Pressor response to 1-sar-8-ala-angiotensin II (saralasin) in hypertensive subjects. An angiotensin II (A II) analogue (1-Sar-8-Ala-angiotensin II) (saralasin) was infused into 418 untreated hypertensive subjects during a 1-day evaluation while blood pressure was recorded every 2 minutes by Arteriosonade. At 5 mug/kg per min, saralasin produced a change in mean blood pressure which correlated significantly (r=-0.54, P less than 0.001) with the stimulated plasma renin activity (PRA) (after intravenous furosemide and ambulation for 2 hours. Saralasin caused a rise inmean blood pressure of at least 7.0 mm Hg in 97 hypertensive subjects, who also had a low stimulated PRA (1.3+/-SEM, 0.1 ng/ml per hour; normal range, 1.7-8.5). On a low sodium diet, the pressor response of hypertensive subjects to saralasin continued and was an even better indicator of a low stimulated PRA. Infusion of saralasin at 10 mug/kg per min into normal subjects on an unrestricted diet, a low sodium diet, and a high sodium diet produced, respectively, no change, a fall (P less than 0.05), and a rise (P less than 0.005) in blood pressure. The same saralasin dose in six hypertensive subjects who showed a pressor response to the analogue in the 1-day study also produced a rise in blood pressure when given on a low sodium diet, and this rise was more than twice that seen in normal subjects on a high sodium diet. Hypertensive subjects who showed the pressor response had a significantly greater (P less than 0.01) pressor sensitivity to A II than did hypertensive nonresponders to saralasin and noraml subjects on an uncontrolled diet. The affinity of the vascular receptors for the analogue was greater in the hypertensive group that showed the pressor response to saralasin. In summary, the pressor response to saralasin, as defined above, occurred in 23% of a large unselected group of hypertensive subjects and was associated with salt loading, a low stimulated PRA, and increased pressor sensitivity to A II.


Length-dependent activation: its effect on the length-tension relation in cat ventricular muscle. In cat papillary muscles at 30 degrees C, bathed with Tyrode's solution containing 2.25 mM Ca2+, the effect of various inotropic interventions (varying the stimulus frequency and continual paired stimulation) on the shape of the steady state length-tension relation was examined at lengths from Lmax, where tension production is maximal, to 0.87 Lmax. The relative steepness of the length-tension curves for peak tension developed (DT) and for maximum rate of tension development (dT/dT) varied inversely with the degree of potentiation. Thus, during paired pulse stimulation the relative decline in DT and dT/dT for a given change in muscle length was significantly less than the decline observed during stimulation at 5 min-1. When a muscle was stretched DT did not reach its final steady level for several minutes, and this slow increase in DT contributed significantly to the steepness of the steady state length-tension relation. The half-time of the slow increase in DT exhibited beat-dependency, and conditions that reduce the transsarcolemmal influx of calcium (reduction in bathing [Ca2+] or the presence of verapamil) significantly prolonged the time course of the slow increase and reduced its magnitude. These results support the hypothesis (1) that there is length-dependence of the excitation-contraction coupling process, such that an increase in muscle length is accompanied by greater activation of the contractile system; and (2) that this is due at least in part to an increased influx of calcium into the muscle cells. The implication of this hypothesis is that the influence of muscle length on myocardial performance (the Frank-Starling relation) should not be regarded as fundamentally different in character from other inotropic interventions.


Relative dipolar behavior of the equivalent T wave generator: quantitative comparison with ventricular excitation in the rabbit heart. We studied the relative dipolar and nondipolar content of signal energy throughout ventricular excitation and recovery in 34 isolated, perfused rabbit hearts, suspended in an electrolyte-filled spherical chamber. Computer-processed signals were derived from 20 evenly spaced tank-surface electrodes, and a single, moving, equivalent cardiac dipole generator was optimally fitted to the recorded potentials for each 1-msec sampling interval. Superimposed, time-based plots of signal energy for the 34 preparations showed ventricular excitation to be strikingly more nondipolar than was recovery. In terms of the summed square ratio of nondipolar residual energies, overall nondipolarity of QRS exceed that of ST-T by 41%. Furthermore, the maximum instantaneous ratio during QRS was considerably greater than during the ST-T. Evaluation of paired differences, comparing nondipolar behavior throughout QRS with all of ST-T, proved highly significant (P less than .005). We also found that in contrast to the considerable mobility exhibited by the equivalent QRS dipole, the ST-T dipole locus remained nearly stationary during most of ventricular recovery. Presumably because repolarization is temporally and spatially a relatively diffuse process, it may generate electrical fields which are notably more dipolar than those caused by depolarization.


The renin-angiotensin-aldosterone system in rabbits with congestive heart failure produced by aortic constriction. Severe constriction of the suprarenal abdominal aorta of 3-kg rabbits to 3.7+/-0.2 mm2 and maintenance of a daily sodium intake of 10 mE q by infusion of 0.9% sodium chloride resulted in a progressive increase in central ear arterial pressure to 106+/-3 (SEM) mm Hg (control=79+/-1). This was accompanied by a progressive increase in left ventricular end-diastolic pressure to 22+/-2 mm Hg (control=3+/-1), plasma renin activity to 21+/-5 ng of angiotensin/hour per ml (control=5+/-1), plasma aldosterone concentration to 99+/-23 pg/ml (control=14+/-4), and plasma sodium concentration to 142+/-1 mEq/liter (control=136+/-1). Urinary excretion of sodium decreased to 3.9+/-0.7 mEq/day and marked fluid retention occurred. We also found that these changes were accompanied by a decrease in hematocrit to 24+/-2% (control=40+/-1), formation of 36+/-9 ml of fluid in the thoracic cavity, 33+/-9 ml of ascites, pulmonary congestion and edema, hepatic congestion, and enlargement and hypertrophy of both the left and right ventricles. All rabbits died of ventricular failure at a time that was partly related to the degree of aortic constriction and that ranged from 2 to 12 days. The model we have established is chronic, highly reproducible, easy to produce, and inexpensive, and resembles the clinical syndrome of right and left congestive heart failure in man. Furthermore, the studies provide evidence for an important role of the renin-angiotensin-aldosterone system in the fluid retention that leads to pulmonary and systemic venous congestion after suprarenal aortic constriction.


Influence of a prostaglandin endoperoxide analogue on the canine pulmonary vascular bed. We evaluated the effects of an analogue of the prostaglandin endoperoxide, PGH2, in the canine pulmonary vascular bed. The analogue increased pulmonary arterial pressure whereas cardiac output and left atrial pressure were unchanged. Although pulmonary vascular resistance was increased markedly, only small increases in systemic vascular resistance were observed. In experiments in which blood flow to a lobe was maintained constant, the analogue produced dose-related increases in lobar arterial and small vein pressure but little change in left atrial pressure. These data suggest that the analogue increased resistance to flow by constricting intrapulmonary veins and upstream vessels presumed to be small arteries. The increase in resistance was similar when the lung was perfused with dextran or with blood. In addition, the analogue increased inflation pressure; however, similar increments in vascular resistance were obtained in ventilated and nonventilated lung lobes. Indomethacin, in doses which abolished responses to arachidonic acid, did not attenuate the response to the analogue. These results suggest that interaction with formed elements, increases in airway tone, or stimulation of prostaglandin synthesis contribute little if anything to the pressor response to the analogue. These data show that the analogue is far more potent than the bisenoic prostaglandins in the pulmonary vascular bed and suggest that endoperoxides may represent an active form of the prostaglandins in the lung.


The diastolic viscous properties of cat papillary muscle. The measurement of ventricular diastolic compliance is complicated by the presence of viscous properties. To approach this problem, cat papillary muscles contracting isometrically at 15/min at 26 degrees C were stretched at different velocities during diastole. At a given length there was no excess of force above that defined by the static force-length curve until velocity of stretch exceeded 1 muscle length/sec. At greater velocities of stretch there was an increase of force with increasing velocity of stretch denoting viscous resistance to stretch. The viscous characteristic was alinear and increased with muscle length. At a given muscle length potentiation of contractile state by paired pulse stimulation caused a change in the diastolic force-length curve but there was no apparent relationship between viscous resistance to stretch and contractile state or the length of the "series viscous element." These results lead one to expect viscous resistance to stretch during rapid filling of the intact left ventricle.


Mechanism of renin release during acute ureteral constriction in dogs. The relationship between renal arterial pressure and renin release was examined in anesthetized dogs during complete or partial ureteral constriction. During complete ureteral occlusion ureteral pressure rose to 95+/-4 mm Hg and renin release increased from 1.7+/-0.7 to 22.3+/-3.1 mug/min; renal blood flow (RBF) was not significantly changed. Renin release was not further increased during subsequent renal arterial constriction; RBF fell in proportion to perfusion pressure, indicating maximum autoregulated arteriolar dilation. During partial ureteral constriction to a ureteral pressure of 65+/-6 mm Hg, renin release was moderately raised but release mechanisms became fully stimulated when renal arterial pressure was reduced to 104+/-3 mm Hg. By further constricted of the renal artery, RBF fell in proportion to perfusion pressure and renin release remained high and constant. In control experiments without ureteral constriction, renal arterial pressure had to be reduced to below 65+/-8 mm Hg to fully stimulate renin release (22.0+/-3.8 mug/ml which is not different from 22.3+/-3.1 mug/min during ureteral occlusion). During partial ureteral constriction, saline infusion (0.9% NaCl at 40 ml/min) raised urine flow, sodium excretion, renal pelvic pressure, and renin release. Thus, the stimulatory effect on renin release of a rise in ureteral pressure exceeded the inhibitory effect of increased sodium excretion. This observation, together with maximum renin release coinciding with complete arteriolar dilation during various combinations of renal arterial and ureteral constriction, is compatible with the conclusion that arteriolar dilation is predominating stimulus to renin release during ureteral constriction.


Role of the thyroid gland in the development and maintenance of spontaneous hypertension in rats. We studied the vascular mechanisms involved  in the prevention of the development of hypertension following thyroidectomy. Ablation of the thyroid gland of 4-week-old spontaneously hypertensive (SH) rats inhibited the development of hypertension and reduced the sensitivity of aortic strips to the vasoconstrictors phenylephrine, norepinephrine, and potassium chloride and the vasodilator isoproterenol. Daily injections of a replacement dose of L-thyroxine caused a complete recurrence of hypertension in these rats. This was accompanied by complete recovery of the aortic sensitivity to the vasconstrictors and isoproterenol. In 10-week-old SH rats thyroidectomy prevented a further increase of blood pressure but did not reverse the hypertention. Here, the aortic sensitivity to vasoactive substances also was reduced but to a lesser extent than in the SH rats thyroidectomized at 4 weeks of age. Hypertension was not obviously associated with hyperfunction of the thyroid gland. Furthermore, we found that at 4 weeks of age, during the prehypertensive period, SH rats have a significantly lower (42%) serum thyroxine level than age-matched normotensive Kyoto Wistar, American Wistar, and Sprague-Dawley rats. However, at 6 and 9 weeks, the serum thyroxine levels of SH rats are similar to those of the normotensive rats. In conclusion, we propose that the reduced sensitivity to endogenous vasoconstrictors in arteries of SH rats following juvenile ablation of the thyroid gland may prevent the development of hypertension in these rats. Moreover, the low serum thyroxine level in SH rats during the prehypertensive period may explain why young SH rats do not develop hypertension before 6 weeks of age.


