Transfer of nitrazepam across the human placenta.

Six women from 14 to 17 weeks pregnant, and 12 woman from 36 to 40 weeks pregnant, were given nitrazepam 5 mg orally about 12 h before legal abortion by hysterotomy in the former group and elective caesarean section in the latter group. The concentration of nitrazepam was determined by gas-liquid chromatography. Binding to plasma proteins was evaluated by separation of the protein-free fraction by ultracentrifugation. In the first group (early pregnancy) the level of nitrazepam was found to be lower in the fetal than in the maternal circulation. The concentration in amniotic fluid was still lower. In the latter group (late pregnancy) the concentration both of unbound and total nitrazepam in maternal and fetal plasma were in equilibrium, which indicated an increase in transplancental transfer in late pregnancy. The percentage of unbound nitrazepam in both cases was 12%.


Effect of exercise on the serum level and urinary excretion of tetracycline, doxycycline and sulphamethizole.

The serum level and urinary excretion of sulphamethizole, tetracycline and doxycycline were studied in healthy volunteers subjected to intensive exercise and bed rest in a cross-over trial. Each group consisted of 7--8 subjects. The exercise or bed rest began 15 min before oral administration of the drug and was continued for the following 4 hours. During exercise serum drug concentration and the area under the serum concentration-time curve for each agent was significantly higher (p less than 0.05) than the corresponding values at rest. Exercise greatly suppressed the renal excretion of tetracycline and doxycycline, but the decrease alone appeared insufficient to account for the pronounced increase in serum drug concentration. Total drug excretion in urine was unchanged. Thus, it seemed most unlikely that overall absorption from the gastrointestinal tract had been altered by exercise. However, the rate of absorption appeared to be more rapid in the exercise than in the rest period. Marked haemoconcentration was not produced by the exercise. In addition to changes in absorption and elimination rates, alteration in the volume of distribution might contribute to the higher serum drug concentration during exercise. Therefore, the level of physical activity should be considered in the interpretation of pharmacokinetic data both in clinical practice and in pharmacokinetic studies.


Human pharmacokinetics and bioavailability of temazepam administered in soft gelatin capsules.

Plasma levels of temazepam were determined in healthy subjects after single oral administration of soft and hard gelatin capsules, and after 7 consecutive night-time doses in soft capsules. Absorption from soft gelatin capsules was significantly faster and produced earlier and higher peak plasma levels. The two pharmaceutical forms did not show any significant difference in relative availability. The apparent half-life of temazepam after night-time administration was significantly shorter than after morning administration, but no change in half-life was observed between the first and seventh night-time doses.


Overall pharmacokinetics during prolonged treatment of healthy volunteers with digoxin and beta-methyldigoxin.

Five healthy volunteers received digoxin 0.4 mg or beta-methyldigoxin 0.4 mg i.v., daily for 14 days, in a randomized cross-over arrangement. By monitoring minimal plasma concentrations during multiple dosing, it was found that the steady state pharmacokinetics of digoxin and beta-methyldigoxin could be estimated even better by a one-compartment than by a two-compartment model. The following mean parameters were calculated: the half life of digoxin of 1.54 +/- 0.31 days was significantly shorter than the half life of 2.29 +/- 0.34 days for beta-methyldigoxin. The distribution volume of 807 +/- 187 liters for digoxin was not significantly larger than the 735 +/- 227 liters for beta-methyldigoxin. Renal digoxin clearance of 191 +/- 25 ml/min was significantly higher than both the renal clearance of beta-methyldigoxin of 111 +/- 23 ml/min and also the creatinine clearance, which indicates tubular secretion of digoxin. There was a 2.8-fold accumulation of beta-methyldigoxin injected once a day, which was significantly higher than the 1.80-fold accumulation of digoxin.


Modification of the binding of sulphamidochlorobenzoic acid to human albumin by palmitic acid contamination of albumin.

Palmitic acid a common contaminant of albumin preparations, competitively inhibits the binding of sulphamidochlorobenzoicacid (SCBA) to human albumin thus decreasing its observed affinity. The effect of palmitic acid depends on its concentration, i.e. the purity and concentration of the albumin preparation used. The correct value for SCBA affinity was obtained by correcting the experimental data according to the palmitic acid concentration by use of a multiligand analysis method.


Failure of methyclothiazide to lower home blood pressure level in "essential" hypertensive and normotensive young men, despite significant plasma volume contraction.

Home blood pressure measurements were used to assess the effect of methyclothiazide in young essential hypertensive and normotensive males. Although plasma volume was reduced by approximately 10 percent, blood pressure was not reduced in either group. The lack of effect on blood pressure was probably not attributable to dosage employed, as doubling the dose (5 to 10 mg) in the normal subjects (who were equilibrated on constant diet) did not significantly increase changes in plasma volume, plasma renin activity, aldosterone excretion, urine sodium or blood pressure. The higher dose did result in greater changes in plasma potassium and uric acid. Homeostatic mechanisms which limit the volume mediated and other antihypertensive effects of methyclothiazide apparently achieved complete compensation in these young males. This suggests that thiazide diuretics may not be the drug of first choice in the treatment of hypertension in young adults. Further studies with other diuretics are clearly necessary before the significance of these findings can be fully assessed.


Cardiovascular response to increasing theophylline concentrations.

The circulatory effects of plateau plasma theophylline concentrations of 5, 10 and 20 mg/l were examined in normal male volunteers using forearm plethysmography, systolic time intervals and echocardiography. Systemic arterial and forearm venous pressures were not significantly altered during theophylline infusions. Forearm blood flow increased an average 9.4% at 5 mg/l, 15.3% at 10 mg/l and 41.2% at 20 mg/l. Forearm venous distensibility was maximally increased by 20.9% at 10 mg/l. Changes in heart rate and systolic time intervals were apparent only at concentrations between 10-20 mg/l. Heart rates increased from 3-16 beats/min. The left ventricular ejection time index and isovolumetric contraction time were significantly reduced with an increase in the PEP/LVET ratio consistent with a reduction in cardiac pre-load and an increase in inotropy. However, the interindividual variability in circulatory responses was great and consistent alterations in cardiac stroke volume and ejection fraction were not observed in either the supine or 60 degrees passive-tilt positions. The variable responses cannot be due to variations in drug disposition between subjects since the range of plasma theophylline values at each concentration plateau was narrow.


Plasma and urinary digoxin in thyroid dysfunction.

The response to a single oral dose of 0.5 mg digoxin has been studied in eight patients, of whom four were hyperthyroid and four were hypothyroid, both before and after treatment for their thyroid dysfunction. The post-dose plasma digoxin levels were significantly lower in the hyperthyroid patients when they were thyrotoxic than when they became euthyroid. In only one hypothyroid patient was the post-dose plasma digoxin level significantly higher before treatment than it was after and in the others the digoxin values reached were either the same as, or lower than, before treatment. There was a significant correlation between the creatinine clearance and the urinary concentrations of digoxin and these both altered with change in thyroid status. Total urinary digoxin excretion did not change. Pharmacokinetic analysis suggested that digoxin was distributed in a way compatible with a two-compartment model and that the volume of the central compartment was high in thyrotoxic patients and low in hypothyroid patients. In both cases it reverted to a median value after treatment. It is recommended that plasma digoxin levels should be monitored in all patients with thyroid dysfunction who require therapeutic digoxin.


Pharmacokinetic investigations in man of two acetyl derivatives of 16alpha-gitoxin.

3H-16-acetyl-16alpha-gitoxin or 3H-penta-acetyl-16alpha-gitoxin were injected iv or administered po to 15 volunteers and 3 patients. The elimination half-life and excretion in urine within 4 days were estimated as a percentage of the administered radioactivity, and metabolic studies on the fate of the administered glycosides were performed. In volunteers the following results were obtained: 3H-16-acetyl-16alpha-gitoxin 1 mg iv.: 50 +/- 11 h, 28.3 +/- 4.1%; 3H-16-acetyl-16alpha-gitoxin 1mg po: 48 +/- 8 h, 25.4 +/- 2.8%; 3H-penta-acetyl-16alpha-gitoxin 2 mg po: 51 +/- 12 h, 20.7 +/- 3.2%, respectively. In 3 patients with a cannulated bile duct 9.9% (mean) of the administered 3H-16-acetyl-16alpha-gitoxin was excreted. By comparison of the radioactivity excreted in urine following the 2 routes of 16-acetate administration, the percentage absorption was calculated to be 88.5%. In serum and urine 16-acetyl-16alpha-gitoxin and 16alpha-gitoxin were found as possible metabolites of both glycosides, in the ratio of 75-85:15-25, and both metabolites were also found in bile. Within 16 h after penta-acetate administration, two additional metabolites (bis-acetyl-derivatives of 16alpha-gitoxin) were detected in serum and urine within 16 h after administration of penta-acetate.


The pharmacokinetics of carbamazepine.

The time-courses of plasma carbamazepine concentrations were followed in six apparently healthy adult subjects who, at different times, took single oral drug doses of 200, 400, 500, 600, 700, 800 and 900 mg. There were some suggestions of impaired bioavailability of the drug when given in tablet form. The following values were obtained for various pharmacokinetic parameters: kabs = 0.176 +/- 0.209 h-1; k = 0.0203 +/- 0.0055 h-1; T1/2 = 37.5 +/- 13.1 h; VD = 0.825 +/- 0.1041 . KG-1; Clearance = 0.0163 +/- 0.0061 1 . kg-1. The elimination rate constant showed a statistically significant increase with increasing drug dose. This may help explain the clinical observation that the rate of rise of steady state plasma carbamazepine concentrations tends to decrease with dose increase in patients taking carbamazepine alone.


Pharmacokinetics of coumarin and its 7-hydroxy-metabolites upon intravenous and peroral administration of coumarin in man.

The pharmacokinetics of coumarin (C) upon i.v. and p.o. administration and its metabolites 7-hydroxy-coumarin (7-HC) and 7-hydroxy-coumarin glucuronide (7-HCG) have been studied. Six healthy volunteers were involved in this investigation. Four of the volunteers participated in a crossover study. Coumarin was administered i.v. and p.o. in dose sizes of 0.25 mg/kg and 0.857 mg/kg, respectively. Coumarin is rapidly absorbed p.o., however the availability to systemic circulation is less than 4%. The rest of the dose appears quantitatively as 7-HC and 7-HCG in systemic circulation suggesting an extensive firstpass effect. Coumarin and 7-HCG are best fitted to an open two-compartment model, whereas 7-HC is best fitted to an open one-compartment model. The biological half-life of both C (0.80 vs. 1.02 h) and 7-HCG (1.47 vs. 1.15 h) was not significantly different for the two routes of administration. The large total clearance of C again suggests a first-pass effect; while that of 7-HCG, which is nearly exclusively eliminated into urine, indicates active tubular secretion of the glucuronide.


