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Biomedical subjects

D MacDonald

Publications and source records attributed to D MacDonald.

At least 19 recordsLinked to original sources
PubMed2007

Measurement of process as quality control in the management of acute surgical emergencies.

BACKGROUND: Quality of care measured by adverse events cannot address errors of process that have no adverse outcomes. The aim of this study was to determine whether process could be used to assess quality of care and whether process analysis could be used to assess interventions designed to improve quality. METHODS: A single-centre prospective cohort study was performed over 12 weeks in an acute surgical admission unit. Data were collected prospectively for the first 24 h of admission on three aspects of process: documentation, general management and presentation-specific criteria. After a period of observation, the impact of three interventions (active observation, increasing awareness and issuing a job description) on the mean number of process errors per patient (process score) was compared. RESULTS: The analysis was based on 566 patients admitted with general surgical pathology. Awareness of being observed failed to improve the process score. Interventions that increased awareness of process reduced the overall process score from 4.79 to 2.38 errors per person (P < 0.001). The mean overall process score in patients with an adverse event was twice that of patients who did not have an adverse event (5.74 (95 per cent confidence interval 4.03 to 7.45) versus 3.43 (3.19 to 3.66)). CONCLUSION: Process can be measured objectively and used as a measure of quality of care. Interventions to increase awareness reduced process error rates and adverse events.

Acute Disease↗
PubMed2006

The effects of dexamethasone and dehydroepiandrosterone (DHEA) on cytokines and receptor expression in a human osteoblastic cell line: potential steroid-sparing role for DHEA.

Osteoporosis and associated fractures are the most common and debilitating complication of glucocorticoid use. The use of alternative anti-inflammatory agents without the deleterious skeletal effects of glucocorticoids is needed. Dehydroepiandrosterone (DHEA) may have immunomodulatory as well as positive effects on bone. For our further understanding of the mechanisms of action of DHEA, as a steroid-sparing agent, we investigated and compared the effects of dexamethasone (DEX) and DHEA on the regulation of the downstream effector pathway of osteoclastogenesis; RANKL/OPG and a range of inflammatory/pro-resorbing cytokines and receptors using a human clonal osteoblastic cell line. The cells were treated with DEX, DHEA, and androstenedione (ANDI). The mRNA expression of RANKL and OPG was determined by real-time PCR after overnight incubation. The regulation of a broad spectrum of cytokines by DEX and DHEA was also investigated using a human cytokine/growth factor and receptor gene array consisting of 268 cytokine-related cDNAs. To confirm some of the gene expression changes, protein production was measured by ELISA. RANKL expression and RANKL/OPG ratio were increased by DEX. This effect was reversed by co-treatment with both DHEA or ANDI. Several pro-inflammatory/resorptive cytokines including IL-6, IL-4, IFN-gamma, macrophage inhibitory factor (MIF) were down-regulated not only by DEX but also by DHEA. In contrast to DEX, DHEA did not lead to suppression of growth factors including vascular endothelial growth factor (VEGF), fibroblast growth factor-5 (FGF-5), insulin-like growth factor-binding protein3 (IGF-BP3). Several new target genes previously documented to influence bone formation were up-regulated by DHEA such as Notch 2, insulin receptor, thrombin receptor (PAR1). The data suggest that DHEA has immunomodulatory properties without the catabolic effects on bone remodeling, observed with glucocorticoid use. DHEA may thus prove useful as a steroid-sparing agent in the management of inflammatory disorders such as SLE or rheumatoid arthritis. Further in vivo studies are indicated.

Androstenedione↗
PubMed2006

LACE-conditioned autologous stem cell transplantation for relapsed or refractory Hodgkin's lymphoma: treatment outcome and risk factor analysis in 67 patients from a single centre.

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a recognized treatment option for patients with relapsed Hodgkin's lymphoma. We have analysed 67 patients who underwent ASCT after LACE (lomustine (CCNU), cytarabine (Ara-C), cyclophosphamide, etoposide) conditioning for relapsed (n=61) or primary refractory (n=6) Hodgkin's lymphoma. The 100-day treatment-related mortality was 3%. With a median follow-up of 67 months (range 3.3-161.0) the probabilities of overall survival (OS) and progression-free survival (PFS) at 5 years were 68 and 64%, respectively. Probabilities for OS and PFS at 5 years for patients with chemosensitive relapse (n=40) were 81 and 78% versus 50 and 35%, respectively, for patients (n=27) with chemoresistant relapse (P=0.012 for OS, P=0.002 for PFS). In multivariate analysis mixed cellularity classical or lymphocyte-depleted classical histology subtype and haemoglobin level of 10 g/dl or less at the time of ASCT were identified as risk factors for worse OS, whereas stage III or IV disease at diagnosis and disease status at ASCT other than complete or partial remission predicted inferior PFS. LACE followed by ASCT is an effective treatment for the majority of patients with chemosensitive relapsed Hodgkin's lymphoma and a proportion of chemorefractory patients also benefit.