Prostaglandins and the control of blood flow in the canine myocardium. A comprehensive study was undertaken to evaluate the effects of inhibition of prostaglandin (PG) synthesis on a variety of reactions in the coronary vascular bed of anesthetized, open-chest dogs. In 23 dogs an electromagnetic flow probe (EMFP) and hydraulic occluder were placed around either the left anterior descending or circumflex branches of the coronary artery and a needle was inserted distral to the EMFP. Injections into the coronary artery of arachidonic acid (AA), bradykinin, adenosine, angiotensin, and PGE2 were given before and after inhibition of PG synthesis by indomethacin (IND) or meclofenamate (MF). The effects of the inhibitors on reactive hyperemia resulting from 5-, 10-, 15-, and 20-second occlusions and the dilation resulting from 90-second exposure to 8% O2 were also examined. In each experiment, inhibition of PG synthesis was ascertained by the elimination of vasodilation to AA. After administration of IND or MF, while baseline coronary blood flow was slightly reduced, the total increment of blood flow to vasodilator agents was not significantly altered. Whereas the peak dilation and volume of reactive hyperemia were decreased, the percent flow debt repaid was unchanged and total increment of coronary flow due to hypoxia-induced vasodilation was not significantly modified. Vasoconstrictor responses to angiotensin were also unchanged. These results indicate that while inhibitors of PG synthesis increase coronary resistance, they do not adversely affect vascular responsiveness. We conclude that prostaglandins play little, if any, role in modulating coronary blood flow.


The relationship between enzymatic and histologic estimates of the extent of myocardial infarction in conscious dogs with permanent coronary occlusion. Relationships between enzyme estimates (EE) and histologic measurements of infarct size (HIS) were analyzed in 14 conscious dogs with permanent occlusion of the circumflex coronary artery. EE were derived from serial CPK, CPK-MM, CPK-MB, and CPK-BB. Estimates were obtained using methods of Shell et al., Norris et al., and Roberts et al. HIS was determined from multiple histologic sections 5-6 days after infarction. In 14 animals, HIS ranged from 0.1-26.6 grams. Regression analysis demonstrated poor correlation (r2 less than 0.06) between EE by each method and HIS. Using the Shell method and restricting the analysis to HIS of less than 13 grams, improved the correlation (r2 = 0.42). Correlation in this subgroup could be further improved by using CPK-MM and MB data, elimination of animals with high background values, or limiting analysis to the portion of the curve where LDH isoenzymes indicated a cardiac zone. When the analysis was restricted to animals with HIS of less than 13 grams, Norris and Roberts modifications as compared to Shell's method improved correlation with CPK-MB but reduced correlation using CPK and CPK-MM data. In this subgroup, each method overestimated extent of HIS; Shell greater than Norris greater than Roberts. In this study it was not possible to distinguish small from large HIS by serum enzyme measurements.


The effect of "ischemic" blood on transmembrane potentials of normal porcine ventricular myocardium. "Ischemic" blood was obtained in pigs from a local coronary vein on release of coronary artery occlusion. The effects of this blood on transmembrane potentials of muscle strips taken from the same heart were compared with control blood. Whereas action potentials remained stable in control blood, ischemic blood collected after more than 15 minutes of coronary occlusion produced shortening of action potential duration, reduction of resting potential, upstroke velocity and amplitude, then postrepolarization refractoriness and finally unresponsiveness. Ischemic blood collected after shorter periods of coronary occlusion produced only mild effects (shortening of action potential and postrepolarization refractoriness). These effects of ischemic blood could not be attributed to increased potassium concentration even in combination with acidosis, hypoxia and hypoglycemia. It appears that during ischemia unidentified factors are released which have potent depressant effects on the excitability of even normal myocardium.


Cryosurgical ablation of the A-V node-His bundle: a new method for producing A-V block. A cryosurgical instrument was used to ablate atrioventricular conduction. The procedure was carried out in 20 dogs and subsequently in three patients with drug resistant, life-threatening supraventricular tachycardias. In patients, the cryosurgical unit lowered the temperature of the His bundle area to 0 degrees C, effecting complete but reversible heart block. Rewarming resulted in resumption of normal atrioventricular conduction. The His bundle region then was cooled to -60 degrees C; complete heart block was produced with two or more 90-120 second freezes. Postoperative evaluations revealed persistent atrioventricular conduction block. The lesion showed no tendency to rupture, form aneurysm, or interfere with valvular function. In the clinical cases, postoperative studies demonstrated a stable pacemaker arising proximal to the branching portion of the His bundle. A potential application of the cryosurgical technique might be ablation of sites of dysrhythmia (i.e., ectopic foci, re-entry circuits, accessory pathways).


Cryosurgical ablation of accessory atrioventricular connections: a method for correction of the pre-excitation syndrome. Cryothermia, a new technique for definitive treatment of the pre-excitation syndrome, is described in two patients. The first patient presented with a normal P-R interval with a delta wave and reciprocating tachycardia. Preoperative electrophysiologic study suggested a free-wall atrioventricular connection on the left posterior atrioventricular (A-V) groove. At surgery, epicardial mapping confirmed the site of pre-excitation on the posterior left ventricular (LV) wall. An electrogram arising from the accessory pathway (AP) was recorded at the site of earliest ventricular activation. Interatrial delay combined with an apparently long accessory pathway to the ventricle caused the P-R interval to appear normal. Local pressure abolished pre-excitation. The site of early ventricular activation was cooled to -60 degrees C with a specially designed cryoprobe. All evidence of pre-excitation and arrhythmias disappeared. The second patient presented with a refractory reciprocating tachycardia and was found to have an AP in the septum capable of only retrograde conduction. Retrograde conduction was abolished by applying a temperature of 0 degrees C to the anulus at this site during tachycardia. Conduction over the AP and reciprocating tachycardia returned with rewarming. Ablation of the AP was obtained by applying a temperature of -60 degrees C for 90 seconds on two occasions to the same area. The His bundle was not injured.


Prevalence and characteristics of disproportionate ventricular septal thickening in patients with acquired or congenital heart diseases: echocardiographic and morphologic findings. Echocardiographic and necropsy studies were performed in 304 patients with various cardiac diseases. The overall prevalence of disproportionate ventricular septal thickening (septal to free wall ratio greater than or equal to 1.3) was 10%. However, it was related to the type of cardiac lesion. Prevalence was high (greater than 20%) in pulmonary stenosis or primary pulmonary hypertension, lower (less than 15%) in Eisenmenger syndrome or aortic or mitral valvular disease and was not present in atrial or ventricular septal defect. In right ventricular overload, prevalence of disproportionate septal thickening correlated with increasing ventricular systolic pressure. None of 16 patients with disproportionate septal thickening studied at necropsy showed marked disorientation of cardiac muscle cells in the ventricular septum, characteristic of genetically transmitted asymmetric septal hypertrophy (ASH). Furthermore, disproportionate septal thickening was demonstrated by echocardiography in only one of 59 first degree relatives of patients with disproportionate septal thickening and associated cardiac diseases. Thus, disproportionate ventricular septal thickening associated with other cardiac diseases usually is due to secondary hypertrophy and is not a manifestation of genetically transmitted ASH.


Reproducibility of thallium-201 myocardial imaging. Seventy-six thallium-201 myocardial perfusion studies were performed on twenty-five patients to assess their reproducibility and the effect ofvarying the level of exercise on the results of imaging. Each patient had a thallium-201 study at rest. Fourteen patients had studies on two occasions at maximum exercise, and twelve patients had studies both at light and at maximum exercise. Of 70 segments in the 14 patients assessed on each of two maximum exercise tests, 64 (91%) were reproducible. Only 53% (16/30) of the ischemic defects present at maximum exercise were seen in the light exercise study in the 12 patients assessed at two levels of exercise. Correlation of perfusion defects with arteriographically proven significant coronary stenosis was good for the left anterior descending and right coronary arteries, but not as good for circumflex artery disease. Thallium-201 myocardial imaging at maximum exercise is reproducible within acceptable limits, but careful attention to exercise technique is essential for valid comparative studies.


Contrast echocardiography in single or common ventricle. Common ventricle is a rare congenital anomaly in which the ventricular chamber receives blood from two separate atrioventricular valves or from a common atrioventricular valve. We used contrast echocardiography during cardiac catheterization to confirm ventricular anatomy and to characterize blood flow dynamics in 35 patients with common ventricle. After injections of dye, a cloud of echoes anterior to the mitral valve echo during the rapid inflow phase of ventricular diastole is indirect evidence of common ventricle with two atrioventricular valves. Common ventricle with an outflow chamber is characterized by a smaller ventricular chamber visualized anterior to both atrioventricular valves which opacifies with subsequent ventricular systole. The arrival of all dye posterior to the only recorded atrioventricular valve further established the presence of a single atrioventricular valve. These contrast flow patterns gave greater specificity to the standard M-mode echocardiographic assessment of patients suspected of having common ventricle.


Hemodynamic effects of dobutamine in patients following open heart surgery. Dobutamine, a new synthetic inotropic agent, was administered by intravenous infusion to 22 patients following open heart surgery. The dosage of dobutamine started from 2 mug/kg/min and was increased stepwise to 4, 6, and 8 mug/kg/min. Cardiac index increased from 2.54 +/- 0.13 to 3.11 +/- 0.19 and 3.50 +/- 0.22 L/min/m2 with 4 and 8 mug/kg/min, respectively. Heart rate increased from 87.6 +/- 2.9 to 96.4 +/- 2.3 and 108.9 +/- 3.2 beats/min with 4 and 8 mug/kg/min, respectively. Systolic and mean aortic pressure and systolic pulmonary arterial pressure were elevated from 126.0 +/- 3.8 to 144.6 +/- 6.0 mm Hg, from 91.8 +/- 2.7 to 96.2 +/- 3.2 mm Hg, and from 33.4 +/- 2.3 to 37.1 +/- 2.5 mm Hg with 8 mug/kg/min, while other pressures were unchanged. Mean left atrial pressure fell significantly from 15.9 +/- 0.6 to 14.8 +/- 0.7 mm Hg. Stroke volume index, stroke work index, and left ventricular work also increased. Premature ventricular beats were observed in only one patient during dobutamine infusion, but no other side effect was observed. We conclude that dobutamine is a potent inotropic agent which increases cardiac output without causing significant tachycardia or arrhythmias, and is useful for the treatment of patients following open heart surgery.


