Allergic contact dermatitis caused by haloprogin. Haloprogin therapy has been used for years, but no cases of allergic contact dermatitis have been observed. On the basis of the results from several series of patch tests and biopsy findings, the first documented case, to my knowledge, of allergic contact dermatitis caused by haloprogin is reported.


[Intracytoplasmic tubulareticular structures. Presence in human lymphosarcoma]. Intracytoplasmic tubuloreticular structures were found in the tumour cells of a human lymphosarcoma. Such structures have been described in a wide variety of conditions in man and in animals, as well as in cell cultures of various origin, but rarely in lymphoid tumours. The different hypotheses concerning their nature are discussed.


Concentrated milk feeds and their relation to hypernatraemic dehydration in infants. The composition of milks usually fed to 25 infants admitted to hospital with a dehydrating illness was studied. 15 hypernatraemic babies had been given feeds of greater sodium concentration and osmolality than those fed to the 10 infants whose plasma sodium was below 150 mEq/l. Hypernatraemic dehydration may be followed by death or permanent brain damage. Most infants in the survey were receiving milk with a sodium content greater than that advised by the manufacturers. Suggestions are made for reducing the sources of error commonly made in the reconstitution of dried milk formulae.


Fat absorption by small babies fed two filled milk formulae. In 3-day fat balances, 7 of 8 infants had appreciably more steatorrhoea when they were fed Cow and Gate V formula than when they were fed SMA. The mean fat excretion (+/- SEM) expressed as a percentage of the amount ingested on Cow and Gate V was 28-1 +/- 3-9 compared with 10-5 +/- 2-3 on SMA. Gas-liquid chromatography of the faecal fat in 2 of 3 infants showed that C16:0 was responsible for most of the excess fatty acid when they were fed Cow and Gate V formula.


Lead content of deciduous teeth of children in different environments. The lead content of teeth of children in five different environments has been measured to determine the relative contribution of different sources of lead. The importance of lead paint in children living in dilapidated housing is clearly observed, but no effect attributable to automobile exhaust or industrial emissions is apparent. High lead levels were found among children living in new public housing projects within the high lead area of the city, even though a lead paint problem presumably should not exist in the projects themselves. The data are analyzed to determine the frequency with which excessive lead contents occur in the problem area in comparison to a low risk area.


[Use of the latex test in the serodiagnosis of enzootic leukosis of cattle]. Two antigenic extracts, prepared by different methods, were tried on 317 serum samples in the microscope-slide agglutination, sedimentation and tube agglutination tests. In comparison with the haematological findings, both antigens and all the tests gave a proportion of non-specific positive results, which made it impossible to obtain specific results. Various ways of reducing the proportion of non-specific reactions were tried, without success.


Estimation of the LD1 and extrapolation of the LD0.1 for five organophosphate pesticides. The oral LD50,s for organophosphate pesticides have been determined in CD-1 strain male and female mice. The values in mg/kg are: Trichlorfon, 800 and 800; Naled, 409 and 330; Dichlorvos, 139 and 133, GC6506, 23.4 and 17.8; Fospirate, 225 and 263 respectively. Toxicity was greater in males with Fospirate and greater in females with Naled and GC6506. The predicted LD1's and the extrapolated LD0.1's have been determined for the 5 organophosphates from an unbalanced design, loaded heavily toward the lower end of the dose-response curve. It has been shown that the slopes of the curves obtained with 50, 100 and 660 animals are parallel for all compound except Fospirate in the 660 mouse experiments. This is probably related to excessive female deaths in the upper segment of the dose-response curve. Sex dependent lethality was observed with Trichlorfon, Dichlorvos and Fospirate with the males being more susceptible than the females except in the case of Fospirate where there was a reversal at the LD50 with greater susceptibility in the females. The conditions for obtaining accurate results in such experiments have been established. The implications of human exposure to low levels of the environmental pollutants have been discussed.


The effect of magnesium sulfate on the absorption of acetylsalicylic acid and lithium carbonate from the human intestine. Magnesium sulfate given orally in a hypertonic or isotonic solution did not alter the absorption of therapeutic doses of acetylsalicylic acid or lithium carbonate, despite a purgative effect in 10 volunteers. The concentration of magnesium in serum remained unchanged during the experiments.


Paraquat poisoning in man.

Paraquat poisoning in man. In three cases of intoxication by Gramoxone¿, the concentration of paraquat dichloride in blood, dialysate, feces, and urine was determined spectrophotometrically after a clean-up of the biological material by means of ion exchange chromatography (with Dowex 50W-X12 or Zeo-Karb 225). Although good results were obtained after clean-up with Dowex 50W-X12, Zeo-Karb was preferred as ion exchange resin, especially when large sample volumes were needed for the determination. The reported findings indicate that: only 5 to 10% of an ingested dose of paraquat dichloride is absorbed in man, Fullers' earth is very useful, and that primary, e.g. immediate, hemodialysis is necessary.


A rapid and specific method for the determination of traces of thallium directly in urine by differential pulse anodic stripping voltammetry. The applicability of differential pulse anodic stripping voltammetry to the direct qualitative and quantitative analysis of thallium in urine has been investigated. Comparisons were made between the hanging mercury drop electrode and the mercury plated wax impregnated graphite electrode. The latter electrode was found to be somewhat more sensitive, with detection limits in the lower ppb range. For quantitative determination, the hanging mercury drop electrode showed better reproducibility. The effects of toxicologically important metals on the analysis of thallium were investigated and their possible interference could be eliminated by a proper choice of operating conditions. The advantages of the proposed method are its sensitivity, speed and low cost in comparison with other methods for detecting and measuring thallium.


[Lethal intoxication with leaves of the yew tree (Taxus baccata) (author's transl)]. A case of a rare lethal intoxication with yew leaves (taxus baccata) is reported. The clinical signs were dizziness (onset 1 hr after yew leaves were ingested), nausea, diffuse abdominal pain, unconsciousness, weak breathing, tachycardia, brief ventricular flutter afterwards a slow pulse, and finally death by respiratory arrest and diastolic cardiac standstill. Particular attention was given to the ECG. It showed an atypical bundle branch block with a maximal QRS-duration of 0.24 sec. A striking resemblence to the ECG in the case of hyperkalemia is seen in that P-waves were absent. Therefore, the possibility is noted that an acute hyperkalemia could be partly responsible for the cardiotoxic effect of the leaf.


