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Biomedical subjects

M Macdonald

Publications and source records attributed to M Macdonald.

At least 19 recordsLinked to original sources
PubMed2003

Nasal carriage of Mycobacterium leprae DNA in healthy individuals in Lega Robi village, Ethiopia.

The number of registered leprosy patients world-wide has decreased dramatically after extensive application of WHO recommended Multiple Drug Therapy (MDT). The annual number of new cases has, however, been almost unchanged in several populations, indicating that the infection is still present at community level. Nasal carriage of Mycobacterium leprae DNA was studied in Lega Robi village in Ethiopia. MDT had been applied for more than ten years, and 718 residents over 5 years old were eligible for the study. During the first survey nasal swab samples were collected from 664 (92.5%) individuals. The results of a Peptide Nucleic Acid-ELISA test for M. leprae DNA interpreted by stringent statistical criteria were available for 589 (88.7%) subjects. Thirty-five (5.9%) individuals without clinical signs of leprosy were positive for M. leprae DNA. Seven PCR positive individuals lived in a household where one or two other members were also positive for M. leprae DNA. During a second survey 8 (46%) of 175 interpretable PNA-ELISA tests were positive. Of 137 individuals tested twice, only two were positive on both occasions whereas 10 were PCR positive only once. The study confirms the widespread distribution of M. leprae DNA in healthy individuals. The feasibility of curbing possible transmission of subclinical infection needs further consideration.

Adolescent↗
PubMed2003

Impact of an interdisciplinary low vision service on the quality of life of low vision patients.

AIM: To investigate the impact of an interdisciplinary low vision service on the vision related quality of life of service users. METHODS: 71 patients were interviewed 2 weeks before their appointment with the service and again 6 months later to assess any changes in their vision related quality of life. The majority of these patients had age related macular degeneration. RESULTS: After contact with the service the majority of patients indicated a reduction in concern about most quality of life issues. They were significantly less anxious about deterioration of their vision, safety within the home, and coping with everyday life. CONCLUSION: Improvements in many areas of their vision related quality of life indicate that this interdisciplinary low vision service has a positive impact on the lives of service users. However many patients were still unable to carry out their preferred everyday activities, and feelings of loneliness and isolation were unchanged. The identification of issues unrelieved by input from the service will be important in planning future service delivery.

Activities of Daily Living↗
PubMed2001

Dendritic cells infected with Mycobacterium bovis bacillus Calmette Guerin activate CD8(+) T cells with specificity for a novel mycobacterial epitope.

Although CD4(+) T cells are essential for protective immunity against Mycobacterium tuberculosis infection, recent reports indicate that CD8(+) T cells may also play a critical role in the control of this infection. However, the epitope specificity and the mechanisms of activation of mycobacteria-reactive CD8(+) T cells are poorly characterized. In order to study the CD8(+) T cell responses to the model mycobacterial antigen, MPT64, we used recombinant vaccinia virus expressing MPT64 (VVWR-64) and a panel of MPT64-derived peptides to establish that the peptide MPT64(190-198) contains an H-2D(b)-restricted CD8(+) T cell epitope. A cytotoxic T lymphocyte response to this peptide could be demonstrated in M. bovis bacillus Calmette Guerin (BCG)-infected mice following repeated in vitro stimulation. When bone marrow-derived dendritic cells (DC) were infected with BCG, the expression of MHC class I molecules by DC was up-regulated in parallel with MHC class II and B7-2, whereas CD1d expression level was not modified. Moreover, BCG-infected DC activated MPT64(190-198)-specific CD8(+) T cells to secrete IFN-gamma, although with a lower efficacy than VVWR-64-infected DC. The production of IFN-gamma by MPT64(190-198)-specific CD8(+) T cells was inhibited by antibodies to MHC class I, but not to CD1d. These data suggest that mycobacteria-specific CD8(+) T cells are primed during infection. Therefore, anti-mycobacterial vaccine strategies targeting the activation of specific CD8(+) T cells by DC may have improved protective efficacy.

Animals↗
PubMed2001

Simplified PCR detection method for nasal Mycobacterium leprae.

