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Biomedical subjects

F Shanahan

Publications and source records attributed to F Shanahan.

At least 181 records · Page 10Linked to original sources
PubMed1993

Familial empirical risks for inflammatory bowel disease: differences between Jews and non-Jews.

The Jewish population has an increased frequency of inflammatory bowel disease compared with their non-Jewish neighbours. Genetic factors have been implicated in the aetiology of this disorder and may contribute to ethnic differences. This study determined the familial empirical risks for inflammatory bowel disease in the first degree relatives of inflammatory bowel disease probands (for both Jews and non-Jews) for the purpose of accurate genetic counselling and genetic analysis. A total of 527 inflammatory bowel disease patients from Southern California (291 Jews and 236 non-Jews) were questioned about inflammatory bowel disease in their first degree relatives (a total of 2493 individuals). Since inflammatory bowel disease has a variable and late age of onset, age specific incidence data were used to estimate the life time risks and to make valid comparisons between the different groups. In the first degree relatives of non-Jewish probands, the life time risks for inflammatory bowel disease were 5.2% and 1.6% when probands had Crohn's disease and ulcerative colitis respectively. These values were consistently lower than the corresponding risks for relatives of Jewish patients -7.8% and 4.5% for Crohn's disease and ulcerative colitis probands respectively (p value for comparison between Jews and non-Jews: 0.028; between ulcerative colitis and Crohn's disease: 0.005). These data provide the requisite basis for genetic counselling for these disorders in the white American population. In addition, these different empirical risks for relatives of Jewish and non-Jewish probands allow rejection of single Mendelian gene models for inflammatory bowel disease, but are consistent with several alternative genetic models.

Adolescent↗
PubMed1993

VIP modulates intracellular calcium oscillations in human lymphoblasts.

Vasoactive intestinal polypeptide (VIP) has been shown to stimulate adenylate cyclase in a human lymphoblast cell line (MOLT 4). In the present study, we monitored fluorescence in cell suspensions and in single fura-2 loaded MOLT 4 lymphoblasts to determine if VIP modulates intracellular calcium concentrations ([Ca2+]i), and if this modulation is mediated by adenylate cyclase. The distribution of [Ca2+]i in resting and stimulated cells was non-homogeneous, with gradients of high [Ca2+]i present in the subplasmalemmal space. In a subset of cells (10-30% of all cells studied), [Ca2+]i showed La(3+)-sensitive, temporal changes in the form of [Ca2+]i oscillations with a baseline [Ca2+]i value of 115 +/- 10 nM, an oscillation amplitude of 150 +/- 18 nM and a mean period of 9.2 +/- 2 s. The remaining non-oscillating cells showed a constant [Ca2+]i level of 75 +/- 5 nM (n = 65 cells from 4 experiments). In the subset of cells with spontaneous [Ca2+]i oscillations, VIP dose-dependently (10(-12) to 10(-8) M) increased the amplitude of oscillations but did not stimulate their frequency. The stimulatory effect of VIP was correlated with baseline [Ca2+]i in these cells, was attenuated in the presence of La3+ (25 microM), but was unaffected by cell depolarization (126 mM KCl). Dibutyryl cyclic AMP (10(-4) to 10(-3) M) and forskolin (10(-4) M) had no effect on [Ca2+]i oscillations, or on [Ca2+]i in cells without oscillations. In cell suspensions, baseline [Ca2+]i was found to be 55.1 +/- 11.2 nM (mean +/- S.E.M., n = 11); VIP, cyclic AMP analogues or forskolin had no significant effect on [Ca2+]i. These findings suggest that: a) VIP modulates the amplitude of [Ca2+]i oscillations generated by a cytosolic [Ca2+] oscillator in a subset of cells at a concentration of 10(-12) M, a thousand-fold below the KD for the VIP receptor; b) baseline [Ca2+] values may be related to both the ability of cells to generate spontaneous [Ca2+] oscillations and of oscillating cells to respond to VIP; c) due to the small number of responding cells, VIP-induced [Ca2+]i changes are not detectable when studied in cell suspensions.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1993

Pneumocystis carinii pneumonia in patients with ulcerative colitis treated with corticosteroids.

