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Biomedical subjects

C S Probert

Publications and source records attributed to C S Probert.

At least 19 recordsLinked to original sources
PubMed2006

Review article: maintenance therapy in patients with ulcerative colitis.

British Society of Gastroenterology guidelines recommend that all patients with ulcerative colitis should receive long-term therapy with a 5-aminosalicylic acid compound to maintain remission. Recent studies have shown that time spent in remission is longer when the maintenance dose is increased from 1.2 to 2.4 g/day, with patients with extensive disease benefiting most from an increase with dosage. A retrospective analysis also found that the frequency of relapse was lower in patients taking more than the median dose of 5-aminosalicylic acid (1.6 g/day) compared with those taking less than the median dose. Similarly, when 5-aminosalicylic acids are used to induce remission, continuing the induction dosage for an extra 4 weeks prolongs remission and reduces the frequency of relapse. However, patients rarely comply fully with the prescribed dose regimen, which can lead to effective under-dosing. The recent discovery that 5-aminosalicylic acids may act in ulcerative colitis by activating peroxisome proliferator-activated receptor-gamma, a nuclear receptor that plays a role in the control of cell proliferation and apoptosis, has given new impetus to the idea that long-term therapy with 5-aminosalicylic acid may reduce the risk of colorectal cancer. Epidemiological studies are beginning to provide evidence to support this view. Accumulating evidence suggests that the next revision of the clinical guidelines should suggest life-long doses of 5-aminosalicylic acid of > or =2 g/day for maintenance of remission in patients with ulcerative colitis.

Administration, Oral↗
PubMed2005

Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebo controlled trial.

BACKGROUND: Pyoderma gangrenosum (PG) is a chronic ulcerating skin condition that often occurs in association with inflammatory bowel disease. There have been a number of reports of PG responding to infliximab, a monoclonal antibody against tumour necrosis factor alpha. AIM: In the first randomised placebo controlled trial of any drug for the treatment of PG, we have studied the role of infliximab in this disorder. SUBJECTS: Patients 18 years of age or older with a clinical diagnosis of PG were invited to take part. METHODS: Patients were randomised to receive an infusion of infliximab at 5 mg/kg or placebo at week 0. Patients were then assessed at week 2 and non-responders were offered open labelled infliximab. The primary end point was clinical improvement at week 2, with secondary end points being remission and improvement at week 6. RESULTS: Thirty patients were entered into the study. After randomisation, 13 patients received infliximab and 17 patients received placebo. At week 2, significantly more patients in the infliximab group had improved (46% (6/13)) compared with the placebo group (6% (1/17); p = 0.025). Overall, 29 patients received infliximab with 69% (20/29) demonstrating a beneficial clinical response. Remission rate at week 6 was 21% (6/29). There was no response in 31% (9/29) of patients. CONCLUSIONS: This study has demonstrated that infliximab at a dose of 5 mg/kg is superior to placebo in the treatment of PG. Open label treatment with infliximab also produced promising results. Infliximab treatment should be considered in patients with PG.

Adult↗
PubMed2005

Combined oral and enema treatment with Pentasa (mesalazine) is superior to oral therapy alone in patients with extensive mild/moderate active ulcerative colitis: a randomised, double blind, placebo controlled study.

BACKGROUND AND AIMS: Oral aminosalicylates are well established in the treatment of active mild/moderate ulcerative colitis (UC) when the disease is extensive (that is, beyond the splenic flexure). The majority of clinical symptoms relate to disease activity in the distal part of the colon and therefore this study was designed to investigate if adding a mesalazine enema to oral mesalazine has additional benefit for patients with extensive mild/moderate active UC. METHODS: A randomised double blind study was performed in 127 ambulatory patients. All received 4 g/day (twice daily dosing) oral mesalazine for eight weeks. During the initial four weeks, they additionally received an enema at bedtime containing 1 g of mesalazine or placebo. Disease activity was assessed using the ulcerative colitis disease activity index, with clinical and endoscopic signs at four and eight weeks. RESULTS: Remission was obtained in 44% (95% confidence interval (CI) 31%, 58%) of the mesalazine enema group (Me) and in 34% (95% CI 21%, 49%) of the placebo enema group (Pl) at four weeks (p = 0.31) and in 64% (95% CI 50%, 76%) of the Me group versus 43% (95% CI 28%, 58%) of the Pl group at eight weeks (p = 0.03). Improvement was obtained in 89% (95% CI 78%, 96%) of the Me group versus 62% (95% CI 46%, 75%) of the Pl group at four weeks (p = 0.0008) and in 86% (95% CI 75%, 94%) of the Me group versus 68% (95% CI 53%, 81%) of the Pl group at eight weeks (p = 0.026). CONCLUSION: In patients with extensive mild/moderate active UC, the combination therapy is superior to oral therapy. It is safe, well accepted, and may be regarded as firstline treatment.

