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G R Sutherland

Publications and source records attributed to G R Sutherland.

At least 199 records · Page 11Linked to original sources
PubMed1996

Age-related transmural peak mean velocities and peak velocity gradients by Doppler myocardial imaging in normal subjects.

Doppler myocardial imaging is a new cardiac ultrasound technique based on the principles of colour Doppler imaging which can determine myocardial velocities by detecting the changes of phase-shift of the ultrasound signal returning directly from the myocardium. To determine the normal range of transmural velocities in healthy hearts a prospective study was carried out involving 42 normal subjects (age from 21 to 78, mean 47 +/- 16 years). Using M-mode Doppler myocardial imaging the peak values of the mean velocity and velocity gradient across the left ventricular posterior wall were measured during standardized phases of the cardiac cycle. Peak mean velocities had the following values during the cardiac cycle: isovolumic contraction - 1.3 +/- 1.2 cm. s-1, early ventricular ejection 4.2 +/- 1.2 cm. s-1, late ventricular ejection 1.8 +/- 1.1 cm. s-1, isovolumic relaxation -2.0 +/- 0.8 cm. s-1, rapid ventricular filling -6.6 +/- 2.2 cm. s-1, atrial contraction -2.8 +/- 1.8 cm. s-1, atrial relaxation 1.2 +/- 1.1 cm. s-1. Peak velocity gradients were: isovolumic contraction 1.3 +/- 1.9 s-1, early ventricular contraction 4.7 +/- 1.9 s-1, late ventricular contraction 1.1 +/- 1.0 s-1, isovolumic relaxation -0.6 +/- 0.5 s-1, rapid ventricular filling 6.1 +/- 3.4 s-1, atrial contraction 2.6 +/- 1.7 s-1, atrial relaxation 0.0 +/- 0.3 s-1. Linear regression analysis showed that with the increase of age, peak velocity gradient decreases during rapid ventricular filling (r = 0.83; P < 0.0001) and increases during atrial contraction (r = 0.86; P < 0.0001) while peak mean velocity increases only during atrial contraction (r = 0.80, P < 0.0001). Thus, there was no correlation between increasing age and systolic peak mean velocity and peak velocity gradient but both diastolic filling phases rapid ventricular filling and atrial contraction demonstrated age-related changes. In summary, this study has determined the age-related range of normal transmural myocardial velocities within the left ventricular posterior wall in healthy hearts during the cardiac cycle. We conclude that these measurements of peak mean velocities and peak velocity gradients, should form the baseline for subsequent Doppler myocardial imaging clinical studies on myocardial diseases processes.

Adult↗
PubMed1996

The effect of mannitol on experimental cerebral ischemia, revisited.

The effect of 20% mannitol on ischemic neuronal injury was examined in male Wistar rats (n = 80) that were randomly divided into forebrain and focal ischemia groups. The animals were further subdivided into control, treatment with mannitol before ischemia (1 g/kg of body weight, 12 min before ischemia), and treatment with mannitol after ischemia (0.25 g/kg of body weight, beginning 20 min after ischemia and then every 6 h for 48 h) groups. Physiological parameters were carefully monitored and maintained within normal limits. The administration of mannitol after ischemia was found to produce a statistically significant improvement in ischemic neocortical injury and selective neuronal necrosis in the neocortex in the forebrain and focal models, respectively. However, treatment with mannitol after ischemia was shown not to favorably alter histopathological outcome in hippocampal levels 2 through 7 in the forebrain model nor did not reduce infarct volume in the focal ischemia group. Treatment with mannitol before ischemia did not produce statistically significant reductions in neuronal injury in either model. These results do not support the findings of previous investigations, which have demonstrated that mannitol affords a significant degree of neuroprotection when administered either before or immediately after vessel occlusion in models of forebrain and focal cerebral ischemia. The neuroprotective effect of mannitol demonstrated in the neocortex of both forebrain and focally ischemic rats may support the theory that the main mechanisms responsible for neocortical injury in ischemia differ from those in the striatum hippocampus. Finally, mannitol's ability to reduce ischemic neuronal injury most effectively when administered after rather than before the production of ischemia is consistent with a possible beneficial influence on the development of delayed cerebral edema.