Adolescent↗
PubMed2006

Neuroanatomical and pharmacological assessment of Fos expression induced in the rat brain by the phosphodiesterase-4 inhibitor 6-(4-pyridylmethyl)-8-(3-nitrophenyl) quinoline.

A major obstacle in the therapeutic development of phosphodiesterase-4 (PDE4) inhibitors is the production of adverse side effects such as nausea and vomiting. Immunohistochemical detection of Fos-like immunoreactivity (FLI) was used to address the neuroanatomical basis for the pharmacological actions of PDE4 inhibitors. The potent and selective PDE4 inhibitors 6-(4-pyridylmethyl)-8-(3-nitrophenyl) quinoline (PMNPQ) and rolipram elevated FLI in brain regions potentially relevant to the anti-depressant and emetic effects of PDE4 inhibition. PMNPQ and rolipram elevated FLI in the locus coeruleus, habenula, paraventricular nucleus of the thalamus, amygdala and nucleus accumbens, all structures with strong limbic connectivity implicated in arousal, memory and affective aspects of behaviour. Consistent with the emetic effects of PDE4 inhibitors such as PMNPQ and rolipram, these compounds elevated FLI in caudal brainstem nuclei such as the area postrema and nucleus of the solitary tract. Administration of the NK(1) antagonist RP 67580 prior to PMNPQ reversed increases in FLI produced by PMNPQ in these regions. RP 67580 did not, however, reduce PMNPQ-induced FLI in limbic structures. These findings suggest that PDE4 inhibitors produce emesis by increasing NK(1) receptor activation in the AP/NTS and implicate brain regions associated with reward and mood such as the amygdala, paraventricular nucleus of the thalamus, habenula and nucleus accumbens in the anti-depressant activity of such compounds.

Analgesics↗
PubMed2004

A clinical trial of creatine in ALS.

BACKGROUND: Mitochondrial dysfunction occurs early in the course of ALS, and the mitochondria may be an important site for therapeutic intervention. Creatine stabilizes the mitochondrial transition pore, and is important in mitochondrial ATP production. In a transgenic mouse model of ALS, administration of creatine prolongs survival and preserves motor function and motor neurons. METHODS: The authors conducted a randomized double-blind, placebo controlled trial on 104 patients with ALS from 14 sites to evaluate the efficacy of creatine supplementation in ALS. The primary outcome measure was maximum voluntary isometric contraction of eight upper extremity muscles, with secondary outcomes including grip strength, ALS Functional Rating Scale-Revised, and motor unit number estimates. Patients were treated for 6 months, and evaluated monthly. RESULTS: Creatine was tolerated well, but no benefit of creatine could be demonstrated in any outcome measure. CI analysis showed that the study, although powered to detect a 50% or greater change in rate of decline of muscle strength, actually made an effect size of greater than 23% unlikely. It was also demonstrated that motor unit number estimation was performed with acceptable reproducibility and tolerability, and may be a useful outcome measure in future clinical trials. CONCLUSION: Any beneficial effect of creatine at 5 g per day in ALS must be small. Other agents should be considered in future studies of therapeutic agents to address mitochondrial dysfunction in ALS. In addition, motor unit number estimation may be a useful outcome measure for future clinical trials in ALS.

Adolescent↗
PubMed2004

Ascaridole-less infusions of Chenopodium ambrosioides contain a nematocide(s) that is(are) not toxic to mammalian smooth muscle.

Infusions of Chenopodium ambrosioides (L.) have been used for centuries in the Americas as a popular remedy against intestinal worm infections. The essential oil of Chenopodium ambrosioides contains high levels of ascaridole, which is a potent anthelmintic, but which has also been responsible for human fatalities, leading to its disuse. Almost 90% of the nematocidal activity of Chenopodium ambrosioides infusions was due to a hydrophilic component different from ascaridole. Synthetic ascaridole and the ascaridole from infusions, extracted into hexane, caused a reduction of carbachol-induced contractions in rat gastrointestinal smooth muscle at concentrations required to kill Caenorhabditis elegans (L.). The herbal infusion and the ascaridole-free hexane-extracted aqueous residue of the above infusion, at nematocidal concentrations, had no detectable effect on smooth muscle contraction in the above system. It would appear that the traditional form of usage of Chenopodium ambrosioides infusions as a vermifuge is safer than the use of the herb's essential oil.

