Regional myocardial blood flow during acute myocardial infarction in the conscious dog. Regional myocardial blood flow was studied in the conscious dog at periods of 5 minutes to 4 days after occlusion of a major branch of the left coronary artery. Dogs were instrumented with aortic electromagnetic flow probes, occlusive cuffs on either the anterior descending or circumflex branch of the left coronary artery, and a left atrial Silastic catheter for injection of microspheres (15 +/- 5 mum) labeled with either 85Sr, 141Ce, or 51Cr. Microspheres were injected into 25 fully conscious dogs during three of the following time periods: control preocclusion and 0.1, 2, 6, 24, or 96 hours postocclusion. In the conscious dog, before occlusion, the endocardial half of the left ventricular myocardium received 28% more blood flow than the epicardial half. After sudden occlusion of a coronary artery branch, there was a marked reduction in blood flow as well as an alteration in distribution of blood flow within the ischemic tissue; blood flow was most severly reduced in the subendocardial center of the ischemic region, less so in the epicardial ischemic region, and least reduced in the marginal region of the infarct. Blood flow was increased to the nonischemic tissue. There was no change in this pattern of reduced blood flow by 6 hours postocclusion, but by 24 hours, flow was moderately increased to all areas except the central subendocardial core, and was further increased at 96 hours. Blood flow to the endocardial half of the left ventricular myocardium averaged 63 ml/100 g per min during the control period, was reduced to 12-18 ml/100 g per min at 0.1-6 hours in the ischemic region, increased to 29 ml/100 g per min at 24 hours, and to 48 ml/100 g per min by 96 hours. These findings indicate that there is a reversal of the flow ratio within ischemic myocardium with relative under-perfusion of the endocardial half of the wall, which is not corrected by 4 days. There is a modest increase of collateral blood flow to ischemic tissue by 24 hours and this increase is considerably augmented by 96 hours, apparently as a result of the growth and enlargement of collateral vessels.


Relationship between blood flow to ischemic regions and extent of myocardial infarction. Serial measurement of blood flow to ischemic regions in dogs. This study was designed to measure early sequential changes in blood flow to ischemic regions after acute coronary occlusion and to determine the relationship between blood flow and the extent of subsequent myocardial infarction. Initial studies were carried out on five dogs which verified using radioisotope-labeled microspheres, 7-10 mum in diameter, to measure changes in blood flow in small myocardial regions after acute coronary artery occlusions. Studies then were carried out on 11 awake dogs chronically prepared with dwelling catheters in the aorta and left atrium and occluders on the left circumflex coronary artery. Microspheres were injected via the left atrial catheter 45 seconds and 2, 6, and 24 hours after complete circumflex coronary occlusion. Six days later myocardial blood flow and the extent of histological infarction were determined for multiple samples from four transmural layers of the entire ischemic zone. Average blood flow to the circumflex region was 0.25 +/- 0.03 (SE), 0.39 +/- 0.05, and 0.53 +/- 0.07 ml/min per g at 45 seconds, and 2, 6, and 24 hours, respectively. When samples from each transmuarl layer were grouped according to increasing ranges of blood flow, the extent of infarction in each layer was inversely related to blood flow. When samples in the same range of blood flow were compared, the extent of infarction in endocardial samples exceeded that in epicardial samples. These data indicate that the relationship between a given measurement of regional blood flow after acute coronary occlusion and the extent of subsequent myocardial infarction varies in different transmural layers and is a function of the time after occlusion that blood flow is measured.


Depression of atrioventricular sensitivity in the dog by successive brief bursts of vagal stimulation. When identical, successive single vagal stimulations, separated in time (T) by 2-60 seconds, are applied in the dog, the peak change in atrioventricular conduction time for the second stimulus, deltaAV2, is less than that of the first, deltaAV1, that is, the ratio deltaAV2/deltaAV1 less than 1.0 (the mean minimum deltaAV2/deltaAV1=0.52). It was further determined that at any one given T, the actual value of deltaAV2/deltaAV1 also was a function of the first stimulus amplitude. The same dependence of deltaAV2/deltaAV1 on the first stimulus amplitude was found when the amplitude was varied either by (1) changing the number of vagal fibers stimulated for both the first and second response, but at a constant AD (the delay in the cardiac cycle at which the stimulus was given), or (2) by stimulating the same number of fibers but changing AD for both the first and second response. Also the same characteristic of deltaAV2/deltaAV1 plotted vs. T was found either (1) when both the first and second responses were produced by stimulation of the same nerve, or (2) when stimulated of the nerve from one side produced the first response and the alternate side the second response. These data suggest that the reason for this deltaAV2/deltaAV1 time-dependent effect lies in changes in receptor responsiveness or in acetylcholine inactivation, but not in mechanisms purely internal to the nerve terminal associated with synthesis, storage, or release of acetylcholine.


Creatine and the control of muscle-specific protein synthesis in cardiac and skeletal muscle. The observation that increased muscular activity leads to muscle hypertrophy is well known, but identification of the biochemical and physiological mechanisms by which this occurs remains an important problem. The hypothesis has been proposed that creatine, an end product of contraction, may be the chemical signal coupling increased muscular activity and increased contractile mass. Two muscle models have been used in experimental tests of this hypothesis: differentiating skeletal muscle cells in culture and the fetal mouse heart in organ culture. Using these culture models, it is possible to alter the intracellular creatine concentration and to measure the effect of increased creatine concentrations on the rates of synthesis and accumulation of both muscle-specific and nonspecific proteins. The results show that muscle-specific protein synthesis in both skeletal and cardiac muscle is selectively stimulated by creatine.


Effects of anoxia and ischemia on protein synthesis in perfused rat hearts. The effect of ischemia on synthesis of myocardial proteins was investigated using a model of perfusion in which low levels of coronary flow were provided to paced hearts worked against a closed aortic outflow tract. These conditions rapidly produced ischemia and ventricular failure, as evidence by reduced coronary flow, increased left atrial pressure, and decreased pressure development. Protein synthesis was inhibited in a subsequent 1-hour period, during which a minimal coronary flow was maintained by retrograde perfusion. ATP, GTP, and creatinine phosphate were depleted in ischemic hearts and AMP accumulated. Production and accumulation of lactate within the tissue increased, whereas palmitate uptake was inhibited. The inhibition of protein synthesis was not associated with reduced levels of intracellular amino acids. During ischemia, decreased levels of ribosomal subunits as compared to paced or unpaced aerobic hearts suggested that peptide chain elongation was slow relative to initiation. Provision of insulin further reduced subunit levels but did not increase protein synthesis, suggesting that the hormone did not prevent inhibition of peptide chain elongation in energy-poor hearts.


Protein degradation in vivo and its regulation. Protein degradation in mammalian cells may be regulated by size of the polypeptide subunit, susceptibility to degradation by proteases, alteration by mutational changes, and interaction with various ligands, including other proteins, lipids, cofactors, or metabolic intermediates. The pathway of degradation is not defined but appears to involve both lysosomal and nonlysosomal proteases.


Hormonal control of cardiac protein and amino acid balance. Isolated hearts of fetal mice in organ culture maintain active protein synthesis and protein degradation. Rates of degradation exceed rates of synthesis and as a result, the hearts are in state of negative protein balance as evidenced by net loss of protein and release of amino acids. Several hormones can alter amino acid metabolism and protein balance by altering synthesis or degradation, or both. In cultured fetal mouse hearts, insulin, the most extensively studies of the hormones increases the rate of protein synthesis by 13 +/- 3.7% and decreases the rate of protein degradation by 22 +/- 4.1% (p less than 0.01 for both). Together, these changes account for a 30-40% reduction in the loss of cardiac protein and in the release of phenylalanine from the heart. These changes are accompanied by a decrease of 21 +/- 2.7% in the total activity of the lysosomal proteinase cathepsin D. and by a reduction in the proportion of the enzyme that is present in the nonsedimentable fraction of the issue homogenate. This suggests that the possibility that insulin may function in part by altering lysosomal enzyme activity or availability, or both. The effects of insulin on protein degradation, amion acid release, and cathepsin D activity persist even when protein synthesis has been inhibited by cycloheximide. These results suggest that insulin plays an important role in the control of cardiac protein synthesis and degradation.


The role of acyltransferases in fatty acid utilization. Glycerophosphate and carnitine as competing acyl acceptors and the oxidation of different long chain acylcarnitines in isolated mitochondria have been investigated. In the presence of low concentrations of palmitate, glycerophosphate is the preferred acyl acceptor in isolated liver mitochondria, indicating that the glycerophosphate acyltransferase has a lower Michaelis constant (Km) for palmityl-CoA than has the carnitine palmityltransferase. Liver mitochondria from starved rats make more palmitylcarnitine and less palmitylglycerophosphate than do mitochondria from starved/refed rats. In heart mitochondria glycerophosphate has less effect on palmitylcarnitine formation because of glycerophosphate acyltransferase activity is lower and the carnitine palmityltransferase activity is higher in liver mitochondria. Carnitine esters of C22 fatty acids, especially erucic acid (22:1omega9,cis) are more slowly oxidized compared to palmitylcarnitine in heart than in liver mitochondria. They also inhibit palmitylcarnitine oxidation. The inhibition is relatively stronger in heart than in liver mitochondria. These observations are discussed in relation to organ differences in the utilization of fatty acids.


Coordination of citric acid cycle activity with electron transport flux. Feedback control between flux through the phosphorylating electron transport chain and the coordination of flux through individual steps of the citric acid cycle have been investigated under a number of different conditions of substrate availability and workloads in the isolated perfused rat heart. The transition from substrate-free perfusion to perfusion with glucose and insulin with no change of workload was associated with increases in the pool sizes of citric acid cycle intermediates except for oxaloacetate, but with an initial imbalance of flux through individual steps in the cycle and transport of anions of the malate-aspartate cycle across the mitochondrial membrane. Flux through citrate synthase initially increased while that through alpha-ketoglutarate dehydrogenase decreased. Of the components of the malate-aspartate cycle, flux through the malate-alpha-ketoglutarate exchange was increased prior to that through the glutamate-aspartate exchange and intramitochondrial aspartate aminotransferase. These changes can be accounted for on the basis of known kinetic controls of the enzyme and transport steps in response to increased pyruvate, acetyl-CoA, and NADH delivery at an approximately constant rate of ATP turnover.


