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Biomedical subjects

T E Miller

Publications and source records attributed to T E Miller.

At least 91 records · Page 5Linked to original sources
PubMed1987

An animal model for chronic infection of the unobstructed urinary tract.

Chronic cystitis due to Escherichia coli is frequently associated with anatomical or functional abnormalities of the lower urinary tract, but there is no satisfactory animal model available to help resolve biological and management problems. We have induced chronic infection of the unobstructed urinary tract in the rat by implanting a small polyurethane sponge into the dome of the bladder, 14 days before bacterial challenge. This manipulation provides a focus of infected urine and leads to the establishment of a chronic cystitis. Both the predisposing factor and the pathological details mimic important features of the disease in man.

Animals↗
PubMed1986

Sustained release of a corticosteroid using polymeric implants.

An effective sustained release method of drug administration, using methylprednisolone incorporated into acrylic bone cement, has been developed. The effect of this form of treatment on peripheral blood leukocytes, lymphoid tissue weight and the inflammatory response has been evaluated. This mode of methylprednisolone administration was compared with conventional systemic therapy and was found to produce rapid and prolonged pharmacological effects at very low plasma levels of drug. A dose response relationship was established and we determined that, for a given quantity of drug, the level and duration of suppression was greater using sustained release therapy. The inflammatory response was also depressed using this mode of administration. These results, coupled with the commercial availability and existing clinical approval of SIMPLEX P bone cement, suggest that further development may lead to useful clinical protocols.

Adrenal Cortex Hormones↗
PubMed1986

Modulation of host defenses against pyogenic microorganisms by cyclosporine.

Modulation of T cell activity by cyclosporine (CsA) predictably predisposes the host to infection with intracellular pathogens normally controlled by cell-mediated immune mechanisms. Little attention, however, has been paid to the effect of this agent on other cellular defense components associated with pathogens such as Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. In the present experiments CsA administration exacerbated acute experimentally induced renal infection and led to a 100-fold increase in bacterial numbers. Furthermore, at a time when lesions in the control group were resolving, CsA-treated animals exhibited purulent abscesses involving up to 80% of the surface area of the kidney. Circulating leukocyte numbers were not reduced in CsA-treated hosts and the mechanism for provocation of infection remains to be explained.

Animals↗
PubMed1986

Mucosal mast cells as a component of the inflammatory response to lower-urinary tract infection.

Globule cells have been observed in mucosae for many years. Recently, a subpopulation of these globule cells in the intestinal mucosa of man and rodents have been identified as unique mast cells. In this communication, intraepithelial globule cells and some lamina-propria mast cells found in the normal rat urinary-bladder wall have been characterized as mucosal mast cells, similar to intestinal mast cells, and differentiated morphologically and histochemically from rat peritoneal mast cells. The number of mast cells in the bladder wall increased significantly during various bladder manipulations, including mechanical trauma, parasitic infestation and bacterial infection. The origin and function of the mucosal mast cells remains unknown.

Animals↗
PubMed1986

Cellular basis of host defence in pyelonephritis. I. Chronic infection.

Infection persists for long periods in chronic pyelonephritis, but the cellular basis of the host-parasite relationship is poorly understood. We have obtained quantitative data on the relationship between the pathogen (E. coli) and cellular defence mechanisms. Depletion of cellular components was carried out using whole body irradiation, methylprednisolone, cyclophosphamide or carrageenan and silica particles. A system of administering cyclophosphamide and methylprednisolone through the use of a slow release carrier, as well as graded doses of irradiation, was then developed to allow the controlled reduction of cellular competence. Quantitative studies in a host with chronic pyelonephritis and normal cellular defence reserves showed that severe depletion of granulocytic cells is necessary before host defence mechanisms are adversely affected. This finding conflicts with the observation that microorganisms survive and persist in the kidney for extended periods. Additionally, noncellular factors may also limit bacterial growth.

Animals↗
PubMed1986

Cellular basis of host defence in pyelonephritis. II. Acute infection.

We have investigated the cellular basis of host defence mechanisms in experimental pyelonephritis. Cellular components of the host defence system were depleted using cyclophosphamide, methylprednisolone or radiation. Depletion of cellular competence did not affect the course of infection during the first 16 h after challenge with Escherichia coli, but after 96 h up to a 1000-fold increase in bacterial numbers in the kidneys of cytodepleted animals was demonstrable. When quantitative aspects of the relationship between cellular competence and host defence were studied, it was found that severe depletion of cellular components was necessary before host defence mechanisms were adversely affected. Thus while cellular mechanisms are quantitatively adequate and contribute to host defence in pyelonephritis they have little impact on the immediate post-infection phase. Non-cellular factors however, do limit bacterial proliferation in the acute phase and may be important determinants in the biology of pyelonephritis.

Acute Disease↗
PubMed1985

Extended immunosuppression with cyclophosphamide using controlled-release polymeric implants.

An effective method of prolonged immunosuppressive therapy using cyclophosphamide incorporated into acrylic bone cement has been developed. We have studied the effect of this form of administration of cyclophosphamide on circulating immune cells and the inflammatory response. When the slow release mode of cyclophosphamide administration was compared with conventional systemic therapy, it was found to produce a more rapid and prolonged immunosuppression. A dose-response relationship was established and the biological effects of varying the composition and surface area of the implant were determined. The inflammatory response, assessed by measuring the mobilisation of cells into subcutaneously implanted sponges, was also depressed using this mode of administration. These results, coupled with the commercial availability and existing clinical approval of Simplex P bone cement, suggest that the procedure could lead to useful clinical protocols.

