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Biomedical subjects

P Fowler

Publications and source records attributed to P Fowler.

At least 19 recordsLinked to original sources
PubMed1992

Fine specificity of the human T cell response to hepatitis B virus core antigen.

The fine specificity of the human T cell response to the hepatitis B virus core antigen (HBcAg) was investigated in 23 patients with acute hepatitis B virus (HBV) infection using a panel of short synthetic peptides covering the entire core region. An immunodominant T cell epitope which was recognized by all except one patient, was identified within the core sequence 50-69. Two further important T cell recognition sites were represented by the amino acid sequences 1-20 and 117-131, which were stimulatory for the T cells of 69% and 73% of the patients, respectively. T cell recognition of the synthetic peptides was HLA class II restricted because the peptide-induced T cell proliferation was inhibited by anti-HLA class II but not by anti-HLA class I monoclonal antibodies. These findings may be relevant to the development of future preventive and therapeutic strategies against HBV infection.

Acute Disease↗
PubMed1992

Effect of sumatriptan, a new selective 5HT1-like agonist, on liquid gastric emptying in man.

Paired studies were carried out on 12 healthy male subjects to compare the effect of intravenous doses of the 5-HT1-like agonist sumatriptan (GR43175; 3 mg), 10 mg metoclopramide and saline control on the rate of gastric emptying of a radiolabelled liquid test-meal. Intravenous administration of metoclopramide accelerated gastric emptying by decreasing the lag period, while intravenous administration of sumatriptan delayed gastric emptying by increasing the lag period. The observation that sumatriptan causes a delay in gastric emptying in normal healthy volunteers, but relieves nausea and vomiting during migraine attacks, suggests that sumatriptan may be acting via a central mechanism to relieve symptoms of nausea and vomiting associated with migraine.

Adult↗
PubMed1992

Hepatitis B virus (HBV)-specific cytotoxic T-cell (CTL) response in humans: characterization of HLA class II-restricted CTLs that recognize endogenously synthesized HBV envelope antigens.

In this study, we show that CD4+, hepatitis B virus (HBV) envelope-specific T-cell clones produced by stimulation with a particulate antigen preparation are able to recognize and kill not only autologous antigen-presenting cells incubated with exogenous HBV envelope antigens but also autologous HLA class II-positive cells expressing endogenously synthesized HBV envelope antigens following infection with recombinant vaccinia viruses or transfection with recombinant Epstein-Barr virus expression vectors. Experiments with lysosomotropic agents and brefeldin A suggest that the endosomal compartment is likely involved in the processing of endogenously synthesized viral proteins for recognition by CD4+ T cells. Our study indicates that HBV envelope-specific, HLA class II-restricted CD4+ cytotoxic T lymphocytes can potentially participate in the immune clearance of HBV-infected cells and the pathogenesis of hepatocellular injury in hepatitis B.

Ammonium Chloride↗
PubMed1992

Hepatitis B virus (HBV)-specific cytotoxic T-cell response in humans: production of target cells by stable expression of HBV-encoded proteins in immortalized human B-cell lines.

To analyze the hepatitis B virus (HBV)-specific cytotoxic T-cell (CTL) response during acute and chronic viral hepatitis, target cells that express HBV-encoded antigens in the context of the appropriate HLA restriction element must be available for each subject studied. Since HBV is not infectious for human cells in vitro, such target cells must be produced by DNA-mediated gene transfer into cultured human primary cells or cell lines. For this purpose, we have developed a panel of Epstein-Barr virus-based episomal expression vectors containing each of the HBV open reading frames under the transcriptional control of the simian virus 40 early promoter. Transfection of Epstein-Barr virus-immortalized B-cell lines with this panel of recombinants consistently leads to stable expression of the HBV envelope, nucleocapsid, and polymerase proteins. The HBV X gene product is transiently expressed following transfection, but stable expression of this protein cannot be maintained on a long-term basis. To assess the suitability of this system for the identification of HBV-specific CTL in humans, a panel of EBO-HBV transfectants of defined HLA haplotype was used to monitor the HBV-specific CTL response in a patient with acute viral hepatitis type B. Transfectants that stably express the HBV nucleocapsid (core) antigen were found to serve as excellent targets for the detection of HLA class I-restricted CTL that recognize endogenously synthesized HBV core antigen in this patient; they were also successfully used to stimulate the specific expansion of these CTL in vitro.

