Therapeutic effects of some cholinolytics in organophosphate intoxications. The therapeutic effects of pipethanate (sycotrol) and two newly synthetized cholinolytics, DPX-8 and ANC-51, were compared with atropine in mice poisoned by DDVP, fluostigmine, phospholine, and paraoxon. The antagonistic activotagonistic activity of tested drugs against acetylcholine-induced contraction of rat ileum and oxotremorine-induced salivation and tremor in the mouse was also studied. The anticholinergic activity of pipethanate, DPX-8, and ANC-51 was weaker than that of atropine. However,the therapeutic effect of pipethanate was higher than that of atropine in mice poisoned by the organophosphates. DPX-8 and ANC-51 afforded a better antidotal effect than atropine only in DDVP-poisoned mice.


A universally applicable rapid bromine test.


Experimental manganese lymphadenopathy in guinea pigs. Experimental manganese lymphadenopathy was produced by guinea pigs by intratracheal inoculation of manganese dioxide (50 mg/300 g body weight) and histopathologic changes in the tracheobronchial lymph nodes were studied up to 180 days. There was slow extracellular transport of manganese dust into the nodes, which did not provoke any significant reaction at early periods. However, at later periods the nodes exhibited a significant increase in the density of dust particles and the reaction consisted of phagocytosis, degeneration of dust laden macrophages, slight proliferation of fibroblasts, together with some reticulinosis corresponding to deposits of dust particles. The significance of these findings have been discussed from the chronic toxicity viewpoint.


Biotransformation of As(III) to As(V) and arsenic tolerance. The paper deals with excretion of As(III) and As(V) in the urine of mice exposed to a toxic concentration of As(III) (250 mg/1) in drinking water. After the exposures of 2, 6, and 8 days, the mice were given i.m. a solution of 74As(III) labeled sodium arsenite in a dose of 1.3 mg As(III)/kg b.w. and an activity of 3 muCi/l ml. After the sacrifice of the animal, the urine was drawn off directly from the bladder. The urine samples were subjected to separation of As(III) from As(V) by using a paper radiochromatography technique. The results showed that unexposed control mice excreted one-half of the administered As(III) in the form of As(V). Mice exposed to arsenic in drinking water exceted already, after 2 days of exposure, four-fifths of the applied As(III) in the form of As(V), after 4 days of exposure the proportion of As(V) was more than 95%, and after 8 days of exposure only traces of As(III) were present. The authors discussed the possibility of the biotransformation of As(III) to As(V) on arsenic tolerance.


In vitro system for toxicological studies on the development of mammalian limb buds in a chemically defined medium. In organ culture systems using the Trowell setup, morphogenetic differentiation (which largely mimics the development reached in vivo within 2--3 days) can be obtained in limb buds of mouse embryos during a culture period of 6 days. We succeeded in improving the technique and in achieving good differentiation of the limb buds in a chemically defined culture medium from which all additions of the heterologous serum used in previous studies were omitted. With this technique of using a chemically defined medium, the following results were obtained: (1) A high degree of reproducibility can be obtained in the grade of differentiation if the experimental conditions are standardized and limb buds of the same developmental stage (somite stage) are used. (2) The technique is applicable to species other than mice, such as rats and rabbits, however, the results obtained so far are not so satisfactory as those acquired with mouse limb buds. (3) In an attempt to offer some colloid osmotic pressure, macromolecules like polyvinylpyrrolidone (Periston), polydextrans (Macrodex) or polypeptides (Haemaccel) were added to the culture medium. None of these macromolecules had a beneficial effect on the differentiation of the limb buds in vitro; in the case of Macrodex the differentiation was even impaired. (4) In comparison with the development in a serum-containing medium, the results attained with a chemically defined medium are just as good when judged from microscopical and some biochemical studies (total content of DNA, RNA, protein, and protein-bound hydroxyproline in the explants). The applicability of the test system for the evaluation of embryotoxic effects is discussed.


Determination of dextropropoxyphene and norpropoxyphene in autopsy material by gas chromatography. A gas chromatographic method for the simultaneous determination of dextropropoxyphene and norpropoxyphene in autopsy material is described. The esters were hydrolyzed before the final determination. The mass spectra of the hydrolyzed esters are presented together with the results of an investigation of 6 cases of fatal intoxications.


X-ray crystallographic and gas chromatographic--mass spectrometric studies on norpropoxyphene. The crystal structure of norpropoxyphene maleate is presented. The conformation is discussed in relation to similar compounds. A gas chromatographic--mass spectrometric investigation indicates that earlier proposed metabolites may be formed during the gas chromatographic separation.


Introduction to the symposium "What is the importance of chronobiology in toxicology and pharmacology?


Circadian fluctuations in the activity of DNA-dependent RNA polymerases I and II in the nuclei isolated from mouse tissues and the significance for pharmacological and toxicological studies on transcription. For pharmacological and toxicological studies on the effect of drugs on transcriptional processes the basic fluctuation in activity during a 24-h period must be known. We have measured the activity of nuclear and mitochondrial DNA-dependent RNA polymerases in cell fractions from mice kept under defined dark/light and feeding schedules. The following results have been obtained: 1. Circadian variations in the activity of RNA polymerases are especially pronounced in the nuclei of liver tissue. These changes depend predominantly on feeding habits and they are comparatively independent on the dark/light schedule. A maximum in the activity of nuclear DNA dependent RNA polymerases can be observed shortely after the beginning of the feeding period. 2. The nuclei isolated from other tissues, such as brain, kidney or embryos during the late stage of embryogenesis shown considerably smaller, if any, fluctuations in connection with the feeding habits. These tissues seem to be especially suitable for pharmacological or toxicological studies on transcriptional processes. 3. While both nuclear DNA-dependent RNA polymerases shown a strong dependence on the feeding habits no obvious circadian viriations can be observed in the activity of the DNA-dependent RNA polymerase localized in the mitochondrial fractions of the same tissue. The regulation of these polymerases in different cell compartments apparently occurs quite independently. The conclusions for the design of experiments on induction processes occurring in liver tissues, drawn from the results presented, are discussed.


Possible influences of circadian rhythms in experimental carcinogenesis. The induction of tumours by chemical carcinogens depends not only on the chemical structure of the substance but also on biological properties of the target cell population, such as enzyme patterns, DNA repair mechanisms and the proliferative state of the cells. Interference with any of these processes can theoretically affect the tumour yield, as can variations due to biological rhythms. A series of investigations of circadian and circannual rhythms in the hairless mouse epidermis (hr/hr) is reviewed. DNA synthesis as well as the mitotic rate undergo great variations in the course of a 24-h period. The respiration and glycolysis in this epidermis undergo strong circannual variations. Evidence that the eventual tumour development after methylcholanthrene application to the skin is modified by circadian variations in DNA synthesis is presented and discussed in relation to pertinent data from other cell systems.


Genetic and hormonal regulation of steroid hydroxylases and drug metabolizing enzymes in rat liver. Two microsomal steroid hydroxylase activities (cholesterol-7alpha-hydroxylase and progesterone-16alpha-hydroxylase) were measured in the livers of Sprague-Dawley and Wistar rats and compared to three other monooxygenase activities (aryl hydrocarbon hydroxylase, p-nitro-anisole-O-demethylase and aminopyrine-N-demethylase). Cholesterol-7alpha-hydroxylase behaves in a very unique manner. It is the only one of the studied enzymes to be more active in the female than in the male, it is very poorly induced by phenobarbital and methylcholanthrene, but responds quickly to the administration of glucocorticoids. In fact, the cholesterol-7alpha-hydroxylase activity presents a very pronounced circadian rhythm which is under the control of the hypothalamo-adrenal axis. Marked differences are also found in the response of the various enzymatic activities to the administration of inducers as well as in their relative activities in untreated male and female animals.


The circadian rhythm of synthesis and catabolism of cholesterol. The circadian rhythms of HMG-CoA reductase and cholesterol-7 alpha-hydroxylase (low values, during light, rising in the evening with maximum at 12.00 p.m.) are investigated in rats under diverse conditions. Intragastral administration of cholestyramine (bile acid-absorbing resin) leads to an increased rhythm of both enzymes. Feeding of cholic acid (or cholesterol) reduces the activity of both enzymes (of HMG-CoA reductase and cholesterol-7 alpha-hydroxylase, respectively). In starved rats enzyme activity and time of day is proportional to the metabolism of a substrate.ies are lowered, too; a damped rhythm reappears after 24 h. A 20% fat diet (containing saturated fatty acids predominantly) markedly reduces the high values. Enzyme activities inhabited after thyroidectomy can be normalized by thyroxin substitution. Thyroxin administration in the normal remains without effect. Four-day insulin treatment of the normal inhibits cholesterol-7 alpha-hydroxylase, has no effect on HMG-CoA reductase. In the untreated diabetic rat cholesterol-7 alpha-hydroxylase is increased, HMG-CoA reductase significantly inhibited. Insulin treatment of the diabetic animal results in normalized values of HMG-CoA reductase whilst cholesterol-7 alpha-hydroxylase is nearly completely suppressed. The rate-limiting enzymes of cholesterol turnover are peripherally regulated by their products via a negative feedback. In contrast, hormones may have synergistic or opposite effects; thus they may represent means of higher regulation. All regulative possibilities discussed (except hypophysectomy) do modifiy the circadian rhythms. This cannot be demonstrated after hypophysectomy. After hypophysectomy circadian rhythms are not detectable any more. To get valid data about biochemical or pharmacological effects on these enzymes the circadian viriations have to be considered by measuring at different times of day (e.g. fat diet); for only the area of enzyme activit


The manipulation of circadian rhythms.

The manipulation of circadian rhythms. In a study on male Wistar (TNO) rats kept under phase-shifted light-dark (12:12) conditions, it was demonstrated that the circadian rhythms of the following functions were effectively synchronized to the new lighting regimen: (a) body temperature, gross motor activity (after 1 week of acclimatization); (b) stomach weight, liver weight, liver glycogen, liver protein and acid phosphatase activity; serum corticosterone, glucose, total protein and inorganic phosphatase (after 4-6 weeks; as concluded from the data pooled of a sex of identical experiments); (c) the in vivo toxicity of approximately LD50 amounts (i.p.) for antimycin A and of E 600. In the individual experiments the various normal functions appeared to be different with respect to sensitivity to light. The overall pooled results indicated that, except for glycogen, the 24-h means of the normal values in the stomach, liver and serum were slightly decreased when compared to the respective means obtained from standard LD (= light: 6:00-18:00)-conditioned control groups (P less than 0.001 for liver weight, liver protein, serum protein and inorganic phosphate). The experimental animals revealed an intermediate or persisting decrease of the growth rate. From the serial biological and toxicological studies performed in the course of 1 year, it is concluded that the synchronizing effect of an altered lighting regiment may be influenced by seasonal factors...


