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The administration of thyroxine to a number of experimental animals has resulted in marked structural and metabolic changes in the myocardium. Thyroxine has been shown to produce myocardial hypertrophy (1, 2) and to increase oxygen consumption and fatty acid utilization by the heart (3). In the dog made hyperthyroid by the administration of large doses of thyroxine, increased free fatty acid utilization by the heart was accompanied by a decreased uptake of glucose (3).In this communication data are presented which show that the administration of i-thyroxine to guinea pigs resulted in an increased rate of long chain fatty acid oxidation and a decreased rate of glucose oxidation by myocardial homogenates. The stimulatory effect on fatty acid oxidation was associated with elevated concentrations of free carnitine and acylcarnitines and increased long chain acyl coenzyme A (CoA)-carnitine acyltransferase (CAT) activity. The decreased glucose oxidation was associated with elevated levels of myocardial hexosemonophosphates and citrate. Citrate, the tissue concentration of which is increased by enhanced fatty acid oxidation, has been identified as one of several compounds that exert rate-controlling influences on glycolysis by inhibiting the activity of phosphofructokinase (PFK) (4, 5). Body weights were obtained before and after the thyroxine treatment was completed. The animals were then killed by a blow on the head. The entire heart was removed immediately, the great vessels were trimmed off at their origin, and the cardiac cavities were opened and freed of blood. The opened hearts were blotted on filter paper and weighed before further analyses were carried out.Hearts from treated animals and their controls used to assess the effect of thyroxine on total heart weight and on the concentrations of protein, ribonucleic acid, and deoxyribonucleic acid were homogenized in 8.0 ml of calcium-free Krebs-Ringer phosphate buffer, pH 7.4. The hearts used for enzymatic assays were placed in a volume of homogenizing medium such that their final protein concentrations were approximately equal.Protein concentration was measured by the biuret method (6). After completion of the biuret reaction the solution was filtered through a layer of Celite in a Buchner type funnel. This served to remove lipids, which produce turbidity of the solution. The results obtained by this procedure agreed closely with those obtained by Kjeldahl nitrogen determination (7).Analyses of myocardial DNA and RNA were done on trichloroacetic acid extracts of whole hearts. The p-nitrophenylhydrazine procedure of Webb and Levy (8) was used for DNA, and the orcinol method of Ceriotti (9) was used for RNA determination.The concentration of FFA in the myocardium was determined by the method of Dole as modified by Trout, Estes, and Friedberg (10). Quantification of triglycerides in the heart was done by the procedure of Van Handel and Zilversmit (11).Assays of palmitate, pyruvate, and glucose oxidations were carried out as previously described (12). Since the ...

Clinical and experimental investigations have shown that the myocardium is highly susceptible to the action of diphtheria toxin (1, 2). Both in man and the guinea pig, one of the earliest alterations in the heart muscle exposed to this toxin is fatty degeneration (2, 3). This morphological observation along with recently acquired evidence that fatty acids are a major metabolic substrate of the heart (4) suggested that the toxin may exert its effect on the myocardium by interfering with fatty acid oxidation.Experiments were designed to test this hypothesis by ascertaining the effect of diphtheria toxin on 1) the capacity of the myocardium to oxidize long-chain fatty acids, 2) the integrity of component parts of the fatty acid oxidation pathway in the heart, and 3) the concentration of myocardial carnitine (DL-7-trimethylamino-P-hydroxybutyrate), a compound known to effect a stimulation of long-chain fatty acid oxidation in the heart (5). MethodsWhite, male guinea pigs weighing 250 to 300 g were used. A standard diet consisting of 50% Purina rabbit chow and 50% oats supplemented with fresh cabbage was used except as indicated. The experimental animals were divided into 4 groups as follows: a) Diphtheria-toxin 1 animals were injected with toxin subcutaneously, the dose being adjusted so that fatty degeneration of the myocardium could be produced regularly in surviving animals within 5 days after treatment; b) diphtheria-antitoxin 1 animals were injected intraperitoneally with 500 U of antitoxin; c) diphtheriatoxin and -antitoxin animals were injected with 500 U of * Submitted for publication August 27, 1963; accepted November 29, 1963. Presented in part at the Fifty-fifth Annual Meeting of the American Society for Clinical Investigation, Atlantic City, N. J., April 1963. This work was supported by U. S. Public Health Service grants H-7061, HE 07780-01, and 5TI GM-516-03.1 Diphtheria toxin, lot #706396, and diphtheria antitoxin, lot #G-138-B, were supplied by Eli Lilly and Co., Indianapolis, Ind.antitoxin 24 hours before administration of the toxin; and d) fasting animals were deprived of food and given water ad libitum. Each experimental animal used for an enzymatic assay was tested simultaneously with a paired untreated mate as a control. For all other determinations, groups of experimental animals were compared with groups of controls.Five to six days after injection of the toxin or the beginning of the fast period, the guinea pigs were sacrificed by a blow on the head. The entire heart was removed immediately, the great vessels were trimmed off at their origin, and the cardiac cavities were freed of blood. A transventricular block of myocardium was placed in 10% neutral, buffered formalin solution and kept at room temperature for at least 24 hours. Frozen sections, 14-As thick, were prepared and stained as follows: a) hematoxylin and eosin, b) oil-red 0 dissolved in acetone alcohol, and c) oil-red 0 followed by hematoxylin. Histological examination was performed on all hearts except for those used for quanti...

