The effects of agents that bind to cytochrome P-450 on hypoxic pulmonary vasoconstriction. The relationship between pulmonary arterial pressure (Ppa) and blood (Q) was determined during normoxia and hypoxia in ventilated pig lungs perfused in situ with the animal's own blood. Hypoxia shifted the Ppa-Q relationship to the right and decreased its slope, indicating pulmonary vasoconstriction. Carbon monoxide (11.5% in the inspired gas) and metyrapone ditartrate (10 mg/min into the perfusate) caused vasodilation when oxygenation was normal and reduced the vasoconstriction caused by hypoxia. Since the only pharmacological property CO and metyrapone are thought to have in common at the concentrations employed is the ability to bind to the heme iron of cytochrome P-450, these results are consistent with the hypothesis that desaturation of this cytochrome leads to pulmonary vasoconstriction. Prostaglandin F2alpha, infused into the pulmonary artery at 0.01 mg/min, when oxygenation was normal, had effects on the Ppa-Q relationship similar to those of hypoxia. The F2alpha response was also reduced by CO and metyrapone, suggesting either that P-450 was involved in the F2alpha response or that CO and metyrapone were toxic to pulmonary vascular smooth muscle. Proadifen hydrochloride (1 mg/min), which is thought to bind to the protein moiety of P-450 also reduced the hypoxic response, but was a vasoconstrictor during normoxia and did not affect the F2alpha response.


Pressor responses to norepinephrine in rabbits with 3-day and 30-day renal artery stenosis. The role of angiotensin II. Pressor responses to norepinephrine (NE) infusions were examined in normal rabbits, in rabbits with renal artery stenosis of over 30 days' duration (chronic renal hypertensive rabbits), and in rabbits with renal artery stenosis of 3 days' duration (3-day clipped rabbits). The 3-day clipped rabbits did not have hypertension, but they showed the same increased pressor responses to NE as did the chronic renal hypertensive rabbits, which was about 2.5 times that of the normal rabbits. Plasma renin activity (PRA) was the same in the 3-day clipped rabbits as in the normal group, but in the chronic renal hypertensive rabbits the PRA was significantly below normal. Infusions of angiotensin II (A II) in either subpressor or pressor amounts potentiated the pressor responses to NE in normal rabbits, whereas, in 3-day clipped rabbits and chronic renal hypertensive rabbits, A II in subpressor or pressor doses did not alter the pressor responses to NE. Infusion of the A II antagonist, [1-sarcosine, 8-isoleucine]angiotensin II, did not alter the pressor responses of normal rabbits to NE, but this A II analogue completely abolished the pressor hyperresponsiveness to NE in the 3-day clipped rabbits and greatly reduced the NE hyperresponsiveness in the chronic renal hypertensive rabbits; this A II antagonist did not alter the control arterial pressure in any of the three groups of rabbits. These studies show that the increased pressor response to NE in rabbits with renal artery stenosis occurs before the onset of hypertension and thus is not merely a result of the hypertension. Also, these results provide evidence that A II plays an important role in the increased pressor responses to NE in hypertensive and prehypertensive rabbits.


Inhibition of prostaglandin synthesis by indomethacin augments the renal vasodilator response to bradykinin in the anesthetized dog. It has been proposed that the increase in renal blood flow (RBF) produced by bradykinin (BK) is mediated or amplified by the intrarenal generation of prostaglandins. The present investigation was designed to explore these relationships further. In anesthetized dogs, the renal arterial infusion of BK (100 ng/kg per min), prior to the intravenous administration of indomethacin, produced a 93 +/- 14% increase in RBF and an increase in the renal venous concentration of a prostaglandin E-like substance ("PGE") from 51 +/- 23 to 235 +/- 73 pg/ml as determined by bioassay. Following indomethacin (5 mg/kg), the same dose of BK produced a 151 +/- 18% increase in RBF (P less than 0.001 compared to the preindomethacin increase) and the concentration of "PGE" remained largely below the threshold of sensitivity of the bioassay system. In three experiments, a highly sensitive and specific radioimmunoassay technique was used to obtain better quantitative estimates of concentrations of E2-like ("PGE2") and F2alpha-like ("PGF2alpha") substances so that determinations of renal efflux could be made. Thus, prior to indomethacin, BK administration increased RBF by 142 +/- 39 ml/min and was associated with a 26-fold increase in renal efflux of "PGE2" and a 12-fold increase in "PGF2alpha." After indomethacin, the effluxes of both "PGE2" and "PGF2alpha" decreased to negligible levels and were not influenced by BK infusion, although RBF increased by 225 +/- 75 ml/min. These results are not compatible with the hypothesis that intrarenal prostaglandins mediate or amplify the renal vasodilator response to BK.


Actions of lidocaine on transmembrane potentials of subendocardial Purkinje fibers surviving in infarcted canine hearts. We compared the effects of lidocaine, 2 X 10(-5) M, on transmembrane resting and action potentials of Purkinje fibers on the endocardial surface of 24- to 72-hour-old myocardial infarcts in dogs with its actions and subendocardial Purkinje fibers in normal hearts. At both proximal (near the tip of the papillary muscle) and distal (toward the apex) recording sites in noninfarcted hearts, lidocaine had no significant effect on maximum diastolic potential (MDP) or Vmax. It shortened action potential duration (APD) only at the proximal site. In infarcted hearts, we arbitrarily divided Purkinje fibers at the infarcted distal site into two groups. Group I consisted of fibers which did not have a severely depressed MDP or Vmax but in which APD was markedly prolonged. Lidocaine had no effect on MDP of these fibers, significantly depressed Vmax, and shortened APD. Group II consisted of fibers in which MDP and Vmax were markedly reduced. Lidocaine also reduced Vmax of these fibers further (by 60%) without altering resting potential. In addition, lidocaine depressed pacemaker activity of Purkinje fibers in infarcts. The drug did not alter conduction of premature impulses in the subendocardial Purkinje network in normal hearts but increased the maximum delay of early premature impulses in Purkinje fibers in infarcted hearts and sometimes resulted in nondriven repetitive activity. Therefore, the effects of lidocaine on transmembrane potentials of Purkinje fibers in infarcts are different from its effects on fibers in normal hearts.


Limitations of routine long-term electrocardiographic monitoring to assess ventricular ectopic frequency. Variations in the frequency of ventricular premature depolarizations (VPDs) were evaluated with three consecutive 24-hour long-term electrocardiography monitor recordings from 15 clinically stable patients with various cardiac disorders. Mean hourly VPD frequencies ranged from 37--1,801 per hour. Data were subjected to 4 and 5 factor nested analyses of variance. The extent of spontaneous variation in arrhythmia frequency that occurred in individual patients from day to day was 23%, between 8-hour periods within days was 29%, and from hour to hour was 48%. In addition, the variability between repeated three-day monitoring periods over time was quantified in five patients and found to be 37%. This analysis determined that to distinguish a reduction in VPD frequency attributable to therapeutic intervention rather than biologic or spontaneous variation alone required a greater than 83% reduction in VPD frequency if only two-24-hour monitoring periods were compared, and greater than 65% reduction if two 72-hour periods were compared. The limitations of routine 24-hour electrocardiographic monitoring must be considered in diagnostic and therapeutic decision-making.


Effects of self-induced starvation on cardiac size and function in anorexia nervosa. Cardiac size, function and rhythm were examined in 11 patients with anorexia nervosa. Mean left ventricular, left atrial and aortic dimensions on echocardiogram were below normal adult values at baseline. In addition to decreased cardiac dimensions--ventricular ectopy, relative hypotension, bradycardia and blunted heart rate--response to exercise were noted. Left ventricular systolic function, however, was unimpaired as indicated by normal echocardiographic fractional shortening, and by normal exercise augmentation of ejection fraction determined by radionuclide cineangiography. Eight of the patients responded to treatment with a mean weight gain of 32%. In these eight, cardiac dimensions increased toward normal: left ventricular dimension increased by 13%; left atrial dimension by 20%; aortic dimension by 15% and estimated left ventricular mass by 20%. We conclude that abnormalities of heart size and rhythm occur in patients with anorexia nervosa. However, cardiac dimensions, including left ventricular mass, may increase following nutritional rehabilitation, accompanied by an increase in heart rate and blood pressure.


Aortic input impedance in heart failure. The input impedance of the systemic circulation was calculated from recordings of pulsatile pressure and flow in the ascending aorta of 20 patients. Ten patients had clinical and hemodynamic evidence of heart failure. The other 10 subjects had no clinical evidence of heart failure and were used as a control group. In the heart failure patients, both input resistance and characteristic impedance (index of aortic distensibility) were significantly increased compared to pressure- and age-matched control subjects. Oscillations of impedance moduli, represented by the difference between maximum and minimum moduli, were also significantly increased in the heart failure patients compared with the control subjects. The increased characteristic input impedance in these heart failure patients suggests that the human aorta is stiffer in heart failure, and the larger oscillations in the impedance spectrum indicate an increase in pressure and flow wave reflections. From reflected wave theory in elastic tubes, reflected pressure waves add to the amplitude of incident pressure waves at the entrance of the system, whereas reflected flow waves subtract from the magnitude of the forward flow. Thus, changes in aortic distensibility could have an important influence on the pulsatile function of the failing left ventricle.


Comparative systemic and regional hemodynamic effects of dopamine and dobutamine in patients with cardiomyopathic heart failure. Thirteen patients with severe cardiac failure underwent a single crossover study of dopamine and dobutamine in order to compare the systemic and regional hemodynamic effects of the two drugs. The dose-response data demonstrated that dobutamine (2.5--10 microgram/kg/min) progressively and predictably increases cardiac output by increasing stroke volume, while simultaneously decreasing systemic and pulmonary vascular resistance and pulmonary capillary wedge pressure. There was no change in heart rate or premature ventricular contractions (PVCs)/min at this dose range. Dopamine (2--8 microgram/kg/min) increased the stroke volume and cardiac output at 4 microgram/kg/min. Dopamine at less than 4 microgram/kg/min provided little additional increase in cardiac output and increased the pulmonary wedge pressure and the number of PVCs/min. At greater than 6 microgram/kg/min, dopamine increased heart rate. During the 24-hour maintenance-dose infusion of each drug (dopamine 3.7--4, dobutamine 7.3--7.7 microgram/kg/min), only dobutamine maintained a significant increase of stroke volume, cardiac output, urine flow, urine sodium concentration, creatinine clearance and peripheral blood flow. Renal and hepatic blood flow were not signfiicantly altered by the maintenance dose of either drug. Systemic and regional hemodynamic data suggest that dobutamine has many advantages over dopamine when infused in patients with cardiac failure.


