Mitral valve prolapse in one hundred presumably healthy young females. Clinical, electrocardiographic, phonocardiographic, and echocardiographic examinations were performed in 100 presumably healthy young females. Treadmill testing and ambulatory electrocardiographic monitoring were performed in a selected group of these subjects. Phonocardiograms, recorded with the subjects supine at rest, after inhalation of amyl nitrite, and in the upright position, revealed a 17% incidence of nonejection clicks and/or late or mid- to late systolic murmurs (PHONO-MSCLSM). Echocardiographic studies were performed in the second, third, fourth, and fifth intercostal space with emphasis on the importance of transducer angulation on the chest. Studies obtained with the transducer perpendicular to the chest in the sagittal plane, or pointing cephalad at a time when both mitral leaflets and left atrium are recorded, are optimal to study the mitral valve systolic motion. With the transducer in this position, 21 subjects were found to have pansystolic or late systolic prolapse, as previously defined on the echocardiogram. The presence of these echocardiographic findings was statistically related to the presence of PHONO-MSCLSM. Other echocardiographic patterns were identified and their relation to PHONO-MSCLSM and transducer position is discussed. Ten subjects with both echocardiographic evidence of mitral valve prolapse and PHONO-MSCLSM were identified (group EP), while 18 other subjects had either echocardiographic or phonocardiographic findings suggestive of mitral valve abnormality (group EorP). Seventy-two subjects had no abnormality (group noEP). The incidence of various clinical, electrocardiographic, and echocardiographic findings in these three groups was determined. Some findings said to be common in patients with proven mitral valve prolapse were seen more frequently in group EP subjects. Echocardiographic and phonocardiographic findings suggesting mitral valve abnormalities were found more commonly than expected in a population of presumably healthy young females.


Spectrum of echocardiographic findings in bacterial endocarditis. Forty-seven echocardiograms were obtained in 32 patients with bacterial endocarditis. Preexistent abnormalities were found in 14 patients. In five of them thought to have bacterial endocarditis on normal valves, echocardiography showed mitral stenosis (one), bicuspid aortic valve (two), and prolapse of mitral valve (two). Definite vegetations were seen in 22 patients--on the aortic valve in seven, the mitral valve in 12, and both valves in three. Ten patients had milder changes suggestive but not diagnostic of vegetations. In 12 patients, surgery confirmed the echocardiographic findings. Fourteen had systemic embolic episodes and all had echocardiographic evidence of vegetations. Abnormalities secondary to bacterial endocarditis, other than vegetations, were common. Twenty-one patients had left ventricular volume overload. Ten had a flail posterior leaflet of the mitral valve, three of which were confirmed surgically. Eight had abnormal coarsely fluttering echoes in the left ventricular outflow tract consistent with a prolapsing aortic valve or underlying aortic vegetations; four were confirmed by surgery. Five had signs of severe aortic regurgitation of recent onset (premature mitral valve closure) and all had confirmation by surgery. Echocardiographic abnormalities persisted after successful medical treatment. We conclude that echocardiography is helpful in patients with bacterial endocarditis. It permits recognition of unsuspected preexistent lesions and the characteristic vegetations, as well as the extent and nature of valvular damage secondary to bacterial endocarditis. However, echocardiography does not differentiate between active and healed lesions.


Myocardial lesions of progressive systemic sclerosis. A cause of cardiac dysfunction. The nature, prevalence, functional significance, and indeed existence of myocardial disease in progressive systemic sclerosis (PSS) has been debated. In this study the clinical and pathological features of 52 autopsied patients were analyzed in an attempt to resolve these questions. A distinctive focal myocardial lesion ranging from contraction band necrosis to replacement fibrosis throughout both ventricular walls was present in 23 patients who had widely patent extramural coronary arteries. There were no morphologic abnormalities of the intramyocardial coronary arteries to account for these lesions. Comparing those patients having severe (13), mild (10), or no (24) PSS myocardial lesions, and patent extramural coronary arteries, there were no major differences in age, sex, frequency and severity of pulmonary, renal or hypertensive disease which could account for the myocardial necrosis and fibrosis. The three groups did differ, however, with regard to clinical cardiac abnormalities: ventricular arrhythmias and conduction disturbances were six and two times as frequent, respectively, in those with severe myocardial PSS compared to the other two groups. A pattern of primary myocardial disease with intractable congestive heart failure resulted from severe myocardial PSS in four patients, angina pectoris with normal coronary arteries was associated with the severe myocardial lesion in three patients, and sudden death in five. The occurrence of contraction band necrosis suggests that the myocardial damage in PSS might be due to intermittent vascular spasm of the type recognized in the digits and possibly kidneys and lungs, i.e., an intramyocardial Raynaud's phenomenon. The findings in our patients clearly show that myocardial progressive systemic sclerosis is a distinct entity with relatively frequent occurrence which may lead to arrhythmias, congestive heart failure, angina pectoris with normal coronary arteries and sudden death.


Reflex vasodilation induced by coronary angiography in human subjects. In order to evaluate the reflex peripheral vascular effects of coronary arteriography, forearm blood flow was measured plethysmographically and forearm vascular resistance calculated before and during coronary angiography with Hypaque-M, 75%, and Renografin-76. The injection of Hypaque into the left coronary artery resulted in a forearm vasodilation which could not be duplicated by an injection of a comparable amount of contrast into the ascending aorta, three centimeters above the coronary ostia. Forearm blood flow rose from 2.95 to 5.41 ml/min/100 ml (83.4%) and forearm vascular resistance fell from 35.8 to 19.9 mm Hg/ml/min/100 ml (44.4%). Renografin injected into the left coronary artery resulted in less forearm vasodilation (21% increase in forearm blood flow and 32% decrease in forearm vascular resistance). When coronary arteriography was repeated following injection of atropine into the brachial artery, no forearm vasodilation occurred. It is suggested that in human subjects myocardial or coronary artery receptors can be activated by the intracoronary injection of iodinated contrast media which results in a forearm vasodilation.


Effects of p-chlorophenoxyisobutyrate on myocardial free fatty acid extraction, ventricular blood flow, and epicardial ST-segment elevation during coronary occlusion in dogs. The effect of p-chlorophenoxyisobutyrate (CPIB) on ST-segment elevation in epicardial electrocardiographic recordings was studied during coronary artery occlusion in dogs. Occlusion alone raised the sum of ST-segment elevations (sigmaST) to 26 +/- 6 mV (mean +/- SEM). Intravenous (i.v.) administration of CPIB 30 min before re-occlusion reduced sigmaST to 14 +/- 3 mV (P less than 0.03). A continuous i.v. infusion of isoproterenol increased sigmaST to 74 +/- 11 mV. Pretreatment with CPIB reduced sigmaST during isoproterenol infusion to 40 +/- 7 mV (P less than 0.005). CPIB had no effect on mean aortic blood pressure, heart rate, or regional myocardial blood flow, as measured by radioactive microspheres. Arterial free fatty acid (FFA) concentrations were reduced by CPIB from 466 +/- 41 to 221 +/- 44 muEq/L (P less than 0.001) in the basal state, and from 1966 +/- 183 to 1429 +/- 209 muEq/L (P less than 0.001) during isoproterenol infusion. The reduction in arterial FFA concentration was associated with a proportionate decrease in the myocardial extraction of FFA. Similar changes were observed when CPIB was administered during an occlusion which had been established 10 min earlier. These observations support other evidence that the severity of acute myocardial ischemic injury in dogs is positively correlated with the myocardial extraction of FFA, and that the severity of the ischemic injury can be reduced by effective antilipolytic therapy.


N-dimethylisopropyl propranolol. Effects on myocardial oxygen demands. N-Dimethylisopropyl propranolol (DMP) is a quaternary derivative which lacks significant beta-adrenergic blocking and local anesthetic effects. It has been reported, nonetheless, to be effective in treating experimental arrhythmias and in limiting the extent of ST-segment elevations following experimental coronary occlusion. The present study examined the effects of DMP on the hemodynamics and myocardial oxygen demands of anesthetized dogs. After a single dose of 3 mg/kg, heart rate fell from 146 +/- 8 to 124 +/- 6 beats/min (P less than 0.0025), and aortic systolic pressure fell from 151 +/- 11 to 141 +/- 9 mm Hg (0.05 less than P less than 0.10), resulting in a 16.8% reduction in the tension-time index. Stroke volume was reduced by 10% despite a 54% increase in left ventricular end-diastolic pressure, suggesting a negative inotropic effect. This was supported by a decrease in maximum extrapolated contractile element velocity from 9.10 +/- 1.05 to 6.61 +/- 65 units/sec (P less than 0.0025). Myocardial oxygen consumption was reduced from 12.0 +/- 1.4 to 9.9 +/- 1.5 ml/min/100 g tissue (P less than 0.05). Myocardial oxygen extraction was unchanged, indicating that the decrease in oxygen consumption resulted from a reduction in myocardial oxygen demand. When heart rate and systolic pressure were artificially restored to control levels, after the administration of DMP, myocardial oxygen consumption remained significantly below the control level. DMP, therefore, appeared to reduce myocardial oxygen demands primarily by its negative inotropic effect. This drug may have application in the treatment of ischemic heart disease.


Measurement of foot artery blood pressure by micromanometry in normal subjects and in patients with arterial occlusive disease. Blood pressure was measured continuously in the posterior tibial or dorsalis pedis arteries using an isovolumetric system (steel cannulas of 0.18 mm, external diameter). The systolic values in the ankle arteries of 13 normal subjects at rest (154.3 +/- 22.3 mm Hg) exceeded the systolic arm pressure (128.9 +/- 20.1 mm Hg, P less than 0.001), while diastolic values (69.9 +/- 8.7 mm Hg) were not significantly different from the arm pressure. In 13 patients with arterial occlusive disease (AOD) the dicrotic notch, normally situated close to the footpoint of the downslope, was either displaced upward or abolished. Both mean systolic and diastolic values (94.9 +/- 35.9 mm Hg and 62.5 +/- 18.5 mm Hg, respectively) and also mean pressure amplitude were reduced compared to the corresponding arm values (158.5 +/- 28.2 mm Hg and 87.7 +/- 6.0 mm Hg, respectively, all P less than 0.001). Comparison between the systolic pressure values measured by micromanometry and by an indirect technique using Doppler ultrasound showed a good correlation (r = 0.87). During postocclusive reactive hyperemia, the initial pressure values were markedly diminished in normal subjects and reached control values within 40 sec. In patients with AOD, however, this reduction in pressure was more pronounced and prolonged. Flow measurements using plethysmography showed flow diversion from the foot to the calf as long as pressure values ranged below 40 mm Hg. This almost painless method appears useful for experimental and diagnostic studies in low pressure areas of the peripheral circulation.