A new case of the fetal gigantism-renal hamartomas-nephroblastomatosis syndrome is described, in which a Wilms' tumor occurred. It is considered that this observation provides strong evidence for the interrelationship between renal dysplasia and renal neoplasia.Cunccr 35 : 12 12-12 17, 1975. CLINICAL AND PATHOLOGIC COMPLEX CHAR-A acterized by bilateral renal hamartomas and nephroblastomatosis, hypertrophy of the islets of Langerhans, gigantism at birth, and unusual facies, has been previously reported in a sibship.'.'" The renal manifestations of this syndrome were considered to provide evidence for the possible origin of Wilms' tumor from foci of embryonic nephrogenic tissue.8 This thesis, however, has not been universally Since the original reports, an additional affected member of the sibship was born and died at the age of 4 days with a Wilms' tumor. This occurrence is considered to support further the hypothesis that Wilms' tumor is derived from residual embryonic nephrogenic tissue. CASE REPORTThe infant, a female, was born by breech delivery after an uncomplicated pregnancy of 40 weeks' duration. Hydramnios was noted, but the quantity of fluid was not measured. Birth weight was 3850 g, length 54 cm, and head circumference 36 cm.The following features were observed on physical examination: generalized hypotonus; enlarged kidneys, more prominent on the left; and unusual facies (Fig. 1). The latter consisted of enophthalmos, small nose with depressed bridge, everted upper lip, and low-set ears. The xiphisternum was broad, bifid, and prominent. A capillary hemangioma measuring 2 X 2 cm was present in the left antecubital fossa. Received for publication May 13, 1974. The course was characterized by lethargy, failure to feed, and polyuria. Serial blood sugar estimations were all more than 30 mg/100 ml.Fluid and electrolyte balance was maintained, but the infant died on the fourth day. Family History and FindingsThe parents, of Jewish Yemenite origin, are second cousins. Of six previous siblings, five died perinatally, with findings similar to those reported above; none however had a Wilms' tumor. The product of the fourth pregnancy was an apparently normal female who is alive and well at the age of 8 years.The obstetric, neonatal, and pathologic findings in the six affected siblin'gs are summarized in Table I . Autopsy FindingsGross: The infant weighed 3800 g. The external features were unremarkable except for those observed clinically. A11 the internal organs were in normal anatomical position.The left kidney (Fig. 2 ) was moderately enlarged, measured 7.0 X 3.5 X 3.8 cm, and weighed 38 g. A large spheroid tumor, 4.5 X 2.5 X 2.5 cm, occupied the superior two-thirds of the kidney. The renal capsule, which was readily removed, was intact over the tumor. Bisection of the kidney revealed a sharply delimited, solid, homogenous tumor, which was yellow-grey and moderately firm. The tumor compressed and distorted but did not invade the adjacent residual renal parenchyma, pelvocalyceal system, or blood vessels. In t...

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