Animals↗
PubMed1996

Dynamic mutation loci: allele distributions in different populations.

To assess the relative contributions of trans-acting factors (replication and repair functions) and cis-acting elements (repeat and flanking DNA composition) to the mechanism of trinucleotide repeat sequence mutation we have analysed the distribution of copy number polymorphisms at 12 loci associated with dynamic mutations in 15 populations of different ethnic origins. Genome wide instability of repeats in a particular population would be evidence of trans-acting factor instigation of the mutation process, whereas instability at a particular locus (perhaps even in several populations) would be evidence that the composition of the particular locus was the most significant factor contributing to mutation. The FRA16A locus is highly polymorphic in only the European population. Some other loci exhibit distinct distributions of alleles between different populations. Therefore sequences in the vicinity of the repeat -- the cis component of a particular locus -- appear(s) to be more important in the mutation mechanism than sporadic genome-wide instability induced by trans-acting factors such as the DNA mismatch repair enzymes.

Alleles↗
PubMed1996

Suggestion of a major gene for familial febrile convulsions mapping to 8q13-21.

Febrile convulsions affect 2 to 5% of all children under the age of 5 years. These convulsions probably have a variety of causes, but a genetic component has long been recognised. A large and remarkable family is described in which febrile convulsions appear to result from autosomal dominant inheritance at a single major locus. A gene for febrile convulsions was excluded from regions of previously mapped epilepsy genes and extension of exclusion mapping, using microsatellite markers, to the entire genome implied that a locus on chromosome 8q13-21 may be involved. Linkage analysis of markers on chromosome 8 gave a multipoint lod score of 3.40, maximised over different values of penetrance and phenocopy rate, for linkage between the gene for febrile convulsions and the region flanked by markers D8S553 and D8S279. This lod score was calculated assuming the disease has a penetrance of 60% and a phenocopy rate of 3%. Although there was no indication of linkage other than to markers on chromosome 8, linkage remains suggestive rather than significant because of the maximisation procedure applied. The support for linkage involving a major gene, as opposed to an alternative hypothesis of a complex inheritance pattern, relied upon the assumption of low penetrance.

Adolescent↗
PubMed1996

Latissimus dorsi muscle: assessment of stimulation after cardiomyoplasty with Doppler US tissue imaging.

PURPOSE: To evaluate Doppler ultrasound (US) tissue imaging for assessment of stimulated skeletal muscle contraction. MATERIALS AND METHODS: Seven patients were studied after left latissimus dorsi cardiomyoplasty. Myograft contraction programmed on alternate cardiac cycles was assessed with Doppler US tissue imaging. Beat-to-beat variation in inferior wall motion was assessed by examining peak myograft velocities during 10 muscle-assisted and 10 nonassisted cardiac cycles. The temporal relationship between electrostimulation and myograft contraction, changes in cardiac geometry, and the effect of alterations in stimulation voltage and muscle synchronization were assessed. RESULTS: Significant beat-to-beat variation in velocity profile could be detected in the proximal myograft in six patients (P < .05). Potentiation of infero-posterior wall motion was measurable in five patients (mean peak systolic wall velocity: nonassisted, 2.5 cm.sec-1 +/- 0.5 [standard deviation]; assisted, 7.8 cm.sec-1 +/- 6.3). The response between stimulation voltage and inferoposterior wall velocity was sigmoid. CONCLUSION: Doppler US tissue imaging depicted the effects of myostimulator programming on muscle contraction and ventricular wall motion.

Cardiomyoplasty↗
PubMed1996

23Na nuclear magnetic resonance spectral changes during and after forebrain ischemia in hypoglycemic, normoglycemic, and hyperglycemic rats.

