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Biomedical subjects

E Miller

Publications and source records attributed to E Miller.

At least 163 records · Page 9Linked to original sources
PubMed1997

Effect of schedule on reactogenicity and antibody persistence of acellular and whole-cell pertussis vaccines: value of laboratory tests as predictors of clinical performance.

The performance of four acellular pertussis vaccines containing between two and five pertussis antigens combined with diphtheria and tetanus toxoids was compared with that of British whole-cell diphtheria/tetanus/pertussis (DTP) vaccine both in laboratory assays for potency, toxicity and immunogenicity, and for reactogenicity and immunogenicity in infants. Clinical responses were evaluated in double blind randomized Phase II trials using 3/5/9 month and 2/3/4 month schedules. The acellular DTPs had much lower toxicity than whole-cell DTP in laboratory tests and were significantly less pyrogenic than whole-cell DTP under both schedules. Local reactions were not consistently lower in acellular than whole-cell vaccinees and varied with the source of the diphtheria and tetanus antigens used. Differences in endotoxin level and content of active pertussis toxin (PT) between acellular DTP vaccines were not clinically significant. The reactogenicity advantage of the acellular vaccines was substantially reduced under the 2/3/4 month schedule due to the reduced reactogenicity of the whole-cell DTP vaccine when given at a younger age. There was no relationship between antigen content measured in micrograms per dose and ELISA antibody responses to filamentous haemagglutinin (FHA) and PT in infants, nor was murine immunogenicity predictive of immunogenicity in humans. Antibody response to PT was attenuated in the whole-cell group under the 2/3/4 month schedule but was unaffected in the group receiving acellular vaccines with individually purified components; antibody response to pertactin (69 kDa antigen) was similar in recipients of the whole-cell and component acellular vaccines under the 2/3/4 month schedule. PT antibody persistence until 4-5 years of age was significantly better in recipients of the component acellular than either the whole-cell vaccine or the co-purified acellular vaccine under the 3/5/9 month schedule. However, diphtheria antitoxin levels were reduced in acellular vaccine recipients under both schedules. Despite significantly lower tetanus potencies of the acellular vaccines in laboratory tests, no differences were found in tetanus anti-toxin responses in children.

Antibodies, Bacterial↗
PubMed1997

Immunosuppression--an overview.

The therapy of immune-mediated diseases in dogs and cats requires effective immunosuppressive therapy. The ideal therapy would suppress the abnormal (anti-self) immune responses while leaving the normal (anti-pathogen) immune responses intact. Unfortunately, such a therapy is not readily available. Current therapeutic strategies designed to suppress aberrant immune responses include combinations of glucocorticoids, cytotoxic drugs, and other immunomodulating agents such as cyclosporine and androgens. Glucocorticoids have a multitude of effects on the immune response at several levels and are both antiinflammatory and immunosuppressive. Cytotoxic drugs such as cyclophosphamide and azathioprine suppress the immune response by inhibiting protein (ie, antibody) synthesis, DNA replication, and cell division. Some cytotoxic drugs cause lysis of immunocompetent cells. Cyclosporine A suppresses production of interleukin-2, a cytokine necessary for the amplification stages of the immune response and critical for the activation of both T and B lymphocytes. Androgens modulate the immune system by as yet poorly defined mechanisms involving alterations in lymphocyte numbers and function as well as mononuclear-phagocytic cell function. Newer immunosuppressive agents are being studied in laboratory animals and human transplant patients that either inhibit do novo synthesis of nucleotides or signal transduction in lymphocytes, thereby reducing the number or function of immunocompetent cells. These newer agents can be combined with more traditional therapies for enhanced immunosuppressive effects.

Animals↗
PubMed1997

The use of cytotoxic agents in the treatment of immune-mediated diseases of dogs and cats.

Cytotoxic drugs are often combined with glucocorticoids in the therapy of immune-mediated diseases. Cyclophosphamide, azathioprine, chlorambucil, and methotrexate are cytotoxic drugs used most commonly for the purpose of immunosuppression. Cyclophosphamide and chlorambucil are alkylating agents, which cause cross-linking of DNA resulting in altered protein production, decreased cell division, and cell death. Azathioprine and methotrexate are anti-metabolites, which cause inhibition of DNA synthesis and a cascade of other effects. These drugs, in general, are more effective if administered during the initial phases of disease when immunocompetent lymphocytes are in a phase of rapid proliferation. This is often impractical in the clinical situation and may explain therapeutic failures. This article focuses on the use of these drugs in the treatment of immune-mediated diseases in dogs and cats and covers mechanisms of action, dosages, and side effects of individual cytotoxic agents.

