[Effects of stereochemically different fatty acids on blood cholesterol in rats]. In the present study some observations about the effects of stereochemically different fatty acids on cholesterolaemia are reported. It is well known that high in EFA diets are useful for cholesterol metabolism: in fact cholesterol is preferably esterificated by EFA. Because of the increasing intake of fats, as high in hydrogenated EFA margarines, it has been verified whether such a technological process, inducing structural modifications, affects or not the ipocholesterolemic effect of EFA, particularly linoleic acid. Actually this research has shown such an effect to fail in presence of trans fatty acids and has pointed out some implications of lipid metabolism which are related to the different stereochemical configurations.


Total fasting and postprandial serum bile acids determination by 3 alpha-hydroxysteroid dehydrogenase in normal subjects. Total serum bile acids (SBA) have been evaluated in 28 healthy subjects by an enzymatic-fluorimetric method using the enzyme 3 alpha-hydroxysteroid dehydrogenase. The healthy subjects showed a value of 2.78 +/- 1.84 microM/1 (mean +/- SD), ranging 0.5 to 4.7 microM/1. In addition, two hours postprandial evaluation of SBA was carried out in five of the above subjects. The mean value of SBA before and after the meal was 2.58 +/- 1.4 and 8.73 +/- 1.7 microM/1 respectively and the postprandial increase was found statistically significant (P less than 0.001). The present method for quantitative determination of SBA seems to be sensitive, reliable and useful as a routine clinical aid.


Tachyphylactic action of high doses of pentagastrin. The study of the human LES was performed with manometrical methods for atropine action on gastrine tachyphylaxis. Our study points out that there is a complex self regulating neuronal circuit in the LES contraction. We discuss some hypothesis for the LES control. In particular ACh could activate an inhibitory adrenergic muscarinic receptor.


Response to nor-epinephrine, isoprenaline and spironolactone derivatives in normal and hypertensive rats. In normal as well as in experimentally hypertensive rats the Blood Pressure and Heart Rate response-time curves are investigated following administration of nor-epinephrine, isoprenaline, spironolactone and K-canrenoate. The results stress the pharmacological effect dependence on integrity of homeostatic blood pressure mechanisms. alpha and beta receptor systems, as well as renine-angiotensine-aldo sterone system show different response-kinetic in mononefrectomized and mononefrectomized plus controlateral renal stenosis rats (Grollmann's model), in comparison with normal. While in normal rats the spironolactones evoke an hypertensive effect in experimentally renal hypertensive rats they reduce pressure to normal values.


[Influence of desoxycorticosterone on the reaction of isolated segments of coronary arteries to noradrenaline in the presence of pyrogallol]. The effect of the desoxycorticosterone on the noradrenaline-induced relaxation of coronary arteries waw studied in vitro, after a known inhibitor of COMT, pyrogallol. Relaxation induced by noradrenaline was enhanced by desoxycorticosterone. Relaxation in response to noradrenaline was increased by desoxycorticosterone. Pyrogallol potentiated the responses of coronary strips to noradrenaline and also reduced or abolished the enhancing effects of desoxycorticosterone. It is concluded that desoxycorticosterone enhances the reponse of coronary smooth muscle to noradrenaline by inhibiting and enzymatic pathway for the inactivation of catecolamines.


[Influence of bioflavonoid (4-methylesculetin) on the reaction of isolated calf hepatic artery to serotonin]. The effect of 4-metilesculetin on strips of calf hepatic arteries was investigated. 4-metilesculetin antagonizes the contraction induced by 5-HT probably through activation of the synthesis of vasodilator prostaglandins.


[Inhibitory effect of methergoline on serotonin induced contraction of isolated strips of coronary arteries]. Metergoline (antiserotonin drug) prevents the contraction induced by serotonin on strips of isolated coronary arteries. Moreover when metergoline is added at the maximal contraction, it induces relaxation of the vascular smooth muscle preceeded by a brevious phase of contraction.


[Shore species varieties in Lake Piediluco ((Umbria: Terni). Food and degree of parasitism of lake fish]. Lake Piediluco is a small natural lake in Umbria, Italy, which is regulated by hydroelectricity demands. Two artificials tributaries flow into it at the north end and create a lotic zona. The lake is rich in algae and hydrophytes. There are many sponge colonies and a great number of rheophil and limnophile caddis flies (40 species), gasteropods and bivalves. In the intestinal content of fishes the trichoptera larvae are very numerous. The fishes, which have been carefully investigated for parasites, are not seriously damaged.


[Mechanisms of detecting organic cholephilic anions in man: comparative studies on plasma depuration of rifamycin-SV. Interference of nicotinic acid and phenobarbital]. We have studied plasmatic half-life of R-SV administered alone and in association with nicotinic acid, before and after treatment with phenobarbital, in 10 normobilirubinaemic subjects and in 10 patients Gilbert's syndrome, used like controls. Ouer results confirm the existence of some alterations of drug-metabolism produced by associated administration of other drugs, in both healthy and hyperbilirubinaemic subjects, and in these one even more.


[Air embolism due to limited high grade barometric depression as evidenced in vivo]. The Authors supply documentary evidence for the aeroembolism of auricular lobe vessels photographed in transillumination of living albino rabbits exposed to high grade barometric depression (850 g/cm2) limited on the top of the head.


[The temporary occlusion of middle cerebral artery in cats--the correlation between the rCBF and the histological changes (author's transl)]. The correlation between the changes of regional cerebral blood flow (rCBF) and the histological changes were examined using the middle cerebral arterial (MCA) occlusion model in cats. A total of 24 adult cats were tracheostomized and anesthetized by inhalation of halothane. The right MCA was clipped by the transorbital approach. Two hours after the application, the clip was removed and the brain was recirculated for two hours. Then, the brain was perfusion-fixated and the histological studies were carried out. The animals were separated into two groups according to the severity of histological damages using light and electron microscope. Severe cortical damage was present in 8 cats (Group A). In the remaining 16 cats, little or no cortical damage was found (Group B). The averaged rCBF values before occlusion were 45.4 +/- 2.3 ml/100 gm/min in group A and 46.5 +/- 1.6 in group B, showing no statistically significant difference. Between these two groups, however, there was a statistically significant difference in the averaged rCBF values during the ischemic period. In group A, the averaged rCBF values during MCA occlusion was only 6.8 +/- 0.9 and in group B, it was 25.3 +/- 0.8. In the recirculation period, there was a prompt and uniform recovery of rCBF in group B. Whereas in group A, a marked diversity of rCBF ranging from oligemia to hyperemia ensued. This is presumably a reflection of inhomogeneous blood flow, or patchy non-filling of the cerebral cortex. The critical values of rCBF as to the occurrence of severe cortical damage in two-hours MCA occlusion is considered to lie between the lowest value of group B and the highest value of group A, i.e., around 12--15 ml/100 gm/min.


[Neuropsychological studies of two subjects after the transection of the splenium of the corpus callosum. (Part 2. The auditory recognition by the dichotic listening test) (author's transl)]. We made the neuropsychological auditory studies of two right-handed subjects who had undergone the transection of the splenium of the corpus callosum for the pineal operation (the teratoma by the histopathological examination). The transection grades were 2.0 cm and 2.5 cm. The truncus and splenium of the second subject were flat by the compression of the tumor. We examined these subjects by the some audiolocigal methods. 1. Pure tone audiometry. 2. Fixed frequency Békésy audiometry. 3. SISI test (short increment sensitivity index test). 4. Speech audiometry. 5. Distorted speech test (filtered speech test). 6. Binaural fusion test. 7. Dichotic listening test. The tasks used for the dichotic listening test were following. Different digits (one pair, three pairs), different words (from two to four syllables) and different vowels and consonants were presented simultaneously to the two ears by means of a dual-channel tape recorder with stereophonic earphone. The result shows that the first subject (whose section of the spelenium was 2.0 cm) shows a slight but not significant superiority on the right ear to the one pair digits and words (p less than 0.1), and the second subject (whose section of the splenium was 2.5 cm and whose splenium and truncus of the corpus callusum were flatten by the compression of the tumor) shows a significant superiority on the right ear to the one pair digits, words, three pairs digits and vowels (p less than 0.05). But there was no definitive abnormalities at the pure tone audiometry, the fixed frequency Békésy audiometry, SISI test, distorted speech test and binaural fusion test of two cases. The result shows that the commissure fibres of the auditory perception of the speech of two hemispheres connect through from splenium to the truncus of the corpus callosum.


[The anti-tumor effect of ACNU and X-irradiation on mouse glioma (author's transl)]. Anti-tumor activities of ACNU and X-irradiation on methylcholanthrene induced glioma in C57BL mice were studied in vitro and in vivo. In vitro experiments using cultured glioma cells (MGB cells), the synchronization of cell cycle was done by excess addition of thymidine, and the anti-tumor cell effect were investigated by mean of determinations of DNA synthesis, mitotic index and the number of the living cells following the treatments. As the results, it appeared obvious that ACNU was most effective on MGB cells in S phase and X-irradiation in M phase. As to the combined therapy of ACNU and X-irradiation, the anti-tumor effect was most remarkable when the cells were treated by X-irradiation in the G2, M phase, which were hervested by addition of ACNU 44 hours before irradiation. However simultaneous treatment of ACNU and X-irradiation on the cells in G1 phase was not so remarkable. In vivo experiments the anti-tumor effect of ACNU and X-irradiation on subcutaneously or intracranially transplanted glioma in mice was investigated. Either ACNU 10 mg/kg or local X-irradiation 1240 rads showed inhibitory effect on the tumor growth and prolonged the survival time of the tumor bearing mice. The combination therapy was more effective than ACNU or X-irradiation alone, particularly combination therapy of ACNU and repeated small doses irradiation of X-ray was remarkably effective. Evidence obtained indicates that the combination therapy of ACNU and X-irradiation have synnergistic anti-tumor effect on experimental mouse glioma.