BACKGROUND AND PURPOSE: The severity of brain injury in animal models of forebrain ischemia increases with blood glucose level. During ischemia, energy failure is slower and maintenance of ion gradients is prolonged as the level of glycemia increases. It is not clear how the level of glycemia influences recovery of ion homeostasis on reperfusion. It has been shown that changes in the intensity of the multiple-quantum 23Na nuclear magnetic resonance (NMR) signals reflect changes in intracellular Na+ levels. We have used 23Na NMR spectroscopy to evaluate the influence of the level of glycemia on changes in Na+ concentration during and after forebrain ischemia in rats. METHODS: Single-quantum (SQ) and double-quantum (DQ) 23Na NMR spectra were measured before and during 10-minute forebrain ischemia and during reperfusion in hypoglycemic, normoglycemic, and hyperglycemic rats. RESULTS: The DQ 23Na NMR signal increased to 210% of preischemia intensity in all rats, but a delay in this increase was observed in normoglycemic and hyperglycemic animals. The rate of the DQ 23Na NMR signal increase was fastest in hypoglycemic (apparent first-order rate constant 0.673 +/- 0.046 min-1, P < .002 compared with normoglycemic animals) and slowest in hyperglycemic (0.285 +/- 0.024 min-1, P < .03) rats. During reperfusion, the signal intensity recovered rapidly in hypoglycemic (0.385 +/- 0.050 min-1) and normoglycemic (0.464 +/- 0.047 min-1) rats, whereas in hyperglycemic animals recovery was slow (0.108 +/- 0.044 min-1, P < .0001 compared with normoglycemic animals). The SQ 23Na NMR signal intensity increased to 117% of preischemia level in hypoglycemic (P < .05 compared with normoglycemic animals) and to 107% in normoglycemic and hyperglycemic animals during reperfusion. CONCLUSIONS: The slower increase in the 23Na DQ NMR signal intensity during forebrain ischemia in rats with higher blood glucose levels suggests that Na+ homeostasis is maintained longer in these animals. On reperfusion, the slower recovery of the DQ 23Na NMR signal intensity in hyperglycemic animals likely indicates a slower recovery of Na+ homeostasis, perhaps contributing to the increased neuronal injury after cerebral ischemia in hyperglycemic animals.

Animals↗
PubMed1996

Effect of age in rodent models of focal and forebrain ischemia.

BACKGROUND AND PURPOSE: The majority of animal experiments examining the nature and treatment of stroke have used relatively young animals ranging in age from 2 to 6 months. However, significant morphological, neurochemical, and behavioral changes occur with aging in rodents particularly during the first 24 months of age. This study examines the effect of age in two models of transient ischemia a forebrain and a focal model in male Wistar rats. METHODS: We induced forebrain ischemia of 12 minutes duration by bilateral carotid artery occlusion with controlled hypotension at a mean blood pressure of 45 mm Hg and using an intraluminal filament technique, induced focal middle cerebral artery occlusion of 100 minutes duration at a mean blood pressure of 60 mm Hg. Physiological parameters were monitored and maintained within normal limits. On day 7 after ischemia, the rats were perfusion-fixed and the brains removed for quantitative histopathology. RESULTS: After forebrain ischemia, older rats showed significantly less CA1 neuronal necrosis than the younger group (P < .003), whereas both striatal and neocortical injury were significantly greater in the older group (P < .05). Among animals subjected to focal ischemia, the volume of infarcted tissue and the number of necrotic neurons in the area adjacent to the infarction were both greater in older rats (P < .05). CONCLUSIONS: This study emphasizes the importance of age in models of forebrain and focal ischemia. The interaction between age-related changes in morphology, neurochemistry, and behavior on the ischemic cascade complicates the interpretation of mechanistic data, and pharmacological effects observed in younger animals may not necessarily translate to an older population.

Aging↗
PubMed1996

The human glycine receptor beta subunit: primary structure, functional characterisation and chromosomal localisation of the human and murine genes.