The usefulness of the enzymatic tests in acute poisonings. In the group of 107 patients poisoned by carbon monoxide (18 patients), ethanol (10), barbiturates (18), glutehimide (10), tranquilizers (19), organic solvents (10),salicylates (3), organochlorines (8), and sulfonamides (5)--the activities of 8 serum enzymes were determined for 6 consecutive days of treatment, the enzymes being as follows: aminotransferases, cholinesterase, alkaline phosphatase, lactate, alpha-hydroxybutyrate, glutamate, and sorbitol dehydrogenase. The antipyrine half-life was also assayed. It has been shown that the poisonings by particular groups of poisons do not bring about characteristic changes in the activity of enzymes that might be of any diagnostic value. The intensity of changes was connected withe depth and duration of toxic coma. Most frequently an increase ensued in the activity of AspAt and AlAt in the third 24-hrs period, and an increase in the activity of SDH in the first 24-hrs period. In the group under examination there were 26 drug abusers in whom a shortening of the antipyrine half-life was discovered. They were less responsive to toxic doses of drugs, and the enzymatic changes in them were less distinct. No changes in the activity of tested enzymes, which are characteristic of toxicomania, were found.


Myeloid hyperplasia in growing rats after chronic treatment with delta 9-THC at behavioral doses. Delta 9-THC at the dose of 1 mg/kg/die was administered subcutaneously in growing rats, from the second to the 30th day of life. A statistically significant myeloid hyperplasia was demonstrated, which persisted up to 4 months after the end of the treatment, together with significant blood granulocytosis.


The excretion in urine of four insecticidal carbamates and their phenolic metabolites after oral administration to rats. 4 insecticidal carbamates: 3-methyl, 5-isopropylphenyl N-methyl-carbamate (Promecarb), 4-methylthio, 3,5 dimethylphenyl N-methylcarbamate (Mesurol), 4-dimethyl-amino, 3,5 dimethylphenyl N-methylcarbamate (Zectran), and 4-benzothienyl N-methyl-carbamate (Mobam) were orally administered to male Wistar rats. The excretion of the unchanged products was followed in 24 hrs urine collections. The corresponding phenols of the different carbamates could be identified as metabolites by gas-chromatography-mass spectrometyr. These metabolites were quantified afterward by gas-liquid chromatography. In all cases only minor quantities of unchanged products and metabolites were excreted in the urine over the 48 hrs after administration.


[Radioimmuno assay of the sulfonylurea AR-DF 26(author's transl)]. A radioimmunological method was developed for 1-cyclohexyl-3-[p-(beta-4,4-dimethyl-7-methoxy-1,3-(2H,4H)-isoquinolinedion-2-yl)phenethyl]-sulfonylurea (AR-DF 26, gliquidone, Glurenorm) estimations in plasma. The antisera were obtained by immunization of rabbits with AR-DF 26-bovine serum albumin (BSA) conjugate. The estimation is based on the competitive displacement in plasma samples of known amounts of labelled AR-DF 26, bound to a specific antibody by unknown amounts of unlabelled AR-DF 26. Concentrations of as low as 1 ng of AR-DF 26 per sample can be measured by this method. The investigations into the specificity of this reaction have shown that the antiserum is extremely specific for AR-DF 26. There is good reproducibility of the results and no differences could be found by variance analysis between different measurements of the same AR-DF 26 concentration. Since more than 70% of the plasma concentration correspond to unchanged AR-DF 26 for a longer period after application, the results of this AR-DF 26-radioimmuno assay is only minimally altered by its metabolites.


[MASCA-model of the biochemical-pharmacological drug research/ part 4: Structure-activity relationships and MANOVA (author's transl)]. The relation between the multivariate structure-activity analysis and the MANOVA is demonstrated on examples adapted from the combination analysis by Zipf, the dose-response and time-response analyses, the pharmacological screening and pharmacokinetics.


Substituted phenylacetylguanidines: a new class of antihypertensive agents. The synthesis of a new series of phenylacetylguanidines is described. Several of them exhibited high antihypertensive activity in the rat. The most potent member of the series is N-amidino-2-(2,6-dichlorophenyl)acetamide hydrochloride [2,6-dichlorophenylacetylguanidine hydrochloride, compound 19], which is now in clinical study under the clinical code number BS 100-141. The structure-activity relationships in this class of compounds are discussed.


Pharmacological actions of the antihypertensive agent N-amidino-2-(2,6-dichlorophenyl)acetamide hydrochloride (BS 100-141). Pharmacological properties characterizing N-amidino-2-(2,6-dichlorophenyl)acetamide hydrochloride (BS 100-141) as a centrally acting antihypertensive agent are described. Its action resembles that of clonidine in many respects but with important differences which are discussed. In DOCA-NaCl--hypertensive conscious rats, BS 100-141 lowers systemic blood pressure with oral doses of 0.3-5 mg/kg. Evidence for a central site of action is provided by the following findings. Infusion of BS 100-141 into the vertebral artery of anaesthetized dogs reduces blood pressure, the same dose being ineffective by i.v. route. Injection into the lateral cerebral ventricle of anaesthetized cats causes a marked reduction in blood pressure and heart rate, the same dose being ineffective when given i.v. The effects of intraventricular injection are inhibited by phentolamine administered by the same route. Intravenous administration of BS 100-141 induces dose-dependent reductions in the splanchnic (sympathetic) nerve activity in the cat. BS 100-141 reduces noradrenaline turnover in the brain stem of the rat as a result of central alpha-adrenoceptor stimulation. Doses which are effective in the hypertensive rat do not reduce dopamine turnover in the corpus striatum. The peripheral, direct alpha-sympathomimetic action of BS 100-141 was demonstrated by the transient increases in blood pressure observed in rats. These increases were unaffected by pretreatment with reserpine, but were antagonized by phentolamine. BS 100-141 was shown to induce contractions of isolated veins and arteries which were competitively inhibited by phentolamine. It stimulates presynaptic cardiac sympathetic alpha-adrenoceptors, thus inhibiting transmitter release to the heart. The sedative effects of BS 100-141 observed in dogs were slight compared to those of clonidine.


Antihypertensive action of indapamide. Comparative studies in several experimental models. 1-(4-Chloro-3-sulfamylbenzamido)-2-methyl-indoline (indapamide), after single oral dose administration, showed antihypertensive activity in genetically hypertensive rats, DOCA/saline hypertensive rats, unilaterally-nephrectomised DOCA/saline hypertensive rats and dogs made hypertensive by renal encapsulation. The activity was observed at doses as low as 1-3 mg/kg and lasted at least 48 h. Increasing the dose level considerably prolonged the duration of action but did not substantially enhance the maximum antihypertensive effect. In genetically hypertensive rats indapamide was 30-300 times more potent than furosemide, spironolactone and chlorthalidone. Indapamide had no effect on blood pressure in normotensive rats. In concentrations of 1 X 10(-5) to 1 X 10(-3) g/ml, indapamide antagonised contractions of arterial and venous strips to angiotensin, epinephrine and norepinephrine revealing a direct vascular action. Indapamide has a prolonged saluretic action which in combination with the direct vascular effects may well account for its antihypertensive activity.