The effect of free fatty acids on myocardial oxygen consumption during atrial pacing and catecholamine infusion in man. The effect of myocardial uptake of free fatty acids (FFAu) on myocardial oxygen consumption (MVO2) in relation to increased heart rate and inotropic stimulation was determined in patients with coronary artery disease. Submaximal atrial pacing and isoproterenol stimulation increased MVO2 by 66% and 142%, respectively, at similar heart rates. Inhibition of lipolysis with beta-pyridyl carbinol almost abolished FFAu and reduced MVO2 significantly. Increased heart rate contributed 47% and FFAu 50% of the raised MVO2 attributed to inotropic stimulation was 30%. Augmentation of FFAu by triglyceride/heparin infusion increased MVO2 significantly above control levels, both during pacing and isoproterenol infusion. We conclude that MVO2 is closely correlated to FFAu, catecholamines sensitize the heart to FFA, and increased FFAu account for a major part of the increased MVO2 during catecholamine stimulation. The importance of reducing heart rate and lipolysis to reduce myocardial oxygen requirements is emphasized.


Relation between left coronary artery stenosis and regional left ventricular function. The effect of stenosis of the left main and proximal anterior descending coronary arteries on anterior left ventricular wall dynamics was investigated in 70 patients with ischemic heart disease by the use of roentgen videometric analysis of left ventricular angiograms. In all patients with ischemic heart disease, mean values for peak rate of systolic wall thickening and diastolic wall thinning were significantly smaller than normal (P less than 0.01). In patients without infarction, there was no correlation between peak rate of systolic anterior wall thickening and stenosis of the coronary artery supplying it, but there was a significant reduction in peak rate of diastolic wall thinning (P less than 0.01) in patients with stenosis greater than 90%; this difference was not apparent at any lower degree of stenosis. This population could not be recognized by any other parameter of global or regional ventricular function; thus, diastole is more sensitive to regional left ventricular dysfunction than systole.


Computed tomography for localization and sizing of experimental acute myocardial infarcts. Computed tomography (CT) has been used to quantitate acute myocardial infarct size in isolated, arrested canine hearts. Acute myocardial infarcts were produced in 20 hearts by either left anterior descending (13 dogs) or circumflex coronary artery ligation (seven dogs). Each animal was given iodinated contrast media intravenously immediately before sacrifice 24--72 hours postinfarction. All infarcts greater than 1 g and one of three infarcts 0.5 g or less were detected by CT imaging. Infarct volume determined by CT correlated with gross infarct weight (r=0.83). CT imaging, however, consistently underestimated infarct volume; underestimation was largest in a group of patchy, predominantly subendocardial infarcts. As adequate equipment and techniques for in vivo studies are developed, CT imaging of the heart may become important in clinical evaluation of myocardial infarction.


A multivariate approach for interpreting treadmill exercise tests in coronary artery disease. To determine the value of a multivariate approach for the analysis of the treadmill exercise tolerance test (ETT), 237 patients referred for evaluation of chest pain who underwent a standard Bruce protocol ETT and coronary arteriography were studied. Predictive value of a positive ETT was 0.78 (43/55) using 1.0--1.9 mm ST segment depression criterion, 0.97 (59/61) using greater than or equal to 2.0 mm ST segment depression. When the 1.0--1.9 mm ST criterion was combined with peak systolic blood pressure-heart rate product (double product) less than or smaller than 23,000, exercise duration less than 6 minutes, and ST depression for greater than 3 minutes into recovery, predictive value improved to 0.89 in 18 patients with any two of the above. Predictive value for multivessel disease was also improved using non-ST criteria. Predictive value of a negative ETT for absence of coronary artery disease was 0.60 (29/48), and was 0.86 (12/14) if double product was greater than or equal to 30,000. Presence of chest pain during ETT did not improve predictive value of any type of test. Digitalis ingestion in 33 patients was not associated with decreased predictive value of a positive test. These data suggest that the predictive value of both positive and negative ETT in a symptomatic population can be improved with a multivariate approach.


Echocardiography of left ventricular masses. The M-mode and two-dimensinal real-time echocardiographic findings in 10 patients with left ventricular masses are discussed. Two patients had left ventricular tumors and eight had left ventricular thrombi. In all cases the diagnosis was confirmed by angiography or surgery. The intracavitary and intramural left ventricular tumors were detected both by M-mode and two-dimensional echocardiography . M-mode echocardiography, however, did not detect the left ventricular thrombus in all instances. Two-dimensional echocardiography was able to identify the four large and inhomogeneous left ventricular thrombi but did not clearly identify four cases of smaller mural thrombi. Echocardiography techniques useful in detection of left ventricular masses are discussed.


Effects of indomethacin on the vascular abnormalities of Bartter's syndrome. We examined the hypothesis that the vascular abnormalities of Bartter's syndrome are due to excess production of prostaglandin. Balance studies and vascular reactivity studies were performed before and after indomethacin (200 mg/day) in a patient with well-documented Bartter's syndrome. During indomethacin, potassium balance became positive, serum potassium rose from 2.1--3 mEq/1 in the absence of potassium supplementation, plasma renin activity decreased from 55--3.2 ng/day and peripheral plasma PGA-like activity fell from 1460 +/- 220 to 456 +/- 71 pg/ml. Before indomethacin, forearm vasoconstrictor responses to brachial arterial infusions of angiotensin II, norepinephrine and to neurogenic reflex stimulation elicited by lower body suction were greatly depressed compared to those of normal subjects. During indomethacin these responses were restored to normal. The dose of intravenous angiotensin II required to increase diastolic blood pressure 20 mm Hg decreased from 160--30 ng/kg/min. These data support the hypothesis that the vascular insensitivity to exogenous angiotensin II, norepinephrine and to neurogenic reflex stimulation observed in this patient with Bartter's syndrome is due to excess prostaglandin. Moreover, stimulation of the renin-angiotensin-aldosterone system in this syndrome appears to be a compensatory adaptation to excess prostaglandin production.


Complete common atrioventricular canal in infancy--surgical repair and postoperative hemodynamics. Fourteen infants with complete common atrioventricular canal (CCAVC) underwent open heart surgery under deep hypothermia and circulatory arrest. There were three operative deaths and two late deaths. Postoperative studies performed in seven of the nine survivors revealed nearly normal hemodynamics. There were no residual shunts, and excellent mitral valve function was observed in six patients. In one patient, residual mitral regurgitation was noted. The pulmonary artery pressures and pulmonary vascular resistances were normal except in one who had severe pulmonary vascular obstructive disease before surgery. The mean left ventricular end-diastolic volume changed from 175 +/- 24% (SEM) before surgery to 106 +/- 7% after surgery (P less than 0.01). The corresponding right ventricular end-diastolic volume changed from 166 +/- 16% to 102 +/- 19% (P less than 0.025). Left ventricular ejection fraction was mildly decreased before and after surgery (0.63 +/- 0.02). Surgical repair of CCAVC is possible during the first year of life, with likely normalization of cardiac size and function. Unsatisfactory results related to pulmonary vascular obstruction may be anticipated if repair is delayed much beyond the first year.


Fulminant beriberi heart disease with lactic acidosis: presentation of a case with evaluation of left ventricular function and review of pathophysiologic mechanisms. Cardiac beriberi is considered a rare disease in western society. A patient with fulminant Shoshin-type beriberi was studied in the acute phase and found to have severe metabolic acidosis, high output biventricular failure, and markedly low systemic vascular resistance. Red blood cell transketolase activity was abnormally low. Following treatment with thiamine, diuretics, digitalis and oxygen, all abnormalities disappeared. The historical background of the disease is reviewed along with a discussion of pathophysiologic mechanisms responsible for the hemodynamic profile and lactic acidosis. Angiographic and hemodynamic data on the patient presented suggest relative depression of left ventricular function in the acute phase of beriberi. Since beriberi is uncommonly encountered, emphasis is placed on diagnostic and therapeutic implications of the disease which may not be widely appreciated.


High-performance liquid-chromatographic separation and fluorescence measurement of biogenic amines in plasma, urine, and tissue. We describe a high-performance liquid-chromatographic method for measuring histamine, norepinephrine, octopamine, normetanephrine, dopamine, serotonin, and tyramine in plasma (2 ml), brain (0.2 g), or urine. These amines are modifed by pre-column derivatization with o-phthalaldehyde, which stabilizes the molecules, facilitates extraction, and improves detection of nanogram amounts. Before separation, samples were neutralized with KOH and immediately derivatized and extracted into ethyl acetate, in which derivatives were stable for longer than 24 h. Interfering amino acids were removed from ethyl acetate by partitioning twice with Na2HPO4 buffer (pH 10.0). Separation was complete in about 90 min on a ""mu Bondapak/phenyl" column, with which a stepwise gradient of methanol/phosphate buffer (pH 5.1) was used. A variable-wavelength fluorometer was used (exciting wavelength, 340 nm; emission wavelength, 480 nm). Amount and response were linearly related from 1 to 200 pmol. Precision (CV) for retention times was 1%, for derivatization and injection 2.5%. Analytical recoveries of the seven amines from 2 ml of plasma fortified with 200 pmol averaged 65% (CV approximately 8%). Data on rat-brain tissue samples are compared with results by the trihydroxyindole method. Application of the method to urine from normal persons and a patient with a brain tumor is demonstrated.


A melting-point-of gallium apparatus for thermometer calibration. We have investigated the equilibrium melting point of gallium as a temperature fixed-point at which to calibrate small thermistor thermometers, such as those used to measure temperature in enzyme reaction analysis and other temperature-dependent biological assays. We have determined that the melting temperature of "6N" (99.999% pure) gallium is 29.770 +/- 0.002 degrees C, and that the constant-temperature plateau can be prolonged for several hours. We have designed a simple automated apparatus that exploits this phenomenon and that permits routine calibration verification of thermistor temperature probes throughout the laboratory day. We describe the physics of the gallium melt, and the design and use of the apparatus.