Control of energy production in myocardial ischemia. Long chain fatty acyl-CoA esters are potent in vitro and in vivo inhibitors of adenine nucleotide translocation in heart mitochondria. Within a short time following production of myocardial ischemia, the dog heart exhibits an increased concentration of long chain acyl-CoA esters associated with a decrease in adenine nucleotide translocase activity. In contrast to liver, the tricarboxylate carrier system for citrate and phosphoenolpyruvate is rather low in heart mitochondria. Phosphoenolpyruvate-stimulated calcium egress from heart mitochondria may, therefore, result from transport of this anion on the adenine nucleotide translocase. During myocardial ischemia effective modulation of these metabolite trasnport systems are disrupted by accumulation of long chain acyl-CoA esters which leads to a decrease in the overall energy charge of the cell.


Mitochondrial structure and function in acute myocardial ischemic injury. Changes in both the structure and function of mitochondria occur in the dog heart as a consequence of severe ischemia produced by acute coronary occlusion. Brief periods of severe ischemia (reversible injury) produced no significant change in mitochondrial ultrastructure and no defects in pyruvate or succinate metabolism. However, periods of ischemia of 40-60 minutes' duration (irreversible injury) produced striking structural changes including swelling, an increase in matrix space, disorganization of cristae, and the appearance of amorphous matrix densities. After 60 minutes of severe ischemia, one or more amorphous densities were present in each mitochondrial profile. These osmiophilic structures contained lipid but have not been characterized further. Their presence was typical of the irreversible state. Mitochondria of irreversibly injured cells were fragile, and consequently were more difficult to isolate than mitochondria of control tissue. Furthermore, after isolation from tissue injured by 60 minutes of ischemia, they showed markedly defective function.


Considerations in the use of biochemical markers of ischemic injury. Results of estimation of infarct size with a selected biochemical marker in blood, creatine phosphokinase (CPK), have suggested that infarct size is an important determinant of prognosis, impaired ventricular function, early ventricular dysrhythmia, and the severity of clinical manifestations. Estimates based on serial changes in serum CPK activity have correlated with morphological estimates and have been employed to evaluate therapeutic interventions. Improved estimates with any biochemical marker require exclusion of noncardiac sources of the marker and characterization of the influence of physiological alterations on parameters in empirical or physiologically based mathematical models utilized. Use of MB CPK instead of total CPK therefore improves enzymatic estimates when infarction is accompanied by release of noncardiac CPK into the circulation. Preliminary results with physiologically based models of CPK release from the infarct and its disappearance from the circulation suggest that release may be diffusion-limited and that the CPK disappearance rate is relatively uninfluenced by profound hemodynamic derangements or myocardial infarctions per se. The substantial inactivation of CPK in lymph in vitro and in situ underscores the importance of defining factors influencing the proportion of a biochemical marker depleted from necrotic myocardium appearing in blood, since the proportion is one parameter used in models employed to quantitatively estimate irreversible ischemic injury.


Combined effects of rate membrane potential, and drugs on maximum rate of rise (Vmax) of action potential upstroke of guinea pig papillary muscle. We studied the effect of increasing the rate of stimulation on the maximum rate of rise of the action potential upstroke (Vmax) in guinea pig papillary muscles at various resting membrane potentials and after the addition of quinidine and lidocaine to the perfusate. Increasing rate caused a decrease in Vmax due to interaction of three factors: (1) a metabolic factor, presumably resetting of the Na-K pump, which caused a decrease in Vmax at all levels of resting potential between -90 and -60 mV, (2) a transient decrease in resting potential which influenced Vmax when the resting potential was less negative than approximately -80 mV, and (3) the recovery characteristics of Vmax which contributed to the decrease in this variable when rate was faster than 5/sec. As a result of these factors the steady state curve relating membrane potential to Vmax was itself rate-dependent. Lidocaine and quinidine exaggerated the rate-dependent decrease in Vmax; however, their effects differed. The effect of quinidine was consistent with its known depressant effect on the Na-K pump. The lidocaine effect was consistent with a slowing of recovery of Vmax. Our results help to explain the effects of an increase in rate on Vmax and conduction velocity in normal, partially depolarized, and drug-treated fibers


Relation between plasma renin activity, angiotensin, and aldosterone and blood pressure in mild untreated hypertension. Plasma renin activity, arterial and venous angiotensin II (A II), plasma aldosterone, and sodium excretion were measured in a group of 101 patients with mild essential hypertension. For the total hour; arterial A II was 5.2 +/- 1.0 pg/ml; venous A II was 4.2 +/- 0.6 pg/ml; and plasma aldosterone was 5.0 +/- 0.45 ng/100 ml. All values were lower corresponding values for normal subjects on a high salt intake despite the fact that salt intake in the normal subjects exceeded that for the hypertensive group more than 3-fold. Moreover, when the range of diastolic blood pressure up to 114 mm Hg was divided into three successive class intervals of increasing severity, there was a negative correlation between diastolic blood pressure and both PRA and plasma aldosterone. Arterial A II showed an anomalous increase in the class interval 105-114 mm Hg, despite the fact that this group exhibited the lowest level of PRA. At diastolic blood pressures above 114 mm Hg, the PRA appears to rise again. The anomalous increase in arterial A II in the presence of marked suppression of PRA is consistent with the presence of a renin activator or accelerator factor in hypertensive plasma as postulated by others. It also identifies a possible mechanism whereby even small increases in PRA could exert an adverse effect on the hypertensive state.


Plasma renin activity during exercise in the dog. Previous workers have suggested that a rise in plasma renin activity (PRA) may mediate some of the hemodynamic changes associated with exercise. To test this hypothesis in nine dogs chronically instrumented for measurement of aortic pressure (catheter) or cardiac output (ascending aorta electromagnetic flow probe) PRA was measured by radioimmunoassay in blood samples drawn before and during running on a level treadmill at 4-8 miles per hour. Exercise caused increases in heart rate from 96 +/- 5 (SE) to 186 +/- 7 beats/min, cardiac output from 2.8 +/- 0.3 to 6.2 +/- 0.6 liters/min, and mean aortic pressure from 115 +/- 5 to 132 +/- 5 mm Hg (P less than 0.01). Mean PRA was 6.6 +/- 0.7 (SE) ng of angiotensin 1/ml per 3 hours before and 7.6 +/- 1.2 ng Ang I during exercise, values that are not different statistically. Propranolol reduced PRA at rest from 8.6 +/- 1.1 to 5.9 +/- 1.1 ng Ang 1 (P less than 0.05), but there was no significant difference between resting and exercise levels, although the increments in heart rate, cardiac output, and mean aortic pressure were reduced. Standing on hindlimbs for 5 minutes did not cause a change in mean aortic pressure or PRA. However, administration of pentolinium reduced mean aortic pressure, and PRA rose from 6.0 +/- 1.1 to 9.8 +/- 1.5 ng Ang I. Exercise, with or without beta-adrenergic blockade, does not cause increased PRA in conscious dogs in which the renin-angiotensin system is normally responsive.


Arterial lesions in repeatedly bred spontaneously hypertensive rats. Repeatedly bred male and female rats of many strains develop hyperglycemia, hyperlipidemia, hypertension, and arteriosclerosis spontaneously. The intensity of their arterial disease and related metabolic derangements appear to be related to their reproductive activity. Repeatedly bred spontaneously hypertensive rats (SHR) were found to have severe hypertension, hyperglycemia, hyperlipidemia, elevated creatine phosphokinase (CPK), serum glutamic oxaloacetic and glutamic pyruvic transaminase (SGOT, SGPT), and lactic dehydrogenase (LDH), as well as high circulating corticosterone levels. Despite these atherogenic metabolic derangements and their severe hypertension, the breeder SHR did not develop the severe, generalized arteriosclerosis found in other strains of breeder rats. Instead, the arterial lesions, consisting of intimal hyalinization and fibrosis, medial hypertrophy, and occlusion of the lumen, were found only in male breeder SHR and were confined to the intratubular arteries of the testes. It is suggested that the severe hypertension, genetic influences, or differences in hypothalamic-pituitary-adrenal-gonadal function in breeder SHR may not have been conducive to the development of arteriosclerosis in this particular strain of rats.


The influence of combined intra-aortic balloon counterpulsation and hyperosomotic mannitol on regional myocardial blood flow in ischemic myocardium in the dog. We investigated the combined effectiveness of intra-aortic balloon counterpulsation and hyperosmotic mannitol (25%) on regional myocardial blood flow during acute coronary insufficiency. Cardiac output and paced heart rate were held constant in chloralose-anesthetized dogs during right heart bypass. Acute coronary insufficiency was produced by ligation of the proximal left anterior descending coronary artery (LAD). Regional myocardial blood flow was measured using radioactive microspheres. Left ventricular end-diastolic pressure, mean aortic pressure, maximum left ventricular dp/dt, and hematocrit were unchanged by combined mannitol infusion and balloon pumping. Studies of combined treatment with balloon pumping and mannitol immediately after the second of two 13-minute consecutive reversible ligations of the LAD demonstrated that (1) collateral coronary blood flow increased 46% (P less than 0.02) in ischemic myocardium compared with mannitol infusion along during the first LAD ligation, and (2) collateral coronary blood flow increased 27% (P less than 0.05) in ischemic myocardium compared with balloon pumping along during the first LAD ligation. Studies in which combined treatment was delayed until 20 minutes after LAD ligation demonstrated that collateral coronary blood flow was elevated by 33% (P les than 0.05) in ischemic myocardium compared to control studies in which balloon pumping alone had no effect. The results suggest that the increase in collateral coronary blood flow was in part a result of an increased transmural pressure gradient produced by balloon diastolic augmentation and the ability of mannitol to reduce coronary vascular resistance in ischemic myocardium.


Turbulent blood flow in humans: its primary role in the production of ejection murmurs. To clarify the postulate that turbulence may produce ejection murmurs, point velocity and sound were measured in the ascending aorta of 13 subjects: six with normal aortic valves, six with aortic valvular disease, and one with a Bjork-Shiley prosthetic aortic valve. Velocity was measured with a catheter-tip hot film anemometer probe, and sound was measured with a catheter-tip micromanometer. Ejection murmurs detected intra-arterially were always found to be associated with turbulent or highly disturbed flow. Conversely, in the absence of intra-arterial sound during ejection, only minor disturbances of flow were detected. A linear relation between the sound energy density and turbulent energy density was shown (r = 0.92) and a linear relation between the acoustic power output (sound intensity) and turbulent power supply (r = 0.87) also was shown. Studies in vitro of sound and point velocity distal to a porcine valve inserted within a cast of the aorta, which permitted precise centering of the transducers along the axis of flow, confirmed these observations. When the power generated by the turbulence exceeded 3 ergs/sec per cm2, the murmurs were audible at the chest wall. The clinical gradation of the intensity of the murmurs increased as the power of turbulence increased. In conclusion, in this study we have demonstrated a clear association between turbulent blood flow and systolic ejection murmurs.