Circadian rhythm of the renin-angiotensin-aldosterone system in the rat. The 24 h-course of plasma renin activity (PRA), plasma aldosterone concentration (PAC), plasma corticosterone concentration (PCC) and of the urinary excretion of sodium, potassium and aldosterone was investigated in male Sprague-Dawley rats under different experimental conditions. The data obtained can be summarized as follows: 1. The renin-angiotensin-aldosterone system (RAAS) of the rat is subject to a circadian rhythm which is largely in phase with the well-known rhythm of the pituitary-adrenal axis. This rhythm can be demonstrated in PRA as well as in plasma concentrations and urinary excretion rates of aldosterone. The rhythm of urinary excretion of electrolytes is unlikely to be due to the rhythm of aldosterone secretion. 2. The light-dark cycle is the main synchronizer for these rhythms: inverting the light-dark cycle for 5 weeks entirely inverts the rhythms of all the parameters cited. 3. A dissociation of the rhythms of PRA and PAC can be observed following sodium restriction or dexamethasone treatment. A role of ACTH IN regulating the rhythmic pattern of aldosterone secretion is suggested by the finding that PAC and PCC follow the same pattern of circadian variations under every experimental condition tested. 4. The responsiveness of the RAAS to stimulation or suppression varies with the time of day. 5. It is suggested that experiments ought to be performed not only during the inactive (light hours) but also during the active (dark hours) phase when investigating the RAAS in the rat. This can conveniently be achieved by the use of an animal room with a reversed lighting regime.


Circadian influences on clinical values in man. 1. The circadian patterns of clinically relevant parameters were studied in 109 young, healthy soldiers. 2. Erythrocytes, hematocrit, creatinine and cortisol exhibited very stable rhythmic patterns which were found by continuous examinations of the same persons as well as in examinations of different persons at different times. 3. The rhythmic patterns of leukocytes, blood glucose and body temperature were strongly influenced by stress caused by the first confrontation with an unknown hospital-like situation or by pain caused by blood sampling.


The relevance of drug-induced organ pigmentation in animals. Postmortem examination of animals from long-term safety evaluation studies often reveals pigment deposition in tissues. A review of several such observations is given and the possible chemical backgrounds of their origin are described, in an attempt to aid the determination of relevance in individual cases. It is suggested that one may be fairly broad-minded in the interpretation of the relevance of such pigments, especially if they are found only in one species, and have no influence on the function of the organs involved. A final answer comes only after administration of the particular drug to man, although he is normally dosed at all events one should not overvalue the relevance of pigmentation found in long-term animal studies.


Teratogenicity and embryotoxicity of some maleinimides. Maleinimide, the teratogenic structural "central part" of the thalidomide molecule, and 5 of its dichloro- and dibromo-derivatives have been investigated teratologically by tests on SWS mice. According to both the electrophilic properties and the spatial requirements of the substituents, the effects were found to be up to 100 times stronger than those of thalidomide, and up to 10 times stronger than those of phthalimide respectively. The results are referred to the distinct electron-acceptor behavior of the maleinimide compounds, which--due to their flat molecular structures--are able to intercalate into the DNA double helix forming EDA complexes with nucleic acid bases as electron-donor molecules. The results can be interpreted as another confirmation of Jönsson's intercalation hypothesis of the thalidomide action.


Neurotoxic effects of dichloroacetylene. In inhalation tests involving lethal as well as sublethal doses of dias examined in rabbits by means ofhistologic and neurofunctional methods. Histologic examination revealed chromatolysis, disintegration of Nissl bodies, and cell shrinkage in proportion to the doses employed in the nuclei of the unpaired brain stem, in the sensory cortical regions and especially in the sensory cranial nerve nuclei. The sensory trigeminal nucleus was involved most severely, followed in decreasing intensity 0y the facial and oculomotor nerves and the motor trigeminal nucleus; the least changes were observed in the acoustic nerve. By testing the protopathic sensitivity of the facial skin it was possible for the first time to produce evidence of a sensory loss in the distribution of the trigeminal nerve by animal experimentation. The neuropathological and functional deficits observed may explain the cranial nerve lesions in human DCA intoxication; however, these lesions seem to be less distinct in experimental animals.


Differential pulse anodic stripping voltammetry as a rapid screening technique for heavy metal intoxications. This paper describes a relatively simple and rapid analytical procedure capable to carry out systematic screening for 10 heavy metals, namely mercury, bismuth, antimony, copper, lead, tin, thallium, indium, cadmium and zinc. Differential pulse anodic stripping voltammetry was chosen because of its simplicity, speed, low cost, low detection limits, screening potential for a wide selection of metals and the combined qualitative and quantitative output. The method of identification is based on measuring peak potentials in 2 different types of electrolyte solution, using 2 different electrodes. Complexing agents are used to mask certain elements.


Binding of inorganic mercury by subcellllar fractions and proteins of rat kidneys. Inorganic mercury, administered to rats in a single dose of 0.5 mg Hg/kg is accumulated in the kidneys mainly in the soluble (54%) and nuclear (30%) fractions, showing decreasing tendency with time. Mitochondrial and microsomal fractions, initially accumulating approx. 11 and 6% of total Hg, show a tendency to increase the absolute level of Hg for the first week after administration. In the soluble fraction low-molecular weight, metallothioneinlike proteins are mainly responsible for the accumulation of mercury, in other fractions proteins of higher molecular weight prevail.


Irreversible protein binding of 14C-imipramine in rats in vivo. Forty-eight hours after a single dose of 14C-imipramine to rats, 14C-radioactivity could be measured in the following organs: liver greater than kidney greater than serum greater than fat greater than spleen greater than duodenum greater than lung greater than muscle and brain. Liver microsomes contained the main part of radioactivity derived from 14C-imipramine. After exhaustive extraction, only the proteins of liver, kidney, spleen, lung and serum contained measurable amounts of radioactive labeling. The greatest amount of 14C-imipramine irreversibly bound to proteins was detected in liver microsomes. The question, as to whether the irreversible protein binding of imipramine, if it occurs during therapy, results in toxic side-effects, is discussed.


Myocardial infarction due to mycotic coronary arterial aneurysm.


Release of highly soluble substances from inert matrices in cases of two-sided attack of the solvent. The present work is an extension of some of our earlier investigations on the release of soluble substances in inert matrices. There have been described the cases of two-sided attack on the inert matrices (PVC and PE) by the solvent. The theoretical considerations of the cases for the two-sided attack were experimentally confirmed. The values of the diffusion coefficients, which correspond to the calculated ones in the cases of one-sided attack, were calculated as well.


Spectral mapping, a technique for classifying biological activity profiles of chemical compounds. A mathematical technique is described that separates potency from spectral information in biological activity spectra. The technique is a preliminary step in the classification of chemical compounds and in the structuring of pharmacological assays. The method is illustrated using previously reported results on 40 neuroleptics in 12 assays on rats. Principal component analysis and cluster analysis are shown to provide complementing information.


Classification of psychoactive drugs by visually evoked potentials in rabbits by means of multiple discriminant analysis. A possible way of predicting the clinical efficacy of new psychoactive drugs. The influence of representatives of various groups of antipsychotic drugs on the visually evoked potential (EP) was investigated with the aid of a modified recording and evaluation technique for the rabbit EEG from cortical and subcortical structures. The starting point was the hypothesis that changes in the EP in animal experiments caused by representative members of these "substance groups" (neuroleptics with predominantly antipsychotic or predominantly sedative effect, and antidepressants with predominantly mood-brightening or predominantly sedative main components) make predictions of the clinical efficacy of "unknown" substances possible on the basis of clinical therapeutic principles of classification. Experiments were carried out with haloperidol and fluphenazine, chlorpromazine, amitriptyline and doxepin, and with imipramine and clomipramine, as representatives of these classes of substances. The hypothesis was checked by attempts to assign amitriptyline and chlorprothixene in varying dosage, haloperidol, benzperidol and mianserine to appropriate classes. As classification and assignment procedure we used stepwise multiple discriminant analysis (SWDA) according to our modification of the BMD 0 7 M Program. The purpose of the latter program, and its applicability to our studies, are described and discussed. It was found 1. that with EP data from animal experiments it is possible to classify various groups of psychoactive drugs on the basis of clinical therapeutic findings, using SWDA; 2. that assignment of "unknown" compounds can be based on this classification; 3. that hence with some caution predictions of the clinical effect of newly developed substances may be made on the basis of findings in animal experiments. The EP variables which contain most information for making up the separation formula and hence are of special importance, are investigated with respect to their possible neurophysiological evidential value, and their significance is discussed. It was found that the EP from the visual cortex are of particular significance for the separation of groups in the form presented here.


Differences in the cardiac actions of the calcium antagonists verapamil and nifedipine. 1. It was investigated whether the calcium antagonistic coronary drugs verapamil and nifedipine have similar antiarrhythmic properties. Their effects on functional refractory period and contractile force in the isolated left guinea pig atrium were compared. To assess their influence on myocardial excitability the relation between threshold voltage and pulse duration was studied in the left guinea pig atrium. Furthermore, the influence on AV conduction was investigated in the conscous dog in haemodynamically equieffective dose ranges. 2. Verapamil as well as nifedipine cause a dose-dependent prolongation of the functional refractory period in the isolated left guinea pig atrium. The slope of the dose-response curve of nifedipine is, however, significantly less steep than that of verapamil. Maximum prolongation of refractory period which can be induced by nifedipine is significantly inferior to that occurring after verapamil; under nifedipine this prolongation is, however, accompanied by a significantly greater reduction in contractility. 3. In the isolated left guinea pig atrium the voltage-duration curve is shifted to the right and the chronaxia value is significantly increased by verapamil. Even in the highest dose possible nifedipine has no effect on atrial excitability. 4. In the conscious dog verapamil considerably prolongs AV conduction time whereas a moderate yet dose-dependent shortening of PQ duration is observed with equieffective nifedipine doses regarding the decrease in blood pressure and increase in heart rate. 5. The results indicate that nifedipine does not exert antiarrhythmic effects comparable to those of verapamil.


Experiments on the detection of the carcinogenic N-nitroso-dimethylamine in the urine of rats after oral administration of the analgesic amidopyrine and nitrite. N-Nitroso-dimethylamine (NDMA) was excreted unchanged in the urine of rats after oral administration of the compound in amounts ranging from 0.003% at a dose of 2 mg/kg to 0.08% at a dose of 15 mg/kg. By measurement of the NDMA excreted after oral administration of amidopyrine and nitrite, the extent of nitrosation in vivo was estimated to be about 30%. For clinical investigation of NDMA formation in patients treated with amidopyrine, however, we consider this method to be too insensitive.