Multilayer film elements for clinical analysis: general concepts. Dry, thin films containing all necessary reagents for clinical analysis by colorimetry have been designed. Reagents in a matrix of hydrophilic polymer are coated on top of a transparent plastic base. A white isotropically porous polymer spreading layer, 80% void volume, is coated over the reagent layer(s). In the analysis, a drop (typically 10 microliter) of undiluted serum or other fluid is touched to the spreading layer. The fluid spreads rapidly and uniformly through the pore structure, filling a void volume corresponding to the drop volume. Water and low-molecular-weight components diffuse from the spreading layer into the reagent layer(s), initiating the reaction sequence. The spreading layer acts also as a white optical diffuser for reflection densitometry. Optical reflection density is linearized through use of the function developed by Williams and Clapper [J. Opt. Soc. Am. 43, 595 (1953)] to convert reflection to transmission density. A wide variety of chemical assays are compatible with this format. As an example, for the glucose film we found coefficients of variation of 1.5% in predicting glucose concentrations in control sera during 20 days. Results for glucose concentrations in several hundred patients' sera by the present method were very cose to those obtained with the Center for Disease Control's hexokinase reference method.


Rapid assessment of isoenzymes by high-performance liquid chromatography. We describe the rapid profiling of isoenzymes by use of microparticulate anion-exchange chromatography supports and a continuous, post-separation enzyme detector in a high-performance liquid chromatograph. Chromatographic analysis and enzyme detection are fully automated and provide excellent reproducibility. Factors affecting the isoenzyme profile and detector response characteristics are assessed. Lactate dehydrogenase and creatine kinase isoenzymes in tissue extracts, control materials used as electrophoretic standards, and serum were profiled by this method to establish the resolution and reliability of the method. We show the clinical use of this method in detecting changes in these isoenzymes in serum associated with acute myocardial infarction.


Automated system for fractionation of blood samples. We describe a prototype system for preparing multiple fractions of blood components (plasma, washed erythrocytes, and hemolysates) by use of automated techniques. The procedure is based on centrifugal separation and sample transfer by induced pressure differentials in a blood-processing vessel (rotor) that has been designed to process 24 samples simultaneously. Erythrocytes are sedimented against the outer walls of individual sample chambers, and plasma is siphoned, by imposition of either a slight positive or negative pressure, into individual reservoirs in a collection ring. Cells are washed in situ; samples of washed cells, either packed or in saline solution, can be recovered. Cellular hemolysates are automatically prepared and transferred to individual, commercially available collection vials, ready for immediate analysis or for storage in liquid nitrogen. The system has potential application in any biomedical area in which many samples are to be expeditiously analyzed and in which one or more of the blood fractions will be used. A separate unit has been designed and developed for the semiautomated cleaning of the rotor.


Development and evaluation of a glucose analyzer for a glucose controlled insulin infusion system ((Biostator). The Glucose-Controlled Insulin Infusion System (Biostator) is a modular, computerized, feedback control system for dynamic control of blood glucose concentrations in diabetics. This on-line glucose analyzer for use with whole blood utilizes a novel enzyme (glucose oxidase)-membrane configuration and an electrochemical cell to measure the H202 generated. The analyzer exhibits both short- and long-range stability, and instrument response and analyte concentration are linearly related over the full range of clinical interest. The response is fast, accurate, and precise, and permits determination of blood glucose within 2 min from the moment the blood leaves the patient. Correlation studies were completed to show the agreement between the Biostator Glucose Analyzer and the FDA's recommended hexokinase/glucose-6-phosphate dehydrogenase procedure on whole blood (e.g., average per cent recovered for 11 concentrations between 250 and 900 mg/liter was: hexokinase, 95.6%, Biostator Analyzer, 95.9%; bias and SDd, respectively, at low, normal, and high glucose values were: 12 and 41 mg/liter at the 500 mg/liter level; 4 and 52 mg/liter at the 1000 mg/liter level, and 4 and 128 mg/liter at the 4000 mg/liter level). No appreciable interference is observed with above-normal concentrations of bilirubin, uric acid, creatinine, sodium salicylate, or dextran. Platelet adhesion, which tends to decrease the useful life of the membrane, has been significantly decreased.


Dual-column cation-exchange chromatographic method for beta-aminoisobutyric acid and beta-alanine in biological samples. A rapid, automated chromatographic method has been developed for the quantitation of the nucleic acid catabolites beta-aminoisobutyric acid and beta-alanine in urine, serum, and other physiological fluids. The analyses were performed on a modified Beckman 121M amino acid analyzer with dual ion-exchange columns and the use of a single sodium citrate buffer (pH 4.38, 0.20 mol/liter). By carefully matching the elution pattern for the two ion-exchange columns and alternating use of these columns, analyses are completed every 40 min. The chromatography, regeneration, and equilibration of the two columns are precisely programmed, thus the detector sees only the elution of beta-aminoisobutyric acid and beta-alanine alternately from each column. Long-term precision and analytical recovery for the two metabolites in urine were 1.9 and 102%, and 3.3 and 101%, respectively. Their normal physiological values were determined in human serum and urine. Their excretion in the urine was also studied as a function of collection time, to validate a more convenient, less costly method of sampling. This study shows that randomly collected samples are acceptable when the concentration of the two metabolites are expressed in terms of creatinine excretion. In addition, the distribution of the free and conjugated forms of the two metabolites in urine and serum was studied. A preparative method was also developed for the quantitative isolation of beta-amino-isobutyric acid from urine samples. The alternating dual-column technique may be applied to any ion-exchange chromatographic method where many analyses must be performed. This method is currently used in our laboratories for measuring these beta-amino acids in urine and serum of patients with various types of cancers.


Determination of drugs in plasma by high-performance thin-layer chromatography. High-performance thin-layer chromatography was used to determine chlorpromazine, amitriptyline, nortriptyline, imipramine, desipramine, phenobarbital, and phenytoin in plasma, to demonstrate the utility of this technique for routine analysis. We quantitated the separated components by use of ultraviolet reflectance spectrometry with detection limits as low as 1 microgram/liter. Regressions of psychoactive agents extracted from plasma were linear over the range of 0 to 300 microgram/liter. The anti-convulsant drugs, phenobarbital and phenytoin, were determined over a range of 0 to 50 mg/liter. Analyses were rapid, reproducible, and well-suited to large-scale programs. Separated components also can be identified in situ by ultraviolet spectrophotometry.


Chromatographic separation and continuously referenced, on-line monitoring of creatine kinase isoenzymes by use of an immobilized-enzyme microreactor. We describe a new concept in continuously referenced monitoring of the isoenzyme activities of creatine kinase (EC 2.7.3.2) after liquid-chromatographic separation. After separation on a diethylaminoethyl-Sephacel column, the three isoenzymes of creatine kinase undergo a series of coupled enzyme reactions, ultimately resulting in the formation of ultraviolet-detectable NADPH. A major advantage of this detection system is the immobilized-enzyme microreactor (2 X 17 mm), which may be removed and stored refrigerated when not in use. A split-stream configuation allows self-blanking of endogenous ultraviolet-absorbing constituents in authentic sera samples, which would otherwise make definitive diagnosis and quantitation difficult or impossible. This system is applicable to the automated analysis of creatine kinase isoenzymes in the clinical laboratory.


Prospective applications of calorimetry in the clinical laboratory. Calorimetric analysis depends on the direct proportionality between the heat changes that occur during chemical reactions and the amount of reacting substances. Potential uses of calorimetry in the clinical laboratory are discussed, with examples. The calorimetric technique does not require optically clear specimens, and if the specificity of the measured reaction is assured, calorimetry can be used for quantitative determinations of components that are present in a complex matrix system such as body fluids. Specific enzymic reactions have been used to measure substrates and enzyme activities in biological specimens calorimetrically, with precision, sensitivity, and accuracy comparable to routine photometric techniques. The application of calorimetry in the clinical laboratory is limited now by its slowness, but development of automated instruments may enable the technique to become competitive with conventional analytical techniques in the clinical laboratory.


Phosphate metabolism in chronic liver disease. Phosphate metabolism was investigated in 26 patients with a spectrum of liver diseases and mean fasting plasma phosphate concentrations were in the low normal range. A standard oral load of phosphate was used to test absorption and was subnormal in the majority of patients with large bile-duct obstruction and alcoholic liver disease. Subnormal results were also seen in patients with primary biliary cirrhosis and cirrhosis secondary to chronic active hepatitis. These abnormalities appeared to be related to vitamin-D deficiency. Tubular reabsorption of phosohate was markedly reduced in 3 of 14 patients. The therapeutic implications of phosphate status in liver disease are important.


Identification of placental alkaline phosphatase in human sera using polyacrylamide gel electrophoresis. Polyacrylamide gradient gel electrophoresis may be used to separate placental alkaline phosphatase from other types of serum alkaline phosphatase. This method, of which specificity is demonstrated by the thermostability and immunological reaction of the placental form, is sensitive enough to detect an activity of 0.02 mU in a sample, and seems suitable for use in investigating placental isoenzyme in serum.


3-Aminopiperid-2-one, an unusual metabolite in the urine of a patient with hyperammonaemia, hyperornithinaemia and homocitrullinuria. The urine of a patient with a disorder characterized by hyperammonaemia, hyperornithinaemia and homocitrullinuria contains abnormal amounts of 3-aminopiperid-2-one. The properties of this compound closely resemble those ascribed previously (Gordon, B.A., Gatfield, P.D. and Taller, E. (1977) Clin. Biochem. 10, 78-82) to ornithine methyl ester. The excretion of the aminopiperidone ranged from 130-1050 micronmol/g creatinine.


3-Amino-2-piperidone in the urine of patients with hyperornithinemia. 3-Amino-2-piperidone, a delta-lactam of ornithine, has been detected in the urine of a number of patients with hyperornithinemia. The distinctive yellow colour formed with a ninhydrin-cadmium reagent should help in the detection of hyperornithinemia by urinary chromatography.


Renal excretion of cystathionine and creatinine in humans at different ages. The renal excretion of cystathionine is not age-dependent when related to body surface. Regarding the urinary creatinine concentration as reference, the excretion of cystathionine in adults is lower than in infants and children. However, this is probably due to a higher urinary concentration of creatinine in adults compared to that in children. Premature infants excrete more cystathionine in their urine than mature infants. The same is true for premature infants on a methionine-enriched formula compared to premature infants on a low methionine formula.


