Methadone maintenance: plasma levels and therapeutic outcome. Twenty-one opiate-dependent subjects were inducted into methadone maintenance treatment (MMT) in a closed metabolic ward. A daily dose of 30 mg of d, 1-methadone was given for 10 to 24 days followed by 60 mg/day for another 10 to 24 days. Analysis of plasma levels at 4-day intervals showed accumulation to a peak followed by a decrease to a lower level, indicative development of dispositional tolerance. The outcome of treatment was assessed after 21 to 43 mo (median, 33 mo). The best record of rehabilitation was obtained in subjects discharged with steady-state plasma concentrations above 200 ng/ml. Lower levels of plasma methadone were associated with higher frequency of urines containing illicit drugs and poorer psychosocial rehabilitation. This study indicates that a pharmacokinetically optimized dosage regimen would be useful in increasing the therapeutic effectiveness of MMT.


Kinetics of chlormethiazole in patients with alcohol withdrawal manifestations. Chlormethiazole administered orally to patients in mild degrees of alcohol withdrawal was generally rapidly absorbed, showed a rapid distributive phase, and had an elimination phase 1 1/2 of 2.6 to 4.7 hr. The plasma concentrations of drug attained following higher oral doses were greater than is usually the case with augmentation of dose. Intravenously infused chlormethiazole in similar patients produced relatively high plasma concentrations of the drug, with distributive and eliminative 1 1/2 similar to those of oral doses. These pharmacokinetic patterns in alcoholic patients more closely resemble those previously reported for normal young subjects than they do for normal aged subjects.


Pharmacokinetics of fentanyl as determined by radioimmunoassay. The pharmacokinetics of fentanyl were determined in human surgical patients using radioimmunoassay. Fentanyl was measured in the serum, cerebrospinal fluid (CSF), and urine of patients receiving 0.1, 0.5, or 1.0 mg/m2 of fentanyl intravenously. The kinetics of the disappearance of fentanyl from the serum were very similar at the three administered doses. At all doses, levels fell rapidly in the first five minutes to approximately 20% of the peak value. Thereafter, serum levels fell more slowly with an observed half-life (t 1/2) of approximately 10 to 20 min. depending on dose. By 2 hr serum levels had stabilized at low values (1, 5, and 8 ng/ml) and continued to decrease very slowly thereafter, with an observed t 1/2 of 1 to 2 hr at the low dose (0.1 mg/m2) and greater than 4 hr at 0.5 and 1.0 mg/m2. The serum elimination curves were dissected and described mathematically in terms of a three-compartment model. Urinary excretion of fentanyl accounted for 15% to 20% of the administered dose. Urinary excretion was very low during the first 2 hr, suggesting that this route of elimination is not important in terminating the actions of fentanyl in man. Fentanyl levels in the CSF of patients given terminating the actions of fentanyl in man. Fentanyl levels in the CSF of patients given the high dose (1 mg/m2) were low, and never exceeded 4 ng/ml. Peak levels of fentanyl in the CSF were not seen until at least 15 min after administration.


Cyproheptadine in levodopa-induced dyskinesia in parkinsonism. The neuroendocrine properties and the beneficial effects of cyproheptadine in tardive dyskinesia led to the testing of this drug in levodopa-induced dyskinesia. Cyproheptadine administered to 6 parkinsonian  patients in doses of up to 42 mg/day was of no significant benefit in either dyskinesia or symptom control. Improvement in appetite was reported by 3 patients. These observations suggested that different mechanisms may be responsible in the pathogenesis of phenothiazine and amine-induced dyskinesia. The failure to control levodopa-induced dyskinesia selectively with serotonin agonists and antagonists and the accentuation of the dyskinesia in the presence of anticholinergic agents further suggest that substances that increase directly central cholinergic activity may be effective in the control of levodopa-induced dyskinesia.


No circadian effect on nortriptyline kinetics in man. Kinetics of a single 100-mg dose of nortriptyline were studied in 10 normal men who took this dose at 9 A.M. in the morning and on another occasion at 9 P.M. Only minimal differences in kinetic parameters were observed, none enough to be of any clinical consequence. A rather high first-pass metabolism of the drug was evident by high plasma concentrations of 10-hydroxynortriptyline. It is thus unlikely that the recent custom of giving single daily doses of tricyclic antidepressants in the evening excludes regimens with more favorable drug kinetics.


Dose-dependent changes in sulfamethazine kinetics in rapid and slow isoniazid acetylators. The pharmacokinetics of sulfamethazine (SMZ) was studied in 44 healthy volunteers. After an oral dose of 10 mg/kg we found the usual distribution of rapid and slow acetylators. The differences in the t1/2s between the phenotypes were not due to variations in renal clearance. Repeat studies at this dose showed very little intraindividual variation in t1/2s. After a 40 mg/kg dose there was an increase in the t1/2 of SMZ in every subject. The implications of these results on methods of phenotyping are discussed.


Pharmacokinetics of warfarin enantiomers: a search for intrasubject correlations. The total body clearance of single doses of R(+)-, S(-)-, and racemic warfarin and the plasma concentration-anticoagulant effect curves for these drugs were determined in 10 healthy men, 21 to 51 yr old. This information was used to calculate the steady-state dose required to decrease prothrombin complex activity to about 30% of normal. This dose (mean +/- SD in mg/70 kg/day) is 17.8 +/- 9.3 for R(+)-warfarin, 6.63 +/- 2.19 for S(-)-warfarin, and 9.4 +/- 1.7 for racemic warfarin. There is a correlation between the maintenance doses of racemic and S(-)-warfarin (r = 0.89, p less than 0.01) but not between those of racemic and R(+)-warfarin (r = 0.30, NS). According to these calculations, the maintenance dose of racemic warfarin required by an individual patient may be a useful predictor of maintenance dose of S(-)-warfarin which will produce a comparable degree of anticoagulation. No such predictability is evident with respect to R(+)-warfarin. The slopes of the log plasma concentration-anticoagulant effect curves for R(+)-and S(-)-warfarin differ significantly. Therefore, the potency ratio of these enantiomers is dose-and concentration-dependent.


Optimal phenytoin therapy: a new technique for individualizing dosage. A simple, new technique (the direct linear plot) for predicting steady-state serum phenytoin concentrations is described. Although no calculations are required, reliable estimates (comparable with those derived by computer) of the Michaelis-Menten parameters can be readily determined and used graphically to predict the individualized dose required to achieve a desired serum concentration.


Kinetics of polythiazide.

Kinetics of polythiazide. An assay for polythiazide, sufficiently sensitive to measure plasma concentrations of this high-potency diuretic agent, has been developed. The assay is based on acid hydrolysis to trifluoroethylthioacetaldehyde and electron-capture gas chromatography. Sensitivity down to 0.2 ng/ml was achieved. In a study in normal human subjects receiving single 1-mg oral doses of polythiazide, the mean plasma half-lives for absorption and elimination were 1.2 and 25.7 hr, respectively. The latter is consistent with the extended duration of action of polythiazide. Approximately 25% of the drug was excreted unchanged in the urine.


The metabolic response to galactose as a measure of hepatic glucose release in man. 1. Galactose utilization after intravenous injection was measured in fed and fasted man together with changes in blood glucose, lactate and insulin. 2. Feeding did not alter blood galactose half-life. 3. The mean increases in blood glucose and lactate were greater in the fasted subjects but their concentrations reached similar values in both fed and fasted states. 4. Plasma insulin increased after galactose in the fasted state, but there was no change in the fed state, indicating that galactose is not insulinogenic. 5. After an intravenous galactose load in the fed state insulin appears to inhibit hepatic glucose release. 6. An intravenous galactose test might be a useful measure of hepatic glucose release under different physiological and pathological conditions.


Bone blood flow and age in the rat.

Bone blood flow and age in the rat. 1. The proportion of the cardiac output delivered to the skeleton and individual bones has been determined in rats of differing ages and weights with radioactive microspheres. 2. There was a decrease in the blood flow to the tibia--fibula, jaw, femur, pelvis, humerus, radius and ulna, and scapula with increase in age and weight of rats, but no change was seen in blood flow to the ribs, spine, skull or whole skeleton. 3. The proportion of the cardiac output delivered to the whole skeleton was approximately 3%. 4. The derived values for skeletal blood flow agree well with estimates by other authors using the technique of bone uptake and blood clearance of 45Ca.


Bartter's syndrome: contrasting patterns of prostaglandin excretion in children and adults. 1. The daily urine excretion has been studied of prostaglandins (PG) E2 and F2alpha, as measured by radioimmunoassay, in eight children and seven adults with Bartter's syndrome. 2. Excretion of both PGE2 and PGF2alpha was significantly higher in the patients with Bartter's syndrome than in 17 normal children. 3. Twelve normal adults excreted significantly more PGE2 and PGF2alpha than did the normal children. In contrast, adults with Bartter's syndrome did not show an increase in prostaglandin excretion.


Motion of the rib cage and the abdomen in tetraplegic patients. 1. We have studied the motion of the abdomen and the rib cage in patients with a transection of the lower cervical spinal cord during normal breathing both in the supine and sitting posture, and compared it with that of normal subjects. 2. In the supine posture the rib cage of a patient moves paradoxically inward, therefore his chest wall is deformed, which explains the high work of breathing. 3. During expiration, beside the recoil of the respiratory system, there is also the recoil of the deformed chest wall, toward its passive configuration, with an expansion of the rib cage above its resting position during the first part of expiration and an alteration of the expiratory flow profile. 4. In a sitting 'relaxed' posture the paradoxical inward motion disappears in the lower rib cage, and it is reduced but still present in the higher rib cage. 5. We conclude that contraction of the diaphragm constricts the 'passive rib cage', either directly through its insertions or indirectly through the reduction of intrathoracic pressure. In seated subjects the diaphragm causes some expansion of the rib cage at its lower level. Therefore the motion of the rib cage is not only related to the balance between the forces developed by the diaphragm and the intercostal muscles, but also to the diaphragm dome configuration, the geometry of the rib cage and the lung volume.


Effect of isometric hand-grip exercise on the carotid sinus baroreceptor reflex in man. 1. The changes in R--R heart interval that result from step-increase and step-decrease in carotid sinus transmural pressure induced by a variable pressure neck chamber were measured in seven normal men. Observations were made at rest, and during isometric hand-grip exercise at 24%, 44% and 64% of maximal voluntary contraction. 2. The response of heart interval to increase in carotid sinus transmural pressure was progressively and markedly diminished according to the strength of hand-grip. This effect was fully developed from the moment of onset of the exertion. 3. The response of heart interval to decrease in carotid sinus transmural pressure was much less consistently affected by hand-grip exercise.