Animals↗
PubMed2003

MRI diagnosis of bilateral adrenal vein thrombosis.

We report a case of bilateral adrenal vein thrombosis in an adult female who had a history of breast cancer. The patient does not have clinical, serological or imaging evidence of metastatic disease 14 months from the initial diagnosis. Adrenal vein thrombosis is a rare entity. There have been no previous reports specifically stating an association between adrenal vein thrombosis and hypercoaguability, but there are many cases in the literature documenting venous thrombosis elsewhere within the body in patients with hypercoaguable states. Laboratory testing performed to exclude a hypercoaguable state, revealed heterozygosity for the Factor V Leiden mutation/activated protein C resistance and elevated factor VIII levels [3660 IU l(-1) (<1500)]. This is the first reported case of bilateral metachronous adrenal vein thrombosis in which MRI established the diagnosis.

Adrenal Glands↗
PubMed2002

Uses and limitations of quantitative structure-activity relationships (QSARs) to categorize substances on the Canadian domestic substance list as persistent and/or bioaccumulative, and inherently toxic to non-human organisms.

Under sections 73 and 74 of the revised Canadian Environmental Protection Act (CEPA 1999), Environment Canada and Health Canada must "categorize" and "screen" about 23,000 substances on the Domestic Substances List (DSL) for persistence (P), bioaccumulation (B), and inherently toxic (iT) properties. Since experimental data for P, B and iT are only available for a few DSL substances, a workshop was held to address issues associated with the use of Quantitative Structure-Activity Relationships (QSARs) to categorize these substances. This paper describes the results of an 11-12 November 1999 International Workshop sponsored by Environment Canada to discuss potential uses and limitations of QSARs to categorize DSL substances as either persistent or bioaccumulative and iT to non-human organisms and to recommend future research needed to develop methods for predicting the P, B and iT of difficult-to-model substances.

Canada↗
PubMed2001

A probabilistic atlas and reference system for the human brain: International Consortium for Brain Mapping (ICBM).

Motivated by the vast amount of information that is rapidly accumulating about the human brain in digital form, we embarked upon a program in 1992 to develop a four-dimensional probabilistic atlas and reference system for the human brain. Through an International Consortium for Brain Mapping (ICBM) a dataset is being collected that includes 7000 subjects between the ages of eighteen and ninety years and including 342 mono- and dizygotic twins. Data on each subject includes detailed demographic, clinical, behavioural and imaging information. DNA has been collected for genotyping from 5800 subjects. A component of the programme uses post-mortem tissue to determine the probabilistic distribution of microscopic cyto- and chemoarchitectural regions in the human brain. This, combined with macroscopic information about structure and function derived from subjects in vivo, provides the first large scale opportunity to gain meaningful insights into the concordance or discordance in micro- and macroscopic structure and function. The philosophy, strategy, algorithm development, data acquisition techniques and validation methods are described in this report along with database structures. Examples of results are described for the normal adult human brain as well as examples in patients with Alzheimer's disease and multiple sclerosis. The ability to quantify the variance of the human brain as a function of age in a large population of subjects for whom data is also available about their genetic composition and behaviour will allow for the first assessment of cerebral genotype-phenotype-behavioural correlations in humans to take place in a population this large. This approach and its application should provide new insights and opportunities for investigators interested in basic neuroscience, clinical diagnostics and the evaluation of neuropsychiatric disorders in patients.

Adult↗
PubMed2001

Solution structure of an A-tract DNA bend.

The solution structure of a DNA dodecamer d(GGCAAAAAACGG)/d(CCGTTTTTTGCC) containing an A-tract has been determined by NMR spectroscopy with residual dipolar couplings. The structure shows an overall helix axis bend of 19 degrees in a geometry consistent with solution and gel electrophoresis experiments. Fourteen degrees of the bending occurs in the GC regions flanking the A-tract. The remaining 5 degrees is spread evenly over its six AT base-pairs. The A-tract is characterized by decreasing minor groove width from the 5' to the 3' direction along the A strand. This is a result of propeller twist in the AT pairs and the increasing negative inclination of the adenine bases at the 3' side of the run of adenine bases. The four central thymine bases all have negative inclination throughout the A-tract with an average value of -6.1 degrees. Although this negative inclination makes the geometry of the A-tract different from all X-ray structures, the proton on N6 of adenine and the O4 of thymine one step down the helix are within distance to form bifurcated hydrogen bonds. The 5' bend of 4 degrees occurs at the junction between the GC flank and the A-tract through a combination of tilt and roll. The larger 3' bend, 10 degrees, occurs in two base steps: the first composed of tilt, -4.1 degrees, and the second a combination of tilt, -4.2 degrees, and roll, 6.0 degrees. This second step is a direct consequence of the change in inclination between an adjacent cytosine base, which has an inclination of -12 degrees, and the next base, a guanine, which has 3 degrees inclination. This bend is a combination of tilt and roll. The large change in inclination allows the formation of a hydrogen bond between the protons of N4 of the 3' cytosine and the O6 of the next 3' base, a guanine, stabilizing the roll component in the bend. These structural features differ from existing models for A-tract bends.For comparison, we also determined the structure of the control sequence, d(GGCAAGAAACGG)/d(CCGTTTCTTGCC), with an AT to GC transition in the center of the A-tract. This structure has no negative inclination in most of the bases within the A-tract, resulting in a bend of only 9 degrees. When ligated in phase, the control sequence has nearly normal mobility in gel electrophoresis experiments.

