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Biomedical subjects

R W Chapman

Publications and source records attributed to R W Chapman.

At least 19 recordsLinked to original sources
PubMed2006

Antinuclear antibodies giving the 'multiple nuclear dots' or the 'rim-like/membranous' patterns: diagnostic accuracy for primary biliary cirrhosis.

BACKGROUND: Serum antinuclear antibodies giving the 'multiple nuclear dots' or the 'rim-like/membranous' patterns are frequently detected by indirect immunofluorescence on HEp-2 cells in patients with primary biliary cirrhosis. AIM: To assess the accuracy of multiple nuclear dot and rim-like/membranous antinuclear antibodies for the diagnosis of primary biliary cirrhosis. METHODS: Sera from 4371 consecutive patients referred to our laboratory were analysed under code for antinuclear antibodies testing by indirect immunofluorescence on HEp-2 cells. RESULTS: Review of the clinical records of the 4371 patients allowed identification of 101 patients with antimitochondrial antibody-positive primary biliary cirrhosis and 22 with antimitochondrial antibody-negative variant. Multiple nuclear dot and/or rim-like/membranous patterns were found in 59 (1.3%) of the 4371 patients: 31 antimitochondrial antibody-positive primary biliary cirrhosis, 17 antimitochondrial antibody-negative primary biliary cirrhosis and 11 non-primary biliary cirrhosis. The specificity for primary biliary cirrhosis of both the antinuclear antibodies pattern was 99%. Positive predictive value and likelihood ratio for a positive test were 86% (95% CI: 72.7-94) and 221 (95% CI: 91.7-544) for multiple nuclear dot, 79% (95% CI: 62.2-90.1) and 132 (95% CI: 56.8-312.7) for rim-like/membranous, respectively. CONCLUSIONS: Multiple nuclear dot and rim-like/membranous antinuclear antibodies are rare findings. Their positivity strongly suggests the diagnosis of primary biliary cirrhosis, irrespective of antimitochondrial antibody status. The high specificity for primary biliary cirrhosis makes them a useful diagnostic tool especially in antimitochondrial antibody-negative patients.

Adult↗
PubMed2005

Review article: current management of primary sclerosing cholangitis.

The management of primary sclerosing cholangitis (PSC) is hindered by incomplete understanding of the pathogenesis of the disease and the lack of good prognostic models. Few large randomized controlled trials of drug therapy have been published. Best practice in the management of PSC is currently based therefore on careful interpretation of the available evidence, close observation of individual patients and clinical experience of the disease. Drug therapy is useful for alleviating symptoms. Ursodeoxycholic acid may slow progression of the disease and reduce the frequency of complications. Consensus is emerging on the issues of screening for the malignant complications of PSC and the indications for liver transplantation are becoming broader and encompassing the earliest stages of cholangiocarcinoma. In view of the rarity of the disease in the general population, large international collaborations to study PSC are necessary to provide clearer answers in areas of uncertainty, and these are now beginning to emerge.

Cholagogues and Choleretics↗
PubMed2005

Role of CXCR2 in cigarette smoke-induced lung inflammation.

It has been hypothesized that the destruction of lung tissue observed in smokers with chronic obstructive pulmonary disease and emphysema is mediated by neutrophils recruited to the lungs by smoke exposure. This study investigated the role of the chemokine receptor CXCR2 in mediating neutrophilic inflammation in the lungs of mice acutely exposed to cigarette smoke. Exposure to dilute mainstream cigarette smoke for 1 h, twice per day for 3 days, induced acute inflammation in the lungs of C57BL/6 mice, with increased neutrophils and the neutrophil chemotactic CXC chemokines macrophage inflammatory protein (MIP)-2 and KC. Treatment with SCH-N, an orally active small molecule inhibitor of CXCR2, reduced the influx of neutrophils into the bronchoalveolar lavage (BAL) fluid. Histological changes were seen, with drug treatment reducing perivascular inflammation and the number of tissue neutrophils. beta-Glucuronidase activity was reduced in the BAL fluid of mice treated with SCH-N, indicating that the reduction in neutrophils was associated with a reduction in tissue damaging enzymes. Interestingly, whereas MIP-2 and KC were significantly elevated in the BAL fluid of smoke exposed mice, they were further elevated in mice exposed to smoke and treated with drug. The increase in MIP-2 and KC with drug treatment may be due to the decrease in lung neutrophils that either are not present to bind these chemokines or fail to provide a feedback signal to other cells producing these chemokines. Overall, these results demonstrate that inhibiting CXCR2 reduces neutrophilic inflammation and associated lung tissue damage due to acute cigarette smoke exposure.

