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Biomedical subjects

C Bolton

Publications and source records attributed to C Bolton.

At least 19 recordsLinked to original sources
PubMed2006

Glutamate-stimulated peroxynitrite production in a brain-derived endothelial cell line is dependent on N-methyl-D-aspartate (NMDA) receptor activation.

There is accumulating and convincing evidence indicating a role for glutamate in the pathogenesis of the human demyelinating disease multiple sclerosis (MS). Studies in experimental autoimmune encephalomyelitis (EAE), the animal model of MS, demonstrate that pharmacological inhibition of specific glutamate receptors suppresses neurological symptoms and prevents blood-brain barrier (BBB) breakdown. The mechanisms through which glutamate influences BBB function during EAE remain unclear. Glutamate triggers the production of nitric oxide and superoxide, which can lead to the formation of peroxynitrite (ONOO(-)). Recent studies have implicated ONOO(-) in the loss of neurovascular integrity during EAE. We propose that glutamate contributes to BBB breakdown via the actions of ONOO(-). The present investigation examined glutamate-induced ONOO(-) formation in the b.End3 brain-derived endothelial cell line. b.End3 cells were incubated with a concentration range of glutamate and ONOO(-) production was assessed over time. Results showed a concentration- and time-dependent increase in ONOO(-) levels in glutamate-treated cells that were suppressed by selective and non-selective inhibitors of ONOO(-)-mediated reactions. Specific activation of b.End3-associated NMDA receptors also resulted in a concentration-dependent increase in ONOO(-) production. The ability of b.End3 cells to respond to the presence of glutamate was confirmed through the detection of NMDA receptor immnuoreactivity in cell extracts. In addition, the use of the NMDA receptor antagonists MK-801 and memantine reduced glutamate-mediated ONOO(-) generation from b.End3 cells. The data reinforce the important relationship between glutamate and the NMDA receptor, positioned at neurovascular sites, which may be of particular relevance to the pathogenesis of demyelinating disease.

Animals↗
PubMed2002

Asbestos-related disease.

Until the 1980s, asbestos was widely used throughout the UK. The incidence of asbestos-related disease is still climbing because of the long delay in developing the disease from the initial exposure. The spectrum of diseases encompasses malignant mesothelioma, asbestosis, asbestos-related lung carcinoma and benign pleural disease, including pleural plaques.

Asbestos↗
PubMed2001

Regional access to acute ischemic stroke intervention.

BACKGROUND AND PURPOSE: Benefit-risk ratios from recombinant tissue plasminogen activator (rtPA) therapy for acute ischemic stroke demonstrate lack of efficacy if intravenous administration is commenced beyond 3 hours of symptom onset. We undertook to enhance therapeutic effectiveness by ensuring equitable access to rtPA for patients affected by acute ischemic stroke within a 20 000 km(2) population referral base served by a tertiary facility. METHODS: Representatives of all provider groups involved in emergency medical services developed a Regional Acute Stroke Protocol (RASP), a coordinated regional system response by dispatch personnel, paramedics, physicians, community service providers, emergency and inpatient staff in community hospitals, and the tertiary facility acute stroke team. RESULTS: As of July 26, 1999, all ambulance services in Southeastern Ontario began bypassing the closest hospital to deliver patients meeting the criteria for the RASP to the Kingston General Hospital. At 12 months, approximately 403 ischemic strokes have occurred in the region, the RASP has been activated 191 times, and 42 patients have received rtPA. CONCLUSIONS: We conclude that (1) acute stroke patients in Southeastern Ontario have improved access to interventions for stroke care; (2) geography of the region is not a barrier to access to interventions for patients with acute stroke; and (3) acute ischemic stroke patients treated with rtPA account for 5% of all acute strokes and 10% of all ischemic strokes in this region.

Aged↗
PubMed2000

The detection and quantitation of inflammation in the central nervous system during experimental allergic encephalomyelitis using the radiopharmaceutical 99mTc-RP128.

