Absorption of digoxin in man after oral and intrasigmoid administration studied by portal vein catheterization. The absorption of digoxin has been studied in fasting patients undergoing transumbilical, portal catheterization for diagnostic purposes. A purely aqueous solution was administered orally in 4 patients and in the sigmoid colon in 2 patients. Blood samples were taken simultaneously from the portal and a peripheral vein. Plasma digoxin concentrations were determined by radioimmunoassay. Digoxin appeared early in the blood after oral administration; the average peak of porto-peripheral concentration differences was at 18 min. After intrasigmoid administration, absorption was slower, and no distinct peaks were found. Calculation of the mean amounts absorbed showed that half the dose had been absorbed via the portal vein during 2 hours in the oral study and during6 hours in the intrasigmoid test. Approximately 2/3 of the dose had been absorbed during 6 hours after oral dosing. The absorption rate was estimated taking into account the decreasing amount of drug left to be absorbed at different times. After cral administration, the mean peak rate was found to correspond to an absorption half-time of 0.78 h, which was more than 20 times faster than the rate after 6 h. The mean rate after intrasigmoid administration appeared to be about 1/3 of that after oral dosing. Physiological factors that might account for these differences in absorption rate are discussed.


Absorption of digoxin in infants.

Absorption of digoxin in infants. The bioavailability of digoxin in solution was studied in 4 newbron infants with heart failure. Serum digoxin concentrations were determined by radioimmunoassay using 125I. Bioavailability was estimated by camparison of the areas under the 8-h serum concentration curves (8-h AUC) after intravenous and oral administration of the glycoside. After oral administration of digoxin (1/4 of the digitalizing dose, 0.05 mg/kg bw), peak serum values of 2.3-4.4 ng/ml were reached within 30-90 min. After intravenous administration of the same amount of the glycoside, there was a rapid decrease in serum concentration during the first 2 h, and after about 4 h the serum concentration curves paralled those obtained after oral dosing. Based on within subject comparison of intravenous and oral 8-h AUC'S, the mean bioavailability of digoxin was estimated to be 72 per cent (range 52-79 per cent). It was concluded that digoxin in solution, given to infants with mild to moderate heart failure, is well absorbed and biologically available to the same extent as in adults.


On the fate of furosemide in man.

On the fate of furosemide in man. 35S-furosemide was administered orally (n=7) or i.v. (n=2) to healthy subjects. The average gastrointestinal uptake estimated by comparison of the urinary recovery of label and the areas under the plasma curves after the two routes of administration was 65%. The half life of radioactivity in the plasma after oral 35S-furosemide was 90 +/- 17 min (estimated on the slope between 2 and 6 h); the corresponding figure after 35S-furosemide i.v. was 47-53 min (slope 0.5-4 h). There was probably a slower phase after 4-6 h. Fractionation of labelled material in urine from two subjects demonstrated that approximately two thirds of the label recovered at 24 h had the same chromatographic properties as furosemide. A major part of the metabolite(s) was probably furosemide glucuronide. There was no evidence that 4-chloro-5-sulfamoylanthranilic acid was formed in man. The total urinary recovery of label (5-7 d) after oral and intravenous administration was 55.1 +/- 3.2 (mean +/- SD) and 82-84%, respectively. After 35S-furosemide i.v., 6-9% of the label was recovered in faeces, and it could not be accounted for solely by biliary excretion of furosemide.


Renal handling of iodamide and diatrizoate. Evidence of active tubular secretion of iodamide. Active tubular secretion of iodamide, a water-soluble contrast medium, was demonstrated by comparing the clearances of iodamide, iothalamate and inulin. Passive tubular back diffusion was not found. The fraction excreted by tubular secretion was significantly reduced at "clinical" plasma concentrations. The glomerular filtration rate was slightly depressed at these concentrations of iodamide and diatrizoate.


Brain concentrations of phenytoin, phenobarbitone and primidone in epileptic patients. Plasma, brain, lumbar CSF, skeletal muscle, skin and bone concentrations of phenytoin, phenobarbitone and primidone have been measured in specimens from patients undergoing temporal lobectomy for chronic epilepsy. A good correlation was found between the plasma and brain concentrations of each drug. Similarly, a good correlation was found between the plasma and CSF concentrations of each drug. Assuming that CSF is an ultrafiltrate of plasma, the percentage of phenytoin, phenobarbitone and primidone which was unbound in plasma was 10-14%, 43% and 81% respectively. Skeletal muscle concentrations of phenytoin and phenobarbitone and the skin concentration of phenytoin, also correlated with the plasma concentrations, but the remaining tissues did not give significant correlations.


Comparative drug elimination in man-diphenylhydantoin and amobarbital. The concentration of 5,5-diphenylhydantoin (DPH) in serum was determined at selected time intervals in seven healthy male volunteers starting 10 h after an oral dose of 400 mg sodium DPH was given. The data were analyzed according to a one-compartment model assuming first-order kinetics. The mean serum half-life was  19.28 h +/- 5.87 (SD). A positive correlation coefficient (r=0.84, p less than 0.05) was found between the serum DPH half-life and the serum amobarbital half-life in the seven subjects. The urinary levels of free plus conjugated 5-(p-hydroxyphenyl)-5-phenyl-hydantoin were determined for 12 h periods over a minimum of two days following the 400 mg oral dose of sodium DPH. Subjects with a short DPH half-life tended to excrete in urine a greater amount of p-HPPH as compared to subjects with a long DPH half-life. In the case of one subject, the urinary excretion of p-HPPH plateaued five days after DPH administration and the apparent elimination half-life determined from the p-HPPH urinary excretion data was 19.16 h as compared to the value of 19.53 h calculated from the DPH serum levels.


Disposition of beta-methyldigoxin in man. The time course of radioactivity in plasma and the excretion in urine and faeces over 7 days were determined in 12 healthy subjects after single oral and intravenous doses of a solution of 3H-beta-methyldigoxin. 62.2 +/- 2.1 and 29.0 +/- 5.2 per cent of the dose were excreted in urine and faeces, respectively, within 7 days of intravenous administration, compared with 55.2 +/- 2.8 and 28.6 +/- 5.7 per cent after oral administration. This indicates almost complete absorption of the glycoside when given in solution. 12 hours after its administration a pseudo-distribution equilibrium was reached and the average half life of tritiated compounds was 1.3 days. By 48 - 96 hours after treatment the average half life was 2.8 days. O-demethylation was revealed as the main metabolic degradation step in man. The rate of Demethylation was higher after oral than i.v. administration. Thus, only 31% of the radioactivity excreted in the urine consisted of unchanged beta-methyl-digoxin after oral administration compared to 51% after i.v. dosing. Only traces of bis- and monoglycosides were excreted in urine, but there were considerable amounts in faeces, where they accounted for more than 35% of the total excretion. Up to 40% of the radioactivity in plasma and urine consisted of polar conjugates during the first 12 hours after administration of beta-methyldigoxin. The mono- and bisglycosides were identified as the main products of conjugation. During the 7 days approximately 15% of the administered dose was metabolized by splitting off glycosidic bonds and conjugation to polar compounds.


Relationship between renal function and elimination kinetics of pindolol in man. In view of a previous report suggesting an increased metabolism of the beta-blocking agent pindolol with decreasing renal function in man, the relationship between renal function and the elimination kinetics of pindolol has been re-examined. There is a statistically significant positive correlation between the renal clearances of pindolol and creatinine but there is no correlation between the non-renal clearance of pindolol and the renal clearance of creatinine. Thus, there is no evidence of an increased metabolism (non-renal clearance) of pindolol with decreasing renal function.


On the absorption and metabolism of 35S-ampicillin. An aqueous solution of 35S-ampicillin and polyethylene glycol (PEG 4000, unabsorbable marker) was administered orally to 6 healthy subjects with gastrointestinal tubes. The minimal absorption of radioactive material, as shown by urinary excretion of label, differed markedly between subjects and averaged 44% (25-67). As the mean cumulative uptake in the proximal jejunum was 31% (24-45), it appeared that some of the radioactivity had been taken up in more distal parts of the gastrointestinal tract. Chromatographic fractionation of gastrointestinal aspirates indicated that more than 95% of the label usually remained attached to the parent compound. The corresponding figure for radioactive material recovered from urine was about 80-85%. A similar degree of decomposition was also found for label excreted in the urine of an additional subject who received 35S-ampicillin intravenously. In this experiment the urine contained 87% of the administered radioactivity.


Serum concentrations of ampicillin and probenecid and ampicillin excretion after repeated oral administration of a pivampicillin-probenecid salt (MK-356). Twenty male volunteers received oral doses (2100, 1050, and 525 mg) of a pivampicillin-probenecid salt in a 1 to 1 molar ratio (MK-356) at 12 hour intervals. After each dose peak serum concentrations of probenecid were observed 2 hours later than peak concentrations of ampicillin. Following the first dose of MK-356 the apparent elimination rate of ampicillin was dose-dependent and did not follow first order kinetics, as it showed a longer apparent half life after a higher dose. An equal dose of MK-356 administered 12 hours later caused an increase in the peak serum ampicillin level greater than expected from the concentration of ampicillin after the preceding dose. In twelve male volunteers who received at random 525 mg of MK-356 or 350 mg of pivampicillin, each three times daily for 4 days, the areas under the ampicillin concentration curve were the same after the first or last dose of either drug. When 2100 or 1050 mg of MK-356 was taken as an initial dose, 30 to 40 per cent of the ampicillin was recovered from urine in the ensuing 12 hours. The results indicate that when at least 400 mg probenecid was coadministered twice daily with 700 mg pivampicillin (MK-356), the peak serum concentrations of ampicillin were increased and its elimination rate slowed following successive doses.


Effect of antiepileptic drugs on the elimination of various tetracycline derivatives. Elimination of the bacteriostatics tetracycline, doxycycline, methacycline, oxytetracycline, demethylchlortetracycline and chlortetracycline was studied in healthy control persons and in patients on long-term antiepileptic therapy. The half-life of doxycycline was significantly shorter in patients than in the controls. The half-lives of other tetracycline derivatives and their excretion in urine were not significantly different between the two groups. Accordingly, in order to maintain an adequate serum level of doxycycline it should be given twice daily to patients on long-term therapy with barbiturates, diphenylhydantoin or carbamazepine. The classical tetracycline derivatives studied may be administered according to conventional principles.