Acute Disease↗
PubMed2004

Tachykinin NK3-receptor deficiency does not inhibit pulmonary eosinophilia in allergic mice.

Tachykinins are important in the development of pulmonary inflammation in mice but the tachykinin receptor subtype mediating this response has not been defined. To elucidate the role of tachykinin NK3-receptors on allergen-induced pulmonary inflammation, studies were performed on ovalbumin (OVA) sensitized and challenged mice with genetic disruption of the tachykinin NK3-receptor (NK3-/-). Aerosol OVA (0.5%) challenge produced eosinophil influx into the bronchoalveolar lavage fluid and lung tissue, goblet cell hyperplasia and damage to the airway epithelium of both NK3-/- mice and in wild type control mice (NK3+/+). There was no difference in the magnitude of these allergic inflammatory pulmonary responses between NK3-/- and NK3+/+ mice. These results find no role for tachykinin NK3-receptors on the pulmonary eosinophilia and lung damage after antigen challenge in mice.

Animals↗
PubMed2004

The role of neutrophils in LPS-induced changes in pulmonary function in conscious rats.

We have previously reported on a model of lipopolysaccharide (LPS)-induced pulmonary inflammation in rats, where LPS-challenged animals develop a significant pulmonary neutrophilia and mucus hypersecretion. In the current studies, we utilized whole body plethysmography and computer assisted data acquisition to examine changes in pulmonary parameters, e.g. frequency (f) tidal volume and Penh as a measure of bronchoconstriction, due to LPS-challenge in conscious rats. Compared to saline challenge, LPS-challenged rats displayed a significant increase in (f) which began within 30 min, peaked by 2 h and remained elevated up to 24 h. Mirroring this increase in (f) was a decrease in the observed tidal volume of LPS-challenged rats. Additionally, compared to saline challenge, LPS-challenge provoked a significant and spontaneous bronchoconstriction, as measured by Penh, 2 h after challenge. In order to further understand these observed LPS-induced pulmonary changes, we utilized two classes of pulmonary obstructive disease standards, namely, bronchodilators and anti-inflammatory agents, and examined their ability to affect the spontaneous bronchoconstriction and the increase in (f) seen at two discrete time points, i.e. 2 and 24 h after LPS-challenge. While ineffective on either the 2 h increase in (f) or the LPS-induced inflammation, animals pretreated with salbutamol (10 mg/kg, p.o.) were protected from the increase in (f) seen at the 24 h time point after LPS-challenge. In contrast, when animals were pretreated with theophylline (10 mg/kg, p.o.) no effect on the LPS-induced pulmonary inflammation or increase in (f) was noted. Meanwhile, in animals pretreated with either betamethasone (3 mg/kg, p.o.) or SB207499 (10 mg/kg, p.o.), a PDE4 inhibitor, doses previously shown to block the LPS-induced neutrophilic inflammation, the persistent increase in (f) seen at 24 h was attenuated, but neither compound was able to attenuate either the increase in (f) or the spontaneous bronchoconstriction seen at 2 h. In summary, the intra-tracheal LPS-challenge of rats results in pulmonary inflammation and dysfunction, which is similar to that seen in COPD patients. We conclude that the early increase in (f) and bronchoconstriction are not dependent upon airway inflammation, but airway inflammation most likely contributes to the persistent increase in (f) seen at 24 h.

Animals↗
PubMed2004

Fatigue in patients with primary sclerosing cholangitis.