Pharmacokinetic and concentration-effect relationships of clonidine in essential hypertension.

The effect of oral doses of 300 microgram of clonidine hydrochloride on blood pressure, sedation and saliva production in 5 essential hypertensives were qualitatively similar to the effects in normotensive subjects. Peak plasma clonidine concentration (1.34 +/- 0.28 ng/ml) and plasma half-life (10.0 +/- 0.8 h) were similar to normotensives. During chronic oral dosing there was no evidence of drug accumulation. Some tolerance to the sedative and salivary flow effects occurred but no tolerance to the hypotensive effect was observed. There was a linear relationship between reduction in saliva flow and plasma levels of clonidine. The hypotensive effect was also related to plasma level at low concentrations. At plasma levels greater than 1.5 ng/ml the hypotensive effect was diminished. This loss of effect at high plasma concentration may be related to the peripheral, post-synaptic alpha-adrenoceptor agonist action of the drug.


Monoaminergic synapses, including dendro-dendritic synapses in the rat substantia nigra.

Intraventricular administration of 1 or 2 mg of the osmiophilic "false transmitter" 5-hydroxydopamine (5-OHDA) was used to label monoamine storage and release sites in the rat substantia nigra. Vesicles containing unusually dense cores indicative of the presence of the marker were seen forming from the Golgi apparatus in the cell bodies of medium-sized neurons of the substantia nigra, pars compacta, and from smooth endoplasmic reticulum in the dendrites of those neurons and in small unmyelinated axons of unknown origin. In serial sections, both axons and dendrites containing synaptic vesicles marked with 5-OHDA were seen to form synapses "en passage" in pars compacta, and some presynaptic dendrites containing vesicles filled by the marker were also observed to form contacts with dendrites in pars reticulata. The only identified postsynaptic elements engaging in monoaminergic synapses in the substantia nigra were dendrites of medium-sized pars compacta neurons.


An attempt to assess the effects of monocular deprivation and strabismus on synaptic efficiency in the kitten's visual cortex.

The relative effectiveness of the two eyes in exciting cells in the visual cortex was assessed, using both natural stimulation and electrical stimulation of the optic discs. It is is argued that supramaximal electrical stimulation of the optic nerve could possibly reveal 'subliminal' synaptic inputs even after monocular deprivation or artificial strabismus has caused a loss of natural input from that eye, if such 'silent' synaptic input still survives. However, in kittens monocularly deprived for various periods of time or made artificially strabismic, there was usually excellent agreement between the relative visual excitability in the two eyes and their relative electrical excitability. In one animal, monocularly deprived continuously until 23 weeks of age, we examined the effect of reversibly turning off signals from the normal eye by pressure blinding. There was no evidence of a very rapid return of sensitivity to either electrical or natural stimulation of the deprived eye.


Analysis of unitary EPSPs mediated by the newly-formed cortico-rubral synapses after lesion of the nucleus interpositus of the cerebellum.

1. Unitary EPSPs were recorded intracellularly from neurons of the red nucleus (RN) by stimulating the cortico-rubral fibers in normal cats as well as those with chronic lesion of interpositus nucleus (IP) of the cerebellum. 2. Two groups of unitary EPSPs were recorded in cats with IP lesion. One consisted of cortico-rubral unitary EPSPs with a shorter time to peak and larger amplitude than those in normal cats. The other consisted of unitary EPSPs of the normal range. 3. The appearance of the fast rising group of cortico-rubral EPSPs caused by IP lesions was theoretically predictable based on Rall's compartmental model by assuming that new synapses were formed close to the soma of the RN cells. 4. The amplitude of the fast rising EPSPs increased more prominently by hyperpolarizing the membrane potential than that of the slowly rising ones. 5. It was concluded that the fast rising group of unitary EPSPs which appeared following IP lesion was due to the formation of new synapses on the proximal portion of the soma-dendritic membrane of RN cell.


Serial and triadic synapses in the cerebellar nuclei of the cat.

A quantitative electron microscopic investigation of the nucleus interpositus in cat cerebellum reveals that about 1.5% of all observed synapses are established between synaptic vescile-bearing profiles. It is shown by serial sections that 70% of these synaptic complexes are triadic arrangements and 30% are serial synapses. Further analysis discloses that the first presynaptic element in the triadic and serial synapses may be one of four different axonal types: (A) Purkinje-cell axons; (B) and (C) afferent fibers containing large round vesicles and originating from the brain stem (probably mossy and climbing fiber collaterals); and (D) axon terminals containing small round vesicles. Indirect evidence suggests that type D profiles are the recurrent axon collaterals of the projective neurons. The second, postsynaptic and presynaptic, vesicle-bearing process in these complexes is either a class D terminal, or a somewhat more "dendrite-like" profile (Class E) containing flattened vesicles, and identified as belonging to processes of local Golgi type II interneurons.


Arthrokinetic nystagmus and ego-motion sensation.

A compelling illusion of body rotation and nystagmus can be induced when the horizontally extended arm of a stationary subject is passively rotated about a vertical axis in the shoulder joint. Lateral nystagmus with the fast phase beating in the opposite direction to the arm movement was found consistently; the mean slow phase velocity increased with increasing actual arm velocity and reached about 15 degrees/sec; the mean position of the eyes was deviated towards the fast phase as in optokinetic nystagmus, and the nystagmus continued after the cessation of stimulation (arthrokinetic after-nystagmus). The existence of an arthrokinetic circularvection and nystagmus indicates a convergence of vestibular and somatosensory afferents from joint receptors. It is concluded that information about joint movements plays an important role within the multisensory processes of self-motion perception.


Spatial distribution of various types of bulbar respiratory neurons in the rabbit.

In anesthetized rabbits, the burst activity of 277 single respiratory neurons was recorded extracellularly. The neurons were classified according to their spike incidence distribution within the respiratory cycle and to their response to lung distension or collapse (alpha or beta type). About one third of the neurons found in all animals were located at the level of the caudal end of the promontorium gliosum, widely scattered over the bulbar cross-section. More rostrally the units were located within a dorsal area neighbouring the tractus solitarius, more caudally within a ventral field surrounding the nucleus ambiguus. Most of the inspiratory neurons (the most frequently encountered type) were found within an antero-medial region of the medulla, extending down to about two thirds of its depth. Most of the inspiratory-expiratory units were found within an intermediate zone extending from antero-dorsal to postero-ventral. Most of the expiratory cells were found postero-ventrally. Most of the expiratory-inspiratory neurons (the rarest type) were again found within an antero-medial region at an intermediate depth. The alpha neurons were located in the rostral and the beta units in the caudal part of the medulla. The average proportion of respiratory neurons to non-respiratory units was estimated as about 1:36 and the total number of bulbar respiratory neurons as 500 on each side.


Abnormalities in the visual system of Xenopus after larval optic nerve section.

One optic nerve was cut in a series of larval Xenopus laevis; in approximately half of these the corresponding eye was also rotated. The resultant primary visual projections were mapped in the adult. Although in most cases the projections were retinotopically normal, some of them were not. These abnormal projections were consistently associated with a very thin optic nerve which reached the tectum via the oculomotor route. Animals with rotated eyes which developed retinotopically organised primary projections had a normal intertectal ipsilateral projection from the rotated eye and a rotated projection from the normal eye, thus confirming earlier findings that a process of binocular interaction determines the formation of intertectal connections. In all frogs with retinotopically abnormal primary projections the intertectal connections from the normal eye were of the type found after enucleation and those from the abnormal side were fragmentary or absent. Since the development of abnormal retinotopic patterns preceded that of intertectal connections the mechanisms of binocular interaction must have broken down in the presence of the abnormal primary projections.


Topographical arrangement of thalamocortical neurons in the centrolateral nucleus (CL) of the cat, with special reference to a spino-thalamo-motor cortical path through the CL.

In the centrolateral nucleus of the thalamus (CL) in the cat, a topographical arrangement of the thalamocortical projection neurons was demonstrated by utilizing retrograde axonal transport of horseradish peroxidase (HRP). Following injections of HRP into the medial or lateral areas of the anterior sigmoid gyrus (ASG), HRP-labeled neurons were located medially or laterally in the caudal levels of the CL, respectively; neurons in the central areas of the CL were labeled after injections of HRP into the rostral areas of the middle suprasylvian or the lateral gyrus. It was also shown by means of the combined HRP and Fink-Heimer method (Blomqvist and Westman, 1975) that the spinothalamic fibers terminated around CL neurons which were labeled with HRP injected into the lateral areas of the ASG. Hence, the caudolateral aspects of the CL were considered to represent a relay of the spino-thalamo-motor cortical paths.


The retinal input to cells in area 17 of the cat's cortex.

The activity of retinal ganglion cells and cortical cells with overlapping receptive fields was simultaneously recorded. The responses to moving stimuli of individual simple cortical cells could be accounted for on the basis of the cell receiving either on-centre or off-centre afferents; instances in which it was necessary to postulate a mixed on- and off-centre input were not found. In six instances cross correlograms of ganglion cell and cortical cell activity showed that the ganglion cell was afferent, via a relay cell in the LGN, to the cortical neurone. The receptive fields of such pairs were almost completely overlapping and concentric. In three cases a sustained ganglion cell projected to a simple cortical cell. In one case a transient ganglion cell projected to a simple cell, and in one case a sustained and a transient ganglion cell projected to the same simple cell.


Effect of aromatic acids on the influx of aromatic amino acids in rat brain slices.

The influx of [3H]phenylalanine, [3H]tyrosine and [3H]tryptophan into brain cells was studied using brain slices from adult rats. Each aromatic amino acid inhibited the influx of the others into the brain cells. Tryptophan inhibited non-competitively the influx of phenylalanine, and phenylalanine similarly that of tyrosine and tryptophan. On the other hand, tyrosine inhibited competitively the influx of phenylalanine, and similarly tryptophan that of tyrosine, and tyrosine that of tryptophan. Among the aromatic organic acids tested, only phenylpyruvate and homogentisate had any inhibitory effect on the influx of the aromatic amino acids. These effects were generally competitive, non-competitive inhibition being obtained only in the inhibition of phenylalanine influx by homogentisate. The existence of only one common transport system for aromatic amino acids appear to be unlikely.