Mitral and tricuspid valve closure in congenital heart disease. Echocardiography was used to evaluate mitral and tricuspid valve closure in patients 1 day to 20 years of age. When possible, simultaneous phonocardiograms were obtained. The difference in time between the Q wave of the electrocardiogram and mitral closure and between Q and tricuspid closure was designated the delta value. Four groups of patients were assessed: 1) normals (40), secundum atrial septal defect (ASD) (10), mitral valve prolapse syndrome (Barlow's syndrome) (13), pulmonary hypertension (12), and pulmonic stenosis (6); 2) Ebstein's anomaly (10); 3) transposition of the great vessels (15); 4) right bundle branch block (RBBB) (25). Ten patients with surgically induced right bundle branch block were studied by phonocardiography alone. Group I had values of 50 msec or less (-5 to 50 milliseconds) and served as controls. Ebstein's anomaly showed prolongation of the delta value to 65 msec or greater in eight out of ten patients. Patients with transposition of the great vessels showed a striking difference from the preceding groups in that an average negative delta value was obtained. Twenty-two patients of group 4 (RBBB) had delta values within the normal range. This study has shown that a delta value greater than 65 msec is suggestive of Ebstein's anomaly. In addition, if the delta value is negative, transposition of the great vessels can be suspected.


The pulmonary vascular bed in patients with complete transposition of the great arteries. Histological material obtained at autopsy from 35 patients over three months of age with complete transposition of the great arteries (TGA) was examined. Two of six patients less than a year of age with an intact ventricular septum and closed ductus arteriosus were found to have pulmonary vascular changes of at least grade 3 severity; in addition, two of seven patients with a large ventricular septal defect in this age group showed changes of similar severity. The reported low incidence of marked pulmonary vascular changes in patients with only an interatrial communication dying during the first year of life would appear to be due in part to the high proportion of cases less than three months old in whom there was not sufficient time for such changes to develop. Although the incidence is not as high as that found beyond a year of age, it is sufficiently high to influence the management of infants beyond three months of age. Hemodynamic studies were performed following atrial baffle repair in 34 patients. All but one of the 16 patients operated upon prior to two years of age had a pulmonary arteriolar resistance (Rpa) less than 3 units M2 at the time of review, including three with a large communication at ventricular or great vessel level who underwent surgery before two months of age. Repair at an older age did not preclude a low Rpa on follow-up, but in 11 of the 18 patients who were two or more years of age at the time of repair it was greater than 3 units M2. None of these latter patients had a large ventricular septal defect or patent ductus arteriosus. Comparison of postoperative hemodynamic data with autopsy studies would suggest that advanced pulmonary vascular disease is associated with earlier death among patients with complete transposition of the great arteries.


Common or single ventricle. An angiocardiographic and hemodynamic study of 42 patients. To correlate anatomy with hemodynamics, the angiocardiographic findings were reviewed in 42 patients with common ventricle (CV). Nine had normally related great arteries (NRGA), 12 d-malposition, 21 l-malposition and 5 a common atrioventricular valve. Selective outlet chamber (OLC) angiocardiograms were available in 14 out of 29 patients with OLCs. OLC position varied from anterior and to the right of the CV to posterior and to the left of it; two categories (anterior and lateral OLC) were delineated by a line 45 degrees to theleft of anterior in the horizontal plane. The OLC was anterior in all patients with NRGA, lateral in most l-malpositions, and almost equally divided between anterior and lateral in d-malposition (P less than 0.05). Complete hemodynamic data were obtained in 29 patients. Complete mixing of venous return occurred in four patients with atresia of one valve. In the remainder complete mixing occurred in 36%, unfavorable streaming in 12% and favorable streaming in 52%. Semilunar valve position and pulmonary stenosis did not affect the nature of mixing. Systemic arterial (SA) minus pulmonary arterial O2 saturation was positive and significantly higher in patients with malposition with lateral OLCs than anterior OLCs (P less than 0.001). However 79% of SA O2 saturation variation could be predicted from pulmonary and systemic blood flow alone.


Right ventricular function in children with tetralogy of Fallot before and after aortic-to-pulmonary shunt. Right and left ventricular volume variables were obtained in 43 tetralogy patients undergoing diagnostic cardiac catheterization. The patient population consisted of 25 preoperative patients (group 1) and 18 patients who had undergone aortic-to-pulmonary shunt procedure (group 2). Volumes were calculated from biplane cineangiocardiograms using Simpson's rule method for the right ventricle (RV) and the area-length methods for the left ventricle (LV). In group 1, RV end-diastolic volume (RVEDV) was not different from normal in the total group and averaged 93 +/- 4% (SEM) of normal. In patients with hemoglobin (Hgb) greater than or equal to 16 g%, however, this variable was significantly (P = 0.044) less than normal. Right ventricular ejection fraction was normal and RV systolic index was significantly (P less than 0.001) reduced, averaging 3.35 +/- 0.18 (SEM) L/min/m2. Left ventricular volume variables in this group were not significantly different from RV volume variables. In group 2, RVEDV in patients with Hgb greater than or equal to 16 g% was significantly (P = 0.037) less than normal, but was normal in patients with Hgb less than 16 g%. Right ventricular ejection fraction averaged 0.52 +/- 0.03 in this group and was significantly (P less than 0.001) less than normal. Right ventricular systolic index (RVSI) averaged 3.51 +/- 0.24 L/min/m2 and was significantly (P = 0.009) less than normal. RVSI in patients with Hgb less than 16 g% averaged 3.90 +/- 0.31 and was not different from normal. In contrast, this variable in patients with Hgb greater than or equal to 16 g% averaged 3.21 +/- 0.34 and was significantly (P = 0.005) less than normal. Left ventricular end-diastolic volume (LVEDV) and LV systolic output in group 2 were significantly higher than RVEDV and RV systolic output. Right ventricular and LV ejection fractions in group 2 were not different. The relatively decreased ejection fraction fraction in tetralogy patients, as compared with patients with valvular pulmonic stenosis and similar volumes and pressures, suggests that the decreased ejection fraction was not due to decreased preload or increased afterload and might be due to impaired ventricular function secondary to chronic hypoxia. Early corrective surgery in these patients might reverse this process. However, patients with severe tetralogy who have small ventricular volume and reduced output might benefit from shunt procedure rather than complete correction.


Clinical conference: Rupture of right ventricle complicating closed chest cardiac massage. Two cases of rupture of the right ventricle following closed chest cardiac massage are presented. This is believed to result from trapping of blood in the right ventricle at levels of systemic arterial pressure. In one case there was massive pulmonary embolism which interfered with egress of blood from the right ventricle. In the other case, application of pressure during a closed chest resuscitative attempt might have closed the right ventricular outflow tract.


Mechanism of atrial sounds in atrial fibrillation. Phonoechocardiographic correlation. Report of a case. Audible atrial sounds were noted in a patient with congestive cardiomyopathy and atrial fibrillation with slow ventricular rate. Oscillatory motion of similar periodicity as fibrillation waves in the ECG and the sounds in the phonocardiogram was demonstrated in aortic and left ventricular walls, mitral, tricuspid and aortic leaflets by echocardiography. This suggests that the fibrillation motion of the atria is forceful enough to cause vibration of the cardiohemic system resulting in the audible sounds.


Double ventricular parasystole. Supernormal phase of conduction as a mechanism of intermittent parasystole. Report of a case. A rare case of spontaneous double ventricular parasystole was studied in depth, together with a critical review of similar cases in the literature. The discussion was focused on 1) the variation of the shortest interectopic interval (SIEI), 2) entrance block and its failure, 3) supernormality as a mechanism of intermittence, and 4) effects of lidocaine and atropine on such an arrhythmia. In double ventricular parasystole a greater than usual variation in the SIEI tended to occur in one of the two parasystolic groups. If, however, such variations were too great in the face of otherwise parasystolic rhythm, presence of intermittence was confirmed. A temporary loss of the entrance block was deemed primarily responsible for the intermittency. That is to say, invasion, discharge, and resetting of one parasystolic focus by another parasystolic impulse during the supernormal phase of the ventricle was considered the cause of an intermittence. In a strict sense, this is the first report in the literature in which the supernormality was clearly indicated as one mechanism of intermittent ventricular parasystole. The advantage of the concept of double ventricular parasystole as compared to single parasystole in defining such a mechanism is stressed.


Membranous subaortic stenosis complicated by aneurysm of the membranous septum and mitral valve prolapse. The clinical, echocardiographic, and catheterization findings in a patient with discrete subaortic stenosis, aneurysm of the membranous interventricular septum, and mitral valve prolapse are presented. Echocardiography showed a subaortic membrane, abnormal aortic valve motion, accentuated systolic anterior motion of the membranous interventricular septum, and prolapsing mitral leaflets. Cardiac catheterization confirmed the diagnoses. The possible functional interrelationship of these lesions is discussed.


Evaluation of a breath actuated pressurized aerosol. Preliminary investigation suggests that some asthmatic patients find it difficult to synchronize the release of a metered dose from a pressurized aerosol with the correct phase of inspiration. An automatic device has been developed to overcome this problem. Information is presented outlining the physical characteristics of the unit and the methods used to establish its performance in patients. It is suggested that the device may have a place in the management of asthma.


A quantitative study on the activation of the alternative pathway of complement by mouldy hay dust and thermophilic actinomycetes. Materials associated with the induction of farmer's lung were incubated with fresh normal human serum in the  presence of magnesium ethylene glycol tetra-acetic acid (MgEGTA) or ethylene diamine tetra-acetic acid (EDTA) and results compared with material known to activate the alternative pathway of complement--zymosan. Results show that Micropolyspora faeni organisms are as active as zymosan in reducing complement (C) levels in the presence of MgEGTA, with a 50% reduction in CH50 at approximately 140 mug/ml. Thermoactinomyces vulgaris organisms produced a 50% CH50 reduction at approximately 1-25 mg/ml and two samples of respirable mouldy hay dust (MHD) at approximately 5-6 mg/ml whereas extracts of M. faeni and T. vulgaris reduced the CH50 titre by 17% and 39% respectively at 16 mg/ml in the presence of MgEGTA. Organisms and extracts did not reduce the CH50 titre in the presence of EDTA even at the maximum concentration quoted by more than 3%, thus it is considered that alternative pathway activation was responsible for C utilization in the presence of MgEGTA. Respirable MHD used less than 4% available C at 4 mg/ml in the presence of EDTA but at 8 mg/ml dust 11% and 28% available CH50 were used compared with 79% and 81% respectively in the presence of MgEGTA. The elution of immunoglobulin binding material from MHD may be responsible for apparent CH50 consumption in the presence of EDTA.