Physiologic evaluation of a new antihypertensive agent: prazosin HCl. The mechanism of action of prazosin hydrochloride, a new antihypertensive agent was studied in 14 patients with essential hypertension. Mean supine blood pressure for the group fell from 148/102 +/- 3/2 (SE) mm Hg at baseline to 139/91 +/- 5/4 after eight weeks of therapy (P less than 0.05). No significant postural hypotension was noted in the patients who responded to therapy. Glomerular filtration rate (endogenous creatinine or inulin clearance) and effective renal plasma flow (PAH clearance) remained unchanged during therapy as did supine and stimulated peripheral plasma renin activity. Cardiac output did not change significantly although plasma volume increased in ten out of 12 patients in whom it was measured (P less than 0.025). Among the patients whose mean blood pressure fell 10 mm Hg or more, peripheral vascular resistance fell significantly (P less than 0.025), and the change in plasma volume was not statistically significant. Among the patients whose mean blood pressure changed less than 10 mm Hg with therapy, there was no significant change in peripheral vascular resistance and plasma volume increased significantly (P less than 0.025). Prazosin hydrochloride appears to be an effective antihypertensive agent which acts by peripheral vasodilatation. It may cause fluid retention. The drug does not appear to affect renal function or renin secretion.


The effect of jejunoileal bypass on the pharmacokinetics of digoxin in man. Seven subjects who underwent jejunoileal bypass surgery for massive obesity participated in a study to examine the relative bioavailability of digoxin before and one to two months after surgery. They were given a loading dose of 1 mg digoxin in divided oral doses followed by oral maintenance doses of 0.5 mg daily. There were no significant differences in the area under the serum concentration time curve, steady state serum levels or 24 hour steady state excretion of digoxin before and after surgery. We conclude that the bioavailability of digoxin from the Lanoxin tablets employed is not impaired in these patients, although urinary d-xylose and 24 hour fecal fat excretion indicated moderate to severe malabsorption after surgery.


Experience with bretylium tosylate by a hospital cardiac arrest team. The effect of bretylium tosylate (BT) was determined in 27 consecutive cases of resistant ventricular fibrillation (VF) encountered by a hospital cardiac arrest team. The VF was sustained and completely resistant to multiple injections of lidocaine, sequential DC shocks at 400 watt-sec and one or a combination of intravenous propranolol, diphenylhydantoin or procainamide. Following 30 min of sustained cardiac massage, BT (5 mg/kg i.v.) was administered. In 20 patients, VF was terminated within 9-12 min after DC shock. Eight of these patients failed to recover while 12 (44%) of all patients resuscitated survived to be discharged from hospital. Eleven out of 20 (55%) of all patients who had a cardiac arrest outside the CCU were survivors; only one out of seven in the CCU were successfully resuscitated. While receiving maintanance BT post-resuscitation (5 mg/kg i.m. q 8-12 hrs x 48 hrs), half the patients developed hypotension and three required vasopressors and/or fluid replacement. The data indicate that BT is a useful agent in patients with sustained VF refractory to repeated lidocaine injections, some other antiarrhythmic agents, and multiple DC shocks.


Asymptomatic left ventricular aneurysm: a sequela of blunt chest trauma. A routine chest X-ray taken four months after blunt chest trauma revealed a left ventricular aneurysm in a totally asymptomatic patient. At surgery a thin-walled, clot-filled aneurysm was successfully removed. This case demonstrates the need for careful follow-up of all patients sustaining blunt chest trauma even though the initial cardiac evaluation may be negative. Our feeling that all such aneurysms should be treated surgically is further reinforced by our operative findings.


Fluoroscope-generated electromagnetic interference in an external demand pacemaker: report of a case. Electromagnetic interference presented as inhibition and resetting of the demand circuitry of a ventricular-inhibited temporary external pacemaker in a 70-year-old man undergoing surgical implantation of a permanent bipolar pacemaker generator and lead. The arrhythmia was found to be due to oversensing of waveforms modulated to simulate myocardial potentials emitted by a faulty fluoroscopy unit used in the vicinity of external temporary transvenous pacing equipment. The documentation of this disruption of pacemaker rhythm reinforces the need for continuous monitoring of patients treated with external demand pacemakers and for the careful maintenance of all electrical equipment.


Coronary arterial origin in persistent truncus arteriosus. Specimens of heart from 30 subjects with persistent truncus arteriosus were studied for the nature and sites of coronary arterial origin. These factors were related to the sinuses of the truncus valve. Bicuspid truncal valve was observed in six cases (20%) and tricuspid in 21 cases (70%). Single coronary artery was observed in four cases (three with tricuspid and one with quadricuspid truncal valves). In three other cases the coronary arteries arose separately but near one another. There was a strong tendency for the left coronary artery to arise from a more posterior level than it does normally from the aorta. It was common for the posterior descending artery to arise from the left circumflex artery. This arrangement was noted in eight of 25 cases (32%) with single posterior descending coronary artery. In five other cases, two posterior descending arteries were present, one arising from the left circumflex and the other from the right coronary artery.


Aschoff bodies in operatively excised atrial appendages and in papillary muscles. Frequency and clinical significance. Among 481 patients undergoing various mitral valve operations, Aschoff bodies were found in 40 (21%) of 191 operatively excised left atrial appendages, in four (2%) of 273 operatively excised left ventricular papillary muscles (1 per patient), and in one (6%) of 17 patients with both left atrial appendage and papillary muscle operatively excised. Of the total of 45 patients with Aschoff bodies, 44 preoperatively had mitral stenosis, and only one, a 10-year-old boy, had pure mitral regurgitation. Sinus rhythm was present in 38 (84%), and atrial fibrillation in seven (16%). Perioperatively, only one of the 45 patients with Aschoff bodies had clinical or laboratory stigmata compatible with acute rhematic fever, and 58% had an illness compatible with acute rheumatic fever at any time.


Characteristics of sinoatrial conduction in patients with coronary artery disease. Electrophysiologic studies were performed in 32 patients with angiographically documented coronary artery disease (CAD). Group I was composed of ten patients (31%) with severe stenosis (greater than or equal to 75%) proximal to the origin of the sinus node artery (SNA); group II was composed of five patients (16%) with moderate (50--75%) proximal stenosis; and group III was composed of 17 patients (53%) with insignificant (0--50%) proximal stenosis. The mean sinoatrial conduction time (SACT) for group I was 119 +/- 18 msec; group II was 84+/- 16 msec; and group III was 72 +/- 5 msec. The SACT was significantly longer in group I than in group III (P less than 0.005). In conclusion 1) in patients with CAD, SACT greater than 72 +/- 5 msec is abnormal; 2) the results suggest a pathogenetic role of CAD in the development of sinus node dysfunction; 3) the SACT is a more sensitive indicator of subtle sinus node dysfunction in CAD patients than is heart rate, sinus node response to artrial extrastimuli, or sinus node recovery time; and 4) the ability to diagnose sinus node dysfunction in its early stages and recognition that coronary artery disease is an etiologic factor may allow for the elucidation of the natural history of the sick sinus syndrome.


Alternans of the ST segment in Prinzmetal's angina. Alternans of the elevated ST segment (STEA) was found in 8 of 21 patients (38%) with Prinzmetal's variant angina. In addition to STEA, all eight patients had varying cardiac arrhythmias: multiple premature ventricular depolarizations in eight, ventricular tachycardia in five, and ventricular fibrillation in three. There was no consistent temporal relationship between the occurrence of STEA and the cardiac arrhythmias. Alternans occurred during periods when no arrhythmias were present. All eight patients underwent coronary angiography. Spontaneous coronary artery spasm was documented angiographically in three patients including two who had minimal or no coronary atherosclerotic disease. Six patients had severe, fixed, occlusive coronary artery disease. Possible mechanisms for STEA include: 1) failure of regions of myocardium to depolarize on alternate beats due to variation in conduction and refractoriness between ischemic and nonischemic zones of myocardium, and 2) electrical alternans of the transmembrane action potential during phase 2 and 3 (repolarization) caused by changes in the rate and extent of electrolyte transfer across cell membranes during ischemia. It is postulated that STEA is an electrocardiographic sign in the surface ECG of a dysequilibrium of refractory periods during ischemia and reflects an unstable electrical state of the myocardium.


The nature and clinical features of myocardial infarction with normal coronary arteriogram. Six new cases of acute myocardial infarction with normal coronary arteriogram are presented and supplemented by 19 collected cases (group I). These are compared with 16 cases of myocardial infarction caused by occlusive coronary artery disease in a comparable population (group ii). The following significant differences between the two groups are established: patients in group I were younger (27.5 years vs 33.7 years, P less than 0.005); at least one risk factor was present in all patients in group II, but in only 40% of group I (P less than 0.0001). effort angina preceded the attack in ten patients of group II, but in none of group I (P less than 0.0001). The attack was unheralded in 24 of the 25 patients in group I, but was preceded by prodromes in 11 of 16 in group II (P less than 0.0001). Attacks of pain following myocardial infarction occurred in five patients of group 2 and II of group II) (P less than 0.001). Results are discussed in the light of the nature of myocardial infarction in group I. No support is found for the coronary spasm theory. The most likely mechanism for development of myocardial infarction in group I is thought to be a thromboembolic "accident." This accident is not necessarily related to atherosclerotic coronary disease and is presumed to be benign in nature.


Effect of the calcium antagonist verapamil on necrosis following temporary coronary artery occlusion in dogs. Calcium metabolism may play an important role in the pathogenesis of myocardial ischemic injury. The effect of the sarcolemmal calcium flux inhibitor, verapamil, on myocardial necrosis was studied in dogs subjected to temporary coronary artery occlusion. One group of dogs was untreated. A second group was given 0.8 mg/kg verapamil intravenously over a 30 min period beginning 10 min prior to coronary occlusion. In a third group, the dose of verapamil was increased until complicated by hypotension or conduction abnormalities. Cardiac necrosis was produced in all dogs by 40 min of left circumflex coronary artery occlusion followed by 2--4 days of reperfusion. At the end of the experiment, animals were sacrificed and necrosis was quantitated histologically in transmural slices through the posterior papillary muscle. Pre-treatment with the lower dose of verapamil resulted in significantly less necrosis (14% treated vs 35% untreated) with minimal hemodynamic consequences. Higher does of verapamil were even more effective in limiting cardiac necrosis despite the development of hypotension and varying degrees of heart block.


