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Biomedical subjects

G D Shelton

Publications and source records attributed to G D Shelton.

At least 19 recordsLinked to original sources
PubMed2007

CNS hypomyelination in Rat Terrier dogs with congenital goiter and a mutation in the thyroid peroxidase gene.

Arrested physical development and neurologic abnormalities were identified in 3 of 5 Rat Terrier puppies at 9 weeks of age. Bilaterally firm symmetrical masses were palpated in the region of the thyroid glands. Low serum total (T4) and free thyroxine (FT4, by equilibrium dialysis) and markedly elevated thyroid stimulating hormone (TSH) concentrations supported the diagnosis of hypothyroidism. At necropsy, the thyroid gland was grossly enlarged and histologically exhibited severe, diffuse hyperplasia of the follicular epithelium. Gross examination of the central nervous system revealed a myelin deficiency, most evident in the corpus callosum. Regional distribution of hypomyelination was confirmed histologically, affecting the corpus callosum and, to a lesser degree, the corona radiata, the longitudinal fibers of the pons, the pyramids, and the lateral funiculi of the spinal cord. Myelin reduction was paralleled by axon reduction, suggesting that hypomyelination was a consequence of reduced axonal formation. A homozygous nonsense mutation in the thyroid peroxidase gene was identified in the affected puppies. The dam and a clinically normal litter mate were heterozygous for this mutation, confirming simple autosomal recessive inheritance of the disease trait. The same mutation, causing congenital hypothyroidism with a goiter was previously described in the Toy Fox Terrier breed. Given the ongoing practice of introducing the Toy Fox Terrier genetic background into some Rat Terrier breeding programs to obtain a smaller stature and the apparent relative incidence of the disorder in the 2 breeds, it is likely that this mutation crossed into the Rat Terrier breed from Toy Fox Terriers fairly recently.

Animals↗
PubMed2006

Myopathy in horses with pituitary pars intermedia dysfunction (Cushing's disease).

Fifteen horses with pituitary pars intermedia dysfunction were studied. The horses were of various breeds and between 15 and 28 years of age. Control horses matched for breed and age were studied for comparison. Evaluations included complete blood cell count and serum biochemical analysis, electromyography, and gluteus medius muscle biopsies for histochemical, morphometric, and ultrastructural analysis. No differences were found between groups of horses on routine laboratory analysis or electromyography. We demonstrated that muscle wasting in diseased horses was the result of atrophy of types 2A and 2B muscle fibers and loss of type 2B myofibers. Mild non-specific non-inflammatory myopathic alterations such as myofiber size variation, internal nuclei, perimysial, endomysial and sarcoplasmic fat accumulation were observed. At the ultrastructural level, subsarcolemmal mitochondrial accumulation and increased lipid droplets were evident. Similar to other species, this study confirmed atrophy of type 2 fibers as the cause of muscle mass loss in horses with Cushing's disease.

Animals↗
PubMed2006

Inherited myopathy of great Danes.

A hereditary, non-inflammatory myopathy occurring in young great Danes with distinctive histological features in muscle biopsy specimens is reviewed. Onset of clinical signs is usually before one year of age and both sexes are affected. Clinical signs are characterised by exercise intolerance, muscle wasting, and an exercise-induced tremor. Although most affected dogs have a severe form of the disease, occasional dogs may have a less pronounced form and survive into adulthood with an acceptable quality of life. Litters containing affected puppies are born to clinically unaffected parents, and an autosomal recessive pattern of inheritance is likely. All recorded cases have had fawn or brindle coat coloration. Elevated serum creatinine kinase concentrations and spontaneous electrical activity in skeletal muscles are frequently found. While originally reported (Targett and others 1994) as a central core myopathy in this breed, the histochemical characteristics of the distinct cytoarchitectural structures differ from those of the well-characterised central core myopathy in human beings. In fact, these structures differ from any known myopathy in human beings and likely represents a unique non-inflammatory myopathy affecting dogs. Until this myopathy is characterised further, the name inherited myopathy in great Danes is suggested.

Animals↗
PubMed2005

Absence of mutations in the survival motor neuron cDNA from labrador retrievers with an inherited myopathy.

The clinical phenotype of hereditary myopathy of labrador retrievers is consistent, but the pathological changes within muscle biopsy specimens can vary from type 1 fibre predominance (type 2 fibre deficiency) to dystrophic changes or overt neurogenic atrophy. The condition shares many clinical and pathological features with the mildest form of human childhood spinal muscular atrophy, and the survival motor neuron gene was therefore evaluated in dogs with the disease. Direct sequencing and comparisons of cdna from the gene in seven labrador retrievers homozygous for the disease and four control dogs revealed no nucleotide mutations leading to changes in the deduced amino acid sequences. A single polymorphism was detected in two of the seven affected dogs, which was characterised by a nucleotide substitution at amino acid position 1155 within the non-coding 3' untranslated region of exon 8. Northern blot analysis indicated that there were no differences in the steady state levels of mrna from the gene of the affected labrador retrievers and control dogs.

