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Biomedical subjects

R W Chapman

Publications and source records attributed to R W Chapman.

At least 55 records · Page 3Linked to original sources
PubMed2000

Simultaneous occurrence of focal nodular hyperplasia and primary sclerosing cholangitis in a young female.

We report the case of a 22-year-old female with primary sclerosing cholangitis who was found, during hepatic imaging, to have a large liver mass. Imaging techniques and histological examination confirmed the mass to be focal nodular hyperplasia. A review of the literature indicates that the simultaneous occurrence of these two hepatic pathologies is unique. The differential diagnosis of hepatic masses in primary sclerosing cholangitis is discussed. Focal nodular hyperplasia needs to be included in the differential diagnosis of hepatic lesions in primary sclerosing cholangitis.

Adult↗
PubMed1999

Immune selection and genetic sequence variation in core and envelope regions of hepatitis C virus.

How Hepatitis C Virus (HCV) causes persistent infection is unknown. One hypothesis is that HCV evades the host immune response through mutation in immune epitopes. We have investigated mutations in the HCV genome to see if they cluster within immune epitopes; and we have studied the effect of antibody deficiency on mutation rates. We studied patients with chronic hepatitis C, 3 with antibody deficiency and 3 with normal immunity. Regions of the core and envelope genes of HCV, encoding cytotoxic (CTL), and B cell epitopes were sequenced at 2 time points, 2 years apart. The diversity of quasispecies increased with time. The HCV genetic mutation rate was higher than previously predicted. The cryptic nucleotide mutation rate in core was similar to that observed in envelope, suggesting that the error rate of the HCV RNA polymerase is similar in both regions. In contrast, the coding mutation rate was decreased in core and increased in envelope. No genetic mutation was seen in any of the core CTL epitopes despite detectable cellular responses. All patients had mutations within a previously described envelope CTL epitope but did not exhibit immune responses to either index or mutated peptides. There was no difference in mutation rates in any cellular or humoral epitopes between patients with antibody deficiency and normal immunity. Thus we have found no evidence that mutations were selected by T-lymphocytes or antibodies. These findings implicate alternative virus-host interactions in the selection of HCV mutations.

Adult↗
PubMed1999

Combined NK(1)and NK(2)receptor antagonists on the bronchoconstrictor response to NKA in dogs.

The major pulmonary effects of tachykinins, including bronchoconstriction, are mediated by activation of both neurokinin-1 (NK(1)) and neurokinin-2 (NK(2)) receptors. In guinea-pigs NK(1)and NK(2)receptor antagonists interact synergistically to inhibit the bronchoconstriction induced by neurokinin-A (NKA). However, the effect of combined NK(1)and NK(2)receptor antagonists on tachykinin-induced bronchoconstriction in most other species has not been evaluated. In this study, the interactive effects of CP 99994, an NK(1)receptor antagonist and SR 48968, an NK(2)receptor antagonist, were evaluated against NKA-induced brochospasm in dogs. Pulmonary resistance (R(L)) and dynamic lung compliance (C(Dyn)) were measured in anesthetized, spontaneously breathing dogs to measure the bronchoconstrictor response to aerosolized NKA (1%). Mean arterial blood pressure (MAP) and minute volume (MV) were also measured to assess the NK(1)receptor mediated cardiorespiratory response to substance P (100 ng/kg, iv). Pretreatment with SR 48968 (0.3-3 mg/kg, po) in the presence of an NK(1)antagonist dose of CP 99994 (10 mg/kg, po) inhibited the NKA-induced bronchospasm. However, the inhibition produced by SR 48968 plus CP 99994 was no greater than that previously shown for SR 48968 alone. Therefore, dual NK(1)/NK(2)receptor antagonists do not interact synergistically against NKA-induced bronchospasm in dogs. This may relate to the fact that dogs, like humans, have the NK(2)receptor as the predominant receptor subtype producing bronchoconstriction.

Animals↗
PubMed1999

Evaluation of omeprazole as a cost-effective diagnostic test for gastro-oesophageal reflux disease.

