Biomedical subjects
D MacDonald
Publications and source records attributed to D MacDonald.
Endothelin-A and -B antagonists protect myocardial and endothelial function after ischemia/reperfusion in a rat heart transplantation model.
OBJECTIVE: Previous studies suggested that endothelin-1 (ET-1) may play a pathophysiological role in myocardial ischemia/reperfusion injury. This study was designed to investigate the effects of the selective ET-A receptor antagonist BQ123 and the selective ET-B receptor antagonist BQ788 on myocardial and endothelial function after reversible deep hypothermic ischemia in a heterotopic rat heart transplantation model. METHODS: Isogenic intraabdominal heterotopic transplantation was performed in Lewis rats. After 1 h of cold ischemic preservation reperfusion was started either after application of placebo (control), BQ123 (3 mumol/kg/min). BQ788 (3 mumol/kg/min), ET-1 (8 pmol/kg/min) or simultaneous infusion of BQ123 or BQ788 and ET-1, respectively (n = 12 each). An implanted balloon was used to obtain pressure-volume relations of the transplanted heart. Myocardial blood flow (MBF) was assessed by the hydrogen-clearance method. Measurements were taken after 1 and 24 h of reperfusion. Endothelium-dependent vasodilation to acetylcholine (ACH) and endothelium-independent vasodilation to sodium nitroprusside were also determined. RESULTS: Both BQ123 and BQ788 significantly improved myocardial and endothelial functional recovery during early reperfusion, whereas ET-1 significantly impaired myocardial and endothelial function. Simultaneous infusion of ET-1 diminished the effects of BQ123 and BQ788. Although myocardial function and baseline MBF were similar in all groups after 24 h of reperfusion, endothelium dependent vasodilation to ACH was still significantly higher in the BQ123 and BQ788 groups and lower in the ET-1 groups (p < 0.05). CONCLUSIONS: These results suggest that endogenous ET release is involved in the pathogenesis of reperfusion injury after heart transplantation. ET-A and ET-B receptor antagonists may be useful to reduce ischemia/reperfusion injury.
Estimated area-under-the-curve monitoring of Neoral in a stable pediatric renal transplant population: one-year experience.
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Endothelin-A receptor antagonist BQ123 protects against myocardial and endothelial reperfusion injury.
BACKGROUND: This study was designed to investigate the effects of the selective endothelin-A receptor antagonist BQ123 on myocardial and endothelial function after reversible deep hypothermic ischemia and reperfusion. METHODS: Isogenic intra-abdominal heterotopic heart transplantation was performed in Lewis rats. After one hour of cold ischemic preservation reperfusion was started after application of either saline vehicle or BQ123 (1 micromol/L). Left-ventricular pressure-volume relations and myocardial blood flow were assessed after one and 24 hours of reperfusion. Responses to endothelium-dependent vasodilator acetylcholine and endothelium-independent vasodilator sodium nitroprusside were also determined. RESULTS: BQ123 significantly improved myocardial contractility, as indicated by the leftward shift of the systolic pressure-volume relation and significantly increased myocardial blood flow during early reperfusion (p < 0.05). Although myocardial function and baseline myocardial blood flow were similar in both groups after 24 hours of reperfusion, endothelium-dependent vasodilatation was still significantly higher in the BQ123 group (p < 0.05). CONCLUSIONS: These results suggest that endothelin-A receptor antagonists may be useful in reducing ischemia/reperfusion injury after heart transplantation by preservation of myocardial and endothelial function.
Morphometric analysis of the temporal lobe in temporal lobe epilepsy.
PURPOSE: Using high-resolution magnetic resonance imaging (MRI), we examined the temporal neocortex and the underlying white matter in patients with unilateral temporal lobe epilepsy (TLE) and in control subjects. METHODS: The images of 27 patients and 42 control subjects were registered into stereotaxic space, corrected for image intensity inhomogeneity, and automatically segmented into gray matter, white matter, and cerebrospinal fluid (CSF) over a predetermined extent of the temporal lobe. The surface between the gray matter and CSF was extracted, indices of curvature (IOC) of the surface were calculated, and a frequency histogram of the IOC was obtained. RESULTS: There was significant bilateral reduction in the total volume of the temporal lobe and in the volume of gray matter. White matter volume was significantly reduced only in the temporal lobe ipsilateral to the seizure focus. There were significant changes in the position and amplitude of peaks in the frequency histogram of the IOC. CONCLUSIONS: The volume of gray matter was negatively correlated with duration of epilepsy, suggesting that neocortical changes may be a consequence of seizures. Changes in the frequency histogram of the IOC suggested an additional alteration in the surface morphology of the temporal lobe in TLE, possibly related to sulcal widening.
Interleukin-9 promotes allergen-induced eosinophilic inflammation and airway hyperresponsiveness in transgenic mice.
Human atopic asthma is a complex heritable inflammatory disorder of the airways associated with clinical signs of allergic inflammation and airway hyperresponsiveness. Recent studies demonstrate that the degree of airway responsiveness is strongly associated with interleukin (IL)-9 expression in murine lung. To investigate the contribution of IL-9 to airway hyperresponsiveness, and to explore directly its relationship to airway inflammation, we studied transgenic mice overexpressing IL-9. In this report we show that IL-9 transgenic mice (FVB/N-TG5), in comparison with FVB/NJ mice, display significantly enhanced eosinophilic airway inflammation, elevated serum total immunoglobulin E, and airway hyperresponsiveness following lung challenge with a natural antigen (Aspergillus fumigatus). These data support a central role for IL-9 in the complex pathogenesis of allergic inflammation.
A comparison of fertility control and lethal control of bovine tuberculosis in badgers: the impact of perturbation induced transmission.
In this paper we use mathematical modelling to consider the broad advantages and disadvantages of fertility control over lethal control for bovine tuberculosis in badger populations. We use a deliberately simple model, attempting to capture only the key transmission processes. The model is parametrized with reference to the long-term Woodchester Park study. Estimates of mortality rate from this study suggest no significant extra mortality risk for animals with evidence of infection as indicated by the presence of anti-Mycobacterium bovis antibodies or M. bovis isolation. We find that large reductions in prevalence are sometimes the consequence of only moderate reductions in population numbers. If we assume that the act of control does not in itself affect transmission rates, then as far as eradication is concerned, both fertility control and mortality control operate through the same epidemiological mechanism, the removal of susceptibles: if one is in principle capable of keeping a population low enough to be infection free then so is the other. It is necessary to continue either form of control at regular intervals to maintain a constant level of infection in the long term. If control were to be stopped, return to precontrol levels of badger population and infection prevalence would be expected within a few years. Fertility control is less effective in reducing population density than lethal control since it can only act, at maximum, to remove one age cohort per year. It is also less effective in reducing transmission as it can only ever remove susceptibles, while lethal control also removes infectious badgers. However, if the social disturbance caused by lethal control does in fact increase contact rates for the remaining infectious badgers, the relative efficacies of the two strategies become a great deal less clear. While we have no quantitative data on the extent to which social perturbation does act to promote transmission, model simulations show that it is possible to develop plausible scenarios in which the lethal control may actually act to increase the absolute numbers of animals infected, while reducing the number of uninfected animals to very low numbers.
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.
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.
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.
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.
Cerebral palsy and intrapartum fetal monitoring.
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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.
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.
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.
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.
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.