Serum IgE levels in healthy children quantified by a sandwich technique (PRIST). Serum IgE was estimated in 226 healthy children aged 0-14 years without obvious atropic disease in their first degree relatives. A paper disc radioimmunoassay technique (PRIST) was used. A number of criteria for selection of cases were established. This led to the exclusion of forty-two potentially atopic children. The remaining group of 184 children is considered representative of normal children and may therefore be used for reference purposes. The IgE levels were found to be lower than in previous investigations, and this is attributed to the refined technique and the method of selection.


City spore concentrations in the European Economic Community (EEC) I. Grass pollen, 1973. Although clinical reports on the prevalence of summer hay fever in different parts of Europe have been published, comparative studies on atmospheric pollen concentrations appear to have been rarely undertaken. The present paper describes observations on the grass pollen content of the air at Bologna, Brussels, London, Munich and Strasbourg and is the first of a series involving international collaboration between workers in cities of the European Economic Community.


Measurement of specific IgE antibodies in nasal secretion--evidence for local production. Serum levels of total and specific immunoglobulin E (IgE) have been determined by radioimmunoassays in sixty-nine allergic subjects. The forty-one subjects with mild symptoms were the most difficult to diagnose, since nine had IgE levels less than 50 U/ml and nineteen had no detectable specific IgE antibodies. Samples of nasal secretions were collected from these nineteen subjects and five were found to have specific IgE antibodies, and in a further eight increased amounts of total IgE. The possibility of locally produced IgE antibodies should therefore be considered when using in vitro tests to diagnose mild or recently acquired allergies, especially when serum IgE levels are less than 50 U/ml.


Pigeon breeder's disease. II. Pigeon antigen induced proliferation of lymphocytes from symptomatic and asymptomatic subjects. Lymphocyte reactivity to pigeon antigens was demonstrated in a patient with severe symptomatic pigeon breeder's disease (PBD). The reactivity of the lymphocytes declined subsequent to cessation of exposure to antigen and in parallel with clinical improvement. Lymphocyte reactivity was also demonstrated in another patient with PBD, in a pigeon breeder with no evidence of PBD, and in a laboratory investigator with a history of exposure to birds other than pigeons. Lymphocyte reactivity in the latter subject increased following cutaneous injection of pigeon serum with the development of delayed-type cutaneous reactivity. Although lymphocyte reactivity to pigeon antigens may be a necessary immunologic feature for production of PBD, this reactivity does not occur only in symptomatic subjects.


Allergy profiles from bloodstains.

Allergy profiles from bloodstains. The radioallergosorbent test (RAST) has been adapted to measure specific IgE antibodies in bloodstains. By incubating several allergen discs simultaneously with one stain extract, an allergy profile can be readily obtained from less than 50 mul of dried blood.


The prevalence of immediate positive skin tests to Dermatophagoides pteronyssinus and grass pollen in schoolchildren. The prevalence of immediate positive reactions to prick testing with house dust mite (Dermatophagoides pteronyssinus) and grass pollen allergens was determined in a random sample of 303 children aged between 8 and 14 years from two Southhampton schools. One hundred and two (33-7%) showed positive reactions, fifty to both D. pteronyssinus and grass pollen, thirty to D. pternyssinus only and twenty-two to pollen only. Allergic symptoms were present in fifty-one of the 102 children with positive skin tests; amongst thirty children with D. pteronyssinus skin sensitivity by itself, only six had sumptoms suggestive of allergic disorder. Significantly more children with positive than with negative tests were reported by their parents to have suffered from  recurrent bronchitis during early childhood.


Comparison of IgE values as determined by different solid phase radioimmunoassay methods. Accurate measurement of low IgE concentrations if technically difficult. In this paper results obtained by a direct sandwich and three inhibition methods of radioimmunoassays are compared. For values above 50 U/ml good correlation was obtained with all methods. Below 50 U/ml, however, the inhibition methods tended to yield falsely high values. For very low concentrations, 1--10 U/ml the best correlation was obtained between the direct sandwich test (PRIST) and the inhibition test using a correction factor to allow for the non-specific effect of serum. The four methods were used to quantify IgE in cord serum samples from healthy individuals. The mean value obtained by PRIST was 0-4 U/ml and by the inhibition test, using a correction factor, 0-6 U/ml respectively. Because of its greater simplicity the direct sandwich test is recommended.


Placental and non-placental leucine aminopeptidases during normal pregnancy. 1. A simple and rapid method discriminating between placental and non-placental leucine aminopeptidases (LAP) existing in pregnancy serum is described, which includes technics of heat inactivation at 60 degrees for 30 minutes and inhibition by 0.02 M L-methionine. 2. Serial determinations of serum total, heat-stable and L-methionine-insensitive LAP activities during normal pregnancy were carried out. 3. The results were ascertained by disc electrophoresis and it was found that the heat-stable enzyme corresponds to normal serum LAP; the L-methionine-insensitive enzyme to pregnancy serum LAP of placental origin; the sum of these two to total serum LAP.


Variation of serum iron concentration in young healthy men: Within-day and day-to-day changes. 1. Serum iron concentration values were determined on a group of 11 healthy young men on blood specimens which were drawn at various hours of the day: 800 h, 1100 h, and 1400 h; on each of four separate days. 2. using a three-way ANOVA (analysis of variance) model, we determined the diurnal variation both for the group as a whole (main hour effect) and for the individual subjects (subject-hour and subject-day-hour interactions). 3. the total combined within-day variation as expressed in coefficients of variation was 12.9% with the peak value seen at 1400 h. 4. on a separate study, blood specimens were obtained at 1100 h on five separate days during a two week period on the same volunteers. 5. using a two-way ANOVA model (subject and day) the day-to-day coefficient of variation was found to be 26.6% for the group. In both cases (within-day and day-to-day) the biological variation was considerably greater than the analytic variation.


A reproducible estimation of triiodothyronine uptake. A simple method for the determination of triodothyronine (T3) uptake using I125-T3 and dextran coated charcoal is described. This reaction is time dependent after the addition of dextran coated charcoal. Effect of temperature, concentrations of I125-T3 and charcoal are reported. Within-run precision has been estimated for normal (CV 4.2%), high (CV 2.7%) and low (CV 6.6%) ranges. Day-to-day precision was similar to within-run precision. Results obtained by this method highly correlate with those obtained using Thyopac-3 reagent kit (Amersham-Searle Laboratories).


Correlation of the "EMIT" antiepileptic drug assay with a gas liquid chromatographic method. Many methodologies have been developed for determining anticonvulsant drug levels in human serum. Unfortunately, most procedures are either time consuming or subject to a variety of interferring substances. The "Enzyme Multiplied Immunoassay Technique" (EMIT) system has been evaluated for its speed, sensitivity, accuracy, and precision. When compared with a gas-liquid chromatographic procedure, the EMIT assay appeared to yield results which were statistically comparable for the drugs diphenylhydantoin, phenobarbital, and primidone. The EMIT assay also demonstrated no significant interference when challenged with extraordinarily high levels of potentially cross reacting drugs. Results obtained with the EMIT assay correlated well with GLC data and rank it as an attractive alternative to many of the existing procedures now being used.


Uric acid lithiasis associated with altered kinetics of hypoxanthine-guanine phosphoribosyltranferase. 1. A patient is described who had uric acid calculi which obstructed both kidneys. Serum uric acid was 34 mg/100 ml upon admission to hospital, and evidence of precipitation of uric acid in joints was obtained. 2. Total activity of hypoxanthine-guanine phosphoribosyltransferase in erythrocytes lysates from this patient was 44% of normal. Kinetic studies revealed that the apparent Michaelis constant of this enzyme for phosphoribosyl pyrophosphate was elevated 15-fold, while these values for hypoxanthine and guanine were in the normal range.


Extraction of digoxin and its metabolites from urine and their separation by Sephadex LH-20 column chromatography. The efficiency with which serveral solvent systems extract digoxin and its metabolites from urine has been studied and column chromatography using Sephadex LH-20 has been used to separate digoxin and its metabolites. These procedures have been evaluated and used to study the excretion of 3H-digoxin-12alpha and its metabolites in urines collected serially in 7 patients and in bile in one. The percentage of the radioactivity excreted as metabolites in urine and bile was found to reach a peak within the first day and then to gradualy decline to minimal amounts in patients with advanced renal failure as well as those with good renal function. The maximum percentage measured as metabolites in 4 patients with the most advanced renal failure was 10%.


Erythrocyte porphyrin analysis in the detection of lead poisoning in children: evaluation of four micromethods. We evaluated four procedures for determination of erythrocyte porphyrin: double extraction with ethyl acetate/acetic acid-HCl, single extraction with ethanol, single extraction with acetone, and direct solubilization with detergent-buffer. The ethyl acetate procedure, when used with two portions of HCl, apparently gives complete recovery of porphyrin and is suitable for reference as a comparison method. The ethanol procedure gives a high and consistent recovery and is technically simpler. The acetone procedure gives low and variable recovery of porphyrin, and the detergent-buffer method is subject to serious hemoglobin interference; neither of these two procedures offers any technical advantage. Stability of samples and methods for standardization were explored. A procedure for expressing results in terms of erythrocyte Zn-protoporphyrin content is given. Because of its stability, coproporphyrin is useful as a daily working standard. The ethyl acetate and ethanol methods are about equally efficient for detecting lead intoxication. Because of its simplicity, the ethanol method seems to be the best for use in screening.


Colorimetry of carbohydrates with m-aminophenol, and its proposed use in measurement of serum amylase activity. In the reaction of m-aminophenol with carbohydrates in a thiourea/acetic acid reagent, addition of borate suppresses chromogen formation for hexoses and pentoses, and enhances it for disaccharides. All reaction products absorb maximally at 520 nm. The relatively greater intensity of the m-aminophenol/maltose reaction product was used in a saccharogenic method for amylase, with low blank readings. This method is compared with two dye/starch procedures.