Basal vascular tone in the kidney. Evaluation from the static pressure-flow relationship under normal autoregulation and at maximal dilation in the dog. In conscious dogs static pressure-flow relationships (I-P curves) were obtained both for the normal autoregulating kidney vasculature and under conditions of maximal vasodilation induced by infusion of papaverine or acetylcholine into the renal artery. Concentration-response curves for the substances infused showed the typical S-shape. Control I-P curves exhibited an autoregulatory plateau; under maximal vasodilation the I-P curves were pressure-passive up to a perfusion pressure of 50 mm Hg, following a power function (1 = a-Pn) with an exponent greater than 1. Under the influence of acetylcholine, renal blood flow was significantly higher than under control conditions even at a perfusion pressure of 20 mm Hg. This indicates that there is an appreciable vascular tone even at a low pressure. The I-P curves under acetylcholine showed a break at about 50 mm Hg, above which the I-P curves were straight lines.


The effects of altered sodium balance and adrenergic blockade on renin release induced in rats by angiotensin antagonism. Circulating angiotensin II is said to inhibit renin release by a direct, intrarenal action. This effect of angiotensin was studied indirectly using the selective angiotensin II antagonist saralasin (1Sar-8-Ala-angiotensin II) in conscious normal, sodium-depleted, and sodium-loaded rats. Saralasin caused a dose-related increase in plasma renin concentration (PRC) in normal and sodium-depleted rats, but had no effect on PRC in sodium-loaded animals. However, saralasin was 300 times more active in sodium-depleted rats than in normal rats. Saralasin caused hypotension and tachycardia in sodium-depleted rats, but not in normals. Propranolol inhibited saralasin-induced renin release by 99% in normal rats and by 75% in sodium-depleted rats but not alter the hypotensive effect of saralasin in the latter. Saralasin potentiated phentolamine-induced renin release, hypotension, and tachycardia in normal rats, and this potentiated renin release was blocked by propranolol. We conclude that a portion of saralasin-elicited renin release in sodium-depleted rats is mediated by hypotensive activation of the carotid baroreceptor reflex which increases sympathetic nervous activity in the kidney. However, in sodium-depleted rats saralasin induced a 42-fold increase in PRC, whereas an equipotent hypotensive dose of the vasodilator hydralazine caused only a 3.5-fold increase in PRC. Thus, we find that saralasin appears to have a selective effect on renin release over and above its hypotensive effect, which suggests an angiotensin-mediated, feedback mechanism inhibitory to renin release. Thus, we have come to the conclusion that for part of saralasin-induced renin release appears to be caused by disinhibition of angiotensin suppression of renin secretion. This "short-loop" feed-back mechanism is closely associated with intrarenal beta-adrenergic receptors, since propranolol impaired saralasin-induced renin release under all circumstances in our experiments.


Experimental myocardial infarction in the cat. I. Reversible decline in contractility of noninfarcted muscle. The contractile state of the noninfarcted myocardium was examined in adult cats after myocardial infarction produced by ligation of several branches of the left coronary artery. At 2 days, 7 days, and 6 weeks after infarction, and after determination of intracardiac pressures, papillary muscles were exicised from the noninfarcted segment of the right ventricle and attached to a myograph for analysis of contractile function. One week after infarction there was a decline in actively developed force at Lmax, caused by a decrease in the rate of force development. In addition, the response to procedures that augment myocardial contractility, such as paired stimulation and increasing the frequency of electrical stimulation, was significantly depressed. Two days after infarction, changes were less significant, although similar in direction. Six weeks after infarction, developed force at Lmax had returned to normal values. The response to procedures augmenting contractility also had returned to normal. There appears to be a distinct, reversible loss of contractility in the remaining viable myocardium in the early phase after experimental infarction.


Modification of the flow-generating capability of the canine heart-lung compartment by the carotid sinus baroreceptor reflex. To quantitatively understand how the carotid sinus baroreceptor reflex modifies the Starling curve (i.e., the aortic flow (AF)-mean right atrial pressure (MRAP) relationship), experiments were performed in closed-chest, naturally breathing, and anesthetized dogs before and after vagotomy. Mean aortic pressure (MAP) was fixed at approximately 100 mm Hg and the pressure in the isolated carotid sinus (ISP) was varied from 75 to 150 mm Hg in steps of 25 mm Hg. At each ISP, MRAP was slowly increased and decreased while measuring AF by a previously implanted electromagnetic flow probe. A family of AF-MRAP relation curves specified at the different ISP's were thus obtained. Third-order polynomials in MRAP and ISP adequately fit these curves. Whether the vagi were intact or cut, there was no significant difference between the AF-MRAP relation curves obtained at an ISP of 75 or 100 mm Hg. However, decreasing ISP from 125 to 100 mm Hg caused a 24% increase in AF, and increasing ISP to 150 mm Hg caused a 15% decrease in AF in the dogs with intact vagus nerves. For the vagotomized dogs, the same decrease or increase in ISP caused a 17% increase or a 21% decrease in AF, respectively. When MAP was allowed to change by the reflex, only insignificant changes in AF occurred. We conclude that the carotid sinus reflex significantly alters the flow-generating ability of the heart-lung compartment by as much as 40% but this becomes clearly observable only if the reflex change in aortic pressure is prevented.


Effects of chronic anemia on the coronary and coronary collateral vasculature in dogs. We compared coronary resistances and collateral (retrograde) flows for a group of normal dogs (hematocrit 40) to values for a group of dogs with severe chronic anemia (hematocrit 17). We used an isolated heart preparation in which the vessels were maximally dilated by dipyridamole. All data were compared for a hematocrit of 40. The results showed a significant decrease in coronary resistances with anemia; average resistances (+/-SE) of the anterior descending, circumflex, and right coronary arteries of the control dogs were 1.04 +/- 0.09,0.74 +/- 0.01, and 2.63 +/- 0.17 mm Hg/[(ml/min)/100 g], respectively, and 0.6 +/- 0.04,0.41 +/- 0.05,and 1.17 +/- 0.15 for the anemic dogs. Average coronary collateral flows increased in anemia but statistical significance could not be shown. We conclude that increased vascularity is a long-term regulatory mechanism in response to a hypoxic stimulus.


Regional cardiac prostaglandin release during myocardial ischemia in anesthetized dogs. Cardiac prostaglandin release was studied in closed-chest dogs during acute coronary occlusion. Aortic and coronary sinus blood was obtained before, and at intervals after, balloon occlusion of the left anterior descending artery in seven dogs. Samples were assayed for prostaglandins F, E, and A by randioimmunoassay. All dogs demonstrated prostaglandin F release, Mean +/- SE postocclusion aortic levels were 0.26 +/- 0.01 ng/ml; coronary sinus levels were 0.67 +/- 0.01 ng/ml (P less than 0.001). In six dogs, prostaglandin E also was released. Mean postocclusion aortic levels were 0.24 +/- 0.01 ng/ml; coronary sinus, 0.44 +/- 0.01 ng/ml (P less than 0.001). There was no release of prostaglandin A. To examine the site of prostaglandin release, simultaneous samples from the aorta, the coronary sinus, and the great cardiac vein were obtained before and after left circumflex artery occlusion in six additional studies. The great cardiac vein drained effluent from nonischemic myocardium, whereas the coronary sinus drainage included blood from both ischemic and nonischemic zones. All six dogs demonstrated prostaglandin F release from the ischemic region. Mean postocclusion aortic prostaglandin F was 0.32 +/- 0.01 ng/ml. Coronary sinus prostaglandin F was 1.69 +/- 0.03 ng/ml (P less than 0.001), whereas the great cardiac vein level remained at 0.34 +/- 0.01 ng/ml (P greater than 0.05). Prostaglandin E was released from both ischemic and nonischemic regions. Mean aortic prostaglandin E was 0.21 +/- 0.01 ng/ml; great cardiac vein, 0.55 +/- 0.02 ng/ml (P less than 0.001); and coronary sinus, 1.07 +/- 0.04 ng/ml (P less than 0.001). These results have led us to conclude that the different local availability of prostaglandins E and F may influence the cardiac response to ischemia.


Vessel caliber and branch-angle of human coronary artery branch-points. Measurements were made of parent and branch vessel diameters and of the included angles of branch-points from postmortem human coronary arteriograms to determine the usefulness of theoretical equations predicting the relationships between parent and branch vessel caliber and between arterial caliber and branch-angle. The formulas were based on the concept that blood vessel size and arrangement provided for blood flow with minimum energy loss. Size relationships between parent vessel and its branches were determined for 42 left main and 53 other epicardial coronary artery branch-points in hearts with angiographically normal arteries. Left main coronary artery branch-points were studied in 68 hearts with various degrees of angiographically defined coronary artery disease. Measured diameters (D) of parent and branch vessels corresponded well to the theoretical formula: (DParent)3 = (DBranch1)3 + (DBranch2)3....,in angiographically normal coronary arteries. The exponent, on the average, is less with increasing grades of vascular disease for left main coronary artery branch-points. Mean area ratio, the sum of the cross-sectional area of the branches divided by the area of parent vessel, decreased with greater arteriographic disease. Area ratio varies with changes in the relative calibers of branch vessels. Fifty-seven branch-angles were determined by graphic analysis of postmortem biplane coronary arteriograms. No relationship could be found between branch-angle and vessel caliber. The included angle between branches varied from 32 degrees to 124 degrees without respect to relative or absolute vessel calibers. The results of these postmortem measurements on human coronary arteriogram suggest that coronary artery caliber may adjust to minimize energy loss at the branch-point but that branch-angle is determined by other factors. Restudy of arteriograms suggests that branch-angle may be determined by branch vessel destination.


The role of angiotensins in aldosterone production. The hypothesis that the COOH-terminal heptapeptide mediates the aldosterone-stimulating activity of angiotensin II was evaluated by comparing the relative effects on aldosterone production of angiotensin II and the heptapeptide to angiotensin analogues that are poorly metabolized to the heptapeptide and to a nonapeptide, des-Asp-1-angiotensin I, that is directly converted to the heptapeptide. In in vivo studies utilizing the adrenocorticotropic hormone-suppressed bilaterally nephrectomized dog, angiotensin II and the heptapeptide produced statistically significant increases in both aldosterone and cortisol secretory rates (P less than 0.001 for both relations). Sar-1-angiotensin II stimulated the production of both steroids to the same extent, but had much longer duration of action. [Poly(oAc)Seryl]angiotensin II was a weak agonist, having only about 30% of the steroidogenic potency of either angiotensin II or the heptapeptide. In equimolar concentrations des-Asp-1-angiotensin I had about one-half of the aldosterone-stimulating activity of the hepatpeptide. In in vitro studies, employing the trypsin-dispersed cat adrenal zona glomerulosa cells, the steroidogenic potency of angiotensin II and the heptapeptide was identical to maximal aldosterone production of 10(-8) M peptide concentration. By contrast, the response to Sar-1-angiotensin II was approximately a 10-fold increase in relative potency, while the response to [poly(oAc)Seryl]angiotensin II demonstrated a 10-fold decrease. These findings suggest that, although the heptapeptide may play an important role in the regulation of aldosterone production, the possibility remains open that angiotensin II could stimulate aldosterone biosynthesis without prior conversion to the heptapeptide.


