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Biomedical subjects

H L Sharp

Publications and source records attributed to H L Sharp.

At least 55 records · Page 3Linked to original sources
PubMed1980

Alpha-1-antitrypsin deficiency in childhood.

alpha 1AT deficiency predisposes children to liver injury and adults to emphysema. Pi typing has clarified that the inherited deficiency is codominant. Amniocentesis is unproved as a reliable technique in detecting the homozygous deficient patient (another controversial issue). Even if this procedure were to become diagnostic, present knowledge cannot predict the clinical course of each individual born with homozygous alpha 1AT deficiency, therefore confronting the physician and parents with a moral dilemma that neither of us feels comfortable with in regard to family counseling. Presently, we can only educate the family with the current state of the art summarized in this review. The fundamental steps in evaluating a child and the involved family are outlined in Table 2. Steps 1, 2 and 5 should be readily available. Pi typing can specifically identify susceptible individuals who can be counseled concerning work habits and known toxins such as smoking and alcohol. Liver biopsy is not essential for diagnostic purposes but may prove to be prognostic concerning the child's ultimate outcome. More certain is the evidence that no infant should be explored for a bile duct lesion during the early cholestatic period because no surgical lesion will be found. Therefore, all children with infantile cholestasis should be evaluated for alpha 1AT deficiency prior to a laparotomy. Although medical therapy is only supportive at the present time, further research should eventually provide therapeutic approaches to the basic defect.

Adolescent↗
PubMed1979

Defects of bile acid synthesis in Zellweger's syndrome.

Abnormal mitochondrial structure and function have been documented in patients with Zellweger's syndrome (cerebrohepatorenal syndrome). In vitro studies have suggested that the formation of C24 bile acids (chenodeoxycholic acid and cholic acid) from C27 cholesterol requires mitochondrial oxidative clevage of the terminal three carbons of the side chain. Therefore, three patients with Zellweger's syndrome were examined for the presence of mitochondrial defects in bile acid synthesis. All three excreted excessive amounts of 3 alpha, 7 alpha-dihydroxy-5 beta-cholestan-26-oicacid, 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholestan-26-oic acid, and 3 alpha, 7 alpha, 12 alpha, 24 xi-tetrahydroxy-5 beta-cholestan-26-oic acid (varanic acid), precursors of chenodeoxycholic acid and cholic acid that have undergone only partial side chain oxidation. These findings give added support to the role of mitochondrial oxidative side chain cleavage in the overall scheme of bile acid synthesis.

Bile Acids and Salts↗
PubMed1978

Furazolidone-induced cardiomyopathy in turkeys. Association with a relative alpha1-antitrypsin deficiency.

A naturally occurring cardiomyopathy (round heart disease) which is potentiated by inbreeding and a cardiomyopathy produced by furazolidone, a nitrofuran derivative, were studied for an associated alpha1-antitrypsin deficiency in two flocks of turkeys (one inbred for round heart disease and a commercial flock). At 4 weeks of age, the furazolidone-fed birds of both flocks demonstrated a marked increase in mortality and cardiac dilatation associated with disordered hepatic metabolism when compared with controls. Although PAS-positive, diastase-resistant globules were observed in the livers of both strains of turkeys fed furazolidone, these globules were present in lysosomes and not in the rough endoplasmic reticulum as in alpha1-antitrypsin deficiency. The control inbred birds with round heart disease did not demonstrate histologic or biochemical evidence of an alpha1-antitrypsin deficiency. It is proposed that furazolidone in the turkey produces primary hepatic damage that is reflected in lowered total serum proteins, including trypsin inhibitory capacity, and that the alterations produced by furazolidone are superimposed on round heart disease in the inbred flock.

Animals↗
PubMed1977

Gallbladder disease in cystic fibrosis.

In 84 consecutive patients with cystic fibrosis, oral cholecystography was abnormal in 39 (46.4%). The incidence of abnormal cholecystograms increased with patient age. The 26 patients with a nonvisualized gallbladder following double-dosage oral cholecystography were evaluated with intravenous cholangiography; 19 (70.3%) of these were abnormal. Ten patients were found to have calculi, an incidence of 11.9%. Awareness of the high incidence of cholecystographic abnormalities and calculi should be helpful in the evaluation of patients with cystic fibrosis, particularly since symptoms of abdominal pain are frequent in such patients and may lead to radiographic investigations.