Pharmacokinetics of the anticonvulsant drug clonazepam evaluated from single oral and intravenous doses and by repeated oral administration. Eight healthy volunteers were given single i.v. and oral doses of clonazepam (2 mg). The disposition curves after i.v. administration showed a biexponential decline and the data were applied to a two-compartment open model. The volume of distribution ((Vd)beta) ranged between 1.5 and 4.4 l/kg and the plasma half-life (t1/2) between 19 and 60 hours. Absorption after oral administration was fast, with peak plasma concentrations within 4 hours in all subjects. Five of the subjects received repeated oral doses of clonazepam 0.5 mg bid for 15 days. The plasma level during steady state (estimated as Cmin within the dose interval) could be predicted from the constants A, B, alpha and beta obtained in the single dose study with a coefficient of variation of 6%. The plasma half-lives after cessation of the subchronic dosing were of the same magnitude as after single doses.


Quantitation of phenobarbital and its main metabolites in human urine. A method for the quantitative determination of phenobarbital and free and conjugated p-hydroxyphenobarbital in urine samples is described. The method includes initial extraction, purification on a small chromatographic column and finally determination by gas chromatography. The barbituric acids are methylated by trimethylanilinium hydroxide which serves as a "flash heater" methylating agent. The conjugate of p-hydroxyphenobarbital, which appears to be a glucuronide, is hydrolysed with hydrochloric acid.


Interaction of indomethacin and acetylsalicylic acid as shown by the serum concentrations of indomethacin and salicylate. A clinical-pharmacological study was performed to determine the effect of acetylsalicylic acid upon the serum concentration of indomethacin. 14 rheumatic patients were given indomethacin orally (25 mg X 4 for 4 days) and concurrently acetylsalicylic acid 3.7 g orally (0.9 g X 3 and 1.0 g X 1 daily), and 21 rheumatic patients were given indomethacin rectally in the morning (100 mg X 1) and concurrently acetylsalicylic acid 3.7 g orally (0.9 g X 3 and 1.0 g X 1 daily). On comparison with treatment with oral or rectal indomethacin alone, it was found that peak serum concentrations of indomethacin were significantly reduced (1% level), the times of the peaks were not shifted, and the areas beneath the serum concentration curves of indomethacin were smaller, but significantly so only if compared with rectal administration. In 12 rheumatic patients given indomethacin by rectum in the evening (100 mg X 1) and concurrently acetylsalicylic acid 3.7 g (0.9 g X 3 and 1.0 g X 1 daily), the serum level of indomethacin on the following morning (after 11 h) did not differ from that found after rectal treatment. A statistically but not biologically significant difference was observed between the mean serum half-lives of indomethacin given orally and rectally. For unknown reasons, concurrent doses of acetylsalicylic acid and indomethacin made the mean serum half-life of indomethacin longer than after its oral administration, but shorter than when the same dose of indomethacin was given rectally. There was no difference between serum levels of salicylate after oral administration of acetylsalicylic acid alone or after a concurrent oral or rectal dose of indomethacin. The results have been related to those reported previously, with respect to the interaction between indomethacin and acetylsalicylic acid, the serum levels of indomethacin after oral and rectal dosing, and the serum half-life of indomethacin based upon a one- or two-compartment model. The clinical relevance of the study is discussed.


Induction of drug metabolism in man after rifampicin treatment measured by increased hexobarbital and tolbutamide clearance. Five healthy volunteers took 1.2 g rifampicin daily for 8 days, and before and afterwards each received hexobarbital (7.32 mg/kg) and tolbutamide (20 mg/kg) by i.v. infusion on two consecutive days. The plasma concentrations of the two drugs were determined during and after infusion. The average elimination half-life of hexobarbital had decreased from 325 to 122 min and of tolbutamide from 418 to 183 min following rifampicin treatment. It was calculated that the metabolic clearance of hexobarbital had increased about three-fold and that of tolbutamide more than two-fold. Significant changes in the distribution kinetics of the two drugs were not observed. The results suggest that rifampicin is capable of inducing drug metabolism in man, which leads to an increased rate of elimination of drugs that undergo biotransformation in the liver.


Disposition of quercetin in man after single oral and intravenous doses. The pharmacokinetics of quercetin, a flavonoid, have been studied in 6 volunteers after single intravenous (100 mg) and oral (4 g) doses. The data after iv administration were analyzed according to a two compartment open model with half lives of 8.8 +/- 1.2 min for the alpha phase and 2.4 +/- 0.2 h for the beta phase (predominant half life), respectively. Protein binding was greater than 98%. The apparent volume of distribution was small at 0.34 +/- 0.03 1/kg. Of the intravenous dose 7.4 +/- 1.2% was excreted in urine as a conjugated metabolite, and 0.65 +/- 0.1% was excreted unchanged. After oral administration no measurable plasma concentrations could be detected, nor was any quercetin found in urine, either unchanged or in a metabolized form. These results exclude absorption of more than 1% of unchanged drug. Recovery in faeces after the oral dose was 53 +/- 5%, which suggests extensive degradation by microorganisms in the gut. The data obtained show that oral administration of flavonoids may be of questionable value.


General theory for rapidly establishing steady state drug concentrations using two consecutive constant rate intravenous infusions. Steady state plasma drug concentrations can be achieved rapidly and safely by a drug input mode consisting of two consecutive constant rate intravenous infusions. A general method for calculating the relative rates of the two infusions is presented. The derivation is independent of the concepts of compartmental distribution and elimination of drugs within the body.


A radioimmunoassay procedure for dexamethasone: plasma and urine levels in man. A sensitive and precise dexamethasone radioimmunoassay method was applied to the determination of dexamethasone levels in the plasma and urine of human subjects who had received small doses of the drug by mouth. While the method can be applied directly to plasma, urine has to be diluted before assay. Very little cross-reaction was observed with two possible metabolites of dexamethasone. Both in the healthy subjects and in the group of patients investigated rapid absorption of dexamethasone from the gastrointestinal tract was observed. However, there appeared to be a large individual variation in the plasma concentration of the drug obtained after doses of the same size.


Absorption of digoxin from the distal parts of the intestine in man. In 12 patients undergoing coloscopy, 0.5 mg digoxin in aqueous alcoholic solution was injected into the transverse colon. The late maximum of the blood level curve at about 2 hours after the administration suggested delayed absorption of the glycoside. However, the 24 hour urinary excretion of 17 +/- 3.4% in 8 patients with normal colonic mucosa demonstrated extensive absorption in the distal part of the bowel. The results have been contrasted with the findings in 4 patients with ulcerative colitis who excreted only 1.66 +/- 0.6% of the given dose in 24 hours.


Excretion of methylproscillaridin in patients with a biliary fistula. Four patients with a biliary fistula received 0.5 mg 3H-methylproscillaridin as a single oral dose. 55% of the dose was excreted in bile, 16% in urine and 3% in faeces. More than 60% of the radioactivity excreted in bile and urine appeared within the first 24 hours. 78% of the radioactivity in bile consisted of CHCl3-insoluble metabolites of methylproscillaridin, incubation of which with beta-glucuronidase led to splitting off glucuronic acid from almost 80%. Methylproscillaridin can be regarded as the principal conjugated compound. TLC-separation of CHCl3-soluble compounds from bile showed identical running of radioactivity with methylproscillaridin, proscillaridin and scillarenin and three unknown metabolites P1, P2, and P3. In urine the CHCl3-soluble fraction averaged 16% to 34% of the total amount and was identified as methylproscillaridin, proscillaridin, scillarenin, P2 and P3. The relative composition of the total radioactivity in faeces amounted to 77% methylproscillardidin, 4% scillarenin and 12% polar metabolites.


Urolithiasis induced with DL-3,a-dimethyltyrosine methylester HCl. I. A scanning electron microscopic investigation. Scanning electron microscopic investigations on rats subjected to DL-3,a-dimethyltyrosine methylester HCl treatment, indicated that the drug in reference induces renal lesions substantiated by proximal tubular epithelial cell regression and eventual exfoliation, coupled by formation of 3,a-dimethyltyrosine calculi both in the upper and lower segments of the urinary tract. The development of calculi was found to be preceded by a moderate to massive precipitation of a fibrin-like substance intermixed with blood cells, and with an occasionally concomitant deposition of exfoliated cells of epithelial origin, to be succeeded by precipitation of crystals.


N-(2-cyanethylene-)urea--an asparagine analogous cytostatic compound? The carcinostatic effect of the hitherto unknown N-(2-cyanethylene) urea is descirbed. The possible mode of action as an asparagine antimetabolite is discussed.


[Ultrastructural observations in the lamina elastica interna and adjacent tissue regions of the arterioles of rats impaired by hypertension of different pathogenesis (author's transl)]. The experiments aim to answer the question whether early changes in the lamine elastica interna of peripheral arteries causing consecutive plasmatic insudation of the vascular wall ("plasmatic vasculosis" according to GOLDBLATT) can be visualized by electron microscopy. Demonstration of early lesions in the elastica interna would facilitate the interpretation of structural changes in the arterial periphery during acute hypertension and its consecutive symptoms.  37 male albino rats, 3 to 4 1/2 months of age, body weight: 250 to 350 g. Controls 19 rats of similar age and body weight, 6 of which were injected the carrier substance of depot angiotensin PVP (VEB Berlin-Chemie). The test arrangement is represented in table 1. 3 hours to 10 weeks after starting the treatment different groups of experimental animals were sacrificed. Several animals were administered tracer substances for demonstration of early disturbances in permeability (ferritin: 20 to 40 mg per 100 g body weight, 3 to 60 min ante mortem; charcoal: 10 to 20 mg per 100 g body weight diluted in 1.5 to 3.0 ml of distilled water 15 to 30 min ante mortem). Electron microscopic investigations were carried out in arterioles of 15 mum to 100 mum in diameter which had been removed from the stomach, colon, jejunum, pancreas, mesenterium, partially from the brain and heart, in cases also from the lungs. For comparable specimens with respect to early ultrastructural changes only such tissue sections were selected that were light microscopically free from lesions. Preparation for electron microscopy was done in the common way. in light microscopically intact arterioles of all 3 groups (see table 1) the well-known disturbances of intimal permeability were electron microscopically observed already after 3 hours of experimentation. These changes occur always in the splanchnic organs and in the heart. Contrarily they do not regularly occur in the brain. In rats impaired by experimental neurosis (group III) the disturbances in perfusion of the intima recede, the consequences of enhanced metabolix activity in the media predominate in the sence of a "non-specific mesenchymal reaction" (HAUSS et al. 1964). However, it should be taken into consideration that this enhanced metabolic activity and cell proliferation may actually warrant the relative stability of the elastic barrier observed in this experimental group. In rats with nephrogenic and angiotensin-induced hypertension the experiments result in principally similar lesions of the lamina elastica interna originating from the vascular lumen. The diverging results in rats impaired by neurotically conditioned disturbed regulation of the blood pressure speak in favor of a prevailing reaction of the media at well preserved structures of the lamina elastica interna.


