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Biomedical subjects

R D Jolly

Publications and source records attributed to R D Jolly.

At least 19 recordsLinked to original sources
PubMed2006

Segmental axonopathy of Merino sheep in New Zealand.

AIM: To investigate an axonopathy of Merino sheep that caused progressive hindlimb ataxia and slight to moderate paresis, with the purpose of understanding its pathogenesis. METHODS: Tissues were fixed in buffered paraformaldehyde or paraformaldehyde and glutaraldehyde, processed into wax and epoxy resin, respectively, and examined by light and electron microscopy. Fresh frozen spinal cord and trigeminal nerve roots were subjected to homogenisation, centrifugation and two-dimensional electrophoresis. Selected protein spots were identified using matrix-assisted laser desorption ionisation (MALDI) mass spectrometry. RESULTS. By light microscopy, there were large pale foamy spheroidal axonal swellings affecting peripheral as well as central axons. By electron microscopy, these were shown to contain many membrane-bound vesicles. The main abnormalities in expressed proteins involved cytoskeletal elements and myosin heavy chain, the latter interpreted as associated with the molecular motor myosin Va. CONCLUSIONS: The disorder is the same as that described in Merinos in Australia as segmental axonopathy, and believed to have an inherited aetiology. The lesions and protein changes indicate abnormalities of the cytoskeleton, its relationship with the myelin sheath, and myosin Va molecular motor. The consequence appears to be abnormal axonal transport and inability to maintain the integrity of axons and their myelin sheaths.

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PubMed2005

Cerebellar cortical abiotrophy in Wiltshire sheep.

AIM: To investigate the nature of a neurological disease in Wiltshire sheep. METHODS: Three affected lambs were examined, humanely killed and necropsied. Selected neurological tissues were examined by light and electron microscopy. RESULTS: Primary neurological lesions were confined to the cerebellum and were characterised by loss of Purkinje cells and the presence of large hypertrophied dendrites of surviving Purkinje cells. These contained stacks of smooth endoplasmic reticulum. There was hyperplasia and cell swelling of Bergmann glia. Mild Wallerian-type degeneration affected white matter in the cerebellum and spinal cord. CONCLUSION: The cerebellar lesions were of a degenerative and reactive rather than hypoplastic nature. These, and the history, suggest a genetic cause with putative inheritance as an autosomal recessive trait. Accordingly, the disorder is described as a cerebellar abiotrophy.

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PubMed2005

Congenital polycystic kidney disease in lambs.

AIM: To describe the pathology and inheritance of a congenital polycystic kidney disease (PKD) of sheep. METHODS: Mode of inheritance of PKD was investigated by evaluation of results of the disorder from planned matings in two consecutive years within subsets of a flock that had a high prevalence of PKD in lambs. Gross pathological and histopathological studies were based on tissues derived from this study. Haematoxylin and eosin (H&E)-stained paraffin sections of kidney, liver, extrahepatic biliary and pancreatic ducts, pancreas and epididymis were used to describe the lesions. RESULTS: Twenty-five lambs affected by PKD, of both sexes, were born, numbers in accord with those expected for an autosomal recessive disorder in the population studied. In all cases for which tissues were available, the renal, bile ductal (intrahepatic and extrahepatic), pancreatic and epididymal tissues had widespread dysplastic changes and associated cyst formation. CONCLUSIONS: The findings of renal cysts in conjunction with cysts in other organs are unifying features in many of the human and animal forms of PKD and suggest a related pathogenic and genetic base consistent with an autosomal recessive disorder.

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PubMed2004

Genetic disorders of sheep in New Zealand: a review and perspective.

Genetic disorders of sheep that have occurred in New Zealand are reviewed and discussed with regard to phenotype, inheritance and, where known, genotype. Inbreeding was a major factor in the emergence of some of them. The various disorders reflect a continuum, ranging from simple monogenic diseases or malformations due to dysfunctional gene products, those monogenic disorders dependant on environmental interactions, malformations due to homeotic gene dysfunctions, and multifactorial diseases for which genetic factors are associated with disease susceptibility. Chromosomal aberrations, although of limited importance, have contributed to an understanding of the physical chromosome map and derivative linkage map of sheep.

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PubMed2004

Myophosphorylase deficiency (glycogen storage disease Type V) in a herd of Charolais cattle in New Zealand: confirmation by PCR-RFLP testing.

AIM: To describe a disease of muscle in Charolais calves and confirm the putative diagnosis of inherited myophosphorylase deficiency. METHODS: Variously stained paraffin sections of muscle prepared from affected calves were used to describe the lesions. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) test was developed and applied to affected calves, their sires, dams and other individuals. RESULTS: The lesions were those of rhabdomyolysis of skeletal muscles and sub-sarcolemmal spaces in normal fibres. The PCRRFLP test confirmed the expected mutation for phosphorylase deficiency of Charolais cattle in two affected calves. In addition, sires, dams and other closely-related individuals of four affected calves tested as heterozygous for the mutation. Other apparently unrelated animals also tested as heterozygous. CONCLUSIONS: The diagnosis of myophosphorylase deficiency was confirmed. The PCR-RFLP test is suitable for use in controlling this recessively-inherited disorder as it can diagnose heterozygous individuals that are otherwise clinically normal.