BACKGROUND: The occurrence of fatigue in primary sclerosing cholangitis (PSC), its impact on quality of life and the role of concomitant inflammatory bowel disease (IBD) and coexisting irritable bowel syndrome (IBS) is unexplored. METHODS: Ninety-three patients with PSC, associated with IBD in 80% of cases and 77 patients with IBD alone, were enrolled in the study. The patients completed the following questionnaires: the Fatigue Impact Scale (FIS), the Psychological General Well-Being Index (PGWB), the Gastrointestinal Symptom Rating Scale (GSRS), the Beck Depression Inventory (BDI) and diagnostic criteria for IBS. Questionnaire data were related to liver tests and the latest liver biopsy in the PSC patients. Two sex- and age matched controls from the general population (GP) were assigned to each PSC patient and these controls completed the FIS and the BDI. RESULTS: Total fatigue score did not differ significantly between patients with PSC and IBD alone. Median total fatigue score among GP subjects was 39 (13-72), which was higher than in PSC (19 (6-52) (P = 0.02)) and in IBD patients (19 (5-35) (P < 0.0001)). PGWB and GSRS scores did not differ between patients with PSC and IBD alone. Depression and general health (PGWB) were independent predictors for total fatigue score in PSC. No correlation was observed between fatigue in PSC and the severity of the liver disease. CONCLUSIONS: Fatigue in patients with PSC is related to depression but not to the severity of the liver disease. Both the PSC and IBD patients had lower total fatigue scores than subjects from the general population. This argues against fatigue as a specific symptom of PSC and IBD patients.

Adaptation, Psychological↗
PubMed2003

Inhibition of experimental acute pulmonary inflammation by pirfenidone.

Pirfenidone, a putative tumor necrosis factor-alpha (TNF-alpha) inhibitor, has recently gained recognition for its therapeutic use in the treatment of idiopathic pulmonary fibrosis. As pulmonary fibrosis may be the result of lung inflammatory processes, we examined the anti-inflammatory potential of pirfenidone in several models of acute pulmonary inflammation. In antigen-induced allergic paradigms, 24 h after antigen challenge, sensitized mice or guinea pigs develop a prominent pulmonary inflammation, reflected by a significant increase in the number of recoverable bronchoalveolar lavage (BAL) total cells and eosinophils. In both species, the pretreatment of animals with pirfenidone (10 and 30 mg/kg) resulted in a dose-dependent inhibition of the antigen-induced pulmonary inflammation, which was reflected by a significant decrease in the BAL eosinophils and total cells by the 30 mg/kg dose. In a non-allergic model of pulmonary inflammation, rats challenged with intratracheal LPS develop a significant increase in BAL neutrophils and total cells, along with significant increases in TNF-alpha and IL-6. Pretreatment with pirfenidone (3 and 30 mg/kg) showed a dose-dependent inhibition of the LPS-induced pulmonary inflammation, reflected by a significant decrease in the number of BAL total and neutrophilic cells at both the 3 and 30 mg/kg dose. However, pirfenidone had no effect on the peak BAL levels of TNF-alpha. In contrast, pirfenidone significantly inhibited BAL levels of IL-6. In summary, we have shown that pirfenidone can inhibit allergic and non-allergic inflammatory cell recruitment and that its pulmonary anti-inflammatory activity is independent of TNF-alpha inhibition.

Animals↗
PubMed2003

The effects of body fat on pulmonary function and gas exchange in cynomolgus monkeys.

Obesity adversely affects lung function in humans often reducing arterial blood oxygenation. To determine if obesity adversely affects lung function in cynomolgus monkeys, which is a species that is often used for pulmonary research, pulmonary mechanics, ventilation, functional residual capacity (FRC), and arterial blood gases were measured using spontaneous respiration and on mechanical ventilation with room air or 100% O(2). Body fat percentage was measured by dual energy X-ray absorption. Blood leptin levels were measured by radioimmune assay. Obese monkeys breathed faster with lower tidal volume, but pulmonary resistance and dynamic lung compliance did not change with body fat. FRC and blood leptin were, respectively, negatively and positively correlated with percent body fat. FRC correlated moderately with ventilatory parameters and strongly with arterial oxygen tension, alveolar-arterial oxygen difference and venous admixture. Therefore, obesity in cynomolgus monkeys had marked, deleterious effects on FRC, ventilation and arterial oxygenation. Obesity may be an important confounding variable in lung function studies in primates.