Inability of methylprednisolone sodium succinate to decrease infarct size or preserve enzyme activity measured 24 hours after coronary occlusion in the dog. Methylprednisolone sodium succinate (50 mg/kg) was given 30 minutes before or after the start of a 90 minute occlusion of the left circumflex coronary artery (LCX) in one group of dogs. In a second group, methylprednisolone sodium succinate was given 15 minutes after permanent occlusion of the left anterior descending artery (LAD). Infarct size was determined by dehydrogenase staining after 24 or 96 hours. Heart slices were incubated with nitro-blue tetrazolium and nonstaining infarcted tissue was dissected and weighed. Myocardial depletion of creatine phosphokinase activity (CPK) and lactate dehydrogenase activity (LDH) were determined 24 hours after temporary LCX occlusion. When measured after 24 hours, methylprednisolone sodium succinate treatment did not reduce infarct size or decrease enzyme loss. After temporary LCX occlusion infarct size was 30.4 +/- 3.6% of left ventricular weight in control dogs and 30.0 +/- 2.3% in treated dogs. No significant difference in infarct size was observed in hearts examined 24 or 96 hours after myocardial infarction. After permanent LAD occlusion, infarct size in control dogs was 39.2 +/- 1.6% of left ventricular weight and 33.7 +/- 3.5% in treated dogs. CPK activity in the LCX area decreased by 26.5 +/- 7% in controls and by 28.1% +/- 7% in treated dogs. Treated dogs sustained a significantly greater fall in arterial blood pressure after LCX occlusion than did controls. During LCX occlusion and upon reperfusion, methylprednisolone sodium succinate treated dogs exhibited a significantly greater number of premature ventricular beats. Since infarct size and enzyme depletion were not reduced when measured after 24 hours, methylprednisolone sodium succinate treatment does not appear to have enhanced myocardial cell viability.


The effect of the Valsalva maneuver on echocardiographic dimensions in man. Physiologic changes in the circulatory system caused by performing the Valsalva maneuver are blunted or absent in patients with congestive heart failure. Previously there has been no noninvasive method for examining cardiac chamber size during this maneuver. M-mode echocardiography was used to evaluate possible changes in cardiac chamber dimensions in 12 normal subjects (group I) and 15 patients with cardiovascular disease (group II). In group I, the left ventricular end-diastolic dimension decreased 11.2% (+/- 1.5%) and the end-systolic dimension 9.5% (+/- 1.32%), with a fall in stroke volume of 29%. The left atrial (LA) dimension decreased 30%. In group II, only the response of the LA dimension is reported. There was a diminished response to Valsalva related to the severity of congestive heart failure. Patients in NYHA classes III and IV decreased LA dimension by only 3.8%, significantly less (P less than 0.001) than those in classes I and II who had essentially normal responses. Echocardiographically-determined changes in left atrial size in response to the Valsalva maneuver may provide an objective, noninvasive means of evaluating and following patients with suspected or proven congestive heart failure. Possible mechanisms for the changes observed are discussed.


Intracardiac pressure-sound correlates of echographic aortic valve closure. Echographic aortic valve closure was compared to the dicrotic notch of the aortic pressure and intracardiac A2 to define the exact temporal relationship of the echographic, pressure, and sound parameters of aortic valve closure. Sixteen children, ages 3--20 years, were evaluated by simultaneous aortic valve echograms, micromanometric aortic root pressure tracings, and intracardiac phonocardiograms recorded at paper speeds of 200 mm/sec. Our observations demonstrated that echographic coaptation of the aortic valve leaflets coincides with the trough of the aortic pressure incisura and the onset of A2. The data suggest that A2 is a result of valve closure.


Suprasternal notch echocardiography. Assessment of its clinical utility in pediatric cardiology. Echocardiographic suprasternal relationships of the transverse aortic arch (TAA), right pulmonary artery (RPA) and left atrium (Y' LAD) were validated and angiographic-echocardiographic measurement correlations were made for each structure. Normal values were determined with respect to body surface area. In normals, regardless of age or body size, mean dimensional TAA/RPA ratio was 1.2:1 and Y' LAD equaled the anterior-posterior, or Z axis, left atrial dimension (Z LAD)- TAA/RPA ratio was increased in aortic stenosis and tetralogy of Fallot and was decreased in ventricular septal defect, atrial septal defect and pulmonary stenosis. Ratio did not correlate with lesions severity as assessed by cardiac catheterization except in pulmonary stenosis. Discrepant Y' LAD values (usually increased Y' LAD and decreased Z LAD) occurred in children with various forms of heart disease. Some had sternal compression but others had normal chests. Children with pectus excavatum showed similar compression. These findings underscore the need for incorporation of a suprasternal examination into the standard echocardiographic examination of children.


Echocardiographic, angiocardiographic, and surgical correlations in right ventricular myxoma simulating valvar pulmonic stenosis. The echocardiographic, angiographic and surgical correlations in a patients with a right ventricular myxoma simulating valvar pulmonic stenosis are presented. A dense mass of echoes was seen in the body of the right ventricle in diastole; in the right ventricular outflow tract throughout the cardiac cycle; and within the pulmonic valve in systole. These echocardiographic findings suggested the presence of a mass high in the right ventricle, which moved throught the pulmonic valve in systole. This impression was confirmed by angiography and surgery. A 53 mmHg gradient across the pulmonic valve was noted at cardiac catheterization. At operation a myxoma which originated above the crista supraventricularis was found. The tumor moved into the main pulmonary artery in systole. Surgical removal of the tumor resulted in the disappearance of the abnormal echoes.


Echocardiographic observations on the association between mitral valve prolapse and asymmetric septal hypertrophy. One hundred and ninety consecutive patients with mitral valve prolapse (MVP) were studied by echocardiography. Asymmetric septal hypertrophy (ASH) was noted in 16 patients. Three patients had syncope which was associated with supraventricular arrhythmias. Three others had episodes of presyncope which were not related to rhythm disturbances. One of the patients with MVP and ASH had a family history of idiopathic hypertrophic subaortic stenosis. The septal thickness ranged from 1.6 to 3.1 cm, mean = 2 cm. The posterior wall thickness ranged from 0.7 to 2.1 cm, mean = 1.0 cm. The ratio of the thickness of the interventricular septum to that of the posterior wall ranged from 1.5 to 2.5, mean = 1.9. The percentage of thickening of the septum in systole was reduced in 13 patients. The excursion of the interventricular septum was reduced in three patients. In nine patients the left ventricular end-systolic dimension was below the lower limit of normal. Percentage fractional shortening of the left ventricle was increased in eight patients. Since MVP predisposes to cardiac arrhythmias which are poorly toletated in the setting of ventricular hypertrophy and reduced left ventricular compliance, the recognition of this combination of MVP and ASH is of clinical importance.


Phonoangiography by autocorrelation.

Phonoangiography by autocorrelation. Phonoangiography, as a noninvasive quantitative analysis of arterial bruits, was conducted just prior to standard invasive radiographic angiography in 135 patients. Sound records from 162 carotid arteries were analyzed with a new processing technique employing a high speed analog acoustic analyzer, the autocorrelator. In 18 arteries with carotid stenosis, a correlation coefficient of 0.87 resulted between phonoangiographic diameter predictions and radiographic diameter estimates. Bruit analysis identified two patients with patent lumen diameters, but tortuous carotid vessels. One hundred thirty-three carotid arteries had no bruits that could be analyzed, but angiograms showed no extracranial stenosis. Four arteries from which bruits could not be analyzed were found to be totally occluded. Carotid phonoangiography appears applicable in approximately one of seven patients now requiring angiography of head and neck vessels. When applicable, phonoangiography is significantly correlated with angiographic findings.


The role of the QT interval in the sudden infant death syndrome. To evaluate the role of QT interval prolongation in the genesis of the sudden infant death syndrome (SIDS), the post-resuscitation electrocardiograms of 21 aborted SIDS infants were reviewed. The infants had been found apneic, cyanotic, limp and unresponsive during sleep and required vigorous physical stimulation and mouth-to-mouth resuscitation. Three subsequently experienced repeat similar episodes from which they could not be resuscitated. Extensive studies eliminated all "known" etiologies for death. The QT intervals of these infants were compared to age and sex matched normal infants as well as to established normal values in the literature; in both the aborted and the subsequent actual SIDS infants, the QT intervals were not significantly different from those of the normal population. Thus, we conclude that QT intervals prolongation does not play a major role in the genesis of the aborted SIDS.


Early and late results of surgical repair of truncus arteriosus. Ninety-two patients had corrective operation for truncus arteriosus between 1967 and 1975. During the first 30 days after surgery, 23 patients died. No significant differences appear between early mortality and sex, type of truncus, variations in pulmonary arterial anatomy, truncal valve regurgitation, associated anomalies, previous operation, or duration of extracorporeal circulation. Greater risk is probably encountered with the higher but still operable levels of pulmonary resistance. Reoperation has been required in three patients. Fifty-nine percent of survivors are symptom-free, with all but two of the remainder (38%) being in NYHA functional class II. The late result is suggestively less satisfactory in patients with significant preoperative truncal valve regurgitation. Some late complications related to deterioration of the earlier aortic homograft conduit may be avoided by use of a porcine valve Dacron conduit. The current operative mortality of 9%, and the well-being of 97% of surviving patients suggest the continued advisability of recommending operation for appropriate patients.


Truncus arteriosus with unilateral absence of a pulmonary artery. Criteria for operability and surgical results. In 15 of 126 (12%) patients with truncus arteriosus who were catheterized at the Mayo Clinic from 1967 through 1975, natural agenesis of one pulmonary artery was present. Ten truncus patients with either natural or acquired absence of one pulmonary artery have undergone definitive operation. The criteria for operability, based on a calculation of pulmonary resistance, are different in patients with single pulmonary artery than in patients with two pulmonary arteries. Study revealed that, if the calculated pulmonary resistance in the patient with single pulmonary artery is halved, this new value provides a more reliable assessment of the reactivity of the pulmonary arteriolar bed than does the total calculated pulmonary resistance value. Follow-up information suggests that the patient with single pulmonary artery may be at potentially high risk of continued progression of pulmonary vascular disease after surgical correction, possibly because of the postoperative obligatory increased flow through the single pulmonary arteriolar bed as a result of the entire cardiac output passing through it. Surgical correction of truncus arteriosus during infancy, before significant pulmonary vascular disease has developed, appears to be particularly desirable in this subgroup of patients with single pulmonary artery.