We report here a simplified method for the detection of nasal carriage of Mycobacterium leprae. DNA extracted from nasal swabs was analyzed by PCR, and M. leprae specific amplicons detected by means of a novel peptide-nucleic-acid-ELISA (PNA-ELISA) method. Parameters for the method were established using swabs taken from untreated lepromatous leprosy patients. We have developed this method to study nasal carriage in endemic populations. However, due to the sensitivity of PCR based techniques, we wished to assess the possibility of false positive samples arising in our method. We therefore examined samples taken from individuals in Norway, a country non-endemic for leprosy, using our technique. A total of 219 nasal swabs were collected and tested in our laboratory in London. All of these were found to be negative by our criteria. In order to corroborate our results, and also to assess the specificity of the method, a small number of these samples were randomly selected, and a known amount of M. leprae DNA added to them. All 219 samples were then retested using the same techniques under "double blind" conditions in our laboratory in India. All of the samples to which M. leprae DNA had been added were successfully identified by this method whereas all other swabs were negative. Taken together, these results suggest that the technique described here is simple, sensitive, and specific for use in large-scale epidemiological studies. This study, part of the larger MILEP 2 study, represents the first use of a PNA-PCR method for an epidemiological study of infection. The method using PNA-ELISA is significantly simpler and more rapid than gel based detection methods. The supply of laboratory consumables and overall detection procedure were simplified and standardized by use of PCR Ready-to-Go beads.

DNA, Bacterial↗
PubMed1999

Resource allocation in integrated delivery systems and healthcare networks: a proposed framework to guide ethical thinking.

Drawing on a management perspective and the literature, this article suggests an ethical framework to be used at the meso or community level of resource allocation in a Canadian setting. The suggested framework enlarges on the program-level framework developed by Meslin et al primarily by building in stakeholder inclusiveness and public accountability, both of which are essential to resource allocation at the population-based level.

Canada↗
PubMed1999

Differential protective efficacy of DNA vaccines expressing secreted proteins of Mycobacterium tuberculosis.

The development of more-effective antituberculosis vaccines would assist in the control of the global problem of infection with Mycobacterium tuberculosis. One recently devised vaccination strategy is immunization with DNA plasmids encoding individual microbial genes. Using the genes for the M. tuberculosis secreted proteins MPT64 (23 kDa), Ag85B (30 kDa), and ESAT-6 (6 kDa) as candidate antigens, DNA vaccines were prepared and tested for immunogenicity and protective efficacy in a murine model of aerosolized tuberculosis (TB). Intramuscular immunization with DNA-64 or DNA-85B resulted in the activation of CD4(+) T cells, which produce gamma interferon (IFN-gamma), and high titers of specific immunoglobulin G antibodies. Further, DNA-64 induced major histocompatibility complex class I-restricted CD8(+) cytotoxic T cells. The addition of a eukaryotic leader sequence to mpt64 did not significantly increase the T-cell or antibody response. Each of the three DNA vectors stimulated a significant reduction in the level of M. tuberculosis infection in the lungs of mice challenged 4 weeks after immunization, but not to the levels resulting after immunization with Mycobacterium bovis BCG. The vaccines showed a consistent hierarchy of protection, with the most effective being Ag85B, followed by ESAT-6 and then MPT64. Coimmunization with the three vectors resulted in a greater degree of protection than that induced by any single vector. This protective efficacy was associated with the emergence of IFN-gamma-secreting T cells earlier than in infected animals immunized with a control vector. The efficacy of these DNA vaccines suggests that multisubunit vaccination may contribute to future vaccine strategies against TB.

Acyltransferases↗
PubMed1999

CCR2-64I polymorphism is not associated with altered CCR5 expression or coreceptor function.

A polymorphism in the gene encoding CCR2 is associated with a delay in progression to AIDS in human immunodeficiency virus (HIV)-infected individuals. The polymorphism, CCR2-64I, changes valine 64 of CCR2 to isoleucine. However, it is not clear whether the effect on AIDS progression results from the amino acid change or whether the polymorphism marks a genetically linked, yet unidentified mutation that mediates the effect. Because the gene encoding CCR5, the major coreceptor for HIV type 1 primary isolates, lies 15 kb 3' to CCR2, linked mutations in the CCR5 promoter or other regulatory sequences could explain the association of CCR2-64I with slowed AIDS pathogenesis. Here, we show that CCR2-64I is efficiently expressed on the cell surface but does not have dominant negative activity on CCR5 coreceptor function. A panel of peripheral blood mononuclear cells (PBMC) from uninfected donors representing the various CCR5/CCR2 genotypes was assembled. Activated primary CD4(+) T cells of CCR2 64I/64I donors expressed cell surface CCR5 at levels comparable to those of CCR2 +/+ donors. A slight reduction in CCR5 expression was noted, although this was not statistically significant. CCR5 and CCR2 mRNA levels were nearly identical for each of the donor PBMC, regardless of genotype. Cell surface CCR5 and CCR2 levels were more variable than mRNA transcript levels, suggesting that an alternative mechanism may influence CCR5 cell surface levels. CCR2-64I is linked to the CCR5 promoter polymorphisms 208G, 303A, 627C, and 676A; however, in transfected promoter reporter constructs, these did not affect transcriptional activity. Taken together, these findings suggest that CCR2-64I does not act by influencing CCR5 transcription or mRNA levels.

