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Biomedical subjects

P R Dorling

Publications and source records attributed to P R Dorling.

At least 19 recordsLinked to original sources
PubMed1994

Bovine glycogenosis type II: the molecular defect in Shorthorn cattle.

The molecular defect in Shorthorn cattle affected with glycogenosis type II was studied. Polyclonal and monoclonal antibodies specific for bovine skeletal muscle acid alpha-glucosidase were raised and used to study the molecular and biochemical defect in seven affected animals. Cultured normal bovine fibroblasts pulsed and chased with [3H] leucine produced a 130 kDa precursor form of acid alpha-glucosidase which was processed via several 100 kDa intermediate forms to the 65 kDa mature form within 26 h. Fibroblasts from affected animals were labelled in vitro and were shown to produce a cross-reactive protein which was identified as the precursor form of the enzyme. The mature form of the enzyme was not found. The precursor form of the enzyme was demonstrated in Western blots of muscle tissue extracts from affected animals. Glycogenosis type II in Shorthorn and Brahman cattle must be caused by a different, independent maturation, since Brahman cattle lack the cross-reactive protein for acid alpha-glucosidase.

Animals↗
PubMed1994

Effect of the ingestion of heliotrope and copper on the concentration of zinc, selenium and molybdenum in the liver of sheep.

Merino wethers were used to examine the effect of feeding heliotrope, with and without additional copper (Cu), on the development of clinical signs, lesions in the liver and concentration in the liver of Cu, zinc (Zn), selenium (Se) and molybdenum (Mo). The feeding of heliotrope reduced liver concentrations of Zn (P < 0.05) and Mo (P < 0.01), but Cu ingestion had no effect on these parameters. The concentration of Se in the liver was only increased when heliotrope was given with copper (P < 0.01); it had previously been shown that Cu and heliotrope ingestion is followed by an interaction which results in a marked increase in the concentration of Cu and the production of extensive lesions in the liver. The increase in liver Se may therefore have represented a passive or active response to liver necrosis, whereas effects on Zn and Mo represented specific metabolic disturbances attributable to heliotrope feeding.

Alkaloids↗
PubMed1993

Identification of galegine, an isoprenyl guanidine, as the toxic principle of Schoenus asperocarpus (poison sedge).

An isoprenyl guanidine, galegine, was isolated from the Western Australian sedge Schoenus asperocarpus (Cyperaceae). Synthetic galegine was shown to reproduce the clinical and pathological features of poisoning by this plant. Preliminary results suggest that the massive thoracic effusion observed in sedge poisoning is the result of a direct effect on pulmonary vascular permeability.

Animals↗
PubMed1992

The effect of copper and heliotrope on the composition of bile in sheep.

The effects of interrupting the enterohepatic circulation (EHC) of bile salts for seven hours and of feeding copper and heliotrope alone and combined for 13 weeks, on bile flow and excretion of copper, zinc, iron and alpha-mannosidase were studied in sheep. Interruption of EHC reduced bile flow rate and increased the concentration of copper, zinc, iron and bile acids while alpha-mannosidase's activity remained stable. Changes in concentration were related to changes in bile volume for copper and zinc only. Total output per hour was not changed. Biliary concentration of copper correlated with alpha-mannosidase's activity in control sheep and those given copper or heliotrope, supporting the hypothesis that lysosomes are involved in biliary secretion of copper in sheep. Increasing the intake of copper increased the rate of excretion of copper in bile. Copper output was lower when heliotrope was fed alone.

Animals↗
PubMed1991

Natural bone marrow transplantation in cattle with Pompe's disease.

Adding acid alpha-glucosidase to cultures of Pompe's disease muscle has resulted in enzyme uptake and reduction in concentration of glycogen. However, bone marrow transplantation has been unsuccessful as a treatment. Immune rejection may have contributed to this failure. Twin calves share a placenta and carry lymphoreticular cells of each other's type, they become lymphoreticular chimeras in utero and immune rejection does not occur. One natural and three sets of twins produced by embryo transfer were studied in Pompe's disease cattle. Chimerism persisted throughout life and the situation was analogous to a transplant of histocompatible bone marrow stem cells. The activity of acid alpha-glucosidase in leucocytes and in biopsies of the semitendinosus muscle and the mean activity in diaphragm, spleen and lymph node obtained after death from affected twins were significantly higher than in single affected calves. Glycogen concentration was lowered in liver, spleen and lymph node but not in muscles. The affected twins showed clinical signs and changes in muscle similar to those seen in affected single calves. It is concluded that bone marrow transplantation is unlikely to be a successful treatment for Pompe's disease.

Animals↗
PubMed1991

Experimental copper and heliotrope intoxication in sheep: morphological changes.