Myocardial metabolism in cyanotic congenital heart disease studied by arteriovenous differences of lactate, phosphate, and potassium at rest and during atrial pacing. To study myocardial metabolism in chronic hypoxia due to cyanotic congenital heart disease, coronary arteriovenous differences of lactate (L), pyruvate (P), inorganic phosphate (Pi) and potassium (K) were measured in 14 cyanotic patients and seven controls, at rest and during atrial pacing. At rest, there was no difference in any parameter between cyanotic and noncyanotic patients. During atrial pacing (150-175/min) for 10 min, a moderate drop in L-extraction occurred in the control patients with some increase in L/P ratio in coronary venous blood. Cyanotic patients fell into two groups: in nine (group I), the arterial oxygen saturation (SaO2) dropped with pacing. Their L-extraction fell sharply, from 28.1 +/- 3.12 to --2.8 5.51 and L production occurred in five. There was a significance increase in coronary venous L/P ratio. Five cyanotic patients (group II) showed no drop in SaO2 with pacing, and L extraction as well as L/P ratio remained stable. Uptake of Pi was noted in all patients at rest, during pacing this disappeared in controls and group I cyanotics but not in group II. No K changes were seen in any patient. Thus, myocardial metabolism is normal at rest in patients with cyanotic CHD; during atrial pacing, a shift toward anaerobic metabolism occurs if SaO2 drops; cyanotic patients whose SaO2 remains stable appear to withstand pacing better than controls.


Platelet survival time in patients with hypoxemia and pulmonary hypertension. Platelet survival time (autologous labeling with 51chromium) was measured in 63 patients in order to evaluate the role of platelets in the thromboembolic complications of patients with hypoxemia and pulmonary hypertension. Thirty-eight of these patients had chronic obstructive airways disease; 13, primary pulmonary hypertension; seven, recurrent pulmonary embolism; four, the Eisenmenger syndrome; and one, multiple pulmonary arteriovenous fistula. Forty-three patients were hypeakly associated with arterial oxygen tension ( r = 0.50), but not with the arterial carbon dioxide tension or the level of pulmonary artery pressure. Sulfinpyrazone lengthened platelet survival in 12 of 24 (50%) treated patients but this drug did not alter either arterial oxygen tension arterial carbon dioxide tension, or pulmonary artery pressure. Our results suggest that hypoxemia is associated with shortened platelet survival time and that platelets may, therefore, be involved in the thromboembolic complications that develop in patients with hypoxemia.


Participation of fast and slow A-V nodal pathways in tachycardias complicating the Wolff-Parkinson-White syndrome. Report of a case. Electrophysiological studies in one patient with type B pre-excitation and dual A-V nodal pathway revealed several types of paroxysmal narrow QRS tachycardia (PSVT). One type of PSVT reflected antegrade fast A-V nodal pathway and retrograde anomalous pathway conduction. This PSVT was characterized by early retorgrade activation of right atrial appendage, P following QRS and cycle length of 290 to 350 msec. A second PSVT reflected antegrade slow A-V nodal pathway and retrograde anomalous pathway conduction. This PSVT was characterized by early retrograde activation of right atrial appendage, P following QRS, and cycle length of 440 msec. A third PSVT reflected A-V nodal re-entrance with antegrade slow pathway and retrograde fast pathway conduction. This PSVT was characterized by normal retrograde atrial activation sequences, P simultaneous with QRS, and cycle length of 320 msec. All PSVT inductions could be explained in terms of antegrade and retrograde properties of fast and slow A-V nodal and anomalous pathways.


De subitaneis mortibus. XXIII. Rheumatoid arthritis and ankylosing spondylitis. The conduction system of the heart was carefully examined at necropsy in two cases of rheumatoid arthritis and one of ankylosing spondylitis. All three patients had cardiac electrical instability and two fo the three died suddenly. The electrophysiological abnormalities of the three patients included paroxysmal atrial fibrillation in the first case, sustained atrial  fibrillation with complete heart block and escape atrioventricular (A-V) junctional rhythm in the second case, and progressively increasing heart block eventually became complete in the third case. The sinus node exhibited extensive focal degeneration with and without associated inflammation in all three hearts, but the sinus node artery was not remarkably abnormal in any of these. All three hearts had important focal degenerative disease in the A-V node and His bundle, and in each of these there was marked narrowing of the local nutrient arteries, amounting to virtual occlusion in two hearts. The probable relationship of these postmortem histological findings to the electrocardiographic disturbances in each patient is discussed. Abnormalities in the cardiac conduction system of the hearts of these three patients are compared to ones previously reported for disseminated lupus erythematosus, polyarteritis nodosa, and scleroderma heart disease.


Rapid two point kenetic determination of plasma lactic acid. 1. Plasma levels of L-lactic acid were determined employing a two-point kinetic, lactic dehydrogenase method without a protein free filtrate preparation. 2. The method was characterized with regards to precision, linearity, recovery and accuracy. 3. Regression analyses were accomplished by comparison of the kinetic and standard enzymatic end point procedures. 4. Clinically significant values are obtained within 50% less time than routine methods presently employed.


A semi-automated enzymatic assay for free glycerol and triglycerides in serum or plasma. 1. A relatively inexpensive semi-automated enzymatic procedure is described for the determination of total glycerol with an Auto Analyzer. Free glycerol is determined without saponification in a deproteinized supernatant. 2. The dilution of triglyceride samples during preparation is such that the samples during preparation is such that the samples can be quantified directly from the free glycerol standards by multiplying by 100. 3. A pyruvate kiluent solution is used in the triglyceride sample preparation to increase the precision by improving the accuracy in determining blank optical densities. 4. The end-point reaction is complete in eight minutes, and the assay is linear up to 6 mg% free glycerol or 600 mg% triglycerides. The within-run and between-run coefficients of variation were both 1.5% for the glycerol assay, and 1.0% and 4.3% for the triglyceride assay. The mean recovery of added glycerol was 100.7% and 102.3% for the glycerol and triglyceride assays respectively.


Hyperprolinemia type II: identification of the glycine conjugate of pyrrole-2-carboxylic acid in urine. The urinary organic acids were studied in two cases of hyperprolinemia Type II, using various combinations of chromatographic, electrophoretic and mass spectrometric techniques. In both cases N-(pyrrole-2-carboxylic acid) was idenfitied as a major urinary metabolite. While there was evidence for an additional conjugate of this pyrrolic acid, no free pyrrole-carboxylate could be detected in the urine from either case.


Urinary p-tyramine in hereditary tyrosinemia: I. Levels as compared to normal individuals, effect of diet, and relationship to urinary tyrosine. 1. A 40-fold increase in urinary p-tyramine was observed in a patient with hereditary tyrosinemia as compared to a control population. 2. The excretion of urinary-free p-tyramine was decreased with the restriction of oral phenylalanine and tyrosine in this patient. The pattern of urinary tyrosine and urinary-free p-tyramine was similar during the period of normal protein diet and restricted diet of phenylalanin and tyrosine. 3. The pattern of urinary-free p-tyramine and tyrosine following oral loads of tyrosine and phenylalanine was similar except for a lag period before a tyramine response was observed. 4. The possibility of the patient with hereditary tyrosinemia providing a model to study the origin of urinary p-tyramine is discussed.


Urinary p-tyramine in hereditary tyrosinemia: II. Origin of urinary p-tyramine. 1. A patient with hereditary tyrosinemia (tyrosinosis) was given oral loads of p-tyramine and tyrosine with and without medication (neomycin) to investigate the respective roles of intestinal bacteria and tissues in accounting for the origin of urinary p-tyramine. 2. The excretion of a high circulating level of p-tyramine following an oral load of p-tyramine in a patient with hereditary tyrosinemia (tyrosinosis) was as conjugated p-hydroxyphenylacetic acid (p-HPAA) and conjugated p-tyramine. 3. Both intestinal bacterial activity and tissue decarboxylation appeared to account for urinary p-tyramine in this patient following an oral load of tyrosine. 4. Sterilization of the gut by oral neomycin and a second load of oral tyrosine further supported a predominate role for tissue decarboxylation in the origin of urinary p-tyramine. 5. The data suggested that a major route of tyrosine metabolism in man may be via tissue decarboxylation of tyrosine.


A precise semi-automated uricase method for determining uric acid in serum or urine. 1. A semi-automated uricase method is described for measuring uric acid in serum or urine directly at 292 nm at reduced cost. 2. The coefficient of variation within and between batch assays, is estimated to be 2.5% and 4.3% respectively, which is less than the estimated daily intrapersonal variation in uric acid levels. 3. Recovery of uric acid added to samples ranges from 98.5% to 101.2% with a mean of 99.6%. 4. The cost of reagents per sample determination is estimated at $0.05, and in batch analyses the mean time required per sample determination is 2-3 minutes.


Effect of structure on the excretion of steroidal acids in human urine and their potential colorimetric assay as 17-oxogenic steroids. Following the oral administration of tritiated coricosterone, cortisol, deoxycorticosterone and progesterone to human subjects, 14.9%, 12.8%, 3.4% and 2.1% of the dose was recovered in the acidic metabolite fraction of 48 h urines after conventional hydrolysis and solvent partition. Neutral and acidic 17-oxogenic steroids (17-OGS) excreted in 24 h urines were also measured with the Zimmermann color reaction. The acidic  17-IGS accounted for 14.1%, 16.4% and 12.1% of the fractionated 17-OGS in the urines of normal and pregnant females and normal males respectively. From structural considerations, it was concluded that only 17-hydroxylated steroidal acids, with a 20-hydroxy-21-oic acid side chain and derived predominantly from cortisol, would be estimated as 17-OGS after oxidation with sodium periodate. 17-Dexy steroidal acids resemble the neutral 17-deoxycorticosteroids in undergoing side chain oxication to 17-aldehydes which do not form Zimmermann chromogens. The excretion of both neutral and acidic 17-OGS was suppressible with dexamethasone administration.


Observations on the determination of serum and red-cell folate levels by a radiometric assay method. Our experience with the Bio-Rad "Quanta-Count" folate radioassay kit has revealed very good in-run precision and good day-to-day reproducibility in the assay of both serum and red-cell folate levels. Ascorbic acid is not required as folate preservative if blood samples are frozen within hours after collection. For the determination of red-cell folates, our data clearly show the need for maintenance of a certain level (6-8 gm%) of protein in the assay system. Protein (albumin or folate-free human serum) must be added to the red-cell lysate to compensate for the serum loss resulting from the high dilution factor necessary. In the absence of this added protein, red-cell values are markedly lower. A good correlation exists between red-cell folate values obtained from the assay of washed red cells and from the assay of whole blood with corrections for serum folate levels.


