[Association of primary hypothyroidism with preconcious puberty. Presentation of clinical case and the effect of acute inhibition of thyrotropin on the gonadal activity].

An 8 2/12 year-old girl with acquired primary hypothyroidism and precociuos puberty is described. Thyroid hormone treatment resulted in the regression of the sexual development, but moderate asymptomatic papilledema appeared as a result of therapy. Serial vaginal smears and measurements of urinary estrogen excretion during acute thyrotropin (TSH) inhibition with 75 mug/day of triiodthyronine (T3), showed a rapid drop in ovaric estrogen production up to prepubertal stage at 17 days of T3 administration. Moreover, a group of children with untreated hypothyroidism was followed through the first 3 to 12 months of thyroid therapy and none developed signs of increased intracranial pressure. These findings as well as the possible pathophysiology involved in this association are discussed.


[Relationships between thyrotropin, growth hormone and insulin in hypothyroidism].

Since growth hormone has been found to be inhibited in many cases of untreated primary hypothyroidism, we tried to investigate whether the high thyrotropin levels or the lack of thyroid hormones is the responsible factor. Six primary hypothyrotic patients were kept euthyroid by means of high and constant doses of thyroid extract. Growth hormone immunoassays were performed before and after three days of thyrotropin stimulation. Immunoassayable insulin was also investigated under the same experimental conditions. Although a moderate inhibition of growth hormone after thyrotopin stimulation was observed, the magnitude of this inhibition was not as marked as it has bee described in untreated primary hypothyrotics. There was no difference in insulin production before and after thyrotropin administration.


[Integration of education and services as a base for the formation of human resources in health care].

It will be necessary to coordinate the University role with health institutional policies concerning the definition of health goals, and personnel functions as the latter should be trained if and when they are offered the opportunities of grasping both theory and practice in an environment closely related to everyday problems and realities. Accordingly, health care changes must precede health educational changes. There are two factors that interfere with a proper integration between the education care system: 1) an excess number of medical (or health students that overcome teaching facilities and 2) the correct trend in health care, based on specialists, attached to large hospital centers in urban environments. No attention is paid in this way to the importance of the health team, to health promotion, health education, preventive measures, etc. In several Mexican schools new curricula have been developed in which students face actual health problems from the beginning of the studies and they are trained as another resource of the health system being involved in all type of health activities in health centers, schools, nurseries, out-patient community clinics, etc.


[A case of intestinal trichobezoar].

Report is made of a case of an unusual localization of a trichobezoar in a 12 year-old girl, who presented vomiting and abdominal pain as chief complaints. She was found to have an 18 X 5 cm palpable abdominal mass, which upon surgery was localized in terminal ileum and in the pathology report was found to be a trichobezoar. The interest of this case is the unusual localization of a single bezoar and the fact that a resection of 25 cm. of small bowel had to be done, as it was found necrotic at the time of surgery.


[Immunopathological study in membranoproliferative glomerulonephritis].

In 39 renal percutaneous biopsies, practiced to 31 patients with membranoproliferative glomerulonephritis (GMP) with subendothelial deposits (DSE), a study with immunofluorescence technique and light microscopy was carried out. In all cases, heavy granular deposits of C3 were detected in the loops of the glomerular capillaries and in a variable proportion of cases, deposits of IgM, IgA, C3PA (factor B) and C1q of similar aspect and localizacion were found. These findings suggest immunologic pathogenesis. In the absence of C1q, no cases with factor B were found; thus, it is possible to assert that the activation of the complement system takes place exclusively through an alternate pathway, as was previously accepted. On the other hand, it was found that the presence of C1q was correlated with a faster evolution to chronic renal failure and with the presence of a higher percentage of glomeruli with extracapillary proliferation (crescents). Thus, it is concluded that activation of C1q in patients with MPG and SED, may play a role in formation of crescent and consequently, it is a sign of poor prognosis.


[Sudden infant death syndrome].

This report is based on a review of the present situation of the sudden infant death syndrome through the presentation of four cases studied at the Unidad de Pediatría, Hospital General de México, S.S.A. All cases were in apparent good health before death. All babies were less than ten months of age. In three cases, necropsy was not performed, and the other one did not show significant abnormalities at the post-mortem examination. A complete review of the literature was made including: historical, epidemiological, genetic, clinical and pathological aspects. Special emphasis is made on the pathophysiology of the syndrome during MOR phase of sleep and muscular hypertrophy of the lungs arteriolae suggesting chronic hypoxia which are the most relevant theories in the sudden infant death syndrome. Psychological aspects and the family management by the physician and detection of possible future victims of the syndrome are finally discussed.


[Mechanism of adaptation of the newborn infant].

An analysis of the mechanisms of adaptation of the newborn infant, immediately after birth, is put forth. Emphasis is placed upon cardiorespiratory and metabolic homeostasis, with a description of the internal medium variations in neonates seeking spontaneous equilibrium. In Mexico City this takes 4 hours. Hypoxia is stressed as one of the most important complications of the neonatal period, requiring rapid and efficient management of the infant to avoid severe complications or even death. Intra and extracardaic hemodynamic changes, stabilization of central arterial pressure as well as sufficient cardiac output, due to proper left ventricle function are described in reference to the cardiovascular sphere. A brief mention is made of the work of both ventricles during the first days of life. The diverse hemodynamic behaviour in different vascular areas of the newborn infant might be due to the concentrations of circulating gases, pH, enzyme factors and circulating hormones.


[Concentration of lead in the blood of children with hyperkinesis].

The concentration of lead in bloods of 25 hyperkinetic children was compared to that found in a corresponding number of healthy children of the same age group. It was found that 3 hyperkinetic children showed levels above 40 mug/100 ml. The findings are discussed and the importance of substances containing this element bears on the child's environment are pointed out. Besides, stress is placed on the consequence that a high concentration of lead in the blood may show on mental development and it is suggested that through studies be carried out in every child with the habit of pica added to hyperkinesia.


[Anhydrotic ectodermal dysplasia].

The purpose of this paper is to report a boy with a typical case of anhydrotic ecotdermal dysplasia, spina bifida occulat, and abnormal dermatoglyphics. Histologic studies of the skin showed absence of sebaceous and sweat gland and hair follicles. The clinical examination of the mother and the histopathological report of her skin suggests sex linked transmission; however, an autosomal dominat gene limited to males can not be excluded.


[Kernicterus. Anatomo clinical correlation in 64 newborn infants].

The case histories and autopsy reports of 64 neonates who died from kernicterus were reviewed. The most outstanding findings were: high incidence of kernicterus with serum indirect bilirubin less than 15 mg.; different clinical picture of the premature in comparison with term neonate; predisposing factors such as respiratory distress and intrauterine malnutrition were often associated in the premature. Preventive, educational and therapeutic measures were discussed at the end.


[Aglossia-adactilia syndrome].

A 7 month-old girl was studied and found to have aglossia--adactylia syndrome. The etiopathogenic aspects of this disorder are discussed.


Echocardiographic assessment of abnormal left ventricular relaxation in man.

In 64 patients requiring cardiac catheterization for chest pain, echocardiograms showing anterior mitral leaflet and left ventricular cavity simultaneously were recorded. These were digitized and their first derivatives computed in order to study time relations between mitral valve and left ventricular wall movement in early distole. In 10 patients with normal left ventricular angiograms and coronary arteriograms, mitral valve opening began 1-1 +/- 9-3 ms (mean +/- SD) before the onset of outward wall movement, and reached peak opening velocity 2-0 +/- 13 ms after maximum rate of change of dimension. Virtually identical time relations were seen in 15 patients with normal left ventricular angiograms but with obstructive coronary artery disease (3-6 +/- 9-3 ms and 0-7 +/- 7-3 ms, respectively). These close relations were lost in patients with segmental abnormalities of contraction on left ventricular angiogram. In 19 such patients with normal septal motion, outward wall movement began 53 +/- 31 ms before the onset of anterior movement of the mitral valve leaflet, and this isovolumic wall movement accounted for 31 per cent of the total diastolic excursion. In 9 patients with reversed septal movement, these abnormalities were greater, 92 +/- 39 ms and 33 per cent, respectively, while in 11 patients with diffuse left ventricular involvement they were small, 5-5 +/- 13 ms and 3 per cent. Frame-by-frame digitization of cineangiograms was used to confirm these findings which appear to reflect an abnormal change in left ventricular cavity shape during isovolumic relaxation.


[Etiology of urinary infections].

The role played by different groups of microorganisms, including aerobic and anaerobic bacteria, viruses, etc., on acute and chronic infections of urinary ducts is discussed, together with general aspects of pathogenesis and diagnosis of such infections.


Analysis of left ventricular wall movement during isovolumic relaxation and its relation to coronary artery disease.

Left ventricular angiograms of 60 patients with ischaemic heart disease and 10 normal subjects were digitized frame by frame in order to study abnormalities of wall movement during the period of isovolumic relaxation. Plots were made of regional wall movement around the cavity throughout the cardiac cycle. In normal subjects 1-5 to 3-0 mm of symmetrical outward wall movement occurred during isovolumic relaxation, associated with an apparent increase of left ventricular volume of 10 +/- 4 per cent. The corresponding peak velocities of wall movement were 4-3 to 5-7 cm/s, significantly less than those recorded in the same region of the cavity after mitral valve opening. In patients with ischaemic heart disease, the following abnormalities were encountered: (1) Abnormal inward movement, which, in single coronary artery disease, occurred in the area supplied by the affected vessel. (2) Abnormal outward movement of more than 6 mm in non-affected areas which appeared to be a compensatory phenomenon. (3) An abnormal cavity shape change towards a more circular configuration before mitral valve opening. (4) Reduced peak rates of wall movement in affected areas during systole and filling. It is concluded that such inward wall movement during isovolumic relaxation is abnormal and a sign of local ischaemia whose presence has significant effects on overall left ventricular function in both systole and diastole.


Acute myocardial infarction. Evaluation of praecordial ST segment mapping.

In 38 patients with acute anterior myocardial infarction or ischaemia, the extent and amplitude of ST segment elevation was measured on the chest wall with a praecordial mapping technique. There was a poor correlation with measurements of clinical severity and with the extent of necrosis as measured by the peak levels of creatine kinase (CK) and the estimated total amount of CK released. In two patients ST segment re-elevation occurred without re-elevation of serum CK and in two other patients reinfarction obvious on enzyme re-elevation occurred without changes in ST segments. Praecordial ST segment mapping appears to have a limited role in measuring or monitoring human infarct size and would be an unreliable tool for evaluation of methods to limit myocardial necrosis. The chest leads of the standard 12-lead electrocardiogram provided sufficient information for clinical evaluation of ST segment elevation.