Young Merino wethers were used to determine the effects of copper and heliotrope, fed together or separately, on the development of toxicity and the concentration of trace elements in the liver and kidney. In one experiment copper and heliotrope were given concurrently, in a second experiment heliotrope was fed for 12 weeks and copper administration commenced 8 weeks later. The 10 sheep fed heliotrope alone did not show signs of clinical illness but one died and was found to have severe liver damage. Eleven sheep were given copper alone and three developed the clinical signs and lesions of haemolysis. Fourteen sheep were given copper and heliotrope and 13 became ill. Of these, three developed haemolysis, eight became jaundiced and two became weak without developing jaundice. The concentrations of copper in the livers of control and heliotrope-treated sheep, were comparable. In the animals given copper alone, the concentration of copper in the liver was twice as high as that in controls and in those given heliotrope and copper, it was three times as high as in the liver of control sheep. Feeding heliotrope alone induced the histological changes of pyrrolizidine alkaloid toxicity in the liver, but this was not associated with an excessive accumulation of copper or the development of clinical illness. However, it did predispose the animals to the effects of a second toxin since giving heliotrope and copper concurrently, or giving copper subsequent to feeding heliotrope, markedly enhanced the toxicity of the two substances and caused an excessive accumulation of copper in the liver.

Animals↗
PubMed1990

Swainsonine toxicosis suppresses appetite and retards growth in weanling rats.

Two groups of weanling rats were treated with swainsonine, the toxin responsible for 'pea-struck' and locoism in grazing animals, for 21 days. The initial dose rate was 46 mg kg-1 d-1 in one group, and 7.6 mg kg-1 d-1 in the other. Food and water intake, urinary volume and bodyweight gain were recorded for each rat and compared with those for pair-fed and ad libitum fed control individuals. At both dose rates, swainsonine caused marked retardation of growth consequent to profound suppression of appetite. In intoxicated rats, intake of water was also diminished.

Alkaloids↗
PubMed1987

Multiple implantation of normal amnion into cattle with generalized glycogenosis type II.

One normal and two carrier calves, and two calves affected by generalized glycogenosis type II were given multiple transplants of normal bovine amnion inserted below the external oblique abdominal muscle in the flank. The interval between transplants was approximately 5 months. The amniotic tissue was not acutely rejected but a host versus graft reaction did occur. The level of acid alpha-glucosidase activity in the amniotic tissue fell rapidly but was still present 2 months after transplantation. Enzyme levels in blood or other tissues did not rise. Excess glycogen deposition and muscle damage occurred in the affected calves and appeared to progress at a rate similar to that in untreated affected animals. One of the affected animals died aged 16 months, which was the same age as the longest surviving non-treated animal in our herd. The other treated animal died aged 24 months.

Amnion↗
PubMed1985

Bovine generalised glycogenosis type II. Uptake of lysosomal alpha-glucosidase by cultured skeletal muscle and reversal of glycogen accumulation.

acid alpha-glucosidase (EC 3.2.1.20) was purified from fetal bovine muscle by affinity chromatography on concanavalin A and Sephadex G-100 and added to the culture medium of mature muscle cultures from animals affected by glycogenosis type II. The enzyme activity in homogenates of treated cultures was significantly increased within 4 h of the addition of enzyme, was maximal by 18 h and the internalised activity was stable for at least 48 h after the removal of the enzyme from the culture medium. The acid alpha-glucosidase activity was internalised with an uptake constant of 300 nM and a Vmax of uptake of 133 nmol/h per mg protein. The glycogen concentration in affected cultures treated with exogenous acid alpha-glucosidase for 24 h had decreased by 20% and after a further 24 h of culture was comparable to the concentration observed in cultures from non-affected animals.

Animals↗
PubMed1985

Mannoside storage and axonal dystrophy in sensory neurones of swainsonine-treated rats: morphogenesis of lesions.

Young rats were treated with swainsonine for up to 200 days at a dose rate that restricted neuronal mannoside storage to neurones not protected by the blood/brain barrier. In lumbar dorsal root ganglion neurones, mannoside storage in the cell body developed in parallel to dystrophic changes at the extremities of peripherally and centrally directed axons. The dystrophic process involved the accumulation of autophagic structures. In the CNS, axonal dystrophy was confined to areas receiving long processes from affected neurones. The results suggest that axonal dystrophy is a direct consequence of the lysosomal storage process in parent cell bodies. The possible relationship of axonal dystrophy to neuronal lysosomal function is discussed.

Alkaloids↗
PubMed1983

Biosynthesis of intestinal microvillar proteins. The effect of swainsonine on post-translational processing of aminopeptidase N.