Administration, Oral↗
PubMed2001

Mucins in the gastrointestinal tract in health and disease.

Mucins form part of the dynamic, interactive mucosal defensive system active at the mucosal surface of the gastrointestinal tract. They are carbohydrate rich glycoproteins with unique molecular structure and chemical properties. The family of mucin (MUC) genes has 13 members that can be divided into secreted and membrane-associated forms each with characteristic protein domains and tissue specific glycosylation. Biosynthetic pathways have been described for the secreted and membrane-associated mucins and their eventual degradation and turnover. Mucins are present at all mucosal surfaces throughout the body in typical combinations and relate to the demands of organ function. Patterns of MUC gene expression with gastrointestinal site specific glycosylation are clearly important but are not yet well defined. Mucin production during fetal development shows distinct patterns that may correlate in many cases with neoplastic expression in adult life. An increasing number of protective proteins have been identified that appear in the adherent mucus layer at the mucosal surface. These proteins are co-secreted with mucins in some cases, interact with mucins at a molecular level through peptide and carbohydrate sites or benefit from the viscoelastic, aqueous environment afforded by the mucus gel to effect their defensive roles. The mechanism of many of these interaction remains to be elucidated but is clearly part of an integrated innate and adaptive mucosal defensive system relying on the mucins as an integral component to provide a mucus gel. Recent improvements in the description of MUC gene expression and mature mucin synthesis in the healthy gastrointestinal tract has formed a basis for assessment of mucosal disease at sites throughout the tract. Pathological patterns of mucin expression in disease appear to follow tissue phenotype, so that gastric and intestinal types can be defined and appear in metaplasia in e.g. esophagus and stomach. Adaptation of previous mucin based, histochemical classification of intestinal metaplasia to assess MUC gene expression has proved helpful and promises greater value if reliably combined with mucin linked glycosylation markers. Few changes in MUC gene expression or polymorphism have been detected in inflammatory bowel diseases in contrast to malignant transformation. Glycosylation changes however, are evident in both types of disease and appear to be early events in disease pathogenesis. Review of the major mucosal diseases affecting the gastrointestinal tract in childhood reveals parallel patterns to those found in adult pathology, but with some novel conditions arising through the developmental stages at lactation and weaning. The impact of bacterial colonization and nutrition at these stages of life are important in the evaluation of mucosal responses in pediatric disease.

Digestive System↗
PubMed2001

Prevalence of an ulcerative colitis-associated CD8+ T cell receptor beta-chain CDR3-region motif and its association with disease activity.

The normal human intestinal mucosa contains clonal T cell expansions. Clonal populations of T cells can be determined through evaluation of the idiotypic, hypervariable region of their T cell receptor (TCR). We have previously reported that there exists a highly conserved TCR pattern among intestinal CD8+ T cells in the majority of ulcerative colitis (UC) patients undergoing colectomy that was not present in normal control individuals. This TCR pattern, or motif, was characterized by particular beta-chain usage (TCRBV3 and TCRBJ1S6) and a defined length in the hypervariable third complementarity determining region (CDR3). The aim of this study was to assess the motif's relationship to disease activity. Subjects were 66 with UC, 19 with Crohn's disease, 14 inflammatory controls, and 6 normal controls. cDNA and gDNA were prepared from colonic biopsies and paraffin blocks, respectively, obtained from study subjects and used to assess TCRBV CDR3 region length and usage, as well as for cloning and sequencing of TCRs. The TCRBV CDR3 region was present in 25 of a series of 48 UC subjects but only 3 of 19 Crohn's disease patients and 3 of 14 inflammatory controls. The motif was more common in UC than either Crohn' s disease or inflammatory controls (chi2 = 7.5, P = 0.006, and chi2 = 4.1, P = 0.04, respectively). The motifs presence was not dependent upon histologic disease activity (either active or inactive UC). Clinical UC disease activity was also not significantly associated with an increased presence of the motif in 14 paired biopsies, which were taken during times of clinical activity or inactivity. There was a trend toward persistence of the motif, as it was present in 6 of 14 subjects over a 3- to 6-month time period. The previously described UC-associated TCRBV CDR3 region motif located in the intestinal CD8+ T-cell subset is found in a significant proportion of UC subjects. The TCR motif does not significantly discriminate active from inactive disease states. The persistent and diffuse nature of this TCR-associated motif in UC suggests that an ongoing T-cell response to a particular antigen(s) is occuring in this disorder.