RP128 is a novel agent which readily chelates 99mTc to form a radiopharmaceutical which binds in vivo to the tuftsin receptor located specifically on neutrophils and monocyte-macrophages, therefore removing the need for in vitro cell labelling prior to intravenous administration. We have assessed the ability of 99mTc-RP128 to detect central nervous system (CNS) inflammation in experimental allergic encephalomyelitis (EAE), an animal model of the human disease multiple sclerosis. The radiopharmaceutical was recorded at significantly increased levels in all EAE diseased CNS tissues, compared to normal and control samples, at 0.5, 1 and 3 h post-injection using a dual radioisotope technique to correct for non-extravasated tracer (P<0.05). Moreover, extravascular accumulation of the agent could be clearly demonstrated in inflammatory tissues with minimal loss of sensitivity when the secondary isotopic correction for blood volume was omitted. In addition, 99mTc-RP128 successfully monitored glucocorticoid suppression of inflammation (P<0.05), recording a typical dose-response to increasing steroid concentration. Clearly, 99mTc-RP128 can quantitatively detect CNS inflammation and assess responses to therapy indicating potential value as an imaging agent both clinically and as a research aid. Furthermore, the rapid in vivo labelling by 99mTc-RP128 of specific inflammatory cells combined with the ability to monitor the progress of anti-inflammatory therapeutics may recommend the agent for use in a variety of inflammatory conditions.

Animals↗
PubMed2000

L-arginine modifies free radical production and the development of experimental allergic encephalomyelitis.

OBJECTIVES AND DESIGN: The present investigation examines the effects of increasing central nervous system (CNS) levels of nitric oxide (NO), via the administration of L-arginine, on the development of experimental allergic encephalomyelitis (EAE). SUBJECTS: EAE was induced in male Lewis rats (200-250 g). TREATMENT: Normal rats were orally dosed with L-arginine (300 mg/kg body weight) once daily for 12 days. EAE-sensitised animals received L-arginine (300 mg/kg body weight) once daily from day 1 to 12 post-inoculation. METHODS: Neurological and histological development of EAE were assessed. In addition, CNS cytosol levels of nitrite, superoxide and hydrogen peroxide were measured. Results were analysed using the Mann Whitney U-test and Chi-squared test. RESULTS: L-arginine administration significantly delayed disease onset (p < 0.05) and reduced the severity of neurological (p < 0.05) and histological (p < 0.001) signs of EAE. Treatment with L-arginine caused a significant elevation in CNS nitrite concentrations (p < 0.05) which in EAE-sensitised animals was associated with a concomitant and dramatic decrease in superoxide (p < 0.05) and hydrogen peroxide (p < 0.05) levels. CONCLUSIONS: The results suggest that NO may act as a protective molecule during the development of EAE possibly via the modulation of oxidant-mediated neuroinflammation.

Animals↗
PubMed1999

Physicians' perceptions of the effect on clinical services of an alternative funding plan at an academic health sciences centre.

BACKGROUND: In July 1994 an alternative funding plan for clinical services (global funding instead of fee-for-service payment) was established at the Southeastern Ontario Health Sciences Centre, Kingston, Ont. This study describes the perceptions of the referring physicians and consultants of the effects of the alternative funding plan 2.5 years after it was initiated. METHODS: A questionnaire was mailed to all physicians in the Kingston area in November 1996. Information was collected on demographics, referring physicians' perceptions of the funding plan's impact on their practices, consultants' perceptions of its impact on their activities, perceptions of referring and consultant physicians of its impact on services provided by consultants, and attitudes toward alternative funding in the context of the Ontario health care system. RESULTS: Of the 772 physicians 531 (68.8%) returned a completed questionnaire (323 referring physicians and 208 consultants). A sizeable proportion of the referring physicians (126 [39.0%]) indicated that they were referring fewer patients to consultants at the study centre. They did not think that their practice volume had increased, but they did report spending more time on complex cases and on patient care after referral or hospital stay, and more time coordinating community care after hospital stay. Of the consultants 81 (38.9%) believed that their time spent on patient care had increased. No consistent impact on time spent on research or teaching activities was perceived. A total of 54 (26.0%) of the consultants were concerned about the impact of the alternative funding plan on quality of care. A significant proportion of the respondents (399 [75.1%]) believed that outpatient waiting times had increased, and 116 (35.9%) of the referring physicians believed that consultants were not as available by telephone. Most (220 [68.1%]) of the referring physicians believed that the funding change had had a negative effect on health care services in the region, and 87 (41.8%) of the consultants agreed. Nevertheless, the respondents believed that other factors such as funding cuts, hospital bed closures and staff layoffs were much more responsible than the alternative funding plan for their negative perceptions. INTERPRETATION: The alternative funding plan appears to have had an impact on the practices of individual physicians. However, it was not the focus for significant opposition or support from either consultants participating in the funding plan or referring physicians.

