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Biomedical subjects

S R Targan

Publications and source records attributed to S R Targan.

At least 55 records · Page 3Linked to original sources
PubMed1999

Crohn's disease-associated genetic marker is seen in medically unresponsive ulcerative colitis patients and may be associated with pouch-specific complications.

PURPOSE: Genetic markers have been used to define subgroups of patients within the broad categories of Crohn's disease and ulcerative colitis that may differ in clinical course and response to medical therapy. The tumor necrosis factor microsatellite haplotype a2blc2d4e1 has been found previously to be present in 24 percent of patients with Crohn's disease and only 5 percent of patients with ulcerative colitis. This study examined associations between this microsatellite haplotype and the postoperative clinical course of patients with ulcerative colitis undergoing ileal pouch-anal anastomosis. METHODS: As part of a large, controlled, prospective study to correlate genetic markers with clinical phenotypes, tumor necrosis factor microsatellite alleles at five loci (a, b, c, d, and e) were determined from genomic DNA by polymerase chain reaction in 32 patients with a clinical and histopathologic diagnosis of ulcerative colitis who underwent ileal pouch-anal anastomosis for medically unresponsive disease. All patients with ileal pouch-anal anastomosis were also studied prospectively for pouch-specific complications. RESULTS: The tumor necrosis factor haplotype a2blc2d4e1 was present in 11 patients. Median follow-up was 19 months. Thirteen patients had a pouch-specific complication (12 pouchitis and 1 pouch-perineal fistula). Six of 11 patients (55 percent) with the haplotype had a pouch-specific complication compared with 7 of the 21 patients (33 percent) who did not possess this haplotype (P = 0.22). Median time from surgery to pouch-specific complication was eight months. Patients with the haplotype had a median time to pouch-specific complication of three months, whereas patients without the haplotype had a median time of 11 months (P = 0.04). In addition, 36 percent of patients with the haplotype had chronic pouch complications vs. only 10 percent of patients without the haplotype (P = 0.05). CONCLUSION: The Crohn's disease-associated tumor necrosis factor haplotype a2blc2d4e1 may define a subgroup of medically unresponsive patients with ulcerative colitis who are predisposed to a higher incidence of pouch-specific complications after ileal pouch-anal anastomosis.

Adult↗
PubMed1999

Serologic testing in inflammatory bowel disease: its value in indeterminate colitis.

Serologic testing in inflammatory bowel disease provides a unique tool to classify these diseases into more homogeneous groups. Serum markers can also be used to identify common antigenic triggers and specific defects in mucosal immune regulation and cytokine imbalance in different parts of the gastrointestinal tract. ANCA (antineutrophil cytoplasmic antibodies) and ASCA (anti-Saccharomyces cerevisiae antibodies), the most extensively studied serologic markers, have been used to classify ulcerative colitis and Crohn's disease into such groups with certain phenotypic characteristics and responses to treatment. Similar studies have been initiated in indeterminate colitis, and these results will help in the future to define the immunopathogenesis, prognosis, and response to certain treatments in patients with this type of disease.

Animals↗
PubMed1999

An open-label pilot study of low-dose thalidomide in chronically active, steroid-dependent Crohn's disease.

BACKGROUND & AIMS: Thalidomide decreases production of tumor necrosis factor alpha, a proinflammatory cytokine associated with Crohn's disease (CD). In this study the safety, tolerance, and efficacy of low-dose thalidomide were evaluated for treatment of moderate-to-severe, steroid-dependent CD. METHODS: Twelve adult male patients with Crohn's Disease Activity Index (CDAI) scores of > or = 250 and < or = 500 despite > or = 20 mg prednisone/day were enrolled. The first 6 patients received 50 mg thalidomide every night, the next 6 received 100 mg every night. Steroid doses were stable during the first 4 weeks of treatment, then tapered during weeks 5-12. CDAI was used to assess response. RESULTS: (1) Disease activity improved consistently in all patients during weeks 1-4: 58% response, 17% remission. (2) Clinical improvement was generally maintained despite steroid taper during weeks 5-12. All patients were able to reduce steroids by >/=50%. Forty-four percent discontinued steroids entirely. In weeks 5-12, 70% of patients responded and 20% achieved remission. (3) Side effects were mild and mostly transient, with the most common being drowsiness, peripheral neuropathy, edema, and dermatitis. CONCLUSIONS: Low-dose thalidomide appears to be well tolerated and effective over a 12-week period. Results of this pilot study support the need for controlled multicenter trials of thalidomide for treatment of CD.