Neurofibrillar changes in goldfish (Carassius auratus L.) brain in relation to environmental temperature.

Neurofibrillar changes occur in the brains of goldfish, Carassius auratus L., maintained at 5 degrees C for 177 days or more under a 12-hour photoperiod. In paraffin sections impregnated by the silver method of Holmes, the light microscopic appearance of the neurofibrillary change was evidenced by black rings 1 micrometer to 2 micrometer in outside diameter. A quantitative study showed the mean number of rings to be: optic tectum layer 3, 1.34 X 10(2)/mm(3), layer 5, 1.14 X 10(2)/MM(3), nucleus prerotundus 4.63 X 10(2)/mm(3), olfactory bulbs, 6.2 X 10(2)/mm3. In the brains of fish kept at 15 degrees C a few rings are found only in some olfactory bulbs and not in any other region of the brain. The brain wet weight also changes and was found to be significantly (p less than 0.01) less in 5 degrees C than in 15 degrees C fish, the mean values being 0.1588 g and 0.2091 g respectively. The significance of the observed changes is discussed. It is suggested that the smaller brain wet weight may reflect a change in the vasculature of the brain and be related to the acclimation process. It is hypothesized that the rings are a morphological expression of a physiological change caused by prolonged exposure to low temperatures; a neuronal response reflecting either early degeneration or a functional adaptation which may involve an alteration in axoplasmic transport. It is suggested that this system is a useful model for the study of relationships between neurofibrillar disturbances and neuronal function.


The relationship of conduction velocity to other physiological properties of the cat's horizontal canal neurons.

The conduction velocity and other physiological characteristics of the first order horizontal canal afferents were studied in 24 anesthesized cats. From their spontaneous discharge patterns, neurons were classified into three groups: regular, intermediate and irregular; The irregular units tended to have a low resting rate, high sensitivity to angular acceleration, frequently exhibited adaptation during prolonged acceleration, and showed a short latency from the time of electric stimulation of the labyrinth to recording the action potential near Scarpa's ganglion. The regular units tended to have a high resting discharge rate, low sensitivity, were mostly non-adapting, and showed longer latency to electric stimulation. The intermediate neurons had a mixed character of regular and irregular units. Based on the very short conduction times (mean 0.34 msec) and the work of Moxon (1971), we conclude the locus of activation of electrical stimulation is neural rather than the receptor cells. Since the latency is due predominantly to conduction in the first order axon, and since there is a direct linear relation between conduction velocity and fiber diameter in the medullated nerve fibers, it is possible to speculate that the regular cells have thin fibers which innervate the slope of the crista, the irregular neurons have thick fibers which innervate the summit of the crista, and the intermediate units have medium caliber fibers which innervate both the slope and summit of the crista ampullaris.


The influence of diabetes mellitus and hypercorticism on the wound healing of experimental myocardial infarction in rats.

In diabetic and glucocorticoid-treated rats myocardial infarction is produced by coronary artery ligation. After the ligation was performed the animals were given 3H-thymidine or 3H-proline at different times. The following parameters were determined: number of DNA- and tropocollagen-synthesizing connective-tissue cells both at the infarction border and infarction site; mean silver-grain density above the nuclei or cells; number of mitoses. The labelling and mitotic indices as well as the standard deviation (in percent) from the mean values were calculated. The following results were obtained: 1. The retarded formation of collagen fibres in diabetic animals is caused by a reduced number of tropocollagen-synthesizing fibroblasts and by a diminished synthesizing performance of the individual cells. 2. Glucocorticoids have a pronounced inhibitory effect on granulation-tissue formation, The 3H--thymidine indices are strikingly low. The synthesis of collagen precursors in the fibroblasts is reduced. The release of tropocollagen from the connective-tissue cells is slowed down.


Experimental allergic encephalomyelitis. Water, sodium and potassium concentration in spinal cord and hemispheres and their changes after dexamethasone treatment.

Water content, Na+, K+ and Cl- concentration were measured in rats with experimentally produced allergic encephalomyelitis. Increase of water content by 10%, accumulation of Na+ by 13%, of Cl- by 20% and decrease of K+ by 10% was observed in the spinal cord, but no substantial changes were found in the brain tissue. The hydration of spinal cord is accompanied by perivascular infiltrates. Dexamethasone, administered from day 5, after injecting sensitising encephalitogenic basic protein, effects normal levels of water content and Na+, K+ and Cl- concentration.


The influence of inorganic phosphate and citrate anions on the effect of glycosaminoglycans during collagen fibril-formation.

Some anions like phosphate, sulfate and citrate delay the fibril-formation. The interaction of phosphate and citrate with chondroitin sulfate-A (CSA) in binding to collagen was investigated in different environmental conditions. By changing the concentration of phosphate from 5 to 50 mM/l and that of CSA from 0.5 to 16 mM/l some kind of competition of the anions was discovered. When different equilibration, systems were used the affinity of CSA to collagen was found to be 10 times greater than that of phosphate at pH 7.2 and I=0.15. As phosphate anions bind to collagen at physiological concentration. phosphate anions may be supposed to influence the biological fibril-formation. On the other hand the CSA exchanges phosphate for collagen. Therefore, glycosamino-glycans (GAG) in connective tissue ground substance in fibrillogenesis may regulate the ion binding and through this the tendency of aggregation of the collagen molecules. The binding of citrate to collagen and its effect and possible role in fibril-formation was also evaluated.


Redistribution and internalisation of anti-AH1e (anti-AHP)- and Concanavalin A-binding sites.

The redistribution and internalisation of two different lectin-binding sites on the same cell was investigated electron microscopically on unfixed rat liver cell cultures. For these purposes an electron microscopic double labeling technique was used for visualisation of the anti-AHel-binding sites by the gold-labeled lectin and for the demonstration of the Concanavalin A-binding sites by the Concanavalin A-peroxidase technique. From the experiments it was evident that the ligand-induced redistribution of the antiAHel-binding sites effects a rearrangement of the Concanavalin A-binding sites. Both markers were found in a clustered distribution on the cell surface. Following the redistribution an internalisation of both lectin-binding sites could be observed on central and peripheral cell parts. In the lateral cell parts an accumulation of the both markers occurred on the plasma membrane.


[Image processing in pathology. IV. Age dependent changes of morphometric features of liver cell nuclei in biopsies].

Several authors reported age dependent changes of single morphometric parameters on liver cell nuclei. In this study a recently developed automatic morphometry system was applied to recording of many liver cell nuclei parameters in histologic sections of liver biopsies simultaneously. The relations of the automatically generated parameters according to the age of the individuals are to be demonstrated.


Experimental investigations on increased resistance to infections with Candida albicans and Staphylococcus aureus Smith by 4-imino-1,4-diazobicyclo-(3.1.0)-hexane-2-on BM 06.002 (prop. INN imexon) in mice.

BM 06.002 increases the resistance of mice to experimentally induced chronic infection with Candida albicans. Furthermore, BM 06.002 leads to increased resistance in the case of experimentally induced infection with Staphylococcus aureus Smith, when a subtherapeutic dose of sulfadiazine is applied. In mice immunosuppressively pretreated with hydrocortisone, BM 06.002 effectuates immunorestauration.


Electron microscopic study of alcoholic liver disease with special attention to the changes of mesenchymal cells of the liver.

The authors investigated electron microscopically the biopsy material of 48 chronic alcoholic liver patients. On the basis of clinical and histological criteria 5 stages were differentiated: fatty liver, fatty liver with increased mesenchymal activity, acute alcoholic hepatitis, chronic alcoholic hepatitis, alcoholic cirrhosis. In each group changes of liver cell organelles and mesenchymal cells were compared. In this investigation it was demonstrated that liver cell damage--except for acute alcoholic hepatitis was not parallel with the severity of the clinical picture. On the contrary, the proliveration of mesenchymal cells, signs of its secretory activity and fibre forming, were in correlation with the progression of liver disease. The authors suggest that an intermediate stage must be taken into account between acute alcoholic hepatitis and alcoholic cirrhosis: the chronic progressive alcoholic hepatitis. It reminds morphologically to a great extent of the active chronic hepatitis and it is characterized not by severity of the injury of liver cell organelles, but by great proliferation of mesenchymal cells and lymphoid infiltration.


Relations between spontaneous and induced arterial lesions in swine and arteriosclerosis in humans.

The rabbit which for practical reasons is so frequently used for experimental arteriosclerosis considerably differs from humans in its metabolism, nourishment, and arterial wall responses to atherogenic noxae. In this respect, domestic pigs show more resemblance to the conditions in man, and they have recently been used for experimental research work in the field of atherosclerosis. Our own investigations performed with a view to constructing an antherosclerosis model being as far as possible resemblant to conditions prevailing in humans have shown that among various forms of diets only one combined form which is rich in cholesterol (1.5 percent) and lipids (15 percent) produces changes in the intima that in certain arterial regions correspond to lesions found in humans. These are lipofibrous beds up to complicated atheromas. The location of the spontaneous changes (without atherogenic diet) suggest that these may be considered as early stages. The various forms of development were studied light- and electron-microscopically; moreover the development of the blood lipids was determined biochemically during the experiment.


Semiquantitative histological examinations of the kidneys of rabbits (64-day, 100-day and 212-day series) with experimentally induced pyelonephritis.

The kidneys of each 8 rabbits of a 64-day series (group E) and a 100-day series (group F) and of 6 rabbits of a 212-day series (group G) with experimentally induced unilateral hematogenous obstructive E. coli pyelonephritis were histologically examined and the glomerular and tubular lesions quantitatively evaluated using an ocular micrometer. An attempt was made to correlate the morphological changes with the results of simultaneous enzyme analyses (acid and alkaline phosphatases, glutaminase I).


Human cell cultures infected by tumor-inducing and non-tumor-inducing viruses, an electron microscopic study.

This study is dealing with the infection patterns of adenovirus type 2 and type 12 on human fibroblast cell lines, KB, WI and MAF. With the exception of Ad -12 leads to WI, many intranuclear viral particles were present. None of these second passages (Ad-2 WI-WI, Ad-12 WI-WI, Ad-2 MAF-MAF, Ad-12 MAF-MAF) was found to have viral production. This indicates that the injections on both WI and MAF cells caused by both Ad-2 and Ad-12 cannot be serially transmitted. However, when these infected cells were used to expose KB cells, significant viral yields were obtained. This shows that the infected cells might still carry the viral specific antigens although no visible virions were observed.


The effect of unilateral papillectomy on the juxtaglomerular granulated cells.