The relationship of urinary kallikrein activity to renal salt and water excretion. 1. We measured urinary kallikrein (kininogenin) excretion in black and white normotensive subjects during a variety of manipulations of salt and water balance. 2. A large intravenous saline load administered while the subjects were on an unrestricted sodium diet did not significantly change urinary kallikrein activity in either racial group. 3. After several days of dietary sodium restriction both racial groups increased their urinary kallikrein activity. An intravenous water load given then further increased urinary kallikrein activity. White subjects were studied for an additional 24 h period, and urinary kallikrein activity returned to pre-water load values, indicating that the excretion of a water load in sodium-depleted subjects is associated with an increase in kallikrein excretion. 4. Black subjects excreted less kallikrein in the urine than white subjects during the initial 24 h periods of unrestricted dietary sodium intake, but there were no other significant racial differences during the other experimental conditions.


Intracellular free amino acids in muscle tissue of patients with chronic uraemia: effect of peritoneal dialysis and infusion of essential amino acids. 1. Free amino acids were determined in the plasma and in the muscle tissue of 14 patients with chronic uraemia; eight were not on dialysis and six were having regular peritoneal dialysis. The concentration of each amino acid in muscle water was calculated with the chloride method. 2. In both groups of patients there were low intracellular concentrations of threonine, valine, tyrosine and carnosine, and high glycine/valine and phenylalanine/tyrosine ratios. Both groups of patients had increased amounts of 1- and 3-methyl-histidine in plasma and in muscle water. 3. The non-dialysed patients had low intracellular concentrations of lysine, and the dialysed patients had high intracellular concentrations of lysine, isoleucine, leucine and of some of the non-essential amino acids. 4. After peritoneal dialysis for 22 h, the plasma concentration of several amino acids decreased but the intracellular concentrations of most amino acids did not change significantly. 5. Intravenous administration of essential amino acids and histidine during the last 4 h of dialysis increased in muscle the total free amino acids, the ratio of essential to non-essential amino acids and the valine and phenylalanine concentrations. 6. The results demonstrated that the plasma and muscle concentrations of several amino acids are grossly abnormal in chronic uraemia. Non-dialysed and dialysed patients exhibit important differences, especially in the intracellular amino acid patterns. Infusion of essential amino acids may result in enhancement of protein synthesis.


Elimination of porcine secretin in pigs. 1. The elimination of immunoreactive secretin was studied in anaesthetized pigs by using constant infusions of pure natural porcine secretin. 2. The mean metabolic clearance rate was 15.4 ml min-1 kg-1, and was independent of the level at which it was determined. The mean distribution space was 64.4 ml/kg. The half-life of secretin after termination of the infusion averaged 2.6 min. 3. During intravenous infusion of secretin in a dose of 27.8 pmol h-1 kg-1 the renal extraction was 52%. Exclusion of the kidneys increased plasma secretin concentration from 26.5 pmol/l to 47.3 pmol/l and increased the half-life to 4.4 min. 4. Exclusion of the liver during infusion of secretin in a dose of 27.8 pmol h-1 kg-1 resulted in an increment in plasma secretin concentration of  7.8 pmol/l and an increase of the half-life to 3.6 min. 5. A gradient of endogenous secretin across the liver was present but no arteriovenous difference was found across the foreleg. 6. Incubation of secretin with whole blood or serum for 20 min at 37 degrees C did not result in any degradation of secretin.


Skeletal blood flow in Paget's disease of bone and its response to calcitonin therapy. 1. Blood flow to the skeleton was measured by the 18F clearance method of Wooton, Reeve & Veall (1976) in 24 patients with untreated Paget's disease. In every patient but one, resting skeletal blood flow was increased. There was a significant positive correlation between skeletal blood flow and serum alkaline phosphatase and between skeletal blood flow and urinary total hydroxyproline excretion. 2. Fourteen patients were re-studied after they had received short-term (7 days or less) or long-term (7 weeks or more) calcitonin. Skeletal blood flow, alkaline phosphatase and urinary hydroxy-proline excretion fell towards normal in every case. There was some evidence from the short-term studies that calcitonin produced a more rapid fall in skeletal blood flow than in alkaline phosphatase. 3. Glomerular filtration rate appeared to increase transiently in response to calcitonin.


Angiotensin II blockade before and after marked sodium depletion in patients with hypertension. 1. Angiotensin II blockade before and after marked sodium depletion in patients with hypertension [unilateral renovascular (eight), bilateral renovascular (four) and essential (four)] was performed by intravenous administration of the angiotensin II antagonist Sar1-Ala8-angiotensin II (saralasin). 2. On normal sodium intake, saralasin decreased mean blood pressure by 8 mmHg in the unilateral renovascular group, by 6 mmHg in the bilateral renovascular group and increased it by 3 mmHg in the essential hypertensive group. After sodium depletion saralasin decreased mean blood pressure by 33 mmHg, 35 mmHg and 18 mmHg respectively. The saralasin-induced decrease in blood pressure significantly correlated with the log of the initial plasma renin activity. 3. Saralasin infusion decreased effective renal plasma flow (ERPF) in all three hypertension subgroups, both on normal sodium intake and after sodium depletion. Glomerular filtration rate decreased in direct relation to the hypotensive effect of saralasin but ERPF showed this relationship only after sodium depletion. On normal sodium intake saralasin increased filtration fraction by 17%, but decreased it by 7% after sodium depletion. 4. It is concluded that the hypotensive action of saralasin closely correlates with the value of circulating plasma renin activity, apparently independent of the aetiology of the hypertension. The decrease in ERPF during saralasin infusion in the patients on normal sodium intake seems mainly related to the agonistic activity of saralasin, but that after sodium depletion to the hypotensive effect of saralasin.


Oxygen transport in children on maintenance haemodialysis. 1. Adaptive mechanisms of oxygen transport by blood have been studied in severely anaemic young patients on maintenance haemodialysis, in conditions of hyperphosphataemia (Pi greater than or equal to 2.2 mmol/l) or normophosphataemia. 2. In hyperphosphataemia whole-blood affinity for oxygen was slightly decreased, as measured by an increase in P50 (the partial pressure of oxygen necessary to half saturate haemoglobin). 2,3-Diphosphoglycerate was increased by 10% (P less than 0.10) whereas Pi, total erythrocyte phosphate and ATP were increased by 100%, 47% and 36% respectively, compared with control values. 3. After correction of hyperphosphataemia a small but significant decrease in P50 and 2,3-diphosphoglycerate, to normal values, was observed whereas the other variables, although significantly lowered, remained above control values. 4. In these severely anaemic and hyperphosphataemic patients P50 and 2,3-diphosphoglycerate are only slightly increased. ATP synthesis appears to be favoured over that of 2,3-diphosphoglycerate. This is possibly due to alterations in the erythrocyte membrane elicited by bi-weekly extracorporeal circulation. Adequate oxygen transport can be achieved only through a drastic increase in blood flow. Correction of hyperphosphataemia adds further to the abnormality. It is concluded that this condition could induce a long-term myocardial fatigue, which might be prevented with occasional small blood transfusions.


Ventilatory responses to exercise and to carbon dioxide in mitral stenosis before and after valvulotomy: causes of tachypnoea. 1. The ventilation and cardiac frequency during progressive exercise and the respiratory responses to breathing carbon dioxide have been measured in 33 female patients with mitral stenosis and in 31 control subjects. Compared with the control subjects, the patients' exercise ventilation and cardiac frequency were increased; the exercise tidal volume at standard minute volume, the vital capacity and the ventilatory response to carbon dioxide were reduced. The extent to which the standardized tidal volume was lower during exercise than during breathing carbon dioxide was correlated with the severity of the stenosis, as gauged by the increase in exercise cardiac frequency above the level predicted from anthropometric measurements. 2. Twenty patients were studied postoperatively. In the 12 who showed clinical improvement the exercise ventilation and cardiac frequency were reduced and the exercise tidal volume at a given minute ventilation was increased. The latter change occurred despite a reduction in vital capacity, which was probably a residual effect of thoractomy. There was no significant change in the response to breathing carbon dioxide. No material change in function was observed in the patients whose condition was not improved by the operation. 3. It is suggested that in mitral stenosis the tachypnoea which occurs during exercise, whilst mainly a mechanical consequence of the reduced vital capacity, is also partly due to pulmonary congestion stimulating intrapulmonary receptors.


The measurement of calcium absorption and absorption rate with an external arm radioactivity counter. 1. A large-volume scintillation counter was used to measure calcium absorption from the ratio of forearm uptake of 47Ca after oral 47CaCl2 (administered with milk) to forearm uptake after intravenously administered 47CaCl2. 2. In some subjects serial measurements of both forearm uptake of 47Ca and blood 47Ca radioactivity were also recorded, and by using deconvolution both total calcium absorption and calcium absorption rate were determined. 3. The forearm ratio determination of 47Ca absorption correlated well with that obtained by deconvolution of either serial blood 47Ca or forearm 47Ca measurements provided that the forearm radioactivity measurements were made at least 8 h after the administration of 47CaCL2. 4. Although the two deconvolution techniques gave similar estimates of total calcium absorption there were discrepancies between their measurements of calcium absorption rate. These discrepancies were reduced but not eliminated by the use of additional lead shielding around the Armac counter.


Intensive iron-chelation therapy with desferrioxamine in iron-loading anaemias. 1. Urinary iron excretion after desferrioxamine has been examined in nine patinets with different iron-loading anaemias. Particular attention has been paid to individual variation in response and the kinetics of iron removal in order to determine the most efficient and convenient method of administration. 2. Twelve-hour subcutaneous infusions of desferrioxamine were comparable with intravenous infusions and gave a mean value of 62% more iron excretion than similar intramuscular bolus doses (range 20--125%). 3. Increasing doses as 12 h subcutaneous infusions produced a linear increase in iron excretion, which was followed by a tendency to reach a plateau. Iron excretion varied greatly between patients, was not related solely to age or estimated iron load, and in most cases was increased by ascorbic acid saturation. 4. Maximum iron-excretion rates were achieved after 3--6 and then maintained throughout an infusion. With bolus injections excretion rates declined rapidly after the first 6 h, during which approximately 60% of the total iron excretion occurred. 5. The dose and method of administration should be 'tailor-made' for each patient. Overnight 12 h subcutaneous infusions can be both as effective as similar doses given over 24 h and a practical way of achieving substantial negative iron balance. 6. Since children receiving regular blood transfusions for congenital anaemias such as thalassaemia usually die at the end of the second decade, this approach to iron chelation offers the possibility of alleviating what have hitherto been fatal-iron loading states.


