value, and 76% negative predictive value for diagnosis of inflammation. Twenty-eight of 120 patients were operated. Surgical pathology showed a good agreement with FC for moderate (P = 0.03) and severe (P = 0.01) Chiorean's index. No relationship was detected for C-reactive protein. FC correlates with the degree of MRE inflammatory activity and with surgical pathology damage in ileal CD. Thus, FC could be a surrogate marker of disease control used to select patients for MRE assessment and therapeutic adjustment.

Inflammatory bowel disease: A descriptive study of 716 local Chilean patients

PubMed Central

Simian, Daniela; Fluxá, Daniela; Flores, Lilian; Lubascher, Jaime; Ibáñez, Patricio; Figueroa, Carolina; Kronberg, Udo; Acuña, Raúl; Moreno, Mauricio; Quera, Rodrigo

2016-01-01

AIM: To demographically and clinically characterize inflammatory bowel disease (IBD) from the local registry and update data previously published by our group. METHODS: A descriptive study of a cohort based on a registry of patients aged 15 years or older who were diagnosed with IBD and attended the IBD program at Clínica Las Condes in Santiago, Chile. The registry was created in April 2012 and includes patients registered up to October 2015. The information was anonymously downloaded in a monthly report, and the information on patients with more than one visit was updated. The registry includes demographic, clinical and disease characteristics, including the Montreal Classification, medical treatment, surgeries and hospitalizations for crisis. Data regarding infection with Clostridium difficile (C. difficile) were incorporated in the registry in 2014. Data for patients who received consultations as second opinions and continued treatment at this institution were also analyzed. RESULTS: The study included 716 patients with IBD: 508 patients (71%) were diagnosed with ulcerative colitis (UC), 196 patients (27%) were diagnosed with Crohn’s disease (CD) and 12 patients (2%) were diagnosed with unclassifiable IBD. The UC/CD ratio was 2.6/1. The median age was 36 years (range 16-88), and 58% of the patients were female, with a median age at diagnosis of 29 years (range 5-76). In the past 15 years, a sustained increase in the number of patients diagnosed with IBD was observed, where 87% of the patients were diagnosed between the years 2001 and 2015. In the cohort examined in the present study, extensive colitis (50%) and colonic involvement (44%) predominated in the patients with UC and CD, respectively. In CD patients, non-stricturing/non-penetrating behavior was more frequent (80%), and perianal disease was observed in 28% of the patients. There were significant differences in treatment between UC and CD, with a higher use of corticosteroids, and immunosuppressive and biological therapies was observed in the patients with CD (P < 0.05 and P < 0.01). Significant surgical differences were also observed: 5% of the UC patients underwent surgery, whereas 38% of the CD patients required at least one surgery (P < 0.01). The patients with CD were hospitalized more often during their disease course than the patients with UC (55% and 35% of the patients, respectively; P < 0.01). C. difficile infection was acquired by 5% of the patients in each group at some point during the disease course. Nearly half of the patients consulted at the institution for a second opinion, and 32% of these individuals continued treatment at the institution. CONCLUSION: IBD has continued to increase in the study cohort, slowly approaching the level reported in developed countries. PMID:27298570

Investigation of celiac disease followed by immune thrombocytopenic purpura diagnosis in patients and comparison with literature

PubMed Central

Sarbay, Hakan; Kocamaz, Halil; Akin, Mehmet; Ozhan, Bayram

2017-01-01

OBJECTIVE: Celiac disease (CD) and Immune thrombocytopenic purpura (ITP) may occur together as a result of similar autoimmune mechanisms. The aim of this study was to assess the frequency of CD in a group of ITP patients and in the literature. METHODS: A total of 29 patients in Pamukkale University Faculty of Medicine Hospital Pediatric Hematology and Oncology Department with ITP were included in the study. Test was performed for the antibodies related to CD. Positive result for celiac antibodies was confirmed with biopsy. The results were compared with the literature. RESULTS: Of the study group, 13 patients (44.8%) were female and 16 (55.2%) were male. The mean age was 7.2±4.7 years and mean platelet count at the time of admission was 13,440±11,110/mm3 (range: 2000-41,000/mm3). Twelve patients (41.4%) were diagnosed as acute ITP, 6 patients (20.7%) as persistent ITP, and 11 patients (37.9%) as chronic ITP, according to the duration of thrombocytopenia. Antibody positivity was detected in 1 patient. Histological evaluation was compatible with CD. Results were compared with studies regarding the prevalence of CD in the population. No significant difference was found. CONCLUSION: Although it is not necessary to perform CD test in every case of ITP, the presence of differential diagnosis of CD is important to prevent unnecessary treatment, especially in ITP patients with growth retardation or malabsorption findings. PMID:28971174

Anti-microbial antibodies in celiac disease: Trick or treat?

PubMed Central

Papp, Maria; Foldi, Ildiko; Altorjay, Istvan; Palyu, Eszter; Udvardy, Miklos; Tumpek, Judit; Sipka, Sandor; Korponay-Szabo, Ilma Rita; Nemes, Eva; Veres, Gabor; Dinya, Tamas; Tordai, Attila; Andrikovics, Hajnalka; Norman, Gary L; Lakatos, Peter Laszlo

2009-01-01

AIM: To determine the prevalence of a new set of anti-glycan and anti-outer membrane protein (anti-OMP) antibodies in a Hungarian cohort of adult Celiac disease (CD) patients. METHODS: 190 consecutive CD patients [M/F: 71/119, age:39.9 (SD:14.1) years], 100 healthy, and 48 gastrointestinal controls were tested for glycan anti-Saccharomyces cerevisiae (gASCA), anti-laminaribioside (ALCA), anti-chitobioside, anti-mannobioside, anti-OMP antibodies and major NOD2/CARD15 mutations. Thirty out of 82 CD patients enrolled at the time of diagnosis were re-evaluated for the same antibodies after longstanding gluten-free diet (GFD). RESULTS: 65.9% of the CD patients were positive for at least one of the tested antibodies at the time of the diagnosis. Except anti-OMP and ALCA, anti-microbial antibodies were exclusively seen in untreated CD; however, the overall sensitivity was low. Any glycan positivity (LR+: 3.13; 95% CI: 2.08-4.73) was associated with an increased likelihood ratio for diagnosing CD. Significant correlation was found between the levels of anti-glycan and anti-endomysial or anti-transglutaminase antibodies. Anti-glycan positivity was lost after longstanding GFD. Anti-glycan antibody titers were associated with symptoms at presentation, but not the presence of NOD2/CARD15 mutations. Patients with severe malabsorption more frequently had multiple antibodies at diagnosis (P = 0.019). CONCLUSION: The presence of anti-glycan antibodies in CD seems to be secondary to the impaired small bowel mucosa which can lead to increased antigen presentation. Furthermore, anti-glycan positivity may be considered an additional marker of CD and dietary adherence. PMID:19701969

Systematic review: treatment pattern and clinical effectiveness and safety of pharmaceutical therapies for Crohn’s disease in Europe

PubMed Central

Lelli, Filippo; Nuhoho, Solomon; Lee, Xin Ying; Xu, Weiwei

2016-01-01

Background Although many clinical trials have been conducted in treatments of Crohn’s disease (CD), whether the trial results were representative of daily practice needs to be supported by studies conducted in real-world settings. Aim This study aims to identify how CD is treated and what are the clinical effectiveness and safety of the pharmaceutical therapies of CD in real-world settings. Methods A systematic literature review was conducted based on Medline®, Embase®, and Cochrane. All publications were assessed for title/abstract and full-text according to a predefined study protocol. Data were extracted and reported. Results A total of 1,998 publications were identified. Fifty studies including six publications reporting treatment pattern and 44 studies reporting clinical effectiveness and safety of pharmaceutical therapies in CD management in Europe were included. 5-Aminosalicylic acid and corticosteroids were reported to be used among 14%–74% of CD patients. Immunomodulators were used by 14%–25% and 29%–31% of CD patients as an initial and follow-up treatment, respectively. Biological therapies were used by 25%–33% of CD patients. A trend toward an increasing use of immunomodulators and biological therapies in Europe has been reported in recent years. Approximately 50% of patients achieved remission on immunomodulator or biologic treatment, although a relapse rate of up to 23% has been reported. Conclusion There is a trend of treatment shift to immunomodulators and biologics in CD management. Clinical effectiveness of immunomodulators and biologics has been demonstrated, though with a lack of sustainability of the effectiveness. PMID:27785086

HLA is unlikely to be a major component of risk in familial inflammatory bowl disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mathew, C.G.; Naom, I.S.; Hodgson, S.V.

1994-09-01

Inflammatory bowel disease (IBD) is a chronic inflammation of the bowel which is confined to the colon in ulcerative colitis (UC) or may affect any part of the gastrointestinal tract in Crohn`s disease (CD). The cause of IBD is unknown, but a genetic component is suggested by a 10-fold increase in risk to first degree relatives, and a higher concordance of disease in MZ versus DZ twins. Distinct associations of HLA DR2 with UC and DR1/DQw5 with CD have been reported. We are searching for susceptibility genes in IBD by linkage analysis in a panel of 43 families with 3more » or more living affected members, which includes 12 families with CD, 17 with UC and 14 {open_quotes}mixed{close_quotes} families with UC and CD. In view of the reported HLA associations in IBD, we have analyzed 5 microsatellite markers from the major histocompatibility complex for linkage to IBD using both parametric and nonparametric methods. LOD scores were calculated for 4 different genetic models, including both dominant and recessive inheritance, and haplotype sharing was analyzed in affected siblings. LOD scores for the MHC locus were negative in the full data set, and in the 3 classes of family (UC,CD,mixed). Haplotype sharing in affected sibs was very close to that expected if no linkage was present. We conclude that genes from the HLA region are unlikely to be a major component of risk in familial IBD. Linkage analysis of genes which cause chronic colitis when disrupted in transgenic mice is in progress.« less

Health determining concepts important to people with Crohn's disease and their coverage by patient-reported outcomes of health and wellbeing☆☆☆

PubMed Central

Dür, Mona; Sadloňová, Martina; Haider, Stefanie; Binder, Alexa; Stoffer, Michaela; Coenen, Michaela; Smolen, Josef; Dejaco, Clemens; Kautzky-Willer, Alexandra; Fialka-Moser, Veronika; Moser, Gabriele; Stamm, Tanja Alexandra

2014-01-01

Background and aims Busy clinical settings often restrict the possibility to focus on concepts that determine health in a positive way, commonly assessed by using patient-reported outcomes (PROs). We aimed to explore which determinants of health (DHs) are important to people with Crohn's disease (CD), to understand possible gender differences and to analyze whether these DHs are covered by PROs used in CD. Methods Two systematic literature reviews were done to identify relevant DHs and clinically relevant PROs. We conducted a qualitative narrative biographical study and mapped the patients' experiences to concepts that determine health in a positive way. Experiences, DHs and the items of the PROs were compared by the WHO International Classification of Functioning, Disability and Health (ICF) as a common framework. Results 15 people with CD with a median age of 46 years (IQR 34–60) and median disease duration of 15 years (IQR 8–30) participated. Self-efficacy, social support, job satisfaction and occupational balance were mentioned most frequently. While participation appeared to have greater meaning to men, appreciation and resilience seemed to be more important for women. Of 18 PROs the Perceived Stress Questionnaire (PSQ), the Inflammatory Bowel disease — Self-efficacy scale (IBD-SES), the Life Orientation Test — Revised (LOT-R) and the Patient Activation Measure 13 (PAM-13) cover most DHs. Conclusions This is the first study elaborating the coverage of patient's perspective by commonly used PROs in CD. The findings could support health professionals to focus on DHs in people with CD in clinical practice and research. PMID:23375212

Transition from childhood to adulthood in coeliac disease: the Prague consensus report

PubMed Central

Ludvigsson, Jonas F; Agreus, Lars; Ciacci, Carolina; Crowe, Sheila E; Geller, Marilyn G; Green, Peter H R; Hill, Ivor; Hungin, A Pali; Koletzko, Sibylle; Koltai, Tunde; Lundin, Knut E A; Mearin, M Luisa; Murray, Joseph A; Reilly, Norelle; Walker, Marjorie M; Sanders, David S; Shamir, Raanan; Troncone, Riccardo; Husby, Steffen

2016-01-01

The process of transition from childhood to adulthood is characterised by physical, mental and psychosocial development. Data on the transition and transfer of care in adolescents/young adults with coeliac disease (CD) are scarce. In this paper, 17 physicians from 10 countries (Sweden, Italy, the USA, Germany, Norway, the Netherlands, Australia, Britain, Israel and Denmark) and two representatives from patient organisations (Association of European Coeliac Societies and the US Celiac Disease Foundation) examined the literature on transition from childhood to adulthood in CD. Medline (Ovid) and EMBASE were searched between 1900 and September 2015. Evidence in retrieved reports was evaluated using the Grading of Recommendation Assessment, Development and Evaluation method. The current consensus report aims to help healthcare personnel manage CD in the adolescent and young adult and provide optimal care and transition into adult healthcare for patients with this disease. In adolescence, patients with CD should gradually assume exclusive responsibility for their care, although parental support is still important. Dietary adherence and consequences of non-adherence should be discussed during transition. In most adolescents and young adults, routine small intestinal biopsy is not needed to reconfirm a childhood diagnosis of CD based on European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) or North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) criteria, but a biopsy may be considered where paediatric diagnostic criteria have not been fulfilled, such as, in a patient without biopsy at diagnosis, additional serology (endomysium antibody) has not been performed to confirm 10-fold positivity of tissue transglutaminase antibodies or when a no biopsy strategy has been adopted in an asymptomatic child. PMID:27196596

Mucosal Healing and the Risk of Ischemic Heart Disease or Atrial Fibrillation in Patients with Celiac Disease; A Population-Based Study

PubMed Central

Lebwohl, Benjamin; Emilsson, Louise; Fröbert, Ole; Einstein, Andrew J.; Green, Peter H. R.; Ludvigsson, Jonas F.

2015-01-01

Background Patients with celiac disease (CD), characterized histologically by villous atrophy (VA) of the small intestine, have an increased risk of ischemic heart disease (IHD) and atrial fibrillation (AF), risks that persist for years after commencing the gluten-free diet. It is unknown whether persistent VA on follow-up biopsy, rather than mucosal healing, affects the risk of IHD or AF. Methods We identified patients with histologic evidence of CD diagnosed at all 28 pathology departments in Sweden. Among patients who underwent a follow-up small intestinal biopsy, we compared patients with persistent VA to those who showed histologic improvement, with regard to the development of IHD (angina pectoris or myocardial infarction) or AF. Results Among patients with CD and a follow-up biopsy (n = 7,440), the median age at follow-up biopsy was 25 years, with 1,063 (14%) patients who were ≥60 years at the time of follow-up biopsy. Some 196 patients developed IHD and 205 patients developed AF. After adjusting for age, gender, duration of CD, calendar period, and educational attainment, there was no significant effect of persistent VA on IHD (adjusted HR 0.97; 95%CI 0.73–1.30). Adjusting for diabetes had a negligible effect (adjusted HR 0.98; 95%CI 0.73–1.31). There was no significant association between persistent VA and the risk of AF (adjusted HR 0.98; 95%CI 0.74–1.30). Conclusions In this population-based study of patients with CD, persistent VA on follow-up biopsy was not associated with an increased risk of IHD or AF. Failed mucosal healing does not influence the risk of these cardiac events. PMID:25635403

Transition from childhood to adulthood in coeliac disease: the Prague consensus report.

PubMed

Ludvigsson, Jonas F; Agreus, Lars; Ciacci, Carolina; Crowe, Sheila E; Geller, Marilyn G; Green, Peter H R; Hill, Ivor; Hungin, A Pali; Koletzko, Sibylle; Koltai, Tunde; Lundin, Knut E A; Mearin, M Luisa; Murray, Joseph A; Reilly, Norelle; Walker, Marjorie M; Sanders, David S; Shamir, Raanan; Troncone, Riccardo; Husby, Steffen

2016-08-01

The process of transition from childhood to adulthood is characterised by physical, mental and psychosocial development. Data on the transition and transfer of care in adolescents/young adults with coeliac disease (CD) are scarce. In this paper, 17 physicians from 10 countries (Sweden, Italy, the USA, Germany, Norway, the Netherlands, Australia, Britain, Israel and Denmark) and two representatives from patient organisations (Association of European Coeliac Societies and the US Celiac Disease Foundation) examined the literature on transition from childhood to adulthood in CD. Medline (Ovid) and EMBASE were searched between 1900 and September 2015. Evidence in retrieved reports was evaluated using the Grading of Recommendation Assessment, Development and Evaluation method. The current consensus report aims to help healthcare personnel manage CD in the adolescent and young adult and provide optimal care and transition into adult healthcare for patients with this disease. In adolescence, patients with CD should gradually assume exclusive responsibility for their care, although parental support is still important. Dietary adherence and consequences of non-adherence should be discussed during transition. In most adolescents and young adults, routine small intestinal biopsy is not needed to reconfirm a childhood diagnosis of CD based on European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) or North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) criteria, but a biopsy may be considered where paediatric diagnostic criteria have not been fulfilled, such as, in a patient without biopsy at diagnosis, additional serology (endomysium antibody) has not been performed to confirm 10-fold positivity of tissue transglutaminase antibodies or when a no biopsy strategy has been adopted in an asymptomatic child. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Predictors of Abdominal Pain in Depressed Pediatric Inflammatory Bowel Disease Patients

PubMed Central

Srinath, Arvind I.; Goyal, Alka; Zimmerman, Lori A.; Newara, Melissa C.; Kirshner, Margaret A.; McCarthy, F. Nicole; Keljo, David; Binion, David; Bousvaros, Athos; DeMaso, David R.; Youk, Ada; Szigethy, Eva M.

2015-01-01

Background Pediatric patients with inflammatory bowel disease (IBD) have high rates of abdominal pain. The study aims were to (1) Evaluate biological and psychological correlates of abdominal pain in depressed youth with IBD, (2) Determine predictors of abdominal pain in Crohn’s disease (CD) and ulcerative colitis (UC). Methods 765 patients ages 9–17 with IBD seen over 3 years at two sites were screened for depression. Depressed youth completed comprehensive assessments for abdominal pain, psychological (depression and anxiety), and biological (IBD-related, through disease activity indices and laboratory values) realms. Results 217 patients with IBD (161 CD, 56 UC) were depressed. 163 (120 CD, 43 UC) patients had complete API scores. In CD, abdominal pain was associated with depression (r=0.33; p<0.001), diarrhea (r=0.34; p=0.001), ESR (r=0.22; p=0.02), low albumin (r=0.24; p=.01), weight loss (r=0.33; p=0.001), and abdominal tenderness (r=0.38, p=0.002). A multivariate model with these significant correlates represented 32% of the variance in pain. Only depression (p=0.03), weight loss (p=0.04), and abdominal tenderness (p=0.01) predicted pain for CD patients. In UC, pain was associated with depression (r=0.46; p=0.002) and nocturnal stools (r=.32; p=.046). In the multivariate model with these significant correlates 23% of the variance was explained, and only depression (p=0.02) predicted pain. Conclusions The psychological state of pediatric patients with IBD may increase the sensitivity to abdominal pain. Thus, screening for and treating comorbid depression may prevent excessive medical testing and unnecessary escalation of IBD medications. PMID:24983975

Prognostic Value of Cd95, Active Caspase-3, and Bcl-2 Expression in Adult Patients With De Novo Acute Lymphoblastic Leukemia.

PubMed

Montiel-Cervantes, Laura Arcelia; Reyes-Maldonado, Elba; Garcia-Chavez, Jaime; Hernandez-Caballero, Alvaro; Molina-Aguilar, Rubiraida; Garcia-Ruiz Esparza, Miriam America; Vela-Ojeda, Jorge

2018-04-18

Acute lymphoblastic leukemia is an aggressive malignant disease with high mortality rates in adults. The expression levels of CD95, active caspase-3, and Bcl-2 were determined in 111 patients with de novo acute lymphoblastic leukemia (ALL) and correlated with overall survival (OS) and disease-free survival (DFS). The immunophenotyped ok leukemia and the expression of CD95, active caspase-3, and Bcl-2, were determined by flow cytometry. Apoptotic variables were correlated by Spearman test, and survival by Kaplan-Meier method. Log-rank test was used to compare survival curves. From a total of 111 patients, 56 cases were B-ALL, 16 T-ALL, 16 B-ALL/CD33 + , and 23 ambiguous lineage-AL (AmbLin-AL). The median expression of CD95 (61.5%) and active-caspase-3 (19.4%) was higher in T-ALL (p < 0.05), whereas Bcl-2 was lower in T-ALL (p < 0.038). There was a highly significant correlation in B-ALL, B-ALL/CD33 + and AmbLin-AL between CD95 and Bcl-2, CD95-Active caspase-3, and Bcl-2-Active caspase-3; while in T-ALL, there was only a correlation between CD95-Active caspase-3, and Bcl-2-Active caspase-3. OS and DFS were better for T-ALL than the other groups, especially in patients having higher values of CD95 and active caspase 3, and lower values of Bcl-2. The worse survival rates were observed in patients with B-ALL/CD33 + , and AmbLin-AL. The prognosis of ALL in adults is influenced by the expression levels of Bcl-2, active-caspase-3, and CD95. Copyright © 2018 IMSS. Published by Elsevier Inc. All rights reserved.

T-lymphocyte Subsets as a Prognostic Factor in a Clinical Course of Chickenpox

PubMed Central

Baljic, Rusmir; Konjo, Hadzan; Hrustemovic, Dzenana; Gazibera, Belma; Katica, Amela; Hukic, Mirsada

2017-01-01

Objective: To investigate possible prognostic values of CD4+, CD8+ T-lymphocytes, CD4/CD8 ratio to clinical course of chickenpox in immunocompetent hosts. Materials and methods: We performed a prospective study which included 69 immunocompetent patients with chickenpox who were addmited to Clinic for infectious disease, Clinical Center University of Sarajevo, in a 18 month period. All patients were divided into two groups depending on clinical presentation on admission. Patients with mild clinical form were dedicated to „outpatient” group, and patients with moderate, severe or life-threatening clinical forms were dedicated to „hospitalized” group. Also 30 healthy volunteers are included in study as a control group. We analyzed values of CD4+, CD8+ percentage, CD4/CD8 ratio with comparison to clinical course of chickenpox. All specimens were taken in acute phase of illness. Results: Values of CD4+ percentage were significantly declined in a group of hospitalized patients, compared to group of outpatients and control group. Values of CD8+ percentage were higher in a group of hospitalized patients, while CD4/CD8 values were lower in comparison to a group of outpatients and control group. Conclusion: We found significant correlation between these parameters and clinical course of chickenpox. PMID:28484347

Decreased proportions of CD4 + IL17+/CD4 + CD25 + CD127- and CD4 + IL17+/CD4 + CD25 + CD127 - FoxP3+ T cells in children with autoimmune thyroid diseases (.).

PubMed

Bossowski, Artur; Moniuszko, Marcin; Idźkowska, Ewelina; Grubczak, Kamil; Singh, Paulina; Bossowska, Anna; Diana, Tanja; Kahaly, George J

2016-08-01

Until now, altered balance of Th1 and Th2 immune cells has been postulated to play an important role in the pathogenesis of autoimmune thyroid diseases (AITD). However, recent studies on thyroid diseases have suggested a new role for Th17 cells that have been classified as a new lineage, distinct from Th1, Th2 and Treg cells. Despite wide interest, the role of Th17 cells in the pathogenesis of inflammatory and autoimmune diseases is still debated. The aim of the study was to estimate the proportions of Th17/Treg T cells in peripheral blood from patients with Graves' disease (GD; n = 29, mean age 15.4 ± 5.1 years), Hashimoto's thyroiditis (HT; n = 39, mean age 15.2 ± 4.1 years) and in healthy controls (n = 49, mean age 14.8 ± 3 years). Polychromatic flow cytometry and several fluorochrome-conjugated monoclonal antibodies were applied to delineate Th17 and Treg cells. The analysis of Th17/Treg T cell proportions in peripheral blood from patients with Graves' disease revealed significantly lower ratios of CD4 + IL17+/CD4 + CD25 + CD127 - (p < 0.0021) and CD4 + IL17+/CD4 + CD25 + CD127 - FoxP3 + (p < 0.0031) than in the control group. In addition, in the case of HT, we observed a significant decrease in the ratios of CD4 + IL17+/CD4 + CD25 + CD127 - (p < 0.0001) and CD4 + IL17+/CD4 + CD25 + CD127 - FoxP3 + (p < 0.0001) T cells in comparison to healthy children. In patients with untreated GD, a statistically significant positive correlation was found between the proportions of CD4 + IL17+/CD4 + CD25 + CD127-, CD4 + IL17+/CD4 + CD25 + CD127 - FoxP3+ T cells and the TRAbs (R = 0.71, p < 0.029; R = 0.72, p < 0.026, respectively) and a positive correlation was noted between the percentage of CD4 + CD - IL - 17 + T cells and the level of TSAbs (R = 0.66, p < 0.037). We conclude that the changes in the proportion of Th17/Treg T cells in peripheral blood and their significant relationship with the level of anti-thyroid antibodies indicate an involvement of these cells in the pathogenesis of AITD.

Genetic Variants of CD209 Associated with Kawasaki Disease Susceptibility

PubMed Central

Kuo, Ho-Chang; Huang, Ying-Hsien; Chien, Shu-Chen; Yu, Hong-Ren; Hsieh, Kai-Sheng; Hsu, Yu-Wen; Chang, Wei-Chiao

2014-01-01

Background Kawasaki disease (KD) is a systemic vasculitis with unknown etiology mainly affecting children in Asian countries. Dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN, CD209) in humans was showed to trigger an anti-inflammatory cascade and associated with KD susceptibility. This study was conducted to investigate the association between genetic polymorphisms of CD209 and the risk KD. Methods A total of 948 subjects (381 KD and 567 controls) were recruited. Nine tagging SNPs (rs8112310, rs4804800, rs11465421, rs1544766, rs4804801, rs2287886, rs735239, rs735240, rs4804804) were selected for TaqMan allelic discrimination assay. Clinical phenotypes, coronary artery lesions (CAL) and intravenous immunoglobulin (IVIG) treatment outcomes were collected for analysis. Results Significant associations were found between CD209 polymorphisms (rs4804800, rs2287886, rs735240) and the risk of KD. Haplotype analysis for CD209 polymorphisms showed that A/A/G haplotype (P = 0.0002, OR = 1.61) and G/A/G haplotype (P = 0.0365, OR = 1.52) had higher risk of KD as compared with G/G/A haplotype in rs2287886/rs735239/rs735240 pairwise allele analysis. There were no significant association in KD with regards to CAL formation and IVIG treatment responses. Conclusion CD209 polymorphisms were responsible for the susceptibility of KD, but not CAL formation and IVIG treatment responsiveness. PMID:25148534

Resolving incomplete single nucleotide polymorphism tagging of HLA-DQ2.2 for coeliac disease genotyping using digital droplet PCR.

PubMed

Hardy, M Y; Ontiveros, N; Varney, M D; Tye-Din, J A

2018-04-01

A hallmark of coeliac disease (CD) is the exceptionally strong genetic association with HLA-DQ2.5, DQ8, and DQ2.2. HLA typing provides information on CD risk important to both clinicians and researchers. A method that enables simple and fast detection of all CD risk genotypes is particularly desirable for the study of large populations. Single nucleotide polymorphism (SNP)-based HLA typing can detect the CD risk genotypes by detecting a combination of six SNPs but this approach can struggle to resolve HLA-DQ2.2, seen in 4% of European CD patients, because of the low resolution of one negatively predicting SNP. We sought to optimise SNP-based HLA typing by harnessing the additional resolution of digital droplet PCR to resolve HLA-DQ2.2. Here we test this two-step approach in an unselected sample of Mexican DNA and compare its accuracy to DNA typed using traditional exon detection. The addition of digital droplet PCR for samples requiring negative prediction of HLA-DQ2.2 enabled HLA-DQ2.2 to be accurately typed. This technique is a simple addition to a SNP-based typing strategy and enables comprehensive definition of all at-risk HLA genotypes in CD in a timely and cost-effective manner. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Characterizing T-cell response in low-grade and high-grade vulval intraepithelial neoplasia, study of CD3, CD4 and CD8 expressions.

PubMed

Gul, Nahid; Ganesan, Raji; Luesley, David M

2004-07-01

The objective of our study was to compare immunocyte infiltrates in vulval epithelium from low-grade and high-grade vulval intraepithelial neoplasia (VIN) lesions to determine if difference in T-cell presence reflected the grade of VIN. Thirty-six vulval specimens were obtained from 24 patients who had previously undergone vulval biopsies for VIN, 14 high-grade diseases (VIN 3 with or without HPV) and 14 low-grade diseases (VIN 1 and VIN 2 with or without HPV). Eight samples of normal vulval tissue were selected from the excision margins of resected vulval biopsies. The lymphocyte surface markers included CD3 (Pan T-cell marker), CD4 (T helper cells), and CD8 (T cytotoxic cells). Each tissue section was visualized under high power magnification and cells were counted in 10 random areas at the dermo-epidermal junction. A significantly higher number of total mean T lymphocytes were detected in VIN specimens compared to normal vulval tissue (P = 0.002). In low-grade VIN, there were significantly more CD8 cells than CD4 when compared to high-grade VIN. This difference in CD4/CD8 ratio was significant (P = 0.001). This study suggests that increased CD8 response in VIN is a feature of low-grade disease and we speculate that this may be a protective mechanism. In high-grade disease, both CD4 cells and CD8 cells are equally present with preservation of normal CD4/CD8 ratio.

Serum Adipocytokine Levels as Surrogate Markers for Disease Activity of Crohn's Disease.

PubMed

Kim, Su Hwan; Jang, Seung Hyeon; Kim, Ji Won; Kim, Byeong Gwan; Lee, Kook Lae; Kim, You Sun; Han, Dong Soo; Kim, Joo Sung

2017-05-01

Determining inflammatory activity is crucial for assessing disease activity and for tailoring therapy in patients with Crohn׳s disease (CD). This study aimed to evaluate adipocytokine levels in patients with CD and to determine whether they can serve as surrogate markers for disease activity. Serum samples and information regarding the clinical features of patients in the CD Network Project registry were collected from March 2009 to February 2012. Patients with CD and disease duration of at least 2 years were enrolled in this study. Fasting serum leptin, adiponectin, obestatin and ghrelin levels were measured, and their correlation with clinical features of the patients was analyzed. Serum adipocytokine levels were evaluated according to disease activity as determined by CD activity index score. A total of 153 patients with CD were included. Serum ghrelin levels negatively correlated with patient age (P = 0.041) and age at diagnosis (P = 0.017), and positively correlated with C-reactive protein (CRP) levels (P = 0.017). Multiple regression analysis showed that serum ghrelin levels were related only to CRP levels (P = 0.032). Like ghrelin, serum leptin levels were also related to CRP levels (P < 0.001). Obestatin and adiponectin levels were not related to CRP levels. Serum adipocytokine levels did not significantly differ across different disease locations or behaviors. Serum ghrelin levels were significantly lower in patients with CD with a history of surgery than in those without (P = 0.007). Serum ghrelin and leptin levels may be useful as surrogate markers for disease activity in patients with CD. Copyright © 2017 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

Perfect count: a novel approach for the single platform enumeration of absolute CD4+ T-lymphocytes.

PubMed

Storie, Ian; Sawle, Alex; Goodfellow, Karen; Whitby, Liam; Granger, Vivian; Ward, Rosalie Y; Peel, Janet; Smart, Theresa; Reilly, John T; Barnett, David

2004-01-01

The derivation of reliable CD4(+) T lymphocyte counts is vital for the monitoring of disease progression and therapeutic effectiveness in HIV(+) individuals. Flow cytometry has emerged as the method of choice for CD4(+) T lymphocyte enumeration, with single-platform technology, coupled with reference counting beads, fast becoming the "gold standard." However, although single-platform, bead-based, sample acquisition requires the ratio of beads to cells to remain unchanged, there is no available method, until recently, to monitor this. Perfect Count beads have been developed to address this issue and to incorporate two bead populations, with different densities, to allow the detection of inadequate mixing. Comparison of the relative proportions of both beads with the manufacture's defined limits enables an internal QC check during sample acquisition. In this study, we have compared CD4(+) T lymphocyte counts, obtained from 104 HIV(+) patients, using TruCount beads with MultiSet software (defined as the predicated method) and the new Perfect Count beads, incorporating an in house sequential gating strategy. We have demonstrated an excellent degree of correlation between the predicate method and the Perfect Count system (r(2) = 0.9955; Bland Altman bias +27 CD4(+) T lymphocytes/microl). The Perfect Count system is a robust method for performing single platform absolute counts and has the added advantage of having internal QC checks. Such an approach enables the operator to identify potential problems during sample preparation, acquisition and analysis. Copyright 2003 Wiley-Liss, Inc.

Umbilical Cord Mesenchymal Stem Cell Treatment for Crohn’s Disease: A Randomized Controlled Clinical Trial

PubMed Central

Zhang, Jian; Lv, Samei; Liu, Xiaojing; Song, Bin; Shi, Liping

2018-01-01

Background/Aims Stem cell therapy has been applied to treat a variety of autoimmune diseases, including Crohn’s disease (CD), but few studies have examined the use of umbilical cord mesenchymal stem cells (UC-MSCs). This trial sought to investigate the efficacy and safety of UC-MSCs for the treatment of CD. Methods Eighty-two patients who had been diagnosed with CD and had received steroid maintenance therapy for more than 6 months were included in this study. Forty-one patients were randomly selected to receive a total of four peripheral intravenous infusions of 1×106 UC-MSCs/kg, with one infusion per week. Patients were followed up for 12 months. The Crohn’s disease activity index (CDAI), Harvey-Bradshaw index (HBI), and corticosteroid dosage were assessed. Results Twelve months after treatment, the CDAI, HBI, and corticosteroid dosage had decreased by 62.5±23.2, 3.4±1.2, and 4.2±0.84 mg/day, respectively, in the UC-MSC group and by 23.6±12.4, 1.2±0.58, and 1.2±0.35 mg/day, respectively, in the control group (p<0.01, p<0.05, and p<0.05 for UC-MSC vs control, respectively). Four patients developed a fever after cell infusion. No serious adverse events were observed. Conclusions UC-MSCs were effective in the treatment of CD and produced mild side effects. PMID:28873511

Population-based cohort study on comparative effectiveness and safety of biologics in inflammatory bowel disease

PubMed Central

Trotta, Francesco; Cascini, Silvia; Agabiti, Nera; Kohn, Anna; Gasbarrini, Antonio; Davoli, Marina; Addis, Antonio

2018-01-01

Background The comparison of effectiveness and safety of anti-tumor necrosis factor-alpha agents for the treatment of inflammatory bowel disease (IBD) is relevant for clinical practice and stakeholders. Objective The objective of this study was to compare the risk of abdominal surgery, steroid utilization, and hospitalization for infection in Crohn’s disease (CD) or ulcerative colitis (UC) patients newly treated with infliximab (IFX) or adalimumab (ADA). Methods A retrospective population-based cohort study was performed using health information systems data from Lazio region, Italy. Patients with CD or UC diagnosis were enrolled at first prescription of IFX or ADA during 2008–2014 (index date). Only new drug users were followed for 2 years from the index date. IFX versus ADA adjusted hazard ratios were calculated applying “intention-to-treat” approach, controlling for several characteristics and stratifying the analysis on steroid use according to previous drug utilization. Sensitivity analyses were performed according to “as-treated” approach, adjusting for propensity score, censoring at switching or discontinuation, and evaluating different lengths of follow-up periods. Results We enrolled 1,432 IBD patients (42% and 83% exposed to IFX for CD and UC, respectively). In both diseases, treatment effects did not differ in any outcome considered, and sensitivity analyses confirmed the results from the main analysis. Conclusion In our population-based cohort study, effectiveness and safety data in new users of ADA or IFX with CD or UC were comparable for the outcomes we tested. PMID:29440933

Virological and immunological characteristics of human cytomegalovirus infection associated with Alzheimer disease.

PubMed

Lurain, Nell S; Hanson, Barbara A; Martinson, Jeffrey; Leurgans, Sue E; Landay, Alan L; Bennett, David A; Schneider, Julie A

2013-08-15

Serum, cerebrospinal fluid (CSF), and cryopreserved lymphocytes from subjects in the Rush Alzheimer's Disease Center Religious Orders Study were analyzed for associations between cytomegalovirus (CMV) infection and clinical and pathological markers of Alzheimer disease. CMV antibody levels were associated with neurofibrillary tangles (NFTs). CSF interferon γ was only detected in seropositive subjects and was significantly associated with NFTs. The percentage of senescent T cells (CD4+ or CD8+CD28-CD57+) was significantly higher for CMV-seropositive as compared to CMV-seronegative subjects and was marginally associated with the pathologic diagnosis of Alzheimer disease (CD4+) or amyloid-β (CD8+). Immunocytochemical analysis showed induction of amyloid-β in human foreskin fibroblasts (HFFs) infected with each of 3 clinical CMV strains. In the same subjects, there was no association of herpes simplex virus type 1 (HSV-1) antibody levels with CMV antibody levels or clinical or pathological markers of Alzheimer disease. HSV-1 infection of HFFs did not induce amyloid-β. These data support an association between CMV and the development of Alzheimer disease.

Virological and Immunological Characteristics of Human Cytomegalovirus Infection Associated With Alzheimer Disease

PubMed Central

Lurain, Nell S.; Hanson, Barbara A.; Martinson, Jeffrey; Leurgans, Sue E.; Landay, Alan L.; Bennett, David A.; Schneider, Julie A.

2013-01-01

Serum, cerebrospinal fluid (CSF), and cryopreserved lymphocytes from subjects in the Rush Alzheimer's Disease Center Religious Orders Study were analyzed for associations between cytomegalovirus (CMV) infection and clinical and pathological markers of Alzheimer disease. CMV antibody levels were associated with neurofibrillary tangles (NFTs). CSF interferon γ was only detected in seropositive subjects and was significantly associated with NFTs. The percentage of senescent T cells (CD4+ or CD8+CD28−CD57+) was significantly higher for CMV-seropositive as compared to CMV-seronegative subjects and was marginally associated with the pathologic diagnosis of Alzheimer disease (CD4+) or amyloid-β (CD8+). Immunocytochemical analysis showed induction of amyloid-β in human foreskin fibroblasts (HFFs) infected with each of 3 clinical CMV strains. In the same subjects, there was no association of herpes simplex virus type 1 (HSV-1) antibody levels with CMV antibody levels or clinical or pathological markers of Alzheimer disease. HSV-1 infection of HFFs did not induce amyloid-β. These data support an association between CMV and the development of Alzheimer disease. PMID:23661800

Cytotoxic Th1 and Th17 cells infiltrate the intestinal mucosa of Behcet patients and exhibit high levels of TNF-α in early phases of the disease

PubMed Central

Emmi, Giacomo; Silvestri, Elena; Bella, Chiara Della; Grassi, Alessia; Benagiano, Marisa; Cianchi, Fabio; Squatrito, Danilo; Cantarini, Luca; Emmi, Lorenzo; Selmi, Carlo; Prisco, Domenico; D’Elios, Mario Milco

2016-01-01

Abstract Background: Gastrointestinal involvement is one of the most serious in Behçet disease, potentially leading to severe complications. Aim of this study was to investigate at mucosal level the T-cell responses in Behçet patients with early intestinal involvement. Methods: We isolated T cells from intestinal mucosa of 8 patients with intestinal symptoms started within 6 months. T lymphocytes were cloned and analyzed for surface phenotype and cytokines production. Results: We obtained 382 T-cell clones: 324 were CD4+ and 58 were CD8+. Within the 324 CD4+ clones, 195 were able to secrete IFN-γ and TNF-α, but not IL-4, nor IL-17 thus showing a polarized Th1 profile, whereas CD4 clones producing both IFN-γ and IL-17 (Th1/Th17 profile) were 79. Likewise, the number of CD8 clones producing type 1 cytokines was higher than those of CD8 clones producing both type 1 and 2 cytokines. Almost all intestinal-derived T-cell clones expressed perforin-mediated cytotoxicity and Fas–Fas Ligand-mediated pro-apoptotic activity. Conclusions: Our results indicate that in the early stages of the disease, both Th1 and Th17 cells drive inflammation leading to mucosal damage via abnormal and long-lasting cytokines production as well as via both perforin- and Fas–Fas ligand-mediated cytotoxicity. Finally, all the T cells at mucosal level were able to produce large amount of TNF-α, suggesting that its production is a property of intestinal T cells of patients with early active intestinal disease. These results support the therapy with anti-TNF-α agents and suggest the use of anti-IL-17 monoclonal antibodies in Behçet patients with early intestinal involvement. PMID:27930541

Epidemiological and clinical characteristics of inflammatory bowel diseases in Cairo, Egypt

PubMed Central

Esmat, Serag; El Nady, Mohamed; Elfekki, Mohamed; Elsherif, Yehia; Naga, Mazen

2014-01-01

AIM: To study the natural history, patterns and clinical characteristics of inflammatory bowel diseases (IBD) in Egypt. METHODS: We designed a case-series study in the gastroenterology centre of the Internal Medicine department of Cairo University, which is a tertiary care referral centre in Egypt. We included all patients in whom the diagnosis of ulcerative colitis (UC) or Crohn’s disease (CD) was confirmed by clinical, laboratory, endoscopic, histological and/or radiological criteria over the 15 year period from 1995 to 2009, and we studied their sociodemographic and clinical characteristics. Endoscopic examinations were performed by 2 senior experts. This hospital centre serves patients from Cairo, as well as patients referred from all other parts of Egypt. Our centre received 24156 patients over the described time period for gastro-intestinal consultations and/or interventions. RESULTS: A total of 157 patients with established IBD were included in this study. Of these, 135 patients were diagnosed with UC (86% of the total), and 22 patients, with CD (14% of the total). The mean ages at diagnosis were 27.3 and 29.7, respectively. Strikingly, we noticed a marked increase in the frequency of both UC and CD diagnoses during the most recent 10 years of the 15 year period studied. Regarding the gender distribution, the male:female ratio was 1:1.15 for UC and 2.6:1 for CD. The mean duration of follow up for patients with UC was 6.2 ± 5.18 years, while the mean duration of follow up for patients with CD was 5.52 ± 2.83 years. For patients with UC we found no correlation between the severity of the disease and the presence of extraintestinal manifestations. Eleven patients had surgical interventions during the studied years: 4 cases of total colectomy and 7 cases of anal surgery. CONCLUSION: We observed a ratio of 6:1 for UC to CD in our series. The incidence of IBD seems to be rising in Egypt. PMID:24574754

Circulating CD4+CD28null and extra-thymic CD4+CD8+ double positive T cells are independently associated with disease damage in systemic lupus erythematosus patients.

PubMed

Ugarte-Gil, M F; Sánchez-Zúñiga, C; Gamboa-Cárdenas, R V; Aliaga-Zamudio, M; Zevallos, F; Tineo-Pozo, G; Cucho-Venegas, J M; Mosqueira-Riveros, A; Medina, M; Perich-Campos, R A; Alfaro-Lozano, J L; Rodriguez-Bellido, Z; Alarcón, G S; Pastor-Asurza, C A

2016-03-01

To determine whether circulating CD4+CD28null and extra-thymic CD4+CD8+ double positive (DP) T cells are independently associated with damage accrual in systemic lupus erythematosus (SLE) patients. This cross-sectional study was conducted between September 2013 and April 2014 in consecutive SLE patients from our Rheumatology Department. CD4+CD28null and CD4+CD8+ DP T-cell frequencies were analyzed by flow-cytometry. The association of damage (SLICC/ACR Damage Index, SDI) and CD4+CD28null and CD4+CD8+ DP T cells was examined by univariable and multivariable Poisson regression models, adjusting for possible confounders. All analyses were performed using SPSS 21.0. Patients' (n = 133) mean (SD) age at diagnosis was 35.5 (16.8) years, 124 (93.2%) were female; all were mestizo (mixed Caucasian and Amerindian ancestry). Disease duration was 7.4 (6.8) years. The SLE Disease Activity Index was 5.5 (4.2), and the SDI 0.9 (1.2). The percentages of CD4+CD28null and CD4+CD8+ DP T cells were 17.1 (14.4) and 0.4 (1.4), respectively. The percentage of CD4+CD28null and CD4+CD8+ DP T cells were positively associated with a higher SDI in both univariable (rate ratio (RR) 1.02, 95% confidence interval (CI): 1.01-1.03 and 1.17, 95% CI: 1.07-1.27, respectively; p < 0.001 for both) and multivariable analyses RR 1.02, 95% CI: 1.01-1.03, p = 0.001 for CD4+CD28null T cells and 1.28, 95% CI: 1.13-1.44, p < 0.001 for CD4+CD8+ DP T cells). Only the renal domain remained associated with CD4+CD28null in multivariable analyses (RR 1.023 (1.002-1.045); p = 0.034). In SLE patients, CD4+CD28null and CD4+CD8+ DP T cells are independently associated with disease damage. Longitudinal studies are warranted to determine the predictive value of these associations. © The Author(s) 2015.

Lymphocyte Antigen 75 Polymorphisms Are Associated with Disease Susceptibility and Phenotype in Japanese Patients with Inflammatory Bowel Disease.

PubMed

Hirayama, Atsuhiro; Joshita, Satoru; Kitahara, Kei; Mukawa, Kenji; Suga, Tomoaki; Umemura, Takeji; Tanaka, Eiji; Ota, Masao

2016-01-01

Recent genome-wide association studies have rapidly improved our understanding of the molecular pathways leading to inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC). Although several reports have demonstrated that gene single nucleotide polymorphisms (SNPs) are associated with susceptibility to IBD, its precise genetic factors have not been fully clarified. Here, we performed an association analysis between lymphocyte antigen 75 ( LY75 ) genetic variations and IBD susceptibility or phenotype. SNPs were genotyped in 51 CD patients, 94 UC patients, and 269 healthy controls of Japanese ethnicity. We detected a significant relationship with CD susceptibility for the rs16822581 LY75 SNP ( P = 0.045). One haplotype (GT, P = 0.042) was also associated with CD susceptibility, while another carrying the opposite SNP (CA) was linked to an absence of surgical history for CD. Our findings confirm that LY75 is involved in CD susceptibility and may play a role in disease activity in the Japanese population.

Plasma-soluble CD30 in childhood tuberculosis: effects of disease severity, nutritional status, and vitamin A therapy.

PubMed

Hanekom, W A; Hussey, G D; Hughes, E J; Potgieter, S; Yogev, R; Check, I J

1999-03-01

Plasma-soluble CD30 (sCD30) is the result of proteolytic splicing from the membrane-bound form of CD30, a putative marker of type 2 cytokine-producing cells. We measured sCD30 levels in children with tuberculosis, a disease characterized by prominent type 1 lymphocyte cytokine responses. We postulated that disease severity and nutritional status would alter cytokine responses and therefore sCD30 levels. Samples from South African children enrolled prospectively at the time of diagnosis of tuberculosis were analyzed. (Patients were originally enrolled in a randomized, double-blind placebo-controlled study of the effects of oral vitamin A supplementation on prognosis of tuberculosis.) Plasma samples collected at the time of diagnosis and 6 and 12 weeks later (during antituberculosis therapy) were analyzed. sCD30 levels were measured by enzyme immunoassay. The 91 children included in the study demonstrated high levels of sCD30 at diagnosis (median, 98 U/liter; range, 11 to 1,569 U/liter). Although there was a trend toward higher sCD30 levels in more severe disease (e.g., culture-positive disease or miliary disease), this was not statistically significant. Significantly higher sCD30 levels were demonstrated in the presence of nutritional compromise: the sCD30 level was higher in patients with a weight below the third percentile for age, in those with clinical signs of kwashiorkor, and in those with a low hemoglobin content. There was minimal change in the sCD30 level after 12 weeks of therapy, even though patients improved clinically. However, changes in sCD30 after 12 weeks differed significantly when 46 patients (51%) who received vitamin A were compared with those who had received a placebo. Vitamin A-supplemented children demonstrated a mean (+/- standard error of the mean) decrease in sCD30 by a factor of 0.99 +/- 0.02 over 12 weeks, whereas a factor increase of 1.05 +/- 0.02 was demonstrated in the placebo group (P = 0.02). We conclude that children with tuberculosis had high sCD30 levels, which may reflect the presence of a type 2 cytokine response. Nutritional compromise was associated with higher sCD30 levels. Vitamin A therapy resulted in modulation of sCD30 levels over time.