B-Lymphocytes↗
PubMed1992

Outcome measures for primary health care: what are the research priorities?

A Delphi technique was used to ask general practitioners for their opinions as to which clinical problems and types of measure they thought most appropriate for the development of outcome measures for use in primary health care. The study comprised two rounds of postal questionnaires, targeted at general practitioners in academic departments throughout the United Kingdom and at trainers in the northern region, with the second questionnaire feeding back opinions from the first. Ninety eight participants suggested one or more areas in which outcome measures could be developed, giving a total of 451 suggestions. Consensus produced in the second round indicated that three clinical conditions were preferred for the development of outcome measures: asthma, diabetes and hypertension. Six categories of outcome measures were developed from the responses given in the first round--level of function, level of clinical control, incidence of complications, iatrogenic problems, patient understanding of a condition, and quality of life. Participants gave these measures different levels of importance according to the clinical problem in question. This Delphi study of doctors' opinions is a first step in the development process of appropriate, practicable measures of outcome for use in primary care and has achieved a degree of consensus among general practitioners.

Attitude of Health Personnel↗
PubMed1991

HLA class I-restricted human cytotoxic T cells recognize endogenously synthesized hepatitis B virus nucleocapsid antigen.

Knowledge of the immune effector mechanisms responsible for clearance of hepatitis B virus (HBV)-infected cells has been severely limited by the absence of reproducible systems to selectively expand and to characterize HBV-specific cytotoxic T lymphocytes (CTLs) in the peripheral blood of patients with viral hepatitis. By using a strategy involving sequential stimulation with HBV nucleocapsid synthetic peptides followed by autologous, or HLA class I-matched, HBV nucleocapsid transfectants, we now report the existence of CTLs able to lyse target cells that express endogenously synthesized HBV nucleocapsid antigen in the peripheral blood of patients with acute viral hepatitis B. The CTL response is HLA-A2 restricted, mediated by CD8-positive T cells, and specific for a single epitope, located between amino acid residues 11 and 27 of HBV core protein; these residues are shared with the secretable precore-derived hepatitis B e antigen. Equivalent lysis of target cells that express each of these proteins suggests that their intracellular trafficking pathways may intersect. The current report provides definitive evidence that HLA class I-restricted, CD8-positive CTLs that recognize endogenously synthesized HBV nucleocapsid antigen are induced during acute HBV infection in humans and establishes a strategy that should permit a detailed analysis of the role played by HBV-specific CTLs in the immunopathogenesis of viral hepatitis.

B-Lymphocytes↗
PubMed1991

Cytotoxic T lymphocytes recognize an HLA-A2-restricted epitope within the hepatitis B virus nucleocapsid antigen.

The absence of readily manipulable experimental systems to study the cytotoxic T lymphocyte (CTL) response against hepatitis B virus (HBV) antigens has thus far precluded a definitive demonstration of the role played by this response in the pathogenesis of liver cell injury and viral clearance during HBV infection. To circumvent the problem that HBV infection of human cells in vitro for production of stimulator/target systems for CTL analysis is not feasible, a panel of 22 overlapping synthetic peptides covering the entire amino acid sequence of the HBV core (HBcAg) and e (HBeAg) antigens were used to induce and to analyze the HBV nucleocapsid-specific CTL response in nine patients with acute hepatitis B, six patients with chronic active hepatitis B, and eight normal controls. By using this approach, we have identified an HLA-A2-restricted CTL epitope, located within the NH2-terminal region of the HBV core molecule, which is shared with the e antigen and is readily recognized by peripheral blood mononuclear cells from patients with self-limited acute hepatitis B but less efficiently in chronic HBV infection. Our study provides the first direct evidence of HLA class I-restricted T cell cytotoxicity against HBV in humans. Furthermore, the different response in HBV-infected subjects who successfully clear the virus (acute patients) in comparison with patients who do not succeed (chronic patients) suggests a pathogenetic role for this CTL activity in the clearance of HBV infection.

Alanine Transaminase↗
PubMed1991

Identification of immunodominant T cell epitopes of the hepatitis B virus nucleocapsid antigen.