BACKGROUND: There is a need for a simple, therapeutic test that is of diagnostic value and can also provide rapid symptom relief in patients who present with classic, mild symptoms suggestive of gastro-oesophageal reflux disease (GERD), when the diagnosis is based on symptom assessment alone. AIM: To assess the diagnostic value of a therapeutic trial of omeprazole 40 mg in a dyspeptic population. METHODS: A total of 90 patients with symptoms suggestive of GERD entered the study. Patients underwent endoscopy and ambulatory oesophageal pH monitoring for 18-24 h. Patients then received omeprazole 40 mg o.m. for 2 weeks. RESULTS: There was a significant correlation between the diagnoses obtained from a trial of omeprazole and the diagnoses obtained from pH monitoring (P < 0. 05). There was no significant correlation between the diagnoses obtained from endoscopy and those obtained from pH monitoring. Both omeprazole and endoscopy were compared to pH monitoring as the 'gold standard' for the diagnosis of GERD and the cost per correct diagnosis with omeprazole was pound47 (95% CI: pound40- pound59) compared to pound480 (95% CI: pound396- pound608) with endoscopy. There was a complete absence of acid-related symptoms in the majority (59%) of patients after 3 days of omeprazole 40 mg therapy and, after 2 weeks, 82% of patients had experienced an improvement in overall symptoms ( 1 grade). CONCLUSIONS: We conclude that omeprazole can be used as a clinically effective tool in the initial management of GERD and that it is of diagnostic value in patients who present with typical symptoms, such as heartburn, when the diagnosis is based on symptom assessment alone.

Adolescent↗
PubMed1999

Effect of Sch 55700, a humanized monoclonal antibody to human interleukin-5, on eosinophilic responses and bronchial hyperreactivity.

This report describes the development and the biology of Sch 55700, a humanized monoclonal antibody to human IL-5 (hIL-5). Sch 55700 was synthesized using CDR (complementarity determining regions) grafting technology by incorporating the antigen recognition sites for hIL-5 onto consensus regions of a human IgG4 framework. In vitro, Sch 55700 displays high affinity (Kd = 20 pmol/l) binding to hIL-5, inhibits the binding of hIL-5 to Ba/F3 cells (IC50 = 0.5 nmol/l) and blocks IL-5 mediated proliferation of human erythroleukemic TF-1 cells. In allergic mice, Sch 55700 (0.1-10 mg/kg, i.p. or i.m.) inhibits the influx of eosinophils in the lungs, demonstrates long duration of activity and the anti-inflammatory activity of this compound is additive with oral prednisolone. In allergic guinea pigs, Sch 55700 (0.03-30 mg/kg i.p.) inhibits both the pulmonary eosinophilia and airway hyperresponsiveness and at 30 mg/kg, i.p. inhibited allergic, but not histamine-induced bronchoconstriction. In allergic rabbits, Sch 55700 blocks cutaneous eosinophilia. Sch 55700 (0.1-1 mg/kg i.p.) also blocks the pulmonary eosinophilia and neutrophilia caused by tracheal injection of hIL-5 in guinea pigs. In allergic cynomolgus monkeys, a single dose of Sch 55700 (0.3 mg/kg i.v.) blocks the pulmonary eosinophilia caused by antigen challenge for up to six months. Sch 55700 is, therefore, a potent antibody against IL-5 in vitro and in a variety of species in vivo that could be used to establish the role of IL-5 in human eosinophilic diseases such as asthma.

Animals↗
PubMed1999

Sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease that progresses to death as a result of liver failure or cholangiocarcinoma. Susceptibility to PSC is associated with the HLA A1-B8-DR3 haplotype, and new associations with HLA C and tumor necrosis factor genes have been detected. A circulating antineutrophil cytoplasmic antibody is found in many patients with PSC, but its antigen or antigens have not been identified. Some studies suggest that this antigen may be an anti-nuclear membrane protein rather than cytoplasmic. Diagnosis of PSC is based on endoscopic retrograde cholangiography, but magnetic resonance cholangiography is a promising noninvasive alternative. Medical treatment remains elusive. In highly selected patients, endoscopic or even surgical treatment can be tried. Orthotopic liver transplantation remains the only effective therapy, but inflammatory bowel disease may run a more aggressive clinical course after this procedure. Sclerosing cholangitis may recur after transplantation, but this has had no clinical implications to date.