Plasma-Soluble CD30 in Childhood Tuberculosis: Effects of Disease Severity, Nutritional Status, and Vitamin A Therapy

PubMed Central

Hanekom, W. A.; Hussey, G. D.; Hughes, E. J.; Potgieter, S.; Yogev, R.; Check, I. J.

1999-01-01

Plasma-soluble CD30 (sCD30) is the result of proteolytic splicing from the membrane-bound form of CD30, a putative marker of type 2 cytokine-producing cells. We measured sCD30 levels in children with tuberculosis, a disease characterized by prominent type 1 lymphocyte cytokine responses. We postulated that disease severity and nutritional status would alter cytokine responses and therefore sCD30 levels. Samples from South African children enrolled prospectively at the time of diagnosis of tuberculosis were analyzed. (Patients were originally enrolled in a randomized, double-blind placebo-controlled study of the effects of oral vitamin A supplementation on prognosis of tuberculosis.) Plasma samples collected at the time of diagnosis and 6 and 12 weeks later (during antituberculosis therapy) were analyzed. sCD30 levels were measured by enzyme immunoassay. The 91 children included in the study demonstrated high levels of sCD30 at diagnosis (median, 98 U/liter; range, 11 to 1,569 U/liter). Although there was a trend toward higher sCD30 levels in more severe disease (e.g., culture-positive disease or miliary disease), this was not statistically significant. Significantly higher sCD30 levels were demonstrated in the presence of nutritional compromise: the sCD30 level was higher in patients with a weight below the third percentile for age, in those with clinical signs of kwashiorkor, and in those with a low hemoglobin content. There was minimal change in the sCD30 level after 12 weeks of therapy, even though patients improved clinically. However, changes in sCD30 after 12 weeks differed significantly when 46 patients (51%) who received vitamin A were compared with those who had received a placebo. Vitamin A-supplemented children demonstrated a mean (± standard error of the mean) decrease in sCD30 by a factor of 0.99 ± 0.02 over 12 weeks, whereas a factor increase of 1.05 ± 0.02 was demonstrated in the placebo group (P = 0.02). We conclude that children with tuberculosis had high sCD30 levels, which may reflect the presence of a type 2 cytokine response. Nutritional compromise was associated with higher sCD30 levels. Vitamin A therapy resulted in modulation of sCD30 levels over time. PMID:10066655

Regulation of EMMPRIN (CD147) on monocyte subsets in patients with symptomatic coronary artery disease.

PubMed

Sturhan, Henrik; Ungern-Sternberg, Saskia N I v; Langer, Harald; Gawaz, Meinrad; Geisler, Tobias; May, Andreas E; Seizer, Peter

2015-06-01

The role of individual monocyte subsets in inflammatory cardiovascular diseases is insufficiently understood. Although the Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) regulates important processes for inflammation such as MMP-release, its expression and regulation on monocyte subsets has not been characterized. In this clinical study, blood was obtained from 80 patients with stable coronary artery disease (CAD), 49 with acute myocardial infarction (AMI) and 34 healthy controls. Monocytes were divided into 3 subsets: CD14(++)CD16(-) (low), CD14(++)CD16(+) (intermediate), CD14(+)CD16(++) (high) according to phenotypic markers analyzed by flow cytometry. Surface expression of EMMPRIN was evaluated and compared with CD36 and CD47 expression. In all patients, EMMPRIN expression was significantly different among monocyte subsets with the highest expression on "classical" CD14(++)CD16(-) monocytes. EMMPRIN was upregulated on all monocyte subsets in patients with AMI as compared to patients with stable CAD. Notably, neither CD47 nor CD36 revealed a significant difference in patients with AMI compared to patients with stable CAD. EMMPRIN could serve as a marker for classical monocytes, which is upregulated in patients with acute myocardial infarction. Copyright © 2015 Elsevier Ltd. All rights reserved.

Increased Incidence of Thyroid Disease in Patients with Celiac Disease: A Systematic Review and Meta-Analysis

PubMed Central

Sun, Xin; Lu, Li; Yang, Rong; Li, Yanbin; Shan, Ling; Wang, Yang

2016-01-01

The prevalence of thyroid disease is likely increased among individuals with celiac disease (CD). In addition, exposure to gluten-free treatment may be associated with a risk of thyroid disease, but this association remains controversial. A systematic review was performed to evaluate the association between thyroid disease and CD. The articles were obtained from the PubMed, Web of Science, Embase, and Chinese WanFang bibliographical databases for the period up to May 2016. The results were analysed in a meta-analysis with odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs). There were 13 articles in this meta-analysis, including 15629 CD cases and 79342 controls. Overall, the prevalence of thyroid disease in patients with CD was significantly increased compared with that in the control groups (OR 3.08, 95% CI 2.67–3.56, P<0.001). Moreover, there was no significant difference in the OR between the gluten-treated and untreated groups (OR 1.08, 95% CI 0.61–1.92, P = 0.786). The results of our meta-analysis support the hypothesis that the prevalence of thyroid disease in patients with CD is increased compared with that in controls, which suggests that CD patients should be screened for thyroid disease. The effect of gluten-free treatment on thyroid disease needs further investigation. PMID:28030626

Age of Diagnosis Influences Serologic Responses in Children with Crohn Disease: A Possible Clue to Etiology?

PubMed Central

Markowitz, James; Kugathasan, Subra; Dubinsky, Marla; Mei, Ling; Crandall, Wallace; LeLeiko, Neal; Oliva-Hemker, Maria; Rosh, Joel; Evans, Jonathan; Mack, David; Otley, Anthony; Pfefferkorn, Marian; Bahar, Ron; Vasiliauskas, Eric; Wahbeh, Ghassan; Silber, Gary; Quiros, J. Antonio; Wrobel, Iwona; Nebel, Justin; Landers, Carol; Picornell, Yoanna; Targan, Stephan; Lerer, Trudy; Hyams, Jeffrey

2009-01-01

Crohn disease (CD) is often associated with antibodies to microbial antigens. Differences in immune response may offer clues to the pathogenesis of the disease. AIM To examine the influence of age at diagnosis on serologic response in children with CD. METHODS Data were drawn from 3 North American multicenter pediatric IBD research consortia. At or shortly after diagnosis, pANCA, ASCA IgA, ASCA IgG, anti-ompC and anti-CBir1 were assayed. Results were compared as a function of age at CD diagnosis (0–7 years vs 8–15 years). RESULTS 705 children (79 <8 yr of age at diagnosis, 626 ≥8yr) were studied. Small bowel CD was less frequent in the younger group (48.7% vs 72.6%; p<0.0001) while colonic involvement was comparable (91.0% vs 86.5%). ASCA IgA and IgG were seen in <20% of those 0–7 yr compared to nearly 40% of those 8–15 yr (p<0.001), while anti-CBir1 was more frequent in the younger children (66% vs 54%, p<0.05). Anti-CBir1 detected a significant number of children in both age groups who otherwise were serologically negative. Both age at diagnosis and site of CD involvement were independently associated with expression of ASCA and anti-CBir1. CONCLUSIONS Compared to children 8–15 yr of age at diagnosis, those 0–7 yr are more likely to express anti-CBir1 but only half as likely to express ASCA. These age-associated differences in antimicrobial seropositivity suggest that there may be different, and as yet unrecognized, genetic, immunologic and/or microbial factors leading to CD in the youngest children. PMID:19107777

Induction with Infliximab and a Plant-Based Diet as First-Line (IPF) Therapy for Crohn Disease: A Single-Group Trial

PubMed Central

Chiba, Mitsuro; Tsuji, Tsuyotoshi; Nakane, Kunio; Tsuda, Satoko; Ishii, Hajime; Ohno, Hideo; Watanabe, Kenta; Ito, Mai; Komatsu, Masafumi; Sugawara, Takeshi

2017-01-01

Background Approximately 30% of patients with Crohn disease (CD) are unresponsive to biologics. No previous study has focused on a plant-based diet in an induction phase of CD treatment. Objective To investigate the remission rate of infliximab combined with a plant-based diet as first-line (IPF) therapy for CD. Methods This was a prospective single-group trial conducted at tertiary hospitals. Subjects included consecutive adults with a new diagnosis (n = 26), children with a new diagnosis (n = 11), and relapsing adults (n = 9) with CD who were naïve to treatment with biologics. Patients were admitted and administered a standard induction therapy with infliximab (5 mg/kg; 3 infusions at 0, 2, and 6 weeks). Additionally, they received a lacto-ovo-semivegetarian diet. The primary end point was remission, defined as the disappearance of active CD symptoms at week 6. Secondary end points were Crohn Disease Activity Index (CDAI) score, C-reactive protein (CRP) concentration, and mucosal healing. Results Two adults with a new diagnosis were withdrawn from the treatment protocol because of intestinal obstruction. The remission rates by the intention-to-treat and per-protocol analyses were 96% (44/46) and 100% (44/44), respectively. Mean CDAI score (314) on admission decreased to 63 at week 6 (p < 0.0001). Mean CRP level on admission (5.3 mg/dL) decreased to 0.2 (p < 0.0001). Mucosal healing was achieved in 46% (19/41) of cases. Conclusion IPF therapy can induce remission in most patients with CD who are naïve to biologics regardless of age or whether they have a new diagnosis or relapse. PMID:29035182

Extensive Modulation of the Fecal Metagenome in Children With Crohn's Disease During Exclusive Enteral Nutrition

PubMed Central

Quince, Christopher; Ijaz, Umer Zeeshan; Loman, Nick; Eren, A Murat; Saulnier, Delphine; Russell, Julie; Haig, Sarah J; Calus, Szymon T; Quick, Joshua; Barclay, Andrew; Bertz, Martin; Blaut, Michael; Hansen, Richard; McGrogan, Paraic; Russell, Richard K; Edwards, Christine A; Gerasimidis, Konstantinos

2015-01-01

OBJECTIVES: Exploring associations between the gut microbiota and colonic inflammation and assessing sequential changes during exclusive enteral nutrition (EEN) may offer clues into the microbial origins of Crohn's disease (CD). METHODS: Fecal samples (n=117) were collected from 23 CD and 21 healthy children. From CD children fecal samples were collected before, during EEN, and when patients returned to their habitual diets. Microbiota composition and functional capacity were characterized using sequencing of the 16S rRNA gene and shotgun metagenomics. RESULTS: Microbial diversity was lower in CD than controls before EEN (P=0.006); differences were observed in 36 genera, 141 operational taxonomic units (OTUs), and 44 oligotypes. During EEN, the microbial diversity of CD children further decreased, and the community structure became even more dissimilar than that of controls. Every 10 days on EEN, 0.6 genus diversity equivalents were lost; 34 genera decreased and one increased during EEN. Fecal calprotectin correlated with 35 OTUs, 14 of which accounted for 78% of its variation. OTUs that correlated positively or negatively with calprotectin decreased during EEN. The microbiota of CD patients had a broader functional capacity than healthy controls, but diversity decreased with EEN. Genes involved in membrane transport, sulfur reduction, and nutrient biosynthesis differed between patients and controls. The abundance of genes involved in biotin (P=0.005) and thiamine biosynthesis decreased (P=0.017), whereas those involved in spermidine/putrescine biosynthesis (P=0.031), or the shikimate pathway (P=0.058), increased during EEN. CONCLUSIONS: Disease improvement following treatment with EEN is associated with extensive modulation of the gut microbiome. PMID:26526081

Predictors of Clinical Response and Remission at One year among a Multicenter Cohort of Patients with Inflammatory Bowel Disease Treated with Vedolizumab

PubMed Central

Allegretti, Jessica R.; Barnes, Edward L.; Stevens, Betsey; Storm, Margaret; Ananthakrishnan, Ashwin; Yajnik, Vijay; Korzenik, Joshua

2017-01-01

Background Vedolizumab (VDZ) has demonstrated long term efficacy in Crohn’s disease (CD) and ulcerative colitis (UC) in phase III trials. Aims Our aim was to evaluate the efficacy of VDZ at week 54 in inflammatory bowel disease (IBD) in a multicenter cohort of patients. Methods Adult patients completing induction therapy with VDZ were eligible for this study. Clinical response and remission was assessed using the Harvey Bradshaw index (HBI) for CD, the simple clinical colitis activity index (SCCAI) for UC and physician assessment. Results Among 136 total patients (96 CD and 40 UC), 76 (56%) demonstrated clinical response or remission at week 54. In univariate analysis, for patients with CD concomitant initiation of immunomodulator therapy (2.71, 95% CI 1.11 – 6.57), the addition of an immunomodulator (OR 11.49, 3.16 – 41.75) and CRP <3 (4.92, 95% CI 1.99 – 12.15) were associated with increased odds of clinical response or remission at week 54. For UC patients hospitalization after VDZ induction was associated with decreased odds of response or remission at week 54 ( OR 0.22, 95%CI 0.05–0.88). On multivariate analysis in CD, addition of an immunomodulator (OR 8.33, 95% CI 2.15–32.26) remained significant predictors of clinical response or remission at week 54. Conclusions Among a multicenter cohort of patients with IBD demonstrating primary response to VDZ, the addition of combination therapy with an immunomodulator is a significant predictor of clinical response or remission at week 54 in patients with CD. PMID:28357697

Impact of vitamin D on the hospitalization rate of Crohn's disease patients seen at a tertiary care center

PubMed Central

Venkata, Krishna V R; Arora, Sumant S; Xie, Feng-Long; Malik, Talha A

2017-01-01

AIM To study the association between vitamin D level and hospitalization rate in Crohn’s disease (CD) patients. METHODS We designed a retrospective cohort study using adult patients (> 19 years) with CD followed for at least one year at our inflammatory bowel disease center. Vitamin D levels were divided into: low mean vitamin D level (< 30 ng/mL) vs appropriate mean vitamin D level (30-100 ng/mL). Generalized Poisson Regression Models (GPR) for Rate Data were used to estimate partially adjusted and fully adjusted incidence rate ratios (IRR) of hospitalization among CD patients. We also examined IRRs for vitamin D level as a continuous variable. RESULTS Of the 880 CD patients, 196 patients with vitamin D level during the observation period were included. Partially adjusted model demonstrated that CD patients with a low mean vitamin D level were almost twice more likely to be admitted (IRR = 1.76, 95%CI: 1.38-2.24) compared to those with an appropriate vitamin D level. The fully adjusted model confirmed this association (IRR = 1.44, 95%CI: 1.11-1.87). Partially adjusted model with vitamin D level as a continuous variable demonstrated, higher mean vitamin D level was associated with a 3% lower likelihood of admission with every unit (ng/mL) rise in mean vitamin D level (IRR = 0.97, 95%CI: 0.96-0.98). The fully adjusted model confirmed this association (IRR = 0.98, 95%CI: 0.97-0.99). CONCLUSION Normal or adequate vitamin D stores may be protective in the clinical course of CD. However, this role needs to be further characterized and understood. PMID:28465638

Striking elevation in incidence and prevalence of inflammatory bowel disease in a province of western Hungary between 1977-2001

PubMed Central

Lakatos, Laszlo; Mester, Gabor; Erdelyi, Zsuzsanna; Balogh, Mihaly; Szipocs, Istvan; Kamaras, Gyorgy; Lakatos, Peter Laszlo

2004-01-01

AIM: An investigation into inflammatory bowel disease and colorectal cancer in Veszprem Province was conducted from 1977 to 2001. METHODS: Both hospital and outpatient records were collected and reviewed comprehensively. The majority of patients were followed up regularly. RESULTS: The population of the province was decreased from 386000 to 376000 during the period. Five hundred sixty new cases of ulcerative colitis (UC), 212 of Crohn’s disease (CD), and 40 of indeterminate colitis (IC) were diagnosed. The incidence rates increased from 1.66 to 11.01 cases per 100000 persons for UC, from 0.41 to 4.68 for CD and from 0.26 to 0.74 for IC. The prevalence rate at the end of 2001 was 142.6 for UC and 52.9 cases per 100000 persons for CD. The peak onset age in UC patients was between 30 and 40 years, in CD between 20 and 30 years. A family history of IBD was present in 3.4 % in UC and 9.9 % in CD patients. Smoking increased the risk for CD (OR = 1.94) while it decreased the risk for UC (OR = 0.25). Twelve colorectal carcinomas were observed in this cohort, the cumulative colorectal cancer risk after 10 years in UC was 2%, after 20 years 8.8%, after 30 years 13.3%. CONCLUSION: The incidence and prevalence rates of IBD have increased steadily in Veszprem Province, now equivalent to that in Western European countries. Rapid increase in incidence rates supports a probable role for environmental factors. The rate of colorectal cancers in IBD is similar to that observed in Western countries. PMID:14760767

The Risk of Relapse after Anti-TNF Discontinuation in Inflammatory Bowel Disease: Systematic Review and Meta-Analysis.

PubMed

Gisbert, Javier P; Marín, Alicia C; Chaparro, María

2016-05-01

To perform a meta-analysis of the risk of relapse after discontinuation of anti-tumor necrosis factor (anti-TNF) therapy in patients with Crohn's disease (CD) and ulcerative colitis (UC), to evaluate risk factors for relapse, and to assess the response to retreatment with the same anti-TNF. Studies evaluating the incidence of relapse after anti-TNF discontinuation in patients with CD or UC who reached clinical remission with anti-TNFs were included. Bibliographies up to January 2015 were searched. Frequency of relapse after discontinuation of anti-TNF agents was determined; meta-analyses were performed using the inverse-variance method. We included 27 studies (21 infliximab and 6 infliximab/adalimumab). The overall risk of relapse after discontinuation of anti-TNF therapy was 44% for CD (95% confidence interval (CI) 36-51%; I(2)=79%; 912 patients) and 38% for UC (23-52%; I(2)=82%; 266 patients). In CD, the relapse rate was 38% at 6 months after discontinuation (short term), 40% at 12 months (medium term), and 49% at >25 months (long term). In UC, 28% of patients relapsed at 12 months. In CD, when clinical remission was the only criterion for stopping anti-TNF therapy, the relapse rate after 1 year was 42%, which decreased to 26% when endoscopic remission was also required. Retreatment with the same anti-TNF induced remission again in 80% of cases (68-91%). Approximately one-third of patients with inflammatory bowel disease in remission under anti-TNF treatment relapsed 1 year after discontinuation. This proportion increased to half in the long term. In CD patients, the risk of relapse was lower when the criterion for discontinuation was endoscopic remission and not only clinical remission. Response to retreatment with the same anti-TNF agent was favorable.

The diagnostic value of a new fecal marker, matrix metalloprotease-9, in different types of inflammatory bowel diseases.

PubMed

Farkas, Klaudia; Saródi, Zoltán; Bálint, Anita; Földesi, Imre; Tiszlavicz, László; Szűcs, Mónika; Nyári, Tibor; Tajti, János; Nagy, Ferenc; Szepes, Zoltán; Bor, Renáta; Annaházi, Anita; Róka, Richárd; Molnár, Tamás

2015-03-01

Only limited data are available regarding the diagnostic accuracy of fecal matrix metalloprotease-9 [MMP-9] for inflammatory bowel disease [IBD]. The aims of our study were to assess the diagnostic accuracy of fecal MMP-9 in patients with active Crohn's disease [CD], ulcerative colitis [UC], and pouchitis, and to compare the diagnostic accuracy of fecal MMP-9 and fecal calprotectin [CP] in IBD. Stool and blood samples were collected in 50 CD, 54 UC, and 34 ileal pouch-anal anastomosis patients before control endoscopies were performed. Biopsies were taken for histologic purposes. The activities of CD, UC, and pouchitis were defined with the use of clinical, endoscopic, and histologic activity scores. Fecal CP and MMP-9 levels were quantified by enzyme-linked immunosorbent assay. Active CD, UC, and pouchitis were detected in 38%, 54%, and 29% of the patients, respectively. A significant correlation was revealed between fecal CP and the clinical activities of CD and UC, and between fecal CP and the endoscopic activity of UC and pouchitis. Fecal MMP-9 did not correlate with any of the activity indices of CD; however, strong associations were shown between fecal MMP-9 and clinical, endoscopic, and histologic activities of both UC and pouchitis. This is the first study assessing the diagnostic accuracy of MMP-9 in different types of IBD. Our results showed that fecal MMP-9 has high sensitivity in the detection of endoscopically active UC and pouchitis. These non-invasive methods help assess intestinal inflammation. Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Altered immunophenotypic features of peripheral blood platelets in myelodysplastic syndromes

PubMed Central

Sandes, Alex F.; Yamamoto, Mihoko; Matarraz, Sergio; Chauffaille, Maria de Lourdes L.F.; Quijano, Sandra; López, Antonio; Oguro, Tsutomu; Kimura, Eliza Y. S.; Orfao, Alberto

2012-01-01

Background Multiparameter flow cytometric analysis of bone marrow and peripheral blood cells has proven to be of help in the diagnostic workup of myelodysplastic syndromes. However, the usefulness of flow cytometry for the detection of megakaryocytic and platelet dysplasia has not yet been investigated. The aim of this pilot study was to evaluate by flow cytometry the diagnostic and prognostic value of platelet dysplasia in myelodysplastic syndromes. Design and Methods We investigated the pattern of expression of distinct surface glycoproteins on peripheral blood platelets from a series of 44 myelodysplastic syndrome patients, 20 healthy subjects and 19 patients with platelet alterations associated to disease conditions other than myelodysplastic syndromes. Quantitative expression of CD31, CD34, CD36, CD41a, CD41b, CD42a, CD42b and CD61 glycoproteins together with the PAC-1, CD62-P, fibrinogen and CD63 platelet activation-associated markers and platelet light scatter properties were systematically evaluated. Results Overall, flow cytometry identified multiple immunophenotypic abnormalities on platelets of myelodysplastic syndrome patients, including altered light scatter characteristics, over-and under expression of specific platelet glycoproteins and asynchronous expression of CD34; decreased expression of CD36 (n=5), CD42a (n=1) and CD61 (n=2), together with reactivity for CD34 (n=1) were only observed among myelodysplastic syndrome cases, while other alterations were also found in other platelet disorders. Based on the overall platelet alterations detected for each patient, an immunophenotypic score was built which identified a subgroup of myelodysplastic syndrome patients with a high rate of moderate to severe alterations (score>1.5; n=16) who more frequently showed thrombocytopenia, megakaryocytic dysplasia and high-risk disease, together with a shorter overall survival. Conclusions Our results show the presence of altered phenotypes by flow cytometry on platelets from around half of the myelodysplastic syndrome patients studied. If confirmed in larger series of patients, these findings may help refine the diagnostic and prognostic assessment of this group of disorders. PMID:22271903

The genetics of celiac disease: A comprehensive review of clinical implications.

PubMed

Dieli-Crimi, Romina; Cénit, M Carmen; Núñez, Concepción

2015-11-01

Celiac disease (CD) is a complex immune-related disease with a very strong genetic component. Multiple genetic findings over the last decade have added to the already known MHC influence numerous genetic variants associated to CD susceptibility. Currently, it is well-established that 6 MHC and 39 non-MHC loci, including a higher number of independent genetic variants, are associated to disease risk. Moreover, additional regions have been recently implicated in the disease, which would increase the number of involved loci. Together, the firmly described genetic variants account for roughly 31% of CD heritability, being 25% explained by the MHC influence. These new variants represent markers of disease risk and turn the identification of the causal genes and the causal variants inside the associated loci, as well as their precise biological role on the disease, into a major challenge in CD research. Numerous studies have been developed with this aim showing the high impact of risk variants on gene expression. These studies also indicate a central role of CD4(+) T cells in CD pathogenesis and point to B cells as important players, which is in accordance with the key steps highlighted by the immunological models of pathogenesis. We comprehensively summarize the current knowledge about the genetic architecture of CD, characterized by multiple low-risk variants located within diverse loci which are most likely affecting genes with immune-related functions. These findings are leading to a better understanding of CD pathogenesis and helping in the design of new treatments. The repertoire of potential drug targets for CD has largely broadened last years, bringing us closer to get alternative or complementary treatments to the life-long gluten-free diet, the only effective treatment so far. Epigenetics and microbiota are emerging as potent factors modulating disease risk and putatively affecting disease manifestation, which are also being explored as therapeutic targets. Copyright © 2015 Elsevier Ltd. All rights reserved.

Interleukin-17 immunity in pediatric Crohn disease and ulcerative colitis.

PubMed

Hölttä, Veera; Klemetti, Paula; Salo, Harri M; Koivusalo, Antti; Pakarinen, Mikko; Westerholm-Ormio, Mia; Kolho, Kaija-Leena; Vaarala, Outi

2013-09-01

The present understanding of inflammatory bowel disease pathogenesis mainly relies on studies of adult patients. Therefore, we studied the balance between T-effector and regulatory cells in pediatric inflammatory bowel disease. Quantitative polymerase chain reaction and immunohistochemistry served to quantify the expression of immunological markers in mucosal biopsies and flow cytometry analysis was used in peripheral blood mononuclear cells. Colonic interleukin (IL)-17+, IL-22, and IL-6 mRNA upregulation and increase in the number of colonic IL-17 cells were demonstrated in both Crohn disease (CD) and ulcerative colitis (UC). Likewise, colonic forkhead box P3 (FOXP3+) mRNA expression and the number of colonic FOXP3 cells were increased both in CD and in UC and were accompanied in CD also with increased numbers of FOXP3+CD25 High CD4 cells in peripheral blood. Ileal relation of IL-17/CD4 cells was increased only in CD. We showed activation of colonic IL-17/IL-22 axis and upregulation of FOXP3 to occur both in pediatric CD and in UC, indicating shared immunological characteristics. Upregulation of IL-17 was restricted to colon in UC, but existed in the ileum and in the colon in active CD.

[Recent Advances of Researches on Expression, Function and Regulation of CD22].

PubMed

Wu, Xiao-Jing; Shao, Zong-Hong

2015-04-01

CD22 is a type I transmembrane protein expressed on most mature B lymphocyte, and plays a significant role in signal transduction pathways. CD22 acts as a co-receptor of the B-cell receptor (BCR) that inhibits the BCR signaling by antigen-receptor interaction. The phosphorylation of CD22 can be triggered by cross-linking of CD22 with the BCR through antigen, then predominantly triggers the dephosphorylation and inactivation of downstream proteins and inhibit the BCR signaling. Autoimmune disease could be caused by the abnormal expression or dysfunction of CD22 which interrupts BCR signaling and then influences the quantity and function of B cells. The further study of the function and regulation of CD22 would help us understanding the pathogenesis of autoimmune disease and setting theoretical basis for its targeting treatment. In this article, the structure and expression of CD22, the ligands of CD22, the regulation of BCR and transmenbrane signaling, the effect of CD22 on B cells, and CD22 and autoimmune diseases were reviewed.

Phenotype at diagnosis predicts recurrence rates in Crohn's disease

PubMed Central

Wolters, F L; Russel, M G; Sijbrandij, J; Ambergen, T; Odes, S; Riis, L; Langholz, E; Politi, P; Qasim, A; Koutroubakis, I; Tsianos, E; Vermeire, S; Freitas, J; van Zeijl, G; Hoie, O; Bernklev, T; Beltrami, M; Rodriguez, D; Stockbrügger, R W; Moum, B

2006-01-01

Background In Crohn's disease (CD), studies associating phenotype at diagnosis and subsequent disease activity are important for patient counselling and health care planning. Aims To calculate disease recurrence rates and to correlate these with phenotypic traits at diagnosis. Methods A prospectively assembled uniformly diagnosed European population based inception cohort of CD patients was classified according to the Vienna classification for disease phenotype at diagnosis. Surgical and non‐surgical recurrence rates throughout a 10 year follow up period were calculated. Multivariate analysis was performed to classify risk factors present at diagnosis for recurrent disease. Results A total of 358 were classified for phenotype at diagnosis, of whom 262 (73.2%) had a first recurrence and 113 patients (31.6%) a first surgical recurrence during the first 10 years after diagnosis. Patients with upper gastrointestinal disease at diagnosis had an excess risk of recurrence (hazard ratio 1.54 (95% confidence interval (CI) 1.13–2.10)) whereas age ⩾40 years at diagnosis was protective (hazard ratio 0.82 (95% CI 0.70–0.97)). Colonic disease was a protective characteristic for resective surgery (hazard ratio 0.38 (95% CI 0.21–0.69)). More frequent resective surgical recurrences were reported from Copenhagen (hazard ratio 3.23 (95% CI 1.32–7.89)). Conclusions A mild course of disease in terms of disease recurrence was observed in this European cohort. Phenotype at diagnosis had predictive value for disease recurrence with upper gastrointestinal disease being the most important positive predictor. A phenotypic North‐South gradient in CD may be present, illustrated by higher surgery risks in some of the Northern European centres. PMID:16361306

Serum levels of soluble CD30 are increased in ulcerative colitis (UC) but not in Crohn's disease (CD)

PubMed Central

Giacomelli, R; Passacantando, A; Parzanese, I; Vernia, P; Klidara, N; Cucinelli, F; Lattanzio, R; Santori, E; Cipriani, P; Caprilli, R; Tonietti, G

1998-01-01

Imbalance in Th1 and Th2 subsets and their derived cytokines seems to be involved in the immune abnormalities underlying UC and CD. CD30 is a member of the tumour necrosis factor/nerve growth receptor superfamily expressed on T cells producing Th2 cytokines and released as a soluble form. In this study high levels of soluble CD30 were found in sera of UC patients independently of disease activity. Furthermore, increased titres of soluble CD30 molecule were shown, in the same patients, by mitogen-stimulated cultures of peripheral blood mononuclear cells. Our data seem to indicate that an activation of Th2 immune response is involved in the pathogenesis of UC, but not of CD. Furthermore, this finding indicates that serum soluble CD30 measurement may be helpful for differentiating these two forms of inflammatory bowel disease. PMID:9528894

High CD8+ and absence of Foxp3+ T lymphocytes infiltration in gallbladder tumors correlate with prolonged patients survival.

PubMed

Fluxá, Paula; Rojas-Sepúlveda, Daniel; Gleisner, María Alejandra; Tittarelli, Andrés; Villegas, Pablo; Tapia, Loreto; Rivera, María Teresa; López, Mercedes Natalia; Catán, Felipe; Uribe, Mario; Salazar-Onfray, Flavio

2018-03-02

Gallbladder cancer (GBC), although infrequent in industrialized countries, has high incidence rates in certain world regions, being a leading cause of death among elderly Chilean women. Surgery is the only effective treatment, and a five-year survival rate of advanced-stage patients is less than 10%. Hence, exploring immunotherapy is relevant, although GBC immunogenicity is poorly understood. This study examined the relationship between the host immune response and GBC patient survival based on the presence of tumor-infiltrating lymphocytes at different disease stages. Tumor tissues from 80 GBC patients were analyzed by immunohistochemistry for the presence of CD3 + , CD4 + , CD8 + , and Foxp3 + T cell populations, and the results were associated with clinical stage and patient survival. The majority of tumor samples showed CD3 + T cell infiltration, which correlated with better prognosis, particularly in advanced disease stages. CD8 + , but not CD4 + , T cell infiltration correlated with improved survival, particularly in advanced disease stages. Interestingly, a < 1 CD4 + /CD8 + T cell ratio was related with increased survival. Additionally, the presence of Foxp3 + T cells correlated with decreased patient survival, whereas a ≤ 1 Foxp3 + /CD8 + T cell ratio was associated with improved patient survival. Depending on the disease stage, the presence of CD8 + and absence of Foxp3 + T cell populations in tumor tissues correlated with improved GBC patient survival, and thus represent potential markers for prognosis and management of advanced disease, and supports testing of immunotherapy.

Epidemiology of inflammatory bowel disease in racial and ethnic migrant groups

PubMed Central

Misra, Ravi; Faiz, Omar; Munkholm, Pia; Burisch, Johan; Arebi, Naila

2018-01-01

AIM To summarise the current literature and define patterns of disease in migrant and racial groups. METHODS A structured key word search in Ovid Medline and EMBASE was undertaken in accordance with PRISMA guidelines. Studies on incidence, prevalence and disease phenotype of migrants and races compared with indigenous groups were eligible for inclusion. RESULTS Thirty-three studies met the inclusion criteria. Individual studies showed significant differences in incidence, prevalence and disease phenotype between migrants or race and indigenous groups. Pooled analysis could only be undertaken for incidence studies on South Asians where there was significant heterogeneity between the studies [95% for ulcerative colitis (UC), 83% for Crohn’s disease (CD)]. The difference between incidence rates was not significant with a rate ratio South Asian: Caucasian of 0.78 (95%CI: 0.22-2.78) for CD and 1.39 (95%CI: 0.84-2.32) for UC. South Asians showed consistently higher incidence and more extensive UC than the indigenous population in five countries. A similar pattern was observed for Hispanics in the United States. Bangladeshis and African Americans showed an increased risk of CD with perianal disease. CONCLUSION This review suggests that migration and race influence the risk of developing inflammatory bowel disease. This may be due to different inherent responses upon exposure to an environmental trigger in the adopted country. Further prospective studies on homogenous migrant populations are needed to validate these observations, with a parallel arm for in-depth investigation of putative drivers. PMID:29391765

Relationship Between Markers of Platelet Activation and Inflammation with Disease Activity in Wegener’s Granulomatosis

PubMed Central

TOMASSON, GUNNAR; LAVALLEY, MICHAEL; TANRIVERDI, KAHRAMAN; FINKIELMAN, JAVIER D.; DAVIS, JOHN C.; HOFFMAN, GARY S.; McCUNE, W. JOSEPH; St. CLAIR, E. WILLIAM; SPECKS, ULRICH; SPIERA, ROBERT; STONE, JOHN H.; FREEDMAN, JANE E.; MERKEL, PETER A.

2013-01-01

Objective There remains a need for biomarkers to guide therapy in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Our objective was to determine whether measures of platelet activation or inflammation are associated with disease activity in Wegener’s granulomatosis (WG). Methods Study subjects were participants in a clinical trial. Soluble CD40 ligand (sCD40L), C-reactive protein, interleukin 6 (IL-6), IL-8, monocyte chemoattractant protein 1 (MCP-1), P-selectin, vascular endothelial growth factor, and proteinase 3 (PR3)-specific ANCA were measured by ELISA using plasma samples obtained at baseline (active disease), at remission, and prior to, during, and after first flares. Disease activity was assessed by the Birmingham Vasculitis Activity Score for WG (BVAS/WG). Association of biomarkers with disease activity was determined with conditional logistic and linear regression. Results Over a mean followup of 27 months, 180 subjects underwent 2044 visits; markers were measured in 563 samples. Longitudinally, all markers other than IL-6 were associated with disease activity. The strongest associations for active disease at baseline versus remission were observed for sCD40L (OR 4.72, 95% CI 2.47–9.03), P-selectin (OR 6.26, 95% CI 2.78–14.10), PR3-ANCA (OR 9.41, 4.03–21.99), and inversely for MCP-1 (OR 0.36, 95% CI 0.22–0.57). BVAS/WG increased by 0.80 (95% CI 0.44–1.16), 0.83 (95% CI 0.42–1.25), and 0.81 (95% CI 0.48–1.15) per unit-increase in PR3-ANCA, sCD40L, and P-selectin, respectively; and decreased by 1.54 (95% CI 0.96–2.12) per unit-increase in MCP-1. Conclusion Cytokines arising from within the circulation, including those of platelet activation, correlate with disease activity in WG. PMID:21411717

Reduced CD5(+) CD24(hi) CD38(hi) and interleukin-10(+) regulatory B cells in active anti-neutrophil cytoplasmic autoantibody-associated vasculitis permit increased circulating autoantibodies.

PubMed

Aybar, L T; McGregor, J G; Hogan, S L; Hu, Y; Mendoza, C E; Brant, E J; Poulton, C J; Henderson, C D; Falk, R J; Bunch, D O

2015-05-01

Pathogenesis of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis is B cell-dependent, although how particular B cell subsets modulate immunopathogenesis remains unknown. Although their phenotype remains controversial, regulatory B cells (Bregs ), play a role in immunological tolerance via interleukin (IL)-10. Putative CD19(+) CD24(hi) CD38(hi) and CD19(+) CD24(hi) CD27(+) Bregs were evaluated in addition to their CD5(+) subsets in 69 patients with ANCA-associated vasculitis (AAV). B cell IL-10 was verified by flow cytometry following culture with CD40 ligand and cytosine-phosphate-guanosine (CpG) DNA. Patients with active disease had decreased levels of CD5(+) CD24(hi) CD38(hi) B cells and IL-10(+) B cells compared to patients in remission and healthy controls (HCs). As IL-10(+) and CD5(+) CD24(hi) CD38(hi) B cells normalized in remission within an individual, ANCA titres decreased. The CD5(+) subset of CD24(hi) CD38(hi) B cells decreases in active disease and rebounds during remission similarly to IL-10-producing B cells. Moreover, CD5(+) B cells are enriched in the ability to produce IL-10 compared to CD5(neg) B cells. Together these results suggest that CD5 may identify functional IL-10-producing Bregs . The malfunction of Bregs during active disease due to reduced IL-10 expression may thus permit ANCA production. © 2014 British Society for Immunology.

Associations between CD24 gene polymorphisms and inflammatory bowel disease: A meta-analysis.

PubMed

Huang, Xiao-Li; Xu, Dong-Hua; Wang, Guo-Pin; Zhang, Shu; Yu, Cheng-Gong

2015-05-21

To evaluate the relationships between CD24 gene polymorphisms and the risk of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD). The PubMed, Web of Science and Cochrane Library databases were searched (up to May 30, 2014). The search terms "CD24", "inflammatory bowel disease", "Crohn's disease", "Ulcerative colitis", "IBD", "CD" or "UC"; and "polymorphism", "mutation" or "variant" were used. Association studies were limited to the English language, but no limitations in terms of race, ethnicity or geographic area were employed. Stata SE12 software was used to calculate the pooled odds ratios (ORs) with 95% confidence intervals (CIs). P < 0.05 was considered statistically significant. The information was independently extracted from each eligible study by two investigators. Two common polymorphisms, C170T (rs8734) and TG1527del (rs3838646), in the CD24 gene were assessed. A total of three case-control studies including 2342 IBD patients and 1965 healthy controls were involved in this meta-analysis. The patients and controls were from Caucasian cohorts. The three articles included in this meta-analysis all conformed to Hardy-Weinberg equilibrium. This meta-analysis revealed that there were no significant associations between the two CD24 polymorphisms and the risk for IBD (all P > 0.05). However, in a disease subgroup analysis, we found that the CD24 C170T polymorphism was associated with an increased risk of UC in a dominant model (OR = 1.79, 95%CI: 1.15-2.77, P = 0.009) and an additive model (OR = 1.87, 95%CI: 1.19-2.93, P = 0.007), but this relationship was not present for CD. The CD24 TG1570del polymorphism was significantly associated with CD in the additive model (OR = 1.24, 95%CI: 1.01-1.52, P = 0.037). Our findings provide evidence that the CD24 C170T polymorphism might contribute to the susceptibility to UC, and the CD24 TG1527del polymorphism might be associated with the risk of CD.

Inflammatory bowel disease incidence in Czech children: A regional prospective study, 2000-2015

PubMed Central

Schwarz, Jan; Sýkora, Josef; Cvalínová, Dominika; Pomahačová, Renáta; Klečková, Jana; Kryl, Martin; Včelák, Petr

2017-01-01

AIM To examine the incidence and trends in pediatric inflammatory bowel diseases (IBDs) over 2000-2015 and project the incidence to 2018. METHODS A 16-year prospective study of IBD patients < 19 years of age was conducted in the Czech Republic (the Pilsen region). All incident IBD cases within a well-defined geographical area were retrieved from a prospectively collected computerized clinical database. Historical Czech data were used for comparison (1990-2001). Our catchment population was determined from the census data. We calculated the incidence by relating the number of newly diagnosed cases to the size of the pediatric population-at-risk in each calendar year. Age/sex, disease type, place of residence, and race/ethnicity were identified. RESULTS In total, 170 new IBD cases [105 Crohn’s disease (CD), 48 ulcerative colitis (UC), and 17 IBD-unclassified (IBD-U)] were identified. The median age at IBD diagnosis was 14.2 years, 59.4% were males, and 97.1% were Caucasians. A male preponderance of IBD (P = 0.026) and CD (P = 0.016) was observed. With 109209 person-years in the catchment area, the average incidence of IBD per 100000 person-years was 10.0 (6.2 for CD, 2.8 for UC, and 1.0 for IBD-U) for children aged 0 to 19 years; for those aged 0 to 15 years, the incidence rate was 7.3 (4.6 for CD, 2.0 for UC, and 0.7 for IBD-U). An increase in incidence with age was observed (P = 0.0003). Over the 16-year period, the incidence increased for IBD patients (P = 0.01) and CD in particular (P < 0.0001), whereas the incidence for UC (P = 0.09) and IBD-U (P = 0.339) remained unchanged. IBD-projected data from 2016 to 2018 were 12.1, 12.3 and 12.6 per 100000 person-years, respectively. CONCLUSION Pediatric-onset IBD incidence is around its highest point. The increase, which is particularly pronounced for CD, may be challenging to relate to causes of pediatric disease. PMID:28652662

CD4+/CD25(high)/FoxP3+/CD127- regulatory T cells in bronchoalveolar lavage fluid of lung cancer patients.

PubMed

Osińska, Iwona; Stelmaszczyk-Emmel, Anna; Polubiec-Kownacka, Małgorzata; Dziedzic, Dariusz; Domagała-Kulawik, Joanna

2016-10-01

The aim of the study was to compare the presence of regulatory T cells (Tregs) in the local lung cancer environment versus systemic immune response based on the examination of bronchoalveolar lavage fluid (BALf) and peripheral blood (PB) from the same patient. 35 patients with lung cancer were investigated. Flow cytometry method with panel of antibodies: anti CD4/CD25/FoxP3/CD127 for Tregs identification was used. We observed significantly higher proportion of Tregs in the BALF than in PB (median 9.4 vs. 5.4%, p<0.05). The increased proportion of Tregs in patients with advanced disease and in adenocarcinoma was found. This study confirmed the usefulness of BALF analysis in evaluation of immune response in lung cancer. Detection of Tregs in the local tumour environment may have therapeutic relevance in individual indication for anti-cancer immune-therapies. Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

Role of capsule endoscopy in suspected celiac disease: A European multi-centre study

PubMed Central

Luján-Sanchis, Marisol; Pérez-Cuadrado-Robles, Enrique; García-Lledó, Javier; Juanmartiñena Fernández, José-Francisco; Elli, Luca; Jiménez-García, Victoria-Alejandra; Egea-Valenzuela, Juan; Valle-Muñoz, Julio; Carretero-Ribón, Cristina; Fernández-Urién-Sainz, Ignacio; López-Higueras, Antonio; Alonso-Lázaro, Noelia; Sanjuan-Acosta, Mileidis; Sánchez-Ceballos, Francisco; Rosa, Bruno; González-Vázquez, Santiago; Branchi, Federica; Ruano-Díaz, Lucía; Prieto-de-Frías, César; Pons-Beltrán, Vicente; Borque-Barrera, Pilar; González-Suárez, Begoña; Xavier, Sofía; Argüelles-Arias, Federico; Herrerías-Gutiérrez, Juan-Manuel; Pérez-Cuadrado-Martínez, Enrique; Sempere-García-Argüelles, Javier

2017-01-01

AIM To analyze the diagnostic yield (DY), therapeutic impact (TI) and safety of capsule endoscopy (CE). METHODS This is a multi-centre, observational, analytical, retrospective study. A total of 163 patients with suspicion of celiac disease (CD) (mean age = 46.4 ± 17.3 years, 68.1% women) who underwent CE from 2003 to 2015 were included. Patients were divided into four groups: seronegative CD with atrophy (Group-I, n = 19), seropositive CD without atrophy (Group-II, n = 39), contraindication to gastroscopy (Group-III, n = 6), seronegative CD without atrophy, but with a compatible context (Group-IV, n = 99). DY, TI and the safety of CE were analysed. RESULTS The overall DY was 54% and the final diagnosis was villous atrophy (n = 65, 39.9%), complicated CD (n = 12, 7.4%) and other enteropathies (n = 11, 6.8%; 8 Crohn’s). DY for groups I to IV was 73.7%, 69.2%, 50% and 44.4%, respectively. Atrophy was located in duodenum in 24 cases (36.9%), diffuse in 19 (29.2%), jejunal in 11 (16.9%), and patchy in 10 cases (15.4%). Factors associated with a greater DY were positive serology (68.3% vs 49.2%, P = 0.034) and older age (P = 0.008). On the other hand, neither sex nor clinical presentation, family background, positive histology or HLA status were associated with DY. CE results changed the therapeutic approach in 71.8% of the cases. Atrophy was associated with a greater TI (92.3% vs 45.3%, P < 0.001) and 81.9% of the patients responded to diet. There was one case of capsule retention (0.6%). Agreement between CE findings and subsequent histology was 100% for diagnosing normal/other conditions, 70% for suspected CD and 50% for complicated CD. CONCLUSION CE has a high DY in cases of suspicion of CD and it leads to changes in the clinical course of the disease. CE is safe procedure with a high degree of concordance with histology and it helps in the differential diagnosis of CD. PMID:28216978

Comparative analysis of activation induced marker (AIM) assays for sensitive identification of antigen-specific CD4 T cells

PubMed Central

Cirelli, Kimberly M.; Dan, Jennifer M.; Morou, Antigoni; Daigneault, Audrey; Brassard, Nathalie; Silvestri, Guido; Routy, Jean-Pierre; Havenar-Daughton, Colin; Crotty, Shane

2017-01-01

The identification and study of antigen-specific CD4 T cells, both in peripheral blood and in tissues, is key for a broad range of immunological research, including vaccine responses and infectious diseases. Detection of these cells is hampered by both their rarity and their heterogeneity, in particular with regards to cytokine secretion profiles. These factors prevent the identification of the total pool of antigen-specific CD4 T cells by classical methods. We have developed assays for the highly sensitive detection of such cells by measuring the upregulation of surface activation induced markers (AIM). Here, we compare two such assays based on concurrent expression of CD69 plus CD40L (CD154) or expression of OX40 plus CD25, and we develop additional AIM assays based on OX40 plus PD-L1 or 4-1BB. We compare the relative sensitivity of these assays for detection of vaccine and natural infection-induced CD4 T cell responses and show that these assays identify distinct, but overlapping populations of antigen-specific CD4 T cells, a subpopulation of which can also be detected on the basis of cytokine synthesis. Bystander activation had minimal effect on AIM markers. However, some T regulatory cells upregulate CD25 upon antigen stimulation. We therefore validated AIM assays designed to exclude most T regulatory cells, for both human and non-human primate (NHP, Macaca mulatta) studies. Overall, through head-to-head comparisons and methodological improvements, we show that AIM assays represent a sensitive and valuable method for the detection of antigen-specific CD4 T cells. PMID:29065175

Comparative analysis of activation induced marker (AIM) assays for sensitive identification of antigen-specific CD4 T cells.

PubMed

Reiss, Samantha; Baxter, Amy E; Cirelli, Kimberly M; Dan, Jennifer M; Morou, Antigoni; Daigneault, Audrey; Brassard, Nathalie; Silvestri, Guido; Routy, Jean-Pierre; Havenar-Daughton, Colin; Crotty, Shane; Kaufmann, Daniel E

2017-01-01

The identification and study of antigen-specific CD4 T cells, both in peripheral blood and in tissues, is key for a broad range of immunological research, including vaccine responses and infectious diseases. Detection of these cells is hampered by both their rarity and their heterogeneity, in particular with regards to cytokine secretion profiles. These factors prevent the identification of the total pool of antigen-specific CD4 T cells by classical methods. We have developed assays for the highly sensitive detection of such cells by measuring the upregulation of surface activation induced markers (AIM). Here, we compare two such assays based on concurrent expression of CD69 plus CD40L (CD154) or expression of OX40 plus CD25, and we develop additional AIM assays based on OX40 plus PD-L1 or 4-1BB. We compare the relative sensitivity of these assays for detection of vaccine and natural infection-induced CD4 T cell responses and show that these assays identify distinct, but overlapping populations of antigen-specific CD4 T cells, a subpopulation of which can also be detected on the basis of cytokine synthesis. Bystander activation had minimal effect on AIM markers. However, some T regulatory cells upregulate CD25 upon antigen stimulation. We therefore validated AIM assays designed to exclude most T regulatory cells, for both human and non-human primate (NHP, Macaca mulatta) studies. Overall, through head-to-head comparisons and methodological improvements, we show that AIM assays represent a sensitive and valuable method for the detection of antigen-specific CD4 T cells.

