Value of systolic time intervals in assessing severity of congenital aortic stenosis in children. Simultaneous recordings have been made of electrocardiogram, phonocardiogram, carotid pulse tracing, left ventricular pressure, and aortic pressure in 27 children with aortic valve stenosis and 3 children with membranous subaortic stenosis. Peak systolic pressure difference ranged from 10 to 110 mmHg (1.3 to 14.6 kPa). None of the patients had congestive heart failure and cardiac output was in the normal range in all. Total electromechanical systole, left ventricular ejection time, and pre-ejection time were corrected for heart rate, age, and sex. Mild stenosis (peak systolic pressure difference less than or equal to 50 mmHg (6.7 kPa)) was present in 18, severe stenosis (peak systolic pressure difference greater than 50 mmHg) in 12 patients. The externally measured pre-ejection time and ejection time proved to be nearly equal to the corresponding intervals measured internally; from these data it is concluded that pre-ejection time and ejection time in children with aortic stenosis can be measured reliably by non-invasive methods. Mean values for corrected total electromechanical systole and ejection time were prolonged, but the corrected pre-ejection time did not differ from the normal value. When corrected time intervals were plotted against severity of the aortic stenosis as expressed by the peak systolic pressure difference or the aortic valve orifice index, a wide scatter was found. It is concluded that a normal ejection time is strong evidence against a peak systolic pressure difference of more than 50 mmHg (6.7 kPa) or an aortic valve orifice index less than 0.70 cm2 per m2 BSA. A prolonged ejection time, however, may occur in mild as well as in severe stenosis. Total electromechanical systole and pre-ejection time have no value in predicting the severity of aortic stenosis in children.


Tissue valves in the mitral position. Five years' experience. Between April 1969 and November 1973 103 patients underwent isolated mitral replacement with three-cusp stented tissue valves. Autologous fascia lata was used in 50 patients, homologous fascia lata in 21, and heterologous pericardium in 32. The early mortality rate (14.6%) was influenced by age, the extent of preoperative cardiac disability, and low cardiac output. The survivors were followed up for periods varying from 8 to 60 months (average 37 months). In general, a factor in late death (13.6%) was high preoperative pulmonary artery pressure. In the autologous fascial series valve failure and infective endocarditis were significantly related to late mortality. The results with homologous fascia and pericardium were better than with autologous fascia valves. The incidence of postoperative mitral regurgitation was singificantly lower in the homologous fascial and pericardial series and none of these grafts had to be removed. The incidence of thromboembolism was low without anticoagulants. Actuarial analysis showed a survival rate at five years of 82.2 per cent. We no longer use autologous fascial valves. Though better results have been obtained with both homologous fascia and pericardium we prefer the physical characteristics of heterologous pericardium and it is easy to obtain.


Circumstances attending 100 sudden deaths from coronary artery disease with coroner's necropsies. The deaths of 100 men due to coronary artery disease which occurred so suddenly and unexpectedly as to merit a coroner's necropsy have been studied, with special reference to the exact circumstances of their occurrence. The most significant relationship of sudden death was with acute psychological stress. Moderate physical activity, the time of day, the day of the week, and a recent meal, especially if accompanied by alcohol, were also significantly related. Very strenuous exercise, the season of the year, the environmental temperature or recent change of it, and chronic psychological stress were not so related. Neither were the actual smoking of a cigarette nor the composition of the meal immediately preceding death. Compared with previous series of proved acute myocardial infarction the necropsies in these cases showed that the right coronary artery had been recently occluded by a thrombus more often than the left anterior descending. Stenosis or occlusion of the right coronary artery bore a significant relation to the suddenness of death. Special analysis of the 52 cases in which neither recent thrombus nor infarction were found did not disclose any circumstances attending death which differed from the remainder. Some comparisons are made with the circumstances attending the onset of symptoms in 100 men studied while recovering from an acute myocardial infarct.


Serum CPK isoenzymes after cardiac catheterization. Exclusion of acute myocardial infarction preoperatively, particularly in patients undergoing cardiac catheterization, is an important requirement for optimal results following coronary revascularization. Unfortunately, activity of conventionally measured serum enzymes (AST, LDH, total CPK) is frequently raised because of enzyme released from non-cardiac sources during the catheterization procedure. however, serum activity of the MB CPK isoenzyme, an isoenzyme found primarily in heart muscle, appears to be more specific. Accordingly, in the present study, total CPK and MB CPK activities were determined in serum samples from 53 patients undergoing diagnostic catheterization, immediately before study and serially for 24 hours afterwards. A comprehensive range of catheterization procedures included selective coronary arteriography in 39 patients by brachial (17) or femoral (22) artery approaches. Myocardial infarction was excluded by clinical and electrocardiographic criteria in all patients before and after the procedure. MB CPK isoenzyme activity was also measured in serum samples from 50 patients with actue myocardial infarction documented electrocardiographically, and in 20 controls admitted to hospital but without cardiovascular disease. In patients with acute myocardial infarction, both total CPK and MB CPK isoenzyme levels were significantly raised (0.78 +/- 0.087 and 0.086 +/- 0.037 IU/ml, respectively), exceeding the upper limit of normal in all cases. MB CPK activity remained within normal limits (less than 0.004 IU/ml) in all 20 subjects without cardiovascular disease. Peak total serum CPK activity exceeded control levels in all patients undergoing catheterization (0.260 +/- 0.033). However, in each case, MB CPK isoenzyme activity remained within normal limits (less than .004). Thus, in contrast to an increase of activity of conventionally used serum enzymes, increased MB CPK isoenzyme activity is a reliable indicator of myocardial infarction, even in patients undergoing cardiac catheterization.


An atrionodal and nodo-Hisian gap phenomenon. Two cases of the gap phenomenon are presented. The first was an example of a gap between the atrium and the AV node. In the second the gap was at the nodo-Hisian junction. At a critical H1H2 interval splitting of the premature His potential occurred. A decrease of the H1H2 interval led to the disappearance of the distal H2 potential and to atrioventricular block. But at even shorter coupling intervals the H1H2 interval lengthened suddenly with resumption of the AV conduction. These observations provide further evidence that the gap phenomenon has a wider spectrum than was previously thought.


Complete heart block. Studies of atrial and ventricular pacemaker site and function. Atrial and ventricular pacemaker function was studied in 20 patients with idiopathic chronic complete heart block using the rate response to an intravenous bolus dose of isoprenaline (5 mug/70 kg bodyweight). Pacemaker responses were compared with those of 16 normal control subjects. None of the patients was having syncopal attacks at the time of admission and they were therefore selected in that none required immediate pacing. Ten of the patients had His bundle electrograms; all were shown to have a pre-His type of atrioventricular block. Two major groups emerge from the responses to isoprenaline. (a) High risk group: 11 of the 14 patients with reduced ventricular pacemaker responses had frequent syncopal attacks; 8 of the patients with Adams-Stokes syncope had a bundle-branch block pattern, while 3 had a narrow QRS. These patients require pacing. (b) Low risk group: a low risk asymptomatic group (5 patients) was identified with atrial and ventricular responses to isoprenaline within normal range. One of these patients had a bundle-branch block pattern, while 4 had a narrow QRS. These patients might be managed without pacing. The atrial response to isoprenaline was reduced in 12 of the 20 cases, 10 of whom also had reduced ventricular responses. All 9 patients with bundle-branch block had reduced ventricular responses, while 7 had reduced atrial responses. This evidence indicates that cardiac conducting tissue pathophysiology is widespread in complete heart bolck. The present work suggests that consideration of the ventricular pacemaker function is important in assessing liability to syncope in complete heart block. While patients with Adams-Stokes attacks require pacing it is suggested that all asymptomatic patients with complete heart block and those with minor symptoms are assessed using studies of both ventricular pacemaker function and site. A low risk group not requiring a pacemaker may emerge after sufficient follow-up assessment.


Creatine kinase release in acute myocardial infarction: correlation with clinical, electrocardiographic, and pathological findings. Creatine kinase (CK) release curves were analysed in 40 patients with acute myocardial infarction. Three groups could be identified. Group A (duration of CK release less than 30 hours) comprised 15 patients whose CK release was completed within 22.8 hours. In these patients chest pain was noted on the first hospital day and necropsy in three showed a homogeneous myocardial infarction. Group B (duration of CK release greater then 30 hours) comprised 16 patients who had a significantly longer CK release time of 42.2 hours (P less than or equal to 0.05). Their chest pain persisted for two to three days and pathological examination in five patients showed a heterogeneous composition of the infarcted myocardium. Group C comprised nine patients who had a second rise of serum CK. This was always associated with chest pain. It reflected an extension of the infarct which accounted on average for 24 per cent of the size of the final infarct. We concluded that a CK release of short duration indicated infarction without extension, CK release of longer duration indicated a gradual extension of infarction, and a repeated CK release resulted from a sudden extension of an infarct. According to these criteria an extension of the infarct occurred in 62 per cent of our patients.


Systolic time intervals in constrictive pericarditis. A study before and after digitalis. Systolic time intervals were studied in 9 patients with documented constrictive pericarditis before and 15 to 20 minutes after intravenous administration of peruvoside (a quick acting digitalis-like glycoside) to determine underlying myocardial dysfunction. Data were compared with those of similarly studied normal subjects and patients with known myocardial dysfunction. Left ventricular ejection time index (LVETI) decreased in normal subjects (P less than 0.01) and in most patients with constrictive pericarditis, and increased marginally in those with myocardial dysfunction (NS) after peruvoside administration. Pre-ejection period index (PEPI) shortened significantly (P less than 0.01) after peruvoside in normal subjects and in patients with myocardial failure, but not in constrictive pericarditis. Likewise the predicted ejection fraction was insignificantly altered in constrictive pericarditis but significantly so (P less than 0.01) in myocardial failure and normal subjects. The response of one patient with constrictive pericarditis to parenteral peruvoside administration was similar to that seen in patients with myocardial failure. This patient had a delayed recovery after pericardiectomy. PEPI/LVETI ratio and ejection fraction were also abnormal in other patients with constrictive pericarditis when compared to normal subjects. Such abnormalities and the unusual response of some patients to administration of peruvoside may reflect underlying myocardial dysfunction in patients with constrictive pericarditis. However, it is possible that the rigid pericardium also contributes to these abnormalities to a varying extent. Systolic time indices and their response to digitalis appear to be a useful, atraumatic method for detecting underlying myocardial dysfunction in patients with constrictive pericarditis.