Creatine kinase isoenzyme patterns in human tissue obtained at surgery. Chromatography on DEAE-Sephadex A-50 was applied to study the quantitative distribution of creatine kinase isoenzymes in extracts of human tissue obtained during surgery. The results are compared with those determined by an immunological method [Clin. Chim. Acta 58, 223 (1975)]. Conflicting results for some organs as reported by the two methods are probably attributable to postmortem autolysis.


Sample stability: a suggested definition and method of determination. We propose defining the stability of any chemical constituent of stored samples in terms that are quantitatively related to the precision of the measurement by which it is determined. We suggest that a constituent may be considered stable, for a stated period and under exactly defined conditions, when the average change in its measured value is less than a chosen number, K, of standard deviations of the data obtained by the measuring method over the concentration range in question. Based on this definition a technique utilizing a graphical truncated normal sequential test is presented as the appropriate experimental and statistical design for measuring stability. The statistical basis for the proposal is presented.


An integrated approach to lipid profiling: enzymatic determination of cholesterol and triglycerides with a centrifugal analyzer. We describe enzymatic methods for determination of cholesterol and triglycerides (triacylglycerols), adapted for use with a centrifugal analyzer. Triglycerides are determined by a two-point kinetic method, which utilizes a single glycerol standard for calibration and provides for a within-run reagent blank correction. The endpoint determination of cholesterol combines the unique blanking capabilities of the centrifugal analyzer to correct for sample and reagent blank interferences. Results correlate well with those obtained by procedures standardized by the Lipid Research Clinics Program for use with a continuous-flow system.


Evaluation of two digoxin radioimmunoassay procedures in which 125I-labeled digoxin is used. We present a comparative evaluation of two commercial kits, the "Quantitope" and "GammaCoat," for radioimmunoassay of digoxin in serum. These kits, in which iodine-125 is used as a label, proved to suitable for digoxin assay as determined by their reproducibility, sensitivity, precision, and a regression analysis. Hemolysis, lipemia, and icterus did not affect results. However, in some cases hypoalbuminemia falsely lowered the assayed digoxin concentration. Recovery of pure digoxin added to native patients' sera having low albumin concentration (24-28 g/liter) ranged from 67-105% with the Quantitope kit and 70-110% with the GammaCoat kit. Low serum albumin concentration did not always decrease the recovery of digoxin; this effect varied from serum to serum, which may indicate that there are factors other than albumin that affect the assay of digoxin.


Evaluation of a dipstick test for glucose in urine. As an example of qualitative tests, a dipstick analysis for glucose in urine has been tested for the influence of modifying factors on the test result. Two different types of dipsticks were examined, "Clinistix" and "S-Gluko-test." Used according to manufacturer's instructions, the latter is more sensitive and selective. By multivariance analysis the following variables were examined: urine samples, inter- and intra-analyst, exposure to light, and dipstick batch. The first three contributed significantly to the total variation in results, inter-specimen variation being the most important. With knowledge of the frequency of testing urines with a given glucose concentration and the probability of the result at that concentration, an expression of the probability of the glucose content of a urine sample can be obtained. Even with the tests of the type examined having a sensitivity and specificity exceeding 95%, 14 of 100 patients suspected of having diabetes mellitus on the basis of a dipstick examination will be found to have a urinary glucose concentration of less than 2 mmol/liter. These figures were found when the prevalence of urines with a glucose concentration exceeding 2 mmol/liter was 17.5%.


Evaluation of a discrete-sample computer-directed clinical analyzer. The operational characteristics of the Gilford System 3500 were evaluated for six months as to accuracy, precision, carry-over, reliability, and ease of operation. Accuracy was evaluated by comparison to manual methods of established accuracy. The tests evaluated and their respective correlation coefficients are as follows: glucose (0.99), blood urea nitrogen (0.99), calcium (0.97), total bilirubin (0.99), aspartate aminotransferase (0.97), alkaline phosphatase (0.98), albumin (0.96), and total protein (0.96). Within-run precision (CV) for three commercial calibration sera of differing analyte concentrations (low, intermediate, and high) were respectively: 0.69, 1.02, 1.18; 5.4, 1.2, 1.09; 0.83, 0.77, 0.86; 5.9, 1.0, 0.86; 6.4, 5.2, 2.1; 3.7, 1.5, 1.3; 0.0, 1.4, 0.97; and 1.2, 1.3, 0.75. Day-to-day precision, similarly evaluated during 101-164 days, met accepted criteria for clinically acceptable precision. Carry-over for each of the eight tests was less than 1%. Instrument reliability has been excellent, and training time is short. In summary, we have found the Gilford System 3500 to be sufficiently precise and fast, easy to operate, highly accurate, and flexible.


Rapid micromethod for blood lead analysis by anodic stripping voltammetry. We describe a rapid microscale procedure for blood lead determination by anodic stripping voltammetry. Results correlate well with those obtained by atomic absorption spectroscopy. The procedure involves use of a metal-exchange reagent, which rapidly releases bound lead from its macromolecular binding sites, thus eliminating a long and cumbersome perchloric acid digestion procedure. Reproducibility and analytical recovery of added lead were both excellent. Our results show that anodic stripping voltammetry is a reliable, sensitive micromethod for routine determination of blood lead.


Cholesterol in amniotic fluid, determined by gas chromatography. Cholesterol was extracted from amniotic fluid, saponified, converted to its trimethylsilyl derivative, and gas chromatographed, with cholesteryl acetate as the internal standard. The method is sufficiently accurate and precise for use with the range of concentrations of cholesterol found in amniotic fluid (5 to 48 mg/litre). Total cholesterol was measured in amniotic fluids collected at different stages of gestation. No significant trend or change was observed nor was cholesterol in the amniotic fluid and the mother's serum correlated at any stage of gestation. Thus we conclude that cholesterol is not a useful indicator of fetal age or maturity. Cholesterol concentrations in amniotic fluid from complicated pregnancies were within the range found for normal pregnancies.


High-performance colorimeter with an electronic bubble gate for use in miniaturized continuous-flow analyzers. We describe a high-performance colorimeter with an electronic bubble gate for use with miniaturized continuous-flow analyzers. The colorimeter has a flow-through cuvette with optically flat quartz windows that allows a bubbled stream to pass freely without any breakup or retention of bubbles. The fluid volume in the light path is only 1.8 mul. The electronic bubble gate selectively removes that portion of the photodector signal produced by the air bubbles passing through the flow cell and allows that portion of the signal attributable to the fluid segment to pass to the recorder. The colorimeter is easy to use, rugged, inexpensive, and requires minimal adjustments.


Assessment of a serum separator device for obtaining serum specimens suitable for clinical analyses. We have evaluated a serum separator device that is designed to effect better separation and isolation of serum from clotted blood. This device consists of an evacuated blood-drawing tube (Vacutainer) containing 1.5 ml of a semi-solid silicon polymer that forms a barrier between serum and clot during centrifugation. We compared test specimens with conventionally processed (Vacutainer) specimens as controls. Eighty-one chemical, toxicological, and immunological reactions, tests, or methods were studied. For several tests we observed changes that are statistically but not clinically significant. The one clinically significant change in serum chemistry values occurred in the case of lactate dehydrogenase, for which values were increased by 5-8% of the upper limit of normal.


Cation-exchange chromatography of guanidine derivatives in plasma of patients with chronic renal failure. Guanidine derivatives are suspected of contributing to the toxic manifestations of uremia. We describe a method for measurement of guanidine derivatives in 5-ml samples of plasma by liquid chromatography. Concentrations of guanidinosuccinate and guanidinobutyrate in plasma were significantly increased both in undialyzed patients with chronic renal failure (5.54 +/- 0.94 and 17.5 +/- 4.07 mg/liter) and those undergoing maintenance hemodialysis (2.35 +/- 0.41 and 19.4 +/- 3.99 mg/liter) when compared to healthy controls (less than 0.4 and 1.0 +/- 0.3 mg/liter, respectively). Creatine and guanidinoacetate concentrations tended to be higher in hemodialysis patients and lower in the undialyzed group of patients with chronic renal failure. This procedure provides a rapid, sensitive, and accurate method for the study of guanidine metabolism in persons with uremia.


Enzymatic method for determination of CO2 in serum. We describe an enzymatic method, requiring only 10 mul of serum, for determining CO2 as bicarbonate or dissolved gas. Phosphoenolpyruvate carboxylase catalyzes the reaction of HCO3- with phosphoenolypyruvate to give oxalacetate. The resulting NADH, in the presence of malate dehydrogenase, is oxidized to NAD+, and the decrease in absorbance at 340 nm is directly proportional to the amount of CO2 present in the sample. Reaction is complete in 3 to 6 min under assay conditions, and is linearly related to CO2 concentrations between 8 and 65 mmol/liter. Analytical recovery is 95-110% (average, 101%). Two laboratories compared values obtained by continuous-flow analysis. The resulting correlation coefficients were 0.966 and 0.987, values for the t-test were t(paired) equals 0.473 and t(paired) equals 0.334, and average day-to-day precisions (three concentrations) were 3.9% and 4.2%.


Measurement of diphenylhydantoin in 0.1-ml plasma samples: gas chromatography and radioimmunoassay compared. Concentrations of diphenylhydantoin in 364 plasma samples have been measured both by radioimmunoassay and with a recently developed gas-chromatographic method, which requires only 0.1 ml of plasma per determination. There was an excellent correlation between values obtained by the two methods (r = 0.986), and in only 11 plasma samples did the results differ by more than 20%. Of the investigated samples, 105 were obtained from uremic patients. For these, an equally good agreement was obtained between the two methods. Within-assay variance was 3.1% for the immunoassay and 3.3% for the gas-chromatographic procedure. Without automatic pipetting equipment, the radioimmunoassay procedure took twice as long as the chromatographic assay, and the cost of chemicals was considerably higher. Nevertheless, the better sensitivity of the radioimmunoassay makes it of great value, especially in children, because plasma samples of 10 to 20 mul can be used.


Improved method for measurement of inorganic phosphate in serum with a centrifugal analyzer. A direct mehtod [Clin. Chim. Acta 46, 113 (1973)] for determination of inorganic phosphate in serum was adapted for use with a centrifugal analyzer. Contamination is minimized and analysis rate maximized by doing the reaction in the reagent wells of the transfer disc and by utilizing the high-speed spectrophotometric and data-reduction capabilities of the centrifugal analyzer. Hemolysis, icterus, and moderate lipemia cause no interference. Grossly lipemic sera and sera from patients with plasma cell dyscrasias can be analyzed by incorporating appropriate blanking and dilution techniques. The method exhibits excellent sensitivity and precision and results correlate well with those from a continuous-flow procedure.