Multi-criteria decision analysis and spatial statistic: an approach to determining human vulnerability to vector transmission of Trypanosoma cruzi.

PubMed

Montenegro, Diego; Cunha, Ana Paula da; Ladeia-Andrade, Simone; Vera, Mauricio; Pedroso, Marcel; Junqueira, Angela

2017-10-01

Chagas disease (CD), caused by the protozoan Trypanosoma cruzi, is a neglected human disease. It is endemic to the Americas and is estimated to have an economic impact, including lost productivity and disability, of 7 billion dollars per year on average. To assess vulnerability to vector-borne transmission of T. cruzi in domiciliary environments within an area undergoing domiciliary vector interruption of T. cruzi in Colombia. Multi-criteria decision analysis [preference ranking method for enrichment evaluation (PROMETHEE) and geometrical analysis for interactive assistance (GAIA) methods] and spatial statistics were performed on data from a socio-environmental questionnaire and an entomological survey. In the construction of multi-criteria descriptors, decision-making processes and indicators of five determinants of the CD vector pathway were summarily defined, including: (1) house indicator (HI); (2) triatominae indicator (TI); (3) host/reservoir indicator (Ho/RoI); (4) ecotope indicator (EI); and (5) socio-cultural indicator (S-CI). Determination of vulnerability to CD is mostly influenced by TI, with 44.96% of the total weight in the model, while the lowest contribution was from S-CI, with 7.15%. The five indicators comprise 17 indices, and include 78 of the original 104 priority criteria and variables. The PROMETHEE and GAIA methods proved very efficient for prioritisation and quantitative categorisation of socio-environmental determinants and for better determining which criteria should be considered for interrupting the man-T. cruzi-vector relationship in endemic areas of the Americas. Through the analysis of spatial autocorrelation it is clear that there is a spatial dependence in establishing categories of vulnerability, therefore, the effect of neighbors' setting (border areas) on local values should be incorporated into disease management for establishing programs of surveillance and control of CD via vector. The study model proposed here is flexible and can be adapted to various eco-epidemiological profiles and is suitable for focusing anti-T. cruzi serological surveillance programs in vulnerable human populations.

Circulating Bone Marrow-Derived CD45-/CD34+/CD133+/VEGF+ Endothelial Progenitor Cells in Adults with Crohn's Disease.

PubMed

Boltin, Doron; Kamenetsky, Zvi; Perets, Tsachi Tsadok; Snir, Yifat; Sapoznikov, Boris; Schmilovitz-Weiss, Hemda; Ablin, Jacob Nadav; Dickman, Ram; Niv, Yaron

2017-03-01

Circulating endothelial progenitor cells (EPCs) are bone marrow-derived stem cells able to migrate to sites of damaged endothelium and differentiate into endothelial cells. Altered EPC level and function have been described in various inflammatory diseases and have been shown to augment vasculogenesis in murine models. Previous studies of EPC in the context of Crohn's disease (CD) have yielded conflicting results. To determine whether the circulating levels of EPCs are changed in the context of CD. CD patients and healthy controls were recruited. Disease activity was assessed by CDAI. Peripheral blood mononuclear cells were isolated and EPC numbers evaluated by FACS analysis using anti-CD34, anti-VEGF receptor-2, anti-CD133, and anti-CD45 markers. Eighty-three subjects, including 32 CD patients and 51 controls were recruited, including 19 (59.4 %) and 23 (45 %) males (p = 0.26), aged 34.8 ± 14.9 and 43.3 ± 18.5 years (p = 0.64), in cases and controls, respectively. Mean CDAI was 147 ± 97, disease duration was 12.7 ± 11.1 years, and 28 (87.5 %) were receiving biologics for a mean duration of 21.7 ± 16.8 months. The mean level of peripheral EPCs in CD patients was 0.050 ± 0.086 percent and 0.007 ± 0.013 % in controls (p < 0.01). There was no significant correlation between EPC levels and age (r = -0.13, p = 0.47), CDAI (r = -0.26, p = 0.15), disease duration (r = -0.04, p = 0.84), or duration of treatment with biologics (r = 0.004, p = 0.99). EPCs are elevated in patients with CD. Further studies are needed to examine the function of EPCs and their possible role as a marker of disease severity or therapeutic response.

CD127 and CD25 expression defines CD4+ T cell subsets that are differentially depleted during HIV infection.

PubMed

Dunham, Richard M; Cervasi, Barbara; Brenchley, Jason M; Albrecht, Helmut; Weintrob, Amy; Sumpter, Beth; Engram, Jessica; Gordon, Shari; Klatt, Nichole R; Frank, Ian; Sodora, Donald L; Douek, Daniel C; Paiardini, Mirko; Silvestri, Guido

2008-04-15

Decreased CD4(+) T cell counts are the best marker of disease progression during HIV infection. However, CD4(+) T cells are heterogeneous in phenotype and function, and it is unknown how preferential depletion of specific CD4(+) T cell subsets influences disease severity. CD4(+) T cells can be classified into three subsets by the expression of receptors for two T cell-tropic cytokines, IL-2 (CD25) and IL-7 (CD127). The CD127(+)CD25(low/-) subset includes IL-2-producing naive and central memory T cells; the CD127(-)CD25(-) subset includes mainly effector T cells expressing perforin and IFN-gamma; and the CD127(low)CD25(high) subset includes FoxP3-expressing regulatory T cells. Herein we investigated how the proportions of these T cell subsets are changed during HIV infection. When compared with healthy controls, HIV-infected patients show a relative increase in CD4(+)CD127(-)CD25(-) T cells that is related to an absolute decline of CD4(+)CD127(+)CD25(low/-) T cells. Interestingly, this expansion of CD4(+)CD127(-) T cells was not observed in naturally SIV-infected sooty mangabeys. The relative expansion of CD4(+)CD127(-)CD25(-) T cells correlated directly with the levels of total CD4(+) T cell depletion and immune activation. CD4(+)CD127(-)CD25(-) T cells were not selectively resistant to HIV infection as levels of cell-associated virus were similar in all non-naive CD4(+) T cell subsets. These data indicate that, during HIV infection, specific changes in the fraction of CD4(+) T cells expressing CD25 and/or CD127 are associated with disease progression. Further studies will determine whether monitoring the three subsets of CD4(+) T cells defined based on the expression of CD25 and CD127 should be used in the clinical management of HIV-infected individuals.

CD22 and autoimmune disease.

PubMed

Dörner, Thomas; Shock, Anthony; Smith, Kenneth G C

2012-10-01

CD22 is a 140-kDa member of the Siglec family of cell surface proteins that is expressed by most mature B-cell lineages. As a co-receptor of the B-cell receptor (BCR), it is known to contribute to the sensitive control of the B-cell response to antigen. Cross-linking of CD22 and the BCR by antigen triggers the phosphorylation of CD22, which leads to activation of signaling molecules such as phosphatases. Signal transduction pathways involving CD22 have been explored in a number of mouse models, some of which have provided evidence that in the absence of functional CD22, B cells have a "hyperactivated" phenotype, and suggest that loss of CD22 function could contribute to the pathogenesis of autoimmune diseases. Modulating CD22 activity has therefore been suggested as a possible therapeutic approach to such diseases. For example, the novel CD22-targeting monoclonal antibody epratuzumab is currently under investigation as a treatment for the connective tissue disorder systemic lupus erythematosus (SLE).

Crohn's Disease Candidate Gene Alleles Predict Time to Progression from Inflammatory B1 to Stricturing B2, or Penetrating B3 Phenotype.

PubMed

Pernat Drobež, Cvetka; Ferkolj, Ivan; Potočnik, Uroš; Repnik, Katja

2018-03-01

Crohn's disease (CD) patients are mostly diagnosed with the uncomplicated inflammatory form of disease; however, the majority will progress to complicated stricturing or penetrating disease over time. It is important to identify patients at risk for disease progression at an early stage. The aim of our study was to examine the role of 33 candidate CD genes as possible predictors of disease progression and their influence on time to progression from an inflammatory to a stricturing or penetrating phenotype. Patients with an inflammatory phenotype at diagnosis were followed for 10 years and 33 CD-associated polymorphisms were genotyped. To test for association with CD, 449 healthy individuals were analyzed as the control group. Ten years after diagnosis, 39.1% of patients had not progressed beyond an inflammatory phenotype, but 60.9% had progressed to complicated disease, with average time to progression being 5.91 years. Association analyses of selected single nucleotide polymorphisms (SNPs) confirmed associations with CD for 12 SNPs. Furthermore, seven loci were associated with disease progression, out of which SNP rs4263839 in the gene TNFSF15 showed the strongest association with disease progression and the frameshift mutation rs2066847 in the gene NOD2 showed the strongest association with time to progression. The results of our study identified specific genetic biomarkers as useful predictors of both disease progression and speed of disease progression in patients with CD.

Investigating the feasibility of stem cell enrichment mediated by immobilized selectins.

PubMed

Charles, Nichola; Liesveld, Jane L; King, Michael R

2007-01-01

Hematopoietic stem cell therapy is used to treat both malignant and non-malignant diseases, and enrichment of the hematopoietic stem and progenitor cells (HSPCs) has the potential to reduce the likelihood of graft vs host disease or relapse, potentially fatal complications associated with the therapy. Current commercial HSPC isolation technologies rely solely on the CD34 surface marker, and while they have proven to be invaluable, they can be time-consuming with variable recoveries reported. We propose that selectin-mediated enrichment could prove to be a quick and effective method for recovering HSPCs from adult bone marrow (ABM) on the basis of differences in rolling velocities and independently of CD34 expression. Purified CD34+ ABM cells and the unselected CD34- ABM cells were perfused over immobilized P-, E-, and L-selectin-IgG at physiologic wall shear stresses, and rolling velocities and cell retention data were collected. CD34+ ABM cells generally exhibited lower rolling velocities and higher retention than the unselected CD34- ABM cells on all three selectins. For initial CD34+ ABM cell concentrations ranging from 1% to 5%, we predict an increase in purity ranging from 5.2% to 36.1%, depending on the selectin used. Additionally, selectin-mediated cell enrichment is not limited to subsets of cells with inherent differences in rolling velocities. CD34+ KG1a cells and CD34- HL60 cells exhibited nearly identical rolling velocities on immobilized P-selectin-IgG over the entire range of shear stresses studied. However, when anti-CD34 antibody was co-immobilized with the P-selectin-IgG, the rolling velocity of the CD34+ KG1a cells was significantly reduced, making selectin-mediated cell enrichment a feasible option. Optimal cell enrichment in immobilized selectin surfaces can be achieved within 10 min, much faster than most current commercially available systems.

The prevalence of abnormal celiac antibodies and celiac disease in patients with suspected irritable bowel syndrome: a prospective multi-center US study

PubMed Central

Cash, Brooks D.; Rubenstein, Joel H.; Young, Patrick E.; Gentry, Andrew; Nojkov, Borko; Lee, Dong; Andrews, A. Hirsohi; Dobhan, Richard; Chey, William D.

2011-01-01

Background & Aims Guidelines recommend that patients with symptoms of non-constipated inflammatory bowel syndrome (NC-IBS) undergo testing for celiac disease (CD). We evaluated the prevalence of CD antibodies and biopsy confirmed CD among patients with NC-IBS in a large US population. Methods In a study conducted at 4 sites, from 2003 to 2008, we compared data from 492 patients with symptoms of NC-IBS to 458 asymptomatic individuals who underwent colonoscopy examinations for cancer screening or polyp surveillance (controls). All participants provided blood samples for specific and non-specific CD-associated antibodies. Additionally, patients with IBS were analyzed for complete blood cell counts, metabolic factors, erythrocyte sedimentation rates, and levels of C-reactive protein and thyroid-stimulating hormone. Any subjects found to have CD-associated antibodies were offered esophagogastroduodenoscopy and duodenal biopsy analysis. Results Of patients with NC-IBS, 7.3% had abnormal results in tests for CD-associated antibodies, compared to 4.8% of controls (adjusted odds ratio=1.49; 95% confidence interval, 0.76–2.90. P=.25). Within the NC-IBS group, 6.51% had antibodies against gliadin, 1.22% against tissue transglutaminase, and 0.61% against endomysium (P>.05 vs controls for all antibodies tested). CD was confirmed in 0.41% of patients in the NC-IBS group and 0.44% of controls (P>0.99). Conclusions Although CD-associated antibodies are relatively common, the prevalence of CD among patients with NC-IBS is similar to that among controls in a large US population. These findings challenge recommendations to routinely screen patients with NC-IBS for CD. More than 7% of patients with NC-IBS had CD-associated antibodies, indicating that gluten sensitivity might mediate IBS symptoms; further studies are needed. PMID:21762658

Isolation of CD4+CD25+ regulatory T cells for clinical trials.

PubMed

Hoffmann, Petra; Boeld, Tina J; Eder, Ruediger; Albrecht, Julia; Doser, Kristina; Piseshka, Biserka; Dada, Ashraf; Niemand, Claudia; Assenmacher, Mario; Orsó, Evelyn; Andreesen, Reinhard; Holler, Ernst; Edinger, Matthias

2006-03-01

The adoptive transfer of donor CD4+CD25+ regulatory T cells has been shown to protect from lethal graft-versus-host disease after allogeneic bone marrow transplantation in murine disease models. Efficient isolation strategies that comply with good manufacturing practice (GMP) guidelines are prerequisites for the clinical application of human CD4+CD25+ regulatory T cells. Here we describe the isolation of CD4+CD25+ T cells with regulatory function from standard leukapheresis products by using a 2-step magnetic cell-separation protocol performed under GMP conditions. The generated cell products contained on average 49.5% CD4+CD25high T cells that phenotypically and functionally represented natural CD4+CD25+ regulatory T cells and showed a suppressive activity comparable to that of CD4+CD25+ regulatory T-cell preparations purified by non-GMP-approved fluorescence-activated cell sorting.

CD27-CD70 interactions in the pathogenesis of Waldenstrom macroglobulinemia.

PubMed

Ho, Allen W; Hatjiharissi, Evdoxia; Ciccarelli, Bryan T; Branagan, Andrew R; Hunter, Zachary R; Leleu, Xavier; Tournilhac, Olivier; Xu, Lian; O'Connor, Kelly; Manning, Robert J; Santos, Daniel Ditzel; Chemaly, Mariana; Patterson, Christopher J; Soumerai, Jacob D; Munshi, Nikhil C; McEarchern, Julie A; Law, Che-Leung; Grewal, Iqbal S; Treon, Steven P

2008-12-01

Waldenström macroglobulinemia (WM) is a B-cell malignancy characterized by an IgM monoclonal gammopathy and bone marrow (BM) infiltration with lymphoplasmacytic cells (LPCs). Excess mast cells (MCs) are commonly present in WM, and provide growth and survival signals to LPCs through several TNF family ligands (CD40L, a proliferation-inducing ligand [APRIL], and B-lymphocyte stimulator factor [BLYS]). As part of these studies, we demonstrated that WM LPCs secrete soluble CD27 (sCD27), which is elevated in patients with WM (P < .001 vs healthy donors), and serves as a faithful marker of disease. Importantly, sCD27 stimulated expression of CD40L on 10 of 10 BM MC samples and APRIL on 4 of 10 BM MC samples obtained from patients with WM as well as on LAD2 MCs. Moreover, the SGN-70 humanized monoclonal antibody, which binds to CD70 (the receptor-ligand partner of CD27), abrogated sCD27 mediated up-regulation of CD40L and APRIL on WM MCs. Last, treatment of severe combined immunodeficiency-human (SCID-hu) mice with established WM using the SGN-70 antibody blocked disease progression in 12 of 12 mice, whereas disease progressed in all 5 untreated mice. The results of these studies demonstrate a functional role for sCD27 in WM pathogenesis, along with its utility as a surrogate marker of disease and a target in the treatment of WM.

Fibrocyte measurement in peripheral blood correlates with number of cultured mature fibrocytes in vitro and is a potential biomarker for interstitial lung disease in Rheumatoid Arthritis.

PubMed

Just, Søren Andreas; Lindegaard, Hanne; Hejbøl, Eva Kildall; Davidsen, Jesper Rømhild; Bjerring, Niels; Hansen, Søren Werner Karlskov; Schrøder, Henrik Daa; Hansen, Inger Marie Jensen; Barington, Torben; Nielsen, Christian

2017-07-18

Interstitial lung disease (ILD) can be a severe extra-articular disease manifestation in Rheumatoid Arthritis (RA). A potential role of fibrocytes in RA associated ILD (RA-ILD) has not previously been described. We present a modified faster method for measuring circulating fibrocytes, without intracellular staining. The results are compared to the traditional culture method, where the number of monocytes that differentiate into mature fibrocytes in vitro are counted. The results are following compared to disease activity in patients with severe asthma, ILD, RA (without diagnosed ILD) and RA with verified ILD (RA-ILD). CD45 + CD34 + CD11b + (7-AAD - CD3 - CD19 - CD294 - ) cells were isolated by cell sorting and stained for pro-collagen type 1. Thirty-nine patients (10 RA, 9 ILD and 10 with severe asthma, 10 with RA-ILD) and 10 healthy controls (HC) were included. Current medication, disease activity, pulmonary function test and radiographic data were collected. Circulating fibrocytes were quantified by flow cytometry. Peripheral blood mononuclear cells were isolated and cultured for 5 days and the numbers of mature fibrocytes were counted. 90.2% (mean, SD = 1.5%) of the sorted cells were pro-collagen type 1 positive and thereby fulfilled the criteria for being circulating fibrocytes. The ILD and RA-ILD groups had increased levels of circulating fibrocytes compared to HC (p < 0.05). Levels of circulating fibrocytes correlated overall to number of monocytes that subsequently in vitro differentiated to mature fibrocytes (r = 0.81, p < 0.001). RA patients with pathologically reduced diffusion capacity for carbon monoxide adjusted for hemoglobin (DLCO c ) in both the RA and in the combined RA + RA-ILD group, had significantly higher levels of both circulating and number of cultured mature fibrocytes (both p < 0.05). In both groups, the level of circulating fibrocytes and number of mature fibrocytes in culture also correlated to a reduction in DLCO c (r = -0.61 an r = -0.58 both p < 0.05). We presented a fast and valid method for measuring circulating fibrocytes using flow cytometry on lysed peripheral blood. Further, we showed for the first time, that the level of circulating fibrocytes correlated with the number of peripheral blood mononuclear cells, that differentiated into mature fibrocytes in vitro. Reduced DLCO c was correlated with high levels of circulating and mature fibrocytes in RA, which have not been reported previously. In such, this study suggests that fibrocytes may exhibit an important role in the pathogenesis of RA-ILD, which requires further clarification in future studies. ClinicalTrials.gov : NCT02711657 , registered 13/3-2016, retrospectively registered.

Development of the Paris definition of early Crohn's disease for disease-modification trials: results of an international expert opinion process.

PubMed

Peyrin-Biroulet, Laurent; Billioud, Vincent; D'Haens, Geert; Panaccione, Remo; Feagan, Brian; Panés, Julian; Danese, Silvio; Schreiber, Stefan; Ogata, Haruhiko; Hibi, Toshifumi; Higgins, Peter D R; Beaugerie, Laurent; Chowers, Yehuda; Louis, Edouard; Steinwurz, Flávio; Reinisch, Walter; Rutgeerts, Paul; Colombel, Jean-Frédéric; Travis, Simon; Sandborn, William J

2012-12-01

We report the findings and outputs of an international expert opinion process to develop a definition of early Crohn's disease (CD) that could be used in future disease-modification trials. Nineteen experts on inflammatory bowel diseases held an international expert opinion meeting to discuss and agree on a definition for early CD to be used in disease-modification trials. The process included literature searches for the relevant basic-science and clinical evidence. A published preliminary definition of early CD was used as the basis for development of a proposed definition that was discussed at the expert opinion meeting. The participants then derived a final definition, based on best current knowledge, that it is hoped will be of practical use in disease-modification trials in CD.

Nutritional status, growth and disease management in children with single and dual diagnosis of type 1 diabetes mellitus and coeliac disease.

PubMed

Mackinder, Mary; Allison, Gavin; Svolos, Vaios; Buchanan, Elaine; Johnston, Alison; Cardigan, Tracey; Laird, Nicola; Duncan, Hazel; Fraser, Karen; Edwards, Christine A; Craigie, Ian; McGrogan, Paraic; Gerasimidis, Konstantinos

2014-05-28

The consequences of subclinical coeliac disease (CD) in Type 1 diabetes mellitus (T1DM) remain unclear. We looked at growth, anthropometry and disease management in children with dual diagnosis (T1DM + CD) before and after CD diagnosis. Anthropometry, glycated haemoglobin (HbA1c) and IgA tissue transglutaminase (tTg) were collected prior to, and following CD diagnosis in 23 children with T1DM + CD. This group was matched for demographics, T1DM duration, age at CD diagnosis and at T1DM onset with 23 CD and 44 T1DM controls. No differences in growth or anthropometry were found between children with T1DM + CD and controls at any time point. Children with T1DM + CD, had higher BMI z-score two years prior to, than at CD diagnosis (p < 0.001). BMI z-score change one year prior to CD diagnosis was lower in the T1DM + CD than the T1DM group (p = 0.009). At two years, height velocity and change in BMI z-scores were similar in all groups. No differences were observed in HbA1c between the T1DM + CD and T1DM groups before or after CD diagnosis. More children with T1DM + CD had raised tTg levels one year after CD diagnosis than CD controls (CDx to CDx + 1 yr; T1DM + CD: 100% to 71%, p = 0.180 and CD: 100% to 45%, p < 0.001); by two years there was no difference. No major nutrition or growth deficits were observed in children with T1DM + CD. CD diagnosis does not impact on T1DM glycaemic control. CD specific serology was comparable to children with single CD, but those with dual diagnosis may need more time to adjust to gluten free diet.

Crohn's Disease: Genetics Update.

PubMed

Wang, Ming-Hsi; Picco, Michael F

2017-09-01

Since the discovery of the first Crohn's disease (CD) gene NOD2 in 2001, 140 genetic loci have been found in whites using high-throughput genome-wide association studies. Several genes influence the CD subphenotypes and treatment response. With the observations of increasing prevalence in Asia and developing countries and the incomplete explanation of CD variance, other underexplored areas need to be integrated through novel methodologies. Algorithms that incorporate specific genetic risk alleles with other biomarkers will be developed and used to predict CD disease course, complications, and response to specific therapies, allowing precision medicine to become real in CD. Copyright © 2017 Elsevier Inc. All rights reserved.

Evaluation of Antibody Response to Polysaccharide Vaccine and Switched Memory B Cells in Pediatric Patients with Inflammatory Bowel Disease

PubMed Central

Fallahi, Gholamhossein; Khodadad, Ahmad; Hashemi, Mojtaba; Mohammadinejad, Payam; Asgarian-Omran, Hossein; Najafi, Mehri; Farhmand, Fatemeh; Motamed, Farzaneh; Soleimani, Khadije; Soheili, Habib; Parvaneh, Nima; Darabi, Behzad; Nasiri Kalmarzi, Rasoul; Pourhamdi, Shabnam; Abolhassani, Hassan; Mirminachi, Babak; Rezaei, Nima

2014-01-01

Background/Aims Inflammatory bowel disease (IBD) is a chronic disease of the gastrointestinal tract, whose etiologies are still unknown. This study was performed to evaluate the humoral immune response in terms of B cell functions in selected IBD patients. Methods Eighteen pediatric patients with IBD, including 12 cases of ulcerative colitis (UC) and six with Crohn disease (CD), were enrolled in this study. The pneumococcal vaccine was injected in all patients, and the IgG antibody level to the polysaccharide antigen was measured before and 4 weeks after injection. The B cell switch-recombination process was evaluated. Results Five patients with IBD (three CD and two UC) had defects in B cell switching, which was significantly higher than in controls (p=0.05). Ten patients had a specific antibody deficiency and exhibited a higher frequency of bacterial infection than the healthy group. The mean increased level of IgG after vaccination was lower in IBD patients (82.9±32.5 µg/mL vs 219.8±59.0 µg/mL; p=0.001). Among the patients who had an insufficient response, no significant difference in the number of switched memory B-cell was observed. Conclusions A defect in B lymphocyte switching was observed in pediatric IBD patients, and especially in those patients with CD. Owing to an increased risk of bacterial infections in those patients with antibody production defects, pneumococcal vaccination could be recommended. However, not all patients can benefit from the vaccination, and several may require other prophylactic methods. PMID:24516697

Blood-based biomarkers used to predict disease activity in Crohn's disease and ulcerative colitis.

PubMed

Burakoff, Robert; Pabby, Vikas; Onyewadume, Louisa; Odze, Robert; Adackapara, Cheryl; Wang, Wei; Friedman, Sonia; Hamilton, Matthew; Korzenik, Joshua; Levine, Jonathan; Makrauer, Frederick; Cheng, Changming; Smith, Hai Choo; Liew, Choong-Chin; Chao, Samuel

2015-05-01

Identifying specific genes that are differentially expressed during inflammatory bowel disease flares may help stratify disease activity. The aim of this study was to identify panels of genes to be able to distinguish disease activity in Crohn's disease (CD) and ulcerative colitis (UC). Patients were grouped into categories based on disease and severity determined by histological grading. Whole blood was collected by PAXgene Blood RNA collection tubes, (PreAnalytiX) and gene expression analysis using messenger RNA was conducted. Logistic regression was performed on multiple combinations of common probe sets, and data were evaluated in terms of discrimination by computing the area under the receiving operator characteristic curve (ROC-AUC). Nine inactive CD, 8 mild CD, 10 moderate-to-severe CD, 9 inactive UC, 8 mild UC, 10 moderate-to-severe UC, and 120 controls were hybridized to Affymetrix U133 Plus 2 microarrays. Panels of 6 individual genes discriminated the stages of disease activity: CD with mild severity {ROC-AUC, 0.89 (95% confidence interval [CI], 0.84%-0.95%)}, CD with moderate-to-severe severity (ROC-AUC 0.98 [95% CI, 0.97-1.0]), UC with mild severity (ROC-AUC 0.92 [95% CI, 0.87-0.96]), and UC with moderate-to-severe severity (ROC-AUC 0.99 [95% CI, 0.97-1.0]). Validation by real-time reverse transcription-PCR confirmed the Affymetrix microarray data. The specific whole blood gene panels reliably distinguished CD and UC and determined the activity of disease, with high sensitivity and specificity in our cohorts of patients. This simple serological test has the potential to become a biomarker to determine the activity of disease.

Soluble CD26/CD30 levels in visceral leishmaniasis: markers of disease activity

PubMed Central

Ajdary, S; Riazi-Rad, F; Jafari-Shakib, R; Mohebbali, M

2006-01-01

Leishmania infantum is the causative agent of zoonotic visceral leishmaniasis (VL). If untreated the disease could be fatal; however, in some cases the infection can run a subclinical course. In subclinical infections a Th1-response predominates, while Th2-responses and/or probably Treg cells are related to unfavourable outcome of the disease in active VL. In the present study we determined the levels of soluble (s) CD26 and CD30 co-stimulatory molecules in sera from patients with active VL, asymptomatic individuals and healthy volunteers. Results showed a significant difference in both sCD26 and sCD30 between infected cases and normal individuals (P ≤ 0·001). However, there was no significant difference in sCD26 levels between asymptomatic cases and patients, although the difference was not significant. sCD30 levels were significantly higher in VL patients than asymptomatic cases (P ≤ 0·001). These findings suggest a possible association between sCD26 and sCD30 levels and the clinical manifestation of L. infantum infection. PMID:16792672

Chronic disease management items in general practice: a population-based study of variation in claims by claimant characteristics.

PubMed

Douglas, Kirsty A; Yen, Laurann E; Korda, Rosemary J; Kljakovic, Marjan; Glasgow, Nicholas J

2011-08-15

To describe how Medical Benefits Schedule (MBS) chronic disease (CD) item claims vary by sociodemographic and health characteristics in people with heart disease, asthma or diabetes. A cross-sectional analysis of linked unit-level MBS and survey data from the first 102,934 participants enrolled in the 45 and Up Study, a large-scale cohort study in New South Wales, who completed the baseline survey between January 2006 and July 2008. Claim for any general practitioner CD item within 18 months before enrolment, ascertained from MBS records. The proportion of individuals making claims for MBS CD items was 18.5% for asthma, 22.3% for heart disease, and 44.9% for diabetes. Associations between participant characteristics and a claim for a CD item showed similar patterns across the three diseases. For heart disease and asthma, people most likely to claim a CD item were women, older, of low income and education levels, with multiple chronic conditions, fair or poor self-rated health, obesity and low physical activity levels. The pattern of claims was slightly different for participants with diabetes in that there was no significant association with number of chronic conditions, smoking or physical activity. Many individuals with self-reported CD do not claim CD items. People with diabetes and individuals with greatest need based on health, socioeconomic and lifestyle risk factors are the most likely to claim CD items.

BIOCHEMICAL CONTROL DURING LONG-TERM FOLLOW-UP OF 230 ADULT PATIENTS WITH CUSHING DISEASE: A MULTICENTER RETROSPECTIVE STUDY.

PubMed

Geer, Eliza B; Shafiq, Ismat; Gordon, Murray B; Bonert, Vivien; Ayala, Alejandro; Swerdloff, Ronald S; Katznelson, Laurence; Lalazar, Yelena; Manuylova, Ekaterina; Pulaski-Liebert, Karen J; Carmichael, John D; Hannoush, Zeina; Surampudi, Vijaya; Broder, Michael S; Cherepanov, Dasha; Eagan, Marianne; Lee, Jackie; Said, Qayyim; Neary, Maureen P; Biller, Beverly M K

2017-08-01

Cushing disease (CD) results from excessive exposure to glucocorticoids caused by an adrenocorticotropic hormone-secreting pituitary tumor. Inadequately treated CD is associated with significant morbidity and elevated mortality. Multicenter data on CD patients treated in routine clinical practice are needed to assess treatment outcomes in this rare disorder. The study purpose was to describe the burden of illness and treatment outcomes for CD patients. Eight pituitary centers in four U.S. regions participated in this multicenter retrospective chart review study. Subjects were CD patients diagnosed at ≥18 years of age within the past 20 years. Descriptive statistical analyses were conducted to examine presenting signs, symptoms, comorbidities, and treatment outcomes. Of 230 patients, 79% were female (median age at diagnosis, 39 years; range, 18 to 78 years). Length of follow-up was 0 to 27.5 years (median, 1.9 years). Pituitary adenomas were 0 to 51 mm. The most common presenting comorbidities included hypertension (67.3%), polycystic ovary syndrome (43.5%), and hyperlipidemia (41.5%). Biochemical control was achieved with initial pituitary surgery in 41.4% patients (91 of 220), not achieved in 50.0% of patients (110 of 220), and undetermined in 8.6% of patients (19 of 220). At the end of follow-up, control had been achieved with a variety of treatment methods in 49.1% of patients (110 of 224), not achieved in 29.9% of patients (67 of 224), and undetermined in 21.0% of patients (47 of 224). Despite multiple treatments, at the end of follow-up, biochemical control was still not achieved in up to 30% of patients. These multicenter data demonstrate that in routine clinical practice, initial and long-term control is not achieved in a substantial number of patients with CD. BLA = bilateral adrenalectomy CD = Cushing disease CS = Cushing syndrome eCRF = electronic case report form MRI = magnetic resonance imaging PCOS = polycystic ovary syndrome.

Nutritional status of children with inflammatory bowel disease in Saudi Arabia

PubMed Central

El Mouzan, Mohammad Issa; Al Edreesi, Mohammed Hadi; Al-Hussaini, Abdulrahman Abdullah; Saadah, Omar Ibrahim; Al Qourain, Abdulaziz Abdullatif; Al Mofarreh, Mohammad Abdullah; Al Saleem, Khalid Abdulrahman

2016-01-01

AIM: To assess the prevalence of nutritional disorders in children with inflammatory bowel disease (IBD) in Saudi Arabia. METHODS: The data from a national cohort of children newly diagnosed with IBD between 2003 and 2012 were analyzed. The diagnosis of IBD and the differentiation between Crohn’s disease (CD) and ulcerative colitis (UC) were confirmed by gastroenterologists according to the standard criteria. The body mass index (BMI) of each child [weight (kg)/height2 (m)] was calculated at the time of diagnosis. The World Health Organization standards and references were used and the BMI for age > +1 and < -2 standard deviation score were used to define overweight and thinness, respectively. Age stratification analysis was performed to investigate any age-related variation in the prevalence of nutritional status between children < 10 years of age and older. RESULTS: There were 374 children from 0.33 to 17 years of age, including 119 (32%) children with UC and 255 (68%) with CD. All of the children were Saudi nationals, and 68 (57%) of the UC and 150 (59%) of the CD children were males. A positive history of anorexia at the time of diagnosis was found in 30 (25%) patients with UC and 99 (39%) patients with CD. The prevalence of thinness was 31%, 35% and 24% in children with IBD, CD and UC, respectively, with a significantly higher prevalence of thinness in children with CD than in children with UC (P = 0.037) only in the age group of 10-17 years (P = 0.030). The prevalence of overweight was 16 %, 15% and 20 % in the children with IBD, CD and UC, respectively, indicating a higher prevalence in UC that was statistically significant only in the age group of 10-17 years (P = 0.020). CONCLUSION: A high proportion of children with IBD presented with overweight instead of the classical underweight. Awareness of this finding is important for patient care. PMID:26855544

Artificial intelligence techniques applied to the development of a decision-support system for diagnosing celiac disease.

PubMed

Tenório, Josceli Maria; Hummel, Anderson Diniz; Cohrs, Frederico Molina; Sdepanian, Vera Lucia; Pisa, Ivan Torres; de Fátima Marin, Heimar

2011-11-01

Celiac disease (CD) is a difficult-to-diagnose condition because of its multiple clinical presentations and symptoms shared with other diseases. Gold-standard diagnostic confirmation of suspected CD is achieved by biopsying the small intestine. To develop a clinical decision-support system (CDSS) integrated with an automated classifier to recognize CD cases, by selecting from experimental models developed using intelligence artificial techniques. A web-based system was designed for constructing a retrospective database that included 178 clinical cases for training. Tests were run on 270 automated classifiers available in Weka 3.6.1 using five artificial intelligence techniques, namely decision trees, Bayesian inference, k-nearest neighbor algorithm, support vector machines and artificial neural networks. The parameters evaluated were accuracy, sensitivity, specificity and area under the ROC curve (AUC). AUC was used as a criterion for selecting the CDSS algorithm. A testing database was constructed including 38 clinical CD cases for CDSS evaluation. The diagnoses suggested by CDSS were compared with those made by physicians during patient consultations. The most accurate method during the training phase was the averaged one-dependence estimator (AODE) algorithm (a Bayesian classifier), which showed accuracy 80.0%, sensitivity 0.78, specificity 0.80 and AUC 0.84. This classifier was integrated into the web-based decision-support system. The gold-standard validation of CDSS achieved accuracy of 84.2% and k=0.68 (p<0.0001) with good agreement. The same accuracy was achieved in the comparison between the physician's diagnostic impression and the gold standard k=0. 64 (p<0.0001). There was moderate agreement between the physician's diagnostic impression and CDSS k=0.46 (p=0.0008). The study results suggest that CDSS could be used to help in diagnosing CD, since the algorithm tested achieved excellent accuracy in differentiating possible positive from negative CD diagnoses. This study may contribute towards developing of a computer-assisted environment to support CD diagnosis. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Associations between STAT3 rs744166 Polymorphisms and Susceptibility to Ulcerative Colitis and Crohn's Disease: A Meta-Analysis

PubMed Central

Peng, Xiulan; Song, Jia; Wang, Jun; Dong, Weiguo

2014-01-01

Background Many studies have investigated the associations between the signal transducer and activator of transcription 3 (STAT3) in the susceptibility to ulcerative colitis (UC) and Crohn's disease (CD). However, the results remain inconsistent. This meta-analysis determined the risk of STAT3 rs744166 polymorphism-conferred UC and CD susceptibility. Materials and Methods Electronic databases, including PubMed, EMBASE and the Cochrane Library, were searched for all eligible studies that evaluated the association between STAT3 rs744166 polymorphisms with UC and CD risk up to August 21, 2014. The pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using fixed- or random-effects models. Results Twelve studies containing 10298 patients with CD, 4244 patients with UC and 11191 controls were included in this meta-analysis. The results indicated that the STAT3 rs744166 polymorphism was associated with CD and UC susceptibility (CD: GA+AA vs. GG, OR = 1.20, 95%CI, 1.11–1.30, I 2 = 0%, P unadjusted<0.00001, P Bonferroni<0.00005, P FDR<0.00001; UC: GA+AA vs. GG, OR = 1.21, 95%CI, 1.08–1.36, I 2 = 1%, P unadjusted = 0.001, P Bonferroni = 0.005, P FDR = 0.00125). In subgroup analyses by ethnicity, the significant association was found only among Caucasians. However, when grouped by age of onset, positive associations were found both among adults and children. In addition, when stratified by study design and genotyping methods, the risk of CD was significantly associated with the STAT3 rs744166 polymorphism in hospital-based and population-based groups and in SNP Array and SNPlex groups. For UC, significant associations were also found in population-based, PCR-RFLP and SNPlex groups. Moreover, these findings were sufficiently robust to withstand the Bonferroni correction and false discovery rate (FDR). Conclusion This meta-analysis indicates that carriers of the STAT3 rs744166 ‘A’ allele have a significantly greater risk of CD and UC, especially among Caucasians. PMID:25286337

Method for semi-automated microscopy of filtration-enriched circulating tumor cells.

PubMed

Pailler, Emma; Oulhen, Marianne; Billiot, Fanny; Galland, Alexandre; Auger, Nathalie; Faugeroux, Vincent; Laplace-Builhé, Corinne; Besse, Benjamin; Loriot, Yohann; Ngo-Camus, Maud; Hemanda, Merouan; Lindsay, Colin R; Soria, Jean-Charles; Vielh, Philippe; Farace, Françoise

2016-07-14

Circulating tumor cell (CTC)-filtration methods capture high numbers of CTCs in non-small-cell lung cancer (NSCLC) and metastatic prostate cancer (mPCa) patients, and hold promise as a non-invasive technique for treatment selection and disease monitoring. However filters have drawbacks that make the automation of microscopy challenging. We report the semi-automated microscopy method we developed to analyze filtration-enriched CTCs from NSCLC and mPCa patients. Spiked cell lines in normal blood and CTCs were enriched by ISET (isolation by size of epithelial tumor cells). Fluorescent staining was carried out using epithelial (pan-cytokeratins, EpCAM), mesenchymal (vimentin, N-cadherin), leukocyte (CD45) markers and DAPI. Cytomorphological staining was carried out with Mayer-Hemalun or Diff-Quik. ALK-, ROS1-, ERG-rearrangement were detected by filter-adapted-FISH (FA-FISH). Microscopy was carried out using an Ariol scanner. Two combined assays were developed. The first assay sequentially combined four-color fluorescent staining, scanning, automated selection of CD45(-) cells, cytomorphological staining, then scanning and analysis of CD45(-) cell phenotypical and cytomorphological characteristics. CD45(-) cell selection was based on DAPI and CD45 intensity, and a nuclear area >55 μm(2). The second assay sequentially combined fluorescent staining, automated selection of CD45(-) cells, FISH scanning on CD45(-) cells, then analysis of CD45(-) cell FISH signals. Specific scanning parameters were developed to deal with the uneven surface of filters and CTC characteristics. Thirty z-stacks spaced 0.6 μm apart were defined as the optimal setting, scanning 82 %, 91 %, and 95 % of CTCs in ALK-, ROS1-, and ERG-rearranged patients respectively. A multi-exposure protocol consisting of three separate exposure times for green and red fluorochromes was optimized to analyze the intensity, size and thickness of FISH signals. The semi-automated microscopy method reported here increases the feasibility and reliability of filtration-enriched CTC assays and can help progress towards their validation and translation to the clinic.

Exclusion-Based Capture and Enumeration of CD4+ T Cells from Whole Blood for Low-Resource Settings.

PubMed

Howard, Alexander L; Pezzi, Hannah M; Beebe, David J; Berry, Scott M

2014-06-01

In developing countries, demand exists for a cost-effective method to evaluate human immunodeficiency virus patients' CD4(+) T-helper cell count. The TH (CD4) cell count is the current marker used to identify when an HIV patient has progressed to acquired immunodeficiency syndrome, which results when the immune system can no longer prevent certain opportunistic infections. A system to perform TH count that obviates the use of costly flow cytometry will enable physicians to more closely follow patients' disease progression and response to therapy in areas where such advanced equipment is unavailable. Our system of two serially-operated immiscible phase exclusion-based cell isolations coupled with a rapid fluorescent readout enables exclusion-based isolation and accurate counting of T-helper cells at lower cost and from a smaller volume of blood than previous methods. TH cell isolation via immiscible filtration assisted by surface tension (IFAST) compares well against the established Dynal T4 Quant Kit and is sensitive at CD4 counts representative of immunocompromised patients (less than 200 TH cells per microliter of blood). Our technique retains use of open, simple-to-operate devices that enable IFAST as a high-throughput, automatable sample preparation method, improving throughput over previous low-resource methods. © 2013 Society for Laboratory Automation and Screening.

Management of Crohn's disease in Taiwan: consensus guideline of the Taiwan Society of Inflammatory Bowel Disease

PubMed Central

Wei, Shu-Chen; Chang, Ting-An; Chao, Te-Hsin; Chen, Jinn-Shiun; Chou, Jen-Wei; Chou, Yenn-Hwei; Chuang, Chiao-Hsiung; Hsu, Wen-Hung; Huang, Tien-Yu; Hsu, Tzu-Chi; Lin, Chun-Chi; Lin, Hung-Hsin; Lin, Jen-Kou; Lin, Wei-Chen; Ni, Yen-Hsuan; Shieh, Ming-Jium; Shih, I-Lun; Shun, Chia-Tung; Tsang, Yuk-Ming; Wang, Cheng-Yi; Wang, Horng-Yuan; Weng, Meng-Tzu; Wu, Deng-Chyang; Wu, Wen-Chieh; Yen, Hsu-Heng

2017-01-01

Crohn's disease (CD) is a chronic relapsing and remitting inflammatory disease of the gastrointestinal tract. CD is rare in Taiwan and other Asian countries, but its prevalence and incidence have been steadily increasing. A steering committee was established by the Taiwan Society of Inflammatory Bowel Disease to formulate statements on the diagnosis and management of CD taking into account currently available evidence and the expert opinion of the committee. Thorough clinical, endoscopic, and histological assessments are required for accurate diagnosis of CD. Computed tomography and magnetic resonance imaging are complementary to endoscopic evaluation for disease staging and detecting complications. The goals of CD management are to induce and maintain remission, reduce the risk of complications, and improve quality of life. Corticosteroids are the mainstay for inducing re-mission. Immunomodulating and biologic therapies should be used to maintain remission. Patients should be evaluated for hepatitis B virus and tuberculosis infection prior to treatment and receive regular surveillance for cancer. These consensus statements are based on current local evidence with consideration of factors, and could be serve as concise and practical guidelines for supporting clinicians in the management of patients with CD in Taiwan. PMID:28670226

The Innate Immune Receptor CD14 Mediates Lymphocyte Migration in EAE.

PubMed

Halmer, Ramona; Davies, Laura; Liu, Yang; Fassbender, Klaus; Walter, Silke

2015-01-01

Multiple sclerosis is the most common autoimmune disease of the central nervous system in young adults and histopathologically characterized by inflammation, demyelination and gliosis. It is considered as a CD4+ T cell-mediated disease, but also a disease-promoting role of the innate immune system has been proposed, based e.g. on the observation that innate immune receptors modulate disease severity of experimental autoimmune encephalomyelitis. Recent studies of our group provided first evidence for a key role of the innate immune LPS receptor (CD14) in pathophysiology of experimental autoimmune encephalomyelitis. CD14-deficient experimental autoimmune encephalomyelitis mice showed increased clinical symptoms and enhanced infiltration of monocytes and neutrophils in brain and spinal cord. In the current study, we further investigated the causes of the disease aggravation by CD14-deficiency and examined T cell activation, also focusing on the costimulatory molecules CTLA-4 and CD28, and T cell migration capacity over the blood brain barrier by FACS analysis, in vitro adhesion and transmigration assays. In the results, we observed a significantly increased migration of CD14-deficient lymphocytes across an endothelial monolayer. In contrast, we did not see any differences in expression levels of TCR/CTLA-4 or TCR/CD28 and lymphocyte adhesion to endothelial cells from CD14-deficient compared to wildtype mice. The results demonstrate an important role of CD14 in migration of lymphocytes, and strengthen the importance of innate immune receptors in adaptive immune disorders, such as multiple sclerosis. © 2015 The Author(s) Published by S. Karger AG, Basel.

Efficacy of vedolizumab as induction therapy in refractory IBD patients: Amulticenter cohort

PubMed Central

Shelton, Edward; Allegretti, Jessica R.; Stevens, Betsy; Lucci, Matthew; Khalili, Hamed; Nguyen, Deanna D.; Sauk, Jenny; Giallourakis, Cosmas; Garber, John; Hamilton, Matthew J; Tomczak, Michal; Makrauer, Fredrick; Burakoff, Robert B; Levine, Jonathan; de Silva, Punyaganie; Friedman, Sonia; Ananthakrishnan, Ashwin; Korzenik, Joshua R.; Yajnik, Vijay

2015-01-01

Background Vedolizumab (VDZ) demonstrated efficacy in Crohn's disease (CD) and ulcerative colitis (UC) in the GEMINI trials. Our aim was to evaluate the efficacy of VDZ at week 14 in inflammatory bowel disease (IBD) in a multicenter cohort of patients. Methods Patients at Massachusetts General Hospital and Brigham and Women's Hospital were considered for inclusion. VDZ (300mg) was administered at weeks 0, 2, 6 and 14. Efficacy was assessed using the Harvey Bradshaw index (HBI) for CD, the simple clinical colitis activity index (SCCAI) for UC and physician assessment, along with C-reactive protein (CRP) and decrease of corticosteroid therapy. Clinical response was defined as decrease in HBI ≥ 3 and SCCAI ≥ 3 and remission as HBI ≤ 4, SCCAI ≤ 2 and physician assessment of response and remission. Results Our study included 172 patients (107 CD, 59 UC, 6 IBD-U, male 48.3%, mean age 40 years and disease duration 14 years). Fourteen patients had an ostomy and 9 an ileoanal pouch and only 35.5% fulfilled eligibility for the GEMINI trials. Previous treatment failures with ≥ 2 anti-TNFs occurred in 70.9%, one-third were on an immunomodulator and 46% systemic steroids at baseline. In CD, 48.9% and 23.9% and in UC, 53.9% and 29.3% had clinical response and clinical remission at week 14. Adverse events occurred in 10.5%. Conclusions VDZ is safe and well tolerated in refractory IBD patients in a clinical practice with efficacy in UC and CD with responses similar to what was seen in clinical trials. PMID:26288002

Assessing the educational needs of Canadian gastroenterologists and gastroenterology nurses: challenges to optimal care in Crohn's Disease.

PubMed

Dupuis, Martin; Marshall, John K; Hayes, Sean M; Cytryn, Kayla; Murray, Suzanne

2009-12-01

A national needs assessment of Canadian gastroenterologists and gastroenterology nurses was undertaken to determine the perceived and unperceived educational and performance barriers to caring for patients with Crohn's disease (CD). A triangulated, mixed-method approach (qualitative and quantitative) was used to determine the nature and extent of knowledge gaps and barriers in the care of patients with CD. Qualitative interviews were conducted with nine gastroenterologists, four gastroenterology nurses and nine patients with CD. Based on this exploratory research, a survey was designed and launched nationally (37 gastroenterologists, 36 gastroenterology nurses). Findings indicated that Canadian gastroenterologists and gastroenterology nurses lacked clarity regarding their roles and responsibilities across the continuum of CD care, and face communication gaps within the health care team, undermining their effectiveness. Gastroenterologists identified challenges in optimal diagnosis due to unclear testing and diagnostic criteria. They recognized knowledge gaps when treating patient subgroups and in prescribing biological therapies. Furthermore, gastroenterologists self-identified gaps in skill, knowledge, and confidence in monitoring disease progression and effectively assessing response to therapy. When managing patients with CD, gastroenterologists expressed challenges with patient issues outside their domain of medical expertise, particularly with the skills needed to facilitate effective patient communication and education that would enhance adherence to recommended treatments. Educational initiatives should address diagnostic and treatment guidelines, as well as enhancement of clinical performance gaps in health care team processes and the patient-professional therapeutic relationship. To impact care and patient outcomes, these initiatives must be relevant to clinical practice settings and applicable to the practice context.