Animals↗
PubMed1997

The use of danazol in the therapy of immune-mediated disease of dogs.

Currently available therapeutic protocols for immune-mediated diseases in dogs and cats can be associated with poor response rates and a high incidence of side effects. The development of multidrug protocols often results in a synergistic effect that more efficiently suppresses the immune response. One drug that may be added to other therapies is danazol, an androgen with immunomodulating properties. Androgens are known to suppress aberrant immune responses, and the fact that immune-mediated diseases are more common in females supports this. Danazol has been used in humans with immune-mediated hemolytic anemia and thrombocytopenia with some success. Danazol appears to reduce the binding of immuno-globulin and complement to the red blood cell or platelet surface and also may alter cytokine concentrations. The use of danazol in dogs with immunemediated hemolytic anemia and thrombocytopenia has been reported; however, the small number of animals evaluated make it difficult to assess its usefulness in veterinary medicine.

Adjuvants, Immunologic↗
PubMed1997

An economic analysis of varicella vaccination for health care workers.

A simulation model was constructed to assess the relative costs and cost-effectiveness of different screening and vaccination strategies for dealing with hospital incidents of varicella exposure, compared with current policies, using data from published sources and a hospital survey. The mean number of incidents per hospital year was 3.9, and the mean annual cost of managing these incidents was pounds 5170. Vaccination of all staff would reduce annual incidents to 2.2 at a net cost of pounds 48,900 per incident averted. Screening all staff for previous varicella, testing those who are uncertain or report no previous varicella, and vaccinating those who test negative for VZV antibodies, reduces annual incidents to 2.3 and gives net savings of pounds 440 per incident averted. Sensitivity analyses do not greatly alter the ranking of the options. Some form of VZV vaccination strategy for health care workers may well prove a cost-effective use of health care resources.

Chickenpox↗
PubMed1997

Expression of an antigen homologous to the human CO17-1A/GA733 colon cancer antigen in animal tissues.

The CO17-1A/GA733 antigen is associated with human carcinomas and some normal epithelial tissues. This antigen has shown promise as a target in approaches to passive and active immunotherapy of colorectal cancer. The relevance of animal models for studies of immunotherapy targeting this antigen in patients is dependent on the expression of the antigen on normal animal tissues. Immunohistoperoxidase staining with polyclonal rabbit antibodies to the human antigen revealed the human homologue on normal small intestine, colon and liver of mice, rats and non-human primates, whereas mouse monoclonal antibodies to the CO17-1A or GA733 epitopes on the human antigen did not detect the antigen. Polyclonal rabbit antibodies, elicited by the murine antigen homologue derived from recombinant baculovirus-infected insect cells, immunoprecipitated the antigen from mouse small intestine, colon, stomach, kidney and lung. The isolated recombinant murine protein bound polyclonal, but not monoclonal, antibodies to the human CO17-1A/GA733 antigen, and recombinant human antigen bound polyclonal antibodies elicited by the murine antigen homologue. Thus, the antigen homologue expressed by animal tissues is similar, but not identical, to the human antigen. These results have important implications for experimental active and passive immunotherapy targeting the CO17-1A/GA733 antigen.

Animals↗
PubMed1997

Predicting bacteremia in patients with sepsis syndrome. Academic Medical Center Consortium Sepsis Project Working Group.

The goal of this study was to develop and validate clinical prediction rules for bacteremia and subtypes of bacteremia in patients with sepsis syndrome. Thus, a prospective cohort study, including a stratified random sample of 1342 episodes of sepsis syndrome, was done in eight academic tertiary care hospitals. The derivation set included 881 episodes, and the validation set included 461. Main outcome measures were bacteremia caused by any organism, gram-negative rods, gram-positive cocci, and fungal bloodstream infection. The spread in probability between low- and high-risk groups in the derivation sets was from 14.5% to 60.6% for bacteremia of any type, from 9.8% to 32.8% for gram-positive bacteremia, from 5.3% to 41.9% for gram-negative bacteremia, and from 0.6% to 26.1% for fungemia. Because the model for gram-positive bacteremia performed poorly, a model predicting Staphylococcus aureus bacteremia was developed; it performed better, with a low- to high-risk spread of from 2.6% to 21.0%. The prediction models allow stratification of patients according to risk of bloodstream infections; their clinical utility remains to be demonstrated.