Animals↗
PubMed2005

Sarcoplasmic masses in equine skeletal muscle.

Sarcoplasmic masses in humans have been associated with various myopathies, although the significance remains elusive. Similar structures have also been observed in equine muscle. The aim of this study was to determine the frequency of such structures in normal and abnormal equine muscle, and to characterize these structures using histological, histochemical, immunohistochemical, ultrastructural, and morphometric analyses. The histological and histochemical appearance was similar to that of human sarcoplasmic masses with a central or subsarcolemmal distribution. Of interest was a predilection for the gluteus medius muscle in younger horses and type 2B fibers. Ultrastructurally they contained disorganized myofibrils and other cellular components that were not membrane bound and were present in both normal and abnormal equine muscle without a specific disease association, suggesting they are a non-pathological degenerative structure. The relatively frequent occurrence of sarcoplasmic masses in horses may make this species a good model for studying the pathogenesis of these structures.

Age Factors↗
PubMed2004

Pyruvate dehydrogenase deficiency in a Sussex spaniel.

A two-year-old, intact female Sussex spaniel was presented with signs of exercise intolerance. Pre- and post-exercise serum lactate and pyruvate concentrations and urinary organic acid screening supported a diagnosis of pyruvate dehydrogenase deficiency, as previously reported in this breed. Dietary therapy was initiated for six months, during which time there was no reported clinical deterioration. A full neurological examination and repeat evaluation of lactate and pyruvate concentrations before and after exercise was conducted one year after diagnosis, at which time the patient had been without dietary modification for six months and had developed more severe exercise intolerance along with evidence of central nervous system dysfunction.

Animals↗
PubMed2003

Laminin alpha2 deficiency-associated muscular dystrophy in a Maine coon cat.

A European case of laminin alpha2 deficiency-associated muscular dystrophy in a 12-month-old, female Maine coon pedigree cat is reported. The history and eventual clinical presentation of this cat differed from those of two cats reported in the USA. In this case, the myopathy was characterised by progressively worsening weakness, muscle atrophy and joint contracture. Tendon reflexes were diminished, and motor nerve conduction velocities were slowed. Muscle biopsy demonstrated a dystrophic phenotype with endomysial fibrosis. Occasional thinly myelinated nerve fibres were present within a peripheral nerve specimen. Poorly myelinated fibres were also found at the root level on necropsy specimens. Immunohistochemical staining revealed the absence of laminin alpha2. The cat's family history did not indicate genetic transmission of the disease.

Animals↗
PubMed2001

Spontaneous remission in canine myasthenia gravis: implications for assessing human MG therapies.

The natural course of autoimmune canine MG was determined in 53 dogs with muscular weakness and a positive acetylcholine receptor antibody titer. Dogs were treated with anticholinesterase therapy, without immunosuppression. Spontaneous clinical and immunologic remission occurred in 47 of 53 dogs within an average of 6.4 months. Neoplasia was identified in the six dogs that did not spontaneously remit. This study questions the value of using canine MG in studies designed to assess the effect of immunotherapies.

Animals↗
PubMed2001

Ablation of Cypher, a PDZ-LIM domain Z-line protein, causes a severe form of congenital myopathy.

Cypher is a member of a recently emerging family of proteins containing a PDZ domain at their NH(2) terminus and one or three LIM domains at their COOH terminus. Cypher knockout mice display a severe form of congenital myopathy and die postnatally from functional failure in multiple striated muscles. Examination of striated muscle from the mutants revealed that Cypher is not required for sarcomerogenesis or Z-line assembly, but rather is required for maintenance of the Z-line during muscle function. In vitro studies demonstrated that individual domains within Cypher localize independently to the Z-line via interactions with alpha-actinin or other Z-line components. These results suggest that Cypher functions as a linker-strut to maintain cytoskeletal structure during contraction.

Actinin↗
PubMed2001

Laminin alpha 2 (merosin)-deficient muscular dystrophy and demyelinating neuropathy in two cats.