Academic Medical Centers↗
PubMed1998

Substituting home care for hospitalization: the role of a quick response service for the elderly.

The purpose of the present study was to examine the role of a rapid access home-based service as a means for the elderly to avoid admission to an acute-care hospital. The setting for the study included emergency departments in three acute care hospitals and a home care program in a mid-size Canadian city. Multiple sources of information were obtained to evaluate the service. Hospital emergency department records and home care records were reviewed. Patients who participated in the service (n = 96) and physicians and nurses (n = 119) who had involvement with the service were surveyed appraising the service in terms of relevance, access, quality and coordination. Study results revealed that elderly women with multiple health problems who lived alone were the most frequent users of the service. The majority of the patients admitted to the service presented with problems of a functional nature that were the result of a fall or mobility problems. The results indicated that the service did avert hospital admissions and facilitated a process by which patients could avoid the intermediate step of hospitalization before placed in a higher level of care or returning to previous levels of functioning. Economic analysis indicated that the value of the service stemmed from the benefits to patients and caregivers rather than from cost savings offered to acute care hospitals.

Activities of Daily Living↗
PubMed1997

Effect of concentrated red grape juice consumption on serum antioxidant capacity and low-density lipoprotein oxidation.

This study examines whether the beneficial antioxidant effects of red wine can be reproduced by nonalcoholic red grape juice concentrate. Seven subjects consumed 125 ml concentrate daily for 7 days. Following first ingestion there was a rise in serum total antioxidant capacity (TAC) from 441 to 478 mumol/l at 60 min (p < 0.005). On day 8, TAC was 50 mumol/l higher than at baseline (p < 0.05). There was reduced susceptibility of low-density lipoprotein (LDL) to oxidation. Red grape juice concentrate ingestion results in increased serum antioxidant capacity and protection of LDL from oxidation and thus nonalcoholic red grape extract may have similar beneficial effects to red wine.

Adult↗
PubMed1997

Regulation of chronic relapsing experimental allergic encephalomyelitis by endogenous and exogenous glucocorticoids.

Expression, development and resolution of the acute form of experimental allergic encephalomyelitis (EAE), typically induced in the highly susceptible Lewis rat, are closely regulated by endogenous corticosteroids. Administration of synthetic glucocorticoids also efficiently controls the manifestation of disease. The pivotal role played by the corticosteroids in modifying the induction and progression of EAE is further emphasised by a reversal of corticoid-mediated effects through adrenalectomy or treatment with the steroid receptor antagonist RU486 (mifepristone). Chronic relapsing EAE (CREAE) is characterised by acute symptoms, periods of remission and re-emergence of disease. The mechanisms governing the development of CREAE are unclear, but may require the regulatory influence of endogenous glucocorticoids. The current study has monitored circulating corticosteroids throughout the course of CREAE in the Biozzi ABH mouse and found that major fluctuations in systemic levels coincide with the relapsing-remitting phases of the disease. Furthermore, increasing circulating adrenocorticoids through administration of the steroidal compound dexamethasone markedly suppresses the occurrence of acute signs. The importance of the glucocorticoids in controlling CREAE is again highlighted by the intensification of symptoms and reduction in the survival rate of inoculated mice receiving RU486 prior to and during the acute phase of disease. The data reinforce the amelioratory actions of exogenous and naturally occurring glucocorticoids in the pathogenesis of EAE and extend earlier observations in the monophasic disease by demonstrating corticosteroid-dependent effects in a relapsing-remitting mouse model.

Animals↗
PubMed1997

MK-801 limits neurovascular dysfunction during experimental allergic encephalomyelitis.