Secretion and irrigation of gastric mucosa during disulfiram effect. Experimental study in the dog. The effect of ethyl alcohol and disulfiram (Antabuse) on the secretion and the irrigation of an isolated and denervated gastric pouch has been studied in the dog. In these conditions, disulfiram increased the differential acidity; the association of ethanol with disulfiram impaired the proteolytic activity of the secretion and induced a hyperirrigation of the gastric mucosa more definite than with ethanol alone. Effects on ethanol absorption from stomach are discussed.


Pharmacological properties of thiazolinobutazone (LAS 11 871). III. General pharmacology, ulcerogenic effects and acute toxicity. 2-Thiazoline - 2 - ammonium-4-n-butyl-1,2-diphenyl-3,5-pyrazolidinedionate (thiazolinobutazone, LAS 11 871, Fordonal) has been compared with phenylbutazone in a variety of pharmacological tests with a view to side effects and toxicity. Thiazolinobutazone was the less toxic (acute LD50) and the less ulcerogenic molecule of the two and, in contrast to phenylbutazone, was not antidiuretic. Some signs of activity on the autonomic and somatic nervous systems were seen following high doses of thiazolinobutazone which appeared to be related to inhibition of cholinesterases.


Bromperidol, a new potent neuroleptic of the butyrophenone series. A comparison of the effects of bromperidol and haloperidol in intracranial self-stimulation. Bromperidol, a new potent and long-acting neuroleptic of the butyrophenone series, and haloperidol were injected s.c. at the doses 0.01, 0.02, 0.04 and 0.08 mg/kg, in rats implanted with electrodes in the lateral hypothalamic region of the medial forebrain bundle. A dose-related response inhibition was found with both compounds and the graphically estimated ED50 value was 0.041 mg/kg for bromperidol and 0.047 mg/kg for haloperidol. These data are in complete agreement with our previous findings that bromperidol is a new potent and specific neuroleptic.


The effect of rifamycin SV on the wound-healing process. The influence of rifamycin SV on the healing process of a wound was studied in animal experiments. Measurement of the degree of cicatrization, determination of the free hydroxyproline in serum, and histological findings helped to demonstrate that local application of rifamycin SV leads to an increased fibrinous conglutination of the lips of the wound at an early phase of the healing process and the subsequent formation of fibres in the regenerative tissue is not impaired.


Pharmacokinetics of coumarin upon i.v. administration in man. The disposition pharmacokinetics of coumarin has been studied after i.v. administration in man, and might be described best by an open two-compartment model. Three dose sizes have been studied, 0.125, 0.2 and 0.25 mg/kg. The mean biological half-life was found to be 1.81, 1.45 and 1.49 h, respectively, for the three dose sizes. Coumarin is extensively distributed. The volume of the central compartment apparently comprises the extracellular and intracellular fluid. The study indicates dose-dependent (non-linear) pharmacokinetics with respect to distribution.


Cobalt-induced experimental epilepsy in cats pharmacologically immunodepressed. An EEG and histological study. The authors made 11 adult cats epileptic by implanting cobalt powder on the left sensorimotor cortex. Some of the animals were treated with the immunodepressant drug, cyclophosphamide (Endoxan), before and after surgery, and others were not. Then the two groups of animals were compared in terms of EEG and histopathological findings. The treatedanimals showed a definite reduction of focal electrical activity both primary and secondary, and a much milder perifocal parvicellular infiltration and cerebral edema. In view of these findings, the authors suggest that in addition to other well-known factors, the pathogenesis of cobalt-induced experimental epilepsy involves immunological mechanisms triggered by the release of nerve tissue antigens as a result of tissue injury caused by cobalt. This would result in the formation of antibodies directed against several brain constituents. Last, the authors submit that a similar autoimmune mechanism may be at play also in the pathogenesis of some forms of focal epilepsy of traumatic origin.


The uptake of potassium ions into isolated heart mitochondria in the presence of calcium ions and k-strophanthin. The conditions of potassium transport were investigated in isolated rabbit hear mitochondria. In the presence of 5 to 40 mM potassium chloride there is a rapid initial phase of potassium influx of less than 2 min duration in which 65-75% of the total K+ uptake occurs. This is followed by a slow phase of K+ uptake of about 45 min during which 25 to 35% of the total potassium was taken up. While the rapid phase is due to passive diffusion, the slow phase is an active process which requires either ATP or respiratory substrates as an energy source. It can be totally abolished by 0.5 mM antimycin A. An increase of the calcium concentration in the incubation medium to more than 5 X 10(-5)M resulted in an inhibition of the energy-dependent uptake of potassium which was directly proportional to the calcium level. k-Strophanthin induced a distinct inhibition only at very high concentration  (greater than 10(-4)M). The inhibition of potassium uptake by 1. 3 or 5 mM calcium chloride was gradually cancelled by increasing k-strophanthin concentrations above 10(-8)M. Maximal cancellation was found with 10(-5)M of k-strophanthin. This concentration almost completely prevented the inhibition by calcium ions. On the other hand, 10(-5)M k-strophanthin had no inhibitory effect on the energy-dependent uptake of 0.5 mumoles of calcium chloride or on the oxidative phosphorylation of 0.5 mumoles of ADP added to the incubation medium.


Cardiovascular effects of an antiarrhythmic aminosteroid ORG 6001 in the anesthetized pig. The hemodynamic effects of 3alpha-amino-5alpha-androstan-2beta-ol-17-one-hydrochloride (ORG 6001), an aminosteroid possessing antiarrhythmic properties, were studied in 14 anesthetized pigs. ORG 6001 was administered i.v. cumulatively until a toxic level was reached. Doses less than 20mg/kg had, in spite of the negative inotropic properties of ORG 6001, no effect on the pump function of the heart, as the afterload was reduced and the filling pressure was not significantly altered. After administration of 40 mg/kg A-V conduction was depressed and second degree A-V block appeared. This was associated with deterioration of the pump function and for 6 of the 14 animals this was fatal. In the survivors, the alterations were reversible after cessation of drug administration. Since ORG 6001 has been shown to be effective against arrhythmias at doses less than 20 mg/kg, though in a different species (dog), it seems likely that it can be used safely for antiarrythmic treatment.


Effects of cinepazide, a new vasoactive substance, on heart and circulation in the dog. The authors report on the action of a new drug, 1-(pyrrolidinyl-1-carbonyl)-methyl-4-(3,4,5-trimethoxycinnamoyl)-piperazine-maleate (cinepazide), on the heart and systemic and coronary circulation. At doses of 1--3 mg/kg i.v. (n=6), systemic blood pressure decreased by 4%, and heart rate increased reflexly by 8%...


Influence of cinepazide, a vasoactive substance, on canine coronary circulation after acute constriction of the left anterior descending coronary artery. The left anterior descending coronary artery was variably constricted mechanically in nine dogs. Blood flow in the left anterior descending (LAD) and circumflex coronary arteries (CCA), aortic pressure and peripheral, i.e. post-stenotic coronary pressure were measured. Myocardial perfusion was determined from the clearance of radioactive xenon injected at a depth of 7 mm into the underperfused area supplied by the LAD artery. The vasoactive drug 1-(pyrrolidinyl-1-carbonyl)-methyl-4-(3,4,5-tri-methoxycinnamoyl)piperazine-maleate (cinepazide) was given at doses of 5-10 mg/kg by i.v. route. 1. Blood flow in the LAD was decreased stepwise to 50% of its initial value. There was practically no more coronary reserve. After drug injection, diastolic aortic pressure, that normally falls, was kept constant by clamping. Heart rate, perfusion pressure, post-stenotic pressure, and blood flow and resistance in the LAD showed practically no change. In the CCA, blood flow increased significantly (p less than 0.005) and flow resistance decreased (p less than 0.001). 133Xe clearance showed an increased myocardial perfusion (p less than 0.02) in the territory supplied by the LAD artery. 2. The lumen of the LAD was narrowed by 53%, i.e., coronary reserve was decreased. This constriction was followed by no haemodynamic reaction. After injection of cinepazide, mean and diastolic aortic pressure (p less than 0.02) and post-stenotic coronary pressure (p less than 0.005) decreased. Blood flow increased by 41% in the CCA and by 31% in the LAD. Coronary resistance in these vessels decreased (p less than 0.001 and 0.005, respectively). Here, too, the 133Xe clearance curve showed an increase in myocardial perfusion in the territory supplied by the LAD artery (+78%).


The distribution and excretion of 14C- and 3H-labelled 4-prenyl-1,2-diphenyl-3,5-pyrazolidinedione (DA 2370) in the rat. The distribution and excretion of radioactivity following a single or multiple oral administration of 3H-and/or 14C-4-prenyl-1,2-diphenyl-3,5-pyrazolidinedione (DA 2370) has been determined in rats. The daily excretion of radioactivity following a single administration (3H and 14C) or multiple doses (3H) fell to less than 1% of the dose in 4 days. A similar fall was observed at the end of 10 days continuous administration. The radioactivity in plasma reached a maximum between 2 and 4 h after administration of the drug (14C). Tissue levels were found to be effectively zero 24 h after administration of the drug for up to 10 days. The very large amounts of radioactivity lost in bile were found to correlate with blood, tissue and faecal levels.


Acute toxicity of various solvents in the mouse and rat. LD50 of ethanol, diethylacetamide, dimethylformamide, dimethylsulfoxide, glycerine, N-methylpyrrolidone, polyethylene glycol 400, 1,2-propanediol and Tween 20. The LD50's of various solvents frequently used in toxicological work to improve the solubility of otherwise poorly soluble compounds were determined in the mouse and rat. The substances investigated were ethanol, dimethylacetamide, dimethylformamide, dimethylsulfoxide, glycerine, N-methylpyrrolidone, polyethylene glycol 400, 1,2-propanediol and Tween 20. The substances were administered under standardized conditions to groups of 10 animals (5 females, 5 males) (mice and rats) at doses that supplied at least 3 values lying between the LD16 and LD84. The median lethal dose and slope were determined with the aid of Finney's programmed probit analysis. The results are tabulated as LD50 ml/kg with 95% confidence limits. It is recommended that when using these solvents for pharmacological and toxicological investigations not more than a quarter of the LD50 should be used because otherwise there will be confusion between the deaths due to the substance being investigated and those due to the solvent.