Interference-microscopical thickness measurements of isolated nephrogenic basement membranes. The results of interference-microscopical thickness measurements of isolated nephrogenic basement membranes are reported and discussed. Tubular and glomerular basement membranes were examined by the shearing technique with total image splitting, the kidneys used having obtained from pigs as well as from human beings. It was not possible to determine a statistically significant difference in thickness between tubular and glomerular basement membranes obtained from pigs. Human glomerular membranes were found to be much thicker in long-time diabetics than in normal subjects. Also, glomerular membranes of young persons are thinner than the membranes of adults.


Starch and chemotaxis. A histological study in the mouse. Primary interest in inflammation centers around the mechanism by which polymorphonuclear leucocytes emigrate from the circulating blood to an area of injury, a process apparently first designated as "chemotaxis" in 1888. Recent experimental studies have emphasized the role of ions in the pathogenesis of thrombi in the circulatory system following the implantation of plastics. The negatively charged leucocytes are attracted by positively charged plastics. Starch granules have a positive charge and, when implanted subcutaneously in the mouse, attract the negatively charged leucocytes. Sixty minutes after the subcutaneous implantation of starch granules in the subcutaneous tissue of mice polymorphonuclear leucocytes had begun to emigrate to the area. The number of leucocytes rapidly increased for 24 to 72 hours and then progressively decreased. By the 5th experimental day the number of leucocytes had decreased markedly and continued to decrease in their emigration to the granules of starch. The positive ionic charge associated with the granules of starch is neutralized by the adsorption of the negatively charged plasma protein ions. It is suggested that chemotaxis is an electrochemical phenomenon.


A technical and methodical design for differential-thermometry of human incisors. The technical design and the practical applicability of a thermistor based, highly sensitive, differential temperature recorder is described. Problems and relevance of differential temperature recording of upper incisors are discussed.


[Renal glutaminase I activities in experimental and human chronic pyelonephritis (author's transl)]. For more exact knowledge on the pathogenesis of pyelonephritis a series of large scale histochemical and biochemical investigations were performed. In this study the author reports his observations on the renal glutaminase I activities in experimental and human pyelonephritis. Details on materials and methods were given in a recent paper [PHILIPPSON, Exp. Path. 8, 182-193 (1973)]. Glutaminase I activities (L-glutamine amidohydrolase, EC 3.5.1.2.) were quantitatively analyzed according to MATTENHEIMER and DEBRUIN (7) in which the reaction was not only produced by cooling but also by simultaneous inhibition by means of 15% trichloric acetic acid. Ammonia was released and determined by Berthelot's reaction as modified by WELLER (18). The results in rabbit kidneys are compiled in the tables 1-3, the observations on human kidneys are represented in table 4. 139 rabbits showed unilateral experimental pyelonephritis, in 19 rabbits pyelonephritis did not develop or "healed up spontaneously". 31 samples of pyelonephritic nephrocirrhotic human kidneys (obtained by surgical operations) and 20 samples of healthy human kidneys were investigated. After separation of renal cortex and medulla the cortex was separated into glomerula and renal tubules by differential centrifugation. Significance was tested by universal comparison of the group mean values by t-test (rabbit and human kidneys separately). 1. In the rabbit glomerula glutaminase I (glut I) activities were increased significantly from the beginning of the experiment up to 100 days. They decreased markedly in the subsequent nephrocirrhotic stage (fig. 1). 2. The glut I activities in the rabbit cortical tubules decreased immediately, intensively and succesively up to the late-chronic nephrocirrhotic stage. 3. The rabbit medullary glut I showed likewise intensive decrease in the acute and subacute phase progressing to very low activities in the nephrocirrhotic stages. 4. In all samples from human pyelonephritic nephrocirrhoses (glomerula, cortical tubules and medulla) extremely decreased glut I activities were demonstrated. 5. The enzyme activities observed and the results of the semiquantitative histological analysis [SORGER and co-workers, Exp. Path. 9, 280-287 (1974)] are closely correlated. 6. In the glomerula of the "spontaneously healed up" tissue the glut I activities were markedly increased whereas they were moderately decreased in the cortical tubules and in the medulla. 7. The dry weights and values of protein content were equal to those earlier reported (PHILIPPSON 1973). 8. In the significance test (universally applied t-test) the overwhelming majority of the values showed high significance (p less than or equal to 0.001). The results are correlated with the observations of the semiquantitative histological analysis (SORGER et al. 1974) and discussed on the basis of data reported in literature.


Endocellular parasitism of Mycobacterium avium in rabbit liver. A morphological study. Yersin's type of experimental tuberculosis was induced in rabbits by intravenous administration of Mycobacterium avium and was studied in situ in the liver. Mycobacteria were only found in Kupffer-cell phagosomes and, at the later stages of the disease, in the phagosomes of the multinuclear giant cells. Ultrastructural changes in Kupffer's cells amounted to an increase in cytoplasm volume and corresponding increase in the number of ribosomes, endoplasmic reticulum and mitochondria. As compared with control animals, Kupffer's cells were more frequent in the experimental rabbits, clustering around sinusoid capillaries. Characteristic changes in mycobacterium ultrastructure were cytoplasmic vacuolisation in some individuals and an almost regular presence of high-density polymorphous structures. The microbial cell walls remained intact.


[Effect of Solanum melongena on experimental atheromatosis. IV. Histological studies on cholesterol-induced atheromatosis in rabbits in mean- and long-term tests (author's transl)]. In earlier studies [see literature (2, 20, 21, 22)] observations concerning the effect of Solanum Melongena (Sol. Mel.) (violet egg plants) on experimentally induced artheromatosis in rabbits were reported. This study aims to investigate histologically the effect of Sol. Mel. on experimental atheromatosis in mean-term (2--4 weeks) and long-term (8--12 weeks) tests. For details of the test arrangement see AUBOCK and MITSCHEK, Exp. Path. 9, 323--335 (1974). From one portion of the material for histological examination cryostat sections were prepared, the other portion was fixed in Bouin's solution or in Baker's formol and paraffin-embedded at 58--60 degrees C (cross sections of the aorta). The specimens were stained as follows: erythrosin in conjunction with haematoxylin; aqueous or alcoholic solutions of toluidine blue (pH 3.5 to 5, and 7); methylene blue (pH 2.5 to 5, and 8); alcian blue (pH 2.5); Schiff-PAS; alcian blue and PAS in combination; Sudan III; elastica-van Gieson (blue) and Weigert's iron haematoxylin. For demonstration of mucopolysaccharides (MPS) the control sections were pretreated in a 10% Takadiastase solution for 10 minutes at 37 degrees C. In liver sections PAS-reactivity was additionally blocked by dimedone (cyclohexanedione) for elective demonstration of glycogen. The tissue sections were studied in transmission--, incident- and dark field illumination. lipid deposits as demonstrated by surface preparation technique could not be seen in paraffin sections after just one day. In the vascular wall histological changes were earliest visible after 10 to 14 days (enlargement of the subendothelial space and honeycombed edema with fine dispersed lipids). At this stage a "haematoxylin-effect" did yet not develop. Sometimes these alterations were also present in the upper layers of the media. They always first occurred in the aortic arch. At this time the Sol. Mel.-treated animals of group II only occasionally developed superficial edemas. Enlargement of the media with edematous infiltration and loosening of the elastic fibers was similar in both cases (figs. 1a and 1b). Fatty degeneration of the liver was already macroscopically visible on day 14; in untreated animals of group I it was more expressive than in group II (figs. 2a and 2b) -- this likewise applied to the cholesterol content (figs. 3a and 3b). After about 30 days in group I the earliest macroscopically visible plaques occurred prevailingly in the aortic arch and in the thoracic aorta. The development of such small foam cell plaques could be continuously observed with a hand lens (fig. 4a). In group II, however, it was not possible to observe any development of plaques with a hand lens, persistence of edemas was demonstrable with such (fig. 4b). Within these, fine dispersed droplets were present (fig. 5) but exact localization was only possible by electron microscopy [see literature(2)].


Influence of an eggplant (Solanum melongena) preparation on cholesterol metabolism in rats). To investigate the mechanism behind the hypocholesteremic properties of Solanum melongena diets containing 1% Sol. mel. leaf or fruit powder, alfalfa, or clofibrate were fed to rats. Sol. mel. did n ot lower the serum plus liver cholesterol pool of rats, whereas alfalfa and clofibrate did. However, all substances tested decreased the absorption of a single dietary dose of [4-14C] cholesterol. It appears that Sol. mel. exerts its reported hypocholesteremic effect in rabbits through an inhibition of absorption of dietary cholesterol. This inhibition is probably brought about partially through the binding of bile salts which are essential for cholesterol absorption.


The influence of l-methionine-d,l-sulfoximine on the labelling of acid soluble fraction and proteins of the brain cortex after intraperitoneal injection of 14c-leucine. Methionine sulfoximine (MSO) inhibits the labelling of the acid soluble fraction and proteins of the brain cortex after the injection of 14C-leucine. The inhibition takes place even during the early stages after the injection of MSO, when no symptoms of paroxysms are observable. The action of MSO on the labelling of the acid soluble fraction and proteins in the brain cortex is obviously different from that in the kidney and liver. Whereas in the brain tissue MSO markedly influences the labelling of the free amino acid pool, in the kidney and liver it seems primarily affect the protein synthetic mechanisms. Also no decrease in labelling of the plasma acid soluble fraction was found on mice, treated with MSO. Experimental data support the idea, that the changes in the metabolism of proteins in the brain are not connected with the onset of the paroxysmal period.