A rapid and simple microfractionation method for the analysis of hexosaminidase A and B activities in small numbers of cultured (amniotic fluid) cells. A simple and rapid microfractionation procedure is described which enables the separate analysis of hexosaminidase A and B activities in as little as a few hundred to a thousand cultured human cells. 25 microliter cell homogenate is added to a pellet of DEAE-cellulose and 50 microliter 0.1 M NaCl in buffer. After centrifugation the hex B and I forms are measured in the supernatant, whereas hex A is determined by direct incubation of the DEAE pellet with methylumbelliferyl substrate. The reliability and reproducibility of the method is compared with that of heat inactivation and column chromatography. The application of the procedure is illustrated by analyses of fibroblasts and cultured amniotic fluid cells from pregnancies at risk for Tay-Sachs disease and by serum assays for the diagnosis and heterozygote testing of this disease.


Serum squalene levels in hepatobiliary diseases. Serum squalene levels did not change in patients with acute hepatitis, chronic active hepatitis and liver cirrhosis, but were significantly reduced in patients with intra- and extrahepatic cholestasis. The ratio of cholesterol to squalene remained normal in patients with acute hepatitis as well as chronic active hepatitis, while being slightly decreased in patients with liver cirrhosis. On the other hand, in patients with cholestasis the ratio was markedly raised. From these observations we confirmed abnormal sterol metabolism in hepatobiliary diseases, and clinical usefulness of the ratio of cholesterol to squalene to distinguish hepatocellular injury and cholestasis.


Determination of total and direct bilirubins in serum with sodium dodecyl sulfate as an accelerator. A new method for the determination of total and conjugated bilirubins in serum with use of sodium dodecyl sulfate (SDS) is described. In the presence of SDS, the reaction of bilirubin with diazotized sulfanilic acid proceeded smoothly and was completed within 15 min at room temperature, thus resulting in a clear solution having a maximal absorbance at 565 nm which was linear up to a level of 200 mg/l bilirubin concentration. The advantages of this method are: (1) a clear reaction mixture results in any case; (2) the result is not affected by hemolysis, lipemic and turbid sera. The proposed method offers a new general application for the measurement of total and conjugated bilirubins in serum.


Serum glycylproline p-nitroanilidase activity in rheumatoid arthritis and systemic lupus erythematosus. Glycylproline p-nitroanilidase activity in serum of patients with advanced rheumatoid arthritis or with systemic lupus erythematosus but with normal hepatic function was found to be significantly lower than that of normal adult controls. Decrease of this enzyme's serum activity was more pronounced in systemic lupus erythematosus. A significant inverse correlation was observed between the enzyme activity and the duration of rheumatoid arthritis.


Improved electrophoretic resolution of LDH isoenzymes in agar-agarose mixtures by utilizing its endosmotic properties. A simple technique is described which gives a better separation of lactate dehydrogenase isoenzymes; by mixing a correct proportion of a gel with a high electroendosmotic property such as agar, and a gel with alow electroendosmotic property such as agarose. The different positions of the application slit in lactate dehydrogenase isoenzyme patterns and the effect on the positioning of the application slit after mixing gels with different electroendosmotic properties are discussed.


Infinite dilution conductimetry of plasma and urine: correlation with osmolality. The infinite dilution conductivity (IDC) of plasma and urine allows a measurement of the electrolyte content in small samples (5 to 15 microliter). The method was compared to the corrected osmolality (II'p) measured by the freezing-point depression. A linear correlation existed between II'p and the IDC: for plasma: II'p = 13.10 sigma o,p + 37.00 (n = 46 and r = 0.9949) for urine: II'u = 12.75 sigma o,u + 16.56 (n = 85 and r = 0.9504). The measurement of the IDC does not depend on protein concentration and can be used instead of the osmometer methods to determine the total plasma and urine electrolyte content.


The absolute configuration of urinary 2-hydroxybutyric acid in patients with ketosis and lactic acidosis. The absolute configurations of urinary 2-hydroxybutyrate and 3-hydroxybutyrate were determined in patients with lactic acidemia and ketosis by capillary gas-liquid chromatography of their O-acetylated (--)-menthyl ester derivatives. 2-Hydroxybutyrate had the L-configuration, whereas 3-hydroxybutyrate was in the D-configuration.


Mechanism for interference of hydrochlorothiazide with the Kober reaction for determination of urinary estriol in pregnancy. Investigation of the mechanism of the lowering effect of hydrochlorothiazide, which was administered orally, in the determination of estriol from the pregnancy urine has been carried out. The isolation and determination of the structure of a copolymer formed from estriol and formaldehyde have suggested the mechanism by which, during the acid hydrolysis process of the glucuronide conjugate of estriol, some copolymers of estriol and formaldehyde generated from hydrochlorothiazide, were formed, thus lowering the observed values of the estriol contents in the urine.


Optimized radioimmunoassay curve fitting program suitable for use on desktop calculators. A simplex search program for the logit-log parameters of radioimmunoassay calibration curves, suitable for use on a small desktop calculator, is described. The technique features a weighted least-square method to extract the maximum information out of the calibration data. A criterion for rejection of outliers is included.


An enzyme-linked immunoassay for ferritin in human serum and rat plasma and the influence of the iron in serum ferritin on serum iron measurement, during acute hepatitis. To measure human serum ferritin and rat plasma ferritin a non-competitive enzyme-linked immunoassay has been developed using horseradish peroxidase as the enzyme. In this assay it proved necessary to use heated rat plasma to obtain reproducible ferritin values. The heating procedure caused a loss of 38% of the plasma ferritin. Rat plasma ferritin values have been corrected for this loss. The standard deviation, from duplicate normal human and rat samples is 10 ng ferritin/ml serum and 69 ng/ml plasma, respectively. (The mean ferritin concentrations are: in human sera, 82 ng/ml and in rat plasma 762 ng/ml.) Mean recovery of added liver ferritin in the human serum is 104% +/- 4% (+/-S.E.M') and in the rat plasma 101% +/- 3% (+/- S.E.M.). Normal ferritin concentrations varied in the human material between 30 ng/ml and 300 ng/ml serum, and in the rat plasma between 500 ng/ml and 1300 ng/ml. During increased body iron and acute hepatitis the ferritin concentrations, in patients as well as in rats, exceeded the upper limit of the normal values in most cases. During human hepatitis high serum ferritin levels combined with high serum iron levels were measured. The high serum iron concentrations could not be explained by the high serum ferritin concentrations, even if the iron content of the ferritin is supposed to be high.


Measurement of plasma renin activity by radioimmunoassay after prolonged cold storage. Measurement of plasma renin activities in four separate quality control pools showed no change when measured by radioimmunoassay after being individually stored at -20 degrees C for up to fifteen months, validating their use as long-term quality controls. These results contradict those reported by some authors.


Volume exclusion errors and the determination of serum zinc. Volume exclusion gives rise to positive errors in the results of plasma or serum zinc determinations by methods in which protein is precipitated and the zinc extracted into solution. The error is amplified if two extraction steps are employed, and may be +20% or more. The same effects must be expected in any analysis involving comparable extraction procedures, whatever the substance being determined.


Decreased tryptophan excretion by depressive patients. The concentration and 24-h urinary excretion of tryptophan has been measured in urine samples from monopolar female depressed patients and female control subjects. Female depressed patients and the control subjects excrete similar amounts of tryptophan. Patients with endogenous features of depression excrete significantly less tryptophan in 24 h than do the patients with reactive features and the control subjects. The relationship between plasma tryptophan concentration and 24-h urine tryptophan excretion in control subjects has been investigated and the results discussed in the light of abnormalities of tryptophan metabolism in depressive illness.


A gas chromatography-mass spectrometry assay of human plasma catecholamines. Dopamine, norepinephrine and epinephrine have been determined by mass fragmentography in plasma of normo- and hypertensive patients. New derivatives of norepinephrine and epinephrine have been prepared, allowing the simultaneous reading of the base peaks of the three amines and of their internal standards with a magnetic-sector mass spectrometer.


An improved method for the determination of human erythrocyte pyrimidine 5'-nucleotidase activity. A radiometric method is described for measuring pyrimidine 5'-nucleotidase activity in human peripheral blood haemolysate. The substrate [14C]uridine monophosphate is converted to [14C]uridine. Two simple and rapid methods to isolate the product of the reaction employing either descending chromatography or elution from DEAE cellulose paper have been developed. With the described methods the specific activity of pyrimidine 5'-nucleotidase of human erythrocytes is 6.7 +/- 2.7 (+/- 1 S.D.) nmol/h/mg protein and this activity appears to be widely distributed in human tissue.


Simultaneous study of cortisol, growth hormone and prolactin nyctohemeral variations in normal and obese subjects. Influence of prolonged fasting in obesity. Hourly integrated concentrations (IC) of growth hormone (GH), prolactin (PRL) and cortisol were determined by a continuous sampling procedure in six obese women, before and at the end of a 12 day fast, and in eight normal controls under basal conditions. Hormonal 24 h IC and nyctohemeral variations were calculated from these data. Nyctohemeral rhythms were investigated by the periodogram method. A significant increase over basal values of 24 h IC of PRL, GH and cortisol was observed at the end of the fasting period. Nyctohemeral variations--but not nyctohemeral rhythm--of IC-GH were found in normal subjects. They were abolished in obese patients under basal conditions but restored during fasting. The circadian rhythm of cortisol was not altered in obesity. A shift of the normal nyctohemeral rhythm of PRL was observed in obese patients, but the normal pattern was restored during fasting.


'Low T3 syndrome' in patients chronically treated with an iodine-containing drug, amiodarone. Cardiac patients treated with the iodine-containing drug 'amiodarone' undergo a significant iodine overload which can last for months after the drug has been withdrawn. Some patients develop hyperthyroidism and others hypothyroidism. In the hyper- or hypothyroid patients, the indices of thyroid function are modified as usually observed in these situations. In the patients remaining euthyroid while taking amiodarone or after its withdrawal, but still under its influence as shown by the iodine overload, a 'low-T3 syndrome' is observed, this state being characterized by a high total T4, a low free T4, a normal T3 resin uptake, a low total T3, a normal free T3, a high r-T3 and a relative TSH-unresponsiveness to TRH.