Synthesis of alpha-methyl-4-(2-thienylcarbonyl)benzeneacetic acid, suprofen, and derivatives. A series of compounds with general structure Het-CO-Ar-CH(CH3)COOH was prepared for pharmacological screening. Different synthetic approaches are described. Alpha-Methyl-4-(2-thienylcarbonyl)benzeneacetic acid (compound III-1, suprofen) was found to show a marked antiwrithing activity. Furthermore this compound proved to be a potent inhibitor of prostaglandin biosynthesis.


Physico-chemical and analytical studies on suprofen. Physico-chemical and analytical studies on alpha-methyl-4-(2-thienylcarbonyl)benzeneacetic acid (R 25 061, suprofen) are reported. The usual description data, purity tests and quantitative analysis methods are given. Spectral (UV, IR, NMR, MS) and chromatographic (TLC) properties are described. Stability tests for the drug substance are added also.


Suprofen, a potent antagonist of acetic acid-induced writhing in rats. A new standardized acetic acid-induced writhing test in rats is described in detail and its methodology is discussed briefly. The described method has proved to be useful for evaluating the anti-writhing activity of narcotic analgesics, non-narcotic anti-inflammatory compounds and narcotic-antagonists with analgesic activity. A direct quantitative comparison of anti-writhing activity was made between orally administered acetyl-salicylic acid, phenylbutazone, indometacin, tolmetin, ketoprofen and alpha-methyl-4-(2-thienylcarbonyl)benzeneacetic acid (suprofen) in a specially designed experiment. Among the known non-narcotic, non-steroidal anti-inflammatory compounds suprofen appeared to be the most potent antagonist of acetic acid-induced writhing in rats, about 200 to 300 times as potent as acetyl-salicylic acid and phenylbutazone, 15 to 30 times as potent as indometacin and tolmetin, and about 6 times as potent as ketoprofen.


Suprofen, a potent antagonist of ultraviolet-erythema in guinea-pigs. A standardized ultraviolet erythema test in guinea-pigs is described in detail. The erythema reaction to 120 sec of UV irradiation was assessed after 1, 2 and 4 h. A direct quantitative comparison of the anti-erythema effect was made between phenylbutazone, indometacin, tolmetin, ketoprofen and alpha-methyl-4-(2-thienylcarbonyl)benzeneacetic acid (suprofen) in a specially designed experiment. All compounds were given by oral gavage 1 h before irradiation. Among the compounds studied suprofen was the most potent antagonist of ultraviolet-induced erythema in guinea-pigs, i.e. about 45 times tolmetin, 25 times phenylbutazone, 10 times indometacin and 5 times ketoprofen activity.


Suprofen, a potent antagonist of sodium urate crystal-induced arthritis in dogs. A standardized sodium urate-induced arthritis test in dogs is described in detail. A microcrystalline suspension of 20 mg/ml in 0.9% NaCl was injected into one of the stifle joints in a volume of 0.5 ml and motor impairment of the dogs was scored every 30 min over a period of 8 h. A direct quantitative comparison was made of the anti-arthritic activity of acetyl-salicylic acid, phenylbutazone, indometacin and alpha-methyl-4-(2-thienylcarbonyl)benzeneacetic acid (suprofen). All compounds were given by oral gavage immediately after the sodium urate injection. Among the compounds studied suprofen was the most potent antagonist of sodium urate-induced arthritis in dogs. Comparing the ED50 values suprofen was about 4 times as potent as indometacin, 9 times as potent as phenylbutazone and 60 times as potent as acetyl-salicylic acid.


The activity of suprofen on nystatin-induced paw oedema in rats. Subplantar injection of nystatin into the rat paw induces acute paw oedema of long duration. In this test the anti-inflammatory activity of alpha-methyl-4-(2-thienylcarbonyl)benzeneacetic acid (suprofen) has been studied using doses from 1.25 up to 160 mg/kg. The lowest dose significantly reducing paw diameter increases was 2.5 mg/kg; more intense and longer lasting reductions appeared progressively with increasing doses. The dose producing 50% inhibition of diameter increase was 2.70 mg/kg 1 h and 1.5 h after administration (lowest ED50). Comparative lowest ED50-values for simultaneously tested reference compounds were 6.2 mg/kg for indometacin, 34 mg/kg for phenylbutazone and 38 mg/kg for acetyl-salicylic acid. Within the first 2 h after administration suprofen exhibited anti-inflammatory activity from 2 to 14 times as potent as did the reference compounds.


The antipyretic effect of suprofen in rats with yeast-induced fever. The antipyretic activity of alpha-methyl--4-(2-thienylcarbonyl)benzeneacetic acid (suprofen) was studied in rats with comparable hyperthermia after s.c. injection of brewer's yeast. The lowest dose effectively reducing fever is 5 mg/kg and restoration of normal body temperature is obtained with 40 mg/kg. Hypothermia is not observed even after treatment with 160 mg/kg. The ED50 (with confidence limits), which reduces fever below 39 degrees C in 50% of the animals, at the time of peak hyperthermia is 10.0 (6.6--15.2) mg/kg. ED50's of simultaneously studied reference compounds are 5.7 (3.9--8.3) mg/kg for indometacin, 38 (24--61) mg/kg for tolmetin, 76 (47--121) mg/kg for phenylburazone and 113 (75--170) mg/kg for acetyl-salicylic acid. Two to four times higher doses of these compounds restore normal body temperature but further increase of the dose induces hypothermia, which is particularly pronounced for acetyl-salicylic acid and phenylbutazone. Suprofen is a potent antipyretic agent, devoid of hypothermic activity even at 32 times the lowest effective dose.


The effects of suprofen in rats with implanted cotton pellets. Implanted cotton pellets with closely adherent granuloma tissue were removed from rats treated orally during 7 consecutive days with solvent or 2.5, 5.0, 10, 20 or 40 mg/kg of alpha-methyl-4-(2-thienylcarbonyl)benzeneacetic acid (suprofen) by gavage. Highly significant decrease (P less than 0.001) of the total cotton pellet dry weight was observed in the groups given 5.0 mg/kg of suprofen or more. The pronounced activity on total cotton pellet weight was obtained without any effect on body weight gain, on food consumption or on the weight of thymus and adrenal glands in the same animals. We conclude that a maximal effect against the proliferative phase of inflammation is obtained with 10 mg/dg of suprofen, in the absence of any steroid-like or toxic side-effect.