Today, Pneumocystis carinii pneumonia (PCP) is typically associated with AIDS. However, in the pre-AIDS era, PCP was known to be associated with various immunodeficiency states, malignancies, and immunosuppressive therapy, particularly the use of corticosteroids. PCP has been reported to occur during immuno-suppressive therapy of some chronic inflammatory states, but it has never been reported in patients with inflammatory bowel disease. We report two patients with ulcerative colitis who developed PCP during high-dose corticosteroid therapy, and review the literature regarding non-AIDS PCP. PCP should thus be added to the list of bronchopulmonary complications in inflammatory bowel disease. This report should give gastroenterologists further impetus to limit immunosuppressive therapy to its minimal effective dose.

Adult↗
PubMed1992

Neutrophil autoantibodies in ulcerative colitis: familial aggregation and genetic heterogeneity.

The possibility that the neutrophil autoantibodies associated with ulcerative colitis represent a genetic marker of susceptibility was investigated by determining their prevalence in unaffected relatives of patients. Neutrophil autoantibodies were detected using an enzyme-linked immunosorbent assay, and positive values were confirmed by indirect immunofluorescence. An increased prevalence of neutrophil antibodies was found not only in the probands (68%, 26/38) but also in their clinically unaffected family members (15.7%, 17/108) compared with controls (2.9%, 1/35) (P less than 0.0001 and P less than 0.05, respectively). These results were confirmed with sera from a second center, where 86.4% (19/22) of probands were positive and 20.9% (9/43) of their relatives were positive. The prevalence of neutrophil autoantibodies in the relatives of probands who were antibody positive (21.4%) was significantly greater than the prevalence in relatives of probands who were antibody negative (7%; P less than 0.05). The findings are consistent with these antibodies being a potential marker of genetic susceptibility to ulcerative colitis and suggest the possibility of genetic heterogeneity within this disease.

Adolescent↗
PubMed1992

Ulcerative colitis-linked antineutrophil cytoplasmic antibody in the cotton-top tamarin model of colitis.

The presence of antineutrophil cytoplasmic antibodies (ANCA) in serum has recently been shown to be a good disease marker for ulcerative colitis. An animal model of colitis expressing serum ANCA would allow prospective studies of the relationship between ANCA expression and development of colitis. The cotton-top tamarin model of spontaneous colitis was investigated for presence of ANCA to evaluate its potential as a model for the study of the immune response in human ulcerative colitis. Results show that cotton-top tamarin neutrophils have antigens recognized by immunoglobulin G (IgG) from the ANCA-positive serum of patients with ulcerative colitis. However, cotton-top tamarins do not generate serum IgG reactive to cotton-top tamarin or human neutrophils even when equal amounts of IgG are used for antigen detection. As new animal models of spontaneous and induced chronic colitis are developed, the presence of ANCA in serum, using the species' neutrophils, will be useful in relating the immune response of the model to that in human ulcerative colitis.

Animals↗
PubMed1992

Medical treatment of inflammatory bowel disease.

Advances in the drug treatment of inflammatory bowel disease include the development of site-specific delivery systems for 5-aminosalicylate (5-ASA), topically active corticosteroids with minimal systemic bioavailability, and a variety of antagonists to specific inflammatory mediators. These novel therapeutic approaches have emerged from pharmaceutical improvements on traditional drugs and also from an improved understanding of the mucosal immune system and the pathogenesis of inflammatory bowel disease.

Adjuvants, Immunologic↗
PubMed1991

Oral mesalamine (Asacol) for mildly to moderately active ulcerative colitis. A multicenter study.