We report laminin alpha 2 (merosin) deficiency associated with muscular dystrophy and demyelinating neuropathy in two cats. The cats developed progressive muscle weakness, and atrophy. Either hypotonia or contractures resulted in recumbency, necessitating euthanasia. Muscle biopsies showed dystrophic changes including marked endomysial fibrosis, myofiber necrosis, variability of fiber size, and perimysial lipid accumulation. Immunohistochemistry showed that laminin alpha 2 chain was absent or reduced, while dystrophin and all the components of the dystrophin-associated glycoprotein complex were present and normal. One cat was examined in detail. Motor nerve conduction velocity (MNCV) was decreased, and ultrastructurally the peripheral nerves showed Schwann cell degeneration and demyelination. Brain imaging was not performed, but white matter changes were not apparent in the brain at necropsy. The disease in these cats is similar to primary or secondary merosin (laminin alpha 2)-deficient congenital muscular dystrophy (CMD) in humans and to dystrophia muscularis in mice.

Animals↗
PubMed2001

Embryonic expression of the tumor-associated PAX3-FKHR fusion protein interferes with the developmental functions of Pax3.

A unique chromosomal translocation involving the genes PAX3 and FKHR is characteristic of most human alveolar rhabdomyosarcomas. The resultant chimeric protein fuses the PAX3 DNA-binding domains to the transactivation domain of FKHR, suggesting that PAX3-FKHR exerts its role in alveolar rhabdomyosarcomas through dysregulation of PAX3-specific target genes. Here, we have produced transgenic mice in which PAX3-FKHR expression was driven by mouse Pax3 promoter/enhancer sequences. Five independent lines expressed PAX3-FKHR in the dorsal neural tube and lateral dermomyotome. Each line exhibited phenotypes that correlated with PAX3-FKHR expression levels and predominantly involved pigmentary disturbances of the abdomen, hindpaws, and tail, with additional neurological related alterations. Phenotypic severity could be increased by reducing Pax3 levels through matings with Pax3-defective Splotch mice, and interference between PAX3 and PAX3-FKHR was apparent in transcription reporter assays. These data suggest that the tumor-associated PAX3-FKHR fusion protein interferes with normal Pax3 developmental functions as a prelude to transformation.

Animals↗
PubMed2001

Titin and ryanodine receptor autoantibodies in dogs with thymoma and late-onset myasthenia gravis.

Similar to human autoimmune myasthenia gravis (MG), canine MG occurs spontaneously and is associated with autoantibodies against the nicotinic acetylcholine receptor (AChR). In addition to AChR, human MG patients with thymoma or late-onset MG have antibodies against titin and ryanodine receptor (RyR). The objective of this study was to establish if dogs with confirmed MG (AChR antibody titer >0.6 nmol/l) also developed titin and RyR antibodies and identify possible associations with thymoma, late age of onset, or severity of clinical signs. Sera from dogs (n=430) with previously diagnosed autoimmune MG (N=415), other immune-mediated neuromuscular disorders including polymyositis (PM) and masticatory muscle myositis (N=5), and control dogs (N=10) were evaluated for the presence of titin antibodies in ELISA using MGT-30 as antigen, a peptide representing the main immunogenic region (MIR) for human titin antibodies. Titin antibody positive sera were further examined for RyR antibodies in Western blots using a RyR fusion protein (pc2-RyR) as antigen, which covers the MIR for human MG sera. Titin antibodies were found in sera of 80/430 dogs. Thymoma was present in 11/80 and age of onset was after 4 years in 66/80 titin positive dogs. Two of the titin positive dogs had PM. RyR antibodies were found in 13/80 sera (8/13 thymoma, 12/13 age of onset after 4 years, and 1/13 PM). Neither titin nor RyR antibodies were found in sera of healthy control dogs. Acute fulminating MG was described in five dogs with both titin and RyR antibodies. From these studies we conclude that titin and RyR antibodies in canine and human MG have a similar association with thymoma, late-onset MG, and possibly with more severe forms of MG.

Age of Onset↗
PubMed2000

Risk factors for acquired myasthenia gravis in cats: 105 cases (1986-1998).

OBJECTIVE: To determine prevalence of initial clinical signs and risk factors for acquired myasthenia gravis (MG) in cats. DESIGN: Retrospective case-control study. ANIMALS: 105 cats from the United States, Canada; and the United Kingdom with a confirmed diagnosis of acquired MG and 510 cats with other neuromuscular disorders, including generalized weakness, megaesophagus, and dysphagia (control group). PROCEDURES: Records were retrieved from a data-base containing results of serum samples tested for acetylcholine receptor antibodies. Signalment, including breed, age, and state or country of origin, month of onset, and initial clinical signs were obtained. An acetylcholine receptor antibody titer > 0.3 nmol/L was diagnostic for acquired MG. Unconditional logistic regression was used for statistical analysis. RESULTS: Compared with mixed-breed cats, the breed with the highest relative risk of acquired MG was the Abyssinian (including Somali). Significant differences between sexes were not detected. There was no compelling evidence for a difference in risk of developing MG between states or countries. Relative risk increased after 3 years of age. The most common clinical signs were generalized weakness without megaesophagus and weakness associated with a cranial mediastinal mass. Focal signs, including megaesophagus and dysphagia without signs of generalized weakness, were also evident. CONCLUSIONS AND CLINICAL RELEVANCE: A breed predisposition for acquired MG in Abyssinians (and related Somalis) was observed. Clinical signs were variable and included generalized weakness, megaesophagus, and dysphagia. A cranial mediastinal mass was commonly associated with MG in cats.