The effects of suprofen in rats with Mycobacterium butyricum-induced arthritis. The activity of alpha-methyl-4-(2-thienylcarbonyl)benzeneacetic acid (suprofen) was studied in rats with established Mycobacterium butyricum-induced arthritis. The arthritic response was evaluated by measuring the diameter changes of the hind paws and tibiotarsal joints, using a new apparatus. Treatment once daily by gavage during 14 days revealed activity at the dose of 1.25 mg/kg and above. The lowest ED50 was 6.2 mg/kg. In comparison with simultaneously studied reference compounds, this corresponded approximately to the activity of phenylbutazone. In the higher dose range, 10 to 40 mg/kg, the reduction of external arthritic symptoms was associated with marked reversal of multiple bone deformations. A treatment schedule with 4 administrations of 2.5 mg/kg/day was significantly more effective than a single daily administration of 10 mg/kg and comparable to that of 10 mg/kg once daily. Mixing of suprofen with the diet, to give the low daily dose of 1.28 mg/kg confirmed the high activity expected from the maintenance of a practically constant compound level in the treated rats. In a comparative study involving suprofen, acetyl-salicylic acid, indometacin, phenylbutazone and tolmetin, all administered over 14 days with the diet in a dose range up to toxic dose levels, dose-related anti-inflammatory and toxic effects were obtained. The potency order and ED50's of the compounds were: indometacin (0.31 mg/kg) greater than suprofen (1.48) greater than tolmetin (18.0) = phenylbutazone (18.2) greater than acetyl-salicylic acid (440). Suprofen had by far the largest safety margin (48), followed by phenylbutazone (20), tolmetin (16), indometacin (8) and acetyl-salicylic acid (2). In conclusion, three major symptoms of adjuvant arthritis: joint inflammation, impaired growth and bone erosion, were markedly reduced by different doses of suprofen, which revealed to be a safe compound when compared to several reference compounds.


Gastrointestinal effects and acute toxicity of suprofen. The acute effects of orally administered, high doses of alpha-methyl-4-(2-thienylcarbonyl)benzeneacetic acid (suprofen) were studied in various tests, related to gastrointestinal functions. A decrease of the diarrheal stools in the castor oil test in rats was the first effect noted; the ED50 in this test was 40 mg/kg. This dose is 540 times higher than the ED50 of suprofen in the acetic acid-induced writhing test in rats (ED50 = 0.074 mg/kg). Temporarily decreased food consumption in rats was first noted after administration of 80 mg/kg. This is more than 1000 times the ED50 in the rat anti-writhing test. The appearance of gastrointestinal lesions was also studied in rats and a direct quantitative comparison was made with indometacin, acetyl-salicylic acid and ketoprofen. The dose of suprofen that produced lesions in 50% of the rats was 200 mg/kg, viz. 2700 times the ED50 in the rat anti-writhing test. Similarly obtained safety margins are 9.0 for indometacin, 78 for acetyl-salicylic acid and 102 for ketoprofen. The mortality after a single oral administration of suprofen was studied in mice, rats, guinea-pigs and dogs. LD50-values, based on mortality 7 days after administration, were 590 mg/kg, 353 mg/kg, 280 mg/kg and more than 160 mg/kg, respectively. Comparative LD50's in mice and rats were 14 and 19 mg/kg for indometacin, 280 and 70 mg/kg for ketoprofen. Therefore the safety margin in rats, with respect to the ED50 in the acetic acid-induced writhing test, is 4770 for suprofen, 156 for ketoprofen and 17.3 for indometacin. In guinea-pigs the safety margin of suprofen is 1470 with respect to the ED50 in UV-erythema and in dogs more than 250 with respect to the ED50 in urate-induced arthritis. From these data we may conclude that suprofen is comparatively safer than the reference compounds studied and that its effects on the gastrointestinal tract appear at doses far above those required for effectiveness in tests related to pain, fever and inflammation.


Pharmacological properties of 2-(2-chloro-p-toluidino)-2-imidazoline-nitrate (Tolonidine), a new antihypertensive agent. I. Action on blood pressure and heart rate. Tolonidine, 2-(2-chloro-p-toluidino)-2-imidazoline-nitrate, a substance structurally related to clonidine, was studied for its effects on blood pressure and heart rate in anesthetized or conscious, normotensive or hypertensive animals (mainly dogs). In all cases, blood pressure was lowered by tolonidine. Initial short-lasting hypertension was observed after each i.v. administration. Heart rate was markedly lowered irrespective of the experimental process. Comparison with clonidine, guanethidine and mecamylamine in hypertensive anesthetized or unanesthetized animals made it possible to place tolonidine with respect to these reference antihypertensive drugs. A close relationship essentially appears between the effects of both derivatives of imidazoline: tolonidine and clonidine, tolonidine being, however, active at higher doses. The analysis of these results will appear at the end of a series of three articles.


A combined study on the distribution of oxytetracycline and polyvinylpyrrolidone in rats. With the purpose of studying the influence of polyvinylpyrrolidone (PVP) on the disposition of oxytetracycline (OTC), OTC was administered i.v. to male rats in two formulations, one of which contained 14C-labelled PVP. From the rats, whole-body sections (30 mum) were taken which were subjected to three analytical procedures: autoradiography to determine the distribution of the PVP-14C, fluorography and bioautography to obtain information on the OTC-distribution. The experimental results suggest equilibrium complex formation between OTC and PVP, it being mainly the complex which is i.v. injected when both products are combined in an injection formulation. Such complex formation can explain the lower toxicity of OTC when injected in combination with PVP as well as the slower build-up of OTC-levels in some organs, compared with that after OTC administration without PVP. Beyond this kinetic effect of PVP on the fate of OTC no evidence was obtained for an influence of PVP on the OTC distribution pattern per se, or on its ultimate antibiotic activity in the different organs. Some details of the OTC and especially of the PVP distribution are discussed.


[Studies on the pharmacokinetics of hexobendine in rats / 2nd communication: Elimination following i.v. administration (author's transl)]. The elimination of 14C and of 3H was studied in rats after i.v. administration of 0.22--0.33 mg/kg of 14C- or 0.67 mg/kg of 3H-labelled N,N'-dimethyl-N,N'-bis-[3-(3',4',5'-trimethoxy-benzoxy)-propyl]-ethylenediamine-dihydrochloride (hexobendine, Ustimon, Reoxyl), respectively. Regarding the obtained results shortcomings in methods are discussed which may falsify the elimination pattern of radioactively labelled substances. Under certain experimental conditions (closed metabolism chamber with absorption of CO2 or H2O, respectively) 99-100% of the administered radioactivity were detected in the excretion products. The appearance of 14CO2 in the expired air was prevented when the bile duct was cannulated and the bile was drained to the outside before reaching the gut with its probably decarboxylating bacteria.


Are there therapeutic indications of intravenous injection of calcium gluconate? 1. The action of i.v. injection of calcium gluconate on a) the release of catecholamines from the adrenals of cats and dogs, b) the adrenergic responses of circulation, nictitating membrane and spleen in cats, and c) the cardiac and circulatory response in dogs has been investigated. 2. Ca2+-effects mediated by release of catecholamines dominate in the cat, as do direct cardiac stimulating actions in the dog. 3. Ca2+-effects of therapeutic significance, if existent at all, could be assumed only with regard to an anti-anaphylactic effect of the catecholamines released by i.v. injected Ca2+.