[Intravenous and oral glucose: production of insulin and growth hormone in the newborn infant].

Insulin production in response to intravenous and high and low oral glucose administration was investigated in 15 healthy fasting newborns. Results show that in spite of the fact that the highest blood glucose was obtained by the intravenous load, the highest insulin levels corresponded to the high oral glucose. The lowest blood glucose levels were found in the cases who received the low oral doses. The amounts of circulating insulin in this group were not significantly different from those in the group with I.V. glucose. In two of the groups where growth hormone was measured, the known paradoxixal increase in response to administered glucose was observed.


Effect of potassium-sparing diuretics on the renin-angiotensin-aldosterone system and potassium retention in heart failure.

The renin-angiotensin-aldosterone system and electrolyte levels in 11 patients with heart failure controlled on digoxin and frusemide were investigated after separate periods of Slow K, spironolactone, and amiloride therapy. When spironolactone or amiloride replaced Slow K, distinct parallel increments in the levels of renin, angiotensin II, and aldosterone resulted. Though plasma potassium was generally higher after spironolactone and amiloride than after Slow K, exchangeable potassium was similar with the three regimens. There was no significant relation between plasma potassium and concurrent exchangeable potassium.


Haemodynamics after Mustard's operation for transposition of the great arteries.

Cardiac catheterization data from 54 investigations after Mustard's procedure were examined to study the influence of the operation on pressure events in the atria, great veins, and pulmonary circulation. Systemic venous atrial pressure tracings were characterized by a rapid, sharp 'y' descent. Pressure gradients between the venae cavae and systemic venous atrium were invariable, whether or not vena caval pathway obstruction was present, the 'y' trough and 'a' wave gradients being greater than the mean gradient. Pulmonary venous atrial pressure tracings were not different from normal except when tricuspid regurgitation was present. It is suggested that the baffle effectively reduces the size and compliance of the systemic venous atrium, but influences the pulmonary venous atrium to a lesser degree. The systolic pressure gradient from the left ventricle to pulmonary artery was decreased postoperatively, suggesting that it may be flow-related; the greatest changes were seen in the group with preoperative ventricular septal defect. The ratio of pulmonary: systemic vascular resistance did not change significantly after operation, and it is suggested that both the pre- and postoperative values were higher than normal. Examination of the left ventricular or pulmonary arterial mean pressure postoperatively should raise the suspicion of a complication, e.g. pulmonary venous obstruction or tricuspid regurgitation.


[Teratoma of the thyroid gland in children].

Two cases of teratoma of the thyroid gland occurring in children are presented. Both tumors were discovered shortly after birth and were not associated with clinical hypothyroidism. One of the patients was thoroughly studied from the endocrinological point of view utilizing several techniques. There was some iodine uptake by the gland, formation of tirosine and thyroid hormones as well as their release into the blood serum. The clinical and pathological features of teratoma of the thyroid are discussed.


Ventricular arrhythmias in syndrome of balloon deformity of mitral valve. Definition of possible high risk group.

Twenty patients clinically identified as having balloon deformity of the mitral valve were studied to assess the incidence of ventricular arrhythmias. Echocardiography and phonocardiography were used to confirm the nature of the mitral valve lesion. Continuous 24-hour electrocardiograms were obtained from all patients and analysed by a computer and 2 observers. One patient has ventricular fibrillation and 3 patients had ventricular tachycardia. There was a high incidence of other less severe forms of ventricular arrhythmias. Eight patients had inferolateral ST and T wave abnormality on the resting electrocardiogram, and were described as having the ausculatatory-electrocardiographic variant of the balloon mitral valve syndrome. The occurrence of serious ventricular arrhythmias (ventricular fibrillation and tachycardia) was significantly more frequent in this group. This raises the possibility that the resting electrocardiogram may identify those patients with balloon deformity of the mitral valve who are at risk from sudden death.


Ventriculo-atrial conduction time during reciprocating tachycardia with intermittent bundle-branch block in Wolff-Parkinson-White syndrome.

Records from patients with the Wolff-Parkinson-White syndrome were reviewed with particular emphasis on the occurrence of bundle-branch block aberration during reciprocating tachycardia and the significance of this observation with respect to accessory pathway location. Increase by greater than 25 ms in the ventriculoatrial interval during reciprocating tachycardia with bundle-branch block, when compared to reciprocating tachycardia with normal intraventricular conduction, occurred only with right or left free wall accessory pathways. No patient with a septal accessory pathway proven by epicardial mapping showed a ventriculoatrial interval prolongation greater than 20 ms during bundle-branch block aberration. Measurement of ventriculo-atrial interval during bundle-branch block abe-ration also helped to diagnose accessory pathways AH and HV intervals as well as ventriculo-atrial times, may give midleading information. In one patient increase in cycle length during left bundle-branch block was the result of prolonged HV interval rather than prolonged ventriculo-atrial interval. In another patient cycle length remained the same during bundle-branch block while the ventriculo-atrial interval increased by an increment identical to the decrease in AH interval.


Developing cardiac rupture as initial sign of acute myocardial infarction.

Pathological data are given of 4 patients in whom the development of cardiac rupture was the initial sign of myocardial infarction. The term 'concealed cardiac rupture' is proposed for this condition. In each instance the clinical diagnosis was 'onset of infarction', whereas the necropsy suggested that the acute onset of symptoms was caused by the start of rupture. The arguments for classifying the cases as 'concealed rupture' are (1) the lack of correlation between histological and clinical dating of the infarct, (2) the observation that the tear may take considerable time before actual epicardial breakthrough occurs, and (3) the fact that a high percentage of infarcts may pass clinically unnoticed.


Annular subvalvular left ventricular aneurysm in Bahia, Brazil.

Two cases of left ventricular aneurysm, a 16-year-old black boy and a 23-year-old white girl, from Bahia, Brazil, are presented. In both patients there was enlargement of the cardiac silhouette and a prominent bulge of the left inferior border. On the right oblique view a ring of calcium at the ventricular opening of the aneurysms was visualized. A left ventriculogram showed a huge aneurysm in the first case and a bulge on the lateral wall of the left ventricle in the other. Cardiac catheterization showed a rise in left and right ventricular end-diastolic pressures and in the mean pulmonary artery pressure. In the first case the contour of the right ventricular pressure curve showed a restrictive pattern. The similarities of these aneurysms with the annular submitral type described in young black Africans are stressed.


Pulmonary hydatid embolization. Report on 2 operated cases and review of published reports.

Two patients with pulmonary hydatid embolization are described and commented upon in the light of 43 similar published cases. The diagnosis was strongly suspected from the medical history and the chest x-ray films and supported by angiocardiography. The angiocardiographic features of this condition have not been described previously in detail. They include amputation and filling defects of pulmonary artery branches, which are typically located proximal to a rounded tumour-like opacity seen on the plain x-ray film. Both patients underwent successful embolectomy.


Massive pulmonary arteriovenous fistula in the newborn.

Although pulmonary arteriovenous fistula as a cause of cyanosis is well recognized, most of the reported cases occur in older children and adults, and its importance as a correctable lesion in the newborn is often overlooked. The details of two babies who presented with cyanosis in the first few days of life are presented to emphasize that this eminently treatable lesion may need to be managed as an emergency.


Muscle potentials simulating pacemaker malfunction.

Interference spikes were noted on the electrocardiogram of a patient with an implanted demand pacemaker. Runaway malfunction was suspected and the generator replaced. Subsequent investigation showec that the interference originated from fasciculation in the left leg caused by underlying neuromuscular disease. Skeletal muscle potentials can produce an electrocardiographic appearance closely resembling 'runaway' pacemaker. Such abnormalities should prompt a search for occult neuromuscular disease.


Electrocardiographic changes produced by interventricular septal rupture.

The electrocardiogram was recorded during spontaneous rupture of the interventricular septum in a patient after myocardial infarction. The electrocardiographic abnormalities included an increase in the sinus rate, elevation of the ST segment, decrease in Q wave size, and increase in the height and width of the P wave.


Improvement in exertional left ventricular dysfunction after revascularization.

The case is reported of a 63-year-old white man with mild angina pectoris, whose systolic pressure fell 30 mmHg (4-0 kPa) with maximal exercise, without chest pain but with accompanying dizziness. Grafting the internal mammary arteries into the mid left anterior descending and obtuse marginal arteries improved regional myocardial perfusion and increased maximal cardiac output 24 per cent and maximal systolic pressure 32 per cent.


Pathology of acute myocardial infarction with particular reference to occlusive coronary thrombi.

Analysis of the pathological findings in 500 cases of fatal acute myocardial infarction showed that in 469 this was localized to one transmural area of the left ventricle; in 31 there was diffuse subendocardial necrosis. In the former occlusive coronary thrombus was found in the related artery in 95 per cent of cases. Variation in the percentage of occlusions found was noted between different prosectors and when coronary artery calcification was present. Only 4 of the 31 patients with subendocardial necrosis had recent occlusion; triple vessel disease was common in this group suggesting general failure of coronary perfusion. It is essential in necropsy studies of the relation of coronary thrombosis to myocardial infarction to be sure that muscle necrosis is present, to distinguish the two forms of myocardial necrosis, and to employ a meticulous dissection technique with decalcification of the arteries when necessary.


Congenital aortic valve disease with rupture of mitral chordae tendineae.

A new clinical entity is described in which free aortic regurgitation from congenital aortic valve disease caused rupture of the chordae to the anterior leaflet of the mitral valve in 7 men aged 45 to 63 years (mean 52 years); 2 of the patients also had rupture of chordae to the posterior leaflet. Comparing these patients with those with ruptured mitral chordae in  association with rheumatic heart disease and patients with spontaneous chordal rupture, differences were evident. No patient had a history of rheumatic fever and none had active infection. The typical clinical presentation was of acute mitral regurgitation into a small left atrium, with severe pulmonary oedema which was often resistant to medical treatment. The cause of chordal rupture in these patients was in part the result of progressive left ventricular dilatation, of direct trauma to the anterior cusp of the mitral valve, and possibly of a genetic factor. The anatomical features of both aortic and mitral valves are described, and in 3 histology of the mitral valve was available; 2 had myxomatous degeneration similar to that seen in patients with spontaneous chordal rupture, and in 1 there was degeneration of collagen tissue. All patients were treated surgically but the mortality was high (5 out of 7,70%). Early operation with replacement of the aortic and mitral valves is recommended if this high mortality is to be reduced.


