Harry B. Neustein

Histiocytoid Cardiomyopathy of Infancy: Deficiency of Reducible Cytochrome b in Heart Mitochondria

Summary: A 3-week-old girl with failure to thrive and cardiomegaly died of cardiac arrest at age 4 weeks. Morphologic studies of the heart showed enlarged muscle fibers with large accumulations of mitochondria, characteristic of histiocytoid cardiomyopathy. Biochemical studies showed markedly decreased succinate-cyto-chrome c reductase and rotenone-sensitive NADH-cytochrome c reductase activities, while other mitochondrial enzymes were normal. In isolated mitochondria, cytochrome spectra showed a severe defect of reducible cytochrome b and a less marked defect of cytochrome cc1, while the content of cytochrome aa3 (cyto-chrome c oxidase) was normal. Histiocytoid cardiomyopathy appears to be due to a defect of complex III (reduced coenzyme Q-cytochrome c reductase) in the respiratory chain of heart mitochondria.

Findings on endomyocardial biopsy in infants and children with dilated cardiomyopathy

Fifteen infants and children with dilated cardiomyopathy underwent transvascular endomyocardial biopsy. The light and electron microscopic findings were reviewed to evaluate the presence of lymphocytes as an indicator of active myocarditis. Both ventricles were biopsied in 13 patients, and the right ventricle only was biopsied in 2. None of the endomyocardial specimens obtained by biopsy revealed an inflammatory process. Interstitial fibrosis, myofiber hypertrophy, degeneration and necrosis were found. Ultrastructural abnormalities of the mitochondria, T tubules or Z bands were noted in approximately one-third of patients. Persistent, active myocarditis is an uncommon cause of dilated cardiomyopathy in children. Immunosuppressive therapy, which may be harmful, should be considered only after myocardial inflammation has been documented by endomyocardial biopsy.

Transvascular endomyocardial biopsy in infants and small children: description of a new technique.

A miniaturized technique for transcatheter endomyocardial biopsy has been developed in the belief that myocardial biopsy performed in infancy, when the disease process in cardiomyopathy may be most active, should yield important etiologic and nosologic information. To obtain six biopsy specimens, three from each ventricle, adds about 1 hour to a diagnostic right and left heart catheterization. A no. 4 or 5 French forceps with a modified soft shaft is guided to the site in theapical septum of the right and left ventricles through a previously molded to measure guide tube of ultrathin radiopaque Teflon. With biplane fluoroscopy the guide tube of ultrathin radiopaque Telflon. With biplane fluorsocopy the guide tube is introduced as a sheath over a matching catheter and the catheter is removed. Contrast medium in injected to verify position, the forceps is introduced and the biopsy specimen is taken. If the forceps is sharp and pressure on the endocardium in light, evidence of biopsy is not discrenible on examination of the heart 1 week later. The method was developed in small dogs and proved safe and effective in rabbits weighing 3 kg. Biopsy has been performed safely in children aged 4 1/2 months to 5 1/2 years and weighing 4.5 to to 19.6 kg.

Cholestatic Effect of Intraperitoneal Administration of Tryptophan to Suckling Rat Pups

Summary: The potential cholestatic effect of amino acids and metabolites of tryptophan were evaluated by use of seven daily intraperitoneal injections to suckling and weanling rat pups. Of the amino acids present in parenteral nutrition solutions, only tryptophan (given at a dose of 4 mM/kg) produced a significant (p < 0.01) elevation of serum cholylglycine (12.8 ± 1.0 μM/liter) as determined by radioimmunoassay, compared to 4.9 ± 0.4 μM/liter in salinetreated control animals. Total serum conjugates of cholic acid, as determined by radioimmunoassay, were similarly elevated, as was serum alanine aminotransferase. Tryptophan injection resulted in elevated cholylglycine concentrations only at doses of 3 mM/kg/day or higher. Animals more than 2 weeks old did not demonstrate elevation of serum cholylglycine. Injection of light-exposed tryptophan in suckling animals caused a greater elevation of cholylglycine (39.0 ± 8.6 μM/liter) than freshly prepared tryptophan solutions (p < 0.005). Tryptophan and its spontaneous degradation products could contribute to the cholestatic liver changes observed during parenteral nutrition therapy.

Transvascular endomyocardial biopsy in infants and small children. Myocardial findings in 10 cases of cardiomyopathy.