[The influence of adrenalectomy on DNA-synthesis in the liver after partial hepatectomy and on corticosterone concentration of the serum in rats (author's transl)]. Problemacy: In an earlier paper we have reported the influence of adrenalectomy on DNA-synthesis in rat liver and found that during the first 2 days the incorporation of H3 thymidine is elevated). (DESSER-WIEST 1974). Therefore we have examined the DNA-synthesis in regenerating live of rats with and without adrenals. 300 g male rats were adrenalectomized and 14 days later 2/3 hepatectomized. One group of animals were bled and the concentration of corticosterone in serum was determined by a radioprotein-binding method (SPATH and JOZAN 1972). The other group of animals were injected with H3thymidine at 9 a.m. All animals were killed between 10:00 a.m. and 10:15 a.m. The incorporation of H3thymidine was determined by the method of BURTON (1969). In adrenalectomized animals, the onset of liver regeneration was found to be retarded for 18 hours, the maximum of DNA-synthesis was depressed. The corticosterone concentration of the serum was 17,8 mug/100 ml serum in contro animals and was undetectable in animals during the first and second day after adrenalectomy, thereafter the steroid level increased. A third of the amount found in control animals was found 14 days after operation. Partial hepatectomy, caused an increase of the corticosterone level in serum of animals with and without adrenals. In castrated and adrenalectomized animals no corticosterone in serum was found. The importance of corticosterone for liver regeneration is discussed.


Histological changes of terminal bronchioles in rats during the exposure to nitrogen dioxide. At long-term exposure to 5 ppm NO2 (w/w), courses of histological changes in the epithelium of the terminal bronchioles of rats were observed. In the course of the experiment the first alterative changes were expressed by the loss of cilia and cell differentiation. The changes were followed by epithelial hyperplasia, leading to conspicuous narrowing of the lumen of bronchioles. After the phase of hyperplasia a phase of reparation followed, leading to the development of nonciliated epithelium without determinable Clara cells, with areas of uniform multi-layered epithelium. At the same time, in the longest interval of 11 weeks new alterative changes analogous to those found at the beginning of the experiment were observed.


[Electron microscopic study on the "ghost bodies" in experimental arteriosclerotic lesions of the vascular wall (author's transl)]. Details on the origin and the pathogenesis of the so-called "ghost bodies" occurring in the arteries and arterioles following experimental lesions of the vascular wall were to be studied under peculiar experimental conditions (immunological injury and cholesterol diet in combination). The experiments were carried out on 26 young rabbits of the same race and equal sex. They were selected from several test groups with experimentally induced arteriosclerosis. For challenge of immunological injury the animals were administered 3 intracutaneous injections of each 3 ml of horse serum at intervals of one week. Afterwards they received one or two intravenous injections of 2-3 ml of horse serum at weekly intervals. Immediately after the last injection the animals were sacrificed. A series of the animals were fed a cholesterol diet for some weeks after previous immunological injury (for details see WEIDENBACH and MASSMANN 1972). From a total of 26 animals always several sections of the aorta were investigated. 5 animals were used for controls. After decapitation of the animals the aortas were removed immediately and fixed in 2.5-3% glutaraldehyde for 2 hours. Afterwards they were postfixed in 1% osmium-Millonig solution for 1 hour. After 15 min the tissue samples were washed in Tyrode solution for 15 min, dehydrated in ascendent aceton grades and contrasted in blocks in the stage of 70% aceton. After embedding in Micropal the material was sectioned by an ultramicrotome OmU2 (Fa, Reichert, Wien) and investigated in electron microscopes of the types SEM 2-3 (100 kV) or KEM 1-2 (60 kV) (VEB Werk für Fernsehelektronik Berlin-Oberschöneweide). Basing on their observations the authors classify as ghost bodies all cytoplasmic protrusions and all constricted extracellular structures which are limited by a membrane and filled with prevailingly filamentous-granular material (figs. 1, 2, 3), occasionaly also including fragments of cell organelles (fig. 4). They develop from cytoplasmic protrusions or bulgings of the processes of smooth muscle cells (figs. 1 and 2). In these protrusions the cytoplasm of the smooth muscle cells is loosened and of filamentous-granular appearance (fig. 1). The cells themselves show all characteristics of a modified or activated smooth muscle cell: they are branched, the organelles display marked secretory-metabolic activity associated with partical loss of the contractile elements whereas degenerative changes of these cells are nearly completely absent. Frequently focal disorganization of the cell membrane with release of the content to extracellular regions can be observed which is locally associated with the development of fibrillar structures.--In the environment of the "ghost bodies" the formation of collagenous fibres is visible (fig. 3). Degenerative changes which point to transition to necrosis can only occasionally be observed...


[DNA-synthesis in the final stages of the S-phase and G-banding in neoplastic cells of the rat (author's transl)]. In literature reports on quantitative studies concerning DNA-synthesis during the final stages of the S-phase in normal cells of men and of rats are available whereas observations on tumor cells are scarce. Therefore, in this study 2 clones isolated from chemically induced tumors in the nervous system of the rat have been investigated to enable comparisons with normal cells. Furthermore, the G-banding pattern was studied in the same material. The experiments were performed on clones from experimentally induced tumors of the rat central nervous system (Rattus norvegicus) which were isolated in the own laboratory. PIE 2-3: Clone from an intermedullary tumor induced by intravenous application of methylnitroso urea (MNU) (dosis: 25 mg/kg at 4 weeks intervals) in a male Hauben rat (experiment no. 1190). After twofold intracerebral transplantation the tumor was cultured and the clone isolated by means of a modified feederlayer-technique (THUST 1975). Following reimplantation PIE-2-3 developed spindle cell sarcomas (THUST and WARZOK 1972). PIE 27-1: This clone was isolated from an MNU-induced adventitial sarcoma in the base of the brain (dosis: 20 mg/kg at 4 weeks intervals) in a male Hauben rat (experiment no. 744). Before cloning this tumor was 47 times intracerebrally transplanted. PIE 27-1 develops in vivo undifferentiated densely packed sarcomas. The clones were in vitro cultured in Eagle's MEM supplemented by of 20% bovine serum and 0.25% lactalbumin hydrolysate, then passaged by means of trypsin solution at a ratio 1:10 at weekly intervals. Autoradiography: 3H-thymidine (specific activity: 14 Ci/mM;N.V. Phillips-Duphar, Holland) was administered to the cultures in a concentration of 0.5 muCi/ml. 30 min before chromosome preparations colcemide (0.01 mug/ml) was added to the corresponding culture flasks. 2.5 hours after 3/-thymidine administration chromosome preparations were processed at 30 min intervals. The preparations were stained with carbol fuchsin and covered with a Formvar membrane (STUBBLEFIELD 1965). For preparation of autoradiographs Kodak AR 10 film was used. After 10 days exposition the preparations were developed for 5 min at 18 degrees C in Kodak D19b. The autoradiographs were photographed at 400-fold initial magnification, afterwards the stripping film was removed and, for better identification of the particular chromosomes, the same mitoses were photographed again. Silver grain countering and mode of evaluation have been described in detail in an earlier study on normal cells (THUST and DIETZ 1972; see also PASSARGE et al. 1969). When the autoradiographs were examined the G-bandings were yet not available. Therefore some chromosome pairs of the rat karyotype could not be differentiated (teleocentric chromosomes X, 4-10 and XX, 4-10, respectively, as well as the metacentric chromosomes no. 11-12, 15-18 and 20). For this reason the evaluation was based on the average length of these chromosomes...


Carcinostatic action of 2-cyanaziridines against a sarcoma in rats. The carcinostatic action of two 2-cyanaziridines against a sarcoma in rats is described. The in vitro behaviour of the up to now unknown 2-cyanaziridines is discussed. Their properties are compared to those of the unsubstituted aziridines.


Manganese induced hepatic lesions in carbon tetrachloride pretreated rats. Manganese sulphate (6 mg/kg) was administered intraperitoneally daily for 30 days in carbon tetrachloride pretreated rats. Histological and histochemical studies in liver tissue revealed extensive damage to hepatic parenchyma in these rats as compared to lesions produced by manganese sulphate alone. These findings suggest that workers, with liver dysfunction ergated in manganese industry may be more susceptible to the toxic effects of this metal.


The influence of polymorphonuclear leukocytes and macrophages on the growth of lymphocytes and fibroblasts in vitro. The influence of polymorphonuclear leukocytes (PMNL) and macrophage plasma, nuclei and lysosome extracts have been tested on lymphocytes and fibroblasts growth in vitro. The stimulatory activity of PMNL lysosomes has been shown on lymphocyte and fibroblast growth. The macrophage lysosomes have shown a similar but lower activity. The role of lysosomes has been suggested in reparation and wound healing processes, presumably in inflammatory cell infiltrated regions.


Determination of the glycogen contents in the brains of perinatal and newborn rabbits under conditions of experimental hypoxia. The glycogen contents of 121 rabbit brains having different levels of hypoxia were determined, calculation being in mg% of glucose per g of brain. It was possible to observe significant reductions in carbohydrate content under conditions of acute and chronic hypoxia. Moderate prepartum accumulation of glycogen in untreated rabbit brains is likely. Chronic reduction in reserve fuel resulted in deficient development of the brain, as is clearly shown by brain weight determinations. This enables a parallel between this condition and intrauterine dystrophia.


[Sephadex induced inflammation in rats (author's transl)]. A single s.c. injection of Dextran is very suitable in producing an inflammatory response in the rat. The Dextran edema has become a standard method. It seems not uhlikely that Sephadex, the Dextran gel widely used in the gelchromatography may have a similar effect. Sephadex, because of its physiochemical properties, would offer some advantages in the studies of inflammatory reactions. But first of all the following questions have to be answered: 1. Does one single s.c. injection of Sephadex produce an inflammation at all and what are the characteristics on the microscopical level? 2 Does it make any difference if Sephadex of different types are injected? Male and female Wistar rats (100-250 g) in groups of 5 animals each. Diet: Rat pellets "Tagger" and tap water ad libitum. Sephadex (Pharmacia Fine Chemicals) of the types G-25 m, G-50 m, G-100, and G-200 were soaked in 0.9% saline for the prescribed time and afterwards preserved until the Sephadex gel had settled on the bottom of the vessels. 1 ml of this Sephadex gel slurry each were subcutaneously injected to the shaved dorsal skin of the rats (right below). At different intervals (3, 6, 24 and 72 hours: 6, 14, 20 and 28 days) the Sephadex depot and the surrounding tissue were exstirpated and examined histologically. During all the procedures the animals were subjected to ether anesthesia. From the tissue samples frozen sections (Kryocut, -30 degrees C) were prepared and stained with hematoxylin and eosin or after van Gieson. Moreover, several preparations were stained after Pappenheim and Weigert (fibrin) or with PAS and toluidine blue. For recording of probable differences in the effect of the particular Sephadex types always 2 values were determined histometrically. The number of exudate cells emigrated between the Sephadex beads within the area of an ocular-net (edge length 1.66 mm) were counted at 500-fold magnification. Furthermore, the number of eosinophils was determined by the technique. However, because of poor occurrence the eosinophils were counted in 10 fields of view. Tests with Sephadex G-10 were omitted as preliminary tests had shown that it is not suitable for s.c. injections because of its gritty consistency (due to poor soaking properties). One single s.c. injection of Sephadex in the rat induces an acute inflammation. The exudative phase marked by a massive leucocytic infiltration (especially PMN leucocytes) is followed by the appearance of mononuclear leucocytes and fibroblasts after the 2nd day. The inflammation declines within approximately 3 weeks. Thereafter the Sephadex depot is encapsulated by a fibrous tissue. A chronic inflammation was never observed. In the microscopical aspect of the inflammation produced by the different types of Sephadex were detectable. The Sephadex lying in the tissue does not change its original shape, it is insoluble and is not disintegrated. The size of the particles prevents the transport into the blood or lymph vessels...


