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Biomedical subjects

C Bolton

Publications and source records attributed to C Bolton.

At least 37 records · Page 2Linked to original sources
PubMed1995

Endogenous corticosteroids modulate lymphoproliferation and susceptibility to experimental allergic encephalomyelitis in the Brown Norway rat.

Successful induction of the experimental autoimmune disease allergic encephalomyelitis (EAE) depends, in part, upon species susceptibility. The Lewis rat is highly susceptible to EAE whereas the Brown Norway (BN) strain is resistant to induction. Endogenous glucocorticoids influence the manifestation of the disease and recovery from neurological deficits. Moreover, abrogation of the curative steroid-mediated effects converts the condition to a terminal state. In the present study treatment of EAE-inoculated BN rats with the steroid antagonist RU486 (Mifepristone) failed to influence the resistance to symptoms. Similarly, adrenalectomy (ADX) prior to sensitisation did not allow the development of clinical EAE but did facilitate neuroperivascular accumulation of inflammatory-type cells. However, RU486 treatment after ADX induced neurological and histological signs of EAE in the majority of animals. Lymphocyte proliferation studies on cells isolated from BN rats treated with RU486 revealed an enhanced responsiveness to mitogenic and antigenic stimulation. These results strongly implicate endogenous steroids in the expansion of immune cell numbers which would be an absolute requirement for the expression of autoimmune-based neurological disease in otherwise resistant rats.

Adrenal Cortex Hormones↗
PubMed1995

Recent advances in the pharmacological control of experimental allergic encephalomyelitis (EAE) and the implications for multiple sclerosis treatment.

The autoimmune, cell-mediated condition experimental allergic encephalomyelitis (EAE) is the representative model for the inflammatory central nervous system disease MS. EAE has been extensively employed to determine the efficacy of pharmacological agents that may be of ultimate use in the treatment of MS. A wide variety of drugs has been examined for activity in EAE but, over the last decade, three groups of compounds have emerged with clear and reproducible ability to modify significantly the onset and progression of the disease. The immunosuppressants, the modulators of catecholamine activity and the antineoplastic agents have convincingly altered the course of EAE and, as a consequence, provided understanding of the mechanisms of disease expression and offered further insight into the pathogenesis of MS. The article stresses the usefulness of EAE as a model to identify prospective pharmacological treatments for MS and, in particular, considers those compounds subsequently assessed for their ability to interfere with the progression of the human disease.

Animals↗
PubMed1995

Measurement of malondialdehyde as a marker of oxygen free radical production during renal allograft transplantation and the effect on early graft function.

We prospectively measured malondialdehyde (MDA), a marker of free radical oxygen damage during 44 renal transplant operations. When corrected for intra-operative changes in plasma volume, there was a significant increase in the ratio of MDA to total cholesterol (x10 3), from a median of 0.32 (0.24-0.44) (interquartile range) to 0.39 (0.31-0.50) at 30 minutes following reperfusion, p < 0.01 and to 0.36 (0.31-0.51) after 60 minutes, p < 0.01; whereas there was no intra-operative increase in MDA in 10 patients undergoing routine elective surgery, who acted as controls. The change in MDA/cholesterol ratio at both 30 and 60 minutes following reperfusion was greater in those patients with poor early graft function (serum creatinine > 250 umol/l at the end of the 1st post-operative week), mean 0.32 (sem 0.08) at 30 min and 0.32 (0.09) at 60 min, compared to those with good function (serum creatinine < 250 umol/l), 0.12 (0.05) and 0.10 (0.04) respectively, p < 0.05. This suggests that the products of oxygen free radical damage can be measured during renal transplantation, and that they may have an adverse effect on early graft function.

Adult↗
PubMed1994

Re-engineering: a prescription for hospitals.