The changes of the juxtaglomerular  index values in the superficial, deep and whole cortical areas of rat kidneys after unilateral papillectomy were analyzed. On the papillectomized side the JGI values showed an increase in the deep, and a decrease in the superficial cortical zone. The changes proved to be significant during the whole experimental period in the juxtamedullary index and between the 4--14 postoperative days in the superficial index values. The tendency of the changes of JGI in the contralateral kidneys was similar to those of the papillectomized kidneys, but significant differences were registered less constantly. These changes are probably the consequences of haemodynamic factors. Papillectomy is considered an incompetent model for studying the regulatory function of macula densa in the synthesis of renin.


[Characteristics of the pharmacological action of piracetam].

As concerns most generally accepted characteristics adopted in pharmacological studies of psychotropic drugs pyracetam is little active, has no effect on the EEG of the cortex and subcortical structures of the brain. At the same time, in a number of tests this drug displayed a well-marked influence on the central nervous system. It restrains convulsive activity provoked by application to the cerebral cortex of strychnine and penicillin solutions, reduces EEG disturbances produced by barbiturates poisoning and acute hypoxia of the brain. Pyracetam also facilitates the process of teaching in rats, improves the execution of a developed conditioned avoidance reaction, protects rats against manifestations of retrograde amnesia induced by an electric shock, applied after development of the conditioned reflex of passive avoidance.


[Comparative characteristics of the action of sydnocarb, phenamine and caffeine on multiple alteration in the orientation of the avoidance response in rats].

The ability of rats to alter orientation of the avoidance response in an Y-shaped maze was determined. Sydnocarb (20 mg/kg) improved the reversal learning of the animals, shortened the latent reaction periods and did not upset passive avoidance. Amphetamine (0.5 mg/kg) and caffein (25 mg/kg) shortened the latency of reactions, but did not affect the reversal learning. In large doses (2 and 5 mg/kg) amphetamine distinctly disturbed the reversal learning, while sydnocarb (50 mg/kg) did not impair the alteration of the avoidance response. In rats poorly amenable to reversal learning during control testing syndnocarb facilitated the alteration of the habit better than other drugs. In animals well amenable to reversal learning, in contrast to amphetamine and caffein, it did not derange their behavior.


[Action of aminazine and tisercin in a changed functional state of the body].

Experiments with rats evidenced that the pain-allaying and hypothermal action of chlorpromazine and tisercin (5 and 1 mg/kg) remains intact with an upset homeostasis against the background of a phlogogenic mixture and inflammation effect, though it becomes less potent. These drugs increase the higher permeability of the blood-histological barrier of the suprarenals caused by the stress (introduction of an irritating mixture) and inflammation.


[Effect of phentolamine on the electroencephalogram and pulse activity of the cortical neurons].

In tests with vigilant immobilized and also urethan anesthetized rabbits the influence of intravenous injection of phentolamine (3--10 mg/kg) on the EEG waves parameters was studied. It is shown that within 45 to 75 minutes following introduction of phentolamine there is observed either shortening or elimination of the EEG activation reaction in response to stimulation of the sciatic nerve. The blocking effect of the intravenous administration of phentolamine is noted also by following dynamic changes in the discharge activity of single neurons.


[Biotransformations of strophanthidin D- and L-arabinosides in the body of rats].

Metabolism of two cardiac glycosides--strophanthidine-3-alpha-L- and strophanthidine-3-alpha-D-arabinozide was studied at the stage of their passage via the liver and on the way of excretion by the kidneys in tests on albino rats by using paper chromatography. It was found that in passing through the liver both glycosides undergo a process of reduction of the aldehyde group at C1O to the alcoholic one. Different time periods of passage with urine were reduced, viz. strophanthidine-3-alpha-D-arabinozide and its metabolite are excreted during 24 hours and strophanthidine-3-alpha-L-arabinozide and the product of its transormation--within the space of 12 hours.


[Effect of sodium selenite, alpha-tocopherol and their combinations on the indices of the functional state of the heart regulation adren- and cholinergic systems in experimental myocardial infarct].

A course-wise administration of sodium selenate (30 gamma/kg), alpha-tocopherol (50 mg/kg) and of their combination in the same doses brings down the catecholamines content in the heart and suprarenals in the acute period of developing myocardial infarction (2nd day) with its subsequent normalization on the 14th day. Under the effect of these drugs the proportion of acetylcholine-like substances in the heart with experimental infarction rises at the expense of an accruing free (unbound with protein) fraction. The cholinesterase activity then gets intensified in the acute period and becomes normal by the 14th day.


[Pharmacological effects of the new psychotropic preparation, mebikar].

By its effects mebicar -- a derivative of bicyclic bis-ureas -- may be refered to psychotropic drugs occupying a middle position between tranquilizers and neuroleptics. The drug inhibits the orientation reaction in albino mice, potentiates the action of narcotic hypnotics, abolishes the conditioned reflex reaction of avoidance, displays central adrenolytic activity, interferes with the norepinephrine metabolism in the brain stem and modifies the permeability of the blood-encephalic barrier, like this is done by the known neuroleptics. The substance is little toxic, does not exert any direct spasmolytic action on the isolated organs.


[Effect of imipramine on the vasomotor tone, blood supply and activity of the heart].

In tests conducted on anesthetized cats it was shown that imipramine used in doses of 1 and 3 mg/kg causes hypertension, increases the vascular tone in the kidneys and limbs. In doses of 5 and 10 mg/kg the drug provokes a short-lived (1--3 minutes) hypertension with a subsequent prolonged drop of the arterial pressure. The tonicity of the kidney and limb arteries changes in the same way as the arterial pressure, but the vascular tone in the heart only falls. In these doses imipramine blocks the adrenergic transmission of the excitation from the sympathetic nerve to the effector, e. g. produces a sympatholytic effect. Imipramine in a dose of 1 mg/kg intensifies the coronary circulation and then the oxygen absorption by the heart increases to a still greater degree. This is attended by the development of tachycardia, a greater cardiac output and an intensified contractility of the myocardium. In doses of 5 and 10 mg/kg imipramine protractedly reduces the cardiac ejection, coronary blood flow and significantly lowers the contractile function of the heart muscle.


[Effect of prostaglandins E1 and E2 on the adrenergic reactions of the cerebral vessels].

Prostaglandins E1 and E2 were found to lower the pressor effects of norepinephrine and sympathetic stimulation with respect to the cerebral vessels in cats. This property is more marked in prostaglandin E1. Inhibition of the prostaglandins biosynthesis with indometacin leads to intensification of the described antagonism between the prostaglandins E1 and E2, on the one hand, and pressor effects of norepinephrine and sympathetic stimulation, on the other. It is admitted as possible that prostaglandins E1 and E2 partake in the mechanisms of adrenergic regulation of the cerebral circulation.


[Oscillatory potentials in the structures of the visual system].

The electroretinogram oscillatory potentials have similar general configuration and frequencies. Under the conditions of experimental dystropia of the retina and also after glycine administration, suppression of the oscillatory potentials formation in retina is accompanied by suppression of the evoked responses formation in the LGB, superior colliculi, visual cortex, and chiasma. The oscillatory potentials in the cerebral structures are related to the primary complex of their evoked responses. The importance of using the oscillatory potentials to study the mechanism of influence of the visual stimuli on the evoked potentials, is discussed.


[Role of protein biosynthesis activation in the mechanism of the negative chronotropic action of the vagus nerve and acetylcholine on the heart].

In rats, the following data were obtained: a) acetylcholine activates the rate of protein biosynthesis in auricles in vitro; b) protein biosynthesis inhibitors (actinomycine D, sarcolysine, neutral rot, tolluidine blue) weaken the negative chronotropic effect of acetylcholine and vagus on the heart; c) anabolic hormones increase the cholinergic effect on heart; d) acetylcholine induces hyperpolarization of the myocardial fibers which is prevented by actinomycine D. The activation of protein biosynthesis followed by hyperpolarization of the pacemaker cells seems to play an important role in the mechanism of negative chronotropic effect of acetylcholine and vagus on the heart.


[Effect of electric stimulation of the hypothalamus on the blood coagulation system of rabbits].

Anterior and posterior hypothalamic areas were electrically stimulated in rabbits implanted electrodes and the blood was studied with the aid of thromboelastograph. The stimulation entail edregular changes in the blood coagulating system leading to hypocoagulation. However, on the background of artificial (heparine administration) or natural hypocoagulation the same stimulation accelerated the blood coagulation. The hypocoagulation occurring on hypothalamic stimulation is supposed to be of the secondary character, while the orientation of changes in the blood coagulating system after the brain stimulation depends on the initial level of hemocoagulation.


[Action of noradrenaline and acetylcholine on the contractile activity of the gastric arteries].

The effects of norepinephrine and acetylcholine on smooth muscle cells of isolated strips of gastric arteries were studied. The gastric arteries revealed small sensitivity to acetylcholine. The norepinephrine effects on smooth muscle cells can be realized through electrogenic and pharmacomechanical activation. The adrenergic control of gastric arteries is fulfilled mainly with alpha-adrenoreceptors participation.


[Effect of trypsinogen on the secretion of the gastric glands].

In chronic experiments on dogs, i. v. administration of trypsinogen (5 mg) raised enzyme--secreting activity of the gastric glands. An increase in pepsinogen secretion by the gastric glands was noted also in acute experiments early after ligation of pancreatic ducts when tryptic activity of the blood was rising. The activating effect of trypsinogen was also revealed on the rat stomach in vitro.


[Role of antral gastrin in regulating gastric secretion and bile flow].

In chronic experiments on dogs with removed mucosa of the antral portion of the stomach, administration of the liver extract into the stomach or intestine decreased the output of hydrochloric acid as compared with intract animals. The liver extract administration caused no raise of gastrin level in the blood serum of the operated animals.


[Role of sorbed enzymes in the digestion and absorption of nutrient substances from the chyme].

In poly--fistula dogs, a significant suppression of the fermentative hydrolysis and of the absorption ability was revealed in excluded from the digestion intestinal loops. The experiments showed that suppression of the cave enzyme sorption in the area of wall digestion was the factor slowing down the flow of feeding substances from the enteral milieau.


[Trace effects of short-term cooling and their importance in the adaptation to cold].