CD147 as a novel biomarker for predicting the prognosis and clinicopathological features of bladder cancer: a meta-analysis

PubMed Central

Li, Hongru; Xu, Yadong; Li, Hui

2017-01-01

Objective To assess the prognostic and clinicopathological characteristics of CD147 in human bladder cancer. Methods Studies on CD147 expression in bladder cancer were retrieved from PubMed, EMBASE, the Cochrane Library, Web of Science, China National Knowledge Infrastructure, and the WanFang databases. Outcomes were pooled with meta-analyzing softwares RevMan 5.3 and STATA 14.0. Results Twenty-four studies with 25 datasets demonstrated that CD147 expression was higher in bladder cancer than in non-cancer tissues (OR=43.64, P<0.00001). Moreover, this increase was associated with more advanced clinical stages (OR=73.89, P<0.0001), deeper invasion (OR=3.22, P<0.00001), lower histological differentiation (OR=4.54, P=0.0005), poorer overall survival (univariate analysis, HR=2.63, P<0.00001; multivariate analysis, HR=1.86, P=0.00036), disease specific survival (univariate analysis, HR=1.65, P=0.002), disease recurrence-free survival (univariate analysis, HR=2.78, P=0.001; multivariate analysis, HR=5.51, P=0.017), rate of recurrence (OR=1.91, P=0.0006), invasive depth (pT2∼T4 vs. pTa∼T1; OR=3.22, P<0.00001), and histological differentiation (low versus moderate-to-high; OR=4.54, P=0.0005). No difference was found among disease specific survival in multivariate analysis (P=0.067), lymph node metastasis (P=0.12), and sex (P=0.15). Conclusion CD147 could be a biomarker for early diagnosis, treatment, and prognosis of bladder cancer. PMID:28977970

Antisocial Behavioral Syndromes and Past-Year Physical Health Among Adults in the United States: Results from the National Epidemiologic Survey on Alcohol and Related Conditions

PubMed Central

Goldstein, Risë B.; Dawson, Deborah A.; Chou, S. Patricia; Ruan, W. June; Saha, Tulshi D.; Pickering, Roger P.; Stinson, Frederick S.; Grant, Bridget F.

2010-01-01

Objective To describe associations of DSM-IV antisocial personality disorder (ASPD), conduct disorder without progression to ASPD (“CD only”), and syndromal antisocial behavior in adulthood without CD before age 15 (AABS, not a DSM-IV diagnosis) with past-year physical health status and hospital care utilization in the general U.S. adult population. Methods This report is based on the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (n=43,093, response rate=81%). Respondents were classified according to whether they met criteria for ASPD, AABS, “CD only,” or no antisocial syndrome. Associations of antisocial syndromes with physical health status and care utilization were examined using normal-theory and logistic regression. Results ASPD and AABS were significantly but modestly associated with total past-year medical conditions, coronary heart and gastrointestinal diseases, and numbers of inpatient hospitalizations, inpatient days, emergency department visits, and clinically significant injuries. ASPD was also associated with liver disease, arthritis, and lower scores on the Short Form-12 version 2 (SF-12v2) Physical Component, Role Physical, and Bodily Pain Scales. AABS was associated with noncoronary heart disease, lower scores on the SF-12v2 General Health and Vitality Scales, and, among men, arthritis. “CD only” was associated with single but not multiple inpatient hospitalizations, emergency department visits, and clinically significant injuries. Conclusions Estimates of burden related to antisocial behavioral syndromes need to consider associated physical health problems. Prevention and treatment guidelines for injuries and common chronic diseases may need to address comorbid antisociality, and interventions targeting antisociality may need to consider general health status, including prevention and management of injuries and chronic diseases. PMID:18348594

Phenotypic & Genotypic Characteristics of Inflammatory Bowel Disease (IBD) in French-Canadians: comparison with a large North American repository

PubMed Central

Bhat, Mamatha; Nguyen, Geoffrey C.; Pare, Pierre; Lahaie, Raymond; Deslandres, Colette; Bernard, Edmond-Jean; Aumais, Guy; Jobin, Gilles; Wild, Gary; Cohen, Albert; Langelier, Diane; Brant, Steven; Dassopoulos, Themistocles; McGovern, Dermot; Torres, Esther; Duerr, Richard; Regueiro, Miguel; Silverberg, Mark S; Steinhart, Hillary; Griffiths, Anne M.; Elkadri, Abdul; Cho, Judy; Proctor, Deborah; Goyette, Philippe; Rioux, John; Bitton, Alain

2009-01-01

BACKGROUND Phenotype characteristics of inflammatory bowel disease (IBD) may differ significantly among ethnic subpopulations. The aim of this study was to characterize the IBD phenotype in French-Canadians, the most prominent founder population in North America. METHODS Using well-characterized phenotype data in the NIDDK-IBD Genetics Consortium repository on IBD patients, we compared phenotypic characteristics of 202 French-Canadians to those of 1287 other Caucasian patients. These included: diagnosis, anatomical location, disease behaviour, extraintestinal manifestations, surgical history, and family history of IBD. RESULTS French-Canadian CD patients were less likely to have stricturing disease (11 vs 21%, P=0.005; OR 0.45, 95% CI: 0.24– 0.85). Using a stringent definition of ethnicity (3 out of 4 grandparents being French-Canadian, as opposed to self-report, n= 148), French-Canadians had a tendency towards developing fistulizing CD (37% vs 28%, p= 0.07), and there was an increased prevalence of sacroiliitis among French-Canadians with IBD (4% vs 2%, p=0.045). Among French-Canadians, the numbers of current smokers in CD (40 vs 25%, p=0.006) and former smokers in UC (35% vs 20%, p=0.03) were significantly higher. The prevalence of one of the three main variant NOD2 SNPs among French-Canadian CD patients was 43.2%. The 3020insC SNP correlated with small bowel disease in French-Canadians (75% versus 0%, P=0.006). CONCLUSION French-Canadians exhibit an IBD phenotype profile distinct from other Caucasian IBD populations, with an accentuated association between smoking status and IBD. This unique profile may have implications regarding the need for a different approach to management of IBD in this population. PMID:19513023

Serum Anti-Glycan Antibody Biomarkers for Inflammatory Bowel Disease Diagnosis and Progression: A Systematic Review and Meta-analysis

PubMed Central

Kaul, Amit; Hutfless, Susan; Liu, Ling; Bayless, Theodore M.; Marohn, Michael R.; Li, Xuhang

2011-01-01

BACKGROUND Anti-glycan antibody serologic markers may serve as useful adjunct in the diagnosis/prognosis of inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). This meta-analysis/systemic review was aimed to evaluate the diagnostic value, as well as the association of anti-glycan biomarkers with IBD susceptible gene variants, disease complications, and need for surgery in IBD. METHODS The diagnostic odds ratio (DOR), 95% confidence interval (CI), and sensitivity/specificity were used to compare the diagnostic value of individual and combinations of anti-glycan markers and their association with disease course (complication and/or need for surgery). RESULTS Fourteen studies were included in the systemic review and nine in the meta-analysis. Individually, ASCA had the highest DOR for differentiating IBD from healthy (DOR 21.1; 1.8-247.3; 2 studies), and CD from UC (DOR 10.2; CI 7.7-13.7; 7 studies). For combination of ≥2 markers, the DOR was 2.8 (CI 2.2-3.6; 2 studies) for CD-related surgery, higher than any individual marker, while the DOR for differentiating CD from UC was 10.2 (CI 5.6-18.5; 3 studies) and for complication was 2.8 (CI 2.2-3.7; 2 studies), similar to individual markers. CONCLUSIONS ASCA had the highest diagnostic value among individual anti-glycan markers. While ACCA had the highest association with complications, ASCA and ACCA associated equally with need for surgery. Although in most individual studies, combination of ≥2 markers had a better diagnostic value as well as higher association with complications and need for surgery, we found the combination performing slightly better than any individual marker in our meta-analysis. PMID:22294465

Factors Associated with the Success of In Vitro Fertilization in Women with Inflammatory Bowel Disease

PubMed Central

Oza, Sveta Shah; Pabby, Vikas; Dodge, Laura E.; Hacker, Michele R.; Fox, Janis H.; Moragianni, Vasiliki A.; Correia, Katharine; Missmer, Stacey A.; Ibrahim, Yetunde; Penzias, Alan S.; Burakoff, Robert; Friedman, Sonia

2016-01-01

Background It is unknown whether certain factors are associated with the success of in vitro fertilization (IVF) in women with inflammatory bowel disease (IBD). Aim This study assessed whether certain characteristics are associated with greater success of live birth following IVF. Methods In a cohort study of 8684 women with IBD seen at two tertiary care centers, we identified 121 women with IBD who underwent IVF. We assessed the effect of numerous factors on likelihood of achieving live birth after IVF. Results Seventy-one patients with ulcerative colitis (UC) and 49 patients with Crohn's disease (CD) were analyzed. Patients with UC who achieved a live birth were younger (p = 0.03), had a shorter duration of disease (p = 0.01), and were more likely to be in remission (p = 0.03) versus those who did not achieve live birth. Patients with CD who achieved live birth were younger (p < 0.001), had lower body mass index (BMI) (p = 0.02), and had lower cycle day 3 follicle-stimulating hormone levels (p = 0.02). There was no difference in likelihood of achieving live birth among patients in remission and those with mild or unknown disease status (p = 0.69), though most CD patients (79.5 %) were in remission. Prior surgery was not associated with live birth in patients with UC (p = 0.31) or CD (p = 0.62). Conclusions As in the general infertility population, younger patients and those with lower BMI were more likely to achieve live birth. History of surgery was not associated with live birth among IBD patients. This is important information for practitioners counseling IBD patients. PMID:26888767

Short health scale: A valid measure of health-related quality of life in Korean-speaking patients with inflammatory bowel disease

PubMed Central

Park, Soo-Kyung; Ko, Bong Min; Goong, Hyeon Jeong; Seo, Jeong Yeon; Lee, Sang Hyuk; Baek, Hae Lim; Lee, Moon Sung; Park, Dong Il

2017-01-01

AIM To evaluate the short health scale (SHS), a new, simple, four-part visual analogue scale questionnaire that is designed to assess the impact of inflammatory bowel disease (IBD) on health-related quality of life (HRQOL), in Korean-speaking patients with IBD. METHODS The SHS was completed by 256 patients with Crohn’s disease (CD) and ulcerative colitis (UC). Individual SHS items were correlated with inflammatory bowel disease questionnaire (IBDQ) dimensions and with disease activity to assess validity. Test-retest reliability, responsiveness and patient or disease characteristics with probable association with high SHS scores were analyzed. RESULTS Of 256 patients with IBD, 139 (54.3%) had UC and 117 (45.7%) had CD. The correlation coefficients between SHS questions about “symptom burden”, “activities of daily living”, and “disease-related worry” and their corresponding dimensions in the IBDQ ranged from 0.62 to 0.71, compared with correlation coefficients ranging from -0.45 to -0.61 for their non-corresponding dimensions. There was a stepwise increase in SHS scores, with increasing disease activity in both CD and UC (all P values < 0.001). Reliability was confirmed with test-retest correlations ranging from 0.68 to 0.90 (all P values < 0.001). Responsiveness was confirmed with the patients who remained in remission. Their SHS scores remained unchanged, except for the SHS dimension “disease-related worry”. In the multivariate analysis, female sex was associated with worse “general well-being” (OR = 2.28, 95%CI: 1.02-5.08) along with worse disease activity. CONCLUSION The SHS is a valid and reliable measure of HRQOL in Korean-speaking patients with IBD. PMID:28596689

The role of 9-O-acetylated ganglioside D3 (CD60) and α4β1 (CD49d) expression in predicting the survival of patients with Sézary syndrome

PubMed Central

Scala, Enrico; Abeni, Damiano; Pomponi, Debora; Narducci, Maria Grazia; Lombardo, Giuseppe Alfonso; Mari, Adriano; Frontani, Marina; Picchio, Maria Cristina; Pilla, Maria Antonietta; Caprini, Elisabetta; Russo, Giandomenico

2010-01-01

Background Sézary syndrome is a rare and very aggressive leukemic variant of cutaneous T-cell lymphoma characterized by extensive skin involvement and a malignant circulating CD4+ T-cell clone which homes to the skin, over-expresses CD60, and lacks CD7, CD26 and CD49d. So far prognostic markers in this disease are limited to treatment with systemic steroids, age, serum lactate dehydrogenase, and a white blood cell count of 20×109/L or higher: no other biological marker with prognostic value, especially related to malignant cells, has been described. Design and Methods We used flow activated cell sorting analysis to compare the distribution of the T-cell receptor-Vβ repertoire and several surface molecules (CD7, CD26, CD49d and CD60) within the circulating CD4+ T-cell population in 62 patients with Sézary syndrome, 180 with mycosis fungoides, 6 with B-cell lymphomas, and 19 with chronic eczema. We calculated the 5-year overall survival of patients with Sézary syndrome after first hospital admission using Kaplan–Meier product–limit estimates and hazard ratios from the Cox proportional hazards model. Results We found that both higher number of CD60+ and lower number of CD49d+ cells within circulating CD4+ T cells at disease presentation were significantly associated with a lower probability of survival. An exceedingly high risk of death was observed for patients with a combination of a high proportion of CD4+CD60+ cells (≥ 0.5×109/L) and low proportion of CD4+CD49d+ cells (<0.5×109/L) (hazard ratio = 12.303, 95% confidence interval 1.5–95.9; P<0.02). In addition, a skewed usage of T-cell receptor-Vβ subfamilies was observed in the circulating T-cell clone for 61.9% of all patients with Sézary syndrome, T-cell receptor-Vβ 2 and 5.1 subfamilies being the most frequently represented (42.8%), followed by T-cell receptor-Vβ 12 and 13.1. Conclusions In this study we showed that up-regulation of CD60 and down-regulation of CD49d on circulating CD4+ T cells are two useful markers for predicting a very poor outcome in patients with Sézary syndrome. PMID:20663947

How does contamination of rice soils with Cd and Zn cause high incidence of human Cd disease in subsistence rice farmers?

USDA-ARS?s Scientific Manuscript database

Rice (Oryza sativa L.) grown on Zn mine waste contaminated soils has caused unequivocal Cd effects on kidney and occasional bone disease (itai-itai) in subsistence rice farmers, but high intake of Cd from other foods has not caused similar effects. Research has clarified two important topics about ...

Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study.

PubMed

Cruz, Conrad Russell Y; Micklethwaite, Kenneth P; Savoldo, Barbara; Ramos, Carlos A; Lam, Sharon; Ku, Stephanie; Diouf, Oumar; Liu, Enli; Barrett, A John; Ito, Sawa; Shpall, Elizabeth J; Krance, Robert A; Kamble, Rammurti T; Carrum, George; Hosing, Chitra M; Gee, Adrian P; Mei, Zhuyong; Grilley, Bambi J; Heslop, Helen E; Rooney, Cliona M; Brenner, Malcolm K; Bollard, Catherine M; Dotti, Gianpietro

2013-10-24

Autologous T cells expressing a CD19-specific chimeric antigen receptor (CD19.CAR) are active against B-cell malignancies, but it is unknown whether allogeneic CD19.CAR T cells are safe or effective. After allogeneic hematopoietic stem cell transplantation (HSCT), infused donor-derived virus-specific T cells (VSTs) expand in vivo, persist long term, and display antiviral activity without inducing graft-vs-host disease; therefore, we determined whether donor VSTs, engineered to express CD19.CAR, retained the characteristics of nonmanipulated allogeneic VSTs while gaining antitumor activity. We treated 8 patients with allogeneic (donor-derived) CD19.CAR-VSTs 3 months to 13 years after HSCT. There were no infusion-related toxicities. VSTs persisted for a median of 8 weeks in blood and up to 9 weeks at disease sites. Objective antitumor activity was evident in 2 of 6 patients with relapsed disease during the period of CD19.CAR-VST persistence, whereas 2 patients who received cells while in remission remain disease free. In 2 of 3 patients with viral reactivation, donor CD19.CAR-VSTs expanded concomitantly with VSTs. Hence CD19.CAR-VSTs display antitumor activity and, because their number may be increased in the presence of viral stimuli, earlier treatment post-HSCT (when lymphodepletion is greater and the incidence of viral infection is higher) or planned vaccination with viral antigens may enhance disease control.

Dietary gluten triggers concomitant activation of CD4+ and CD8+ αβ T cells and γδ T cells in celiac disease

PubMed Central

Han, Arnold; Newell, Evan W.; Glanville, Jacob; Fernandez-Becker, Nielsen; Khosla, Chaitan; Chien, Yueh-hsiu; Davis, Mark M.

2013-01-01

Celiac disease is an intestinal autoimmune disease driven by dietary gluten and gluten-specific CD4+ T-cell responses. In celiac patients on a gluten-free diet, exposure to gluten induces the appearance of gluten-specific CD4+ T cells with gut-homing potential in the peripheral blood. Here we show that gluten exposure also induces the appearance of activated, gut-homing CD8+ αβ and γδ T cells in the peripheral blood. Single-cell T-cell receptor sequence analysis indicates that both of these cell populations have highly focused T-cell receptor repertoires, indicating that their induction is antigen-driven. These results reveal a previously unappreciated role of antigen in the induction of CD8+ αβ and γδ T cells in celiac disease and demonstrate a coordinated response by all three of the major types of T cells. More broadly, these responses may parallel adaptive immune responses to viral pathogens and other systemic autoimmune diseases. PMID:23878218

Decreased levels of serum omentin-1 in patients with inflammatory bowel disease.

PubMed

Yin, Jian; Hou, Peng; Wu, Zhiqiang; Nie, Yanxiao

2015-01-10

Inflammation is involved in the mechanism of inflammatory bowel disease (IBD). Omentin, a newly discovered adipokine, is thought to play an anti-inflammatory role. This study aimed to determine whether serum levels of omentin-1 are associated with the presence and disease activity of IBD. This study consisted of 192 patients with IBD: 100 with Crohn's disease [CD], 92 with ulcerative colitis [UC], and 104 healthy subjects. Serum levels of omentin-1 were measured using enzyme-linked immunosorbent assay (ELISA). Serum omentin-1 levels were significantly decreased in CD and UC patients compared with healthy controls. Multivariable logistic regression analysis revealed that serum omentin-1 levels were inversely associated with the presence of CD and UC. Active CD and UC patients both had significantly decreased levels of serum omentin-1 compared with inactive CD and UC patients. In both CD and UC patients, serum omentin-1 levels were significantly associated with decreased levels of body mass index (BMI) and C-reactive protein (CRP). Decreased serum omentin-1 levels could be considered as an independent predicting marker of the presence and disease activity of IBD.

Multi-criteria decision analysis and spatial statistic: an approach to determining human vulnerability to vector transmission of Trypanosoma cruzi

PubMed Central

Montenegro, Diego; da Cunha, Ana Paula; Ladeia-Andrade, Simone; Vera, Mauricio; Pedroso, Marcel; Junqueira, Angela

2017-01-01

BACKGROUND Chagas disease (CD), caused by the protozoan Trypanosoma cruzi, is a neglected human disease. It is endemic to the Americas and is estimated to have an economic impact, including lost productivity and disability, of 7 billion dollars per year on average. OBJECTIVES To assess vulnerability to vector-borne transmission of T. cruzi in domiciliary environments within an area undergoing domiciliary vector interruption of T. cruzi in Colombia. METHODS Multi-criteria decision analysis [preference ranking method for enrichment evaluation (PROMETHEE) and geometrical analysis for interactive assistance (GAIA) methods] and spatial statistics were performed on data from a socio-environmental questionnaire and an entomological survey. In the construction of multi-criteria descriptors, decision-making processes and indicators of five determinants of the CD vector pathway were summarily defined, including: (1) house indicator (HI); (2) triatominae indicator (TI); (3) host/reservoir indicator (Ho/RoI); (4) ecotope indicator (EI); and (5) socio-cultural indicator (S-CI). FINDINGS Determination of vulnerability to CD is mostly influenced by TI, with 44.96% of the total weight in the model, while the lowest contribution was from S-CI, with 7.15%. The five indicators comprise 17 indices, and include 78 of the original 104 priority criteria and variables. The PROMETHEE and GAIA methods proved very efficient for prioritisation and quantitative categorisation of socio-environmental determinants and for better determining which criteria should be considered for interrupting the man-T. cruzi-vector relationship in endemic areas of the Americas. Through the analysis of spatial autocorrelation it is clear that there is a spatial dependence in establishing categories of vulnerability, therefore, the effect of neighbors’ setting (border areas) on local values should be incorporated into disease management for establishing programs of surveillance and control of CD via vector. CONCLUSIONS The study model proposed here is flexible and can be adapted to various eco-epidemiological profiles and is suitable for focusing anti-T. cruzi serological surveillance programs in vulnerable human populations. PMID:28953999

Association between vascular access failure and microparticles in hemodialysis patients

PubMed Central

Ryu, Jung-Hwa; Lim, Su-Young; Ryu, Dong-Ryeol; Kang, Duk-Hee; Choi, Kyu Bok; Kim, Seung-Jung

2012-01-01

Background Vascular access failure, a major cause of morbidity in hemodialysis (HD) patients, occurs mainly at stenotic endothelium following an acute thrombotic event. Microparticles (MPs) are fragments derived from injured cell membrane and are closely associated with coagulation and vascular inflammatory responses. Methods We investigated the relationship between levels of circulating MPs and vascular access patency in HD patients. A total of 82 HD patients and 28 healthy patients were enrolled. We used flow cytometry to measure endothelial MPs (EMPs) identified by CD31+CD42− or CD51+ and platelet-derived MPs (PMPs) identified by CD31+CD42+ in plasma samples of participants. Vascular access patency was defined as an interval from the time of access formation to the time of first access stenosis in each patient. MP counts were compared according to access patent duration. Results The levels of EMP (both CD31+CD42− and CD51+) and CD31+CD42+PMP were significantly higher in patients than in healthy participants. Levels of CD31+CD42−EMP and CD31+CD42+PMP showed a positive correlation. In non-diabetic HD patients, CD31+CD42−EMPs and CD31+CD42+PMPs were more elevated in the shorter access survival group (access survival <1 year) than in the longer survival group (access survival ≥ 4 years). Conclusion Elevated circulating EMP or PMP counts are influenced by end-stage renal disease and increased levels of EMP and PMP may be associated with vascular access failure in HD patients. PMID:26889407

B and T Lymphocyte Attenuator Down-regulation by HIV-1 Depends on Type I Interferon and Contributes to T-Cell Hyperactivation

PubMed Central

Zhang, Zheng; Xu, Xiangsheng; Lu, Jiyun; Zhang, Shuye; Gu, Lanlan; Fu, Junliang; Jin, Lei; Li, Haiying; Zhao, Min; Zhang, Jiyuan; Wu, Hao; Su, Lishan; Fu, Yang-Xin

2011-01-01

Background. Nonspecific T-cell hyperactivation is the main driving force for human immunodeficiency virus (HIV)–1 disease progression, but the reasons why the excess immune response is not properly shut off are poorly defined. Methods. Eighty-five HIV-1–infected individuals were enrolled to characterize B and T lymphocyte attenuator (BTLA) expression and function. Infection and blockade assays were used to dissect the factors that influenced BTLA signaling in vitro. Results. BTLA expression on overall CD4+ and CD8+ T cells was progressively decreased in HIV-1 infection, which was directly correlated with disease progression and CD4+ T-cell differentiation and activation. BTLA+CD4+ T cells from HIV-1–infected patients also displayed an altered immune status, which was indicated by reduced expression of naive markers but increased activation and exhaustion markers. Cross-linking of BTLA can substantially decrease CD4+ T-cell activation in vitro. This responsiveness of CD4+ T cells to BTLA-mediated inhibitory signaling was further found to be impaired in HIV-1–infected patients. Furthermore, HIV-1 NL4-3 down-regulated BTLA expression on CD4+ T cells dependent on plasmacytoid dendritic cell (pDC)-derived interferon (IFN)-α. Blockade of IFN-α or depletion of pDCs prevents HIV-1-induced BTLA down-regulation. Conclusions. HIV-1 infection potentially impairs BTLA-mediated signaling dependent on pDC-derived IFN-α, which may contribute to broad T-cell hyperactivation induced by chronic HIV-1 infection. PMID:21592997

A prospective study of appetite and food craving in 30 patients with Cushing’s disease

PubMed Central

Geer, Eliza B.; Lalazar, Yelena; Couto, Lizette M.; Cohen, Vanessa; Lipton, Lianna R.; Shi, Wei; Bagiella, Emilia; Conwell, Irene; Bederson, Joshua; Kostadinov, Jane; Post, Kalmon D.; Freda, Pamela U.

2015-01-01

Context Glucocorticoid (GC) exposure increases food intake, but the mechanisms in humans are not known. Investigation of appetite and food craving has not been done in patients with chronic GC exposure due to Cushing’s disease (CD), either before or after treatment, and could provide insight into mechanisms of food intake and obesity in these patients. Purpose To examine whether surgical remission of CD changes appetite (prospective consumption, hunger, satisfaction, and fullness) and food cravings (sweet, salty, fatty, and savory); and to identify predictors of appetite and craving in CD remission. Methods 30 CD patients, mean age 40.0 yr. (range 17–70), mean BMI 32.3 ± 6.4, were prospectively studied before and at a mean of 17.4 mo. after remission. At each visit fasting and post-test meal (50% carbohydrate, 35% protein, 15% fat) appetite and craving scores were assessed. Results Remission decreased prospective consumption, sweet and savory craving (p<0.05), but did not change hunger, satisfaction, fullness, or fat craving, despite decreases in BMI and fat mass. In CD remission, serum cortisol predicted lower satisfaction and fullness, and masses of abdominal fat depots predicted higher hunger and consumption (p<0.05). Conclusions Chronic GC exposure in CD patients may stimulate the drive to eat by enhancing craving, rather than regulating the sensation of hunger. Continued alterations in appetite regulation due to abdominal fat mass and circulating cortisol could play a role in the cardiovascular and metabolic risk that has been reported in CD patients despite remission. PMID:26496766

Comparative effectiveness of infliximab and adalimumab in Crohn’s disease and ulcerative colitis

PubMed Central

Ananthakrishnan, Ashwin N.; Cagan, Andrew; Cai, Tianxi; Gainer, Vivian S.; Shaw, Stanley Y; Savova, Guergana; Churchill, Susanne; Karlson, Elizabeth W.; Kohane, Isaac; Liao, Katherine P.; Murphy, Shawn N.

2016-01-01

Introduction The availability of monoclonal antibodies to tumor necrosis factor α (anti-TNF) has revolutionized management of Crohn’s disease (CD) and ulcerative colitis (UC). However, limited data exists regarding comparative effectiveness of these agents to inform clinical practice. Methods This study consisted of patients with CD or UC initiation either infliximab (IFX) or adalimumab (ADA) between 1998 and 2010. A validated likelihood of non-response classification score utilizing frequency of narrative mentions of relevant symptoms in the electronic health record (EHR) was applied to assess comparative effectiveness at 1 year. IBD-related surgery, hospitalization, and use of steroids was determined during this period. Results Our final cohort included 1,060 new initiations of IFX (68% for CD) and 391 of ADA (79% for CD). In CD, the likelihood of non-response was higher in ADA than IFX (OR 1.62, 95% CI 1.21 – 2.17). Similar differences favoring efficacy of IFX was observed for the individual symptoms of diarrhea, pain, bleeding, and fatigue. However, there was no difference in IBD-related surgery, hospitalizations or prednisone use within 1 year after initiation of IFX or ADA in CD. There was no difference in narrative or codified outcomes between the two agents in UC. Conclusion We identified a modestly higher likelihood of symptomatic non-response at 1 year for ADA compared to IFX in patients with CD. However, there were no differences in IBD-related surgery or hospitalizations suggesting these treatments are broadly comparable in effectiveness in routine clinical practice. PMID:26933751

Laboratory screening markers in gastroenterology--state of the art.

PubMed

Kocna, Petr; Vanickova, Zdislava; Zima, Tomas

2013-06-01

Screening tests for gastrointestinal diseases acceptable for population with a high sensitivity and high specificity can now be offered by clinical laboratories. This paper summarizes major recent advances in this area of laboratory medicine. Relevant articles published within the last 5 years in the NLM (National Library of Medicine) PubMed - Medline database covering the three gastrointestinal diseases - colorectal cancer, coeliac disease, and atrophic gastritis were included for this overview. In Europe, colorectal cancer (CRCA) is the second most frequent malignant disease. Quantitative immunochemical analysis of the stool for haemoglobin provides the best screening test to date, with both sensitivity and specificity approaching 95%. Even though coeliac disease (CD) affects approximately 1% of the general population, it remains largely unrecognised. Recommended methods for screening currently involve the detection of IgA and IgG antibodies against tissue transglutaminase and deamidated gliadin peptide. Evaluations of screening are now discussed for other diseases of the gastrointestinal tract - such as chronic atrophic gastritis (CAG), and inflammatory bowel disease (IBD). Detection of infection by Helicobacter pylori and stomach-specific plasmatic biomarkers, especially pepsinogen I/II ratio, could help with the prevention of gastric carcinomas. The use of faecal calprotectin as a screening test could substantially reduce the number of invasive methods necessary for the diagnostic work-up of patients with IBD. Screening tests for CRCA and CD have been used worldwide for many years. Screening strategies for gastrointestinal diseases are suggested in the text, based on recent basic science, clinical papers as well as our own experience.

Is the efficacy of successful infliximab induction therapy maintained for one year lasting without retreatment in different behavior types of Crohn's disease?

PubMed

Molnár, T; Farkas, K; Miheller, P; Nyári, T; Szepes, Z; Herszényi, L; Müzes, Gy; Nagy, F; Tulassay, Zs; Wittmann, T

2008-12-01

The high cost of infliximab inhibits the regular retreatment of all patients in Hungary with Crohn's disease (CD) after beneficial induction therapy. This study is set out to evaluate the medium-term efficacy of induction therapy with infliximab without retreatment in CD patients with chronic activity and/or fistulae refractory to conventional therapy. A retrospective 1-year review was undertaken of all CD patients with successfully induced remission or fistula closure with 3 infusions of infliximab. Infliximab was administered in a dose of 5 mg/kg 3 times, in weeks 0, 2 and 6. Clinical remission was defined as symptom resolution and an estimated Crohn's Disease Activity Index (CDAI) <150 and complete fistula closure. We evaluated the clinical response, the estimated CDAI, the number of draining fistulae, the dosages of steroid and immunosuppressive drugs at 6 and 12 months after the last infusion, and the needs for hospitalization and surgical intervention during this period. Breslow (Generalized Wilcoxon) test was used as the statistical method. The data of the 50 patients (19 luminal, 31 fistulizing disease; average age 29. 3 [13-59] years, disease localization: 23 colon, 13 ileum, 13 ileocolon, 1 duodenum) were suitable for analysis. Infliximab induction therapy without retreatment resulted in a beneficial effect lasting for at least 1 year in 22 of the 50 patients (44%). 11 of the 19 patients (57.9%) with luminal disease remained in steroid-free complete remission, while the fistulae persisted closed in only 11 of the 31 patients (35.5%) (p<0.05). Infliximab induction therapy alone may result in sustained remission mainly in patients with luminal disease. These results suggest the need for maintenance therapy with infliximab after successful therapy induction in patients with fistulae, while luminal CD patients could possibly participate in regular retreatment only if needed. If these data are confirmed, this modification of the therapeutic procedure could well increase the cost-effectiveness of infliximab.

Appropriateness of therapy for fistulizing Crohn's disease: findings from a national inflammatory bowel disease cohort.

PubMed

Pittet, V; Juillerat, P; Michetti, P; Vader, J-P; Burnand, B; Rogler, G; Beglinger, C; Seibold, F; Mottet, C; Felley, C; Gonvers, J-J; Froehlich, F

2010-10-01

About 30-50% of patients with Crohn's disease (CD) develop fistulae, implying significant disease burden and complicated clinical management. To assess appropriate use of therapy for fistulizing CD patients enrolled in the Swiss Inflammatory Bowel Disease Cohort using criteria developed by the European Panel on the Appropriateness of Crohn's disease Therapy. Specific questionnaires were used to gather information on disease and its management. We assessed appropriateness of therapy at enrolment for adult CD patients with one or several fistulae. Two hundred and eighty-eight CD patients had fistulizing disease, of which 80% had complex fistulae and 32% currently had active draining fistulae. Mean age (s.d.) at diagnosis was 27 years (11), 51% males. Of the patients, 78% were judged as having globally an appropriate therapy, which was more often given for complex fistulae (87%) than for simple fistulae (67%). Antibiotics, azathioprine/MP, methotrexate and conservative surgery were almost always appropriate. Anti-tumor necrosis factor α was considered globally appropriate (91%), although most often with an uncertain indication. The 5ASA compounds, steroids and aggressive surgery were most often inappropriate (84%, 58% and 86% respectively). Formal appropriateness criteria for CD therapy were applied to a national cohort of IBD patients. For more than three-quarters of the patients with fistulizing CD, therapy was globally appropriate. © 2010 Blackwell Publishing Ltd.

Phenotypic and Functional Characterization of Herpes Simplex Virus Glycoprotein B Epitope-Specific Effector and Memory CD8+ T Cells from Symptomatic and Asymptomatic Individuals with Ocular Herpes

PubMed Central

Khan, Arif A.; Srivastava, Ruchi; Spencer, Doran; Garg, Sumit; Fremgen, Daniel; Vahed, Hawa; Lopes, Patricia P.; Pham, Thanh T.; Hewett, Charlie; Kuang, Jasmine; Ong, Nicolas; Huang, Lei; Scarfone, Vanessa M.; Nesburn, Anthony B.

2015-01-01

ABSTRACT Herpes simplex virus 1 (HSV-1) glycoprotein B (gB)-specific CD8+ T cells protect mice from herpes infection and disease. However, whether and which HSV-1 gB-specific CD8+ T cells play a key role in the “natural” protection seen in HSV-1-seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical herpes disease) remain to be determined. In this study, we have dissected the phenotypes and the functions of HSV-1 gB-specific CD8+ T cells from HLA-A*02:01 positive, HSV-1 seropositive ASYMP and symptomatic (SYMP) individuals (with a history of numerous episodes of recurrent ocular herpes disease). We found the following. (i) Healthy ASYMP individuals maintained a significantly higher proportion of differentiated HSV-1 gB-specific effector memory CD8+ T cells (TEM cells) (CD45RAlow CCR7low CD44high CD62Llow). In contrast, SYMP patients had frequent less-differentiated central memory CD8+ T cells (TCM cells) (CD45RAlow CCR7high CD44low CD62Lhigh). (ii) ASYMP individuals had significantly higher proportions of multifunctional effector CD8+ T cells which responded mainly to gB342–350 and gB561–569 “ASYMP” epitopes, and simultaneously produced IFN-γ, CD107a/b, granzyme B, and perforin. In contrast, effector CD8+ T cells from SYMP individuals were mostly monofunctional and were directed mainly against nonoverlapping gB17–25 and gB183–191 “SYMP” epitopes. (iii) Immunization of an HLA-A*02:01 transgenic mouse model of ocular herpes with “ASYMP” CD8+ TEM cell epitopes, but not with “SYMP” CD8+ TCM cell epitopes, induced a strong CD8+ T cell-dependent protective immunity against ocular herpes infection and disease. Our findings provide insights into the role of HSV-specific CD8+ TEM cells in protection against herpes and should be considered in the development of an effective vaccine. IMPORTANCE A significantly higher proportion of differentiated and multifunctional HSV-1 gB-specific effector memory CD8+ T cells (TEM cells) (CD45RAlow CCR7low CD44high CD62Llow) were found in healthy ASYMP individuals who are seropositive for HSV-1 but never had any recurrent herpetic disease, while there were frequent less-differentiated and monofunctional central memory CD8+ T cells (TCM cells) (CD45RAlow CCR7high CD44low CD62Lhigh) in SYMP patients. Immunization with “ASYMP” CD8+ TEM cell epitopes, but not with “SYMP” CD8+ TCM cell epitopes, induced a strong protective HSV-specific CD8+ T cell response in HLA-A*02:01 transgenic mice. These findings are important for the development of a safe and effective T cell-based herpes vaccine. PMID:25609800

Detection of acute lymphoblastic leukemia involvement in pleural fluid in an adult patient with ataxia telangiectasia by flow cytometry method.

PubMed

Keklik, Muzaffer; Koker, M Yavuz; Sivgin, Serdar; Camlica, Demet; Pala, Cigdem; Cetin, Mustafa; Kaynar, Leylagul; Unal, Ali; Eser, Bulent

2014-09-01

Ataxia-telangiectasia (AT) is a rare multisystem, neurodegenerative genetic disorder. Patients should be closely monitored due to risk of malignancy development. Due to its wide clinical heterogeneity, it often leads physicians to an inaccurate or missed diagnosis, and insight into this rare disease is important. Pediatric patients may develop lymphomas and acute lymphoblastic leukemia (ALL). However, in adults, there are limited numbers of reports regarding association of AT and ALL. Rarely, ALL cases may present with pleural fluid involvement. In our study, we presented an adult case with AT, in which ALL involvement was detected in pleural fluid by flow cytometry (FC). A 20-years old male presented to emergency department with fever, shortness of breath and cough, as he had been followed with a diagnosis of AT. The following findings were detected in laboratory tests: Hb, 11.5 g/L; WBC, 36 × 10(9)/L; Plt: 140 × 10(9)/L. Blastic cells were observed in peripheral blood smear. On chest radiography, pleural fluid appearance was observed. On thorax CT, pleural fluid was detected in both hemithorax. Cytoplasmic CD3(+) and superficial CD3 (+), CD45 (+), CD5 (+), CD7 (+) and CD38 (+) was found in the flow cytometric evaluation of peripheral blood. Superficial CD3 (+), CD2 (+), CD5 (+) and CD7 (+) were found in flow cytometric evaluation of pleural fluid. These findings were considered as consistent with pleural involvement of T-ALL. FC is a potentially useful diagnostic tool for clinical practice and it is a convenience method which has an important role in detection of ALL in patients with pleural fluid.

Anemia at the time of diagnosis of inflammatory bowel disease: Prevalence and associated factors in adolescent and adult patients.

PubMed

Lucendo, Alfredo J; Arias, Ángel; Roncero, Óscar; Hervías, Daniel; Verdejo, Cristina; Naveas-Polo, Carmen; Bouhmidi, Abdelmouneim; Lorente, Rufo; Alcázar, Luis Miguel; Salueña, Irina; García-Quiñones, Julio A; Carrillo-Ramos, María Jesús

2017-04-01

The prevalence, characteristic and determinants of anemia, at the time of inflammatory bowel disease (IBD) diagnosis have yet to be fully elucidated. Retrospective cross-sectional study. Analytical data and disease characteristics obtained upon diagnosis of 1278 IBD patients [Crohn's disease/ulcerative colitis (CD/UC): 718/560] were collected. Anemia was present in 41.2% of patients at diagnosis (47% and 33.8% of CD and UC patients, respectively; p<0.001), being severe in 5.5%. Iron deficiency anemia represented 69.6% of cases, with no differences between CD and UC. Female sex was the strongest risk factor for anemia in both CD and UC (OR 7.11; 95%CI 4.18-12.10 and 6.55; 95%CI 3.39-12.63, respectively), followed by elevated (≥2mg/dL) C-reactive protein (OR 4.08; 95%CI 2.39-6.97 and 4.58; 95%CI 2.26-9.27, respectively). Current smoking was a risk factor for anemia in CD (OR 2.23; 95%CI 1.24-4.02), but a protective one in UC (OR 0.36; 95%CI 0.14-0.92). A penetrating CD behavior increased the risk of anemia (OR 3.34; 95%CI 1.36-8.21); in UC, anemia increased with disease extension (E2+E3) (OR 1.80; 95%CI 1.13-2.86). Female sex and disease activity are major determinants of anemia at IBD diagnosis. Anemia is associated with disease behavior in CD and with disease extension in UC. Copyright © 2016. Published by Elsevier Ltd.

An Evil Backstage Manipulator: Psychological Factors Correlated with Health-Related Quality of Life in Chinese Patients with Crohn's Disease

PubMed Central

Liu, Song; Hong, Zhiwu; Li, Xiaoting; Yao, Min; Yan, Dongsheng; Ren, Huajian; Wu, Xiuwen; Wang, Gefei; Gu, Guosheng; Xia, Qiuyuan; Han, Gang; Li, Jieshou

2013-01-01

Health-related quality of life (HRQoL) is recommended as one of essential parameters to evaluate treatment effect and clinical outcome in patients with Crohn's disease (CD). Recent studies reported that psychological factors might play a role in HRQoL in Western and American CD patients. Sufficient evidences in Chinese CD patients are still unavailable. This study is dedicated to investigate the correlation of various psychological factors with HRQoL in Chinese CD patients. We prospectively collected 40 active and 40 quiescent CD patients in China and found that psychological factors, especially neuroticism and anxiety, significantly correlate with and affect HRQoL in both active and quiescent CD groups. This is the first report revealing correlation between psychological factors and HRQoL in Chinese CD patients. Therefore, we assume that our results can contribute to a better understanding of etiology and tailoring of management in Chinese patients with Crohn's disease and are beneficial to our colleagues to compare the heterogeneous characteristics of Crohn's disease in different ethnic groups. PMID:24453858

Is tremor related to celiac disease?

PubMed

Ameghino, Lucia; Rossi, Malco Damian; Cerquetti, Daniel; Merello, Marcelo

2017-06-14

Neurological features in celiac disease (CD) are not rare (5%-36%), but tremor is scarcely described. Subjects with CD and healthy controls completed an online survey using WHIGET tremor rating scale. One thousand five hundred and twelve subjects completed the survey, finally 674 CD patients and 290 healthy subjects were included. A higher prevalence of tremor in CD patients was observed in comparison to controls (28% vs 14%, P < 0.001). Frequency of family history of tremor in CD patients with and without tremor was 25% and 20% ( P = 0.2), while in the control group it was 41% and 10% ( P < 0.001). Controls with tremor showed a higher frequency of family history of tremor when compared to CD patients with tremor (41.5% vs 24.6%, P = 0.03). The results suggested that tremor in CD might be more frequent and possibly related to the disease itself and not due to associated essential tremor.

The Roles of CD147 and/or Cyclophilin A in Kidney Diseases

PubMed Central

Wang, Chunting; Zhang, Jicheng; Qie, Guoqiang

2014-01-01

CD147 is a widely expressed integral plasma membrane glycoprotein and has been involved in a variety of physiological and pathological activities in combination with different partners, including cyclophilins, caveolin-1, monocarboxylate transporters, and integrins. Recent data demonstrate that both CyPA and CD147 significantly contribute to renal inflammation, acute kidney injury, renal fibrosis, and renal cell carcinoma. Here we review the current understanding of cyclophilin A and CD147 expression and functions in kidney diseases and potential implications for treatment of kidney diseases. PMID:25580061

Analysis of fat and muscle mass in patients with inflammatory bowel disease during remission and active phase.

PubMed

Rocha, Raquel; Santana, Genoile Oliveira; Almeida, Neogélia; Lyra, Andre Castro

2009-03-01

Inflammatory bowel disease (IBD) is often associated with malnutrition. The aim of this study was to compare the body composition of outpatients with IBD during remission and active phase. In order to evaluate disease activity we used Crohn's Disease Activity Index for Crohn's disease (CD) patients and Lichtiger's Index for ulcerative colitis (UC) patients. All patients underwent the analysis of BMI, arm muscle area (AMA) and triceps plus subscapula skinfold thickness (TST+SST) to identify total, muscle and fat mass, respectively. In total 102 patients were evaluated (CD, n 50; UC, n 52) and the majority was young women. Malnutrition according to BMI was found in 14.0 % of patients with CD and 5.7 % of UC patients. Muscle mass depletion was detected in more than half of the CD and UC patients. The BMI, TST+SST and AMA values were lower in the active phase only in CD patients (P < 0.05). Fat mass depletion was associated with active phase in both CD and UC patients. Body composition parameters obtained using BMI, TST+SST and AMA were not correlated with the presence of fistula in CD patients (P>0.05). In conclusion, patients without signs of malnutrition had fat mass depletion especially in the active phase and muscle mass depletion occurred both in CD and UC patients.

Anti-inflammatory intestinal activity of Combretum duarteanum Cambess. in trinitrobenzene sulfonic acid colitis model

PubMed Central

de Morais Lima, Gedson Rodrigues; Machado, Flavia Danniele Frota; Périco, Larissa Lucena; de Faria, Felipe Meira; Luiz-Ferreira, Anderson; Souza Brito, Alba Regina Monteiro; Pellizzon, Cláudia Helena; Hiruma-Lima, Clélia Akiko; Tavares, Josean Fechine; Barbosa Filho, José Maria; Batista, Leônia Maria

2017-01-01

AIM To evaluate the anti-inflammatory intestinal effect of the ethanolic extract (EtOHE) and hexane phase (HexP) obtained from the leaves of Combretum duarteanum (Cd). METHODS Inflammatory bowel disease was induced using trinitrobenzenesulfonic acid in acute and relapsed ulcerative colitis in rat models. Damage scores, and biochemical, histological and immunohistochemical parameters were evaluated. RESULTS Both Cd-EtOHE and Cd-HexP caused significant reductions in macroscopic lesion scores and ulcerative lesion areas. The vegetable samples inhibited myeloperoxidase increase, as well as pro-inflammatory cytokines TNF-α and IL-1β. Anti-inflammatory cytokine IL-10 also increased in animals treated with the tested plant samples. The anti-inflammatory intestinal effect is related to decreased expression of cyclooxygenase-2, proliferating cell nuclear antigen, and an increase in superoxide dismutase. CONCLUSION The data indicate anti-inflammatory intestinal activity. The effects may also involve participation of the antioxidant system and principal cytokines relating to inflammatory bowel disease. PMID:28293082

Mondor's disease of penis: a forgotten disease

PubMed Central

Kumar, B; Narang, T; Radotra, B; Gupta, S

2005-01-01

Background: Mondor's disease of penis is an uncommon genital condition involving the penile sulcus in a circumferential manner. Although this disorder is almost always self limited, it is associated with considerable psychological stress and sexual disharmony. Methods: All patients attending the sexually transmitted disease clinic during 1991–2003 were examined for evidence of Mondor's disease of penis. Detailed history and clinical findings were recorded in a specially designed proforma. Histopathological examination and staining with CD31 and CD34 monoclonal antibodies was also done in 11 patients. Results: 18 out of 1296 patients attending the sexually transmitted diseases (STD) clinic during the study period were found to have penile Mondor's disease, giving an incidence of 1.39%. 17 patients had history of one or more episodes of STDs. Histopathological specimens showed prominent vessels with plump endothelial cells and thickened blood vessel walls. The occasional vessel showed complete occlusion of its lumen. Conclusions: In our study we did not find any evidence of lymphatic involvement. Non-lymphatic vessels, mainly veins, were predominantly involved. In our opinion Mondor's phlebitis of penis or Mondor's disease of penis are better terms to describe the condition rather than non-venereal sclerosing lymphangitis. PMID:16326851

Identification of Multipotent Stem/Progenitor Cells in Murine Sclera

PubMed Central

Tsai, Chia-Ling; Wu, Pei-Chang; Fini, M. Elizabeth; Shi, Songtao

2011-01-01

Purpose. The sclera forms the fibrous outer coat of the eyeball and acts as a supportive framework. The purpose of this study was to examine whether the sclera contains mesenchymal stem/progenitor cells. Method. Scleral tissue from C57BL6/J mice was separated from the retina and choroid and subsequently enzyme digested to release single cells. Proliferation capacity, self-renewal capacity, and ability for multipotent differentiation were analyzed by BrdU labeling, flow cytometry, reverse transcriptase–polymerase chain reaction, immunocytochemistry, and in vivo transplantation. Results. The scleral stem/progenitor cells (SSPCs) possessed clonogenic and high doubling capacities. These cells were positive for the mesenchymal markers Sca-1, CD90.2, CD44, CD105, and CD73 and negative for the hematopoietic markers CD45, CD11b, Flk1, CD34, and CD117. In addition to expressing stem cell genes ABCG2, Six2, Notch1, and Pax6, SSPCs were able to differentiate to adipogenic, chondrogenic, and neurogenic lineages. Conclusions. This study indicates that the sclera contains multipotent mesenchymal stem cells. Further study of SSPCs may help elucidate the cellular and molecular mechanism of scleral diseases such as scleritis and myopia. PMID:21788434

Variability of Late-Night Salivary Cortisol in Cushing Disease: A Prospective Study.