Adult↗
PubMed1997

The effect of propofol on midazolam metabolism in human liver microsome suspension.

We have studied the inhibitory effects of propofol on the metabolism of midazolam using human liver microsomes. In addition, we also investigated whether the lipid in which propofol is solubilised inhibits the metabolism of midazolam. Only high concentrations of propofol (> 100 mmol), greater than those found in clinical practice, inhibited the metabolism of midazolam. The lipid had no effect on the metabolism of midazolam. This study differs from other laboratory studies looking at the inhibitory effects of propofol. These showed inhibition at concentrations similar to those seen in patients. The reasons for the differences may be explained by the use of different substrates or methodology. Propofol may be an enzyme inhibitor, but this remains to be shown to be important in patients.

Anesthetics, Intravenous↗
PubMed1997

The European Sero-Epidemiology Network.

The purpose of serological surveillance is to monitor levels of immunity to particular diseases within a population in order to enhance the quality of information on which public health measures, such as vaccination programmes, are based. Serological surv

Journal Article↗
PubMed1997

New interface metaphors for complex information space visualization: an ECG monitor object prototype.

Wearable augmented reality medical (WARM) interfaces could provide ubiquitous point-of-care decision support and enhance the quality and efficiency of clinicians' efforts. Creation of such systems involves the design and evaluation of new information displays that leverage the representational and presentational capabilities of three-dimensional AR environments. We describe our first efforts in this process: the implementation of interface objects for display of real-time electrocardiographic monitoring information and an evaluation methodology using a simulated clinical environment. Our pilot data confirm the utility of presentation modes that place simultaneous information tasks in close proximity, and highlight issues encountered in designing new representations of medical information.

Analysis of Variance↗
PubMed1997

Epidemiological determinants of pertussis.

In countries with pertussis immunisation programmes, the main epidemiological determinant of the disease is the quality of protection induced by the vaccine and the coverage level achieved. Epidemiological data from England and Wales provide strong evidence that whole-cell pertussis vaccines can give good protection against both clinical disease and transmission of infection, and can generate herd immunity at high coverage levels. Models of pertussis transmission indicate that, even in the absence of waning immunity, the incidence of the disease is likely to increase in older age groups in countries with sustained high coverage. Active surveillance to detect the occurrence of pertussis in adults is required as the ascertainment of such cases through passive clinical reporting systems is low. Comprehensive post-licensing surveillance of the effectiveness of acellular pertussis vaccines will be essential to assess their long-term protection against both clinical disease and transmission of infection, and to determine the optimum boosting strategy.

Humans↗
PubMed1996

Cloning of monoclonal autoantibodies to epitopes of oxidized lipoproteins from apolipoprotein E-deficient mice. Demonstration of epitopes of oxidized low density lipoprotein in human plasma.

Many reactive products may be formed when LDL undergoes lipid peroxidation, which in turn can react with lipids, apoproteins, and proteins, generating immunogenic neoepitopes. Autoantibodies recognizing model epitopes of oxidized low density lipoprotein, such as malondialdehydelysine, occur in plasma and in atherosclerotic lesions of humans and animals. Because apo E-deficient mice develop particularly high titers of such autoantibodies, we used their spleens to clone 13 monoclonal antibodies to various epitopes of oxidized LDL ("E0 antibodies"). Binding and competitive RIAs demonstrated significant differences in fine specificity even between E0 antibodies initially selected for binding to the same screening antigen. For example, some E0 antibodies selected for binding to malondialdehyde-LDL also recognized copper oxidized LDL, acrolein-LDL, or LDL modified by arachidonic or linoleic acid oxidation products. Circulating IgG and IgM autoantibodies binding to copper-oxidized LDL, 4-hydroxynonenal-LDL, acrolein-LDL, and LDL modified with arachidonic or linoleic acid oxidation products were found in apo E-deficient mice, suggesting that the respective antigens are formed in vivo. Epitopes recognized by some of the E0 monoclonal antibodies were also found on human circulating LDL. Each of the E0 monoclonal antibodies immunostained rabbit and human atherosclerotic lesions, and some of them yielded distinct staining patterns in advanced lesions. Together, this suggests that the natural monoclonal antibodies recognize different epitopes of complex structures formed during oxidation of lipoproteins, or epitopes formed independently at different lesion sites. Our data demonstrate that a profound immunological response to a large number of different epitopes of oxidized lipoproteins occurs in vivo. The availability of "natural" monoclonal autoantibodies should facilitate the identification of specific epitopes inducing this response.