Sexual differences in the metabolism of salicylates. During 6 h the plasma level of salicylates was followed after oral administration of aspirin. The plasma levels of salicylic acid were significantly lower in bull than in heifer calves during the whole observation period. The toxicity of the drug was higher in female animals.


[The effect of silybin-dihemisuccinate on regulation disorders in phospholipid metabolism in acute galactosamine intoxication in the rat]. 1. 24 h after application of 900 mg D-galactosamine/kg body weight, an increase of total lipids, triglycerides, phosphatidyl-choline and phosphatidic acid concentrations, and also a decrease of total phospholipids and phosphatidylethanolamine can be determined in the whole rat liver. After administration of [1-14C]-palmitate, specific radioactivity of phosphatidyl-choline is diminished without alteration of specific radioactivity of other lipid fractions. Prophylactic application of silybin-dihemisuccinate abolished completely decrease of phosphatidyl-ethanolamine and diminished increase of total lipids and triglyceride concentrations. 2. Specific radioactivity of total lipids in serum of galactosamine-intoxicated rats is enhanced, specific radioactivity of triglycerides and phospholipids is diminished, simultaneously, total lipids concentration is reduced. 3. In the microsomal fraction of galactosamine-injured livers, a decrease of specific radioactivity of total phospholipids and phosphatidyl-choline can be observed. Prophylactic administration of silybin abolishes diminution of specific radioactivity of phosphatidyl-choline partially. 4. Diminution of specific radioactivity of total lipids, total phospholipids and phosphatidyl-ethanolamine, induced by galactosamine intoxication in the mitochondrial fraction, is normalized by application of silybin. 5. Diminished triglyceride infiltration in siybin-treated rats may be based onnormalization of inhibited phosphatidyl-choline turnover.


Inhibition, by drugs, of galactosamine induced hepatitis in the rat. Four compounds, prednisolone, sodium phenobarbitone, azathioprine and orotic acid, were tested for their ability to inhibit galactosamine induced hepatitis in the rat. Prednisolone offered total protection at doses of 100 mg/kg and above; sodium phenobarbitone and orotic acid modified the response to galactosamine and azathioprine was without effect.


An investigation of the hepatotoxicity of D-galactosamine in different species of animal. An examination of the hepatotoxicity of d-galactosamine has been made in the golden hamster and the mouse and the results compared to those previously investigated in the rat. The order of species found susceptible to the hepatotoxic effects of d-galactosamine was golden hamster greater than rat greater than mouse.


[Azo dyes and vitamin A reserves in the liver]. Amaranth and Sunset Yellow FCF, added to the basic diet at 1200, 3000, 10 000 and 20 000 mg/kg, influence, after 10 days' administration to rats, neither the percentage of vitamin A stored in the liver in relation to the quantity of vitamin taken, nor the hepatic reserve expressed in IU/g of liver.


[Teratogenic action of ethyl-nitrosourea in Göttingen miniature pigs (author's transl)]. By i.p. application of 70 or 100 mg/kg ethyl-nitrosourea, resp., to gravide Göttingen miniature pigs on days 14 or 16, resp., of gestation massive malformations of the skeletal system were produced. The experiments demonstrated the teratogenic effect of ethylnitrosourea on non-rodents, ascertained the period of determination of the skeletal system in pigs, confirmed the concentration effect in teratogenesis as well as the ineffectiveness of biological barriers with adequately high dosages.


Potentiated chemotherapeutic activity of 3,6-diamino-10-methyl-acridinium by combination with glycine or DL-alpha-alanine on the Ehrlich carcinoma. Glycine or DL-alpha-alanine potentiated the chemotherapeutic action of 3,6-diaminoacridinium without increasing its toxicity when these amino acids were combined with it simultaneously. On the contrary, valine in combination with 3,6-diaminoacridinium diminished slightly the chemotherapeutic effect as compared to the monotherapy with 3,6-diaminoacridinium. The monotherapy with the applied amino acids in the same dosage showed no tumor inhibition.


[Chromaffine tumours: diagnosis and catamnestic features based on the data collected at the Institute of Experimental Therapy between 1949 and 1974 (author's transl)]. From 1949 to 1974, urine samples of 1669 patients with unclarified arterial hypertension were tested for non-conjugated catecholamines. Chromaffine tumours--among them one pheochromoblastoma and two families with inherited forms--were found in 1.1% of all cases. With the procedure applied, adrenergic alpha- and/or beta-mimetic actions on the circulation of cats can be identified when the excretion of total catecholamines is increased by the factor 1.5 to 2.0. Hence, chromaffine tumours with smaller excretion rates (about 200 mug/24 h) are also detectable, so in one case where the excretion of vanillyl-mandelic acid was normal. Thus all prerequisites concerning sensitivity and specificity of a screening method are fulfilled. The large variety of symptoms of chromaffine tumours becomes obvious from the catamnestic data of 19 patients indicating problems which may arise in differential diagnosis.


Investigations on rapeseed oil toxicology. A series of investigations on humans and mice, performed in this laboratory in the years 1973-74 is presented. To assess the exposure levels of the Italian population to rapeseed oil ingestion, the serum of 70 apparently healthy railway workers, as well as the adipose tissue and myocardium of 16 subjects deceased for different causes were analyzed, with a gas chromatographic method, to ascertain if erucic acid or its metabolites were present. 40 out of 70 subjects had measurable erucic acid in the serum ranging from 0.3 to 3.8% of the total fatty acids (mean 1.1 +/- 0.14) in the presence or absence of behenic acid, probable metabolite of erucic acid in humans. Furthermore 26 subjects had measurable behenic acid alone. Each of the 16 subjects had measurable erucic acid in adipose tissue ranging from 0.3 to 6.8% of the total fatty acids (mean 2.6 +/- 0.5) always in the presence of gadoleic acid (present in rapeseed oil, product of beta-oxidation of erucic acid and only partially deriving from other sources) ranging from 1.1 to 4.9% (mean 2.2 +/- 0.3). 13 subjects out of 14 analyzed had measurable erucic acid in the myocardium ranging from 0.2 to 2.2% (mean 0.7 +/- 0.18) while 9 subjects had measurable gadoleic acid. Erucic acid was absent in the human tissues in Italy in the years 1967-68. Regarding the studies on mice, the deposition of erucic and gadoleic acids in some organs of young mice supplied with 50% of daily calories for three days in rapeseed oil was investigated. The deposition of the two fatty acids amounts to about 10% of the total fatty acids in the heart and liver and considerably less in skeletal muscle and kidney. In the mouse liver there is also a decrease in hexobarbital metabolism following rapeseed oil ingestion.