PubMed

Sandouk, Zahrae; Johnston, Philip; Bunch, Dustin; Wang, Sihe; Bena, James; Hamrahian, Amir; Kennedy, Laurence

2018-03-01

The frequency of variable hormonogenesis in patients with Cushing disease (CD) but without cyclical symptoms is unclear. To assess the frequency of variable hormonogenesis in patients presenting with CD. Over a 6-month period, patients with confirmed or suspected CD provided late-night salivary samples for up to 42 consecutive nights. Of 19 patients confirmed to have CD, 16 provided at least 7 consecutive salivary samples, and 13 provided at least 21; these 16 patients are the subjects of this report. Twelve patients had at least three peak and two trough levels of late-night salivary cortisol (LNSC) but in only two patients were strict criteria for cyclical hormonogenesis fulfilled; variation was assessed as random in the others. Eight patients had de novo CD, and eight had recurrent/persistent disease. All patients with recurrent/persistent CD had two or more normal results, and in four of these patients, >50% of LNSC were normal. In six patients with de novo disease with at least one normal LNSC level, the maximum levels ranged from 1.55 to 15.5 times the upper limit of normal. Extreme fluctuations of cortisol production, measured by sequential LNSC, are common in CD. In newly diagnosed disease, this may only occasionally impair diagnostic ability, whereas in most patients with recurrent/persistent disease after pituitary surgery, LNSC is frequently within the reference range, with potential to cause diagnostic problems.

Frequency of paroxysmal nocturnal hemoglobinuria in patients attended in Belém, Pará, Brazil

PubMed Central

de Brito Junior, Lacy Cardoso; Cardoso, Maria do Socorro de Oliveira; Rocha, Euzamar Gaby; Anijar, Herika; Cunha, Mariana; Saraiva, João Carlos Pina

2011-01-01

Background Paroxysmal nocturnal hemoglobinuria is a hematological disease with complex physiopathology. It is genetically characterized by a somatic mutation in the PIG-A gene (phosphatidylinositol glycan anchor biosynthesis, class A), in which the best known antigens are DAF (decay accelerating factor or CD55) and MIRL (membrane inhibitor of reactive lysis or CD59). Objective To determine the frequency of paroxysmal nocturnal hemoglobinuria in patients attended at the HEMOPA foundation from November 2008 to July 2009. Method Thirty patients, with ages ranging from two to 79 years old and suspected of having paroxysmal nocturnal hemoglobinuria were examined. All patients were immunophenotyped by flow cytometry for the CD5, CD59, CD16 and CD45 antigens. Results Paroxysmal nocturnal hemoglobinuria was identified in nine of the thirty patients investigated. Another 3 cases had inconclusive results with CD59-negative labeling only for neutrophils. The highest frequency of paroxysmal nocturnal hemoglobinuria patients (7/9) and inconclusive cases (2/3) were between 19 years old and 48 years old, with a median of 28 years. Conclusion These results show the importance of flow cytometry to identify cases in which patients are deficient in only one antigen (CD59). PMID:23284241

Disease severity in familial cases of IBD.

PubMed

Andreu, M; Márquez, L; Domènech, E; Gisbert, J P; García, V; Marín-Jiménez, I; Peñalva, M; Gomollón, F; Calvet, X; Merino, O; Garcia-Planella, E; Vázquez-Romero, N; Esteve, M; Nos, P; Gutiérrez, A; Vera, I; Cabriada, J L; Martín, M D; Cañas-Ventura, A; Panés, J

2014-03-01

Phenotypic traits of familial IBD relative to sporadic cases are controversial, probably related to limited statistical power of published evidence. To know if there are phenotype differences between familial and sporadic IBD, evaluating the prospective Spanish registry (ENEIDA) with 11,983 cases. 5783 patients (48.3%) had ulcerative colitis (UC) and 6200 (51.7%) Crohn's disease (CD). Cases with one or more 1st, 2nd or 3rd degree relatives affected by UC/CD were defined as familial case. In UC and CD, familial cases compared with sporadic cases had an earlier disease onset (UC: 33 years [IQR 25-44] vs 37 years [IQR 27-49]; p<0.0001); (CD: 27 years [IQR 21-35] vs 29 years [IQR 22-40]; p<0.0001), higher prevalence of extraintestinal immune-related manifestations (EIMs) (UC: 17.2% vs 14%; p=0.04); (CD: 30.1% vs 23.6%; p<0.0001). Familial CD had higher percentage of ileocolic location (42.7% vs 51.8%; p=0.0001), penetrating behavior (21% vs 17.6%; p=0.01) and perianal disease (32% vs 27.1%; p=0.003). Differences are not influenced by degree of consanguinity. When a sufficiently powered cohort is evaluated, familial aggregation in IBD is associated to an earlier disease onset, more EIMs and more severe phenotype in CD. This feature should be taken into account at establishing predictors of disease course. © 2013.

Disease-specific Alterations in the Enteric Virome in Inflammatory Bowel Disease

PubMed Central

Norman, Jason M.; Handley, Scott A.; Baldridge, Megan T.; Droit, Lindsay; Liu, Catherine Y.; Keller, Brian C.; Kambal, Amal; Monaco, Cynthia L.; Zhao, Guoyan; Fleshner, Phillip; Stappenbeck, Thaddeus S.; McGovern, Dermot P.B.; Keshavarzian, Ali; Mutlu, Ece A.; Sauk, Jenny; Gevers, Dirk; Xavier, Ramnik J.; Wang, David; Parkes, Miles; Virgin, Herbert W.

2015-01-01

SUMMARY Decreases in the diversity of enteric bacterial populations are observed in patients with Crohn’s disease (CD) and ulcerative colitis (UC). Less is known about the virome in these diseases. We show that the enteric virome is abnormal in CD and UC patients. In-depth analysis of preparations enriched for free virions in the intestine revealed that CD and UC were associated with a significant expansion of Caudovirales bacteriophages. The viromes of CD and UC patients were disease- and cohort-specific. Importantly, it did not appear that expansion and diversification of the enteric virome was secondary to changes in bacterial populations. These data support a model in which changes in the virome may contribute to intestinal inflammation and bacterial dysbiosis. We conclude that the virome is a candidate for contributing to, or being a biomarker for, human inflammatory bowel disease and speculate that the enteric virome may play a role in other diseases. PMID:25619688

Induction of IL-10 and TGFβ from CD4+CD25+FoxP3+ T Cells Correlates with Parasite Load in Indian Kala-azar Patients Infected with Leishmania donovani

PubMed Central

Bhattacharya, Pradyot; Ghosh, Smriti; Ejazi, Sarfaraz Ahmad; Rahaman, Mehebubar; Pandey, Krishna; Ravi Das, Vidya Nand; Das, Pradeep; Goswami, Rama Prosad; Saha, Bibhuti; Ali, Nahid

2016-01-01

Background Visceral leishmaniasis (VL) is distinguished by a complex interplay of immune response and parasite multiplication inside host cells. However, the direct association between different immunological correlates and parasite numbers remains largely unknown. Methodology/Principal Findings We examined the plasma levels of different disease promoting/protective as well as Th17 cytokines and found IL-10, TGFβ and IL-17 to be significantly correlated with parasite load in VL patients (r = 0.52, 0.53 and 0.51 for IL-10, TGFβ and IL-17, respectively). We then extended our investigation to a more antigen-specific response and found leishmanial antigen stimulated levels of both IL-10 and TGFβ to be significantly associated with parasite load (r = 0.71 and 0.72 for IL-10 and TGFβ respectively). In addition to cytokines we also looked for different cellular subtypes that could contribute to cytokine secretion and parasite persistence. Our observations manifested an association between different Treg cell markers and disease progression as absolute numbers of CD4+CD25+ (r = 0.55), CD4+CD25hi (r = 0.61) as well as percentages of CD4+CD25+FoxP3+ T cells (r = 0.68) all correlated with parasite load. Encouraged by these results, we investigated a link between these immunological components and interestingly found both CD4+CD25+ and CD4+CD25+FoxP3+ Treg cells to secrete significantly (p<0.05) higher amounts of not only IL-10 but also TGFβ in comparison to corresponding CD25- T cells. Conclusions/Significance Our findings shed some light on source(s) of TGFβ and suggest an association between these disease promoting cytokines and Treg cells with parasite load during active disease. Moreover, the direct evidence of CD4+CD25+FoxP3+ Treg cells as a source of IL-10 and TGFβ during active VL could open new avenues for immunotherapy towards cure of this potentially fatal disease. PMID:26829554

Increase of Alternatively Activated Antigen Presenting Cells in Active Experimental Autoimmune Encephalomyelitis.

PubMed

Wasser, Beatrice; Pramanik, Gautam; Hess, Moritz; Klein, Matthias; Luessi, Felix; Dornmair, Klaus; Bopp, Tobias; Zipp, Frauke; Witsch, Esther

2016-12-01

The importance of CD11c + antigen-presenting cells (APCs) in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) is well accepted and the gate keeper function of perivascular CD11c + APCs has been demonstrated. CD11c can be expressed by APCs from external sources or by central nervous system (CNS) resident APCs such as microglia. Yet, changes in the gene expression pattern of CNS CD11c + APCs during disease are still unclear and differentially expressed genes might play a decisive role in EAE progression. Due to their low numbers in the diseased brain and due to the absence of considerable numbers in the healthy CNS, analysis of CNS CD11c + cells is technically difficult. To ask whether the CD11c + APC population contributes to remission of EAE disease, we used Illumina deep mRNA sequencing (RNA-Seq) and quantitative real time polymerase chain reaction (qRT-PCR) analyses to identify the transcriptome of CD11c + APCs during disease course. We identified a battery of genes that were significantly regulated during the exacerbation of the disease compared to remission and relapse. Three of these genes, Arginase-1, Chi3l3 and Ms4a8a, showed a higher expression at the exacerbation than at later time points during the disease, both in SJL/J and in C57BL/6 mice, and could be attributed to alternatively activated APCs. Expression of Arginase-1, Chi3l3 and Ms4a8a genes was linked to the disease phase of EAE rather than to disease score. Expression of these genes suggested that APCs resembling alternatively activated macrophages are involved during the first wave of neuroinflammation and can be directly associated with the disease progress.

[Coronary disease extension determines mobilization of endothelial progenitor cells and cytokines after a first myocardial infarction with ST elevation].

PubMed

Jiménez-Navarro, Manuel F; González, Francisco Jesús; Caballero-Borrego, Juan; Marchal, Juan Antonio; Rodríguez-Losada, Noela; Carrillo, Esmeralda; García-Pinilla, José Manuel; Hernández-García, José M; Pérez-González, Rita; Ramírez, Gemma; Aránega, Antonia; de Teresa Galván, Eduardo

2011-12-01

Multivessel coronary disease is still a postinfarction prognostic marker despite new forms of reperfusion, such as primary angioplasty. The aim of this study was to determine the time sequence of various sets of endothelial progenitor cells and angiogenic cytokines (vascular endothelial growth factor, hepatocyte growth factor) according to the degree of extension of the postinfarction coronary disease. We studied the release kinetics in 32 patients admitted for a first myocardial infarction with ST elevation, grouped according to whether they had single or multivessel disease, and 26 controls. The patients had a higher number of endothelial progenitor cells and angiogenic cytokines than the controls at all 3 measurements (admission, day 3, and day 7) of the following subsets: CD34, CD34+CD133+, CD34+KDR+, and CD34+CD133+KDR+CD45+(weak); this latter was higher on day 7. The levels of these cell subsets were all higher in the patients with single-vessel disease and at all 3 measurements. The vascular endothelial growth factor levels were raised during the first week and the hepatocyte growth factor showed an early peak on admission for infarction. No significant differences were seen in the cytokines according to coronary disease extension. Although the release kinetics of different subsets of endothelial progenitor cells in patients with a first acute myocardial infarction with ST elevation was similar in those with single vessel disease to those with multivessel disease, the number of circulating endothelial progenitor cells was greater in the patients with single vessel disease. The vascular endothelial growth factor levels were raised during the first postinfarction week and the hepatocyte growth factor were higher on admission. Copyright © 2011 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.

Flow cytometric detection of endothelial microparticles (EMP): effects of centrifugation and storage alter with the phenotype studied.

PubMed

van Ierssel, Sabrina H; Van Craenenbroeck, Emeline M; Conraads, Viviane M; Van Tendeloo, Viggo F; Vrints, Christiaan J; Jorens, Philippe G; Hoymans, Vicky Y

2010-04-01

Endothelial microparticles (EMP) are released into the circulation in case of endothelial disturbance, and are therefore increasingly investigated as a biomarker reflecting disease activity. Numerous pre-analytic methods have been proposed for their flow cytometric enumeration, but standardization is still lacking. In this study we evaluated the influence of centrifugation and storage conditions on EMP quantification. Platelet-poor plasma (PPP) from 10 healthy volunteers was prepared by centrifugation at 1,550 g for 20 minutes twice. A first aliquot of PPP was analyzed immediately, a second after storage at 4 degrees C for 7 hours. A third and fourth aliquot were snap-frozen and stored at -80 degrees C for 7 and 28 days. A final aliquot was further centrifuged at 10,000g for 10 minutes and analyzed immediately. EMP were defined as CD31+CD42b-, CD62E+, CD144+ or CD144+CD105+ particles, smaller than 1.0 microm. High speed centrifugation led to a significant loss of CD31+CD42b- EMP (p=0.004). A good correlation between PPP and high speed centrifuged PPP was only found for CD144+ EMP (Kendall tau b=0.611, p=0.025). Storage at 4 degrees C did not affect EMP quantification. However, freezing at -80 degrees C increased CD31+CD42b- and CD62E+ EMP counts, and lowered CD144+ EMP (p<0.05). Nevertheless, the agreement among the different storage conditions was relatively good (Kendall coefficient of concordance >0.487; p<0.05). The flow cytometric detection of EMP varies with the centrifugation protocol and the storage method used, and these changes also depend on the phenotype studied. The results of this study caution against comparing study results gathered with different EMP laboratory protocols. (c) 2010 Elsevier Ltd. All rights reserved.

Immunomodulatory activity of interleukin-27 in human chronic periapical diseases.

PubMed

Li, Juan; Wang, Rong; Huang, Shi-Guang

2017-01-01

This study aims to observe expression of IL-27 on different cells in periapical tissues of different types of human chronic periapical diseases. Periapical tissue specimens of 60 donors, including healthy control (n=20), periapical granuloma group (n=20) and radicular cysts group (n=20), were fixed in 10% buffered formalin, stained with hematoxylin and eosin for histopathology. Then specimens were stained with double- immuno-fluorescence assay for identification of IL-27-tryptase (mast cells, MCs), IL-27-CD14 (mononuclear phagocyte cells, MPs) and IL-27-CD31 (endothelial cells, ECs) double-positive cells in periapical tissues. The results indicated that compared with healthy control, the densities (cells/mm 2 ) of IL-27-tryptase, IL-27-CD14 and IL-27-CD31 double-positive cells were significantly increased in human chronic periapical diseases (periapical granuloma group and radicular cysts group) ( P <0.001). The density of IL-27-tryptase double positive cells in radicular cysts group was significantly higher than those in periapical granuloma group ( P <0.001). Densities of IL-27-CD14 and IL-27-CD31 double-positive cells in periapical granuloma group had no significant difference with those in radicular cysts group ( P =0.170 and 0.138, respectively). IL-27-CD14 double positive cells density achieved to peak among three cell groups in radicular cysts groups. In conclusion, IL-27 expressed in MCs, MPs and ECs of human chronic periapical diseases with different degrees. IL-27-tryptase double-positive cells may participate in pathogenic mechanism of chronic periapical diseases, especially for formation of fibrous in periapical cysts. IL-27-CD14 and IL-27-CD31 double-positive cells may participate in immunologic response to resist periapical infection, and they may play an dual role in pathogenesis and localization of periapical diseases.

Evaluation of 22 genetic variants with Crohn's disease risk in the Ashkenazi Jewish population: a case-control study.

PubMed

Peter, Inga; Mitchell, Adele A; Ozelius, Laurie; Erazo, Monica; Hu, Jianzhong; Doheny, Dana; Abreu, Maria T; Present, Daniel H; Ullman, Thomas; Benkov, Keith; Korelitz, Burton I; Mayer, Lloyd; Desnick, Robert J

2011-05-06

Crohn's disease (CD) has the highest prevalence among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Caucasian populations (NJ). We evaluated a set of well-established CD-susceptibility variants to determine if they can explain the increased CD risk in the AJ population. We recruited 369 AJ CD patients and 503 AJ controls, genotyped 22 single nucleotide polymorphisms (SNPs) at or near 10 CD-associated genes, NOD2, IL23R, IRGM, ATG16L1, PTGER4, NKX2-3, IL12B, PTPN2, TNFSF15 and STAT3, and assessed their association with CD status. We generated genetic scores based on the risk allele count alone and the risk allele count weighed by the effect size, and evaluated their predictive value. Three NOD2 SNPs, two IL23R SNPs, and one SNP each at IRGM and PTGER4 were independently associated with CD risk. Carriage of 7 or more copies of these risk alleles or the weighted genetic risk score of 7 or greater correctly classified 92% (allelic count score) and 83% (weighted score) of the controls; however, only 29% and 47% of the cases were identified as having the disease, respectively. This cutoff was associated with a >4-fold increased disease risk (p < 10e-16). CD-associated genetic risks were similar to those reported in NJ population and are unlikely to explain the excess prevalence of the disease in AJ individuals. These results support the existence of novel, yet unidentified, genetic variants unique to this population. Understanding of ethnic and racial differences in disease susceptibility may help unravel the pathogenesis of CD leading to new personalized diagnostic and therapeutic approaches.

Virus-induced dysfunction of CD4+CD25+ T cells in patients with HTLV-I-associated neuroimmunological disease.

PubMed

Yamano, Yoshihisa; Takenouchi, Norihiro; Li, Hong-Chuan; Tomaru, Utano; Yao, Karen; Grant, Christian W; Maric, Dragan A; Jacobson, Steven

2005-05-01

CD4(+)CD25(+) Tregs are important in the maintenance of immunological self tolerance and in the prevention of autoimmune diseases. As the CD4(+)CD25(+) T cell population in patients with human T cell lymphotropic virus type I-associated (HTLV-I-associated) myelopathy/tropical spastic paraparesis (HAM/TSP) has been shown to be a major reservoir for this virus, it was of interest to determine whether the frequency and function of CD4(+)CD25(+) Tregs in HAM/TSP patients might be affected. In these cells, both mRNA and protein expression of the forkhead transcription factor Foxp3, a specific marker of Tregs, were lower than those in CD4(+)CD25(+) T cells from healthy individuals. The virus-encoded transactivating HTLV-I tax gene was demonstrated to have a direct inhibitory effect on Foxp3 expression and function of CD4(+)CD25(+) T cells. This is the first report to our knowledge demonstrating the role of a specific viral gene product (HTLV-I Tax) on the expression of genes associated with Tregs (in particular, foxp3) resulting in inhibition of Treg function. These results suggest that direct human retroviral infection of CD4(+)CD25(+) T cells may be associated with the pathogenesis of HTLV-I-associated neurologic disease.

Interethnic diversity of the CD209 (rs4804803) gene promoter polymorphism in African but not American sickle cell disease.

PubMed

Noble, Jenelle A; Duru, Kimberley C; Guindo, Aldiouma; Yi, Li; Imumorin, Ikhide G; Diallo, Dapa A; Thomas, Bolaji N

2015-01-01

Elucidating the genomic diversity of CD209 gene promoter polymorphism could assist in clarifying disease pathophysiology as well as contribution to co-morbidities. CD209 gene promoter polymorphism has been shown to be associated with susceptibility to infection. We hypothesize that CD209 mutant variants occur at a higher frequency among Africans and in sickle cell disease. We analyzed the frequency of the CD209 gene (rs4804803) in healthy control and sickle cell disease (SCD) populations and determined association with disease. Genomic DNA was extracted from blood samples collected from 145 SCD and 231 control Africans (from Mali), 331 SCD and 379 control African Americans and 159 Caucasians. Comparative analysis among and between groups was carried out by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Per ethnic diversification, we found significant disparity in genotypic (23.4% versus 16.9% versus 3.2%) and allelic frequencies (48.7% versus 42.1% versus 19.8%) of the homozygote mutant variant of the CD209 (snp 309A/G) gene promoter between Africans, African Americans and Caucasians respectively. Comparative evaluation between disease and control groups reveal a significant difference in genotypic (10.4% versus 23.4%; p = 0.002) and allelic frequencies (39.7% versus 48.7%; p = 0.02) of the homozygote mutant variant in African SCD and healthy controls respectively, an observation that is completely absent among Americans. Comparing disease groups, we found no difference in the genotypic (p = 0.19) or allelic (p = 0.72) frequencies of CD209 homozygote mutant variant between Africans and Americans with sickle cell disease. The higher frequency of CD209 homozygote mutant variants in the African control group reveals a potential impairment of the capacity to mount an immune response to infectious diseases, and possibly delineate susceptibility to or severity of infectious co-morbidities within and between groups.

Interethnic diversity of the CD209 (rs4804803) gene promoter polymorphism in African but not American sickle cell disease

PubMed Central

Noble, Jenelle A.; Duru, Kimberley C.; Guindo, Aldiouma; Yi, Li; Imumorin, Ikhide G.; Diallo, Dapa A.

2015-01-01

Elucidating the genomic diversity of CD209 gene promoter polymorphism could assist in clarifying disease pathophysiology as well as contribution to co-morbidities. CD209 gene promoter polymorphism has been shown to be associated with susceptibility to infection. We hypothesize that CD209 mutant variants occur at a higher frequency among Africans and in sickle cell disease. We analyzed the frequency of the CD209 gene (rs4804803) in healthy control and sickle cell disease (SCD) populations and determined association with disease. Genomic DNA was extracted from blood samples collected from 145 SCD and 231 control Africans (from Mali), 331 SCD and 379 control African Americans and 159 Caucasians. Comparative analysis among and between groups was carried out by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Per ethnic diversification, we found significant disparity in genotypic (23.4% versus 16.9% versus 3.2%) and allelic frequencies (48.7% versus 42.1% versus 19.8%) of the homozygote mutant variant of the CD209 (snp 309A/G) gene promoter between Africans, African Americans and Caucasians respectively. Comparative evaluation between disease and control groups reveal a significant difference in genotypic (10.4% versus 23.4%; p = 0.002) and allelic frequencies (39.7% versus 48.7%; p = 0.02) of the homozygote mutant variant in African SCD and healthy controls respectively, an observation that is completely absent among Americans. Comparing disease groups, we found no difference in the genotypic (p = 0.19) or allelic (p = 0.72) frequencies of CD209 homozygote mutant variant between Africans and Americans with sickle cell disease. The higher frequency of CD209 homozygote mutant variants in the African control group reveals a potential impairment of the capacity to mount an immune response to infectious diseases, and possibly delineate susceptibility to or severity of infectious co-morbidities within and between groups. PMID:25755928

Serum anti-glycan antibodies in paediatric-onset Crohn's disease: association with disease phenotype and diagnostic accuracy.

PubMed

Sładek, Małgorzata; Wasilewska, Agata; Swiat, Agnieszka; Cmiel, Adam

2014-01-01

Antibodies reacting with various microbial epitopes have been described in inflammatory bowel disease (IBD) and are associated with a specific diagnosis and clinical presentation. To evaluate the profile of new anti-glycan antibodies, their potential association with disease phenotype and diagnostic accuracy in paediatric Crohn's disease (CD). Blood samples from 134 paediatric IBD patients (109 CD, 25 ulcerative colitis (UC)) and 67 controls were blindly analysed for anti-Saccharomyces cerevisiae (ASCA), anti-chitobioside carbohydrate (ACCA), anti-laminaribioside carbohydrate (ALCA), and anti-mannobioside carbohydrate (AMCA) antibodies using commercially available assays. The serological response to glycans was correlated with clinical disease characteristics. At least one of the tested anti-glycan antibodies was present in 75% of CD patients. Despite the high frequency of reactivity to glycan epitopes, a limited overlap of serological markers was observed. In total, 49% of ASCA-negative patients presented with one of the following: ACCA, ALCA, or AMCA. The occurrence of one antibody from the anti-glycan panel was independently associated with complicated disease phenotype and ileocolonic disease location. A higher level of immune response as assessed by the quartile sum scores for ACCA, ALCA, and AMCA was linked with older age at diagnosis (10-17 years) and ileocolonic disease location. The ASCA had the greatest accuracy for diagnosis and differentiation of CD. Qualitative and quantitative serologicalal response to glycan epitopes was associated with distinct clinical presentation in paediatric CD patients. This raises the possibility for the use of these markers to differentiate subgroups of CD patients with more sever clinical presentation. The ASCA was the most accurate serological marker for CD; however, testing for the new anti-glycan antibodies may constitute an adjunctive tool in a specific group of patients to aid in the differentiation of CD with absent ASCA from ulcerative colitis.

Accurate secondary structure prediction and fold recognition for circular dichroism spectroscopy

PubMed Central

Micsonai, András; Wien, Frank; Kernya, Linda; Lee, Young-Ho; Goto, Yuji; Réfrégiers, Matthieu; Kardos, József

2015-01-01

Circular dichroism (CD) spectroscopy is a widely used technique for the study of protein structure. Numerous algorithms have been developed for the estimation of the secondary structure composition from the CD spectra. These methods often fail to provide acceptable results on α/β-mixed or β-structure–rich proteins. The problem arises from the spectral diversity of β-structures, which has hitherto been considered as an intrinsic limitation of the technique. The predictions are less reliable for proteins of unusual β-structures such as membrane proteins, protein aggregates, and amyloid fibrils. Here, we show that the parallel/antiparallel orientation and the twisting of the β-sheets account for the observed spectral diversity. We have developed a method called β-structure selection (BeStSel) for the secondary structure estimation that takes into account the twist of β-structures. This method can reliably distinguish parallel and antiparallel β-sheets and accurately estimates the secondary structure for a broad range of proteins. Moreover, the secondary structure components applied by the method are characteristic to the protein fold, and thus the fold can be predicted to the level of topology in the CATH classification from a single CD spectrum. By constructing a web server, we offer a general tool for a quick and reliable structure analysis using conventional CD or synchrotron radiation CD (SRCD) spectroscopy for the protein science research community. The method is especially useful when X-ray or NMR techniques fail. Using BeStSel on data collected by SRCD spectroscopy, we investigated the structure of amyloid fibrils of various disease-related proteins and peptides. PMID:26038575

Killing of Escherichia coli by Crohn's Disease Monocyte-derived Macrophages and Its Enhancement by Hydroxychloroquine and Vitamin D

PubMed Central

Flanagan, Paul K.; Chiewchengchol, Direkrit; Wright, Helen L.; Edwards, Steven W.; Alswied, Abdullah; Satsangi, Jack; Subramanian, Sreedhar; Rhodes, Jonathan M.

2015-01-01

Background: Crohn's disease (CD) is associated with defective innate immunity, including impaired neutrophil chemotaxis, and mucosal invasion by bacteria, particularly adherent and invasive Escherichia coli that replicate inside macrophage phagolysosomes. We compared CD and healthy control (HC) macrophages for their abilities to kill E. coli and generate neutrophil chemoattractants and also assessed the effects of hydroxychloroquine (HCQ) and vitamin D on killing of phagocytosed E. coli. Methods: Peripheral blood monocyte-derived macrophages from CD and HC were compared for bacterial killing and generation of neutrophil chemoattractants in response to CD-derived E. coli. Escherichia coli replication was also assessed in the presence and absence of HCQ, alone and with antibiotics, and vitamin D. Results: Monocyte-derived macrophages from patients with CD were similar to HC in allowing replication of phagocytosed CD-derived E. coli: HM605 {CD: N = 10, mean fold replication in 3 hr = 1.08 (95% confidence interval [CI], 0.39–1.78); HC: N = 9, 1.50 (95% CI, 1.02–1.97); P = 0.15} and also in generation of neutrophil chemoattractants in response to E. coli (mean fold chemotaxis relative to control: CD = 2.55 [95% CI, 2.31–2.80]; HC = 2.65 [95% CI, 2.46–2.85], P = 0.42). HCQ and 1,25 OH2-vitamin D3 both caused dose-dependent inhibition of intramacrophage E. coli replication 3-hour postinfection; HCQ: 73.9% inhibition (P < 0.001) at 1 μg/mL, accompanied by raised intraphagosomal pH, and 1,25 OH2-vitamin D3: 80.7% inhibition (P < 0.05) at 80 nM. HCQ had synergistic effects with doxycycline and ciprofloxacin. Conclusions: CD and HC macrophages perform similarly in allowing replication of phagocytosed E. coli and generating neutrophil chemoattractants. Replication of phagocytosed E. coli was substantially decreased by HCQ and vitamin D. These warrant further therapeutic trials in CD in combination with relevant antibiotics. PMID:25839777

[CD69 expression on T cell surface in patients with obstructive sleep apnea hypopnea syndrome].

PubMed

Chen, Y H; Wang, P F; Wang, H J; Hu, X; Li, Z Y; Xiong, H Q

2017-02-20

Objective: To investigate the detection and significance of T cell CD69 expression in peripheral blood of patients with obstructive sleep apnea hypopnea syndrome (OSAHS). Method: According to AHI, 81 OSAHS patients diagnosed by PSG were divided into 3 groups: light, medium and heavy, with 27 cases in each group; 27 patients without OSAHS as control group. Flow cytometry was used to detect the expression rate of CD69 in T cells, to analyze the correlation between the expression rate of CD69 on T cells and the gender, age, BMI, and PSG index. Result: ①The CD69 expression rate of T cells in peripheral blood of OSAHS patients with snoring degree increases gradually ( P < 0.05); Comparison between the two shows that there was no significant difference in CD69 expression rate on T cells between the control group and the mild group ( t = 1.649, P > 0.05); there were significant differences between the other groups ( P < 0.05). ②The CD69 expression rate of T cells in peripheral blood of OSAHS patients has no correlation with BMI, age and gender ( P > 0.05), were positively correlated with AHI, negatively correlated with LSaO₂ ( P < 0.01). ③The CD69 expression rate of T cells and AHI in 27 cases of severe OSAHS patients with a comprehensive treatment has significantly reduced, LSaO₂ increased significantly ( P < 0.01). Conclusion: Increased expression of CD69 in peripheral blood T cells may be one of the mechanisms of OSAHS complicated with cardiovascular disease. Detection of CD69 expression rate in T cells for reflecting the degree of disease in patients with OSAHS, assessment of risk of cardiovascular damage, have certain clinical significance. Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.

Endoglin (CD105) expression in the development of haemorrhoids.

PubMed

Chung, Y-C; Hou, Y-C; Pan, A C-H

2004-02-01

Conventional pathogenesis of haemorrhoid emphasized the anchoring connective tissue system, whereas the vascular changes were ignored. The aim of this study was to clarify vascular changes of haemorrhoid disease. Forty-six samples of grade III and grade IV haemorrhoid tissue were selected for an in vitro study. We assessed the expressions in endoglin (CD105), an accessory protein in transforming growth factor-beta receptor complex, in CD34 and in vascular endothelial growth factor by using an immunohistochemical method. Microvascular density was calculated to correlate the expression of endoglin. Microvascular density was higher in haemorrhoid tissue than in normal anal and lower rectal tissues. CD34 was demonstrated in whole vessels in the haemorrhoids. However, endoglin, a proliferative marker of neovascularization, was present in only 25 of 46 (54%) haemorrhoidal vessels, and its immunoactivity was prominent in venules larger than 100 micro m. Thrombosis formation and stromal vascular endothelial growth factor was significantly associated with the presence of endoglin immunoactivity. The results of this study suggest that neovascularization is one important phenomenon of haemorrhoid disease, along with conventional venous dilatation and arteriovenous communication. In addition, thrombosis and stromal vascular endothelial growth factor might be important factors in promoting vascular proliferation.

Celiac disease: Serologic prevalence in patients with irritable bowel syndrome

PubMed Central

Mehdi, Zobeiri; Sakineh, Ebrahimi; Mohammad, Farahvash; Mansour, Rezaei; Alireza, Abdollahi

2012-01-01

Background: The prevalence of irritable bowel syndrome (IBS) in the community is 10%–20% and have symptom based diagnostic criteria. Many symptoms of celiac disease (CD) with 1% prevalence in some communities can mimic IBS. Sensitive and specific serologic tests of CD can detect asymptomatic cases. The purpose of this study was to compare the level of anti-tissue-transglutaminase (tTG) IgA in IBS patients and controls group. Materials and Methods: This case-control study was performed at a University hospital in which 107 patients with IBS who met the Rome II criteria for their diagnosis were compared with 126 healthy age and sex-matched controls. Both groups were investigated for CD by analysis of their serum tTG IgA antibody with human recombinant antigen. Titers were positive containing over 10u/ml and borderline if they were between 4 and 10 u/ml. Result: 86 percent of IBS patients were female. The mean antibody level was 0.837 u/ml in IBS group and 0.933 u/ml in control group without any significant difference. Discussion and Conclusion: Results of this study may intensify disagreement on the situation of CD in IBS patients. PMID:23826010

Health-Related Quality of Life Impairment and Indirect Cost of Crohn’s Disease: A Self-Report Study in Poland

PubMed Central

Kawalec, Paweł; Mossakowska, Małgorzata; Pilc, Andrzej

2016-01-01

Background and Aims Evidence on indirect cost of Crohn’s disease (CD) is available but typically provides information on the loss of productivity at paid work of patients. In the present study, the quality of life and indirect costs of CD patients were assessed (overall and by disease severity). Methods A self-report questionnaire-based study among adult Polish patients with CD was performed. We collected data on patients’ characteristics, quality of life, loss of productivity, consumption of medical resources, and out-of-pocket expenses. The disease severity was determined using the patient’s version of the Harvey-Bradshaw index. Productivity costs were assessed from the social perspective, using a human capital approach. The cost of absenteeism, presenteeism and permanent work disability was valuated using the gross domestic product per worker. The patients’ productivity loss at unpaid work was measured by time inputs of others to assist patients. The productivity loss among informal caregivers and patients’ productivity loss at unpaid work were valuated with the average wage in Poland. The results were adjusted for confounders. Results The responses from 200 patients (47% in remission) were analysed. The mean utility index was 0.839 (SD 0.171). The total indirect cost was estimated at €462.47 per patient per month (24.0%, absenteeism; 35.0%, work disability; 30.4%, presenteeism; 0.4%, productivity loss at unpaid work; and 10.4%, informal care). A significant correlation of the quality of life and productivity losses with disease severity was observed. Compared with active disease, the remission subgroup had a higher utility index by 16% (p<0.001) and lower indirect costs by 71% (p = 0.003) for absenteeism, 41% (p = 0.030) for presenteeism, 76% (p<0.001) for productivity loss at unpaid work, and 75% (p<0.001) for informal care. Conclusions Our study revealed the social burden of CD and high dependency of indirect costs and quality of life on the severity of CD in Poland. PMID:27992531

The Impact of Thyroid Autoimmunity on Thyroid Function in 12-year-old Children With Celiac Disease.

PubMed

Norström, Fredrik; van der Pals, Maria; Myléus, Anna; Hammarroth, Solveig; Högberg, Lotta; Isaksson, Anders; Ivarsson, Anneli; Carlsson, Annelie

2018-01-25

Celiac disease (CD) is associated with thyroid autoimmunity and other autoimmune diseases. However, data are lacking regarding the relationship between thyroid autoimmunity and thyroid function, especially in regard to CD. Our aim was to investigate the impact of thyroid autoimmunity on thyroid function in 12-year-old children with CD compared to their healthy peers. A case-referent study was conducted as part of a CD screening of 12-year-olds. Our study included 335 children with CD and 1,695 randomly selected referents. Thyroid autoimmunity was assessed with antibodies against thyroid peroxidase (TPOAb). Thyroid function was assessed with thyroid stimulating hormone and free thyroxine. TPOAb positivity significantly increased the risk of developing hypothyroidism in all children. The odds ratios (with 95% confidence intervals) were: 5.3 (2.7-11) in healthy 12-year-olds, 10 (3.2-32) in screening-detected CD cases, 19 (2.6-135) in previously diagnosed CD cases, and 12 (4.4-32) in all CD cases together. Among children with TPOAb positivity, hypothyroidism was significantly more common (odds ratio 3.1; 95% CI 1.03-9.6) in children with CD (10/19) than in children without CD (12/46). The risk of thyroid dysfunction due to thyroid autoimmunity is larger for those with CD than their healthy peers. Our study indicate that a gluten-free diet does not reduce the risk of thyroid dysfunction. Further studies are required for improved understanding of the role of the gluten-free diet for the risk of autoimmune diseases in children with CD.

Frequency of celiac disease in adult patients with typical or atypical malabsorption symptoms in isfahan, iran.

PubMed

Emami, Mohammad Hassan; Kouhestani, Soheila; Karimi, Somayeh; Baghaei, Abdolmahdi; Janghorbani, Mohsen; Jamali, Nahid; Gholamrezaei, Ali

2012-01-01

Aim. Atypical presentations of celiac disease (CD) have now been shown to be much more common than classical (typical) form. We evaluated the frequency of CD among adult patients with typical or atypical symptoms of CD. Materials and Methods. Patients referred to two outpatient gastroenterology clinics in Isfahan (IRAN) were categorized into those with typical or atypical symptoms of CD. IgA antitissue transglutaminase antibody was assessed and followed by duodenal biopsy. In patients for whom endoscopy was indicated (independent of the serology), duodenal biopsy was taken. Histopathological changes were assessed according to the Marsh classification. Results. During the study period, 151 and 173 patients with typical and atypical symptoms were evaluated (mean age = 32.8 ± 12.6 and 35.8 ± 14.8 years, 47.0% and 56.0% female, resp.). Frequency of CD in patients with typical and atypical symptoms was calculated, respectively, as 5.9% (9/151) and 1.25% (3/173) based on positive serology and pathology. The overall frequency was estimated as at least 9.2% (14/151) and 4.0% (7/173) when data of seronegative patients were also considered. Conclusions. CD is more frequent among patients with typical symptoms of malabsorption and these patients should undergo duodenal biopsy, irrespective of the serology. In patients with atypical symptoms, serological tests should be performed followed by endoscopic biopsy, and routine duodenal biopsy is recommended when endoscopic evaluation is indicated because of symptoms.

The multidisciplinary health care team in the management of stenosis in Crohn’s disease

PubMed Central

Gasparetto, Marco; Angriman, Imerio; Guariso, Graziella

2015-01-01

Background Stricture formation is a common complication of Crohn’s disease (CD), occurring in approximately one-third of all patients with this condition. Our aim was to summarize the available epidemiology data on strictures in patients with CD, to outline the principal evidence on diagnostic imaging, and to provide an overview of the current knowledge on treatment strategies, including surgical and endoscopic options. Overall, the unifying theme of this narrative review is the multidisciplinary approach in the clinical management of patients with stricturing CD. Methods A Medline search was performed, using “Inflammatory Bowel Disease”, “stricture”, “Crohn’s Disease”, “Ulcerative Colitis”, “endoscopic balloon dilatation” and “strictureplasty” as keywords. A selection of clinical cohort studies and systematic reviews were reviewed. Results Strictures in CD are described as either inflammatory or fibrotic. They can occur de novo, at sites of bowel anastomosis or in the ileal pouch. CD-related strictures generally show a poor response to medical therapies, and surgical bowel resection or surgical strictureplasty are often required. Over the last three decades, the potential role of endoscopic balloon dilatation has grown in importance, and nowadays this technique is a valid option, complementary to surgery. Conclusion Patients with stricturing CD require complex clinical management, which benefits from a multidisciplinary approach: gastroenterologists, pediatricians, radiologists, surgeons, specialist nurses, and dieticians are among the health care providers involved in supporting these patients throughout diagnosis, prevention of complications, and treatment. PMID:25878504

[Cutaneous involvement in chronic inflammatory bowel disease : Crohn's disease and ulcerative colitis].

PubMed

Richter, L; Rappersberger, K

2016-12-01

Over recent decades, both the incidence and prevalence of chronic inflammatory bowel disease have continued to rise in industrialized countries; the disease is frequently associated with extracutaneous involvement and comorbidity. The purpose of this work was to investigate the frequency and specificity of mucocutaneous manifestations in Crohn's disease (CD) and ulcerative colitis (UC). An extensive search in peer-reviewed journals via PubMed was performed; presented is a summary and analysis of various studies and data, including data of patients treated at our department. CD and UC are frequently associated with mucocutaneous symptoms; however, primary/specific disease-associations are exclusively seen in CD patients. These include peri-anal and -stomal fistulas and ulcerations, "metastatic" Crohn's disease as well as oral granulomatous disease. Moreover, in both CD and UC, there occur several other inflammatory skin conditions such as erythema nodosum, pyoderma gangrenosum, hidradenitis suppurativa, chronic oral aphthous disease, Sweet syndrome, pyostomatitis vegetans, and bowel-associated dermatosis-arthritis syndrome. Malnutrition syndromes (zinc and vitamin deficiencies) are only rarely observed. On skin and oral/genital mucous membranes various different inflammatory manifestations may be observed during the course of CD or UC. However, most data about a direct pathogenic relationship of the gastrointestinal and dermatologic disorders are quite heterogeneous or even contradictory. Nevertheless, knowledge of these conditions and their possible association with CD and UC could be crucial for early diagnosis and initiation of an appropriate therapy and thus be essential to prevent secondary tissue damage.

An inducible model of abacterial prostatitis induces antigen specific inflammatory and proliferative changes in the murine prostate

PubMed Central

Haverkamp, Jessica M.; Charbonneau, Bridget; Meyerholz, David K.; Cohen, Michael B.; Snyder, Paul W.; Svensson, Robert U.; Henry, Michael D.; Wang, Hsing- Hui

2011-01-01

Background Prostatitis is a poorly understood disease and increasing evidence suggests inflammation is involved in other prostatic diseases, including prostate cancer. Methods The ability of pre-activated CD8 T cells to induce prostatitis was examined by adoptive transfer into POET-3 mice or POET-3/Luc/Pten−/+ mice. Characterization of the inflammatory response was determined by examining leukocyte infiltration by histological analysis, flow cytometry and by evaluating cytokine and chemokine levels in prostate tissue. The impact of inflammation on the prostate was evaluated by monitoring epithelial cell proliferation over time. Results Initiation of inflammation by ovalbumin specific CD8+ T cells (OT-I cells) resulted in development of acute prostatitis in the anterior, dorsolateral and anterior prostate of POET-3 and POET-3/Luc/Pten−/+ mice. Acute prostatitis was characterized by recruitment of adoptively transferred OT-I cells and importantly, autologous CD4+ and CD8+ T cells, myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg). In concert with leukocyte infiltration elevated levels of pro-inflammatory cytokines and chemokines were observed. Inflammation also resulted in marked epithelial cell proliferation that was sustained up to 80 days post adoptive-transfer of OT-I cells. Conclusions The POET-3 model represents a novel mouse model to study both acute and chronic prostate inflammation in an antigen-specific system. Further, the POET-3 mouse model can be crossed with other genetic models of disease such as the C57/Luc/Pten−/− model of prostate cancer, allowing the impact of prostatitis on other prostatic diseases to be evaluated. PMID:21656824

Screening of celiac disease in Down syndrome - Old and new dilemmas

PubMed Central

Pavlovic, Momcilo; Berenji, Karolina; Bukurov, Marko

2017-01-01

Celiac disease (CD) is a common and well defined autoimmune disorder caused by gliadin and related proteins of wheat, rye, and barley. Epidemiologic studies confirmed that CD is highly associated with other autoimmune diseases and with Down syndrome (DS). The symptomatic form of CD in patients with DS is more frequent than asymptomatic forms. However, growth impairment, anemia, intermittent diarrhea, and constipation are symptoms and signs typically of children with DS without CD. Late identification of the disease can lead to various complications, sometimes even very severe. Therefore, systematic screening for CD is essential in the management of children and adolescents with DS. Many medical organizations recommend screening in this group of patients. However, current policy statements vary in their recommendations for screening and there is still a need for establishing uniform diagnostic criteria. PMID:28798921

Screening of celiac disease in Down syndrome - Old and new dilemmas.

PubMed

Pavlovic, Momcilo; Berenji, Karolina; Bukurov, Marko

2017-07-16

Celiac disease (CD) is a common and well defined autoimmune disorder caused by gliadin and related proteins of wheat, rye, and barley. Epidemiologic studies confirmed that CD is highly associated with other autoimmune diseases and with Down syndrome (DS). The symptomatic form of CD in patients with DS is more frequent than asymptomatic forms. However, growth impairment, anemia, intermittent diarrhea, and constipation are symptoms and signs typically of children with DS without CD. Late identification of the disease can lead to various complications, sometimes even very severe. Therefore, systematic screening for CD is essential in the management of children and adolescents with DS. Many medical organizations recommend screening in this group of patients. However, current policy statements vary in their recommendations for screening and there is still a need for establishing uniform diagnostic criteria.

CD127 and CD25 Expression Defines CD4+ T Cell Subsets That Are Differentially Depleted during HIV Infection1

PubMed Central

Dunham, Richard M.; Cervasi, Barbara; Brenchley, Jason M.; Albrecht, Helmut; Weintrob, Amy; Sumpter, Beth; Engram, Jessica; Gordon, Shari; Klatt, Nichole R.; Frank, Ian; Sodora, Donald L.; Douek, Daniel C.; Paiardini, Mirko; Silvestri, Guido

2009-01-01

Decreased CD4+ T cell counts are the best marker of disease progression during HIV infection. However, CD4+ T cells are heterogeneous in phenotype and function, and it is unknown how preferential depletion of specific CD4+ T cell subsets influences disease severity. CD4+ T cells can be classified into three subsets by the expression of receptors for two T cell-tropic cytokines, IL-2 (CD25) and IL-7 (CD127). The CD127+CD25low/− subset includes IL-2-producing naive and central memory T cells; the CD127−CD25− subset includes mainly effector T cells expressing perforin and IFN-γ; and the CD127lowCD25high subset includes FoxP3-expressing regulatory T cells. Herein we investigated how the proportions of these T cell subsets are changed during HIV infection. When compared with healthy controls, HIV-infected patients show a relative increase in CD4+CD127−CD25− T cells that is related to an absolute decline of CD4+CD127+CD25low/− T cells. Interestingly, this expansion of CD4+CD127− T cells was not observed in naturally SIV-infected sooty mangabeys. The relative expansion of CD4+CD127−CD25− T cells correlated directly with the levels of total CD4+ T cell depletion and immune activation. CD4+CD127−CD25− T cells were not selectively resistant to HIV infection as levels of cell-associated virus were similar in all non-naive CD4+ T cell subsets. These data indicate that, during HIV infection, specific changes in the fraction of CD4+ T cells expressing CD25 and/or CD127 are associated with disease progression. Further studies will determine whether monitoring the three subsets of CD4+ T cells defined based on the expression of CD25 and CD127 should be used in the clinical management of HIV-infected individuals. PMID:18390743

Evaluation of Human FcγRIIA (CD32) and FcγRIIIB (CD16) Polymorphisms in Caucasians and African-Americans Using Salivary DNA

PubMed Central

van Schie, Rob C. A. A.; Wilson, Mark E.

2000-01-01

Two classes of low-affinity receptors for the Fc region of immunoglobulin G (IgG) (FcγR) are constitutively expressed on resting human neutrophils. These receptors, termed FcγRIIa (CD32) and FcγRIIIb (CD16), display biallelic polymorphisms which have functional consequences with respect to binding and/or ingestion of targets opsonized by human IgG subclass antibodies. The H131-R131 polymorphism of CD32 influences binding of human IgG2 and, to a lesser extent, human IgG3 to neutrophils. The neutrophil antigen (NA1-NA2) polymorphism of CD16 influences the efficiency of phagocytosis of bacteria opsonized by human IgG1 and IgG3. These polymorphisms may influence host susceptibility to certain infectious and/or autoimmune diseases, prompting interest in the development of facile methods for determination of CD32 and CD16 genotype in various clinical settings. We previously reported that genomic DNA from saliva is a suitable alternative to DNA from blood in PCR-based analyses of CD32 and CD16 polymorphisms. In the present study, we utilized for the first time this salivary DNA-based methodology to define CD32 and CD16 genotypes in 271 Caucasian and 118 African-American subjects and to investigate possible linkage disequilibrium between certain CD32 and CD16 genotypes in these two ethnic groups. H131 and R131 gene frequencies were 0.45 and 0.55, respectively, among Caucasians and 0.59 among African-Americans. NA1 and NA2 gene frequencies were 0.38 and 0.62 among Caucasians and 0.39 and 0.61 among African-Americans. Since FcγRIIa and FcγRIIIb synergize in triggering neutrophils, we also assessed the frequency of different CD32 and CD16 genotype combinations in these two groups. In both groups, the R/R131-NA2/NA2 genotype combination was more common than the H/H131-NA1/NA1 combination (threefold for Caucasians versus sevenfold for African-Americans). Whether individuals with the combined R/R131-NA2/NA2 genotype are at greater risk for development of infectious and/or autoimmune diseases requires further investigation, which can be conveniently performed using DNA from saliva rather than blood. PMID:10882671

Systemic and mucosal immune reactivity upon Mycobacterium avium ssp. paratuberculosis infection in mice.