Pulmonary valve echo motion in pulmonary regurgitation. Four cases are presented to illustrate the echo patterns of pulmonary valve motion in patients with pulmonary regurgitation caused by pulmonary hypertension, idiopathic dilatation of the pulmonary artery, or congenital absence of the pulmonary valve or in association with pulmonary stenosis. Absence of the pulmonary 'a' wave, fluttering of the e-f slope, and midsystolic closure or 'notching' of the valve were noted with pulmonary hypertension. In the case with idiopathic dilatation of the pulmonary artery a normal echo pattern of pulmonary valve motion along with distinct dilatation of the pulmonary artery at the valvular level were present. Pronounced dilatation and systolic expansion of the pulmonary artery along with dilatation of the right ventricle were seen with congenital absence of the pulmonary valve. No pulmonary valve could be demonstrated on multiple scans from the right ventricle to pulmonary artery. In Case 4 large 'a' waves (14 mm) were noted, indicating a reversal of the normal end-diastolic gradient across the valve and suggesting that pulmonary regurgitation in this case was associated with right ventricular outflow obstruction. Study of the echo pattern of pulmonary valve motion may therefore provide useful information in establishing the cause of pulmonary regurgitation.


Candida endocarditis treated with a combination of antifungal chemotherapy and aortic valve replacement. A case of Candida albicans endocarditis is described in which treatment with 5-fluorocytosine was started after aortic valve replacement, but relapse followed discontinuance of treatment. At a second operation the aortic valve was replaced under 5-fluorocytosine cover and treatment was continued with both 5-fluorocytosine and amphotericin-B. No resistance to 5-fluorocytosine developed, and the candida infection was eradicated. The patient is well 22 months after his operation.


A case of prosthetic valve endocarditis caused by Corynebacterium hofmanni and Candida albicans. The case is described of a 49-year-old woman who developed endocarditis in relation to the prosthetic valve two months after insertion of a Starr-Edwards mitral valve prosthesis. Initially Corynebacterium hofmanni was isolated from blood culture. Later, while the patient was receiving antibacterial chemotherapy, Candida albicans was also isolated and she was treated with 5-fluorocytosine. A cure was effected without the need for further valve replacement.


His bundle electrogram during bidirectional tachycardia. The case is reported of a 66-year-old woman with bidirectional tachycardia caused by digitalis intoxication. His bundle records demonstrated the presence of two foci, one junctional and the other a fascicular one.


Reproducibility of exercise tests in patients with symptomatic ischaemic heart disease. In 50 patients with ischaemic heart disease prospective analyses of the reproducibility of exercise tests at 3-month intervals were performed. The same method of testing was used repeatedly in a smaller group of patients 3 or more times at 6- to 8-week intervals. No significant differences were found in maximal heart rate, maximal systolic blood pressure, rate-pressure product, and total work. Symptoms resulting in the discontinuation of exercise were unchanged in 94 per cent of patients. The evaluation of the electrocardiographic recordings revealed good agreement in 94 per cent of patients. The evaluation of the electrocardiographic recordings revealed good agreement in ST segment depression and ST segment elevation. The reproducibility of arrhythmic events was very poor. The standardized electrocardiographic exercise test is, therefore, recommended for objective evaluation of various interventions in patients with manifest ischaemic heart disease, both in short-term and long-term follow-up studies.


Quantitation of infarct size in man by means of plasma enzyme levels. A method is described in which the extent of myocardial infarction in man is assessed by mathematical analysis of the rise in plasma enzyme levels after infarction. Five enzymes are used in this study: lactate dehydrogenase (LDH); alpha-hydroxybutyrate dehydrogenase (alpha-HBDH); aspartate aminotransferase (GOT); creatine phosphokinase (CPK); and phosphohexoseisomerase (PHI). It is shown that a reasonable assessment of the total enzyme release, reflecting the extent of the infarcted area, can be made when a sufficient number of blood samples are taken after infarction. This could provide a method by which to judge therapeutic effects of intervention in the course of a myocardial infarction, as demonstrated in this study by the assessment of the effect of urokinase on the enzyme release after an infarct.


Cardiovascular malformation in infant deaths. 10-year clinical and epidemiological study. The infant mortality from cardiovascular malformations in a region with a population of 2 million inhabitants during a 10-year period has been studied. The study involved validation of the diagnoses and judgement whether the cardiovascular malformation was the dominating or a contributing cause of death. It is shown that the incidence of fatal cardiovascular malformations is probably overestimated in the official death statistics. Evaluation of the clinical findings and necropsy reports are important aids in obtaining more reliable figures of the incidence. The rate of referral of infants with cardiovascular malformations has increased during the period of this study, so that the number of operable lesions not referred has decreased. The infant mortality rate, found in this study, of 1.33 per 1000 liveborn babies constitutes about 20 per cent of all liveborn infants with cardiovascular malformations. The most common lesions found in those who died belonged to the group constituting the hypoplastic left heart syndrome. The proportion of this type of malformation, about 20 per cent of all those dying, is higher than in other similar studies. This difference can probably be explained by variations in selection and classification.


Surdocardiac syndrome of Jervell and Lange-Nielsen, with prolonged QT interval present at birth, and severe anaemia and syncopal attacks in childhood. A case of the surdocardiac syndrome of Jervell and Lange-Nielsen, with prolonged QT interval in the electrocardiogram at birth, is described. The affected girl presented 3 1/2 years later with severe iron deficiency anaemia, despite apparently adequate nutrition. At the age of 4 1/2 years she had a sudden attack of unconsciousness. Treatment with the beta-adrenoceptor blocker practolol was started and 3 years after initiation of this treatment she has been free from syncopal attacks. The QT interval remains prolonged. Her brother also had severe iron deficiency anaemia and had several attacks of unconsciousness before he died suddenly at the age of 3 1/2 years.


Circulatory changes in acute glomerulonephritis at rest and during exercise. In order to evaluate the effects of acute glomerulonephritis on the circulation, 6 patients were investigated at rest and during moderate exercise. With the patients in a state of rest the cardiac index and the stroke volume index were significantly higher in acute glomerulonephritis than normal, despite significantly raised right and left atrial pressures. Oxygen consumption was significantly increased (P less than 0.01) and the arteriovenous oxygen difference was narrowed significantly (P less than 0.001) in acute glomerulonephritis as compared to normal subjects. The calculated increase in cardiac output was due to both a rise in oxygen consumption and a narrowing of arteriovenous oxygen difference, the latter being more significant. The exercise-induced changes in cardiac output in the patients with glomerulonephritis were not different from those in normal subjects. These results showed that the circulatory changes in the oliguric stage of acute glomerulonephritis resemble those in the hyperkinetic states; the raised mean right atrial and pulmonary wedge pressures do not indicate the presence of heart failure when resting cardiac output is above normal level and response to exercise is normal.


Syndromes of asplenia and polysplenia. A review of cardiac and non-cardiac malformations in 60 cases withspecial reference to diagnosis and prognosis. This review presents the cardiac and non-cardiac malformations in 60 cases with asplenia and polysplenia with special reference to distinguishing factors which may be helpful in the clinical recognition of these syndromes. The asplenia cases were predominantly male and presented with cyanosis. They frequently had transposition of the great arteries (72%) with pulmonary stenosis or atresia (88%) and total anomalous pulmonary venous drainage (72%). Deaths were caused by cardiac failure and anoxia in 57 per cent of cases. Most of the patients died in the first year of life (79%), but longer survival is possible in the asplenia syndrome. The polysplenia cases were predominantly female and survived longer. The characteristic clinical findings were the relatively more benign presenting signs and the leftward or superiorly orientated P wave axis on the electrocardiogram. Conotruncal abnormalities were less common and total anomalous pulmonary venous drainage did not occur. On angiography the inferior vena caval drainage via the azygos system was clearly identified and this was present in all cases at surgery. Our study indicated that the cardiac anomalies in polysplenia were less severe than they were in asplenia and therefore the prognosis in the former syndrome is likely to be more favourable. Three families had two affects sibs but no single genetic factor could be identified. The aetiology of these syndromes remains undetermined.


Atrio-His bundle tracts.

Atrio-His bundle tracts. The atrio-His bundle tracts are very rare; only two have been found in 687 hearts studied histologically. These tracts have a similar appearance to those of the atrioventricular bundle and form a complete bypass of the atrioventricular node. In their presence the electrocardiogram may show a short or normal PR interval. They may be responsible for some cases of very rapid ventricular response to supraventricular arrhythmias.


Effects of amiodarone on thyroid function in patients with ischaemic heart disease. Thyroid function was evaluated clinically and biochemically in 12 patients with ischaemic heart disease receiving 200 mg oral amiodarone three times daily for periods up to 6 weeks. During drug administration, no patient developed clinical or laboratory evidence of hypothyroidism, but serum levels of T3 tended to fall and those of T4 increased but not to levels outside the normal range. Amiodarone produced a significant reduction in heart rate with prolongation of the QTc interval of the electrocardiogram without altering either the PR interval or the QRS duration. These effects of the drug were still present 4 weeks after cessation of treatment. In spite of the high iodine content, amiodarone does not, therefore, depress thyroid function to any important degree during chronic administration and its antianginal action does not appear to be caused by the production of generalized hypothyroidism.


Localization of lesion in patients with idiopathic orthostatic hypotension. The different components of the baroreceptor reflex were studied in 8 patients with idiopathic orthostatic hypotension. The reflex arc was interrupted in all patients and the lesion was most probably localized to the efferent sympathetic fibres. This was suggested by the negative cold pressor test, the absence of pressor response to mental arithmetic, and loss or reflex sweating. Selective sparing of sympathetic vasodilator fibres was probable in 2 patients. Cardiac acceleration after atropine was less than in normal subjects suggesting some degree of cardiac denervation. The present study indicates that lesions in efferent sympathetic fibres are a common cause of idiopathic orthostatic hypotension. Other components of the reflex arc were intact in this series of patients.