Angiotensin II and angiotensin III in rat blood. Angiotensin II and its metabolites, [des-Asp-1]-angiotensin II (angiotensin III), [des-(Asp-1,Arg-2)]angiotensin II, and [des-(Asp-1,Arg-2,val-3)]angiotensin II, were measured in arterial and venous plasma from normal rats. Paper chromatography was used to separate the peptides which were measured with a radioimmunoassay method using an angiotensin II antiserum which had a 100% cross-reaction with each of these metabolites. A mean of 33% of the immunoreactive material in arterial plasma was angiotensin II, 58% angiotensin III, and 9% [des-(Asp-1,Arg-2)]angiotensin II/[des-(Asp-1,Arg-2,Val-3)]angiotensin II. A similar distribution was found in venous plasma. This and other evidence indicates that angiotensin-induced aldosterone secretion in the rat, unlike that in other mammalian species so far studied, may be mediated by angiotensin III.


Interactions between sino-aortic reflexes and cardiovascular effects of sleep and emotional behavior in the cat. The role of sino-aortic reflexes in the control of circulation during normal behavior was investigated by comparing cardiovascular reactions during various but reproducible types of behavior before and after bilateral sino-aortic deafferentation. Chronic deafferentation caused little change in baseline blood pressure, but a subtler, important role of sino-aortic reflexes was revealed by examining the integrated cardiovascular responses to behavioral stimuli. During desynchronized sleep, the buffering action of sino-aortic reflexes prevented a marked and diffuse vasodilation, with an action that was particularly evident on muscle blood vessels. During emotional behavior, especially when emotion was accompanied by movement, sino-aortic reflexes opposed the consequences of muscle vasodilation by inducing tachycardia and vasoconstriction in the viscera and in noncontracting muscles. A reciprocal type of interaction between behavior and sino-aortic reflexes was shown by testing the amplitude of the carotid occlusion response before and during desynchronized sleep; the latter condition was consistently associated with decreased effectiveness of the reflex response. The possibility is considered that this might indicate central suppression of the carotid sinus reflex during desynchronized sleep and that a similar inhibitory interference might occur during emotional behavior. Alternatively, reduction of the reflex response might result from a shift of the stimulus-response curve on either side of its steep portion.


Hyperplasia of vascular smooth muscle in experimental hypertension in the rabbit. Evidence for smooth muscle cell hyperplasia was sought in elastic and muscular vessels of rabbits 2 weeks after hypertension had been induced by partial constriction of the abdominal aorta above both kidneys. In those arteries taken from the circulation proximal to the constriction, specifically the common carotid artery and the aorta, vessel length, wall thickness, weight, and deoxyribonucleic acid content were increased in proportion to the rise in arterial pressure. There was no change in the extracellular space of muscular arteries as measured by [14C]inulin. [3H]Thymidine uptake measured in a gastric artery increased in proportion to the rise in arterial pressure. As demonstrated by light microscope autoradiography, [3H]thymidine was incorporated into cells in all layers of the artery wall but predominantly into the smooth muscle cells. There was no change in the size of arteries below the ligature where the arterial pressure was within normal limits. The data demonstrated that the increase in vessel wall dimensions in this animal model of hypertension is due in part, during the acute phase, to an increase in the number of cells, particularly vascular smooth muscle cells.


The natriuretic and hypotensive effects of potassium. The chronic effects of potassium loading on sodium balance and related variables were studied in two groups of dogs. The first group was intact except for the presence of indwelling arterial and venous cannulas. On the 1st day, increasing daily potassium intake from a normal level (30 mEq/day) to 200 mEq/day produced a 0.47-mEq increase in plasma potassium with a 56% increase (P greater than 0.01) in sodium excretion in spite of a 58% increase in plasma aldosterone concentration. After 6 days of potassium loading the cumulative negative sodium balance averaged 44 mEq while 22Na space decreased 6.7% (P less than 0.025). In this group arterial pressure did not change measurably. The same experimental protocol was repeated in a second group of dogs that were chronically adrenalectomized and maintained on fixed levels of aldosterone (50 mug/day) and hydrocortisone (1 mg/day). With aldosterone levels held constant the same increase in potassium intake produced a 1st day increase in potassium concentration of 1.20 mEq/liter and 217% (P less than 0.001) increase in sodium excretion. After 5 days of high potassium intake, the cumulative negative sodium balance totaled 84 mEq. Sodium space decreased 7.5% (P less than .005) during the course of the 5-day high potassium intake period. Potassium loading caused a fall in mean arterial pressure in this group; pressure fell from the control level of 110 +/- mm Hg to 87 +/- 4 mm Hg (P less than .001) after 3 days of high intake. By the 5th day of the experiment, pressure stabilized at 96 +/- 3 mm Hg, 13% less than (P less than 0.01) the control level. The results suggest that changes in plasma potassium concentration within physiological limits may have long term effects on sodium balance.


Studies on membrane-bound renin in the mouse and rat. Membrane-bound renin was isolated from the submaxillary gland and kidney of the white Swiss Webster mouse and from the kidney of the rat. Administration of the male sex hormone testosterone or an anabolic steroid, such as nandrolone phenpropionate (Durabolin), induces renin activity in microsomal fraction of the submaxillary gland of the young female mouse. Actinomycin D blocks this induction partially. Renin that sedimented with the microsomal fraction was isolated from the homogenized kidney of the mouse by density gradient centrifugation. Microsomal renin was also isolated from rat kidney disrupted by the N2 cavitation technique. The enzyme in the microsomal fraction that had been washed extensively was only partially active, but freezing and thawing or Triton X-100 activated microsomal renin. The same microsomal fraction contained active kallikrein. In pilot studies a plasma membrane-enriched fraction was isolated from the microsomal fraction of the homogenized rat kidney cortex that had both renin and kallikrein activity.


Mitral atresia with normal aortic valve: a study of eighteen cases and a review of the literature. Eighteen cases of mitral atresia with normal aortic valve plus 68 cases from the literature are analyzed. A new classification based on anatomical findings is proposed. Pulmonary stenosis or atresia is frequent in the type with transposition of the great arteries. The rare instances of normal or large left ventricle are due to a large ventricular septal defect, or to straddling or displaced tricuspid valve. The clinical, radiologic and electrocardiographic findings have been summarized and correlated with the different physiopathological situations. In our catheterized cases an oxygen saturation step-up was found in the right atrium together with left atrial hypertension. In seven cases mitral atresia was demonstrated by selective left atrial contrast injection. The average age at death was six months. Among the cases surviving one year or more, the association of atrial septal defects or pulmonary stenosis was frequent. Enlargement of the interatrial communication, accompanied by other palliative measures, is the only available surgical procedure.


Anomalies of the aortic arch and ventricular septal defects. This investigation presents additional evidence for the hemodynamic influence of intracardiac anomalies on the development of the aortic arch, based on measurements of different parts of the great vessels. Criteria are given to define the normal aortic arch and the different anomalies of the aortic arch, such as interruption, atresia, tubular hypoplasia, hypoplasia, abnormal long segment and juxtaductal coarctation. Two types of of malignment venentricular septal defects are described to illustrate how prenatal intracardiac flow disturbances can account for various aortic arch patterns. An explanation is proposed as to how reduced blood flow through the embryonic preductal aorta may contribute to the pathogenesis of all dimensional anomalies of the aortic arch.


XVIII. Persistent fetal dispersion of the atrioventricular node and His bundle within the central fibrous body. In the hearts of two victims of sudden unexpected death (one age 20 years and the other 11 years) there was abnormally delayed persistence of the pattern of fetal dispersion of the A-V (atrioventricular) node and His bundle within the central fibrous body. This pattern is characterized by a splayed or excessively fragmented histological appearance of these structures viewed in cross-section. Some of the fronds of A-V nodal tissue formed loops connecting one portion of the node to another. Other fragments of nodal tissue appeared isolated within the central fibrous body, occasionally connecting directly to the crest of the interventricular septum. A number of the A-V nodal fragments were undergoing resorptive degeneration. Directly adjacent to the A-V node of the 11-year-old subject there was an island of cartilage within the central fibrous body. Since these anatomically separated fragments of A-V nodal tissue were so numerous and varied widely in size and thickness, in length, in histological organization, and in their apparent state of preservation probably extant during life, it is suggested that they form potential routes for abnormal conduction or impulse formation within the A-V junctional region and that some of these electrophysiological disturbances might be quickly lethal.


Left axis deviation: a spectrum of intraventricular conduction block. The effects of left axis shift (greater than -30 degrees) on intraventricular conduction time (IVCT) were studied in 63 subjects in whom electrocardiograms before and after appearance of the left axis shift were available. Subjects with electrocardiographic evidence of left or right ventricular hypertrophy, left or right bundle branch block, myocardial infarction, pre-excitation and those receiving antiarrthymic drugs were excluded. The IVCT increased by an average of 25 msec when the QRS axis shifted to -30 degrees or beyond. When the individual AQRS was related to the IVCT a linear correlation (r = -0.8) was observed. It appears that a continuum relation between the AQRS and the IVCT exists throughout the counterclockwise range of +90 degrees to -90 degees. In all leftward shifts in AQRS from from +90 degrees there is a prolongation in IVCT. Our observations indicate that all leftward shifts in AQRS, including the extreme left axis shift (left anterior hemiblock), represent a spectrum of intraventricular conduction block.