PubMed

Koc, Arzu; Bargen, Imke; Suwandi, Abdulhadi; Roderfeld, Martin; Tschuschner, Annette; Rath, Timo; Gerlach, Gerald F; Hornef, Mathias; Goethe, Ralph; Weiss, Siegfried; Roeb, Elke

2014-01-01

Mycobacterium avium ssp. paratuberculosis (MAP) is the cause of Johne's disease, an inflammatory bowel disorder of ruminants. Due to the similar pathology, MAP was also suggested to cause Crohn's disease (CD). Despite of intensive research, this question is still not settled, possibly due to the lack of versatile mouse models. The aim of this study was to identify basic immunologic mechanisms in response to MAP infection. Immune compromised C57BL/6 Rag2-/- mice were infected with MAP intraperitoneally. Such chronically infected mice were then reconstituted with CD4+ and CD8+ T cells 28 days after infection. A systemic inflammatory response, detected as enlargement of the spleen and granuloma formation in the liver, was observed in mice infected and reconstituted with CD4+ T cells. Whereby inflammation in infected and CD4+CD45RB(hi) T cell reconstituted animals was always higher than in the other groups. Reconstitution of infected animals with CD8+ T cells did not result in any inflammatory signs. Interestingly, various markers of inflammation were strongly up-regulated in the colon of infected mice reconstituted with CD4+CD45RB(lo/int) T cells. We propose, the usual non-colitogenic CD4+CD45RB(lo/int) T cells were converted into inflammatory T cells by the interaction with MAP. However, the power of such cells might be not sufficient for a fully established inflammatory response in the colon. Nevertheless, our model system appears to mirror aspects of an inflammatory bowel disease (IBD) like CD and Johne's diseases. Thus, it will provide an experimental platform on which further knowledge on IBD and the involvement of MAP in the induction of CD could be acquired.

Systemic and Mucosal Immune Reactivity upon Mycobacterium avium ssp. paratuberculosis Infection in Mice

PubMed Central

Suwandi, Abdulhadi; Roderfeld, Martin; Tschuschner, Annette; Rath, Timo; Gerlach, Gerald F.; Hornef, Mathias; Goethe, Ralph; Weiss, Siegfried; Roeb, Elke

2014-01-01

Mycobacterium avium ssp. paratuberculosis (MAP) is the cause of Johne's disease, an inflammatory bowel disorder of ruminants. Due to the similar pathology, MAP was also suggested to cause Crohn's disease (CD). Despite of intensive research, this question is still not settled, possibly due to the lack of versatile mouse models. The aim of this study was to identify basic immunologic mechanisms in response to MAP infection. Immune compromised C57BL/6 Rag2 −/− mice were infected with MAP intraperitoneally. Such chronically infected mice were then reconstituted with CD4+ and CD8+ T cells 28 days after infection. A systemic inflammatory response, detected as enlargement of the spleen and granuloma formation in the liver, was observed in mice infected and reconstituted with CD4+ T cells. Whereby inflammation in infected and CD4+CD45RBhi T cell reconstituted animals was always higher than in the other groups. Reconstitution of infected animals with CD8+ T cells did not result in any inflammatory signs. Interestingly, various markers of inflammation were strongly up-regulated in the colon of infected mice reconstituted with CD4+CD45RBlo/int T cells. We propose, the usual non-colitogenic CD4+CD45RBlo/int T cells were converted into inflammatory T cells by the interaction with MAP. However, the power of such cells might be not sufficient for a fully established inflammatory response in the colon. Nevertheless, our model system appears to mirror aspects of an inflammatory bowel disease (IBD) like CD and Johne's diseases. Thus, it will provide an experimental platform on which further knowledge on IBD and the involvement of MAP in the induction of CD could be acquired. PMID:24728142

CD147 (EMMPRIN/Basigin) in kidney diseases: from an inflammation and immune system viewpoint.

PubMed

Kosugi, Tomoki; Maeda, Kayaho; Sato, Waichi; Maruyama, Shoichi; Kadomatsu, Kenji

2015-07-01

The glycosylated transmembrane protein CD147/basigin, also known as extracellular matrix metalloproteinase (MMP) inducer (EMMPRIN), contributes to cell survival, migration and cancer invasion. In normal kidneys, high expression of CD147 is detected only in the basolateral side of tubular epithelial cells (TECs). The pathophysiological roles of CD147 in the kidneys are diverse, ranging from involvement in the occurrence of acute kidney injury (AKI) that is frequently accompanied by ischemia, inflammation and a loss of self-tolerance to the progression of chronic kidney disease (CKD) that is caused by an imbalance in extracellular matrix protein turnover. In AKI induced by ischemia, it is the CD147 on neutrophils, rather than that on TECs, that coordinately participates in massive neutrophil recruitment via acting as a physiological ligand for E-selectin, which is specifically enhanced in the endothelium upon inflammatory stimulation. In the CKD that follows AKI, a molecular circuit involving CD147, MMPs and transforming growth factor-β may be involved in the pathogenesis of progressive fibrosis through hyaluronan production and macrophage infiltration. Whereas CD147 thus plays deleterious roles in ischemic and fibrotic kidney injuries, CD147 expression on lymphocytes might decrease the disease activity of lupus nephritis (LN) by functioning as a potential negative regulator of the extraordinary proliferation of lymphocytes that occurs in this disease. In line with these basic studies, our clinical data indicate the potential of plasma CD147 to function as a critical biomarker for both ischemic AKI and LN. CD147 is also involved in crosstalk between the kidneys and distant organs, which may be mediated by chemotactic cytokines that are derived from circulating inflammatory cells and damaged organs. Disruption of such a vicious chain reaction involving CD147 would therefore be required in order to overcome kidney diseases. Multidisciplinary research regarding CD147 functions may open a new avenue for targeting therapeutics for kidney diseases. © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Intestinal alkaline phosphatase in the colonic mucosa of children with inflammatory bowel disease

PubMed Central

Molnár, Kriszta; Vannay, Ádám; Szebeni, Beáta; Bánki, Nóra Fanni; Sziksz, Erna; Cseh, Áron; Győrffy, Hajnalka; Lakatos, Péter László; Papp, Mária; Arató, András; Veres, Gábor

2012-01-01

AIM: To investigate intestinal alkaline phosphatase (iAP) in the intestinal mucosa of children with inflammatory bowel disease (IBD). METHODS: Colonic biopsy samples were taken from 15 newly diagnosed IBD patients and from 10 healthy controls. In IBD patients, specimens were obtained both from inflamed and non-inflamed areas. The iAP mRNA and protein expression was determined by reverse transcription-polymerase chain reaction and Western blotting analysis, respectively. Tissue localization of iAP and Toll-like receptor (TLR) 4 was investigated by immunofluorescent staining. RESULTS: The iAP protein level in the inflamed mucosa of children with Crohn’s disease (CD) and ulcerative colitis (UC) was significantly decreased when compared with controls (both P < 0.05). Similarly, we found a significantly decreased level of iAP protein in the inflamed mucosa in CD compared with non-inflamed mucosa in CD (P < 0.05). In addition, the iAP protein level in inflamed colonic mucosa in patients with UC was decreased compared with non-inflamed mucosa in patients with CD (P < 0.05). iAP protein levels in the non-inflamed mucosa of patients with CD were similar to controls. iAP mRNA expression in inflamed colonic mucosa of children with CD and UC was not significantly different from that in non-inflamed colonic mucosa with CD. Expression of iAP mRNA in patients with non-inflamed mucosa and in controls were similar. Co-localization of iAP with TLR4 showed intense staining with a dotted-like pattern. iAP was present in the inflamed and non-inflamed mucosa of patients with CD, UC, and in control biopsy specimens, irrespective of whether it was present in the terminal ileum or in the colon. However, the fluorescent signal of TLR4 was more pronounced in the colon compared with the terminal ileum in all groups studied. CONCLUSION: Lower than normal iAP protein levels in inflamed mucosa of IBD patients may indicate a role for iAP in inflammatory lesions in IBD. Based on our results, administration of exogenous iAP enzyme to patients with the active form of IBD may be a therapeutic option. PMID:22783049

Striving for more good days: patient perspectives on botulinum toxin for the treatment of cervical dystonia

PubMed Central

Poliziani, Michele; Koch, Marco; Liu, Xierong

2016-01-01

Background The recommended reinjection interval for botulinum neurotoxin (BoNT) formulations in the treatment of cervical dystonia (CD) is generally ≥12 weeks, though intervals ≥10 weeks are approved for incobotulinumtoxinA in Europe. However, recurring symptoms can occur before the end of this period. Using qualitative research, we sought a greater understanding of disease burden, unmet patient needs, and barriers to treatment. Methods We conducted online semistructured, focus-group discussions, and online forum follow-up discussions among patients with CD, focusing on disease burden, patient needs, injection cycle preferences, and relationships with health care professionals. A subset of patients was also questioned in telephone interviews about individual experiences of CD and BoNT treatment. All participants were UK residents who had received onabotulinumtoxinA or abobotulinumtoxinA for CD for ≥1 year. Results Thirty-one patients (81% female; mean duration of CD 16.4 [range 4–31] years; mean BoNT injection cycle length 12.8 weeks) participated in the online focus-group and forum follow-up discussions. Of these, seven patients participated in telephone interviews. All had recurring symptoms between treatments, which substantially impacted on their work, family, and social life. Symptom severity fluctuated throughout an injection cycle and differed between patients and across injection cycles. Participants’ relationships with health care professionals and treatment satisfaction varied greatly. Many participants wanted longer-lasting and/or more stable symptom relief with shorter and/or more flexible injection intervals, according to individual needs. Lack of health care resources, long journeys to treatment centers, and immunogenicity/side-effect concerns were perceived as the main barriers to more flexible treatment. Conclusion The high burden of recurring primary and secondary symptoms of CD considerably affects patients’ quality of life. Patient-led assessments of disease burden revealed that personalized, more flexible, and/or shorter BoNT injection intervals may reduce the day-to-day impact of CD. Collaboration between patients, clinicians, and health care systems may effect change and improve treatment for patients with CD. PMID:27578965

CD44 Splice Variants as Potential Players in Alzheimer's Disease Pathology.

PubMed

Pinner, Elhanan; Gruper, Yaron; Ben Zimra, Micha; Kristt, Don; Laudon, Moshe; Naor, David; Zisapel, Nava

2017-01-01

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive deficits, deposition of amyloid-β (Aβ) plaques, intracellular neurofibrillary tangles, and neuronal cell death. Neuroinflammation is commonly believed to participate in AD pathogenesis. CD44 is an inflammation-related gene encoding a widely-distributed family of alternatively spliced cell surface glycoproteins that have been implicated in inflammation, metastases, and inflammation-linked neuronal injuries. Here we investigated the expression patterns of CD44S (which does not contain any alternative exon) and CD44 splice variants in postmortem hippocampal samples from AD patients and matched non-AD controls. The expression of CD44S and CD44 splice variants CD44V3, CD44V6, and CD44V10 was significantly higher in AD patients compared to non-AD controls. Immunohistochemistry of human hippocampal sections revealed that CD44S differentially localized to neuritic plaques and astrocytes, whereas CD44V3, CD44V6, and CD44V10 expression was mostly neuronal. Consistent with these findings, we found that the expression of CD44V6 and CD44V10 was induced by Aβ peptide in neuroblastoma cells and primary neurons. Furthermore, in loss of function studies we found that both CD44V10-specific siRNA and CD44V10 antibody protected neuronal cells from Aβ-induced toxicity, suggesting a causal relationship between CD44V10 and neuronal cell death. These data indicate that certain CD44 splice variants contribute to AD pathology and that CD44V10 inhibition may serve as a new neuroprotective treatment strategy for this disease.

Screening of celiac disease in patients with autoimmune thyroid disease from Southern Brazil.

PubMed

Teixeira, Laila M; Nisihara, Renato; Utiyama, Shirley Ramos da Rosa; Bem, Ricardo S de; Marcatto, Cristina; Bertolazo, Michelli; Carvalho, Gisah A de

2014-08-01

The objective of this study was to determine the prevalence of celiac disease (CD) in adults with autoimmune thyroid disease (ATD) from the endocrinology outpatient setting in a university hospital in Southern Brazil. From the years 2007 to 2011, 254 patients with ATD were enrolled consecutively, Grave's disease was diagnosed in 143 (56.3%) and Hashimoto's thyroiditis in 111 (43.7%) of them. All patients answered a questionnaire related to symptoms that could be associated with CD and serum samples to screen for IgA anti-endomysial (EmA-IgA) were collected. EmA-IgA-positive patients were offered upper gastrointestinal endoscopy and biopsy of duodenum. A total of 254 patients were included; 222 (87.4%) female, mean age 45.4 ± 13.43 years (18 to 79 years). EmA-IgA was positive in seven patients (2.7%) and five done endoscopy with biopsy. Of these, three diagnosis of CD was confirmed (1.2%). All the three patients with CD had higher EmA-IgA titration, were female and had Hashimoto's thyroiditis. Like other patients with ATD, CD patients had nonspecific gastrointestinal symptoms, such as heartburn and gastric distention. In our study, one in each 85 patients confirmed the diagnosis of CD. We found a prevalence of 1.2% (1:85) of confirmed CD among Brazilian patients with ATD. Although some IgA-EmA positive patients had Graves' disease and one was male, all three patients with confirmed CD were female and had Hashimoto's thyroiditis.

The Diagnostic Role of Magnetic Resonance Enterography as a Complementary Test to Colonoscopy in Active Crohn's Disease.

PubMed

Aryan, Arvin; Azizi, Zahra; Teimouri, Azam; Ebrahimi Daryani, Nasser; Aletaha, Najme; Jahanbakhsh, Ali; Nouritaromlou, Mohammad Kazem; Alborzi, Forough; Mami, Masoud; Basirat, Vahid; Javid Anbardan, Sanam

2016-04-01

BACKGROUND According to recent studies comparing magnetic resonance enterography (MRE) with ileocolonoscopy for assessing inflammation of small bowel and colonic segments in adults with active Crohn's disease (CD), we aimed to compare the accuracy of these two diagnostic methods in Iranian population. METHODS During 2013-2014 a follow-up study was done on 30 patients with active CD in a gastroenterology clinic affiliated to Tehran University of Medical Sciences. MRE and ileocolonoscopy were performed for all the patients. All statistical analyses were performed using SPSS (version 18) and p-value<0.05 was considered as statistically significant. RESULTS Of the 30 patients with active CD, 11(36.7%) were men and 19 (63.3%) were women with mean age of 37.30±13.66 years (range: 19-67 years). MRE had sensitivity and specificity of 50% and 90% with positive predictive value (PPV) and negative predictive value (NPV) of 71.43 and 78.26, respectively for localizing sigmoid lesions and ileum had sensitivity and specificity of 84.21 and 45.45 with PPV and NPV of 72.73 and 62.50, respectively. CONCLUSION While moderate sensitivity and high specificity of MRE in localizing colonic lesions makes it an appropriate confirmatory test after colonoscopy, the reported high sensitivity and moderate specificity of MRE versus colonoscopy in detecting ileal lesions makes it a suitable screening test for ileal lesions. Finally we can conclude that MRE can be an important complementary test to colonoscopy in detecting active disease.

Expansion of CD14+CD16+ monocytes producing TNF-α in complication-free diabetes type 1 juvenile onset patients.

PubMed

Myśliwska, Jolanta; Smardzewski, Marcin; Marek-Trzonkowska, Natalia; Myśliwiec, Małgorzata; Raczyńska, Krystyna

2012-10-01

We concentrated on the complication-free phase of juvenile onset type 1 diabetes mellitus (T1DM) searching for associations between concentration of inflammatory factors TNF-α, CRP and VEGF and two monocyte subsets the CD14(++)CD16(-) and CD14(+)CD16(+). We analysed a randomly selected group of 150 patients without complications (disease duration 2.74 ± 2.51 years) at the start of the project and 5 years later. They were compared with 24 patients with retinopathy (6.53 ± 3.39 years of disease) and 30 healthy volunteers. Our results indicate that in the complication-free period the concentration of TNF-α significantly increased and continued to increase after retinopathy was established. After 5 years the percentage and absolute number of CD14(+)CD16(+) monocytes doubled in complication-free patients. Our study indicates that the size of CD14(+)CD16(+) monocyte subset may be used alternatively to CRP values as an indicator of inflammation grade. Our results imply the necessity of trials using anti-TNF-α therapy in the complication-free phase of the disease. Copyright © 2012 Elsevier Ltd. All rights reserved.

Obesity in adolescents with celiac disease: two adolescents and two different presentations.

PubMed

Balamtekin, Necati; Demir, Hülya; Baysoy, Gökhan; Uslu, Nuray; Yüce, Aysel

2011-01-01

Celiac disease (CD) usually presents with diarrhea and growth retardation in childhood. Obesity is one of the paradoxical conditions in children with CD. We present two adolescents with CD and obesity. One of these patients was diagnosed as CD with malnutrition. His body weight had returned to normal after a gluten-free diet, and after stopping the diet, he had become obese. The second patient was an obese adolescent presenting with dyspeptic symptoms who was diagnosed as CD. Although rare, pediatricians should remember that obesity might be seen in CD before or after the diagnosis.

Platelets Toll-like receptor-4 in Crohns disease.

PubMed

Schmid, Werner; Novacek, Gottfried; Vogelsang, Harald; Papay, Pavol; Primas, Christian; Eser, Alexander; Panzer, Simon

2017-02-01

Platelets are activated in Crohn's disease (CD) and interplay with leukocytes. Engagement of Toll-like receptor-4 (TLR-4), which is expressed in human platelets, may be involved in crosstalks between platelets and leukocytes leading to their mutual activation for host defense. Human neutrophil peptides (HNPs), lipoprotein binding peptides, and sCD14 were determined by enzyme-linked immunosorbent assays in 42 patients with active CD, in 43 patients with CD in remission, and in 30 healthy individuals. Neutrophil-platelet aggregates and binding of the TLR-4 monoclonal antibody to platelets were determined by flow cytometry. Levels of HNPs were higher in patients with CD than in controls (P = 0.0003 vs. active CD and P = 0.01 vs. CD in remission). Likewise, neutrophils with adhering platelets were higher in patients with active CD than in controls (P = 0.004). Binding of the TLR-4 antibody in patients with active CD was similar to that in controls, while patients in remission had significantly higher binding capacities (P = 0.59 and P = 0.003). Incubation of plasma from patients with active disease or patients in remission with platelets from healthy controls confirmed lower binding of the TLR-4 antibody in the presence of plasma from active diseased patients compared to controls (P = 0.039), possibly due to high levels of lipopolysaccharides, as suggested by high levels of sCD14 and lipoprotein binding protein. Our study indicates involvement of platelet TLR-4 in enhancing the secretion of antimicrobial peptides from neutrophils. While platelet aggregation can be due to a variety of mechanisms in inflammatory disease, the mutual activation of platelets and neutrophils may augment host defense. © 2016 Stichting European Society for Clinical Investigation Journal Foundation.

Markers of activated inflammatory cells correlate with severity of liver damage in children with nonalcoholic fatty liver disease.

PubMed

De Vito, Rita; Alisi, Anna; Masotti, Andrea; Ceccarelli, Sara; Panera, Nadia; Citti, Arianna; Salata, Michele; Valenti, Luca; Feldstein, Ariel E; Nobili, Valerio

2012-07-01

Concomitantly to the obesity epidemic, nonalcoholic fatty liver disease (NAFLD) has become the leading cause of liver disease in children. NAFLD encompasses a spectrum of histological damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), with possible progression to cirrhosis. There is growing evidence that the immune system plays a pivotal role in the initiation and progression to NASH but the cellular nature of the hepatic inflammation is still unknown. The present study includes 34 children with biopsy-proven NAFLD. Liver damage was evaluated by the NAFLD activity score (NAS), and the inflammatory infiltrate was characterized by immunohistochemistry for CD45, CD3 and CD163 which are markers of leukocytes, T cells and activated Kupffer cells/macrophages, respectively. Our results have shown that CD45+ (P<0.0001) and CD163+ (P<0.0001) cells were markedly increased in children with severe histological activity (NAS≥5) compared to children with lower activity (NAS<5), whereas CD3+ cells were significantly lower (P<0.01) in children with severe histological activity. There was a significant association between the numbers of CD45+, CD3+ and CD163+ cells, regarding both the portal tract and liver lobule, and the severity of steatosis, ballooning and fibrosis (P<0.01). These data suggest that the severity and composition of the inflammatory infiltrate correlate with steatosis and the severity of disease in children with NAFLD. Moreover, a decrease in CD3+ cells may be involved in the pathogenesis of liver damage. Future studies should evaluate whether it can predict the progression of liver disease independently of established histological scores.

Mycobiome of the Bat White Nose Syndrome Affected Caves and Mines Reveals Diversity of Fungi and Local Adaptation by the Fungal Pathogen Pseudogymnoascus (Geomyces) destructans

PubMed Central

Rajkumar, Sunanda S.; Li, Xiaojiang; Okoniewski, Joseph C.; Hicks, Alan C.; Davis, April D.; Broussard, Kelly; LaDeau, Shannon L.; Chaturvedi, Sudha; Chaturvedi, Vishnu

2014-01-01

Current investigations of bat White Nose Syndrome (WNS) and the causative fungus Pseudogymnoascus (Geomyces) destructans (Pd) are intensely focused on the reasons for the appearance of the disease in the Northeast and its rapid spread in the US and Canada. Urgent steps are still needed for the mitigation or control of Pd to save bats. We hypothesized that a focus on fungal community would advance the understanding of ecology and ecosystem processes that are crucial in the disease transmission cycle. This study was conducted in 2010–2011 in New York and Vermont using 90 samples from four mines and two caves situated within the epicenter of WNS. We used culture-dependent (CD) and culture-independent (CI) methods to catalogue all fungi (‘mycobiome’). CD methods included fungal isolations followed by phenotypic and molecular identifications. CI methods included amplification of DNA extracted from environmental samples with universal fungal primers followed by cloning and sequencing. CD methods yielded 675 fungal isolates and CI method yielded 594 fungal environmental nucleic acid sequences (FENAS). The core mycobiome of WNS comprised of 136 operational taxonomic units (OTUs) recovered in culture and 248 OTUs recovered in clone libraries. The fungal community was diverse across the sites, although a subgroup of dominant cosmopolitan fungi was present. The frequent recovery of Pd (18% of samples positive by culture) even in the presence of dominant, cosmopolitan fungal genera suggests some level of local adaptation in WNS-afflicted habitats, while the extensive distribution of Pd (48% of samples positive by real-time PCR) suggests an active reservoir of the pathogen at these sites. These findings underscore the need for integrated disease control measures that target both bats and Pd in the hibernacula for the control of WNS. PMID:25264864

CD151 supports VCAM-1-mediated lymphocyte adhesion to liver endothelium and is upregulated in chronic liver disease and hepatocellular carcinoma

PubMed Central

Wadkin, James C. R.; Patten, Daniel A.; Kamarajah, Sivesh K.; Shepherd, Emma L.; Novitskaya, Vera; Berditchevski, Fedor; Adams, David H.; Weston, Chris J.

2017-01-01

CD151, a member of the tetraspanin family of receptors, is a lateral organizer and modulator of activity of several families of transmembrane proteins. It has been implicated in the development and progression of several cancers, but its role in chronic inflammatory disease is less well understood. Here we show that CD151 is upregulated by distinct microenvironmental signals in a range of chronic inflammatory liver diseases and in primary liver cancer, in which it supports lymphocyte recruitment. CD151 was highly expressed in endothelial cells of the hepatic sinusoids and neovessels developing in fibrotic septa and tumor margins. Primary cultures of human hepatic sinusoidal endothelial cells (HSECs) expressed CD151 at the cell membrane and in intracellular vesicles. CD151 was upregulated by VEGF and HepG2 conditioned media but not by proinflammatory cytokines. Confocal microscopy confirmed that CD151 colocalized with the endothelial adhesion molecule/immunoglobulin superfamily member, VCAM-1. Functional flow-based adhesion assays with primary human lymphocytes and HSECs demonstrated a 40% reduction of lymphocyte adhesion with CD151 blockade. Inhibition of lymphocyte adhesion was similar between VCAM-1 blockade and a combination of CD151/VCAM-1 blockade, suggesting a collaborative role between the two receptors. These studies demonstrate that CD151 is upregulated within the liver during chronic inflammation, where it supports lymphocyte recruitment via liver endothelium. We propose that CD151 regulates the activity of VCAM-1 during lymphocyte recruitment to the human liver and could be a novel anti-inflammatory target in chronic liver disease and hepatocellular cancer prevention. NEW & NOTEWORTHY Chronic hepatitis is characterized by lymphocyte accumulation in liver tissue, which drives fibrosis and carcinogenesis. Here, we demonstrate for the first time that the tetraspanin CD151 supports lymphocyte adhesion to liver endothelium. We show that CD151 is upregulated in chronic liver disease and hepatocellular carcinoma (HCC) and is regulated on endothelium by tissue remodeling and procarcinogenic factors. These regulatory and functional studies identify CD151 as a potential therapeutic target to treat liver fibrosis and HCC. PMID:28473332

CD151 supports VCAM-1-mediated lymphocyte adhesion to liver endothelium and is upregulated in chronic liver disease and hepatocellular carcinoma.

PubMed

Wadkin, James C R; Patten, Daniel A; Kamarajah, Sivesh K; Shepherd, Emma L; Novitskaya, Vera; Berditchevski, Fedor; Adams, David H; Weston, Chris J; Shetty, Shishir

2017-08-01

CD151, a member of the tetraspanin family of receptors, is a lateral organizer and modulator of activity of several families of transmembrane proteins. It has been implicated in the development and progression of several cancers, but its role in chronic inflammatory disease is less well understood. Here we show that CD151 is upregulated by distinct microenvironmental signals in a range of chronic inflammatory liver diseases and in primary liver cancer, in which it supports lymphocyte recruitment. CD151 was highly expressed in endothelial cells of the hepatic sinusoids and neovessels developing in fibrotic septa and tumor margins. Primary cultures of human hepatic sinusoidal endothelial cells (HSECs) expressed CD151 at the cell membrane and in intracellular vesicles. CD151 was upregulated by VEGF and HepG2 conditioned media but not by proinflammatory cytokines. Confocal microscopy confirmed that CD151 colocalized with the endothelial adhesion molecule/immunoglobulin superfamily member, VCAM-1. Functional flow-based adhesion assays with primary human lymphocytes and HSECs demonstrated a 40% reduction of lymphocyte adhesion with CD151 blockade. Inhibition of lymphocyte adhesion was similar between VCAM-1 blockade and a combination of CD151/VCAM-1 blockade, suggesting a collaborative role between the two receptors. These studies demonstrate that CD151 is upregulated within the liver during chronic inflammation, where it supports lymphocyte recruitment via liver endothelium. We propose that CD151 regulates the activity of VCAM-1 during lymphocyte recruitment to the human liver and could be a novel anti-inflammatory target in chronic liver disease and hepatocellular cancer prevention. NEW & NOTEWORTHY Chronic hepatitis is characterized by lymphocyte accumulation in liver tissue, which drives fibrosis and carcinogenesis. Here, we demonstrate for the first time that the tetraspanin CD151 supports lymphocyte adhesion to liver endothelium. We show that CD151 is upregulated in chronic liver disease and hepatocellular carcinoma (HCC) and is regulated on endothelium by tissue remodeling and procarcinogenic factors. These regulatory and functional studies identify CD151 as a potential therapeutic target to treat liver fibrosis and HCC. Copyright © 2017 the American Physiological Society.

Paradoxical arthritis occurring during anti-TNF in patients with inflammatory bowel disease: histological and immunological features of a complex synovitis.

PubMed

Alivernini, Stefano; Pugliese, Daniela; Tolusso, Barbara; Bui, Laura; Petricca, Luca; Guidi, Luisa; Mirone, Luisa; Rapaccini, Gian Ludovico; Federico, Francesco; Ferraccioli, Gianfranco; Armuzzi, Alessandro; Gremese, Elisa

2018-01-01

Paradoxical arthritis under tumour necrosis factor inhibitor (TNF-i) for inflammatory bowel disease (IBD) has been described. This study aims to evaluate the histological features of paired synovial tissue (ST) and colonic mucosa (CM) tissue in patients with IBD developing paradoxical arthritis under TNF-i. Patients with IBD without history of coexisting joint involvement who developed arthritis under TNF-i were enrolled. Each patient underwent ST biopsy and ileocolonoscopy with CM biopsies. ST and CM paired samples were stained through immunohistochemistry (IHC) for CD68, CD21, CD20, CD3 and CD117. Clinical and immunological parameters (anticitrullinated peptides antibodies (ACPA)-immunoglobulin (Ig)M/IgA rheumatoid factor (RF)) were collected. Psoriatic arthritis (PsA) and ACPA/IgM-RF/IgA-RF negative rheumatoid arthritis (RA) were enrolled as comparison. 10 patients with IBD (age 46.0±9.7 years, 13.2±9.9 years of disease duration, 2.5±1.6 years of TNF-i exposure, six with Crohn's disease and four with ulcerative colitis, respectively) were studied. At ST level, IHC revealed that patients with IBD with paradoxical arthritis showed more similar histological findings in terms of synovial CD68 + , CD21 + , CD20 + , CD3 + and CD117 + cells compared with PsA than ACPA/IgM-RF/IgA-RF negative RA. Analysing the CM specimens, patients with IBD showed the presence of CD68 + , CD3 + , CD117 + and CD20 + cells in 100%, 70%, 60% and 50% of cases, respectively, despite endoscopic remission. Finally, addition of conventional disease-modifying antirheumatic drugs and switch to ustekinumab were more effective than swapping into different TNF-i in patients with IBD with paradoxical arthritis. Patients with IBD may develop histologically proven synovitis during TNF-i, comparable to PsA. The inhibition of inflammatory pathways alternative to TNF (IL12/1L23) may be an effective therapeutic option for severe paradoxical articular manifestations.

Crohn’s disease and extra intestinal granulomatous lesions.

PubMed

Tomasello, G; Scaglione, M; Mazzola, M; Gerges Geaga, A; Jurjus, A; Gagliardo, C; Sinagra, E; Damiani, P; Carini, F; Leone, A

2018-01-01

Crohn’s disease (CD) is an inflammatory bowel disease with a multifactorial etiology. Clinical features include mucosal erosion, diarrhea, weight loss and other complications such as formation of granuloma. In CD, granuloma is a non-neoplastic epithelioid lesion, formed by a compact aggregate of histiocytes with the absence of a central necrosis, however, the correlation among CD and the formation of granulomas is unknown. Many cases of granulomas in the extracellular site, related to CD, have been reported in the literature. These granulomas, at times, represented the only visible manifestation of the pathology. Extra intestinal granulomas have been found on ovaries, lungs, male genitalia, female genitalia, orofacial regions and skin. From the data in the literature it could be hypothesized that there is a cross-reaction of the immune system with similar antigenic epitopes belonging to different sites. This hypothesis, if checked, can place CD not only among inflammatory bowel disease but also among inflammatory diseases with systemic involvement.

Unusual Onset of Celiac Disease and Addison's Disease in a 12-Year-Old Boy.

PubMed

Miconi, Francesco; Savarese, Emanuela; Miconi, Giovanni; Cabiati, Gabriele; Rapaccini, Valentina; Principi, Nicola; Esposito, Susanna

2017-07-29

Celiac disease (CD) is an autoimmune disorder deriving from an aberrant adaptive immune response against gluten-containing grains in genetically predisposed subjects. In a number of patients, CD is associated with one or more other autoimmune diseases. Primary Addison's disease (AD) and CD may co-exist, although this association is relatively uncommon in children. In addition, it is not precisely defined whether a gluten-free diet influences the course of AD. A case of CD in a 12-year-old boy presenting as acute adrenal insufficiency is described here. A gluten-free diet had a significant therapeutic role in this case, wherein most of the clinical signs and symptoms of AD disappeared in a few days. In addition, the dosage of cortisol acetate, initially administered to treat the AD, was able to be rapidly reduced. This case highlights that CD can be associated with AD in children, and a gluten-free diet seems to positively influence the course of AD.

Combined use of reverse transcriptase polymerase chain reaction and flow cytometry to study minimal residual disease in Philadelphia positive acute lymphoblastic leukemia.

PubMed

Muñoz, L; López, O; Martino, R; Brunet, S; Bellido, M; Rubiol, E; Sierra, J; Nomdedéu, J F

2000-07-01

The Philadelphia chromosome in acute lymphoblastic leukemia (Ph+ ALL) is associated with a poor prognosis given the high frequency of chemoresistance and leukemia relapse. Minimal residual disease (MRD) detection before cytogenetic and hematologic relapse could be useful in early therapy. The most suitable methods for detecting MRD in Ph+ ALL are flow cytometry (FC) and reverse transcriptase polymerase chain reaction (RT-PCR). However, since both techniques carry the risk of false-negative results the combined use of these two techniques could overcome this problem. We report our experience using this approach in 47 bone marrow samples obtained from 10 Ph+ ALL patients. Twenty-seven marrow aspirates were taken from patients in clinical remission (CR). The samples were considered positive for MRD by FC when two conditions were met: 1) detection of an abnormal B-cell differentiation pattern and 2) presence of more than 1x10(-3) cells coexpressing CD22/CD34/CD45 or CD66/CD34/CD10. After FC analysis, RNA was purified using standard methods. FC was positive in 23/27 samples in CR (sensitivity 85%). RT-PCR was successfully performed in 23 samples in CR. RT-PCR was positive in 18/23 samples (sensitivity 78%). There were 5 samples with discordant results. FC was positive in 3 samples with a negative RT-PCR and FC was negative in 2 samples with a positive RT. All the 10 patients relapsed and only 1 is currently alive after an allogeneic stem cell transplantation (alloSCT). The median (range) time from MRD detection to relapse in patients treated with chemotherapy was 42 (39-71) days. These data suggest that RT-PCR may be negative despite the presence of neoplastic cells identified by their immunophenotypic traits. We conclude that immunologic and molecular techniques can be used in tandem for monitoring MRD in Ph+ ALL.

Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study

PubMed Central

Cruz, Conrad Russell Y.; Micklethwaite, Kenneth P.; Savoldo, Barbara; Ramos, Carlos A.; Lam, Sharon; Ku, Stephanie; Diouf, Oumar; Liu, Enli; Barrett, A. John; Ito, Sawa; Shpall, Elizabeth J.; Krance, Robert A.; Kamble, Rammurti T.; Carrum, George; Hosing, Chitra M.; Gee, Adrian P.; Mei, Zhuyong; Grilley, Bambi J.; Heslop, Helen E.; Rooney, Cliona M.; Brenner, Malcolm K.; Bollard, Catherine M.

2013-01-01

Autologous T cells expressing a CD19-specific chimeric antigen receptor (CD19.CAR) are active against B-cell malignancies, but it is unknown whether allogeneic CD19.CAR T cells are safe or effective. After allogeneic hematopoietic stem cell transplantation (HSCT), infused donor-derived virus-specific T cells (VSTs) expand in vivo, persist long term, and display antiviral activity without inducing graft-vs-host disease; therefore, we determined whether donor VSTs, engineered to express CD19.CAR, retained the characteristics of nonmanipulated allogeneic VSTs while gaining antitumor activity. We treated 8 patients with allogeneic (donor-derived) CD19.CAR-VSTs 3 months to 13 years after HSCT. There were no infusion-related toxicities. VSTs persisted for a median of 8 weeks in blood and up to 9 weeks at disease sites. Objective antitumor activity was evident in 2 of 6 patients with relapsed disease during the period of CD19.CAR-VST persistence, whereas 2 patients who received cells while in remission remain disease free. In 2 of 3 patients with viral reactivation, donor CD19.CAR-VSTs expanded concomitantly with VSTs. Hence CD19.CAR-VSTs display antitumor activity and, because their number may be increased in the presence of viral stimuli, earlier treatment post-HSCT (when lymphodepletion is greater and the incidence of viral infection is higher) or planned vaccination with viral antigens may enhance disease control. This study is registered at clinicaltrials.gov as #NCT00840853. PMID:24030379

Disease susceptibility genes shared by primary biliary cirrhosis and Crohn's disease in the Japanese population.

PubMed

Aiba, Yoshihiro; Yamazaki, Keiko; Nishida, Nao; Kawashima, Minae; Hitomi, Yuki; Nakamura, Hitomi; Komori, Atsumasa; Fuyuno, Yuta; Takahashi, Atsushi; Kawaguchi, Takaaki; Takazoe, Masakazu; Suzuki, Yasuo; Motoya, Satoshi; Matsui, Toshiyuki; Esaki, Motohiro; Matsumoto, Takayuki; Kubo, Michiaki; Tokunaga, Katsushi; Nakamura, Minoru

2015-09-01

We previously identified TNFSF15 as the most significant susceptibility gene at non-HLA loci for both primary biliary cirrhosis (PBC) and Crohn's diseases (CD) in the Japanese population. The aim of this study is to identify further disease susceptibility genes shared by PBC and CD. We selected 15 and 33 genetic variants that were significantly associated with PBC and CD, respectively, based on previously reported genome-wide association studies of the Japanese population. Next, an association study was independently performed for these genetic variants in CD (1312 CD patients and 3331 healthy controls) and PBC (1279 PBC patients and 1015 healthy controls) cohorts. Two CD susceptibility genes, ICOSLG rs2838519 and IL12B rs6556412, were also nominally associated with susceptibility to PBC (P=3.85 × 10(-2) and P=8.40 × 10(-3), respectively). Three PBC susceptibility genes, CXCR5 rs6421571, STAT4 rs7574865 and NFKB1 rs230534, were nominally associated with susceptibility to CD (P=2.82 × 10(-2), P=3.88 × 10(-2) and P=2.04 × 10(-2), respectively). The effect of ICOSLG and CXCR5 variants were concordant but the effect of STAT4, NFKB1 and IL12B variants were discordant for PBC and CD. TNFSF15 and ICOSLG-CXCR5 might constitute a shared pathogenic pathway in the development of PBC and CD in the Japanese population, whereas IL12B-STAT4-NFKB1 might constitute an opposite pathogenic pathway, reflecting the different balance between Th1 and Th17 in the two diseases.

Appropriateness of early management of newly diagnosed Crohn's disease in a European population-based cohort.

PubMed

Juillerat, Pascal; Pittet, Valérie; Mottet, Christian; Felley, Christian; Gonvers, Jean-Jacques; Vader, John-Paul; Burnand, Bernard; Froehlich, Florian; Wolters, Frank L; Stockbrügger, Reinhold W; Michetti, Pierre

2010-12-01

The European Panel on the Appropriateness of Crohn's disease Therapy (EPACT) has developed appropriateness criteria. We have applied these criteria retrospectively to the population-based inception cohort of Crohn's disease (CD) patients of the European Collaborative Study Group on Inflammatory Bowel Disease (EC-IBD). A total of 426 diagnosed CD patients from 13 European centers were enrolled at the time of diagnosis (first flare, naive patients). We used the EPACT definitions to identify 247 patients with active luminal CD. We then assessed the appropriateness of the initial drug prescription according to the EPACT criteria. Among the cohort patients 163 suffered from mild-to-moderate CD and 84 from severe CD. Among the mild-to-moderate disease group, 96 patients (59%) received an appropriate treatment, whereas for 66 patients (40%) the treatment was uncertain and in one case (1%) inappropriate. Among the severe disease group, 86% were treated medically and 14% required surgery. 59 (70%) were appropriately treated, whereas for one patient (1%) the procedure was considered uncertain and for 24 patients (29%) inappropriate. Initial treatment was appropriate in the majority of cases for non-complicated luminal CD. Inappropriate or uncertain treatment was given in a significant minority of patients, with an increased potential risk of adverse events.

A key requirement for CD300f in innate immune responses of eosinophils in colitis.

PubMed

Moshkovits, I; Reichman, H; Karo-Atar, D; Rozenberg, P; Zigmond, E; Haberman, Y; Ben Baruch-Morgenstern, N; Lampinen, M; Carlson, M; Itan, M; Denson, L A; Varol, C; Munitz, A

2017-01-01

Eosinophils are traditionally studied in the context of type 2 immune responses. However, recent studies highlight key innate immune functions for eosinophils especially in colonic inflammation. Surprisingly, molecular pathways regulating innate immune activities of eosinophil are largely unknown. We have recently shown that the CD300f is highly expressed by colonic eosinophils. Nonetheless, the role of CD300f in governing innate immune eosinophil activities is ill-defined. RNA sequencing of 162 pediatric Crohn's disease patients revealed upregulation of multiple Cd300 family members, which correlated with the presence of severe ulcerations and inflammation. Increased expression of CD300 family receptors was also observed in active ulcerative colitis (UC) and in mice following induction of experimental colitis. Specifically, the expression of CD300f was dynamically regulated in monocytes and eosinophils. Dextran sodium sulfate (DSS)-treated Cd300f -/- mice exhibit attenuated disease activity and histopathology in comparison with DSS-treated wild type (WT). Decreased disease activity in Cd300f -/- mice was accompanied with reduced inflammatory cell infiltration and nearly abolished production of pro-inflammatory cytokines. Monocyte depletion and chimeric bone marrow transfer experiments revealed a cell-specific requirement for CD300f in innate immune activation of eosinophils. Collectively, we uncover a new pathway regulating innate immune activities of eosinophils, a finding with significant implications in eosinophil-associated gastrointestinal diseases.

Microbiome and Gluten.

PubMed

Sanz, Yolanda

2015-01-01

Celiac disease (CD) is a frequent chronic inflammatory enteropathy caused by gluten in genetically predisposed individuals that carry disease susceptibility genes (HLA-DQ2/8). These genes are present in about 30-40% of the general population, but only a small percentage of carriers develops CD. Gluten is the key environmental trigger of CD, but its intake does not fully explain disease onset; indeed, an increased number of cases experience gluten intolerance in late adulthood after many years of gluten exposure. Consequently, additional environmental factors seem to be involved in CD. Epidemiological studies indicate that common perinatal and early postnatal factors influence both CD risk and intestinal microbiota structure. Prospective studies in healthy infants at risk of developing CD also reveal that the HLA-DQ genotype, in conjunction with other environmental factors, influences the microbiota composition. Furthermore, CD patients have imbalances in the intestinal microbiota (dysbiosis), which are not fully normalized despite their adherence to a gluten-free diet. Therefore, it is hypothesized that the disease can promote dysbiosis that aggravates CD pathogenesis, and dysbiosis, in turn, can initiate and sustain inflammation through the expansion of proinflammatory pathobionts and decline of anti-inflammatory mutualistic bacteria. Studies in experimental models are also contributing to understand the role of intestinal bacteria and its interactions with a predisposed genotype in promoting CD. Advances in this area could aid in the development of microbiome-informed intervention strategies that optimize the partnership between the gut microbiota and host immunity for improving CD management. © 2015 S. Karger AG, Basel.

Gamma delta T cell responses associated with the development of tuberculosis in health care workers.

PubMed

Ordway, Diane J; Pinto, Luisa; Costa, Leonor; Martins, Marta; Leandro, Clara; Viveiros, Miguel; Amaral, Leonard; Arroz, Maria J; Ventura, Fernando A; Dockrell, Hazel M

2005-03-01

This study evaluated T cell immune responses to purified protein derivative (PPD) and Mycobacterium tuberculosis (Mtb) in health care workers who remained free of active tuberculosis (HCWs w/o TB), health care workers who went on to develop active TB (HCWs w/TB), non-health care workers who were TB free (Non-HCWs) and tuberculosis patients presenting with minimal (Min TB) or advanced (Adv TB) disease. Peripheral blood mononuclear cells (PBMC) were stimulated with Mtb and PPD and the expression of T cell activation markers CD25+ and HLA-DR+, intracellular IL-4 and IFN-gamma production and cytotoxic responses were evaluated. PBMC from HCWs who developed TB showed decreased percentages of cells expressing CD8+CD25+ in comparison to HCWs who remained healthy. HCWs who developed TB showed increased gammadelta TCR+ cell cytotoxicity and decreased CD3+gammadelta TCR- cell cytotoxicity in comparison to HCWs who remained healthy. PBMC from TB patients with advanced disease showed decreased percentages of CD25+CD4+ and CD25+CD8+ T cells that were associated with increased IL-4 production in CD8+ and gammadelta TCR+ phenotypes, in comparison with TB patients presenting minimal disease. TB patients with advanced disease showed increased gammadelta TCR+ cytotoxicity and reduced CD3+gammadelta TCR- cell cytotoxicity. Our results suggest that HCWs who developed TB show an early compensatory mechanism involving an increase in lytic responses of gammadelta TCR+ cells which did not prevent TB.

EHealth: self-management in inflammatory bowel disease and in irritable bowel syndrome using novel constant-care web applications. EHealth by constant-care in IBD and IBS.

PubMed

Pedersen, Natalia

2015-12-01

Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are chronic gastrointestinal disorders of unknown aetiology of increasing incidence and changing disease activity or severity. Approximately 60-80% of IBD patients suffer from IBS. Monitoring and treatment goals of IBD are to optimise the disease course by prolonging remission periods and preventing or shortening periods of active disease. Constant-care web-monitoring and treatment approaches with active patient involvement have been proven effective in UC, increasing patients' adherence and improving the disease outcomes.   To assess the feasibility and efficacy of the novel constant-care eHealth applications in: i) CD patients treated with infliximab (IFX), ii) UC patients with active disease on mesalazine, iii) IBS patients and iv) IBD patients with IBS on a low FODMAP diet (LFD).   New constant-care web applications www.cd.constant-care.dk, www.meza.constant-care.dk and www.ibs.constant-care.dk in IBD patients were developed and assessed in this thesis. An integrated inflammatory burden measure of disease activity, consisting of a subjective (clinical indices) and of an objective (faecal calprotectin) part and a treatment guide to drug doses and intervals, was incorporated into the web applications and used by patients. Web-guided IFX treatment in CD demonstrated patients' inter- and intra-individual variability in infusion intervals and provided patients with individualised treatment according to their needs. Web-guided treatment with multimatrix mesalazine was efficacious in a majority of UC patients with mild-to-moderate disease activity. Web-guided IBS-monitoring in IBD and in IBS patients on LFD was shown to be a feasible method that actively involved patients in their disease management and had a positive short-term impact on the disease. Moreover, the new constant-care concepts were demonstrated to be safe and to have a positive impact on quality of life and adherence to treatment and helped to reduce the costs.   The novel constant-care web applications have proven feasible in improving the disease outcomes in CD patients on IFX, in UC patients on mesalazine, and in monitoring IBS. These applications are expected to be implemented in the clinical practice of gastroenterology in Denmark in the coming years. Future studies will help to assess whether the natural disease course can be improved in the long-term.

The distribution of immunomodulatory cells in the lungs of patients with idiopathic pulmonary fibrosis

PubMed Central

Nuovo, Gerard J.; Hagood, James S.; Magro, Cynthia M.; Chin, Nena; Kapil, Rubina; Davis, Luke; Marsh, Clay B.; Folcik, Virginia A.