Effects of sustained isometric handgrip on praecordial accelerocardiogram in normal subjects and in patients with heart disease. The effects of isometric exercise on the maximum amplitude of the praecordial accelerocardiogram (as represented by the DE deflection) have been compared in 6 normal subjects (group 1), 12 patients with aortic stenosis (group 2), and 16 patients with myocardial disease (group 3). Whereas the tachycardia and pressor effects of isometric exercise were identical in all three groups, the normal subjects showed a significant decrease in DE during handgrip of 10 +/- 4 per cent (P less than 0.05) as compared with the insignificant increases of 8.5 +/- 6 per cent (P greater than 0.5), and 4 +/- 3.5 per cent (P greater 0.3) observed in the patients in groups 2 and 3. This response in the normal subjects differed significantly from the responses observed in the patients in groups 2 (P less than 0.02) and 3 (P less than 0.01). Of the patients in each of groups 2 and 3, 50 per cent responded abnormally to handgrip in that they showed a significant increase in DE. In the patients with aortic stenosis this subgroup of patients differed from the remainder in that they had a higher resting cardiac index (P less than 0.05). In the patients with myocardial disease this subgroup was characterized by a significantly lower resting left ventricular end-diastolic pressure (P less than 0.02). It seems, therefore, that those patients who increase DE in response to handgrip tend to have better left ventricular function at rest than those who do not. We suggest that this may be because of increased beta adrenergic activity at rest and during isometric exercise in the subgroup who respond to handgrip with an increase in DE.


RR interval variations in young male diabetics. The beat-to-beat (RR interval) variation in resting heart rate was used to detect possible autonomic nerve damage in a group of 42 young asymptomatic male diabetics, employing a sensitive electrocardiographic computer technique. Compared with 25 age-matched controls, the diabetics showed both a significantly smaller mean RR interval (P less than 0.005) and less RR interval variation (P less than 0.001). Whereas only 4 of the diabetic subjects had shorter mean RR intervals, 22 (52%) of the diabetics had RR interval variations that were less than any of the normal subjects. This reduction in heart rate variation has not been previously reported in diabetics without clinical features of autonomic neuropathy and might provide a sensitive method of assessing early autonomic nerve involvement in diabetes.


Long-term survival of patients with incomplete bundle-branch block complicating acute myocardial infarction. Electrocardiograms and His bundle electrograms were reviewed in 28 patients with incomplete bilateral bundle-branch block complicating acute myocardial infarction. All had a His bundle electrogram at the time of pacemaker insertion; 10 had a second one. Of 23 patients with an initially abnormal HV interval (55 ms or greater), 15 died (65%), while only one died (20%) in the group of 5 with a normal HV interval. This difference is not statistically significant. Sequential His bundle electrograms were done in 6 of the 8 survivors with an initially abnormal HV interval, and 4 showed 10 to 15 ms decrease in HV interval. The disappearance of incomplete bilateral bundle-branch block occurred significantly more often in patients who survived (7 of 12) when compared with those who did not survive (2 of 16) (P less than 0.05). It is concluded that long-term survival is po-sible after incomplete bilateral bundle-branch block complicating acute myocardial infarction. The characteristics of the survivors include an initially normal HV interval, transient incomplete belateral bundle-branch block and a decreasing HV interval if it were initially abnormal.


Surgical implications of right aortic arch with isolation of left subclavian artery. Few cases have been reported of the combination of right aortic arch with isolation of the left subclavian artery in childhood because of the absence of symptoms from this pairing of defects and the difficulty of its recognition by routine examination. All the reports have been associated with congenital heart disease. We report 4 cases. In one of them, the diagnosis was made during an attempt to create a left Blalock-Taussig anastomosis and the technique was modified. The diagnosis can be made before operation with an aortogram. This procedure should be carried out to show the aortic arch branches in cases where palliative surgery is contemplated.


Variations in clinical presentation of Fallot's tetralogy in infancy. Angiographic and pathogenetic implications. Striking variability has been observed in the presenting features in infancy of patients subsequently shown to have tetralogy of Fallot. Some patients presented with severe cyanosis in the neonatal period while others had a systolic murmur and cyanosis only on crying. In these latter patients cyanosis became present at rest over the subsequent months. Yet others presented with episodic attacks of unconsciousness, and a final group presented with dyspnoea and heart failure, accompanying a left-to-right shunt. Angiography demonstrates corresponding variations in the anatomy of the ventricular outflow tracts. In the severely cyanosed patients, the conus septum was deviated so as to obstruct the pulmonary outflow tract, and was best visualized in the lateral projection. In the patients with increasing cyanosis or episodic attacks of unconsciousness, the conus septum again obstructed the pulmonary infundibulum, but was obliquely orientated, not being seen clearly on either lateral or frontal projections. The episodic attacks were considered to be related to infundibular spasm, as previously shown to occur in Fallot's tetralogy. In contrast, increasing cyanosis was believed to be related to hypertrophy of infundibular musculature. In the patients with an initial left-to-right shunt, the arteries were orientated side-by-side so that the conus septum was observed in the frontal projection. Again, subsequent cyanosis was related to ventricular hypertrophy producing outflow tract obstruction. These findings are interpreted in the setting of a recent study, indicating that Fallot's tetralogy is produced by rotation of the embryonic conus together with sinistro-anterior deviation of the conus septum.


Comparative study of sinoatrial conduction time and sinus node recovery time. Atrial stimulation were performed in 5 normal patients (group A) and 4 patients with electrocardiographic evidence of sinoatrial disease (group B). The technique of premature atrial stimulation was used to calculate sinoatrial conduction time. Rapid atrial pacing was applied to measure maximum sinus node recovery time. In 4 cases both stimulation methods were repeated after intravenous administration of atropine Group A had a sinoatrial conduction time of 56 ms +/- 11 (SD) and a maximum sinus node recovery time of 1122 ms +/- 158. In 3 out of 4 patients with sinus node dysfunction a prolongation of sinoatrial conduction time could be demonstrated (145, 105, and 150 ms). In addition, one showed probable sinus node exit block after premature atrial stimulation. Sinus node recovery time was excessively prolonged in 2 (3880 and 3215 ms) and normal in the other 2 patients with sinoatrial disease (1330 and 1275 ms). Atropine leads to a decrease of sinoatrial conduction time. Results indicate that sinus node recovery time may not be a reliable indicator of sinus node automaticity if sinoatrial conduction is disturbed. The premature atrial stimulation technique makes it possible to study the pattern of sinoatrial conduction and to evaluate its reaction to therapeutic drugs.


Effect of coexistent coarctation of pulmonary trunk in natural history of complete absence of pulmonary valve with ventricular septal defect. A case of complete absence of the pulmonary valve in association with a ventricular septal defect and a pulmonary artery coarctation is described. Despite these defects the patient had minimal symptoms, probably because the pulmonary artery coarctation acted as a natural banding and limited the pulmonary regurgitant flow and reduced the left-to-right shunt across the ventricular septal defect. The patient was operated on at the age of 40 and the ventricular septal defect was closed but the pulmonary artery coarctation was left alone. In view of the long-term survival in this case, it is suggested that pulmonary artery banding would reduce the symptoms and increase the life expectancy of patients with congenital absence of the pulmonary valve and a ventricular septal defect.


Complete heart block and systemic lupus erythematosus. An 18-year-old girl with systemic lupus erythematosus developed progressive electrocardiographic abnormalities over a period of 16 years, culminating in complete heart block with Adams-Stokes attacks. A permanent ventricular pacing system was implanted successfully.


Significance of exercise-induced second degree atrioventricular block. A case of second degree, type II, atrioventricular block precipitated by exercise is presented. It is suggested that exercise and other vagolytic manoeuvres may be used as a means of differentiating type I from type II atrioventricular block: the conduction disturbance of type I improves with exercise, whereas that of type II deteriorates with exercise.


Malignant hyperpyrexia: Investigation of a family after a fatal case. The relatives of a patient who died from malignant hyperpyrexia were examined clinically and biochemically. One fo the deceased's children, an identical twin, undergoing an anesthetic, was found to develop malignant hyperpyrexia on exposure to nitrous oxide. The creatine phosphokinase concentrations in this family were unhelpful as a method of identifying susceptible individuals.


Neurological fragility in the newborn: Influence of medication in labour. New anaesthetic and analgesic drugs continue to be introduced in labour, with little apparent concern about possible effects on the foetus or neonate beyond the more gross changes reflected by the Apgar score. A review is presented of some drugs currently used and some of the newer methods available for the assessment of the neonate. It is important that attention should be given to the subtler effects of drugs on the nervous system in addition to the gross effects on the respiratory and other systems as judged by the Apgar score. It is also essential to correlate neurobehavioural status of the newborn infant with an accurate assessment of gestational age, in order to produce a scale of reference against which effects of drugs administered in labour can be judged.


Respiratory failure as a seizure phenomenon. A case report. Recurrent acute respiratory failure in an epileptic subject is described. The first episode of respiratory failure occurred while the patient was having frequent epileptic fits and was probably secondary to cerebral oedema with temporal herniation. The second occurred suddenly after 27 days during which the patient had been free from seizures. It is suggested that this episode of acute respiratory failure was the result of an epileptic seizure without any motor symptoms.


Influence of liver metabolism on the actions of althesin and thiopentone. To examine the role of liver metabolism on the actions of Althesin, its duration of action and circulatory effects were measured under the following experimental conditions in the rat: (a) non pretreated rats; (b) non pretreated rats: injection through the portal vein; (c) rats with cholestasis; (d) rats with induced microsomal enzymes; (e) rats with a depressed microsomal enzymatic synthesis. The experiments were repeated in the same animals by injecting equivalent doses of thiopentone. The effects of Althesin depend upon the functional conditions of the liver, while a relationship of this kind does not occur with thiopentone.


Surface anaesthetic properties of the new local anaesthetic amid etidocaine (Duranest): A laboratory evaluation. The surface local anaesthetic properties of the new local anaesthetic amid etidocaine (Duranest) were studied in experimental animals. Etidocaine produced topical local anaesthesia of high intensity, rapid onset and with a comparatively long duration of action following corneal, intranasal and intratracheal application. The surface anaesthetic activity of etidocaine was substantially greater than that of lignocaine, similar to that of bupivacaine but less than that of amethocaine. When applied to the mucous surfaces of the nose and the respiratory tract, etidocaine was less toxic than amethocaine and bupivacaine but more toxic than lignocaine. The data justify a clinical evaluation of etidocaine as a surface anaesthetic.