[Morphological changes of platelets in disturbed cerebral microcirculation--a clinical study using a scanning electron microscope (author's transl)]. Many factors are known that contribute to the pathogenesis of the cerebral microcirculatory disturbances, but, there are few reports investigating the roles of the intravascular components directly. The present study was undertaken to evaluate morphological changes of platelets in patients with cerebral damage, in relation to neurological signs, especially consciousness levels. Morphological changes of platelets were observed in 72 patients with intracranial organic lesions. These lesions included subarachnoid hemorrhages, hypertensive cerebral hemorrhages, cerebral infarctions, brain tumors, chronic subdural hematomas, and acute epidural hematomas. Two blood samples were taken, one from the internal jugular vein (the blood after cerebral perfusion), the other from the cubital vein (systemic blood). After fixative procedures with 1% glutaraldehyde, the differences in the three-dimensional structures of platelets were compared, using a scanning electron microscope. In general, remarkably activated forms of platelets were found in the blood after cerebral perfusion in cases with severely impaired consciousness in the acute stage. But, in cases without severe neurological deficits, such changes of platelet forms were rarely seen. A close relationship was suggested between the degree of neurological damage (especially consciousness levels) and that of platelet activation in the acute stage. In the chronic stage, these changes of platelets in the cerebral blood disappeared. Changes of platelet forms were not found in the systemic blood from the cubital vein, even in the acute stage. It is clinically suggested that morphological changes of platelets play an important role in the pathogenesis of the disturbed cerebral microcirculation. Obstruction of cerebral microvasculature may be caused, mechanically by the activated platelets themselves, and/or chemically by vasoconstrictive substances released from these platelets. Therefore, in the treatment of these intracranial organic lesions, it is concluded that the possible roles of activated platelets should be taken into consideration.


[Sphenoethmoidal meningoencephalocele associated with agenesis of corpus callosum and median cleft lip and palate--report of two cases (author's transl)]. Two cases of sphenoethmoidal meningoencephalocele are reported. Patients are a 1 year 7 month old boy and a 3 year old boy. Although sphenoethmoidal meningoencephalocele is reasonably classified as a type of basal meningoencephalocele, the authors could not find out any reports on cases designated as such. The reason must be in difficulty to differentiate the sphenoethmoidal type from the transsphenoidal type. Authors could differentiate them using CT scan. Two other cases were found in cases reported as transsphenoidal type. Further, it is assumed that these four cases including our two cases were accompanied with agenesis of corpus callosum and median cleft lip and palate. Despite the fact that the respective anomalies are rare, they are completely the same, which signifies the possibility that 1) sphenoethmoidal meningoencephalocele, 2) agenesis of corpus callosum and 3) median cleft lip and palate are a single unit of congenital anomalies. It probably should be considered that the cause for these malformations were present even before the formation of the lips which takes place earliest, that is, sixth week of gestation.


Diagnosis of left ventricular thrombi by two-dimensional echocardiography. Sixteen patients had two-dimensional echocardiographic diagnosis of the presence or absence of left ventricular thrombi and anatomical, radiological, or clinical confirmation of the diagnosis. Eleven patients had positive diagnoses, which were confirmed in 10 and possibly incorrect in one. Five other records were reviewed because the patients had undergone aneurysmectomy after two-dimensional echocardiograms: three were true negative and two were false negative studies.


Displacement of pacemaker leads--a 10-year survey. Displacement of endocardial pacemaker leads from the initial site at the time of implantation is a major cause of unpredictable pacemaker failure. In this survey, we have made a retrospective study of the effectiveness of the attempts made by two manufacturers to design leads to reduce the frequency of this occurrence. The cumulative displacement records of 5 types of leads (Medtronic types 5818, 6904, 6901, and 6950, and Cardiac Pacemakers Inc. type 4210) have been studied, and show that Medtronic 5818 and 6950, and CPI 4210 leads are superior in this respect.


Assessment of endocardial leads for permanent cardiac pacing. Catheter tip dislocation is the main complication of permanent pacemaker implantation using the subclavian vein. In this study of 50 patients we compared the incidence of complications using two endocardial electrodes specially designed to prevent tip dislocation. One catheter had a helical endocardial electrode and the other had retractable nylon barbs. The helical electrode was superior in every respect and we recommend its use for pacing through the subclavian vein.


Nomogram to calculate oxygen consumption. A nomogram has been devised for the rapid derivation of the oxygen consumption from the expired minute volume and the fractional concentrations of expired CO2 and O2.


Value of electrocardiogram in predicting and estimating infarct size in man. The value of the electrocardiogram in assessing infarct size was studied using serial estimates of the MB isomer of creatine kinase (CK MB) in plasma, serial 35 lead praecordial maps in 28 patients with anterior myocardial infarction, and serial 12 lead electrocardiograms in 17 patients with inferior myocardial infarction. In patients with anterior infarcts, sigma ST, sigma R, sigma Q, sigma R/(Q+S), and the number of sites with ST elevation more than 2 mm or with QS waves, were obtained from each map. Correlation between both maximum sigma Q and maximum sigma ST with cumulative CK MB was highly significant. There was also a significant correlation between sigma R and sigma R/(Q+S) with cumulative CK MB. There was no significant correlation between maximum number of sites with ST elevation or with Q or QS waves and cumulative CK MB. Maximum sigma ST and number of sites with ST elevation predicted maximum sigma Q and number of sites with QS or Q waves at a time when infarction was not complete. In patients with inferior infarcts, there was a significant correlation between maximum sigma Q and maximum sigma ST in leads II, III, and a VF, and cumulative CK MB. This study shows that all the waves in the electrocardiogram are useful in assessing infarct size. The fact that maximum sigma ST predicts final sigma Q may be used to assess the efficacy of interventions designed to salvage ischaemic myocardium.


Familial aggregation of coronary heart disease in a high incidence area (North Karelia, Finland). Occurrence of coronary heart disease was assessed in families of 211 men under the age of 56 from East Finland. Fifty men were survivors of recent myocardial infarctions, 55 had died of myocardial infarction, 53 suffered from uncomplicated angina pectoris, and 53 were healthy reference men. Overall prevalence of coronary heart disease was similar in familes of all case probands. By age 70, case fathers had a 6 times greater cumulative risk (a 36% chance) of dying from coronary heart disease than reference fathers, whereas there was only a small difference between case and reference mothers. Cumulative risk of developing fatal or non-fatal coronary heart disease by age 65 was 4.5-fold for case brothers (70%) and 2.6-fold for case sisters (40%), when compared with reference sibs. The risk was greatest for case sibs with a parental, especially a maternal, history of premature coronary heart disease. Clinical manifestations of coronary heart disease showed similarities within sibships. Cardiac deaths were commonest in sibs of the fatal myocardial infarction probands, whereas angina was commonest in sibs of the angina pectoris probands.


Haemodynamic effects of acute beta-adrenergic receptor blockade in congestive cardiomyopathy. Acebutolol ('Sectral'), a cardioselective beta-blocking drug, was administered intravenously in a dose of 25 mg to 10 patients with congestive cardiomyopathy. All of them were in a stable condition on antifailure regimens. The drug resulted in a statistically significant decline in left ventricular contractility as judged by peak left ventricular dP/dT and the contractility index. The mean aortic blood pressure also fell. There was a significant increase in end-diastolic and end-systolic left ventricular volumes. Mean values for heart rate, ejection fraction, left ventricular stroke work index, and cardiac output also fell, but the results were not statistically significant. Left ventricular distensibility as judged by the slope of the diastolic pressure-volume relation also improved significantly. A reduction in myocardial energy requirements, improved compliance, and lowering of arterial pressure would be haemodynamically advantageous. However, further cardiac dilatation and reduction contractility--the basic defects in congestive cardiomyopathy--could lead to further deterioration.


Relation of plasma aldosterone concentration to diuretic treatment in patients with severe heart disease. To assess the relation of hyperaldosteronism and potassium depletion to the intensity of diuretic therapy we have measured plasma aldosterone by radioimmunoassay and total exchangeable potassium by radioisotope dilution in 24 patients when they were stable at the end of their preparation for cardiac operation. Some patients required intensive frusemide therapy to reach an optimal state for operation and many showed hyperaldosteronism. Plasma aldosterone was significantly related to daily dose of frusemide (r=0.77). Depletion of total exchangeable potassium expressed in terms of predicted weight was significantly related to plasma aldosterone (r= -0.64). The reduction in total exchangeable potassium is interpreted as chiefly related to loss of lean tissue mass from the wasting that leads to cardiac cachexia, but evidence is presented on the basis of measurements of extracellular fluid volume as sulphate space (20 patients) of entry of sodium into the cells which may indicate a true cellular potassium loss. Although plasma potassium is usually easily maintained with oral potassium supplements or aldosterone antagonists, we postulate that intensive diuretic therapy in severe heart disease may provoke hyperaldosteronism which accentuates potassium loss and may contribute to wasting and to intracellular potassium depletion in critical tissue, such as myocardium.


PRediction of infarct size by enzymatic techniques: modification of a method and clinical application. In an attempt to develop improved methods of prediction of infarct size by enzymatic methods, Shell's original algorithm has been critically evaluated in an unselected series of patients. Poor performance of the model is partly the result of a systematic source of error associated with its mathematical formulation. A new model devoid of such limitations has therefore been developed. Residual deviations between predicted and observed CK release seem to be related to frequent and unpredictable extensions of infarction which could be verified by independent clinical, electrocardiographic, and enzymatic criteria. The modified model may possibly be applied to the evaluation of agents aimed at limiting the spread of irreversible injury.


Pericardial tamponade in systemic sclerosis (scleroderma). The frequency of pericardial disease in scleroderma found at necropsy in high. The clinical recognition of pericarditis with or without effusion is rare and tamponade with haemodynamic impairment is exceptional. Three patients with scleroderma presented with an acute syndrome of dyspnoea, chest pain, and cardiomegaly requiring pericardiocentesis for relief of pericardial tamponade. One patient died. The mechanism of the pericardial effusion remains unknown. The haemodynamic data recorded from one patient suggested that pericardial fibrosis in scleroderma may predispose to pericardial tamponade.


Infective endocarditis with glomerulonephritis associated with cat chlamydia (C. psittaci) infection. A patient with glomerulonephritis and endocarditis is described who had evidence of feline Chlamydia psittaci infection. Treatment with antichlamydial drugs resulted in resolution of the glomerulonephritis and the endocarditis. It is recommended that screening for chlamydia is included in the investigation of patients with suspected or obscure endocarditis.


Isolated congenital absence of coronary sinus. A case is reported in which contrast angiography showed complete absence of the coronary sinus, the cardiac veins draining separately into left and right atria. Normal systemic venous drainage was demonstrated by contrast cross-sectional echocardiographic methods and later confirmed by conventional angiographic injections. In addition, angiography showed a stenosis in the anomalous cardiac vein draining into left atrium accounting for the presence of a continuous murmur for which the patient was initially referred.