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PubMed2003

Microphthalmia in Texel lambs.

AIM: To describe an outbreak of congenital microphthalmia in Texel lambs in New Zealand. METHODS: Affected eyes were fixed in 10% formol saline, processed routinely for histopathology and stained with haematoxylin and eosin, Holme's silver and haematoxylin with and without luxol fast blue, and luxol fast blue alone. RESULTS: Macroscopically, the globes and optic nerves were hypoplastic. Histologically, all embryonic components of the eye were present, but the lens, ciliary body, iris and retina were dysplastic. Axons of the hypoplastic optic nerve were poorly myelinated. CONCLUSIONS: Congenital microphthalmia occurs in Texel sheep in New Zealand, and is likely inherited as an autosomal recessive trait.

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PubMed2002

Mitochondrial dysfunction in the neuronal ceroid-lipofuscinoses (Batten disease).

There are at least eight genetic entities known as the ceroid-lipofuscinoses in humans which share clinical and pathological features that have caused them to be grouped together under the eponym of Batten disease. They present pathologically as lysosomal storage diseases but are also characterised by severe neurodegeneration. Although the biochemical defects appear primarily centred on lysosomes and defects in proteolysis, the link between this and pathogenesis of neuronal death is poorly understood. The pathogenesis of neurodegeneration has been studied particularly in two animal models these being the English setter dog and the New Zealand Southhampshire sheep (OCL6). In these, and some of the human entities, there is evidence of mitochondrial dysfunction. This includes the accumulation of subunit c of ATP synthase as a component of storage material in at least six of eight genetic forms of the disease; structural abnormalities of mitochondria and selective loss of neurons in areas of the brain that are particularly metabolically active. Direct evidence of dysfunction comes from mitochondrial function tests in fibroblasts and, in animal models, isolated liver mitochondria. Supporting evidence of mitochondrial dysfunction was shown by disturbances in proportions of energy-rich phosphates in fibroblasts in some of these diseases. If these various defects were reflected in neurons, then it would support the hypothesis that neuron death was associated with energy-linked excitotoxicity.

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PubMed2002

Polyglucosan body disease in a mixed-breed dog.

AIM: To describe the histopathology of a previously unrecorded canine disease and deduce the cause of the lesions. METHODS: Formalin-fixed tissues were processed into paraffin wax and epoxy resin for light and electron microscopy of variously stained sections of liver, brain, heart muscle and kidney. RESULTS: Periodic acid Schiff (PAS) -positive bodies in liver and myocardium were typical of a polyglucosan body disease. Neurons contained coarse granular material that stained similarly to the polyglucosan bodies. CONCLUSION: The nature, distribution and histochemistry of lesions observed are consistent with a putative diagnosis of Glycogen storage disease type IV, an inherited metabolic defect associated with a deficiency of glycogen-branching enzyme not previously reported in dogs.

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PubMed2002

Neuronal ceroid-lipofuscinosis in Borderdale sheep.

AIM: To describe the gross and histological lesions of a neurological disease in Borderdale sheep characterised clinically by blindness and circling, as a basis to its classification. METHODS: Formalin-fixed tissues were processed into paraffin wax and epoxy resin for light and electron microscopy of variously stained sections. RESULTS: Lesions were those of a lysosomal storage disease with severe neurodegeneration of the cerebral cortex. The staining reactions, autofluorescence and ultrastructure of storage material allowed the diagnosis of neuronal ceroid-lipofuscinosis associated with the accumulation of subunit-c of mitochondrial ATP synthase. CONCLUSIONS: The severity of neurodegeneration and minor differences in the ultrastructure of storage material implied that this was a different disease from other forms of ovine ceroid-lipofuscinosis that accumulate subunit-c of mitochondrial ATP synthase. An autosomal recessive mode of inheritance is considered probable. Although of only minor economic importance, this disease may be important to research into the group of ceroid-lipofuscinoses as a whole.

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PubMed2002

Progressive ataxia and seizures in a Cocker Spaniel: a new type of neurodegenerative disease with novel intra-neuronal inclusions.

AIMS: To describe the histopathological lesions of a new canine disease characterised by progressive ataxia, head tremor and seizures, and to deduce the cause of the lesions. METHODS: Formalin-fixed tissues were processed into paraffin wax and epoxy resin for light and transmission electron microscopy of variously stained tissue sections. RESULTS: Significant lesions relevant to the disease were found only in the brain. They consisted of hypoplasia of the cerebellum and the presence of large pale inclusions in the perikaryon of neurons in the neocortex and in macrophages. The inclusion material was not compartmentalised and did not stain for carbohydrate, mucopolysaccharide or lipid. This material displaced nuclei to the periphery of the cells where they were seen as basophilic distorted crescent-shaped structures. CONCLUSIONS: The inclusions were probably made of polymerised protein similar, though not identical, to those of Pick, Lewy and Collins bodies that characterise a variety of chronic neurodegenerative diseases of humans. A genetic basis to this disease was considered probable.