Several lines of experimental evidence suggest that inclusion of core sequences in the hepatitis B vaccine may represent a feasible strategy to increase the efficacy of the vaccination. In order to identify immunodominant core epitopes, peripheral blood T cells purified from 23 patients with acute hepatitis B and different HLA haplotypes were tested with a panel of 18 short synthetic peptides (15 to 20 amino acids [AA]) covering the entire core region. All patients except one showed a strong T cell proliferative response to a single immunodominant 20 amino acid sequence located within the aminoterminal half of the core molecule. Two additional important sequences were also identified at the aminoterminal end and within the carboxyterminal half of the core molecule. These sequences were able to induce significant levels of T cell proliferation in 69 and 73% of the patients studied, respectively. T cell response to these epitopes was HLA class II restricted. The observations that (a) polyclonal T cell lines produced by PBMC stimulation with native HBcAg were specifically reactive with the relevant peptides and that (b) polyclonal T cell lines produced with synthetic peptides could be restimulated with native HBcAg, provide evidence that AA sequences contained within the synthetic peptides represent real products of the intracellular processing of the native core molecule. In conclusion, the identification of immunodominant T cell epitopes within the core molecule provides the molecular basis for the design of alternative and hopefully more immunogenic vaccines.

Amino Acid Sequence↗
PubMed1991

Limitations of the panoramic radiograph's focal trough: a case report.

This report of a 10-year-old boy illustrates the limitations of the focal trough in panoramic radiography. Because of the patient's large overjet, a supernumerary upper incisor tooth was not visible on a panoramic radiograph. The positioning of the patient within the panoramic machine is critical in obtaining the best possible detail from the radiograph, particularly where there are variations in the anterior occlusal relationship.

Child↗
PubMed1990

The social and demographic characteristics of women dying from cervical cancer in Nottingham.

Cervical cancer accounted for 57 deaths to women in Nottingham District in 1986 and 1987. 28% were women aged under 50 years of age. Using age specific death rates, the greatest risk was among women aged 60-69 years. However, when expressed as a proportion of all deaths, cervical cancer represents 8.5% of deaths in women aged 25-45, but only 0.6% of deaths to women over 46. There was no significant difference in relative risk between the five social classes, even when social class V was compared to aggregated data for social classes I-IV. This supports other evidence that the social class gradient in cervical cancer mortality is lessening. There was no excess risk shown to women resident in the inner city or in areas of social deprivation. This finding is in contrast to the work of others who have shown an increased incidence in areas of social deprivation. The evidence from this study would support those who suggested over 20 years ago that it is not social deprivation or occupation that constitute an increased risk to women, but sexual behaviour and other habits such as smoking.

Adult↗
PubMed1990

Adrenergic control of circulating lymphocyte subpopulations. Effects of congestive heart failure, dynamic exercise, and terbutaline treatment.

The current studies were undertaken to explore the relationship between enhanced sympathetic nervous activity and lymphocyte subset distribution in three settings: congestive heart failure, dynamic exercise, and beta-adrenergic agonist treatment. We compared the number and subset distribution of circulating lymphocytes in 36 patients with congestive heart failure and 31 age-matched control subjects. The number of circulating lymphocytes was lower in heart failure than in control. This was due to a reduction in Tsuppressor/cytotoxic and natural killer cells without significant alteration of Thelper cells. The extent of the alteration was similar in patients with idiopathic and ischemic heart failure, but the reduction was more pronounced in patients with New York Heart Association class III-IV than in class I-II. The plasma catecholamine elevation in heart failure was also independent of etiology but more pronounced in the more severely ill patients. We also assessed lymphocyte subsets after acute stimulation of sympathetic activity by dynamic exercise and after treatment with the beta-adrenergic agonist terbutaline. Dynamic exercise until exhaustion increased the number of circulating lymphocytes in healthy controls and heart failure patients in a subset-selective manner. By contrast, a 7-d treatment with terbutaline caused a reduction in the circulating number of lymphocytes in some subsets that was identical to that seen in heart failure patients. We conclude that prolonged sympathetic activity reduces the number of circulating lymphocytes by a beta-adrenergic mechanism. Such alterations might be involved in the pathophysiology of heart failure and other disease states involving increased activity of the sympathetic nervous system.

