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N MacDonald

Publications and source records attributed to N MacDonald.

At least 19 recordsLinked to original sources
PubMed2002

Retrofitting of a satellite repeat DNA-based murine artificial chromosome (ACes) to contain loxP recombination sites.

A satellite DNA-based mammalian artificial chromosome (ACes) was generated and subsequently modified by targeting of a loxP-red fluorescent protein (RFP) expression cassette via homologous recombination into a ribosomal DNA (rDNA)-containing locus. Clones containing correctly targeted ACes were identified by PCR from populations of RFP-expressing cells enriched by FACS sorting and were further characterized by fluorescent in situ hybridization. The targeted ACes maintained its ability to be purified to near homogeneity. Studies are currently underway to further characterize the functionality, carrying capacity, stability and transfectability of this modified ACes.

Animals↗
PubMed2002

A pilot survey of medical students' perspectives on their educational exposure to palliative care in two Canadian universities.

BACKGROUND: Graduating medical students from the class of 1999 from McGill University and the University of Alberta completed a self-administered, anonymous, pilot survey to determine students' perspectives on how their educational experience in common palliative care topics contrasted with their educational experience in the diagnosis and management of hypertension, non palliative aspects of breast cancer, and patients dying of acquired immune deficiency syndrome (AIDS). METHODS: A Likert scale ranging from "excellent," scored 1, "very poor," scored 5, was used. Students also estimated the number of hours they spent, during their training, in operating rooms, on home visits to terminally ill patients, and in interprofessional teaching. RESULTS: Sixty of 114 (53%) students from McGill University, and 53 of 110 (48%) students from the University of Alberta responded to the survey. The mean ratings of education experience in the various topics for both universities combined were as follows: hypertension, 2.03; breast cancer, 2.33; cancer pain, 3.42; communicating with dying patients, 3.32; and caring for patients with AIDS, 4.15. The average number of hours spent in the operating room, on home visits to terminally patients, and in interprofessional teaching for both universities combined were 155 hours, 4.2 hours, and 16 hours, respectively. Of the responding students from both universities 83% favored increased palliative care teaching. CONCLUSION: Despite the disproportionate number of hours spent in operating rooms compared to palliative care community exposure, only two students, one from each university, favored shortening surgical rotations to allow for increased time for palliative care education. Recommendations, including increasing palliative care education during clinical clerkships, are provided to improve medical students' perceptions of their educational experiences in palliative care education.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype.

OBJECTIVE: To analyze the association of polymorphisms in the tau gene with pathologically confirmed corticobasal degeneration (CBD). BACKGROUND: The authors previously described an extended tau haplotype (H1) that covers the human tau gene and is associated with the development of progressive supranuclear palsy (PSP). The authors now extend this analysis to CBD, a neurodegenerative condition with clinical and neuropathologic similarities to PSP. Like PSP, CBD is associated with accumulation of aggregates containing the 4-repeat isoforms of tau. Because of difficulty in diagnosis of CBD, the authors only analyzed cases with pathologically confirmed CBD. METHODS: The authors collected 57 unrelated, neuropathologically confirmed cases of CBD. Tau sequencing in these cases failed to show the presence of pathogenic mutations. Polymorphisms that spanned the tau gene were analyzed in all CBD cases and controls. RESULTS: Analyzing tau polymorphisms in CBD cases showed that the frequency of H1 and H1/H1 was significantly increased when analyzing all cases and when separating by country of origin. H1 frequency in all CBD cases was 0.921, compared with a control frequency of 0.766 (X(2) = 9.1, p = 0.00255 [1df], OR 3.56 [8.43 > CI 95% > 1.53]). The H1/H1 frequency was also significantly higher at 0.842 compared with 0.596 in age-matched controls (X(2) = 17.42, p = 0.00016, 2df), OR 3.61 [7.05 > CI 95% > 1.85]). CONCLUSIONS: The CBD tau association described here suggests that PSP and CBD share a similar cause, although the pathogenic mechanism behind the two diseases leads to a different clinical and pathologic phenotype.