Animals↗
PubMed1985

Experimental candidosis: paw oedema in the analysis of a local infection.

Existing models of Candida albicans infection are semi-quantitative and do not allow continuous observations to be made on individual animals. We have used the inflammatory response in the footpad as an indirect measure of the number of yeast cells in a localised lesion. C. albicans infection of the footpad has been used in series of experiments in which changes in yeast-cell numbers in the local lesion have been compared with the degree of footpad oedema. Studies in animals treated with cyclophosphamide or amphotericin have confirmed that paw oedema parallels yeast-cell numbers in the local lesion. This quantitative approach will be helpful in the study of localised infection with C. albicans and other fungi and in the evaluation of antifungal agents.

Amphotericin B↗
PubMed1985

Host immune status in uraemia. VI. Leucocytic response to bacterial infection in chronic renal failure.

Infection often complicates renal failure and frequently causes death, but the association between renal failure, impaired immunity and infection has not been proved. A recent study showed that patients on dialysis did not show an expected leucocytic response to infection, suggesting that the blunted response was evidence of the immunocompromised state of the uraemic patient. In this study, the relationship between leucocytic responses and infectious challenge was investigated in an animal model of chronic renal failure. Bacteraemia, peritonitis and a chronic lung infection were induced in normal and uraemic rats; the leucocytic response was then monitored. In all three infections, the total white blood cell response was significantly less in the uraemic animals. Neutrophil numbers actually increased, but this response was disguised by a pronounced depression in lymphocyte numbers. Our conclusion is that, although the leucocytic response of the uraemic host to infection may be depressed, the changes to individual leucocyte components in the peripheral blood are sufficiently characteristic to provide useful evidence of infection.

Animals↗
PubMed1985

Genetic factor(s) influence scar formation in experimental pyelonephritis.

Two inbred strains of rat have been identified that show markedly different responses to experimentally induced renal infection. Experiments involving these two strains and their F1 progeny have shown that a genetic factor either protects the host from a tissue-destructive inflammatory response (autosomal dominant gene) or potentiates lesion formation (autosomal recessive gene). The data are the first indication that genetic factors may determine the degree of renal damage in pyelonephritis.

Animals↗
PubMed1985

Immunopotentiation in infectious disease, I. Effect of bestatin on the immune response.

Few immunomodulators are available for the control of infectious disease. One reason has been the lack of a suitable protocol for evaluating such agents. We have presented a series of assays of immune function that will allow a standardized approach to this problem. The value of this protocol has been established using long-term low dose, and short-term high dose, administration of bestatin, a small molecular weight microbial product. The experiments were done using both normal and immunocompromised animals. Bestatin had no effect on circulating leukocytes or the reticuloendothelial system. Leukocyte mobilization and T cell responsiveness in immunocompromised animals were enhanced following bestatin treatment. The antibody response to SRBC doubled in normal animals while the same treatment schedule resulted in a marked reduction in the response to Escherichia coli lipopolysaccharide. These results have established the value of the protocol and identified some new immunomodulating properties of bestatin which may be useful in the control of infectious disease.

Adjuvants, Immunologic↗
PubMed1985

Immunopotentiation in infectious disease, II. Effect of bestatin on experimental infection.

A two-stage protocol designed to evaluate putative immunomodulators for use in infectious disease has been proposed. In this report the effect of bestatin on a series of clinically relevant, and sub-lethal infections is described. Pyelonephritis, peritonitis and bacteremia were induced with Escherichia coli, while Klebsiella pneumoniae was used to produce a lung infection. Bestatin had no effect on the course of these infections. In a further experiment we assessed the effect of combined bestatin/antibiotic therapy on the course of renal infection. Again no effect was observed. These findings are consistent with the known immunomodulatory properties of bestatin. This methodology will be used to evaluate selected agents for their potential in infectious disease and should lead to useful clinical protocols.

Adjuvants, Immunologic↗
PubMed1984

Host resistance to Candida albicans in uraemia.

In renal failure, infection is a frequent complication and cause of death, which suggests that uraemia impairs immunity. In a comparison of Candida albicans fungaemia, peritonitis and subcutaneous infection in normal and severely uraemic rats, uraemia did not affect the course of these infections. C. albicans is an important pathogen in immunocompromised hosts and we conclude that uraemia is unlikely to be the primary factor that increases host susceptibility to infection with this fungus.

Animals↗
PubMed1983

Host immune status in uremia. V. Effect of uremia on resistance to bacterial infection.

Infection is a frequent complication and cause of death in renal failure. Although it is widely accepted that uremia has an adverse effect on host resistance to infectious disease, this association has not been proven. In the present experiments, the relationship between uremia and susceptibility to infection has been investigated using an animal model of chronic, severe uremia. Lung infections (using Pseudomonas aeruginosa and Klebsiella pneumoniae), bacteremia, peritonitis and subcutaneous infection (using Escherichia coli) were induced in uremic and normal rats and the course of infection compared. The ability of the uremic host to clear Ps. aeruginosa from the lung was marginally impaired in the first 24 hr after the challenge but was normal in the later stages of the infection. Similarly, in the bacteremia study, secondary invasion of the lungs by several other species of bacteria occurred in 33% of the uremic animals. We found no other evidence of impairment of immunity in uremia in the infections that we studied and, taken overall, the results support arguments that uremia per se is unlikely to be an important factor predisposing patients with renal failure to infection.

Animals↗