Endocardial cushion defects: an anatomical study of 54 specimens.

An anatomical study of 54 specimens with endocardial cushion defect is described. The material was divided into two groups, according to the morphology and attachments of the anterior component of the anteroseptal mitral leaflet. We suggest that there is no divided or undivided anterior common leaflet. There are always two anterior leaflets, a mitral and a tricuspid one, separated by a commissure; depending on the degree of straddling of the mitral component over the interventricular septum, this will protrude into the interventricular septum or into the anterior papillary muscle of the right ventricle. Thus, the commissure separating the mitral and the tricuspid components will lie over the interventricular septum or will be quite separate in the right ventricle. In the latter case the straddling mitral component gives the false appearance of an undivided anterior common leaflet. The septal tricuspid leaflet was found to be underdeveloped or absent but we were not able to find any clefts or divisions in it. We suggest that this leaflet derives solely from the division of the posteroinferior endocardial cushion into two halves, right and left. The left half later becomes the posterior component of the normal anteroseptal mitral leaflet. Associated anamalies are also reviewed.


Influence of heart rate increase on uncorrected pre-ejection period/left ventricular ejection time (PEP/LVET) ratio in normal individuals.

In 26 normal volunteers, increase in heart rate from mean 73-94 +/- 1-97 to 103-61 +/- 2-72/min, by either intravenous atropine administration or rapid right atrial pacing, produced definite changes in the uncorrected systolic time intervals. As expected, total electromechanical systole (QS2) and left ventricular ejection time (LVET) were shortened, while the pre-ejection period (PEP) was unaffected. There was a consistent and significant increase of the PEP/LVET ratio (P less than 0-001). It is postulated that when this ratio is taken to express left ventricular contractility, it should probably be corrected for heart rate. Appropriate regression equations for such a correction were calculated (PEP/LVET=0-249 + 0-0168 HR).


Plasma urea in hypertensive patients.

The annual increase in plasma urea was measured in 253 hypertensive patients. On average there was a significant increase in plasma urea with time which did not depend on the sex of the patient or the type of hypertension. It did, however, depend on the initial level of plasma urea. A table giving the upper limits for expected annual increment may prove useful in clinical assessment. The relation between plasma urea and presenting blood pressure and age was examined in 1217 patients seen at the Hammersmith Hospital hypertension clinic from 1952 to 1967. The plasma urea was significantly related to both age and diastolic and systolic blood pressure. It was higher in men than in women up to 60 years of age, but not above that age, and it increased with presenting mean blood pressure in both sexes, but the increase was greater in men. There was a quadratic relation between age and plasma urea in both men and women. In both sexes the plasma urea increased between the ages of 60 and 80.


Circulatory response to vasodilator therapy in congestive cardiomyopathy.

Vasodilator therapy has been shown to have beneficial effects in heart failure. In order to evaluate the haemodynamic actions of vasodilator administration in primary congestive cardiomyopathy, sodium nitroprusside was infused intravenously at a rate of 15 to 100 mug/min to 12 patients. Mean arterial pressure fell 15 per cent from 86+/-3-0 to 72+/-2-4 mmHg (11-40 +/- -4 to 9-6 +/- 0-3 kPa), and there was a small but significant decrease in mean heart rate from 96 +/- 4-8 to 90 +/- 4-4 beats/min. These changes were accompanied by a significant decrease in mean pulmonary artery pressure from 40 +/- 2-2 to 26 +/- 2-8 mmHg (5-3 +/- 0-3 kPa to 3-5 +/- 0-4 kPa), mean pulmonary capillary wedge pressure from 25 +/ -2-2 to 16 +/- 2-1 mmHg (3-3 +/- 0-3 to 2-1 +/- 0-3 kPa), and left ventricular end-diastolic pressure from 27 +/- 1-8 to 17 +/- 1-5 mmHg (3-6 +/- 0-3 to 2-3 +/- 0-2 kPa). Cardiac index increased by an average of 48 per cent from 2-1 to 3-1 l/min per m2, and left ventricular stroke work index increased from 18-4 +/- 1-6 to 21-3 +/- 1-9 g m/m2. These results show that pronounced left ventricular dysfunction in patients with congestive cardiomyopathy is improved during vasodilator therapy.


Acute massive mitral regurgitation from prosthetic valve dysfunction.

Two cases of prosthetic valve dysfunction resulting in acute massive mitral regurgitation are reported; emergency operation was successful in both cases. Survival following complete dislodgement of the occluder of a disc valve, as occurred in one case, does not appear to have been reported before. The diffculty in diagnosis of sudden cardiac decompensation in patients with prosthetic valves is stressed, as is the need for urgent operation.


Retrograde conduction in complete atrioventricular block Study using His bundle recordings.

Using His bundle recordings and ventricular stimulation retrograde conduction was studied in 57 cases of complete AV block. VA conduction was observed in 13 patients. Of the 13, 12 had AV block distal to H, and during cardiac pacing 5 of them showed a retrograde His bundle potential. In all cases the AV node-His pathway was implicated in the transmission of the retrograde impulse. There was no retrograde atrial response in the remaining patients. VA block usually occurred at the same level as AV block. Nevertheless, two cases of AV block distal to H were associated with concealed retrograde conduction which stopped within the AV node.


Echocardiographic findings after acute carbon monoxide poisoning.

Myocardial lesions are frequently seen at necropsy after fatal carbon monoxide poisoning. Clinically, while there have been numerous reports of chest pain and electrocardiographic changes associated with acute carbon monoxide poisoning, other evidence for left ventricular abnormality has not been reported. The echocardiographic findings in five cases of non-fatal poisoning are presented here. Abnormal left ventricular wall motion was shown by echocardiography in 3 cases. Motion returned to normal in 2 of the 3 in follow-up tracings. Echocardiograms on 3 of the 5 patients showed mitral valve prolapse. Though the mitral valve prolapse may have been present before the poisoning, the reported high incidence of papillary muscle lesions in fatal cases suggests a possible relation of the prolapse to the effects of the carbon monoxide poisoning.


Non-ejection systolic clicks and mitral systolic murmurs in black schoolchildren of Soweto, Johannesburg.

A survey was conducted on 12 050 Black schoolchildren, aged 2 to 18 years, in the South Western Townships of Johannesburg (Soweto), and the prevalence of non-ejection systolic clicks and late systolic murmurs was determined. One or both of these auscultatory findings were detected in 168 children, yielding a prevalence rate of 13-99 per 1000 in the school population. A female preponderance of 1-9:1 was present and there was a strong linear increase in prevalence with age, with a peak rate of 29-41 per 1000 in 17-year-old children. A non-ejection click was the only abnormal auscultatory finding in 123 children (73%) and a mitral systolic murmur in 8 (5%), whereas in 37 (22%) both these findings were present. Of the latter 37 children, the murmur was late systolic in 32; in 5 it was early systolic. Auscultation in different postures was important in the detection of both non-ejection clicks and mitral systolic murmurs. Experience in the detection of these auscultatory findings influenced the frequency with which they were heard. Electrocardiographic abnormalities compatible with those previously described in the billowing mitral leaflet syndrome were present in 11 of 158 children. The aetiology of these auscultatory findings in this community remains unknown. In the same survey, a high prevalence rate of rheumatic heart disease was recorded and the epidemiology of the non-ejection clicks and these mitral systolic murmurs showed similarties to that of rheumatic heart disease. Though the specific billowing mitral leaflet syndrome almost certainly accounts for some of these auscultatory findings, a significant proportion may have early rheumatic heart disease. Further elucidation of this problem is necessary.


An echocardiographic study of the interventricular septum in constrictive pericarditis.

Ten patients with constrictive pericarditis were studied echocardiographically with specific reference to inter-ventricular septal dynamics. Abnormal movement of the interventricular septum was present in 8 patients and consisted of flattening in systole and unusual posterior motion in diastole. The aetiology of this type of movement is at present unknown but may be related to restriction of normal cardiac rotational dynamics. The interventricular septum also showed diminished degree of thickening (mean 21-2%). The amplitude of excursion was generally at the upper limit of or greater than normal. Left ventricular posterior wall amplitude of excursion was normal. Flattening of left ventricular posterior wall diastolic movement was seen in 4 patients. Right ventricular end-diastolic dimension was slightly increased (1-2 to 1-7 cm/m2) in 5 of 8 patients with abnormal septal motion, but no haemodynamic evidence of diastolic volume overload was found. Posterior pericardial thickening was noted echocardiographically when posterior calcification was present. We conclude that the most common though non-specific feature of the echocardiogram in patients with constrictive pericarditis is abnormal septal motion. Flattening of left ventricular posterior wall diastolic movement, posterior pericardial thickening, and epicardial-pericardial separation may also occur.


Clinical experience with technetium-99m stannous polyphosphate for myocardial imaging.

Myocardial imaging with technetium-99m stannous polyphosphate was performed on 46 patients. Eleven patients had no cardiac disease, 22 had acute myocardial infarction, and 13 had stable arteriosclerotic heart disease. Distinct patterns of myocardial activity were noted: (1) the patients with no obvious cardiac disease showed no cardiac activity; (2) stable arteriosclerotic heart disease showed faint, ill-defined cardiac activity, primarily in the anterior or inferior aspect of the left ventricle; (3) acute myocardial infarction showed intense, focal, well-defined activity, with a shape that characterized the location of the infarct.


Anxiety after a heart attack.