OBJECTIVE: To evaluate the efficacy and safety of a pH-sensitive, polymer-coated oral preparation of mesalamine in patients with mildly to moderately active ulcerative colitis. DESIGN: A multicenter, double-blind, placebo-controlled randomized trial. SETTING: Five university-based medical centers, one inflammatory bowel disease center, and three private practice sites. PATIENTS: A total of 158 patients with newly or previously diagnosed active ulcerative colitis. INTERVENTION: A pH-sensitive, polymer-coated oral preparation of mesalamine (5-aminosalicylic acid) was used at 1.6 and 2.4 g/d for 6 weeks. MEASUREMENTS: Efficacy was measured by scores for stool frequency, rectal bleeding, patient's functional assessment, sigmoidoscopic findings, and physician's global assessment. Stringent criteria for disease activity were established prospectively. RESULTS: The analysis of protocol-compliant patients showed a significant improvement at 3 weeks in patients taking 2.4 g/d of mesalamine compared with patients taking placebo (32% versus 9%; P = 0.003). At 6 weeks, both the 1.6 g/d (43%) and 2.4 g/d (49%) doses were significantly superior to placebo (23%) (P = 0.03 and P = 0.003, respectively). In addition, more patients worsened in the placebo group compared with the 2.4 g/d group (50% versus 19%; P = 0.003); however, there was no statistically significant difference in worsening between the 1.6 g/d mesalamine group and the placebo group. The oral mesalamine tablet was well tolerated, and no clinically significant changes were observed in hematologic, hepatic, or renal laboratory profiles. CONCLUSION: Colon-targeted oral mesalamine at 2.4 g/d is effective therapy for mildly to moderately active ulcerative colitis. It is well tolerated and should provide a viable therapeutic alternative to sulfasalazine.

Administration, Oral↗
PubMed1991

p53 is frequently mutated in Burkitt's lymphoma cell lines.

A panel of 12 Burkitt's lymphoma cell lines and four other B cell lines were tested for the presence of mutations in p53. Protein analysis using a mutant-specific antibody and sequencing of both cDNA and genomic DNA revealed changes relative to the standard p53 protein sequence in 12 of the 16 lines studied, including 10 of the BL lines. Mutation of p53 in the BL lines was usually accompanied by loss of the other allele of p53. Testing of the mutated p53 cDNAs for gain of transforming activity or loss of growth suppression activity showed that several of the BL mutants were functionally altered from wild-type p53.

Alleles↗
PubMed1991

Anti-neutrophil cytoplasmic antibodies in ulcerative colitis. Comparison with other colitides/diarrheal illnesses.

Previous studies from this laboratory showed that serum anti-neutrophil cytoplasmic antibodies, distinct from those associated with active Wegener's granulomatosis, are present in the majority of patients with ulcerative colitis. In this study, the specificity of anti-neutrophil cytoplasmic antibodies for ulcerative colitis as compared with other colitides and diarrheal illness was determined. In a blinded study, test samples of serum were screened for anti-neutrophil immunoglobulin G in a fixed neutrophil enzyme-linked immunosorbent assay. Levels of neutrophil binding by immunoglobulin G and titers of anti-neutrophil immunoglobulin G in sera from patients with ulcerative colitis and patients with ulcerative colitis post colectomy were each significantly greater than the levels and titers for normal controls and patients with a variety of other colitides and diarrheal illnesses. Levels of neutrophil binding for colonic Crohn's disease, bacterial/amoebic colitis, the irritable bowel syndrome with diarrhea, and other miscellaneous diarrheal illnesses were not significantly different than the levels for normal controls. Although the levels of binding for collagenous colitis were significantly less than the levels for ulcerative colitis, they were significantly greater than the levels for normal controls. Patterns of neutrophil binding by serum samples that were positive in the enzyme-linked immunosorbent assay were determined by indirect immunofluorescence. Perinuclear staining was the predominant pattern shown by sera from patients with ulcerative colitis. The combination of a positive value in the enzyme-linked immunosorbent assay and a perinuclear immunofluorescence pattern was 60% sensitive and 94% specific for ulcerative colitis. It is concluded that anti-neutrophil cytoplasmic antibodies in ulcerative colitis are not simply an epiphenomenon related to inflammation of the colon. Identification of the antigen(s) to which these autoantibodies are directed may facilitate understanding of the underlying immune response and may allow development of an assay that is more sensitive and specific for ulcerative colitis.

Adult↗
PubMed1991

Isolation and characterization of a cDNA clone corresponding to the mouse t-complex gene Tcp-1x.