Studies of the neuromuscular blocking effects of BW 403C65 in frog and cat muscle. BW 403C65, an isoquinolinium bisquaternary compound, was investigated for its neuromuscular blocking properties. In vitro in from preparations, low concentrations induced an increase in miniature endplate potentials (m.e.p.p.) frequency without altering their amplitude. With increasing concentrations m.e.p.p. frequency returned to control value and amplitude started to decrease concomitantly with the decreased sensitivity of the endplate to iontophoretically applied acetylcholine and depression of the twitch tension. Acetylcholine released at the neuromuscular junction was also decreased. In vivo in the cat preparation  the intra-arterial injection of low doses of the drug produced an increase in the strength of the muscle twitch, and the development of contracture, as well as the appearance of post-drug repetition at the ventral roots. Greater doses produced a progressive decline in post-tetanic potentiation with prolonged return to control.


Myocardial sparing effect of fentanyl during halothane anaesthesia in dogs. The cardiovascular effects of fentanyl (Sublimaze) were studied in seven mongrel dogs. A constant infusion of the drug was used to produce an apnoeic end-point while concomitant cardiovascular changes were monitored. After one hour the infusion was repeated while ventilation was controlled and atropine was given to eliminate the haemodynamic effect of changes in PaCO2 and heart rate. When PaCO2 was allowed to increase fentanyl reduced heart rate and mean arterial pressure markedly while left ventricular dp/dt was depressed moderately at the time of respiratory arrest. When heart rate and PaCO2 were kept constant there was little variation in the cardiovascular measurements during fentanyl infusion. We conclude that fentanyl allows relative myocardial sparing in dogs when used at clinically effective concentrations.


The effect of carbon dioxide on cerebral blood flow and cerebral metabolism in dogs. In 11 normally oxygenated, normotensive mongrel dogs, blood flow and oxidative metabolism of the brain was studied during normocapnia and during respiratory alkalosis and respiratory acidosis. During respiratory alkalosis (mean PaCO2 17.8 mm Hg) CBF decreased significantly from 61.0 to 33.9 ml/100 g/min (44%) while arteriovenous-substrate differences increased and the rates of oxygen and glucose metabolism remained constant. Cerebral venous-arterial difference of lactate was increased significantly as compared with the resting state. During hypercapnia CBF increased significantly from 61.0 (resting state) to 115.7 ml/100 g/min (89%) (mean PaCO2 64.7 mm Hg). The arteriovenous-substrate differences decreased while the cerebral metabolic rates remained constant. The data show that the relationship between PaCO2 and CBF in the range 20-65 mm Hg PaCO2 is expressed by a linear relationship: y = 2.88 + 1.69x; in this range, the oxidative metabolism of the brain is unchanged and the increased cerebral lactate production in respiratory alkalosis is not necessarily linked to tissue hypoxia.


The inhibition of cholinesterases by pancuronium. Pancuronium causes a powerful  and highly selective inhibition of human serum cholinesterase in vitro. The inhibition was studied in serum from 14 individuals of both sexes (5-60 years of age) with normal reactions to suxamethonium. Pancuronium, in a concentration of 2.3 x 10(-7) M, caused a 50% inhibition of the enzymatic hydrolysis of acetylcholine, when this substrate was present in a concentration of 10 x 10(-3) M. The same I50 value was also found for a commercial preparation of human serum cholinesterase. The inhibition was reversible and competitive in type. Pancuronium inhibition of the acetylcholinesterase in human red blood cells and from the electric eel was more than one thousand times weaker. Thus pancuronium is one of the most selective inhibitors of serum cholinesterase described so far. The in vivo activity of the serum cholinesterase in four patients receiving pancuronium 0.1 mg/kg decreased, during the first 3 min, by 60-80%, from the pre-induction value. After this a slow recovery occurred with 40% depression remaining at 45 min after the injection. The tachycardia produced by pancuronium may be related to this selective inhibition of serum cholinesterase. It is suggested that relaxants which selectively inhibit serum cholinesterase also selectively block the cardiac muscarinic receptors.


The effect of extradural analgesia combined with light general anaesthesia and spontaneous ventilation on arterial blood-gases and physiological deadspace. Arterial Po2 and Pco2 were measured at half-hourly intervals in eleven patients anaesthetized for lower limb vascular surgery with a combination of nitrous oxide 67% and halothane 0.3-0.5% in oxygen, and an extradural injection of bupivacaine. Values for the alveolar-arterial oxygen tension difference, physiological deadspace and deadspace-tidal volume ratio were calculated. Although both the alveolar-arterial oxygen tension difference and physiological deadspace were large, spontaneous ventilation was adequate to maintain both Po2 and Pco2 of arterial blood at acceptable values. Over the course of 2 hr following the extradural injection there were no significant changes in any measured value.


Effect of pentobarbitone on hypoxic ventilatory drive in man: Preliminary study. The effect of an intramuscular injection of pentobarbitone 2 mg/kg on the hypoxic ventilatory drive was measured in 10 volunteers. Five subjects showed significant depression of the ventilatory response to hypoxia 30 min after administration. This depression persisted for 90 min. The other five subjects showed no change from control responses. The two groups appeared to differ in their levels of physical fitness as measured by differences in resting heart rate and maximal oxygen uptake.


Intracranial pressure during recovery from nitrous oxide and halothane anaesthesia in neurosurgical patients. Seven patients with intracranial disorders were studied during recovery from anaesthesia with nitrous oxide and halothane. Arterial, intracranial, and central venous pressure, and arterial carbon dioxide tension were measured and compared with the patient's clinical state. No patient had evidence of increased brain volume when the dura was closed. All had been hyperventilated during the surgical procedure. Cessation of hyperventilation and the continued administration of anaesthetics was followed by a moderate increase in intracranial pressure and a reduction in cerebral perfusion pressure, but critically low values were not seen. Spontaneous respiration returned when the PaCO2 was in the range of 33-51 mm Hg. When spontaneous respiration was judged to be normal, anaesthesia was interrupted and the endotracheal tube was removed. In the following minutes, until the patients were awake, the intracranial pressure decreased to normal or near normal values, with minimal change in PaCO2. In these seven patients in whom there were no signs of brain swelling, the skull was closed, the patients were allowed to resume spontaneous respiration, and anaesthesia was terminated without major changes in intracranial pressure or cerebral perfusion pressure. However, hyperventilation is advocated after operation in patients with marked brain swelling.


Biliary excretion of diazepam in man.

Biliary excretion of diazepam in man. In a study of diazepam metabolism, diazepam 10 mg was administered i.m. to four patients who had biliary T-tube drainage. Blood and bile diazepam metabolite concentrations were measured for 12 hr. The expected fluctuations in blood diazepam concentrations were seen, and conjugated diazepam metabolites were present in human bile. Bile diazepam concentrations were insufficient to account for an enterohepatic circulation.


Passive serum sickness in the mouse: effect of interstrain differences on glomerular deposition of immune complexes. Glomerular uptake of passively administered immune complexes in mice differs in different inbred strains. The amount of immune material deposited in the glomeruli in the strains examined is inversely related to the susceptibility to immune complex induced anaphylaxis. The significance of these findings is discussed.


Electron microscopy of the sequence of events in the atheroembolic occlusion of cerebral arteries in an animal model. Atheromatous material was removed from human atheromas, suspended in sterile saline in the ratio of 1 g to 5 ml and ground to allow passage through a needle; 0-5 ml of this suspension was injected into the left common carotid artery of 16 rabbits. Six animals died after the injection. The remaining animals were killed after various time intervals and the occluded arteries studied by electron microscopy. The general pattern of the embolic event in the cerebral arteries was that there were 3 groups of changes. Firstly, an immediate period of atherothrombotic occlusion occurred, which was followed by some resolution of the obstruction so as to leave the cholesterol crystals of the embolus stuck in the vessel walls as the only remaining element of the embolus in some cases. Finally, there was a late period in which the cholesterol crystals were isolated from the lumen of the vessel and surrounded by macrophages, fibroblastic cells and collagen. Endothelial lined channels developed in the original obstruction.


A comparative study of liver changes produced by inoculating pregnant rats with Salmonella dublin or with its endotoxin. Rats were inoculated with viable Salmonella cublin organisms or a crude Salm. dublin endotoxin at the 14th day of pregnancy. They were killed at intervals up to 96 h after inoculation and the pathogenesis of the liver lesions compared. The immediate effects on the liver of both inoculations were the same but there were differences in the later stages. In the endotoxin inoculated rats the initial liver lesions regressed but in the bacteria inoculated rats fat accumulated in the periportal and mid-lobular areas as the initial lesions regressed, and there was nuclear enlargement and mitosis. These lesions may represent the response of the liver to a continued bacteriaemia and endotoxaemia originating from the uterine lumen.


The effect of normal spleen cells on 3H-thymidine uptake by target cells in vitro. When tumour cells (line L cells) were grown in culture with syngeneic normal non-immune C3H/He mouse spleen cells or in the cell free supernatant of these spleen cells they incorporated less tritiated thymidine (3H-Tdr) than when grown by themselves. Despite this effect there was no depression in either cell growth or DNA synthesis. Autoradiographic studies revealed that the decrease of 3H-Tdr incorporation into tumour cells in the presence of spleen cells was not due to inhibition of cell entry into S phase but due to the amount of 3H-Tdr the tumour cells incorporated. Since the medium of spleen cell cultures was found to contain DNA and the addition of calf thymus DNA to fresh growth medium also resulted in decreased 3H-Tdr uptake by the tumour cells, it was concluded that line L cells utilize DNA released by spleen cells into the medium for de novo DNA synthesis. On the basis of these findings, it is suggested that caution be used in interpreting decreased 3H-Tdr uptake as determined by scintillation counting as evidence for a cytostatic effect exerted by lymphoid cells or their supernatants in vitro.


Stimulation of murine amyloidosis by a dializable product from pretreated donors. Amyloid was obtained in recipient mice by implantation into their peritoneal cavity of a dialysis bag containing spleen cells obtained from donor mice which were treated with casein for 6 days and while no amyloid was found in their implanted spleens. The transplantations were performed with 2 cell systems, one containing whole spleen suspension and the other washed cells. Amyloid was obtained in the recipient mice within 6 days after the implantation and in a more massive quantity than in mice treated by casein for a similar period.