The effect of premature atrial depolarization on sinus node automaticity in man. Sino-atrial conduction time (SACT) may be calculated from the difference between the length of the return cycle and the spontaneous cycle, using programmed premature atrial stimulation during spontaneous sinus rhythm. This approach to sinoatrial conduction assumes that sinus node automaticity is not changed by premature depolarization. In order to validate this assumption, we compared the length of the post-return cycles to the spontaneous cycle length in 71 patients. Patients were grouped according to clinical diagnosis and the value of calculated SACT. At long coupling intervals at which no reset of the sinus node occurred there was only a small prolongation of the post-return cycles (less than 8.4 msec, on an average) compared to the spontaneous cycle length. This suggests no or only an insignificant effect of premature depolarization on the sinus node. However, during test stimuli leading to reset of the sinus node, the post-return cycles were significantly prolonged between 20 to 30 msec, on an average. The response of the individual cases sometimes varied to a great extent. In patients who demonstrated a progressive linear prolongation of the return cycles at decremental shortening of the test interval, there was no significant prolongation of the post-return cycles versus the spontaneous cycle length. We conclude that 1) premature depolarization of the sinus node may have a depressant effect on sinus node automaticity, which, if present, is usually small; 2) calculation of SACT using the extrastimulus technique may overestimate true SACT.


The vectorcardiogram in right bundle branch block: correlation with cardiac failure and pulmonary disease. Frank vectorcardiograms (VCG) and clinical records of 243 patients with right bundle branch block (RBBB) were compared. The patients were classified into three categories on the basis of VCG criteria. The first category included 100 patients with a normal frontal axis, and the second category included 44 patients with concomitant left anterior hemiblock. The third category consisted of 99 patients with RBBB and myocardial infarction. The VCGs were classified into three types accoriding to the QRS configuration in the transverse plane. In type I the initial forces were anterior and counterclockwise and the afferent limb crossed the midline posterior to E point; in type II the initial forces were anterior and counterclockwise and the afferent limb crossed the midline posterior to E point; in type II the initial forces were anterior and counterclockwise and the afferent limb crossed the midline anterior to or through E point; and in type III the entire transverse loop was clockwise and anterior to E point. The patients were further classified according to the presence or absence of cardic failure or severe pulmonary disease. In patients with RBBB and a normal axis, cardiac failure or severe pulmonary disease was found in five of 49 patients wtih type I, 17 of 31 with type II, and 18 of 20 with type III pattern. In patients with RBBB and left anterior hemiblock, significant disease was found in one of 17 with type I, five of 16 with  type II, and eight of 11 with type III pattern. These data show that, in patients with RBBB, the position of the afferent limb in the transverse plane can be used to predict cardiac failure or severe pulmonary disease.


The conducting tissues in primitive ventricular hearts without an outlet chamber. We have studied the disposition of the cardiac conducting tissues in four hearts from situs solitus individuals possessing primitive ventricles without outlet chambers. These hearts correspond to the type of univentricular heart defined as common ventricle by Lev. All the hearts studied possessed normally positioned great arteries. Two groups, each consisting of two hearts, could be distinguished. The first type possessed a small posterior ridge which divided the posterior portion of the primitive ventricle into right and left ventricular sinuses. The papillary muscles to the atrioventricular valves were separate structures and arose on each side of this posterior ridge. The conducting tissues in these hearts arose from an atrioventricular node situated in the atrial septum but deviated posteriorly. The atrioventricular bundle pierced the fibrous annulus posteriorly and descended on the posterior ridge, lying to its left side. A bifurcation was not identified, and bundle branches were not present. The other two hearts had no posterior ridge. A common posterior papillary muscle supported both atrioventricular valves, and in one a marked anterior muscle bar produced obstruction of the pulmonary outflow tract. The connecting atrioventricular node was situated laterally in the right atrioventricular valve orifice, and the atrioventricular bundle descended into the right parietal wall of the primitive ventricle. A bifurcation and bundle branches were not observed. The disposition of conducting tissue in these hearts differs from that found in "primitive ventricle with outlet chamber" in that the connecting atrioventricular node and bundle are situated anteriorly and are intimately related to the transposed pulmonary artery outflow tract in the latter anomaly. The surgical significance of these findings is emphasized.


Review of the pocket-electrocardiograph (PECG) in a large general medical clinic. Two hundred and twenty patients were selected for testing with the patient-activated Pocket Electrocardiography (PECG) because angina pectoris and similar diagnoses could not be excluded. They were selected during a 30-month period from the population of approximately 12,000 new patients visiting a general medical clinic at Nippon Medical School Hospital. The test confirmed the preliminary diagnosis in 79.1%; 9.6% were not confirmed and 11.3% did not have an attack during the PECG examination. The PECG examination is useful in the differential diagnosis of angina pectoris, cardiac neurosis, phantom arrhythmia, and arrhythmia when the routine ECG examinations are essentially negative.


The influence of left ventricular stroke volume on aortic root motion: an echocardiographic study. Aortic root motion was studied in 24 normal volunteers at rest and during the Valsalva maneuver, isometric exercise, and amyl nitrite inhalation. In addition root motion was correlated with the stroke volumes determined at cardiac catheterization in 24 patients. The root has distinct systolic movement, the amplitude and duration of which were easily measured both at rest and during the interventions. At rest,the mean (+/-1 SE) systolic amplitude of the anterior aortic wall was 11.2 +/- 0.5 mm and that of the posterior wall 9.5 +/- 0.3 mm. During the strain phase of the Valsalva maneuver anterior wall amplitude fell to 8.2 +/- 0.4 mm and the posterior wall to 7.3 +/- 0.5 mm (P less than 0.001). With release, anterior wall amplitude rebounded to 12.5 +/- 0.8 mm and the posterior wall to 10.8 +/- o.5 mm, values greater than control (P less than 0.01). With isometric exercise there was no change in amplitude compared to rest; however, amyl nitrite caused an increase in the anterior wall to 13.5 +/-0.8 mm and posterior wall to 11.9 +/-0.6 mm (P less than 0.01). In the patient group the amplitude of posterior wall motion correlated weakly with cardiac index (r = 0.63) and stronger with stroke index (r = 0.78). This study quantifies the echocardiographic pattern of normal aortic root motion. The findings indicate that the aortic root motion is an index of stroke volume; they further suggest that root motion is acutely sensitive to variations in stroke volume since its amplitude changed in accord with the documented effects of the employed maneuvers on stroke volume.


Quantitative ultrasonographic studies of lower extremity flow velocities in health  and disease. Quantitative Doppler ultrasonographic flow velocity determinations are reported from 39 normal control subjects and 80 patients with angiographically documented peripheral arterial disease, in whom femoral, posterior tibial and dorsalis pedis arteries were studied. The mean control values of the most useful parameters were: femoral artery: peak forward velocity (PFV) cm/sec: 40.7 +/- 10.9, deceleration (Dec.) cm/sec2:250.9 +/- 60.0, peak/mean velocity (P/MV): 4.8 +/- 1.6; posterior tibial artery: PFV: 16.0 +/- 10.0, Dec.: 129.8 +/- 75.7, P/MV: 4.8 +/- 2.5; dorsalis pedis artery: PFV: 168 +/- 5.7, Dec.: 137.9 +/- 54.5, P/MV: 6.0 +/- 4.1. The values of these measurements in the patients with arterial occlusive disease were all significantly lower, and also permitted distinguishing those with multilevel disease from those with a single site of occlusion. Quantitative evaluation of the Doppler ultrasonogram permits obtaining detailed functional information on the degree of arterial flow impairment in patients with peripheral arterial occlusive disease.


Myocardial ischemia due to infrarenal aortic cross-clamping during aortic surgery in patients with severe coronary artery disease. Hemodynamic measurements were performed and ECG recorded before and shortly after infrarenal aortic cross-clamping during operation for abdominal aortic aneurysm in five patients without evidence of heart disease (group I) and in ten patients with severe coronary artery disease (group II). All patients sustained an increase in systemic arterial pressure. Group I demonstrated a decrease in pulmonary artery, pulmonary capillary wedge (PCW), and central venous pressures when the aorta was clamped, whereas group II demonstrated an increase. The difference in response of the groups is significant (P less than 0.05). All three patients who responded to cross-clamping with increases of 7 mm Hg or greater in PCW demonstrated myocardial ischemia during cross-clamping. None of the values measured prior to cross-clamping predicted with certainty the response to cross-clamping. Sodium nitroprusside reversed the elevation of left ventricular filling pressure in all three patients, and in two patients, relieved evidence of myocardial ischemia concurrently. In the third patient, ventricular irritability was abolished by lidocaine and did not recur. We conclude that infrarenal aortic cross-clamping may cause myocardial ischemia in patients with severe coronary artery disease. This ischemia may be predicted by a rise in PCW at the time of cross-clamping, and vasodilator therapy is indicated in such patients.


Diagnosis of acute myocardial infarction in a community hospital: significance of CPK-MB determination. Twice-daily CPK-MB determinations were performed but not made availabe to the physicians of 179 consecutive patients with precordial pain admitted to a community hospital to evaluate the diagnostic importance of this isoenzyme. Physician decision was based upon history and once-daily ECG and total enzymes (CPK, SGOT, LDH). Following hospital discharge, each patient's clinical record was reviewed to determine the physician diagnostic decision. The patients were subdivided into three groups. The first group consisted of 46 patients with diagnostic QRS changes and elevated total enzymes. All 46 had physician diagnosis of acute myocardial infarction and CPK-MB was present in 44 (96%). The second group included 55 patients with nondiagnostic QRS but elevated total enzymes. Physician diagnosis was acute myocardial infarction in 28 (51%) but 16 (57%) of these had no CPK-MB. The third group contained 50 patients with nondiagnostic QRS and normal enzyme levels. Six (12%) had physician diagnosis of acute myocardial infarction but none had CPK-MB. Thus, absence of CPK-MB failed to confirm physician diagnosis of acute myocardial infarction when based upon history and total enzymes in the absence of QRS changes in 22 of 34 (65%) patients.


Experimental myocardial infarction. XIII. Sequential changes in left ventricular pressure-length relationships in the acute phase. Diastolic pressure-length relationships of an ischemic region of the canine left ventricle were measured over a six-hour period following left anterior descending coronary artery ligation, and their evolution was compared with the extent of systolic aneurysmal bulging. Normalized ischemic segment length excursion, which after coronary artery ligation may be taken as a measure of systolic aneurysmal bulging, increased during the first hour after ligation but thereafter declined toward control values. Concurrently, reciprocal changes were demonstrated in the slope of the end-diastolic pressure-length curves obtained during transient pressure loading of the left ventricle. These data show that the magnitude of acute systolic aneurysmal bulging followed experimental coronary artery ligation is determined not only by loss of contractile function, but also by changes in passive pressure-length relationships of the myocardium. Moreover, the results indicate that development of akinesis in experimental ischemia, heretofore demonstrated only in the chronic phase of infarction, may begin within hours of the onset of myocardial ischemia.