The inhibitory glycine receptor (GlyR) is a pentameric receptor comprised of alpha and beta subunits, of which the beta subunit has not been characterised in humans. A 2106 bp cDNA, isolated from a human hippocampal cDNA library, contained an open reading frame of 497 amino acids which encodes the beta subunit of the human GlyR. The mature human GlyR beta polypeptide displays 99% amino acid identity with the rat GlyR beta subunit and 48% identity with the human GlyR alpha 1 subunit. Neither [3H]strychnine binding nor glycine-gated currents were detected when the human GlyR beta subunit cDNA was expressed in the human embryonic kidney 293 cell line. However, co-expression of the beta subunit cDNA with the alpha 1 subunit cDNA resulted in expression of functional GlyRs which showed a 4-fold reduction in the EC50 values when compared to alpha 1 homomeric GlyRs. Glycine-gated currents of alpha 1/beta GlyRs were 17-fold less sensitive than homomeric alpha 1 GlyRs to the antagonists picrotoxin, picrotoxinin and picrotin, providing clear evidence that heteromeric alpha 1/beta GlyRs were expressed. The beta subunit appears to play a structural rather than ligand binding role in GlyR function. Fluorescence in situ hybridisation was used to localise the gene encoding the human GlyR beta subunit (GLRB) to chromosome 4q32, a position syntenic with mouse chromosome 3. In situ hybridisation using the human GlyR beta subunit cDNA showed that the murine GlyR beta subunit gene (Glrb) maps to the spastic (spa) locus on mouse chromosome 3 at bands E3-F1. This is consistent with the recent finding that a mutation in the murine GlyR beta subunit causes the spa phenotype. It also raises the possibility that mutations in the human beta subunit gene may cause inherited disorders of the startle response.

Amino Acid Sequence↗
PubMed1996

An automated system for regulating brain temperature in awake and freely moving rodents.

In rodents, postischemic hypothermia can provide robust and long-term functional and histological neuroprotection, even when intervention is delayed for several hours following ischemia. This generates a need to follow temperature precisely for many hours, perhaps several days if a hypothermic effect is to be studied or excluded. Such protracted temperature control (> 24 h) is difficult and often lethal when performed under general anesthesia. In awake animals, manual temperature control is safer, but exceedingly time consuming and tedious, and is impractical for large experiments. The present method allows for continuous brain temperature measurement and control in free-moving rats and gerbils. Brain temperature was measured by wireless AM probes while feedback regulation was achieved by servo-control of a lamp, fan and water misting system. Hypothermia was easily induced and maintained for 24 h at 32 degrees C in both gerbils and rats. Gerbils also tolerated 24 h at 32 degrees C followed by 24 h at 34 degrees C. This 'exposure technique' is capable of safely producing lengthy periods of mild hypothermia in rats and gerbils. Furthermore, this method can clamp temperature when temperature-altering drugs are given. For example, temperature was maintained in MK-801 drugged gerbils. The system is, therefore, eminently suitable for drug neuroprotection studies in brain ischemia.

Animals↗
PubMed1995

Complete nucleotide sequence, expression, and chromosomal localisation of human mixed-lineage kinase 2.