Parallel electrophoretic fractionation of alkaline phosphatase and serum protein on cellulose acetate strips: clinical evaluation. We describe here a simple, time-saving method for separating alkaline phosphatases on cellulose acetate, with a parallel detection of serum protein pattern. The staining procedure is based on a coupling reaction between the reaction product of alpha-naphthol with Fast Red Violet LB. The enzymatic reaction is done by bringing the cellulose acetate strip containing the phosphatase band into contact with the surface of a solid agar/substrate mixture. The whole procedure requires 80 min. The method has some features in common with other recently proposed procedures but is more reproducible and rapid because of the choice of the reagents and an improved yield of the coupling step.


Direct determination of serum chloride with a semiautomated discrete analyzer. I show how mercuric thiocyanate reagent can be used in assaying serum chloride economically, rapidly, and precisely. I used a semiautomated discrete analyzer with direct concentration read-out capability but the method can easily be applied to many mechanized instruments. Linearity between concentration and color is obtained by adding appropriate amounts of mercuric nitrate to the reagent. As many as 300 samples can be assayed per hour, and the method is excellent for emergency use.


Detection of circulating carcinoembryonic antigen (CEA) by counter-immunoelectrophoresis. A sensitive method is described for detecting circulating carcinoembryonic antigen (CEA) by combined use of counter-immunoelectrophoresis and intensifiers. Perchloric acid extraction of serum was followed by counter-immunoelectrophoresis against monospecific antiserum to CEA. A precipitin line formed was intensified further by electrophoretic binding of anti-gammaG gamma-globulin and Amido Black staining. Less than 10 ng CEA/ml was detectable. Using this method, a total of 84 sera from patients with or without malignancy was examined. The results obtained were in general agreement with those reported by radioimmunoassay. The method appears to be useful as a diagnostic aid, since it requires neither labeled preparations of purified CEA nor special equipment for assay.


Hypercalcitoninemia in infancy.

Hypercalcitoninemia in infancy. Immunoreactive calcitonin (iCT) was measured in 19 infants with neonatal hypocalcemia. The infants had a variety of neonatal diseases and stresses. iCT levels were generally elevated to two to 20 times the adult values. Poor correlation existed between the infant age and the level of iCT or between iCT alone and the serum calcium. However, there was significant correlation between the serum calcium and the ratio of the iCT to infant age from conception, suggesting that both infant age and iCT levels in combination may be related to hypocalcemia. Also, it appears that a variety of neonatal stresses may be associated with increased sensitivity to the hypocalcemic effect of iCT, as well as increased levels of iCT.


Elevated serum enzymes in patients with wasp/bee sting and their clinical significance. Seventeen patients who had been admitted to hospital for wasp/bee sting were studied. Mild pyrexia was encountered in 7 patients, rash/urticaria in 3, angioneurotic oedema in 2, oliguria in 2, microscopic haematuria and albuminuria in 3, transient hypotension in 1. However, there were frequent elevations of serum glutamic-oxaloacetic transaminase (9 out of 17 patients), serum creatine phosphokinase (14 out of 17 patients) and serum lactate dehydrogenase (8 out of 14 patients), indicating presence of damage to muscle fibres. This was confirmed by the histological findings of a muscle-biopsy from the most severe case. Elevation of serum glutamic-pyruvic transaminase was found in 6, and elevation of serum isocitrate dehydrogenase in 5 out of 14 patients, suggesting presence of liver damage. The above enzyme elevations appeared short-lived except in the clinically most severe patient (case 9) who developed acute tubular necrosis. All patients except the latter suffered no clinical sequelae and there was no correlation between their clinical condition and the presence or degree of elevations of serum enzymes.


Inhibition of brain glutamate decarboxylase by glutarate, glutaconate, and beta-hydroxyglutarate: explanation of the symptoms in glutaric aciduria? Glutaric aciduria is a disorcer of lysine, tryptophan, and hydroxylysine metabolism characterized by intermittent metabolic acidemia, dystonia, athetosis and mental retardation. It is due to a recessively inherited deficiency of glutaryl-CoA dehydrogeanse, the enzyme(s) which catalyze the dehydrogenation of glutaryl-CoA to glutaconyl-CoA and decarboxylation of the latter to crotonyl-CoA. Abnormal quantities of glutaric, beta-hydroxyglutaric, and glutaconic acids are found in the urine of these patients. The nature of the movement disorder prompted study of the effects of the abnormally excreted metabolites on brain glutamate decarboxylase, an enzyme implicated in the pathogenesis of Huntington's chorea. Glutamate decarboxylase activity was examined in rat and rabbit brain acetone powders, stabilized with pyridoxal phosphate and glutathione. Glutarate, beta-hydroxyglutarate, and glutaconate were competitive inhibitors of this emzyme, Ki values being 1.3 X 10(-3) mol/l, 2.5 X 10(-4) mol/l, respectively. This inhibition may explain the neurological accompaniments of this syndrome.


Plasma protein profiling: the diagnostic evaluation of disorders in plasma protein composition by a new immunoelectrophoretic method. A new electroimmunoprecipitation technique is presented by means of which a great variety of antigens e.g. plasma proteins can be simultaneously and quantitatively determined with a single-step electrophoretic separation. The essential features of the new technique are: (a) subdivision of the antibody gel into gel strips containing monospecific antibodies to individual plasma proteins. (b) sample application as a "sample gel" filling a trough over the width of the immunoplate. Quantitation is based on the fact that the distance an antigen can migrate within a gel containing a defined amount of specific antibody directed against the antigen is determined by the concentration of the appropriate antigen within the sample. The area where the antigen is finally completely consumed by immunoprecipitation and antibody present in excess is sharply delineated. The applicability of the method in simultaneous quantitative determination of 15 plasma proteins is demonstrated with plasma from healthy blood donors and patients with various diseases. The advantage of the new technique as compared to commonly used clinical acetate folia electrophoresis is the high degree of specificity for the determination of a great number of individual, diagnostically meaningful plasma proteins. The advantage over common quantitative two-dimensional immunoelectrophoresis is its uncomplicated way of evaluation. The potential clinical application of the new quantitative immunoelectrophoretic technique in diagnostic screening and differential diagnosis is discussed.


Variations in serum iron and total iron binding capacity with the time of intake of combined oral contraceptives. Serum iron and total iron binding capacity (TIBC) were estimated in 145 healthy subjects in the reproductive stage of life, using lyndiol and eugynone for a period of 1-72 months, and results were compared with those of 30 healthy individuals, of the same class, also in reproductive stage of life. Serum iron variation did not follow any clear pattern. TIBC increased in 80% of the subjects to a value equivalent to 3-110% of the mean control. There was also a clear increase observed in immunoelectrophoretic pattern of transferrin, following the use of oral contraceptives.


Phenylacetic oil: a possible simple test for fat absorption. The preparation of a phenyl[1-14C]acetic acid oil is described. The absorption pattern of the phenylacetate in this oil is similar to that of oleic acid in triolein when examined in rats under conditions that may interfere with digestion and/or absorption. The safety of this compound, which is a normal metabolite, was established by the absence of the 14C label in various tissues five days after its administration to rats. When tested in 18 normal human volunteers 66.6 +/- 16.0 (S.D.) percent of the phenylacetate was recovered in a five hour urine collection. In two patients with malabsorption, less than 30% of the label was recovered in the urine over the same period. The half-life of the phenylacetate was determined to be 1-1.5 h. Our preliminary results indicate that phenylacetic oil may serve as a useful simple clinical test for fat absorption.


Increased urinary excretion of L-xylulose in patients with liver cirrhosis. The urinary excretions of L-xylulose, xylitol and D-glucarate after the oral administration of glucuronolactone (5 g) were measured in normal healthy persons, patients with diabetes mellitus, acute hepatitis in recovery stage, chronic hepatitis and liver cirrhosis. In normal subjects, the mean value of L-xylulose excretion was 14.6 +/- 1.4 mumol/2 h with a range from 6.5 to 21.8. Marked increase of L-xylulose excretion was observed in cirrhotic patients, the mean value was 97.1 +/- 19.8 with a range from 22.0 to 236.6. Though some cases of acute and chronic hepatitis showed higher values than the normal range, no case exceeded 50 mumol/2 h. The urinary excretion of xylitol in cirrhotic patients was also higher than normal no increase was observed in D-glucarate excretion. The values of L-xylulose excretion in cirrhosis were correlated with the values of serum total bilirubin, albumin, albumin/globulin ratio, lactate dehydrogenase and prothrombin time. These findings indicate that the measurement of L-xylulose in urine after the oral glucuronolactone loading provides a useful tool for evaluation of the severity of liver cirrhosis.


A direct method for the estimation of ornithine carbamoyltransferase activity in serum. Ornithine carbamoyltransferase (EC 2.1.3.3) activity was estimated by determining the amount of citrulline produced. The citrulline was colorimetrically measured by using a diacetylmonoxime-thiosemicarbazide reaction without deproteinization. The color complex which had the maximum absorbance at 515 nm was stable at room temperature in daylight for at least several hours. The proposed method was superior to other methods already reported in sensitivity, stability and simplicity.


[Identification and characterization of proteins from human bronchial secretion (author's transl)]. An analysis of bronchial mucus proteins was carried out by crossed immunoelectrophoresis. Before electrophoretic migration, sputum was treated with Ecteola-cellulose, which retains acid mucins. The proteins were then extracted by a phosphate/saline buffer pH 7.5. Crossed immunoelectrophoresis of the "bronchial extracts" was carried out with an anti-human serum: fifteen proteins were detected. Among them, IgA and protease inhibitiors play an important role in bronchial pathology. Bronchial extracts were also studied with immune serums against milk proteins, whole saliva and proteins of bronchial mucus. Bronchotransferrin, amylase and two esterases were characterized. Four other proteins were also detected with immune serums against bronchial mucus-proteins: their biological role is still unknown.


Reactivation of the apoenzyme of aspartate aminotransferase in serum. Apoenzyme of aspartate aminotransferase in serum can be reactivated conveniently by addition of 100 mumoles/l pyridoxal phosphate to the reaction mixture, without extending the usual minimum pre-incubation period in the operation of the LKB 8600 reaction rate analyzer. Normal sera contain some apoenzyme, the amount of which, as well as that of holoenzyme, is greatly increased by damage to skeletal muscle. This may be due to direct injury or to the indirect effects of anoxia; e.g., following surgery with extracorporeal circulation. Myocardial infarction also increases the levels of both apo- and holoenzymes, but changes in the two levels follow similar time courses and apo- and holo-aminotransferases disappear from the circulation at similar rates.