Clinical evaluation of the Technico Stat/Ion system. 1. We describe our evaluation of the Technicon Stat/Ion, an instrument which performs sodium, chloride and bicarbonate analysis simultaneously. 2. All four of the assays resulted in linear response over the entire clinical range with insignificant carryover between specimens. 3. Precision studies for within-run variation were: sodium 0.3 percent, potassium 0.7 percent, chloride 0.5 percent and bicarbonate 1.6 percent. Day-to-day precision was similar to the within-run precision. 4. Comparison methods for sodium, potassium, chloride and bicarbonate utilizing flame photometry, chloridometry and titration of released carbon dioxide respectively showed the following linear regression and correlation coefficients: sodium y=0.96+5.5 (a=0.988) potassium y=1.01x+0.0 (a=.996) chloride y=0.99x+1.0 (a=.993)bicarbonate y=1.0x+1.2 (alpha=.969).


The in vitro effect of drugs on biochemical parameters determined by a SMAC system. 1. We have studied the in vitro effect of 39 drugs on 17 biochemical parameters determined by a SMAC System. Only two drugs were found to interfere: ascorbic and theophyline. 2. The ascorbic acid lowers the glucose and the bilirubine values; it increases the creatinine and the uric acid concentration. At concentration smaller than 5 mg/dl of this drug, these effects are negligible. 3. We have found a new drug interference: theophylline inhibits the alkaline phosphatase and LDH activities. This effect is not negligible on alkaline phosphatase for therapeutic levels of this drug; the action on LDH can be ignored at normal therapeutic range. 4. For a given drug, we have found different interference with biochemical parameters determined with various commercial lyophlised control sera or a liquid pool of sera. This indicates that the type of sera used in drug interference studies must be described.


Elevation of serum alkaline phosphatase activity and related enzymes in diabetes mellitus. Of 101 consecutive hospitalised diabetic patients, 29 had elevated serum enzyme activities attributable to recognized clinical entities; 17% of the remainder had raised alkaline phosphatase (AP) activity, 15% had raised aspartate aminotransferase (GOT) activity, and 12% raised lactate dehydrogenase (LDH) activity in serum. Ketoacidosis and death within 3 months were commoner among patients with elevated serum enzyme activities than among those with normal enzymes. Study of 200 consecutive new untreated diabetics when first seen at an out-patient clinic revealed 15 with clinically explainable abnormal serum enzyme activities. Of the remainder, 11% had raised AP activity, 12% raised GOT activity, and 21% raised LDH activity in serum; these patients tended to have higher blood sugar concentrations than the subjects with normal serum enzymes. These abnormalities seem to be an intrinsic feature of diabetes mellitus which do not relate to duration, complications, or treatment of the disease. They do not seem to be directly related to hepatic involvement.


In vitro cholesterol esterification in human serum. We report a simple, convenient, and reproducible method, involving the use of radiolabeled cholesterol dispersed in Tween 20 as a tracer and endogenous lipoproteins as a substrate, for measuring the rate of serum cholesterol esterification in vitro. The reaction of lecithin acyltransferase (EC 2.3.1.43) was enhanced by the presence of Tween 20, which probably accelerates the exchange between radiolabeled cholesterol and endogenous lipoprotein cholesterol. In sera from 65 normal subjects, the in vitro cholesterol esterification rate was significantly correlated (r=0.47,P=0.001) with age. The mean rate of esterification of 31 subjects 30 years old or younger was significantly lower than that of 34 subjects 31 to 64 years of age. We found no significant difference in the rate of esterification between men and women. The rate of cholesterol esterification (nmol/ml per h) was significantly correlated with the concentration of endogenous free cholesterol in serum, but the fractional rate (the percentage of radiolabeled cholesterol esterified per hour) was inversely proportional to the endogenous free cholesterol. The fatty acid composition of the cholesteryl esters formed by the acyltransferase reaction may provide an index in recognizing some specific disorder.


L-p-Bromotetramisole, a new reagent for use in measuring placental or intestinal isoenzymes of alkaline phosphatase in human serum. L-p-Bromotetramisole is proposed as a new reagent for use in determining intestinal and (or) placental isoenzymes of alkaline phosphatase in human serum. Its main advantage over L-phenylalanine is its high discriminating potency at very low concentrations. For highest accuracy, the samples may even be "titrated" with the inhibitor. Analytical recoveries of intestinal and placental isoenzymes in serum are complete, and results correlate well with those by other methods. At the appropriate concentrations, L-p-bromotetramisole gives nearly identical results on a variety of sera, irrespective of the buffer used. Within-day CV's were 6.1 and 2.1 for 20% and 60% of the resistant isoenzyme activity, respectively. The day-to-day CV was 3.45 for a sample containing 53.3% of the resistant isoenzyme (n=15). The well-known increase in placental isoenzyme activity with time of gestation could be confirmed on 612 sera from pregnant women. The activities of the intestinal isoenzyme in sera from healty blood donors (n = 126) and hospitalized patients (n = 135) agree with previous findings obtained by the other techniques.


Ion pair extraction technique with azure A, for differentiating biles of normal subjects and patients with liver disease from patients with Crohn's disease with small bowel involvement. The ion pair extraction technique with Azure A solution, chloroform/methanol (equal volumes), and dilute sulfuric acid, was used to study bile-rich duodenal aspirates of (a) healthy volunteers and patients with (b) cholestatic liver disease, (c) Crohn's disease with small bowel involvement, and (d) those with primarily colon involvement. Duplicate aliquots of extracted duodenal aspirates from these four groups were subjected to ion pair extraction, with and without prior acetylation, and the absorbance ratios at 645 nm without acetylation/with acetylation ("acetylation index") compared; values (+/- SD) obtained were 0.052 +/- 0.0098, 0.038 +/- 0.014, 0.136 +/- 0.048, and 0.077 +/- 0.056, respectively, for the four groups. The acetylation index for group c was significantly (P less than 0.001) different from that of groups a and b. All other intergroup comparisons were not significant. The acetylation index correlated positively (r = 0.922) with the ratio of glycine- to taurine-conjugated bile acids, measured independently, implying that it reflects this ratio.


Alkaline phosphatase activity in the plasma of children and adolescents. We determined plasma (serum alkaline phosphatase activity in 854 healthy students of the Rochester, Minnesota, public schools. Prepubertal girls had somewhat greater upper limits than did boys, and there was a low trend of increasing activity in both sexes. At the beginning of adolescence increasing activities were observed, which peaked at ages 11 to 12 years in girls and at ages 13 to 14 in boys. Adult values were not reached until six to eight years later. In 180 pairs of siblings, a significant intraclass correlation was noted. A possible role of alkaline phosphatase in the regulation of protein synthesis is suggested.


Urinary free norepinephrine and dopamine determined by reverse-phase high-pressure liquid chromatography. We used reverse-phase high-pressure liquid chromatography to measure free norepinephrine and dopamine simultaneously in human urine. Samples were treated with alumina, and the catecholamine(s) then eluted from it were directly injected onto a reverse-phase column (octadecyl-silica stationary phase), with 0.17 mol/liter acetic acid as the mobile phase and ultraviolet detection at 280 nm. The assay detects concentrations in urine as low as 5 mug/liter. Assay of 24-h urines (n = 10) gave within-run and day-to-day coefficients of variation of 3.7 and 4.7% for norepinephrine, and 2.6 and 3.5% for dopamine, respectively. Comparison studies with the traditional trihydroxyindole fluorometric method showed the liquid-chromatographic procedure to be more precise and subject to less interference. This relatively rapid procedure for urinary free norepinephrine and dopamine provides an efficient, reproducible method, readily adaptable to routine clinical use.


Evaluation of a semi-automated blood urea nitrogen analyzer. We compared results for urea concentrations in plasma and serum as measured with the Kimble Blood Urea Nitrogen Analyzer method as the test method with those determined by continuous-flow analysis (AutoAnalyzer 1 method) as the comparison method. We evaluated accuracy and precision for patients' samples, National Bureau of Standards Standard Reference Material, College of American Pathologists Survey Validated Reference Materials, and College of American Pathologists Quality Assurance Service control materials. We found the test method to be more accurate and precise than the comparison method.


Copper, zinc, magnesium, and calcium in plasma and cerebrospinal fluid of patients with neurological diseases. We investigated whether information on concentrations of some trace-mental concentrations in blood plasma or cerebrospinal fluid, or both, could be of value in diagnosis or management of various neurological diseases, and whether concentrations in plasma could serve as a means of estimating the protein or metal concentrations in cerebropsinal fluid. Samples of both from 82 patients were analyzed for copper, zinc, magnesium, and calcium by atomic absorption spectrophotometry. Protein concentrations in cerebrospinal fluid were also determined. Metal and protein concentrations in plasma and in cerebrospinal fluid were not strongly enough correlated to permit the estimation of one from the other. However, the correlation coefficients between calcium in plasma and cerebrospinal fluid (r = 0.41), magnesium and protein in cerebrospinal fluid (r = 0.40), magnesium in plasma and calcium in cerebrospinal fluid (r = 0.36), and magnesium and calcium in cerebrospinal fluid (r = 0.66) were statistically significant (P less than .01). Patients with cerebral infarctions had abnormally high copper concentrations in their plasma and cerebrospinal fluid. The ratio of plasma copper to plasma zinc was also significantly higher in cases of cerebral infarction.


Separation of serum creatine kinase isoenzymes by ion-exchange column chromatography. We describe a practical, technically convenient DEAE-Sephadex chromatographic column and a three-fraction salt-gradient elution procedure, with which serum creatine kinase activity is rapidly and quantitatively separated into the isoenzyme components with excellent analytical recovery of the total activity applied. The homogeneity of the isoenzyme fractions was demonstrated by electrophoresis and rechromatography. Sera assessed by the Mercer fractionation [Clin. Chem. 20, 36 (1974)] and the present procedure showed excellent agreement.


Spectrofluorometry of free and protein-bound plasma tryptophan. We report a rapid, simple, and sensitive spectrofluorometric procedure for total serum or plasma tryptophan. Plasma deproteinization, tryptophan extraction, and pH optimization are all carried out with a buffered cellulose/ethanol reagent. The fluorescence is measured at an emission wavelength of 350 nm, on excitation of 290 nm. Tryptophan fluorescence relative to concentration is linear up to 50 mg/liter. The high precision, evidenced by a between-run coefficient of variation of 3.1%, negates the need for duplicate analysis of samples. Analytical recovery of tryptophan from plasma up to 50 mg/liter is 90-100%. We observed no significant difference between values for tryptophan in serum and plasma from the same individual. Assay of up to 32 samples requires 60 min. Commonly used anti-depressants have no detectable effect on tryptophan determination by this procedure.