Effects of procainamide on the dispersion of recovery of excitability during coronary occlusion. In 14 mongrel dogs, refractory periods were determined in nonischemic and acutely ischemic zones of myocardium during control conditions, 15 minutes after coronary ligation, and 10 and 20 minutes after a procainamide infusion. Following coronary ligation, refractory periods in the nonischemic area remained unchanged (100.8% of control) while in the ischemia area they decreased to 88.6% of control (P less than 0.02) causing a dispersion of refractoriness of 12.2%. After the administration of procainamide, refractory periods lengthened in the nonischemic as well as in the ischemic areas but the changes were such that the temporal dispersion caused by the coronary ligation was reduced from 12.2% to 5.5% (P less than 0.01) after 10 minutes, and to 5.0% (P less than 0.02) after 20 minutes of drug infusion. It is concluded that procainamide exerts different overall effects on the nonischemic and acutely ischemic canine myocardium. It is postulated that this action may play a role in the suppression of re-entrant arrhythmias.


Noninvasive detection of intracardiac thrombosis: 131-I fibrinogen cardiac survey. Cardiac survey following administration of 131-1 autologous fibrinogen is a noninvasive technique for the detection of intracardiac thrombosis. Fibrinogen is isolated from plasma by a rapid salting-out method with ammonium sulfate and is iodinated with chloramine T. The purity of 131-fibrinogen, expressed as clottable radioactivity, is greater than 90%. Cardiac survey consisting of serial gamma camera imaging or rectilinear scanning after intravenous administration of 131-I fibrinogen was conducted in dogs with freshly induced thromobosis of the left atrial appendage. An accumulation of radioactivity was detectable in the area of the left atrium and confirmed in each of nine dogs sacrificed. Similarly, 20 patients with heart disease predisposing to intracardiac thrombosis were surveyed. Eight of nine patients with positive studies and 11 of 11 with negative studies were confirmed subsequently at surgery or autopsy. Cardiac survey with 131-I fibrinogen is a simple and noninvasive method of detecting intracardiac thrombosis.


Scanning electron microscopy of surface irregularities and thrombogenesis of polyurethane and polyethylene coronary catheters. Following routine coronary arteriography,  surface irregularities and thrombogenesis of the inner and outer wall of six Ducor polyurethane and six RPX polyethylene coronary catheters were studied by scanning electron microscopy. Polyurethane catheters had rough and highly irregular external and internal surfaces. All catheters showed adherent thrombi on their external surface. The internal surface of three catheters showed evidence of thrombosis. Polyethylene differed from polyurethane in several respects. Although the external surface had an irregular and wavelike appearance, the internal surface was smooth and regular. Two polyethylene catheters showed thrombi on their external surface. The internal surface of one catheter showed single platelets in one area. These results confirm recent reports showing that internal and external surface irregularities play a major role in the initiation of thrombosis in and on intravascular catheters. They stress the need for high quality catheter materials with smooth and regular surfaces in the prevention of thromboembolic complications from coronary arteriography.


Alterations of right ventricular systolic time intervals by chronic pressure and volume overloading. Right ventricular (RV) systolic time intervals and hemodynamic parameters were determined by micromanometric techniques in 13 subjects with normal right ventricles (NRV). These data were compared to those of 16 patients with pulmonary hypertension (PH) or predominant pressure overloading and 13 individuals with uncomplicated secundum atrial septal defects (ASD) or predominant volume overloading. In PH, the QP2 interval tends to remain within the normal range due to reciprocal changes in isovolumic contraction (ICT) and ejection (RVET) times. Elevations of pulmonary artery diastolic pressure are associated with increases in the mean rate of isovolumic pressure rise (MRIPR) (r = 0.84), but the latter change does not fully compensate for the widened ventriculoarterial diastolic pressure difference and ICT becomes prolonged (P less than 0.001). Factors other than stroke index depression which may contribute to the decreased duration of RVET (P less than 0.001) include tricuspid regurgitation and elevation of pulmonary vascular impedance. In ASD, QP2 is significantly prolonged (P less than 0.025) due to a significant increase in RVET (P less than 0.005). In contrast to NRV, a linear correlation of RVET and stroke index was not present, which suggested an alteration of ejection dynamics in this group. Despite a high incidence of complete or incomplete right bundle branch block the interval from QRS onset to rapid RV pressure upstroke was not prolonged. This is most probably the result of peripheral bundle branch block of genesis of the QRS pattern by right ventricular hypertrophy.


Identification of ethylmalonic acid in urine of two patients with the vomitting sickness of Jamaica. Large amounts of ethylmalonic acid have been identified in urines from two patients with the vomitting sickness of Jamaica. The amounts were 178 and 882 mug per mg creatinine which are 70 and 350 times, respectively, over control values. Other short and medium chain dicarboxylic acids including glutaric and adipic acids and those with eight and ten carbon chain, saturated and cis-unsaturated, were also detected in large quantities as in the case of hypoglycin treated rats; urine. However, the large increase of urinary ethylmalonic acid in these two human cases is in a sharp contrast to the findings in hypoglycin treated rats in which urinary ethylmalonic acid increased only 3 times over control. It appears that ethylmalonic acid is produced in the cases with the vomiting sickness of Jamaica by carboxylation of n-butyryl-CoA which is not oxidized further due to the inhibition by hypoglycin A. In case of hypoglycin-treated rats, n-butyryl-CoA is mainly conjugated with glycine or deacylated to free butyric acid.


Double sequential counterimmunoelectrophoresis (DCIEP): an improved method for detection of hepatitis-B antigen (HBAg). A method is described for increasing the sensitivity of conventional counterimmunoelectrophoresis (CIEP), i.e. double sequential counterimmunoelectrophoresis (DCIEP). Our method consists of a second electrophoretic migration made after the classical CIEP, where instead of HB antibody (from polytransfused patients), the anodic wells are filled with an antihuman-gammaglobulin antiserum. DCIEP is significantly more sensitive than CIEP (P less than 0.01), the number of positive sera in chronic lever diseases being 28.7% compared with 17.5%.


Comparative study of two methods for hepatitis B antigen (HBAg) detection: double sequential counterimmunoelectrophoresis (DCIEP) and Ausria II-125I radioimmunoassay. Double sequential counterimmunoelectrophoresis (DCIEP) (an improved method that we have developed) and Ausria II-125I (an indirect solid-phase radioimmunoassay) were compared for HBAg detection in chronic liver diseases. 26.8% of the patients were positive using DCIEP and 41.8% were positive with Ausria II125I. The conventional counterimmunoelectrophoresis (CIEP) is less sensitive than DCIEP, the level of positive results being 18.8% (P less than 0.001)9


A rapid method for the measurement of plasma glucose concentration. A modification of the manual glucose oxidase-gum guaiacum method of Shipton, B., Wood, P.J. and Marks, V. ((1975) Med. Lab. Tech. 32,33), for use with plasma, is described. The method enables rapid measurement of plasma or serum glucose concentration between 1 and 22 mumol/1 using 10 mul of sample and a single colour reagent. Experience of the method in routine use has shown that the coefficient of variation, beteen batch, is 2.1% and the time taken for analysis of 1 sample, standards and a quality of control sample is 12 min (including centrifugation of blood to obtain plasma).


Cartilage collagen in osteoarthrosis.

Cartilage collagen in osteoarthrosis. Pronase digestion of osteoarthrotic cartilage collagen indicated that this type of pathological collagenous structure is more susceptible to proteolytic degradation than human controls or bovine and calf articular cartilage. There were some differences between individual patients in the collagen susceptibility to pronase cleavage. Also, different zones of the same diseased femoral head exhibited varied susceptibility. It is suggested that changes in collagen stability are reflected in cartilage permeability and in this way also in alterations in the supply of nutrients.


Dopamine-beta-hydroxylase activity in serum following acute myocardial infarction: an evaluation of this parameter for routine use as an index of sympathetic activity. Dopamine-beta-hydroxylase activity was measured in sera from 114 normal males and from 11 patients on the 1st, 2nd, 3rd, 5th and 10th day following acute myocardial infarction. A significant elevation of dopamine-beta-hydroxylase levels (P less than 0.001) was found during the first two days after infarction when compared with the 10th-day values. Only a few activities were above the reference range. Temporary elevations of glucose and glycerol levels were also found. Assay of serum dopamine-beta-hydroxylase may be a useful parameter of sympathetic activity in longitudinal studies in which each individual is used as his own reference.


Diluted human serum as a suitable diluent in the preparation of bilirubin reference solutions. From a concentrated solution of bilirubin in dimethylsulfoxide (about 13 mmol/1, standardized spectrophotometrically) and a serum diluted 1/3 (whose native bilirubin is lowered by exposure to phototherapy lamps) a bilirubin-enriched serum is prepared (bilirubin concentration about 130 mumol/1 = 7.5 mg/dl) wherein all the bilrubin is bound to albumin. Such an enriched serum behaves in the diazo-reaction in the same way as a bilirubin-enriched serum prepared with undiluted serum and can, therefore, be used as a working standard in serum bilirubin assays.


A critical examination of the value of combined determinations of lecithin:cholesterol acyltransferase and lipoprotein-X in the differential diagnosis of liver disease. The suggestion that combined determinations of lecithin: cholesterol acyltransferase activity and lipoprotein-X can be used to distinguish between patients with intrahepatic cholestasis and extrahepatic biliary obstruction has been studied. Of 21 patients who were lipoprotein-X positive and in whom an unequivocal diagnosis was made, 11 had intrahepatic cholestasis and 10 extrahepatic obstruction. The range of plasma lecithin:cholesterol acyltransferase activity was similar in the two groups and did not enable distinction to be made between them.


A note on the practical aspects of the assay of N-acetyl-beta-glucosaminidase in human urine. 1. Some practical aspects of the assay of urinary N-acetyl-beta-glucosaminidase activity were studied in patients with renal disease. 2. Centrifugation and dialysis of urine were not necessary prior to assay. 3. When enzyme activity was related to urinary creatinine random urine samples could be used. 4. Since preservatives used to prevent bacterial growth may inhibit enzyme activities, samples should be assayed immediately after collection or stored at 4 degrees C or 20 degrees C. 5. Mild visible haemoglobinuria, eg. derived from lysed red blood cells did not interfere with the enzyme assay.