Assessment of Hypervitaminosis D during the first trimester of pregnancy on the mouse embryo. Preliminary report. The effect of hypervitaminosis were studied in pregnant mice during 0-3 and 4-7 days of gestation. After pregnancy was determined, mothers received 50 000 I.U. of vitamin D2 during the first gestational period. During the first half of the first trimester, the vitamin D treatment did not significantly influence maternal weight, fetal weight, implantation rate and survival of the embryo. The number of mothers with malformed fetuses significantly increased during critical treatment periods (from 4-7 days of pregnancy.


Effect of short- and long-term administrations of some drugs on rat intestinal flora. Short communication. Two schedules of treatment were adopted for an experimental evaluation of drug induced alterations in mid-small intestinal flora of normal rats. Test substances were given orally twice daily for 3 days at large doses and once daily for 30 days at lower doses. Indometacin, benzydamine, phenylbutazone, pheprazone, picosulfol, magnesium sulfate, tolbutamide, phenformin, dexamethasone acetate and prednisolone acetate were tested. Drug-induced alterations in rat intestinal flora resulted more evidently following multiple short-time treatments.


Antagonism of maximal metrazol seizures in rats and its relevance to an experimental classification of antiepileptic drugs. The antagonism of various components of maximal Metrazol-seizures (MMS) (i.e. tonic hindpaw extension, tonic backward extension of the forepaws, generalized clonic seizures and tremors), ataxia and loss of righting reflex-activity have been studied in a standardized procedure comparing 41 antiepileptics and related compounds. Appropriate analyses (Cluster Analysis and Principal Component Analysis) resulted in the distinction of seven clusters which could be considered along two continua. A first continuum is characterized by a progressive strengthening of loss of righting reflex-inducing properties, a decreasing dissociation of ataxia and loss of righting reflex and the disappearance of a selective anticonvulsant effect. The second continuum is characterized by an increasing relative potency of ataxia-inducing properties, an increasing dissociation of ataxia and loss of righting reflex and a decreasing antagonism of tremors. Three main types of anticonvulsants could be defined: drugs with a complete anti-MMS effect antagonizing both clonic and tonic seizures; drugs selectively abolishing tonic seizures, i.e., tonic extension of hind- and forepaws; and drugs exclusively blocking tonic hind-paw extension. The neurological and clinical significance of these different types of anticonvulsant activity has been discussed. Finally, the described modification of the maximal Metrazol-seizures test is proposed for routine screening purposes.


Influence of silymarin on drug metabolizing enzymes in rat and man. Male rats weighing 100-130 g were treated orally with a daily dose of 1 X 10 mg Legalon (active principle: silymarin)/100 g b.w. daily for 4 or 10 days. 4 and 10 days after the beginning of the pretreatment a significant increase of the activity of the mixed function oxidation system (Cytochrome P-450, aminopyrine demethylation, p-nitroanisole demethylation) was observed. No alteration of the body weight, the liver wet weight, the microsomal protein content, the cytochrome b5 content and the activities of glucose-6-phosphatase (G-6-Pase) and of a glucoronidase (4-methylumbelliferone) took place after the Legalon treatment. 4 h after the oral administration of 0.5 ml CCl4/kg b.w. the activity of the mixed function oxidation system and of the G-6-Pase was markedly decreased. This effect could not be prevented by the oral administration of 1 X 10 mg Legalon/100 g b.w. 6 h prior to CCl4 application. In human subjects the treatment with daily doses of 3 X 70 mg Legalon during 28 days had no influence on the metabolism of aminopyrine and phenylbutazone. From our results it is concluded that Legalon despite its effects in experimental animals has no influence on drug metabolism in man, when applied in therapeutic amounts.


Studies of the kinetics and metabolism of 17 beta-heptanoyl-17 alpha-ethinyl-4-oestren-3-one-7-3H (norethisterone enanthate) in humans following intramuscular injection. The kinetics and metabolism of 17 beta-heptanoyl-17 alpha-ethinyl-4-oestren-3-one-7-3H (7-3H-norethisterone enanthate, NET-En) after i.m. injection in two female subjects is described. 177.4 mg and 174.5 mg NET-En were injected. Maximum 3H-activity in plasma was reached 8 to 14 days after the injection. In terms of NET-En it amounted to 70-100 mug/100 ml. Maximum NET concentration was reached on the 4th to 8th day and amounted to about 1 mug/100 ml. After 4 weeks NET concentration was still about 0.05 to 0.1 mug/100 ml and even after 6 weeks NET was still detectable in plasma. In 14 days the two subjects excreted about 13% of the administered dose in the urine and about 15% and 21%, respectively, in the faeces. On the basis of a rough calculation, the subjects eliminated about 60% and 55% of the radioactivity with urine and faeces within 42 days.


Experimental evaluation in man of analgesic effects. A device operated by compression has been studied in order to define a method of measuring analgesic effects. Three analgesics (metamizol, acetylsalicylic acid and ketobemidone) and placebo have been tested in man to verify the adequacy of this apparatus and its sensitivity.


A study of the EEG sleep patterns and the sleep and dream experience of a group of schizophrenic patients treated with sulpiride. The modifications of spontaneous sleep in schizophrenic patients following N-ethyl-2(2-methoxy-5-sulfamido-benzamidomethyl)-pyrrolidine (sulpiride, Dobren) administration are reported in this study. No significant modifications in the quantitative distribution of the various sleep phases (LST, SWS, REM) were observed, while a significant percent increase of SWS was noted, together with a significant decrease in the number of awakenings during the night and an increase of the sleep onset time. The patients' own difficulty to fall asleep, however, decreased significantly, and also a significant increase of dream recall could be observed.


Vitreoretinal reactions and persistent hyaloid vessels. In cases with persistent primary vitreous in full-term infants there were vitreoretinal reactions including vitreoretinal anastomoses of blood vessels, vitreoretinal strands, traction folds of the retina, avascular retinal areas, hypoplasia of retinal blood vessels, rarefaction of retinal ganglion cells, and ischaemic structural changes of the retina. New vessel formation on the surface of avascular retinal areas was supplied from persistent hyaloid blood vessels. This finding may be of some importance in explaining those cases histologically resembling classical retrolental fibroplasia with no history of prematurity or oxygen treatment.


Malignant lymphoma of the thyroid.

Malignant lymphoma of the thyroid. Two cases of malignant lymphoma are reported and the clinical features of a further 6 cases collected over a 10-year period are presented. The literature is reviewed and the treatment, prognosis and relationship to Hashimoto's disease are discussed. It is suggested that lymph node biopsy at the time of operation is important in confirming the diagnosis and that the prognosis may be more hopeful than has previously been suggested.


Some aspects of sexually transmitted disease in Swaziland. A survey of sexually transmitted diseases was attempted in Swaziland. Time and the terms of reference limited its scope, but much interesting information was gathered. Neither the prevalence nor the relative frequency of the different diseases in the community could be ascertained, but there was evidence to support the local impression that the sexually transmitted diseases present an increasing problem in Swaziland. An important problem was that of case finding and two aspects of this are stressed: (1) A general lack of knowledge concerning the venereal diseases; (2) The large number of men infected by 'casual' girl friends who cannot easily be traced, and who form a reservoir of infection in the community. A survey was conducted in Swaziland between July 6 and September 28, 1973 to obtain information about sexually transmitted diseases.  The survey sample was limited to the outpatient department of the government hospital at Mbabane.  Patients included were those who reported at the outpatient department with an STD during the 3 month period of the survey and those of their contacts who could be pursuaded to attend and were found to be infected.  Of 240 patients seen during the course of the survey, 124 were suffering from presumed gonorrhea, 67 had genital sores, and 23 reported with both.  A further 26 had positive Venereal Disease Research Laboratory (VDRL) reactions and were assumed to have syphilis with or without some other STD.  Of the 26 patients whose VDRL test was positive, 3 had lesions usually associated with primary syphlis and 3 had condylomate lata.  The rest were cases of presumed latent syphilis presenting with another infection.  With 1 exception cases of urethral discharge in men appeared to be due to gonorrhea.  No cases of nonspecific urethritis were seen and the explanation of this is obscure.  About 29% of the women and 4% of the men were infested with T. vaginalis.  It was not possible to determine the prevalence of venereal diseases, but the evidence collected supported the local impression that these conditions were increasing.  The need for a vigorous program of contact tracing is clear from the small proportion of female patients attending the clinic.  Only 24% of those with a sexually transmitted disease and only 20% of those with a positive VDRL test were females, whereas in a survey undertaken by staff of the local public health unit in 1967, 54% of those with a positive Wassermann reaction were female.  The large number of casual partners admitted by men in the 4 weeks before infection implies that this is a major source of infection.  Recommendatons made for improving the situation include:  offering education in the schools; developing a universal system for tracing contact for the whole country; and making a vigorous attempt to screen all pregnant women by means of the VDRL test.


Born before their time into this breathing world.


Circular dichroism studies of some oligosaccharides containing 2-acetamido-2-deoxy-D-glucopyranose and D-mannopyranose residues.


Sexually transmitted diseases in Rhodesia. Part II.


Bromocriptine potentiation of gastric acid secretion in cats. Bromocriptine administered both orally and intravenously potentiated gastric acid secretion in response to submaximal pentagastrin stimulation in cats. Bromocriptine did not increase the maximum acid secretion in response to pentastrin, not did it stimulate basal acid secretion. Potentiation was observed in normal and vagotomized animals which precludes involvement of the vagi in the response. The mechanism of action of this compound on the stomach does not appear to be mediated through stimulation of dopaminergic receptors as no potentiation was observed with dopamine infusions. It is argued that the bromocriptine potentiation of gastric acid secretion may be a demonstration of 5-hydroxytryptamine or alpha-adrenergic antagonism. However, the potentiation observed with daily oral bromocriptine treatment had disappeared by the eighth day and may correlate with the disappearance of gastric side effects noted in patients on bromocriptine  treatment.


A comparison of drostanolone propionate (Masteril) and nandrolone decanoate (Deca-durabolin) in the treatment of breast carcinoma.


Treatment of Taenia saginata infection with mixture of areca nuts and pumpkin seeds. In January and February 1974, 32 adults (20 males and 12 females) and a 13-year-old girl with taeniasis saginata were treated with the mixture of boiled areca nuts and pumpkin seeds at Mastoban, Jen-ai District, Nantou County, Taiwan. A total of 48 worms including 42 scolices were recovered from 29 cases. Side-effects were observed in 4 cases including 3 with complaints of dizziness, tinnitus, nausea and vomiting, and one with coma and abdominal pain. Mixtures of 75-150 g areca nuts and 50-100 g pumpkin seeds were judged effective and safe.