Animals↗
PubMed2002

Alverine citrate fails to relieve the symptoms of irritable bowel syndrome: results of a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Alverine citrate has been used in the treatment of irritable bowel syndrome for many years. AIMS: To compare the efficacy and safety of a new formulation of alverine citrate, a 120-mg capsule, with placebo given three times daily for 12 weeks. METHODS: One hundred and seven patients with irritable bowel syndrome were entered into this three-centre, double-blind, randomized, placebo-controlled, parallel group trial. The primary end-point was relief of abdominal pain indicated by improvement in the scores for severity and frequency. Secondary efficacy variables included scores for other clinical symptoms and for overall well-being. RESULTS: The severity and frequency of abdominal pain improved in 66% and 68% of patients treated with alverine citrate vs. 58% and 69% of the placebo group, but these differences were not significant. The mean percentage reduction in the scores for abdominal pain from baseline to the final assessment, although greater in the alverine citrate group (43.7%) compared with the placebo group (33.3%), was not statistically significant. CONCLUSIONS: Alverine citrate is no better than placebo at relieving the symptoms of irritable bowel syndrome. Future trials should be designed to take into account the high and persistent placebo response seen in this condition.

Abdomen↗
PubMed2002

Cigarette smoking, appendectomy, and tonsillectomy as risk factors for the development of primary sclerosing cholangitis: a case control study.

BACKGROUND AND AIMS: The strong clinical association between primary sclerosing cholangitis (PSC) and ulcerative colitis (UC) suggests common factors in their pathogenesis. Smoking, previous appendectomy, and tonsillectomy have been associated with a decreased risk of developing UC. In this study, our aim was to examine these risk factors in patients with PSC with and without underlying inflammatory bowel disease (IBD). METHODS: The smoking habits and history of previous appendectomy and/or tonsillectomy of 170 patients with PSC, 41 without underlying IBD, 170 patients with UC but normal liver function tests, and 170 age and sex matched community controls were obtained by questionnaire. RESULTS: A total of 112 PSC patients (66%) had never smoked compared with 66 controls (39%). Only 12 PSC patients (7%) were current smokers versus 43 controls (25%). The resultant odds ratio of having PSC was 0.17 (95% confidence interval (CI) 0.08-0.35) among current smokers and 0.33 (95% CI 0.21-0.52) among ever (former+current) smokers. Among former smokers, the odds of having PSC were also significantly decreased (odds ratio 0.45, 95% CI 0.26-0.73; p<0.05). In the subgroup of PSC patients without IBD, only 5% were current smokers versus 26% of matched controls, and never smokers were overrepresented (68% v 37%). The rate of previous appendectomy was similar in all three study groups (14%, 12%, and 13%) but the frequency of tonsillectomy was reduced in the PSC group (21% v 31%; p=0.05). CONCLUSION: PSC, like UC, is a disease of non-smokers as the odds of having PSC was significantly decreased among current and former smokers. The association between non-smoking and PSC was independent of whether the PSC patient had underlying IBD. Previous tonsillectomy but not appendectomy may also be associated with a decreased risk of PSC but this warrants further study.

Adult↗
PubMed2002

Patients with small duct primary sclerosing cholangitis have a favourable long term prognosis.

BACKGROUND: Patients with cholestatic liver function tests and histological features of primary sclerosing cholangitis (PSC) but a normal cholangiogram are considered to have small duct PSC. The natural history of this condition is unknown. METHODS: Thirty three patients with small duct PSC were identified among patients admitted for diagnostic workup of cholestatic liver function tests in one centre in the UK (Oxford) and one centre in Norway (Oslo). A total of 260 patients with large duct PSC were compared, and prognosis in terms of death, cholangiocarcinoma, biochemical features, histological features, and symptoms analysed. RESULTS: Mean age at diagnosis was 38 years and 39 years in small duct and large duct PSC, respectively. Mean follow up was 106 months in small duct and 105 months in large duct patients. Four patients originally considered to have small duct developed large duct PSC. Two of these underwent liver transplantation during follow up. Of the remainder who did not develop large duct PSC, two patients died during follow up: one of liver failure and the other of cardiac death unrelated to her liver disease. A total of 122 (47%) large duct patients either required liver transplantation (34 patients) or died (88 patients). Small duct patients had a significantly better survival compared with large duct patients. Among small duct patients, none developed cholangiocarcinoma compared with 28 of 260 (11%) large duct patients. CONCLUSIONS: Patients with small duct PSC seem to have a good prognosis in terms of survival and development of cholangiocarcinoma. Small duct PSC progresses to large duct PSC in a small proportion of patients.