Effect of epidural analgesia on the glycoregulatory endocrine response to surgery. Plasma concentrations of glucose, insulin, glucagon, cortisol, growth hormone and prolactin were measured repeatedly in ten females undergoing abdominal hysterectomy during general anaesthesia. In addition to general anaesthesia five of the patients had continuous epidural analgesia effective for the first 26 postoperative hours. Plasma glucose was elevated during surgery and postoperatively, but not in patients having epidural analgesia. Insulin was low and unchanged in both groups. Glucagon was unchanged and similar in both groups. Cortisol was lower during surgery in the epidural group, but not postoperatively. Growth hormone increased during surgery in four of five patients receiving general anaesthesia alone, but no changes were observed in the epidural group. Prolactin was greatly elevated in all patients immediately after induction of anaesthesia and then fell rapidly during surgery, similarly in both groups. It is concluded that epidural analgesia can inhibit the hyperglycaemic response to surgical stress, but this effect cannot be uniformly correlated to changes in peripheral plasma levels of insulin, glucagon, cortisol, growth hormone or prolactin.


Further observations on postpartum ovarian refractoriness: effect of gonadal stimulation in women receiving bromocryptine. It has been reported previously that the administration of human menopausal gonadotrophins (HMG) to lactating and non-lactating women from day 5 to day 9 postpartum elicited no significant elevation of urinary oestrogens or serum oestradiol within 15 days after delivery. In order to study further the role of prolactin on this ovarian refractoriness, five women receiving 7-5 mg of bromocryptine (CB-154) daily were given HMG at a dose of 300 iu per day, from day 5 to day 10 post-delivery. In all women serum oestradiol and urinary oestrogens showed no significant elevation within the 2 weeks after delivery. Serum prolactin was elevated in all cases and fell to normal nonpregnant levels immediately after CB-154 was administered. The suggestion that prolactin may possess antigonadotrophic activity at the ovarian level is not supported by the data presented here. The deficient ovarian response to gonadotrophin stimulation could be due to either the intraovarian effect of the high amounts of circulating steroids produced during gestation or to some unknown mechanism.


Case of hyperthyroidism due to a chromophobe adenoma. A A 23-year-old man with secondary hypogonadism was also found to be thyrotoxic. Results of thyroid function tests were in the hyperthyroid range but the serum TSH was inappropriately high. A pituitary tumour was demonstrated and following hypophysectomy he became biochemically hypothyroid. Evidence is presented and discussed that his hyperthyroidism was due to excessive TSH production by the pituitary tumour.


Total thyroidal content of iodine in thyrotoxic patients measured by in vivo neutron activation analysis. This paper describes an in vivo method for measuring total thyroidal iodine stores by activation analysis, its evaluation and measurements in thyrotoxic patients. There was good correlation between measurements of solutions of iodine and post-mortem thyroids by activation analysis and chemical analysis. Measurements in thyrotoxic patients showed low levels in untreated and treated (antithyroid drugs) patients and a marked increase in patients studied whilst in clinical remission. The practical importance of this method of measurement of thyroidal iodine stores is that it is a reliable in vivo measurement obtained at a single visit and should enable the definition of the relationship of thyroidal iodine stores to pathophysiology and prognosis.


Maternal thyroid function, iodine deficiency and fetal development. In an area of New Guinea where there is dietary iodine deficiency, measurements of thyroid function have been made on women of child-bearing age, several of whom were pregnant at the time. The outcome of these pregnancies, and also of those occurring in the four preceding years, were examined in relation to indices of thyroid function. More stillbirths, infant deaths and endemic cretins occurred among the offspring of women who showed biochemical evidence of iodine deficiency, without clinical evidence of hypothyroidism. This situation differs from that of untreated myxoedema or congenital hypothyroidism in women, which is usually associated with altered menstrual function, infertility or repeated abortion. Mechanisms that may account for these differences and the possible implications are discussed.


A comparison of the effect of levodopa and somatostatin on the plasma levels of growth hormone, insulin, glucagon and prolactin in acromegaly. The acute suppressive effects of L-dopa and somatostatin (growth hormone release inhibiting hormone) on the elevated plasma GH concentrations of seven patients with acromegaly were compared. In addition the effects of the two agents on fasting concentrations of plasma glucose, insulin, glucagon and prolactin were studied. In six of the seven patients hourly samples for GH assay were taken from 08.00 to 20.00 hours on a control day. Synthetic cyclic somatostatin (100 mug) was infused intravenously in an albumin/saline solution over 75 min with a Harvard constant infusion pump. Levodopa 500 mg was given orally. Somatostatin infusion produced a reduction in plasma GH concentrations in six of seven patients (mean reduction 55%). L-Dopa produced a reduction in plasma GH concentrations in the same six patients (mean reduction 52%). The minimum GH concentrations achieved in the two tests were comparable and did not differ significantly from the minimum GH concentrations recorded during the 12 h control study. Mean plasma insulin and glucagon concentrations were also significantly reduced during the somatostatin infusion (P less than 0-025; P less than 0-05 respectively). Plasma glucose concentrations did not change. L-Dopa did not alter mean plasma glucose, insulin or glucagon values. Somatostatin did not alter prolactin values but L-Dopa suppressed basal values to less than 2 ng/ml in five patients. This study shows that the plasma GH change after the administration of L-dopa and somatostatin in acromegaly is comparable and confirms the pancreatic effects of somatostatin.


Plasma dopamine-beta-hydroxylase activity in phaeochromocytoma. Plasma dopamine-beta-hydroxylase (DbetaH) activity, a marker of catecholamine secretion that occurs via exocytosis, was determined preoperatively in eight patients with phaeochromocytoma. Despite very elevated urinary catecholamine concentrations, mean plasma DbetaH activity was 32-6 +/- 3 u/l and was not significantly different from apparently healthy subjects. Seven days after surgery, one subject exhibited a 60% postoperative decrease of enzyme activity. These results suggest that diffusion across plasma membranes is the predominant mechanism of catecholamine release from phaeochromocytomas. The postoperative change in one patient suggests tumour heterogeneity and that exocytosis may contribute to the process of catecholamine release in some patients.


Assessment by continuous cardiac monitoring of minimum duration of preoperative propranolol treatment in thyrotoxic patients. The effect of the beta-blocker, propranolol (40 mg 6-hourly orally) has been studied on the tachycardia of six patients with untreated thyrotoxicosis. Heart rate was monitored continuously using a light portable ECG recorder which allowed the patients to undertake normal activities during the recording periods. The most marked reduction in heart rate was evident at 24 h after starting propranolol treatment. In three of the patients there was only a minor further fall in heart rate despite continued propranolol administration, but in the remaining patients the reduction in heart rate with each successive day of treatment was more marked. These results suggest that if propranolol were to be used alone in the preparation of patients before partial thyroidectomy for thyrotoxicosis, a dose of 40 mg 6-hourly for 3-4 days might be sufficient.


Trisomy of chromosome 20.

Trisomy of chromosome 20. A neonate with ususual facial features and multiple congenital malformations expired at 4 hours of age. An autopsy revealed severe anomalies of the gastrointestinal system and spinal dysplasia. Cytogenetic evaluation of fibroblasts cultured from a lung biopsy revealed a karyotope of 47,XX,+20.


An extra small metacentric chromosome identified as a deleted chromosome no. 17. In an 11-year-old girl with multiple congenital abnormalities and mental retardation, an extra, small, metacentric chromosome was identified by banding methods as a deleted chromosome No. 17. This represents the first reported case of partial trisomy 17.


Familial carcinoma of the pancreas.

Familial carcinoma of the pancreas. A sibship is reported in which four brothers died of adenocarcinoma of the pancreas in the seventh or eighth decade of life. None of the patients had a history of pancreatitis, other malignant neoplasms, or exposure to a known pancreatic carcinogen. This family seems to exhibit a genetic predisposition to pancreatic carcinoma late in life, but the mode of inheritance and the relative importance of genetic and environmental factors in the development of these tumors are unclear.


The genetics of and associated clinical findings in humero-radial synostosis. This paper compares the manifestations of sporadic, dominantly inherited and recessively inherited humero-radial synostosis with the aim of determining ways of separating these forms on clinical grounds. The genetic forms are characterized by bilateral involvement and by lack of the distal ulnar malformations and the absence of digits that are common in the sporadic cases. The majority of patients with the dominantly inherited form have a characteristic pattern of anomalies, including brachymesophalangy, and the recessive cases have a high frequency of malformations in addition to those of the limbs. Consanguinity is frequent in the families of recessive cases. Four additional patients are presented; two of them illustrate many of the features of the phocomelic syndrome reported by Herrmann et al. (1969). A possible teratogenic cause of these cases is discussed.


Congenital generalized fibromatosis: an autosomal recessive condition? Congenital generalized fibromatosis is a rare condition which is often misdiagnosed and given an erroneously poor prognosis. Five new cases are presented in this report, all initially having been diagnosed as neurofibromatosis. The histopathological findings are presented and the differential diagnosis is discussed. The natural history of the disorder appears to include an initial phase of proliferation soon after birth with appearance of new tumor masses. Providing these do not involve vital viscera, the patient survives with regression and eventual disappearance of all lesions. Spontaneous regression occurred in all five patients reported. Two sets of sibs occurred in the cases described. The possible genetic aspects of this are discussed and the pertinent literature reviewed.


Lysosomal enzyme levels in human amniotic fluid cells in tissue culture. IV. %A N-acetyl-beta-D-glucosaminidase. Total and % A hexosaminidase were similar for primary cultures and later passages of amniotic fluid cells. The culture variables-through serial passage, within a passage and replicate primary cultures-resulted in some variation in total hexosaminidase, but an insignificant change in % A hexosaminidase. They are unlikely to give rise to any problems in the antenatal diagnosis of Sandhoff's and Tay-Sachs diseases.


Analbuminemia in an American Indian girl. Analbuminemia was fortuitously detected in a nonedematous 12-year-old American Indian girl with atopic dermatitis, mild bronchial asthma, a mild seizure disorder, and hyperlipoproteinemia with a corneal arcus. Immunologic methods revealed trace amounts (17 mg/100 ml) of apparently normal serum albumin. The patient's parents were remotely related. The pedigree and clinical findings were compatible with autosomal recessive transmission of analbuminemia. Heterozygotes had subnormal levels of serum albumin. The Gc-locus is closely linked to the structural albumin locus. Gc-protein levels were normal in the patient and together with normal chromosomal banding studies make it unlikely that a chromosomal deletion caused analbuminemia. Gc-types in the family were compatible with, but did not prove, linkage of analbuminemia to the Gc-locus. These findings suggest a "thalassemia"-like mutation for this disorder.