The effect of a dose of dimethylnitrosamine on the toxicity of a subsequent dose and on the toxicity of carbon tetrachloride in mice. Mice were given a first dose of dimethylnitrosamine (DMN) and the LD50 of a second dose determined at various times later. The total dose (sum of the 2 doses) tolerated under these conditions increased slowly as the interval between the 2 doses increased, to a maximum that was maintained until the 6th day. The LD50 of the second dose then returned slowly to normal by the 10th day. The data suggest that the biochemical lesion in DMN induced liver necrosis developed relatively slowly.


Synthesis of plasma haemopexin, albumin and fibrinogen by the regenerating rat liver. The concentration of plasma haemopexin was significantly increased 24 and 48 h following both partial hepatectomy and laparotomy in the rat. Increased haemopexin synthesis was demonstrated by studies on the in vivo incoporation of isotope labelled amino acids and in vitro perfusion of the isolated liver. In vivo studies also indicated increased synthesis of plasma fibrinogen. No change was found in the incorporation of amino acids into plasma albumin apart from a transient rise 4 h after laparotomy but albumin production by the perfused rat liver 48 h after partial hepatectomy appeared enhanced. The observed changes in rat haemopexin and fibrinogen synthesis may represent a nonspecific acute phase response to surgical trauma.


Recurrent necrosis of the skin and the mouth. A patient suffering from an unusual syndrome, in which the following triad was present, is described: (1) Recurrent necrosis of the skin and mouth; and necrosis following intradermal injection of saline. (2) Disappearance of the necrotic episodes following the administration of prednisone. (3) Mental retardation. This syndrome does not appear to have been previously reported.


Methotrexate pneumonitis in a psoriatic. A life-threatening respiratory disease, characterized by fever, cough, dyspnoea, cyanosis and wide-spread bilateral pulmonary infiltrates, developed in a 40-year-old patient receiving intermittent methotrexate therapy for psoriasis. Blood eosinophilia accompanied the illness. A prominent feature in the clinical picture was a discrepancy between auscultatory findings and the pronounced changes in the chest X-ray. Systemic corticosteroids produced rapid improvement. It is suggested that the pulmonary syndrome represents a hypersensitivity reaction.


The diagnostic significance of immunoglobulin and fibrin deposition in lichen planus. Direct immunofluorescent (IF) staining was performed on biopsy specimens from fifty-three patients with active lichen planus. In fifteen of these cases uninvolved skin sites were also examined. Globular or cytoid body-like deposits of immunoglobulins, mainly IgM, were detected in forty-six of the active lesions, and in half the uninvolved skin biopsies. The deposition of fibrin in the papillary dermis and around follicular structures was seen only in the active lichen planus papules. The significance of these findings was assessed by comparison with the IF results obtained in 252 biopsies from various cutaneous disorders, stained by the same technique during the period of this study. Although the presence of immunoglobulin cytoid bodies and fibrin was found to be highly characteristic of lichen planus, these findings were not specifically diagnostic. Morphologically identical deposits were seen not infrequently in lupus erythematosus and in eczema. Active lesions of dermatitis herpetiformis, erythema multiforme and other rare dermatoses also showed these cytoid body-like immunoglobulin deposits.


Deficiency of circulating IgA and IgM in adult patients with lichen planus. Investigations on thirteen consecutive adult patients with classical lichen planus revealed a significant lowering in the levels of circulating IgA and IgM. Patients with lichen planus may have an immunological defect which makes them susceptible to infection with an unknown virus.


The effects of catecholamine and related compounds on the adenyl cyclase system in the epidermis. The effect of various hormones and drugs on the adenyl cyclase system of pig and human epidermal slices was studied in vitro. Adrenaline and isoproterenol in the presence of theophylline increased the epidermal cyclic AMP level 20-fold in 5 min. Noradrenaline also stimulated cyclic AMP accumulation but to a much lesser degree. The adrenaline stimulation was marked even in the absence of the phosphodiesterase inhibitor, theophylline. Theophylline potentiated the effect of adrenaline at the concentration  of 2-10 mM although theophylline alone did not elevate the cyclic AMP level significantly. The Km for adrenaline stimulation of the adenyl cyclase system of pig epidermis was 7-7 X 10(-7) M. A beta-adrenergic antagonist, propranolol, markedly inhibited the adrenaline stimulation while alpha-antagonists, phentolamine or priscoline, showed little effect. The results are in accord with the view that the epidermis possesses an active adenyl cyclase system with beta-adrenergic receptors.


The effect of treatment on plasma uroporphyrin levels in cutaneous hepatic porphyria. Seven patients undergoing treatment for cutaneous hepatic porphyria had serial measurements of their plasma uroporphyrin. In each case there was a progressive fall during treatment but even in remission the levels did not return to normal. There was a significant correlation between urinary and plasma uroporphyrin concentrations.


The percutaneous penetration of nandrolone decanoate. A study has been carried out on the penetration of nandrolone decanoate through human cadaver skin in vitro using radioactive tracer material. The radiochemical purity of the material desorbed from the dermal skin surface is very much less than that of the material absorbed into the epidermal surface. These observations are a consequence of the low level of overall penetration of the skin by the steroid. There is also a possibility that a small percentage of the steroid is being metabolized by micro-organisms present in the skin samples.


Secondary syphilis: a clinico-pathological review. The histological appearances found in biopsies from fifty-seven patients with secondary syphilis have been correlated with the clinical morphology of the eruptions. Considerable variation of histological pattern was encountered, and the frequency with which some of the classically described changes were found to be absent or inconspicuous is stressed. Of particular interest were the findings that, in nearly one-quarter of the biopsies, plasma cell infiltration was either absent or very sparse, and that vascular damage was seen in less than half. Where present, the vessel changes were almost entirely confined to swelling of the endothelial cells. Proliferation of the endothelial cells was most uncommon. The epidermis was very frequently involved in the inflammatory process. Exocytosis, spongiosis, parakeratosis, and acanthosis were the most frequent changes. No consistent histological difference between papular and papulo-squamous lesions could be found but macular lesions demonstrated more superficial and less intense dermal infiltration as well as less severe epidermal involvement. In late secondary lesions, the infiltrate became granulomatous, but in other respects the duration of the exanthem could not be correlated with the pathology. The differential diagnosis from pityriasis lichenoides and other inflammatory dermatoses is discussed and the value of histopathology in the diagnosis of secondary syphilis is emphasized.


Evaluation of coal tar fractions for use in psoriasiform diseases using the mouse tail test. III. High boiling tar oil acids. Twelve phenolic fractions of creosote and anthracene oils derived from a high temperature tar were applied in an ointment base to mouse tail skin. After treatment with the higher boiling acids, formerly parakeratotic scale areas underwent granular layer induction and 'basket-weave' keratin was produced. Changes in distribution of acid phosphatase and in horny layer fluorescence were consistent with the conversion to an orthokeratotic state. It is suggested that some of these phenols may be of value in the treatment of chronic psoriasis.


Evaluation of dithranol and a 'synthetic tar' as anti-psoriatic treatments using the mouse tail test. Dithranol and 'Psorox' were evaluated for granular layer induction in parakeratotic regions of mouse tail skin. The lack of this specific activity suggests that they both have different primary actions in the healing psoriatic lesion.


Granuloma annulare and necrobiosis lipoidica treated by jet injector. A Porto-jet injector was employed to treat forty-five cases of granuloma annulare and five cases of necrobiosis lipoidica with triamcinolone acetonide or sterile normal saline. Complete clearance of granuloma annulare lesions was achieved in nearly 70% of those receiving triamcinolone and in 44% with saline. Inadequate penetration of lesions was responsible for a number of failures. The rate of recurrence after treatment was high but retreatment was usually successful. In three cases of necrobiosis lipoidica complete resolution occurred, while in one, partial improvement was obtained. No serious complications of this type of treatment were observed.


Urticaria and hyperthyroidism.

Urticaria and hyperthyroidism. A thyrotoxic patient presented with urticaria and this appeared to respond to beta-blockade with practolol. Symptoms did not recur when radioactive iodine treatment took effect in spite of stopping the beta-blocker. Possible mechanisms are discussed and it is stressed that more emphasis should be placed on this association.


Intra-epidermal carcinoma of the eyelid margin. Twenty-two cases of intra-epidermal carcinoma of the ciliary margin have been diagnosed in a 15-year survey. The clinical appearance is variable, resembling in some instances a benign warty lesion, and in others a fully developed squamous cell carcinoma. As the lesion grows it produces keratotic plugging of the lash follicles and nodules on the lid margin; in due course this results in loss of the related cilia. When dermal invasion occurs the resultant squamous cell carcinoma is potentially dangerous because of the involvement of the adnexal structures, which on the ciliary margins are particularly large and penetrate deeply into the lid substance. Adequate biopsy which includes at least one lash follicle is essential for accurate diagnosis, and treatment requires complete excision with a reasonable margin for safety. Of the twenty-two patients, nineteen were male and three female; fourteen of the men involved had handled oils and greases for prolonged periods.


Survey of skin disorders in the urban black population of South Africa. Numerous and different methods of survey have been suggested and developed in recent years, but none of them appears to be entirely satisfactory. Insufficient classification, inadequate follow-up, incongruous rotation of investigators, notable variations in attendance, racial differences of the population submitted to statistical study, and other minor factors may account for possible errors and differences in evaluating the findings. We have conducted a survey, over a 3-year period, of the incidence of skin diseases affecting our urban black population, living in the township of Soweto (800,000 inhabitants) and attending our dermatological service at Baragwanath Hospital. Although this population is made up of a dozen different ethnic groups, they are fully urbanized and live under similar conditions and according to similar customs. We believe that the statistical data derived from these patients represent a significant expression of a uniform community.


