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Biomedical subjects

D MacDonald

Publications and source records attributed to D MacDonald.

At least 55 records · Page 3Linked to original sources
PubMed1997

Ongoing Y-chromosome instability defines sub-clonal variants in radiation-induced leukaemias in the mouse.

Forty primary leukaemias that arose in vivo as a consequence of 3 Gy X-irradiation of inbred mouse strains were analysed for Y-chromosome aberrations by conventional cytogenetics and fluorescent in situ hybridization (FISH). Compared with control mice which were X-irradiated but which exhibited no overt signs of leukaemia, the loss and gain of Y-chromosomes in leukaemic spleen cells defined subclonal variants in the radiation-induced haemopoietic malignancies that arose in CBA/H, DBA/2 and (C57BL/6 x DBA/2)F1 mice. This Y-chromosome instability was significantly higher than that observed in spleen cells of age-matched (or older) irradiated control mice that had not developed overt leukaemia. The detection of Y-chromosome aberrations is considered in the context of the high numbers of potential gene regulatory sequences in the murine Y-chromosome and the potential for the insertional activation of cellular genes during multi-stage radiation leukaemogenesis.

Acute Disease↗
PubMed1997

Supratentorial low-grade glioma in adults: an analysis of prognostic factors and timing of radiation.

PURPOSE: To review the outcomes of patients with low-grade glioma diagnosed by modern imaging and treated at a center where postponing radiotherapy was common practice. METHODS: We reviewed the records of patients (age > or = 18 years) with pathologically confirmed supratentorial low-grade fibrillary astrocytoma, oligodendroglioma, and mixed glioma treated at a regional cancer center in Canada between 1979 and 1995. RESULTS: Median survival for the entire group (N = 167; mean age 40.6 years) was 10.5 years with 5- and 10-year survival rates of 72% and 50%, respectively. Median progression-free survival was 4.9 years with 5- and 10-year progression-free rates of 50% and 12%, respectively. Overall and progression-free survivals were longer for patients with an oligodendroglioma or mixed glioma than with astrocytoma (median 13 v 7.5 years, P = .003; progression-free 5.6 v 4.4 years, p = .054). Age at diagnosis < or = 40 years, seizures at presentation, minimal residual tumor after surgery, Karnofsky performance status > or = 70, and oligodendroglioma or mixed glioma pathology were associated with significantly longer median survival on univariate and multivariate analyses. Radiotherapy deferred until tumor progression (v immediate radiotherapy) was associated with longer survival on univariate analysis, but an imbalance in other variables accounted for this advantage such that timing of radiotherapy was not an independent (favorable or adverse) prognostic factor on multivariate analysis. CONCLUSION: Patients with low-grade glioma diagnosed by modern imaging can be expected to live a long time; timing of radiotherapy may be a less important determinant of survival than nontreatment variables and residual tumor bulk.

Actuarial Analysis↗
PubMed1996

Serial changes in cardiac output during normal pregnancy: a Doppler ultrasound study.

OBJECTIVES: To determine the direction and magnitude of change in cardiac output (CO) during pregnancy. STUDY DESIGN: We performed serial measurements of CO on five occasions from 24 weeks gestation to term and once during the puerperium in 26 normal pregnancies (156 measurements) using Doppler ultrasound measurement of flow velocity profiles and aortic root cross sectional area. RESULTS: CO increased to 7.0 l/min by 32 weeks gestation, 49% above baseline values. It fell to 5.7 l/min by term, 21% above baseline. The peak in CO corresponded with an increase in heart rate to 91 beats/min, 32% above baseline. Stroke volume peaked at 36 weeks gestation, by which time CO had already begun to decline. CONCLUSIONS: CO increased in a linear fashion until 32 weeks gestation and then declined to term, but to a value still greater than the postpartum baseline. These findings have obvious management implications for patients with serious heart disease complicating pregnancy.

Blood Pressure↗
PubMed1996

In vivo morphometry of the intrasulcal gray matter in the human cingulate, paracingulate, and superior-rostral sulci: hemispheric asymmetries, gender differences and probability maps.