The thermoregulation traces (O2 consumption, electrical activity of cervical muscles deep rectal temperature and subcutis temperature) were observed to 30 min. at ambient temperatures + 20--24 degrees and + 6--7 degrees through 1, 5, 10 and 30 days after cooling. The after-effect (traces) of cooling depends on conditions of cooling. Single or double cooling followed by a fall in core temperature to 30 degrees as well as intermittent cold exposures (15 two-min. exposures at--20 degrees) without the core temperature falling and a cold long--term (4--5 weeks) exposure at + 2--4 degrees cause a prolonged after. The short-term cooling increases the trace reactions throuth 5--10 days after cooling. Their traces are similar to changes in a cold acclimation rats.


[Magnesium load and its removal by the kidneys in rats].

Administration of 0.25% -- 2.0% solutions of MgCl2 (5 ml/100 g) into the stomach of unanesthetized rats revealed that it is the 0.75% solution which is most efficiently removed. The kidney removes 3.9% of administered magnesium within 4 hrs, and 18.9%--within 24 hrs. All the administered fluid is absorbed within 3 hrs, but 32% of magnesium salts remain in the gastro--intestinal tract. The liver is no depot for the magnesium, the latter being distributed over different organs and tissues. Within 24 hrs magnesium is removed by the kidney and intestine, for on the 5th day after daily administration of 790 Mequiv. of magnesium per 100 g ob body weight during 4 days, its concentration in the blood serum does not differ from initial values.


[Senescence of endocrine function with special reference to the hypothalamic-pituitary-gonadal axis in the rat (author's transl)].

In the control theories, aging is under genetic and environmental control. Endocrine function plays an important role in this control system by mediating between the environmental influence and the presumptive "aging gene". Therefore, the intrinsic aging of the hypothalamus, such as the changes in sensitivity to feedback suppression or stimulation, may lead to homostatic failure and then age-related pathology. As the subject of study we have selected the senile changes in the hypothalamic-pituitary-ovarian axis in the rat of the Wistar strain. The cessation of estrous cycle and the onset of persistent estrus or repetitive pseudopregnancy usually take place as early as at the end of the first half of life in rats. In this paper the results of the following experiments are briefly dealt with: (i) reciprocal transplantation of ovaries between young and old rats (the term "old" designates here "incapable of reproduction"), (ii) comparison of LH and FSH binding abilities in the ovarian preparations, (iii) comparison of serum and pituitary concentrations of LH, FSH and prolactin and the modifications after ovariectomy or by the administration of pharmacological drugs, and (iv) the difference between young and old rats in intensity of dopamine fluorescence in the hypothalamus. The results of these experiments seem to point to the hypothalamic-pituitary part rather than more peripheral organs (ovaries) as being primarily responsible for the outcome of the senile changes in the female rat.


The effect of somatostatin on platelets: in vivo and in vitro studies.

The influence of somatostatin on platelets was studied in healthy volunteers. After a bolus injection of 250 microgram somatostatin followed by a three hour infusion at a rate of 250 microgram somatostatin/hr a statistically significant fall of platelet count and impairment of platelet aggregation was observed. The aggregation inhibiting effect of somatostatin at the end of the three hour infusion is clinically unimportant as compared to the effect of aspirin. In vitro concentrations up to 10.0 microgram somatostatin per ml do not show any effect on platelet aggregation and platelet stickiness. Endocrinologically active doses of somatostatin in short term infusions are very unlikely to cause bleeding disorders.


[The prevalence and incidence of juvenile onset insulin-dependent diabetes mellitus in France (author's transl)].

From notification of cases the prevalence and incidence of juvenile diabetes has been estimated in the population of France. Only diabetes treated with insulin has been considered. The prevalence of diabetes in children at the end of 1975 was one per 4,200 children who had not yet reached their 15th birthday. The number of cases increased regularly with each year of age. There are more boys than girls with diabetes but the sex ratio does not, in fact, differ significantly from that of the normal population. The incidence for 1975 was one per 27,000 children aged 0 to 14 years, i.e. one new juvenile diabetic per year can be expected in a population of 100,000 inhabitants of all ages. Diabetes was diagnosed more often in the children in October, November, December, January and February regardless of age (0 to 4; 0 to 19). Comparison of the french data with information collected from published literature and from other personal sources shows some similarities but also many marked differences between countries. Some of these differences may be due to different methods of ascertainment. Standardisation of methods is a prerequisite for comparability of data.


Effect of insulin on thyroid hormone blood levels in normal and thyroidectomized dogs.

Administration of insulin brings about an increase of thyroid hormone blood concentration. This study investigated the possibilities that the elevation is due to increased thyroid secretion or to liberation of hormone from hepatic stores. Monocomponent insulin was administered to intact dogs by jugular perfusion (25 mU/kg/min. for 15 min.) and to thyroidectomized dogs either as single dose i.m. (1 U/kg) or by jugular perfusion (as above). All animals showed at least halving of blood glucose concentration. In normal dogs, circulating labeled thyroid hormone increased with a 2-fold T3 rise. In thyroidectomized dogs, blood T3 as well as T4 remained persistently low, while plasma 125I-T4 disappearance slope was unchanged. When intact animals were held in a glycemic steady state by infusing insulin alone at low dose (0.5 mU/kg/min. for 15 min.) or insulin at the experimental dose (25 mU/kg/min. for 15 min) with simultaneous glucose infusion, blood T3, T4 and labeled PBI showed no changes. These data suggest that the increase of circulating thyroid hormones under insulin administration is due to a stimulation of thyroid secretion. The effect of insulin appears to result from induced hypoglycemia.


Inhibition of L-dopa induced growth hormone release in normal and diabetic subjects by glucose administration.

Administration of L-dopa 1 g induced an increase of plasma growth hormone (GH) levels in seven of ten healthy volunteers and in six of ten hyperglycemic insulin-dependent diabetic subjects; the maximal GH response was higher in normal subjects. Addition of 100 g glucose orally to the L-dopa completely abolished the GH response of both groups. The difference between the effect of endogenous hyperglycemia and the effect of a sudden increase of blood sugar after glucose administration on L-dopa induced GH release in diabetic subjects may be explain by the resetting of the hypothalamic control for pituitary GH release to higher levels of blood glucose.


HLA antigens in Sardinian patients with diabetes mellitus.

HLA-B8 and HLA-Bw15, two antigens associated with juvenile diabetes mellitus in Caucasians of North Europe, have a very low frequency in Sardinian population, who nevertheless have a high frequency of diabetes. The association between diabetes and HLA in Sardinian population has therefore been investigated in 60 patients with diabetes, mellitus (32 with juvenile diabetes and 28 with maturity onset diabetes) and 96 normal, unrelated random controls. No disturbance of HLA distributions was found in maturity onset diabetes, but the frequencies of B8 and Bw35 were increased among juvenile diabetics (18.7 percent and 28.1 percent respectively, compared with 2.0 and 11.4 percent in healthy controls). B18 antigen frequency was also increased, although not significantly, in juvenile diabetes mellitus (65.6 percent compared with 50 percent in controls). In contrast the frequency of HLA-Bw15 in two groups of diabetics differed little from that of controls.


An uncontrolled trial of clomipramine (Anafranil) in the treatment of phobic and obsessional states in general practice.

A small, open, multicentre trial of clomipramine (Anafranil, Geigy Pharmaceuticals) in the management of phobic and obsessional states was performed in general practice. New rating devices were used. Twenty-seven patient suffering from a variety of phobias and obsessions were treated with doses of clomipramine up to a maximum of 225 ng daily for six weeks. In phobic subjects best results were obtained in social phobias, agoraphobia and diffuse phobic anxiety, situational anxiety, interference, avoidance and autonomic effects all responding. An improvement of between 33% and 47% was seen in obsessional symptoms.


A large open multicentre trial of clomipramine (Anafranil) in the management of phobic disorders.

In a large, open, multicentre trial, conducted in general practice, 765 patients suffering from agoraphobia or social phobias were treated with clomipramine (Anafranil, Geigy Pharmaceuticals). Four hundred and eight patients completed a twelve-week course of treatment. Of 285 withdrawals, 139 were due to side-effects. Good results were obtained on all measures of phobias in those patients who completed the study, the improvements being of the order of 70-80%, and over 50% of patients being symptom-free.


The measurement of obsessionality: first validation studies of the Lynfield obsessional/compulsive questionnaires.

The difficulties encountered in attempts at the rating and quantification of obsessional behaviour are outlined and some of the reasons for such difficulties are mentioned. The development of the Lynfield Obsessional-Compulsive Questionnaire from the Leyton Obsessional Inventory is discussed together with the advantages and disadvantages attendant upon its administration. The author concludes that the Lynfield Obsessional-Compulsive Questionnaire promises well as a measure for assessing change and that, following further validity and reliability tests, it may be used in multicentre trials of treatment procedures.


The management of phobic disorders in general practice.

Over two thousand patients have been treated with a flexible drug regime, having presented with a wide spectrum of disorders. Common aetiology was found in these patients and all could be said to be phobic, and as such many produced "side-effects" which could by predicted with accuracy--and overcome. A method is described for inducing increased patient compliance and decreased drop-out rate.


Clomipramine (Anafranil) in depressive patients with obsessive neurosis.

The authors express the view that, clinically, clomipramine (Anafranil, Geigy Pharmaceuticals) seems to be the treatment of choice for obsessive-compulsive illness. Clomipramine possesses a specific anti-obsessional property which is distinct from its antidepressant property. The optimal therapeutic dose from this study appears to be in the range of 175 mg to 225 mg a day. Minor reversible adverse reaction gradually decreases with the increase of duration of treatment.


Treatment of obsessive-compulsive neurosis with clomipramine (Anafranil).

An uncontrolled clinical study was carried out to evaluate the therapeutic efficacy of clomipramine (Anafranil, Geigy Pharmacueticals) in a group of twenty obsessive-compulsive neurotic patients. Clomipramine proved to be extremely useful in alleviating obsessive-compulsive neurosis as well as phobia. This finding was not secondary to the improvement in anxiety or depression which occurred, as the degree of improvement in obsessive symptoms far exceeded the improvement in the other symptoms.


A comparison of clomipramine hydrochloride (Anafranil) and behaviour therapy in the treatment of obsessive neurosis.

A six-week trial of 300 mg clomipramine hydrochloride (Anafranil, Geigy Pharmaceuticals) was compared to a six-month twice weekly therapeutic programme with two widely used behavioural techniques, flooding and thought-stopping. Clomipramine had a substantial ameliorating effect on the number and severity of obsessional symptoms, reducing the total obsessive symptomatology by half. The trends suggested that the drug was as effective as flooding and more effective than thought-stopping in reducing the ruminative symptoms, and was especially effective in reducing pervading doubt. It was considerably less effective than behaviour therapy in reducing the compulsive symptoms. This suggests, and confirms the authors' clinical impression, that a combination of pharmacotherapy and behaviour therapy is the optimal treatment of choice for ritualistic patients who are almost always very ruinative, doubtful and highly anxious. Clomipramine had the most substantial anxiolytic effect of three groups and seemed to be as effective as behaviour therapy in reducing phobias.