Thin layer chromatography and counter-current analysis in porphyrias. The porphyrin metabolism of 100 patients with porphyria and 351 of their relatives has been studied. Thin layer chromatography of methyl esters of the urinary porphyrin was undertaken in sixty-six patients with different types of porphyria, and forty-five relatives, seventeen patients with hepatic cirrhosis, three patients with lead poisoning and twenty normal control subjects. This investigation was also made on the stools of thirty-six patients with porphyria, and then of their relatives. Countercurrent analysis of the bile of nine selected patients with porphyria was also undertaken. The results provide some evidence that symptomatic hepatic porphyria may be familial. Thin layer chromatography was decisive in the characterization of a new type of porphyria described recently by the authors (hepato-erythrocytic porphyria). The counter-current examination of the bile showed the absence of the 'S 411' porphyrin in all the nine cases investigated.


The use of thin layer chromatography in the separation of free porphyrins and porphyrin methyl esters. Thin layer chromatographic techniques for the separation and subsequent quantification of free porphyrins, coproporphyrin isomers and the methyl esters of porphyrins are described including a 2-dimensional system. The relevant RFs for a wide range of porphyrins are given. These methods have been in use in Cardiff and Barcelona for a number of years and were used in the survey of cases described by Pinol et al. (1975) which resulted in the discovery of the new porphyria, hepato-erythrocytic porphyria.


A new method for the measurement of itch and the response to treatment. Two new methods are described for the quantitative measurement of itch: the principle is to measure scratch which is the major objective correlate of itch. The first method is to record whole body movement at night by a vibration transducer on a bed leg; this gives qualitative and quantitative information. The second method is to measure limb movement with movement-sensitive meters; this give only quantitative data but is quicker and more easily carried out. The subjective sensation of itch was found to correlate well with nocturnal scratch, confirming the basic assumption of the method. Itching as measured by scratch occurs throughout the night and increased severity of itch is accompanied by an increase in the number of bouts of itch and not in their duration. Nocturnal restlessness is associated with an increase in leg movement and so can be dissociated from itch-provoked scratch, which is mostly done by the hands. The response of pruritus to treatment was demonstrated by both methods.


Cowden disease. Report of two additional cases. Two patients with Cowden disease, a syndrome consisting of cutaneous papules and nodules on the face, oral mucous membranes and dorsal aspects of the forearms and hands in association with tumours of the thyroid gland, breasts, gastro-intestinal tract, and female reproductive tract, are reported. This disease is important to the physician because recognition of these cutaneous lesions may allow early diagnosis of internal neoplasia.


Methaemoglobin in man living at high altitude. Methaemoglobin has been found in the red cells of subjects living permanently at high altitudes (above 3500 m). The level of methaemoglobin appeared to be inversely related to the red cell count and was much increased in anaemic subjects. The methaemoglobinaemia disappeared when the subjects descended to low altitude. The mechanism of this methaemoglobinaemia is not clear. Its presence appears to be related to the hypoxia of altitude, for toxic factors, enzymopenia and the presence of haemoglobin M were eliminated. The regulation of the oxygen dissociation curve in this condition is discussed.


Chronic granulomatous disease and the Kell blood groups. Fifteen antigenic determinants are known to be related to the Kell blood group. Some boys with X-linked chronic granulomatous disease have the very rare McLeod or Ko phenotype on their red cells. Serological studies of the McLeod type suggest that the weak Kell antigens that are present differ qualitatively and quantitatively from those on red cells of common Kell type. A new antigen, Kx, has been characterized and shown to be present on red cells and neutrophil leucocytes. Lack of red-cell Kx is associated with the McLeod phenotype, lack of leucocyte Kx is associated with chronic granulomatous disease.


Changes in folate metabolism in baboons Papio cynocephalus treated with 2-methyl-2-aminopropanol-B12. After the intramuscular administration of the vitamin B12 analogue, 2-methyl-2-aminopropanol-B12, to vitamin B12-depleted baboons (Papio cynocephalus) the effects on vitamin B12 and folate metabolism have been studied. The 'apparent' serum vitamin B12 and the serum folate concentrations increased, the liver folate concentrations decreased, and the liver vitamin B12 concentrations were unchanged. The analogue caused a marked increase in the amount of formiminoglutamic acid excreted after a histidine load whereas the amount of methylmalonic acid excreted after a valine load decreased. The rate of red blood cell regeneration after venesection was normal in baboons treated with the analogue and there was no evidence of megaloblastic haemopoiesis. Two baboons given the analogue developed a partial loss of utilization and lack of co-ordination in the hind limbs.


The effect of cytotoxic and anti-inflammatory drugs on the phagocytosis of neutrophil leucocytes. The phagocytosis of heat-killed Candida albicans by neutrophil leucocytes was inhibited in vitro by phenylbutazone and acetylsalicylic acid and by the cytotoxic drugs vincristine, vinblastine, cytosine arabinoside, daunorubicin and busulphan, but not by mustine hydrochloride or procarbazine. In vivo studies in man have shown a significant reduction in phagocytosis after phenylbutazone ingestion, but not following an oral dose of aspirin. Possible explanatory mechanisms of drug action on neutrophil phagocytosis are discussed.


Phagocytes and C4 in paraproteinaemia.

Phagocytes and C4 in paraproteinaemia. Immunological studies were performed on patients with multiple myeloma. A defect in polymorphonuclear leucocyte (PMN) function as evidenced by diminished adherence of these cells to nylon fibre columns was detected in 16, and low levels of the fourth component of complement (C4) were observed in 14, of the 26 patients studied. Twelve of the patients with low C4 exhibited the defect in PMN adhesiveness whereas only four of the 12 patients with normal C4 showed the defect. The PMN defect was not caused solely by the low C4, since PMNs from seven patients with hereditary angioedema, which is associated with low levels of C4, did not show the defect. The low C4 and defect in PMN adhesiveness occurred primarily in patients with IgG myeloma; all but one of the patients with IgA myeloma, macroglobulinaemia, or light chain disease were normal in both parameters. Results of skin window studies indicated that patients with the PMN defect also had a defect in the early PMN inflammatory response. The defect in PMN adhesiveness could be completely corrected by incubating the cells in normal plasma. Binding of the C4 to paraprotein could not be demonstrated, and C1 activation was found to be caused only by one of 10 isolated paraproteins studied. These studies indicate that patients with paraproteinaemia have immunological abnormalities in addition to low immunoglobulin levels and suggest that these abnormalities may be involved in the pathogenesis of the recurrent infections commonly associated with this disease.


A basophilic micro-organism infecting human red cells. Clusters and chains of basophilic micro-organisms were found on the red cells of a woman who suffered from malignant melanoma. The infection was clinically silent for at least 7 years. During her last year of life the patient became febrile and anaemic. Her spleen enlarged and the basophilic bodies on her red cells became coarser. The infecting organism is referred to only as a 'basophilic agent', since its relationships to recognized genera are uncertain. Similar epierythrocytic parasites occur in a wide variety of animals. Though these infections are often latent, they profoundly modify host immune responses.


The value of age- and sex-matched controls for coagulation studies. Several coagulation parameters and plasminogen levels were studied in 80 normal people divided into eight paired and sex-matched age groups: prepubertal children, postpubertal children, young adults, and adults over 50. The data indicate that factor-VII and -IX activities increase with age, with a cluster of lower activity for children and higher activity for adults. Factor-VIII levels appear to decrease with age, although this effect could be due to greater anxiety in the pre- and postpubertal children at the time of venipuncture. The adults showed no significant change in factor-VIII activity with age, but partial data indicate that factor-VIII levels are higher in adults with blood group A than those with blood group O. The age-related changes in factor-VII, -IX, and possibly -VIII activities did not vary between sexes. By contrast, plasminogen increased strikingly with age in males and decreased with age in females. With fibrinogen, a similar effect was found for adults, though not for the entire population. These findings indicate the importance of using appropriate age- and sex-matched controls for coagulation and plasminogen assays, especially in patients with mild inherited or acquired coagulation disorders.


Hereditary factor VII and IX deficiencies in a large kindred. A large kindred with combined deficiencies of factors VII and IX is presented. The deficiencies appeared to be independent and the data were not consistent with a diagnosis of haemophilia BM. The identification of mildly affected family members, including carriers of haemophilia B and heterozygotes for factor-VII deficiency, was facilitated by comparison with the 95% confidence interval of an age- and sex-matched control population. The bleeding patterns were those of mild to moderate haemophilia B and did not appear to have been modified by the presence of factor-VII deficiency.


Coagulation in an agarose gel and its application to the detection and measurement of factor VIII antibodies. Evidence has been presented that fibrin formation may be detected directly in agarose gels containing citrated plasma when they are treated with thrombin or calcium chloride. A new assay is described for haemophilic factor-VIII antibody based on inhibition of fibrin formation within an agarose gel containing normal plasma.


Factor-V activation by thrombin and its role in prothrombin conversion. Purified coagulation factors and specific antibodies to factor V and factor X were used to investigate the action of thrombin on factor V and the mechanism by which thrombin-treated factor V influences prothrombin activation. The formation of a complex or complexes between phospholipid, factor V, factor Xa and calcium was demonstrated by column chromatography on Sephadex gel, and by immunological analysis of the column fractions including the use of solid-phase antibodies. Kinetic experiments demonstrated that generation of thrombin from purified prothrombin was accomplished by this complex. Pre-treatment of factor V with trace quantities of thrombin resulted in increased yield and rate of thrombin generation. It was shown that phospholipid became saturated when incubated with increasing concentrations of factor V and that the initial saturating concentration of the latter was reduced by pre-treatment with thrombin. The findings confirm that optimum conversion of prothrombin to thrombin is accomplished by a complex or complexes of phospholipid, factor V, factor Xa and calcium and it is suggested that thrombin plays an autocatalytic role in these reactions.