An objective measurement of anxiety at defined intervals after the onset of acute cardiac symptoms was made in 203 men admitted to the Coronary Care Unit, Royal Infirmary of Edinburgh, and in 83 patients in a Teesside coronary survey. Of the Teesside patients, 50 were treated at home, 22 were admitted initially to a coronary care unit, and 11 were admitted directly to a general medical ward. In the Edinburgh patients the level of anxiety was high early in the illness, fell rapidly, and rose again towards the end of their stay in hospital. At 4 months it was that of a normal population. After transfer from the coronary care unit the group was not more anxious than other patients in the ward. Reaction to the illness was unrelated to its physical severity. Patients who reacted badly at the beginning were less likely to return to work. The pattern of anxiety in the Teesside patients resembled that of the Edinburgh group, and reaction to illness was largely independent of physical aspects. Treatment in hospital, either through a coronary care unit initially or in a medical ward, did not increase emotional distress. At 3 months patients treated initially in a coronary care unit were less anxious than the others. Throughout the period of study the Teesside patients were more anxious than the Edinburgh patients and outcome was not related to anxiety. Social and environmental differences may account for this.


Intractable paroxysmal tachycardia caused by a concealed retrogradely conducting Kent bundle. Demonstration by epicardial mapping and cure of tachycardias by surgical interruption of the His bundle.

Electrophysiological and epicardial mapping studies are described in a patient without pre-excitation who had intractable recurrent paroxysmal supraventricular tachycardia. Electrophysiological studies revealed fixed VA conduction times during both rapid ventricular pacing and coupled ventricular stimulation. Catheter mapping of atrial activation during retrograde conduction and during induced paroxysmal supraventricular tachycardia revealed early distal coronary sinus activation (posterior left atrium) relative to the low septal, low lateral, and high lateral right atrium. These studies suggested the presence of a concealed left-sided bypass tract. The patient underwent surgical interruption of the His bundle for control of paroxysmal supraventricular tachycardia. Epicardial mapping of the atria (during ventricular pacing) confirmed the presence of a concealed left-sided bypass tract. Surgery produced antegrade av block (while retrograde conduction was maintained) and total cure of paroxysmal supraventricular tachycardia. This is the first reported case of a concealed retrograde extranodal pathway documented by epicardial mapping.


Angiographic demonstration of blood supply of right atrial myxoma.

A 53-year-old woman underwent cardiac catheterization for assessment of coronary arterial disease. An unexpected finding of a gradient between right atrium and right ventricle led to the discovery of an unsuspected right atrial myxoma. The diagnosis was established by the presence of a filling defect in the right atrial angiocardiogram and by the demonstration of "tumour vessels" by selective right coronary angiography. Selective coronary angiography can visualize the blood supply to an intracardiac tumour and thus confirm the diagnosis preoperatively.


Electrical alternans of TU wave in Romano-Ward syndrome.

A case is presented in which an exceptional electrical alternans of the TU wave occurred in association with the Romano-Ward syndrome. This appears to be the first reported example of this association. Ventricular fibrillation was documented during the syncopal attacks. There was no evidence of abnormality of the serum electrolytes.


Diazepam in acute myocardial infarction. Clinical effects and effects on catecholamines, free fatty acids, and cortisol.

Diazepam is a valuable drug in cases of acute myocardial infarction. The 10 mg intravenous loading dose and the subsequent 15 mg oral dose of diazepam administered three times daily produced safe, pleasant sedation, and reduced the need for analgesics. A much reduced excretion of catecholamines was recorded. It is presumed that diazepam causes a lower stress reaction, which is beneficial in diminishing the incidence of malignant arrhythmias and preventing the existing myocardial injury from spreading.


Calcific coronary embolization associated with cardiac valve replacement. Necropsy x-ray study.

The hearts of 14 patients dying early after replacement of a calcified aortic or mitral valve were examined for the presence of calcific coronary emboli. The incidence of embolization as shown by x-ray film was 92-9 per cent. The number of emboli in individual cases ranged from 4 to 119. Replacement of an aortic valve was associated with a more severe embolization than replacement of a mitral valve. Th mechanisms of calcific embolization are discussed and preventive surgical measures suggested.


Pancarditis affecting the conducting system and all valves in human African trypanosomiasis.

This paper describes the pathological features of 10 cases of human African trypanosomiasis occurring in Uganda over an 8-year period. Three cases were clinically proved, and in all 10 cases chronic meningoencephalitis and myocarditis were present. There was chronic pancarditis in 6 cases, and in 3 of these there was a generalized focal valvulitis and in 2 lesions of the conducting system. Previous descriptions of carditis in human African trypanosomiasis are briefly reviewed, and the present findings are compared with some cardiomyopathies as well as American human and experimental trypanosomiasis.


Mobitz II AV block within the His bundle, with progression to complete heart block.

A case of a 48-year-old woman with frequent syncopal episodes is reported. The electrocardiogram showed high degree AV block with narrow QRS complexes. The His bundle electrogram displayed a split His deflection indicating impairment of conduction within the His bundle of the Mobitz II type. The AH interval was prolonged and Wenckebach phenomenon occurred at the same atrial pacing rate before and after atropine administration. During spontaneous or induced high grade AV block an escape rhythm originating in the distal His bundle was observed. A secondary study performed one year later showed progression to complete AV block. Both His potentials were present, one following the atrial and the other preceding the ventricular deflection. The H'V interval was prolonged and a further lengthening was seen after ajmaline. All these findings indicated proximal, mid, and distal disease of the His trunk.


The pharmacokinetics of ephedrine after oral dosage in asthmatics receiving acute and chronic treatment.

1 Ephedrine plasma levels have been measured in ten asthmatic patients given a singel dose of ephedrine hydrochloride (22 mg) along and in combination with theophylline and a barbiturate. 2 Pharmacokinetic assessment of the data indicated no significant intra-subject changes in kinetic parameters before or after chronic treatment with ephedrine HCl (11 mg three times a day) alone or in combination. 3 Tolerance to these therapeutic doses, if it occurs, is therefore not disposition-related but rather to pharmacodynamic changes.


A sensitive assay of 5-fluorouracil in plasma by gas chromatography-mass spectrometry.

1 A gas chromatographic-mass spectrometric method was developed for determining 5-fluorouracil in plasma, using methylated thymine as an internal standard. 2 5-fluorouracil was extracted from plasma by a novel procedure which removed plasma components interferring with the sensitivity of the assay. The method included heating the plasma, washing with ether and extracting the drug under optimum conditions. 3 The sensitivity of the assay was 10 ng/ml plasma, sufficient to determine the low concentrations of 5-fluorouracil found in plasma during continuous infusion of the drug in patients receiving chemotherapy for cancer.


Simultaneous quantitative gas-chromatographic analysis of ethosuximide, phenobarbitone, primidone and diphenylhydantoin.

1 Therapeutic serum concentrations of ethosuximide, phenobarbitone, primidone, and dipheylhydantoin were assayed from 1 ml of human serum. The extraction procedure was common to all four drugs and three internal standards. 2 Subsequent isothermal gas chromatographic analysis of serum extracts produced well resolved peaks for the underivatized quantitation of ethosuximide and phenobarbitone. Primidone and diphenylhydantoin were determined as methylated derivatives. 3 Mean coefficients of variation for the assay of each drug were less 7% on a newly packed and conditioned column and less than 10% after the technique had been in continuous use for 3 months. 4 The advantage of quantitation relative to peak area ratios rather than peak height ratios was minimal for the determination of ethosuximide, primidone and diphenylhydantoin but appeared significant for the assay of phenobarbitone.


Renal function, protein binding and pharmacological response to diazoxide.

1 The effect of rapid (10s) injections of diazoxide was studied in ten hypertensive patients with varying degrees of impairment of renal function. 2 There was a significant correlation between the patient's plasma urea concentration and reduction in mean arterial blood pressure. Diazoxide was also shown to be less highly protein bound in patients with renal failure. 3 It is suggested that the explanation for the increased hypotensive effect of diazoxide observed in patients with reduced renal function is related to higher unbound drug concentrations.


Comparative effects of acebutolol and practolol on the lipolytic response to isoprenaline.

1 The effects of beta-adrenoceptor blockade on the metabolic responses to isoprenaline have been studied in an in vitro system of isolated fat cells and in six normal subjects. 2 The inhibitory effects of varying concentrations of acebutolol, practolol and propranolol on free fatty acid (FFA) release produced by isoprenaline (10(-7) M) were compared in isolated fat cells prepared from rat epididymal adipose tissue. Acebutolol and practolol, at equimolar concentrations, showed a similar inhibitory effect whilst propranolol was approximately 100 times more potent then either drug. At 10(-5)M concentration of propranolol, lipolysis was virtually abolished whilst at the same molar concentration, acebutolol and practolol halved the response. 3 Six healthy volunteers received three successive 15 min intravenous isoprenaline challenges (0.03 mug kg-1 min-1) per individual experiment. The first acted as a control whilst the following two were given either after single oral doses of placebo, acebutolol or practolol. The mean (+/- s.e. mean) basal FFA level was 0.77 +/- 0.06 mE1/1 and subsequent resting values after the administration of placebo or beta-adrenoceptor blocker were not significantly different. 4 Acebutolol inhibited the respective mean rises in FFA, produced by both post-control isoprenaline challenges, by (mean +/- s.e. mean) 70 +/- 4% and 84% +/- 5%. The comparable figures for practolol were 33 +/- 15% and 24 +/- 20%. The higher serum concentration of acebutolol produced greater inhibition but correlation of log serum concentration of the drug with percentage inhibition of FFA rise did not achieve significance. 5 Administration of isoprenaline, acebutolol or practolol did not significantly alter serum glucose, triglyceride or cholesterol levels. 6 Acebutolol and practolol effectively blocked the isoprenaline-induced tachycardia. The degree of blockade produced by practolol was greater than its inhibitory effect on FFA release. The diatolic fall in blood pressure in response to isoprenaline was abolished by acebutolol suggesting that its beta-adrenoceptor blocking action encompasses peripheral vascular sites. The comparable effect with practolol was a partial inhibition of the diastolic fall.


Human pharmacokinetic and pharmacodynamic studies on the atenolo (ICI 66,082), a new cardioselective beta-adrenoceptor blocking drug.

The beta-adrenoceptor blocking effects of orally administered atenolol on tachycardia induced by intravenous isoprenaline or by exercise have been studied in normal volunteers, and compared with the effects of similar doses of propranolol. The blood levels of atenolol at various times after oral administration were determined by g.l.c. and correlated with the degree of inhibition of tachycardia. Atenolol was shown to be a beta-adrenoceptor blocker in man, as in animals, in that it antagonized the chronotropic effects of isoprenaline and of exercise. The inhibitory effect of atenolol on exercise-induced tachycardia was evident at a concentration in blood of 0.2 mug/ml and virtually complete at 0.5 mug/ml. Higher concentrations than this did not produce significantly greater blockade. The effects of atenolol on exercise-induced tachycardia were similar to those of propranolol but it was less effective in blocking the rise in heart rate and fall in diastolic blood-pressure induced by intravenous infusion of isoprenaline. This separation of effects is considered characteristic of drugs causing preferential blockade of cardiac beta-adrenoreceptors. The half-life of atenolol in blood was calculated to ablut 9 hours.