Adult↗
PubMed1999

Lack of effect of intravenous administration on time to respond to azathioprine for steroid-treated Crohn's disease. North American Azathioprine Study Group.

BACKGROUND & AIMS: Azathioprine is effective for Crohn's disease but acts slowly. A loading dose may decrease the time to response. METHODS: A placebo-controlled study was conducted in patients with active Crohn's disease despite prednisone treatment. Patients were randomized to a 36-hour infusion of azathioprine, 40 mg/kg (51 patients), or placebo (45 patients) followed by oral azathioprine, 2 mg/kg, for 16 weeks. Prednisone was tapered over 5 weeks. The primary outcome measure was complete remission at week 8, defined by discontinuation of prednisone and a Crohn's Disease Activity Index of </=150 points. Erythrocyte concentrations of the azathioprine active metabolite, 6-thioguanine nucleotide, were measured. RESULTS: At week 8, 13 patients (25%) were in complete remission in the azathioprine-loaded group compared with 11 patients (24%) in the placebo group. The frequency of complete remission did not increase after 8 weeks in either group. Both groups achieved steady state of 6-thioguanine nucleotide by week 2, and no differences were found in mean concentrations between the groups. There were no significant differences in the frequency of adverse events between the groups. CONCLUSIONS: A loading dose does not decrease the time to response in patients with steroid-treated Crohn's disease beginning azathioprine therapy. Steady state of erythrocyte 6-thioguanine nucleotide and complete response occurred earlier than previously reported.

Administration, Oral↗
PubMed1999

Current theories on the causes of inflammatory bowel disease.

The understanding of the pathogenesis of CD and UC has greatly expanded over the last decade. The combination of abnormalities in the immune system, the contribution of nonimmune cells in the intestinal mucosa, a variety of genetic risk determinants, and random environmental factors may all be necessary to induce what clinically presents as IBD. It is likely that several agents can initiate an immune response that in the intestinal microenvironment and the genetic background of the patient finally leads to pathology.

Acute Disease↗
PubMed1999

Cytokine-based therapies in inflammatory bowel disease.

Cytokine-based therapy for inflammatory bowel disease (IBD) has significantly advanced in the last year. This review highlights some of the exciting progress that has occurred. The efficacy of anti-tumor necrosis factor (TNF) monoclonal antibody therapy in Crohn's disease has promoted further research and the development of other anti-TNF therapies, such as thalidomide, phosphodiesterase type IV inhibitors, and new-generation anti-TNF monoclonal antibodies. Current research is also focused on more proximal events in the inflammatory cascade to modify T-cell regulation and to decrease the production and activity of proinflammatory proteins, cytokines, and nuclear regulatory factors. Concurrently, the emerging role of interleukin (IL)-11, IL-12, and IL-18 in the perpetuation of chronic inflammation continues to stimulate much interest. All of these new advancements reveal an exciting future for IBD therapy.

Journal Article↗
PubMed1999

A genome-wide search identifies potential new susceptibility loci for Crohn's disease.

Chronic inflammatory bowel disease (IBD) presents as two major clinical forms, Crohn's disease (CD) and ulcerative colitis (UC). Genetic epidemiological studies and animal models suggest that inherited factors play significant roles in the susceptibility to both forms of IBD. From four genome-wide scans, putative susceptibility loci on chromosome 16 (IBD1 for CD), and on chromosomes 1, 3, 4, 6, 7, 10, and 12 for IBD, have been identified. Several other groups, including ours, have confirmed linkage to the loci on chromosomes 12 and 16. The aim of this study is to identify other potential susceptibility loci for CD with a genome-wide search approach. In our sample of 222 individuals from 46 families (20 Jewish and 26 non-Jewish), with a total of 65 sibpairs diagnosed with CD, we observed a novel locus with suggestive linkage [multipoint logarithm of the odds score (Mlod) > 2] at chromosome 14q11.2 (Mlod = 2.8, p = 0.0002). In addition, suggestive linkage was observed in our Jewish families at chromosome 17q21-q23 (Mlod = 2.1, p = 0.01) and chromosome 5q33-q35 (Mlod = 2.2, p = 0.0003). The syntenic regions of the latter locus are mapped within two putative loci on mouse chromosomes 11 and 18, which were identified in a mouse IBD model induced by dextran sulfate sodium (29). Our preliminary results provide potential evidence for several susceptibility loci contributing to the risk of CD. The observation of man-mouse synteny may accelerate the identification of CD susceptibility gene(s) on human chromosome 5.