2011-01-01

We have characterized the immune system involvement in the disease processes of idiopathic pulmonary fibrosis in novel ways. To do so, we analyzed lung tissue from 21 cases of idiopathic pulmonary fibrosis and 21 (non-fibrotic, non-cancerous) controls for immune cell and inflammation-related markers. The immunohistochemical analysis of the tissue was grouped by patterns of severity in disease pathology. There were significantly greater numbers of CD68+ and CD80+ cells, and significantly fewer CD3+, CD4+, and CD45RO+ cells in areas of relatively (histologically) normal lung in biopsies from idiopathic pulmonary fibrosis patients compared to controls. In zones of active disease, characterized by epithelial cell regeneration and fibrosis, there were significantly more cells expressing CD4, CD8, CD20, CD68, CD80, CCR6, S100, IL-17, tumor necrosis factor-α, and retinoic acid-related orphan receptors compared to histologically normal lung areas from idiopathic pulmonary fibrosis patients. Inflammation was implicated in these active regions by the cells that expressed retinoid orphan receptor-α, -β, and -γ, CCR6, and IL-17. The regenerating epithelial cells predominantly expressed these pro-inflammatory molecules, as evidenced by co-expression analyses with epithelial cytokeratins. Macrophages in pseudo-alveoli and CD3+ T cells in the fibrotic interstitium also expressed IL-17. Co-expression of IL-17 with retinoid orphan receptors, and epithelial cytoskeletal proteins, CD68, and CD3 in epithelial cells, macrophages, and T-cells, respectively, confirmed the production of IL-17 by these cell types. There was little staining for Foxp3, CD56, or CD34 in any idiopathic pulmonary fibrosis lung regions. The fibrotic regions had fewer immune cells overall. In summary, our study shows participation of innate and adaptive mononuclear cells in active-disease regions of idiopathic pulmonary fibrosis lung, where the regenerating epithelial cells appear to propagate inflammation. The regenerative mechanisms become skewed to ultimately result in lethal, fibrotic restriction of lung function. PMID:22037258

The Effect of Oligofructose-Enriched Inulin on Faecal Bacterial Counts and Microbiota-Associated Characteristics in Celiac Disease Children Following a Gluten-Free Diet: Results of a Randomized, Placebo-Controlled Trial

PubMed Central

Jarocka-Cyrta, Elżbieta; Markiewicz, Lidia Hanna

2018-01-01

Celiac disease (CD) is associated with intestinal microbiota alterations. The administration of prebiotics could be a promising method of restoring gut homeostasis in CD. The aim of this study was to evaluate the effect of prolonged oligofructose-enriched inulin (Synergy 1) administration on the characteristics and metabolism of intestinal microbiota in CD children following a gluten-free diet (GFD). Thirty-four paediatric CD patients (mean age 10 years; 62% females) on a GFD were randomized into two experimental groups receiving Synergy 1 (10 g/day) or placebo (maltodextrin; 7 g/day) for 3 months. The quantitative gut microbiota characteristics and short-chain fatty acids (SCFAs) concentration were analysed. In addition, side effects were monitored. Generally, the administration of Synergy 1 in a GFD did not cause any side effects. After the intervention period, Bifidobacterium count increased significantly (p < 0.05) in the Synergy 1 group. Moreover, an increase in faecal acetate and butyrate levels was observed in the prebiotic group. Consequently, total SCFA levels were 31% higher than at the baseline. The presented trial shows that Synergy 1 applied as a supplement of a GFD had a moderate effect on the qualitative characteristics of faecal microbiota, whereas it stimulated the bacterial metabolite production in CD children. PMID:29439526

The Effect of Oligofructose-Enriched Inulin on Faecal Bacterial Counts and Microbiota-Associated Characteristics in Celiac Disease Children Following a Gluten-Free Diet: Results of a Randomized, Placebo-Controlled Trial.

PubMed

Drabińska, Natalia; Jarocka-Cyrta, Elżbieta; Markiewicz, Lidia Hanna; Krupa-Kozak, Urszula

2018-02-12

Celiac disease (CD) is associated with intestinal microbiota alterations. The administration of prebiotics could be a promising method of restoring gut homeostasis in CD. The aim of this study was to evaluate the effect of prolonged oligofructose-enriched inulin (Synergy 1) administration on the characteristics and metabolism of intestinal microbiota in CD children following a gluten-free diet (GFD). Thirty-four paediatric CD patients (mean age 10 years; 62% females) on a GFD were randomized into two experimental groups receiving Synergy 1 (10 g/day) or placebo (maltodextrin; 7 g/day) for 3 months. The quantitative gut microbiota characteristics and short-chain fatty acids (SCFAs) concentration were analysed. In addition, side effects were monitored. Generally, the administration of Synergy 1 in a GFD did not cause any side effects. After the intervention period, Bifidobacterium count increased significantly ( p < 0.05) in the Synergy 1 group. Moreover, an increase in faecal acetate and butyrate levels was observed in the prebiotic group. Consequently, total SCFA levels were 31% higher than at the baseline. The presented trial shows that Synergy 1 applied as a supplement of a GFD had a moderate effect on the qualitative characteristics of faecal microbiota, whereas it stimulated the bacterial metabolite production in CD children.

Uncomplicated Diverticular Disease: Innate and Adaptive Immunity in Human Gut Mucosa before and after Rifaximin

PubMed Central

Cesaro, Paola; Petruzziello, Lucio; Casciano, Fabio; Costamagna, Guido; Pandolfi, Franco

2014-01-01

Background/Aim. Uncomplicated diverticular disease (UDD) is a frequent condition in adults. The pathogenesis of symptoms remains unknown. Bacteria are able to interact with Toll-like receptors (TLRs) and to induce inflammation through both innate immunity and T-cell recruitment. We investigated the pattern of TLRs 2 and 4 and the intestinal homing in patients with UDD before and after a course of Rifaximin. Methods. Forty consecutive patients with UDD and 20 healthy asymptomatic subjects were enrolled. Among UDD patients, 20 were assigned to a 2-month course of treatment with Rifaximin 1.2 g/day for 15 days/month and 20 received placebo. Blood sample and colonic biopsies were obtained from patients and controls. The samples were collected and analyzed at baseline and at the end of treatment. Flow cytometry was performed using monoclonal antibodies (CD3, CD4, CD8, CD103, TCR-gamma/delta, CD14, TLR2, and TLR4). Results. In UDD, TLR2 and TLR4 expression on immune cell subpopulations from blood and mucosa of the affected colon are altered as compared with controls. Rifaximin treatment induced significant modifications of altered conditions. Conclusions. Our data show the role of TLRs in the development of inflammation in UDD. TLRs distribution is altered in UDD and these alterations are reversed after antibiotic treatment. This trial is registered with ClinicalTrials.gov: NCT02068482. PMID:25133198

Atrial Electromechanical Properties in Coeliac Disease.

PubMed

Efe, Tolga Han; Ertem, Ahmet Goktug; Coskun, Yusuf; Bilgin, Murat; Algul, Engin; Beton, Osman; Asarcikli, Lale Dinc; Erat, Mehmet; Ayturk, Mehmet; Yuksel, Ilhami; Yeter, Ekrem

2016-02-01

Coeliac disease (CD) is an autoimmune and inflammatory disorder of the small intestine. There is reasonable evidence linking inflammation to the initiation and continuation of atrial fibrillation (AF) in inflammatory conditions. Atrial electro-mechanic delay (EMD) was suggested as an early marker of AF in previous studies. The objectives of this study were to evaluate atrial electromechanical properties measured by tissue Doppler imaging and simultaneous electrocardiography (ECG) tracing in patients with CD. Thirty-nine patients with coeliac disease (CD), and 26 healthy volunteers, matched for age and sex, were enrolled in the study. Atrial electromechanical properties were measured by using transthoracic echocardiography and surface ECG. Interatrial electro-mechanic delay (EMD), left intraatrial EMD, right intratrial EMD were calculated. There was no difference between CD patients and healthy volunteers in terms of basal characteristics. Patients with CD had significantly prolonged left and right intraatrial EMDs, and interatrial EMD compared to healthy controls (p= 0.03, p= 0.02, p<0.0001, respectively). Interatrial EMD was positively correlated with age, disease duration, anti-gliadin IgG, anti-endomysium and disease status. In multiple linear regression, interatrial EMD was independently associated with disease duration, anti-endomysium and disease status after adjusting for age and sex. In the present study, atrial EMDs were found significantly higher in patients with CD compared with healthy individuals. Measurement of atrial EMD parameters might be used to predict the risk of development of AF in patients with CD. Copyright © 2015 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

Antilaminaribioside and antichitobioside antibodies in inflammatory bowel disease.

PubMed

Rejchrt, S; Drahosová, M; Kopácová, M; Cyrany, J; Douda, T; Pintér, M; Bures, J

2008-01-01

Testing antilaminaribioside (ALCA) and antichitobioside (ACCA) antibodies in 89 Crohn's disease (CD), 31 ulcerative colitis (UC) and 50 controls, mean values were 38.6 and 53.0 ELISA units for CD, 34.0 and 32.6 for UC, 34.5 and 36.4 for controls, respectively. There was no significant difference of ALCA values between CD and UC (p = 0.401), CD and control subjects (p = 0.698) or UC and controls (p = 0.898). ACCA were significantly higher in CD compared with UC (p = 0.011) but not with the controls (p = 0.095). No significant difference of ACCA values between UC and controls (p = 0.107) was found. ALCA and ACCA values significantly correlated in CD (r = 0.548, p < 10(-4)) and UC (r = 0.885, p < 10(-4)) but not in controls (r = 0.153, p = 0.287). The positive predictive value for CD was only 20 (ALCA) and 8 % (ACCA), the negative ones (to exclude CD) 25 (ALCA) and 86 % (ACCA). Small and/or large bowel involvement or disease type (i.e. stenosing, perforating or inflammatory) of CD did not differ in the two values. The idea that ALCA and ACCA may be useful either to differentiate between CD, UC and healthy subjects or to stratify CD was not confirmed.

HIV-Infected Children Have Elevated Levels of PD-1+ Memory CD4 T Cells With Low Proliferative Capacity and High Inflammatory Cytokine Effector Functions.

PubMed

Foldi, Julia; Kozhaya, Lina; McCarty, Bret; Mwamzuka, Mussa; Marshed, Fatma; Ilmet, Tiina; Kilberg, Max; Kravietz, Adam; Ahmed, Aabid; Borkowsky, William; Unutmaz, Derya; Khaitan, Alka

2017-09-15

During human immunodeficiency virus (HIV) disease, chronic immune activation leads to T-cell exhaustion. PD-1 identifies "exhausted" CD8 T cells with impaired HIV-specific effector functions, but its role on CD4 T cells and in HIV-infected children is poorly understood. In a Kenyan cohort of vertically HIV-infected children, we measured PD-1+ CD4 T-cell frequencies and phenotype by flow cytometry and their correlation with HIV disease progression and immune activation. Second, in vitro CD4 T-cell proliferative and cytokine responses to HIV-specific and -nonspecific stimuli were assessed with and without PD-1 blockade. HIV-infected children have increased frequencies of PD-1+ memory CD4 T cells that fail to normalize with antiretroviral treatment. These cells are comprised of central and effector memory subsets and correlate with HIV disease progression, measured by viral load, CD4 percentage, CD4:CD8 T-cell ratio, and immune activation. Last, PD-1+ CD4 T cells predict impaired proliferative potential yet preferentially secrete the Th1 and Th17 cytokines interferon-γ and interleukin 17A, and are unresponsive to in vitro PD-1 blockade. This study highlights differences in PD-1+ CD4 T-cell memory phenotype and response to blockade between HIV-infected children and adults, with implications for potential immune checkpoint therapies. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Antagonism of scavenger receptor CD36 by 5A peptide prevents chronic kidney disease progression in mice independent of blood pressure regulation

PubMed Central

Souza, Ana Carolina P.; Bocharov, Alexander V.; Baranova, Irina; Vishnyakova, Tatyana; Huang, Yuning G.; Wilkins, Kenneth J.; Hu, Xuzhen; Street, Jonathan M.; Alvarez-Prats, Alejandro; Mullick, Adam E.; Patterson, Amy P.; Remaley, Alan; Eggerman, Thomas L.; Yuen, Peter S.T.; Star, Robert A.

2016-01-01

Scavenger receptor CD36 participates in lipid metabolism and inflammatory pathways important for cardiovascular disease and chronic kidney disease (CKD). Few pharmacological agents are available to slow the progression of CKD. However, apolipoprotein AI-mimetic peptide 5A antagonizes CD36 in vitro. To test the efficacy of 5A, and to test the role of CD36 during CKD, we compared wild type to CD36 knockout mice and wild type mice treated with 5A, in a progressive CKD model that resembles human disease. Knockout and 5A-treated wild type mice were protected from CKD progression without changes in blood pressure and had reductions in cardiovascular risk surrogate markers that are associated with CKD. Treatment with 5A did not further protect CD36 knockout mice from CKD progression, implicating CD36 as its main site of action. In a separate model of kidney fibrosis, 5A-treated wild type mice had less macrophage infiltration and interstitial fibrosis. Peptide 5A exerted anti-inflammatory effects in the kidney and decreases renal expression of inflammasome genes. Thus, CD36 is a new therapeutic target for CKD and its associated cardiovascular risk factors. Peptide 5A may be a promising new agent to slow CKD progression. PMID:26994575

Phenotypic and functional characterization of herpes simplex virus glycoprotein B epitope-specific effector and memory CD8+ T cells from symptomatic and asymptomatic individuals with ocular herpes.

PubMed

Khan, Arif A; Srivastava, Ruchi; Spencer, Doran; Garg, Sumit; Fremgen, Daniel; Vahed, Hawa; Lopes, Patricia P; Pham, Thanh T; Hewett, Charlie; Kuang, Jasmine; Ong, Nicolas; Huang, Lei; Scarfone, Vanessa M; Nesburn, Anthony B; Wechsler, Steven L; BenMohamed, Lbachir

2015-04-01

Herpes simplex virus 1 (HSV-1) glycoprotein B (gB)-specific CD8(+) T cells protect mice from herpes infection and disease. However, whether and which HSV-1 gB-specific CD8(+) T cells play a key role in the "natural" protection seen in HSV-1-seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical herpes disease) remain to be determined. In this study, we have dissected the phenotypes and the functions of HSV-1 gB-specific CD8(+) T cells from HLA-A*02:01 positive, HSV-1 seropositive ASYMP and symptomatic (SYMP) individuals (with a history of numerous episodes of recurrent ocular herpes disease). We found the following. (i) Healthy ASYMP individuals maintained a significantly higher proportion of differentiated HSV-1 gB-specific effector memory CD8(+) T cells (TEM cells) (CD45RA(low) CCR7(low) CD44(high) CD62L(low)). In contrast, SYMP patients had frequent less-differentiated central memory CD8(+) T cells (TCM cells) (CD45RA(low) CCR7(high) CD44(low) CD62L(high)). (ii) ASYMP individuals had significantly higher proportions of multifunctional effector CD8(+) T cells which responded mainly to gB342-350 and gB561-569 "ASYMP" epitopes, and simultaneously produced IFN-γ, CD107(a/b), granzyme B, and perforin. In contrast, effector CD8(+) T cells from SYMP individuals were mostly monofunctional and were directed mainly against nonoverlapping gB17-25 and gB183-191 "SYMP" epitopes. (iii) Immunization of an HLA-A*02:01 transgenic mouse model of ocular herpes with "ASYMP" CD8(+) TEM cell epitopes, but not with "SYMP" CD8(+) TCM cell epitopes, induced a strong CD8(+) T cell-dependent protective immunity against ocular herpes infection and disease. Our findings provide insights into the role of HSV-specific CD8(+) TEM cells in protection against herpes and should be considered in the development of an effective vaccine. A significantly higher proportion of differentiated and multifunctional HSV-1 gB-specific effector memory CD8(+) T cells (TEM cells) (CD45RA(low) CCR7(low) CD44(high) CD62L(low)) were found in healthy ASYMP individuals who are seropositive for HSV-1 but never had any recurrent herpetic disease, while there were frequent less-differentiated and monofunctional central memory CD8(+) T cells (TCM cells) (CD45RA(low) CCR7(high) CD44(low) CD62L(high)) in SYMP patients. Immunization with "ASYMP" CD8(+) TEM cell epitopes, but not with "SYMP" CD8(+) TCM cell epitopes, induced a strong protective HSV-specific CD8(+) T cell response in HLA-A*02:01 transgenic mice. These findings are important for the development of a safe and effective T cell-based herpes vaccine. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Genital and reproductive organ complications of Crohn disease: technical considerations as it relates to perianal disease, imaging features, and implications on management.

PubMed

Kammann, Steven; Menias, Christine; Hara, Amy; Moshiri, Mariam; Siegel, Cary; Safar, Bashar; Brandes, Steven; Shaaban, Akram; Sandrasegaran, Kumar

2017-06-01

A relatively large proportion of patients with Crohn disease (CD) develop complications including abscess formation, stricture, and penetrating disease. A subset of patients will have genital and reproductive organ involvement of CD, resulting in significant morbidity. These special circumstances create unique management challenges that must be tailored to the activity, location, and extent of disease. Familiarity with the epidemiology, pathogenesis, imaging features, and treatment strategies for patients with genital CD can aid imaging diagnoses and guide appropriate patient management. The purpose of this study is to illustrate the spectrum of CD in the genital tract and reproductive organs and discuss the complex management strategies in these patients as it relates to imaging. Given the impact on patient outcome and treatment planning, familiarity with the epidemiology, pathogenesis, imaging features, and treatment of patients with genital Crohn disease can aid radiologic diagnoses and guide appropriate patient management.

A systematic review of measurement of endoscopic disease activity and mucosal healing in Crohn's disease: recommendations for clinical trial design.

PubMed

Khanna, Reena; Bouguen, Guillaume; Feagan, Brian G; DʼHaens, Geert; Sandborn, William J; Dubcenco, Elena; Baker, K Adam; Levesque, Barrett G

2014-10-01

Crohn's disease (CD) is a chronic idiopathic inflammatory disorder of the gastrointestinal tract. Recently, mucosal healing has been proposed as a goal of therapy because clinical symptoms are subjective. Evaluative indices that measure endoscopic disease activity are required to define mucosal healing for clinical trials. The primary objective of this systematic review was to assess the existing evaluative indices that measure disease activity in CD and evaluate their role as outcome measures in clinical trials. A systematic literature review was performed using MEDLINE (Ovid), EMBASE (Ovid), PubMed, the Cochrane Library (CENTRAL), and DDW abstracts to identify randomized controlled trials and controlled clinical trials that used a relevant evaluative index from inception to February 2013. The data obtained from these trials were reviewed and summarized. The initial literature searches identified 2300 citations. After duplicates were removed, 1454 studies remained. After application of the apriori inclusion and exclusion criteria, 109 articles were included and 3 were identified with handsearches. In total, 9 evaluative indices for CD were identified and reviewed. The Crohn's Disease Endoscopic Index of Severity (CDEIS) and the Simple Endoscopic Score in Crohn's Disease (SES-CD) are indices with the most extensively described operating properties. Both the endoscopic evaluative instrument selected and the definition chosen for mucosal healing affect the validity of assessing endoscopic disease activity during a clinical trial for CD. Currently, the CDEIS and SES-CD have the most data regarding operating properties; however, further validation is required.

Anti-Saccharomyces cerevisiae antibodies (ASCA) in Crohn's disease are associated with disease severity but not NOD2/CARD15 mutations.

PubMed

Walker, L J; Aldhous, M C; Drummond, H E; Smith, B R K; Nimmo, E R; Arnott, I D R; Satsangi, J

2004-03-01

Anti-Saccharomyces cerevisiae antibodies (ASCAs) have been proposed as serological markers, which may differentiate Crohn's disease (CD) from ulcerative colitis (UC) and predict disease phenotype. Their importance in pathogenesis is unproven. We investigated the relationship between ASCAs, disease phenotype and NOD2/CARD15 genotype in CD and whether ASCAs were related to antibodies to other fungal proteins. Serum from 228 patients [143 CD, 75 UC, 10 with indeterminate colitis (IC)] and 78 healthy controls (HC) were assayed for ASCA. Antibodies (IgA, IgG) to other fungal proteins (Fusarium species ATC20334, Mycoprotein) were measured in the same samples using an in-house enzyme-linked immunosorbent assay (ELISA) assay. ASCAs were present in 57% of CD, 19% of UC, 30% of IC and 8% of HCs. ASCA-positive status was a predictor for CD with sensitivity of 57%, specificity of 87%, positive predictive value of 78% and negative predictive value of 68%. ASCA was associated with proximal (gastroduodenal and small bowel involvement) rather than purely colonic disease (P < 0.001) and with a more severe disease phenotype and requirement for surgery over a median follow-up time of 9 years (P < 0.0001). No associations with NOD2/CARD15 mutations were seen. There was no association between ASCA and antibodies to MP (IgA or IgG). These data implicate ASCA as a specific marker of disease location and progression in CD, emphasizing the heterogeneity within IBD.

Anti-Saccharomyces cerevisiae antibodies (ASCA) in Crohn's disease are associated with disease severity but not NOD2/CARD15 mutations

PubMed Central

WALKER, L J; ALDHOUS, M C; DRUMMOND, H E; SMITH, B R K; NIMMO, E R; ARNOTT, I D R; SATSANGI, J

2004-01-01

Anti-Saccharomyces cerevisiae antibodies (ASCAs) have been proposed as serological markers, which may differentiate Crohn's disease (CD) from ulcerative colitis (UC) and predict disease phenotype. Their importance in pathogenesis is unproven. We investigated the relationship between ASCAs, disease phenotype and NOD2/CARD15 genotype in CD and whether ASCAs were related to antibodies to other fungal proteins. Serum from 228 patients [143 CD, 75 UC, 10 with indeterminate colitis (IC)] and 78 healthy controls (HC) were assayed for ASCA. Antibodies (IgA, IgG) to other fungal proteins (Fusarium species ATC20334, Mycoprotein) were measured in the same samples using an in-house enzyme-linked immunosorbent assay (ELISA) assay. ASCAs were present in 57% of CD, 19% of UC, 30% of IC and 8% of HCs. ASCA-positive status was a predictor for CD with sensitivity of 57%, specificity of 87%, positive predictive value of 78% and negative predictive value of 68%. ASCA was associated with proximal (gastroduodenal and small bowel involvement) rather than purely colonic disease (P < 0·001) and with a more severe disease phenotype and requirement for surgery over a median follow-up time of 9 years (P < 0·0001). No associations with NOD2/CARD15 mutations were seen. There was no association between ASCA and antibodies to MP (IgA or IgG). These data implicate ASCA as a specific marker of disease location and progression in CD, emphasizing the heterogeneity within IBD. PMID:15008984

Human CD22 Inhibits Murine B Cell Receptor Activation in a Human CD22 Transgenic Mouse Model.

PubMed

Bednar, Kyle J; Shanina, Elena; Ballet, Romain; Connors, Edward P; Duan, Shiteng; Juan, Joana; Arlian, Britni M; Kulis, Michael D; Butcher, Eugene C; Fung-Leung, Wai-Ping; Rao, Tadimeti S; Paulson, James C; Macauley, Matthew S

2017-11-01

CD22, a sialic acid-binding Ig-type lectin (Siglec) family member, is an inhibitory coreceptor of the BCR with established roles in health and disease. The restricted expression pattern of CD22 on B cells and most B cell lymphomas has made CD22 a therapeutic target for B cell-mediated diseases. Models to better understand how in vivo targeting of CD22 translates to human disease are needed. In this article, we report the development of a transgenic mouse expressing human CD22 (hCD22) in B cells and assess its ability to functionally substitute for murine CD22 (mCD22) for regulation of BCR signaling, Ab responses, homing, and tolerance. Expression of hCD22 on transgenic murine B cells is comparable to expression on human primary B cells, and it colocalizes with mCD22 on the cell surface. Murine B cells expressing only hCD22 have identical calcium (Ca 2+ ) flux responses to anti-IgM as mCD22-expressing wild-type B cells. Furthermore, hCD22 transgenic mice on an mCD22 -/- background have restored levels of marginal zone B cells and Ab responses compared with deficiencies observed in CD22 -/- mice. Consistent with these observations, hCD22 transgenic mice develop normal humoral responses in a peanut allergy oral sensitization model. Homing of B cells to Peyer's patches was partially rescued by expression of hCD22 compared with CD22 -/- B cells, although not to wild-type levels. Notably, Siglec-engaging antigenic liposomes formulated with an hCD22 ligand were shown to prevent B cell activation, increase cell death, and induce tolerance in vivo. This hCD22 transgenic mouse will be a valuable model for investigating the function of hCD22 and preclinical studies targeting hCD22. Copyright © 2017 by The American Association of Immunologists, Inc.

Formin like 1 expression is increased on CD4+ T lymphocytes in spontaneous autoimmune uveitis.

PubMed

Degroote, Roxane L; Uhl, Patrizia B; Amann, Barbara; Krackhardt, Angela M; Ueffing, Marius; Hauck, Stefanie M; Deeg, Cornelia A

2017-02-10

The membrane protein expression repertoire of cells changes in course of activation. In equine recurrent uveitis (ERU), a spontaneous autoimmune disease in horses with relapsing and ultimately blinding inner eye inflammation, CD4+ T lymphocytes are the crucial pathogenic cells activated in the periphery directly prior to an inflammatory episode. In order to find relevant changes in the membrane proteome associated to disease, we sorted CD4+ lymphocytes and compared protein abundance from the generated proteome datasets of both healthy horses and ERU cases. We detected formin like 1, a key player in actin dependent cellular processes such as phagocytosis, cell adhesion and cell migration, with significantly higher abundance in the CD4+ cell membrane proteome of horses with ERU. In transmigration experiments, we demonstrated higher migration rate of cells originating from diseased animals connecting formin like 1 to the migratory ability of cells. These findings are the first description of formin like 1 in association to processes involved in migration of inflammatory CD4+ T cells across the blood-retinal barrier in a spontaneous ocular autoimmune disease and suggest formin like 1 to play a role in the molecular mechanisms of ERU disease pathogenesis. Data are available via ProteomeXchange with identifier PXD005384. This comparative proteomic study of membrane proteins of CD4+ T cells identified a novel protein, formin like 1, with expression on the plasma cell membrane of equine CD4+ T cells and a significant change of abundance on CD4+ T cells of horses with a spontaneous autoimmune disease. Functional studies in a cell culture model for transmigration at the blood-retinal barrier (BRB) unraveled a strong impact of formin like 1 on migratory processes of CD4+ T cells across the BRB, a key event in uveitis pathogenesis. These findings provide novel knowledge about changes in the CD4+ immune cell membrane proteome in a spontaneously and naturally occurring autoimmune disease in horses with high relevance for veterinary medicine. Additionally, this model has proven translational quality for human medicine and provides novel proteomic information on autoimmune uveitis in man. Copyright © 2017 Elsevier B.V. All rights reserved.

A Meta-Analysis of Genome-Wide Association Scans Identifies IL18RAP, PTPN2, TAGAP, and PUS10 As Shared Risk Loci for Crohn's Disease and Celiac Disease

PubMed Central

Boucher, Gabrielle; Beauchamp, Claudine; Trynka, Gosia; Dubois, Patrick C.; Lagacé, Caroline; Stokkers, Pieter C. F.; Hommes, Daan W.; Barisani, Donatella; Palmieri, Orazio; Annese, Vito; van Heel, David A.; Weersma, Rinse K.; Daly, Mark J.; Wijmenga, Cisca; Rioux, John D.

2011-01-01

Crohn's disease (CD) and celiac disease (CelD) are chronic intestinal inflammatory diseases, involving genetic and environmental factors in their pathogenesis. The two diseases can co-occur within families, and studies suggest that CelD patients have a higher risk to develop CD than the general population. These observations suggest that CD and CelD may share common genetic risk loci. Two such shared loci, IL18RAP and PTPN2, have already been identified independently in these two diseases. The aim of our study was to explicitly identify shared risk loci for these diseases by combining results from genome-wide association study (GWAS) datasets of CD and CelD. Specifically, GWAS results from CelD (768 cases, 1,422 controls) and CD (3,230 cases, 4,829 controls) were combined in a meta-analysis. Nine independent regions had nominal association p-value <1.0×10−5 in this meta-analysis and showed evidence of association to the individual diseases in the original scans (p-value <1×10−2 in CelD and <1×10−3 in CD). These include the two previously reported shared loci, IL18RAP and PTPN2, with p-values of 3.37×10−8 and 6.39×10−9, respectively, in the meta-analysis. The other seven had not been reported as shared loci and thus were tested in additional CelD (3,149 cases and 4,714 controls) and CD (1,835 cases and 1,669 controls) cohorts. Two of these loci, TAGAP and PUS10, showed significant evidence of replication (Bonferroni corrected p-values <0.0071) in the combined CelD and CD replication cohorts and were firmly established as shared risk loci of genome-wide significance, with overall combined p-values of 1.55×10−10 and 1.38×10−11 respectively. Through a meta-analysis of GWAS data from CD and CelD, we have identified four shared risk loci: PTPN2, IL18RAP, TAGAP, and PUS10. The combined analysis of the two datasets provided the power, lacking in the individual GWAS for single diseases, to detect shared loci with a relatively small effect. PMID:21298027

CD30-Positive T-Cell Lymphoproliferative Disease of the Oral Mucosa in Children: A Manifestation of Epstein-Barr Virus-Associated T-Lymphoproliferative Disorder.

PubMed

Hong, Mineui; Ko, Young Hyeh

2015-11-01

Eosinophilic ulcer of the oral mucosa (EUOM) is a very rare, benign, self-limiting ulcerative lesion of the oral cavity of unknown pathogenesis, and belongs to the same spectrum of CD30(+) T-cell lymphoproliferative disease (LPD) of the oral mucosa. The etiology and pathogenesis of the disease are unknown. We report two cases in children who were initially diagnosed with EUOM and CD30(+) T-cell LPD, respectively. However, retrospective analysis revealed that a majority of infiltrated atypical T cells were positive for Epstein-Barr virus (EBV). The present cases suggest that the pathogenesis and etiology of EUOM or CD30(+) T-cell LPD occurring in children are different from those in adults. EUOM or CD30(+) T-cell LPD in children is a manifestation of EBV-positive T-cell LPD, and should therefore be distinguished from the disease in adults.

Medical Management of Crohn Disease

PubMed Central

Scott, Frank I.; Osterman, Mark T.

2013-01-01

Crohn disease (CD) is one of the major subtypes of inflammatory bowel disease and can occur in any segment of the alimentary tract. There have been significant advances in the medical therapy of CD over the past several decades. For mild CD, the oral corticosteroid derivative budesonide has demonstrated superior efficacy compared with traditional therapies such as 5-aminosalicylic acid, and can be used concurrently with these agents. For the management of moderate to severe disease, the immunomodulators azathioprine, 6-mercaptopurine, and methotrexate, as well as the antitumor necrosis factor-alpha (TNF-α) agents infliximab, adalimumab, and certolizumab pegol, have become the mainstay of therapy, with growing interest in combining these agents for maximal effect. Immunomodulators and anti-TNF-α agents have also demonstrated benefit in fistulizing CD. There has been growing evidence suggesting that both of these agents, along with the antibiotics metronidazole and ornidazole, are also effective in preventing postoperative recurrence of CD. PMID:24436652

Health Care Seeking Behavior of Persons with Acute Chagas Disease in Rural Argentina: A Qualitative View.

PubMed

Llovet, Ignacio; Dinardi, Graciela; Canevari, Cecilia; Torabi, Nahal

2016-01-01

Chagas disease (CD) is a tropical parasitic disease largely underdiagnosed and mostly asymptomatic affecting marginalized rural populations. Argentina regularly reports acute cases of CD, mostly young individuals under 14 years old. There is a void of knowledge of health care seeking behavior in subjects experiencing a CD acute condition. Early treatment of the acute case is crucial to limit subsequent development of disease. The article explores how the health outcome of persons with acute CD may be conditioned by their health care seeking behavior. The study, with a qualitative approach, was carried out in rural areas of Santiago del Estero Province, a high risk endemic region for vector transmission of CD. Narratives of 25 in-depth interviews carried out in 2005 and 2006 are analyzed identifying patterns of health care seeking behavior followed by acute cases. Through the retrospective recall of paths for diagnoses, weaknesses of disease information, knowledge at the household level, and underperformance at the provincial health care system level are detected. The misdiagnoses were a major factor in delaying a health care response. The study results expose lost opportunities for the health care system to effectively record CD acute cases.

Health Care Seeking Behavior of Persons with Acute Chagas Disease in Rural Argentina: A Qualitative View

PubMed Central

Dinardi, Graciela; Canevari, Cecilia; Torabi, Nahal

2016-01-01

Chagas disease (CD) is a tropical parasitic disease largely underdiagnosed and mostly asymptomatic affecting marginalized rural populations. Argentina regularly reports acute cases of CD, mostly young individuals under 14 years old. There is a void of knowledge of health care seeking behavior in subjects experiencing a CD acute condition. Early treatment of the acute case is crucial to limit subsequent development of disease. The article explores how the health outcome of persons with acute CD may be conditioned by their health care seeking behavior. The study, with a qualitative approach, was carried out in rural areas of Santiago del Estero Province, a high risk endemic region for vector transmission of CD. Narratives of 25 in-depth interviews carried out in 2005 and 2006 are analyzed identifying patterns of health care seeking behavior followed by acute cases. Through the retrospective recall of paths for diagnoses, weaknesses of disease information, knowledge at the household level, and underperformance at the provincial health care system level are detected. The misdiagnoses were a major factor in delaying a health care response. The study results expose lost opportunities for the health care system to effectively record CD acute cases. PMID:27829843

Levels of soluble CD30 in cord blood and peripheral blood during childhood are not correlated with the development of atopic disease or a family history of atopy.

PubMed

Holmlund, U; Bengtsson, A; Nilsson, C; Kusoffsky, E; Lilja, G; Scheynius, A; Sverremark-Ekström, E

2003-11-01

The CD30 molecule has been linked to Th2 responses. Furthermore, elevated levels of the soluble form of CD30 (sCD30) in blood as well as of the expression of CD30 on the plasma membrane of T cells are associated with atopic disease. To assess the potential usefulness of sCD30 levels as a prognostic indicator of and/or diagnostic marker for the development of atopic disease in children. sCD30 levels in cord blood and peripheral blood from 36 2-year-old (10 atopic and 26 non-atopic) and 74 7-year-old (35 atopic and 39 non-atopic) children were determined employing an ELISA procedure. Atopy was diagnosed on the basis of clinical evaluation in combination with a positive skin prick test. No significant correlation between sCD30 levels in cord blood and the development of atopic disease at 2 or 7 years of age was observed. At 7 years of age, the circulating sCD30 levels in children with atopic disease (median 41 U/mL, range 6-503 U/mL) did not differ from the corresponding values for non-atopic subjects (median 41 U/mL, range 8-402 U/mL). The same was true for children at 2 years of age. Furthermore, the sCD30 levels of children who had developed atopic eczema/dermatitis syndrome by the age of 7 years (median 49 U/mL, range 14-503 U/mL) were not significantly elevated in comparison with those of the non-atopic children. Finally, neither sCD30 levels in cord blood nor peripheral blood at 2 or 7 years of age could be linked to a family history of atopy. These findings indicate that the sCD30 concentration in cord blood is not a reliable prognostic indicator of, nor a useful diagnostic marker for, atopic disease in children up to 7 years of age. If such correlations do exist, they might be masked by age-dependent variations in the circulating levels of sCD30, which may reflect individual differences in the maturation of children's immunological responses.

Expression of the stem cell factor in fibroblasts, endothelial cells, and macrophages in periapical tissues in human chronic periapical diseases.

PubMed

Shen, S Q; Wang, R; Huang, S G

2017-03-08

Stem cell factor (SCF), an important stem cell cytokine, has multiple functions. Fibroblasts (FBs), mature mast cells, endothelial cells (ECs), and eosinophil granulocytes can produce SCF in the inflammatory process. Therefore, we aimed to observe SCF expression in FBs, ECs, and macrophages (MPs) in periapical tissues in human chronic periapical disease and investigate the effects of cells expressing SCF in pathogenesis of the disease. Healthy (N = 20), periapical cyst (N = 15), and periapical granuloma (N = 15) tissues were fixed in 10% formalin for 48 h, embedded in paraffin, and stained with hematoxylin and eosin to observe histological changes. SCF expression was observed in FBs, ECs, and MPs in periapical tissues by double immunofluorescence. CD334, CD31, and CD14 are specific markers of FBs, ECs, and MPs, respectively. Results showed that densities of CD334-SCF double-positive FBs, CD31-SCF double-positive ECs, and CD14-SCF double-positive MPs were significantly increased in periapical tissue groups (P < 0.01). There were no significant differences in CD334-SCF double-positive FB and CD31-SCF double-positive EC levels between the two periapical tissue groups (P > 0.05). CD14-SCF double-positive MP density was considerably higher in periapical granulomas than in cysts (P < 0.01). FB, EC, and MP levels were significantly high and densities of CD334-SCF double-positive FBs, CD31-SCF double-positive ECs, and CD14-SCF double-positive MPs improved considerably in chronic periapical tissues, suggesting that the cells might be related to occurrence, development, and pathogenesis of chronic periapical disease.

High amount of dietary fiber not harmful but favorable for Crohn disease.

PubMed

Chiba, Mitsuro; Tsuji, Tsuyotoshi; Nakane, Kunio; Komatsu, Masafumi

2015-01-01

Current chronic diseases are a reflection of the westernized diet that features a decreased consumption of dietary fiber. Indigestible dietary fiber is metabolized by gut bacteria, including Faecalibacterium prausnitzii, to butyrate, which has a critical role in colonic homeostasis owing to a variety of functions. Dietary fiber intake has been significantly inversely associated with the risk of chronic diseases. Crohn disease (CD) is not an exception. However, even authors who reported the inverse association between dietary fiber and a risk of CD made no recommendation of dietary fiber intake to CD patients. Some correspondence was against advocating high fiber intake in CD. We initiated a semivegetarian diet (SVD), namely a lacto-ovo-vegetarian diet, for patients with inflammatory bowel disease. Our SVD contains 32.4 g of dietary fiber in 2000 kcal. There was no untoward effect of the SVD. The remission rate with combined infliximab and SVD for newly diagnosed CD patients was 100%. Maintenance of remission on SVD without scheduled maintenance therapy with biologic drugs was 92% at 2 years. These excellent short- and long-term results can be explained partly by SVD. The fecal bacterial count of F prausnitzii in patients with CD is significantly lower than in healthy controls. Diet reviews recommend plant-based diets to treat and to prevent a variety of chronic diseases. SVD belongs to plant-based diets that inevitably contain considerable amounts of dietary fiber. Our clinical experience and available data provide a rationale to recommend a high fiber intake to treat CD.

Computational modeling of heterogeneity and function of CD4+ T cells

PubMed Central

Carbo, Adria; Hontecillas, Raquel; Andrew, Tricity; Eden, Kristin; Mei, Yongguo; Hoops, Stefan; Bassaganya-Riera, Josep

2014-01-01

The immune system is composed of many different cell types and hundreds of intersecting molecular pathways and signals. This large biological complexity requires coordination between distinct pro-inflammatory and regulatory cell subsets to respond to infection while maintaining tissue homeostasis. CD4+ T cells play a central role in orchestrating immune responses and in maintaining a balance between pro- and anti- inflammatory responses. This tight balance between regulatory and effector reactions depends on the ability of CD4+ T cells to modulate distinct pathways within large molecular networks, since dysregulated CD4+ T cell responses may result in chronic inflammatory and autoimmune diseases. The CD4+ T cell differentiation process comprises an intricate interplay between cytokines, their receptors, adaptor molecules, signaling cascades and transcription factors that help delineate cell fate and function. Computational modeling can help to describe, simulate, analyze, and predict some of the behaviors in this complicated differentiation network. This review provides a comprehensive overview of existing computational immunology methods as well as novel strategies used to model immune responses with a particular focus on CD4+ T cell differentiation. PMID:25364738

Inhibition of Type 1 Cytokine–mediated Inflammation by a Soluble CD30 Homologue Encoded by Ectromelia (Mousepox) Virus

PubMed Central

Saraiva, Margarida; Smith, Philip; Fallon, Padraic G.; Alcami, Antonio

2002-01-01

CD30 is up-regulated in several human diseases and viral infections but its role in immune regulation is poorly understood. Here, we report the expression of a functional soluble CD30 homologue, viral CD30 (vCD30), encoded by ectromelia (mousepox) virus, a poxvirus that causes a severe disease related to human smallpox. We show that vCD30 is a 12-kD secreted protein that not only binds CD30L with high affinity and prevents its interaction with CD30, but it also induces reverse signaling in cells expressing CD30L. vCD30 blocked the generation of interferon γ–producing cells in vitro and was a potent inhibitor of T helper cell (Th)1- but not Th2-mediated inflammation in vivo. The finding of a CD30 homologue encoded by ectromelia virus suggests a role for CD30 in antiviral defense. Characterization of the immunological properties of vCD30 has uncovered a role of CD30–CD30L interactions in the generation of inflammatory responses. PMID:12235215

Increased duodenal expression of miR-146a and -155 in pediatric Crohn’s disease

PubMed Central

Szűcs, Dániel; Béres, Nóra Judit; Rokonay, Réka; Boros, Kriszta; Borka, Katalin; Kiss, Zoltán; Arató, András; Szabó, Attila J; Vannay, Ádám; Sziksz, Erna; Bereczki, Csaba; Veres, Gábor

2016-01-01

AIM: To evaluate the role of microRNA (miR)-146a, -155 and -122 in the duodenal mucosa of pediatric patients with Crohn’s disease (CD) and the effect of transforming growth factor-β (TGF-β) on these miRs in duodenal epithelial and fibroblast cells. METHODS: Formalin-fixed, paraffin-embedded biopsies derived from the macroscopically inflamed (CD inflamed: n = 10) and intact (CD intact: n = 10) duodenal mucosa of pediatric CD patients and control children (C: n = 10) were examined. Expression of miR-146a, -155 and -122 was determined by real-time polymerase-chain reaction (PCR). The expression of the above miRs was investigated in recombinant human TGF-β (1 nmol/L, 24 h) or vehicle treated small intestinal epithelial cells (CCL-241) and primary duodenal fibroblast cells derived from healthy children as well. RESULTS: Expression of miR-146a was significantly higher in the inflamed duodenal mucosa compared to the intact duodenal mucosa of children with CD (CD inflamed: 3.21 ± 0.50 vs CD intact: 0.62 ± 0.26, P ≤ 0.01) and to the control group (CD inflamed: 3.21 ± 0.50 vs C: 1.00 ± 0.33, P ≤ 0.05). The expression of miR-155 was significantly increased in the inflamed region of the duodenum compared to the control group (CD inflamed: 4.87 ± 1.02 vs Control: 1.00 ± 0.40, P ≤ 0.001). The expression of miR-122 was unchanged in the inflamed or intact mucosa of CD patients compared to controls. TGF-β treatment significantly decreased the expression of miR-155 in small intestinal epithelial cells (TGF-β: 0.7 ± 0.083 vs Control: 1 ± 0.09, P ≤ 0.05) and also the expression of miR-146a (TGF-β: 0.67 ± 0.04 vs Control: 1 ± 0.15, P ≤ 0.01) and miR-155 (TGF-β: 0.72 ± 0.09 vs Control: 1 ± 0.06, P ≤ 0.05) in primary duodenal fibroblasts compared to corresponding vehicle treated controls. TGF-β treatment did not influence the expression of miR-122. CONCLUSION: The elevated expression of miR-146a and -155 in the inflamed duodenal mucosa of CD patients suggests the role of these miRs in the pathomechanism of inflammatory bowel disease. Anti-inflammatory TGF-β plays an important role in the regulation of the expression of these miRs. PMID:27468194

Breast Implant-Associated, ALK-Negative, T-Cell, Anaplastic, Large-Cell Lymphoma: Establishment and Characterization of a Model Cell Line (TLBR-1) for This Newly Emerging Clinical Entity

PubMed Central

Lechner, Melissa G.; Lade, Stephen; Liebertz, Daniel J.; Prince, H. Miles; Brody, Garry S.; Webster, Howard R.; Epstein, Alan L.

2014-01-01

BACKGROUND Primary lymphomas of the breast are very rare (0.2–1.5% of breast malignancies) and the vast majority (95%) are of B-cell origin. Recently, 40 cases of clinically indolent anaplastic large-cell kinase (ALK)-negative, T-cell, anaplastic, non-Hodgkin lymphomas (T-ALCL) have been reported worldwide. METHODS A tumor biopsy specimen from a patient in this series was obtained for characterization. By using a human stromal feeder layer and IL-2, a novel cell line, TLBR-1, was established from this biopsy and investigated by using cytogenetics and various biomolecular methods. RESULTS Immunoperoxidase staining of the tumor biopsy showed a CD30/CD8/CD4 coexpressing T-cell population that was epithelial membrane antigen (EMA)+ and perforin+. Multiplex polymerase chain reaction (PCR) of TCRγ genes showed monoclonality that suggested a T-cell origin, yet pan-T markers CD2/5/7, anaplastic large-cell kinase (ALK)-1, pancytokeratins, CD20, CD56, and Epstein-Barr virus (EBV) by in situ hybridization (ISH) were negative. TLBR-1 is IL-2 dependent, has a relatively long doubling time (55 hours), and displays different cellular shapes in culture. Cytogenetic analysis of tumor and TLBR-1 cells confirmed a highly anaplastic cell population with a modal number of 47 chromosomes lacking t(2;5). PCR screens for EBV and human T-lymphotropic virus types 1 and 2 (HTLV-1/2) were negative. Fluorescence-activated cell-sorting (FACS) analysis showed strong positivity for CD4/8, CD30, CD71, and CD26 expression, and antigen presentation (HLA-DR+CD80+CD86+), IL-2 signaling (CD25+CD122+), and NK (CD56+) markers, and Western blots demonstrated strong Notch1 expression. Severe combined immunodeficiency (SCID) mouse TLBR-1 heterotransplants recapitulated the histology and marker characteristics of the original tumor. CONCLUSIONS TLBR-1, a novel ALK-negative, T-cell, anaplastic, large-cell lymphoma, closely resembles the original biopsy and represents an important tool for studying this newly recognized disease entity. PMID:21425149

High levels of circulating VEGFR2+ Bone marrow-derived progenitor cells correlate with metastatic disease in patients with pediatric solid malignancies.

PubMed

Taylor, Melissa; Rössler, Jochen; Geoerger, Birgit; Laplanche, Agnès; Hartmann, Olivier; Vassal, Gilles; Farace, Françoise

2009-07-15

Pediatric solid malignancies display important angiogenic potential, and blocking tumor angiogenesis represents a new therapeutic approach for these patients. Recent studies have evidenced rare circulating cells with endothelial features contributing to tumor neovascularization and have shown the pivotal role of bone marrow-derived (BMD) progenitor cells in metastatic disease progression. We measured these cells in patients with pediatric solid malignancies as a prerequisite to clinical trials with antiangiogenic therapy. Peripheral blood was drawn from 45 patients with localized (n = 23) or metastatic (n = 22) disease, and 20 healthy subjects. Subsets of circulating vascular endothelial growth factor receptor (VEGFR)2+-BMD progenitor cells, defined as CD45-CD34+VEGFR2(KDR)+7AAD- and CD45(dim)CD34+VEGFR2+7AAD- events, were measured in progenitor-enriched fractions by flow cytometry. Mature circulating endothelial cells (CEC) were measured in whole blood as CD31+CD146+CD45-7AAD- viable events. Data were correlated with VEGF and sVEGFR2 plasma levels. The CD45-CD34+VEGFR2(KDR)+7AAD- subset represented <0.003% of circulating BMD progenitor cells (< or =0.05 cells/mL). However, the median level (range) of the CD45(dim)CD34+VEGFR2+7AAD- subset was higher in patients compared with healthy subjects, 1.5% (0%-10.3%) versus 0.3% (0%-1.6%) of circulating BMD progenitors (P < 0.0001), and differed significantly between patients with localized and metastatic disease, 0.7% (0%-8.6%) versus 2.9% (0.6%-10.3%) of circulating BMD progenitors (P < 0.001). Median CEC value was 7 cells/mL (0-152 cells/mL) and similar in all groups. Unlike VEGFR2+-BMD progenitors, neither CECs, VEGF, or sVEGFR2 plasma levels correlated with disease status. High levels of circulating VEGFR2+-BMD progenitor cells correlated with metastatic disease. Our study provides novel insights for angiogenesis mechanisms in pediatric solid malignancies for which antiangiogenic targeting of VEGFR2+-BMD progenitors could be of interest.