Digoxin pharmacokinetics: multicompartmental analysis and its clinical implications.

The kinetics of digoxin have been investigated in healthy volunteers using an isotopic tracer technique. A three compartment open kinetic model has been proposed as the simplest model consistent with the plasma, urinary and faecal data obtained. The renal clearance of digoxin (mean +/- s.d.) was found to be 119+/-10 ml/min, which did not differ significantly from the glomerular filtration rate (110+/-14 ml/min). Digoxin extra-renal clearance (mean+/-s.d.) was found to be 47+/-7 ml/min. The model predicts that the tissue concentration attained after four 0.25 mg oral doses spread over 24 h can be achieved within a period of 4 h following a single oral loading dose of 1 mg. Maintenance doses can be derived from a simple formula based on the glomerular filtration rate, extra-renal clearance and bioavailability of the digoxin preparation used.


Can digoxin dose requirements be predicted?

A search for patient variables relevant to digoxin dose requirements was made in fourty-three patients with a wide range of renal and hepatic function. The daily dose of digoxin to achieve a mean serum concentration of 1.5 ng/ml, the standardized dose, was calculated for each patient. The standardized dose correlated significantly with the following variables, in descending order of correlation coefficient; creatinine clearance, serum creatinine concentration, body weight and serum albumin concentration. An equation containing the two independent variables, creatinine clearance and serum albumin concentration, had a significantly stronger correlation with standardized dose than creatinine clearance alone. Attempts were made in each patient to predict the standardized dose using both empirical prescribing methods and the published nomograms. Although a maximum of 70% of the variance of the standardized dose was explained, this corresponded approximately to one patient in three having a predicted dose outside the 95% confidnece limits for the standardized dose. There remain important sources of individual variation in digoxin dose requirements yet to be identified. Future application of empirical prescribing methods, such as multiple linear regression and Bayes' theorem, to prescription for large, defined patient groups may improve dose prediction for individual patients.


A study of factors influencing drug disposition in chronic liver disease, using the model drug (+)-propranolol.

The pharmacokinetics, following i.v. administration of (+)-propranolol (40 mg) have been compared to in vitro measurement of protein binding and biochemical parameters of liver function in six normal subjects and twenty patients with stable chronic liver disease. The clearance of (+)-propranolol decreased with evidence of increasing severity of impairment of liver function correlating significantly with a fall in serum albumin, a rise in bilirubin and a prolongation in prothrombin index. The clearance of (+)-propranolol correlated with and was numerically similar to the clearance of indocyanine green in normal subjects and also in patients with chronic liver disease. Protein binding was decreased in chronic liver disease, but this change was not related to changes in plasma proteins. In normal subjects and patients without ascites the volume of distribution increased with decreases in protein binding. Ascites was associated with a further increase in the volume of distribution. The considerable variation in half-life largely depends on changes in liver blood flow, the degree of protein binding and the plasma protein pool size.


beta-Adrenoceptor blocking activity and duration of action of pindolol and propranolol in healthy volunteers.

The beta-adrenoceptor blocking activities of pindolol and propranolol have been investigated in healthy male volunteers. Pindolol was about forty times more potent than propranolol in reducing isoprenaline-induced tachycardia. Pindolol (5 mg) and propranolol (u99 mg) were approximately equiactive in reducing exercise-induced tachycardia, 2 h after oral administration. The duration of action of pindolol is significantly longer than that of propranolol; 24 h after pindolol (kmg), 36+/-5% of the masimum effect were still present, and after propranolol (100 mg) 16+/-4% remained. Despite the long duration of action of pindolol, there was no evidence for cumulation during oral administration of 5 mg t.d.s. for 5 days.


The effect of end-stage renal failure and haemodialysis on the elimination kinetics of sotalol.

A single oral dose of sotalol (160 mg) was administered to control subjects with normal renal function and patients with chronic renal failure in the interdialysis period to estimate the elimination kinetics of the drug. Sotalol concentrations in body fluids were measured fluorimetrically using a modified Garrett and Schnelle (1971) method. Mean plasma half-life (T 1/2) was approximately 5 h in normals, 42 h in patients off-dialysis. During haemodialysis the mean plasma half-time was on the average 7 hours. Comulative urinary excretion of the drug was considerably lower in the patient group: 9% of the dose in 48 h as opposed to 61% in normals. Comparison of sotalol concentrations in plasma versus ultrafiltrate from the coil kidney indicates that the drug in vivo is negligible bound to plasma proteins in remal patients. The net-lowering effect of a 6 to 7 h haemodialysis on the plasma concentration decay line was by 20%. Post-dialysis plasma concentration data suggest that the rate at which sotalol returns to plasma from body tissues appears to be the rate-controlling factor in the elimination of sotalol by haemodialysis.


The influence of smoking on the intersubject variation in pentazocine elimination.

The cumulative urinary excretion over 24 h of pentazocine, under conditions of acidic urinary pH, has been measured in smokers and non-smokers using both male and female subjects (seventy subjects in total). A restricted urban population was studied. An overall three-fold inter-subject variation in elimination was observed. The cumulative urinary excretion of pentazocine was normally distributed in both smokers and non-smokers. Smokers metabolize 40% more pentazocine than non-smokers. It is concluded that induction is principally responsible for the observed subject variability.


The influence of various factors in the in vitro distribution of haloperidol in human blood.

Haloperidol is 89.6+/-0.3% bound (mean+/-s.e. mean) in human plasma under in vitro conditions and the free drug distributes rapidly between the plasma and the cellular elements of blood. The cell/plasma partition ratio was 1.12+/-0.06 (mean+/-s.e. mean). Alteration of plasma binding by dilution with buffer showed that uptake of haloperidol by the cellular elements of blood was proportional to free drug concentration. Bishydroxycoumarin (95 ot 286 mug/ml) reduced plasma binding of haloperidol and the displaced haloperidol was taken up by the cellular blood elements. The experiments indicate that the cellular compartment of blood as well as the plasma compartment may act as a sink for haloperidol and drug displacement interactions should therefore be interpreted with a knowledge of both of these compartments.


The effects of low doses of amylobarbitone sodium and diazepam on human performance.

The effects of diazepam (2.5 and 5 mg) and amylobarbitone sodium (50 and 100 mg) on performance and subjective effects were assessed in a group of twelve healthy subjects under standardised conditions. Treatments were administered orally at weekly intervals according to a balanced design and under double-blind conditions. The tests of performance most sensitive to drug effects in these healthy subjects were either prolonged and monotonous and gave the subject no feedback on performance, or required short term memory for efficient execution. Auditory vigilance was significantly impaired (P less than 0.05) between 45 min and 1 h 45 min after all drug treatments except amylobarbitone sodium (100 mg), compared with performance after lactose. At the same time false reports were significantly increased after amylobarbitone sodium (100 mg) compared with all other active drugs but not with lactose. These effects had disappeared 4-5 h post drug. Short term memory was impaired 1h 45 min after all treatments and impairment was dose related. No significant effects occurred 5h after treatment. Simple auditory reaction time was prolonged 2 h after the highest doses of amylobarbitone sodium and diazpam, and by amylobarbitone sodium (50 mg) 5 h 15 min after treatment. At this time the effects of diazepam had worn off. Digit symbol substitution was impaired by amylobarbitone sodium (50 and 100 mg), and diazepam (5 mg) after 2 h 45 minutes. No significant changes in visual search or tapping occurred after active drugs compared with lactose. Subjective ratings indicated both mental and motor impairment 2 h 45 min after all active preparations compared with scores after lactose though significant changes followed diazepam (2.5 mg) infrequently. Both correct detections and false reports in auditory vigilance tended to fall over the 6 separate days of testing, indicating an increase in caution. Visual search, short term memory, tapping and digit symbol substitution significantly improved with time, but there was no change in reaction time. From the limited information obtained by sampling blood at 3 and 6 h, no relationship between change in performance and plasma level was found in these subjects.


The influence of premedication, anaesthesia, age and weight on glucose uptake into human isolated skeletal muscle.

The effect of the anaesthetic procedures and of the sex, age and weight of each patient on glucose uptake and glycogen content of human skeletal muscle has been studied in vitro in the presence and absence of insulin. Statistical analysis indicated that the relationships between age and both glucose uptake and the response to insulin were significant, older patients in general having higher uptakes. The blucose uptake was highly correlated with the three obesity indices (ponderal index, body mass index and percentage of the ideal weight). The anaesthetic agents had no significant effect on glucose uptake. The choice of premedication appeared to have a small effect on the basal glucose uptake level, but as the choice of premedication was also age related and age itself was a significant factor, this effect may not be of importance. It is concluded that the age and the degree of obesity of the patients ought to be taken into account when studying samples of human muscle.


Methods for collecting individual components of mixed saliva: the relevance to clinical pharmacology.

Methods are described for collecting constituents of mixed saliva, viz. parotid, submandibular, monor gland and sublingual saliva and gingival fluid. Literature is cited which showed that using these techniques, few antibiotics could be found in mixed saliva or its main components but all were detected in gingival fluid. Rifamicin and clindamycin were found in all components.


Assessment of antipyrine kinetics by measurement in saliva.

The half-life of antipyrine has been estimated from saliva samples in ten subjects by a gas chromatographic method. Half-life, apparent volume of distribution and total body clearance estimated from saliva and plasma concentrations of antipyrine are not significantly different. The concentration of antipyrine in saliva is independent of flow rate within the range expected in healthy subjects in response to mechanical and sapid stimuli. Antipyrine estimation in saliva could facilitate many areas of phaamacokinetic research limited by the difficulty of obtaining serial plasma samples.


Factors affecting drug binding in plasma of elderly patients.