Dissociation of clot retraction from platelet granule fusion and degranulation: an ultrastructural study of Reptilase-human platelet-rich plasma clots. Human platelet-rich plasma clots, formed with Reptilase, do not retract. Electron microscopy of such a clot reveals platelets of normal shape and ultrastructural features surrounded by fibrin. When ADP is added before Reptilase, the clot strongly retracts. A sequential ultrastructural study of this process shows that, before visible fibrin formation, the platelets form small clusters and show shape change, granule centralization and pseudopod formation. Upon immobilization of the platelets by fibrin, the pseudopods develop into large cytoplasmatic protrusions, which allow cell contact. During the retraction process, the platelet granules remain intact; some granule fusion only becomes apparent in fully retracted clots. When Thrombofax is added to platelet-rich plasma before Reptilase, the clots formed also retract. With this aggregation inducer, granule fusion occurs earlier and in more platelets. Platelet pseudopod enlargement and fibrin concentration around the platelet mass are similar to that in ADP-treated samples. Inhibitors of granule fusion and secretion (suprofen, indomethacin) do not modify ADP-Reptilase nor Thrombofax-Reptilase clot retraction but reduce the incidence of granule fusion in Thrombofax-Reptilase clots. Retraction of Thrombofax-Reptilase clots is unaffected by concentrations of apyrase which completely block ADP-Reptilase clot retraction. Prostaglandin E1, papaverine and amitryptiline inhibit both ADP-and Thrombofax-Reptilase clot retraction, platelet pseudopod formation and cell-to-cell adhesion. These findings suggest that interaction of fibrin with the mass of fused granules (granulomere) or platelet secretion are not responsible for clot retraction. Rather, contraction around adhesion sites formed by cytoplasmic protrusions from adjacent platelets would seem to be involved.


Changes in blood catecholamine levels and blood coagulation and fibrinolytic activity in response to graded exercise in man. Measurements of catecholamines, fibrinogen, factor VIII, thrombelastography, euglobulin lysis time and platelet adhesiveness have been carried out on venous blood obtained from normal males exposed to exercise on a bicycle ergometer at various work loads. Significant increases in adrenaline, factor VIII and fibrinogen were found only after exercise to exhaustion at 1500 kpm min-1 whereas the euglobulin lysis time was inversely proportional to the excercise load. There was no change in platelet adhesiveness. These findings support the results of studies using adrenaline infusions or adrenergic blockade which suggest that stress-induced increases in factor VIII are mediated via adrenergic stimulation but that activation of fibrinolysis is not dependent on adrenaline.


'Hairy' cell leukaemia (leukaemic reticuloendotheliosis): a scanning electron microscopic study of eight cases. Eight cases of 'hairy' cell leukaemia (leukaemic reticuloendotheliosis) were evaluated by scanning electron microscopy. The surface of critical-point-dried 'hairy' cells was characterized by prominent and exaggerated broad-based, ruffled membranes and scattered small clusters of stub-like microvilli. The surface morphology resembled that of normal and leukaemic monocytes, but differed from that of normal and leukaemic lymphocytes. Some cells with features of both lymphocytes and monocytes were difficult to categorize; the overall impression of the surface architecture of most 'hairy' cells suggests, however, that they are related to the monocytic series. From the examination of these cases it is evident that scanning electron microscopy may be used as a means of distinguishing chronic lymphocytic leukaemia from 'hairy' cell leukaemia on the basis of surface ultrastructure.


Folate deficiency in the alcoholic--its relationship to clinical and haematological abnormalities, liver disease and folate stores. Clinical and laboratory observations were made on 84 patients regularly taking more than 80 g of alcohol daily. Macrocytosis was present in 84.5%, but only 13% were anaemic. Twenty-seven of the 57 bone marrows sampled were abnormal, 20 showing megaloblastic changes, mostly mild in degree. Serum, red cell, and liver folate levels were reduced in 28%, 35% and 31% of patients respectively. Liver folate concentration showed good correlation with serum and red cell folates. The folate deficiency was more severe in those patients, more often female, who had inadequate diets or drank wine and spirits rather than beer. The amount of alcohol consumption and extent of liver damage did not affect folate status. The findings suggest that folate deficiency is common among alcoholics in this country. More frequently, however, patients had macrocytosis, sometimes with megaloblastosis, in the absence of folate deficiency emphasizing the direct toxic effect of alcohol on the developing erythroblast.


Thymoma associated with pure red cell aplasia, immunoglobulin deficiency and an inhibitor of antigen-induced lymphocyte transformation. A case of thymoma associated with pure red cell aplasia and hypogammaglobulinaemia is described in which the anaemia was of abrupt onset, following removal of the tumour. Tests of immunological function showed abnormalities of both humoral and cellular immunity. The patient was found to have a serum inhibitor of antigen-induced lymphocyte transformation which disappeared after immunosuppressive therapy at the same time that erythroblasts reappeared in the marrow. It is suggested that the triad of thymoma, pure red cell aplasia and immunoglobulin deficiency are manifestations of 'pluripotent' stem cell failure; in this case the inhibitor of lymphocyte transformation may have been related to the factor which also inhibited red cell maturation.


Endogenous production of carbon monoxide as measured simultaneously in blood and gas phase. Endogenous carbon monoxide (CO) production rates and total body haemoglobin content were determined simultaneously in blood and gas phase in 15 individuals. At 24% oxygen (O2) concentration in the closed rebreathing system, a correlation was obtained which revealed that a 1 mumole rise in CO in the gas phase of the  system was the result of 48.94 +/- 5.3 (SE) mumoles of CO rise in the body. Three individuals had heat-damaged red cells reinjected intravenously to determine if the recovery rate of the subsequently produced CO was proportionate in both the gas phase and blood phase. Changes in blood CO concentration were not consistently detected by gas phase analysis. Prediction of CO production rates utilizing gas phase data alone did not reflect accurately CO production rates determined from blood carboxyhaemoglobin rises.


Methods of evaluating the sequestration site of red cells labelled with 51Cr: a review of 96 cases. Teh technical conditions for surface counting and the methods for splenic and liver sequestration after injection of 51Cr-labelled cells were studied in 96 patients. A comparative study of different sites of positioning of the detection probes leads us to recommend the mid-line at the third intercostal space for the precordial area, the point of maximum count-rate obtained at each measurement for the splenic area, with the patient in right lateral decubitus position and the probe vertical, and a point situated on the midclavicular line 4 cm above the right costal margin for the liver area. A comparative study of different methods of calculation leads us to recommend the method known as 'excess counts', but with a correction of the gross values based on the evolution of circulating radioactivity and not of the count-rate measured over the precordial area. Measurement of urinary excretion of radioactivity showed that only a minor part was due to the loss of the tracer from the sequestration sites, and that the level varied only slightly between subjects. Thus the loss of tracer does not interfere with the interpretation of external counting data. Much of the disagreement regarding interpretation of the results of external counting in clinical practice is due to technical problems. Standardization of techniques of measurement and interpretation of results, selecting those which this study indicates as the most reliable, would permit better exchange of information between laboratories and clearer conclusions as to the practical use of surface counting.


Differences between human Fe1-transferrin molecules. Two molecular forms of Fe1-transferrin molecule can be demonstrated by anion-exchange chromatography on columns of DEAE-cellulose, pH 7.90. It is believed that co-ordination of each metal-binding site by ferric ions induces dissimilar changes in molecular conformation in the region of the binding sites which, in the case of one site, results in the molecule behaving as a weaker anion during anion-exchange chromatography. If so, this could be entirely in accord with current views that the two binding sites of transferrin do not share equal properties of iron exchange with cells. At physiological levels of transferrin iron-saturation, it is likely that two populations of Fe1-transferrin molecules form the bulk of the iron-transferrin complex.


A congenital haemolytic anaemia with thermal sensitivity of the erythrocyte membrane. Microspherocytes, measuring 2-3 mum in diameter, and cells with blunted projections or triangular in shape characterized the erythrocoyte morphology in three children with congenital haemolytic anaemia. Since the erythrocyte morphology resembled that associated with thermal injury, heat-induced changes in erythrocyte morphology and membrane composition were studied. Erythrocytes developed filaments and spheroid bodies which fragmented, resulting in microspherocyte transformation. Normal cells required exposure to 49 degrees C, whereas the patients' cells fragmented at 45 degrees C. Fragmentation was also observed during incubation of patients' cells at 37 degrees C for 17h. The heat-induced transformation of the patients' cells was associated with an increase in the membrane cholesterol:phospholipid and cholesterol:protein ratios. The phospholipid:protein ratio was unchanged. This suggests that fragmentation produces a selective loss of membrane components. Splenectomy ameliorated the haemolytic process. We propose that the patients' red-cell morphology is the result of in vivo fragmentation, and that the spleen is the major site of microspherocyte and poikilocyte destruction.


The ultrastructure of dyserythropoiesis in aplastic anaemia. Electron microscopy of erythropoiesis in aplastic anaemia has demonstrated some unique features of dyserythropoiesis at the ultrastructural level, which contribute to understanding of the morphological features which are seen in the light microscope. The findings provide further evidence for the presence of qualitative defects in erythropoiesis in aplastic conditions. The alterations seen included bi- and multinucleated cells, intercellular bridges containing microtubules, internuclear chromatin bridges, irregular nuclear shapes, juxta-nuclear and peripheral cisternal structures, ringed sideroblasts, a diversity of intranuclear inclusions, nuclear clefts in both eu- and heterochromatin, and a variety of anomalies of the nuclear membrane. The significance of the occurrence of these anomalies in aplastic anaemia is considered and the role of the nuclear membrane and of endoplasmic reticulum in the pathogenesis of aplastic anaemia is discussed.


Erythropoietin responsiveness in polycythaemia vera. A liquid bone marrow culture technique was used to study erythropoiesis in polycythaemia vera. Three patients with the diagnosis of polycythaemia vera treated only by phlebotomy were compared to three healthy volunteers. Erythropoiesis in vitro was assessed by counts of nucleated red cells and 3H-thymidine incorporation into erythroid precursors. Human urinary erythropoietin was found to stimulate erythropoiesis in cultures from the polycythaemia patients as well as normals. The erythropoietin effect was blocked by a rabbit anti-erythropoietin antibody. These results suggest that some erythroid precursor cells maintain an intact erythropoietin response mechanism in polycythaemia vera. They also support clinical studies of this disorder indicating that some regulation by erythropoietin may occur in vivo.


Effects of vincristine on normal and stimulated megakaryocytopoiesis in the rat. Vincristine was given to rats in which thrombocytopoiesis was either normal or acutely or chronically stimulated by injections of heterologous antiplatelet serum. A single dose of 0.3 mg/kg was given intravenously. The drug produced an early and a delayed megakaryocytopenia suggesting that it was toxic to differentiated megakaryocytes as well as to proliferating stem cells. The results support the hypothesis that vincristine-induced thrombocytosis may be due to homeostatic adjustments which, in turn, are activated as a result of drug-induced cytotoxicity.