Amino Acid Sequence↗
PubMed2001

An investigation of the association of the prothrombin G20210A gene mutation and inflammatory bowel disease: Factor II and IBD.

BACKGROUND: A thrombotic etiology for inflammatory bowel disease (IBD) has been proposed as a result of its association with thromboembolic complications, smoking, the oral contraceptive pill, and the response of ulcerative colitis (UC) patients to heparin. We have previously demonstrated an increased prevalence of the Factor V Leiden mutation in UC and wished to investigate the frequency of the recently discovered prothrombin G20210A gene mutation in IBD. The aim of the study was to investigate the hypothesis that the prothrombic state associated with the prothrombin G20210A gene mutation is involved in the etiology of IBD. PATIENTS AND METHODS: A prospective cohort study of patients attending the Bristol Royal Infirmary and Gloucestershire Royal Hospital's IBD clinics was performed. Thirty-nine patients with IBD (24 with Crohn's disease and 15 with UC) and 100 historical controls were screened for the presence of the prothrombin gene mutation using a heteroduplex-based polymerase chain reaction technique. None of the patients with IBD had a personal history of thromboembolism, while three of them had a family history. RESULTS: No IBD patients had the prothrombin gene mutation compared with four (4%) controls (allelic frequency 2%). CONCLUSION: There does not appear to be an association of the prothrombin gene mutation with IBD and therefore it is unlikely to be involved in the etiology of IBD.

Cohort Studies↗
PubMed2000

Audit of cyclosporin use in inflammatory bowel disease: limited benefits, numerous side-effects.

BACKGROUND: The failure of standard treatments for inflammatory bowel disease (IBD) has led to the use of immuno-modulatory therapy. Most reports of the use of cyclosporin are from single specialist centres. AIM: To survey the use of cyclosporin in IBD in Bristol's three teaching hospitals. PATIENTS AND METHODS: Over a 4-year period, all patients receiving cyclosporin for IBD were identified and the following data recorded: diagnosis, duration of disease, initial treatment, date initiated, dose of cyclosporin, side-effects, initial clinical response, and current patient status. RESULTS: Thirty-three patients were identified, of whom 26 had ulcerative colitis (UC), six had Crohn's disease and one had indeterminant colitis. The most frequent indication was as 'rescue' therapy in acute severe UC. The overall initial response rate was 63%, but this was only maintained in 30% long-term patients, with over half of them reporting side-effects. Four patients had life threatening side-effects. CONCLUSION: Although the initial response rates are encouraging, the long-term results are poor and at the expense of a high incidence of side-effects. We feel that the use of cyclosporin in IBD should be reconsidered until more information from randomized controlled studies becomes available.

Adult↗
PubMed2000

Measles, month of birth, and Crohn's disease.

BACKGROUND: The rise in the incidence of Crohn's disease (CD) suggests the role of an environmental factor in the development of the disease in susceptible individuals. Perinatal exposure to infection has been proposed as such an environmental factor. AIM: To investigate the influence of birth date on the development of CD in later life. PATIENTS AND METHOD: Four registers of patients with CD, diagnosed from 1972 to 1989, were combined, and data from 1624 patients were examined. The birth dates of CD patients were compared with national birth figures for three decades (1941-50, 1951-60, and 1961-70) to avoid temporal changes in birth trends, and year of birth was compared with epidemic measles years between 1951 and 1967. Risk ratios with 95% confidence intervals (CI) and chi(2) tests were performed. RESULTS: There were marginal differences between the birth dates of the CD patients and those predicted from the general population. Further analysis of both season of birth and year halves revealed a very weak association with the first half of the year (relative risk 1.14 (95% CI 1.01-1.30)). There was no association between developing CD and birth during measles epidemics between 1951 and 1967. CONCLUSIONS: In utero or perinatal exposure to seasonal environmental factors are unlikely potential aetiological agents in the later development of CD.

Adult↗
PubMed2000

Mucins and inflammatory bowel disease.