Placental transfer of tritium-labelled prostaglandin A1 in the rat. Pregnant Long Evans rats were treated with 25 muCi 3 H-prostaglandin A1 on either gestational day 15, 18 or 21. The highest concentrations of radioactivity were found in maternal kidneys, lungs and liver. The levels of radioactivity in the gut and also in amniotic fluid markedly increased with time after isotope administration. Significant levels of radioactivity were present in fetal tissues and in the placenta.


Tumor-inducing effect of trinitroso-trimethylene-triamine (TTT) when orally applied in dimethylsulphoxide (DMSO) for solvent. By oral application of TTT, disolved in concentrated DMSO, it was possible by means of a long-term experiment to produce tumors in female rats (Wistar strain). Contrary to all previous findings the tumor-inducing effect of this substance has been proved in this way for the first time.


[Experimental xenogenic immune pancreatitis. 1. Histological findings in the mouse exocrine pancreas after treatment with anti-mouse pancreas rabbit serum (author's transl)]. In the pathogenesis of some forms of chronic pancreatitis an immunological influence has been discussed. Therefore, experimental studies of the exocrine pancreas after immunological damage should be done. In this communication histological findings on the mouse exocrine pancreas are presented after treatment with anti-mouse pancreas rabbit serum. a total of 71 adult male white mice was divided into 4 groups treated in the following way: 1. 35 animals with anti-mouse pancreas rabbit serum 2. 14 animals with normal rabbit serum 3. 16 animals with physiological saline 4. 6 animals remained untreated. The sera under study and the saline were, without exception, administered intraperitoneally with single doses of 0.3 ml once, resp. twice daily for 0 up to 16 days. Constantly, 3 hours before sacrifice, the animals received the last injection. For histological examination, the fresh pancreas was fixed in formaline. After embedding in paraffin, sections were stained by the following methods: hematoxyline-eosin, trichrome according to Goldner, Giemsa staining, PAS-reaction, and tryptophane demonstration according to ADAMS (1957).


Fibrogenic response in murine lungs to asbestos. Pulmonary fibrogenic response was investigated in mice following intratracheal inoculation of amosite, anthophylite and tremolite varieties of Indian asbestos and studies were made over a period of 150 days. At early periods all the varieties produced acute inflammatory reaction in the lungs. Thick reticulum fibers were encountered at later periods with amosite, while only thin reticulum fibers developed with anthophyllite or tremolite variety. The formation of asbestos bodies did not take place with any of the asbestos varieties even at 150 days. The deviation in the pulmonary fibrogenic response in mice has been attributed to species difference.


Electron microscopic study on the injurious effects of chlorpromazine on rat liver cells. The authors examined the effect of chlorpromazine administration on rat liver cells. The early alterations were limited to the pericanalicular region, but the dilatation of bile canaliculi and the destruction of canalicular microvilli, both characteristic of rats with cholestasis were not observed. It is suggested that beside the Golgi apparatus, the smooth surfaced endoplasmic reticulum, the plasma membranes of liver cells also have an important role in the formation of vesicles and vacuoles in the pericanalicular region. The progressive proliferation of the smooth surfaced endoplasmic reticulum is thought to be related to an increased overburdening of the biotransformation system of liver cells, which is the result of chronic drug administration. In the last period of the experiment there was a decrease in the quantity of rough surfaced endoplasmic reticulum and increased fatty infiltration, mitochondrial alterations in some liver cells and simultaneously numerous regenerating liver cells were observed. All these alterations are attributed by the authors to the direct liver injuring effect of chlorpromazine.


On the effect of prednisolone on hamster bone. Over a period of 10.8 weeks 0.4, 4.0 or 40.0 mg, respectively of prednisolone bisuccinate/kg/day were injected intramuscularly into Syrian golden hamsters with a body weight of about 100 g. The dosage of 4.0 mg of prednisolone/kg did not produce any osteoporotic changes. The modulus of elasticity and the fracture load of the bones under investigation did not differ from the values obtained in control animals. At a dosage of 0.4 mg of prednisolone/kg/day the values of analysis (density, ash/cm3, calcium/cm3 and hydroxyproline/cm3) decreased by 5-8 percent, and at a dosage of 40.0 mg of prednisolone/kg/day even by 20-34 per cent as compared with the control group. The modulus of elasticity and the fracture load were significantly changed.


Giant osmiophilic lamellated bodies after temporary ischemia of the rat lung. Following temporary ischemia of the rat lung an atelectasis was observed after resorption of the extravasate. To determine whether changes in osmiophilic lamellated bodies (OLB) precede and perhaps  cause the atelectasis the upper lobe of the right lung was in eight white Wistar-rats subjected to temporary ischemia of 10 minutes. The two axial diameters of the intracellular OLB and their precursors were measured on electron micrographs 10 minutes, 60 minutes, 1 day and 2 days after cessation of the ischemia. The mean diameters were compared by statistical methods. Already after 10 minutes the usual elliptic cut surfaces of OLB were found to be more circular presumably because of swelling caused by an osmotic insufficiency of their membranes. After 2 days, the mean diameter of OLB had doubled, while shape and structure stayed normal. At the same time, the small precursor stages were missing. Consequently, we assume that formation of new OLB--represented by small non-lamallated osmiophilic bodies--and the incorporation of lipids into existing lamellar bodies are processes independent of each other. After a short, temporary ischemia only the formation of new osmiophilic bodies seems to be interrupted and this is associated with a quick growth of existing OLB. However, apparently these cannot be excreted in due time. The result could be lack of surfactant, which would account for the postischemic atelectasis.


Ultrastructural response of hepatocytes to thymectomy and pregnenolone-16alpha-carbonitrile. In young female rats, thymectomy causes RER alterations and a slight increase in SER. PCN augments SER in the hepatocytes of both intact and thymectomized rats. Thymectomy prolongs zoxazolamine paralysis and PCN treatment decreases the duration of zoxazolamine paralysis both in intact and operated rats.


Wheat germ agglutinin and Ticinus communis agglutinin as specific saccharide stains in light and electron microscopy. Two plant agglutinins, wheat germ agglutinin and Ricinus communis agglutinin, were used for light and electron microscopic detection of certain carbohydrate-containing cell surface components and extracellular polysaccharides. For light microscopic studies on various tissues fluorescein isothiocyanate coupled lectins were prepared. The ferritin coupling of the lectins for electron microscopy was performed by glutarldehyde in the presence of the specific hapten. The specificity of the reactions was demonstrated by blocking with the hapten.


Malformations induced by hormones in mice and their transmission to the offspring. A fore foot defect occurring after gonadotropin stimulated ovulation in the offspring of Swiss albino mice is described as an abnormality which is transmitted to the offspring of several inbred generations. This malformation is a combination of postaxial oligodactylism and polydactylism, in literature so far not described previously. The defect originally observed after hormone treatment (postaxial oligodactylism) occurred most frequently. With others it has been considered whether the defect of the foot, which is in all probability subject to polygenic control, manifests itself as a result of selective factors during embryogenesis. A possible mutagenic effect of the sex hormones on the germ cells is also under consideration. This view is supported by clinical observations.


Lens culinaris lectin receptors in the plasma membrane of rat liver cells: comparative electron microscopic studies on normal cells, on cells in vivo transformed by diethylnitrosamine and on Zajdela ascites hepatoma cells. The distribution of the Lens culinaris lectin receptors on normal rat liver cells, on rat liver cells in vivo transformed by diethylnitrosamine and on Zajdela ascites hepatoma cells of the rat is investigated by means of the Lens culinaris lectin-peroxidase method and by ferritin conjugated Lens culinaris lectin. The normal rat liver cells show a continuous labeling at the outer membrane surface by the lectin complexes, whereas the transformed rat liver cells exhibit a strong tendency for patchy distribution of the cell surface label. The discontinuous cell surface label in the transformed rat liver cells is obviously caused by an internalization of plasma membrane areas. The importance of these morphological findings in their relationship to Lens culinaris lectin mediated agglutination  of rat liver cells and the membrane fluidity in general are discussed. In the experiments no hints to a rotation of the Lens culinaris lectin receptors from the outer membrane surface to the inner membrane surface of rat liver cells can be found.


Diabetogenic effects of N-nitrosomethylurea with special regard to species variations. The effect of N-nitrosomethylurea on the blood-glucose and the pancreatic islet light microscopic picture was studied in the Chinese hamsters, golden hamsters, guinea pigs, mice, rats and sand rats. The Chinese hamsters were most susceptible. Only in this species did a dose of 50 mg/kg body weight cause blood-glucose elevations and pancreatic islet damage. At a dose of 100 mg/kg body weight of N-nitrosomethylurea, blood-glucose elevations were recorded in the golden hamster together with damage to the islets and the exocrine pancreatic parenchyma. A toxic dose of 200 mg/kg body weight resulted in hyperglycemia and islet cell destruction in the rat and in slight alterations in the islets of mice. N-nitrosomethylurea was non-diabetogenic to guinea pigs and sand rats. The ethyl derivate of nitrosourea was less toxic and diabetogenic to the Chinese hamsters in comparison with the methyl derivate.