Previously applied mostly in large, private sector corporations, "re-engineering" is fast becoming a tool that hospitals can use to break away from the old to find a new and better way of doing things. Re-engineering, however, first requires strong leadership which is committed to employee involvement and re-inventing the process design to meet the needs of the customers. Once the transition has been completed, the processes and the organization must continue to be managed differently. This article reviews the processes involved in re-engineering, and discusses the implementation of the initiative at the Sunnybrook Health Science Centre in Toronto.

Hospital Restructuring↗
PubMed1994

A comparison of antioxidant status and free radical peroxidation of plasma lipoproteins in healthy young persons from Naples and Bristol.

Ischaemic heart disease mortality is much lower in Southern Italy than in the U.K. and this is not entirely explained by differences in classical risk factors. Differences in antioxidant intake, affecting free radical peroxidation of plasma lipoproteins, may be relevant. Therefore, dietary intake, antioxidant status and plasma lipid peroxidation were compared in healthy young persons eating typical regional diets from Naples (22) and Bristol (26). The Naples group consumed more fresh tomatoes, more fat as monounsaturates (from olive oil) and had higher plasma levels of the lipid antioxidants vitamin E (mean (SD; 95% CI) 29.1 (4.5; 26.8 to 31.3) vs 25.1 (3.86; 23.4 to 26.8) mumol.l-1, P = 0.005) and beta-carotene (4.74 (1.2; 4.14 to 5.34) vs 2.85 (0.8; 2.5 to 3.2) mumol.l-1, P < 0.001). Intakes of vitamin C, total uncooked fruit and vegetables, plasma vitamin A, serum selenium and copper levels were similar. All indices of plasma lipid peroxidation were significantly lower in the Naples group: conjugated dienes (median (interquartile range; non-parametric 95% CI)) 29 (21.5-39.9; 24 to 36.7) vs 41.5 (37-48.5; 38 to 44.5) mumol.l-1, P < 0.001; diene conjugation index 1.38 (1.02-1.55; 1.06 to 1.49) x 10(-2) vs 1.57 (1.43-1.74; 1.44 to 1.71) x 10(-2), P = 0.019; lipid peroxides (geometric mean (95% CI) 1.24 (1.12 to 1.37) vs 4.58 (3.84 to 5.46) mumol.l-1, P < 0.001.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Nifedipine does not affect free radical induced lipid peroxidation following renal allograft reperfusion.

We prospectively measured lipid peroxidation following reperfusion during 44 renal allograft transplant operations. Twenty-four (55%) recipients were taking nifedipine pre- and then postoperatively, and 20 (45%) were not. There were no differences between the groups in terms of recipient or donor status. Plasma malondialdehyde (MDA), mean 2.2 (0.2) mumol/L (SEM) vs. 1.73 (0.1) was greater in the group not prescribed nifedipine, p < .05, as were cholesterol; 5.89 (0.3) mmol/L vs. 5.58 (0.3) and triglycerides; 2.19 (0.2) mmol/L vs. 1.82 (0.2). Following allograft reperfusion there was a significant increase in the ratio of MDA/cholesterol (x 10(3)) (MDA corrected for changes in plasma volume) from 0.33 (0.03) in the nifedipine group to 0.38 (0.02) at 30 min after reperfusion and 0.38 (0.03) at 60 min, p < .01, and similarly from 0.4 (0.04) to 0.48 (0.03) at 30 min and 0.47 (0.05) after 60 min in the other group, p < .01. There was no difference in the percentage change in MDA/cholesterol ratio between the groups; 27 (5)% vs. 19 (6) at 30 min and 20 (8) vs. 15 (8) at 60 min for the nifedipine and no-nifedipine groups, respectively. There was no difference in postoperative renal function between the groups. This study suggests that the oral administration of nifedipine may not prevent the production of lipid peroxides, as measured by changes in plasma malondialdehyde, following renal allograft reperfusion and that it does not affect renal function in the early postoperative period.

Adult↗
PubMed1993

Lipocortin 1 (annexin 1) immunoreactivity in the cervical spinal cord of Lewis rats with acute experimental allergic encephalomyelitis.