Noradrenaline producing phaeochromocytomas with absent pressor response to beta-blockade. In 2 patients with phaeochromocytoma, effective beta-blockade was obtained with propranolol (40 mg twice a day for 3 days) or acebutolol (400 mg twice a day for 3 days) without any effect on the blood pressure. In both patients the excretion of noradrenaline predominated over that of adrenaline, a picture found in most cases of phaeochromocytoma. A hypertensive response to beta-blockade might be expected in patients with an adrenaline-secreting tumour. It cannot be a regular event or constitute a diagnostic test in patients with suspected phaeochromocytoma.


Aggregation of coronary risk factors in families of men with fatal and non-fatal coronary heart disease. The occurrence of main coronary risk factors was assessed in the families of 211 men under age 56 from East Finland. Fifty men were survivors of a recent myocardial infarction, 55 had died of myocardial infarction, 53 suffered from uncomplicated angina, and 53 were healthy reference men. Familial hyperlipidaemia was twice and familial hypertension three times as common in case as in reference families; other risk factors were equally common in both. Familial hypercholesterolaemia was commonest in the families of men with fatal myocardial infarction, and multiple type familial hyperlipidaemia in those of men with angina. Any increase in familial aggregation of coronary heart disease was invariably paralleled by increased aggregation of hyperlipidaemia and hypertension, with the most impressive aggregation of both traits in case families with a maternal history of early coronary death. It is concluded that most of the familial aggregation of coronary heart disease is mediated by familial aggregations of hyperlipidaemia and hypertension.


Haemodynamic and electrocardiographic accompaniments of resting postprandial angina. The early postprandial changes in 10 patients with angiographically proven coronary artery disease and history of postprandial angina were studied by the continuous recording on magnetic tape of the electrocardiogram and haemodynamic variables. The significant changes 20 minutes after a meal not followed by angina included increases in cardiac index and stroke index, with a decrease in systemic vascular resistance. When angina developed after a meal, there were significant increases in mean systemic arterial blood pressure, heart rate, pulmonary capillary wedge pressure, and systemic vascular resistance with decreases in stroke index at the onset of pain rather than at the onset of ischaemic electrocardiographic abnormalities. The first haemodynamic variable to change was pulmonary capillery wedge pressure which tended to increase coincident in time with the electrocardiographic abnormalities. In all cases, postprandial angina occurred within 25 minutes after a meal. In every instance, there was little or no change in the product of heart rate and systolic arterial blood pressure at the onset of the ischaemic electrocardiographic abnormalities at a time when the pulmonary capillary wedge pressure had begun to rise. Postprandial angina, like many cases of rest angina, may rise on the basis of a primary decrease in myocardial perfusion, the nature of which is unclear but merits further investigation.


Exercise testing in men with significant left main coronary disease. The exercise tests of 26 male patients with significant left main disease were compared with those of 51 patients with three-vessel disease and 38 patients with two-vessel disease. Exercise-induced ischaemia (chest pain and/or greater than 1 mm ST segment change) occurred in 100 per cent of left main, 69 per cent of three-vessel, and 45 per cent of two-vessel disease patients. Though the mean peak work load was significantly higher in the two-vessel disease group than in those with three-vessel of left main disease, there was a wide overlap between groups. No intergroup differences were found in mean peak heart rates. In patients taking propranolol, no differences in mean peak work loads and heart rates were seen. The study showed that the absence of an exercise-induced abnormal electrocardiographic response virtually excludes left main disease. As judged by exercise performance, the presence of left main disease did not correlate with the severity of the patient's symptomatology. Propranolol did not influence the frequency of an ischaemic response in patients with left main or three-vessel disease.


Projection of electrocardiographic signs in praecordial maps after exercise in patients with ischaemic heart disease. Praecordial surface maps of the electrocardiogram were recorded before and after exercise using 16 electrodes covering the left hemithorax. The ST segment and R and S wave changes were measured in the praecordial maps from 20 individuals with no detectable cardiovascular disease. These showed no significant alteration in ST segments of R/S. In contrast in 40 patients with angiocardiographically proven coronary artery disease it was possible clearly to outline the distribution, severity, and time course of praecordial areas of ST segment depression (36 patients) and ST segment elevation (10 patients). In addition these praecordial areas of ST segment changes were accompanied by a regional and significant fall in the R/S. The praecordial electrocardiogram with exercise complements the anatomical information obtained from the coronary arteriogram by clearly outlining electrocardiographic projections of regional myocardial ischaemia or cell death.


Vasomotor responses to the Valsalva manoeuvre in normal subjects and in patients with diabetes mellitus. Cardiovascular responses to the Valsalva manoeuvre were examined in 19 non-diabetic subjects and 32 diabetic patients, some with signs of autonomic dysfunction. All the non-diabetic subjects showed an overshoot in systemic arterial pressure and a bradycardia after the manoeuvre, and in 11 of them only forearm vasoconstriction occurred. However, in eight non-diabetic subjects a forearm vasodilatation was observed at some stage after the Valsalva manoeuvre. Similar patterns of vasomotor responses were seen in some of the diabetic patients. However, those diabetics with postural hypotension showed a systemic arterial hypotension after the Valsalva manoeuvre with no significant change in forearm vascular resistance. Such a response is abnormal but forearm vasodilatation alone may not be.


Effect of ventricular function on left ventricular ejection time in aortic stenosis. Since recognition of factors which modify the duration of ejection in aortic stenosis is of clinical importance, the relations among rate-corrected left ventricular ejection time, aortic valve area, and determinants of ventricular performance were studied in 54 catheterised patients. In patients with a normal cardiac index, increasing duration of ejection was linearly related to increasing obstruction. In patients with failing ventricles, on the other hand, the ejection time was less prolonged, and the duration of ejection was unrelated to valve area. At fixed valve area, relation with cardiac output, stroke volume, heart rate, mean aortic valve pressure gradient, mean aortic pressure, and left ventricular end-diastolic pressure could not adequately explain the observed scatter in ejection time. This suggests a multifactorial basis for the wide range of ejection times observed with severe aortic stenosis.


Syndrome of valvular pulmonary stenosis and valvular aortic stenosis with atrial septal defect. Clinical and morphological findings are described in 2 adults with combined valvular pulmonary and aortic stenosis with atrial septal defect, an extremely rare combination of lesions. The direction of the shunt via the atrial septal defect in this combination appears to be dependent on the relative degree of outflow obstruction on the right side compared with the left side of the heart. In 1 patient the degree of obstruction at the pulmonary valve was nearly three times that at the aortic valve and, therefore, the shunt was right to left and the patient was severely cyanotic. In the other patient, the degree of obstruction at the pulmonary valve was slightly less than that at the aortic valve and, therefore, the shunt was entirely left to right and the patient was acyanotic. Diagnosis of an associated obstructive lesion on the left side of the heart in a patient with an obstructive lesion on the right side of the heart is essential because operative relief of the right-sided obstruction without relief of the left-sided obstruction may lead to rapid, fatal pulmonary congestion.


Multilevel block in the atrioventricular node during atrial tachycardia and flutter alternating with Wenckebach phenomenon. The electrocardiograms of 100 patients with rapid and regular PP intervals during atrial arrhythmias (because of atrial tachycardia or flutter, or pacing) were examined for periods of irregular atrioventricular conduction. This irregular conduction corresponds to an alternating Wenckebach phenomenon, of a type that can be determined from simple rules. The different types of conduction encountered in different patients and the changes seen in the same patient suggest that the atrioventricular node functions physiologically with 3 levels of sequential block. The different prevalence of the 2 types of alternating Wenckebach block may reflect functional differences at the level of the atrioventricular node.


Free adrenaline and noradrenaline excretion related to occupational stress. Urinary levels of free adrenaline and noradrenaline were measured in two groups of healthy male industrial workers exposed to alternate four-day periods of working conditions with and without time stress, to test the hypothesis that the sympathetic nervous system is overactivated by occupational stress. Thirty confectionary workers alternated piece-work (payment by results) and work with a fixed daily wage while 30 metal workers alternated work on an assembly line with work off it. Under time stress urinary free adrenaline was 450 per cent and noradrenaline 230 per cent of the levels for similar work without time stress but involving equal oxygen consumption. These differences were statistically highly significant and they persisted on retesting after six months of alternating work regimens. They support the concept that occupational stress in industrial workers influences the adrenosympathetic system and they indicate a possible method for assessing the effects of high levels of sympathetic activity on the aetiology of ischaemic heart disease.


Renal artery stenosis with severe hypertension. A rare case with detailed assessment of renin-angiotensin system before and after development of lesion. The rare opportunity arose to assess in detail the renin-angiotensin system before and after the development of a renal artery stenosis with severe hypertension. Peripheral plasma concentrations of renin, angiotensin II, and aldosterone were known to be normal before the development of renal artery stenosis, and there were no lateralising features on renal vein sampling. Acute hypertension associated with very high peripheral plasma concentrations of renin and angiotensin II, and with pronounced lateralisation on renal vein sampling followed the development of acute unilateral renal artery stenosis. These measurements all returned to normal after nephrectomy, conforming with the pattern of changes previously established only in experimental animals.


Transposition of the great arteries associated with a double left ventricular outflow tract. A case is described in which, at semilunar valve level, the aorta and pulmonary artery arose from inappropriate ventricles. Despite this, the outflow tracts to both vessels originated from the left ventricle. Embryologically, it is speculated that this anomaly is the result of normal rotation of the proximal conus, without concomitant truncal inversion, and excessive leftward shift of the proximal conus and conal septum or anterior and rightward deviation of the anterior segment of the ventricular septum. Surgical repair using a double conduit between the right ventricle and pulmonary artery and left ventricle and aorta, respectively, was unsuccessful.


Superior vena cava stenosis at site of intersection of two pacing electrodes. Superior vena cava obstruction is described in a patient with two endocardial pacing electrodes. At necropsy a severe stenosis of the venous lumen was found at the site of intersection of the two catheters. There was no evidence of thrombus formation. Venous wall stenosis is an unusual complication of transvenous pacing and is probably favoured by the presence of two electrodes.


An animal model for the investigation of adverse responses to i.v. anesthetic agents and their solvents. In man the number of adverse responses to the Cremophor-containing anaesthetic agents Althesin and propanidid (Epontol) has been reported to be greater than that encountered with thiopentone. The response of the mini-pig to repeated injection of a range of i.v. anaesthetics and their solvents has been investigated in an attempt to ascertain the possible role of Cremophor in the production of these responses. A second injection of Cremophor EL or the Cremophor/Micellophor-containing agents Althesin and propanidid (Epontol), given 7 days after the first, produced a high frequency of adverse responses. On only one occasion, when alphaxalone and alphadolone were given in a mixture of alcohol and propylene glycol, was an abnormal response seen on the first administration of any agent. The second administration of alphaxalone and alphadolone in the same solvent produced abnormal responses in two of four pigs. No such responses were seen when propanidid was administered in alcohol and propylene glycol or when this solvent mixture was given alone. No abnormal responses were seen following the repeated administration of thiopentone. A marked increase in arterial pressure, and an immediate but transient marked decrease in the numbers of circulating polymorphonuclear leucocytes, were consistent findings in animals showing adverse responses. No abnormal responses were found when the interval between two administrations of Althesin was extended to 3 weeks.