The relation between plasma androstenedione, plasma oestrone and androstenedione to oestrone conversion rates in post-menopausal women with and without fractures. 1. Plasma androstenedione, plasma oestrone and the conversion of plasma androstenedione into oestrone were measured in 19 post-menopausal women without fractures (six of them oophorectomized) and 18 with vertebral or femoral neck fractures (four of them oophorectomized). 2. In the series as a whole, the main determinant of the plasma oestrone level was the plasma androstenedione concentration. Only in the small oophorectomized group did the variation in conversion rate make a significant contribution to the variation in plasma oestrone. 3. The conversion rates were not different as between non-fracture and fracture cases but the mean plasma androstenedione and oestrone concentrations were lower (though not significantly) in the latter.


Hepatic metabolism of aminopyrine in patients with chronic renal failure. 1. To evaluate potential alterations in hepatic metabolism of drugs occurring in patients with renal insufficiency the fate of aminopyrine was studied in 17 patients with chronic renal failure and in 27 normal subjects. 2. Although patients with chronic renal failure exhibited large variations, their aminopyrine plasma disappearance times (mean 0.62 +/- SD 0.24 h-1) were significantly higher than those found in normal subjects (0.30 +/- 0.07 h-1, P less than 0.002). 3. 14CO2 derived from [dimethylamine-14C]aminopyrine disappeared from breath more rapidly in patients with chronic renal failure and a history of analgesic abuse (0.40 +/- 0.04 h-1) than in control subjects (0.22 +/- 0.03 h-1, P less than 0.01) and in other patients with chronic renal failure (0.24 +/- 0.04 h-1). 4. Dialysis treatment and serum creatinine concentrations were not correlated with the rates of aminopyrine metabolism. Two additional patients, however, with combined renal and hepatic disease, exhibited markedly slowed rates of aminopyrine demethylation. 5. Although chronic renal failure by itself might not alter microsomal drug metabolism it is concluded that, in patients with a history of abuse of phenacetin-containing analgesics, marked acceleration in aminopyrine N-demethylation may be observed.


Characterization of immunoreactive angiotensin in canine cerebrospinal fluid as Des-Asp1-angiotensin II. 1. Immunoreactive angiotensin II was measured in cerebrospinal fluid of four normal dogs. 2. The migration of this immunoreactive angiotensin II on polyacrylamide-slab gel electrophoresis was identical with the migration of the heptapeptide, Des-Asp1-angiotensin II, in each case. 3. The biological activity of the material from canine cerebrospinal fluid in a pressor bioassay was similar to that of Des-Asp1-angiotensin II. 4. The pressor activity of the canine material was abolished by treating the pressor bioassay rat with a competitive antagonistic analogue, Sar1-Ala8-angiotensin II. 5. The results suggest that the biologically active immunoreactive angiotension II present in normal canine cerebrospinal fluid is composed mainly of the heptapeptide fragment of angiotensin II, Des-Asp1-angiotensin II.


Metabolism in vitro of 25-hydroxycholecalciferol in chicks fed on phosphorus-deficient diets. 1. Three groups of 10-days-old chicks were fed on one of three diets having phosphorus contents of 0.08 mol/kg, 0.14 mol/kg or 0.21 mol/kg. Ten days later duodenal calcium absorption by the ligated loop technique in vivo, and plasma calcium and phosphorus concentrations, were measured. In addition the metabolism in vitro of 25-hydroxycholecalciferol [25-(OH)D3] by kidney homogenates was studied. 2. In the low phosphorus group (0.08 mol/kg) calcium absorption and the activity of 25-(OH)D3-1-hydroxylase were significantly higher than those of the high phosphorus group (0.21 mol/kg). However, in the medium phosphorus group (0.14 mol/kg), calcium absorption was significantly higher although the activity of 25-(OH)D3-1-hydroxylase was not significantly higher when compared with the high phosphorus group (0.21 mol/kg). 3. It is concluded that in phosphorus deprivation, unlike in calcium deprivation, a diet very low in phosphorus is required to stimulate the renal 25-(OH)D3-1-hydroxylase activity.


Lipolytic activities in post-heparin plasma in man measured with different substrate emulsions. 1. Post-heparin lipolytic activity in man has been studied by using a triglyceride substrate emulsion containing different emulsifiers. 2. The lipolytic activity measured was profoundly influenced by the type of emulsifier used in the substrate. Substrate stabilized by synthetic emulsifiers give higher lipolytic activity than Intralipid, which contains egg phospholipids as emulsifiers. This difference was solely explained by higher salt-resistant lipase activities found with emulsions containing synthetic emulsifiers. The salt-inhibited lipase activity, which has properties as a lipoprotein lipase, was not influenced by the type of emulsifier. 3. When used under specified conditions Intralipid seems to be virtually specific for extrahepatic post-heparin lipolytic activity.


Subcellular distribution of hydrolase activities for glycine and leucine homopeptides in human jejunum. 1. The subcellular distribution of peptidase activities in the normal human jejunum against glycine and leucine homopeptides has been investigated with an analytical fractionation technique. 2. An 8000 g-min supernatant was prepared from homogenates of Crosby capsule biopsy specimens and subjected to isopycnic centrifugation in a Beaufay automatic zonal rotor. 3. The distribution of subcellular organelles in the gradient was established by measurement of organelle-specific marker enzymes. 4. A sensitive fluorimetric assay for glycine peptidase was developed and used for the localization of peptidase activity with peptides composed of from two to five glycine residues as substrates. 5. Glycine peptidase activity was located in the cytosol and in the brush-border membrane but the distribution of activity varied markedly with the chain-length of substrate; the longer the peptide the greater the proportion of activity associated with the brush border. Leucine peptidase showed a similar variation in cytosol--brush border distributions. 6. The results are consistent with concepts that suggest absorption and intracellular hydrolysis of small peptides and brush-border digestion of larger peptides.


Prosthetic valve endocarditis.

Prosthetic valve endocarditis. PVE is increasingly frequent and often lethal. The classic features of infective endocarditis may be absent early in the course of the illess. Therefore, patients with prosthetic heart valves and fever must be considered candidates for this infection until another cause for the fever can be established. Five to six blood cultures will document the persistent bacteremia of PVE in most cases. Treatment consists of parenteral penicillins for sensitive organisms plus valvular re-replacement for intractable heart failure mechanical malfunction of the valve, persistent sepsis, or multiple major emboli. In spite of aggressive therapy, the mortality remains high. Therefore, appropriate prophylaxis is warranted in patients with prosthetic valves who must undergo procedures that might lead to bacteremia.


Treatment of acquired chronic esophagopleural fistula by endoscopic cauterization. Successful treatment of an eight-year-old esophagopleural fistula by means of endoscopic cauterization with an alkaline solution is reported. Previous therapeutic attempts with other more conventional measures had failed. The technique of the successful treatment is described. No complications could be attributed to its use.


Audible atrial sounds in atrial flutter modulating an aortic regurgitant murmur. Echocardiographic and phonocardiographic correlates. The findings in a patient with atrial flutter whose audible atrial sounds uniquely modulated an aortic regurgitant murmur are presented, with phonocardiographic and echocardiographic correlates, which suggest a ventricular origin for these sounds.


Acute cavitary histoplasmosis.

Acute cavitary histoplasmosis. A case of acute cavitary histoplasmosis in the upper lobes is documented. The relationship of this entity to chronic cavitary histoplasmosis is discussed.


Echocardiographic features of an aneurysm of the left sinus of Valsalva. The echocardiographic features of an aneurysm of the left sinus of Valsalva are described and correlated with angiographic findings. The echocardiogram showed the presence of a thin line of echoes occurring proximal to the anterior leaflet of the mitral valve and moving in and out of apposition with the posterior aortic wall. During systole, this line of echoes moved away from the aorta into the left atrium, and during diastole, the line moved into the aorta. Recognition of these features provides a potential noninvasive way to diagnose aneurysms of the left sinus of Valsalva prior to rupture.


Fatal tension pneumopericardium complicating tracheostomy. The findings in a patient who developed a fatal pneumopericardium following tracheostomy are reported. This complication of tracheostomy does not appear to have been reported previously in the literature.. When recognized, pneumopericardium is a treatable lesion, and clinicians should be aware of this potential complication.


Anterograde and retrograde bradycardiac block in the His-Purkinje system. Finding in a patient with acute myocardial infarction. A patient with an acute inferior myocardial infarction developed a complete atrioventricular block and intermitent periods of atrioventricular conduction with QRS complexes showing right bundle branch block associated with left anterior hemiblock. Recordings of the His bundle electrogram showed that the atrioventricular block was infrahisian and that in periods of resumed atrioventricular conduction, the His-ventricle (H-V) interval was long. Ventricular escape beats showed concealed conduction to the atrioventricular node. Anterograde atrioventricular conduction was always resumed through the left posterior division when the preceding division when the preceding intervals between ventricular escape beats and the atrium (V-A intervals) were shorter than 580 msec. The same phenomenon occurred with right ventricular pacing. A retrograde His potential could be observed. Retrograde conduction of ventricular escape beats and ventricular paced beats was blocked if the H-V interval and the interval between the His bundle and the ventricular paced beat (H-V interval) were long (more than 600 msec and 550 msec, respectively). The existence of an intermittent anterograde and retrograde bradycardiac infrahisian block was inferred from the previously mentioned data; a fixed retrograde atrial nodal block was also present.


Idiopathic muscular hypertrophy of the esophagus. Postmortem incidental finding in six cases and review of the literature. Six cases of idiopathic muscular hypertrophy of the esophagus were found at autopsy in a relatively short period of time. As has been the experience in previously reported cases, our finding was incidental at the autopsy in all of the cases. In only one of our patients were there relevant symptoms and radiographic changes that could be attributed to the disease. How often patients with muscular hypertrophy of the esophagus have the clinical syndrome of diffuse esophageal spasm remains unclear. It is therefore evident that only by awareness of this entity can studies of esophageal funtion, x-ray films, and appropriate treatment prevent serious morbidity and occasional mortality from the disease.


The adult respiratory distress syndrome associated with miliary tuberculosis. Miliary tuberculosis is an unusual cause of acute, catastrophic pulmonary failure. In this report, we describe three patients with miliary tuberculosis who developed the adult respiratory distress syndrome. The diagnosis of tuberculosis was suspected early, appropriate therapy was initiated, and two patients survived. The experience with these cases serves to reemphasize the importance of maintaining a high index of suspicion for treatable precipitating disorders in patients with acute respiratory failure.