Oestradiol secretion in men and pre-menopausal women. Blood samples were obtained from a group of regularly-cycling normal women (n = 13) and a group of normal men (n = 5) at 15 min intervals for periods ranging from 9-14 h whilst the subjects remained resting quietly in bed. The concentration of plasma oestradiol was measured in a radioimmunoassay which had been carefully optimised and the mean concentration and coefficient of variation calculated for each subject. Plasma oestradiol concentrations were found to fluctuate rapidly in all subjects. The largest sample-to-sample variation was found in regularly cycling women near mid-cycle, and the least variation occurred in the male subjects. The coefficients of variation were approximately twice the intra-assay variation confirming that the observed pulsatile patterns of secretion were not due to technical errors. An analysis of variance performed on the mean hourly concentrations from each subject showed a significant variation (P less than 0.001) between sampling periods with peaks occurring during the first hour of sampling (08.00-09.00 hours). This result is suggestive of the presence of a circadian rhythm although it is not conslusive.


Sex hormone concentrations in post-menopausal women. Plasma sex hormone concentrations (testosterone, (T), androstenedione (A), oestrone (E1) and oestradiol (E2) were measured in forty post-menopausal women more than 4 years post-normal menopause. Correlations between these and age, years post-menopause (YPM), degree of obesity and fat mass respectively were studied. T and A, as well as E1 and E2 were positively correlated (P less than 0.01), but no statistically significant correlation between A and E1 was observed. Sex hormone concentrations in this group of postmenopausal women (greater than 4YPM) did not show any variation as a function of age, with the possible exception of E2 which showed a tendency to decrease in the late post-menopause. E1 and to a lesser extent E2 as well as the E1/A ratio were significantly corelated with degree of obesity or fat mass, suggesting a possible role of fat tissue in the aromatization of androgens. Neither the T/A nor the E2/E1 ratios were correlated with fat mass, suggesting that the reduction of 17 oxo-group does not occur in fat tissue. The E1/A ratio was significantly higher than the reported conversion rate of A in E1. This might suggest the existence of an additional precursor of plasma E1.


The effect of propranolol on thyroid hormones and oxygen consumption in thyrotoxicosis. The possibility that propranolol may exert its beneficial actions in thyrotoxicosis by an effect on thyroid hormone concentrations has been investigated by measuring these and oxygen consumption in a group of thyrotoxic patients before and after treatment with propranolol. Following treatment a significant fall in plasma T3 concentration and oxygen consumption occurred and a direct correlation was found between these two variables. Propranolol may, therefore, exert some of its beneficial effects in thyrotoxicosis by an action on T3 metabolism.


Bromocriptine treatment of males with pituitary tumours, hyperprolactinaemia, and hypogonadism. Plasma prolactin concentrations were measured in thirty-four males with pituitary tumours and twenty-two patients (65%) were found to have hyperprolactinaemia. Plasma testosterone concentrations were subnormal in twenty-nine patients. Ten patients with hyperprolactinaemia were treated with bromocriptine; prolactin was restored to normal values in eight patients but testosterone secretion remained deficient. Two patients were resistant to bromocriptine. Some improvement in libido and potency was obtained after restoration of normal prolactin concentrations in four cases in spite of persistently low testosterone secretion. For maximal improvement in sexual function treatment with both bromocriptine and testosterone was required.


Influence of lower body negative pressure upon arginine vasopressin release. Lower body negative pressure (9-12 kPa) was applied to ten normal subjects. Large increases in plasma arginine vasopression concentration occurred only in subjects that experienced syncopal symptoms and developed hypotension. Blood samples obtained from the superior vena cava at 1/2 min intervals during application of negative pressure showed that maximal plasma vasopressin concentrations occurred with hypotension. Chromatography of the presyncopal plasma on Sephadex G-25 gave a large peak which eluted in the position of synthetic arginine vasopressin.


Correlations between prolactin and progesterone, oestradiol-17-beta and oestriol during early human pregnancy. The correlations between serum prolactin and progesterone, oestradiol-17-beta and oestriol were determined in 125 pregnant females between the sixth and fourteenth week of pregnancy. No significant correlations were found between prolactin and progesterone. Correlations between prolactin and oestradiol-17-beta and oestriol were mostly positive, but only significant during the twelfth week of pregnancy.


Presymptomatic diagnosis of adult onset polycystic kidney disease by ultrasonography. Results of an ongoing prospective study of progeny of patients with adult-onset polycystic kidney disease using grey-scale ultrasound and high-dose nephrotomography are reported. Six asymptomatic subjects out of 17 at risk for polycystic kidney disease were found by ultrasonography to have multiple renal cysts; this included two unrelated children aged 18 months and 6 y who had normal high-dose nephrotomography. We suggest that ultrasonography may be the method of choice for presymptomatic detection of polycystic kidney disease. Serial studies of at-risk individuals by sonography will be useful in determining the earliest age of detection, the latest age of ultrasonography presentation, and in following the natural history of polycystic kidney disease.


The Dyggve-Melchior-Clausen syndrome in adult siblings. The clinical and radiographic features of three adult siblings with mental deficiency and dwarfism due to the Dyggve-Melchior-Clausen syndrome are documented. The consanguinity of the unaffected parents is further evidence to support the concept of autosomal recessive inheritance of this disorder. The fact that this is the fifth reported kindred of Lebanese extraction emphasises the geographic predilection of the abnormal genes.


H-Y antigen in human intersexuality.

H-Y antigen in human intersexuality. The status of H-Y antigen was studied in 10 intersexual cases (three pure gonadal dysgenesis with XY genotype, three Klinefelter's syndrome, two true hermaphroditism with XX genotype, two male hermaphroditism) and in 18 normal adult subjects (nine males and nine females). In all these subjects, fluorescent staining and G-banding on chromosomes from cultured leukocytes confirmed their karyotype. Interestingly, H-Y antigen was found to be negative in XY females with dysgenetic gonads (PGD), while in the remaining intersexual states (viz Klinefelter's syndrome, true hermaphroditism and male hermaphroditism), it was found to be positive. These observations confirm that morphological differentiation of testis is controlled by H-Y antigen, and indicate that in the absence of the H-Y antigen, the gonad in pure gonadal dysgenetic patients (46, XY) could not be differentiated into testis, Further, it appears that H-Y antigen in no way influences the secretory function of testis.


Charcot-Marie-Tooth disease: data for genetic counseling relating age to risk. One hundred and nine individuals from complete sibships at risk for autosomal dominant Charcot-Marie-Tooth (CMT) disease in 15 unrelated families were evaluated by physical examination and motor nerve conduction studies. Penetrance of the gene was 28% in the first decade, but was essentially complete by the middle of the third decade. The average age of onset of symptoms was 12.2 y, with a standard deviation of 7.3. Persons at risk who have no clinical manifestations and who are over age 27 have less than a 3% probability of having inherited the CMT gene.


Biochemical investigations in cultured skin fibroblasts from patients with Duchenne muscular dystrophy. Cultured skin fibroblasts from patients with Duchenne muscular dystrophy were studied with a double-labeling procedure. Preliminary evaluation of the growth characteristics and average viability of dystrophic cells did not show any major abnormalities. Analysis of doubly labeled fibroblast mixture did not disclose any consistent anomaly in the distribution of subcellular fractions or in the major protein components of dystrophic fibroblasts.


The cherry red spot-myoclonus syndrome: a newly recognized inherited lysosomal storage disease due to acid neuraminidase deficiency. A newly discovered lysosomal storage disorder, apparently transmitted as an autosomal recessive trait, presents with cherry red spots in childhood, progressive debilitating myoclonus, insidious visual loss, and normal intelligence. Somatic and bony abnormalities are not evident clinically. Neuronal lipidosis and vacuolated Kuppfer cells are found upon tissue examination. The diagnosis can be most easily confirmed by chromatographic screening for urinary sialyloligosaccharides. The primary enzyme defect is a deficiency of an acid neuraminidase isoenzyme which cleaves sialyloligosaccharides. I discuss here the clinical phenotype in four patients, the chemical abnormality, the pathogenesis, the enzyme defect and the molecular genetics of this disorder.


Apparently non-deleted ring-1 chromosome and extreme growth failure in a mentally retarded girl. A girl, who was the product of the first recognized conception by healthy and chromosomally normal parents, and who was born 5 weeks before term with a birth weight of only 1,690 g, was found to have a ring-1 chromosome, r(1), in almost all cells analysed. A minor proportion of cells had a normal diploid chromosome complement including two regular No. 1 homologues. A few cells contained a large dicentric ring, and two monocentric ring-1 chromosomes were simultaneously observed in a few other cells. Q- and G- banding revealed the r(1) chromosome to be apparently non-deleted. The patient phenotypically resembled the three previously described human subjects with r(1) chromosomes, especially with respect to her remarkable growth failure and metal retardation. From consideration of data available on general development in subjects with an autosomal ring chromosome, it appears likely that the presence of such a ring chromosome per se in an early foetal chromosome complement may predispose to significantly retarded intrauterine and postnatal growth. Various genetical implications, including mitotic irregularities with subsequent loss of cells at division, are thought to account for the significant reduction of body mass in these patients.


Incidence and natural history of "head at risk" factors in Perthes' disease. Twenty-eight cases of Perthes' disease were evaluated roentgenographically a minimum of 4 years after diagnosis (range, 4-17 years). The original roentgenograms were examined to see if a prognosis was possible of the final result on the basis of: (1) "head at risk" factors, or (2) Catterall's degree of epiphyseal involvement. Five "head at risk" factors more accurately predicted the course of Perthes' disease than Catterall's degree of epiphyseal involvement. The latter may change as the disease progresses. There is a definite decreasing incidence of a good radiological result with an increasing number of risk factors. The 5 risk factors are: Gage's sign; lateral subluxation; calcification lateral to the epiphysis; diffuse metaphyseal reaction and a transverse epiphyseal plate. The ability to predict the probable course of the disease and the final result should allow early institution of a more rational treatment program.


The adductor transfer in the high-risk hip in myelodysplasia: a preliminary report. Hip instability occurs in meningomyelocele patients with lumbar level paralysis because of muscle imbalance. Transferring the hip adductor origins to the ischium can be used as the primary procedure to restore muscle balance and prevent hip instability in myelodysplasia patients if performed by the age of one year. Twelve lumbar meningomyelocele patients underwent bilateral adductor transfers. Secondary procedures, such as iliopsoas release or transfer or varus derotation osteotomy, were done in 14 hips. Ten hips needed no further surgery. Twenty of 24 hips were clinically and roentgenographically stable and showed roentgenographic evidence of improving hip development. Instability was associated with scoliosis, congenital dislocation, and age greater than one year at the time of the transfer.


