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R W Chapman

Publications and source records attributed to R W Chapman.

At least 37 records · Page 2Linked to original sources
PubMed2001

Effect of tachykinins on airway function in cynomolgus monkeys.

Tachykinins have been implicated as important mediators of asthma. This study used neurokinin A (NKA) and substance P (SP) to evaluate the effect of tachykinins on airway mechanics in cynomolgus monkeys. NK(1)-(CP 99,994) and NK(2)-(SR 48968) receptor antagonists were used to evaluate the role of NK(1)and NK(2)receptors on responses to NKA and SP. Lung resistance (R(L)) and dynamic lung compliance (C(Dyn)) were measured in anesthetized, mechanically ventilated cynomolgus monkeys following aerosol or intravenous challenge with NKA, SP or the standard bronchoconstrictor, histamine. Inhaled NKA or SP had variable effects on R(L)and C(Dyn)whereas aerosolized histamine (0.01-1 mg/ml) dose-dependently increased R(L)and decreased C(Dyn). Intravenous NKA (1-100 microg/kg), SP (1-30 microg/kg) or histamine (1-100 microg/kg) increased R(L)and decreased C(Dyn). Pretreatment with SR 48968 (0.1 and 1 mg/kg, i.v.) blocked bronchoconstrictor responses to i.v. NKA, whereas CP 99,994 (0.1 and 1 mg/kg, i.v.) was without effect. Bronchoconstrictor responses to i.v. SP were partially blocked by SR 48968 and CP 99,994. In conclusion, both NKA and SP produce bronchonconstriction in cynomolgus monkeys and this effect is more pronounced when they are given by the iv route. Furthermore, both NK(1)and NK(2)receptors are involved in the bronchonconstrictor response to exogenously administered tachykinins in cynomolgus monkeys.

Administration, Inhalation↗
PubMed2001

Bronchoconstrictor reactivity to NKA in allergic dogs: a comparison to histamine and methacholine.

Airway hyperresponsiveness to neurokinin A (NKA) occurs in inflammatory airway diseases like asthma. In this study, bronchoconstrictor reactivity to NKA was measured in beagle dogs neonatally sensitized to and challenged with ragweed. Comparisons were made to histamine and methacholine. Lung resistance (R(L)) and dynamic lung compliance (C(Dyn)) were measured in anesthetized, spontaneously breathing dogs before and after aerosol challenge with NKA, histamine or methacholine. The concentration of these agents increasing R(L)by 25% above baseline (PC(25)) was calculated before and 24 h after aerosolized ragweed challenge. Before ragweed, the bronchoconstrictor reactivity to NKA was four-fold higher in ragweed-sensitized dogs (PC(25)=0.036+/-0.006%) compared to non-sensitized controls (PC(25)=0.177+/-0.030%, P<0.05). On the other hand, there was no difference in the bronchoconstrictor reactivity to histamine or methacholine between these two groups. Twenty-four hours after ragweed challenge to sensitized dogs, NKA reactivity was unchanged from pre-ragweed values but histamine and methacholine reactivity was increased by 2-3-fold. These results demonstrate airway hyperresponsiveness to NKA, histamine and methacholine in allergic beagle dogs although hyperresponsiveness to NKA exists in these allergic dogs before an antigen challenge. This animal model may prove to be useful to evaluate the role of tachykinins in hyperractive airway diseases.

Administration, Inhalation↗
PubMed2001

Immune gene discovery by expressed sequence tag analysis of hemocytes and hepatopancreas in the Pacific White Shrimp, Litopenaeus vannamei, and the Atlantic White Shrimp, L. setiferus.

A pilot program was undertaken in immune gene discovery in two sister species of litopenaeid shrimp, the Pacific white shrimp, Litopenaeus vannamei and the Atlantic white shrimp, L. setiferus. RNA from the hemocytes and hepatopancreas of single individuals from each species was recovered, 4 cDNA libraries (one from each tissue/species) were made by a PCR-based method and a total of approximately 2045 randomly selected clones were sequenced. A total of 268 expressed sequence tags (ESTs) were found that corresponded to 44 immune function genes. The most common immune-function ESTs (172) were antimicrobial peptides, which were restricted to the hemocyte libraries. Lectins were the largest group of immune-function ESTs found in the hepatopancreas. Analysis of these libraries indicates that EST approaches are effective for immune gene discovery in shrimp and that the diversity of these PCR-generated libraries would support full-scale EST collection.