Cortisol production rate determined by radio gas-chromatography. We describe a ratio gas-chromatographic method for determination of cortisol production rate by measuring the isotope dilution of urinary cortisol metabolites. The method was calibrated by analyzing [3H]tetrahydrocortisol and [3H]tetrahydrocortisone of known specific activities. Results are reasonably well reproducible, the coefficients of variation ranging from 8-15% of allotetrahydrocortisol/tetrahydrocortisol and from 9-19% for tetrahydrocortisone. Correlation coefficients were 0.966 and 0.998 for tetrahydrocortisone and allotetrahydrocortisol/tetrahydrocortisol, respectively, when the method was compared with a method involving thin-layer chromatography and colorimetry. Only one chromatographic step is needed for both purification and quantitation, thus time and effort are saved.


Faster estimation of reserve bilirubin binding capacity of serum from the neonate by thin-layer chromatography on sephadex. Knowledge of the reserve bilirubin-binding capacity is useful in management of hyperbilirubinemia in the newborn. We describe thin-layer gel chromatography that permits measurement of this variable, with a 250-mul sample of serum, within 50 min. Single samples from four different infants can be analyzed on the same plate. The capacity of 40 sera from jaundiced and of 19 sera from nonjaundiced infants was measured. Results by thin-layer Sephadex gel chromatography and column Sephadex chromatography correlated well. Dithiothreitol, added to the standard bilirubin solution, protected bilirubin from oxidation for at least six days, which obviated the time consuming preparation of standard solution before such determination.


Evaluation of the Du Pont aca alpha-amylase procedure. The procedure used with the Du Pont aca for alpha-amylase (1,4,-alpha-D-glucan glucanohydrolase, EC 3.2.1.1) was evaluated in our laboratory and compared with the Roche Diagnostics "Amylochrome" and Perkin-Elmer Coleman 91 amylase assays. The within-run coefficients of variation (CV) for samples of fresh normal sera were: aca 5.8% and 4.3% on two different lots of reagent, Amylochrome 7.4%, and Coleman 91 3.3%. In sera with abnormally high amylase activity, the respective CV's were: aca, 1.2% and 0.8%; Amylochrome, 2.0%; and Coleman 91, 2.8%. Day-to-day precision studies on fresh and lyophilized normal and abnormal sera gave CV's in the following ranges: aca, 1.8% to 6.7%; Amylochrome, 3.0% to 5.2%; and Coleman 91, 4.5% to 5.9%. Results by the aca procedure were linearly related to activity to about 10-fold the upper limit of normal amylase activity. For serum, correlations were: r = 0.977 for aca vs. Coleman 91 and r = 0.974 for aca vs. Amylochrome. For urine they were: r = 0.978 for aca vs. Coleman 91 and r = 0.975 for aca vs. Amylochrome. Mean recovery from 53 supplemented samples was 98%. Icterus, hemolysis, and lipemia did not interfere with method correlation of aca vs. Coleman 91 or Amylochrome.


Biological variability in aspartate aminotransferase activity in serum of healthy persons, and effect of in vitro supplemantation with pyridoxal 5-phosphate. Aspartate aminotransferase (EC 2.6.1.1) activities in sera from nine healthy individuals were monitored during two weeks, both with and without first supplementing the serum with pyridoxal phosphate. Pyridoxal phosphate supplementation caused a mean increase of 39% (range, 33-55%) in measured activity. The biological variability during the two-week period was independent of pyridoxal phosphate supplemantation. The intra-individual variability (CV) was 5.3% and 5.1% with and without pyridoxal phosphate supplementation, respectively; the corresponding inter-individual variability was 13.2% and 13.6%. We conclude that the reference interval will be insensitive to intra-individual fluctuations in aspartate aminotransferase activity in serum, whether or not the serum is supplemented with pyridoxal phosphate.


Determination of cadmium in blood by use of atomic absorption spectroscopy with crucibles--and a rational procedure for dry-ashing. A simple, minimal-reagent procedure for analysis of cadmium in blood is introduced. Blood samples from workers occupationally exposed to cadmium were collected with heparin. Titon X-100 surfactant was added, and 15-mul aliquots of the blood were pipetted into small nickel sampling cups and placed in  a holder for 100 cups, which was enclosed in a stainless steel box. After the samples were dried and ashed in a muffle oven at various times and temperatures, cadmium was determined in an air/acetylene flame in an atomic absorption instrument with a deuterium arc background corrector. Absorbance measurements were made by signal-averaging facilities in the instrument. The conditions for analysis are specified. The method appears to be accurate and reproducible, with a CV of about 6% in the range 35-160 nmol/liter. The detection limit was 3.0 nmol/liter of blood. With the new procedure, many blood samples can be dried and ashed in parallel, which favors both simplicity and precision.


Differential serum amylase determination by use of an inhibitor, and design of a routine procedure. We describe a new method for measuring pancreatic and salivary-type amylases in serum that requires no electrophoresis or chromatography. An inhibitor protein (from wheat) with a 100-fold greater specificity for human salivary than for human pancreatic amylase was used to analyze mixtures of the two enzymes. The concentration of pancreatic and salivary amyalase was determined in 141 normal sera (72 men and 69 women). Statistically significant differences were found for serum pancreatic amylase between mean and women, higher values being shown in women. No sex-related difference was found for the salivary component of serum amylase. With this method, the increase in serum amylase activity in pancreatitis was shown to be attributable to the pancreatic component. In mumps, the increase is attributable to the salivary component. In pancreatic insufficiency, serum pancreatic amylase activities were significantly lower than in the controls. Our method is simple and rapid; our results agree well with those of other authors who used chromatographic or electrophoretic methods.


Creatine kinase isoenzyme MB in myocardial infarction: methods compared. Several methods are available for specifically identifying and assessing the activity of MB isoenzyme of creatine kinase in serum. We compared two electrophoretic techniques with three column-chromatographic ones for efficacy in the diagnosis of myocardial infarction. No technique was considered absolute, but we found surprisingly large errors of diagnosis in the column-chromatographic techniques, attributable to incomplete elution.


Interference of sodium azide with measurement of serum uric acid by the direct acid ferric reduction procedure. We examined the effect of sodium azide on the quantitation of serum uric acid by the direct acid ferric reduction procedure. Ferric phenanthroline was used as redox indicator. Sodium azide, in a concentration commonly used as preservative (2 g/liter, 27.2 mmol/liter), increased the absorption at 505 nm and increased apparent uric acid values in specimens, as shown by calculations based on an azide-free standard. Spectral studies indicated that this interference was a result of the color produced by sodium azide in the reaction mixture. The mechanism for azide interference was the interaction of sodium azide and ferric ions to form ferric azide, which also absorbs extensively at 505 nm.


Micro-scale anticonvulsant assay with use of nitrogen/phosphorus detector and on-column methylation compared with a macro-scale procedure involving flame-ionization detection. We report a modified micro-scale gas-chromatographic procedure for determining phenobarbital, primidone, and diphenylhydantoin in serum with use of a nitrogen/phosphorus detector. Serum, 20 mul, is extracted into chloroform, the solvent is evaporated, and the residue dissolved in dilute (32 mmol/liter) trimethylanillinium hydroxide, which yields the methyl-derivatives of the drugs upon on-column injection. Within-run precision (CV) for the three drugs was 1.0, 2.1, and 1.4+, respectively, at concentrations of 19.2, 13.2, and 18.9 mg/liter; run-to-run precision at these concentrations was 4.4, 3.8, and 2.8%. Comparison of the 20-mul micro-scale procedure (y) with our conventional, flame-ionization macro-scale procedure (x), in which on-column methylation is used and which requires 1 ml of serum, gave the following respective results: y = 1.01 X -- 0.16 mg/liter, r = 0.992, y = 1.02 X + 0.29 mg/liter, r = 0.973; and y = 0.96x + 0.04 mg/liter, r = 0.996.


Micro-scale method for theophylline in body fluids by reversed-phase, high-pressure liquid chromatography. We describe a micro-scale method for determining serum theophylline. The chromatography system includes a muBondapack C18 column and acetonitrile, 70 ml/liter of sodium acetate buffer (10 mmol/liter, ph 4.0) as the mobile phase. Test serum or plasma, 30 mul, is mixed with an equal quantity of a solution containing the internal standard, beta-hydroxyethyltheophylline in acetonitrile/sodium acetate buffer (20 mmol/liter, pH 4.0), 7/43 by vol. After the precipitate is removed by centrifugation, the mixture is chromatographed and the amount of theophylline calculated from the ratio between peak heights for theophylline and the internal standard. Advantages include easy sample preparation, involving only addition of internal standard and centrifugation before injection, long column life, and the suitability of the internal standard, which is adjusted to a peak height equivalent to 20 mg of theophylline per liter for easy computation of results.


Improved electroimmunoassay of factor VIII-related antigen. Factor VIII-related antigen migrates poorly into gel during electrophoresis in agarose, probably in major part because of the relatively high sulfate content of the commonly used agars. A recently available low-sulfate residue agar, substituted for standard agar preparations in electroimmunoassay, allows Factor VIII antigen to travel more rapidly, producing "rockets" that are well defined and easily measured, making the assay easier and more reliable.


Morphology of the placenta in fetal I-cell disease. Placentas were studied from three interrupted pregnancies of a mother whose first liveborn child had I-cell disease (mucolipidosis II). I-cell disease of the fetus was shown by investigation of the amniotic fluid, fetal cells and the aborted fetus in two pregnancies, but in the third case placenta was the only available product of conception. In every placenta extensive vacuolization of the syncytiotrophoblastic layer of the chorionic villi and chorionic mesenchymal cells was found. In electron microscopy the inclusions were identical to those of other tissues in I-cell disease. The importance of histological study of placenta in unexplained spontaneous abortions needs to be emphasized, since this may be the only way of detecing new cases of lysosomal storage diseases.


Adrenoleukodystrophy (Siemerling-creutzfeldt disease): Heterozygote with two clonal fibroblast populations. On the fifth day after subcultivation,, fibroblasts of two unrelated patients with adrenoleukodystrophy (Siemerling-Creutzfeldt disease (SCD)) developed typical morphologic anomalies which could be seen by light microscopy. From skin biopsy material of an obligatorily heterozygous womam, both normal and morphologically defective colonies could be isolated. These findings suggest that the morphologic alterations are an expression of the defect in Siemerling-Creutzfeldt disease. Futhermore, they suggest that the SCD locus is subject to lyonization.


46, X,X-X terminal rearrangement/45, X mosaicism in a child with short stature. A phenotypically female child, investigated because of short stature, had abnormally large, often bipartite Barr bodies and a mosaicism of 45, X cells and cells with 46 chromosomes which included an exceptionally large metacentric chromosome (Xp+). G- and C-banding established that the chromosome was derived from two substantially entire X chromosomes joined short arm-to-short arm, and was likely to be an isodicentric X with functional inactivation of one centromere.