Increased permeability of the blood-brain barrier (BBB) is a characteristic of the demyelinating disease multiple sclerosis and the animal counterpart experimental allergic encephalomyelitis (EAE). In physically traumatized cerebral tissue neurovascular damage, linked with activation of the cerebroendothelial-bound N-methyl-D-aspartate receptor, can be treated with the antagonist MK-801. We have examined the ability of MK-801 to modify BBB leakage and the development of disease during EAE. Prophylactic MK-801, at 0.15 mg kg(-1) body weight suppressed neurovascular breakdown, measured by a dual radioisotope technique, and significantly reduced neurological deficits (P < .05), but not perivascular lesions. A 2-fold increase in administered MK-801 completely prevented abnormal extravasation in cerebella (P < .01) and significantly inhibited BBB disruption in medulla-pons (P < .05) and cervical spinal tissues (P < .01). High-dose treatment also restricted disease development (P < .01) and lesion formation (P < .05). Therapeutic MK-801, at 0.30 mg kg(-1) body weight, completely counteracted neuroendothelial leakage in cerebella (P < .05) and inhibited BBB dysfunction in remaining tissues without restricting inflammatory cell invasion. However, doubling the dose did not further enhance suppression of neurovascular breakdown. Our use of MK-801 to control major features of EAE strongly implicates N-methyl-D-aspartate receptor-dependent mechanisms in disease development and prompts consideration of a role for the receptor in the pathogenesis of human demyelinating conditions.

Animals↗
PubMed1996

A pharmacological study on the role of nitric oxide in the pathogenesis of experimental allergic encephalomyelitis.

OBJECTIVE AND DESIGN: The study examines the effects of nitric oxide synthase (NOS) inhibitors on the development of neurological EAE and the levels of nitrite in the central nervous system (CNS) during established disease. MATERIALS: EAE was induced in male Lewis rats (200-250 g). TREATMENT: Rats received NG-nitro-L-arginine methyl ester (L-NAME) (30 mg/kg body weight) day 7 to 12 post-inoculation (P.I.), 7-nitroindazole (10 mg/kg) day 7 to 11 P.I. or aminoguanidine (200 or 400 mg/kg) day 1 to 12 P.I. METHODS: Neurological symptoms were assessed and CNS cytosol nitrite and protein levels measured. Results were analysed using the Mann Whitney U-test and the Fischer exact probability test. RESULTS: Symptoms of EAE were associated with a significant elevation in CNS nitrite (p < 0.001). Treatment with NOS inhibitors caused a marked reduction in nitrite levels (p < 0.01). However, in some experiments, vehicle administration also reduced CNS nitrite content (p < 0.05). Although neurological disease was suppressed in EAE-sensitised rats receiving L-NAME (2 +/- 0.3 vs 3 +/- 0.3 mean peak severity +/- SEM) and 7-nitroindazole (1 +/- 0.3 vs 3 +/- 0.3, p < 0.01) comparable inhibition was achieved by respective vehicle treatment (p < 0.01). In contrast, neither aminoguanidine nor corresponding vehicle altered disease development. CONCLUSIONS: Drug-induced reductions in CNS nitrite levels during EAE are not always associated with a suppression of neurological symptoms, which suggests NO is not of primary importance in disease pathogenesis. In addition, the study emphasises the strict requirement for appropriate controls when assessing the efficacy of drugs on the course of EAE.

Animals↗
PubMed1996

Lack of influence of intestinal transit on oxidative status in premenopausal women.

OBJECTIVE: There are reasons for believing that diet can alter the risk of malignancy by alteration of the body's oxidative status. Intestinal contents and enterohepatically recirculated substances are influenced by intestinal transit rate. A low fibre diet has been linked to the increase in constipation seen in countries consuming a westernized diet, as well as to the aetiology of many diseases. We studied the effects of altering intestinal transit rates and of wheat bran on oxidative status. DESIGN: 40 premenopausal women were randomized to receive dietary supplements of wheat bran, senna or loperamide for the length of two menstrual cycles. Dietary records, whole gut transit time (WGTT) and plasma lipid peroxides, measured as TBARS (specifically malondialdehyde) were determined at the beginning and end of each intervention. SETTING: University department of Medicine, Bristol Royal Infirmary. RESULTS: 36 volunteers completed the study. WGTT increased in those receiving loperamide and decreased in those receiving senna. The decrease in WGTT was not significant in those receiving wheat bran. Diets did not change. There were no changes in TBARS, cholesterol, triglyceride or TBARS adjusted for cholesterol and triglyceride, during any intervention. CONCLUSIONS: Dietary supplementation with wheat bran and pharmacological alteration of intestinal transit had no influence on oxidative status or on plasma cholesterol or triglycerides.