Chromosome Mapping↗
PubMed1999

Identification of a novel mycobacterial histone H1 homologue (HupB) as an antigenic target of pANCA monoclonal antibody and serum immunoglobulin A from patients with Crohn's disease.

pANCA is a marker antibody associated with inflammatory bowel disease (IBD), including most patients with ulcerative colitis and a subset with Crohn's disease. This study addressed the hypothesis that pANCA reacts with an antigen(s) of microbial agents potentially relevant to IBD pathogenesis. Using a pANCA monoclonal antibody, we have previously identified the C-terminal basic random-coil domain of histone H1 as a pANCA autoantigen. BLAST analysis of the peptide databases revealed H1 epitope homologues in open reading frames of the Mycobacterium tuberculosis genome. Western analysis of extracts from six mycobacterial species directly demonstrated reactivity to a single, conserved approximately 32-kDa protein. Direct protein sequencing, followed by gene cloning, revealed a novel 214-amino-acid protein, an iron-regulated protein recently termed HupB. Sequence analysis demonstrated its homology with the mammalian histone H1 gene family, and recombinant protein expression confirmed its reactivity with the 5-3 pANCA monoclonal antibody. Binding activity of patient serum immunoglobulin G (IgG) to HupB did not correlate with reactivity to histone H1 or pANCA, indicating the complex character of the pANCA antigen. However, anti-HupB IgA was strongly associated with Crohn's disease (P < 0.001). These findings indicate that the 5-3 pANCA monoclonal antibody detects a structural domain recurrent among mycobacteria and cross-reactive with a DNA-binding domain of histone H1. The association of HupB-binding serum IgA with IBD provides new evidence for the association of a mycobacterial species with Crohn's disease.

Amino Acid Sequence↗
PubMed1999

Linkage of Crohn's disease to the major histocompatibility complex region is detected by multiple non-parametric analyses.

BACKGROUND: There is evidence for genetic susceptibility to Crohn's disease, and a tentative association with tumour necrosis factor (TNF) and HLA class II alleles. AIMS: To examine the potential of genetic linkage between Crohn's disease and the MHC region on chromosome 6p. METHODS: TNF microsatellite markers and, for some families, additional HLA antigens were typed for 323 individuals from 49 Crohn's disease multiplex families to generate informative haplotypes. Non-parametric linkage analysis methods, including sib pair and affected relative pair methods, were used. RESULTS: Increased sharing of haplotypes was observed in affected sib pairs: 92% (48/52) shared one or two haplotypes versus an expected 75% if linkage did not exist (p=0.004). After other affected relative pairs were included, the significance level reached 0.001. The mean proportion of haplotype sharing was increased for both concordant affected (pi=0.60, p=0.002) and unaffected sib pairs (pi=0.58, p=0. 031) compared with the expected value (pi=0.5). In contrast, sharing in discordant sib pairs was significantly decreased (pi=0.42, p=0. 007). Linear regression analysis using all three types of sib pairs yielded a slope of -0.38 at p=0.00003. It seemed that the HLA effect was stronger in non-Jewish families than in Jewish families. CONCLUSIONS: All available analytical methods support linkage of Crohn's disease to the MHC region in these Crohn's disease families. This region is estimated to contribute approximately 10-33% of the total genetic risk to Crohn's disease.

Alleles↗
PubMed1999

Fas activates the JNK pathway in human colonic epithelial cells: lack of a direct role in apoptosis.

Fas is expressed constitutively by colonic epithelial cells, and its ligand is expressed by intraepithelial and lamina propria lymphocytes. Fas ligation induces apoptosis in colonic epithelial cells and is implicated in the epithelial damage seen in ulcerative colitis. To understand the pleiotropic effects of Fas in the intestinal mucosa, we have examined signaling pathways activated by Fas in HT-29 colonic epithelial cells. HT-29 cells were stimulated with anti-Fas in the presence or absence of interferon-gamma (IFN-gamma). Activation of mitogen-activated protein kinase pathways was assessed by kinase assay, Western blots, and promoter-reporter assays. Electromobility shift assays were used to assess activator protein-1 (AP-1) binding activity. IFN-gamma increases expression of Fas on HT-29 cells. Signaling via Fas receptor, as determined by induction of c-Jun NH2-terminal kinase (JNK) activity and transcriptional activation of AP-1, is enhanced in IFN-gamma-primed cells. Dominant-interfering mutants of the JNK pathway do not block Fas-mediated apoptosis. Signaling through Fas results in activation of JNK and AP-1 binding activity that is increased in the presence of IFN-gamma. Inhibition of JNK does not block Fas-mediated apoptosis in these cells. Fas-Fas ligand interactions in the intestinal mucosa may lead to complex signal transduction cascades and gene regulation that culminate in apoptosis, cytokine secretion, or other novel functions.