Animals↗
PubMed2001

Primary sclerosing cholangitis associated with rheumatoid arthritis and HLA DR4: is the association a marker of patients with progressive liver disease?

In four cases we describe the unique association of primary sclerosing cholangitis (PSC) and rheumatoid arthritis (RA). In three of the cases the liver disease was unusually progressive, proceeding to cirrhosis in 14, 18 and 48 months from diagnosis. The three cases with progressive liver disease and ulcerative colitis were all HLA type DR4. The fourth patient also suffered from coeliac disease in addition to PSC and RA and has remained asymptomatic over 7 years of follow-up. RA in association with PSC may serve as a clinical marker of patients at high risk of progression to cirrhosis who need to be kept under particularly close observation. In addition, PSC needs to be considered in the differential diagnosis of all patients with RA and cholestatic liver function tests. This is especially important given the link between PSC and an increased risk of colonic carcinoma, and thus the need for surveillance colonoscopy.

Adult↗
PubMed2001

Wilson's disease presenting with rapidly progressive visual loss: another neurologic manifestation of Wilson's disease?

Wilson's disease (WD) is a rare autosomal recessive disorder of copper metabolism resulting in copper-induced tissue damage that primarily involves the liver and central nervous system. The neurologic manifestations of WD almost universally involve a derangement of basal ganglia function or psychiatric disturbance. We report the case of a 46-year-old man presenting with end-stage liver disease caused by WD who had associated rapidly progressive optic neuropathy. We also discuss the possible association between the two conditions.

Hepatolenticular Degeneration↗
PubMed2001

A functional polymorphism of the stromelysin gene (MMP-3) influences susceptibility to primary sclerosing cholangitis.

BACKGROUND AND AIMS: We have investigated the influence of a biallelic polymorphism of the promoter region of stromelysin (matrix metalloproteinase 3) on susceptibility to primary sclerosing cholangitis (PSC). The 5A allele is associated with increased transcription, compared with wild-type (6A). METHODS: An allelic association study was performed: in stage 1, 52 PSC patients (43 with inflammatory bowel disease [IBD]) and 99 healthy subjects (HS) were genotyped. In stage 2, 59 PSC patients (49 IBD), 84 patients with uncomplicated ulcerative colitis, and 72 HS were genotyped. RESULTS: In stage 1, 5A carriage rate (90.4% vs. 72.7%; P = 0.012) and 5A allelic frequency (65.4% vs. 48.5%; P = 0.005) were increased, and 6A homozygosity was reduced in PSC (9.6% vs. 27.3%; P = 0.012). In stage 2, 5A allelic carriage was increased in PSC (93.2% vs. 76.4% in HS; P = 0.0092) and 6A homozygosity was reduced (6.8% vs. 23.8% in HS; P = 0.0092). Portal hypertension was associated with 5A homozygosity in PSC (P = 0.035; odds ratio [OR], 3.88). In the combined data set, 5A allelic frequencies (63.5% vs. 49.4%; P = 0.001; OR, 1.78) and 5A carriage rates (91.9% vs. 74.2%; P = 0.0002; OR, 3.92) were increased, and 6A homozygosity was reduced in PSC (8.1% vs. 25.7%; P = 0.0002; OR, 0.25). Overall, portal hypertension was associated with 5A homozygosity (P = 0.0192; OR, 3.12). CONCLUSIONS: Stromelysin polymorphism may influence susceptibility and disease progression in PSC.

Adult↗
PubMed2001

A preliminary trial of high-dose ursodeoxycholic acid in primary sclerosing cholangitis.