Adult↗
PubMed2001

Tryptase-induced airway microvascular leakage in guinea pigs: involvement of tachykinins and leukotrienes.

Tryptase, a serine protease synthesized by and stored in mast cells, is implicated as an important mediator in the pathogenesis of airway inflammation. In this study, tryptase was evaluated for its ability to induce microvascular leakage into the airways of guinea pigs. Dose- and time-dependent increases in airway microvascular leakage were produced by intratracheal tryptase (0.3-3 microg). Intratracheal tryptase (3-30 microg) had no effect on airway tone as measured by pulmonary insufflation pressure. Tryptase-induced airway microvascular leakage was partially blocked by the tachykinin NK1 receptor antagonist CP 99994 [(+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine] and an inhibitor of leukotriene formation SCH 37224 (1-(1,2-dihydro-4-hydroxy-2-oxo-1-phenyl-1,8-naphthyridin-2-yl)pyrrolidinium, hydroxide inner salt). Neither CP 99994 nor SCH 37224 inhibited tryptase proteolytic activity in-vitro. Pretreatment of guinea pigs with histamine H1 receptor antagonists or a tachykinin NK2 receptor antagonist had no affect on the airway microvascular leakage induced by tryptase. It is speculated that tryptase may be important in the pathogenesis of airway inflammation, particularly in disorders that involve increased airway microvascular leakage such as asthma.

Analysis of Variance↗
PubMed2001

Th2 cytokines and asthma. The role of interleukin-5 in allergic eosinophilic disease.

Interleukin-5 is produced by a number of cell types, and is responsible for the maturation and release of eosinophils in the bone marrow. In humans, interleukin-5 is a very selective cytokine as a result of the restricted expression of the interleukin-5 receptor on eosinophils and basophils. Eosinophils are a prominent feature in the pulmonary inflammation that is associated with allergic airway diseases, suggesting that inhibition of interleukin-5 is a viable treatment. The present review addresses the data that relate interleukin-5 to pulmonary inflammation and function in animal models, and the use of neutralizing anti-interleukin-5 monoclonal antibodies for the treatment of asthma in humans.

Animals↗
PubMed2001

Five-year follow-up of patients with primary antibody deficiencies following an outbreak of acute hepatitis C.

This report is the 5-year follow-up of those 25 UK patients with primary antibody deficiencies infected with hepatitis C virus (HCV), type 1a, from one batch of contaminated anti-HCV-screened intravenous immunoglobulin in 1993-1994. Of these patients, who were reported previously (1, 2), 2 cleared HCV spontaneously, 18 received early interferon-alpha (IFN) treatment for 6 months, and 5 declined treatment or treatment was contraindicated. The clinical course of this cohort was followed prospectively using serial standardized questionnaires. Seven patients (54% of those who had completed therapy) had a sustained response (normal transaminase levels, negative serum HCV RNA) for 5 years posttreatment. Eight patients died: 3 from decompensated cirrhosis, 2 from pneumonia but with evidence of liver failure, and 3 from unrelated causes. One further patient developed decompensated cirrhosis but was successfully transplanted. Seven patients remain chronically infected; only 1 patient is symptomatic but 1 further patient has evidence of progressive fibrosis on liver histology. In conclusion, within 5 years, rapid end-stage HCV liver disease has been seen in 6/25 (24%) patients. Seven patients, (54% of those fully treated) remain well after treatment, making 9/25 (36% of the cohort) clear of virus after 5 years. Those who completed early treatment with IFN had a relatively high sustained response rate compared to previous studies in both immunodeficient and immunocompetent patients.

Acute Disease↗