The binding of salicylate, sulphadiazine and phenylbutazone to plasma proteins has been studied in young and elderly subjects. Elderly patients had significantly reduced concentrations of plasma albumin, compared with subjects under 40 years of age. Sifnificant increases in free levels of all three drugs were found in elderly patients receiving multiple drug therapy, and a correlation obtained with the number of drugs being taken. It is suggested that because of their low albumin levels, elderly patients may be more susceptible to the effects of multiple drug therapy on drug binding. The clinical implications of these observations are discussed.


Haemodynamic long-term effects of a new beta-adrenoceptor blocking drug, atenolol (ICI 66082), in essential hypertension.

1 Thirteen men with untreated essential hypertension in WHO stage I were studied on an outpatient basis to evaluate the haemodynamic long-tern effect of a new beta-adrenoceptor blocker, atenolol. 2 Oxygen consumption, heart rate, cardiac output (Cardiogreen) and intraarterial branchial pressure were recorded at rest in a supine and sitting position and during steady state work at 300, 600 and 900 kpm/min. 3 The subjects were treated with atenolol (dose 100-200 mg/day) as the sole drug for 1 year and the haemodynamic study was repeated. 4 The blood pressure was reduced approximately 18% both at rest and during exercise, the heart rate approximately 25% and the cardiac output 16% at rest supine and 27% at rest sitting. During exercise the reductions in cardiac output were approximately 20%. The calculated total peripheral resistance was not decreased compared to pretreatment values. The mean arterial pressure-heart rate product was reduced almost 40%. 5 Apart from temporary muscular fatigue during the first weeks, no side-effects were seen. 6 Atenolol is an effective blood pressure lowering drug in mild and moderate hypertension, but the drop in blood pressure is associated with marked reduction in heart rate and cardiac output at rest as well as during exercise.


The effect of pindolol on plasma renin activity and blood pressure in hypertensive patients.

1 The effect of pindolol administered to twenty-six patients with hypertension of unknown origin was compared with respect to blood pressure and plasma renin activity change after increase of the dose over a period of 6 weeks. 2 There was no clear correlation between the fall of plasma renin activity, which in some patients was very marked, and the fall in blood pressure. Some patients with a fall in plasma renin activity did not drop their pressure. Conversely, some with a fall of pressure did not drop their plasma renin activity. 3 The addition of hydrochlorothiazide to the pindolol finally caused further lowering of the blood pressure in all but one patient and the plasma renin activity rose in all but two patinets. There was no clear correlation between change in plasma renin activity and the effect on blood pressure.


Ethanol oxidizing enzyme activites in liver disease.

1 The activites of hepatic alcohol dehydrogenase, catalase and the reduced nicotinamide adenine dinucleotide phosphate (NADPH) dependent ethanol oxidizing system were determined in liver biopsies from nine patients with liver disease and seven control subjects with non evidence of liver disease. 2 Alcohol dehydrogenase and catalase activites were significantly lower in the patients with liver disease. 3 The activity of the NADPH dependent ethanol oxidizing system was significantly greater in the patients with liver disease, when its activity was expressed in terms of mg protein or g wet weight liver. 4 It is suggested that the greater activity of the NADPH dependent system may compensate for the low alcohol dehydrogenase activites found in patients with liver disease and maintain normal rates of ethanol metabolism.


Agonist and antagonist effects of Sar1-ala8--angiotensin II in salt-loaded and salt-depleted normal man.

1 Three normal subjects were infused with Sar1-ala8-angiotensin II (Saralasin, P113) whilst on a high sodium (200 mEq + normal diet) and a low sodium (10 mEq diet) intake. 2 On the high sodium intake when angiotensin II and plasma renin activity (PRA) were suppressed, P113 infusion (5-10 mug kg-1 min-1) caused a slight rise in BP and a marked drop in urine flow and sodium excretion, with a fall in glomerular filtration rate, and effective renal plasma flow. 3 On the low sodium intake, when angiotensin II and PRA were increased, P113 infusion (5-10 mugkg-1 min-1) caused no change in blood pressure, urine flow or sodium excretion. However, when P113 was infused at an incremental rate starting at 0.25 mug kg-1 min-1 there was a fall in standing BP, which was maximal at an infusion rate of 1 mug kg-1 min-1, and this fall in standing BP was largely abolished as the rate of infusion was increased to 10 mug kg-1 min -1. 4 These results show firstly that angiotension II is involved in maintaning standing blood pressure during dietary sodium depletion in normal man and secondly that P113 does have agonist as well as antagonist activity in normal man, the effect depending on the level of angiotension II and sodium intake. When looking for angiotensin II mediated hypertension it may ne important to use an incremental rate of infusion of P113 as the agonist activity of larger doses may mask its hypotensive action.


Studies on the metabolism of meptazinol, a new analgesic drug.

1 The absorption, metabolism and excretion of the new analgesic meptazinol has been studied in male volunteers following oral and intravenous administration of a mixture of the [1-14C] and [7-3H] labelled compound. 2 After oral dosage, absorption from the gastrointestinal tract was rapid as evidenced by the early attainment of peak plasma radioactivity levels and near complete as shown by only small amounts of radioactivity recovered in the faeces. 3 Although the absorption of the drug was good, the systemic bioavailability was relatively low. Plasma levels of the unchanged drug remained below the limit of detection (20 ng/ml) after an oral dose of 200 mg. However, after intravenous administration of only 20 mg the peak plasma level was approximately 58 ng/ml. Subsequent elimination was rapid and proceeded in an apparently mono exponential manner with a half-life of approximately 2 hours. 4 Excretion of radioactivity was rapid irrespective of the dosage route and took place chiefly via the urine. Over 60% of the administered radioactivity was recovered in the 0-24 h urine collection. Less than 10% of the administered dose was excreted in the faeces. 5 Less than 5% of the drugs was excreted unchanged. The major metabolite appeared to be the glucuronide conjugate of the parent drug. No evidence was found for N-demethylation of the compound. A minor metabolite of the drug which accounted for approximately 7% of the recovered radioactivity has been tentatively identified as 6-ethyl - 6 - (3-hydroxyphenyl) - 1 - methyl-hexahydroazepin - (2H)-2-ONE.


Modification by diazepam or thioridazine of the psychomotor skills related to driving: a subacute trial in neurotic out-patients.

Forty-five out-patients with clinically manifested anxiety were tested in order to study the effects of 2 weeks' treatment with placebo, diazepam (5-10 mg three times daily) or thioridazine (25-50 mg three times daily) on their psychomotor skills related to driving. When compared with placebo, diazepam increased the number of mistakes in reaction and co-ordination tests and also decreased ability to discriminate the fusion of flickering light. When compared to other groups, reactive and co-ordinative skills were more impaired in patients treated with thioridazine which also impaired divided attention. Aubjectively thioridazine was not experienced as effective an anxiolytic as diazepam.


Distribution and removal of human serum albumin-technetium 99m instilled intranasally.

The efficacy of antiviral drugs and vaccines administered intranasally may depend upon the technique of application. The distribution and time-course of removal of human serum albumin-technetium 99m (HSA-Tc 99m)-instilled intranasally were studied in eleven healthy volunteers using a gamma camera and an anterior sodium iodide scintillation detector. In 100 randomized studies material was delivered as drops in the supine position or as a spray to seated subjects. A significantly higher proportion of 'good' distributions (62 in 73 tests) was obtained with drops compared with spray (1 in 27). The volume administered was varied between 0.10 ml and 0.75 ml and the concentration of HSA was changed from 3 to 30% with no significant effect upon the distribution of time-course of removal; pertechnetate in isotonic saline was distributed and removed in a manner comparable to HSA-Tc 99m. Activity recorded by the detector showed an initial rapid fall associated with removal of most of the material from the nasal cavity, followed by a slower decline associated with the removal of material mainly from the anterior region of the nose. A multidose study confirmed that frequent administration by drops is required to maintain a high level of activity in the nasal cavity. Using this technique it should be possible to correlate measurements of antiviral efficacy and vaccines take-rates with certain characteristics of intranasal applicators; such studies may lead to the design of better devices.


Serum and lung tissue levels of cephradine in thoracic surgery.

Serum and lung tissue levels in fifteen patients who underwent thoracic surgery were determined by the agar-diffusion plate method after i.m. administration of cephradine (500 mg). The mean value of the serum level 30 to 120 min after administration was 6.5 mug/ml, the mean lung tissue level was 2.6 mug/g. The lung tissue levels reached 40% of the simultaneous serum level. Four patients received cephradine for the treatment of post-operative chest infections. This antibiotic has an important therapeutic role in cases of thoracic-surgical infections.


Serum concentrations and bioavailability of rifampicin and isoniazid in combination.

The bioavailability of rifampicin and isoniazid from formulations containing these drugs in combination has been compared to that from formulations containing either drug alone. No formulation-related differences in either rates or extent of bioavailability were found after administration of each formulation. Mean peak serum concentrations of rifampicin (8.2-11.7 mug/ml) occurring 2 to 4 h after doses of 600 mg, and isoniazid (3.6-4.8 mug/ml) occurring 0.5 to 1 h after doses of 300 mg, were similar to those reported in the literature.


A radioimmunoassay method for prednisolone: comparison with the competitive protein binding method.

Cross reactivity of prednisolone with an antiserum raised against dexamethasone-21-hemisuccinate conjugated with bovine serum albumin was utilized to develop a radioimmunoassay for prednisolone in unextracted plasma. The results are in good agreement with those obtained with a standard competitive protein binding method employing prior extraction and separation of the synthetic from endogenous steroids.


The relationship between liver volume, antipyrine clearance and indocyanine green clearance before and after phenobarbitone administration in man.

Liver volume and the clearances of antipyrine and indocyanine green have been measured before and after administration of phenobarbitone (180 mg/day) for 3 weeks to ten healthy subjects. The measurement of liver volume by an ultrasound scanning technique yielded reproducible results which were consistent with predictions of liver size by allometric methods. Before phenobarbitone, antipyrine clearance correlated with liver volume, but there was no correlation between indocyanine green clearance and liver volume. Phenobarbitone administration increased the clearance of antipyrine significantly by 90 +/- 14% but there was no significant change in indocyanine green clearance or liver volume. After phenobarbitone the correlation between antipyrine clearance and liver volume persisted. There was no correlation between indocyanine green clearance and liver volume. These results suggest that in non-medicated subjects some of the difference in antipyrine clearance is due to difference in functional hepatic parenchymal mass and that phenobarbitone increases the drug metabolising capacity per unit of hepatic mass but not total liver size.


Clinical pharmacokinetic studies of perphenazine.