Effects of metoprolol on systemic haemodynamics, myocardial performance and the coronary circulation during halothane anaesthesia. The effects of metoprolol 1 mg kg-1 i.v. on the systemic and coronary circulations and on myocardial performance were studied in nine open-chested dogs ventilated with halothane 0.8% in oxygen at normocarbia. In terms of the chronotropic effect, this dose of metoprolol produced a substantial shift to the right of the dose-response curve to isoprenaline; substantial reductions of arterial pressure (10%), cardiac output (21%), aortic blood acceleration (13%), left ventricular dP/dt max (13%) and left ventricular power (25%) were observed. Both preload, represented by left ventricular end diastolic pressure, and afterload, represented by systemic vascular resistance, increased. Left circumflex coronary blood flow and myocardial oxygen consumption decreased by approximately the same amount as peak ventricular power.


Inhibition of neuronal and extraneuronal uptake of noradrenaline by ketamine in the isolated perfused rat heart. The effect of ketamine on the uptake of 3H-noradrenaline in the isolated perfused rat heart was studied. A dose-dependent inhibition of uptake by both neuronal and extraneuronal processes was found. These effects may account for the positive chronotropic and pressor effects of the drug.


Metabolism of synthane: comparison with in vivo and in vitro defluorination of other halogenated hydrocarbon anaesthetics. Aerobic defluorination of the inhalation anaesthetic agent, synthane, was compared with that of methoxyflurane, enflurane and halothane and with two other anaesthetics, isoflurane and sevoflurane. In vitro, in microsomes prepared from phenobarbitone-induced and control livers, synthane and halothane were not defluorinated. The relative order of defluorination of the other anaesthetics was methoxyflurane greater than enflurane greater than isoflurane. In vivo, following 4 h of 1.2% (MAC) synthane anaesthesia, urinary inorganic fluoride excretion was increased by only a trivial amount and only in phenobarbitone-treated rats; polyuria was not observed. Synthane is the least metabolized of the fluorinated ether anaesthetics; its administration will not result in inorganic fluoride nephropathy. An index of nephrotoxic potential for fluorinated anaesthetic agents was formulated utilizing in vitro fluoride production data and oil: gas partition coefficients.


Ambient air contamination in a dental outpatient theatre. The extent of air contamination by halothane in an operating session was correlated with the number of patients, the total usage of halothane, refilling a vaporizer and the number of hyperventilating patients per session. Trichloroethylene content of theatre air correlated only with total usage and refilling a vaporizer. A very strong personal association (P smaller than 0.001) was found between the anaesthetist and the extent of air contamination with halothane. The association was weaker (0.05 less than P less than 0.1) for trichloroethylene. The median ambient air contamination with halothane in the vicinity of the faces of anaesthetists and dental surgeons was between six and nine times greater than the median air contamination at the fixed sampling sites (P smaller than 0.005).


Laminar flow enclosure-a possible risk to the patient. A retrospective comparison was made between two groups of 50 adult patients who underwent open-heart surgery in an operating suite with two adjacent rooms, one of which was equipped with a laminar flow enclosure. Core and body surface temperatures were measured at 15-min intervals for the 1st h after commencement of surgery. Patients in a laminar flow enclosure showed a significantly greater decrease in core temperature with time. Possible means of counteracting this are suggested.


Plasma concentrations of alphaxalone during continuous infusion of Althesin. Plasma concentrations of alphaxalone have been measured during various rates of continuous infusion of Althesin used to supplement nitrous oxide-oxygen anaesthesia in man. There was an approximately linear relationship between the plasma concentration of alphaxalone and the rate of infusion of Althesin. The rate of uptake of alphaxalone into the liver did not appear to be impaired in the presence of the steroid myoneural blocking agent pancuronium, or in patients with hepatic cirrhosis.


Dose-related haemodynamic effects of continuous infusions of Althesin in man. The cardiovascular effects of infusions of Althesin at various rates to supplement nitrous oxide anaesthesia have been studied in seven spontaneously breathing patients and11 patients ventilated artificially to normal PaCO2. During spontaneous breathing, increasing rates of Althesin infusion were associated with increases in heart rate and cardiac output. The modest decrease in arterial pressure (-5%) was the result of a decrease in vascular resistance. Increasing rates of Althesin rates of Althesin infusion (up to eight times the minimum infusion rate) caused dose-dependent decreases of arterial pressure and systemic vascular resistance, whereas heart rate and cardiac output were increased slightly at all rates of infusion.


Metabolic effects of induced hypotension with trimetaphan and sodium nitroprusside. In two groups of patients undergoing induced hypotension with sodium nitroprusside or trimetaphan blood concentrations of lactate, pyruvate and standard bicarbonate did not differ significantly between the groups. In the nine patients who received trimetaphan there was a progressive, but statistically non-significant, decrease in mean lactate. Nitroprusside (15 patients) was associated with a small increase in mean lactate, but at low dosage there was a small decrease. No relationship to dose rate of nitroprusside was found with these short-term infusions. It is concluded that sodium nitroprusside can be used safely for induced hypotension at doses less than 1.5 mg kg-1 and that simple blood-gas analysis is adequate for the assessment of toxic effects when greater doses are given.


Increased carbon dioxide production in two patients with malignant hyperpyrexia and its control by dantolene. Two patients with successfully treated malignant hyperpyrexia are reported. Carbon dioxide output, calculated from the respiratory minute volume and PaCO2, was found to be greatly increased in both patients. In the patient who received dantolene 7.5 mg kg-1 the carbon dioxide output decreased rapidly to normal values, whereas in the other patient carbon dioxide output remained increased for several hours.


An endobronchial cuff indicator for use in thoracic surgery. A simple apparatus and a method are described by which an exact end-point can be attained in inflating the bronchial cuff of a double-lumen tube, and accidental collapse of the cuff detected.


Performance studies with diazepam and its hydroxylated metabolites. 1 Visuo-motor coordination has been used to study the immediate and residual effects of benzodiazepines on performance in man. The technique provides dose and time response data related to the decrement and the persistence of impaired performance. 2 With the overnight ingestion of flurazepam hydrochloride 30 mg and nitrazepam 10 mg, performance was impaired to 16 h and, at least, 19 h, respectively. Performance was not impaired after the overnight ingestion of diazepam, 5 and 10 mg, temazepam 10, 20 and 30 mg or oxazepam 15 and 30 mg. However, with temazepam 30 mg there was a trend toward impaired performance,, and with oxazepam 45 mg, performance was impaired 10 h after ingestion. With morning ingestion, coordination was impaired 0.5 and 2.5 h after diazepam 10 mg, at 0.5 h after temazepam 20 mg, and after oxazepam 30 mg at 2.5 and 4.5 hours. 3 The studies suggest that diazepam 5-10 mg, temazepam 10-20 mg and oxazepam 15-30 mg may be of use in the management of sleep disturbance when impaired performance the next day is to be avoided.


Effects of hypnotic and sleep-inducing drugs on objective assessments of human psychomotor performance and subjective appraisals of sleep and early morning behaviour. 1 An acute dose comparison against placebo of the effects of nitrazepam 5 mg and temazepam 15 and 30 mg on measures of arousal and performance and on subjective assessment of sleep was carried out in 20 subjects with a history of using night-time medication for insomnia. 2 Amylobarbitone (100 mg) was included as an active control and each drug was given in hard gelatin capsules. Subjects reported improved sleep with nitrazepam 5 mg and temazepam 30 mg, but there was evidence of impaired performance the next day with temazepam 30 mg. 3 The effect of temazepam 20 mg prepared in the Scherer formulation was compared against placebo in a further ten subjects. The subjects reported improved sleep without evidence of impaired performance the next day.


Clinical significance of prescribing hypnotics in general practice. 1 The causes of insomnia are considered, including those amenable to improvement of the sleep environment and medical treatment. 2 The use of hypnotics is discussed and the investigation of new drugs in general practice reviewed.


Effect of the antihistamines, brompheniramine maleate and triprolidine hydrochloride, on performance in man. 1 Effects of brompheniramine maleate (4 and 12 mg) and triprolidine hydrochloride (2.5 and 10 mg) on visuo-motor coordination, and on subjective assessments of performance, well-being and sleep were each studied in six subjects at 0.5, 1.5, 3.0, 5.0 and 7.0 h after ingestion. The doses refer to immediate and sustained release preparations respectively. 2. Triprolidine hydrochloride (2.5 mg) had an immediate effect on performance which persisted to 3.0 h, and the sustained release preparation (10 mg) impaired performance from 1.5 to 5.0 h. Brompheniramine maleate (4 mg) impaired performance from 1.5 to 3.0 h, and the sustained release preparation (12 mg) impaired performance at 1.5 h. There were no consistent changes in the subjective assessments of performance, or of well-being and sleep. 3. The studies emphasize the variable effects of antihistamines on performance, and suggest that effects on performance of sustained release preparations may be similar to those of the usual form. Sustained release preparations may provide an advantage in clinical practice if the antihistaminic activity is prolonged.


Impairment of drug metabolism in polycystic non-parasitic liver disease. 1. Drug-metabolizing capacity in cases of polycystic non-parasitic liver disease was investigated using plasma antipyrine clearance as an index. 2. The four subjects with maternally inherited polycystic liver metabolized antipyrine at a significantly slower rate than the six other members of the family. 3. This reduction in antipyrine metabolism is due to the loss of active liver parenchyma, and is probably also influenced by alterations in the vascular bed due to compression by the enlarged cysts.