The results of Charnley arthroplasty of hip performed for protrusio acetabuli. The results of total hip replacement in protrusio acetabuli using the Charnley technique have been very satisfactory. The immediate and late complications have been in no way different from those in ordinary cases of osteoarthritis and rheumatoid arthritis as performed in this hospital. There was no difference in the successful results whether a bone graft or cement alone had been used, and nothing to suggest that wire mesh need be used even in the severe cases. The diagnosis of idiopathic protrusio is 4 times more frequent than that of secondary protrusio. There was an incidence of 10 females for every male suffering from protrusio acetabuli. About half of the patients required bilateral low friction arthroplasties.


Osteomalacia as a contributing factor in fracture of the femoral neck in the elderly in Quatar. Eighty-seven patients with femoral neck fractures were investigated for possible evidence of osteomalacia. Eighteen patients were under the age of 50, or had sustained the fracture following severe injury. No evidence of osteomalacia was demonstrated in this group. In the remaining 69 patients the fracture was associated with a trivial injury, and in some patients no history of injury could be obtained. Only 16 (23.2%) of these showed evidence of osteomalacia; in 7 (10.1%) the disease was suspected. This occurred more often in women than men, and in trochanteric rather than cervical fractures.


Stabilization of Thompson femoral head prosthesis with a porous stem coating: a case report. A 40-year-old woman with a femoral neck fracture was treated with a proplast coated Fred Thompson prosthesis. Two years later the prosthesis was found to be securely stabilized to the femoral shaft with tissue ingrowth into the coating.


The effects of walking velocity and age on hip kinematics and kinetics. Kinematic and kinetic parameters of gait have a significant dependency on subject age and walking velocity. Hip flexion-extension, stride length, hip resultant force, hip resultant moment, and hip contact force all increase with increasing velocity. All of these parameters except hip resultant force are significantly affected by the age of the subject. The evaluation of patients with lower extremity problems utilizing such gait parameters must be conducted with an appreciation of normal values corrected for subject size, age, and walking velocity.


The assessment of the internal rotation gait in cerebral palsy: an electromyographic gait analysis. A study of 12 cerebral palsied children with internal rotation revealed three patterns of electromyographic activity: (1) Diagnostic pattern--where a simple muscle group stood out as the responsible agent--notably the medial hamstrings; (2) Nondiagnostic pattern--nonrecurring pattern; (3) Nondiagnostic pattern--recurring "mass limb reflex" pattern. In all cases, electromyography was useful for: (1) confirmation of clinical impressions. Electromyographic confirmation of phasic hamstring overactivity gives a firm basis for tendon surgery with expectancy of good results. (2) Detection of the responsible muscle group where clinical methods fail to do so. It detects the "at risk" patients, where follow up with tendon surgery at the appropriate time could be performed with predictable results. (3) Selection of patients who are likely to respond to tendon surgery, and those unlikely to benefit from it. The adductors and internal rotators may play only a secondary role in children whose predominant problem is internal rotation during gait. The medial hamstrings stand out as the most important single muscle group causing this problem. Consequently, it is important to analyze gait problems with the patient walking, and examine electromyographs during walking in the overall assessment of a patient with dynamic gait problem.


Use of the Fogarty embolectomy catheter as an "internal tourniquet". The Fogarty embolectomy catheter has been found useful in minimizing blood loss in large surgical procedures about the hip and pelvis. Its utility lies in the ability to achieve temporary intraluminal occlusion of the common iliac artery while the proposed surgical procedure is being carried out. The technique of instrumentation is simple, rapid, and can be carried out using no special instruments other than the catheter itself. The instrumentation adds little, if any, additional time to the surgical procedure, and in fact may significantly shorten it by achieving earlier definitive hemostasis. Fogarty catheters, a part of the regular armamentarium of vascular surgeons, are readily available at most institutions.


The immunogenicity of allograft knee joint transplants. Joint allotransplantation has been employed in the management of osteoarthritis affecting primarily one compartment of the knee. Biological resurfacing and realignment of the knee has been the goal. The immunological results of six patients posttransplant were studied with the lymphocyte microcytotoxicity test. Definite immunogenicity was demonstrated at an early stage. The sera from the recipients posttransplant was noted to abrogate the in vitro cytotoxicity suggesting the presence of blocking factors. The actual clinical significance of this phenomenon was difficult to judge insofar as no evidence of allograft joint rejection was seen.


A case report of total knee arthroplasty infected by Pasteurella multocida. A 72-year-old woman with a total knee prosthesis was infected with Pasteurella multocida organisms from a cat bite. The joint was successfully salvaged by surgical debridement, closed tube irrigation utilizing .25% acetic acid and appropriate antibiotics.


GSB knee joint: a further possibility, principle, results. The GSB Knee joint is a nonconstrained hinge joint, which combines the advantages of the so-called condylar or surface prosthesis with those of the constrained hinge joints. This report is of observations on the results and complications in 150 arthroplasties performed over a 5 year period.


Nontraumatic osteomyelitis of the patella. Nontraumatic, hemotogenous osteomyelitis is a childhood disease uncommonly encountered and rare in the patella. The initial signs are usually intraarticular, because of the sterile effusion. The primary pathology in the patella is easy to overlook. The infection generally does not penetrate the joint cavity and most cases can be treated conservatively, or by local debridement. Arthrotomy is not necessary and could involve the joint with the infection.


Function after patellectomy.

Function after patellectomy. Twenty cases of patellectomy for fracture and 14 cases of patellectomy for chondromalacia evaluated for postoperative strength, endurance, pain and functional complaints, revealed satisfactory results in 85% of the fracture group and 79% of the chondromalacia group. Some quadriceps weakness was usually present, but quadriceps strengthening overcame the loss of mechanical efficiency caused by patellectomy. A vigorous rehabilitation program should be followed for at least one year after surgery to secure the fullest recovery of function.


Primary coccidioidal synovitis of the knee: a report of four cases and review of the literature. Primary coccidioidal synovitis of the knee is a rare disorder and controversy exists in the literature over the efficacy of treatment with synovectomy and Amphotericin B therapy. Four cases are presented illustrating features of the natural history, diagnosis, and treatment of the disease.


Arthrographic demonstration of pigmented villonodular synovitis of the knee. Arthrography of the knee is most frequently used for diagnosis of conditions affecting the cartilage and menisci. In a 40-year-old man with pigmented villonodular synovitis, arthrography demonstrated a characteristic pattern of multiple filling defects. Arthrography may prove to be as useful for diagnosis of synovial lesions as for other intraarticular lesions.


The torn or degenerated meniscus and its relationship to degeneration of the weight-bearing areas of the femur and tibia. Data was collected on 300 cadaver knees dissected for the prime purpose of studying chondromalacia of the patella. Simultaneous observations were also made on the state of the meniscus and the articular cartilage in the tibio-femoral joint. The data did not seem to support the oft-repeated statement that the torn meniscus is the primary cause of unicompartmental osteoarthritis. Investigations were also carried out on 69 additional cadaver knees and 100 consecutive unselected arthroscoped knees in which there was damage either to the meniscus or the adjacent joint surfaces. In 60% of the combined series of cadaver and arthroscoped knees, the meniscal changes could not be correlated with the condition of the articular cartilage. In the remaining 40% in which there was coexisting pathology in the meniscus and the articular cartilage, a cause and effect relationship could not be established, but there was no evidence that a torn meniscus posed a significant threat to the articular cartilage.


Problem areas in the diagnosis and treatment of ligament injuries of the knee. The importance of the correct and early diagnosis of these soft tissue injuries to the knee cannot be overemphasized. There is a definite place for non-operative management of carefully selected patients. Realistic goals and expectations of surgery must be discussed with the patient to avoid postoperative misunderstandings. A more aggressive approach to cruciate ligament injuries, early mobilization of repairs and reconstructions, and a better understanding of the complexities of rotatory instability represent some of the recent, major advances in knee ligament surgery. Well supervised and constructed rehabilitation programs in the care of these injuries are essential if satisfactory results are to be achieved.


Medial collateral ligament injuries of the knee: a rationale for treatment. Isolated MCL I and MCL II lesions evidence good recovery of integrity and function under non-operative modes of treatment. Isolated MCL III lesions may also be treated by non-operative management, but with the expectation of a slightly less successful result. However, there is an 80% incidence of concomitant ligament injury with this grade of lesion. The prognosis following injury to the MCL is significantly influenced by the presence of concurrent compromise of other ligaments, particularly that of the anterior cruciate ligament. Resolution of knee instability and dysfunction following a mixed MCL injury of any grade severity is best accomplished through operative intervention. Therefore, it is the authors' opinion that isolated MCL III and all mixed MCL lesions are best managed with operative treatment. Because of the apparent influence compromise of other ligament structures have on the recovery of MCL function, an attempt must be made to repair all acutely injured structures at the time of surgery. The keystones of a satisfactory result are early and accurate diagnosis, prompt treatment, and when indicated, complete surgical repair.


Neutral fat globules in traumatized knees. Synovial fluid was analyzed for neutral fat globules using a modified Gurd test in 146 patients with various knee disorders. The presence of liquid neutral fat without an intra-articular fracture is an ominous sign of a significant soft tissue injury. Mechanically damaged knees contain neutral fat globules that are not found in normal or osteoarthritic knees. While liquid neutral fat may suggest a surgically amendable ligamentous and/or meniscal injury, 10% of the injured knees containing fat had an intra-articular fracture.


Gross pathological changes in the knee joint of the aged individual: a study of 300 cases. The incidence of chondromalacia of the pattella and degenerative arthritis of the knee is based on conjectural rather than objective autopsy observations. The notion that chondromalacia is a disabling, troublesome and almost universal disease affecting most older individuals is chiefly derived from clinical impressions of physicians who treat arthritis plus a few reports of European authors published some 50 years ago. The present investigation of 300 cadaver knees, whose average age was 70 years, demonstrates a much lower incidence of degenerative lesions of the articular cartilage than might be expected. There was minimal or no damage to the patella in 62% of the cases and an even lower incidence of 23% in the weight-bearing areas of the joint. Eighty-two per cent of the menisci were essentially normal, as were 96% of the cruciates. In patients in the U.S.A., articular cartilage of the knee resists the wear and tear of a normal lifespan remarkably well and infrequently undergoes progressive degradation.