Blood Donors↗
PubMed1998

Using the balanced scorecard to align strategy and performance in long-term care.

The Sisters of Charity of Ottawa Health Service (SCOHS) is a Canadian health care corporation that has adapted Kaplan and Norton's balanced scorecard to enhance strategic management and measurement in a multisite health care facility comprising long term care, continuing complex care, rehabilitative services, palliative care and ambulatory care. This article discusses how the SCOHS has incorporated the following principles into the balanced scorecard: demonstration of cause and effect; inclusion of outcomes and performance drivers; linkage to fiscal and utilization indicators; and integration of the mission and values of the organization. Examples of corporate level outcomes and performance measures are provided in the form of lead and lag indicators.

Delivery of Health Care, Integrated↗
PubMed1997

Acceleration of VO2 kinetics in heavy submaximal exercise by hyperoxia and prior high-intensity exercise.

We examined the hypothesis that O2 uptake (VO2) would change more rapidly at the onset of step work rate transitions in exercise with hyperoxic gas breathing and after prior high-intensity exercise. The kinetics of VO2 were determined from the mean response time (MRT; time to 63% of total change in VO2) and calculations of O2 deficit and slow component during normoxic and hyperoxic gas breathing in one group of seven subjects during exercise below and above ventilatory threshold (VT) and in another group of seven subjects during exercise above VT with and without prior high-intensity exercise. In exercise transitions below VT, hyperoxic gas breathing did not affect the kinetic response of VO2 at the onset or end of exercise. At work rates above VT, hyperoxic gas breathing accelerated both the on- and off-transient MRT, reduced the O2 deficit, and decreased the VO2 slow component from minute 3 to minute 6 of exercise, compared with normoxia. Prior exercise above VT accelerated the on-transient MRT and reduced the VO2 slow component from minute 3 to minute 6 of exercise in a second bout of exercise with both normoxic and hyperoxic gas breathing. However, the summated O2 deficit in the second normoxic and hyperoxic steps was not different from that of the first steps in the same gas condition. Faster on-transient responses in exercise above, but not below, VT with hyperoxia and, to a lesser degree, after prior high-intensity exercise above VT support the theory of an O2 transport limitation at the onset of exercise for workloads >VT.