Clinical experience in the treatment of phobic disorders.

The author describes his experience in treating phobic disorders with both parenteral and oral clomipramine. Other techniques are mentioned and it is suggested that it is not only possible, but also desirable, to incorporate some of these in a regime of parenteral therapy for hospital in-patients. It is recommended that oral administration of clomipramine be used in the case of out-patients.


Clinical experience in the treatment of obsessional states (1).

This paper describes the treatment of thirty-three patients who were suffering with obsessional symptoms and who were given the drug clomipramine (Anafranil, Geigy Pharmaceuticals). The symptoms were classified into phobic ruminations, non-phobic ruminations and rituals as well as into the less familiar group of normal and bizarre obsessions. Progress was assessed using the Shapiro card method and a brief description of this method is given. The results show that clomipramine possesses a specific anti-obsessional quality and that the use of this preparation is an effective treatment for obsessional patients. The paper also discusses certain aspects of therapy as well as suggesting an aetiological basis of obsessional symptoms.


Some aspects of the measurement of phobias and obsessions.

Two assessment schemes for assessing obsessional and phobic disorders are described. The schemes were constructed with the phenomenology and epidemiology of the disorders in mind and were designed for use in the setting of general practice.


Clinical experience in the treatment of obsessional states (2).

There is no adequate classification of obsessive/compulsive phenomena and they frequently co-exist with other psychiatric symptoms, notably depression. Seven years experience in the use of intravenous clomipramine in these conditions is reviewed. Good results have been obtained in the treatment of depression, and obsessive/compulsive/phobic states, and mixed patients. The results in neuroses and personality disorders are poor. It is concluded that clomipramine is the treatment of choice for obsessive/compulsive disorders, with or without accompanying depression.


Pharmacokinetic studies in obsessional patients.

As part of a larger controlled study, 9 patients with chronic obsessive-compulsive rituals received oral clomipramine (Anafranil, Geigy Pharmaceuticals) and behavioural treatment. Dosage was 20 mg clomipramine during the first three days of treatment, increasing gradually over the next few weeks to a maximum daily dose of 200 mg clomipramine unless side-effects dictated a lower dose. Blood was sampled at weekly intervals and the plasma fraction analyzed simultaneously for clomipramine and its primary metabolic breakdown product, N-desmethylclomipramine, using a double radioisotope derivative technique. Plasma concentrations of clomipramine and desmethylclomipramine were observed to rise as the administered dose was increased during the first few weeks of treatment. However, within seven to fourteen days of constant daily dosing steady-state levels were reached in the plasma of clomipramine and its metabolite. Higher plasma levels were found with higher doses. Steady plasma clomipramine levels appeared to be related to dosage, the mean steady-state plasma concentrations between weeks 5 and 11 of treatment being 99 ng/ml, 145 ng/ml and 180 ng/ml, in patients receiving daily doses of 100, 150 and 200 mg clomipramine, respectively. In contrast, plasma metabolite levels did not show any apparent relationship to dosage. In most patients, the concentration of desmethylchlomipramine in the plasma was approximately twice that of the parent compound.


A clinical trial of clomipramine and diazepam in the treatment of phobic and obsessional illness.

A double-blind comparative study of clomipramine and diazepam was carried out in patients suffering from phobic and obsessional disorders. Nineteen doctors submitted 58 patients. Seventeen patients withdrew from the trial, twelve because of side-effects. Forty-one patients completed the trial and of these 14 were on clomipramine and 27 were taking diazepam. Patients were assessed for phobias, obsessions, general psychiatric symptoms and side-effects and each was rated on a special symptom inventory at 0, 2, 4 and 6 weeks of treatment. A General Health Questionnaire and Burns Questionnaire was completed for each patient at the beginning and end of the study. General level of anxiety for diffuse phobic anxiety and situational anxiety for illness and death fears responded better to clomipramine than to diazepam. Global assessment showed significantly more progress on clomipramine than diazepam between weeks 4 and 6.


The relationship between sucking and grasping in the human newborn: a precursor of hand-mouth coordination?

The relationship between grasping and sucking, a possible precursor of hand-mouth coordination, was examined in human newborns of varying gestational ages. Grasping was elicited by rapidly tilting the infant backwards while he rested on a padded board and held a grasp bar. Infants were tilted 4 times under each of 3 conditions: grasping, sucking, and grasping-while-sucking. The dependent variables were strength and duration of grasp and frequency and amplitude of sucks during the 15 sec following the tilt. The results indicated that grasping did not affect sucking but that sucking increased the strength and the duration of the grasp. Furthermore, either response system was more highly correlated with indices of maturity of the central nervous system when elicited in the presence rather than the absence of the other. We conclude that in human newborns sucking may be dominant over grasping but that both are part of an integrated system which may form the basis for the development of hand-mouth coordination.


Early environmental influences on conditioned and unconditioned ingestional and locomotor behaviors.

For 34-44 days after weaning one group of rats was raised in a socially enriched environment, whereas another group was raised in isolated individual cages without handling. Following this differential rearing subjects were tested for ingestional neophobia and its attenuation, enhancement of ingestional neophobia by aversive drug administration, taste-aversion learning and extinction, open-field activity, and passive shock-avoidance learning. Although the differential rearing influenced open-field activity and shock-avoidance this manipulation did not have a significant effect on the various measures of conditioned and unconditioned ingestional behaviors. The results provide further evidence for the distinctiveness of gustatory-visceral and telereceptor-cutaneous sensory systems.


Effects of feeding on state and cardiac regulation in the infant.

The effects of feeding on polygraphic state patterns and associated cardiac rates were examined in 8 normal infants using data collected during 12-hr continuous monitoring sessions at 1 week and at 1, 2, 3, 4, and 6 months of age. The distribution of states and corresponding heart rate values were tabulated for each minute during 2-hr periods preceding and following wakenings with and without feedings. Rapid eye movement (REM) sleep was significantly more prevalent immediately following a waking accompanied by feeding than waking alone. Moreover, a distinct relationship was demonstrated between feeding periods and the ongoing sleep cycle. In younger infants (1 week to 1 month), heart rates in quiet sleep (QS) and REM were higher after feeding than before, suggesting a general arousal influence. This was not the case with nonfeeding wakenings. In older infants (2-3 months), heart rates were higher after nonfeeding periods than before, but similar before and after feeding periods.


Acquisition and retention of a passive-avoidance task as a function of age in mice.

In Experiment I groups of mice between 16 to 100 days of age were tested for retention of a passive-avoidance response between 1 min and 96 hr following a single training trial at 2 shock intensities. In general, although almost all age groups displayed reliable retention at all retest intervals, some retention losses were found among the youngest age groups at the longer retention intervals. Higher shock intensity resulted in longer retest latencies, primarily among the youngest mice. In Experiment II mice 16, 25, and 100 days of age were trained to criterion on the passive-avoidance task and retested on a single trial following retention intervals of 24, 96, 192, and 384 hr. Young mice exhibited severe retention losses relative to 100-day-old mice at the longer intervals, even though they did not show deficiencies in acquisition. Neurological maturity at the time of original training appears to account for the age-related memory differences.


Construction of low-variability litters of preweaning mice.

Mouse litter variation at weaning stems from a combination of genetic makeup, intrauterine experience, and postnatal maternal care. The 1st 2 factors may be matched at birth by making up separate litters out of littermate pairs whose birth weights are equal (+/-.02 g). Maternal competence may be matched by exchanging the mothers between the 2 cages each day. These tactics yield litters at weaning whose variability has been very much reduced. The range of litter-average body weights has been reduced from about 40 percent to about 5 percent and the range of litter-average brain weights has been reduced from about 15 percent to about 1-2 percent.


DNA-dependent RNA polymerases from Artemia salina. IV. appearance of nuclear RNA polymerase activity during pre-emergence development of encysted embryos.

Dessicated and encysted gastrulae of the brine shrimp Artemia salina remain metabolically dormant until they are rehydrated. At this time development resumes, culminating in the hatching of free swimming nauplius larvae. The resumption of embryogenesis provides a convenient system for studying biochemical events which accompany development of a eukaryotic organism, and in particular Artemia has proven useful for studies of the transcriptional regulation of gene expression. Encysted gastrulae of Artemia yielded only trace amounts of DNA-dependent RNA polymerase activity when crude nuclear pellets were subjected to sonication at high ionic strength. Furthermore, when crude nuclear pellets from encysted gastrulae and developing nauplius larvae were mixed prior to sonication, subsequent solubilization of proteins from the mixture did not yield RNA polymerase activity; sonication of the pellet from nauplii alone resulted in the solubilization of large quantities of RNA polymerases I and II as we have previously found [1]. RNA polymerases I and II were detectable in sonicates of crude nuclear pellets after 1-h incubation of Artemia cysts in sea water. This presents the possibility that dormant gastrulae of the brine shrimp contain RNA polymerase which is inactive, and that the rapid appearance of nuclear enzymatic activity which accompanies the resumption of development may not require de novo synthesis of the polymerase.


[Glycoprotein changes in acute myocardial infarction (author's transl)].

The changes of 11 plasma glycoproteins have been recorded during the first month in 22 patients with acute myocardial infarction; the quantitations have been performed by radial immunodiffusion on plates. The IgM proteins are significantly augmented and, with lesser degree, the alpha1 acid glycoprotein, the alpha1 antitrypsin and the haptoglobin are significantly augmented too. The peak is noted on the tenth day (the alpha1 acid glycoprotein only has its peak in twentieth day). To explain these changes we can consider: 1) the inflammatory reaction; 2) the repair reaction; 3) the autoimmune response. The complete explanation of these findings needs time: in the mean time we could use the IgM changes as a test in the second stage diagnosis of the acute myocardial infarction as well as the tests used so far.


[Effectiveness of nifedipine on exercise tolerance in patients with angina pectoris. Comparison with a nitroderivative and a beta-blocking agent].