Genotype↗
PubMed2001

A flow cytometry technique for measuring chromosome-mediated gene transfer.

BACKGROUND: Using artificial chromosome expression systems (ACes), we have developed a unique and rapid screening technique to quantify delivery of foreign DNA into cells in vitro. Delivery was measured within 24 h after transfection, using flow cytometry to detect the transfer of ACes labeled with thymidine analogue. This technique can be used to optimize delivery parameters of ACes and heterologous DNA into cells and eventually tissue. METHOD: Chinese hamster ovary (CHO) cells carrying artificial chromosomes were grown in media supplemented with iododeoxyuridine (IdUrd). The 60-mb artificial chromosome was purified by flow cytometry sorting and transfected into Chinese hamster lung fibroblast cells (V79-4) or mouse connective tissue cells [LM(tk-)] using LipofectAMINE 2000trade mark, a cationic lipid, and Superfecttrade mark, a cationic dendrimer. The cells were incubated with an FITC-conjugated anti-bromodeoxyuridine (BrdUrd) antibody and analyzed by flow cytometry. IdUrd-incorporated artificial chromosome expressing green fluorescent protein (GFP) was transfected into V79-4 cells. Delivery was measured at 24 h and GFP expression was detected at 48 h. RESULTS: The delivery of intact artificial chromosomes into V79-4 and LMtk- cells was detected within 2 h and up to 48 h post-transfection. Maximum delivery rates of 20% and 14% were observed using LipofectAMINE 2000 and Superfect, respectively. Flow cytometry data correlated with microscopic observations. IdUrd incorporation resulted in less quenching after staining with Hoechst 33258 and chromomycin A3 than BrdUrd incorporation. The fluorescence intensity of the FITC-conjugated anti-BrdUrd antibody was greater with IdUrd-incorporated chromosomes than with BrdUrd-incorporated chromosomes. CONCLUSION: The results indicate that IdUrd-labeled artificial chromosomes can be detected 24 h after transfection. This efficient, sensitive, high-throughput detection technique is being used to evaluate and optimize other transfer technologies (e.g., electroporation and sonoporation), different delivery reagents, and protocols in a variety of cells in vitro. This work represents the first step in utilizing artificial chromosomes as nonviral vectors for gene therapy.

Animals↗
PubMed2001

Waiting time for breast cancer surgery in Quebec.

BACKGROUND: Currently there is no agreement on the optimal time to treatment of breast cancer; however, given the considerable emphasis on early detection, one would expect a similar emphasis on early treatment. The purpose of our study was to assess the time interval to surgery from initiation of diagnosis among Quebec women with breast cancer and to examine the influence on waiting time of age, pattern of care and cancer stage. METHODS: Records of physician fee-for-service claims and of hospital admissions were obtained for all Quebec women who underwent an invasive procedure for the diagnosis or treatment of breast cancer between 1992 and 1998. Waiting time was calculated as the number of days between the first diagnostic procedure and surgical treatment. RESULTS: There were 29,606 episodes of breast cancer surgery among 28,100 women: 5922 mastectomies and 23,684 lumpectomies. The absolute number of episodes of breast cancer treated with surgery rose from 3626 in 1992 to 5162 in 1998. The overall median waiting time was 34 days (interquartile range [IQR] 19-62); 13.5% of the women waited longer than 90 days. The median waiting time rose from 29 days (IQR 15-54) in 1992 to 42 days (IQR 24-72) in 1998, representing a relative increase of 37% (95% confidence interval [CI] 32%-43%) after adjusting for age and cancer stage. The median waiting time increased with the number of diagnostic procedures, from 24 days (IQR 14-42) with 1 procedure to 48 days (IQR 27-84) with 3 procedures to 72 days (IQR 43-121) with 4 procedures, representing adjusted relative increases of 97% (95% CI 91%-103%) and 194% (95% CI 181%-208%), respectively. The proportion of women receiving 3 or more diagnostic procedures before surgery increased steadily over the study period, from 19.2% in 1992 to 33.0% in 1998. The median waiting time was shorter with more advanced stages of cancer: 53 days (IQR 30-86) for carcinoma in situ, 35 (IQR 20-62) for localized disease, 28 (IQR 16-49) for regional disease and 24 (IQR 11-52) for disseminated disease. INTERPRETATION: Waiting time between initial diagnosis and first surgery for breast cancer has increased substantially in Quebec between 1992 and 1998. Possible explanations include increased demand, decreased resources and changes in patterns of care.