Cystic fibrosis: a cell culture study on an adult patient population. Skin fibroblast cultures from an adult population of cystic fibrosis (CF) patients have been studied to determine any possible genetic or clinical significance of the two classes described for cultured CF skin fibroblasts (Danes 1973). On the basis of clinical course, the 46 adult patients from 43 unrelated families studied were divided into two groups (40 typical, 6 atypical). The cultured fibroblasts from 37 of the 40 patients with typical CF were Class I (metachromatic, cystic fibrosis factor activity (CFFA) in the culture medium, and metabolic cooperation with normal fibroblasts), and the cultures from the remaining three patients were Class II (ametachromatic, no CFFA in the culture medium and no metabolic cooperation with metachromatic CF fibroblasts). During the 4-year research period one of the 37 patients from Class I and all three Class II patients with typical CF succumbed. The cultured skin fibroblasts from two of the six patients who had an atypical course for CF were Class I and four were Class II. When the parents of three of these atypical CF Class II patients were studied, the cultured fibroblasts from one parent in each family in each family were Class I and the other Class II. The affected offspring from such Class I-II matings may represent genetic compounds.


Mucolipidosis II and III: different residual activity of beta-galactosidase in cultured fibroblasts. A biochemical difference is found between the mucolipidoses II and III which may be correlated with their clinical phenotypes. In homogenates of mass-cultured I-cells from patients with MLII (I-cell disease), the residual specific activity of beta-galactosidase is between 3 and 5 times lower than that in the I-cells from patients with MLIII (pseudopolydystrophy). This difference is confirmed in several coverslip culture experiments where conditions of inoculation, propagation, harvest and enzyme assays are rigidly controlled. MLIII cells also hydrolyse the natural substrates asialofetuin-(H)3-galactoside and GM1- (H)3-galactoside more easily. This observation offers support to the hypothesis that beta-galactosidase may play a role in the physiopathology of these mucolipidoses.


Segregation within a family of two mutant alleles for hexosaminidase A. A healthy adult female was found to have low levels of hexosaminidase A in serum, leukocytes and fibroblasts when these were assayed with artificial substrates. Fibroblast assay with GM2 ganglioside gave values consistent with a Tay-Sachs heterozygote. Studies of this non-Jewish family revealed evidence for segregation of two mutant alleles for hexosaminidase A.


Behavioral treatment of hyperkinetic children. An experimental evaluation of its usefulness. Although drug therapy is helpful in the control of many children with hyperkinesia, alternative and adjunctive therapies are needed also, for a number of reasons: 1) not all of these children improve with medication; 2) the drugs may have adverse physiologic effects which at the least dictate caution in their use; 3) medication alone does not always return responding children to normal functioning; and 4) drug action cannot often be used to help with problems occurring in the children's home setting after school hours. The data here presented suggest strongly that behavior therapy can be effective for hyperkinesia.


The growth and development of low birth weight infants receiving intensive neonatal care. Preliminary observations on 28 such infants. This study reports the growth and development of 28 survivors who had a birth weight of less than or equal to 1,000 g and were cared for at a Regional Neonatal Intensive Care Unit. Only eight (30%) had neurologic abnormalities including spastic hemiparesis, retrolental fibroplasia, hydrocephalus, motor retardation, and some delay in language skills. The other survivors had normal physical examinations and developmental progress judged by a variety of screening examinations up to age four years, three months. The average caloric intake during the first week was 61 kg/da, although over half never reached that level until day 4. Nearly all the infants have had standard growth patterns thus far.


The practical management of vesicoureteral reflux in children. A review of 12 years' experience with 236 patients. Early recognition, adequate treatment, close observation, and systematic follow-up over a long period are essential to renal salvage in the child with vesicoureteral reflux. The decision whether and when to operate is made on a balance of factors by the pediatrician-urologist team. Among 236 patients with reflux diagnosed during childhood, reflux was stopped in 55 per cent of those treated medically and in 98 per cent of the more severe cases who were treated by ureteral reimplantation. Chronic pyelonephritis appeared or worsened during medical management in 12 per cent; no child showed new pyelonephritic scars or worsening of pyelonephritis after ureteral reimplantation.


Disposition of digitoxin in renal failure. The disposition of digitoxin was studied for a period of 8 days in 6 uremic patients given a single oral dose of 1 mg 3H-digitoxin. In plasma, the time-course of radioactivity indicated a diminished absorption velocity of tritium compared to that of control subjects already reported and, after reaching of a pseudostate-equilibrium at 24 hr, an exponential decline with a mean half-life of 8.0 days. In urine, smaller amounts of tritiated compounds were eliminated in uremic patients (8.7% of the dose) than in controls (22.5%). The average fecal excretion of digitoxin and its metabolites was not significantly increased. Chloroform extraction and thin-layer chromatography in plasma, urine and feces suggested no qualitative alteration in the metabolism of digitoxin. Calculations of the total body tritium content (body stores) after each 24-hr interval and its pharmacokinetic behavior showed that the elimination of digitoxin is determined by the transfer constant from tissue to plasma. The differences in elimination kinetics of digitoxin and its metabolites of uremic patients and healthy subjects were not significant.


Observations on the pharmacokinetics of acebutolol. Using a balance, randomized, crossover design, single intravenous (1 mg/kg) or oral (3 X 100 mg) doses of acebutolol were administered at weekly intervals to 6 healthy volunteers. For each subject venous blood samples and timed urine collections were obtained after each treatment. Plasma and urinary acebutolol levels were measured by a spectrophotometric method that measures acebutolol and its N-acetyl metabolite (which has equivalent cardiac activity). Using a computer program, various pharmacokinetic parameters were estimated from the date of each subject. From the intravenous data (obtained up to 6 hr after dosing), the following mean (+/-SD) values were found: distribution half-life (T 1/2D), 0.60 (+/-0.43) hr, plasma elimination half-life (T 1/2El), 3.2 (+/-1.1) hr, apparent volume of distribution (VD), 224 (+/-69) L, and apparent VD/kg, 3.0 (+/-0.8) L/kg. Using the oral data (obtained up to 10 hr after dosing), the value for T 1/2El was 3.2 (+/-0.9) hr. The mean cumulative urinary recovery (expressed as % dose) after the intravenous route was about 60%, while that after the oral route was of the order of 35%, suggesting that about half of the oral dose reached the systemic circulation. The mean creatinine clearance of the 6 subjects was 103 (+/-7) ml/min, while the value (obtained between 2 and 4 hr after intravenous dosing) for renal clearance of acebutolol as measured was 298 (+/-68) ml/min and the corresponding plasma clearance was 818 (+/-64) ml/min. These results support the occurrence of substantial nonrenal elimination and renal tubular secretion.


Plasma protein binding and placental transfer of bupivacaine. The maternal venous and umbilical venous plasma concentrations of bupivacaine were determined at delivery following epidural administration of the drug to 31 women in labor. In each case the umbilical venous plasma concentration of bupivacaine was lower than the maternal venous plasma concentration. There was no significant difference between the concentration of unbound bupivacaine in umbilical venous and maternal venous plasma at delivery. The difference in umbilical and maternal plasma concentrations of bupivacaine appears to be a consequence of greater bupivacaine binding to maternal than to fetal total plasma protein. The intersubject variation of the ratio of bupivacaine concentration in fetal plasma/bupivacaine concentration in maternal plasma was found to be related to individual variation in the extent of protein binding of bupivacaine in maternal and umbilical plasma and correlated positively with the variation of the ratio of total protein concentration in umbilical and maternal plasma.


Pharmacokinetics of methotrimeprazine after single and multiple doses. Concentrations of methotrimeprazine and a metabolite, methotrimeprazine sulfoxide, were measured in plasma after a single intramuscular dose and after single and multiple oral doses of methotrimeprazine. The highest plasma concentrations of methotrimeprazine were found 30 to 90 min after intramuscular injection, and 1 to 3 hr after oral administration. On average 50% of orally administered drug reached the general circulation as unchanged methotrimeprazine. The apparent volume of distribution (Vbeta) was 23 to 42 L/kg body weight, and the biologic half-life, 15 to 30 hr. The sulfoxide could not be traced in plasma after a 25-mg intramuscular dose, but was found in higher plasma concentrations than the unmetabolized drug after single and multiple oral doses. This could be due to oxidation of the drug either in the gastrointestinal lumen or in the intestinal wall, or during its first passage through the liver. The apparent half-life of the sulfoxide was on average 30% shorter than the half-life of methotrimeprazine.


Biliary elimination of diazepam in man.

Biliary elimination of diazepam in man. The metabolism of 14C-5-diazepam has been studied in 5 patients with T tube biliary drainage. A single bolus of 40 to 50 muCi was given intravenously and blood, urine, and bile were analyzed from 5 to 14 days. The mean half-life of elimination from blood was 93.2 hr; the major metabolite noted in blood was N-desmethyl-diazepam. In urine the average recovery of radioactivity was 48.9% and consisted of 3 OH-diazepam, 4'OH-diazepam, and oxazepam. In bile the average recovery of radioactivity was 5.35% (corrected to a bile flow of 700 ml was 15.0%) and consisted of the same metabolites as in the urine. Essentially no diazepam or N-desmethyl-diazepam was found, and therefore an enterohepatic circulation cannot be held to account for the prolonged half-life of these substances in man.


Sodium salicylamide: relative bioavailability and subjective effects. The bioavailability of sodium salicylamide (NaSAM) in solution of salicylamide (SAM) tablets was compared in 6 healthy human volunteers. Bioavailability was assessed by plasma level determinations of nonmetabolized salicylamide (free SAM) and salicylamide plus conjugated metabolites (total SAM) for 3 hr following oral doses of 0.65, 1.30, 1.95, and 2.60 gm of salicylamide. The availability of NaSAM was found to be superior to SAM and dose-dependent. Mean peak levels of free SAM and total SAM were higher and were reached earlier after NaSAM liquid than after SAM tablets. Significantly higher mean levels of free SAM were found at the 1.95 and 2.60 gm dose levels after NaSAM administration than after SAM. Mean total SAM concentration was significantly higher after NaSAM at all dosage levels. The sedative effects of salicylamide were assessed with a self-scoring questionnaire. Sedation seemed to increase with increasing dose of both NaSAM and SAM. The sedative response occurred earlier after NaSAM than after SAM. Side effects were minor and transient in nature, occurred at the higher dosage levels, and were predominantly lightheadedness and dizziness. Because NaSAM produces higher drug levels and has a more rapid onset of subjective effects, we conclude that it represents a potentially superior dosage form.


The effect of arterial oxygen tension on antipyrine half-time in plasma. Hospital patients with depressed arterial oxygen tensions (PaO2) from pulmonary disease were given antipyrine orally or intravenously. The half-time (t1/2) of disappearance from plasma was measured. Other patients with normal PaO2 measurements were treated similarly. Patients whose PaO2 was 55 or below had longer t1/2 times than those of patients with a PaO2 above 55. This observation parallels that made previously in rats.