[Influence of some cytostatic drugs on semiconservative DNA-synthesis and DNA-repair in normal and cancer cells (author's transl)]. The action of cyclophosphamide, vincristine, vinblastine and procarbacine on the enzymes of the excision repair and on the semiconservative DNA-synthesis was investigated. To get a view of the total repair enzyme complexes the incorporation of 3H-thymidine into DNA after UV- and Gamma-irradiation was measured, and sedimentation profiles in alkaline sucrose were carried out. The drugs were also tested after being metabolized. The 4 drugs had no influence in an in vitro system on DNA-repair using spleen cells. Vinblastine and procarbacine showed an inhibitory effect on semiconservative DNA-synthesis. Using Yoshida ascites cells for the investigations we found an inhibition of the exonuclease-polymerase system by cyclophosphamide and procarbacine and a supression of ligase reaction by vinblastine and vincristine. Different degrees of inhibition of DNA-synthesis in Yoshida ascites cells could be seen after use of the 4 cytostatic drugs.


[Marginals to mycotoxin research (author's transl)]. Several food additives, i.e. enzyme preparations, colouring agents permitted for use in foods and xylitol, have been tested for a possible content of aflatoxins, sterigmatocystin and patulin. The author further reports on a potential mycotoxin carrier which is sold as dietary speciality, and discusses two strange promotional practices for cheese.


[Alcohol absorption and elimination in different alimentary conditions (author's transl)]. The continuous enzymatic in vivo estimation of blood alcohol was used for plotting curves of blood alcohol concentrations in 24 double-experiments from 4 to 6 h duration. Absorption and elimination of alcohol were observed under the influence of the food eaten before. Two hours after a light meal test persons drank whisky and blood alcohol curves were recorded determining increase, maximum and elimination. The curves varied especially in the phases of absorption. In a second test compared with the curves after a light meal the retardation of absorption was examined after drinking the juice of "Sangritta picante" spice in addition. Delayed alcohol absorption could be verified. After taking a fat meal the retardation of absorption was found even greater. Recorded after fasting for more than 12 h the curves showed a slower increase in blood alcohol concentration and a higher maximum in comparison with the curves after a light meal.


[On the therapy of secondary glaucoma (author's transl)]. Description of the most frequent secondary glaucomas. The most important points of their medicamental and operative therapy are compiled. The importance of gonioscopical findings is emphasized in particular.


[Optimating the availability of homologous quaternary ammonium compounds/3rd communication: The influence of salts on in vitro distribution of benzilic acid esters of homologous dimethyl-(2-hydroxyethyl)-alkyl-ammoniumbromides (author's transl)]. The addition of NaBr, Na-butansulfonate or Na-trichloracetat increases the partition coefficients of homologous quaternary cholinesters of benzilic acid between n-octanol and water. In a three-phase model (water/n-octanol/water) thus the rates of equilibration increase considerably for hydrophilic compounds.


Hypolipemic activity of clofibrate-related compounds. Ethyl-2(p-chlorophenoxy)-2-methylpropionate (clofibrate) related compounds were synthesized from substituted aryloxy acetic acids (III) either by esterification with selected alcohols (3,3,5-trimethylcyclohexanol and oxyalkyltheophyllines), by introduction into heterocyclic ring system (triazine type) or by amidation (aminotriazines and p-aminobenzoates). Lipid lowering effect was tested in normolipemic and hyperlipemic rats against clofibrate as reference. Some of these derivatives show high activity at low dosage, even under hyperlipemic conditions, whereas clofibrate is only slightly effective. From pharmacological results it can be suggested that the nature of acid group substituent is the main factor for efficacy, while the role of alpha-substituent is important for differentiation of activity against cholesterol and/or triglyceride.


Microbiologic and pharmacologic properties of a new ampicillin derivative: Ampicillin-guaiacolsulfonate. Ampicillin-guaiacolsulfonate, a new derivative of ampicillin, preserves the antibacterial properties of ampicillin, is suitable for infection owing to its good water solubility and it has far higher stability in dry state than has sodium ampicillin. Ampicillin-guaiacolsulfonate is better orally absorbed in rabbit than is ampicillin. In vitro experiments carried out with the model system by Rosano and Schulman, and measurements of the intestinal absorption in the everted sac jejunal preparation, carried out with 14C-labelled compounds, demonstrate that the new ampicillin derivative is better absorbed by the intestine because of an increase in the intestinal permeability of the molecule itself.


Relation between structure and cholinergic activity. II. Synthesis and muscarinic activity of some sulfur analogs of 2-methyl-4-trimethylammoniomethyl-1,3-dioxolane-iodide. The synthesis of 2-methyl-5-trimethylammoniomethyl-1,3-oxathiolane and some homologs are described. The stereochemical aspects are discussed on the basis of the NMR-spectra. The muscarinic activity of the oxathiolane is compared with the activities of the corresponding dioxolane and dithiolane.


[Rodenticidal action of warfarin/4th communication: Binding to serum albumin of mice and rats (author's transl)]. The binding properties of 3-(1'-phenyl-2'-acetylethyl)-4-hydroxycoumarine (warfarin-Na) to serum albumin of mice and rats were determined by using the equilibrium dialysis. The binding percentage (beta), the binding capacity (K), and the association constant (K1) were calculated. The results are characteristic for a strong binding of warfarin to serum albumin of rats but only a small one to serum albumin of mice, caused probably by the different albumin structures of these species.


Protein binding of flavoxate and of 3-methylflavone-8-carboxylic acid. The protein binding properties of piperidino-3-methylflavone-8-carboxylate (flavoxate, F) and of its main metabolite, i.e. 3-methylflavone-8-carboxylic acid (M), were investigated by dialysis-equilibrium technique. During the dialysis, F hydrolyzes to a notable extent into M. Therefore a true equilibrium of F could not be obtained. With this limitation, the results show that F has a small protein affinity. The protein binding properties of M were separately investigated with bovine albumin, human albumin and with human, rat, rabbit and dog plasma. The Freundlich's isotherms, which describe the affinities of albumin to M, were calculated. They show that unconjugated M, possibly present in plasma, is by 99.5% in a protein-bound form.


Synthesis and pharmacological properties of some 1-aryl-4(1H)-pyrido(2,3-d)pyrimidones. Some 1-aryl-4(1H)-pyrido[2,3-d]pyrimidones were synthesized from the corresponding 2-anilinonicotinamides by cyclization with triethyl-orthoformate. This series of compounds is a new one with interesting antiinflammatory and hypno-sedative properties.


Inhibition of cholinesterase by 5-hydroxytryptamine. On the basis of structural relationships between 5-hydroxytryptamine (5-HT, serotonine) and eserine, the effect of 5-HT on partially purified brain cholinesterase (ChE) was studied. The addition of 5-HT to brain ChE in vitro resulted in its inhibition, and the constants characterizing this inhibition, namely, the inhibition rate ki (5.44 X 10(2) mol-1/l - min-1), the equilibrium constant K (1.86 X 10(-3), and the rate constant for spontaneous reactivation kr (1.01 min-1) were determined. The inhibition of AChE by 5-HT in vitro was found to be of the competitive type.