Adult↗
PubMed2001

PTEN methylation is associated with advanced stage and microsatellite instability in endometrial carcinoma.

Loss of heterozygosity and mutations in the PTEN (MMAC1) tumor suppressor gene are frequent in endometrial carcinoma. Promoter hypermethylation has recently been identified as an alternative mechanism of tumor suppressor gene inactivation in cancer, but its importance in the PTEN gene in endometrial carcinoma is unknown. The purpose of our study was to assess the frequency of promoter methylation of the PTEN gene and to determine its correlation with clinicopathologic variables in a prospective and population-based series of endometrial carcinomas with complete follow-up. Presence of PTEN promoter methylation was seen in 26 of 138 patients (19%). Methylation was significantly associated with metastatic disease (p = 0.01) and a microsatellite unstable phenotype (p = 0.006). In conclusion, we find that PTEN promoter methylation is relatively frequent in endometrial carcinoma. Its association with metastatic disease and microsatellite instability implicates its importance in the development of this tumor type.

Alleles↗
PubMed2001

Predictive model for immunotherapy of alopecia areata with diphencyprone.

BACKGROUND: Immunotherapy with diphencyprone (diphenylcyclopropenone) is used in the treatment of alopecia areata (AA). Response rates have varied in the literature. OBJECTIVES: To determine the efficacy of diphencyprone therapy for AA in the largest reported cohort of patients; to identify patient and treatment factors predictive of therapeutic success; and to develop a practical model for predicting patient response. METHODS: The medical records of 148 consecutive patients treated with diphencyprone were reviewed. A clinically significant response to diphencyprone therapy was defined as a cosmetically acceptable response or greater than 75% terminal hair regrowth. Survival analyses using the Kaplan-Meier method and the Cox proportional hazards model were performed to determine significant factors predictive of regrowth and relapse. RESULTS: Using a survival analysis model, the cumulative patient response at 32 months was 77.9% (95% confidence interval, 56.8%-98.9%). Variables independently associated with clinically significant regrowth were age at onset of disease and baseline extent of AA. Older age at onset of AA portended a better prognosis. A cosmetically acceptable end point was obtained in 17.4% of patients with alopecia totalis/universalis, 60.3% with 75% to 99% AA, 88.1% with 50% to 74% AA, and 100% with 25% to 49% AA. A lag of 3 months was present between initiation of therapy and development of significant hair regrowth in the first responders. Relapse after achieving significant regrowth developed in 62.6% of patients. CONCLUSIONS: Response to diphencyprone treatment in AA is affected by baseline extent of AA and age at disease onset. A prolonged treatment course might be necessary. A predictive model has been developed to assist with patient prognostication and counseling.

Adolescent↗
PubMed2000

The Immunization Monitoring Program Active (IMPACT) prospective five year study of Canadian children hospitalized for chickenpox or an associated complication.

BACKGROUND: Varicella vaccine was approved for use in Canada in 1998. A major goal of universal varicella vaccine programs is to reduce severe infection and associated complications. Baseline data are essential against which to judge the effectiveness of routine childhood immunization. OBJECTIVE: To describe morbidity and mortality among children hospitalized for chickenpox. Methods. From January 1, 1991, to March 31, 1996, chickenpox admissions to 11 pediatric referral centers were actively identified. Patient and illness characteristics were compared for 3 subgroups defined by prior health: healthy; unhealthy but immunocompetent; immunocompromised. RESULTS: Of 861 cases 488 (56.7%) were healthy, 75(8.7%) were unhealthy and 298 (34.6%) were immunocompromised. The immunocompromised children differed from healthy/unhealthy cases in mean age (6.4 vs. 4.0/4.6 years, respectively, P < 0.0001); median interval from rash onset to admission (2 vs. 5/5 days, P < 0.0001); complication rate (20% vs. 90%/79%; P = 0.001); and rate of acyclovir therapy (98% vs. 24%/39%; P = 0.001). Unhealthy vs. healthy cases had a higher frequency (P < 0.01) of intensive care (13.3% vs. 4.7%), ventilation (9.3% vs. 2.0%) and death (4% vs. 0.2%). CONCLUSION: These data provide a baseline for morbidity/mortality resulting from chickenpox before varicella vaccine use in Canada.