The influence of food on the bioavailability of new formulations of erythromycin stearate and base. 1. The effect of food on the bioavailability of two new formulations of erythromycin, 1) erythromycin stearate, 500 mg (Erythrocin, 250 mg capsule-shaped tablets) and 2) erythromycin base, 500 mg (Eryc, 250 mg capsules containing enteric-coated pellets) was studied in 16 healthy subjects. 2. The study was a balanced, randomized Latin square design and was conducted on 4 days. The four treatments were erythromycin stearate immediately before (EB) and after EA) breakfast and erythromycin base immediately before (eB) and after (eA) breakfast. 3. The mean +/- s.d. maximal plasma erythromycin concentrations were 2.09 +/- 1.06, 0.37 +/- 0.40, 1.8+ +/- 1.15 and 1.91 +/- 1.57 micrograms/ml and the mean +/- s.d. times at which these occurred were 1.3 +/- 0.7, 2.3 +/- 0.9, 4.4 +/- 1.9 and 4.3 +/- 1.1 h for EB, EA, eB and eA respectively. 4. The mean +/- s.d. areas under the curves (0 to 8 h) were 4.99 +/- 2.41, 1.04 +/- 1.57, 4.93 +/- 2.98 and 4.98 +/- 3.14 for EB, EA, eB and eA respectively. 5. The bioavailability of erythromycin stearate was significantly reduced by the prior administration of food, whereas the absorption of the base was not inhibited by food.


Variability of plasma catecholamine levels: age, duration of posture and time of day. 1. In order to define factors which influence plasma catecholamine levels, and which might be controlled in the interests of reproducability and comparability, plasma noradrenaline plus adrenaline (NA + A) was measured repeatedly in normal subjects by a double isotope technique. 2. Age and posture were important determinants for plasma NA + A levels, whereas time of day was less important. 3. Levels were higher in old men aged 70--92 years than in young men aged 19--28 years, measured after 30 min or 9 h (overnight) recumbency, or after 5 min standing. 4. Duration of recumbency and of upright posture were both important. Recumbent levels were lower after 9 h (overnight) than after 30 min (mid-morning). Upright posture caused an increase in levels within 2 min. Levels peaked between 5 and 20 min, were lower after 12 h than after 20 min, but upright levels were always higher than levels after 9  h recumbency. 5. During continuous recumbency, levels were lowest at 24.00 h, and increased thereafter. During a second hospitalisation, levels at 09.00 h were again higher than levels at 06.00 h after overnight recumbency. 6. Variability of levels obtained by repeated sampling was lower while sitting, during a normal upright day, than after 30 min recumbency. Upright legels may be a better index of cardiovascular sympathetic activity.


Blood pressure reduction by incremental infusion of labetalol in patients with severe hypertension. 1. Labetalol was given by incremental intravenous infusion to nineteen severely hypertensive patients, of whom nine were refractory to previous oral antihypertensive therapy. 2. Smooth reduction of arterial pressure was achieved in twelve subjects; one remained resistant to labetalol up to 160 mg/h; a sudden fall in pressure occurred in the remaining six. No serious complications were encountered. Blood pressure control was accompanied by slight byt significant reduction in heart rate and in plasma angiotensin II and aldosterone concentrations. 3. The administration of labetalol in this way appears to be a useful technique in patients requiring rapid reduction of arterial pressure, although close and continuous supervision is necessary.


A study of the disposition of alpha-methyldopa in newborn infants following its administration to the mother for the treatment of hypertension during pregnancy. 1 The nine infants participating in this study were born to mothers who received continuous therapy with alpha-methyldopa (0.75-2.0 g/day) for several weeks extending to the time of delivery. 2 The concentration of free and total (free plus conjugated) alpha-methyldopa was determined by gas chromatography-mass spectrometry in amniotic fluid, umbilical cord plasma and maternal plasma at delivery; also in urine collected over time intervals from neonates during the first days after birth. 3 The results indicate that alpha-methyldopa administered to the mother is present in the infant at birth at a level comparable to the maternal level and persists for some days. The ratio of conjugated to free drug increases with time after birth. 4 The excretion of free and conjugated alpha-methyldopa in the urine indicated that the drug is slowly eliminated in the neonate by excretion in the urine and apparently by metabolism, mainly to the sulphate conjugate. 5 The concentration of free and conjugated alpha-methyldopa in amniotic fluid tended to be higher than in umbilical cord plasma but lower than in neonatal urine, conjugated drug predominated.


The effect of intravenous disopyramide phosphate on recurrent paroxysmal tachycardias. 1 Reccurent paroxysmal atrial, atrioventricular and ventricular tachycardias in 50 patients without acute coronary insufficiency, heart failure or metabolic abnormlity were treated with disopyramide phosphate in a dose of 2 mg/kg body weight infused over 5 min. 2 Conversion to sinus rhythm within 10 min of the completed infusion occurred in 10 of 14 (71%) patients with paroxysmal 'lone' atrial fibrillation, 3 of 7 (43%) patients with paroxysmal atrial flutter, 6 of 9 (67%) patients with paroxysmal atrial tachycardia, 5 of 9 (56%) patients with paroxysmal atrioventricular tachycardia associated with the Wolff-Parkinson-White syndrome and 8 of 11 (73%) patients with paroxysmal ventricular tachycardia. 3 Side effects: significant systemic hypotension in 3, high grade AV block in 1, an increased ventricular response producing symptoms in 4, post conversion asystole in 1 land sinus bradycardia in 2. 4 The anti-arrhythmic effect and arrhythmogenic side effects may be related to both the direct membrane stabilizing effect and the anticholinergic effect of disopyramide.


Gentamicin pharmacokinetics in kwashiorkor. 1 Single dose intravenous gentamicin kinetics (2.4 mg/kg) were studied in six children with kwashiorkor. It was observed, that therapeutic drug concentrations were achieved which should be neither oto- nor nephrotoxic. 2 Due to the diminished glomerular filtration and renal plasma flow seen in the acute phase of kwashiorkor, gentamicin half-life was prolonged (229.0 +/- 94.8 min) at this time returning to normal (178.5 +/- 99.5 min) with nutritional rehabilitation.


The kinetics of salivary elimination of cyclophosphamide in man. 1 The concentrations of cyclophosphamide in plasma and saliva were determined in seven patients following administration of single doses of cyclophosphamide during chemotherapy for lymphoma. 2 The saliva/plasma ratio was 0.77 +/- 0.24 (s.d.) and showed no time-dependence being rapidly established following intravenous and oral administration. 3 The T 1/2 of cyclophosphamide (8.38 +/- 2.25 h) determined from salivary measurements was not significantly different from that in plasma (8.24 +/- 2.60 h). It  was not possible to estimate the apparent volume of distribution or total body clearance utilizing the salivary cyclophosphamide concentration without appropriate correction for the saliva/plasma concentration ratio. 4 The binding to the plasma protein of normal plasma of cyclophosphamide was 13.4 +/- 5.3%. The Scatchard plot for binding to bovine serum albumin indicates only weak binding to non-specific sites. 5 Salivary cyclophosphamide therefore indicates the concentration of the unbound fraction of plasma cyclophosphamide.


Pharmacokinetics of pemoline in plasma, saliva and urine following oral administration. 1 Pemoline concentrations were measured in plasma and saliva following a single oral dose (37.5 or 50.0 mg) to healthy volunteers. In addition urinary excretion rates and cumulative urinary excretion of the parent compound and its oxazolidinedione metabolite were determined. 2 The plasma curves exhibited a mean elimination half-live of 11.0 +/- 1.2 h (n=4). Peak levels were reached at 2.7 +/- 0.6 h (n=4). The saliva concentrations were about 50% lower than the corresponding plasma concentrations during the elimination phase. During the absorption phase irregularities in the saliva to plasma concentration ratios were observed. 3 In urine 47.0 +/- 8.4% of the dose (n=6) administered was excreted as unchanged drug and only 3.7 +/- 0.8% (n=3) as the oxazolidinedione metabolite. Urinary half-lives were slightly shorter than the corresponding plasma half-lives.


Kinetics of placentally transferred phenytoin and its p-hydroxylated metabolites in newborn infants. 1 The kinetics of phenytoin and its main metabolites, unconjugated and conjugated 4-hydroxy-phenytoin were studied in newborn infants of epileptic mothers that were treated with phenytoin during the pregnancy. 2 In two of the infants phenytoin was eliminated by an apparent zero-order process followed by an apparent first-order process. In the other two infants the mode of elimination could not be characterized. 3 The decline of plasma conjugated 4-hydroxy-phenytoin was parallel to that of phenytoin. In contrast, the plasma concentration of unconjugated 4-hydroxy-phenytoin remained grossly constant during the first 3 to 4 days.


Pharmacokinetics of metoclopramide intravenously and orally determined by liquid chromatography. 1 A rapid and sensitive method, based on liquid chromatography, has been developed for determination of metoclopramide concentrations in plasma and urine samples. Concentrations down to 15 nmol/1 (5 ng/ml) of plasma and 100 nmol/1 (30 ng/ml) of urine could be determined with a relative standard deviation of less than or equal to 10%. The method was used to study disposition of metoclopramide in healthy volunteers following single doses intravenously and orally as aqueous solution and a slow release tablet. 2 The initial distribution after intravenous administration was very rapid. The elimination half-life postdistribution was 4.9 h. The apparent volume of distribution, Vd, was 3.0 1/kg body weight. On average 19% was excreted unchanged after intravenous administration of 5 and 10 mg (15 and 30 mumol) of drug. The rate of absorption of metoclopramide was delayed after administration of a slow release tablet and the maximum plasma concentration was about 50% lower than after a solution. The extent of bioavailability was the same following the two different formulations suggesting a first-pass elimination of 25-40%.


Comparative effects of imipramine and dothiepin on salivary rate in normal volunteers. 1 Imipramine induced significant reduction in salivary rate compared to placebo in a cross-over, double-blind study of twelve normal volunteers. In contrast, there was no significant difference between the reduction in salivary rate induced by dothiepin and placebo. 2 Comparison of salivary rates showed no significant difference between the drugs in the initial and cross-over treatment periods. However, pooled observations from the initial and cross-over treatment periods indicated that imipramine produced a significantly greater reduction in salivary rate than dothiepin. 3 The results suggest that dothiepin would cause far less dryness of mouth compared to imipramine. This feature might ensure greater therapeutic compliance.


Fenamates may antagonize the actions of prostaglandin endoperoxides in human myometrium. 1 The prostaglandin endoperoxide analogue U-46619 potently contracted human isolated myometrium, suggesting that prostaglandin H2 (PGH2) may be a major stimulant of myometrial contractions. 2 Sodium mefenamate, flufenamate or meclofenamate 2 microgram/ml greatly reduced contractions of the myometrium induced by the PGH2 analogue. 3 Flufenamate, but not the other two drugs, also significantly inhibited contractions to acetylcholine. 4 Sodium meclofenamate 2 microgram/ml did not consistently antagonize contractions to PGF2alpha. 5 The relief of dysmenorrhoea by fenamates may be explained both by inhibition of PG synthesis, and by antagonism of contractions to PGH2 produced by incompletely blocked PG synthesis.