A gas-chromatographic method was used for the study in man of the kinetics of perphenazine (PPZ) and its sulphoxide metabolite (PPZ-SO). Various forms of PPZ administration were applied in eighteen schizophrenic patients and four healthy volunteers. Following an i.v. dose of 5 or 6 mg a considerable fluctuation in the plasma concentration was noted before the exponential elimination phase. The average terminal half-life of PPZ was approximately 9.5 hours. PPZ-SO showed up quickly but in low concentrations. After an oral dose of 6 mg no PPZ was detected in plasma and PPZ-SO only as traces. During continuous oral medication, 12 mg three times daily, a low systemic availability and a high PPZ-SO/PPZ ratio was found suggesting a marked first pass effect. PPZ-enanthate given i.m. fortnightly resulted in PPZ-levels comparable to those seen after continuous oral medication, but PPZ-SO concentration were much lower. No accumulation was observed. The systemic clearance rate (average approximately 100 1/h) was the same after PPZ-enanthate i.m. and PPZ i.v., but varied three-fold individually. Side effects were mostly, but not always, registered concomitant with high plasma levels of PPZ.


The ralationship between changes in 5-HT induced platelet aggregation and clinical state in patients treated with fluphenazine.

Platelet aggregation responses to 5-HT and adenosine diphosphate were examined in a population of eighteen patients treated with fluphenazine decanoate for longer than one year. 5-HT induced aggregation was enhanced in ten subjects. This enhancement was similar to that previously described in patients receiving chlorpromazine. Patients who showed enhanced 5-HT induced aggregation showed less rateable psychopathology and less extrapyramidal side-effects than patients who did not show enhancement. These findings suggest that platelet aggregation responses could be used to identify patients who could be safely withdrawn from long-term neuroleptic therapy.


Effects of aspirin and prostaglandin E2 on secondary phase aggregation responses of schizophrenic patients treated with chlorpromazine.

We investigated the effects of oral aspirin 900 mg upon the platelet aggregation responses to 5-hydroxytryptamine, dopamine or N-dimethyl dopamine in schizophrenic patients chronically treated with chlorpromazine. Most subjects showed enchanced aggregation responses (that is appearance of secondary phase aggregation) to these agents prior to aspirin administration. When aggregation was re-tested 23.5 h after aspirin the secondary phase of the enhanced aggregation responses was abolished. Addition of 0.14-0.3 mumol/l prostaglandin E2 15 s after inducing aggregation partially restored the secondary phase. The observed secondary phase of aggregation may be due to increased prostaglandin synthesis or release.


Macrophages and lymphoid tissues in mice with concomitant tumour immunity.

The growth in mice of subcutaneous isografts of any of 5 methylcholanthrene-induced fibrosarcomas was associated with macrophage stimulation, reflected in an increased incidence of DNA-synthesizing cells among marcophages in the uninjected peritoneal cavity. This occurred at some stage with 4 tumours that induced concomitant immunity and one that did not. Some degree of splenomegaly also occurred with all 5 tumours. The spleens of all the tumour-bearing mice showed histological evidence of increased haemopoietic activity. Histological changes in the lymphoid elements of the spleen were very different with different tumours, ranging from lymphoid stimulation to lymphoid atrophy. The lymph nodes draining the sites of primary isografts which induced concomitant immunity showed signs of stimulation in the paracortical areas, followed by plasmacytopoiesis in the medullary areas. Stimulation of the paracortical areas was not detected in the nodes draining sites of injection of a tumour not inducing concomitant immunity. Nodes draining the sites of challenge isografts in mice exhibiting concomitant immunity showed plasmacytopiesis.


Carcinoembryonic antigen and glucose phosphate isomerase in a human colonic cancer model (GW-39).

Levels of carcinoembryonic antigen (CEA) and glucose phosphate isomerase (GPI) have been compared in the circulating blood of hamsters bearing intra-muscular grafts of GW-39 human colonic tumour. CEA in the sera of GW-39 tumour-bearing hamsters ranged from 2-6 to 8-4 ng/ml (mean = 4-5 +/- 1-7 ng/ml). GPI in the sera of normal hamsters ranged from 332 to 749 iu/1 (mean = 602 +/- 110 iu/1) while those with 14-week-old intra-muscular grafts of a hamster amelanotic melanoma, (A.Mel.3), or GW-39 human colonic carcinoma had a range of 664 to 1267 iu/1 (mean = 1024 +/- 220 iu/1) and 1430 to 4719 iu/1 (mean = 2065 +/- 601 iu/1) respectively. Thus, the ratio of enzyme activity in GW-39, A.Mel.3, and normal hamsters was 3-4:1-7:1, indicating a significant elevation (P less than 0-01) in animals bearing a human colon carcinoma or a hamster melanoma, with particularly high values obtained in hamsters with GW-39. Sequential determinations of CEA and GPI in a group of hamsters transplanted intra-muscularly with GW-39 tumours revealed that both markers increased proportionately with duration of tumour growth, suggesting that both serum CEA and GPI may be used as measures of tumour growth. The concentration of GPI in GW-39 human colonic carcinoma xenografts was also significantly higher than that measured in normal human colon, primary human colonic cancer, or normal hamster tissues. These results support the view that GPI, in addition to CEA, is a quantitatively increased marker in this tumour model, and is liberated into the circulation in proportion to the increase in tumour mass.


Altered enzyme expression in "differentiated" murine neuroblastoma cells.

Out of 17 enzymes studied, only 9 were detectable by starch gel electrophoresis in mouse neuroblastoma cells in culture. Prostaglandin E1 (PGE1) and 4(-3-butoxy-4-methoxybenzyl)-2-imidazolidinone (R020-1724), a specific inhibitor of cAMP phosphodiesterase, were used to induce "differentiation". Lactate and 6-phosphogluconate dehydrogenases and adenylate kinase were expressed as single bands in untreated neuroblastoma and induced "differentiated" cells, but the electrophoretic mobility of these enzymes in PGE1-treated cells was slower than that in malignant and R020-1724-treated cells. Three bands of glucose 6-phosphate dehydrogenase were detectable in PGE1-treated cells, whereas the R020-1724-treated cells had two bands and the untreated neuroblastoma cells had only one band. Aldolase was also expressed as a single band; however, the activity of this enzyme was much higher in PGE1-treated cells, whereas the activity was bately detectable for R020-1724-treated and untreated neuroblastoma cells. Some of the enzymes which are present in vivo are absent in vitro. Alkaline phosphatase is present in brain but is absent in neuroblastoma cells in vivo and in vitro. Two bands each of triose phsophate isomerase, fumarase and aldolase are present in brain, but only one band of these enzymes is present in neuroblastoma cells. Although PGE1 and R020-1724 induce many differentiated functions in neuroblastoma cells in a similar manner, PGE1 appears to change characteristically the expression of several enzymes.


Detailed cytogenetic study of a metastatic bronchial carcinoma.

Karyotyping and marker analysis of G- and C-banded metaphases from a metastatic bronchial carcinoma revealed a dominant stemline with five markers and four sidelines with additional markers. One to three minute bodies were noted in the majority of cells and these were classified as markers. On the basis of this analysis it was possible to postulate an evolutionary pathway within the tumour whereby the stemline was derived from existing sidelines.


Relevance of hydroxyproline excretion to bone metastasis in breast cancer.

In 181 consecutive patients with breast cancer, urinary hydroxyproline excretion has been critically evaluated in conjunction with clinical, biochemical, radiological and scintigraphic parameters. The urinary hydroxyproline/creatinine ratio is a sensitive index of the presence of bone metastases. Urinary hydroxyproline excretion is a reliable method of selecting those patients whose elevated serum alkaline phosphatase is secondary to bone disease rather than liver idsease. The estimation of hydroxyproline excretion furthermore gives information on the activity of bone metastasis, and its response to treatment, which cannot be given by radiological or scintigraphic methods. It is doubtful whether urinary hydroxyproline estimation will help to detect bone metastases before they are apparent on scintigrams. When the bone scan is doubtful, as often occurs in older subjects, hydroxyproline excretion has been found to be helpful in classifying the patient. When scintigraphy is not available, an elevation of hydroxyproline excretion, together with an elevation of Ca/cr ratio or alkaline phosphatase activity, may pre-date by several months the radiological demonstration of osseous metastases.


Serum ferritin concentration in early breast cancer.

The concentration of circulating ferritin was measured in 250 normal adult women and 229 women presenting with early breast cancer. Ferritin concentrations are higher in cancer patients than in normal women. Patients with an intial circulating ferritin concentration above 200 mug/1 have a higher tumour recurrence rate during the subsequent 4 years.


Allogeneic grafts of spontaneous canine melanomas and their cell culture strains in neonatal immunosuppressed dogs.

Canine melanoma has been transplanted to allogeneic neonatal recipients receiving continuous immunosuppression with anti-lymphocyte serum. One spontaneous melanoma was directly transplanted into 8 recipients, 6 of which developed tumours. 5/5 melanoma cell cultures were transplantable, with 19 tumour takes in 31 allogeneic recipients. Serial passage was performed in the case of two melanomas. Tumour development required continuous immunosuppression and the site was dependent upon the route of inoculation and other factors. Transplanted cell cultures were all amelanotic in vitro and in vivo, except in the case of one melanoma which reverted to a melanotic morphology after in vivo growth.


Decreased resistance to intravenous tumour-cell challenge during reticuloendothelial depression following surgery.

The influence of surgical stress on resistance to i.v. challenge with Walker 256 tumour cells was investigated in rats, with respect to the functional state of the reticuloendothelial system (RES). Phagocytic activity of the RES was evaluated by colloid (gelatinized [131I] "RE test lipid emulsion") clearance, and opsonin levels were determined by bioassay. Reticuloendothelial clearance capacity was significantly (P less than 0-05) depressed 60 min following surgery (coeliotomy plus jejunal enterotomy) as quantified by both humoral and cellular parameters of RE function. Phagocytic depression was primarily due to impaired hepatic Kupffer cell function and related to a deficiency in the phagocytic supporting capacity of plasma, also referred to as opsonic or recognition factor (RF) capacity. During the postoperative period of RES colloid clearance depression, pulmonary localization of the blood-borne test particulate matter increased. Rats challenged with 51Cr-labelled viable tumour cells at a dose of 1-0 X 106 i.v., either prior to or during the postoperative period of RE depression, manifested a significant (P less than 0-05) increment in pulmonary localization of the viable tumour cells, and a decrease (P less than 0-05) in hepatic clearance. Evaluation of survival patterns demonstrated a significant (P less than 0-01) decrease in host resistance to i.v. tumour cell challenge (2 X 103 cells) during the postoperative period of RE depression and hypo-opsonaemia. Sham-anaesthetized control animals survived 17-9 +/- 0-8 days, while animals challenged during the period of RE depression survived 7-9 +/- 0-4 days. An increased incidence of respiratory distress and nasal discharge was observed in the animals with impaired survival. Thus, surgical manipulation may transiently compromise RES systemic host defence and may be reflected in an increment in the pulmonary localization of blood-borne tumour cells. The relationship of this altered pattern of tumour cell distribution to the impaired survival remains to be determined, and warrants investigations.