Adolescent↗
PubMed2000

American Academy of Pediatrics. Technical report: transmissible spongiform encephalopathies: A review for pediatricians. Committee on Infectious Diseases.

Transmissible spongiform encephalopathies (TSEs) are a family of rare, slowly progressive, and universally fatal neurodegenerative syndromes affecting animals and humans. Until recently, TSEs were of little interest to pediatricians. However, since the outbreak in adolescents and the association of TSEs with new-variant Creutzfeldt-Jakob disease (nvCJD), interest among pediatricians and the general public has increased. Even before bovine spongiform encephalopathy and nvCJD were linked, the recognition that iatrogenic Creutzfeldt-Jakob disease (CJD) had been acquired from administration of cadaveric human growth and gonadotropic hormones and from corneal and dura mater transplants prompted medical vigilance. Furthermore, recent concern about the potential for transmission of CJD by blood and blood products has raised awareness among public health and regulatory agencies, pediatricians, and the public, although no epidemiologic data support this concern. Because of worldwide concern (although no cases have been reported in North America), this review focuses on the potential impact of TSEs, particularly CJD and nvCJD, on the pediatric population.

Humans↗
PubMed2000

Monitoring signals for vaccine safety: the assessment of individual adverse event reports by an expert advisory committee. Advisory Committee on Causality Assessment.

Monitoring vaccine safety is a complex and shared responsibility. It can be carried out in many ways, one of which is the reporting of individual cases of adverse reactions thought to be due to vaccination. The task is difficult because ascribing causality to an individual case report is fraught with challenges. A standardized evaluation instrument--known as the causality assessment form--was therefore developed for use by an expert advisory committee to facilitate the process. By following the several sections in this form, the members of the committee are taken through a series of points to establish causality. These points include the basic criteria for causation such as biological plausibility, the time elapsed between the vaccine administration and the onset of the adverse event, and whether other factors (drugs, chemicals or underlying disease) could account for the adverse symptoms. The form concludes with a consensus assessment of causality, a commentary about the assessment, and advice for further study or follow-up. This method of assessing the more serious cases of adverse reaction reported to vaccination has proven useful in evaluating ongoing safety of vaccines in Canada. Through analyses such as this, new signals can be identified and investigated further.

Adverse Drug Reaction Reporting Systems↗
PubMed2000

Methylation of hMLH1 in a population-based series of endometrial carcinomas.

Microsatellite instability (MSI) is a characteristic feature of hereditary nonpolyposis colorectal cancer and is also observed in sporadic colorectal and endometrial cancers. Alterations in the mismatch repair genes hMLH1 and hMSH2 are important for the development of MSI. It has recently been demonstrated that hypermethylation of the hMLH1 promoter region is associated with MSI and appears to be a common mechanism for gene inactivation. For endometrial carcinoma, however, previous studies have been relatively small and have not been population based. We therefore wanted to assess the frequency and prognostic significance of hypermethylation of the hMLH1 and hMSH2 genes in conjunction with hMLH1 protein expression in a prospective and population-based series of endometrial carcinoma patients with known MSI status and complete follow-up. A total of 138 patients were studied, and methylation of hMLH1 was found in 23% of tumors with conclusive results, whereas methylation of hMSH2 was seen in only 1% of tumors. Methylation of hMLH1 was significantly correlated with MSI (P < 0.001). Loss of nuclear staining of hMLH1 protein was seen in 14% of the cases and was significantly correlated with hMLH1 methylation and MSI (P < 0.001). Normal expression of hMLH1 was seen in all of the unmethylated tumors (100%). Of the 14 MSI-positive tumors that were also methylated, all but 1 (93%) showed a loss of nuclear expression of hMLH1. None of the tumors with loss of hMLH1 expression or hMLH1 methylation were aneuploid (P for both < or = 0.05), and loss of hMLH1 expression and hMLH1 methylation was significantly correlated with lack of p53 overexpression (P for both < or = 0.05). Nuclear hMLH1 staining and hMLH1 methylation did not significantly influence survival. In conclusion, hMLH1 methylation was common and was significantly correlated with loss of hMLH1 protein expression, MSI, diploid tumors, and lack of p53 overexpression. In contrast, hMSH2 methylation was infrequent in this prospective and population-based series of endometrial carcinomas.