BACKGROUND & AIMS: Ursodeoxycholic acid (UDCA) is used for the treatment of cholestatic liver diseases including primary biliary cirrhosis (PBC) for which it has a positive effect on laboratory values, may delay the development of liver failure and prolong the transplant-free disease period. Standard doses of UDCA (8-15 mg/kg daily) have been shown to be ineffective in the treatment of primary sclerosing cholangitis (PSC). We report on the findings (clinical, biochemical, histological, and cholangiographic) and side effects of a 2-year double-blind placebo-controlled preliminary study of high-dose UDCA in PSC patients. METHODS: Twenty-six patients with PSC were randomized to high-dose (20 mg/kg daily) UDCA or placebo. Cholangiography and liver biopsy were performed at entry and after 2 years. Symptoms, clinical signs, and liver biochemical tests were recorded at 3 monthly intervals. RESULTS: High-dose UDCA did not influence symptoms, but there was a significant improvement in liver biochemistry (serum alkaline phosphatase, P = 0.03; gamma-glutamyl transferase, P = 0.01) and a significant reduction in progression in cholangiographic appearances (P = 0.015) and liver fibrosis as assessed by disease staging (P = 0.05). In the treatment group, a significant increase in total bile acids and saturation with UDCA >70% confirmed patient compliance. No significant side effects were reported. CONCLUSIONS: High-dose UDCA may be of clinical benefit in PSC, but trials with a larger number of participants and of longer duration are required to establish whether the effect of high-dose UDCA on liver biochemistry, histology, and cholangiography in patients with PSC is translated into improved long-term survival.

Adult↗
PubMed2001

Sclerosing cholangitis.

Primary sclerosing cholangitis is a chronic cholestatic disease that may have an autoimmune basis. Most patients have a circulating antineutrophil cytoplasmic antibody that appears to be targeted against a 50-kD nuclear envelope protein. The clinical applications of this antibody have not yet been defined. Other autoantibodies directed against antigens, such as cathepsin G, elastase, and anticardiolipin, may also be detected in some patients. It is suggested that primary sclerosing cholangitis may have a bacterial cause. Helicobacter gene sequences have been detected in liver tissues in primary sclerosing cholangitis. The role of Helicobacter spp and other bacteria in the etiopathogenesis of primary sclerosing cholangitis remains to be determined. Primary sclerosing cholangitis may overlap with autoimmune hepatitis in some cases, although the real prevalence of this association remains to be determined. Many prognostic models have been created, but they lack cross-validation, and their clinical usefulness remains limited. Endoscopic retrograde cholangiography remains the gold standard for diagnosis, but magnetic resonance imaging may be a viable alternative in many cases. Clinical trials with cladibrine, pentoxifylline, and budesonide have failed to demonstrate benefits. Orthotopic liver transplantation remains the only effective treatment.

Journal Article↗
PubMed2001

Evaluation of serologic disease markers in a population-based cohort of patients with ulcerative colitis and Crohn's disease.

BACKGROUND: The sensitivity of assays for antineutrophil cytoplasmic antibody (ANCA), anti-Saccharomyces cerevisiae antibody (ASCA), and antipancreatic antibody (PAB) in different laboratories is unknown. Likewise, the sensitivity and diagnostic usefulness of these assays in patients with inflammatory bowel disease (IBD) in the community is unknown. METHODS: An incidence cohort of 290 patients with IBD were offered participation in the study. Blood was obtained from 162 patients (56%) (83 with ulcerative colitis, 79 with Crohn's disease) who agreed to participate. ANCA was determined in five laboratories. ASCA in two laboratories, and PAB in one laboratory. RESULTS: In ulcerative colitis, the sensitivity of ANCA determined in five laboratories varied widely, ranging from 0-63%. In Crohn's disease, the sensitivity of ASCA determined in two laboratories did not vary significantly, ranging from 39-44%; and the sensitivity of PAB determined in one laboratory was 15%. The optimal diagnostic usefulness was obtained from one laboratory where the positive predictive values of a positive ANCA assay combined with a negative ASCA assay for ulcerative colitis, and a negative ANCA combined with a positive ASCA for Crohn's disease, were 75% and 86%, respectively. CONCLUSIONS: In patients with IBD, the sensitivity of ANCA varied widely in different laboratories, whereas the prevalence of ASCA was similar. The positive predictive values of the ANCA assay combined with the ASCA assay for ulcerative colitis and Crohn's disease are high enough to be clinically useful.

Adolescent↗
PubMed2001

Association of the tumour necrosis factor alpha -308 but not the interleukin 10 -627 promoter polymorphism with genetic susceptibility to primary sclerosing cholangitis.

BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown aetiology. Abnormalities in immune regulation and genetic associations suggest that PSC is an immune mediated disease. Several polymorphisms within the tumour necrosis factor alpha (TNF-alpha) and interleukin 10 (IL-10) promoter genes have been described which influence expression of these cytokines. This study examines the possible association between polymorphisms at the -308 and -627 positions in the TNF-alpha and IL-10 promoter genes, respectively, and susceptibility to PSC. METHODS: TNF-alpha -308 genotypes were studied by polymerase chain reaction (PCR) in 160 PSC patients from Norway and the UK compared with 145 ethnically matched controls. IL-10 -627 genotypes were studied by PCR in 90 PSC patients compared with 84 ethnically matched controls. RESULTS: A total of 16% of Norwegian PSC patients and 12% of British PSC patients were homozygous for the TNF2 allele compared with 3% and 6% of respective controls. The TNF2 allele was present in 60% of PSC patients versus 30% of controls (OR(combined data)=3.2 (95% confidence intervals (CI) 1.8--4.5); p(corr)=10(-5)). The association between the TNF2 allele and susceptibility to PSC was independent of the presence of concurrent inflammatory bowel disease (IBD) in the PSC patients; 61% of PSC patients without IBD had TNF2 compared with 30% of controls (OR(combined data)=3.2 (95% CI 1.2--9.0); p(corr)=0.006 ). There was no difference in the -627 IL-10 polymorphism distributions between patients and controls in either population. The increase in TNF2 allele in PSC patients only occurs in the presence of DRB1*0301 (DR3) and B8. In the combined population data, DRB1*0301 showed a stronger association with susceptibility to PSC than both the TNF2 and B8 alleles (OR(combined data)=3.8, p(corr)=10(-6) v OR(combined data)=3.2, p(corr)=10(-5) v OR(combined data )=3.41, p(corr)=10(-4), respectively). CONCLUSIONS: This study identified a significant association between possession of the TNF2 allele, a G-->A substitution at position -308 in the TNF-alpha promoter, and susceptibility to PSC. This association was secondary to the association of PSC with the A1-B8-DRB1*0301-DQA1*0501-DQB1*0201 haplotype. No association was found between the IL-10 -627 promoter polymorphism and PSC.

Adult↗
PubMed2001

Modern management of oesophageal varices.

Haemorrhage from oesophageal varices is a life threatening emergency with a mortality rate in the order of 30%-50%. In the last three decades there have been many advances in the treatment and prevention of variceal bleeding. Over recent years the introduction of new pharmaceutical agents that reduce portal pressure, endoscopic variceal ligation, transjugular intrahepatic portosystemic shunt, and the availability of liver transplantation have further increased the therapeutic options available to the physician treating this disorder. This article reviews the literature regarding therapies available in the treatment of haemorrhage from oesophageal varices and provides guidelines to aid the physicians in clinical decision making.

Algorithms↗
PubMed2001

Effect of anti-mIL-9 antibody on the development of pulmonary inflammation and airway hyperresponsiveness in allergic mice.

Interleukin (IL)-9 is a T-cell-derived cytokine with pleiotropic activities on T helper 2 cells, B cells, and mast cells. IL-9 may therefore play an important role in the development of allergic pulmonary inflammatory diseases. In this study, an antimouse IL-9 (anti-mIL-9) antibody (Ab) was evaluated against pulmonary eosinophilia, histopathologic changes in lung tissues, serum immunoglobulin (Ig) E levels, and airway hyperresponsiveness (AHR) to methacholine in mice sensitized and challenged with ovalbumin (OVA). Additionally, steady-state levels of IL-4, IL-5, IL-13, and interferon-gamma messenger RNA (mRNA) in the lungs were measured. The anti-mIL-9 Ab (200 microg/mouse, intraperitoneally) was given as either four doses during the sensitization period or as a single dose before OVA challenge. Sensitized mice challenged with OVA displayed marked pulmonary eosinophilia, epithelial damage, and goblet cell hyperplasia. OVA challenge also increased mRNA levels of IL-4, IL-5, and IL-13 in the lungs. AHR was also increased twofold in sensitized, challenged mice. Treatment of sensitized, challenged mice with four doses of anti-mIL-9 Ab significantly reduced pulmonary eosinophilia, serum IgE levels, goblet cell hyperplasia, airway epithelial damage, and AHR, but had no effect on IL-4, IL-5, and IL-13 mRNA levels in the lungs. A single dose of the antibody was ineffective on all measures. These results indicate that an antibody to mIL-9 inhibits the development of allergic pulmonary inflammation and AHR in mice.

