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Biomedical subjects

M E Haskins

Publications and source records attributed to M E Haskins.

At least 73 records · Page 4Linked to original sources
PubMed1982

Enhancement of residual arylsulfatase B activity in feline mucopolysaccharidosis VI by thiol-induced subunit association.

The molecular pathology of the deficient arylsulfatase B activity in feline mucopolysaccharidosis (MPS) VI was investigated. Compared with the highly purified normal feline hepatic enzyme, the purified MPS VI residual activity had a 100-fold higher Michaelis constant (K(m)), an altered electrophoretic mobility, half the apparent native molecular weight, and markedly decreased thermo-, cryo-, and pH stabilities. Molecular weight and alkylation studies were consistent with the normal enzyme being a homodimer and the residual MPS VI enzyme a monomer. When incubated with various sulfhydryl reagents, the residual specific activity was enhanced several-fold, whereas the activity of the purified normal enzyme was un-affected or slightly inhibited. In the presence of dithiothreitol (DTT) and cysteamine, a lysosomotropic aminothiol, the residual activity had an electrophoretic mobility and native molecular weight similar to those of the normal feline enzyme. These findings suggested that the monomeric residual enzyme was dimerized in the presence of thiol-reducing agents. To determine if thiol-induced subunit association could therapeutically increase the residual activity and degrade the accumulated dermatan sulfate, in vitro and in vivo experiments were undertaken. When 2 mM DTT or cysteamine was incubated with heparinized whole blood from an MPS VI cat, the leukocyte residual arylsulfatase B activity increased 11- and 20-fold, respectively, and the accumulated dermatan sulfate was degraded in the presence of both thiol reagents. Intravenous administration of DTT (50 mg/kg) effected an immediate, but transient, increase in leukocyte residual activity; however, the substrate levels were not significantly decreased. In contrast, intravenous administration of cysteamine (15 mg/kg) increased leukocyte residual activity more than sixfold 30 min postinfusion; concomitantly, the leukocyte substrate was decreased to 35% of the initial level immediately after infusion and to about 45% of preinfusion values during the 120-min period studied. These results suggest that the defective residual activity in feline MPS VI can be therapeutically manipulated by thiol-induced subunit association. Furthermore, this animal analog provides a prototype for the investigation of human inborn errors of metabolism resulting from enzymatic defects that might be amenable to enzyme manipulation therapy.

Animals↗
PubMed1981

An improved method for heterozygote identification in feline and human mucopolysaccharidosis VI, arylsulfatase-B deficiency.

An improved method has been developed for the detection of heterozygotes for feline and human mucopolysaccharidosis VI. Arylsulfatase-A and -B activities were assayed in leukocyte extracts following separation of the enzymes by batch chromatography on DEAE cellulose. Determination of arylsulfatase-B specific activities did not permit accurate heterozygote identification, whereas the arylsulfatase-A to arylsulfatase-B activity ratio discriminated all 16 obligate heterozygotes for the feline and human disorders.

Animals↗
PubMed1981

Feline mucopolysaccharidosis VI: purification and characterization of the resident arylsulfatase B activity.

Hepatic arylsulfatase B (ASB) from normal and mucopolysaccharidosis VI (MPS VI) cats was purified over 2,800- and 1,800-fold, respectively, and their physical and kinetic properties were characterized. In contrast to the normal feline enzyme, the partially purified MPS VI residual activity had a 100-fold greater Km value and was markedly less stable to thermal, cryo-, and pH-inactivation. In addition, the MPS VI enzyme had a more negative charge as determined by its migration on polyacrylamide gel electrophoresis and its elution profile on cation exchange chromatography. Finally, the MPS VI activity had approximately half the apparent molecular weight of the normal feline enzyme, which was a homodimer, suggesting that the genetic mutation in feline MPS VI altered the subunit association as well as the kinetic and stability properties of the mutant protein.

Animals↗
PubMed1980

Myocarditis induced by parvoviral infection in weanling pups in the United States.

In a nationwide survey from January 1978 through September 1979, acute parvovirus-induced myocarditis was identified in 76 of 147 (52%) pups in 19 litters. The affected pups were from 12 states. Birth of all pups registered with the American Kennel Club during this period increased during the spring months, peaking in May, which was correlated in 4 to 8 weeks with the greatest number of cases in the study. Serologic data available for 4 dams, for 6 of their surviving pups, and for 3 contact pups indicated that all had been exposed to parvovirus. In 2 kennels, cases of acute myocarditis were preceded within 2 months by cases of severe gastroenteritis in older litters on the same premises.

Animals↗
PubMed1980

Pseudoachondroplastic dysplasia in miniature poodles: clinical, radiologic, and pathologic features.

The clinical, radiologic, and pathologic features of pseudoachondroplastic dysplasia were studied in 13 affected Miniature Poodles. The disease became evident when pups were about 3 weeks old. Normal-appearing and affected pups were in the same litter, and both sexes were affected. Abnormal locomotion with abducted hindlimbs and flattened rib cages were accompanied by short, bent limbs and enlarged joints. Radiographically, areas of stippling and patchy densities were evident in the epiphyses. Histologically, these densities were identified as areas of bone associated with retarded ossification. After growth is completed, the epiphyses, ossify, but the bones are shortened and deformed. General health appears normal, except for restricted locomotion due to secondary arthritis and difficult breathing in dogs with a deformed thorax.

Achondroplasia↗
PubMed1980

The pathology of the feline model of mucopolysaccharidosis VI.

Three cats with feline arylsulfatase-B--deficient mucopolysaccharidosis were studied by light and transmission electron microscopy. Membrane-bound cytoplasmic inclusions were present in hepatocytes, bone marrow granulocytes, vascular smooth muscle cells, and fibroblasts in skin, cornea, and cardiac valves. Central nervous system lesions were restricted to mild ventricular dilatation, perithelial cell vacuolation, and, in one animal, cord compression by vertebral exostoses. The lesions in these cats closely resembled those described in human patients with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome).

Animals↗
PubMed1979

Mucopolysaccharidosis in a domestic short-haired cat--a disease distinct from that seen in the Siamese cat.

A 10-month-old male domestic short-haired cat was examined because of progressive lameness, a broad face with depressed nasal bridge, small ears, corneal clouding, and multiple bone dysplasia. The cat excreted excessive amounts of glycosaminoglycan (a component of connective tissue) in its urine and had evidence of lysosomal storage of glycosaminoglycans in fibroblasts and neurons. Activity of alpha-L-iduronidase, a lysosomal enzyme involved in glycosaminoglycan degradation, was deficient in cultured fibroblasts and leukocytes. The mucopolysaccharidosis was distinct from that seen in Siamese cats in terms of the pathologic changes and the specific enzyme deficiency.

Animals↗
PubMed1979

Myocarditis of probable viral origin in pups of weaning age.

Myocarditis in 4- to 8-week-old pups from 10 litters was characterized by sudden death. Histopathologic findings included mononuclear cellular infiltration and interstitial fibrosis in the myocardium of the left ventricle. Basophilic intranuclear inclusion bodies were seen in myocardial cells in 4 of 18 pups necropsied, suggesting a viral origin of the disease. Other pathologic changes were variable, but all were attributable to cardiac failure. Of 8 surviving pups examined, 7 had evidence of cardiac failure, including pulmonary edema, cardiomegaly, and cardiac arrhythmias.

Animals↗