Adaptor Proteins, Signal Transducing↗
PubMed2000

The Canadian Palliative Care Education Group.

The Canadian Palliative Care Education Group, a committee of the Canadian Society of Palliative Care Physicians, carries out surveys from time to time on the status of palliative care education in Canadian medical schools. We describe the organization of the Canadian Palliative Care Education Group and report on a survey carried out in the 1996-97 academic year. Our data suggest that the emphasis on palliative care varies widely amongst the 16 Canadian medical schools, in concert with the availability of academic staff positions in palliative care. We conclude that the need for palliative care education is supported by rhetoric which remains to be matched by proportionate tangible investment.

Canada↗
PubMed1999

Risk factors for resistance to "first-line" antimicrobials among urinary tract isolates of Escherichia coli in children.

BACKGROUND: There are increasing concerns regarding antimicrobial resistance in Canada. Data are limited on the prevalence, patterns of resistance and risk factors associated with resistant organisms, including coliforms, in children. This study was done to address these issues as they relate to urinary tract isolates of Escherichia coli in a tertiary care pediatric centre in Ottawa. METHODS: A surveillance study was conducted from December 1992 to December 1994. Susceptibility testing of urinary tract isolates of E. coli was performed using a panel of antimicrobial agents. A case-control study was also conducted for subjects with isolates resistant to trimethoprim-sulfamethoxazole (T-S), this drug being used a representative "first-line" agent. RESULTS: A total of 1636 consecutive isolates were obtained from 967 subjects. Of the 1636 isolates, 736 (45.0%) were resistant to ampicillin, 514 (31.4%) were resistant to T-S, 363 (22.2%) were resistant to both ampicillin and T-S, and 27 (1.7%) were resistant to both ampicillin and gentamicin. In the case-control study 274 children with isolates resistant to T-S were matched with 274 children who had T-S-sensitive isolates obtained during the study period or the preceding or subsequent 6 months. Multivariate analyses indicated that subjects who had received antimicrobials for more than 4 weeks in the previous 6 months were about 23 times more likely to have isolates resistant to T-S than were subjects without this risk factor (odds ratio [OR] 23.4, 95% confidence interval [CI] 12.0-47.6). Children with genitourinary tract abnormalities were 2.4 times more likely to have resistant isolates than those without such abnormalities (95% CI 1.2-4.5). Compared with children who had no hospital admissions in the previous year, those with 1 admission in that period were more likely to have resistant isolates (OR 2.3, 95% CI 1.4-7.5), as were those with 2 or more admissions in that period (OR 3.2, 95% CI 1.1-4.8). Compared with children aged 2-6 years, children under 2 years of age were less likely to have resistant isolates (OR 0.3, 95% CI 0.2-0.8). INTERPRETATION: Selective antimicrobial pressure and multiple admissions to hospital were among the risk factors associated with antimicrobial resistance. The finding of a low but definite level of resistance to both ampicillin and gentamicin is important for the selection of empiric therapy for sepsis in neonates. The role of inexpensive first-line agents in the outpatient treatment and prevention of urinary tract infections requires re-examination, particularly in children who have recently received antimicrobial therapy.

Anti-Bacterial Agents↗