Determination of mycelial steroids with the aid of polyene antibiotics. II. Quantitative determination of the mycelial steroids of Mucor hiemalis. UV absorption spectrum of polyene antibiotics was dramatically altered in the presence of steroids. The introduction of a steroid to an aqueous solution of polyene antibiotics resulted in a change in the ratio of absorbance of peak 3 (with shorter wavelength) to peak 1 (with longer wavelength), E3/E1. Interactions between 28 steroids and 4 polyene antibiotics were studied and the results revealed that the structures of steroids essential for the optimal interaction with polyene antibiotics were C-17 side chain, substitution C-3 hydroxyl group, intact steroid nucleus and aromatic A-ring. The ratio of E3/E1 was used for the determination of steroids in mycelium of Mucor hiemalis and the result was in good agreement with that obtained from gas chromatograph. The (-) strain had a greater change in the ratio of absorbance, E3/E1, than that of the (+) strain. The ratio of absorbance, E3/E1, decreased in the following order: the (-) strain, the (-) strain with the addition of the filtrate of (+) strains, the mated strains, the (+) with the addition of the filtrate of (-) strain and the (+) strain.


Missing evidence of a correlation between Hashimoto-thyroiditis and HLA antigens [proceedings].


The prevalence of venereal diseases among food and liquor-handlers in public places in Kampala, Uganda.


Distribution of HLA-antigens in Graves' disease and in autonomous adenoma of the thyroid [proceedings].


HLA antigens in Japanese patients with Graves' disease and Hashimoto's disease [proceedings].


Pattern of source of infection of venereal diseases.


Antithiamine factor in cotton seed (Bombex malabericum)--its isolation and characterization. 1. The antithiamine factor isolated from cotton seed (Bombex malabericum) was a light yellow amophous substance. 2. 1 mg of this antithiamine factor inactivated 20.5 mug of thiamine hydrochloride. 3. The antithiamine factor was characterized as 3,5-dimethoxy salicylic acid.


Social aspects of venereal disease aboard a U.S. navy destroyer. This paper describes the social characteristics of venereal disease patients aboard a US Navy destroyer. The research team administered questionnaires to 247 crew members at the outset of the ship's 7 month-overseas deployment. When the ship returned to home port, the research staff gathered demographic and occupational information plus disciplinary records, job performance ratings, and complete dispensary visit information for the deployment period. The morbidity data indicated that 48% of the entire crew experienced at least one case of VD, and of these VD patients, 38% had multiple infections. A set of variables that best predicted VD incidence was determined by means of multiple regression analysis. These variables included disciplinary record, pay grade, division or type of job ("blue-collar" versus "white-collar"), and education. Other variables that correlated with VD incidence were age, length of service, marital status, performance ratings, and verbal aptitude scores.


Study of rickettsioses in Slovakia. III. Experimental infection of Apodemus flavicollis Melch. by rickettsiae of the spotted fever (SF) group isolated in Slovakia. Experimental studies of infection of Apodemus flavicollis, and for comparison of rickettsiaemia in Clethrionomys glareolus and of susceptibility and antibody formation in white mice, with rickettsiae of the SF group isolated in Slovakia, gave the following results: the species A. flavicollis reacted by the formation of antibodies on subcutaneous administration of rickettsiae, strain B, in an amount of 10(0.5) EID 50/0.25 ml, whereas the white mouse only in an amount of 10(2.5). Rickettsiae, strain B, administered in an amount of 10(3.5) EID 50/0.25 ml subcutaneously to A. flavicollis were found in smears from the liver and spleen of the inoculated animals up to the 25th day following infection, on detection by the isolation test on chick embryo yolk sacs in the spleen on day 5 and 7, in lymph nodes on day 7 and in the brain on day 15 following infection; on detection by the method of injecting suspension from the organs into the haemocoelom of ticks regularly in the spleen and liver up to the 10th day, in the brain, kidney and lymph nodes regularly up to the 15th and irregularly in the lungs also up to the 15th day, then regularly in the testes up to the 5th day and in the heart, blood and peritoneum up to the 3rd day after infection.


Bromocriptine in Parkinsonism: long-term treatment, dose response, and comparison with levodopa. Thirty-seven patients with Parkinsonism were treated with bromocriptine 2.5-300 mg daily. Bromocriptine, alone or combined with levodopa, caused a 20-30% reduction in disability scores in 11 patients treated for one year. Tolerance did not develop during this period. Bromocriptine treatment was not of value in six patients who had previously not responded or who had lost their response to levodopa. However, in four of five patients with response swings on levodopa due to rapid changes in plasma dopa levels, the addition of bromocriptine caused a more stable response. Dose response curves to bromocriptine 12.5, 25, 50, and 100 mg and to levodopa 250, 500, 1000, and 2000 mg were studied in seven patients. Levodopa 2 g had a greater therapeutic effect and caused a greater rise in plasma growth hormone concentration than bromocriptine 100 mg. Levodopa caused emesis more commonly and hallucinations less commonly than bromocriptine. Bromocriptine appears to be a less potent stimulant than dopamine, and has both pre- and post-synaptic effects. Metoclopramide 60 mg oral was given 30 minutes before bromocriptine or levodopa to establish whether this caused dopamine-receptor blockade. Metoclopramide acted as a competitive antagonist to the anti-Parkinsonism and growth hormone effect of both drugs and in individual cases prevented emesis and hallucinations. The fall in blood pressure due to bromocriptine or levodopa was not antagonised by metoclopramide. Central and peripheral vascular dopamine receptors may be different in nature.


Sclerosing spinal pachymeningitis. A complication of intrathecal administration of Depo-Medrol for multiple sclerosis. Reported complications of intrathecal steroid therapy include aseptic meningitis, infectious meningitis, and arachnoiditis. We report a case of sclerosing spinal pachymeningitis complicating the attempted intrathecal administration of Depo-Medrol for multiple sclerosis. The lesion is characterised by concentric laminar proliferation of neomembranes within the subdural space of the entire spinal cord and cauda equina, resulting from repeated episodes of injury and repair to the spinal dura mater by Depo-Medrol. There is clinical and laboratory evidence that Depo-Medrol produces meningeal irritation and that the vehicle is the necrotising fraction.


New neonatal problems of blood coagulation and fibrinolysis. II. Thromboplastic effect of amniotic fluid and its relation to lung maturity. Pulmonary hyaline membrane disease in newborn infants is considered an abnormality in the alveolar lining layer. Quantitative analysis of this surfactant is necessary for the intrauterine diagnosis of lung maturity of the fetus. The presence of surfactant in amniotic fluid has been demonstrated by the shaking method [1]. But it is also well known that amniotic fluid has a thromboplastic effect [3,6]. In order to compare the correlation between the shaking method and the thromboplastic effect of the amniotic fluid, recalcification time and partial thromboplastin time were measured with and without amniotic fluid using an aggregation-meter. In each of 15 cases, a shortening of these times was recorded after the addition of amniotic fluid after the 30th week of pregnancy. In all cases the addition of amniotic fluid resulting in shortening these times. Surfactant seems to have enhancing effect on the coagulation. These results demonstrate the presence of surfactant in amniotic fluid in agreement with the results of the shaking method. Although these methods are of limited utility as quantitative assays for surfactant, they are of sufficient accuracy and of great value for clinical diagnosis.


Prenatal prediction of respiratory distress syndrome. Measurement of surface properties and Lecithin/Sphingomyelin ratio in human amniotic fluid. 118 samples of amniotic fluid were taken from 102 patients in the 25th to the 43th week of pregnancy by amniotomy or by transabdominal amniocentesis. 76 samples were obtained from patients with normal pregnancies without evidence for either induction or retardation of lung maturity; they served to establish normal values. In 37 cases samples were taken within 72 hours prior to delivery, the decisive period for the prediction of a respiratory distress syndrome. In seven cases a respiratory distress syndrome occured which was diagnosed by an independent pediatrician. The following tests were performed for all samples: 1. Surface tension was measured biomechanically using the Wilhelmy balance and a surface tension area diagram (Fig. 1) was made: A platimum plate is immersed into the liquid placed in the trough; the surface tension is measured via a transducer. The surface film of th liquid to be studied is compressed cyclically from an initial area of 100% to 20% by a moveable barrier and is expanded afterward. Platinum plate and barrier are connected to an X-Y recorder. The surface tension area diagrams are interpreted on the basis of the following criteria: see article 2. The determination of the L/S ratio (simultaneous comparison with the standard method): The method of GLUCK as modified by BORER(planimetric interpretation of the the spots) was employed. Both methods produced normal values. For the biomechanical measurements a classification into three groups was made (25th-30th, 31st-35th, 36th-43rd week of pregnancy) (Tab.I);the L/S ratio showed the usual steep increase from the 36th week of pregnancy onwards. In cases with RDS (Tab.II) surface tension-area-diagrams show high values for gamma max and a slight decrease in surface tension on compression (high gamma min values); the stability index is low, the hysteresis is reduced. Fig. 3. Up to the 34th week of pregnancy the 2:1L/S ratio assumed as the threshold for a sufficient surfactant concentration does not permit a clear interpretation; in subsequent weeks all cases fail to coincide with the normal pattern of distribution (Fig.2). Both the L/S ratio and the criteria of the surface tension area diagrams show significant differences in cases with and without RDS. The prognostic validity of both methods was tested for the probability of predicting occurrence of RDS, probability of RDS occurence and probability of non-occurrence of FDS. The prognostic value seems equal to the L/S Ratio.


Influence of molecular variations of ionophore and lipid on the selective ion permeability of membranes: I. Tetranactin and the methylation of nonactin-type carriers. The manner in which molecular structure of the carrier and the lipid composition of the membrane modulate the membrane selectivity among monovalent cations has been investigated for nonactin, trinactin, and tetranactin, which differ only in their degrees of methylation, and for membranes made of two lipids, phosphatidyl ethanolamine and glyceryl dioleate, in which "equilibrium" and "kinetic" aspects of permeation, respectively, are emphasized. Bilayer permeability ratios for Li, Na, K, Rb, Cs, Tl,and NH4 have been characterized and resolved into "equilibrium" and "kinetic" components using a model for carrier-mediated membrane transport which includes both a trapezoid energy barrier for translocation of the complex across the membrane interior and a potential-dependence of the loading and unloading of ions at the membrane-solution interfaces. The bilayer permeability properties due to tetranactin have been characterized in each of these lipids and found not only to be regular but to be systematically related to those of the less methylated homologues, trinactin and nonactin. This analysis has led to the following conclusions: (1) The change in lipid composition alters the relative contributions of "kinetic" vs. "equilibrium" components to the observed carrier-mediated selectivity. (2) Increased methylation of the carrier increases the contribution of the "kinetic" component to the selectivity relative to that of the "equilibrium" component and additionally alters the "equilibrium component sufficiently that an inversion of Cs--Na selectivity occurs between trinactin and tetranactin. (3) For all ions and carriers examined, the "reaction plane" for ion-carrier complexation and the width for the "diffusion barrier can be represented by the same two parameters, independent of the ion or carrier, so that in all cases the complexation reaction senses 10% of the applied potential and the plateau of the "diffusion barrier" extends across 70% of the membrane interior.