The Philadelphia Pulmonary Neoplasm Research Project. Symptoms in occult lung cancer. In a prospective study of 6,027 older men screened every six months for ten years by means of chest photofluorograms and questionnaires regarding symptoms, 121 developed lung cancer after the first examination. Eighty-five men with lung cancer had the opportunity to be screened eight times before the tumor was detected by chest x-ray film, but only 33 actually reported that often. These 33 men were compared with matched controls for symptoms before the neoplasm was detected radiologically. The common symptoms of expectoration and chronic cough showed a significant increase in frequency over time in the cases of cancer, while only expectoration showed a slight increase in the controls. Uncommon symptoms more suggestive of lung cancer (hemoptysis and worsening cough) occurred in only four men prior to detection of cancer. Symptoms are seldom useful in the detection of occult lung cancer, but the appearance of expectoration and chronic cough in older male smokers should raise a suspicion of this disease.


Electrocardiographic manifestations and clinical significance of atrioventricular nodal alternating Wenckbach periods. Atrioventricular nodal alternating Wenckebach periods were defined as episodes of 2:1 atrioventricular block in which there was a gradual increase in transmission intervals of conducted beats ending in two or three consecutively blocked atrial impulses. This is one of the mechanisms whereby 2:1 atrioventricular block progresses into 3:1 or 4:1 atrioventricular block. Alternating Wenckebach periods appear during rapid atrial pac,ng (even in the absence of depressed atrioventricular nodal function), provided that the atria can be captured at a rate fast enough to allow for the occurrence of this phenomenon. Treatment of atrial flutter with digoxin and quinidine produces alternating Wenckebach's periods, with associated electrocardiographic changes specific for the type of drug given. In patients with "atrial tachycardia with atrioventricular block" due to digitalis intoxication or with primary disease of the conducting system or with acute myocardial infarction, there are coexisting severe arrhythmias and clinical symptoms requiring almost immediate pharmacologic or electrical therapy. We conclude that atrioventricular nodal alternating Wenckebach's periods are common and frequentyly transient and that they occur in a variety of clinical conditions, most of which are benign; however, contrary to what is commonly accepted, some episodes appear in clinical settings requiring prompt pharmacologic or electrical treatment.


The role of leukocytes in ethchlorvynol-induced pulmonary edema. Intravenous administration of ethchlorvynol (Placidyl) is known to produce noncardiogenic pulmonary edema in animals and humans. Since intrapulmonary sequestration of leukocytes has been observed to occur following injection of ethchlorvynol, we evaluated the role of these elements of the blood in producing pulmonary edema. In vivo studies in dogs showed intrapulmonary trapping of leukocytes, as evidenced by increasing leukocyte differences between blood from the pulmonary artery and arterial blood. In both animals with normal leukocyte counts and those depleted of leukocytes (less than 500 cells per millimeter), pulmonary edema occurred, as evidenced by increased pulmonary water after injection of ethchlorvynol. Preparations of isolated lung perfused with either whole blood or leukocyte-poor plasma had similar gains in weight following injection of ethchlorvynol, in spite of marked differences in leukocyte counts. We conclude that intrapulmonary sequestered leukocytes do not play a role in ethchlorvynol-induced pulmonary edema.


Intrathoracic manifestations of Degos' disease (malignant atrophic papulosis). Degos' disease (malignant atrophic papulosis) is a rare multisystemic disease with characteristic cutaneous lesions, abdominal symptoms and often rapidly fatal course. Our review of the reported intrathoracic involvement in the more than 60 reported cases of Degos' disease suggests that pleuritis and pericarditis are manifestations of the underlying pathophysiologic process. Seventeen of these reported cases were said to have intrathoracic lesions, which were, in most cases, incidental findings at autopsy. We present an illustrative report of a case in which chronic pleuritis and pericarditis were the major causes of morbidity in a 32-year-old woman with Degos' disease.


Echocardiographic features of flail aortic valve. This patient had an attack of subacute bacterial endocarditis involving the aortic valve. He developed fulminating congestive heart failure secondary to acute aortic regurgitation, terminating in the prosthetic replacement of his aortic valve. The echo from the aortic valve demonstrated marked coarse fluttering of the cusps, both in systole and in diastole. The two cusps did not coapt in diastole. The echo from the mitral valve showed features of acute regurgitation. The carotid pulse tracing showed marked slurring in its descending limb. The postoperative echocardiogram showed absence of these findings. We suggest that a diagnosis of flail aortic valve be considered in patients suffering from significant isolated aortic regurgitation in the absence of calcification of the aortic valve and with a negative VDRL test for syphilis.


Pulmonary arteriovenous fistula. Preoperative evaluation with a Swan-Ganz catheter. A balloon-tipped catheter was used in the preoperative assessment of a patient with a solitary pulmonary arteriovenous fistula and coexistent chronic obstructive pulmonary disease and ischemic heart disease. Studies before and two months following surgical excision of the fistula showed that the increase in arterial oxygenation (49 mm Hg vs 77 mm Hg) and the reduction in the fraction of the shunted cardiac output (37% vs 6%) closely approximated the predicted preoperative estimates.


Endobronchial metastasis from cancer of the breast. Endobronchial metastasis is reported to occur in less than 5% of the autopsies of patients dying with extrathoracic malignant neoplasms. Frequently associated primary tumors include those of the kidney, pancreas, colon, ovary, and thyroid. To our knowledge, this is the first report of a case of cancer of the breast which metastasized to the mucosa of a major bronchus. The possible factors involved in the widespread, early unusual spread in this 25-year-old woman are discussed.


Right ventricular infarction.

Right ventricular infarction. Serial hemodynamic measurements were made in a patient with a massive infarction of the right ventricle complicated by cardiogenic shock, right ventricular failure, and tricuspid insufficiency. A favorable hemodynamic response was obtained by reducing afterload with administration of sodium nitroferricyanide (nitroprusside) while maintaining preload with infusion of fluids.


Intermediate coronary care. Observations on the validity of the concept. Recognition of significant mortality among hospitalized patients with myocardial infarction after dismissal from the coronary care unit (CCU) has led to the introduction of the intermediate coronary care unit (ICCU). It had been hoped that protracted monitoring during the convalescent phase of acute myocardial infarction might prevent sudden death, as in the CCU. Study of patterns of survival among 1,361 patients with acute myocardial infarction included 814 patients treated prior to the establishment of an ICCU and 557 managed in such a unit. Analysis of the two groups (including such high-risk factors as congestive heart failure, tachyarrhythmias, previous infarction, cardiac enlargement, and other unfavorable manifestations) failed to reveal a reduction in mortality after introduction of the ICCU. Thus, the value of the ICCU cannot be demonstrated in terms of mortality. Other benefits of the ICCU are projected, which include more sophisticated evaluation of the patient prior to discharge from the hospital and expanded opportunities for education of patients. A definite role of the ICCU in the total management of the patient with coronary arterial disease is postulated.


Pulmonary resection in metastatic carcinoma. Resection of pulmonary metastases in osteogenic sarcoma has been reported by us to result in a five-year survival rate of 27 percent. A later report of surgical management of pulmonary metastases from all types of sarcomas showed a five-year survival rate of 26%. This report reviews the experience with 188 patients treated surgically for pulmonary metastasis from a variety of carcinomas, demonstrating that a similar rate of survival is obtainable by surgical excision of these metastases. A total of 188 patients underwent 242 thoractomies for metastatic pulmonary carcinomas. The most frequent sites of origin were the colon, melanoma, breast, and testicular carcinoma. Surgical treatment of these metastases is justified when the following criteria are adhered to: (1) primary site controlled or controllable; (2) no extrapulmonary metastatic sites demonstrable; (3) good surgical risk; and (4) no effective treatment available by nonsurgical means.


Pulmonary consolidation associated with infusion of a glucose-insulin-potassium solution in acute myocardial infarction. From 1972 to 1975, we have observed seven patients with localized pulmonary consolidation distal to the tip of a Swan-Ganz catheter. These seven instances occurred in a population of over 300 patients receiving a hypertonic solution of glucose, insulin, and potassium for acute myocardial infarction. In four patients the glucose-insulin-potassium solution was instilled directly into the right pulmonary artery from the tip of the Swan-Ganz catheter. In the subsequent three patients the solution was administered via the right atrial port and thus perfused the entire pulmonary vascular bed. The roentgenographic appearance of this localized pulmonary consolidation is indistinguishable from infarction caused by pulmonary thromboembolus or wedging of the catheter.


Tuberculosis and alcoholism. A partial solution through detection. Alcoholism and tuberculosis often coexist, and patients with this combination have the most frequent failures of therapy. Several intriguing alternatives to standard outpatient chemotherapy are now available. The brief MAST interview (a shortened version of the Michigan Alcoholism Screening Test) has been demonstrated to be effective in identifying alcoholism in public health clinics for tuberculosis in New Orleans and Birmingham, Ala., with scores indicating populations of alcoholic patients of 25% and 28%, respectively. The test could be administered without interrupting the routine of the clinic. We believe that the problem of inadequate therapy in the alcoholic patient with tuberculosis is significant and widespread and is not being handled well is most places. Identification of the potential problem patient at first contact will be most helpful in choosing candidates for specialized forms of therapy, including short-term and supervised treatment, begun before failure of therapy ensues.


Clinicopathologic characteristics of pulmonary acinar sarcoidosis. In 101 patients with histopathologic and clinical features compatible with sarcoidosis, a radiologic acinar pattern occurred in about 20% and was always accompanied by bilateral hilar lymphadenopathy. The radiologically acinar pattern histopathologically revealed noncaseating epithelioid granulomas and accumulations of macrophages in the alveolar spaces. Blood vessels were usually not affected by granulomas. On the other hand, a reticulonodular pattern histopathologically showed granulomas with centrally situated veins. The acinar form seems to represent the early stage of pulmonary sarcoldosis, producing primarily intra-alveolar lesions.


Diastolic rumbles in normally functioning porcine mitral valves. Fourteen of 22 patients (64%) with normally functioning porcine prosthetic valves in the mitral position had apical diastolic rumbles on phonocardiogram and by auscultation. Six (27%) had opening snaps. Factors necessary for the production of a diastolic rumble appear to include central flow, a flexible stent, and the presence of biologic material. Clinicians should be aware that diastolic murmurs and snaps occur in the normally functioning porcine valve.


Clinical experience with a new transvenous atrial lead. Although systems using atrial pacemakers offer potential clinical advantages for many patients now receiving ventricular devices, atrial systems have been used in less than 1% of the implantations of permanent pacemakers. The unavailability of clinically successful, easily positioned atrial leads is regarded as the most significant factor in the underutilization of atrial pacing systems. A permanent transvenous atrial lead has been developed and has performed well in 16 months of evaluation in 28 patients. Acute thresholds for voltage at a pulse width of 1 msec ranged from 0.40 v to 2.0 v (average, 1.1 v). Acute peak-to-peak amplitudes of the atrial electrogram were notably high, ranging from 2.5 mv to 7.5 mv (average, 5.1 mv) as measured oscilloscopically. Intermittent failure of sensing occurred in three patients during the period immediately after implantations. Spontaneous dislodgment of the lead from the right atrial appendage occurred in two patients. Atrial sensing and pacing functions remained intact in the first case, and no revision was performed. The lead was repositioned in the second patient and has remained in good position. No complications relating to the lead have been noted in the remaining patients.