Protein kinases play pivotal roles in the control of many cellular processes. In a search for protein kinases expressed in human epithelial tumour cells, we discovered two members of a novel protein kinase family [Dorow, D. S., Devereux, L., Dietzsch, E. & de Kretser, T. A. (1993) Eur. J. Biochem. 213, 701-710]. Due to the unique mixture of structural domains within their amino acid sequences, we named the family mixed-lineage kinases (MLK). We initially isolated clones encoding partial cDNAs of MLK1 and 2 from a human colonic cDNA library. The MLK2 cDNA was subsequently used to screen a human brain cDNA library and we have now cloned and sequenced a 3454-bp cDNA encoding the full-length MLK2 protein. The predicted MLK2 polypeptide has 954 amino acids and contains a src homology 3 (SH3) domain, a kinase catalytic domain, a double leucine zipper and basic domain, and a large C-terminal domain. The 22-amino-acid N-terminal region has four glutamic acid residues immediately following the initiator methionine. Beginning at amino acid 23, the 55-amino-acid SH3 domain contains a 5-amino-acid insert in a position corresponding to inserts of 6 and 15 residues in the SH3 domains of n-src and the phosphatidylinositol 3'-kinase. Adjacent to the SH3 domain is a kinase catalytic domain with conserved motifs associated with both serine/threonine and tyrosine specificity. Beginning nine residues C-terminal to the catalytic domain, there are two leucine/isoleucine zippers separated by a 13-amino-acid spacer sequence and followed by a stretch of basic residues. The polybasic sequence contains a motif that is similar to nuclear localisation signals from several proteins. The C-terminal domain is composed of 491 amino acids of which 17% are serine or threonine and 16% are proline. This domain also has a biased ratio of basic to acidic amino acids with a calculated pI of 9.38. When used as a probe to examine mRNA expression in human tissues, a MLK2 cDNA hybridised to a species of 3.8 kb that was expressed at highest levels in RNA from brain and skeletal muscle. The 3454-bp cDNA was also used for fluorescence in situ hybridisation to localise the MLK2 gene to human chromosome 19 q13.2.

Amino Acid Sequence↗
PubMed1995

The effect of manganese on the oxidation of chemicals by lignin peroxidase.

It has recently been discovered that lignin peroxidase isozyme H2 (LiPH2) has the ability to oxidize Mn2+ (Khindaria et al., 1995). Furthermore, at pH 4.5, the physiological pH of Phanerochaete chrysosporium, LiPH2 oxidizes Mn2+ at a much faster rate (25 times) than veratryl alcohol (VA). The ability of Mn2+ to act as a redox mediator for indirect oxidations catalyzed by LiPH2 was therefore investigated. In the presence of physiologically relevant levels of oxalate and Mn2+, the rate of LiPH2-catalyzed oxidation of all substrates studied was dramatically increased. Up to 10-fold stimulations were observed compared to the rates of oxidation of substrate in either the presence or absence of VA. We propose that the stimulation is due to the ability of LiPH2 to oxidize Mn2+, producing the strong oxidant Mn3+, at a high rate. The rates of oxidation of the substrates showed a hyperbolic dependence on Mn2+ in the presence of oxalate, a chelator which was required for maximal activity. The oxalate dependence of the oxidation rates correlated well with the concentration of the 1:1 complex of Mn(2+)-oxalate. The relative concentrations of the substrates and H2O2 and the rate constants for their reactions with Mn3+ determined which chemical was oxidized by the enzymatically produced Mn3+. The importance of the ability of Mn(2+)-oxalate to stimulate the oxidation of chemicals by LiPH2 is discussed.

Basidiomycota↗
PubMed1995

Molecular cloning of the cDNA encoding human skeletal muscle triadin and its localisation to chromosome 6q22-6q23.

We have cloned and sequenced the cDNA encoding triadin, a junctional terminal cisternae protein from human skeletal muscle. The cDNA, 2941 base pairs in length, encodes a protein of 729 amino acids with a predicted molecular mass of 81,545 Da. Hydropathy analysis indicates that triadin of human skeletal muscle has the same topology in the myoplasmic, transmembrane and sarcoplasmic reticulum luminal domains as that of triadin from rabbit skeletal muscle. The number and relative position of potential modulation sites are also conserved between the human and rabbit proteins. The cDNA sequence of the predicted sarcoplasmic reticulum luminal domain of human triadin diverged from that of rabbit, with an observed similarity of 82%, translating to an identity of 77% in amino acid sequence. Two insertions of 9 and 12 residues in the amino acid sequence were observed in the predicted luminal domain of triadin, although the structural and functional consequences of such insertions are expected to be minimal. Using fluorescence in situ hybridisation, we have assigned the gene encoding human triadin to the long arm of chromosome 6 in the region 6q22-6q23. Our structural analysis of human triadin supports a central role for this protein in the mechanism of skeletal muscle excitation/contraction coupling.

Amino Acid Sequence↗