The interaction of varying doses of dipyridamole and acetyl salicylic acid on the inhibition of platelet functions and their effect on bleeding time. 1 In normal volunteers maximum reductions in platelet functions, collagen aggregation, adhesion and PF4 availability, were achieved using combined doses of 50 mg three times daily dipyridamole + 180 mg ASA or 75 mg three times daily dipyridamole + 120 mg ASA daily. 2 These doses did not prolong the bleeding time. 3 A synergistic effect has been demonstrated with 25 mg dipyridamole three times daily and 60 mg ASA. 4 At higher doses the effects on platelet functions were additive up to the maximal response. 5 The effect of low doses of ASA on platelet function was cumulative. 6 As lower doses of ASA in the combination studied inhibit platelet functions maximally without altering the bleeding time and probably without inhibiting prostacyclin, we suggest that these combinations of dipyridamole and ASA merit consideration in future clinical trials.


Probenecid: an unexplained effect on cephalosporin pharmacology. 1 The influence of probenecid on serum levels and urinary excretion of orally administered cephradine and cefaclor has been investigated. 2 Probenecid caused serum levels of both antibiotics to be increased and also prolonged. Urinary excretion of antibiotic activity was slightly but not significantly decreased by probenecid during the initial 6 h postdosing. It was significantly increased in 6-12 h urine, but only a small percentage of the doses were excreted during that period. 3 The increased serum levels of antibiotic were greater than could be accounted for by reduced elimination rate alone. Possible mechanisms to account for increased circulating levels of antibiotic in the presence of probenecid are discussed in the light of previous observations on probenecid induced changes in tissue distribution of beta-lactam antibiotics.


Response of the solid Guerin epitheliomas of rats to fractionated irradiation and a new 4-nitroimidazole. The transplantable Guerin epithelioma in Wistar rats was used to test the in vivo effectiveness of 1-(2-hydroxy-3-methoxypropyl)-2-methyl-4-nitroimidazole (P1) as a tumour-cell radiosensitizer after its oral administration at relatively low doses. The radiosensitizing ability of P1 was compared with that of metronidazole. The results indicate that P1 is less toxic than metronidazole, and greater concentrations of P1 in blood and tumour tissues are obtained for the same administered dose of the compounds. The radiosensitizing ability of P1, determined from tumour-regression rates and local-control percentage at 130 days, was higher than that of metronidazole.


Effects of pretreatment with phenobarbitone and phenytoin on the pharmacokinetics and toxicity of phenytoin on the pharmacokinetics and toxicity of misonidazole in mice. Concentrations of the hypoxic cell radiosensitizer misonidazole (MIS) and its O-demethylated metabolite Ro 05-9963 were determined in plasma (or blood), brain and tumour after injection of 1 g/kg MIS i.p. to control mice or mice pretreated with 4-6 daily injections of phenobarbitone or phenytoin. Analysis was by high-performance liquid chromatography (HPLC). Phenobarbitone and phenytoin did not alter the peak MIS concentration in plasma, brain or tumor. However, the apparent elimination half-life (t 1/2) for MIS was reduced by 20-67%, and the area under the curve (AUC) was decreased by 23-49% in plasma, brain and tumour. The decrease in MIS t 1/2 was associated with an initially increased Ro 05-9963 metabolite concentration. However, the AUC for total 2-nitromidazole (MIS + Ro 05-9963) in plasma, tumour and brain was reduced by 20-50%. Urinary excretion of MIS and its metabolites accounted for 15-42% of the injected dose, and was unaltered by pretreatment with phenobarbitone or phenytoin. Tumour/plasm and brain/plasma concentration ratios for MIS, and tumour/plasma ratios for Ro 05-9963 were very similar, but the brain/tumour ratios for Ro 05-9963 were considerably lower. Tissue/plasma ratios were unaltered by pretreatment with phenobarbitone or phenytoin. The acute LD50 for MIS was increased from 1.54 to 1.90 g/kg after phenobarbitone pretreatment and 1.78 g/kg after phenytoin pretreatment. In addition, pretreatment with either compound shortened the duration of the MIS-induced decrease in body temperature. These data suggest that pretreatment with microsomal-enzyme-inducing agents may reduce the toxicity of MIS without affecting the radiosensitization. The significance of these findings for the mechanism of MIS toxicity is also discussed.


Timing of indomethacin in the control of prostaglandins, osteoclasts and bone destruction produced by VX2 carcinoma in rabbits. Rabbits were injected with VX2 cancer cells into the left thigh or tibia, and given indomethacin 1-16 mg/kg daily starting on the day before tumour implantation or 7, 14 or 21 days after implantation. Indomethacin at 2 mg/kg and above from before tumour implantation reduced osteoclast proliferation and the amount of prostaglandin-like material extracted from homogenates of excised tumours, but the inhibition of bone destruction in vivo was significant only with indomethacin at 4 mg/kg and above. Indomethacin at 8 mg/kg reduced osteoclast proliferation and bone destruction, but the effect was statistically significant only when given within 7 days of inoculation with the tumour. The place of indomethacin and other inhibitors of prostaglandin synthesis has not yet been established in the management of patients with skeletal metastases. Drug administration might need to be started at the time of diagnosis and removal of the primary tumour, rather than when skeletal metastases are evident.


Erythropoiesis and iron metabolism in Hodgkin's disease. Recently developed techniques for the investigation of iron kinetics were used to study the disturbance of iron metabolism in 19 untreated patients with Hodgkin's diseases (HD). The erythroid abnormality in newly diagnosed HD appears to be confined to those patients with systemic symptoms of weight loss, night sweats and fever, and consists of depression of marrow erythroid activity. These patients had a significnatly lower haemoglobin and serum iron concentration and a higher serum ferritin concentration, both when compared to normal subjects and to those patients with HD who lacked systemic symptoms. Ineffective erythropoiesis and red-cell destruction were not significantly increased. The present findings, confirm that HD patients with systemic symptoms have a depression of erythropoiesis, and that in these patients the marrow fails to respond to the stimulus of mild anaemia.


Serum immunoglobulins G, A, M, D and E concentrations in lymphomas. Serum immunoglobulin levels were measured in 105 patients with untreated Hodgkin's disease (HD) and 80 with non-HD lymphomas. Significant increases in IgG and IgE occurred in the whole HD group. When compared with the histological types of HD, increases of IgG, IgA AND IgE were seen in nodular sclerosis and of IgE alone in mixed-cellularity and lymphocyte-predominant types. In relation to the stage of disease spread, increases of IgG, IgA AND IgE occurred in Stages II and III, while in Stage IV, although IgE was raised, IgM in males and IgD fell significantly. Paired serum samples taken 10-14 months apart showed falls of IgM and IgD after radiotherapy, and of all Ig classes except IgD after chemotherapy. Decreased levels of IgM in females, IgG and IgA were found in the non-HD lymphomas. When analysed in terms of lymphnode histology, decreased IgG, IgA, IgM and IgE occurred in well differentiated lymphocytic lymphomas, decreased IgA alone in poorly differentiated lymphocytic lymphomas and decreased IgD in nodular types of lymphoma.


Isoenzymes of hexokinase, 6-phosphogluconate dehydrogenase, phosphoglucomutase and lactate dehydrogenase in uterine cancer. Electrophoresis of cytosol prepared from normal and malignant tissue samples of uterine cervix and endometrium revealed interesting differences which may be relevant to the characteristic alterations in glucose metabolism associated with tumour development. Hexokinase II was detected in 30% of the cancer material from both sources, but in none of the samples of normal cervix. A duplet band of 6-phosphogluconate dehydrognease was seen in the majority of the cancer samples but in no sample of normal cervix; it appeared to be partly due to ageing of the sample, and is not phenotypically related to the malignant process. Analysis of genetic variance for phosphoglucomutase at the PGM1 locus revealed a highly significant excess of the PGM1-1 phenotype in patients with cancer of the endometrium, which may reflect susceptibility to endometrial cancer in patients with this phenotype. At the PGM2 locus, samples of malignant cervix were deficient in "Band f" compared with normal cervix samples, all of which showed this band. Conversely, gene products of the PGM3 locus were found in most samples of malignant cervix and a small minority of normal cervix samples. Compared with the isomorphic distribution of lactate dehydrogenase enzymes in normal uterine tissue, cancers showed a shift towards either a more anodal or a more cathodal pattern. The former may be associated with tumours enjoying a good oxygen supply, and the latter with tumours which, because of their depth or poor blood supply have to function under less aerobic conditions.


Competition between foetal tissue and macrophage-dependent natural tumour resistance. Prolonged interaction in vitro between C. parvum-induced adherent predominantly phagocytic rat peritoneal cells and syngeneic or xenogeneic tumour targets consistently produces marked cytotoxicity. In the presence of irradiated foetal liver cells, expression of cytotoxicity is blocked in a dose-dependent manner. The ability of liver cells to compete with tumour targets is rapidly lost after birth. Irradiated liver cells from adult donors showed no such competition with tumour cells. The in vivo growth in ascites form of rat fibrosarcoma cells of low immunogenicity is significantly enhanced by irradiated foetal liver cells administered locally shortly before or on the day of tumour-cell challenge. The findings may provide an indication as to the nature of the structures recognized as non-self by mononuclear phagocytes.


Lung cancer in Greater Bombay: correlations with religion and smoking habits. The resident population of Greater Bombay was analysed for the incidence of lung cancer and other variables of possible significance to lung cancer incidence. During a 10-year period from 1964-73, 2177 lung cancer cases (1861 males, 316 females) were registered, from a population pool consisting of 5.24 million persons (3.07 million males, 2.17 million females). The average annual incidence of lung cancer was 13.6 per 10(5) males but only 3.3 per 10(5) females, age-adjusted to the Standard World Population. The incidence in non-Parsi males (14.0) was almost double the figure in Parsi males (6.8). There was however no significant difference in incidence between non-Parsi (3.8) and Parsi females (3.3). Time-trend analyses did not reveal statistically significant differences in the incidence of lung cancer in any particular (male or female) age group. The data from death certificates for the same 10-year period 1964-73, showed that the age-adjusted rates (standardized to the world population) were 11.0 and 3.3 per 10(5), for males and females, in the total population. In a retrospective study, 792 males with lung cancer (42.6% of 1861 male cancer patients) for whom detailed smoking history is available, were matched for age and community with randomly selected controls, obtained from the voters list of the Greater Bombay Corporation, and significant statistical association was found between tobacco smoking and lung cancer. All smokers appear to be at high risk (16.8) compared with non-smokers. The relative risk in bidi smokers was however 19.3, even higher than in cigarette smokers (896). Hindu, Muslim and Christian smokers are apparently at identical risks. A dose-reponse relationship was found in bidi and cigarette smokers.