Therapeutic properties of oral ambruticin (W7783) in experimental pulmonary coccidioidomycosis of mice. Oral administration of ambruticin (W7783) (by gavage) was lifesaving in mice infected intranasally with arthrospores of Coccidioides immitis. Doses of 25 and 50 mg/kg of body weight, given twice daily by different schedules for from 17 to 60 days, eradicated the fungus from 71 to 100% of the infected mice. Lower doses (5 or 10 mg/kg once or twice daily by an intermittent 50-day regimen) prevented death in all instances but produced many fewer biologic cures. The animals tolerated all these doses well but were adversely affected by doses of 200 mg/kg given daily. Resistance to the drug was not induced by prolonged treatment. Dose-related fungicidal and fungistatic properties in vitro correlated with doses that were life-sustaining or curative (or both) in vivo.


Elimination of the delta wave in the Wolff-Parkinson-White syndrome. A misleading indicator of therapeutic effectiveness. A 66-year-old white woman with a greater than 20-year history of electrocardiographic evidence of the Wolff-Parkinson-White syndrome, including documented recurrent supraventricular tachycardias, was studied. Despite the disappearance of the delta wave after initiation of therapy with digoxin and quinidine sulfate, the patient continued to have frequent episodes of supraventricular tachycardia. At a time when the serum levels of digoxin and quinidine were in the therapeutic range, extensive electrophysiologic studies were performed. Supraventricular tachycardia at a rate of 160 beats per minute was initiated by induced atrial premature depolarizations. The circuit of tachycardia involved anterograde conduction through the pathway of the atrioventricular node and His bundle and retrograde conduction through the bypass tract. We concluded that elimination of the delta wave and other electrocardiographic characteristics of the Wolff-Parkinson-White syndrome cannot be relied upon to indicate successful pharmacologic prophylaxis for induction of tachyarrhythmia associated with this syndrome.


Body surface and intracardiac recordings in a patient with Wolff-Parkinson-White syndrome (type A) with complete infra-His bundle block. Electrocardiograms, vectorcardiograms and His bundle electrograms were recorded in a patient with Wolff-Parkinson-White syndrome (type A) who developed complete infra-Hisian block and advanced A-V block in the Kent bundle. The atrial impulses reaching the ventricles exclusively through the Kent bundle produced QRS complexes and vector loops showing diffuse (leftward initial and rightward pre-terminal) delays and slurrings. These abnormalities were not due to Wolff-Parkinson-White type A coexisting with right bundle branch block, but reflected the activation sequence characteristic of arrival of excitation; spontaneous impulse formation; or electrical stimulation, at the postero-superior wall of the left ventricle. Intracardiac recordings were a complement to body surface recordings in the study of Wolff-Parkinson-White syndrome complicated by A-V conduction disturbances.


Transient unilateral hypoperfusion of the lung following mediastinoscopy. Two cases of pulmonary hypoperfusion occurring after mediastinoscopic examination were demonstrated on lung scans. In one case, this finding on the ninth day required a pulmonary angiographic study that yielded normal findings. Repeat lung scans were normal. We propose that localized mediastinal edema or bleeding after mediastinoscopic examination can produce defects of hypoperfusion, and we urge caution in the interpretation of lung scans up to nine days after mediastinoscopic examination.


Echocardiographic diagnosis of atrial septal aneurysm in an infant with hypoplastic right heart syndrome. Echocardiographic findings are described in a patient with hypoplastic right heart syndrome (pulmonary atresia type with intact ventricular septum and small right ventricular cavity) who had an associated atrial septal aneurysm. An unusual appearance of echoes behind the aorta bulging into the left atrium in diastole on both the M-mode and cross-sectional echo suggested this diagnosis prior to cardiac catheterization. The angiographic findings confirmed the diagnosis of right ventricular hypoplasia, pulmonary atresia and the large atrial septal aneurysm. The infant died after surgery and the atrial septal aneurysm was observed at autopsy. The importance of the diagnosis of the atrial septal aneurysm and its association with restriction of right-to-left atrial shunting prompts this report.


The echocardiographic diagnosis of rupture of a papillary muscle. The echocardiographic diagnosis of acute rupture of a papillary muscle is described. The pertinent findings included (1) decreased systolic motion of the posterior wall, (2) exaggerated septal motion, (3) left ventricular enlargement and pattern suggesting left ventricular diastolic overload, and (4) bizarre fluttering of posterior leaflet of the mitral valve in diastole, suggesting an unhinging of the mitral valvular apparatus. The echocardiogram is a useful noninvasive tool in the diagnosis of this often fatal complication of myocardial infarction.


Intravenous self-administration of metallic mercury in attempted suicide. Report of a case with serial roentgenographic and physiologic studies over an 18-month period. This report describes a 23-year-old white man who injected metallic mercury from a thermometer into his antecubital vein in an attempt at suicide. Despite the persistence of mercury throughout both pulmonary fields on chest x-ray films over an 18-month period of observation, no clinical or physiologic derangement of pulmonary function has developed. In addition, no clinical or biochemical evidence of acute or chronic mercury poisoning in any other organ has appeared during these 18 months, even though metallic mercury is seen in the abdominal viscera on roentgenographic examination. The literature on suicidal and accidental poisoning with metallic mercury is reviewed.


Successful management of massive pulmonary embolism occurring during cardiopulmonary bypass for mitral valve replacement. Massive pulmonary embolism occurred during cardiopulmonary bypass in a patient requiring mitral valve replacement. Successful management of this unusual problem is described.


Idiopathic dilatation of peripheral pulmonary arteries. We describe a patient with idiopathic dilatation of the peripheral pulmonary arteries radiologicaly mimicking pulmonary arteriovenous fistulae. Isolate involvement of the peripheral arteries in this patient supports a developmental defect in the arterial walls as the etiology.


Tri-monocycline: a minocycline complex for parenteral use. II. Blood levels, tissue contents and excretion of the antibiotic in animal experiments and after intravenous administration to humans. Tri-minocycline prepared by mere dissolution of minocycline in an aqueous solution of a recommended complexing agent or using a preconstituted ready-for-use injection of the complex was administered intravenously to rabbits. Serum values were lower, tissue values higher than after injection of other tri-tetracyclines. Basing on these experimental quantitative data, single doses of tri-minocycline equivalent to 50-150 mg minocycline hydrochloride were administered once or twice daily to 13 adult patients during 1-6 days intravenously, without any serious or unusual side-effects. On average, 12% of the injected antibiotic was excreted in the urine, not later than 96 h after the last dose.


Pharmacodynamic interference between rifampicin and isoniazid. This study includes 30 children below the age of 3 years, distributed in three groups of 10 children each. One group received 15 mg/kg/day of rifampicin (RAMP), the other received 15 mg/kg/day of isoniazid (INH) and the third received both drugs (RAMP + INH) at the same doses. Plasma levels of RAMP and INH were determined. At the same time, some hepatic function parameters were analyzed: bilirubin, transaminases, alkaline phosphatases and prothrombin. Plasma levels of INH administered alone show significantly higher levels on the 7th day with respect to the 1st day, thus demonstrating a marked tendency towards the accumulation of successive doses. Very significant differences exist between initial and final values of transaminases in the RAMP + INH group. There are no significant differences in the other two groups. These data suggest a hepatic overload when both drugs are simultaneously administered.


Occlusive arterial disease of the child and young adult. Clinical electroencephalographical analysis of 26 cases. 26 patients suffering from acute arterial disease, predominant in childhood and young adults, have been studied. Convulsive symptom and electroencephalographic (EEG) findings are especially analyzed. The series are grouped following the Hilal classification, based on angiographical aspects. The incidence and etiological facts as well as the clinical and the angiographical findings, are summarized. The EEG analysis shows the high incidence of localized or lateralized abnormalities (23 out of 26), closely related with the clinical signs. However, there is no close relationship between these findings and the conscious state of the stage of the disease. An attempt is made to correlate the added diffuse and/or paroxysmal activities with the brain damage suspected by the angiographical signs. Seizures are present in 10 cases, 9 of them as initial symptoms predominantly of the focal type. There seems to be no relationship between the incidence and type of fits and the angiographical findings. Follow-up study shows that seizures do not modify the immediate course of the disease nor the persistence of this sequela in 9 of the controlled patients. The histopathological findings of cerebral vessel involvement are reported.


Intracranial supratentorial cysts in children excluding tumor and parasitic cysts. The intracranial, liquid-containing cysts in children (excluding tumor and parasitic cysts) are relatively frequent in neurosurgical practice. They raise several problems about their nosology, etiology, clinical and radiological diagnosis, and treatment which are analyzed in a series of 36 cases of supratentorial cysts. The most frequent clinical feature is increased head circumference (22 cases) followed by epileptic fits (18 cases), as well as mental and motor retardation (19 cases). Fundi were found abnormal in only one case out of three. Electroencephalogram was abnormal in almost every case, showing either spikes, spikes and waves or localized slow waves, or an asymmetric depression of the electrical activity. Radiological investigation is essential for diagnosis. Plain radiographs of the skull may show an asymmetry (11 cases). Carotid angiogram and pneumoencephalography give the diagnosis of the lesion without accuracy as to the histology. Computerized axial tomography shows the position of the liquid cavity within the head. The surgical approach (simple shunting [6], direct approach [19], or both [7]) should be carefully considered according to anatomical variety and age of the child. An anatomical classification is proposed, based on the radiological, surgical and pathological findings. Three types of cysts are defined: external cysts (cortical or extracortical) which may or may not be communicating with the ventrioles or the subarachnoid space; internal cysts which again may or may not be communicating; and the corticoventricular cysts. The ultrastructural study represents further progress in the attempt to define the exact anatomical type.


Miliary fungal granulomata confined to the brain: mechanism of meningitis. An unusual case of multiple giant cell granulomata due to Candida albicans confined to the brain of a premature neonate is reported, with evidence to suggest that this fungal meningitis is preceded by a parenchymal focus.


Subarachnoid hemorrhage in children.

Subarachnoid hemorrhage in children. 45 cases of subarachnoid hemorrhage in children were surveyed. 73 percent of the causes were arteriovenous malformations and spontaneous intracerebral hematomata. Arteriovenous malformations in children may grow in size which may be due to the fact that besides the nidus demonstrated by angiography there are surrounding abnormal vascular groups, the reserved nidus. If one fails to extirpate this reserve nidus at the time of surgical excision of the arteriovenous malformation, it may become nidus several years later and may bleed again. The follow-up results of surgery in subarachnoid hemorrhage cases were fairly good.