The mouse t complex on chromosome 17 is known to harbour many genes which have an important role in spermatogenesis. One of these, Tcp-1 has been cloned and shown to code for a protein probably essential for acrosome formation. During the isolation of a cDNA for Tcp-1 two other homologous sequences were recognized and described as Tcp-1x and Tcp-1y. In this paper we describe the isolation of a cDNA which has been shown by in situ hybridization to correspond to the Tcp-1x gene. Sequence analysis has confirmed that a 140 bp region of homology between Tcp-1 and Tcp-1x lies in the 3' portion of both genes. Northern blotting has revealed that the Tcp-1x gene is expressed abundantly in liver where two transcripts are detectable and hybrid selection shows that the gene codes for a 37 kDa protein. A search of the DNA database has failed to find any significant homology between Tcp-1x and any other sequences apart from Tcp-1.

Amino Acid Sequence↗
PubMed1991

Triggered human mucosal T cells release tumour necrosis factor-alpha and interferon-gamma which kill human colonic epithelial cells.

T cell activation can lead to local tissue injury in organ culture studies of human fetal jejunum, either directly through cytotoxicity or indirectly by the release of cytotoxic cytokines. The goal of this study was to establish in vitro whether cytotoxic cytokines can be released by isolated colonic T cells and what cytokine interactions are required for killing of human colonic epithelial cells. Cytokine-containing supernatants were induced by incubating unseparated lamina propria lymphocytes (LPL) or mucosal T cell subpopulations (separated by indirect panning) with anti-CD3 and/or K562 target cells for 18 h at 37 degrees C. Cytokines were measured by cytotoxicity assays using L929 (murine fibroblast) and HT-29 (human colonic tumour) lines as target cells in combination with blocking anti-cytokine antibodies. Supernatants derived from unseparated, CD4+ (greater than 95% pure) and CD8+ (greater than 90% pure) LPL were cytotoxic to L929 targets (350 U/ml, 230 U/ml and 100 U/ml tumour necrosis factor-alpha, respectively). All or nearly all of the cytotoxicity was due to the presence of tumour necrosis factor-alpha (little or no tumour necrosis factor-beta was detected). These same supernatants were cytotoxic (up to 32% lysis at 1/4 dilution) to HT-29 targets in a 48-h 111In release assay. Recombinant tumour necrosis factor-alpha and interferon-gamma alone produced minimal killing of HT-29, but together killed the HT-29 target cells. Anti-tumour necrosis factor-alpha or anti-interferon-gamma alone blocked killing of HT-29 target cells by LPL-derived supernatants, although anti-tumour necrosis factor-beta had no effect upon killing of HT-29. These results demonstrate that human LPL T cells, triggered by addition of anti-CD3 and target cells, produce tumour necrosis factor-alpha and interferon-gamma, both of which are required for optimal killing of HT-29. Simultaneous release of these cytokines in the vicinity of epithelial cells during immune responses could play an important role in the mucosal damage in chronic inflammatory states such as inflammatory bowel disease.

Antibodies, Monoclonal↗
PubMed1991

Prevalence and severity of periodontal disease in patients with inflammatory bowel disease.

Previous reports have demonstrated that oral mucosa and periodontal lesions occur in patients suffering from inflammatory bowel disease (Crohn's disease [CD] and ulcerative colitis [UC]). It is unknown whether periodontal disease is an occasional or regular finding in these patients. The purpose of this study was to assess the prevalence and severity of periodontal disease in patients with inflammatory bowel disease (IBD). The periodontal status of 107 consecutive patients seeking treatment for inflammatory bowel disease was assessed. Examination of the mid- and mesiobuccal aspects of one quadrant on one jaw and the contralateral quadrant of the opposite jaw revealed the 93.5% of the CD patients and 95.1% of UC patients had at least one site with probing attachment loss of 2 mm or greater, and a mean probing attachment loss 1.4 +/- 0.9 mm and 1.5 +/- 1.0 mm, respectively. We found that 28.3% of CD patients and 29.5% of UC patients possessed at least 1 site with a pocket probing depth of 4 mm or greater; the mean pocket probing depth in these patients was 2.4 +/- 0.2 mm and 2.3 +/- 0.2 mm, respectively. Compared with the assessment of Oral Health of United States Adults, IBD patients revealed a 11.9% higher prevalence (P less than or equal to 0.01) but 0.6 mm lower severity (P less than or equal to 0.01) of periodontal disease. The magnitudes of these differences suggest no clinical implications for the management of periodontal disease in IBD subjects.

Adolescent↗