[Histological studies on the antiphlogistic effects caused by natural antiinflammatory factors (author's transl)]. The dextran gel Sephadex causes a marked inflammatory response in rats when injected subcutaneously. This effect was used as a model of experimental inflammation. Sephadex and the resulting inflammatory exudate were gained and used again to study their antiphlogistic effects in the identical model. Histological reactions of the Sephadex induced acute inflammation were analyzed with and without presence of the exudate. Male and female Wistar rats (100-250 g). Sephadex  G-200 (Pharmacia Fine Chemicals). Sephadex B-200 (1 ml, swollen in 0.9% NaCl) was injected subcutaneously in the control group (C), whereas the experimental groups were injected with either untreated Sephadex taken from 1,3 and 5 days old inflammatory deposits (group A) or with Sephadex, extracted from those deposits but subsequently washed free by 0.9% NaCl (group B). Only the inner and not yet organized part of the Sephadex deposit was used in both experimental groups. In group A, B and C the histological effects were examined 24h after injection. The number of eosinophils amongst the exudate cells was counted. 100 mast cells of the perifocal region were examined in order to measure the percentage of degranulated cells. A smear differential count was performed using subepidermic parts of the Sephadex deposit. Sephadex injection caused a very marked inflammatory reaction which was studied extensively. Similar results were obtained either using fresh Sephadex or washed Sephadex from inflammatory deposits. However, Sephadex from inflammatory deposits without wash induced only mild inflammatory reactions. All signs of acute inflammation were less pronounced. Hence, the phlogistic efficacy of Sephadex is reduced by the simultaneous presence of exudate. The most significant antiphlogistic effects were seen when exudate containing Sephadex  from 3 days old inflammatory deposits was used. The significance of soluble parts of the exudate in these antiphlogistic effects is discussed.


The morphological changes in the sinusoid in bone marrow studied with administration of soluble immune complexes--structural changes of sinusoid in allergic process. The morphological changes of the sinusoidal endothelia in the bone marrow of a guinea pig have been studied with the administration of soluble immune complexes. There were noted sinusoidal distension with distinct endothelial and plasma stasis with a few blood cells.


Structural patterns and histological behaviour of experimental sarcomas. II. Ultrastructural cytology. In continuation of our investigations on methylcholanthrene-induced rat sarcomas, in analogy to light microscopical results, various cytological differentiations could be demonstrated by the electron microscope. Some tumour cells are comparable to the cellular counterpart in normal connective tissue, whereas most of the tumour cells show various series of cytological traits of different types of normal connective tissue cells simultaneously. The vast majority of tumour cells exhibited characteristics of fibroblasts and histiocytes coincidently. However, classical fibroblasts and histiocytes were seldom present. One part of the tumour cells showed structural features as known from so-called myofibroblasts and smooth muscles cells. Furthermore, vasoformative potencies of sarcomas with imitation of endothelial and pericytic cells must be emphasized. With respect to the histogenesis of these sarcomas possible origin from the microvasculature is discussed.


Modification of the surface structure of murine peritoneal macrophages following chemotherapy. A scanning electron microscopic study. The effects on peritoneal macrophages of some chemotherapeutic agents administered subcutaneously to conventional male AB/Jena mice were studied. beta-[1-ethyl-(5-bis-(beta-chloroethyl)-aminobenzimidazolyl-(2)]-DL-alanine (IMET 2925), beta-[1-phenyl-5-bis-(beta-chloroethyl)-amino-benzimidazolyl-(2)]-DL-alanine (IMET 3164), and gamma-[1-phenyl-5-bis-(beta-chloroethyl)-amino-benzimidazolyl-(2)]-butyric acid (IMET 37/70) evoked a pronounced variation of the cell surface consisting in a shortening, coarsening and reduction in number of the microvili and other projections. Likewise, 1.3-bis(piperidinomethyl)-5-ethyl-5-phenyl-barbituric acid induced a flattening of the surface, but the structures appeared to be increased in number per area. Chlorambucil, 6-mercaptopurine, and 5-fluoro-uracil failed to provoke any obvious change in the threedimensional cell surface structure. These morphological findings are consistent with functional results reported previously.


Fatty acid pattern of cerebral lipids in cyanide encephalopathy. From the analysis of the fatty acid spectrum of the individual lipid fractions of the cerebral white matter in cyanide induced encephalopathy would appear that essentially the phosphatidyl ethanolamine and plasmalogen fractions showed appreciable deviations from the control spectra. The observed changes in the cholesteryl ester composition did not correlate with the macrophage reaction, which is known to appear as late as 14 days after HCN intoxication when morphological signs of demyelination become apparent. Neither was there a correlation between the alterations of the phosphatide fatty acid composition and that of cholesteryl esters. It thus would appear that esterification of cholesterol in the myelin of rats occurring during early stages following cyanide intoxication constitutes one of the primary factors injuring the myelin sheath. The same conclusion seems to be applicable to the changes in fatty acid composition of the white matter phospholipids.


Nephrotoxicity of Cortinarius speciosissimus: a histological and enzyme histochemical study. The nephrotoxicity of the mushroom species Cortinarius speciosissimus was studied in the rat. Dried, homogenized mushroom was given orally via gastric tubing. The development of the kidney damage was followed by both histological and enzyme histochemical methods. The first signs of kidney damage were interstitial infiltrates occurring mainly in the outer medullary zone, observed two days after the administration of the mushroom. Focuses of inflammation, which gradually scarred, appeared after four days. Chiefly necrotic changes occurred in the tubuli of the cortical zone. Valine residue cleaving aminopeptidase disappeared from the necrotic tubuli at a noticeably greater rate than arginine residue cleaving aminopeptidase. A high activity of arginine residue cleaving aminopeptidase was observed in the inflammatory focuses located in the outer medullary zone, showing the important role of this enzyme in kidney inflammation.


Ultramicroscopic investigations of the exocrine pancreas of the dog after vagotomy. The exocrine pancreas of 20 dogs was investigated electron microscopically before and 3, 4, 10, 11 and 14 days after bilateral truncular vagotomy. Up to the tenth day of the experiment a disturbance of the secretion of the acinar cells could be found with a sustained increase in enzyme protein synthesizing and lysosomal activity, irregular formation of zymogen granules and probably continuous extrusion of the enzyme proteins. The possible regulation mechanisms after vagotomy are discussed.


Effects of swimming on dystrophic Syrian hamster heart. Morphological and histopathological heart changes were determined for sixteen dystrophic Syrian hamsters (B10 14.6 strain) and sixteen normal hamsters. Eight animals were randomly assigned to each of the following groups: dystrophic swim (DYS-SWM), dystrophic sedentary (DSY-SED), normal swim (NOR-SWM), and normal sedentary (NOR-SED). The daily swimming  program consisted of an initial 30-minute swim which was gradually extended to 60 minutes  by the end of eight weeks. Weights up to 3% body weight were attached during swimming to increase the work load. Sedentary animals received no experimental treatment. Four animals in each group were sacrificed at 4 and 8 weeks after the initiation of treatments. In comparison with the two groups of sedentary animals, the NOR-SWM group had a greater heart weight/body weight ratio at both 4 and 8 weeks (P less than .05), while the DYS-SWM group had an increased ratio only at 8 weeks (P less than .05). Subjective histopathological evaluation of heart lesions showed that the DYS-SED group had many large areas of inflammatory reaction with infrequent diffuse areas of calcification. In contrast, the DYS-SWM group had fewer and smaller areas of inflammatory reaction with moderate amounts of calcification.


Quantitative changes of canine diaphragm muscle cells following electrostimulation. 1. In 12 dogs the right part of the diaphragm was stimulated 4, 5, 8, 11, and 14 weeks by means of a pacemaker. 2. Essential findings have been the increase of the amount of glycogen after 5 weeks, the increase of myofilaments per myofibril after 8 weeks, and the increase in the share of mitochondria in the 11th week. After 14 weeks all values have reached again their initial level as the result of an adaptation. 3. From the quantitative structural findings it can be taken that the diaphragm musculature is not changed by the electrostimulation in such a way that the functional preconditions for covering heart muscle deficiencies by diaphragm flaps are given.


Experimental allergic serous rabbit endocarditis and cardiav valvular lesions in rheumatoid arthritis. --A comparative study. Fibrosis of the chordae tendinae pathogenetically comparable to the rheumatoid arthritis (RA) conditioned alterations in the chordae tendineae was to be induced experimentally using the model of allergic-hyperergic rabbit endocarditis. 2. Furthermore, 45 hearts of RA autopsy cases were compared with 200 control heart. All heart valves and chordae tendineae were examined for occurence of diffuse fibroses, adhesions and rufflings as well as for ulcerations and thrombi. The degree of the pathological changes was  classified in ""slight'', ""mean'', and ""severe'' (see table 1). 3. The tissue lesion can either lead to endothelial injury resulting in verruciform endocarditis or it can change over from recurrent edema with subsequent edematous sclerosis to etiologically ambiguous nonspecific fibrosis. 4. The persistent allergic-hypergic irritation in rabbit endocarditis likewise caused fibrosis of the chordae tendineae. During the progress of the disease the lesions are ranging from acute edema over edematous sclerosis to fibrosis. In the relatively short experimental period adhesions of the chordae tendineae and sheat-like depositon of newly formed connective tissue as common in allergic processes in RA were not observed. The pathogenetic reactions due to experimental endocarditis were comparable with those in RA.


Concanavalin A receptors on normal rat liver cells, on rat liver cells in vivo transformed by diethylnitrosamine and on Zajdela ascites hepatoma cells of the rat: morphokinetic analysis of cell surface dynamics. Comparative electron microscopic investigations were performed in living cultures of normal rat liver cells, of rat liver cells in vivo transformed by diethylnitrosamine and on Zajdela ascites hepatoma cells of the rat concerning the mobility of the Concanavalin A cell surface receptors. The cells were incubated in Concanavalin A and peroxidase and subsequently washed. They were then reincubated for various periods at +37 degrees C in PBS prior to fixation. In the case of the Zajdela ascites hepatoma cells the cells were reincubated after Concanavalin A incubation followed by fixation and peroxidase incubation. The cytochemical procedure allowed us to show differences in the mobility of Concanavalin A surface receptors between normal and transformed rat liver cells. The cell surface label disappeared completely within 15 min of reincubation in the transformed cells, whereas in normal cells the same degree of loss in surface label was visible after 120 min reincubation. In both cases an internalization of labelled plasma membrane areas occurred. After complete disappearance of cell surface label in diethylnitrosamine transformed cells a complete relabelling of the cell surface occurred after 60 min reincubation caused by an exocytosis.