Plasma carnitine and body composition.

Plasma carnitine and body composition. Plasma carnitine has been determined in 16 men and 45 women without known muscular disorders. Mean values were 57.3 mumoles/l +/- 12.8 (S.D.) for men and 46.5 mumoles/l +/- 12.4 (S.D.) for women. The difference was statistically significant. Of the variables tested, a positive significant relationship was found between plasma carnitine and age, but not for different variables of body composition, e.g. body cell mass or plasma cholesterol and triglycerides. The daily urinary excretion of carnitine has been compared in a healthy individual during two periods, one on an ordinary diet and one on a gruel diet, giving a constant carnitine intake. The mean value of carnitine excretion (241 mumoles per 24 h) of the two periods did not differ and although the variance was less on the gruel diet, no statistical difference was found.


Aminopeptidase B in human serum.

Aminopeptidase B in human serum. The activity of arginine aminopeptidases in human serum was studied with special reference to the possible involvement of enzymes resembling aminopeptidase B (APB). The serum samples were obtained from 10 patients with various acute inflammatory processes, both during the acute phase and after treatment with penicillin. The administration of penicillin to the patients did not result in noticable changes in the chromatographic pattern of the APB-like enzyme. The disappearance of the acute symptoms did not significantly affect the overall specific activity of arginine aminopeptidases in serum. The results showed that human serum does contain, contrary to earlier reports, an enzyme corresponding to APB, even though in very low concentrations. The low enzyme activity was revealed by prolonged reaction times and by the use of larger samples in chromatography than earlier. The APB-like enzyme in serum may have derived from blood cells.


Intermittent treatment with human growth hormone (GH) in isolated GH deficiency and in multiple pituitary hormone deficiencies. The results of intermittent GH treatment of 3-7 1/2 years duration in seven patients with isolated GH deficiency (IGHD) and five patients with multiple pituitary hormone deficiencies (MPHD) are presented. This therapeutic schedule was found to be comparably effective to those using a continuous-administration schedule. In contradistinction to the findings obtained with the latter, there was no progressive decline in growth velocity. The patients with IGHD were found to respond better than the patients with MPHD both in the first course as well as in consequent courses. In the intervals between courses, the growth velocity was less than in the pretreatment period in both groups. It is concluded that optimal results can be obtained by instituting an initial course of continuous treatment of 1 year's duration for the IGHD patients and of 2 years' duration for the MPHD patients, followed by an intermittent therapeutic schedule. This regime not only leads to the same growth achievement obtained with long-term continuous administration of GH but allows conservation of supplies of this very scarce hormone.


Glucocorticoid maintenance therapy following adrenalectomy: assessment of dosage and preparation. Plasma cortisol was monitored repeatedly after oral administration of cortisol and cortisone (cortisone acetate) to seven adrenalectomized patients with pituitary-dependent Cushing's syndrome. The amount of glucocorticoid administered was 25 mg cortisol or 33 mg cortisone/g urine creatinine/24 h. Peak plasma cortisol levels were within recommended values in all patients after cortisone and in three of the patients after cortisol. The remaining four patients had elevated peak plasma cortisol levels after cortisol. Transcortin binding capacity in plasma was normal. It is concluded that cortisol as well as cortisone is suitable for oral glucocorticoid substitution therapy in patients with normal liver function, but that cortisone apparently gives a marginally smoother plasma cortisol curve. However, it is essential to monitor plasma cortisol after institution of glucocorticoid maintenance therapy, since different and unpredictable plasma cortisol levels may exist after a given amount of glucocorticoid, although the dose required correlates reasonably well with creatinine excretion in urine.


Total body potassium content in males with X and Y chromosome abnormalities. Total body potassium has been measured in chromatin positive males (Klinefelter's syndrome) and males with a 47,XYY karyotype. In patients with an extra X chromosome the level of potassium was very significantly less than in normal males. Its concentration referred to lean body mass, estimated from the patient's height and weight, was also greatly reduced and not significantly different from values found in normal women. In 47,XYY males individual  values were low but there was no reduction in the mean value for the group if allowance was made for the obesity of some XYY subjects. The significance of these findings, however, is difficult to assess as their height frequently exceeded that of the controls on which the predicted potassium values were based. From these findings it would seem that when characteristics which are normally associated with the female sex occur in males, as in Klinefelter's syndrome, there is also a reduction in body potassium either in the total content or the lean tissue concentration, or in both. By comparison, 47,XYY males appear to be more normal in these respects but further normal data is required in order to interpret the results. The possibility that abnormal androgen production in the chromatin positive men may be influencing the potassium levels is the subject of further investigation.


The adrenocortical status of patients with thyroid disease. Plasma cortisol, cortisol resin uptake ratio and free cortisol index was measured in twenty-seven euthyroid, ten hypothyroid and fifteen hyperthyroid subjects. No difference was observed between euthyroid subjects and patients with thyroid disease for any of the three parameters tested. The significance of these findings is discussed in the light of earlier reports linking thyroid activity with the levels of corticosteroid binding globulin.


Aarskog syndrome: new oral-facial findings. The Aarskog syndrome is characterized by short stature with typical facial, digital and genital anomalies. A further case is reported which presented with the uncommon finding of ophthalmoplegia and three previously unreported oral-facial findings: enamel dysplasia, a "col" deformity of the anterior mandible and a paresis of the facial muscles innervated by the VII cranial nerve. The implications of genetic heterogeneity in this nosologic classification are discussed.


Familial branchio-oto-renal dysplasia: a new addition to the branchial arch syndromes. The present report concerns a two-generation family of nine individuals in which the father and three of the six living children all had: (1) a mixed hearing loss with a Mondini type cochlear malformation and stapes fixation; (2) cup-shaped, anteverted pinnae with bilateral prehelical pits: (3) bilateral branchial cleft fistulas; and (4) bilateral renal dysplasia and anomalies of the collecting system. The father and one affected son also had aplasia of the lacrimal ducts. A fourth child who died at 5 months of age was reported to have branchial cleft fistulas and bilateral polycystic kidneys at autopsy. In addition, the concept of noso-embryologic communities is presented. Such groups are composed of syndromes whose total phenotypic spectra not only overlap but also share common elements in embryogenesis. This concept is illustrated with a group of branchial arch syndromes that are related in this way.


A dermatoglyphic study of 219 Italian schizophrenic males. The quantitative and qualitative finger and palm ridge characteristics of a sample of Italian schizophrenic males showed minor deviations which were neither pathognomonic of the illness as a whole, nor of its Leonhard sub-groups. In essence there was a slight tendency for an increase in finger loops, particularly on middle fingers, with a decrease of whorls, and the palmar ridges tended to a more transverse course than usual. Compared with two sets of controls there was an excess of short schizophrenic males.


Chromosome studies in ovarian hypoplasia. Six phenotypic female patients characterized by an average stature, infantile body constitution, underdeveloped external and internal reproductive organs and secondary sex characteristics and amenorrhoea are described. In each of them laparotomy and histological study disclosed ovarian hypoplasia. The karyotype was 46,XX in all patients except one. However, the metaphase analysis extending over a greater than usual number of cells revealed an autosomal ring (15) in 5 to 26% of cells. The patients also showed phenotype signs of D chromosome anomalies. The authors agree with the previously suggested autosomal gene effect in sex differentiation.


Dominant ichthyosis vulgaris with an ultrastructurally normal granular layer. It has been suggested that ultrastructural studies of keratohyalin granules in the granular layer of the skin can clearly distinguish the dominant type from the X-linked recessive type of ichthyosis vulgaris. The distinctive features are found in the granular layer and the keratohyalin granules. In the dominant form the granular layer is absent or reduced in size and the keratohyalin granules are minute and crumbly in appearance. In the recessive form the granular layer and keratohyalin granules are normal. A family which probably has dominant ichthyosis vulgaris is described. The stratum granulosum and keratohyalin granules as determined by both light and electron microscopy are normal. In view  of the inconstant morphologic appearance of the stratum granulosum in ichthyosis vulgaris, it is suggested that distinction between the dominant and X-linked forms should not be based on the structural characteristics of the granular layer alone, but rather on a combined evaluation of the pedigree, clinical features and the appearance of the stratum granulosum.


Split-hand and split-foot deformity inherited as an autosomal recessive trait. A intermarried consanguineous family with split-hand and -foot deformity occurring in two sibship is presented. Both the sibship resulted from marriage between first cousins. This report, together with those of Ray (1960) and Freire-Maia (1971), further demonstrates that split-hand and -foot deformity can be inherited as an autosomal recessive trait.


Essential tremor, nystagmus and duodenal ulceration. A "new" dominantly inherited condition. The familial occurrence of essential tremor combined with (congenital) nystagmus, duodenal ulceration and a narcolepsy-like sleep disturbance caused by an autosomal dominant gene with high penetrance and fairly uniform expressivity is reported in a family of Swedish-Finnish ancestry. Twelve of 17 affected family members had essential tremor which began between 30-40 years of age and which could be controlled temporarily by alcohol; this resulted in alcoholism in several affected individuals. The most severly affected persons showed cerebellar signs which may reflect a possible pathogenetic relationship of the syndrome to the genetic cerebellar atrophies. Nystagmus, observed in 12 of 17 affected family members (eight of whom were also affected with tremor) usually was congenital and accompanied by refractive errors. Duodenal ulcers occurred almost exclusively in individuals with the neurological syndrome, and preceded its onset in some cases. The ulcer disease therefore seems to be a component manifestation of the syndrome and is interpreted as a pleiotropic effect of the gene which also causes the nystagmus, tremor and sleep disturbance.


Histidinuria: a renal and intestinal histidine transport deficiency found in two mentally retarded children. Two siblings presenting slight mental retardation showed an abnormal elimination of histidine, their blood levels for the same amino acid being normal. The percentage of tubular resorption of histidine was calculated in both boys, and the values were 40.1 per cent (case 1) and 52.8 per cent (case 2). All other amino acids essayed were normal. After an oral overload test with histidine, a low intestinal absorption was found in the two boys, the values of this test in the parents being intermediate between those of the children and of the three normal controls and corresponding to heterozygosity. In view of the studies carried out on the two boys, it is possible to conclude that they are suffering from an impairment in their histidine membrane transport system which affects the kidney and intestines. Since they are siblings a genetically determined trait may be suspected.