Autoradiography↗
PubMed2001

Measurement of cortical thickness using an automated 3-D algorithm: a validation study.

A validation study was conducted to assess the accuracy of the algorithm developed by MacDonald et al. (1999) for measuring cortical thickness. This algorithm automatically determines the cortical thickness by 3-D extraction of the inner and outer surfaces of the cerebral cortex from an MRI scan. A manual method of tagging the grey-csf and grey-white interface was used on 20 regions (10 cortical areas found in each hemisphere) in 40 MRIs of the brain to validate the algorithm. The regions were chosen throughout the cortex to get broad assessment of the algorithm's performance. Accuracy was determined by an anatomist tagging the csf-grey and grey-white borders of selected gyri and by allowing the algorithm to determine the csf-grey and grey-white borders and the corresponding cortical thickness of the same region. Results from the manual and automatic methods were statistically compared using overall ANOVA and paired t tests for each region. The manual and automatic methods were in agreement for all but 4 of the 20 regions tested. The four regions where there were significant differences between the two methods were the insula left and right, the right cuneus, and the right parahippocampus. We conclude that the automatic algorithm is valid for most of the cortex and provides a viable alternative to manual methods of determining cortical thickness in vivo. However, caution should be taken when measuring the regions mentioned previously where the results of the algorithm can be biased by surrounding grey structures.

Adult↗
PubMed2001

A simplified one-pot synthesis of 9-[(3-[18F]fluoro-1-hydroxy-2-propoxy)methyl]guanine([18F]FHPG) and 9-(4-[18F]fluoro-3-hydroxymethylbutyl)guanine ([18F]FHBG) for gene therapy.

9-[(3-[18F]Fluoro-1-hydroxy-2-propoxy)methyl]guanine ([18F]FHPG, 2) has been synthesized by nucleophilic substitution of N(2)-(p-anisyldiphenylmethyl)-9-[[1-(p-anisyldiphenylmethoxy)-3-toluenesulfonyloxy-2-propoxy]methyl]guanine (1) with potassium [18F]fluoride/Kryptofix 2.2.2 followed by deprotection with 1 N HCl and purification with different methods in variable yields. When both the nucleophilic substitution and deprotection were carried out at 90 degrees C and the product was purified by HPLC (method A), the yield of compound 2 was 5-10% and the synthesis time was 90 min from EOB. However, if both the nucleophilic substitution and deprotection were carried out at 120 degrees C and the product was purified by HPLC, the yield of compound 2 decreased to 2%. When compound 2 was synthesized at 90 degrees C and purified by Silica Sep-Pak (method B), the yield increased to 10-15% and the synthesis time was 60 min from EOB. Similarly, 9-(4-[18F]fluoro-3-hydroxymethylbutyl)guanine ([18F]FHBG, 4) was synthesized with method A and method B in 9% and 10-15% yield, respectively, in a synthesis time of 90 and 60 min, respectively, from EOB. Compound 2 was relatively unstable in acidic medium at 120 degrees C while compound 4 was stable under the same condition. Both compound 2 and compound 4 had low lipid/water partition coefficient (0.126 +/- 0.022, n=5 and 0.165 +/- 0.023, n=5, respectively). Although it contains non-radioactive ganciclovir ( approximately 5-30 microg) as a chemical by-product, compound 2 synthesized by method B has a similar uptake in 9L glioma cells as that synthesized by method A, and is a potential tracer for imaging herpes simplex virus thymidine kinase gene expression in tumors using PET. Similarly, compound 4 synthesized by method B contains approximately 10-25 microg of penciclovir as a chemical by-product. Thus, the simplified one pot synthesis (method B) is a useful method for synthesizing both compound 2 and compound 4 in good yield for routine clinical use, and the method is readily amenable for automation.