Animals↗
PubMed2000

Liver transplantation for primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown aetiology that is progressive in most symptomatic patients, advancing toward cirrhosis and liver failure. Liver transplantation is the only therapeutic option for patients with end stage liver disease resulting from this disorder. The results of transplantation for PSC are excellent with one-year survival rates of 90-97% and five-year survival rates of 80-85%, but are closely related to pre-transplant Child-Pugh stage. Recurrence of PSC after liver transplantation is common, occurring in up to 20% of patients, but it appears to have little effect on patient survival, as survival of patients with recurrent PSC is similar to that of those without evidence of recurrence. Cholangiocarcinoma is a catastrophic complication of PSC and as yet no reliable screening method exists. The results of liver transplantation for patients with clinically apparent cholangiocarcinoma are extremely poor, however in patients in whom a microscopic tumour is detected in the explanted liver, survival is similar to those transplanted with PSC without cholangiocarcinoma. Activity of inflammatory bowel disease (IBD) appears to be more severe after transplantation, especially in units where steroid immunosuppression is withdrawn early. Colon cancer appears within the first few years after transplantation in approximately 7% of patients with IBD who are transplanted for PSC. Annual colonoscopy in this population seems prudent.

Bile Duct Neoplasms↗
PubMed2000

Inhibition of pulmonary eosinophilia and airway hyperresponsiveness in allergic mice by rolipram: involvement of endogenously released corticosterone and catecholamines.

This study investigates the role of adrenal-derived catecholamines and corticosterone on the inhibition by rolipram, a phosphodiesterase (PDE)-4 inhibitor, of pulmonary eosinophilia and airway hyperresponsiveness (AHR) in allergic mice. The following experimental groups were studied in mice sensitized and challenged with ovalbumin (OVA): normal, adrenalectomized, propranolol (beta-adrenoceptor antagonist) and metyrapone (corticosterone synthesis inhibitor) treated. These interventions were studied both in the absence and in the presence of rolipram. Eosinophil numbers in the bronchoalveolar lavage (BAL) and AHR to methacholine were measured 24 h after OVA challenge. Treatment of sensitized mice with rolipram (0.3 - 10 mg kg(-1), p.o.), inhibited pulmonary eosinophilia and the AHR to methacholine in OVA-challenged mice. Adrenalectomy increased the number of eosinophils in the BAL of OVA-challenged mice but had no effect on AHR to methacholine. Adrenalectomy attenuated both the rolipram-induced inhibition of BAL eosinophilia and AHR to methacholine in OVA challenged mice. Propranolol (10 mg kg(-1), p.o.) had no effect on the inhibition of eosinophilia by rolipram but attenuated the inhibition of AHR to methacholine in OVA challenged mice. On the other hand, metyrapone (10 mg kg(-1), p.o.) attenuated the inhibition of eosinophilia by rolipram but had no effect on the inhibition of AHR to methacholine in OVA challenged mice. Metyrapone-treatment alone increased the number of eosinophils in the BAL of OVA-challenged mice. These results identify an important role for adrenal-derived catecholamines and corticosterone on the inhibition of pulmonary eosinophilia and AHR by rolipram in allergic mice.

Animals↗
PubMed2000

Sclerosing cholangitis.

Primary sclerosing cholangitis is a chronic cholestatic liver disease of unknown etiology. Immunogenetic factors are considered important in its pathogenesis. The genetic susceptibility to primary sclerosing cholangitis is associated, in part, with the HLA HLA-DRB1, DQA1, DQB1 haplotype. Liver histology in primary sclerosing cholangitis is characterized by a portal inflammatory infiltrate mostly composed of memory T cells. Many patients eventually will develop cholangiocarcinoma, and inactivation of the p16 tumor-suppressor gene might be involved in neoplastic transformation. Alcohol consumption might be a risk factor for cholangiocarcinoma, and, in some patients, elevation of serum CA19-9 marks the neoplastic transformation. To date, no medical treatment has been proven effective. Endoscopic therapy might be useful in some patients, but controlled studies are lacking. Liver transplantation remains the only effective treatment. Posttransplant survival and quality of life are continuously improving despite the fact that the disease may recur in some patients after transplantation. Nevertheless, patient selection and timing of indication for liver transplantation remain uncertain.

Journal Article↗