The effect of low-dose pre-operative X-irradiation of implanted mouse mammary carcinomas on local recurrence and metastasis.

Pre-operative X-irradiation of s.c. implanted first-generation mammary tumours in C3H mice, using either 500 rad or two fractions of 350 rad, produced no improvement in the success of surgery in causing local control or in reduction of distant metastases. The metastasis rate was just significantly higher after the two-fraction treatment of the implanted tumour than after surgical removal alone. The results are in agreement with previously published results on carcinomas and a sarcoma but contrast with those for murine lymphomas.


Toxicity, distribution and elimination of the cancerostatic lectins abrin and ricin after parenteral injection into mice.

The survival time of mice after i.v. injection of the cancerostatic lectins, abrin and ricin was recorded. The LD50 dose was found to be 10-13 ng and 55-65 ng per mouse for abrin and ricin, respectively. Increasing amounts of toxin reduced the survival time, reaching a minimum of about 10 h. Lactose injected with ricin, provided partial protection against ricin, as measured by the survival time. Abrin and ricin labelled with 125I, and shown to retain their full toxic activity, were injected into mice. Most of the radioactivity found in the organs was present in the form of intact toxins, at least up to 5 h after injection. After i.v. injection the highest concentration/g tissue was found in spleen, followed by kidneys, heart, liver and thymus. The relative concentration in liver was considerably higher for ricin than for abrin. Similar results were found after i.p. injection. When lactose was administered together with ricin, almost 80% of the ricin injected was found in the liver after 30 min, compared to 48% without lactose, and the amount in other organs was concurrently reduced. The elimination of total radioactivity was much faster for ricin than abrin. The radioactivity found in the urine was largely present in non-trichloroacetic acid precipitable form, indicating that the toxins were extensively degraded before excretion.


The effect of isoprenaline on induction of tumours by methyl nitrosourea in the salivary and mammary glands of female wistar rats.

Pretreatment of rats with isoprenaline sulphate (IPR) stimulated DNA synthesis in both salivary and mammary gland tissues. Salivary gland tumours induced by N-methyl-N-nitrosourea (MNU) were observed for the first time in rats, but occurred only in IPR-pretreated animals given MNU during the period of IPR-stimulated DNA synthesis. The cumulative index of MNU-induced mammary tumours and the number of tumours per tumour-bearing rat were increased by IPR-pretreament only if the animals received MNU during the period of IPR-stimulated DNA synthesis.


Epithelioma adenoides cysticum: genetic update.

Epithelioma adenoides cysticum (EAC) is a well-known genodermatosis which follows an autosomal dominant mode of inheritance. Questions still remain, however, concerning an apparent excess of females with EAC. An analysis of nineteen previously published pedigrees and one newly ascertained pedigree, which in the aggregate included over 175 cases of EAC, induced no excess of affected females, but rather, a marked deficit males. This deficiency was not the consequence of sex linkage or decreased viability, and was most evident in large pedigrees and sibships, sibships not including the probands, and late birth orders. In these situations, the penetrance of EAC in male gene carriers was only 50%, but was close to 100% in female gene carries. Under maximum detection conditions, i.e. small pedigrees, small sibships, sibships containing the proband, and early birth orders, the penetrance in males increased to 85% and was again close to 100% in females. These findings suggested that the deficit of affected males was best explained by a comination of lessened expressivity and penetrance, effects which were magnified under situations of poor detection. A review of familial cases of EAC indicated no consistent associated anomalies such as those that characterize the naevoid basal cell carcinoma syndrome.


Histopathological spectrum of erythema multiforme.

Lesions of erythema multiforeme from seventy-five patients have been studied histologically. In addition to peculiar intercellular epidermal oedema, subepidermal separation and a lymphohistiocytic inflammatory infiltrate in the papillary dermis, epidermal cell necrosis was observed in a variable percentage of the lesions. While dermal disturbance was a predominant finding in the macular lesions, focal or generalized keratinocytic necrosis was seen in the macular, papular, bullous and iris lesions in that order of frequency. Significant numbers of eosinophils were present in the inflammatory infiltrate in 60% of the bullous and 28% of the macular lesions. Our findings suggest that erythema nultiforme represents a tissue reaction with spectral expression, one end presenting as a predominantly dermal disturbance and the other merging into the adult type of toxic epidermal necrolysis. Yet, the histological features remain sufficiently characteristic for differentiation from other erythematous and vesiculobullous eruptions.


Changes in transepidermal water loss and the composition of epidermal lecithin after applications of pure fatty acid triglycerides to skin of essential fatty acid-deficient rats.

The importance of various unsaturated fatty acid triglycerides to the repair of faulty skin barrier function was studied in essential fatty acid-deficient rats. Following cutaneous application of the pure triglycerides for up to 5 days, the hitherto high rate of transepidermal water loss, characteristic of essential fatty acid deficiency in rats, was reduced by the triglycerides of linoleic and gamma-linolenic acids. Incorporation of the applied fatty acids into the lecithin of the epidermis accompanied these changes in water loss, indicating that cutaneously applied triglycerides may be metabolized by the skin and incorporated into complex lipids. Other fatty acid triglycerides, including alpha-linolenic, dihomo-gamma-linolenic, arachidonic and omega-7-heneicosatrienoic acid, did not lower the rate of transepidermal water loss, although all were incorporated into epidermal structural lipids. The non-essential oleic acid also had no effect upon the rate of transepidermal water loss. These data suggest that of the two main essential fatty acids that occur in skin, linoleic acid and arachidonic acid, the former specifically plays an important role in regulating barrier function whereas the later may have a separate function, such as serving as a precursor of prostaglandins.


The diffusion of nandrolone through hydrated human cadaver skin.

Effective diffusion constants have been determined for the permeation of nandrolone through whole and stripped human abdominal cadaver skin in vitro. From the values obtained, the diffusion constant for nandrolone in the stratum corneum has been inferred. The experimental approach used yields reproducible results for skin samples taken from a single individual. There is also a surprising degree of uniformity in the values obtained for skin from different individuals.


The fate of Staphylococcal exfoliatin in newborn and adult mice.

The distribution and excretion of the staphylococcal exfoliatin was investigated following in vivo administration of highly purified 125I-labelled exfoliatin fractions to adult and newborn mice. Adult mice excrete approximately one-third of a test dose by 3 hours as compared to a fifteenth of a test dose excreted by newborn mice. Accordingly, blood tracer radioactivity reaches a relatively higher peak and shows a slower decline in newborns than in adults. The urine of adult mice contains considerable biologically active exfoliating material. Both nephrectomized and carbon tetrachloride-poisoned adult mice injected with exfoliatin develop generalized exfoliation whereas comparable doses in untreated controls have no effect. On the other hand, subtotal hepatectomy, followed by injection of exfoliatin, does not lead to exfoliation. We conclude that renal immaturity is a critical factor responsible for the susceptibility of neonates to generalized staphylococcal scalded skin syndrome.


Hypersensitivity to bacteria in eczema. II. Titre and immunoglobulin class of antibodies to staphylococci and micrococci.

The amounts of agglutinating antibody to staphylococcal and micrococcal phenol-extracted (probably teichoic acids) and protein antigens, prepared from Baird Parker types S1, SIV and M1, were no greater in eczematous than in control persons. Most antibody to phenol-extracted to phenol-extracted antigens was IgM which frequently activated complement to lyse red cells which had adsorbed the bacterial antigen. IgG antibody against phenol-extracted staphylococcal antigen (Staph. aureus, Baird Parker Type S1) was shown to be specific antibody combining by the F(ab)2 portion of the molecule. The phenol-extracts did not contain staphylococcal Protein A that binds to the Fc portion of IgG. Furthermore, the presence of Protein A in the protein or total antigen extracts did not appear to modify the results of the tanned cell agglutination test. The occurrence of immediate or of 4 h, Arthus-like skin test responses to staphylococcal or micrococcal antigens was unrelated to the agglutinin or complement-lysis titre of the relevant antibody.


Infantile eczema: A long-term follow-up study.

A 15-17 year follow-up study was conducted on ninety-nine patients who had suffered from infantile eczema. The persistance of the eczema and the occurrence of related conditions were noted. The persistence of eczema was shown to be greater in those patients with a positive family history of eczema and in those who had developed asthma or hay-fever. An attempt was made to see if the persistence of eczema was affected by the position of the child in the family, and some factors provoking relapses were noted. The patients were also questioned with regard to their achievements in academic examinations, and to their social, artistic and sporting activities. The results showed a success rate in examinations not significantly higher than average. It was not possible to show if there is a particular type of atopic personality. There was no constant characteristic in social or artistic patterns. The group as a whole were normal at the milestones of early development, i.e. walking, talking and reading, and also normal with regard to weight and height.


Psychological profile of patients with atopic dermatitis.

Tests designed to measure psychopathological characteristics common to the neurotic population were administered to patients with atopic dermatitis, patients with other dermatological disorders and to a control group of normal individuals. The parameters tested were manifest anxiety, neurosis, extroversion, depression, hypochondriasis and hysteria. The scores were statistically analyzed. The results showed that patients with atopic dermatitis responded significantly differently from patients with other dermatological diseases and from the control group in specific psychometric scales. Moreover, patients with skin conditions other than atopic dermatitis also responded significantly differently from the control group. The study clearly shows that patients with atopic dermatitis have a characteristic psychological profile not shared by the other two groups. The atopic dermatitis patients tend to be in a state of high manifest anxiety, depressed, neurotic and hypochondriac.