Transvascular endomyocardial biopsy specimens from nine children with congestive cardiomyopathy and one with hypertrophic cardiomyopathy were studied by light microscopy using sections 1 mu thick cut from Epon embedded tissue and by electron microscopy. There was a disparity between the severity of the physiologic impairment and the morphologic abnormalities. Interstitial fibrosis was present only in the one case in which significant viral antibody titers were obtained. The sizes of the cardiac muscle cells varied abnormally in all specimens. Cardiac muscle cells in two patients contained abnormal mitochondria, and a leptomeric fibril was found in one patient. Virologic cultures of the tissues were negative and no viral particles were identified by electron microscopy. An attempt was made to correlate the clinical and pathologic findings.

Fucosidosis: Clinical, Pathologic, and Biochemical Studies of Five Patients

Fucosidosis is an inherited metabolic disorder in which deficiency of a-1-fucosidase activity results in accumulation of fucosyl compounds in lysosomes (6, 7, 24). Clinical manifestations reported include progressive motor and mental deterioration, coarseness of facial features, cardiomegaly, hepatomegaly, skeletal abnormalities and short stature (1,5,6,8,13). Initially many of the patients exhibit hypotonia, but progressive spasticity develops with time.

Restrictive cardiomyopathy with pseudotumor formation of the left ventricle

SummaryA 4-year-old girl had the insidious onset of congestive heart failure without apparent cause. Evaluation by echocardiography, thallous chloride Tl 201 scintigraphy, and angiography suggested the presence of either a neoplasm or restrictive cardiomyopathy with a localized mass effect on the left ventricle. Pathological specimens obtained by transvascular endomyocardial biopsy and at surgery defined the pathology to be restrictive cardiomyopathy. Analysis of myocardium by electron microscopy demonstrated a previously undescribed abnormality of the contractile elements involving the myofilaments and Z bands, with generalized secondary glycogen deposition.

961 THE MORPHOLOGICAL DIAGNOSIS OF THE WISKOTT-ALDRICH SYNDROME (WAS)

We have previously reported abnormalities in the membrane glycoproteins of the T lymphocytes and platelets of WAS patients. Deficiencies in a 115,000 dalton lymphocyte glycoprotein (GPL-115) appear to be diagnostic of WAS. To determine if the membrane glycoprotein abnormalities have morphological consequences, normal and WAS peripheral blood lymphocytes (PBL) and thymocytes were fixed in 1.2% glutaraldehyde and examined by scanning electron microscopy (SEM). Using a 1 to 4 grading scale based upon the character of the lymphocyte surface projections (4 = villus projections on > 75% of lymphocyte surface area; 3 = villus projections on < 75% of surface area; 2 = ridge projections; 1 = no projections), normal PEL had an average score of 3.60±.10(SE); thymocytes, 2.00±.02; WAS PBL, 2.76±.07 (n = 14). The decreased score of WAS lymphocytes was due to a decrease in the percentage of cells with villus projections and an increase in the percentage of cells with ridge or no projections. SEM has been used to confirm the diagnosis of WAS on the cord blood lymphocytes of one patient. WAS represents the first lymphoid immunodeficiency in which morphological abnormalities have been identified that can be used for diagnostic purposes.

MYOCARDIAL BIOPSY IN INFANCY AND CHILDHOOD: MODIFIED SMOOTH MUSCLE CELLS IN ENDOCARDIAL ELASTOMYOFIBROSIS

Ten patients, aged 4.5 months to 7 years with cardiomyopthies (9 congestive) had transvascular myocardial biopsies by a miniaturized technique. 4 had endocardial thickening defined as >20μ of left ventricle (LV). LV endocardium was not thick ened in the one patient with LV myocardial interstitial fibrosis. LV endocardial thickening resulted from the increase ot two layers adjacent to the myocardium, the smooth muscle (SM) layer (normally only a few SM cells) and the subendocardial layer (normally connective tissue, capillaries, ummyelinated nerves and a few cells). Thickening was due to increase in cells, elastic fibers and collagen fibers without inflammatory cells or increased capillaries. Cell morphology changed from (a) an innermost (toward the lumen) layer of dark SM cells with surface vesicles and myofilaments to (b) light SM cells with fewer vesicles and myofilaments to (c) “leiomyoid” cells resembling both SM cells and fibroblasts, partly lacking basement membrane but containing fusiform densities, myofilaments, rough endoplasmic reticulum. ribosomes and Golgi to (d) typical fibroblasts. Light SM cells may be able to divide. Elastin is found adjacent to leiomyoid cells and may be formed by these cells. These findings may shed light on the genesis of “endocardial fibroelastosis.”

DNA synthesis in freshly excised regenerating rat liver tissue: A model for large animal studies

Abstract The ability of liver to synthesize DNA during the regenerative response can be monitored from freshly excised liver segments removed percutaneously. The results obtained by this method parallel closely those obtained by the standard methods, employing intravenous labeled isotope injection and timed multiple animal sacrifice.