The effect of nifedipine on effort angina was investigated by means of exercise tests with bycicle ergometer and compared, in the same patients, with the effects of a nitroderivative and a betablocking agent. Five patients with stable effort angina entered the study, after an hemodynamic and contrasto-graphic control. According to the protocol of a latin square 5 X 5, all the patients received in a random sequence the following treatments: placebo, 1 c. orally; isosorbide dinitrate, 5 mg sublingually; propranolol, 40 mg orally; nifedipine, 10 mg sublingually; nifedipine, 10 mg orally. No significant change of any of the considered parameters was observed after the placebo. Isosorbide dinitrate and nifedipine produced significant increases of the duration of work before appearance of pain and EKG positivity, and of total work performed before anginal pain. Only the duration of work before EKG positivity was improved by propranolol. The comparisons between treatments showed no significant difference of the effects of the administered doses of isosorbide dinitrate and nifedipine. The improvements observed after propranolol were significantly lower than that observed after isosorbide dinitrate and oral nifedipine. On the basis of the observed changes of cardiac rate, maximal arterial pressure, ejection time index and triple product, the authors evaluate the possible mechanism of action of nifedipine.


[Mitral valve prolapse in a family group. Clinico-instrumental findings].

Clinical and echo-phonomechanocardiographic reports. The results concerning 7 subjects with mitral valve prolapse (M.V.P.), all members of the same familiar group, are reported. The anamnestic investigation for cardio-vascular deseases, Marfan's syndrome or other abnormalities referred to mesenchimopathies has been negative. No subject with M.V.P. has referred subjective cardio-vascular symptoms nor radiological, ecgraphic and echo-phonomechanocardiographic signs of reduced cardiac function, have been pointed out. The phonomechanocardiographic tracings have shown a variable and low-amplitude click. The echocardiographic tracings have shown a U-shaped (3 cases) and double U-shaped (1 case) pansystolic, early systolic (2 cases) and of doubtful classification (1 case) prolapse. The hypothesis of an autosomal dominant form of inheritance of the desease with not yet clear mechanism of genetic transmission is confirmed. Furthermore, environmental and genetic factors that interfere with the orderly valvular formation at a certain stage of the fetal development, are referred. The Authors remark the necessity of further investigations, among more familiar groups, for identifying the genetic-environmental factors, that, eventually, could have any implication in the ethiopathogenetic mechanism of the disease. The report of "silent" forms and the not yet completely known evolution of the M.V.P. don't justify its not-recognition.


[Aspects of pulmonary rheography in normal subjects (author's transl)].

The Authors studied the postural variations of right pulmonary circulation in 30 normal subjects with rheographic technique. In lying position the rheograms remain without modifications concerning the derivations's area (superior or middle or inferior right pulmonary lobes). In standing position the rheogram of superior lobe increases his area, that of inferior lobe decreases and that of middle lobe remains unvariated. This pattern of behaviour is early modified by cardiac or pulmonary diseases. Also if this technique is easy to perform and in our experience is reproducible, we think that we must  accept his limits in view of lack of a very accurate and exact calibration.


[Value of echocardiography in the diagnosis of dissecting aneurysm of the aorta].

A revision of 1300 echocardiograms of adults showed 14 patients whose echocardiographic diagnosis of aortic root dissecting aneurism (D.A.). Of these, 8 didn't have any anamnestic, clinical or instrumental evidence of D.A. In the other 6, admitted to our department with a suspected D.A., echocardiography proved to be useful in confirming such diagnosis in 4, in excluding it in 1, but gave a false positive diagnosis of D.A. in the sixth, affected by a diffuse carcinomatosis with pleuropericardial blood effusion. From the examination of the present experience, the Authors deem echocardiography is a useful diagnostic tool in the screening of D.A. when the following conditions are fulfilled: 1) presence of all the major criteria of Nanda and Gramiak, especially the aortic root anterior wall dilatation beyond 16 mm; 2) an almost suggestive story and clinical evidence of D.A. The usefulness of an echocardiographic pattern recently described as diagnostic of D.A. (loss of continuity between the borders of the anterior aortic wall with interventricular septum, and/or posterior aortic wall with mitral anulus) was confirmed: it was detected in 3 of the 4 D.A. patients but in none of the others. The presence of a false positive and the possibility of technical artifacts nevertheless induce caution in the interpretation of the echocardiographic pattern alone.


[Death caused by acute cardiac insufficiency due to rupture of the metal cage of a Braunwald-Cutter prosthesis. Description of a case].

A case of a man aged 39 who died one year after aortic valve replacement by a Braunwald-Cutter prosthesis is reported. A massive aortic incompetence due to falling out of the plastic ball owing to the rupture of an arm of the cage, induced an intractable cardiac future. On necroscopy the ball was found in the aorta at the level of the renal arteries.


Effect of splenectomy in tumor-bearing mice and gastric cancer patients.

In order to investigate the effect of splenectomy on tumor growth, splenectomy was performed in DDS mice transplanted subcutaneously with Ehrlich ascites tumor cells before and after the transplantation. It was found that, in the first control group receiving sham operation, all the mice died of tumor; in the second group that underwent splenectomy 1 week before the transplantation the tumor regressed in every case; in the third group that received splenectomy 5 days after transplantation when tumor became established, the tumor regression was observed in 85% of the animals, and in the fourth group that underwent splenectomy 10 days after transplantation, all the animals died of tumor earlier than the sham-operated first group. In the follow-up observations of 389 patients with gastric cancer who underwent gastrectomy alone and 89 cases who received gastrectomy combined with splenectomy, the 5-year survival rate of the latter group tended to show a better prognosis in a relatively early stage. It was concluded that splenectomy might inhibit the growth of tumor in a certain early stage, in both animals and humans, and the possible mechanism of this effect of splenectomy was discussed from the immunological aspects.


Transferrin patterns in the Eastern India in normal and malignant cases.

A series of 200 normal serum samples obtained from healthy blood donors belonging to different religious communities and casters were examined for transferrin phenotypes by vertical polyacrylamide gel electrophoresis. Of these, 196 showed the common CC phenotype, while 4 showed CD phenotype, without any correlation with the caste or community. In another study involving 102 cases of malignancy, no relationship was observed between th transferrin phenotype and the type of malignancy, except in the case of Hodgkin's disease, which showed B2C phenotype.


Establishment of a human rectal cancer cell line producing carcinoembryonic antigen.

A permanent cell line (S-7512) was established by cell culture from the subcutaneous metastatic tumor of a human rectal cancer and has been maintained for 18 months. Cultured cells grew as isolated and piled-up colonies of epithelial cells, each with a scanty cytoplasm and a large nucleus containing several nucleoli. The average doubling time of this cell line was 57 hr and plating efficiency was 30.1 approximately 45.2% in a liquid medium. The modal chromosome number was 115 but a marker chromosome was not evident. Electron microscopic examination revealed many microvilli, free ribosomes, and abundant glycogen granules. Heterotransplantation of the cultured cells produced a large tumor and its microscopic examination showed the same histological appearance as the original tumor (carcinoma simplex). Carcinoembryonic antigen level of the spent medium of the confluent culture was 235.50 ng/3.2 X 10(6) cells.


Damage and repair of DNA in urinary bladder epithelium of rats treated with N-butyl-N-(4-hydroxybutyl) nitrosamine.

N-Butyl-N-(4-hydroxybutyl) nitrosamine (BBN), which selectively induced urinary bladder tumors in several experimental animal species, was found to cause damage of DNA in the bladder epithelium. Wistar strain rats were given 100 mg/kg of BBN intravesically and killed after 2, 6, 12, 24, or 48 hr. DNA damage was examined by measuring the change in sedimentation pattern in an alkaline sucrose gradient. Amount of DNA in each fraction was determined by fluorescence spectrophotometry. At 2 hr, the sedimentation profile shifted from heavier (No 15, control peak) to lighter (Nos. 2 approximately 4) fractions, and the maximum effect appeared at 6 hr as a single peak in the lighter fractions. At 12 hr, damaged DNA was in the process of repair as two peaks were present, one light and one heavy. At 48 hr, the sedimentation profile showed a single peak identical with that of controls indicating complete repair of DNA.


Effect of various factors on the induction of liver tumors in animals by quinoline.

Tumorigenic effect of a diet containing quinoline on the liver of various animals and the synergistic or antagonistic effect by other chemicals on quinoline hepatocarcinogenesis in rats were examined. It was concluded that 4,4'-diaminodiphenylmethane (0.1%) and 3-methylcholanthrene (0.0067%) had a significant inhibitory effect on liver carcinogenesis due to quinoline in rats, but 1-naphthyl isothiocyanate (0.06%) and p-hydroxypropiophenone (1.0%) had no inhibitory effect in the present observations. Transmission electron-microscopic study demonstrated the fine structure of vascular tumors induced by quinoline. On the other hand, it was found that quinoline induced liver tumors in both sexes of mice and rats but not in hamsters or guinea pigs. Male rats were more susceptible than females to the tumorigenic action of quinoline, and mice showed the least susceptibility. Histological changes in the liver of rats or mice induced by quinoline were clasified as hemangioendotheliomas or hemangiosarcomas and hepatocellular carcinomas. Several rats treated with quinoline had hemangiosarcomatous metastatic foci in the lung.


Kinetics of preneoplastic epithelia of the the intestinal mucosa induced in Buffalo rats by oral administration of N,N'-2,7-fluorenylenebisacetamide.

A diet containing 0.025% of N,N'-2,7-fluorenylenebisacetamide (2,7-FAA) was administered orally to 18 Buffalo rats for 3 months and to 21 rats for 5 months which corresponded to non-neoplastic stage and preneoplastic stage of carcinogenesis of the intestinal mucosa, respectively. The mitotic index, labeling index, and generation time of the epithelia of the intestinal mucosa of these stages were examined by autoradiography. 1) The mitotic index and labeling index decreased in the rats fed 2,7-FAA for 3 months than those of the non-treated controls. 2) Decrease of both indices was also observed in the rats fed 2,7-FAA for 5 months, except for the proximal part of the colon. 3) Around 1-hr prolongation of the generation time was observed in the epithelia of rats fed 2,7-FAA for 3 months compared with the non-treated control rats, and this was mainly due to the prolongation of the duration of the G1 phase. 4) Two- or three-hour prolongation of the generation time was observed in the epithelia of rats fed 2,7-FAA for 5 months compared with the non-treated control rats, and this was mainly due to the prolongation of the duration of the S phase.


Effect of iodoacetamide or Tween 60 on methylnitrosocyanamide carcinogenesis in rat glandular and forestomach.