X-linked nonspecific mental retardation. Report of a large kindred. A seven-generation pedigree of apparent X-linked, nonspecific mental retardation is reported. There are 19 known affected males who appear to have received the gene through normal mothers. Retardation, lack of fine motor coordination, hyperactivity and a speech defect are the characteristics of affected individuals studied.


Aplastic anemia followed by leukemia in congenital trisomy 8 mosaicism. Ultrastructural studies of polymorphonuclear cells in peripheral blood. The case of a 40-year-old patient with congenital trisomy 8 and sex chromosome mosaicism is discussed. The main clinical features were: mental retardation, thick and darkly pigmented skin, prominent forehead, convergent strabismus, high arched palate, flexion contractures of the extremities, and numerous skeletal abnormalities. The patient developed severe aplastic anemia followed by an interim period of preleukemia which developed into acute leukemia. Electron microscope examination of the white blood cells at the stage of the aplastic anemia showed ultrastructural abnormalities similar to those observed in other genetic disorders with a predisposition to leukemia, as well as in leukemia.


Identical tetramelic monodactyly in two brothers. We report almost identical tetramelic monodactyly in two brothers. On the hands and on the feet, only the 5th fingers and the 5th toes were present. Aplastic and hypoplastic defects were found to some degree in the remaining skeletal parts of the hands and feet. All observed deformities were symmetrical. No other defects of either the upper or the lower extremities were found. Both brothers had no other malformation or dysplasias and were apparently of normal intelligence. There were no further cases in the ancestry.


Microphotometry of banded human chromosomes II. Technique for microphotography of banding patterns. As part of a study of chromosome banding patterns by microphotometric measurements of photographic negatives, banded chromosomes were microphotographed in order to evaluate the importance of the size of the condensor (illumination) aperture for obtaining high resolution. The resolution was found to be closely correlated to the numerical aperture of the objective, but within wide limits it was independent of the condensor aperture. The reason is assumed to be light scattering caused by the object, which results in illumination of the full objective aperture. The optimal photographic method was found to include the use of a 63x oil planapochromate objective (NA 1.4) and a total microscope magnification of 250x.


48, XXXY Klinefelter syndrome and nail-patella syndrome in the same child. A patient is described who in addition to having the 48, XXXY Klinefelter syndrome has the autosomal dominant nail-patella syndrome, inherited through his mother from the grandfather. Clinical signs of both syndromes were found. Chromosomal investigation with BUDR incorporation and acridine orange staining showed that one X chromosome stained intensively, while the other X chromosomes were elongated and weakly stained. Difference in degree of stretching of the supernumerary chromosomes was noted. The occurrence of the two rare syndromes in the same patient is assumed to be fortuitous.


Cytogenetics of 50 patients with mental retardation and multiple congenital anomalies and 50 normal subjects. Madison blind study IV. The chromosomes of 50 idiopathic mentally retarded patients with at least three other anomalies and 50 normal subjects were analyzed from randomized coded slides. The chromosomally abnormal cases were also studied by means of Q-banding. Seven of the patients showed a chromosome anomaly. Two had an extra G-like chromosome, which in case M99 consisted mainly of 16p (he had also a small Y chromosome shared by his father and brother), and in case M8 of 9p. The mother and sister of M99 were balanced translocation carriers. Case M18 (published separately) has approximately half of 12p deleted. Case M60 had a deletion of 20q and trisomy for a segment which most probably came from 7p. Case M49 had a deletion of 1p and increased centric heterochromatin in 1q: the latter abnormality was shared by the father and a sister. Case M83 displayed low-grade mosaicism for cells with an extra small ring of unknown origin. Case M38 had the brightly fluorescent distal part of the Y chromosome duplicated, and the father had the same chromosome. In the five first cases the phenotype was presumably caused by the chromosome anomaly, and in the mosaic this is a possible cause. In the normal subjects, two persons had minor chromosome anomalies: case M68 had a pericentric inversion in the Y chromosome, which was found also in the father and the brother, and case M10 had a telocentric no. 21. Three of the patients (M18, M49 and M99) can be regarded as type specimens for new syndromes in the sense that the chromosome anomalies causing the respective phenotypes have been identified for the first time.


Polycystic kidney disease in a patient with the oral-facial-digital syndrome - type I. Bilateral polycystic kidneys and chronic renal failure were observed in a 48-year-old woman with the classic clinical features of the oral-facial-digital syndrome, Type I (OFD-I). Since this association has been previously reported in two other patients, these findings suggest that polycystic kidneys may be a hitherto unrecognized manifestation of the oral-facial-digital syndrome.


A case of trisomy 20?

A case of trisomy 20? Chromosome determination in a girl who at birth had an abnormal appearance and a cat's cry, and later a poor weight gain and psychomotor retardation, showed a probable trisomy of chromosome pair no. 20. The analysis was made by means of photometric examination of G-banded chromosomes from lymphocyte cultures. The deviating chromosome was identified in fibroblast cultures as well.


An isochromosome of the short arms of the no. 18 chromosome in a mentally retarded girl. A 2.5-year-old girl with several congenital anomalies is described. Chromosomal analysis suggests the presence of a small extra metacentric chromosome which was identified as isochromosome 18p by means of R-banding and C-banding.


Autosomal recessive muscular dystrophy in Manitoba Hutterites. A slowly progressive type of muscular dystrophy affecting 11 known members of several Southern Manitoba Hutterite colonies is described. Though encompassing the facial characteristics of the facio-scapulo-humeral type and the proximal distribution of the limb-girdle type, it was felt that this disease represents a distinct type of muscular dystrophy with autosomal recessive inheritance. Since all "affected" colonies can be traced to one founding colony in South Dakota, the disease may have been introduced from Europe between 1874 and 1879. Furthermore, normal fertility and a high degree of inbreeding in a genetically isolated population have contributed to the maintenance of the disease in the population.


Cerebellar ataxia and hypergonadotropic hypogonadism in two kindreds. Chance concurrence, pleiotropism or linkage? Two kindreds with Marinesco-Sjögren's syndrome in three sibships are described. In five of the six affected, but in none of the unaffected sibs, a hypergonadotropic hypogonadism was observed. In one of the kindreds a high degree of inbreeding was revealed, and inbreeding likely also existed in the other kindred. The two families were not related. Marinesco-Sjögren's syndrome is known to be a distinct clinical entity, governed by autosomal recessive inheritance, and this also applies to hypergonadotropic hypogonadism. Several heredo-degenerative nervous disorders are accompanied by a hypogonadotropic hypogonadism, which is believed to be secondary to the neurological disorder, as in traumatic paraplegia. A hypergonadotropic hypoganadism cannot readily be explained in this way. We consider genetic linkage between two independent disorders as the most likely explanation for the observed concurrence.


Inheritance of hypoplastic left heart syndrome (HLHS): further observations. From a survey of newborn infants using truncate ascertainment of families through affected offspring, 64 cases of hypoplastic left heart syndrome (HLHS) were found. Pedigree information was obtained from 42 families. The incidence of HLHS, based on 64 affected infants, was 36.5/100,000 births. The incidence of HLHS with aortic and/or mitral atresia was 25.1/100,000 births. The recurrence among later siblings was about 2 %. Autosomal recessive hypothesis of transmission of this disorder was not supported. Using Edwards' formula, the observed recurrence among later siblings was compatible with polygenic inheritance.


Partial trisomy of the long arm of chromosome 7. A baby with partial trisomy 7, 46, XY,t (5;7) (q35;q31) resulting from a familial translocation (5q+,7q-) is reported. The clinical abnormalities of this case closely resemble those of previously reported cases of partial trisomy 7. It is suggested that partial trisomy 7 may represent a clinical entity.


Senior-Loken syndrome (nephronophthisis and tapeto-retinal degeneration): a study of 8 cases from 5 families. The association of nephronophthisis and tapeto-retional degeneration was described by both Senior and Loken in 1961, but prior to 1974 only 28 cases had been published. This report describes 8 new cases in 27 members of 5 families. The severe juvenile type produces blindness in infancy and death from renal failure before the age of ten. The adult type is characterized by later onset, slower progression of the renal disease and milder ocular manifestations. The eye disease may be congenital amaurosis of Leber type, pigmentary retinal degeneration or retinitis punctata albescens and the electroretinogram (ERG) is of value in the diagnosis of these varieties of hereditary tapeto-retinal degeneration. Renal involvement is often asymptomatic. Defective urinary concentration leading to polyuria and polydipsia is the earliest sign. Proteinuria is inconstant and urinary sediment is often normal. Two patients had aminoaciduria. The disease progresses inexorably to chronic renal failure. One patient has been successfully transplanted and two others are on chronic hemodialysis. Renal histological changes are those of nephronophthisis with tubulointerstitial lesions and multiple cysts. Senior-Loken syndrome appears to be transmitted by a single autosomal recessive pleotropic gene of variable expression. Degeneration of neuroepithelium and renal tubular epithelium, both tissues of ectodermal origin, may represent a genetically determined enzyme abnormality.


Reversible encephalopathy following cephacetril therapy in high doses in a patient on chronic intermittent hemodialysis. A patient on chronic intermittent hemodialysis at home showed signs of acute encephalopathy after an 8-day's treatment with a total dose of 78 g cephacetril (Celospor). Features included papilledema, loss of visual fields, severe generalized EEG changes and bilateral occipital abnormalities on a brain scintigram. Psychopathological findings consisted of a severe psychosis. The visual fields defects were the last sign of the encephalopathy to disappear.


The use of heparin in the treatment of idiopathic rapidly progressive glomerulonephritis. 14 cases of idiopathic rapidly progressive glomerulonephritis (I. R. P. G. N.) treated by heparin between 1968 and 1974 were collected by the authors. Extra-capillary crescents (E. C. C.) occurred in 75 to 100% of glomeruli in ten patients and in 50 to 75% in four. Gross proteinuria, hematuria and renal failure were always present. 9 patients were admitted with primary oligo-anuric renal failure. 11 patients were treated by repeated hemodialysis before and during anticoagulant treatment. Heparin was given by intra-venous injection every 3 hours for one to two months with Howell times range from 150 to 200% of control. Heparin was the only treatment in 6 cases, and was given with dipyridamole in 4, with prednisone in 3 and with azathioprine in one case. 5 severe or fatal hemorragic complications were observed. The clinical course was usually unfavorable with 5 early deaths, 3 provisional steady-states with 2 late deaths. Six patients were treated by periodic hemodialysis. Repeat kidney biopsies were obtained in 8 patients. The findings suggest that heparin affects mainly the E. C. C. and fibrinoid deposits but not glomerular sclerosis. The inefficiency of all current treatments of primary oligo-anuric IRPGN is stressed. In patients with better initial renal function choice between anticoagulant and/or immuno-depressive drugs must be scrutinized in individual cases bearing in mind potential iatrogenic complications. In equivocal cases, patients should be referred to the chronic hemodialysis and/or transplantation program.