Adult↗
PubMed1997

Modulation of macrophage function for defence of the lung against Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a common respiratory tract pathogen in certain groups of compromised hosts, most notably those with cystic fibrosis. The pathogenicity of P. aeruginosa may depend in part upon its capacity to resist normal phagocytic cell clearance. We have recently shown that phagocytosis of P. aeruginosa by macrophages is a unique two-step process; binding is glucose-independent but ingestion occurs only in the presence of D-glucose or D-mannose. P. aeruginosa is the only particle we have found which is ingested by macrophages in a glucose-dependent manner. Since glucose is present in only negligible quantities in the endobronchial space, P. aeruginosa may be pathogenic by virtue of its capacity to exploit the opportunity presented in the lower airway to resist normal nonspecific phagocytic defences. The purpose of the studies reported here is to better understand the glucose-dependent phagocytosis of P. aeruginosa and to design novel therapies to facilitate phagocytic cell clearance of it from the lower respiratory tract. We have shown that phagocytosis of unopsonized P. aeruginosa depends upon facilitated transport of glucose into macrophages via the GLUT1 isoform. After transport into the macrophage, the glucose must be metabolized to trigger phagocytosis of P. aeruginosa; pretreatment with 2-deoxyglucose or 5-thioglucose abrogates glucose-dependent ingestion. We have recently demonstrated that pulmonary alveolar macrophages (as opposed to all other macrophage phenotypes studied) lack the capacity to transport glucose and to phagocytose unopsonized P. aeruginosa; however, after the cells have been cultured in vitro for 48 hours, they are able to perform both functions. Whereas most macrophages (such as peritoneal cells) primarily depend upon glycolysis for metabolic energy, pulmonary alveolar macrophages reside in a high oxygen tension environment and appear to utilize oxidative phosphorylation. Treatment of freshly explanted pulmonary alveolar macrophages with sodium azide (to poison oxidative respiration) dramatically enhances both glucose transport and glucose-dependent phagocytosis of P. aeruginosa. We are currently investigating the compromised phagocytic function of pulmonary alveolar macrophages and the mechanism by which azide enhances glucose transport and phagocytosis of P. aeruginosa. Although physiological measurements have indicated that glucose is removed from the endobronchial space by an active transport process of the lung epithelium, the types of glucose transporters that are expressed in the lung are as yet unknown. Using RT-PCR, we have amplified a product from human and murine lung RNA which has a high degree of homology with members of the sodium-dependent glucose transporter (SGLT) family. The ultimate goal of these studies is to design novel agents for enhancing the phagocytic function of pulmonary alveolar macrophages. Delivery of simple glucose by aerosol would not be effective because (i) it would be exported by sodium-dependent active transport and (ii) pulmonary alveolar macrophages lack the capacity to transport glucose. Various approaches for targeting glucose to alveolar macrophages by receptor-mediated endocytosis are under investigation.

Animals↗
PubMed1996

Is paclitaxel and cisplatin a cost-effective first-line therapy for advance ovarian carcinoma?

BACKGROUND: Paclitaxel and cisplatin use for the treatment of advanced ovarian carcinoma (AOC) has been shown to increase median survival duration. An evaluation was performed on the economic consequences of treating AOC patients with combined paclitaxel and cisplatin chemotherapy compared with current usual care, i.e., combined cyclophosphamide and cisplatin chemotherapy. METHODS: Linear modeling techniques combined with retrospective chart analysis were used to predict the clinical progression and treatment of AOC patients until death. Cost-effectiveness analysis comparing paclitaxel and cisplatin and usual care was performed from a simplified Ministry of Health perspective. RESULTS: Assuming a 50% increase in survival for paclitaxel and cisplatin patients, an assumption supported by recent clinical trial data, this treatment showed an average lifetime cost per patient of $50,054 Cdn compared with a cost of $36,837 Cdn for usual care. The incremental cost of the paclitaxel and cisplatin treatment over the usual treatment was $20,355 Cdn per life year gained. These results withstood extensive sensitivity analyses. CONCLUSIONS: Paclitaxel, in combination with cisplatin, appears to be a cost-effective first-line treatment for AOC. A moderate increase in incremental cost compares favorably with other life-saving strategies currently in use. As more data become available for the use of paclitaxel, this pilot study will provide a basis for more extensive economic evaluation of paclitaxel.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Governance for quality: getting to the heart of it.

This article discusses the information a board needs to ensure that a systematic and strategic approach is taken to the management of quality throughout the organization; the outcomes of care/service meet professional standards, external requirements and key expectations of clients; and care/service is continually being improved. A practical framework for the reporting of quality management issues and their implications is provided, within the context of a chronic care/long-term care setting with multiple levels of care. The constraints presented by issue-based reporting are also addressed briefly.

Canada↗
PubMed1994

Expression of mRNA encoding FMRFamide-related peptides (FaRPs) in the nervous system of Helix aspersa.