Adult↗
PubMed1989

Accuracy of nonorthogonal magnetic resonance imaging in acute disruption of the anterior cruciate ligament.

A controlled, prospective study of 30 patients with suspected acute internal derangement of the knee was undertaken to evaluate the sensitivity, specificity, predictive value, and accuracy of nonorthogonal (oblique) sagittal magnetic resonance imaging (MRI) in the assessment of anterior cruciate ligament (ACL) injuries. Thirty patients with acute hemarthroses underwent MRI within 12 days of injury, followed by arthroscopy within 24 h of the MRI. A control population of 30 chondromalacia patients underwent similar evaluation. In the acute hemarthrosis patient population, the incidence at arthroscopy of acute complete ACL tears was 60% (18/30); of partial ACL tears, 13.3% (4/30); and of chronic tears, 10% (3/30). A normal ACL was found in 16.6% (5/30) of patients. In the MRI evaluation of patients with suspected ACL injury the following results were obtained for both acute and chronic complete disruption on orthogonal (sagittal) and nonorthogonal (oblique sagittal) imaging, respectively: sensitivity, 61 (16/26) versus 100%; specificity, 70 (21/34) versus 100%; positive predictive value, 61 (16/26) versus 100%; negative predictive value 70 (24/34) versus 100%; and accuracy, 66 (40/60) versus 100%. In the evaluation of partial ACL injury, four partial tears were correctly diagnosed on nonorthogonal MRI, with one false-positive diagnosis. Orthogonal imaging failed to correctly identify any of the partial ACL injuries. Two patients in the control population demonstrated evidence of chronic ACL tears. We believe that we have demonstrated the superiority of T2-weighted nonorthogonal sagittal over conventional orthogonal sagittal ACL MRI in the evaluation of ACL injury.

Arthroscopy↗
PubMed1989

A new method for isolation of human lymphocyte subsets reveals differential regulation of beta-adrenergic receptors by terbutaline treatment.

We adapted a technique for isolation of mononuclear leukocyte (MNL) subsets with immunomagnetic beads to the study of beta-adrenergic receptors. Mixed MNL cells were sequentially incubated with monoclonal antibodies specific for certain MNL subsets. Sheep antimouse antibodies coupled to magnetic beads were then added, and the desired MNL subset was pulled out with a magnet. This method yielded subsets with high purity and did not alter beta-receptor density or function. Healthy volunteers were treated for 7 days with the beta 2-selective agonist terbutaline (5 mg t.i.d.). Terbutaline treatment decreased beta-receptor number and isoproterenol-stimulated cyclic adenosine monophosphate (cAMP) generation in natural killer cells, helper T cells, and suppressor/cytotoxic T cells but not in B cells. The decrease was greatest in suppressor/cytotoxic T cells and least in helper T cells. Thus beta-adrenergic receptor regulation by agonists appears to differ among MNL subsets.

Adult↗
PubMed1988

Monoclonal antibodies to human antigens recognise feline myeloid cells.

Immunological techniques have been used to study the expression of a series of cell surface antigens in cat haemopoietic tissues. Forty-two monoclonal antibodies raised against well-defined antigens of human origin were tested by indirect immunofluorescence on feline blood, bone marrow, spleen and thymus. Myeloid cells from all tissues reacted with antibodies to CD9, CD10 and CD18 antigens. No antibodies specific for T or B lymphocytes were found to react with cat lymphoid cells. Osteoclasts, isolated from juvenile bone marrow, were found to express the 23C6 human osteoclast-specific antigen. The potential use of such antibodies in experimental and diagnostic veterinary haematology are discussed.

Animals↗
PubMed1985

Outpatient stabilization programme--an innovative approach in the management of diabetes.

An outpatient stabilization programme for diabetic patients was established to overcome the disadvantages of inpatient treatment. The day to day management of patients was carried out by experienced nurse/educators under the supervision of physicians. The telephone was used extensively for communication between the patients and staff of the Diabetes Centre. In a 12 month period, 73 patients were commenced on insulin and 83 patients (62 on insulin) had their diabetic control re-stabilized. In both groups of patients there was a significant fall in glycosylated haemoglobin levels indicating improved metabolic control. Results were similar to those for patients admitted to hospital for stabilization. There are important social and economic benefits from the avoidance of repeated hospitalization.

Academic Medical Centers↗