Apoptosis↗
PubMed1999

Definition of ocular antigens in ciliary body and retinal ganglion cells by the marker antibody pANCA.

PURPOSE: A subset of patients with anterior uveitis express the marker, perinuclear anti-neutrophil cytoplasmic antibody (pANCA). In this study, recombinantly isolated pANCA monoclonal antibodies were used to search for ocular cells expressing the pANCA antigen. METHODS: Paraffin sections of human ocular tissues obtained after death were analyzed by immunohistochemistry to identify cell types expressing pANCA antigen. Microdissected eye-bank ocular tissue was characterized by western blot analysis to confirm antigen expression and identify candidate protein species. RESULTS: Immunohistochemical analysis with pANCA monoclonal antibodies revealed cytoplasmic antigen expression in retinal ganglion cells and ciliary body epithelium. pANCA antigen expression was restricted to tissues bearing these cell types by western blot analysis. A common set of epitope-positive protein species was shared by the two tissues (28 kDa, 80 kDa, and 90 kDa). Comparison of ocular tissues from seven subjects revealed no heterogeneity in antigen expression. CONCLUSIONS: In this study, novel cytoplasmic antigens of the pANCA marker antibody expressed in ciliary body and retinal tissue were identified. Validation of these antigens as targets of inflammation in pANCA+ uveitis requires further biochemical and immunologic analysis.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1998

Activation of the CD2 pathway in lamina propria T cells up-regulates functionally active AP-1 binding to the IL-2 promoter, resulting in messenger RNA transcription and IL-2 secretion.

The aim of this study was to identify molecular mechanisms involved in transcriptional regulation of IL-2 expression following CD2 and CD3 activation in lamina propria (LP) T cells. Studies used T cells from normal, ulcerative colitis, and Crohn's disease mucosa and freshly isolated PBMC, PBMC stimulated with IL-2 alone, and PBMC stimulated with IL-2 and cocultured with B cell lines (LP-like T cells). Electrophoretic mobility shift assays were performed with nuclear extracts from cells activated with either anti-CD2 or anti-CD3 Abs. CD2 signaling in LPMC and LP-like T cells led to a pattern of sustained up-regulation of AP-1-binding complexes, whereas CD3 activation resulted in only transient up-regulation. While the pattern of regulation of AP-1 binding observed in normal, uninflamed, or inflamed Crohn's disease LPMC is similar, differences in intensity of AP-1 binding were observed. Activation of LP-like T cells mimics the up-regulation of AP-1 with a kinetic profile similar to that observed with freshly isolated LPMC from Crohn's disease-inflamed tissue. The AP-1 complex formed following CD2 activation is composed of jun/fos heterodimers. The CD2-enhanced responsiveness is reflected in functional analysis experiments utilizing transfection of both multimeric-TRE or IL-2 promoter-luciferase constructs directly into normal, ulcerative colitis, or Crohn's disease LPMC. Our data suggest that activation of LP T cells from normal, ulcerative colitis, or Crohn's disease mucosa through the CD2 pathway leads to induction of AP-1 complexes that bind to the IL-2 promoter, and may play a pivotal role in modulating IL-2 production in the gut.

Animals↗
PubMed1998

Diagnostic accuracy of serological assays in pediatric inflammatory bowel disease.

BACKGROUND & AIMS: Accurate serological assays are desirable for the diagnosis of inflammatory bowel disease (IBD) types in the pediatric age group. The aim of this study was to test the diagnostic accuracy of modified assays for perinuclear (p) antineutrophil cytoplasmic antibodies (ANCAs) and anti-Saccharomyces cerevisiae antibodies (ASCAs) in patients with pediatric ulcerative colitis (UC) and Crohn's disease (CD) and in those without IBD. METHODS: With observers blinded to patients' diagnoses, serum specimens were analyzed for immunoglobulin (Ig) A and IgG ASCAs and ANCAs by enzyme-linked immunosorbent assay. The perinuclear location of ANCAs visualized by indirect immunofluorescence was confirmed by its disappearance after administration of deoxyribonuclease. RESULTS: IgA and IgG ASCA titers were significantly greater and highly specific for CD (95% for either, 100% if both positive). pANCA was 92% specific for UC and absent in all non-IBD controls. The majority of patients with CD positive for pANCA had a UC-like presentation. Disease location, duration, activity, complications, and treatment with immunosuppressive drugs did not have an impact on the ASCA or pANCA assay results. After resection, UC patients remained pANCA positive, in contrast to patients with CD, in whom ASCA titers decreased toward normal values postoperatively. CONCLUSIONS: ASCA and pANCA assays are highly disease specific for CD and UC, respectively. These serological tests can assist clinicians in diagnosing and categorizing patients with IBD and may be useful in making therapeutic decisions.