Fenfluramine and 5-hydroxytryptamine?. Part 1: Is fenfluramine or norfenfluramine involved in the decrease of brain 5-hydroxytryptamine. Both fenfluramine and de-ethylated fenfluramine decrease the brain stores of 5-hydroxytryptamine (5-HT). As the fenfluramine metabolite is present in the brain of the rat after fenfluramine injection, it could be suggested that the depletion of brain 5-HT elicited by fenfluramine is mediated by its metabolite. Comparative studies on 5-HT lowering effects and drug brain levels, indicate a primary effect of fenfluramine, following by the rising involvement of the de-ethylated compound in the sustained effect.


Effect of nialamide and reserpine on brain free amino acids of rat dependent on and withdrawn from morphine. The brain free amino acid levels were estimated in rats dependent on and withdrawn from morphine. The effects of nialamide and reserpine on the levels of brain free amino acids were investigated during the development of physical dependence on morphine and after the abrupt withdrawal of morphine. The relationships between brain free amino acid levels, and physical dependence and withdrawal syndrome, the relationships between the degree of the manifestations in abstinence under the effects of nialamide and reserpine, and the changes in brain amino acid levels are discussed.


[Animal experiments on the effect of triamterene and amiloride on heart and circulation and the toxicity of digoxin (author's transl)]. 1. In anesthetized cats 2,4,7-triamino-6-phenyl-pteridine (triamterene) (5 mg/kg i.v.) causes a short-lasting increase in blood pressure, a decrease in heart rate, whereas the contractility (see article) remains unchanged. N-Amidino-3,5-diamino-6-chloropyrazinecarboxamide (amiloride) (5 mg/kg i.v.) causes a fall of blood pressure, an increase in heart rate, and an increase in contractility. 2. In cats the i.v. toxicity of digoxin is diminished by pretreatment with triamterene or amiloride; the arrhythmias and the cardiac arrest are significantly delayed in the course of an infusion of digoxin. In guinea-pigs a pretreatment with triamterene only delays the arrhythmias but not the lethal effect of digoxin or g-strophanthin. 3. In the isolated atria of the guinea-pig triamterene and amiloride (5 mug or 50 mug/ml) lowers the rate of contraction and prolongs the functional refractory period. The force of contraction is increased by triamterene and diminished by amiloride.


[The effect of atenolol on contractility and hemodynamics of the infarcted heart in comparison to propranolol and practolol (author's transl)]. In animals without myocardial infarction the new beta-sympathicolytic agent atenolol (4-[2'-hydroxy-3'-iso-propylaminopropoxy]-phenyl acetamide, ICI 66 082) dose-dependently decreased heart rate, systolic aortic pressure and cardiac output. Coronary mean flow, coronary resistance, stroke volume, left ventricular enddiastolic pressure and total peripheral vascular resistance did not change significantly. Atenolol significantly reduced myocardial contractility, expressed by (dp/dtmax), Vpm, t-(dp/dtmax) and pre-ejection period. Furthermore, the comparative studies in animals with myocardial infarction and concomitant reduced cardial efficiency revealed, that atenolol has neither a positive intrinsic activity as has practolol nor a negative intrinsic activity as has propranolol. The dose-contractility relation of atenolol resembles that of practolol: in low dosages a strong decrease is achieved, in higher dosages no further reduction of the contractility parameters is observed. Because of the strong negative inotropic and blood pressure lowering effect it is suggested to use atenolol only with great caution in patients with reduced cardiac efficiency.


[Effect of pentoxyfylline on the organ distribution of 47Ca and on intestinal Ca absorption and secretion in the rat (author's transl)]. The influence of 3,7-dimethyl-1-(5-oxo-hexyl)-xanthine (pentoxyfylline, Trental) on organ distribution of 47Ca and on intestinal Ca absorption and secretion was studied in rats. Oral application of 4 mg/kg bodyweight pentoxifylline was followed after 30 min by a significantly higher accumulation of orally applied 47Ca in the intestinal wall as compared to untreated controls, while in other organs the 47Ca activity was lower than in control animals. When 47Ca was given i.p. and pentoxifylline at the same dose was applied orally 24 h later, there was no difference in organ distribution of 47Ca between treated rats and untreated controls after 30 min. There was likewise no difference in serum Ca concentration. On the other hand, i.v. infusion of 20.8 mg/kg bodyweight pentoxifylline was followed by a significant fall of serum Ca. At the same time, there was a significant reduction of intestinal Ca net absorption, as demonstrated by the intestinal perfusion technique, while Ca net secretion was not influenced. The possible mechanisms causing the pentoxifylline induced reduction of serum Ca concentration are discussed.


[Cardiovascular effects of glycerol-1-(2-diethyl-amino-ethylether)-3-(2-methoxyphenylether) in the anaesthetized cat (author's transl)]. The cardiovascular effects of a new antiarrhythmic drug derived from the local anaesthetics glycerol-1-(2-diethylaminoethylether)-3-(2-methoxyphenylether) (Brufacain), was examined on 10 anaesthetized cats and compared in parallel experiments to alpha-diethylamino-acetate-2,6-xylidide (lidocaine). The following parameters were determined: 1. ventricular fibrillation threshold, 2. ECG, 3. systolic and diastolic blood pressure, 4. cardiac output. Both agents increased the ventricular fibrillation threshold: Brufacain and lidocaine led to a significant deviation up to 50 min after the end of the infection. In the ECG the P-P distance after 10 and 20 min for Brufacain and after 20 min for lidocaine was significantly prolonged. The ECG showed for lidocaine a shortening of the QRS complex after the 40th min and for Brufacain initially a Q-T prolongation, both with statistical significance. A significant increase in blood pressure was noted 30 and 40 min after the injection of Brufacain. Lidocaine caused a significant decrease in blood pressure beginning 10 min after the injection. The cardiac output was significantly decreased 10, 30, 50 and 60 min after administration of Brufacain and 10 and 40 min after administration of lidocaine.


Bis-(p-hydroxyphenyl)-pyridyl-2-methane: The common laxative principle of Bisacodyl and sodium picosulfate. After both oral and rectal administration in humans (4,4'-diacetoxy-diphenyl)-(pyridyl-2)-methane (bisacodyl, Dulcolax) and 4,4'-(2-pyridyl-methylene)-diphenol-disulfuric acid semiester disodium (sodium picosulfate, Laxoberal) are hydrolyzed to bis-(p-hydroxyphenyl)-pyridyl-2-methane (BHPM). In both cases BHPM is responsible for the laxative action. Experiments in rats and guinea pigs have shown that the hydrolysis of picosulfate, in contrast to that of bisacodyl, is attributable to the microorganisms of the intestinal flora.