Age Factors↗
PubMed1999

Inherited predisposition to myasthenia gravis in Newfoundlands.

Acquired myasthenia gravis was diagnosed in 6 Newfoundlands from 2 distinct lineages. Three dogs, including 1 pair of littermates, from each lineage were affected. History and clinical signs did not differ from that reported for other dogs with acquired myasthenia gravis. Although a genetic predisposition for development of certain autoimmune diseases in several species has been identified, the immunopathogenesis of myasthenia gravis is multifactorial and includes hormonal, environmental, and infectious disease factors. The high incidence of myasthenia gravis in these 2 distinct lineages of Newfoundlands, a breed with a low relative risk for development of this disease, suggests an underlying genetic mechanism. However, mode of inheritance could not be determined from this small number of dogs. Regardless, breeders should be alerted to this disorder, and they should consider removing Newfoundlands with acquired myasthenia gravis from breeding programs.

Animals↗
PubMed1999

Acquired myasthenia gravis: what we have learned from experimental and spontaneous animal models.

Acquired myasthenia gravis (MG) is a disorder of neuromuscular transmission in which muscle weakness results from an autoantibody mediated depletion of acetylcholine receptors (AChR) at the neuromuscular junction. Experimental autoimmune myasthenia gravis, described in rodents and rabbits, has provided a good model of the effects of the autoimmune response against AChR and has shown that the specificities of the immune response in MG are those that would be obtained by immunization with native AChR. It has provided little information, however, about what initiates and sustains the immune response in MG. Acquired MG occurs spontaneously in dogs and may be the most common neuromuscular disorder that can be diagnosed in this species. As in human MG, an autoimmune response against AChR has been demonstrated and AChR autoantibodies have been implicated in the pathogenesis. The variability in clinical presentation, methods of diagnosis, and occurrence with other autoimmune diseases and neoplasia are identical to that of humans. Future studies of spontaneous canine autoimmune MG may provide clues to the determination of what factors initiate and sustain the autoimmune response to AChR, and in the study of specific suppression of the autoimmune response against AChR.

Animals↗
PubMed1999

Necrotizing myopathy induced by overexpression of interferon-gamma in transgenic mice.

A transgenic mouse model has been established in which the cytokine interferon-gamma (IFN-gamma) is overexpressed through the action of the acetylcholine receptor epsilon promoter acting at the neuromuscular junction. While originally developed as a model for the study of the pathogenesis of myasthenia gravis, there are important differences from both human myasthenia gravis and its animal model, experimental autoimmune myasthenia gravis. By 4 months of age there was a well-established inflammatory, predominantly necrotizing myopathy, with marked dystrophic calcification. Dystrophic and degenerative changes in terminal axons and adjacent Schwann cells were also apparent. The acetylcholine receptor was not the primary target of the inflammatory response, since at 10 weeks of age the receptor content was not decreased and antibodies were not detected bound to the receptor. The IFNgamma transgenic mouse model may provide a clinically relevant model of necrotizing myopathy for investigation of the pathological changes associated with, and presumably precipitated by, overexpression of the pro-inflammatory cytokine interferon-gamma on the neuromuscular junction, intramuscular nerves and myofibers.

Animals↗
PubMed1999

Malonic aciduria in Maltese dogs: normal methylmalonic acid concentrations and malonyl-CoA decarboxylase activity in fibroblasts.

A family of Maltese dogs with malonic aciduria is reported. The propositus presented at 3 years of age with episodes of seizures and stupor with hypoglycaemia, acidosis, and ketonuria. Urinary organic acid assays showed elevated malonic acid without elevation of methylmalonic acid. Cultured fibroblasts had normal malonyl-CoA decarboxylase activity. Treatment with frequent feedings of a low-fat diet high in medium-chain triglycerides resulted in normalization of clinical signs and a resolution of the malonic aciduria. Two full siblings of the propositus had died at a young age of undiagnosed metabolic and neurological disease. Urine organic acid assays were performed on other family members. A half-sister showed mild malonic aciduria and other organic acid changes similar to the propositus, while the mother and half-brother showed mildly elevated ketone bodies. This family suggests further genetic and clinical heterogeneity in the malonic acidurias.

Animals↗