Acrolein↗
PubMed1996

Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids. Recognition of cardiolipin by monoclonal antibodies to epitopes of oxidized low density lipoprotein.

The optimal clinical management of patients with antiphospholipid antibody syndrome (APS) is uncertain because of a lack of an underlying hypothesis to explain why antiphospholipid autoantibodies (aPL) form to such ubiquitous compounds as phospholipids (PL). In this paper, we demonstrate that many, if not most, aPL are actually directed at neoepitopes of oxidized PL, or neoepitopes generated by adduct formation between breakdown products of oxidized PL and associated proteins. Each cardiolipin (CL) molecule contains four unsaturated fatty acids and is highly susceptible to oxidation, particularly upon exposure to air. Yet, standard anticardiolipin antibodies (aCL) immunoassays routinely bind CL to microtiter wells by evaporation of the ethanol solvent overnight at 4 degrees C. Using a variety of techniques, we demonstrated that rapid oxidation occurs when CL is plated and exposed to air. Sera from apo E-deficient mice, which have high autoantibody titers to oxidized low density lipoprotein, showed a striking time-dependent increase in binding to CL that was exposed to air for increasing periods of time. Monoclonal antibodies to oxidized LDL, cloned from the apo E-deficient mice, also bound to oxidized CL. Both sera and affinity-purified aCL-IgG from APS patients bound to CL progressively as it was oxidized. However, the monoclonal antibodies from apo E-deficient mice, or sera or aCL-IgG from APS patients did not bind to a reduced CL analog that was unable to undergo peroxidation. These data demonstrate that many aPL are directed at neoepitopes of oxidized phospholipids, and suggest that oxidative events may be important in the pathophysiology of APS. In turn, this suggests new therapeutic strategies, possibly including intensive antioxidant therapy.

Animals↗
PubMed1996

A survey of population-based drug databases in Canada.

OBJECTIVE: To identify the population-based drug databases in Canada and to determine their comprehensiveness and accessibility for performing pharmacoepidemiologic and outcomes research. DESIGN: Survey (four-part mailed questionnaire). SETTING: Public and private third-party drug plans across Canada. PARTICIPANTS: All provincial and territorial drug plan or pharmacare managers as well as selected private plan managers including health benefit consultants, group insurers and claims adjudicators/pharmacy benefit managers (CA/PBMs). OUTCOME MEASURES: Patient, drug and pharmacy information; potential for electronic linkages to other provincial databases (e.g., physician, hospital, vital statistics); accessibility of information; population profile. RESULTS: Of the 32 recipients of the questionnaire 29 (91%) responded and 18 (56%) completed the survey. Most databases were reported to contain patient information (e.g., patient identification number, age, sex and medication history) and prescription drug information (e.g., drug identification number, strength, quantity and cost). Six provinces and one territory reported the capability to link to other databases (e.g., hospital and physician databases). One CA/PBM reported some links to selected long-term disability data. All of the government databases except those in British Columbia and the Yukon Territory allowed use of the data for research purposes. Manitoba and Saskatchewan included all residents of the province in their database; the others included selected groups (e.g., residents 65 years of age or older, people on social assistance or people covered by private group insurance). CONCLUSION: A number of public and private population-based databases are available for use in pharmacoepidemiologic and outcomes research.

Canada↗
PubMed1996

Case series analysis of adverse reactions to vaccines: a comparative evaluation.

A modified cohort method has been proposed for estimating the relative incidence of rare adverse reactions after vaccination. The method requires only a sample of the cases, thus avoiding the need for following large population cohorts or selecting controls. This case series method has statistical power equivalent to that of the full cohort method when the risk periods after vaccination are short and vaccine coverage is high. The method also eliminates confounding by variables associated with both the outcome and avoidance of vaccination. In this paper, the cohort, case-control, and case series methods are reviewed, and their underlying assumptions and performances are compared. Theoretical results are illustrated using data on febrile convulsions after measles-mumps-rubella vaccination in the United Kingdom.

Adverse Drug Reaction Reporting Systems↗