Volumes of the intrasulcal gray matter were measured in three cerebral sulci located on the medial wall of the human frontal lobe: cingulate sulcus (CS), paracingulate sulcus (PCS), and superior-rostral sulcus (SRS). The measurements were carried out on T1-weighted 3-D high-resolution magnetic-resonance (MR) images acquired in 105 young right-handed volunteers (42 female and 63 male). Before the measurement, the images were transformed into a standardized stereotaxic space (Talairach and Tournoux [1988] Human Brain: 3-Dimensional Proportional System. An Approach to Cerebral Imaging. Stuttgart, New York: Georg Thieme Verlag), thus removing inter-individual differences in brain size. The intrasulcal gray matter was segmented in a semi-automatic manner. Significant gender differences were found in the volume of the CS (female > male) and the PCS (male > female). Hemispheric asymmetries were observed between the left and right volumes of the intrasulcal gray matter in the anterior (right > left) and posterior (left > right) segments of the CS, as well as between the left and right volumes of the PCS (left > right). There was no interaction between the asymmetries and gender. In addition, significant positive correlations were found between the left and right gray-matter volumes in the anterior (r = 0.43) and posterior (r = 0.66) segments of the CS, whereas significant negative correlations were observed between the gray-matter volumes of the anterior segment of the CS and those of the PCS (left hemisphere: r = -0.48; right hemisphere: r = -0.42). The observed hemispheric asymmetries in the CS and PCS gray-matter volumes are consistent with the proposed role of these structures in the integration of emotions with cognition (CS) and in the control of speech/vocalization (PCS). The pattern of inter-hemispheric correlations in the sulcal gray-matter points to an increasing asynchrony in the foetal development of primary (CS), secondary (SRS), and tertiary (PCS) sulci, respectively. The presence of negative correlations between the two neighbouring sulci (CS and PCS) suggests that a process of compensation could underlie interactions between adjacent primary and tertiary sulci. Besides the above volumetric analysis, we also provide average (probability) maps of the three sulci; the use of such maps for the parcellation of the medial frontal lobe and localization of "peaks" obtained in blood-flow activation studies is discussed.

Brain Mapping↗
PubMed1996

Photoaffinity labeling of the human substance P (neurokinin-1) receptor with [3H2]azido-CP-96,345, a photoreactive derivative of a nonpeptide antagonist.

An azido derivative of [3H2](2S, 3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl) methyl)-1-azabicyclo[2.2.2]octon-3-amine (CP-96,345), a potent nonpeptide antagonist of the substance P (SP) (neurokinin-1) receptor, was synthesized and shown to have an affinity for the human SP receptor similar to that of the parent compound, CP-96,345. When Chinese hamster ovary cells expressing the human SP receptor were photolabeled with this compound and analyzed with the use of sodium dodecyl sulfate-polyacrylamide gel electrophoresis and fluorography, several radioactive bands were observed, including a major band centered at molecular mass 80 kDa, the expected value for the SP receptor expressed in Chinese hamster ovary cells. Only the labeling of the 80-kDa protein was specific: nonradiolabeled CP-96,345 but not its optical enantiomer, CP-96,344 was a potent inhibitor of photoincorporation. SP prevented photolabeling only at concentrations higher than expected from its binding affinity but similar to those shown in a competition binding assay to displace radioiodinated analogue of CP-96,345. Antiserum generated against a synthetic peptide corresponding to the carboxyl terminus of the human SP receptor immunoprecipitated only the 80-kDa photoaffinity labeled protein, confirming that it is the human SP receptor. Interestingly, a second antiserum that was generated against the third extracellular loop of the G protein-coupled receptor no longer immunoprecipitated the receptor when covalently labeled with [3H2]azido-CP-96,345. This result indicates either that attachment of the antagonist modified the antigenic region directly, suggesting involvement of this domain in the binding of CP-96,345, or that the loss of recognition by the antiserum is secondary to a change in conformation induced by the covalent attachment of the antagonist at a different site.

Affinity Labels↗
PubMed1995

New glucose-6-phosphate dehydrogenase mutations associated with chronic anemia.

We have identified the glucose-6-phosphate dehydrogenase mutations responsible for enzyme deficiency in nine individuals with chronic nonspherocytic hemolytic anemia. We found the variants Tokyo, Iowa, Shinshu, and Guadalajara in British subjects and Kobe in an Italian. In addition we have determined the variant Corum has the mutation 820 G-->A and have found in British subjects the mis-sense mutations 224 T-->C, 488 G-->A and 833 C-->T which have not been described before. Some, but not all, of the mutations involve amino acids located near putative substrate binding sites.

Anemia, Hemolytic↗
PubMed1995

Cloning and sequence of a gene encoding the pyruvate dehydrogenase E1 beta subunit of Schizosaccharomyces pombe.

A 4906-bp DNA fragment, which complemented Schizosaccharomyces pombe strains partly defective in pyruvate dehydrogenase (PDH), was cloned and sequenced. The fragment contained an open reading frame (ORF) of 366 amino acids (aa), which showed 62% identity with the Saccharomyces cerevisiae gene encoding the PDH E1 beta subunit, and significant similarity to subunits from a number of other 2-oxo-acid dehydrogenase complexes from mammals, Gram+ and some Gram- bacteria. The clone hybridised to a 1.6-1.7-kb mRNA from wild type, and the 5' ends of the mRNA were mapped 73-83 bp upstream from the AUG start codon of the ORF. No other ORFs were found in this 4.9-kb segment of the Sz. pombe genome. Plasmids containing the ORF complemented the PDH-defective strains of Sz. pombe both for growth and for enzyme activity.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1995

Localization of the 8;13 translocation breakpoint associated with myeloproliferative disease to a 1.5 Mbp region of chromosome 13.