Pre- and postoperative cerebrospinal fluid absorption studies in patients with myelomeningocele shunted for hydrocephalus. Nine infants with myelomeningocele and hydrocephalus had cerebrospinal fluid formation and absorption studies before insertion of a ventriculoperitoneal shunt. Six were also tested postoperatively. The preshunt formation rate varied from 0.21-0.42 ml.min-1 and the cerebrospinal fluid absorption rate or CSF conductance (Ccsf) varied from 0.008 to 0.031 ml.min-1.mm Hg-1. The postoperative formation rate varied from 0.21 to 0.39 ml.min-1. The postoperative CSF conductance (Ct) was calculated as the sum of Ccsf and the shunt conductance (Cs). The relationship between the Ccsf and Cs curves was determined by matching the sum of these curves to the postoperative data points using the method of least-squares. The data suggests that the shunt may work directly or indirectly to establish a new resting pressure; the latter by stabilizing the sagittal sinus pressure which preoperatively increased concomitantly with the CSF pressure and thus enhanced an already-existing absorption deficit.


[1st experiences with the alpha-receptor blockader phentolamine in achalasia]. Through direct research on isolated human esophagus muscle systems in achalasia patients we found a deviation in the distribution pattern of the contractory alpha-receptors and dilatory beta-receptors in the region of the lower esophagus sphincter in favour of the alpha-receptors. Consequently, the motility of the lower esophagus sphincter was extremely impaired. On the basis of these results, we treated achalasia patients with the alpha receptor blocking drug phentolamine. All patients were soon symptom-free subjectively and improved objectively. Surgical intervention was avoidable in all cases.


[Surgical management of achalasia].

[Surgical management of achalasia]. As long as its etiology is uncertain, achalasia can only be treated symptomatically. Basically, conservative dilation treatment and operative cardiomyotomy can be performed. Although dilation treatment can save the patient the operative procedure, it has relative disadvantages. For this reason since 1973 we treat achalasia through cardiomyotomy with Nissen's fundoplication method. We have operated on 25 cases using this method. These are examined and the results reported.


[Early relaparatomy].

[Early relaparatomy]. Of 3682 patients with abdominal surgery, 142 (3.86%) had emergency early reoperation. The average lethality was 43%. The highest lethality, 60%, was found in those with severe peritonitis; the lowest, 30%, in those with local infection. In comparison with the results of other authors and with previous evaluations, our results demonstrate that despite altered operative indications, increased age of patients, and high-risk operations, the lethality has not increased. The causes and reasons of this positive tendency are discussed.


[Recurrent hyperparathyroidism following subtotal parathyroidectomy]. Recurrent hyperparathyreoidism occurred in 3 of 9 patients in terminal renal failure from 9 months to 2 years after an initially successful subtotal parathyroidectomy. In all cases we find temporary remission of clinical signs of hyperparathyreoidism after surgery. Our clinical experience provided by followup in these patients showed an insufficient biochemical and clinical control. We find recurrence in 3 cases and repeat neck exploration was indicated for 2 patients.


[Embolization of a Mobin-Uddin filter].

[Embolization of a Mobin-Uddin filter]. A case of Mobin-Uddin-Filter embolisation (28 mm filter) into the right pulmonary artery is presented. Via a right thoracotomy filter and thrombi could easily be extracted. Indication, avoidance of malposition, and the question of whether the filter should be extracted after embolisation are discussed.


[Erroneous diagnosis in superficial course of the aorta. Demonstration using ultrasound]. In hyperlordosis of the lumbar spine, the abdominal aorta becomes well palpable and behaves like a pulsating tumor in the lower abdomen. This normal finding often cannot be differentiated from pathologic changes by clinical investigation alone. Sonography offers a simple method, without risk, for the definitive diagnosis of the abdominal aorta.


[Cytological and histological methods for assessing lung tumours (author's transl)]. The accuracy of different histological and cytological methods were analysed in 240 patients with primary lung cancer. The diagnosis had been confirmed by either biopsy, surgery or autopsy. Using multiple diagnostic procedures a positive pre-operative diagnosis was obtained in 86.5%. Where the tumour was endoscopically visible and accessible to direct biopsy the correct diagnosis was made in 97.5%. In case of more peripheral tumour localisation positive results were obtained by cytological tests in 76.5%. The most accurate method of diagnosis was direct forceps biopsy of visible tumours (91% positive). Bronchial washing was positive in 64%, post-bronchoscopic sputum analysis in 60%, pre-bronchoscopic sputum in 55% and bronchial brushing in 30%.


[Treatment of solitary pyogenic liver abscess (author's transl)]. A solitary pyogenic liver abscess usually requires open surgical drainage. Digital exploration of the cavity is important for eliminating any loculations and avoiding complications after the drainage procedure. Chronic liver abscesses which are enclosed by a fibrous capsule and thus may simulate a neoplastic tumor are best treated by atypical liver resection close to the abscess or by a procedure similar to pericystectomy. Early radical operation is indicated for a complicated liver abscess whenever two drainage procedures have failed and the patient's condition is deteriorating. In such a case the development of sepsis and (or) multiple abscesses caused by an internal fistula to the bile duct system are a potential and increasing danger. Anatomical liver resection, though the most radical operation, carries a comparatively low risk as its mortality rate is less than 10%. The prognosis of solitary abscess has improved during the last decade due to an earlier diagnosis and adequate surgical drainage in combination with antibiotics. Anaerobic liver abscesses have the best prognosis.


[Cyclophosphamide and bladder carcinoma (case report) (author's transl)]. A bladder carcinoma developed in a 40-year-old man who was being treated with trofosfamide (Ixoten), a cyclophosphamide derivative, for Hodgkin's disease. The case suggests the need for differentiated replacement of this group of cytostatics.


Determination of ADP-ribose and poly(ADP-ribose) by a new radioimmunoassay. A specific and sensitive radioimmunoassay for ADP-ribose has been developed on the basis of the selective conversion of ADP-ribose to 5'-AMP by alkaline treatment. Antibodies highly specific against 5'-AMP allowed quantification of ADP-ribose converted to 5'-AMP in the range of 1-40 pmol, and in the presence of large quantities of nucleic acids or 3'-AMP. Poly(ADP-ribose) could also be determined when degraded to ADP-ribose by poly(ADP-ribose) glycohydrolase. Determination of the chain length of purified polymer was possible by a parallel determination of ADP-ribose residues after glycohydrolase treatment and of 5'-AMP from the non-reducing end obtained by phosphodiesterase catalyzed hydrolysis. The high specificities of the alkaline conversion of ADP-ribose to 5'-AMP and of the radioimmunoassay for 5'-AMP allowed quantification of protein-bound ADP-ribose residues in crude tissue extracts as verified by comparison with chromatographically purified samples.


Purification and properties of monomeric cytochrome f from charlock, Sinapis arvensis L. Monomeric cytochrome f has been purified to homogeneity, as judged by polyacrylamide gel electrophoresis, isoelectric focusing and analytical ultracentrifugation, from the leaves of charlock, Sinapis arvensis L. The cytochrome was obtained in an aqueous extract following extraction of leaf lipids with butan-2-one, and was subsequently purified by acetone precipitation and chromatography on DEAE-cellulose, Sephadex G-100 and hydroxylapatite. The purified cytochrome had adsorbance ratios of A422/A280 = 7.3 and A554/A280 = 1.07 in the reduced form. There was no indication of the presence of an absorbance band at 695 nm in the oxidised form. The cytochrome had a midpoint redox potential of +365 mV and was oxidised very rapidly by parsley plastocyanin. The molecular weight of the cytochrome was approximately 27 000 as determined by sedimentation equilibrium and by polyacrylamide gel electrophoresis in the presence of dodecylsulphate. The sedimentation coefficient (so20,w) of cytochrome f was 2.48 S. The cytochrome had an isoelectric point at pH 5.50 determined by isoelectric focusing in polyacrylamide gels.


Control of teichoic acid synthesis in Bacillus licheniformis ATCC 9945. Analysis of cell walls of Bacillus licheniformis ATCC 9945 grown under phosphate limitation showed that teichoic acid could be replaced by teichuronic acid under these conditions. Teichuronic acid, however, was always present in the walls to some extent irrespective of the growth conditions. The enzymes involved in teichoic acid synthesis were investigated and the synthesis of these was shown to be repressed when the intracellular Pi level fell. CDP-glycerol pyrophosphorylase was studied in some detail and evidence is presented to show that the enzyme is inactivated under phosphate-limited conditions. The mechanism of inactivation is unknown but it has been shown that it does not require protein synthesis de novo.


Enzyme leakage and multipoint attachment of agarose-bound enzyme preparations. The solvolytic detachment of leucine aminopeptidase from Sepharose-enzyme conjugates with multiple and single anchoring bonds has been studied under a variety of conditions by radiochemical and enzymological methods. The release of the single-point-fixed conjugate could be described by a leakage function, derived previously, yielding the first-order rate constant of the cleavage of the enzyme-matrix bond. The nucleophile hydroxylamine increased the detachment rate considerably. The release of the immobilized enzyme was incomplete in all experiments even after prolonged times. The enzyme leakage from multipoint-attached conjugates was still high enough to prohibit a long-term use of such preparations in routine work at room temperature.


Characteristics of a coupled cell-free transcription and translation system directed by vaccinia cores. 1. A coupled transcription and translation system is described in which protein synthesis is directed by mRNA synthesised in situ by vaccinia virus cores. The cell-free system is based on a micrococcal-nuclease-treated reticulocyte lysate. 2. The polypeptides made in vitro include many authentic early vaccinia proteins, but also other proteins which were not detected in infected cells. 3. Concentrations of cores which inhibit host cell protein synthesis in vivo caused a delayed inhibition of translation in vitro; this was partly, but not entirely, due to dsRNA associated with the cores. 4. The mRNA made was methylated by core enzymes. Inhibition of methylation reduced the rate of translation tenfold; unmethylated RNA bound ribosomes poorly, but was nevertheless translated faithfully.


Isolation of 4.5-dihydroxyisophthalic acid an inhibitor of brain glutamate decarboxylase, produced by a Streptomyces species. A potent inhibitor of brain glutamate decarboxylase (L-glutamate 1-carboxy-lyase, EC 4.1.1.15) was isolated from cultures of a Streptomyces species, and its structure was found to be 4,5-dihydroxyisophthalic acid. The metabolite inhibited beef brain glutamate decarboxylase 50% at a concentration of 0.12 microgram/ml (0.61 micron). The kinetic analysis indicated that 4,5-dihydroxyisophthalic acid was a competitive inhibitor having a Ki value of 0.18 micron.