The post-translational processing of pig small-intestinal aminopeptidase N (EC 3.4.11.2) was studied in organ-cultured mucosal explants. Exposure of the explants to swainsonine, an inhibitor of Golgi mannosidase II, resulted in the formation of a Mr-160000 polypeptide, still sensitive to endo-beta-N-acetylglucosaminidase H. Swainsonine caused only a moderate inhibition of transport of the enzyme through the Golgi complex and the subsequent expression in the microvillar membrane. This may imply that the trimming of the high-mannose core and complex glycosylation of N-linked oligosaccharides is not essential for the transport of aminopeptidase N to its final destination. A different type of processing was observed to take place in the presence of swainsonine, resulting in a considerable increase in apparent Mr (from 140000 to 160000). This processing could not be ascribed to N-linked glycosylation, since treatment of the Mr-160000 polypeptide with endo-beta-N-acetylglucosaminidase H only decreased its apparent Mr by 15000. The susceptibility of the mature Mr-166000 polypeptide, but not the Mr-140000 polypeptide, to mild alkaline hydrolysis suggests that aminopeptidase N becomes glycosylated with O-linked oligosaccharides during its passage through the Golgi complex. Aminopeptidase N was not labelled by [3H]palmitic acid, indicating that the processing of the enzyme does not include acylation.

Acetylglucosaminidase↗
PubMed1983

Swainsonine affects the processing of glycoproteins in vivo.

Rats, sheep and guinea pigs treated with swainsonine excrete 'high mannose' oligosaccharides in urine. The major rat and guinea pig oligosaccharide is (Man)5GlcNAc, whereas sheep excrete a mixture of oligosaccharides of composition (Man)2-5GlcNAc2 and (Man)3-5GlcNAc. The presence of these oligosaccharides suggests that Golgi alpha-D-mannosidase II as well as lysosomal alpha-D-mannosidase is inhibited by swainsonine resulting in storage of abnormally processed asparagine-linked glycans from glycoproteins. Altered glycoprotein processing appears to have little effect on the health of the intoxicated animal, but the accompanying lysosomal storage produces a disease state.

Alkaloids↗
PubMed1983

Lysosomal hydrolases in macrophages exposed to swainsonine.

Swainsonine reversibly inhibits macrophage lysosomal acid alpha-mannosidase in vitro. When supplied to cultured cells for periods of up to 24 h, swainsonine penetrates the cells and produces a dose- and time-dependent inhibition of cellular alpha-mannosidase. Exposure of macrophages to swainsonine for 24 h, followed by continued incubation in the absence of this agent, produces elevated cellular activity of alpha-mannosidase, relative to unexposed controls; prolonged incubation of macrophage cultures with swainsonine for 1-2 weeks results also in significant increases in cell protein, lactate dehydrogenase activity and in that of another lysosomal enzyme, beta-hexosaminidase.

Alkaloids↗
PubMed1983

Cardiomyopathy in generalised glycogenosis type II in cattle.

The clinical, electrocardiographic and postmortem findings in five cattle affected by generalised glycogenosis type II are described. Three of the affected animals showed generalised muscle weakness for some months before being killed at 11, 15 and 16 months of age. Of the remaining two, one developed severe respiratory distress when 3 months old and died within 6 h of first being noticed to be ill. The other animal showed respiratory distress on exertion at 5 months of age, became recumbent and died when 7 months old. The sum of the QRS complex amplitudes in ECG leads I, II, a VR, aVL and aVF of the affected animals was significantly increased from the control or carrier animals, but only the two affected animals which showed clinical and pathological signs of congestive heart failure had increased heart weight to body weight, left and right ventricular weight to body weight ratios. In view of the lack of correlation between the increased QRS amplitudes and the presence of cardiac enlargement, it is suggested that the increased QRS amplitudes are a reflection of a conduction disorder. It is further suggested that QRS complex abnormalities in generalised glycogenosis in man, particularly in the late onset form may be due to a similar phenomenon.

Animals↗
PubMed1983

Suspected ergotism in two heifers.

A syndrome similar to gangrenous ergotism was seen in 2 Friesian heifers grazing meadow hay containing perennial rye grass seed heads parasited by an ergot presumed to be Claviceps purpurea. Clinical signs were bilateral hind limb lameness and gangrene. There was angiographic evidence of vasoconstriction in the lower hind limbs with necrosis of all tissues in the distal region of both hind limbs.

Animals↗
PubMed1983

Nephrotic syndrome and collagenizing glomerulopathy in PVG/c rats treated with the alpha-mannosidase inhibitor "swainsonine".

Weanling PVG/c rats treated with the alpha-mannosidase inhibitor swainsonine developed increasing proteinuria which terminated as a severe nephrotic syndrome after 35 to 45 days. This was associated with a glomerulopathy characterized by the production of collagen fibrils adjacent to endothelial and mesangial cells, foot process expansion, subepithelial projections of the basement membrane, and splitting of the lamina densa. The swainsonine-induced glomerulopathy appeared to be an exacerbation of a spontaneous abnormality in this strain of rat.

Alkaloids↗