Adult↗
PubMed1995

Changes in the cellular distribution of lipocortin-1 (Annexin-1) in C6 glioma cells after exposure to dexamethasone.

Glucocorticoid-induced changes in cellular levels of Lipocortin-1 (LC-1) (Annexin 1) in C6 glioma cells were determined by electrotransfer and immunoblotting techniques. Separate cell protein fractions were prepared to study the influence of the glucocorticoid steroid, dexamethasone, on LC-1 localisation. Cells were grown in steroid-depleted medium and exposed to dexamethasone (10(-8) and 10(-7) M) for 2, 6, and 16 hr. The glucocorticoid-dependent changes in cellular content of LC-1 were both dose- and time-related. Increases above control levels in intracellular and extracellular LC-1 content were detected with the greatest changes occurring at the cell surface. The glucocorticoid-dependent alteration in LC-1 distribution in C6 glioma cells was attenuated by the protein synthesis inhibitor, cycloheximide, indicating the involvement of de novo LC-1 synthesis. The significance of these results is discussed in relation to the current concept that some of the anti-inflammatory effect of glucocorticoids occurs through the action of extracellular LC-1.

Annexin A1↗
PubMed1995

Dexamethasone induces an increase in intracellular and membrane-associated lipocortin-1 (annexin-1) in rat astrocyte primary cultures.

1. The antiinflammatory actions of glucocorticoid steroids are thought to occur through induction of the protein lipocortin-1 (LC-1; annexin-1). The purpose of the current study was to investigate whether astrocytic LC-1 content was increased in the presence of a synthetic glucocorticoid, dexamethasone. 2. Steroid-induced changes in cellular levels of LC-1 in astrocytes were determined by electrotransfer and immunoblotting techniques. Separate cell fractions were investigated to study the influence of dexamethasone on astroglial LC-1 content. The effect of culture state on LC-1 expression was also examined. 3. Intracellular LC-1 content was found to decrease after initiation of culture, with a substantial rise in both cell proliferation and LC-1 expression occurring after the replenishment of medium containing steroid-free serum. A further increase in intracellular LC-1 occurred upon incubation with dexamethasone. The glucocorticoid-induced change in intracellular LC-1 was a time-dependent event and coincided with an increase in membrane-associated LC-1. 4. The findings in this study indicate that astrocytic LC-1 content is influenced by cell culture conditions and, in the presence of glucocorticoid steroids, the cellular localization of LC-1 is altered. This may indicate that LC-1 has functions at more than one cellular locality.

Animals↗
PubMed1995

Inhibition of blood-brain barrier disruption in experimental allergic encephalomyelitis by short-term therapy with dexamethasone or cyclosporin A.

Double radioisotope measurement of neurovascular integrity in Lewis rats inoculated for experimental allergic encephalomyelitis (EAE) showed abnormal elevation of albumin extravasation in the cerebellum, medulla-pons and cervical spinal cord at the time of clinical manifestation. Therapeutically administered dexamethasone (Dex) (0.1-1 mg/kg body weight) or cyclosporin A (CsA) (25-75 mg/kg body weight) dose-dependently reduced albumin movement across the blood-brain barrier (BBB). Dex at a dose of 1 mg/kg completely suppressed abnormal BBB permeability in all tissues (P < or = 0.001), while CsA at the highest dose of 75 mg/kg achieved highly significant (P < or = 0.001), but not complete, suppression of aberrant barrier leakage in the areas studied. The implications of these findings to possible drug action at the immunocompromised cerebrovasculature are discussed.

Animals↗