Deep venous thrombosis following Charnley arthroplasty. A venographic investigation has been carried out on 50 patients undergoing Charnley total hip replacement. The overall incidence of thrombus formation was 54%. Most of the thrombi formed in the second postoperative week, with a preponderance for the operated side, and were sevenly distributed throughout the venous system. The preoperative assessment both clinical and venographic was of no value in predicting thrombus formation postoperatively. The fact that few thrombi formed in the "sensitive area" indicates that the Charnley technique of arthroplasty and the heat generated using acrylic cement has little part to play in the formation of postoperative thrombi, rather that a generalized hypercoagulable state is induced by the operation.


Extracortical attachment of bioceramic endoprostheses to long bones without bone cement. Dense, highly pure A12O3 ceramic not only shows excellent wear resistance and tissue biocompatibility, but also has sufficient mechanical strength for loaded endoprostheses. The necessary diameter size of the material to sustain adequate shear stresses can be achieved, if the endoprosthesis is attached extracortically to the conically truncated long bone according to the principle of the conical sleeve. Extracortical attachment of the endoprosthesis causes minor nutritive damage since long bones derive their vascular supply mainly from the medullary cavity. In this way a primary stable and loadable connection is established, which is a prerequisite for permanent anchorage of the implant through new bone formation. After experiments in 12 dogs bioceramic endoprostheses were implanted in a total of 40 human patients using this technique of extracortical attachment (12 hip joints, 24 proximal humeri, 4 special constructions). Thirty-six of these implants were stable after observation periods ranging from one to 49 months. A stable anchorage of the prostheses to the pre-existing bone through new bone formation could be demonstrated histologically. The above preliminary results show that bioceramic endoprostheses can be "incorporated" in the skeleton and possibly also withstand the functional stresses.


An evaluation of a method of trochanteric fixation using three wires in the Charnley low friction arthroplasty. The crossed wire technique of trochanteric reattachment, with ambulation from the second day after the arthroplasty, resulted in 2.3% of complete detachments, and 2.7% of fibrous union at one year (total failure rate of 5%). Of 75 trochanters which had a fibrous union at 3 months, 2 later became completely detached, 27 remained as a fibrous union and 46 progressed to complete or partial bony union by one year. The incidence of defective trochanteric union was 2.3 times more frequent in arthroplasties performed by residents in training than it was in those performed by senior staff, (10.8% and 4.6% respectively at 3 months and 5.6% and 2.4% respectively at 12 months). The incidence of defective trochanteric union in bilateral arthroplasties was double the rate in unilateral operations, (14% and 7% respectively). Eighty-six and one half per cent of the arthroplasties which developed defective union of the trochanter showed follow-up radiographic evidence of defective fixation, though 13.5% were apparently satisfactory on discharge. Roughly 79% (79.2%) of the cases which developed defective union of the trochanter developed broken wires within one year of the arthroplasty. Relief from pain by total joint arthroplasty was not significantly influenced by defective trochanteric union (mean postoperative grade for pain 5.8).


The number of total joint replacements in the United States. By comparing estimates from several sources an assessment can be made of the number of total joint replacement procedures performed annually in the United States. Approximately 80,000 hips and 40,000 knee joints were replaced in the U.S. during 1976. Total hip replacement has been accepted by the orthopedic community as an efficacious mode of treatment of the many painful and disabling forms of arthritis. A substantial patient population could benefit from perfection of designs for treating joints other than the hip.


A new power tool for removal of methylmethacrylate from the femur. An air turbine drill will remove methylmethacrylate from the medullary canal of the proximal femur in cases of failed total hip replacement and from the distal femur in cases of failed long stem total knee replacement. This power tool is expensive, but the high cost is partially offset by multiple other uses: cutting burr holes in the skull, doing osteotomies, cutting bone grafts and making windows in the femur. The power of the instrument and effectiveness of the burrs make it important to have instruction and direct experience in its proper use prior to use in the operating room.


The Amsterdam suspension. Balanced suspension after hip surgery. The Amsterdam Suspension is an easily applied, mechanically efficient and inexpensive apparatus for use in postoperative treatment of patients with either hip fractures or arthroplasties. Amsterdam suspension allows lower extremity exercises to be started in the immediate post surgical period by markedly reducing the gravitation load on the extremity.


Gluteal compartment syndromes: a report of three cases and management utilizing the Wick catheter. Contusion or prolonged compression of the buttock produced severe local injury in 3 cases. Rhabdomyolysis with acute renal failure occurred in 2 of these cases, and one of them had an associated sciatic nerve palsy. The affected muscles included the gluteus maximus, gluteus medius, and the tensor fascia latae. Clinically and experimentally, these muscles were shown to be functionally enclosed within separate compartments like the peripheral limb muscles. Prompt decompression in the two cases with pressures exceeding 30 mm Hg resulted in muscle and nerve recovery.


Efficacy of graded-compression antiembolism stockings in patients undergoing total hip arthroplasty. A prospective randomized trial evaluated graded-compression antiembolism stockings for prevention of leg vein thrombosis as assessed by Doppler ultrasound, in patients undergoing total hip replacement. The study was terminated after the evaluation of 18 patients revealed a significantly greater incidence of deep vein thrombosis, documented by phlebography, in patients without stockings (5 of 10) compared to those with stockings (none of 8, p less than 0.03). Three of the patients with thrombosis developed pulmonary emboli. Although the sample size of this study is small, the implication that graded-compression stockings reduce the incidence of leg vein thrombosis is strong and is supported by the results of other recent trials. These findings are at variance with earlier studies which failed to document efficacy of elastic stockings, which involved products which did not provide graded limb compression.


Persistent sciatic artery and sciatic artery aneurysm: a hazard in hip surgery. During a posterior approach to the hip joint great caution must be exercised in protecting a persistent sciatic artery. Inappropriate trauma could either cause peripheral embolization, propagation of mural clots, or rupture. Prior to ligation, arteriography is critical because, despite the presence of strong femoral or popliteal pulses, the persistent sciatic artery may be the main conduit to the lower extremity.


The histological characteristics of congenital coxa vara: a case report of a five year old boy. In a 51/2 year old boy with unilateral coxa vara who died of unrelated causes histological sections were made of the proximal femora and pelvic growth plates. The proximal femora were also perfused to study the pattern of arterial supply. Evidence of active endochondral ossification was not detectable in growth plates of the affected right femur, the clinically and roentgenographically normal left femur and the pelvis, including a Salter Type II fissure fracture. The endochondral ossification defect found in growth plates of the proximal right femur and pelvis was associated with a reduction in the number and caliber of intraosseous arteries supplying the metaphyseal sides of the growth plates in the proximal femur and those supplying the subchondral region and extraosseous medial ascending cervical arteries on the surface of the femoral neck. This deficiency in endochondral ossification resembles a form of dwarfism associated with a coxa vara and a generalized growth plate disorder.


Biomechanical aspects of Salter osteotomy. A mathematical model of a Salter osteotomy in an adult male pelvis reveals that during innominate osteotomy, the center of the hip joint moves distally, posteriorly, and medially. The acetabulum extends by an angle roughly equivalent to the angle of osteotomy opening. Adduction of the acetabulum takes place to a lesser extent. Hip abductors and flexors tighten minmally following innominate osteotomy. Augmentation of abduction occurs as a result of medial acetabular displacement rather than gross alteration of the abductor muscles themselves. Theoretical considerations suggest that the surgeon should strive to obtain maximum correction at the osteotomy site while avoiding levering at the greater sciatic notch.


Combined valgus derotation osteotomy and cervical osteoplasty for severely slipped capital femoral epiphysis: mechanical analysis and report preliminary results using compression screw fixation and early weight bearing. Although considerable remodeling can occur in slipped capital femoral epiphysis, it is generally conceded that the severely-slipped epiphysis requires corrective osteotomy to restore adequate range of motion, and to prevent early degenerative changes. A study of artifically-created severe slips in cadaver specimens demonstrated that removal of the cervical prominence, as well as valgus-derotational osteotomy is necessary to restore good range of motion and provide a satisfactory weight-bearing surface. Clinical trial in 6 patients also demonstrated that the cervical prominence is a barrier to flexion, internal rotation, and abduction even after a valgus derotational osteotomy. The Watson-Jones approach afforded adequate exposure of the anterior femoral neck and head as well as the femoral shaft to allow excision of the cervical prominence, insertion of internal fixation, and adjustment of valgus and rotation under direct vision. The Richards compression screw proved to be ideal for fixation in the proper degree of valgus, and for allowing rotary alignment of the distal fragments. Early results were very good, and all patients had near-normal hip flexion, internal rotation, and abduction; and most were able to bear weight in the early postoperative period. The operation appears to offer a workable solution to the problem posed by the severly slipped capital femoral epiphysis, but more definitive conclusions must await the results of a larger series.


Base of the neck extracapsular osteotomy for correction of deformity in slipped capital femoral epiphysis. This is a report on a University of Illinois Hospital series of cases of extracapsular base of the neck osteotomy for slipped capital femoral epiphyses. The osteotomy was performed on 20 hips in 16 patients, with a 71/2 year average follow-up. The results of this procedure are encouraging and illustrate the advantages of technical simplicity and minimal risk of avascular necrosis. The method does not create any additional deformity. The only disadvantage is that the correction could be limited. The maximum correction of posterior tilt was 55 degrees and the maximum correction of varus deformity was 50 degrees.


Detection of heterotopic calcification with 99mTc-pyrophosphate in spinal cord injury patients. Whole body 99mTc-pyrophosphate scans were obtained and correlated with skeletal radiographs for detection of heterotopic calcification in 122 spinal injury patients. There were 27 patients with recent injury (less than 6 months) and 95 with injury of 6 months to 25 years duration. Ectopic calcification was detected in 8 of the 27 patients (30%) with recent injury and in 32 of the 95 (34%) with injury of over 6 months duration. Ectopic calcification seen on radiographs were also seen on scans in all instances. The scan was a sensitive indicator of the ectopic calcification particularly at its early stage, and detected its presence before observable radiographic changes in 5 patients with injury of 1-3 months duration. In 3 of the 5 patients, the ectopic calcification mimicked deep vein thrombosis in presentation, and the scan was valuable in identifying the nature of the complication.


Reproducibility of ventilation studies.

Reproducibility of ventilation studies. Differences in ventilation patterns were observed in several instances in two consecutive ventilation studies with 127 Xe and 133Xe gas involving a group of 20 patients with COPD and other pulmonary disorders. Included were differences in the distribution of a tracer gas bolus during the initial inspiration, the distribution of gas tracer after equilibration and during gas washout, artifacts external to the lung, and variations in the half-time for gas washout. The observed discrepancies are clinically significant and could lead to erroneous or ambiguous diagnoses.