The effect of iodoacetamide or Tween 60 on carcinogenicity of methylnitrosocyanamide (MNC) in rats was examined. A significant increase in the incidence of the forestomach tumors (P less than 0.01) was observed in rats treated with MNC and iodoacetamide simultaneously. Moreover, there were 2 cases of glandular stomach tumors in rats treated with MNC and Tween 60 simultaneously. They were one well-differentiated adenocarcinoma and one polypoid hyperplasia. This result indicates that MNC under certain conditions is carcinogenic to the glandular stomach of rats in addition to the forestomach. Tween 60 might act by facilitating direct contact between MNC and the glandular stomach mucosa.


Chronic toxicity of 2-(2-furyl)-3-(5-nitro-2-furyl) acrylamide (AF-2) in mice, with special reference to carcinogenicity in the forestomach.

Chronic toxicity of 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide (AF-2), which had been widely used in Japan as a food additive, was studied in both sexes of ICR/JCL mice by feeding a diet containing AF-2 in a concentration of 0.4% or 0.08%. The experiments confirmed its definite carcinogenicity in the forestomach, with dose dependency; more than 70% of mice fed the higher dose developed tumors, the majority of which were squamous cell carcinomas with metastatic growths, whereas, with a lower dose, fewer tumors occurred, following a longer latent period. In addition, possible leukemogenicity was suggested by a higher incidence in AF-2-fed females (10.8%) over that in control females (3.2%). The development of non-neoplastic lesions in the liver and kidneys, and of amyloidosis in various organs was also observed in some of AF-2-fed mice.


Carcinoma of the esophagus of rabbits induced with N-methyl-benzylamine and sodium nitrite.

Esophageal carcinomas were induced in three of five rabbits given 0.25% N-methylbenzylamine and 0.16% NaNO2 in their drinking water. The three rabbits with carcinoma had consumed more than 94 g of NaNO2 and had survived for more than 536 experimental days. The esophageal carcinomas were a slightly elevated type, and no polypoid lesions were seen. They were classified histologically as squamous cell carcinomas or adenosquamous carcinomas, or both. No metastases were found. The other two of the five rabbits died early in the experiment before any esophageal carcinoma had developed.


Kinetics of tumor cell death by hyperthermic treatment and x-ray irradiation.

Kinetics of cell death by hyperthermic treatment at 44 degrees was analyzed using cultured mouse mammary carcinoma cells, and compared with that after X-irradiation. The cells treated with hyperthermia began to die randomly with a mean lethal time of 10 hr after a lag time of 10 hr. After irradiation, the lag time and mean lethal time were 40 and 34 hr, respectively. Early appearance of dead cells by hyperthermic treatment indicates that the critical target is related to cellular metabolism.


Effect of carbon tetrachloride on carcinogenicity of petasites japonicus and transplantability of induced tumors.

Effect of carbon tetrachloride on the carcinogenicity of the flower stalk of Petasites japonicus was examined in 3 experimental groups of inbred strain ACI rats. Group 1 received 4% petasites diet until termination of the experiment and intragastric administration of CC14, once every 2 weeks, for a total of 15 times. Group 2 received only 4% petasites diet, and Group 3 CC14 and a basal diet. Another group of rats which were fed a basal diet served as a control groups. Both Group 1 and 2 showed the same incidence of hemangioendothelial sarcoma of the liver (6/22). However, the incidence of hyperplastic liver nodules (19/22) and liver cell adenomas (8/22) in Group 1 was significantly higher than in Group 2 (2/22, 0/22). No hyperplastic liver nodules or liver cell adenomas were noted in Group 3. These results indicate that the administration of CC14 probably enhanced the carcinogenic activity of Petasites japonicus in hepatocellular tumorigenesis. Three hemangioendothelial sarcomas of the liver induced in rats in Groups 1 and 2 were subcutaneously transplanted and established as transplantable tumor lines.


Observations on benign gastric ulcer simulating gastric carcinoma.

We have re-evaluated over-diagnosed cases which were first diagnosed, pre-operatively, as gastric cancer yet later confirmed as benign lesion (excavated lesion, in particular) in the post-operative histological examination of resected stomachs. We have experienced a total number of 1,358 cases which, being detected through mass survey, were diagnosed as cancer and, consequently, operated upon. On the other hand, 61 benign cases were misdiagnosed as cancer, 28 cases being protruded lesions and 33 cases excavated lesions. Among the misdiagnosed cases of excavated lesions, 27 cases were gastric ulcers or their scars, the remaining 6 cases being gastritis or gastric erosion. In 22 out of 33 cases of misdiagnosis, the wrong diagnosis was made by relying solely upon X-ray and endoscopy. Even after the addition of cytology, there were still 9 cases of misdiagnosis. Since, however, biopsy was introduced, there have been only 2 cases of wrong diagnosis. We may safely say that through these findings the absolute necessity of biopsy for the attainment of an accurate diagnosis of early gastric cancer has been sufficiently attested.


Treatment of the intestinal tuberculosis.

Twenty-seven cases of patients with intestinal tuberculosis were reported. Seventeen cases showed good response to antituberculosis chemotherapy. The numbers and size of ulceration, pseudopolyp and deformity of intestinal tract were checked by endoscopic and X-ray studies on comparative evaluation between prechemotherapeutic and postchemotherapeutic stage. In these cases, subjective symptoms were disappeared parallel with the marked improvement on X-ray and endoscopic findings. These data suggest that with current well planned antituberculosis chemotherapy program, tuberculous colitis is controlled fairly while tuberculous enteritis in controlled inadequately. Therefore, surgical procedures are commly indicated to the treatment of tuberculous enteritis.


Clinical course and prognosis of one hundred and two patients with hepatic coma 1958 through 1975.

The clinical course and prognosis of hepatic coma were examined in 102 patients treated in the period from 1958 to 1975. The diagnoses included 9 fulminant hepatitis, 7 subacute hepatitis, 53 liver cirrhosis without liver carcinoma (40 cases of the acute type, 10 cases of the chronic type and 3 cases of another type, according to Sherlock's classification of hepatic coma) and 33 liver cirrhosis with primary liver carcinoma. Four of 9 fulminant hepatitis patients gained consciousness within 1 week and recovered completely. Seven subacute hepatitis patients died within 2 weeks after onset of hepatic coma. In the period from 1958 to 1969, 20% of liver cirrhosis patients with the acute type of coma recovered from coma, and in the period from 1970 to 1975, 45% of patients recovered. Seven of 10 patients with the chronic type of coma died between 4 months and 9 years after the onset of coma. Three other patients are presently still alive. The median survival time was 2.5 years. Nine primary liver carcinoma patients with coma were hospitalized from 1958 to 1969 and 24 from 1970 to 1975. Hepatorenal syndrome was present in 31  of 71 examined patients. Twenty-three patients with hepatorenal syndrome were in the period from 1970 to 1975.


Heterotopic pancreas in surgically resected stomach.

The heterotopic pancreas collected from the surgically resected stomachs were studied clinico-pathologically. The number of cases of heterotopic pancreas were 64; 43 in the stomach and 21 in the duodenal bulbus. They were corresponded to 1.2% in the 5446 resected stomachs. The operated cases with this lesion were frequently found in the age of thirty to fifty with male predominance. Thirty eight cases of them were combined with other gastro-duodenal diseases, especially gastric or duodenal ulcers. About 90% of these lesions were found in the pylorus and antrum. They were situated frequently in the greater curvature, posterior and anterior wall, and rarely in the lesser curvature. Their size was ranged about 0.3 to 4.7 cm in diameter, and about 80% of them within 3 cm in diameter. Macroscopically, 49 polypoid, 8 nipple-like, 7 flat and 1 thickening folded lesions were found, respectively. The bridging folds were found in 9 cases, 13.8%. Microscopically, 30, 29 and 6 lesions of type I, II, and III types according to Heinrich's classification were found, respectively. The ulcer formation of the mucosal surface of the heterotopic pancreas was found at rate of 10%, and cystic transformation in about 6%.


A diagnostic approach to inflammatory disease of the pancreas by means of endoscopic retrograde cholangio-pancreatography.

Role of ERCP in the diagnosis of inflammatory lesions of the pancreas was evaluated and following conclusions were obtained. 1) Following criteria were considered to be practical for clinical diagnosis of chronic pancreatitis by ERCP; a) More than moderate irregularity or rigidity of margin, dilatation, or irregularity in caliber of PDS, whether extensive or localized, or b) Cyst formation or c) Obstruction of PDS. These criteria permit to diagnose 100% of pancreatolithiasis, 82% of chronic pancreatitis without pancreatolithiasis and 64% of histologically diagnosed chronic pancreatitis but about 13% of "false positive results" must be taken into consideration. 2) ERCP plays an important role in detecting and locating localized or scattered lesions without noticable abnormalities in P-S test. It is also useful in deciding an indication for surgical intervention. However, it has limitations in detecting minimal to moderate pancreatitis. Some of these cases are often picked up by P-S test. 3) Combined approach with ERCP and P-S test is required for diagnosis of inflammatory lesions of the pancreas and either one is incomplete by itself.


Studies on exogenous and endogenous interaction of gastrin and secretin in a case of achalasia.

Studies were carried out in a case of achalasia. Administration of secretin caused relaxation of the spastic condition of LES, and high levels of serum gastrin and lower levels of plasma secretin are suggested to be related with the abnormally spastic condition of LES in the patient.


[Chromosome translocations in the sex cells of mice subjected to chronic low-dose gamma-irradiation].

Translocation induction in mouse spermatogonia by continuous whole-body gamma irradiation (radium 226) was studied. Total doses, delivered at a rate of 13.0 +/- 1.3 X 10(-4) rad/min for various time intervals, were 97, 195, 294 and 442 rad. Cytological examination within 3 to 4 months after irradiation indicated the presence of translocations in 0.16, 0.30, 0.75 and 1.29 percent respectively, of primary spermatocytes at diakinesis metaphase I. Data on translocation induction (Y) as related to total irradiation dose (D) were best fitted to a second power parabola equation (Y=5.1 X 10(-6)D2 + 7.32 X 10(-4) X D). The results obtained confirm that chronic gamma irradiation is of low genetic efficiency, and support the suggestion that there exists a dose-rate threshold under which no more changes in exposure efficiency will occur.


[Comparative analysis of the spectrum of radiation-induced structural mutations in diploid and tetraploid cells of mouse bone marrow].

A comparative analysis of the spectrum of radiation-induced mutations was carried out in diploid mouse bone marrow cells and in tetraploid cells obtained from the latter by means of colchicine treatment. It is established that solitary chromatid deletions prevail among aberrations induced at the G2--S stage. This is the difference of the spectrum of induced chromatid rearrangements in animal cells from that in plant cells. It is assumed that the differences observed are caused by the specificity of supramolecular organization of chromatin in animal and plant  cells.