There are five reported cases of an atypical myeloproliferative disorder in which the leukemia cells have a consistent t(8;13)(p11;q12) translocation. We analyzed the breakpoint in metaphases from two of these patients by fluorescence in situ hybridization using a series of yeast artificial chromosomes (YACs) derived from the 13q12 region. We found that a YAC containing the FLT1 and FLT3 oncogenes was localized distal to the 13q12 breakpoint and was not rearranged. YAC66, a YAC that lies immediately adjacent to the chromosome 13 centromere, was localized proximal to the 13q12 breakpoint and was not rearranged. A third YAC, which is located between FLT1 and YAC66, was unrearranged in normal metaphase chromosomes, but showed hybridization signals on both derivative chromosomes in both cases. Thus, the breakpoints in these two cases are localized to the same 1.5 Mbp region of 13q12. This may be the site of an unidentified gene involved in the pathogenesis of some types of leukemia.

Bone Marrow↗
PubMed1995

SARP: a value-based approach to hospice admissions triage.

As hospices become established and case referrals increase, many programs are faced with the necessity of instituting waiting lists. Prioritizing cases for order of admission requires a triage method that is rational, fair, and consistent. This article describes the SARP method of hospice admissions triage, which evaluates prospective cases according to seniority, acuity, risk, and political significance. SARP's essential features, operative assumptions, advantages, and limitations are discussed, as well as the core hospice values which underlie its use. The article concludes with a call for trial and evaluation of SARP in other hospice settings.

Emergencies↗
PubMed1994

The use of the percentage change in Oswestry Disability Index score as an outcome measure in lumbar spinal surgery.

STUDY DESIGN: A retrospective analysis of the change in the Oswestry Low Back Pain Disability Questionnaire in a heterogeneous group of 144 operatively managed patients was undertaken to examine the change in disability index as an outcome measure. OBJECTIVES: To establish the percent change in disability index as an outcome measure able to identify risk factors for poor results in lumbar spinal surgery. METHODS: Epidemiologic, diagnostic, and surgical variables were examined as risk factors using step-wise multiple linear regression analysis at both follow-up times (6 months and 2 years), with percent change in disability index used as the outcome measure. RESULTS: At 6-months follow-up, previous surgery, female gender, workers' compensation, a lower initial disability index score, increasing age, and spinal fusion alone as an operative procedure were independently and significantly negatively correlated with outcome. Further analysis revealed that for patients with spinal canal stenosis, the magnitude of the initial disability index did not correlate with outcome, whereas patients with low back pain or a prolapsed intervertebral disc fared better if they had high initial disability scores. Data at 2-years follow-up were less adequate. However, previous surgery on the spine and low initial disability score were significant negative predictors of outcome at 6-month and 2-year follow-up. CONCLUSIONS: The findings indicate that the absolute value and change in these scores after surgery vary from patient to patient, but that their percentage change is likely to be the best marker of outcome when such subjective scoring systems are used.

Disability Evaluation↗
PubMed1994

Association between calcium regulatory hormones and other factors and bone mineral density in elderly Chinese men and women.

BACKGROUND: The purpose of the study was to determine if bone mineral density (BMD) in elderly Chinese subjects was associated with indices of calcium metabolism (parathyroid hormone, vitamin D), osteocalcin, and other nonbiochemical factors. METHOD: 104 men (mean age 74 +/- 6 yrs) and 213 women (mean age 76 +/- 8 yrs) with no previous history of fractures were recruited from old age hostels and community centers. BMD was measured with dual energy X-ray absorptiometry. RESULTS: BMD in both sexes was associated with body mass index (BMI), arm circumference, and skinfold thicknesses. Additionally, in women there was a positive association with grip strength and load-bearing activities, a negative association with age in all sites except for the lumbar spine, and negative associations with indices of bone turnover (osteocalcin, urinary hydroxyproline/creatinine and calcium/creatinine ratios). After adjusting for BMI, women with hypertension or taking antihypertensive drugs had higher mean BMD at the lumbar spine. Multivariate analyses showed that only BMI predicted BMD in men, while age, BMI, and arm circumference were predictors of BMD in women. CONCLUSION: Indices of calcium metabolism were not correlated with BMD in this elderly Chinese population, suggesting that the age-related rise in parathyroid hormone and reduced intestinal absorption of calcium may not be important factors in determining BMD in elderly Chinese men and women.

25-Hydroxyvitamin D 2↗