Spontaneous recovery from acute experimental allergic encephalomyelitis (EAE) by the Lewis rat is probably mediated by endogenous corticosteroids. It has been proposed that the anti-inflammatory actions of the glucocorticoids may be effected via the induction of mediator proteins termed lipocortins and recently we have demonstrated increased levels of lipocortin 1 in the central nervous system (CNS) of EAE-diseased rats (Bolton C., A-J. Elderfield and R.J. Flower (1990), J. Neuroimmunol. 29: 173-181). In this study, utilizing antisera raised against recombinant human lipocortin 1, immunohistochemistry and light microscopy have been used to determine the distribution of the protein in the cervical spinal cord of Lewis rats during EAE. In normal animals lipocortin 1 immunoreactivity was localized predominantly in the walls of larger blood vessels and to a lesser extent capillaries. The same staining pattern was found in adjuvant-inoculated controls. In sections from EAE-inoculated animals there was no change during the induction phase, but with the onset of clinical symptoms and the appearance of inflammatory infiltrates in the CNS, a marked increase in lipocortin 1 immunostaining was observed. This additional staining was due to widespread immunoreactivity of the lesions, was maximal at the height of disease and decreased following recovery and lesion regression. Within the lesions the vast majority of infiltrating lymphocytes and macrophages were positive for lipocortin 1, including some very heavily stained macrophage-like cells. Measurement of corticosterone in the sera of these animals showed that changes in lipocortin 1 immunostaining in the CNS during EAE closely parallel serum corticosterone levels.

Acute Disease↗
PubMed1992

The efficacy of cyclosporin A, FK-506 and prednisolone to modify the adoptive transfer of experimental allergic encephalomyelitis (EAE).

The in vitro potency of the immunosuppressants Cyclosporin A (CsA), FK-506 and Prednisolone was assessed using the adoptive transfer model of EAE in the Lewis rat. Co-culture of encephalitogen-sensitised splenic leukocytes with Prednisolone did not inhibit the transfer of disease to naive histocompatible recipients despite significant suppression of neuroantigen-stimulated leukocyte proliferation by the drug. The addition of CsA (100 nM) to cultures inhibited the induction of adoptive EAE but a lower dose of the agent (10 nM) did not prevent the development of clinico-histopathological signs of disease. FK-506 (1 nM) was 100 times more effective than CsA at suppressing adoptive EAE thus emphasising the usefulness of the model in determining the relative efficacy of compounds to modify cell-dependent autoimmune disease.

Animals↗
PubMed1992

Lipocortins (annexins) 1, 2, 4 and 5 are increased in the central nervous system in multiple sclerosis.

Western blotting and densitometry have been used to investigate the lipocortin content of post-mortem central nervous system (CNS) tissue samples from multiple sclerosis (MS) patients and normal controls. Lipocortins 1, 2, 4 and 5 were all detected in normal control grey and white matter. In white matter samples from MS patients these lipocortins were found to be significantly increased, a further elevation in lipocortin content was observed in MS plaque tissue. The implications of these findings with respect to the role of these proteins in inflammatory CNS disease and a possible mechanism of steroid action in the therapy of MS are discussed.

Adult↗
PubMed1989

The effects of the anti-glucocorticoid RU 38486 on steroid-mediated suppression of experimental allergic encephalomyelitis (EAE) in the Lewis rat.

Lewis rats, sensitised for the autoimmune condition EAE received a range of doses of the steroid dexamethasone at various times post-inoculation in an attempt to modify the clinical course of the disease. Depending upon the dosing regime employed microgram quantities of the steroid were sufficient to significantly inhibit the clinical development of EAE and milligram doses of the drug completely suppressed the emergence of disease. Administration of the potent anti-glucocorticoid RU38486 to sensitised animals intensified the clinical course of EAE and reversed the steroid-induced inhibition of the disease. Furthermore, after the characteristic loss of neurological symptoms in rats receiving dexamethasone and RU38486, readministration of the anti-glucocorticoid resulted in clinical relapses in the majority of animals. The study emphasises the potent effects of exogenous, physiologically relevant doses of steroid on the course of EAE and, as a result of the observations made using RU38486, considers the role of endogenous steroids in the control of the disease in the rat.