Tonsillectomy: an excision biopsy.

Tonsillectomy: an excision biopsy.


Accumulation of 57Co-poly-L-lysine by tumors: an effect of the tumor electrical charge.


Relationship between experimental results in mammals and man. II. Cytogenetic analysis of bone-marrow cells after treatment of cytembena and cyclophosphamide- cytembena combination. Cytogenetic analysis and the micronucleus test of bone-marrow cells was used to study the possible extrapolation of results from experimental animals to man. Cytembena was given i.p. in doses of 5, 10, 20, 40 and 80 mg/kg body wt. to Wistar rats and in doses of 20, 40 and 80 mg/kg body wt. to ICR mice and to Chinese hamsters. Five patients with various types of malignancy, so far medically untreated, received 20 mg Cytembena/kg body wt i.v. A combination of Cytembena and cylophosphamide was applied i.p. in single equal doses 1 : 1 of 5,10, 20, and 40 mg/kg body wt to ICR mice, Chinese hamsters and Wistar rats. Patients were given i.v. 20 mg Cytembena and 20 mg cyclophosphamide/kg body wt. Bone-marrow cells were examined 24 h after the administration. The frequency of abnormal metaphases and chromosomal breaks after Cytembena treatment was low; nonetheless, the indicated dose-effect relationship was found in all the rodents used. The frequency of chromosomal breaks was 2--3 times higher in rodents in comparison with man, after treatment with a dose of 20 mg Cytembena/kg body wt. Highest frequencies of induced aberrations were found in mice. The rodents appeared to be 3--4 times more sensitive to the induction of chromosomal breaks and abnormal metaphases than man, after a dose of 20 mg Cytembena and 20 mg cyclophosphamide/kg body wt. The micronucleus test may be regarded as a screening method for assessing mutagenic activity of chemical compounds. Chromosomal analysis and the micronucleus test were about equally convincing in detecting mutagenic effects even with the lowest doses of drugs used. However, the dose-effect relationship was more pronounced in chromosomal aberrations than in the micronucleus test.


Time lapse cinematographic demonstration of humoral and cell mediated immunity in squamous cell carcinoma of the lung. Out of 42 attempts in one case a cell line derived from biopsy material of a squamous cell carcinoma of the lung has been established. Tumor-associated-antigen could be demonstrated by indreict immunofluorescence. The effect of allogeneic cytotoxic antibodies, absorbed with normal human lung and sera, on the target cells is shown. Blood lymphocytes obtained from patients with squamous cell carcinoma of the lung proved to be cytotoxic against this cell line. The cell to cell interactions of this phenomenon and the effect of cytotoxic antibodies are shown by time lapse cinematography.


Serum cholesterol levels of Seventh-day Adventists. Serum cholesterol levels and dietary habits were surveyed in 27 male and 34 female Seventh-day Adventist. All subjects studied were lacto-ovo-vegetarians and a few consumed some meat products. Their serum cholesterol levels, significantly lower than those of the United States general population, showed no sex difference but increased with age and were higher in overweight males. Their levels, however, were much higher than those of true vegetarians which was most likely attributable to their consumption, even though to a limited acount, of dairy foods.


Statistical analysis of the 24 hour blood pressure using pressure frequency histograms.


Infant milk powder feeds compared on a common basis.


Intrathecal hydrocortisone in the treatment of tuberculous meningitis (preliminary report).


Imported milk: a threat to health?

Imported milk: a threat to health?


Effect of prolactin and the anit-prolactin bromocriptin on the testosterone uptake and metabolism in androgen-sensitive and insensitive canine organs. Prolactin promotes the growth and function of the prostate in low doses, whereas high doses or previous castration reduce this effect. The antiprolactin bromocriptin should reverse the prolactin action. In the castrated dog the highest accumulation of H3-testosterone given i.v. occurred in the prostate as compared with muscle, urethra, penis, liver and kidney. Prolactin pretreatment increased the radiosteroid uptake only in the liver. Converseley, bromocriptin suppressed the tracer incorporation into the liver, but increased prostatic accumulation. The highest testerone reduction occurred in the prostate of the untreated castrated dogs as compared with other organs. Prolactin suppressed 5 alpha -dihydrotestosterone formation but otherwise did not significantly influence testosterone turnover. Bromocriptin, however, stimulated dihydrotestosterone formation in the prostate and caused complete inhibition of hepatic testosterone reduction.


Purification of Aspergillus niger alpha-amylase.


Production of Candida utilis on slop by-product of fermentation industries. The slop (vinas) liquor, a major by-product a alcohol fermentation industries, has been used as growth medium for production of the torula yeast, Candida utilis. Supplementation of the slop with 0.2% ammonium sulphate and 1% to 5% molasses improved the cell yield significantly. The crude slop gave better results than the diluted or centrifuged liquors. Under optimal conditions, more than 15 grams of yeast were obtained on dry weight basis. The application feasibility of these results is presented.


Effect of some pesticides on the efficiency of the inoculated Rhizobium associated with broad bean plants. The effect of some pesticides on the efficiency of the inoculated rhizobium in broad bean plants (Vicia faba) was studied in greenhouse experiments. Different pesticides were used in this work, including insecticides, herbicides, nematocides, and a molecide in different concentrations. The study revealed the following conclusions. Application of insecticides in different concentrations generally affected the formation of efficient nodules on the root system of broad bean plants. The inhibitory effect was also reflected to some extent on the dry weight of the plants and total nitrogen fixed by rhizobia in association with the mentioned plants. Birlane (insecticide) was found to be the most inhibitory insecticide on the inoculated rhizobium. Some of the insecticides, such as Temik and Dursban, at lower concentration were found to be a stimulant to symbiotic N-fixation, giving higher amounts of nitrogen fixed in the macrosymbiont.


Possible role of solar radiation on the viability of some air fungi in Egypt. The high occurrence of Alternaria humicola and the moderate occurrence of Stemphylium verruculosum, Rhizopus nigricans, and Epicoccum nigrum in the air of Egypt could be correlated to their apparent resistance to solar radiation. Cladosporium herbarum, Aspergillus niger, and Penicillium oxalicum, although highly occurring, were light-sensitive. The miniumum solar radiation in November, coupled with the highest total fungal catch, dominated by Cladosporium herbarum, reveals the importance of solar radiation as a factor with direct effect on the air fungal population.


Actinomycetes in the desert of Kuwait.

Actinomycetes in the desert of Kuwait. The distribution of actinomycetes in two desert localities in Kuwait was investigated. The genus Streptomyces was dominant in the two studied localities. Attempts to classify this genus in groups and species were made. Species producing straight or wavy spore chains were dominating in the two localities. Species producing oval spores and smooth spore surfaces were widely distributed. The most frequent is the cinereus series. Streptomyces aburaviensis and S. wedmorensis were more frequent in Cyperus locality, while S. calvus was the dominant one in Rhanterium locality. Each locality was characterized by different groups and species.


Airborn bacteria in the atmosphere of Kuwait.


Volatile and gaseous exudates of either germinating seeds or roots of okra plant in relation to okra wilt disease, caused by some Fusarium species.


Simple method for carbon determination in microbiological experiments. A wet combustion method for the carbon determination was developed. It has been proved that the method can be successfully used for the determination of biochemical changes in microbe cultures, the soil, in composts, in farmyard manures etc. The samples are combusted in evacuated flasks by means of chromic sulphuric mixture, and the CO(2) evolved is determined interferometrically.


The effect of some organic substances on the mycelium of the fungus Ustilago nuda (Jens.) Rostr. Research was performed for studying the effect of some organic compounds, considered by many authors as the products ob barley seed metabolism generated after anaerobic seed treatment, on the mycelium of the fungus Ustilago nuda (Jens.) Rostr. The author examined the effectiveness of ethylacohol, acetaldehyde, acetic acid, succinic acid, lactic acid, and hydroquinone in concentrations from 1 M to 10(-6) M, and the effectiveness of extracts from disinfected seeds in doses from 10 g to 0.001 g/l. The effect of the mentioned solutions was examined as exerted on the growth of dicaryotic mycelium and on the growth of the haploid promycelium of the fungus. The dicaryotic mycelium of Ustilago nuda (Jens.) Rostr. was cultivated on potato agar with benzoic acid. The presence of the acid prevents mitosis, and the chlamydospores germinate on the nutritive medium with two fibres having binuclear cells. The haploid promycelium was cultivated  on potato agar; chlamydospores germinated with one four-cell fibre, and individual cells are mononuclear and haploid. Only later, a dicarytic mycelium is created in a complex process. In all the substances used, the concentration of 1 M was found to stop further growth of mycelium. The concentration of 10(-1) M of acetic acid and hydroquinone also stopped growth, the same concentration of acetaldehyde, lactic acid, succinic acid, ethylacohol stimulated mycelium growth in comparison with the control. The concentration of 10(-6) M stimulated mycelium growth in a majority of cases. Extracts from disinfected seeds did not influence mycelium growth significantly in all cases in comparison with the control. The results were similar in the two types of mycelium.


Effect of phosphate fertilization and seed inoculation with ""Okadin'' at high rate on yield of broadbean and lentil. The effect of phosphate fertilization and seed inoculation with ""Okadin'' preperation of rhizobia strains on the yield of broadbean and lentil was tested in field experiments during the seasons 1969 to 1972 in the farm of Faculty of Agriculture, Assiut University. Superphosphate was added at the rate of 0, 50, 100, or 200 kg/fa., and ""Okadin'' preparation, specific for the kind of legume planted, was applied to the seeds at 10 times the recommended rate. Application of superphosphate at any of the tested rates did not significantly affect total yield obtained, seeds yield, or the nitrogen content of seeds of lentil or braodbean. Seed inoculation with Okadin showed no significant effect on the yield of broadbean, but resulted in significant reduction in the yield of lentil seeds in the two seasons of the experiment.


The lack of detectable immune complexes in rat anaphylaxis. Attempts were made to detect soluble immune complexes (IC) in sera of rats submitted to anaphylactic shock 12 days following BPV plus antigen treatment, and their in vitro formation following the addition of specific antigens to sera or heparinized platelet rich plasma of sensitized rats. We failed to detect ICs or IC formation by studying Hageman factor activation and platelet aggregation or by using a very sensitive radio-assay of ICs. It is established that the anaphylactic activation of Hageman factor as well as the aggregation of platelets are not mediated by immune complexes, therefore, other explanations must be found.