The primary structure of bovine pancreatic phospholipase A2. The complete amino acid sequence of bovine phospholipase A2 (EC 3.1.1.4) was determined. This enzyme has a molecular weight of 13 782 and consists of a single polypeptide chain of 123 amino acids cross-linked by seven disulfide bridges. The main fragmentation of the polypeptide chain was accomplished by digesting the reduced and thialaminated derivative of the protein with trypsin, staphylococcal protease and cyanogen bromide. A number of chymotryptic peptides were used for alignment and to obtain overlaps of at least two residues. The sequence of the peptides was determined by Edman degradation by means of direct phenylthiohydantoin identification in combination with identification as dansyl amino acids. Although 71% of all residues of phospholipase A2 from bovine, porcine and equine sources are conserved, bovine phospholipase A2 differs from the others by the total number of residues and by substitutions at 20 (porcine) and 33 (equine) positions.


Use of synthetic analogs for a study on the structure-activity relationship of apamin. [Lys13,Lys14]Apamin, [Lys13]apamin and [Lys14]apamin, three structural analogs of the bee venom neurotoxin, have been obtained by solid-phase peptide synthesis while an attempt to obtain [Cit13]apamin failed, probably at the step of reoxidation of cysteines. After the chemical purity of these three derivatives had been assessed, further chemical modifications led to three new peptides: [Ac-Cys1,Lys(Ac)4,Lys(Ac)13]apamin, [Ac-Cys1,Lys(Ac)4,Lys(Ac)14]apamin and [Har4,Har13,Har14]apamin. These six analogs have been tested for their neurotoxicity, i.e. determination of LD50 for mouse by subcutaneous injection. A lethal potency is observed only when the region 13-14 of the sequence contains a double positive charge. One arginyl residue is necessary for a high biological activity, while its location in position 13 or 14 is of minor importance. When homoarginine (Har) replaces arginyl residues the neurotoxicity is lowered.


Evidence for a dimeric form of Artemia salina extracellular hemoglobins with high-molecular-weight subunits. The brine shrimp, Artemia salina, produces at least three chemically and ontogenetically distinct extracellular hemoglobins (Hb-I, Hb-II and Hb-III). The estimated molecular weights of these hemoglobins are 240000-260000, containing 14 heme groups based on the iron and heme contents of a molar species. Hb-II, which corresponds to a minimal molecular weight of about 18 000 per heme [Moens, L. and Kondo, M. (1977) Biochem. J. 165, 111-119]. Denaturation of the reduced and alkylated hemoglobins with 8 M guanidine hydrochloride revealed apparently one polypeptide chain having a molecular weight of 126 000. Thus a single native hemoglobin molecule should be composed of two of these high-molecular-weight subunits each of which is bound with seven hemes. Upon sodium dodecyl sulfate/polyacryamide gel electrophoresis of either native hemoglobins or isolated subunits it was found that the 126 000-Mr polypeptide was cleaved specifically into two unequally-sized fragments of Mr 50 000 and 80 000. Further denaturation of native hemoglobins with urea at pH 2.5 or 11 followed by sodium dodecyl sulfate gel electrophoresis confirmed these results. The amino acid compositions determined for native Hb-II and its subunit and fragments are found to be very similar, implying that no specifically localized amino acid sequences are present and that the subunit globin chain could be composed of seven similar repeat units (Mr approximately 18 000) being linked covalently to one another. The amino acid compositions of Hb-I and Hb-III showed only minor differences to that of Hb-II.


Ribosomal proteins of HeLa cells.

Ribosomal proteins of HeLa cells. Ribosomal proteins from HeLa cells were analyzed by two-dimensional polyacrylamide gel electrophoresis (Kaltschmidt-Wittmann) and dodecylsulfate polyacrylamide gel electrophoresis (Laemmli). 35 proteins are associated with the small ribosomal subunit and 47 proteins with the large ribosomal subunit. The HeLa ribosomal proteins S6, S32, L40b,c, L41 and L42 are phosphorylated in vivo and in vitro. Minor differences between HeLa and rat liver ribosomal proteins were revealed by their direct coelectrophoresis.


Comparative dromotropic activity of timolol and propranolol in anesthetized dogs. The comparative dromotropic activity of timolol (TML) and propranolol (PPL) was studied by means of His bundle electrograms in two groups of pentobarbital-anesthetized dogs: group I, 7 non-atropinized dogs; group II, 8 atropinized dogs. beta-Blocking agents were injected in 4 cumulative doses in each dog at 3 days' interval. The effects upon heart rate (HR), and A-V nodal (AH), His--Purkinje (HV) and intraventricular (QS) conduction times were measured. The dromotropic effects of PPL and TML during atrial electrical stimulation and their effects upon chronotropic and dromotropic isoprenaline-induced changes were compared. TML exerted a 9--10 times more potent negative chronotropic effect than PPL and a 4--5 times more potent negative dromotropic effect than PPL on AH conduction time. PPL and TML increased the duration of HV only in higher doses. This effect which was not modified by isoprenaline may be related to their membrane depressant effect. Neither TML, nor PPL nor isoprenaline modified QS duration. TML was 25 times more potent than PPL to antagonize the chronotropic action of isoprenaline and 11--8 times more potent than PPL to antagonize the dromotropic action of isoprenaline upon AH. Parasympathic blockade with atropine did not modify the negative dromotropic activity of PPL and TML but modified their chronotropic effects.


Inhibition of dopamine release in the cat caudate nucleus by nigral application of glycine. "Encéphale isolé" cats were implanted with two push-pull cannulae, one in the left caudate nucleus and the other in the ipsilateral substantia nigra. L-3,5(-3)H-Tyrosine was introduced continuously into the caudate nucleus to study the release of 3H-DA. Glycine (10(-5)M) added to the superfusing medium of the push-pull cannula inserted into the substantia nigra reduced (25%) the spontaneous release of 3H-DA. Conversely, strychnine (10(-5)M) slightly stimulated the 3H-transmitter release. The inhibiting effect of glycine (10(-5)M) on 3H-DA release was no longer seen in the presence of strychnine (10(-5) M). The results support the hypothesis of a tonic glycinergic inhibitory control of the activity of the nigrostriatal dopaminergic neurons.


Delimitation of neuronal substrates necessary for the analgesic action of baclofen and morphine. The loci of neuronal substrates necessary for the analgesic action of baclofen and of morphine were determined by systematic transection of the rat cerebrospinal axis. Severe reduction in the analgesic capacity of both drugs, assessed with the tail flick test, occurred after section of the thoracic spinal cord, indicating that necessary substrates are located rostral to this level. These data also suggest that baclofen-induced analgesia does not primarily result from a pharmacological blockade of nociceptive information at the first sensory synapse in the spinal cord. Neither baclofen- nor morphine-induced analgesia was altered by transection of the brain stem between the superior and inferior colliculi, but the action of both drugs was greatly reduced following section of the medulla 3 mm rostral to the obex. Thus, the rostral margin of neuronal substrates mediating the effects of both drugs lies somewhere in the pons or anterior third of the medulla. This observation is compatible with the notion that analgesia induced by baclofen and morphine involves, at least in part, common neuronal substrates.


Vasoconstrictor hyperresponsiveness: an early pathogenic mechanism in the spontaneously hypertensive rat. Factors which play a primary role in the initiation and development of hypertension in spontaneously hypertensive rats (SHR) are incompletely defined. To test the possibility that early changes in vascular function play a primary etiologic role, hindquarters of 3-week-old SHR and Wistar-Kyoto normotensive rats (WKY) were perfused at constant flow with plasma substitute. The vasculature of SHR exhibited higher resistance to flow than that of WKY. The threshold constrictor response to norepinephrine (NE) was elicited at a significantly lower concentration (6X) than required in WKY, while threshold to BaCl2 was not different. At concentrations of BaCl2 above threshold, SHR exhibited marked hyperresponsiveness compared to WKY. This resulted in a greater maximum response and thus a steeper slope. The ED50 for BaCl2 was not different. A similar dose--response relationship (greater maximum, steeper slope) was observed with NE except that the ED50 as well as threshold was significantly lower in SHR than in WKY. These data show that vasoconstrictor hyperresponsiveness and increased vascular resistance are present at the time when the hypertension is first detectable. The hyperresponsiveness includes two distinct components: (1) A specific hypersensitivity to NE and (2) non-specific hyperresponsiveness which could derive from altered excitation--contraction  coupling and/or from a structural mechanism already present when pressure differences begin to appear.


The depression of thalamic nociceptive neurones by D-ala2,D-leu5-enkephalin. The activity of single thalamic nociceptive neurones was recorded extracellularly. BW 180C, (D-ala2,D-leu5-enkephalin) applied locally, by iontophoresis (10--40 nA) or systemically by i.v. injection (1.5--6 mg/kg) markedly depressed the evoked excitation of these neurones following peripheral noxious stimulation. This effect could be antagonised by naloxone. Enhanced enzymic stability did not appear to prolong the duration of action of BW 180C iontrophoretically applied to these neurones.


Cactecholamines and the oedematous reaction to oestradiol in the rat uterus. The effect of catecholamines on the 4 h oedematous reaction to estradiol in the immature rat uterus was investigated. Isoprenaline was found to augment the reaction to suboptimal doses of estradiol (0.25--0.5 microgram/kg. This effect was reversed by d,l-propranolol. Adrenaline and noradrenaline were found to inhibit the reaction to oestradiol 2 microgram/kg. The effect of adrenaline was reversed by phenotalmine.


Effect of pentoxifylline and aminophylline on biogenic amine metabolism of the rat brain. In the brain of rats injected with pentoxifylline [3,7-dimethyl-1(5-oxo-hexyl)-xanthine] or aminophylline the following was observed: (i) dose-dependent increases of tryptophan and 5-hydroxyindoleacetic acid levels and of 5-hydroxytryptophan and dihydroxyphenylalanine accumulation after treatment with the decarboxylase inhibitor benserazide HCl; (ii) acceleration of norepinephrine turnover following alpha-methyl-p-tyrosine; (iii) increase of 3-methoxytyramine accumulation following pargyline. On a molar basis pentoxifylline was more potent than aminophylline in affecting brain biogenic amine metabolism.


The discovery of nature's biosynthetic pathways. Uro'gen-III is a key intermediate on the biosynthetic pathways to the vitally important natural pigments haem, chlorophyll and the cytochromes. How the unexpected structure of uro'gen-III is synthesized by living things has long been a major puzzle. Studies based on 13C-labelling are described which show a) that a single intramolecular rearrangement occurs and b) that this step occurs after the open-chain linear tetrapyrrole system has been built. A second study involves stereospecific labelling with deuterium and tritium to elucidate the absolute stereochemistry of the enzymic reaction sequence which produces the vinyl groups of haem. The third and last section of the lecture is focussed on the biosynthetic intermediates lying between uro'gen-III and  cobyrinic acid on the pathway to vitamin B12. An octacarboxylic isobacteriochlorin is isolated from a vitamin B12-producing organism and this is shown to be identical with sirohydrochlorin, previously obtained by Kamin and Siegel as the metal-free prosthetic group of certain sulphite-reducing bacteria. The structure and absolute stereochemistry of sirohydrochlorin are studied and comment is made on the evolutionary interest of these findings.