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PubMed2002

Neuronal ceroid lipofuscinosis in Merino sheep.

OBJECTIVE: To characterise neuronal ceroid lipofuscinosis (NCL) in Merino sheep. DESIGN: A prospective clinical, pathological, biochemical and genetic study. PROCEDURE: NCL cases were studied from a medium-wool Merino flock, the stud of origin of its replacement rams, and an experimental flock established at the University of Sydney. RESULTS: Behavioural changes and visual impairment were first detected at 7 to 12 months of age and progressed, with associated motor disturbances and at later stages seizures, to premature death by 27 months of age. At necropsy there was severe cerebrocortical atrophy associated with neuronal loss, astrocytosis and the presence in neurons of eosinophilic intracytoplasmic storage bodies with the characteristics of a lipopigment. In the retina there was progressive loss of photoreceptor cells. Storage bodies isolated from fresh brain, liver and pancreas formed electron-dense aggregates and coarse multilamellar and fine fingerprint profiles ultrastructurally, and consisted mainly of the hydrophobic protein, subunit c of mitochondrial ATP synthase. A homozygosity mapping approach localised the gene causing the disease in Merino sheep to the chromosomal region (OAR7q13-15) associated with NCL in South Hampshire sheep. CONCLUSION: NCL in Merino sheep is a subunit c-storing disease, clinically and pathologically similar to NCL in South Hampshire sheep. We propose that the disease in both breeds represents mutation at the same gene locus in chromosomal region OAR7q13-15.

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PubMed2001

Histological diagnosis of mucopolysaccharidosis IIIA in a wire-haired dachshund.

A four-year-old wire-haired dachshund developed progressive neurological signs of ataxia, intention tremor and finally dysuria. Two years later, histopathology showed that neurons throughout the brain and spinal cord were distended with lipopigment which was also present in macrophages. Ultrastructurally, the pigment in the neurons occurred predominantly as electron-dense membranous whorls and stacks. There were a few vacuolated macrophages in the meninges. Hepatocytes were highly vacuolated and electron microscopy suggested that they were empty membrane-bound vesicles. The disease was diagnosed as mucopolysaccharidosis IIIA because of its similarity to other biochemically confirmed cases in the same breed and in a New Zealand huntaway dog. Additional lesions included calcium oxalate uroliths, severe secondary calcification of tissues including the brain and storage deposits in some neurons, and lesions which may have been associated with high levels of the substrate, heparan sulphate.

Animals↗
PubMed2001

Submitochondrial distribution and delayed proteolysis of subunit c of the H+-transporting ATP-synthase in ovine ceroid-lipofuscinosis.

The neuronal ceroid-lipofuscinose (NCL) are recessively inherited lysosomal storage diseases in children and animals. The major stored protein in many of these diseases is subunit c of the mitochondrial inner membrane H+-transporting ATP-synthase. Previous studies of naturally occurring ovine ceroid-lipofuscinosis (OCL) in South Hampshire sheep showed that the genes and transcripts for subunit c were normal and inferred that this protein was expressed normally in mitochondria prior to storage in lysosomes. Accumulation in mitochondria has not been conclusively established and we have therefore used the South Hampshire model to demonstrate approximately 1.8-fold normal levels of subunit c in mitochondrial inner membranes prepared from liver. Other mitochondrial inner membrane and ATP-synthase proteins that could be detected by mass spectrometry (MS) or two-dimensional electrophoresis (2-DE) were present in normal amounts. The accumulating subunit c showed normal post-translational modification but was abnormally resistant to proteolysis. These results are consistent with the hypothesis that OCL may result from a mitochondrial disorder that affects turnover of correctly expressed subunit c, although we cannot exclude the possibility that a postmitochondrial defect delays processing of subunit c out of mitochondria.

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PubMed2001

ATP synthase activity in ovine ceroid lipofuscinosis [OCL6].

We measured ATP synthase activities in mitochondria isolated from livers of lambs with ceroid lipofuscinosis (OCL6) and compared them with those from similar isolations from obligate heterozygous and control lambs. Addition of excess Ca2+ to the incubation mixture resulted in an up-regulation of activity in mitochondria from control lambs but down-regulation in those from OCL6 affected lambs. The mean change in activity with Ca2+ for heterozygous animals was midway between those from control and affected groups being significantly different from control but not from affected. The change in ATP synthase activity to added Ca2+ was also measured in isolated mitochondria from affected and control lambs from 3 days to 25 months of age. As above, there was down-regulation to the addition of Ca2+ in affected lambs. There was a fall in percentage change to Ca2+ with age in both affected and control lambs. This was not significantly different in affected lambs indicating it was not associated with the stage of disease. The above in vitro results, if extrapolated to neurons in vivo, imply a potential dysfunction of mitochondria in OCL6 lambs that could lead to calcium mediated neurotoxicity and neuron death due to production of free radicals as implicit in the energy-linked excitotoxic hypothesis.

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