Adolescent↗
PubMed1977

Preservation of canine hearts after warm ischemia (zero to thirty minutes) and one to two days of hypothermic storage. A comparative analysis of crystalloid and colloid solutions with different osmolarity and ion composition.

The effect of extracellular crystalloid (Ringer's) and colloid (silica gel fraction [SGF]) solutions, and intracellular crystalloid (Sacks) and colloid (modified silica gel fraction [MSGF]) solutions for canine heart preservation in a 24 to 48 hour model of hypothermic storage and zero to 30 minutes of warm ischemia was compared. Canine hearts flushed with an intracellular colloid solution (MSGF) had better survival rates after transplantation than did the hearts flushed with intracellular crystalloid solutions (Sacks). Better survival results also were observed in the group of hearts flushed with extracellular colloid (SGF) solutions than extracellular crystalloid (Ringer's) solutions. The most important theoretical factor in heart preservation appears to be hyperosmolarity and elevated concentration of potassium, proteins, and glucose.

Animals↗
PubMed1977

Metabolic liver disease of childhood.

The broad topic of metabolic liver disease may be divided into three pathophysiologic groups -- storage diseases, cholestatic syndromes, and metabolic defects contributing to hepatocellular necrosis. The important disease entities in each group have been discussed in terms of incidence, clinical course, inheritance, diagnostic criteria, pathogenesis, hepatic pathology, and therapy. An approach to the evaluation of metabolic liver disease has been proposed. It is hoped that this review will be helpful to the clinician who is engaged in the primary care of children.

Child↗
PubMed1977

Hepatic lesions and hemolysis following administration of 3alpha, 7alpha, 12alpha-trihydroxy-5beta-cholestan-26-oyl taurine to rats.

Patients with a metabolic block in the conversion of THCA into cholic acid develop cirrhosis and hemolysis, and die of hepatic failure. In these patients, THCA is largely conjugated to taurine (tauro-THCA) and excreted instead of being converted into cholic acid. In the present study, the effects of tauro-THCA on hemolysis, bile flow, and hepatic morphology were evaluated in bile fistula rats. All rats infused with tauro-THCA at rates of 0.25, 0.50 or 0.75 micronmol/min developed hemolysis with hemoglobinuria. A direct toxic effect of tauro-THCA on washed human red blood cell membranes was demonstrated at a concentration of 8 X 10(-4) M. Liver biopsy sections from rats infused for a 2 hr period with tauro-THCA were examined by electron microscopy and showed dilation of the rough endoplasmic reticulum and distortion of mitochondrial membranes. Cholestasis was not induced, since tauro-THCA actually caused a greater choleretic response for a given rate of bile salt excretion than did taurocholate. This study raises the possibility that the clinical liver disease seen in patients with a metabolic block in the conversion of THCA into cholic acid may be caused by tauro-THCA.

Anemia, Hemolytic↗
PubMed1976

Immunodeficiency, xanthomas and obstructive liver disease.

Chronic obstructive liver disease and secondary hyperlipidemia developed in an immunodeficient boy. Sequential addition of cholestyramine and phenobarbital to his medical regimen, following an initial response to bile drainage, resulted in the disappearance of xanthomas and pruritus, and the restoration of normal serum concentrations of lipids and bile acids. This improvement may result from shifting the bile acid pool from the peripheral blood compartment to the enterohepatic circulation.

Bile Acids and Salts↗
PubMed1976

Aspartylglucosaminuria: unique biochemical and ultrastructural characteristics.

The observation of vacuolated lymphocytes in a coarsely featured two year old female with hepatosplenomegaly, mitral insufficiency, and mild psychomotor retardation led to the first diagnosed case of aspartylglucosaminuria in the United States. Although physical characteristics and bone roentgenograms were consistent with a mucopolysaccharide disorder, analysis of the urine showed no mucopolysaccharide elevation. The chromatographic, enzymatic, and ultrastructural studies confirming the diagnosis are presented.

Amidohydrolases↗
PubMed1976

Cardiac valvular anomalies in Fabry disease. Clinical, morphologic, and biochemical studies.