Synaptic vesicles and other organelles of human mossy fibre endings. A morphometric study. The mossy fibre ending organelles of 6 men were studied, using morphometric methods. The numerical densities of agranular, coated and dense core vesicles, as well as the number of agranular vesicles per micrometer2 of the synaptic surface and per synapse were calculated.


Induction of developmental anomalies in mice by maternal stress. The short-time restraint of pregnant mice on day 8 of gestation led to a significant increase of the anomaly rate in fetuses. This effect may be due to stress factors of endocrine origin.


Activation of the carcinogen N-hydroxy-2-acetylaminofluorene by rat mammary peroxidase. A peroxidase preparation from rat mammary gland parenchymal cells, a target tissue of arylamine carcinogens, was shown to activate the carcinogen N-hydroxy-2-acetylaminofluorene via a nitroxyl free radical intermediate to the more active carcinogens nitrosofluorene and N-acetoxy-2-acetylaminofluorene. Hydrogen peroxide, cumene hydroperoxide, and linoleic acid hydroperoxide were effective as substrates. The antioxidants ascorbate, propyl gallate and reduced glutathione prevented the free radical activation route.


DNA-dependent-DNA-polymerase: possible limiting influence on cell reproduction during viral leukemogenesis. Evidence is presented that during viral leukemogenesis spleen cell nuclei show an increase in labelling index and mean grain count, that is not accompanied by any changes in the nuclear level of DNA-polymerase-alpha. It is suggested that polymerase production remains under the control of the normal cell mechanisms and the virus may affect cell proliferation by altering the primer-template levels.


The mitigating effect of dietary antioxidants on chemically-induced carcinogenesis. The effect of a dietary antioxidant mixture on 3-methylcholanthrene mediated carcinogenesis in hairless mice was investigated. The antioxidant mixture significantly reduced the frequency of premalignant lesions and their subsequent development into tumors. The similarities in response of chemical and UV light-carcinogenesis to these antioxidants suggest some congruity in the mechanisms of the carcinogenic process.


The endocrine nature of the paranganglia of man. Brightly fluorescent paraganglia were found in the retroperitoneal tissue of adult man. The histofluorescence properties of the paraganglia indicate the presence of tryptophyl peptides, which might be of endocrine importance.


The effect of epinephrine on granulocyte adhesion. Preincubation of blood from normal human volunteers with epinephrine significantly decreased the granulocytes ability to adhere to nylon fibres. Possible significance for the in vivo correlation is discussed.


Accumulation of 2-micron latex particles in mouse Peyer's patches during chronic latex feeding. 2-micron latex particles accumulated in macrophages in intestinal Peyer's patches of mice given latex suspensions as drinking fluid for 2 months. The number of particles accumulating was a direct (but nonlinear) function of the number ingested. Some of the latex particles were still present in Peyer's patches 6 weeks after the cessation of latex feeding.


Rejection of worm load through singly and repeatedly sensitized peritoneal exudate cells during experimental ancylostomiasis. Sensitized peritoneal exudate cells from Swiss albino mice donors infected with a single dose of 1000 A. caninum larvae could expel a challenge dose of 500 larvae from recipients at a faster rate when compared to cells from repeatedly infected (250 + 250 + 500) donors. However, at 36 h after challenge, the larval expulsion was almost the same in both the groups. Because of the bowel sensitization by the cells, some larvae (not expelled) in the 1st group, readily migrated into muscles where they met allergic immobilization and death due to infiltration of inflammatory cells and their exudates at these sites.


Mitogenicity of autolysates of Trypanosoma congolense. Autolysates of Trypanosoma congolense, in subcytotoxic amounts, were found to be highly mitogenic in vitro for the spleen cells of normal mice. Significant amounts of [3H]-thymidine were also incorporated by the responding spleen cells of nu/nu (athymic) mice. In contrast, the spleen cells of cyclophosphamide-treated mice were unresponsive. The findings suggest that a potent B-cell-mitogen is generated by the autolysing T. congolense organism.


The attenuation of prostaglandin-induced luteolysis in decidual tissue-bearing pseudopregnant rats. Decidual tissue (DT)-bearing pseudopregnancy (PSP) rats, in contrast to hysterectomized PSP rats, were resistant to a luteolytic regimen of either PGF2alpha or PGE2 when examined for the duration of PSP diestrus. The PG treatments, however, caused a marked fall in the serum progesterone levels on days 10 and 12, although the levels in DT-bearing rats on day 10 were significantly higher than in the hysterectomized rats.


Dynamics of estrogen binding by uterine cells in vivo. The dynamics of the in vivo binding and release of tritiated estradiol in different uterine cell types are described. The very early binding of estrogens by the cytosol-nuclear and the eosinophil receptor systems is in accordance with the hypothesis that some estrogenic effects are mediated by these receptor systems.


Bovine TSH-stimulation of fish thyroid peroxidase activity and role of thyroxine thereon. bTSH augmented the fish thyroid peroxidase activity in a dose-response manner. Thyroxine could not modulate the effect of exogenous bTSH, but it decreased the peroxidase activity in a control system when administered alone. The data therefore suggest similar negative feedback control system for TSH-regulation as operative in the case of mammals.


Microbiological transformation of biflavone. Incubation of 5,5'-7,7'-tetramethoxy-8,8'-biflavone with Aspergillus niger results in the formation of 4,4'-dihydroxy-5,5'-7,7'-tetramethoxy-8,8'-biflavan.


Transition metals in calf thymus deoxyribonucleoprotein. Fe, Ni, Cu and Zn were found by energy-dispersive X-ray fluorescence in calf thymus deoxyribonucleoprotein. The X-ray analyses indicated the absence of Cr, Mn and Co.


A study of the cytoplasmic factors controlling the rate of catalase synthesis in rat liver. A new quantitative method for assessment of the biological activity of the cytoplasmic factors-regulators, controlling the rate of catalase synthesis in rat liver on post-transcriptional stage, has been worked out. The nature of these factors has been established.


The hydrolysis of some L-amino acid-p-nitranilides with the normal and pregnant's serum aminopeptidases. From 4 serum aminopeptidases (2 of pregnant and 2 of nonpregnant women's sera), the placental lysosomal (mol. wt 320,000) splits Lys-NAp only. B-Cys-NAp is hydrolyzed from the both placental enzymes, i.e. lysosomal and microsomal (mol. wt 145,000) AP. Ala-NAp is split by both nonpregnant serum AP more readily than Leu-NAp.


Kinetics of division in PHA-stimulated pig lymphocytes. Our results indicate that pig lymphocytes in culture complete their 1st division at 24 h. At 36 h there are 9% of cells in 2nd division. 3rd mitosis appears at 48 h; and at 72 h there are cells engaged in the 4th division.


Nucleotide metabolism in the rat liver following whole-body x-irradiation. Evidence has been presented to show that, like synthesis of RNA, syntheses of ribonucleotide precursors of RNA in the rat liver were stimulated for 6--18 h following whole-body X-irradiation (1000 R).


A fungitoxic principle from the leaves of lawsonia inermis lam. During antifungal screening of higher plants, the leaves of Lawsonia inermis were found to exhibit strong fungitoxicity. On chemical investigation, the antifungal factor was found to be 2-hydroxy-1,4-naphthoquinone (Lawsone). The minimum effective dose against test organism was found to be 1000 ppm. Lawsone was found to exhibit fungicidal activity, wide fungitoxic spectrum and nonphytotoxicity.


Susceptibility of chick neural retina to viral multiplication in vitro during embryonic development. Decrease in the susceptibility of embryonic chick neural retina cultures to the multiplication of various viruses was observed with increasing age of the embryo. In contrast the retinal cells supported the multiplication of Sindbis virus irrespective of the age when they were infected with the viral RNA. These results suggest that the restricted multiplication of the viruses observed is due to the modulated inability of the cell to process the adsorbed viruses for subsequent replication.


The relationship between membrane potential and ATP content in rat liver during ischemia. Both ischemia and ethionine decreased the membrane potential and ATP content in rat liver. In ethionine-treated rat liver, ischemia brought about a further decrease in membrane potential without significant decrease in ATP content.


5-hydroxytryptamine induced changes in body temperature of newborn kittens and guinea-pigs and the effect of indomethacin thereon. During the first days of life 10 microgram i.c.v. 5-HT evoked a primary, short-lasting hyperthermia in kittens and hypothermia in guinea-pigs. In both species, a secondary late hyperthermia occurred that could be prevented by indomethacin pretreatment.


Construction of a thin film PO2-electrode using gold paste. A thin film gold electrode for biological oxygen consumption was constructed using gold paste. This electrode is easy to construct, has high sensitivity and is disturbed only slightly by bubbling of the surrounding fluid. As an application, the electrode was used to measure oxygen consumption of the skin and yielded a reasonable value.


A tonic component in the motility of the upper urinary tract (renal pelvis-ureter). In isolated muscle strips of porcine renal pelvis and ureter, the calcium antagonist nifedipine (3.10(-7) moles/l) completely suppressed spontaneous phasic mechanical activity and the phasic components of an adrenaline-induced activation (P-component). In the presence of nifedipine, adrenaline induced in pelvis preparations (but not in the ureter) a tonic contraction (T-component) which was on average 61% of the control reaction (SD +/- 26%; n = 35).


Projections from nucleus accumbens to globus pallidus and substantia nigra in the rat. Stimulation of nucleus accumbens produces inhibition and facilitation of neuronal activity in the ipsilateral globus pallidus and substantia nigra. Small lesions in the accumbens reduce pallidal but not nigral GABA content.


Positive after-image, PAI: early erasure by saccadic eye movement or Jendrassik manoeuvre. Positive after-images (PAIs) evoked by low intensity stroboscopic flash are erased by voluntary large amplitude saccadic eye movements. The duration of the PAI is shortened by a Jendrassik manoeuvre. The results suggest that muscle spindle afferent impulses conducted centrally are involved in the erasure phenomenon. The duration of the PAI is modifiable by drugs. The social implications of PAI are considered briefly.


[Serotonin metabolism in chronic alcoholism (author's transl)]. Serotonin was determined in platelets of 47 patients with alcoholism during the state of withdrawal as well as in a group of healthy persons. The results show that serotonin values were significantly lower in the group of patients with alcoholism as compared with the control group of healthy persons.