Implications of liver activity associated with 133Xe ventilation lung scans. A series of 35 xenon-133 (133Xe) ventilation studies yielded nine cases demonstrating accumulation of activity in the liver. Maximum intrahepatic deposition of radioxenon occurred during the washout phase of the study. In addition to those clinical instances which make this phenomenon possible, i.e., obesity, alcoholic-induced liver steatosis and diabetes mellitus, we found that hyperlipidemia and coronary artery disease also favor xenon-133 localization into the hepatic parenchyma. It is concluded that the lipid avidity of 133Xe facilitates its liver accumulation hyperlipidemic patients and in patients with coronary artery disease, and that this action may be explored to further understand deranged metabolic pathways in the liver of these patients. Hepatic accumulation of 133Xe during ventilation studies must be considered when assessing regional ventilation/perfusion relationships.


Radionuclide brain scan findings in superior sagittal sinus thrombosis. Superior sagittal sinus thrombosis is a serious condition requiring early diagnosis. This paper presents our experience with two cases and describes the findings. In one case radionuclide brain imaging was the first study performed. In the other, the diagnosis was made at arteriography with scanning used for follow-up.


Technique of scanning for Meckel's diverticulum. 99mTc-pertechnetate scanning is now recognized as a useful means of detecting Meckel's diverticula. When these contain gastric mucosa and present with ulceration and bleeding, the ectopic gastric mucosa can be identified by its secretion of 99mTc-pertechnetate. However, the secretions of normal gastric and salivary glands can pool in the gut and simulate a Meckel's diverticulum. We believe the diagnostic procedure of choice to include both continuous nasogastric suction and continuous sequential gamma camera images. To support this view, we present cases illustrating 1) that 99mTc-pertechnetate can appear in the bowel within the first few minutes of administering 99mTc-pertechnetate, even in the absence of a Meckel's diverticulum; 2) that rapid sequential camera views are helpful but not definitive in distinguishing such bowel activity from a Meckel's diverticulum; and 3) that continuous nasogastric suction most successfully eliminates this interference.


Demonstration of a radionuclide pattern in phenochromocytomas in children. Scintigraphic findings in a child with pheochromocytomas is illustrated. The patient demonstrated a hypervascular lesion during the radionuclide angiogram, and renal displacement on subsequent static images.


Clinical experience with [111 In] indium chloride scanning in inflammatory diseases. Forty-eight patients were scanned with 111 In-chloride in an attempt to identify the cause of fever. Fifteen true positive scans, 30 true negatives, and 3 false negatives were found. Of the 15 true positives, 7 cases of abdominal or pelvic abscess, and 8 cases of alcoholic hepatitis were detected. The 3 false negatives included: 1) an abscess in the anterior abdominal wall; 2) an abscess in the right upper quadrant at the site of a necrotic gallbladder; and 3) a tuberculous abscesss of the lumbar spine. Examples from the different categories, pitfalls in interpretation and advantages and disadvantages of scanning with 111In-chloride will be presented. These studies indicate that 111In-chloride is a safe, reliable scanning agent for abscesses below the diaphragm especially in patients who cannot undergo adequate bowel preparation.


Liver/pleural cavity scan for diagnosis of subphrenic abscess. The interpretation of a combined liver/lung scan can be difficult in patients with pleural or pulmonary disease. A procedure is suggested to circumvent these difficulties by injecting 99mTc-sulfur colloid into the pleural cavity. A scan of the pleural cavity can then replace the lung scan in the conventional liver/lung scan. Two examples of liver/pleural cavity scans are shown.


Perfusion vascularity mismatch in liver hemangiomas. Perfusion defect in the dynamic study and slow filling of the lesion by a blood pool agent were observed in three cases with large cavernous hemangiomas of the liver. This finding is explained by the low perfusion and the large blood volume of cavernous hemangiomas. When such a lesion is suspected a late blood pool study should be performed in order to demonstrate the true vascularity of the lesion.


Diagnosis of extra-hepatic abnormalities on dynamic study over thoraco-abdominal region prior to hepatic imaging. Findings on 262 thoraco-abdominal dynamic studies done at the time of hepatic imaging were reviewed. Twenty-nine extra-hepatic abnormalities were diagnosed solely on the basis of these studies, including pericardial and pleural effusions and decreased perfusion to one lung. Half of these abnormalities were not suspected clinically. The dynamic study is an important part of hepatic imaging and should be performed routinely. Besides aiding in differential diagnosis of various hepatic lesions, extra-hepatic abnormalities can be discovered.


Clinical application of 201Tl scintigraphy in patients with cold thyroid nodules. 201Tl-chloride scintigraphy was performed in 45 patients with cold thyroid nodules. The 201Tl scintigram was positive in 17 of 18 thyroid patients with cancer (94.4%), 8 of 20 patients with an ademoma (40.0%), 1 of 2 adenomatous goiter patients (50.0%), and all of 5 cases of chronic thyroiditis (100.0%). When the cold nodule was demonstrated to be positive with 201Tl, the statistical chance of the lesion being a cellular one was 100.0% and a risk of its malignancy was 54.8%. On the other hand, the nodule with negative 201Tl concentration had a 14.3% chance of cellularity and a 7.1% risk of malignancy. Thus, 201Tl scintigraphy is of use in the differential diagnosis of the cold thyroid nodule.


Substernal thyroid carcinoma detected by 67Ga scan in a patient with normal 131I scan. A patient with a superior mediastinal mass on an admission chest radiograph was initially evaluated by an 131I thyroid scan which failed to demonstrate a substernal thyroid. However, the tomographic 67Ga scan clearly showed an abnormal uptake in the area corresponding to the mass lesion on radiographic examination. Subsequent resection and biopsy of the substernal mass revealed a poorly differentiated follicular carcinoma with foci of anaplastic carcinoma. The differential diagnosis of the anterior mediastinal mass and the usefullness of the tomographic gallium scan are briefly discussed.


67Ga-citrate scanning in hypernephroma.

67Ga-citrate scanning in hypernephroma. 67Ga scanning was performed in 26 patients with hypernephroma (17 with only a primary lesion of hypernephroma, 4 with both primary and metastatic lesions, 2 with hypernephroma and pyelonephritis, and 3 with only a metastatic lesion after nephrectomy). In patients with primary lesions alone, the positive finding rate by 67Ga scanning was low (26%), and in metastatic lesions that by scanning was high (86%). The practical conclusions are as follows: 67Ga scanning is of littel use as a diagnostic aid in primary lesion of hypernephroma, but may be useful in case with metastases with inflammatory disease.


The clinical presentations of Rocky Mountain spotted fever. Comments on recognition and management based on a study of 63 patients. Rocky Mountain spotted fever continues to increase in the United States and the case-fatality ratio remains unchanged despite the availability of effective antibiotics. The apparent reason for the continuing deaths from this disease is the failure of physicians to consider the diagnosis in patients presenting with febrile exanthems in the late spring and summer months. A clinical diagnosis should be based on the history of tick exposure and the presence of fever and the typical exanthem. Serologic tests are useful mainly in retrospect. This article reviews the clinical experience with Rocky Mountain spotted fever in an endemic area in recent years and discusses problems in the diagnosis and management.


Anaerobic bacteremia as observed in a children's hospital. Clinically this may signify true anaerobic sepsis. To ascertain the significance of anaerobic bacteremia in a children's hospital, the records of all patients whose blood cultures grew anaerobes during a 24-month period were reviewed. Anaerobes were isolated from 144 out of 1,126 blood cultures yielding bacteria. Anaerobic diphtheroid grew in 122 out of 143 anaerobic cultures, but only 4 out of 122 were isolated from patients with anaerobic sepsis. Nine per cent of the total episodes of anaerobic bacteremia occurred in 13 children who met out criteria for anaerobic sepsis; two oor more blood cultures obtained within a three-day period growing anaerobic bacteria, or an aerobe and an anaerobe, in a febrile child or one with an apparent infectious focus. Bacteroides accounted for 7 out of 13 (64 per cent) of the relevant isolates, while anaerobic diphtheroids 4 out of 13 (26 per cent) and anaerobic gram-positive cocci accounted for the remainder 2 out of 13 (18 per cent). Only one infant, with polymicrobial bacteremia, died, suggesting that anaerobic bacteremia is associated with less mortality in children than in adults. Anaerobic sepsis occurred in children who have had recent abdominal surgery, or who are immunosuppressed.


Clinically significant adverse effects in a Phase 1 testing program. Twelve years' experience with a Phase I drug testing program in normal prison volunteers is reported. Involved in 805 protocol studies were 29,162 participants over 614,534 subject days. During this period there were 64 significant medical events of which 58 were adverse drug reactions and 6 were complications. One subject has residual hip changes due to an infectious complication, another on placebo died from cerebrovascular hemorrhage while asleep. There was complete recovery from all adverse drug reactions and the other 4 complications encountered. Thus a clinically significant medical event occurred once every 9,602 days subject exposure or about once every 26.3 years of individual subject participation.


The rate of development of new drugs in the United States, 1963 through 1975. Information was obtained on 1,103 new chemical entities (NCEs) first tested in man from 1963 through mid-1975 by 36 U. S.-owned and 10 foreign-owned pharmaceutical companies operating in the U. S. Of these NCEs 1,029 reached the stage of IND filing. The portion of the U. S. industry responsible for the NCEs was relatively concentrated; 7 of the 36 companies accounted for half of the NCEs and 4 of these accounted for one-third. Although the annual worldwide rate of testing of NCEs by U. S. companies appeared to rise and then fall from 1963 through 1966, since 1966 the rate has been fairly constant. With time, however, a higher proportion of U. S.-owned NCEs is being first studied in man abroad. The annual rate of IND filings for U. S.-owned NCEs generally declined from 1965 to 1972, whereas the rate was fairly constant for foreign-owned NCEs over the entire period. The overall success rate in drug development has been low; nearly 90% of the NCEs studied in man are dropped prior to NDA submission, but about 88% of the NDAs submitted are approved for market. The 1974-1975 data indicate that the mean durations of the IND and NDA phase were then 4 and 2 years, respectively. However, there were variations in the time required for DNA approval between different pharmacologic areas. The data described in this paper represent the first baselines against which future trends in the processes of drug development and approval can be measured.