The neurologic significance of celiac disease biomarkers

PubMed Central

Lennon, Vanda A.; Pittock, Sean J.; Kryzer, Thomas J.; Murray, Joseph

2014-01-01

Objective: To report neurologic phenotypes and their etiologies determined among 68 patients with either (1) celiac disease (CD) or (2) no CD, but gliadin antibody positivity (2002–2012). Methods: Neurologic patients included both those with the CD-prerequisite major histocompatibility complex class II human leukocyte antigen (HLA)-DQ2/DQ8 haplotype, and those without. The 3 groups were as follows: group 1 (n = 44), CD or transglutaminase (Tg)-2/deamidated gliadin immunoglobulin (Ig)A/IgG detected; group 2 (n = 15), HLA-DQ2/DQ8 noncarriers, and gliadin IgA/IgG detected; and group 3 (n = 9), HLA-DQ2/DQ8 carriers, and gliadin IgA/IgG detected. Neurologic patients and 21 nonneurologic CD patients were evaluated for neural and Tg6 antibodies. Results: In group 1, 42 of 44 patients had CD. Neurologic phenotypes (cerebellar ataxia, 13; neuropathy, 11; dementia, 8; myeloneuropathy, 5; other, 7) and causes (autoimmune, 9; deficiencies of vitamin E, folate, or copper, 6; genetic, 6; toxic or metabolic, 4; unknown, 19) were diverse. In groups 2 and 3, 21 of 24 patients had cerebellar ataxia; none had CD. Causes of neurologic disorders in groups 2 and 3 were diverse (autoimmune, 4; degenerative, 4; toxic, 3; nutritional deficiency, 1; other, 2; unknown, 10). One or more neural-reactive autoantibodies were detected in 10 of 68 patients, all with autoimmune neurologic diagnoses (glutamic acid decarboxylase 65 IgG, 4; voltage-gated potassium channel complex IgG, 3; others, 5). Tg6-IgA/IgG was detected in 7 of 68 patients (cerebellar ataxia, 3; myelopathy, 2; ataxia and parkinsonism, 1; neuropathy, 1); the 2 patients with myelopathy had neurologic disorders explained by malabsorption of copper, vitamin E, and folate rather than by neurologic autoimmunity. Conclusions: Our data support causes alternative to gluten exposure for neurologic dysfunction among most gliadin antibody–positive patients without CD. Nutritional deficiency and coexisting autoimmunity may cause neurologic dysfunction in CD. PMID:25261501

Intestinal Barrier Function and the Gut Microbiome Are Differentially Affected in Mice Fed a Western-Style Diet or Drinking Water Supplemented with Fructose.

PubMed

Volynets, Valentina; Louis, Sandrine; Pretz, Dominik; Lang, Lisa; Ostaff, Maureen J; Wehkamp, Jan; Bischoff, Stephan C

2017-05-01

Background: The consumption of a Western-style diet (WSD) and high fructose intake are risk factors for metabolic diseases. The underlying mechanisms are largely unclear. Objective: To unravel the mechanisms by which a WSD and fructose promote metabolic disease, we investigated their effects on the gut microbiome and barrier function. Methods: Adult female C57BL/6J mice were fed a sugar- and fat-rich WSD or control diet (CD) for 12 wk and given access to tap water or fructose-supplemented water. The microbiota was analyzed with the use of 16S rRNA gene sequencing. Barrier function was studied with the use of permeability tests, and endotoxin, mucus thickness, and gene expressions were measured. Results: The WSD increased body weight gain but not endotoxin translocation compared with the CD. In contrast, high fructose intake increased endotoxin translocation 2.6- and 3.8-fold in the groups fed the CD + fructose and WSD + fructose, respectively, compared with the CD group. The WSD + fructose treatment also induced a loss of mucus thickness in the colon (-46%) and reduced defensin expression in the ileum and colon. The lactulose:mannitol ratio in the WSD + fructose mice was 1.8-fold higher than in the CD mice. Microbiota analysis revealed that fructose, but not the WSD, increased the Firmicutes:Bacteroidetes ratio by 88% for CD + fructose and 63% for WSD + fructose compared with the CD group. Bifidobacterium abundance was greater in the WSD mice than in the CD mice (63-fold) and in the WSD + fructose mice than in the CD + fructose mice (330-fold). Conclusions: The consumption of a WSD or high fructose intake differentially affects gut permeability and the microbiome. Whether these differences are related to the distinct clinical outcomes, whereby the WSD primarily promotes weight gain and high fructose intake causes barrier dysfunction, needs to be investigated in future studies. © 2017 American Society for Nutrition.

Season and region of birth as risk factors for coeliac disease a key to the aetiology?

PubMed Central

Namatovu, Fredinah; Lindkvist, Marie; Olsson, Cecilia; Ivarsson, Anneli; Sandström, Olof

2016-01-01

Background Coeliac disease (CD) incidence has increased in recent decades, characterised by variations according to sex, age at diagnosis, year of birth, month of birth and region of birth. Genetic susceptibility and exposure to gluten are the necessary factors in CD aetiology, although several environmental factors are considered. Methods A nationwide prospective cohort longitudinal study was conducted consisting of 1 912 204 children aged 0–14.9 years born in Sweden from 1991 to 2009. A total of 6569 children were diagnosed with biopsy-verified CD from 47 paediatric departments. Using Cox regression, we examined the association between CD diagnosis and season of birth, region of birth and year of birth. Results Overall, CD risk was higher for children born during spring, summer and autumn as compared with children born during winter: adjusted HR for spring 1.08 (95% CI 1.01 to 1.16), summer 1.10 (95% CI 1.03 to 1.18) and autumn 1.10 (95% CI 1.02 to 1.18). Increased CD risk was highest if born in the south, followed by central Sweden when compared with children born in northern Sweden. Children diagnosed at <2 years had an increased CD risk if born in spring while those diagnosed at 2–14.9 years the risk was increased for summer and autumn births. The birth cohort of 1991–1996 had increased CD risk if born during spring, for the 1997–2002 birth cohort the risk increased for summer and autumn births, while for the birth cohort of 2003–2009 the risk was increased if born during autumn. Conclusions Season of birth and region of birth are independently and jointly associated with increased risk of developing CD during the first 15 years of life. Seasonal variation in infectious load is the likely explanation. PMID:27528621

Combined immunization using DNA-Sm14 and DNA-Hsp65 increases CD8+ memory T cells, reduces chronic pathology and decreases egg viability during Schistosoma mansoni infection

PubMed Central

2014-01-01

Background Schistosomiasis is one of the most important neglected diseases found in developing countries and affects 249 million people worldwide. The development of an efficient vaccination strategy is essential for the control of this disease. Previous work showed partial protection induced by DNA-Sm14 against Schistosoma mansoni infection, whereas DNA-Hsp65 showed immunostimulatory properties against infectious diseases, autoimmune diseases, cancer and antifibrotic properties in an egg-induced granuloma model. Methods C57BL/6 mice received 4 doses of DNA-Sm14 (100 μg/dose) and DNA-Hsp65 (100 μg/dose), simultaneously administrated, or DNA-Sm14 alone, once a week, during four weeks. Three groups were included: 1- Control (no immunization); 2- DNA-Sm14; 3- DNA-Sm14/DNA-Hsp65. Two weeks following last immunization, animals were challenged subcutaneously with 30 cercariae. Fifteen, 48 and 69 days after infection splenocytes were collected to evaluate the number of CD8+ memory T cells (CD44highCD62low) using flow cytometry. Forty-eight days after challenge adult worms were collected by portal veins perfusion and intestines were collected to analyze the intestinal egg viability. Histological, immunohistochemical and soluble quantification of collagen and α-SMA accumulation were performed on the liver. Results In the current work, we tested a new vaccination strategy using DNA-Sm14 with DNA-Hsp65 to potentiate the protection against schistosomiasis. Combined vaccination increased the number of CD8+ memory T cells and decreased egg viability on the intestinal wall of infected mice. In addition, simultaneous vaccination with DNA-Sm14/DNA-Hsp65 reduced collagen and α-SMA accumulation during the chronic phase of granuloma formation. Conclusion Simultaneous vaccination with DNA-Sm14/DNA-Hsp65 showed an immunostimulatory potential and antifibrotic property that is associated with the reduction of tissue damage on Schistosoma mansoni experimental infection. PMID:24886395

Is the virulence of HIV changing? A meta-analysis of trends in prognostic markers of HIV disease progression and transmission

PubMed Central

Herbeck, Joshua T.; Müller, Viktor; Maust, Brandon S.; Ledergerber, Bruno; Torti, Carlo; Di Giambenedetto, Simona; Gras, Luuk; Günthard, Huldrych F.; Jacobson, Lisa P.; Mullins, James I.; Gottlieb, Geoffrey S.

2013-01-01

Objective The potential for changing HIV-1 virulence has significant implications for the AIDS epidemic, including changing HIV transmission rates, rapidity of disease progression, and timing of ART. Published data to date have provided conflicting results. Design We conducted a meta-analysis of changes in baseline CD4+ T-cell counts and set point plasma viral RNA load over time in order to establish whether summary trends are consistent with changing HIV-1 virulence. Methods We searched PubMed for studies of trends in HIV-1 prognostic markers of disease progression and supplemented findings with publications referenced in epidemiological or virulence studies. We identified 12 studies of trends in baseline CD4+ T-cell counts (21 052 total individuals), and eight studies of trends in set point viral loads (10 785 total individuals), spanning the years 1984–2010. Using random-effects meta-analysis, we estimated summary effect sizes for trends in HIV-1 plasma viral loads and CD4+ T-cell counts. Results Baseline CD4+ T-cell counts showed a summary trend of decreasing cell counts [effect=−4.93 cells/µl per year, 95% confidence interval (CI) −6.53 to −3.3]. Set point viral loads showed a summary trend of increasing plasma viral RNA loads (effect=0.013 log10 copies/ml per year, 95% CI −0.001 to 0.03). The trend rates decelerated in recent years for both prognostic markers. Conclusion Our results are consistent with increased virulence of HIV-1 over the course of the epidemic. Extrapolating over the 30 years since the first description of AIDS, this represents a CD4+ T cells loss of approximately 148 cells/µl and a gain of 0.39 log10 copies/ml of viral RNA measured during early infection. These effect sizes would predict increasing rates of disease progression, and need for ART as well as increasing transmission risk. PMID:22089381

[Skin biopsy in diagnosis of chronic graft-versus-host disease in patients after allogeneic haematopoietic stem cell transplantation: pathologist's point of view on quantitative scoring system].

PubMed

Grzanka, Dariusz; Styczyński, Jan; Debski, Robert; Krenska, Anna; Pacholska, Małgorzata; Prokurat, Andrzej I; Wysocki, Mariusz; Marszałek, Andrzej

2008-01-01

Pathology diagnosis of chronic graft-versus-host-disease (GVHD) after allogeneic haematopoietic stem cell transplantation (allo-HSCT) is an important issue in clinical follow-up, in spite of frequent difficulties in interpretation., related to dynamic changes occurring in the skin during the disease, as well as to sequelae of basic disease and immunosuppressive therapy. Recently presented Consensus NIH (National Health Institute, Bethesda, USA) of histopathologic (HP) analysis is still complex and intrinsically divergent, thus clinically difficult to implement. Analysis of clinical value of histological evaluation results of skin biopsy in children after allo-HSCT and its correlation with clinical status. Ten skin biopsies were taken from 7 patients (4 boys, 3 girls, age 3-15 years) after allo-HSCT (6 MFD, 1 MMUD) and analyzed after hematoxylin/eosine and immunohistochemical (CD3, CD45T, CD20) staining. Pathology analysis was based on commonly accepted criteria enabling simple and unambiguous interpretation. Results were compared with clinical data and indications for immunosuppressive therapy. It was found that reliable and coherent interpretation can be made when following parameters were taken into account: 1. in epithelium: the presence of apoptosis, archetypical changes and vacuolar degeneration in the basilar layer, presence of CD3/CD45 in the epidermis; 2. in the dermis: the extent of collagenization, presence of melanophages and lymphocyte infiltrations; 3. in the eccrine glands epithelium: eccrine glands atrophy and presence of lymphocytes. A new scoring system of skin biopsy analysis in patients with chronic GVHD based on the modified NIH Consensus was proposed. The preliminary clinical value of histological results was assessed. Skin biopsy evaluation based on limited qualitative and quantitative analysis of lymphocyte infiltrates together with studies on intensity of apoptosis, collagenization and archetypical changes is a valuable diagnostic method complementary to clinical records, enabling easier undertaking of therapeutic decisions.

A systematic review of cost-effectiveness studies comparing conventional, biological and surgical interventions for inflammatory bowel disease

PubMed Central

Dusheiko, Mark; Burnand, Bernard; Pittet, Valérie

2017-01-01

Background Inflammatory bowel disease (IBD) is a chronic disease placing a large health and economic burden on health systems worldwide. The treatment landscape is complex with multiple strategies to induce and maintain remission while avoiding long-term complications. The extent to which rising treatment costs, due to expensive biologic agents, are offset by improved outcomes and fewer hospitalisations and surgeries needs to be evaluated. This systematic review aimed to assess the cost-effectiveness of treatment strategies for IBD. Materials and methods A systematic literature search was performed in March 2017 to identify economic evaluations of pharmacological and surgical interventions, for adults diagnosed with Crohn’s disease (CD) or ulcerative colitis (UC). Costs and incremental cost-effectiveness ratios (ICERs) were adjusted to reflect 2015 purchasing power parity (PPP). Risk of bias assessments and a narrative synthesis of individual study findings are presented. Results Forty-nine articles were included; 24 on CD and 25 on UC. Infliximab and adalimumab induction and maintenance treatments were cost-effective compared to standard care in patients with moderate or severe CD; however, in patients with conventional-drug refractory CD, fistulising CD and for maintenance of surgically-induced remission ICERs were above acceptable cost-effectiveness thresholds. In mild UC, induction of remission using high dose mesalazine was dominant compared to standard dose. In UC refractory to conventional treatments, infliximab and adalimumab induction and maintenance treatment were not cost-effective compared to standard care; however, ICERs for treatment with vedolizumab and surgery were favourable. Conclusions We found that, in general, while biologic agents helped improve outcomes, they incurred high costs and therefore were not cost-effective, particularly for use as maintenance therapy. The cost-effectiveness of biologic agents may improve as market prices fall and with the introduction of biosimilars. Future research should identify optimal treatment strategies reflecting routine clinical practice, incorporate indirect costs and evaluate lifetime costs and benefits. PMID:28973005

Inhibition of Autoimmune Chagas-Like Heart Disease by Bone Marrow Transplantation

PubMed Central

Guimaro, Maria C.; Alves, Rozeneide M.; Rose, Ester; Sousa, Alessandro O.; de Cássia Rosa, Ana; Hecht, Mariana M.; Sousa, Marcelo V.; Andrade, Rafael R.; Vital, Tamires; Plachy, Jiří; Nitz, Nadjar; Hejnar, Jiří; Gomes, Clever C.; L. Teixeira, Antonio R.

2014-01-01

Background Infection with the protozoan Trypanosoma cruzi manifests in mammals as Chagas heart disease. The treatment available for chagasic cardiomyopathy is unsatisfactory. Methods/Principal Findings To study the disease pathology and its inhibition, we employed a syngeneic chicken model refractory to T. cruzi in which chickens hatched from T. cruzi inoculated eggs retained parasite kDNA (1.4 kb) minicircles. Southern blotting with EcoRI genomic DNA digests revealed main 18 and 20 kb bands by hybridization with a radiolabeled minicircle sequence. Breeding these chickens generated kDNA-mutated F1, F2, and F3 progeny. A targeted-primer TAIL-PCR (tpTAIL-PCR) technique was employed to detect the kDNA integrations. Histocompatible reporter heart grafts were used to detect ongoing inflammatory cardiomyopathy in kDNA-mutated chickens. Fluorochromes were used to label bone marrow CD3+, CD28+, and CD45+ precursors of the thymus-dependent CD8α+ and CD8β+ effector cells that expressed TCRγδ, vβ1 and vβ2 receptors, which infiltrated the adult hearts and the reporter heart grafts. Conclusions/Significance Genome modifications in kDNA-mutated chickens can be associated with disruption of immune tolerance to compatible heart grafts and with rejection of the adult host's heart and reporter graft, as well as tissue destruction by effector lymphocytes. Autoimmune heart rejection was largely observed in chickens with kDNA mutations in retrotransposons and in coding genes with roles in cell structure, metabolism, growth, and differentiation. Moreover, killing the sick kDNA-mutated bone marrow cells with cytostatic and anti-folate drugs and transplanting healthy marrow cells inhibited heart rejection. We report here for the first time that healthy bone marrow cells inhibited heart pathology in kDNA+ chickens and thus prevented the genetically driven clinical manifestations of the disease. PMID:25521296

Overview of Celiac Disease in Russia: Regional Data and Estimated Prevalence

PubMed Central

Erdes, Svetlana I.; Antishin, Anton S.

2017-01-01

Celiac disease (CD) is an autoimmune enteropathy triggered by the ingestion of dietary gluten from some cereals mainly in individuals carrying the HLA-DQ2 and/or HLA-DQ8 haplotypes. As an autoimmune disease, CD is manifested in the small intestine in the form of a progressive and reversible inflammatory lesion due to immune response to self-antigens. Indeed, CD is one of the most challenging medicosocial problems in current gastroenterology. At present, the global CD prevalence is estimated at approximately 1% based on data sent from different locations and available CD screening strategies used. However, it is impossible to estimate global CD prevalence without all the data from the world, including Russia. In this review, we summarize the data on the incidence and prevalence of CD across geographically distinct regions of Russia, which are mostly present in local Russian scientific sources. Our conclusion is that the situation of CD prevalence in Russia is higher than is commonly believed and follows global tendencies that correspond to the epidemiologic situation in Europe, America, and Southwest Asia. PMID:28316996

Overview of Celiac Disease in Russia: Regional Data and Estimated Prevalence.

PubMed

Savvateeva, Lyudmila V; Erdes, Svetlana I; Antishin, Anton S; Zamyatnin, Andrey A

2017-01-01

Celiac disease (CD) is an autoimmune enteropathy triggered by the ingestion of dietary gluten from some cereals mainly in individuals carrying the HLA-DQ2 and/or HLA-DQ8 haplotypes. As an autoimmune disease, CD is manifested in the small intestine in the form of a progressive and reversible inflammatory lesion due to immune response to self-antigens. Indeed, CD is one of the most challenging medicosocial problems in current gastroenterology. At present, the global CD prevalence is estimated at approximately 1% based on data sent from different locations and available CD screening strategies used. However, it is impossible to estimate global CD prevalence without all the data from the world, including Russia. In this review, we summarize the data on the incidence and prevalence of CD across geographically distinct regions of Russia, which are mostly present in local Russian scientific sources. Our conclusion is that the situation of CD prevalence in Russia is higher than is commonly believed and follows global tendencies that correspond to the epidemiologic situation in Europe, America, and Southwest Asia.

Activation of CD40 with Platelet Derived CD154 Promotes Reactive Oxygen Species Dependent Death of Human Hepatocytes during Hypoxia and Reoxygenation

PubMed Central

Bhogal, Ricky H.; Weston, Christopher J.; Curbishley, Stuart M.; Adams, David H.; Afford, Simon C.

2012-01-01

Background Hypoxia and hypoxia-reoxygenation (H-R) are pathogenic factors in many liver diseases that lead to hepatocyte death as a result of reactive oxygen species (ROS) accumulation. The tumor necrosis factor super-family member CD154 can also induce hepatocyte apoptosis via activation of its receptor CD40 and induction of autocrine/paracrine Fas Ligand/CD178 but the relationship between CD40 activation, ROS generation and apoptosis is poorly understood. We hypothesised that CD40 activation and ROS accumulation act synergistically to drive human hepatocyte apoptosis. Methods Human hepatocytes were isolated from liver tissue and exposed to an in vitro model of hypoxia and H-R in the presence or absence of CD154 and/or various inhibitors. Hepatocyte ROS production, apoptosis and necrosis were determined by labelling cells with 2′,7′-dichlorofluorescin, Annexin-V and 7-AAD respectively in a three-colour reporter flow cytometry assay. Results Exposure of human hepatocytes to recombinant CD154 or platelet-derived soluble CD154 augments ROS accumulation during H-R resulting in NADPH oxidase-dependent apoptosis and necrosis. The inhibition of c-Jun N-terminal Kinase and p38 attenuated CD154-mediated apoptosis but not necrosis. Conclusions CD154-mediated apoptosis of hepatocytes involves ROS generation that is amplified during hypoxia-reoxygenation. This finding provides a molecular mechanism to explain the role of platelets in hepatocyte death during ischemia-reperfusion injury. PMID:22295117

The NOD2 Single Nucleotide Polymorphism rs72796353 (IVS4+10 A>C) Is a Predictor for Perianal Fistulas in Patients with Crohn's Disease in the Absence of Other NOD2 Mutations.

PubMed

Schnitzler, Fabian; Friedrich, Matthias; Wolf, Christiane; Stallhofer, Johannes; Angelberger, Marianne; Diegelmann, Julia; Olszak, Torsten; Tillack, Cornelia; Beigel, Florian; Göke, Burkhard; Glas, Jürgen; Lohse, Peter; Brand, Stephan

2015-01-01

A previous study suggested an association of the single nucleotide polymorphism (SNP) rs72796353 (IVS4+10 A>C) in the NOD2 gene with susceptibility to Crohn's disease (CD). However, this finding has not been confirmed. Given that NOD2 variants still represent the most important predictors for CD susceptibility and phenotype, we evaluated the association of rs72796353 with inflammatory bowel disease (IBD) susceptibility and the IBD phenotype. Genomic DNA from 2256 Caucasians, including 1073 CD patients, 464 patients with ulcerative colitis (UC), and 719 healthy controls, was genotyped for the NOD2 SNP rs72796353 and the three main CD-associated NOD2 mutations rs2066844, rs2066845, and rs2066847. Subsequently, IBD association and genotype-phenotype analyses were conducted. In contrast to the strong associations of the NOD2 SNPs rs2066844 (p=3.51 x 10(-3)), rs2066845 (p=1.54 x 10(-2)), and rs2066847 (p=1.61 x 10(-20)) with CD susceptibility, no significant association of rs72796353 with CD or UC susceptibility was found. However, in CD patients without the three main CD-associated NOD2 mutations, rs72796353 was significantly associated with the development of perianal fistulas (p=2.78 x 10(-7), OR 5.27, [95% CI 2.75-10.12] vs. NOD2 wild-type carriers). Currently, this study represents the largest genotype-phenotype analysis of the impact of the NOD2 variant rs72796353 on the disease phenotype in IBD. Our data demonstrate that in CD patients the IVS4+10 A>C variant is strongly associated with the development of perianal fistulas. This association is particularly pronounced in patients who are not carriers of the three main CD-associated NOD2 mutations, suggesting rs72796353 as additional genetic marker for the CD disease behaviour.

Scenarios, personas and user stories: user-centered evidence-based design representations of communicable disease investigations.

PubMed

Turner, Anne M; Reeder, Blaine; Ramey, Judith

2013-08-01

Despite years of effort and millions of dollars spent to create unified electronic communicable disease reporting systems, the goal remains elusive. A major barrier has been a lack of understanding by system designers of communicable disease (CD) work and the public health workers who perform this work. This study reports on the application of user-centered design representations, traditionally used for improving interface design, to translate the complex CD work identified through ethnographic studies to guide designers and developers of CD systems. The purpose of this work is to: (1) better understand public health practitioners and their information workflow with respect to CD monitoring and control at a local health agency, and (2) to develop evidence-based design representations that model this CD work to inform the design of future disease surveillance systems. We performed extensive onsite semi-structured interviews, targeted work shadowing and a focus group to characterize local health agency CD workflow. Informed by principles of design ethnography and user-centered design we created persona, scenarios and user stories to accurately represent the user to system designers. We sought to convey to designers the key findings from ethnographic studies: (1) public health CD work is mobile and episodic, in contrast to current CD reporting systems, which are stationary and fixed, (2) health agency efforts are focused on CD investigation and response rather than reporting and (3) current CD information systems must conform to public health workflow to ensure their usefulness. In an effort to illustrate our findings to designers, we developed three contemporary design-support representations: persona, scenario, and user story. Through application of user-centered design principles, we were able to create design representations that illustrate complex public health communicable disease workflow and key user characteristics to inform the design of CD information systems for public health. Copyright © 2013 Elsevier Inc. All rights reserved.

Emerging Epidemic of Inflammatory Bowel Disease in a Middle Income Country: A Nation-wide Study from Iran.

PubMed

Malekzadeh, Masoud M; Vahedi, Homayoon; Gohari, Kimiya; Mehdipour, Parinaz; Sepanlou, Sadaf G; Ebrahimi Daryani, Nasser; Zali, Mohammad-Reza; Mansour-Ghanaei, Fariborz; Safaripour, Alireza; Aghazadeh, Rahim; Vossoughinia, Hassan; Fakheri, Hafez; Somi, Mohammad H; Maleki, Iradj; Hoseini, Vahid; Ghadir, Mohammad-Reza; Daghaghzadeh, Hamed; Adibi, Payman; Tavakoli, Hamid; Taghavi, Alireza; Zahedi, Mohammad-Javad; Amiriani, Taghi; Tabib, Masoud; Alipour, Zainab; Nobakht, Hossein; Yazdanbod, Abbas; Sadreddini, Masoud; Bakhshipour, Alireza; Khosravi, Ahmad; Khosravi, Pejman; Nasseri-Moghaddam, Siavosh; Merat, Shahin; Sotoudehmanesh, Rasoul; Barazandeh, Farhad; Arab, Peyman; Baniasadi, Nadieh; Pournaghi, Seyyed-Javad; Parsaeian, Mahboubeh; Farzadfar, Farshad; Malekzadeh, Reza

2016-01-01

The burden of inflammatory bowel disease (IBD) hasn't been reported in Iran. We aimed to estimate the prevalence and incidence of IBD and its trend in Iran at national and subnational level from 1990 to 2012. We conducted a systematic review of English and Persian databases about the epidemiology of IBD. We also collected outpatient data from 17 provinces of Iran using almost all public and private referral gastroenterology clinics. Prevalence and incidence rate was calculated at national and subnational levels. The Kriging method was used to extrapolate provinces with missing data and GPR model to calculate time trends of rates at subnational level. We found 16 case series, two population-based studies, and two review articles. We collected 11,000 IBD cases from outpatient databases. Among them, 9,269 (84.26%) had ulcerative colitis (UC), 1,646 (14.96%) had Crohn's disease (CD), and 85 had intermediate colitis (IC). A total of 5,452 (49.56%) patients were male. Mean age at diagnosis was 32.80 years (CI: 13 - 61) for UC and 29.98 years (CI: 11 - 58) for CD. Annual incidences of IBD, UC, and CD in 2012 were 3.11, 2.70, and 0.41 per 100,000 subjects respectively. Prevalence of IBD, UC, and CD in 2012 were 40.67, 35.52, and 5.03 per 100,000 subjects respectively. The incidence of UC and CD showed a significant increase during the study period (P for trend < 0.05). The incidence and prevalence of IBD are increasing in Iran. Establishing a national IBD registry seems necessary for comprehensive care of IBD patients in Iran.

Efficacy of 6-mercaptopurine treatment after azathioprine hypersensitivity in inflammatory bowel disease

PubMed Central

Nagy, Ferenc; Molnár, Tamás; Szepes, Zoltán; Farkas, Klaudia; Nyári, Tibor; Lonovics, János

2008-01-01

AIM:To investigate the efficacy of 6-mercaptopurine (6-MP) in cases of azathioprine (AZA) hypersensitivity in patients with inflammatory bowel disease. METHODS: Twenty nine previously confirmed Crohn’s disease (CD) (n = 14) and ulcerative colitis (UC) (n = 15) patients with a known previous (AZA) hypersensitivity reaction were studied prospectively. The 6-MP doses were gradually increased from 0.5 up to 1.0-1.5 mg/kg per day. Clinical activity indices (CDAI/CAI), laboratory variables and daily doses of oral 5-ASA, corticosteroids, and 6-MP were assessed before and in the first, sixth and twelfth months of treatment. RESULTS: In 9 patients, 6-MP was withdrawn in the first 2 wk due to an early hypersensitivity reaction. Medication was ineffective within 6 mo in 6 CD patients, and myelotoxic reaction was observed in two. Data were evaluated at the end of the sixth month in 12 (8 UC, 4 CD) patients, and after the first year in 9 (6 UC, 3 CD) patients. CDAI decreased transiently at the end of the sixth month, but no significant changes were observed in the CDAI or the CAI values at the end of the year. Leukocyte counts (P = 0.01), CRP (P = 0.02), and serum iron (P = 0.05) values indicated decreased inflammatory reactions, especially in the UC patients at the end of the year, making the possibility to taper oral steroid doses. CONCLUSION: About one-third of the previously AZA-intolerant patients showed adverse effects on taking 6MP. In our series, 20 patients tolerated 6MP, but it was ineffective in 8 CD cases, and valuable mainly in ulcerative colitis patients. PMID:18666323

NKX2-3 and IRGM variants are associated with disease susceptibility to IBD in Eastern European patients

PubMed Central

Meggyesi, Nora; Kiss, Lajos S; Koszarska, Magdalena; Bortlik, Martin; Duricova, Dana; Lakatos, Laszlo; Molnar, Tamas; Leniček, Martin; Vítek, Libor; Altorjay, Istvan; Papp, Maria; Tulassay, Zsolt; Miheller, Pal; Papp, Janos; Tordai, Attila; Andrikovics, Hajnalka; Lukas, Milan; Lakatos, Peter Laszlo

2010-01-01

AIM: To investigate variants of immunity-related GTPase family M (IRGM) and NKX2-3 genes and genotype-phenotype in Eastern European patients with inflammatory bowel disease (IBD). METHODS: We analyzed 1707 Hungarian and Czech subjects with Crohn’s disease (CD) (n = 810, age: 37.1 ± 12.6 years, duration: 10.7 ± 8.4 years) and ulcerative colitis (UC) (n = 428, age: 43.7 ± 15.0 years, duration: 12.6 ± 9.9 years), as well as 469 healthy controls. IRGM rs13361189, NKX2-3 rs10883365 and ECM1 rs13294 polymorphisms were tested by LightCycler allele discrimination. Detailed clinical phenotypes were determined by reviewing the medical charts. RESULTS: NKX2-3 rs10883365 variant allele was associated with increased risk for CD (P = 0.009, OR = 1.24, 95% CI = 1.06-1.48) and UC (P = 0.001, OR = 1.36, 95% CI = 1.13-1.63), whereas variant IRGM allele increased risk for CD (P = 0.029, OR = 1.36, 95% CI = 1.03-1.79). In contrast, ECM1 rs13294 was not associated with either CD or UC. In CD, the variant IRGM allele was associated with a colon-only location (P = 0.02, OR = 1.62, 95% CI = 1.07-2.44), whereas in UC, the ECM1 variant was associated with cutaneous manifestations (P = 0.002, OR = 3.36, 95% CI = 1.48-7.63). Variant alleles did not predict resistance to steroids or azathioprine, efficacy of infliximab, or need for surgery. CONCLUSION: NKX2-3 and IRGM are susceptibility loci for IBD in Eastern European patients. Further studies are needed to confirm the reported phenotype-genotype associations. PMID:21049557

Barriers to Treatment Access for Chagas Disease in Mexico

PubMed Central

Manne, Jennifer M.; Snively, Callae S.; Ramsey, Janine M.; Salgado, Marco Ocampo; Bärnighausen, Till; Reich, Michael R.

2013-01-01

Background According to World Health Organization (WHO) prevalence estimates, 1.1 million people in Mexico are infected with Trypanosoma cruzi, the etiologic agent of Chagas disease (CD). However, limited information is available about access to antitrypanosomal treatment. This study assesses the extent of access in Mexico, analyzes the barriers to access, and suggests strategies to overcome them. Methods and Findings Semi-structured in-depth interviews were conducted with 18 key informants and policymakers at the national level in Mexico. Data on CD cases, relevant policy documents and interview data were analyzed using the Flagship Framework for Pharmaceutical Policy Reform policy interventions: regulation, financing, payment, organization, and persuasion. Data showed that 3,013 cases were registered nationally from 2007–2011, representing 0.41% of total expected cases based on Mexico's national prevalence estimate. In four of five years, new registered cases were below national targets by 11–36%. Of 1,329 cases registered nationally in 2010–2011, 834 received treatment, 120 were pending treatment as of January 2012, and the treatment status of 375 was unknown. The analysis revealed that the national program mainly coordinated donation of nifurtimox and that important obstacles to access include the exclusion of antitrypanosomal medicines from the national formulary (regulation), historical exclusion of CD from the social insurance package (organization), absence of national clinical guidelines (organization), and limited provider awareness (persuasion). Conclusions Efforts to treat CD in Mexico indicate an increased commitment to addressing this disease. Access to treatment could be advanced by improving the importation process for antitrypanosomal medicines and adding them to the national formulary, increasing education for healthcare providers, and strengthening clinical guidelines. These recommendations have important implications for other countries in the region with similar problems in access to treatment for CD. PMID:24147169

Low CD4+ T cell count as a major atherosclerosis risk factor in HIV-infected women and men

PubMed Central

Kaplan, Robert C; Kingsley, Lawrence A; Gange, Stephen J; Benning, Lorie; Jacobson, Lisa P; Lazar, Jason; Anastos, Kathryn; Tien, Phyllis C; Sharrett, A Richey; Hodis, Howard N

2009-01-01

Objective To assess the association of HIV infection, HIV disease parameters (including CD4+ T-cell counts, HIV viral load, and AIDS) and antiretroviral medication use with subclinical carotid artery atherosclerosis. Design Cross-sectional study nested within a prospective cohort study Methods Among participants in the Women's Interagency HIV Study (1,331 HIV-infected women, 534 HIV-uninfected women) and Multicenter AIDS Cohort Study (600 HIV-infected men, 325 HIV-uninfected men), we measured subclinical carotid artery lesions and common carotid artery intima-media thickness (CIMT) using B-mode ultrasound. We estimated adjusted mean CIMT differences and prevalence ratios (PRs) for carotid lesions associated with HIV-related disease and treatments, with multivariate adjustment to control for possible confounding variables. Results Among HIV-infected individuals, a low CD4+ T cell count was independently associated with an increased prevalence of carotid lesions. Compared to the reference group of HIV-uninfected individuals, the adjusted PR for lesions among HIV-infected individuals with CD4+ T-cell count <200 cells/mm3 was 2.00 (95% confidence interval 1.22, 3.28) in women and 1.74 (95% confidence interval 1.04, 2.93) in men. No consistent association of antiretroviral medications with carotid atherosclerosis was observed, except for a borderline significant association between protease inhibitor use and carotid lesions in men (with no association among women). History of clinical AIDS and HIV viral load were not significantly associated with carotid atherosclerosis. Conclusions Beyond traditional cardiovascular disease risk factors, low CD4+ T-cell count is the most robust risk factor for increased subclinical carotid atherosclerosis in HIV-infected women and men. PMID:18670221

ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Agents targeting lymphoid or myeloid cells surface antigens [II]: CD22, CD30, CD33, CD38, CD40, SLAMF-7 and CCR4).

PubMed

Drgona, L; Gudiol, C; Lanini, S; Salzberger, B; Ippolito, G; Mikulska, M

2018-03-20

The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies. To review, from an Infectious Diseases perspective, the safety profile of agents targeting CD22, CD30, CD33, CD38, CD40, SLAMF-7 and CCR4 and to suggest preventive recommendations. Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family. The risk and spectrum of infections in patients receiving CD22-targeted agents (i.e. inotuzumab ozogamicin) are similar to those observed with anti-CD20 antibodies. Anti-Pneumocystis prophylaxis and monitoring for cytomegalovirus (CMV) infection is recommended for patients receiving CD30-targeted agents (brentuximab vedotin). Due to the scarcity of data, the risk posed by CD33-targeted agents (gemtuzumab ozogamicin) cannot be assessed. Patients receiving CD38-targeted agents (i.e. daratumumab) face an increased risk of varicella-zoster virus (VZV) infection. Therapy with CD40-targeted agents (lucatumumab or dacetuzumab) is associated with opportunistic infections similar to those observed in hyper-IgM syndrome, and prevention strategies (including anti-Pneumocystis prophylaxis and pre-emptive therapy for CMV infection) are warranted. SLAMF-7 (CD319)-targeted agents (elotuzumab) induce lymphopenia and increase the risk of infection (particularly due to VZV). The impact of CCR4-targeted agents (mogamulizumab) on infection susceptibility is difficult to distinguish from the effect of underlying diseases and concomitant therapies. However, anti-Pneumocystis and anti-herpesvirus prophylaxis and screening for chronic hepatitis B virus (HBV) infection are recommended. Specific management strategies should be put in place to reduce the risk and/or the severity of infectious complications associated to the reviewed agents. Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

[Immunological balance of CD8+CD28+/CD8+CD28- T lymphocytes can predict gastrointestinal hemorrhage in patients with inflammatory bowel disease].

PubMed

Dai, Shi-Xue; Gu, Hong-Xiang; Wu, Gang; Zhong, Tao; Jian, Hong-Jian; Zhan, Yong-le; Zhang, Min-Hai; Gao, Yong; Xu, Jun; Chen, Dong-Sheng; Liao, Guang-Jie; Feng, Yan-Ling; Liu, Hong-Bo; Zou, Ying; Chi, Hong-Gang

2016-12-20

To evaluate the sensitivity and specificity of CD8 + CD28 + /CD8 + CD28 - T lymphocyte balance in predicting the gastrointestinal hemorrhage (GH) in patients with inflammatory bowel disease (IBD). Forty-nine IBD patients, including 30 with ulcerous colitis (UC) and 19 with Crohn's disease (CD), were enrolled to test peripheral blood CD8 + CD28 + and CD8 + CD28 - T cells using flow cytometry. All the patients were followed up for one year. The receiver-operating characteristic (ROC) curves were used to test the efficiency of CD8 + CD28 + /CD8 + CD28 - T lymphocyte balance to predict GH. The differences in lasting time of remission (LTR) under different factors were compared using Kaplan-Meier survival analysis, and the correlation between CD8 + T lymphocytes and the factors were analyzed. The utilization rates of immunosuppressant, steroids, and biological agent (BA) were significantly higher in CD patients than in UC patients (P=0.003, 0.043 and 0.002, respectively). The frequencies of CD8 + CD28 + T cells were obviously higher in UC patients than those in CD patients (t=3.022, P=0.004). CD8 + CD28 + T cells, CD8 + CD28 - T cells, and especially CD8 + CD28 + /CD8 + CD28 - ratio (area under curve of 0.977, P=0.000; cut-off value of 1.14 [13.95%/12.24%] with a sensitivity of 93.3% and a specificity of 91.2%) showed good efficiencies in predicting GH (P<0.01). The mean and median of LTR of IBD patients who did not receive BA or surgical treatment were significantly longer (Χ 2 =9.730, P=0.002; Χ 2 =15.981, P=0.000). CD8 + CD28 + /CD8 + CD28 - ratio was significantly related to both BA (P=0.009) and surgery (P=0.038). Both decreased CD8 + CD28 + T cells and elevated CD8 + CD28 - T cells are closely correlated with GH, and their ratio can predict the occurrence of GH with a high sensitivity and specificity and is correlated with BA and surgery at the cut-off value of 1.14.

Presence of Antigen-Experienced T Cells with Low Grade of Differentiation and Proliferative Potential in Chronic Chagas Disease Myocarditis

PubMed Central

Cabeza-Meckert, Patricia; Viotti, Rodolfo; Garelli, Fernando; Favaloro, Liliana E.; Favaloro, Roberto R.; Laguens, Rubén; Laucella, Susana A.

2014-01-01

Background The main consequence of chronic Trypanosoma cruzi infection is the development of myocarditis in approximately 20–30% of infected individuals but not until 10–20 years after the initial infection. We have previously shown that circulating interferon-γ-secreting T cells responsive to Trypanosoma cruzi antigens in chronic Chagas disease patients display a low grade of differentiation and the frequency of these T lymphocytes decreases along with the severity of heart disease. This study thought to explore the expression of inhibitory receptors, transcription factors of type 1 or regulatory T cells, and markers of T cell differentiation, immunosenescence or active cell cycle in cardiac explants from patients with advanced Chagas disease myocarditis. Methodology/Principal Findings The expression of different markers for T and B cells as well as for macrophages was evaluated by immunohistochemistry and immunofluorescence techniques in cardiac explants from patients with advanced chronic Chagas disease submitted to heart transplantation. Most infiltrating cells displayed markers of antigen-experienced T cells (CD3+, CD4+, CD8+, CD45RO+) with a low grade of differentiation (CD27+, CD57−, CD45RA−, PD-1−). A skewed T helper1/T cytotoxic 1 profile was supported by the expression of T-bet; whereas FOXP3+ cells were scarce and located only in areas of severe myocarditis. In addition, a significant proliferative capacity of CD3+ T cells, assessed by Ki67 staining, was found. Conclusions/Significance The quality of T cell responses and immunoregulatory mechanisms might determine the pattern of the cellular response and the severity of disease in chronic Trypanosoma cruzi infection. PMID:25144227

Correlation between thyroidal and peripheral blood total T cells, CD8+ T cells, and CD8+ T- regulatory cells and T-cell reactivity to calsequestrin and collagen XIII in patients with Graves' ophthalmopathy.

PubMed

Al-Ansari, Farah; Lahooti, Hooshang; Stokes, Leanne; Edirimanne, Senarath; Wall, Jack

2018-05-22

Purpose/aim of the study: Graves' ophthalmopathy (GO) is closely related to the thyroid autoimmune disorder Graves' disease. Previous studies have suggested roles for thyroidal CD8 +  T cells and autoimmunity against calsequestrin-1 (CASQ)-1 in the link between thyroidal and orbital autoimmune reactions in GO. A role for autoimmunity against CollXIII has also been suggested. In this study, we aimed to investigate correlations between some thyroidal and peripheral blood T-cell subsets and thyroidal T-cell reactivity against CASQ1 and CollXIII in patients with GO. Fresh thyroid tissues were processed by enzyme digestion and density gradient to isolate mononuclear cells (MNCs). Peripheral blood MNCs were also isolated using density gradient. Flow-cytometric analysis was used to identify the various T-cell subsets. T -cell reactivity to CASQ1 and CollXIII was measured by a 5-day culture of the MNCs and BrdU uptake method. We found a positive correlation between thyroidal CD8 +  T cells and CD8 +  T-regulatory (T-reg) cells in patients with GO. Thyroidal T cells from two out of the three patients with GO tested (66.7%) showed a positive response to CASQ1, while thyroidal T cells from none of the six Graves' Disease patients without ophthalmopathy (GD) tested showed a positive response to this antigen. Thyroidal T cells from these patient groups however, showed no significant differences in their response to CollXIII. Our observations provide further evidence for a possible role of thyroidal CD8 +  T cells, CD8 +  T-reg cells and the autoantigen CASQ1 in the link between thyroidal and orbital autoimmune reactions of GO.

Systematic review with meta-analysis: the efficacy of a second anti-TNF in patients with inflammatory bowel disease whose previous anti-TNF treatment has failed.

PubMed

Gisbert, J P; Marín, A C; McNicholl, A G; Chaparro, M

2015-04-01

One-third of patients with Crohn's disease (CD) or ulcerative colitis (UC) receiving anti-TNFs do not respond to treatment, and a relevant proportion experience loss of response or intolerance. To investigate the efficacy and safety of a second anti-TNF agent after primary/secondary failure or intolerance to a first drug. studies evaluating the efficacy of infliximab (IFX), adalimumab (ADA) and certolizumab-pegol (CZP) as the second anti-TNF in CD or UC. Bibliographical searches (PubMed/Embase). percentage of response/remission; the meta-analysis was performed using the inverse variance method. We included 46 studies (37 CD, 8 UC, 1 pouchitis). The CD studies comprised 32 switching IFX→ADA, 4 IFX→CZP and 1 ADA→IFX. Overall, the second anti-TNF after the failure of IFX in CD induced remission in 43% and response in 63% of patients. The remission rate was higher when the reason to withdraw the first anti-TNF was intolerance (61%) than after secondary (45%) or primary failure (30%); response rates were, respectively, 72%, 62% and 53%. All UC studies switched IFX→ADA, six of them reporting remission rates ranging from 0% to 50%. Adverse events rate ranged from 0% to 81% in CD, most of them mild (serious adverse event 0-21%, discontinuation rate <20%). The efficacy of a second anti-TNF in CD patients largely depends on the cause for switching. The remission rate is higher when the reason to withdraw the first anti-TNF is intolerance (61%), compared with secondary (45%) or primary failure (30%). Further studies of switch ADA→IFX are needed to evaluate this strategy. PROSPERO-registry-number: CRD42014012943. © 2015 John Wiley & Sons Ltd.

A prospective study of the effect of pregnancy on CD4 counts and plasma HIV-1 RNA concentrations of antiretroviral-naive HIV-1 infected women

PubMed Central

Heffron, Renee; Donnell, Deborah; Kiarie, James; Rees, Helen; Ngure, Kenneth; Mugo, Nelly; Were, Edwin; Celum, Connie; Baeten, Jared M.

2014-01-01

Background In HIV-1 infected women, CD4 count declines occur during pregnancy, which has been attributed to hemodilution. However, for women who have not initiated antiretroviral therapy (ART), it is unclear if CD4 declines are sustained beyond pregnancy and accompanied by increased viral levels, which could indicate an effect of pregnancy on accelerating HIV-1 disease progression. Methods In a prospective study among 2269 HIV-1 infected ART-naïve women from 7 African countries, we examined the effect of pregnancy on HIV-1 disease progression. We used linear mixed models to compare CD4 counts and plasma HIV-1 RNA concentrations between pregnant, postpartum and non-pregnant periods. Results Women contributed 3270 person-years of follow-up, during which time 476 women became pregnant. In adjusted analysis, CD4 counts were an average of 56 (95% CI 39-73) cells/mm3 lower during pregnant compared to non-pregnant periods and 70 (95% CI 53-88) cells/mm3 lower during pregnant compared to postpartum periods; these results were consistent when restricted to the subgroup of women who became pregnant. Plasma HIV-1 RNA concentrations were not different between pregnant and non-pregnant periods (p=0.9) or pregnant and postpartum periods (p=0.3). Neither CD4 counts nor plasma HIV-1 RNA levels were significantly different in postpartum compared to non-pregnant periods. Conclusion CD4 count declines among HIV-1 infected women during pregnancy are temporary and not sustained in postpartum periods. Pregnancy does not have a short term impact on plasma HIV-1 RNA concentrations. PMID:24442226

TCRαβ+/CD4+ Large Granular Lymphocytosis

PubMed Central

Lima, Margarida; Almeida, Julia; dos Anjos Teixeira, Maria; Alguero, Maria del Carmen; Santos, Ana Helena; Balanzategui, Ana; Queirós, Maria Luís; Bárcena, Paloma; Izarra, Antonio; Fonseca, Sónia; Bueno, Clara; Justiça, Benvindo; Gonzalez, Marcos; San Miguel, Jesús F.; Orfao, Alberto

2003-01-01

Large granular lymphocyte (LGL) leukemia is a well-recognized disease of mature T-CD8+ or less frequently natural killer cells; in contrast, monoclonal expansions of CD4+ T-LGL have only been sporadically reported in the literature. In the present article we have explored throughout a period of 56 months the incidence of monoclonal expansions of CD4+ T-LGL in a population of 2.2 million inhabitants and analyzed the immunophenotype and the pattern of cytokine production of clonal CD4+ T cells of a series of 34 consecutive cases. Like CD8+ T-LGL leukemias, CD4+ T-LGL leukemia patients have an indolent disease; however, in contrast to CD8+ T-LGL leukemias, they do not show cytopenias and autoimmune phenomena and they frequently have associated neoplasias, which is usually determining the clinical course of the disease. Monoclonal CD4+ T-LGLshowed expression of TCRαβ, variable levels of CD8 (CD8−/+dim) and a homogeneous typical cytotoxic (granzyme B+, CD56+, CD57+, CD11b+/−) and activated/memory T cell (CD2+bright, CD7−/+dim, CD11a+bright, CD28−, CD62L− HLA-DR+) immunophenotype. In addition, they exhibited a Th1 pattern of cytokine production [interferon-γ++, tumor necrosis factor-α++, interleukin (IL-2)−/+, IL-4−, IL-10−, IL-13−]. Phenotypic analysis of the TCR-Vβ repertoire revealed large monoclonal TCR-Vβ expansions; only a restricted number of TCR-Vβ families were represented in the 34 cases analyzed. These findings suggest that monoclonal TCRαβ+/CD4+/NKa+/CD8−/+dim T-LGL represent a subgroup of monoclonal LGL lymphoproliferative disorders different from both CD8+ T-LGL and natural killer cell-type LGL leukemias. Longer follow-up periods are necessary to determine the exact significance of this clonal disorder. PMID:12875995