Correlation between cancer mortality and alcoholic beverage in Japan. Geographical correlations between standardized, mortality ratios (SMRs) of cancers and consumption of different types of alcoholic beverages (saké synthetic saké, shochu, beer, wine, and whisky), of cigarettes, and urbanization were examined for all 46 prefectures in Japan. Suggestive correlations were observed between cancer of the oesophagus in males and both shochu and whisky (r = 0.27 and 0.22 respectively), between cancer of the rectum in males and wine (r = 0.45), and between cancer of the prostate and shochu (r = 0.50). These correlations were also confirmed in the partial correlations between SMRs of cancers and consumption of alcoholic beverages, controlling for the two variables urbanization and consumption of cigarettes. Alhtough cancers of other sites were also correlated with certain types of alcoholic beverages, their associations seemed to be secondary to other factors. The validity of higher-order partial correlations and the problems of correlation study are also referred to.


Cancer mortality in 1970-1972 among Polish-born migrants to England and Wales. The 1970-72 cancer mortality of Polish migrants to England and Wales is compared with the cancer mortality prevailing in England and Wales and in Poland. Small numbers limit the analyses to the most frequent cancer sites only. The main findings are: (a) Compared with mortality rates in both their country of birth and of adoption, Polish migrants displayed intermediate values for cancers of the stomach, intestinal tract, and lung. For age-groups over 74 years, lung-cancer mortality among the migrants appears, however, to be higher than in both Poland and England and Wales. (b) A distinctly higher mortality among Polish migrants than either in Poland or England and Wales was apparent for lymphomas in both sexes, and for leukaemia and oesophageal cancer in males. (c) Female breast-cancer mortality among Polish migrants was much higher than in Poland, being close to the high mortality rates prevailing in England and Wales. The present findings are compared with the results of similar studies of Polish migrants to the United States and Australia and reasons for observed differences are advanced.


Tumorigenicity of the hypolipidaemic peroxisome proliferator ethyl-alpha-p-chlorophenoxyisobutyrate (clofibrate) in rats. Ethyl-alpha-p-chlorophenoxyisobutyrate), a hypolipidaemic drug which induces hepatomegaly and proliferation of peroxisomes in liver cells of rats and mice, was fed to 15 male F344 rats at a dietary concentration of 0.5% (v/w) for up to 28 months. Hepatocellular carcinomas developed in 10/11 (91%) rats killed between 24 and 28 months. Other tumours included carcinoma of the pancreas (2 rats), leiomyoma of the small intestine (1 rat) and a large dermatofibrosarcoma (1 rat). Clofibrate is the third hypolipidaemic peroxisome proliferator demonstrated to be hepatocarcinogenic in rats. These studies suggest that hypolipidaemic agents which are capable of producing a sustained hepatomegalic and peroxisome-proliferative effect also induce liver tumours.


Host treatments affecting artificial pulmonary metastases: interpretation of loss of radioactively labelled cells from lungs. The effect has been examined of various host treatments (C. parvum injection, immunization, thoracic irradiation, cyclophosphamide injection, and anticoagulation) on both lung colony formation and clearance of radioactive cells from the lungs after i.v. injection of tumour cells. Two tumour-host models have been used: the non-immunogenic KHT tumour in C3H/Km mice, and the immunogenic EMT6 tumour in BALB/c/Ka mice. Even for the at most weakly immunogenic KHT tumour, the number of artificial pulmonary metastases could be modified by a factor of up to 10(4) by different host treatments before i.v. inoculation of tumour cells. For all pretreatments except immunization, the shape of the curve of loss of radioactivity from the lungs vs time was biphasic, with an initial steep portion representing intravascular death of the tumor cells, followed 1--2 days after tumour-cell injection by a shallow exponential curve. It was concluded that the shallow slope represented spontaneous death of tumour cells in the perivascular tissues. Essentially all the injected tumour cells lodged initially in the lungs, and this was unaffected by the different host treatments. Furthermore, except for specific immunization, cell death in the perivascular tissues was also unaffected by host treatment. However, the survival of the tumour cells during the 24 h after injection (before they became extravascular) was extremely dependent on the particular host pretreatment. It would appear from these studies that host treatments such as C. parvum injection or anticoagulation can markedly affect the number of blood-borne pulmonary metastases, but they will only be effective if given before the tumor cells arrive in the lung vasculature.


Levels of adenosine deaminase in some experimental animal tumours and the possible therapeutic effect of the ADA inhibitor 2-deoxy-coformycin. The intracellular adenosine deaminase activities (ADA) in 12 different experimental animal tumours were measured. Unlike the leukaemic lymphoblasts of man, those of two spontaneous rat leukaemias did not have elevated levels of the enzyme. Very high levels were found in a rat plasma-cell tumour (IR 461) and an attempt was made to treat such tumours with the specific enzyme inhibitor, 2-deoxy-coformycin. The shortage of this drug prevented a systematic study, but a daily dose of 8 mg/kg had a significant inhibitory effect on the growth of tumours.


Cell-cycle inhibition by misonidazole of human cells cultivated in vitro under aerobic conditions. By means of flow cytometric recording of DNA histograms and counting of cells in synchronized populations, we have found that misonidazole (MIS) in clinically relevant concentrations induces cell-kinetic changes in human cells (NHIK 3025) cultivated in vitro under aerobic conditions. The effect seems to be a general lengthening of the cell cycle, affecting all phases. However, induction of this effect is phase-dependent, since only cells exposed to MIS during mitosis and/or early G1 will suffer significant cell-cycle prolongation. In exponentially growing populations this effect of MIS leads to a transient increase in the fraction of G1 cells and a corresponding decrease in the fraction of S cells. The possible significance of this effect for the clinical use of MIS is discussed.


Variation of melanoma incidence with latitude in North America and Europe. The relationship between melanoma incidence and latitude was investigated in North American and Europe, using the data collected by 43 population-based cancer registries. In North America melanoma incidence increased with decreasing latitude, supporting the role of UV light in the induction of melanoma. Within England the data from the National Cancer Registration scheme also showed that trend of decreased frequency of melanoma with decreasing latitude. In contrast, across Europe the trend was in the opposite direction, of increasing melanoma incidence with increasing latitude. It is suggested that across Europe there is a range of skin colour from dark in the south to light in the north, which gives rise to a range of susceptibility to the induction of melanoma by UV. The effect of this susceptibility must be large enough to overwhelm the opposing effect of decreased UV intensity at higher latitudes, and this emphasizes the dangers of excessive solar exposure to fair-skinned individuals. The populations of England may be a sufficiently random mix of skin colour, owing to repeated invasions, for the effect of UV intensity to be observed.


Synthesis and secretion of albumin in rats during treatment with a carcinogenic dose of N-2-acetylaminofluorene. The chronic administration of N-2-acetylaminofluorene (N-2-AAF) to rats causes a loss of hepatic cytoplasmic RNA, particularly from the endoplasmic-membrane fractions. At the end of the complete carcinogenic dose, the level of amino-acid incorporation into proalbumin is normal, despite the loss of 35% of membrane-bound RNA. The secretion of albumin, however, is inhibited. This inhibition of secretion is apparently the result of a change in membrane flow and differentiation; transfer of nascent protein from smooth-surfaced vesicles to the Golgi apparatus is blocked. The significance of these findings is discussed.


Mercuric chloride-induced renal tubular necrosis in the rat. A light microscopic study of the renal tubulonecrotic lesion in rats given a small dose of HgCl2 is described. The changes consist of a rapidly developing vacuolation of the cytoplasm with loss of basophilic staining within 4 h that leads to cell breakdown, fragmentation and dissolution by 48 h. Nuclear changes appear to set in later. Permanent patchy fibrotic lesions were found in the kidneys at 10 days. The animals pass a large amount of urine of low osmolarity, low Na+, K+ and Cl- for a period of 3 days accompanied by an increased water intake. Nevertheless there appeared to be no water or ionic imbalance between daily inputs and outputs. Blood urea levels were greatly increased for 3 days, but did not return to normal by the 10th day.


A histopathological study of the effects of intravenously administered lambda carrageenan in the mouse, with particular reference to the macrophage system. Intravenously administered lambda-carrageenan rapidly precipitates in the marginal zone of the spleen, the hepatic sinuses and the capillaries of the heart, lung, kidney and adrenal gland. Extensive coagulative necrosis of the liver and myocardium is seen at 24 h. Phagocytosis occurs at 3 days, and is associated with transformation of the lymphocytes of the splenic white pulp. Circulating carrageenan-containing macrophages adhere to vascular endothelium in the lung and at 6 days are situated beneath it. At 30 days carrageenan granulomas have formed in the spleen and liver, probably as a result of macrophage recirculation.


Myocardial infarction in spontaneously hypertensive rats with superimposed adrenal-regeneration hypertension. The elevated blood pressure of spontaneously hypertensive rats (SHR) was further exacerbated by subjecting these animals to surgically induced adrenal-regeneration hypertension (ARH). When chronic abnormally high blood pressure had been in effect for 12 weeks, the animals were subjected to an acute and massive myocardial infarction with isoprenaline. Hypertensive but intact SHR survived better than ARH-treated animals. Circulating enzyme (CPK, SGOT, SGPT and LDH), lipid and glucose levels and BUN manifested much greater excursions commensurate with more extensive myocardial infarction in ARH-treated than in intact SHR. ARH-treated SHR displayed a high incidence of atrial and ventricular thrombi associated with frequent left ventricular aneurysm formation. It is suggested that the more extensive myocardial connective tissue and ground-substance degeneration in ARH-treated SHR is due to the impoverished steroidogenic capacity of their regenerated adrenal glands.


Thrombosis induced in vivo in the femoral artery of rats. An electron microscopic study of myointimal growth. Minor injury and thrombosis, induced in a short arterial segment by the successive applications of a weak electric current and a dilute solution of ADP, is followed by rapid reconstitution of the endothelium and protracted growth of the medial smooth-muscle cells (SMC). Previous investigations of their early stages have shown that both processes are platelet-dependent. In the present investigation the arterial-wall reaction was followed up to the eighth day. By that time the growth of SMC had abated and the artery wall had regained a normal structure. Locally repeating the electric treatment consistently caused an infiltration of the inner media by blood elements, notably platelets. Rupture of the lamina elastica interna (LEI) was an additional feature in one out of 6 repeatedly treated arteries. Despite greater initial damage, repair of the artery wall proceeded normally in the majority of cases. In 2 out of 7 arteries, however, the SMC of the inner media exhibited cytologic evidence of still active stimulation and disordered growth on the eighth day. In one of the 2 arteries, the LEI had ruptured over wide areas where myointimal thickening was observed. Intimal denudation was brief in all cases so that the release of mitogenic factors by insudated platelets and the disruption of the LEI are more likely to have been the effective agents of myointimal growth.