Presurgical dietary history and the behavior of control and septal lesioned rats. Rats reared under dietary enrichment or standard diet from 25 days of age underwent septal or control surgery 2 months later. Enrichment differentially altered septal or control behavior as measured by: exploration tests: fluid consumption of water, saccharin, and quinine; and the acquisition of an active avoidance task.


Following and visual imprinting in ducklings across a wide age range. Ducklings ranging in age from 20-125 hr were exposed to a moving silent object in an open circular apparatus until a criterion of 300 sec of following was met. All ducklings met the criterion, and age did not correlate with the time required. In subsequent choice tests most ducklings approached the imprinting object over a novel object, and age did not correlate with choice behavior. Results indicate that imprinting can occur over a fairly wide age range, and that the traditional critical period for imprinting may, in part, be an artifact of laboratory methods.


Influence of age and sex on the behavior of rats deprived of the rearing response. Rearing on the hind legs, one component of "general activity" was restricted in male and female rats both before (25 days) and after (50 days) the development of this response. In contrast to previous restriction studies the animals were kept in groups and allowed free locomotor activity in the cage environment. After 8 weeks, open-field testing showed that selective restriction decreased the frequency of rearing behavior, particularly unsupported rearing which requires physical coordination and balance. Effects were greater for females (which usually rear more than males) and for animals restricted at weaning (25 days).


Developmental and genetic variables in mouse startle response habituation. A behavioral task insensitive to inherent sensory and motor limitations, specifically a startle response habituation technique, was used to investigate genetic (strains) and developmental (age) effects on behavior. All mice tested using two procedures exhibited evidence for habituation which was dependent on strain, age, and length of the testing process. Exploitation of this simple technique may permit clarfication of more complex types of behavior.


Impairment of conditioned active avoidance in adult rats given corticosterone in infancy. Intensive corticosterone treatment given to rats during the 1st postnatal week irreversibly decreases DNA accumulation in the cerebrum and cerebellum. After such hypercorticism in infancy rats were tested as adults in 2 conditioned active avoidance tasks. In comparison with litter-mate controls, the treated rats were impaired in the acquisition of 2-way active avoidance but not in the acquisition of 1-way active avoidance. These data are consistent with other observations suggesting a hyperresponsiveness or hyperemotionality following corticosterone treatment in infancy.


Effects of differential rearing condition on heart rate conditioning and response suppression. Rats were reared in either an enriched or isolated environment for 60 days following weaning. Neither rearing environment nor sex affected heart rate conditioning. However, when the CS used during conditioning was subsequently presented in a drinking situation, males reared in isolation showed a greater degree of response suppression than did similarly reared females. Males and females reared in the enriched environment did not differ in degree of response suppression.


Arousal and temporal factors imprinting in mallards. A number of factors affecting the learning processes in laboratory imprinting were examined. Two factors alone explained the degree to which young ducklings learn the characteristics of a given model: the length of exposure to the model, and the endogenous arousal state of the duckling. A third, the effect of muscular exertion is not warranted. The characteristics of some models are more rapidly learned than others, and the significance of this fact for biochemical studies of learning is discussed. In this study ease of learning coincided with innate preference; this suggests the presence of a neural filtering mechanism in the duckling which alters the assimilation of information into the CNS and hence controls both innate preference and learnability.


Long term changes in nest condition and pup grouping following handling of rat litters. Observation of rat litters over the entire preweaning period revealed long term changes to result from handling pups. Handled litters had fewer good nests and were less likely to be found in a single group than control litters. These differences are not attributable to the disturbances per se, as litters where the mother was removed did not differ significantly from undisturbed controls. The differences occurred predominantly in the daytime when maternal activity was at its lowest.


Excess neonatal thyroxine: effects on learning in infant and adolescent rats. Previous reports have suggested that neonatal thyroxine administration may enhance learning ability in rats as infants but the rats become deficient in learning as they grow older. This experiment compared neonatally thyroxine-injected rats with injected and nonhanded controls on passive and active avoidance and a geotactic cold-escape discrimination. Thyroxine-injected infant rats were superior to controls on active avoidance, inferior on passive avoidance, and equal on discriminated escape. Adolescent rats which had received postnatal thyroxine were inferior to controls in Lashley III maze acquisition whether or not they had received supplementary thryoxine at the time of training. These data suggest that differences in locomotor activity, rather than in learning ability, account for early behavioral effects and that changes other than endocrine disturbances account for the adult deficits. The results are compatible with previous contentions that excess neonatal thyroxine disrupts the timing of brain development.


Maternal growth hormone and growth and function. Factors regulating somatic growth postnatally have been proposed to affect brain growth and subsequent function when applied prior to birth. This study pertains to the role of growth hormone administered to pregnant rats and the subsequent growth of the progeny. The results showed a significant increase in brain weight and cortical neurone number as determined by the incorporation of labelled thymidine into DNA and subsequent autoradiography. At maturity, learning performance on a series of conditional discrimination tasks was found to be enhanced.


The effect of chronic protein malnutrition on trans-callosal evoked responses in the rat. Studies were carried out on the trans-callosal evoked response in rats born of dams fed either a low (8%) or normal (25%) protein diet beginning 5 weeks prior to mating and throughout gestation and lactation. After weaning, pups were fed the same diets as their mothers. Bipolar (surface vs depth) stainless steel stimulating and recording electrodes were positioned at corresponding loci in the right and left sensorimotor cortices. Trans-callosal evoked responses were measured under urethane anesthesia using twice-threshold bipolar pulses of .1 msec duration at ages 13, 21, and 60-66 days. Evoked response latency was significantly greater in malnourished animals at 13 days of age, whereas at adulthood no latency differences were seen. Poststimulation excitability (15-100 msec range) was not significantly affected by the dietary treatment. These results are interpreted as corroborating previous reports on rats undernourished during development using sensory evoked potentials. By avoiding the use of extrinsic sensory stimulation, the present study demonstrates a dietary effect upon ontogeny of cortical evoked potentials independent of any possible effect on sensory receptor mechanisms.


Light-dark discrimination and reversal learning in early postnatal kittens. During the early postnatal period kittens were trained in a visual discrimination task involving light-dark stimuli in order to determine the age of onset of visual control of learned behavior. A Y water maze was used with escape from water as the reinforcer. The results indicate that kittens are able to master the discrimination within the 5th week of life. The relevance of this result to electrophysiological measures of maturation is discussed.


Effects of testing age and fostering experience on seizure susceptibility of rats treated prenatally with chlorpromazine. Offspring of rats treated with 2 mg/kg body weight chlorpromazine (CPZ) on Days 5-8 of gestation had lower seizure thresholds than offspring of saline-treated controls at 30, 60, 90, and 120 days of age. The CPZ-treated offspring were also heavier than controls prior to weaning. Further analysis using cross-fostered litters indicated that at least part of the drug effect on seizure thresholds took place before birth, although a postnatal component was also demonstrated. A striking effect of the fostering experience itself on the seizure threshold prevented conclusions about the relative importance of prenatal and postnatal influences.


Prehatch color stimulation effects on color pecking preferences and color discrimination learning in white leghorn chicks. Four experiments assessed the effects of stimulating chick embryos with colored light at 2 intensity levels. Both posthatch color pecking preferences (Experiments 1 and 2) and color discrimination learning (Experiments 3 and 4) were unaffected. These results affirm and extend a prior finding of no pre- and posthatch colored light stimulation effect on posthatch color preferences in ducklings. The color pecking preferences found replicated prior findings with chicks. However, they differed from the approach color preferences observed in color discrimination learning.


The development and modification of object preferences in domestic white leghorn chicks. This study examined in domestic chicks the time-course of adaptation to a new object after having established strong preferences for a previous stimulus (during the first 3 days of life). By interchanging the stimuli to which the animal was exposed, and by confining the animal exclusively with the new object for some period of time, the new preference was expected to develop as a function of the duration of exposure. The results confirm that expectation with a monotonic increase in preference as a function of hours of exposure. The establishment of a preference for the new object was rapid, as indicated by a significant shift in preference after 5 hr.


The use of habituation in the study of the effects of infantile malnutrition. Habituation of the orienting response (OR) was used to assess possible attentional deficits associated with infantile malnutrition. The procedure involved the presentation of 40 trials of a pure tone stimulus to 8 marginally nourished and 8 malnourished 13 1/2-month-old male infants. The results showed that the initial OR to stimulus onset, as measured by the magnitude of cardiac deceleration, was significantly larger in marginally nourished than in malnourished infants. Within-group comparisons revealed that marginally nourished infants showed significant increases in OR magnitude to changes in tonal frequency whereas the malnourished infants did not. The results were taken as evidence of an attentional deficit associated with infantile malnutrition that is likely to interfere with subsequent learning.


The development of convulsive seizures in the grasshopper mouse (Onychomys torridus). Open-field tests were administered to 29 male and 50 female southern grasshopper mice (Onychomys torridus) at 10-day intervals from 30-100 days of age. Convulsive seizures were observed to occur in 9 males and 23 females during at least 1 of the open-field tests. No significant differences appeared in the seizure characteristics of male and female subjects. The potential of O. torridus as an animal model of human epilepsy is discussed.


The development of intersession habituation and emergence in socially reared and isolated rats. Male and female hooded rats were weaned at 17 days and then reared in isolation or in social groups. Intersession habituation of locomotor activity in the open field was tested at 15, 25, and 45 days. Contrary to some previous reports, the 15-day-old animals showed significant habituation. At 45 days, however, the isolates showed very little habituation compared to the social animals. The isolates showed a similar pattern of development in their emergence into the open field. Apparently, isolation does not result in an arresting of development, but rather in the formation of behavior patterns otherwise absent in normally reared rats.


Closed reduction reaming and nailing in fractures of the femoral shaft. Küntscher's treatment of fractures of the femoral shaft consists of andomedullary closed reduction nailing after reaming. This easy and safe method is the method of choice, as demonstrated by an analysis of our results in 187 fractures. The operative technique, indications, contraindications, advantages and complications of the method are discussed.


Dyschondrosteosis.

Dyschondrosteosis. The authors present three cases of dyschondrosteosis occurring in a single family unit. The characteristics of the "major" and "minor" forms of this genetically derived chondrosteodysplasia are described. The other members of the family examined presented no signs of the disease, but they were very young. The possibility of successful surgical correction of the deformities caused by dyscondrosteosis is stressed.