There is a layer of mucus lining the gastrointestinal tract, which acts as both a lubricant and as a physical barrier between luminal contents and the mucosal surface. The mucins that make up this layer consist of a protein backbone with oligosaccharides attached to specific areas of the protein core. These areas are called the variable number tandem repeat regions. The degree of glycosylation of the mucins is central to their role in the mucus barrier. The oligosaccharides are variable and complex. It has been demonstrated that the degree of sulphation and sialylation and the length of the oligosaccharide chains all vary in inflammatory bowel disease. These changes can alter the function of the mucins. Mucins are broadly divided into two groups, those that are secreted and those that are membrane bound. The major mucins present in the colorectum are MUC1, MUC2, MUC3, and MUC4. Trefoils are a group of small peptides that have an important role in the mucus layer. Three trefoils have been demonstrated so far. They seem to play a part in mucosal protection and in mucosal repair. They may help to stabilise the mucus layer by cross linking with mucins to aid formation of stable gels. Trefoils can be expressed in the ulcer associated cell lineage, a glandular structure that can occur in the inflamed mucosa. There seem to be differences in the expression of trefoils in the colon and the small bowel, which may imply different method of mucosal repair.

Glycosylation↗
PubMed1999

An investigation of the association of the factor V Leiden mutation and inflammatory bowel disease.

BACKGROUND: A thrombotic aetiology for inflammatory bowel disease (IBD) has been proposed as a result of its association with thrombo-embolic complications, smoking, the oral contraceptive pill and the response of ulcerative colitis (UC) patients to heparin. The factor V Leiden (FVL) mutation is the commonest inherited risk factor for thrombo-embolism. AIM: The aim of the study was to investigate the hypothesis that the pro-thrombotic state associated with the FVL mutation is involved in the aetiology of IBD. PATIENTS AND METHODS: A prospective cohort study of patients attending the Bristol Royal Infirmary IBD outpatient clinic was performed. Fifty-four patients with IBD (30 with Crohn's disease (CD) and 24 with UC) and 55 historical controls were screened for the presence of FVL using the activated protein C (APC) ratio. Abnormal APC ratios were confirmed to be due to FVL using a heteroduplex-based polymerase chain reaction (PCR) technique. RESULTS: Five patients had the FVL mutation, compared to two controls. One of the patients was homozygous. Two of the patients had CD and three UC. The differences between controls and IBD patients was significant when the allelic frequency of the FVL mutation in patients with UC was compared with controls, with a risk ratio of 2.27, but with limited data. CONCLUSION: There appears to be a weak association between FVL and UC. This association is not strong enough to imply a causal relationship, but may be responsible for some of the thrombo-embolic complications.

Activated Protein C Resistance↗
PubMed1999

Predicting therapeutic outcome in severe ulcerative colitis by measuring in vitro steroid sensitivity of proliferating peripheral blood lymphocytes.

BACKGROUND: Up to 29% of patients with severe ulcerative colitis (UC) fail to respond to steroid treatment and require surgery. Previous studies have failed to show a clear correlation between failure of steroid treatment in severe UC and measures of disease severity. The reasons for treatment failure therefore remain unknown. AIM: To investigate the hypothesis that patients with severe UC who fail to respond to steroid treatment have steroid resistant T lymphocytes. METHODS: Eighteen patients with severe UC were studied. After seven days' treatment with high dose intravenous steroids they were classified as complete responders (CR), incomplete responders (IR), or treatment failures (TF). Within 48 hours of admission blood was taken and the antiproliferative effect of dexamethasone on phytohaemagglutinin stimulated peripheral blood T lymphocytes was measured. Maximum dexamethasone induced inhibition of proliferation (I(max)) was measured. RESULTS: In vitro T lymphocyte steroid sensitivity of TF and IR patients was significantly less than that of CR patients. Both TF and 3/5 IR patients had an I(max) of less than 60%; all CR patients had an I(max) of greater than 60%. No significant correlation was seen between response to treatment and disease severity on admission. When in vitro T lymphocyte steroid sensitivity was remeasured three months later, there was no difference between the groups. CONCLUSIONS: Results suggest that T lymphocyte steroid resistance is an important factor in determining response to steroid treatment in patients with severe UC and may be more predictive of outcome than disease severity.

Adult↗
PubMed1999

Evidence of T cell receptor beta-chain patterns in inflammatory and noninflammatory bowel disease states.