The toxic effects of long-term, oral administration of L-tryptophan in rats with portacaval shunt. The oral, long-term administration of 200 mg/kg of L-tryptophan to rats previously submitted to a portacaval shunt causes significant loss of body weight, muscular hypertonicity and aggressivity, as well as marked alterations of the liver structure. Conversely, the same treatment is well tolerated by control animals. It is postulated that the derangement of tryptophan metabolism normally occurring in rats with portacaval shunt is by itself insufficient to induce behavioural changes and liver damage, which, on the contrary, develop when tryptophan metabolism is further altered by the administration of the amino acid to the animals for a long period of time.


The effect of Gaboon viper venom on iron exchange in the rat. Plasma iron turnover (PIT) has been measured by means of 59Fe in rats treated with the haemorrhagic venom of the Gaboon viper (Bitis gabonica). Venom was administered on 3 occasions over a period of 9 days and after this time PIT had fallen from 1045 micrograms/kg/day in normal animals to 449 micrograms/kg/day in envenomated animals. Plasma iron half-life was markedly increased from 64.8 min to 417.6 min and this change was associated with a reduced uptake of 59Fe by the liver. However, marrow and spleen uptake of 59Fe was normal, as were the red-cell indices, MCH, MCV and MCHC. There was a slight reduction in total red-cell numbers and haemoglobin concentration as a result of the mild internal haemorrhage induced by the venom. It is concluded that Gaboon viper venom produces a marked disturbance of iron handling by the liver without an associated change in erythropoiesis. The mild haemorrhage was insufficient to produce a microcytic hypochromic anaemia. The results of the study provide further confirmation of the belief that standard ferrokinetic measurements give only limited information on erythropoietic status.


Activated charcoal haemoperfusion via an extracorporeal circuit in the unrestrained and unanaesthetized rat. Repeated haemoperfusion over activated charcoal was performed in unanaesthetized and unrestrained rats, using a specially designed system. This allowed the effects of haemoperfusion on body weight, organ weight and various biochemical and haematological parameters to be studied, without the possible influence of repeated stress and exposure to anaesthetic agents. The procedure was well tolerated, even after 4 consecutive haemoperfusions. Changes in body weight occurred, but no significant difference was noticed between animals subjected to 4 consecutive haemoperfusions and those perfused through empty columns. Organ weight of liver and spleen were comparable to control values, but kidney weight increased after haemoperfusion over activated charcoal, but not in control animals. A progressive rise in leucocyte count was found after successive haemoperfusions, but levels returned to normal 21 days after their initial operative procedure. Platelet counts fell after charcoal haemoperfusion, but returned to within normal levels before the next perfusion.


Histological grading and sequential morphological changes during the production of acute duodenal ulcers. A method of grading histological changes in the duodenum and the sequential morphological appearances during the development of acute duodenal ulceration is described. After s.c. infusion of ulcerogenic doses of gastric secretagogues, rats were killed hourly and the duodenal lesions were graded from 1, which was the earliest change seen consisting of focal necrosis of the tips of villi to 6, which showed perforation of duodenal ulcer. For the first 4 h the duodenum was normal but after this there was progressive necrosis of the mucosa and submucosa, and inflammatory-cell infiltration. From 18 h rats were shown to have duodenal ulcers with or without perforation.


Pathogenicity of different strains of Rift Valley fever virus in Swiss albino mice. Laboratory mice were inoculated with 3 different strains of Rift Valley fever virus (RVFV): namely, the prototype, the Nigerian, and the Lunyo variant strains of RVFV. Animals were inoculated with either infective mouse brain or serum by the i.c. or i.p. route and organs of inoculated animals examined for virus content and histopathological changes. Animals inoculated with either the classical or the Nigerian encephalitis only, to a ditropism involving mild lesions in the brain and liver or the typically severe RVFV hepatitis. The type of lesion shown was dependent on the source of inoculum and the route of inoculation. On the other hand, animals inoculated by the i.c. route with the infective brain material of the Lunyo variant virus showed a mild encephalitis, while the use of the i.p. route or infective blood source of the Lunyo virus resulted in the development of typical RVFV hepatitis. Typical intranuclear eosinophilic inclusion bodies were found in both the brain and liver of animals inoculated with the Lunyo variant virus. These inclusion bodies were found only in the livers of mice inoculated with the infective blood material of either the prototype or the Nigerian strain. There was no correlation between the virus titres in the different organs and the severity of histopathological lesions.


The effects of steroids and glucagon on the morphological changes in the duct-ligated pancreas of the rat. Ligation of the rat pancreatic duct produced degeneration of the exocrine acinar tissue, inflammatory cell infiltration and fibrosis. The injection of methyl prednisolone for 5 days following duct ligation produced a marked reduction in the inflammatory-cell infiltrate whereas the administration of glucagon or a combination of glucagon and methyl prednisolone produced only a mild reduction in acinar degeneration. Administration of the drugs for 5 days after duct ligation and examination of the pancreas after 3 months showed no differences in the degree of cellular infiltration and acinar degeneration between controls and those that had received glucagon or glucagon and methyl prednisolone. However, those rats that had received only methyl prednisolone showed fibrosis, a minimal inflammatory-cell infiltrate and a considerable reduction in exocrine tissue. Mild degranulation of the islets of Langerhans was observed in those rats that received methyl prednisolone, alone or in combination with glucagon, and at 3 months the islets appeared normal. The implications for pancreatic transplantation are discussed.


8-MOP plasma levels in PUVA problem cases with psoriasis. 8-MOP plasma levels of psoriatic patients poorly responsive to PUVA treatment (PUVA problem cases) (N = 14) and of psoriatic patients with adequate response to photochemotherapy (N = 7) were measured for 8 h after oral ingestion of 0.6-0.8 mg/kg body weight, using a gas chromatographic method. We investigated whether there are any differences in the course of the plasma kinetics between the two groups. Problem patients showed significantly lower 8-MOP plasma levels than the control group. Furthermore, the 8-MOP plasma levels increased more rapidly in the control group than in these problem patients. Deviations in time of the maximum 8-MOP plasma levels from the expected 2 h peak could be observed in 50% of the problem cases compared to only 14% of the control patients. There is no correlation between the dose and the 8-MOP plasma level achieved in the two groups, i.e. higher doses do not result in high levels. In individual cases there is not always a correlation between the plasma maximum of 8-MOP at the time of UV-A irradiation and the response to treatment. Adjustment of the UV-A irradiation to coincide with the maximum plasma levels led to an improvement in therapeutic results for three problem patients.


Psoralen photochemotherapy of psoriasis. The value of PUVA therapy in selected patients with severe psoriasis has been confirmed. Suppression of the disease was incomplete in those patients whose disease was unstable, with associated seborrhoeic dermatitic features. No consistent change in the proportion of epidermal cells in DNA synthesis could  be demonstrated during regression of the psoriasis as a result of PUVA therapy.


Histological changes produced in skin by equally erythemogenic doses of UV-A, UV-B, UV-C and UV-A with psoralens. The sequential light microscopic histological changes produced in human skin by a single exposure of UV-A, UV-B, UV-C and oral 8-methoxypsoralen plus UV-A (PUVA) causing approximately equal degress of delayed erythema response, have been evaluated. UV-C and UV-B affect the epidermis to a greater degree than UV-A, while UV-A affects the dermis to a greater degree than UV-B and UV-C. PUVA has prominent effects on both epidermis and dermis, differing in degree from those changes induced by UV-A, UV-B, and UV-C and are longer lasting. The sequence of histological changes following UV exposure is completed more rapidly after exposure to shorter UV wavelengths.


Levamisole therapy for multiple warts.

Levamisole therapy for multiple warts. Levamisole, a wide-spectrum antiparasitic drug, increases cellular immunity in vivo and in vitro. Patients with verruca vulgaris may have defective cell mediated immune mechanisms. Levamisole was given to twenty-two patients with multiple warts, 5 mg/kg body weight on 3 consecutive days every fortnight. Patients' lymphocytes were studied for E-rosette formation before therapy. E-rosette counts were lower in patients compared with controls and a significant increase was obtained after in vitro incubation with levamisole. Seventeen patients were cured in 1-4 months, there were four failures and one patient showed marked improvement. It is concluded that patients with multiple warts have defective cell-mediated mechanisms as far as the E-rosette count is concerned and that levamisole increases in vitro E-rosette formation and is useful in the treatment of these patients.


Hereditary hypotrichosis. A previously undescribed syndrome. A syndrome of hereditary hypotrichosis with an unusual natural history and clinical features was encountered in a Caucasian family of four generations with a total of twenty-four members of whom eleven were affected. The mode of inheritance was autosomal dominant with variable penetrance. The loss of hair involved the scalp, eyebrows, eyelashes and body hair, manifesting itself in the school years and progressing to almost complete baldness. There were no associated abnormalities and no sex limitation. Clinical, genetic, biochemical, mechanical, histological and immunological aspects were studied. Essential differences between this type of hereditary hypotrichosis and others previously recorded are stressed.


Cutis mamorata telangiectatica congenita in two sisters. Cutis marmorata telangiectatica congenita was observed in two adult sisters. The condition appeared at birth and did not change much with age. In one sister the condition was accompanied by hypertension, acrocyanosis and ulceration of the big toe. On the basis of a comparison of the symptoms in patients and their relatives, the authors assume that Van Lohuizen syndrome is a dominantly inherited genetic disorder with low penetrance and great intrafamilial variability.


5-Methoxypsoralen (Bergapten) in photochemotherapy of psoriasis. 5-Methoxypsoralen (5-MOP, Bergapten) was evaluated as a potential photosensitizing drug in oral photochemotherapy of psoriasis. Treatment results indicate that (1) 5-MOP is as effective as, and in high doses more effective than, 8-methoxypsoralen in clearing psoriatic lesions; (2) therapeutic doses of 5-MOP do not lead to erythema; the acute side-effects of 8-MOP PUVA therapy--erythema, blistering, pruritus--are thus avoided; (3) even high doses of 5-MOP are not followed by nausea. 5-MOP PUVA therapy thus represents a real alternative to 8-MOP PUVA, its advantages over 8-MOP PUVA being greater safety and patient acceptance.