Hereditary giant platelet syndrome. Absence of collagen-induced coagulant activity and deficiency of factor-XI binding to platelets. The platelets from two related patients with the hereditary giant platelet syndrome were examined. They were larger than normal but otherwise ultrastructurally normal; they contained increased storage pools of adenine nucleotides and heparin-neutralizing activity and took up serotonin at an increased rate. They aggregated normally with ADP and collagen but failed to aggregate with bovine factor VIII and Ristocetin. Some change in shape occurred with ADP, and the reduction in adenylate energy change after addition of ADP to platelet-rich plasma was smaller than normal. Platelet coagulant activities including contact product forming activity, intrinsic factor-Xa forming activity and platelet factor 3 activity were normal or increased, but collagen-induced coagulant activity was absent whether tested in washed platelet suspensions or platelet-rich plasma. Platelet washing experiments showed decreased binding of factors V and VIII to hereditary giant platelets and no detectable factor XI in washed platelet suspensions. It is concluded that (1) the hereditary giant platelets studied lacked a binding mechanism for factors, V, VIII and XI; (2) the normal development of collagen-induced coagulant activity apparently depends upon the binding of factor XI to the platelet membrane; and (3) the defective prothrombin consumption observed in these patients may have resulted from the failure of their platelets to bind factor XI.


Labile aggregation stimulating substance (LASS): the factor from storage pool deficient platelets correcting defective aggregation and release of aspirin treated normal platelets. Mixtures of equal volumes of Hermansky-Pudlak (HP) syndrome (adenine nucleotide storage pool deficient) and aspirin treated (AT) platelets (inhibited release of adenine nucleotides) undergo irreversible aggregation when exposed to collagen or adrenaline, whereas neither alone will do so. The present investigation has explored the basis for the mutual correction. Correction in the mixed system was accompanied by release of significant amounts of [14C]5-hydroxy-tryptamine from the AT platelets, whereas very little isotope was released when AT platelets alone were exposed to collagen. The correction of aggregation and the release of isotope could both be suppressed by pre-treating HP platelets with aspirin. Labile aggregation stimulating substance (LASS) composed of two closely linked intermediates of prostaglandin (PG) E2 and PGF2alpha biosynthesis, produced using a microsomal fraction of HP platelets, could correct the aggregation and secretion defect of AT platelets exposed to collagen. These findings indicate that HP platelets when mixed with AT platelets and exposed to collagen secrete a substance which is responsible for the correction. LASS, identified as the factor involved, acted as an intercellular messenger which mediated the correction by overcoming the influence of aspirin on normal cells.


The effect of urea on sickling.

The effect of urea on sickling. The effect of urea on the oxygen affinity of sickle cells and normal cells was studied up to a concentration of about 1.0 M. Besides the increase in oxygen affinity found in both normal and sickle cells there was a further increase found only in the sickle cells. This specific increase was caused by the direct inhibition of the polymerization of deoxygenated Hb-S by the urea and was used to measure the extent of this inhibition. Even at concentrations of 1.0 M the urea did not fully inhibit the polymerization. At the urea concentrations recommended for treatment of sickle cell crises and for the oral treatment of the disease there was only a very slight inhibition of polymerization. The small increase in oxygen affinity brought about by these concentrations of urea (equivalent to a log P50 change of 0.016) will cause some additional minimal inhibition of sickling at physiological partial pressures of oxygen. Oxygen dissociation measurements of Hb-A in dilute solution showed that 0.95 M urea had no effect on the interaction of 2,3-DPG and chloride with haemoglobin nor on the haem-haem interactions. This implies that the quaternary 'deoxy' form of the haemoglobin may still form and that the action of urea in inhibiting the polymerization is through interference with the intermolecular bonds rather than by inducing a conformational change which disrupts the bonding. Unless urea at the concentrations recommended for treatment inhibits the sickling of the cells by some mechanism other than its effect on the haemoglobin (such as by an effect on the membrane), these results suggest that it is of little use for the treatment of sickle cell disease.


Alpha thalassaemia in adults with sickle-cell trait. Mild forms of alpha thalassaemia are difficult to detect in adults. Since alpha thalassaemia existing with structural defects of the beta chain of haemoglobin may lead to decreased levels of the abnormal haemoglobin, we examined individuals having sickle-cell trait for the possible coexistence of alpha thalassaemia. Patients with sickle-cell trait having haemoglobin-S (Hb-S) levels less than commonly expected were compared to two control groups--one with sickle-cell trait and the usual levels of Hg S and one with normal haemoglobin. Twenty-one patients with sickle-cell trait having Hb-S concentrations below 35% had 65.8% Hb A, 31.8% Hb S, and a mean corpuscular volume of 81.6 fl. Studies of the relative rates of alpha-, betaS- and betaA-chain synthesis in 14 of these individuals showed a mean alpha:beta ratio of 0.76. In patients with normal haemoglobin as well as in sickle-cell trait with Hb-S levels above 35%, this ratio was unity. These findings are consistent with the presence of alpha thalassaemia in patients with sickle-cell trait who have lower than usual levels of Hb S and microcytosis.


A rapid method for obtaining the half saturation tension of small blood samples using a standard Clark electrode system. A method is described which allows the half saturation tension (T50 value) of blood to be obtained within 5 min on samples of 100 mul volume, using a standard Clark PO2 electrode A PO2-time trace is recorded on a blood/buffer suspension from which the oxygen is removed at a constant rate using yeast cells. The T50 value is then derived graphically. The values taken for 210 traces show the graphical solutions to lie within +/- 0.5 mmHg of the tensions calculated from complete dissociation curves. Values from a further 590 traces show the T50 estimates are also reproducible with a standard error of less than 0.3 mmHg.


Restoration of normal red cell size after treatment in megaloblastic anaemia. The return of the MCV to normal after treatment in megaloblastic anaemia follows a biphasic pattern. The initial more rapid decline in MCV is due to disappearance of pretreatment macrocytes from the circulation and the rate of fall is determined by their mean cell life. The second slower component is probably due to a mixture of pretreatment macrocytes and new macrocytes, the result of a young red cell population. The MCV often returned to normal most rapidly in the most severely megaloblastic patients due to a very short mean red cell life span. However, there was no significant correlation between either initial MCV or red cell count and the time after treatment for a return of a normal MCV.


Acute leukaemia with eosinophilia or acute eosinophilic leukaemia: a dilemma. A young male patient is described with acute leukaemia whose bone marrow and peripheral blood contained abundant cells of the eosinophilic series in all stages of maturation. These cells, proven histochemically to be true eosinophils, were abnormal in both maturation and proliferation. Upon electron microscopic study of bone marrow and peripheral blood, abnormalities in the eosinophilic series were identified as early as the promyelocytic stage as well as in the most mature eosinophil seen. The clinical and morphologic picture of this patient's disease raises the possibility of this being an acute eosinophilic leukaemia.


Quantitation of the ABO system antigens by means of isoprecipitating antisera. A quantitative method for the determination of blood group specific substances A and B on red blood cells was developed, using them to absorb isoprecipitating antisera anti-A and anti-B, followed by estimation of the residual antibody by means of a counterimmunoelectrophoretic technique with standard solutions of A and B substances prepared from saliva. The method was tested on a population of A2B donors. The mean amount of A substance in A2B RBC was 131 X 10(-12) +/- 217 X 10(-12) u/cell in the population of 95 donors. The A substance thus determined agreed significantly with values obtained by classical haemagglutinating titration. The mean amount of B substance in A2B RBC was 222 X 10(-12) +/- 178 X 10(-12) m/cell. The amounts of both the A and B substances were not correlated on the same RBC. Several peaks of the distribution curve of both substances confirmed the non-homogeneity of the populations, there being a wide standard deviation presumably due to differences in the antigen content of different subgroups.


Mechanism of plasminogen activator and factor VIII increase after vasoactive drugs. Adrenaline, nicotinic acid (NA), vasopressin (LVP) and other drugs affecting vascular motility are known to increase plasminogen activator (PA) and factor-VIII plasma levels in man. To evaluate the hypothesis that NA, LVP and adrenaline release PA from the endothelial cells of the vessel wall through their common effect on vascular motility, PA has been characterized by means of a histochemical technique on vein biopsies obtained from human volunteers after infusion of the compounds. Furthermore, the effect of single and repeated administration has been compared in order to investigate whether the pattern of PA and factor-VIII variations in plasma is similar with the three drugs. There was no major difference in the PA content of the veins following the marked and sustained increase of the corresponding plasma activities. A simple explanation is that the intensity and duration of the stimulus may not be sufficient to deplete the large stores of the vessel walls. The magnitude, time course and duration of the plasmatic response after single and repeated infusions was on the whole different and peculiar for each drug. A derivative of LVP which is free of vasoactive actions was more effective than LVP in inducing the responses, which could also be elicited in two anephric subjects. These findings suggest that vasoactivity is unlikely to provide the clue to a common pathway for the fibrinolysis and coagulation response after the compounds, and support the existence of different specific receptors.


Haemoglobin synthesis in human fetal liver maintained in short-term tissue culture. Human fetal liver maintained in tissue culture has been examined as a model system for studying the factors involved in the switch from fetal to adult haemoglobin production. In erythropoietin-treated cultures alpha-, beta- and gamma-chain synthesis remains active for up to 12 days. Globin-chain synthesis is balanced and the alpha/beta + gamma-chain production ratio remains constant up to about 8 days; in longer cultures gamma-chain production declines before that of beta chains. It is concluded that the system may be useful for examining factors involved in the switch from gamma- to beta-chain production provided that these are acting on cells already committed to the erythroid compartment.


Fibrinogen metabolism in acute hepatitis and active chronic hepatitis. Coagulation studies, including those of radioactive fibrinogen metabolism, were performed in seven patients with acute viral hepatitis and 12 patients with active chronic hepatitis. An increased fractional catabolic rate for fibrinogen was observed in four patients from the first group, and seven from the second. The catabolic rate was increased in those patients with the greatest degree of hepatic necrosis as demonstrated by the raised serum aminotransferase levels. There was no correlation between the rate of fibrinogen catabolism and the standard clotting tests, but the SDPS test (indicating the presence of fibrin monomers in the circulation) was consistently positive in those cases where the catabolic rate was increased.