T cell activation, as defined by expression of relevant cell surface molecules, such as the interleukin-2 receptor (CD25), is increased in many chronic relapsing diseases, including inflammatory bowel disease (IBD). These T cells are generally activated through contact of their clonotypic T cell receptor (TCR) with a peptide antigen presented by a major histocompatibility complex molecule. One of the putative antigenic contact sites for the TCR is the third complementarity determining region (CDR3) of the TCR beta-chain variable region (TCRBV). Therefore, analysis of the TCRBV CDR3 provides insight into the diversity of antigens encountered by a given T cell population. This study evaluated the TCRBV CDR3 usage of the activated intestinal lymphocytes from human subjects with IBD, diverticulitis (inflammatory control), and a normal tissue control. Public patterns, as demonstrated by shared TCRBV CDR3 amino acid sequences of activated intestinal T cell subpopulations, were observed. In particular, a public pattern of TCRBV22, a conserved valine in the fifth position, and use of TCRBJ2S1 or TCRBJ2S5 was present in three of four Crohn's disease subjects while not present in the ulcerative colitis subjects. However, the private patterns of TCRBV CDR3 region amino acid sequences were far more striking and easily demonstrated in all individuals studied, including a normal noninflammatory control. Thus we conclude that selective antigenic pressures are prevalent among an individual's activated intestinal lymphocytes.

Amino Acid Sequence↗
PubMed1998

An audit of the investigation and treatment of folic acid deficiency.

On the suspicion that folate deficiency was not being thoroughly investigated we conducted a retrospective study of management in a teaching hospital. Notes from 84 consecutive patients with low red cell folates (mean age 69.5 years, range 21-95, M:F 33:51) were reviewed for haemoglobin, mean cell volume, dietary history, alcohol consumption, drug history, relevant medical history, relevant investigations, treatment, repeat measurement of red cell folate and diagnosis of deficiency. In 52 (61.9%, mean age 72.9 years, range 33-95, M:F 21:51) no diagnosis was reached. In only 32 (38.1%, mean age 63.9 years, range 21-89, M:F 12:20) was a definitive diagnosis established: 5 had coeliac disease, 1 had Crohn's disease, 9 had drug-associated deficiency (4 methotrexate, 3 phenytoin, 1 trimethoprim and 1 valproate), 1 had combined variable immunodeficiency and 16 had dietary deficiency. In most cases of folic acid deficiency no attempt was made to establish aetiology. We recommend that younger patients without an obvious cause are investigated initially by dietary assessment and measurement of anti-endomysial antibody and by duodenal biopsy with small-bowel follow-through if clinically indicated.

Adult↗
PubMed1997

Analysis of human common bile duct-associated T cells: evidence for oligoclonality, T cell clonal persistence, and epithelial cell recognition.

The phenotype of T cells associated with the common bile duct (CBD) is unknown. We investigated the hypothesis that they behave like other intraepithelial lymphocytes (IEL). Thus, we sought to determine the phenotype, TCR repertoire, and epithelial recognition of T cells obtained during endoscopic retrograde cholangiopancreatography. Three subjects were studied: two with primary sclerosing cholangitis and one normal control. After establishing a short-term T cell line, cells were 1) stained with mAbs for flow cytometric analysis, 2) analyzed for TCRB chain transcript expression, and 3) used as effector cells for cytotoxicity and proliferation. Flow cytometry revealed that for all the subjects 98% of the T cells were TCR-alpha beta-positive. Immunohistology of the CBD showed that the epithelium and lamina propria contained significant numbers of CD3+ CD43+ CD45RO+ lymphocytes. Complementarity-determining region 3 length displays suggested that the CBD-derived lines were oligoclonal. This was confirmed by cloning and random sequencing of PCR amplification products using TCRBV region family-specific primers; TCRB chain sequences were reiterated in all transcripts analyzed. In one case, two expanded TCRB clones could be identified that were persistent in the bile duct over a 1-yr period. The CBD-derived lines were cytolytic in a redirected lysis assay and caused cytolysis of an intestinal epithelial cell line (Caco-2). This recognition was likely preferential for intestinal epithelial cells, since a CBD-derived line exhibited proliferation to two intestinal epithelial cell lines (HT-29 and Caco-2) but not three other lines (HepG2, human foreskin fibroblast, and KD). We conclude that the CBD contains IELs that share several characteristics with intestinal IELs.

Animals↗