Clinical significance of the house dust mite (Dermatophagoides pteronyssinus) in asthmatic children in Japan. Clinical studies were conducted to evaluate the role of the house dust mite. Dermatophagoides pteronyssinus, as an allergen in children's asthma in Japan. Skin testing and Prausnitz-Küstner type skin testing showed good correlations between the allergenicity of house dust and the mite. A positive Prausnitz-Küstner type skin reaction to house dust was neutralized by a mite extract. Radioallergosorbent test showed good correlation between house dust and the mite (r=0.687). The mite exhibited in vitro inhibition of radioallergosorbent test to house dust. The inhalation provocation test resulted in an acute respiratory attack in one of the patients. These results suggest that the house dust mite is an important allergen in asthmatic children in Japan.


Inheritance of asthma in families and its linkage to HLA haplotypes. Four families in which asthma occurred in more than three members, and in which there were at least three children, were studied in terms of clinical symptoms, serum IgE levels determined by RIST and RAST, and HLA haplotypes. No association between clinical asthma and serum IgE level was found, but a close association between asthma and a particular HLA haplotype in a family was demonstrated. It was therefore postulated that a disease susceptibility gene closely linked to an HLA gene complex may play a role in the development of asthma.


Why a meniscectomy fails.

Why a meniscectomy fails. The clinical and roentgenological data on 30 patients with unsatisfactory recovery or recurrent symptoms after meniscectomy were analysed. The meniscectomy was regarded as having been the wrong choice of therapy in four patients and as ineffective therapy in 11. In 10 patients other knee lesions dominated postoperatively, in three the recovery was delayed for no obvious reason but the symptoms slowly disappeared, and in the remaining two patients a degenerative osteoarthritis developing some time after the meniscectomy was regarded as the cause of the recurring symptoms. We conclude that with an optimal clinical and arthrographic analysis and with careful operative tecnique as many as 17 arthrotomies (out of 30 primary and 13 reoperations) in the material presented could have been avoided.


Medicine by satellite telephone--a new breakthrough.


The place of total thyroidectomy in the management of 909 patients with thyroid disease. An analytic review of 909 total thyroidectomies reveals complications and sequelae comparable to those that follow subtotal operations for Graves' disease, nodular goiter, and chronic thyroiditis. It is suggested that when surgery is indicated for the management of these diseases, nothing less than total thyroidectomy should be performed because of the important additional advantages obtained with this operation.


Transcription of adenovirus DNA by RNA polymerase III of bovine lymphoid tissue.


Use of chestnut in the feeding of infants allergic to cow's milk or intolerant to lactose. The aminoacid contents of native chestnut and its powdered form were studied. It was found that it has low cystine and methionine contents but if it is supplemented accordingly, the chestnut pulp can well be used for infant feeding. More than 50 infants were fed with chestnuts, and only in two cases was there intolerance. The aminoacid content of supplemented chestnut formula was lower than that of cow's milk and soy bean, but equal to that of human milk and as its essential aminoacid ratio was high, the infant's development was normal. Chestnut pulp is recommended as an alternative to soybean in the treatment of lactose intolerance and cow's milk allergy.


Temporal patterning of sexual behavior in the female rat.


Effect of pre- and post-surgical active BCG immunotherapies on murien EAkR lymphosarcoma. A combined treatment modality incorporating surgery plus BCG immunotherapy was administered to (DBA/2 X C57B/6) F1 mice grafted with EAkR lymphosarcoma. 30% of mice survived free of disease when BCG was injected intravenously two days after operation consisting of tumorectomy plus excision of the regional lymph node performed on the 8th day after tumor inoculation. Similar results were obtained when BCG was injected subcutaneously 6 days before surgery. Pre-operative intravenous and post-operative subcutanous BCG administration failed to cure the animals just as BCG or surgery alone.


Effects of the removal of the regional lymph nodes on the survival of mice bearing B 16 melanoma or EAkR lymphosarcoma. This work presents data concerning the effect of tumor excision accompanied or not by the removal of the regional lymph node (RLN) on the survival time of mice bearing the EAkR lymphosarcoma or the B16 melanoma. The operations were performed at various times to study this effect in relation to tumor volume. Early tumorectomy, on day 6 for the EAkR lymphosarcoma, on day 10 for the B16 melanoma, prolonged significantly the survival time. The additional removal of the RLN abolished this beneficial effect. In the case of the EAkR lymphosarcoma, a beneficial effect on the survival time was in contrast observed after a total excision of the tumor accompanied by RLN removal performed on day 8. The two surgical procedures were ineffective in increasing the survival time when they were applied after the 8th day for the EAkR lymphosarcoma and after the 10th day for the B16 melanoma. These results suggest that the preservation of the RLN may be favorable for the host at least at an early stage of the tumor growth.


Venereal herpes-like molluscum contagiosum: treatment with tretinoin. Molluscum contagiosum spread by sexual contact may be mistaken for other venereal diseases. The occurrence of a penile lesion resembling herpes progenitalis, and successful therapy of genital mollusca with topical tretinoin (vitamin A acid) is described.


New topical agents for dermatophytosis.

New topical agents for dermatophytosis. Several new synthetic antifungal agents have recently become available for topical use. Reported experiences with haloprogin, miconazole and clotrimazole are reviewed. Topical preparations of these agents are nonirritating and effective in the treatment of superficial fungus infections. They are effective in the management of tinea versicolor and cutaneous candidiasis as well as dermatophytosis.


Allergy to ingredients of vehicles.

Allergy to ingredients of vehicles. Common ingredients of vehicles such as perfumes, antibacterial agents, emulsifiers and other surface active agents, propylene glycol, lanolin and wool alcohols were tested in eczema patients over a three-year period. Perfume allergy was detected in 3.6% of the cases, sensitivity to thiomersal in 2%, to sorbic acid in 0.8%, to parabens in only 0.3%, and to wool alcohols in 1.2%. Reactions to emulsifiers were seen over 1% of those tested.


Herpes simplex and verrucae of the genitalia.


Diagnosis of anogenital ulcers.

Diagnosis of anogenital ulcers.


Nonspecific genital infections.

Nonspecific genital infections.


Nongonococcal urethritis.

Nongonococcal urethritis. Nongonococcal urethritis may now account for most cases of symptomatic urethritis seen at VD clinics in the United States. Well-controlled etiologic studies in nongonococcal urethritis have implicated Chlamydia in over 40% of cases but the etiology of Chlamydia-negative cases remains uncertain. Tetracycline provides effective antimicrobial therapy, but tests for cure are often inadequate, and distinguishing relapse and reinfection is difficult. For tetracycline-allergic patients, erythromycin should be used. Control measures to decrease transmission of nongonococcal urethritis are not well established.


Skin changes of the sunset years.

Skin changes of the sunset years.


Social class and morbidity in clinically treated alcoholics. The lifetime physical disease profiles of 122 lower and 724 middle class non-skid row alcoholics admitted to an inpatient treatment facility were compared to further clarify the significance of social class as a determinant of morbidity in alcoholics. The overall severity of physical disease and the frequency of all recorded lifetime illness diagnoses were greater in the lower than in the middle class. The former experienced more trauma, genitourinary disorders, venereal disease and malnutrition, as well as small excesses of respiratory and nervous system disorders. There were no class differences in the lifetime frequencies of liver and biliary tract, gastrointestinal, cardiovascular, endocrine and metabolic, integumentary, locomotor and haemopoietic disorders, or in the incidences of a number of disease entities including acute brain syndromes and chronic brain damage. The drinking patterns of the classes were similar, but the average duration of hazardous drinking was longer and the average current consumption was greater in the lower class. There were no class differences, however, in the average duration of hazardous drinking before the first occurrence of certain diseases. The referral sources of the classes were significantly different. Possible explanations for the differences between the findings of this and earlier studies are discussed.


Epidemiology of cutaneous leishmaniasis in Iran: B. Khorassan Part V: Report on a focus of zoonotic cutaneous leishmaniasis in Esferayen. During August and September 1975, an epidemiological investigation was carried out in another focus of cutaneous leishmaniasis in Khorassan province namely the Esferayen district located in the north western part of this province. The disease in Esferayen area is of zoonotic type having Rhombomys opimus as reservoir and P. papatasi as vector.


Immune deposit nephritis in infectious mononucleosis. A 22-year-old white male (L.V.) died of gram-negative septicemia complicating infectious mononucleosis (IM) that was associated with jaundice and oliguric renal failure. The kidney showed mesangial granular deposits of IgM and C3, mesangial electrondense deposits, and interstitial infiltrates of infiltrates of mononuclear cells, including atypical lymphocytes. Eluates obtained from kidney, spleen and liver contained Paul--Bunnell (PB) antibodies. Presence of PB antigens in these tissues was indicated by absorption of PB antibodies from IM sera, with the sediments resulting from tissue elutions. The IgM mesangial deposits were partially eluted with acid buffer at 56 degrees C and then reconstituted by incubation with IM sera or with immunoglobulins eluted from tissues of patient L.V. The presence in renal structures of PB antigens, IgM heterophile antibody, C3 and electron-dense deposits is consistent with the hypothesis that heterophile immune complexes were localized in the kidney and that they contribute in the pathogenisis of IM nephritis.


Nutritional requirements of infants and need for supplementing milk diet with infant weaning foods.


Alterations in pulmonary surfactant following sympathectomy.


Studies of an inhibitor of the thrombin-fibrinogen reaction localized in rat liver microsomes. Interference with the polymerization step. A heat-stable, macromolecular inhibitor of the thrombin-fibrinogen reaction localized in rat liver microsomes has been shown to interfere with the polymerization step in the fibrinogen-fibrin conversion. The inhibitor had no effect on thrombin activity as measured with the synthetic, chromogenic substrate BZ-Phe-Val-Arg-pNA. The amount of fibrin formed and the release of fibrinopeptide A were not affected by the inhibitor. Recording of turbidity at 350 nm and 600 nm indicated an inhibition of the lateral aggregation of the end-to-end fibrin polymers. The inhibitor was localized in both the luminal and membrane fractions of the microsomes. The inhibitor activity was not affected by warfarin treatment of the rats.