Resection of metaphyseal and epiphyseal neoplasms: the use of the patella for osteo-articular reconstruction. The patella can be a useful autogenous transplant for joint reconstruction after resection of epiphyseal and metaphyseal neoplasms. The cartilaginous surface can be used to replace an articular surface destroyed by tumour or removed by resection. Six cases are presented and illustrated, in which this procedure enabled useful joint function to be preserved.


Experimental scoliosis induced by prolonged minimal electrical stimulation of the paravertebral muscles. Experimental scoliosis was produced in the rabbit by unilateral electrical stimulation of the paravertebral muscles. The scoliosis was shown to be structural and progressive even after stimulation was stopped. The biochemical and histochemical changes in the intervertebral discs were studied.


Valgus osteotomy of the hip.

Valgus osteotomy of the hip. The author's technique of valgus osteotomy is described. The advantages claimed are wide and easy correction combined with distal displacement of the great trochanter, restoration of physiological valgus, lengthening of the limb, and rigid and secure fixation. The indications, contra-indications, technique and results are discussed in an analysis of ninety-eight operated cases.


Multiple primary idiopathic scoliosis.

Multiple primary idiopathic scoliosis. This paper deals with a type of idiopathic scoliosis with more than two primary curves (three, four or five). These can be classified, together with double primary curves, under the general term "multiple primary idiopathic scoliosis", and should therefore replace "combined or double primary curves" in Schulthess' traditional classification. The author contends that the apparent rarity of multiple primary curves is due to inadequate observation, and discusses their etiology, clinical features, diagnostic criteria, natural history, prognosis and treatment.


Cystinosis of bone.

Cystinosis of bone. The authors describe a case of cystinosis of bone that presented initial difficulties in diagnosis. They discuss the clinical features and the radiographic appearances, which demonstrated numerous zones of osteoporosis with a markedly monomelic distribution in the left leg. The condition arose as a result of trauma. Numerous accumulations of intracellular cystine crystals were revealed by the ultramicroscopic study of bone fragments obtained by biopsy, and this led the authors to diagnose the case as cystine thesaurismosis of bone. The case is of interest not only because of its exceptional rarity (it is, perhaps, the first reported case of cystinosis localized exclusively in bone), but also because it was only possible to arrive at a diagnosis by means of ultramicroscopic investigation.


The treatment of severe fractures of the lower end of the femur with Judet's screw-plate. Severe fractures of the lower end of the femur have increased in frequency as road accidents have become more common. Good anatomical reconstruction is essential in order to conserve useful joint function, and this can only be achieved by internal fixation. Judet's screw-plate has been used with success in these cases and is presented in its technical and clinical aspects. The quality of the results obtained is documented in an analysis of 22 operations.


The effects of heroin on catecholamine metabolism in man. In a study of the effects of heroin administration in nine human subjects, urinary catecholamines and metabolites were examined during an initial drug-free baseline period, a ten-day period of heroin administration and a subsequent period of methadone detoxification. All catecholamines and metabolites tended to be increased over baseline values on the first day of heroin administration. However, markedly different patterns of change emerged on subsequent days of heroin administration. Norepinephrine and normetanephrine remained increased throughout heroin administration. Epinephrine was increased during the early phase of heroin administration but returned to baseline values during the latter phase of heroin administration. After the increase on the first day of heroin administration, metanephrine decreased and substantial decrements below baseline values occurred during the latter phase of heroin administration. After increasing on the first day of heroin administration, 3-methoxy-4-hydroxy-mandelic acid (VMA) returned to approximately baseline values. During heroin administration, an increase in 3-methoxy-4-hydroxyphenylglycol (MHPG) excretion was observed in a subgroup of four of the nine subjects studied. This is in contrast to the increase in normetanephrine excretion and the decrease in metanephrine excretion that was observed in the entire group of nine subjects. It is conceivable that persistance of, or development of, tolerance might account for the failure to observe an increase in MHPG excretion in all of the subjects. It appeared as if the increase in MHPG excretion began on the day prior to the administration of heroin in the subgroup of patients with increased MHPG excretion during heroin administration, suggesting the possibility of an anticipatory or conditioned response, with the anticipation of heroin producing an increase in MHPG excretion.


Blood platelet monoamine oxidase activity in anergic schizophrenics. Blood platelet monoamine oxidase (MAO) activity was evaluated in twenty-four anergic, schizophrenic outpatients during a double-blind study comparing a chlorpromazine-imipramine combination to thio-thixeneplacebo. Platelet MAO activity was determined on blood samples drawn after a two-week drug-free washout and once weekly over a four-week on-drug period. Schizophrenic patients could be classified according to their blood platelet MAO activity into either a low-MAO or a high-MAO group. In neither group of this population of schizophrenics did blood platelet MAO activity correlate with any of the primary or secondary symptoms of schizophrenia. Ten alcoholics and seven volunteer non-patients could similarly be divided into low- and high-MAO groups. Mean blood platelet MAO activity for these groups was not significantly different from the mean values of the low and high-MAO groups of the schizophrenics. These findings do not support published reports of low blood platelet activity as a genetic marker for schizophrenia. Discriminate function analysis of symptomatology ratings at baseline was used to characterize the low- and high-MAO schizophrenic patient groups. Individuals in the low-MAO group were distinguished by hyperactivity, anergia and sleep disturbance.


The role of serotonin and norepinephrine in sleep-waking activity. A critical review of the evidences relating the biogenic amines serotonin and norepinephrine to the states of slow-wave and rapid eye movement (REM) sleep is presented. Various alternative explanations for specific chemical regulation of the individual sleep states, including the phasic events of REM sleep, are evaluated within the overall framework of the monoamine theory of sleep. Several critical neuropsychopharmacological studies relating to metabolsim of the amines in relation to sleep-waking behavior are presented. Models of the chemical neuronal circuitry involved in sleep-waking activity are derived and interactions between several brainstem nuclei, particularly the raphé complex and locus coeruleus, are discussed. Activity in these aminergic systems in relation to oscillations in the sleep-waking cycles is evaluated. In particular, the assessment of single cell activity in specific chemical systems in relations to chemical models of sleep is reviewed. Overall, it appears that the biogenic amines, especially serotonin and norepinephrine, play key roles in the generation and maintenance of the sleep states. These neurotransmitters participate in some manner in the "triggering" processes necessary for actuating each sleep phase and in regulating the transitions from sleep to waking activity. The biogenic amines are, however, probably not "sleep factors" or direct inducers of the sleep states. Rather, they appear to be components of a multiplicity of interacting chemical circuitry in the brain whose activity maintains various chemical balances in different brain regions. Shifts in these balances appear to be involved in the triggering and maintenance of the various states comprising the vigilance continuum.


A role for dopamine in the psychopharmacology of electrical self-stimulation. The psychopharmacology of electrical self-stimulation of the lateral hypothalamus was studied using 6-hydroxydopamine, alpha-methyltyrosine, U-14, 624, and d-amphetamine. Reduction of brain dopamine, but not norepinephrine, with 6-hydroxydopamine produced an acute depression of responding which eventually recovered to pretreatment levels. A low dose of alpha-methyltyrosine, which did not affect responding in control rats, significantly depressed responding in the rats with brain dopamine reduced. This treatment did not alter responding of rats with norepinephrine reduced by 6-hydroxydopamine. A dopamine-beta-hydroxylase inhibitor, U-14, 624, depleted norepinephrine an additional 70% yet failed to alter self-stimulation in any of the groups. In other experiments, the 6-hydroxydopamine treatment which reduced brain dopamine was found to block the facilitation of self-stimulation produced by d-amphetamine. This facilitation of lateral hypothalmic self-stimulation was not influenced by treatments which reduced brain norepinephrine. An experiment suggesting that dopamine is of importance to locus coeruleus self-stimulation is also described. Implications of these data indicating a role for dopamine in self-stimulation responding are discussed in relation to the "catecholamine hypothesis of self-stimulation".


[Empyema and subdural effusion after meningitis. 2 cases of unusual location]. A 12-year old child and a 2-month old infant developed, in the wane of a purulent meningitis, the former, an infratentorial subdural empyema, the latter, a large, encapsulated, haemoorhagic, aseptic subdural effusion, in the right parieto-temporo-occipital region. In both cases, signs of intracranial hypertension dominated the clinical picture. Neuroradiological investigations permitted diagnosis and localisation of the expansive processes, whose subdural position was recognized at operation and confirmed by histopathological examination. According to the literature, purulent meningitis is a rare cause of subdural empyema, except in infants; the solely infratentorial location is also unusual. Sterile subdural effusion is a more common complication of purulent meningitis in infancy, but the unilateral posterior supratentorial location is also a peculiar feature. Subdural collections after memingitis may be aseptic and possibly haemorrhagic, or septic and purulent; these different modes of presentation correspond perhaps to different degrees or stages of subdural pathological changes in the neighbourhood of leptomeningeal infection.


[Incisural block. Radiological diagnosis]. Radioisotope cisternography is the best method for studying the third circulation. A new mode of representation is proposed for understanding the importance of the various foramina and the main direction of the bulk flow. The incisura tentorii plays an important role in the cranial leptomeningeal space. Particular emphasis is given to the cisternographic and pneumographic patterns of its stenosis and occlusion. Incisural block may be anatomical (primary) or functional (secondary). That distinction gives the choice between different shunting procedures. Its significance is demonstrated and illustrated in various situations.


[Postoperative radiotherapy of hemispheric glioma in the adult. A propos of 134 cases]. We are dealing here with a series of 134 hemispheric gliomas of the adult subject submitted to irradiation after surgical exeresis. The 2 years survival rate reaches 51 p. 100 for stage I and II astrocytomas (15/29) and 3,3 p. 100 for glioblastomas (30/91), the I year survival rate for the latter ones reaching 33 p. 100. The analytic study of medical literature lets appear that if roentgentherapy remains controverted in the case of stage I and II astrocytomas, it is recognized as useful, by all the authors, in the glioblastomas. Modalities and technique of the irradiation are object of an analytic study. Authors are favourable to post-operative irradiation stage I and II astrocytomas exhibiting pejorative features (focalized 6.000 to 6.500 rads) and to systematic post-operative irradiation in the glioblastomas over extended fields, either spreaded on irradiation (6.000 rads) or concentrated irradiation (two series of 1.800 rads). This latter technique has provided identical results as the spreaded on irradiation and represents a less heavy procedure. Mention is made of roentgentherapy in the supratentorial ependymomas (3 cases) and in the oligodendrogliomas (6 cases), followed by an analytic study of the complications consecutive to roentgentherapy of the encephalic tumors.