The cardiovascular abnormalities were investigated in two unrelated hemizygous males with Fabry disease who had clinical mitral insufficiency. Postmortem examination of their hearts revelaed anatomic, ultrastructural and biochemical abnormalities resulting from defective activity of the lysosomal enzyme, alpha-galactosidase A. The ultrastructural and biochemical studies demonstrated the marked accumulation of the major glycosphingolipd substrate, trihexosyl ceramide, in the lyosomes of all the cardiac tissues examined; the greatest concentrations were found in the mitral valve and elft ventricular myocardium. Intriguingly, digalactosyl ceramide, a glycosphingolipid substrate not detectable in normal lung, vessel or cardiac tissues, was found increased only in the lung and right heart tissues. Morphologic and chemical examination of cardiac and systemic vessels demonstrated accumulation of trihexosyl ceramide in lysosomes of the vascular endothelium. These studies demonstrate that the progressive accumulation of trihexosyl ceramide in the lysosomes of the cardiac structures and vascular system leads to the multiple cardiovascular manfiestation of Fabry disease.

Ceramides↗
PubMed1976

The glycoprotein-degrading potential of peripheral leukocytes in cystic fibrosis.

In this study, the potential problems and discrepancies in cill culture techniques were avoided by isolating leukocytes from the peripheral blood of patients with cystic fibrosis and healthy human volunteers and preparing homogenates to determine the specific activities of 5 lysosomal enzymes involved in the degradation of glycoproteins. Four lysosomal hydrolases involved in the breakdown of the carbohydrate side chain were assayed using artificial substrates. The fifth enzyme, aspartylglucosamine amido hydrolase, which cleaves the linkage between this side chain and the peptide backbone, was assayed with natural substrate. No differences in enzyme activities between the 2 leukocyte sources were observed. Because no enzyme activities were deficient and no compensatory increases were noted, we concluded that the thick, glycoprotein-rich, exocrine secretions in cystic fibrosis cannot be attributed to a defect in their catabolism.

Acetylglucosaminidase↗
PubMed1976

Mannosidosis: clinical, morphologic, immunologic, and biochemical studies.

The primary metabolic defect in mannosidosis is the deficiency of the acidic alpha-mannosidase A and B activites which results in the lysosomal accumulation of mannose-rich substrates. Out studies demonstrate that the enzymatic diagnosis of suspect homozygotes can be made reliably using plasma, isolated leukocytes, or cultured skin fibroblasts assayed carefully at the appropriate acidic pH. Immunologic studies of a mannosidosis homozygote revealed significant abnormalities of neutrophil function; these included a depressed chemotactic responsiveness and impaired phagocytosis of bacteria. Lymphocyte transformation studies showed a 20% of normal response to purified phytohemagglutinin and a 25% of normal response to concanavalin A. Three major components of alpha-mannosidase activity in normal human liver were resolved by ion exchange chromatography on DEAE-cellulose and electrophoresis on cellulose acetate gels. Electrophoresis of the liver extract from homozygote I with mannosidosis revealed only one band of activity which coelectrophoresed with the alpha-mannosidase C isozyme partially purified from normal liver. However, ion exchange chromatography revealed the presence of residual hepatic acidic activities; the residual A isozyme was eluted in a position corresponding to that of normal alpha-mannosidase A whereas the residual B activity was eluted at a slightly more electronegative position than that of normal B isozyme. The apparent Km values for alpha-mannosidase activity as determined from Linweaver-burk plots were 1.1 mM for normal liver and 0.9 mM for normal leukocytes. In contrast, the residual activity in these sources from homozygote 1 could not be saturated within the solubility range of the substrate; the apparent Km value was estimated at 15.4 mM in liver extracts. Zinc significantly lowered the apparent Km value of the acidic activity in normal liver (from 1.2 to 0.24 mM), whereas this metallic ion had little effect on the values for mannosidosis hepatic activity (from 15.4 to 12.3 mM). Unlike zinc, cobalt had its major effect on the acidic activity in the mannosidosis liver extract, lowering the apparent Km from 15.4 to 3.9 mM, whereas the apparent Km for the normal activity was increased from 1.2 to 1.9 mM. The residual acidic activities were markedly stimulated by zinc in both leukocytes (approximately 300%) and plasma ( approximately 400%) from the homozygotes and to a lesser extent in those sources from normal individuals. In contrast, cobalt enhanced the residual acidic activities in leukocytes (approximately 500%) and plasma (approximately 200%) from the homozygotes while inhibiting these acidic activities (78.9% and 47.7%, respectively) in normal individuals.

Carbohydrate Metabolism, Inborn Errors↗