Journal Article↗
PubMed1999

Influence of central antitussive drugs on the cough motor pattern.

The present study was conducted to determine the effects of administration of centrally active antitussive drugs on the cough motor pattern. Electromyograms of diaphragm and rectus abdominis muscles were recorded in anesthetized, spontaneously breathing cats. Cough was produced by mechanical stimulation of the intrathoracic trachea. Centrally acting drugs administered included codeine, morphine, dextromethorphan, baclofen, CP-99,994, and SR-48,968. Intravertebral artery administration of all drugs reduced cough number (number of coughs per stimulus trial) and rectus abdominis burst amplitude in a dose-dependent manner. Codeine, dextromethorphan, CP-99,994, SR-48,968, and baclofen had no effect on cough cycle timing (CTtot) or diaphragm amplitude during cough, even at doses that inhibited cough number by 80-90%. Morphine lengthened CTtot and inhibited diaphragm amplitude during cough, but these effects were not dose dependent. Only CP-99,994 altered the eupneic respiratory pattern. Central antitussive drugs primarily suppress cough by inhibition of expiratory motor drive and cough number. CTtot and inspiratory motor drive are relatively insensitive to the effects of these drugs. CTtot can be controlled independently from cough number.

Animals↗
PubMed1999

Eotaxin and nitric oxide production as markers of inflammation in allergic cynomolgus monkeys.

BACKGROUND: Cynomolgus monkeys have a natural hypersensitivity to Ascaris suum antigen. Inhalation of antigen produces immediate and delayed allergic reactions and an influx of inflammatory cells into the lungs. This study investigated the production of nitric oxide (NO) and the chemokine eotaxin during this allergic response. The effect of bronchoscopy alone on lung inflammatory cells was also investigated along with the time course of the eosinophil influx into the lung. METHODS: Allergic cynomolgus monkeys were challenged with antigen. Bronchoalveolar lavage (BAL) was performed before and after challenge, and end-tidal NO was measured before and 24 h after challenge. Eotaxin was measured in the BAL fluid 6, 24 and 72 h after challenge. One group of animals was treated with dexamethasone before challenge to block the influx of cells into the lung. RESULTS: BLA alone induced an influx of neutrophils, but not eosinophils, into the lung 24 h later. A single antigen challenge produced a marked increase in BAL eosinophils that was apparent at 6 h but increased at 72 h after challenge. The increase at 6 h was largely blocked by dexamethasone. Three antigen challenges produced elevated BAL eosinophil levels that persisted for at least 8 weeks. Eotaxin levels rose dramatically 6 h after challenge and remained the same after 24 h. By 72 h, the eotaxin levels had returned to baseline. The increase in eotaxin at 6 h was nonsignificantly reduced by dexamethasone. Exhaled NO levels doubled 24 h after challenge and were not affected by dexamethasone. CONCLUSIONS: Eotaxin and NO production were increased after airway challenge in allergic monkeys. The rise in NO was not blocked by dexamethasone. The effects of bronchoscopy on the BAL can be avoided by using alternate lungs on consecutive occasions. Eosinophils persist in the BAL for many weeks after antigen challenge.

Animals↗
PubMed1999

Effects of chronic anti-interleukin-5 monoclonal antibody treatment in a murine model of pulmonary inflammation.