Animals↗
PubMed1989

Breast milk fatty acids in mothers of children with atopic eczema.

The total lipid fatty acid composition of mature breast milk has been analysed in a group of twenty-five mothers of children with atopic eczema, and compared with breast milk from twenty-two controls. Total lipids were extracted into chloroform-methanol (2:1, v/v) and the methyl esters prepared by alkalicatalysed trans-esterification were separated by gas-liquid chromatography and identified by comparison with standard fatty acid methyl esters. Results show that mothers of children with atopic eczema have a significantly greater proportion of linoleic acid, and a smaller proportion of dihomo-gamma-linolenic acid in their total breast milk lipid than the controls. Proportions of total derived fatty acids were similar between groups and there were no differences in the principal saturated and monounsaturated fats. It was concluded that mothers of children with atopic eczema have an abnormal breast-milk fatty acid composition. This supports previous evidence of a defect of conversion of linoleic acid into its long-chain polyunsaturated metabolites in the condition.

Adult↗
PubMed1986

The production of prostaglandin and the regulation of cell division in neonate rat primary mixed glial cultures.

The production of prostaglandins has been studied in neonate rat primary mixed glial cultures. A correlation was found between inhibition of [3H]thymidine incorporation in the cultures and production of prostaglandin, which was stimulated by the addition of supernatant from Con A-activated rat splenocytes. Inhibition of prostaglandin synthesis in the cultures by indomethacin results in a striking increase in incorporation of [3H]thymidine into the cultures, an effect which was reversed by the addition of exogenous PGE2, but not PGF2 alpha. PGE was the principal prostaglandin detected, with both macrophages/microglia and astrocytes contributing to the output. A possible role for prostaglandins in the modulation of inflammatory responses in the central nervous system is discussed.

Animals↗
PubMed1986

A study of the prostaglandin and thromboxane content of the central nervous tissues with the development of chronic relapsing allergic encephalomyelitis.

Levels of PGE, PGF2 alpha, 6-oxo-PGF1 alpha and thromboxane (TXB2) in spinal cords and cerebellums of guinea pigs at different stages of chronic relapsing allergic encephalomyelitis (CREAE) were compared with those in Freund's adjuvant-treated, age-matched controls. PGE and TXB2 levels were found to be increased in spinal cords during acute and relapse phases of the disease. The number of lesions in the spinal cord was similarly increased in acute and relapse stages. There was, however, no similar correlation between number of lesions and eicosanoid levels in the cerebellum with the clinical stages of the disease based on hind limb paralysis. In the acute phase and remission lesion numbers were low, and high levels, similar to those found in the spinal cord, were only found in the relapse phase. Eicosanoid levels were high in the acute phase and remission, and generally low in relapse. The spinal cord levels of eicosanoids in remission and relapse correlated well with previous data obtained from the CSF of patients with multiple sclerosis.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Effects of cyproterone acetate and a long-acting LHRH analogue on serum lipoproteins in patients with carcinoma of the prostate.

Fasting serum lipoproteins were measured in 10 untreated patients with carcinoma of the prostate (Group I), 17 patients with non-malignant urological disorders (Group II), and 12 patients on cyproterone acetate (Group III) and 5 on a long-acting luteinizing hormone-releasing hormone (LHRH) analogue (Group IV) for at least 2 months for carcinoma of the prostate. Total high-density lipoprotein (HDL) cholesterol levels were significantly lower in patients in Group III than all the other groups. Very low-density lipoprotein (VLDL) triglyceride levels were significantly higher in patients in Group III than those in Groups II and IV. These results suggest a potentially adverse effect of cyproterone acetate, but not of the long-acting LHRH analogue, on serum lipids, which is likely to be of relevance only in younger patients.

Buserelin↗