Bradycardia preceding apneic attacks in low-birthweight infants. The relationship and management. Two premature infants had frequent episodes of prolonged apnea. The apneic spells were not due to the more commonly known causes of apnea in infancy, but were consistently preceded by severe bradycardia. Atropine or ephedrine produced favorable therapeutic results. Since severe bradycardia may be a cause of sudden death in infants, its recognition and treatment is important in the management of apneic infants.


Sensory mapping.

Sensory mapping. The primary aim in reconstructive surgery of the upper extremity is to provide tactile gnosis to sensory depleted areas. It is essential for restoration of function and successful rehabilitation of the injured hand. Neurovascular free flaps may provide the answer to this catastrophic problem and transform a useless appendage into a functional gripping hand. Sensory mapping techniques can greatly assist the surgeon in precisely defining new donor sites for these transfers. Cutaneous sensibility, cutaneous sensation, and hand function are subjects of great complexity. Much more investigative and clinical work is needed in this challenging field to improve our evaluation of the sensory injury to the hand and to provide new avenues for restoring functional sensibility in the upper extremity.


The fate of circulating lactate dehydrogenase-5 in the rabbit. 1. In an attempt to determine the mechanism whereby enzymes are removed from the circulating plasma, purified rabbit-muscle lactate dehydrogenase-5 was labelled with 125I and injected intravenously into rabbits. During the first hour after injection enzyme activity and radioactivity disappeared from the plasma at comparable fast rates, which are attributed mainly to distribution of the enzyme throughout the extracellular fluid. This was followed by a phase lasting about 7 h during which enzyme activity disappeared at a faster rate than the radioactivity, an observation indicating either intravascular breakdown of the enzyme protein or its degradation in the tissues, followed by release of labelled fragments into the circulation. Enzyme activity then reached a constant value and the plasma radioactivity continued to decrease at a slower exponential rate; it is suggested that this is due to removal of breakdown products. 2. The radioactivity of the tissues was measured at various time-intervals after injection. After 2 h and 8 h highest concentrations were found in the spleen, liver, jejunum and duodenum. Relatively high concentrations were also found in the intestinal juices throughout the period of study, an observation which suggests that discharge via the small intestine is a major route whereby inactivated enzyme fragments are removed from the circulation. 3. About 5% of the injected radioactivity was recovered in the faeces during the first 3 days, and the urine accounted for 73% during the same period. About 35% of the urinary radioactivity was shown by silver nitrate precipitation and by chromatography to consist of free iodide and the remainder appeared to consist of radio-iodinated amino acids or peptides. Free mono- and di-iodotyrosine were identified among the products. These results suggest that further breakdown in the intestine is followed by absorption of the products, which are excreted in the urine.


Effect of liver failure on the cerebral circulatory and metabolic responses to hypoxia in the goat. 1. Six unanaesthetized goats were used to evaluate the effect of liver failure on the hypoxic responsiveness of cerebral blood flow. The animals breathed air and several different hypoxic gas mixtures enriched with sufficient CO2 to maintain an isocapnic state. The cerebral metabolic rate for O2 (CMRo2) was also measured in four of these goats. 2. In baseline studies there was a linear relationship between cerebral blood flow and arterial O2 saturation (Sa,o2) measured at different levels of isocapnic hypoxia. The slopes of the cerebral blood flow/Sa,o2 response lines were used to quantify the response of cerebral blood flow to hypoxia. In the healthy goat, CMRo2 was not depressed by hypoxia until the O2 tension (Po2) in arterial and cerebral venous blood had fallen below critical threshold values of approximately 3-2 and 2-2 kPa (24 and 16 mmHg) respectively. 3. Liver failure was accompanied by a fall in cerebral blood flow and CMRo2. There was also a depression in the response of cerebral blood flow to hypoxia and a disproportionate reduction of cerebral O2 delivery in hypoxia. CMRo2 was further reduced at arterial and cerebral venous Po2 values, which were much higher than the critical threshold values for producing hypoxic CMRo2 depression in health. 4. It is concluded that the brain becomes more vulnerable to the adverse effects of hypoxia during liver failure. This may be of practical importance in the management of patients with arterial hypoxaemia or other complications (e.g. anaemia or shock), which may reduce cerebral oxygen delivery.


The pattern of venous drainage of surgically created side-to-side arteriovenous fistulae in the human forearm. 1. The forearm and hand circulation in nine patients with a surgically created side-to-side fistula between the radial artery and a nearby superficial vein in the lower forearm has been investigated. 2. Dilated veins on the dorsum of the hand communicated with the fistula without intervening valvular obstruction. Skin temperature of both forearm and hand was greater on the side with the fistula in all cases. 3. Inflation of an occlusion cuff distal to the fistula markedly reduced apparent fistular flow. 4. It is concluded that the fistulae result in increased blood flow to the hand by retrograde flow from the fistula into the hand veins. Hand as well as forearm must be included in the plethysmographic measurement of blood flow in such cases.


Measurement by venous occlusion plethysmography of blood flow through surgically created arteriovenous fistulae in the human forearm. 1. Plethysmographs containing the hand plus forearm were used to measure blood flow in patients with a srugically created arteriovenous fistula in one forearm. 2. Apparent flow rate was stable over a limited range of collecting pressures; the absolute value of these pressures varied from patient to patient. 3. After arterial occlusion, blood flow increased by a similar amount on the normal side and on the side with the fistula. 4. Occlusion of fistular flow produced no significant change in heart rate. 5. Fistular flow, estimated as the difference between flow on the two sides, averaged 525 ml/min in seventeen patients.


The role of the colon in urea metabolism in man. 1. The urea content of ileostomy effluent has been measured by the urease method as an indirect estimate of the urea concentration in the lumen of the normal ileum. 2. The plasma disappearance of intravenously administered[14C]urea was used to study intestinal urea breakdown. Normal subjects on high and low protein diets and patients with either excised (i.e. with ileostomies) or excluded colons were studied. 3. The 24 h intestinal urea breakdown was considerably greater than the quantity of  urea estimated to be entering the colon from the ileum and across the colonic mucosa. 4. Intestinal urea breakdown increased with increase in dietary protein and decreased with, but was not abolished by, exclusion or excision of the colon. 5. Our results suggest that the colonic lumen is not the only site of intestinal ureolysis and that significant quantities of urea must be broken down either at a juxtamucosal site or in the ileum.


A comparison of the clearance of urographic contrast medium (sodium diatrizoate) by peritoneal and haemodialysis. 1. The clearance of isotopically labelled sodium diatrizoate by haemodialysis was measured in vitro, with simulated extracellular fluid, and in vivo in eleven patients, at varying rates of fluid or plasma flow. Clearance was also measured in five patients undergoing peritoneal dialysis. In all instances simultaneous measurements of urea clearance were made and the diatrizoate/urea clearance ratio was calculated. 2. In haemodialysis studies, diatrizoate and urea clearances showed a linear increase with increasing 'extracellular fluid' or plasma flow through the dialyser diatrizoate/urea clearance ratio fell. 3. The clearance of diatrizoate in vivo was slightly less than clearance in vitro at corresponding flow rates, but the diatrizoate/urea clearance ratio showed no significant difference. 4. Diatrizoate and urea clearances during peritoneal dialysis were very much lower than during haemodialysis but the diatrizoate/urea clearance ratios were within the same range. 5. The rapid removal of diatrizoate in patients with renal failure requires haemodialysis.


Acid hydrolase activities and lysosomal integrity in liver biopsies from patients with iron overload. 1. Iron, acid phosphatase and N-acetyl-beta-glucosaminidase were assayed in liver biopsies from control subjects and patients with primary and secondary haemochromatosis. 2. The activities of the lysosomal enzymes were significantly higher in liver biopsies from patients with iron overload than in those from other patient groups. 3. Lysosomes from the livers of patients with iron overload were strikingly more fragile than those of control subjects as demonstrated by assays of latent and sedimentable N-acetyl-beta-glucosaminidase. 4. Lysosomal integrity was essentially normal in biopsies from patients with a wide variety of chronic liver diseases. 5. It is suggested that iron accumulation damages lysosomal membrane, releasing acid hydrolases into the cytoplasm and thus initiating cell damage.


Absence of an acute effect of calcium or parathyroid hormone administration on plasma renin activity in man. 1. There was no significant change in plasma renin activity over 6 h in five subjects given calcium gluconate or in four subjects given parathyroid hormone. 2. It is concluded that acute hypercalcaemia does not increase plasma renin activity and is unlikely to play a role in the hypertension found with primary hyperparathyroidism.


Effects of halothane on pulmonary inactivation of noradrenaline and prostaglandin E2 in anaesthetized dogs. 1. The inactivation of noradrenaline and prostaglandin E2 was studied in the pulmonary circulation of anaesthetized dogs. 2. Under chloralose anaesthesia  and ventilation with air, the inactivation of noradrenaline was 20% and that of prostaglandin E2 was 91%. These values are in agreement with results from previous work. 3. When the dogs were ventilated with halothane-air mixtures, the inactivation of prostaglandin E2 was unaffected but that of noradrenaline was significantly reduced. 4. This effect of halothane is probably due to an interaction with the transport system for noradrenaline associated with cell membranes. 5. Analogous changes in pulmonary noradrenaline inactivation could occur in patients anaesthetized with halothane.


Pulmonary hypertension in patients using oral contraceptives. A report of six cases. Six young women who had taken progestational agents for a period of time ranging from six months to five years developed symptoms and signs of pulmonary hypertension. Cardiac catheterization confirmed the presence of severe pulmonary hypertension without evidence of other cardiac or pulmonary abnormalities to explain this phenomenon. Three of the patients had potential predispositions to pulmonary hypertension, including a corrected patent ductus arteriosus with mild pulmonary hypertension in one, collagen vascular disease in a second, and family history of pulmonary hypertension in a third. Three patients had no known predisposing factors. Although the relationship between oral contraceptives and severe pulmonary hypertension is problematic, there have been isolated reports of cases of pulmonary hypertension secondary to oral contraceptive usage. These cases and the possible pathophysiologic mechanisms responsible are discussed.