The maturation of eosinophils in bone marrow, their migration to pulmonary tissue, and their subsequent degranulation and release of toxic granule proteins contributes to the pathophysiology observed in asthma. Interleukin-5 (IL-5) is essential for these processes to occur. Therefore, much emphasis has been placed on attempts to inhibit the production or activity of IL-5 in order to attenuate the inflammatory aspect of asthma. In this report, the immunological consequences of long-term exposure to an antibody recognizing IL-5 (TRFK-5) were studied in a murine pulmonary inflammation model. A single dose of TRFK-5 (1 mg/ kg, intraperitoneally) reversibly inhibited antigen-dependent lung eosinophilia in mice for at least 12 wk and inhibited the release of eosinophils from bone marrow for at least 8 wk. Normal responses to aerosol challenge were attained after 24 wk. In mice treated acutely with antibody (2 h before challenge), 50% inhibition of pulmonary eosinophilia occurred when 0. 06 mg/kg TRFK-5 was administered (intraperitoneally; ED50), resulting in 230 ng/ml (IC50) in serum. In mice treated with one dose of TRFK-5 (1 mg/kg) and rested before challenge, the antibody exhibited a half-life of 2.4 wk. After 18 to 19 wk, antigen challenge-induced eosinophilia was inhibited by 50% and serum levels of TRFK-5 were 25 ng/ml. TRFK-5 remaining in mice 8 wk after a single injection of TRFK-5 was sufficient to inhibit at least 50% of the eosinophilia induced in blood 3 h after injection of recombinant murine IL-5 (10 microg/kg, intravenously). To assess the biologic effect of long-term exposure of mice to antibody, several parameters of immune-cell function were measured. Throughout the extended period of activity of TRFK-5 (>/= 12 wk) there were no gross effects on antigen-dependent increases in T-cell recruitment into bronchoalveolar fluid (BALF), in IL-4 and IL-5 steady-state mRNA levels in lung tissue, or in immunoglobulin E (IgE) and IgG levels in serum. There was a small increase in IL-5 steady-state mRNA production in TRFK-5-treated mice after 2 h or 2 wk, but this was not observed at other times examined. In untreated mice, IL-5 steady-state mRNA production in response to antigen challenge decreased > 6-fold with age, although at all time points there was an increase in mRNA levels following challenge. Therefore, at later times, 25 ng/ml rather than 230 ng/ml of TRFK-5 inhibited BALF eosinophilia, probably because of reduced IL-5 levels. Twenty-four weeks after treatment with TRFK-5, when challenge-induced eosinophilia was restored, there was an excess of CD4(+) T cells in BALF from challenged mice. However, these T cells had no measurable effects on other responses to challenge, including cytokine production, B-cell accumulation, and immunoglobulin production in serum. Thus, the biologic duration of TRFK-5 was several months, and its activity was due to the presence of antibody above a therapeutic threshold rather than to any profound effect on the immune system.

Animals↗
PubMed1999

Combination therapy for chronic hepatitis C: interferon and ribavirin.

Hepatitis C virus (HCV) infection is one of the commonest causes of liver cirrhosis and hepatocellular carcinoma. This review deals with treatment of chronic HCV infection with a combination of interferon and ribavirin. Recent trials have shown that approximately 40% of patients will clear HCV with combination treatment. This is an important advance in the treatment of this serious viral infection.

Antiviral Agents↗
PubMed1999

Risk factors for biliary tract carcinogenesis.

Cholangiocarcinoma has a worldwide distribution which accounts for about 10-15% of all cases of primary hepatobiliary malignancy. Although, in the majority of cases, no aetiological factor can be identified, a number of risk factors have been shown to be important in the development of cholangiocarcinoma; most of these factors share long standing inflammation and chronic injury of the biliary epithelium. Primary sclerosing cholangitis is an uncommon disease, characterized by stricturing, fibrosis and inflammation of the biliary tree which is closely associated with chronic inflammatory bowel disease, particularly ulcerative colitis. It is commonly associated with cholangiocarcinoma and between 10-20% of patients with primary sclerosing cholangitis will go on to develop a cholangiocarcinoma. The rare congenital fibropolycystic diseases of the biliary system are associated with increased risks of cholangiocarcinoma, particularly choledochal cysts and Caroli's disease. Choledochal cysts are associated with a 10% overall incidence of cholangiocarcinoma: there is a 1% cumulative risk which plateaus after 15-20 years. However, the risk is diminished in children who present under the age of 10 years where the over all risk is 0.7%. This compares with the 14% over all risk of patients presenting over the age of 20 years. In the Far East, other forms of chronic inflammation associated with cholangiocarcinoma include infestation with liver flukes. Clonorchis sinensis and Opisthorchis viverinni. Cholangiocarcinoma is also rarely seen in association with cirrhosis and has been weakly linked to hepatitis C infection.