Effect of the root extract of Fagara zanthoxyloides on blood coagulation. The clot-promoting activity of the aqueous extract of Fagara-zanthoxyloides Lam plant is described for the first time. It significantly shortened the PTT (K) of normal and factor VIII deficient plasma while it manifested no such action on factor IX-deficient plasma. This activity could be demonstrated in the residue of the lyophilized aqueous extract after its successive extraction with ether, chloroform and methanol. It could not be attributed to the purified fractions: Zanthoxylol or its modified form 3, 4-dihydro-2,2-dimethyl-2H-1 benzopyran-6-butyric acid (DBA), hesperidin, Fagaramide or the ether soluble fraction of the aqueous extract.


The influence of ethanol feeding on the activities of factors II, VII, VIII, IX and X in rats. The effect of chronic administration of ethanol to rats in a controlled regimen upon the activities of the coagulation factors II, VII, VIII, IX and X has been studied. No significant differences were found for factor II, IX and X between the ethanol-treated rats and the control group given an isocaloric diet with carbohydrate replacing ethanol. Factor VII activity was somewhat higher and factor VIII activity decreased significantly in the experimental group when ethanol treatment was combined with an approximately two-fold increase in dietary polyunsaturated fatty acid.


Bleeding disorder with abnormal wound healing, acid-soluble clots and normal factor XIII. An unusual bleeding disorder clinically resembling factor XIII deficiency is presented. The only detectable coagulation abnormality was rapid clot dissolution in 1% monochloroacetic acid. This abnormality was ascribed to the sustained increase of  a pepsin-like plasma protease which is activated at low pH. Asystematic search for similar phenomena revealed that massive blood transfusion may also enhance plasma-clot solubility in acid, possibly by release of a red cell protease. We conclude that the acid clot solubility test is not a specific indicator of factor XIII deficiency, but this simple assay is recommended for further studies of acid plasma protease activity. The diagnostic relevance and pathophysiologic importance of increased pepsin-like activity in plasma remain to be elucidated.


Plasma factor XIII and platelet factor XIII in hyperlipaemia. Plasma factor XIII activity measured by a quantitative assay was found to be significantly higher in hypertriglyceridaemic patients (type IV and combined hyperlipoproteinaemia), as compared to normolipaemic controls. No such elevation in plasma factor XIII activity was found in patients with type Ha hyperlipaemia. Plasma pseudocholinesterase was found to parallel the elevated factor XIII activity in hypertriglyceridaemic subjects. In contrast, platelet factor XIII activity was not raised in hyperlipaemic subjects, and plasma factor XIII was found to be normal in a normolipaemic subjects with thrombocythaemia. It was concluded that there is no significant contribution from platelets to plasma factor XIII activity, and that the observed increase in plasma factor XIII in hypertriglyceridaemia results from enhanced hepatic synthesis of the enzyme.


Demonstration of reactivity to airborne and food allergens in cutaneous vasculitis by variations in fibrinopeptide A and other blood coagulation, fibrinolysis and complement parameters. In a 32-year-old woman and a 40-year-old man with cutaneous vasculitis, etiological allergic responses to foods and airborne allergens were found. During provocation tests, observations were made on blood levels of fibrinopeptide A(FPA) and coagulation factors, fibrinogen degradation products (FDP) and serum complement components. Skin biopsies were taken for microscopic and immunofluorescence analysis. In case 1, anaphylactoid allergy to milk and reaginic and anaphylactoid hypersensitivity to grass pollens were found. Dermal provocations with grass pollens gave arthralgia, hematomas, serum C3 fluctuation, factor VII reduction and fibrinolysis. During peroral milk challenge, transient increases in FPA and FDP levels were observed before symptoms appeared. In case 2, anaphylactoid hypersensitivity responses to bacteria, animal danders, foods and pollens were found. Two inhalations with sheep-wool extract resulted in a typical skin eruption. The first also gave an early reduction of C3 and then FPA liberation. Nasal birch-pollen test gave an increase of FPA in the latent period and then typical nodules. At least no low molecular weight FDP were detected during provocations. In patients with vasculitis reactions to exogenous allergens, FPA and FDP estimations after provocations may discriminate harmful from innocuous allergens and reveal individual response patterns in coagulation and fibrinolysis systems.


The effect of the fibrinogen concentration and the leukocyte count on intravascular fibrin deposition from soluble fibrin monomer complexes. Fibrin formation from fibrin monomer (FM) complexes was studied in experimental animals utilizing a previously described technique for quantitating fibrin deposition. A uniform thrombin infusion was used to produce FM, fibrinolysis being inhibited by EACA. In vivo complex formation between FM and 125I-fibrinogen was demonstrated chromatographically. A direct correlation was found between blood fibrinogen concentration and fibrin deposition in organs. By contrast, an inverse correlation between fibrinogen concentration and both enzymatic or non-enzymatic fibrin formation was found in vitro. The mechanism by which fibrinogen potentiates FM precipitation in vivo could not be explained by coprecipitation of fibrinogen in the complex which could not be demonstrated. The inhibitory effect of HN2 on fibrin deposition despite the associated hyperfibrinogemia induced by this drug is believed to underscore the importance of leukocytes in certain types of fibrin deposition. A correlation between the leukocyte count and fibrin formation from FM was also found. It was concluded that the risk of intravascular fibrin deposition is increased by a raised fibrinogen level especially when accompanied by leukocytosis.


Inhibitory effect of acetylsalicylic acid on human platelet function in normal volunteers and in women using a combined oral contraceptive regime. Six parameters related to the release reaction were measured simultaneously in 10 human volunteers prior to the intake of one single dose of 1 g acetylsalicylic acid and 1, 4, 5, 6 and 7 days alter: deltaE5 with diluted collagen, deltaE10 with Thrombofax and the serotonin-14C release by undiluted and diluted collagen, by Thrombofax and by bovine plasma. The duration of the inhibitory effect varied according to the test used. It was the most prolonged (through the 7th day) if serotonin-14C release by diluted collagen was measured. A systematic investigation of the platelet release reaction in women taking a combined oral contraceptive was also performed. There were no statistically significant differences from a control group. No difference in acetylsalicylic acid sensitivity, measured 24 hours after intake of 1 g of aspirin, could be demonstrated.


Thrombin elaboration in endotoxin-induced intravascular fibrin deposition. A leukocyte dependent process distinct from systemic hypercoagulability. Intravascular coagulation was induced by two appropriately spaced doses of endotoxin and by infusion of thromboplastin. The resulting fibrin deposition was measured by a previously described quantitative technique. Evidence of thrombin elaboration was obtained indirectly by measurement of fibrin monomer (FM) and by the detection and isolation of a thrombin-induced anticlotting activity. Venous segments were isolated at intervals and examined for thrombus formation following 40 minutes of stasis. Endotoxin triggered thrombin elaboration was not detectable in the circulation for at least one hour and was not accompanied by any thrombosis in isolated venous segments. No thrombin elaboration was found in leukopenic rabbits given endotoxin. In the thromboplastin infused animals, the quantity of fibrin deposited in the organs was comparable to that found after endotoxin. However, thrombin was found in the blood immediately and was associated with thrombosis in the isolatet venous segments. Less thrombin-induced anticoagulant activity was found after thromboplastin than after endotoxin. The findings suggest that endotoxin-induced intravascular coagulation is probably not caused by a mechanism of systemic hypercoagulability due to the release of thromboplastic material into the blood stream. A focal process of thrombin elaboration involving leukocytes is postulated. The study is believed relevant to patients with disseminated intravascular coagulation in whom venous thromboembolism is rarely found despite evidence of extensive microvascular fibrin deposition.


Effect of aspirin on platelet phospholipids. It was observed that the acetylsalicylic acid "in vitro" (final concentration 10(-4) M) as well as "in vivo" (1 g of aspirin) caused a platelet phospholipids variation which basically consisted of: 1. A diminution of the phospholipids/proteins rate of 22%. 2. A reduction of sphingomyelin "in vivo" of 27.66% and "in vitro" of 16.82%. 3. An increase in phosphatidyl choline "in vivo" of 12.24% and "in vitro" 10.28%. The possible effects that these changes might have on the platelet function are evaluated.


Impairment of ADP-induced platelet aggregation by hashish components. ADP-induced aggregation of washed human platelets is inhibited by the hashish components delta1-tetrahydrocannabinol (THC) and cannabidiol (CBD). The inhibition is counteracted by added ADP. When the cannabinoids are present at concentrations higher than 10(-5)M, the platelets aggregate non-reversibly, independently of an added inducer, apparently due to lysis and release of endogenous inducers. THC is clearly more potent than CBD in exhibiting the biphasic effect. Collagen- and thrombin-induced aggregation of washed platelets are hardly affected by the cannabinoids. THC and CBD also curtail ADP-induced reversible aggregation in platelet-rich plasma, while serotonin release and irreversible aggregation, caused by either ADP, collagen or thrombin, are not affected by the cannabinoids in platelet-rich plasma. The data point to associated sites for ADP and the cannabinoids on the platelet membrane.


A new therapy in post-traumatic intravascular coagulation?


Platelets in the urine: further evidence.


Recurrent thromboembolism with spontaneous platelet aggregation.


An inverse relation between platelet factor 4 in the platelet and in the plasma.


An environmental sanitation plan for the Mediterranean seaboard. Pollution and human health.


Nature and properties of C3Hf natural antitumor cytotoxins directed against murine lymphosarcoma cells. The nature and some biological properties of the natural antitumor cytotoxins previously found in normal C3Hf serum, have been investigated. By immunoelectronmicroscopy study, employing rabbit hybrid antibodies with specificity for mouse Ig and ferritin, the C3Hf cytotoxins were shown to belong to immunoglobulins. By gel filtration, by inhibition experiments of the cytotoxic serum activity with monospecific anti-IgG and anti-IgM sera, and by 2-mercaptoethanol treatment of the C3Hf serum, the cytotoxic immunoglobulins were demonstrated to belong to the IgM class. They were not inactivated by heating until 60 degrees C and were able to activate guinea pig, rabbit, and human complement. The highest cytotoxic activity of the normal C3Hf serum was found when cells and serum were incubated at the low temperature, suggesting a low binding affinity of the cytotoxic IgM.


The longest symbiotic bacterium as found in a membracid insect. An insect tumour cell, carrying germs, contains nuclei and also cellular debris as protoplasmic and nuclear degradation bodies. In histological sections the nucleus may be seen surrounded by such bodies, cut across, which then appear round in form. They have therefore been mistaken for yeast-like germs, called "Cicadomyces". But in smears the protoplasmic debris is stained blue and reveals bizarre shapes. T. assamensis is an exception and offers the key to properly interpret the bodies named Cicadomyces. Its symbiote is a long filamentous bacterium and persists in protoplasmic debris, the so-called Cicadomyces. Since Cicadomyces themselves cannot be infected by germs as long as themselves, the former can only represent cellular degradation bodies.