Chemical Phenomena↗
PubMed2001

Hais cuaj txub kaum txub--to speak of all things: a Hmong cross-cultural case study.

Cross-cultural medicine is a field that describes how disparate value and belief systems concerning health and disease affect the delivery of health care. This report describes the conflict between a Hmong immigrant family and the Western medical establishment over the care of their child with end stage renal disease [ESRD]. The health care providers, social service agencies and medical center failed to adequately respond to the needs of the family. The medical staff [nephrologist, nurse coordinator, dietician, social worker, and CPS worker] worked with a transcultural nurse, Hmong community health worker and the family, to design and negotiate a treatment plan that would be acceptable to the family and the health care team. Trust was reestablished between the family and the healthcare providers and the medical outcome for the child improved.

Journal Article↗
PubMed2001

Evidence of genetic instability in 3 Gy X-ray-induced mouse leukaemias and 3 Gy X-irradiated haemopoietic stem cells.

PURPOSE: If radiation-induced genetic instability is causal in mouse radiation leukaemogenesis, then genetic instability should be detectable in the irradiated target untransformed haemopoietic stem cell, and evidence of genetic instability detected in the clonal radiation-induced leukaemia. We have tested this hypothesis using the CBA/H mouse model of radiation-induced acute myeloid leukaemia (r-AML). MATERIALS AND METHODS: Fluorescence in situ hybridisation (FISH) was employed to screen for chromosomal aberrations in mouse 3 Gy X-ray-induced r-AMLs and in the clonal descendents of control and 3 Gy X-irradiated bone marrow haemopoietic stem cells using the in vitro clonogenic CFU-A colony assay. RESULTS: High levels of clonal non-specific chromosomal aberrations were detected in the r-AML (approximately 4-5 aberrations/r-AML), and ongoing chromosomal instability as defined by subclonal variants detected in 5/10 r-AML. A similar analysis of CFU-A colonies revealed chromosomal aberrations in 25% of colonies derived from irradiated bone marrow (2% in controls). However, 66% of the aberrant colonies (2% in controls) exhibited ongoing genetic instability as defined by non-clonal chromosomal aberrations. Overall, 6% (121/1884) of the CFU-A cells derived from irradiated bone marrow were aberrant (0.05% in controls) of which 12% (15/121) were subclonal. No one CFU-A cell exhibited aberrations on more than one of the three chromosomes painted. CONCLUSIONS: The high levels of non-specific genetic damage observed in the r-AMLs is therefore attributed to the accumulation of genetic lesions in the target haemopoietic stem cell over a longer time-scale after exposure than assessed in the in vitro CFU-A clonogenic assay. This is consistent with the long latency of the multi-stage radiation leukaemogenic process, and a role for radiation-induced genetic instability is inferred.

Animals↗
PubMed2001

Posterior-stabilized and cruciate-retaining total knee replacement: a randomized study.

A randomized controlled study was done to compare the clinical, radiographic, and quality of life outcomes between posterior-stabilized and cruciate-retaining primary total knee implants. One hundred forty-three patients were enrolled in the study. Patients ranged in age from 57 to 89 years, had a primary diagnosis of osteoarthritis, and an intact functioning posterior cruciate ligament. Patients were excluded if they had a flexion contracture greater than 15 degrees, a varus deformity greater than 20 degrees, or a valgus deformity greater than 15 degrees. Patients were randomized to one of two study groups, posterior-stabilized AMK total knee implants (76 patients) or cruciate-retaining AMK total knee implants (67 patients). One hundred eight patients have had a minimum 2-year followup including 57 patients in the posterior-stabilized group and 51 patients in the cruciate-retaining group. Seventy-three patients have had a minimum 3-year followup including 37 patients in the posterior stabilized group and 36 patients in the cruciate-retaining group. The overall total Knee Society clinical rating score at 2 years averaged 157.1 points in the posterior-stabilized group and 156.5 points in the cruciate-retaining group. At 3 years, the scores averaged 156.8 points in the posterior-stabilized group and 163.5 points in the cruciate-retaining group. The range of motion component of the Knee Society score averaged 113.6 degrees for the posterior-stabilized group and 108.5 degrees for the cruciate-retaining group at 2 years, and 108.3 degrees in the cruciate-retaining group and 108.5 degrees in the posterior-stabilized group. Based on the various parameters analyzed, there were no notable differences between the groups with a posterior-stabilized and a cruciate-retaining total knee implant at 2 years. This trend seemed to be the same at 3 years.

Aged↗