Biliary Tract Neoplasms↗
PubMed1999

Failure to keep clinic appointments: implications for residency education and productivity.

BACKGROUND AND OBJECTIVES: Missed clinic appointments significantly impact continuity of care, resident education, and clinical productivity. This national survey analyzed the awareness of family practice residency clinics regarding their missed appointment rate and the use of reminder systems. METHODS: We mailed a questionnaire to all 468 family practice residency programs in the United States and mailed two follow-up surveys to nonrespondents. RESULTS: The overall survey response rate was 60%. More than one third of the clinics reported a no-show rate of > 21%. When asked how the clinic arrived at their no-show rate, 64 (17.7%) respondents stated that the reported rate was an estimate. More than one third of all clinics did not use a patient reminder system for clinic appointments. When comparing clinics with high (> 20%) and low (< 20%) no-show rates, there was no statistically significant difference between the use or nonuse of mailed, telephone, or combined reminder systems. CONCLUSIONS: The clinic appointment no-show rate varies greatly among family practice residency programs. Even with the widely reported use of reminder systems, one third of programs continue to have no-show rates above 20%. This study is unusual in that there was no statistically significant difference in no-show rates between programs, based on the use of reminder systems. In an era of cost containment and increased accountability, appointment failures are a factor that will require additional study and intervention by family practice residency programs nationwide.

Appointments and Schedules↗
PubMed1998

A method to measure dual NK1/NK2-antagonist activity in dogs.

The major pulmonary effects of tachykinins are produced by activation of both NK1- and NK2-receptors. A variety of animal models have been used to profile activity of the tachykinins, particularly rodents and guinea pigs, but little information exists regarding methods to evaluate NK1- and NK2-receptor antagonist activity in dogs. This study describes a simple method in dogs to measure NK1- and NK2-receptor agonist and antagonist activity of drugs in the same preparation. We measured pulmonary resistance (RL), dynamic lung compliance (CDyn), minute volume (MV), and mean arterial blood pressure (MAP) before and after challenge with aerosolized NKA (1%) and i.v. SP (100 ng/kg) to quantify responses to the tachykinin challenge. Challenge with NKA produced an increase in RL and a decrease in CDyn, and this bronchospasm was inhibited by the NK2-antagonist SR 48968 (ID50 RL=1.3 mg/kg and ID50 CDyn=1.3 mg/kg, p.o.). The NK1-antagonist, CP 99994 was inactive against NKA-induced bronchospasm at doses up to 10 mg/kg, p.o. When the dogs were challenged with SP, there was a fall in MAP and an increase in MV and both responses were inhibited by CP 99994 (ID50 MV=2.3 mg/kg and ID50 BP=4.5 mg/kg, p.o.), but not by SR 48968 at doses up to 3 mg/kg, p.o. These results identify that NK2-receptors mediate the bronchoconstrictor effect of NKA, and NK1-receptors mediate the hypotension and respiratory stimulation due to SP in dogs. This method offers many advantages for evaluating the effects of tachykinin antagonists including the fact that it is relatively simple to perform and has the capacity to assess both NK1 and NK2 antagonist activity in the same preparation.

Animals↗
PubMed1998

The management of primary sclerosing cholangitis.

Primary sclerosing cholangitis is a chronic cholestatic liver disease characterized by a progressive, obliterating fibrosis of the intrahepatic and extrahepatic bile ducts. The pathogenesis of PSC is unknown, but it is thought to be an immune-mediated disease. Although the role of cupruretics, immunosuppressants (corticosteroids, azathioprine, tacrolimus, methotrexate), antifibrogenic agents, and ursodeoxycholic acid in the treatment of primary sclerosing cholangitis is reviewed, none of these agents has been shown to retard or reverse the rate of disease progression. Of these therapies, ursodeoxycholic acid at high doses looks the most promising, but large trials are needed to establish whether treatment with high-dose ursodeoxycholic acid influences the morbidity and mortality associated with primary sclerosing cholangitis.

Adrenal Cortex Hormones↗