Adolescent↗
PubMed1998

Antineutrophil cytoplasmic antibody subtypes in children and adolescents after ileal pouch-anal anastomosis for ulcerative colitis.

BACKGROUND: Perinuclear antineutrophil cytoplasmic antibodies occur frequently in adult patients with chronic pouchitis after colectomy and ileal pouch-anal anastomosis for ulcerative colitis. The purpose of the study was to determine the prevalence of perinuclear antineutrophil cytoplasmic antibodies and cytoplasmic antineutrophil cytoplasmic antibody in children and adolescents who undergo colectomy and ileal pouch-anal anastomosis for ulcerative colitis and familial adenomatous polyposis. METHODS: Five groups of children and adolescents (age, <20 years) were studied, with the following histories: acute pouchitis and history of ulcerative colitis; chronic pouchitis and history of ulcerative colitis; pouchitis with Crohn's disease features and a history of ulcerative colitis; no pouchitis and a history of ulcerative colitis; and familial adenomatous polyposis, with or without pouchitis. Antineutrophil cytoplasmic antibody levels and titers were detected in postoperative sera by enzyme-linked immunosorbent assay, and positive results were subtyped by indirect immunofluorescence. RESULTS: The frequency of perinuclear antineutrophil cytoplasmic antibodies and cytoplasmic antineutrophil cytoplasmic antibody in patients with a history of ulcerative colitis were 67% and 15%, compared with a 0% presence in patients with familial adenomatous polyposis (p < 0.001). There was no significant correlation between the frequency of perinuclear antineutrophil cytoplasmic antibodies and ulcerative colitis patient subgroups (patients with and without pouchitis, 66% and 75%). Similarly, there was no significant correlation between the frequency of cytoplasmic antineutrophil cytoplasmic antibodies among ulcerative colitis patient subgroups (patients with and without pouchitis, 19% and 8%). The frequency of cytoplasmic antineutrophil cytoplasmic antibody in patients with Crohn's disease features (50%), was increased, but this difference was not significant. CONCLUSIONS: There is a high frequency of perinuclear antineutrophil cytoplasmic antibodies in children and adolescents who undergo ileal pouch-anal anastomosis for ulcerative colitis, whether or not they have pouchitis. The frequency of cytoplasmic antineutrophil cytoplasmic antibody is lower in this patient population. Additional studies will be required to determine whether the presence of cytoplasmic antineutrophil cytoplasmic antibody is associated with the postoperative development of features of Crohn's disease.

Adenomatous Polyposis Coli↗
PubMed1998

Anti-Saccharomyces cerevisiae mannan antibodies combined with antineutrophil cytoplasmic autoantibodies in inflammatory bowel disease: prevalence and diagnostic role.

BACKGROUND: Perinuclear antineutrophil cytoplasmic autoantibodies (pANCA) are a well recognised marker for ulcerative colitis. Antibodies to oligomannosidic epitopes of the yeast Saccharomyces cerevisiae (ASCA) are a new marker associated with Crohn's disease. AIMS: To assess the value of detecting pANCA and/or ASCA for the diagnosis of ulcerative colitis and Crohn's disease. METHODS: Serum samples were obtained from 100 patients with Crohn's disease, 101 patients with ulcerative colitis, 27 patients with other miscellaneous diarrhoeal illnesses, and 163 healthy controls. Determination of pANCA and ASCA was performed using the standardised indirect immunofluorescence technique and an ELISA, respectively. RESULTS: The combination of a positive pANCA test and a negative ASCA test yielded a sensitivity, specificity, and positive predictive value of 57%, 97%, and 92.5% respectively for ulcerative colitis. The combination of a positive ASCA test and a negative pANCA test yielded a sensitivity, specificity, and positive predictive value of 49%, 97%, and 96% respectively for Crohn's disease. Among patients with miscellaneous non-inflammatory bowel disorders, three were ASCA positive and two were pANCA positive. One control was ASCA positive. The presence of ASCA in patients with Crohn's disease was associated with small bowel involvement. CONCLUSION: ASCA and pANCA are strongly associated with Crohn's disease and ulcerative colitis, respectively. Combination of both tests could help the diagnosis of inflammatory bowel disease.

Adult↗