The FMRFamide-related peptides (FaRPs) of Helix fall into two groups with often different pharmacological effects: the tetrapeptides FMRFamide and FLRFamide (tetraFaRPs) and the heptapeptides, which have the general structure XDP(F or Y)LRFamide (heptaFaRPs). Previously, we have shown that each group of FaRPs is encoded within a separate type of cDNA clone, a situation which corresponds to two distinct mRNA species existing in the CNS of Helix. Here, we report on the expression patterns of the two FaRP mRNAs both through embryo-genesis and in the fully differentiated regions of the adult nervous system. The levels and locations of FaRP mRNAs were studied by molecular and in situ hybridization using antisense riboprobes. The onset of expression of FaRP mRNAs occurs in Helix embryos about half-way between egg laying and hatching. First detection of the FaRPs themselves occurs about 2 days later. In embryos, as in the adult CNS, the heptaFaRP mRNA is at least five times more abundant than the tetraFaRP mRNA. In adults, the tetraFaRP mRNA is located primarily in the cerebral ganglia, most obviously in the C3 neuron, but also in a crescent-shaped cluster of small neurons lying anterior to C3. Occasional neurons expressing the tetraFaRP mRNA are detected in the parietal ganglia, but these have not yet been mapped. In contrast, the heptaFaRP mRNA is expressed almost exclusively in the parietal ganglia: in large clusters of about 100 neurons lying near to the anterior surface. The most interesting aspect of FaRP mRNAs is that their expression is not only exclusive to a relatively small number of specified neurons, but that expression appears to be mutually exclusive, that is, a particular neuron expresses only the mRNA for tetra-FaRPs or heptaFaRPs, never both. These results are discussed in relation to what we now know about the structure of the individual mRNA molecules.

Age Factors↗
PubMed1993

Phase I study of 5-fluorouracil and leucovorin by a 14-day circadian infusion in metastatic adenocarcinoma patients.

Initial experimental and clinical studies have indicated that 5-fluorouracil (5-FU) toxicity can be reduced by delivering 5-FU at around 4 a.m. More recent data have suggested that the toxicity might be reduced even more with delivery at around 9-10 p.m. The current study determined the maximum tolerated dose (MTD) for 5-FU and leucovorin (LV) delivered as a continuous circadian infusion over 14 days every 28 days, with the peak of the infusion occurring at around 3-4 a.m. The peak drug delivery was shifted to 9-10 p.m. in all patients developing toxicity of > or = grade II (Eastern Cooperative Oncology Group) to determine if this timing further reduced toxicity and enabled increased dose intensity. A total of 14 patients with metastatic adenocarcinoma received an admixture of 5-FU and LV via a programmable portable infusion pump, with 62.5% of the 24-h dose being given over 7 h around the infusion peak. The starting dose level of 5-FU (200 mg/m2 daily) and LV (5 mg/m2 daily) was that established as the highest tolerable dose rate in a previously reported phase I study using a 14-day flat infusion of 5-FU and LV. The LV dose was first escalated to 20 mg/m2 daily, followed by escalations of the 5-FU dose. A total of 51 courses were evaluable for toxicity. The dose-limiting toxicity was oral mucositis and hand-foot syndrome. More dose intensity could be delivered using a circadian infusion peaking at around 3-4 a.m. than was possible with a flat infusion of these drugs. Toxicity was reduced even further with peak drug delivery at around 9-10 p.m. The recommended dose for phase II studies using this schedule is 250 mg/m2 5-FU daily and 20 mg/m2 LV daily with the peak of the infusion occurring at 9-10 p.m. This is a 300% and 25% higher dose for LV and 5-FU, respectively, than was found to be safe for a flat infusion.

Adenocarcinoma↗
PubMed1993

High prevalence of mefloquine-resistant falciparum malaria in eastern Thailand.

In order to assess the risk and predictors of mefloquine resistance we monitored a cohort of 113 patients in eastern Thailand who had been treated for uncomplicated falciparum malaria with a single dose of 15 mg/kg of the drug and followed up for 42 days. The overall treatment failure rate at day 42 was 59.1% (95% confidence interval (CI) = 50%, 68%) with only 2.7% of the patients being lost to follow-up. There were 6.4% RIII, 20.9% RII, 31.8% RI, and 40.9% sensitive responses, based on a modified WHO classification. A low haemoglobin level on the day of treatment and diarrhoea during the first two days after treatment were independent predictors of treatment failure. These findings remained statistically significant in a Cox proportional hazards model, after controlling for other baseline characteristics and adverse effects. Although a history of digestive disorders prior to treatment was associated with diarrhoea on day 2 (P = 0.024), it was in itself not a predictor of treatment failure (adjusted hazard ratio = 1.16; 95% CI = 0.35, 2.14). A total of 60 patients with an R response were hospitalized for 7 days to receive supervised treatment with quinine-tetracycline. Only three had a positive thick smear for asexual forms of Plasmodium falciparum 14 days later, and quinine-tetracycline therefore remains a good alternative treatment for mefloquine-resistant falciparum malaria.

Adolescent↗