X-linked skeletal dysplasia with mental retardation. A syndrome compatible with an X-linked trait is described, affecting four male cousins in three sibships. The body had skeletal anomalies, including short stature, ridging of the metopic suture, fusion of cervical vertebrae, thoracic hemivertebrae, scoliosis, sarcral hypoplasia and short middle phalanges. In addition, they had moderate developmental retardation, and abducens palsies. Three of the four had glucose intolerance, and one was born with an imperforate anus. Of five female obligate carriers studied, three had fusion of cervical vertebrae, three had some shortening of the middle phalanges and three had glucose intolerance. The syndrome in this family was compared to previously reported syndromes, and the conclusion was reached that it represents a previously unreported X-linked syndrome with minor manifestations in carrier females.


Heterozygote detection in phenylketonuria. Phenylalanine loading was carried out on 105 parents of children with phenylalanine hydroxylase deficiency and 33 apparently normal individuals with no family history of phenylketonuria. The best discriminant was found to be the logarithmic transformation of the slope of the rise in serum tyrosine multiplied by the maximum serum tyrosine concentration over the maximum serum phenylalanine concentration obtained after an oral load with a pure solution of L-phenylalanine. The overlap between heterozygotes for penylketonuria and normal homozygotes was 2.4 percent. The distribution of the discriminant values suggested three heterozygous phenotypes for phenylalanine hydroxylase deficiency, and the phenotypic combination of parents could be correlated to the phenotype of their affected offspring, i.e. classical phenylketonuria, mild phenylketonuria of hyperphenylalaninemia. The probability of heterozygosity for phenylketonuria was determined by means of the distribution of the discriminant values of the heterozygotes and that of normal homozygotes. The likelihood of being a heterozygote was corrected for the genetic background of the person requiring genetic counseling, and was finally expressed as the percentage probability of being a heterozygote for phenylketonuria.


Congenital dislocation of the hip joint in northern Sweden. The incidence of neonatally diagnosed congeital dislocation of the hip joint (CDH) was found to vary between three hospitals in Northern Seden. The incidence was 10.0, 7.1 and 3.5 per thousand in hospitals A, B and C, repectively. The incidence increased during the period 1960-73 in hospitals A and B, but not in hospital C. At these hospitals the number of cases needing prolonged orthopaedic treatment showed an inverse relationship to the incidence of neonatally diagnosed CDH.


A case of double trisomy in a liveborn infant: 48, XXY, "13. Ambigouous genitalia, microcephaly, microphthalmia, hyoptelorism, single choanal opening, low-set ears, simian creases, Tetralogy of Fallot, bilateral hydronephrosis, and absence of the left ureter characterized an infant the died 1 hour postpartum with the karyotype 48,XXY,+13.


Cystic fibrosis: Evidence for a genetic compound from a family study in cell culture. Although the majority of patients with cystic fibrosis (CF) show a typical clinical course, a minority with the same clinical phenotype at the time of initial diagnosis have an atypical (mild) course. Skin fibroblast cultures were established from 49 members of the family of one such atypical CF adult patient, previously identified (Danes et al. 1976) as CF Class II (ametachromatic and no metabolic cooperation with CF Class I fibroblasts), the offspring of Class I (metachromatic, metabolic cooperation with normal fibroblasts)/Class II mating. The culture phenotype for Class I was traced on the maternal side and for Class II on the paternal side through consecutive generations and the culture phenotype of each class segregated. This family study added experimental evidence to support the hypothesis that the atypical (mild) clinical features and course of this adult CF patient were due to two different CF genes combining to produce a genetic compound expressing a mild form of CF.


Two XX males in one family and additional observations bearing on the etiology of XX males. Two XX males who were second cousins are reported. A genetic mechanism producing maleness is suggested. The putative factor had been transmitted solely through males, which excludes the possibility of a heritable X-Y interchange. Recent reports on fluorescent Y chromatin in Sertoli cells of XX males prompted investigations into the fluorescence patterns of testicular cells. Sertoli cells from three XX males displayed brightly fluorescent spots, but it was concluded that they did not represent Y chromosomes. Evidence for this conclusion was obtained from the study of testicular fluorescence in XX, XXY and XY males. No visually detectalbe cytogenetic evidence for an increase in length or altered banding pattern of one of the X chromosomes was found in three XX males. We conclude that an autosomal gene is the most likely explanation of the male differentiation in the two XX males presented here.


A case report of a presumptive +i(18p) associated with serum IgA deficiency. The case of a 4-month-old male infant with retarded psychomotor development and multiple anomalies is presented. Cytogenetic studies on peripheral blood and skin cultures revealed a normal male complement with a supernumerary small metacentric chromosome. According to its size and its banding patterns, the metacentric chromosome was postulated to be an isochromosome for the short arm of number 18. A deficiency of serum IgA was observed in this patient.


The distribution of ancestral secondary cases in Parkinson's disease. Recent evidence suggests a genetic mode of transmission of Parkinson's disease. A multifactorial mechanism is likely, but autosomal dominance with reduced penetrance has not been excluded. The distribution of ancestral second-degree relatives with Parkinson's disease was evaluated in 12 families. Affected relatives were bilaterally distributed more often than would be expected for autosomal dominance. The distribution of ancestral secondary cases suggests a multifactorial etiology for most cases of Parkinson's disease. The possibility of dominant gene inheritance in some families is not entirely ruled out.


Genetic heterogeneity of hypoxanthine-phosphoribosyl transferase in human fibroblasts of 3 families. Incorporation of hypoxanthine, resistance to 8-azaguanine and activation by lyophilisation have been studied in cultured human fibroblasts. Cells from one family where there was a boy with Lesch-Nyham syndrome, from two families with variant H-PRT mutations and three cell strains from patients with the Lesch-Nyham syndrome were investigated. Cells from patients with the Lesch-Nyham syndrome showed almost no hypoxanthine incorporation and resistance to concentrations of 8-azaguanine up to 10(-3) M, whereas cells of patients with partial H-PRT deficiency demonstrated variant patterns of hypoxanthine uptake and partial resistance to 8-azaguanine. Lyophilisation of fibroblast sediment from patients with the Lesch-Nyhan syndrome and patients with variant H-PRT mutations showed activation of the deficient or partially deficient H-PRT enzyme. No such activation was observed in healthy controls. Activation of lyophilised fibroblast extract from patients and controls was not obtained. These results suggest that H-PRT could be associated with the cell membranes.


Dermatoglyphics in Cri du Chat syndrome. The dermatoglyphics of 33 Japanese (20 females and 13 males) with Cri du Chat syndrome were compared with 544 male and 129 female controls. In these cases, 18 cases were described only with regard to simian crease and distal axial triradius. It was found that these patients showed high frequencies of certain characteristics such as whorl pattern, arch pattern, thenar pattern, bilateral simian creases and distally displaced axial triradii on both palms (t').


The 9p- deletion syndrome. A patient with a 45, XX-9, -15, +t(9/15) constitution due to maternal 3:1 meiotic disjunction. Deletion of the short arm of chromosome 9, derived from a 3:1 meiotic segregation in the mother, carrier of a balanced 9/15 translocation, was found in a 3-year-old female. Severe psychomotor retardation with delayed speech, brachicephaly, flat occiput hypertelorism and long upper lip were the main signs in the girl.


Physiology of aging: metabolic changes during the climacteric and menopausal periods. Endocrine regulation is altered with age. Changes in hormone secretory rates, patterns of secretion, and responses to physiologic and pharmacologic stimuli have been demonstrated. Target tissue sensitivity to hormones appears to be age related and to involve hormone receptor mechanisms, enzymatic responses, and carrier proteins. The aging process reflects changes in cellular structure and metabolism that decrease the function and efficiency of tissues. Structural changes occur with age and are characterized by a loss of elastic tissue, accumulation of highly crosslinked collagen, reduction in ground substance, and an increase in a cellular fluorescent pigment called lipofuscin. These changes decrease the pliability of tissues and alter membrane permeability. Modifications in protein synthesis and enzymatic systems may predispose the aged to autoimmune and neoplastic disease. Endocrine diseases are common in the aged and often may be atypical in their presentation. Cancer is common in the elderly and may be associated with endocrine manifestations because the tumor is producing hormones. Physicians must be aware of these syndromes so that a correct diagnosis can be established, treatment instituted, and the quality of life improved. Laboratory test results in the aged must be carefully interpreted because most aged patients are taking medications that interfere with endocrine tests and also the normal range for the elderly has not been clearly established. Abnormal laboratory diagnostic tests are common in the aged and do not always imply endocrine disease. No hormone can reverse the natural process of aging; however, hormones do regulate all metabolic functions and the neuroendocrine system plays a key role in all phases of growth, maturation, and aging.


Infections in elderly women.

Infections in elderly women. The topic of infections in elderly women is reviewed. In this age group consideration must be given to possible underlying disease and to the patient's age when antibiotic therapy is to be utilized. Preventive measures are stressed in the care of elderly women with infections.


Ambulatory care of aging women: a gynecologist's point of view. The purpose of this presentation has been to describe, in a very general way, the gynecologic problems of elderly women and of the system available to provide gynecologic services to them on an ambulatory basis. Several suggestions to improve care are made. Some can be implemented readily, but others will require new and additional personnel. I firmly believe that the care of aging women will soon require the creation of new facilities and development of new equipment and of new approaches much like the care of other special groups has required.


Preventative aspects of liability in obstetrics and gynecology. It would be impossible to devise a complete list of "Do's and Don'ts" for the physician to follow in preventing legal involvement. Indeed, such a list, even if considered complete, would not benefit the physician as much as would an overall feel for this whole area of patient interaction. When about to engage in some specific activity, the physician should consult the helpful medical-legal articles in publications that are readily available, e.g., articles on artificial insemination (1, 10), sex therapy (12), and human experimentation (9, 11, 15, 17). The physician must never undertake an action for which he/she does not have the training, the experience, and the emotional security to perform. If complications occur, exact and detailed documentation of the circumstances and the steps taken to correct the complication should be made. All this should be explained to the patient, if she is in a condition to understand, or to relatives. The physician needs to assume a humble attitude, but should not be defensive or make guiltridden admissions. When surgical procedures are undertaken, there should always be adequate pathology to justify the procecure. The physician should avoid pressuring the patient for a quick consent and should avoid statements that might invoke excessively optimistic expectations on the part of the patient (7).


Congenital idiopathic clubfoot.

Congenital idiopathic clubfoot. Using a relatively conservative approach to the problem, the results were fair to good in two-thirds of the patients in a series of 23 congenital idiopathic clubfeet with an average follow-up of 6 and one-half years.