The effect of brocresine (NSD-1055) on basal and stimulated gastric acid secretion in chickens. The effect of the histidine decarboxylase inhibitor 4-bromo-3-hydroxybenzyloxyamine-dihydrogenphosphate (brocresine, NSD-1055) on basal and histamine-, pentagastrin- and carbachol-stimulated gastric acid secretion was investigated in unanaesthetized gastric fistula chickens. Basal secretion was initially reduced by brocresine for 45 min and then slightly stimulated for 90 min. The histamine stimulated gastric secretion was competitively inhibited by brocresine. The acid response to low doses of pentagastrin and carbachol was enhanced, that to high doses unchanged. The results can be explained in the light of the assumption that a metabolic product of brocresine, 3-hydroxy-4-bromo-benzyl-alcohol stimulates gastric acid secretion.


Pharmacological properties of 2-(2-chloro-p-toluidino)-2-imidazoline-nitrate (tolonidine), a new antihypertensive agent. II. Action on cardiac contraction, circulatory parameters, autonomic receptors and diuresis. Tolonidine, 2(2-chloro-p-toluidino)-2-imidazoline-nitrate, is a substance chemically related to clonidine. In the anesthetized dog, tolonidine administered i.v. decreased the amplitude of ventricular contractions, reduced aortic blood flow and increased peripheral vascular resistances. In the bivagotomized pithed rat, tolonidine induced a long-lasting increase in blood pressure with no secondary hypotension, thus suggesting peripheral sympathomimetic properties, however, contractions of seminal vesicles in vitro were not obtained. The product proved to have no peripheral sympatholytic or parasympatholytic properties. In the dog and the rat, diuresis was hardly changed. These properties are closely related to those of clonidine, which was studied comparatively. A general discussion is proposed at the end of a third article.


[Placental transfer of psychotherapeutics of the thioxanthene type (author's transl)]. The hitherto existing investigations on the placental transfer of psycholeptic drugs mostly do not answer the question whether the active compounds themselves or their metabolites or both get into the fetus. As published informations on this problem partly are contradictory the placental transfer of psycholeptic drugs was investigated with the thioxanthenes flupentixol and chlorprothixen for examples. After oral application to rats on the 15th and 20th days of gestation the intact thioxenthenes themselves as well as their sulfoxides and desalkylated metabolites were detectable in placenta, uterus and fetus. The last mentioned substances and the intact thioxanthenes were determined quantitatively. The concentration (mug/g tissue) in the fetus is lower than in uterus and placenta. The results are discussed.


Concentrations of ampicillin in human urogenital tissue, serum and urine after intake of pivampicillin. The ampicillin concentrations in serum, urine, kidney, urinary bladder, prostate gland, testis, muscle and skin from 64 urological patients with normal renal function were determined with the agar diffusion method after oral doses of 700 mg of the pivaloyloxymethyl ester of ampicillin (pivampicillin, Pondocillin). The tissue samples were obtained at urological operations, prostatectomy, nephrectomy and orchiectomy. The serum concentration was highest between 2 and 4 h and the urine concentration between 4 and 6 h after intake. The serum concentration was considerably lower than reported in literature, which was shown to 0e due either to the effect of preoperative medication or anesthesia, or to both.


[Advantages of the initial therapy of acute schizophrenia with large doses of droperidol/A comparative study (author's transl)]. The treatment of acute schizophrenic disorders with large doses of droperidol was compared to clozapine and clopenthixol in a special study. Apart from the clinical protocol, psychometric test for the assessment of social behaviour and thought disorders were used. The advantages of the treatment with droperidol, especially in highly disturbed acute schizophrenic patients, are shown and discussed by means of the results of psychological tests and clinical experience.


An appraisal of lumbar epidural blockade in labour in patients with multiple pregnancy. A series of 102 patients with a multiple pregnancy (including three sets of triplets) delivered vaginally is presented. An epidural block was provided for 55 of these patients, and comparisons were made between these patients and those who did not have an epidural block. There was a higher incidence of low Apgar-minus-colour (A-C) scores at one minute among the second twins of at least 36 weeks gestation in the epidural series, but no other remarkable contrasts in the (A-C) scores of the respective group of infants. In the non-epidural series two second twins of at least 36 weeks gestational age apparently suffered severe cerebral trauma. Of the 91 liveborn infants in the non-epidural series, five died (two with intracranial haemorrhage, three with hyaline membrane disease); of the 112 liveborn infants in the epidural series, two died (both with hyaline membrane disease). The incidence of instrumental delivery of infants presenting by the vertex, and of breech extraction, was markedly higher in the epidural series. The mean interval between full dilatation of the cervix and delivery of the first twin was greater in the epidural series, but the mean interval between delivery of the first and second infant was smaller in the epidural series. It is concluded that the provision of an epidural block for labour and delivery to patients with a multiple pregnancy is beneficial to the infants.


[Non-identical subunits of 7S globulin (gossipulin-1) from cotton seeds]. 7S globulin is isolated from cotton seeds and is designated as "Gossipulin-1". Three different amino acids (glycine, aspartic acid and leucine) are found to follow the N-terminal amino acid which is indicative of a non-identity of its subunits. Gossipulin-1 dissociated in 0.1 M HCl, depending on the time of incubation, into 3.87, 2.39 and 1.35 subunits. It had a sedimentation constant of 0.37S in alkaline medium and of 1.24S on 8 M urea. A sedimentation peak of 1.1S was discovered in reduced and alkylated Gossipulin-1.


Studies of cellular proliferation in human leukemia. VIII. The generation time and growth fraction in lymphosarcoma in a leukemic phase during advanced and early relapsing disease. The kinetics of cell proliferation were studied in a patient with lymphosarcoma in a leukemic phase both before treatment when the disease was very advanced and again at the earliest sign of bone marrow relapse following a drug-induced remission. During advanced disease, the pulse 3H-TdR labeling index (LI) was 11%, the mitotic index (MI) was 0.4% the growth fraction (GF) was 0.6, and the generation time (TG), as measured by the median grain count halving time, was estimated to be 160 hours. The patient went into remission for 25 days after a short course of therapy with prednisolone and arabinosylcytosine (Ara-C). During early relapsing disease, the LI was 17%; MI, 1.1%; GF, 1.0; and TG, 85 hours. The results of this study suggest that the rate of cell proliferation slows in leukemia as the tumor mass increases in volume, and that the slower growth is due to an increase in cell generation time, a decrease in the growth fraction, and an increased rate of spontaneous cell loss.


Vincristine-induced myocardial infarction. A patient with lymphosarcoma treated with weekly injections of vincristine developed an acute myocardial infarction immediately after the second injection of vincristine. After he recovered from the infarction, the treatment was continued and he developed an additional myocardial infarction. In vivo and in vitro studies have not revealed any effect of vincristine on the clotting mechanism. The possible causes for the association of vincristine-treated lymphoma and myocardial infarction are discussed.


Non-hodgkin's lymphoma in children. Correlation of CNS disease with initial presentation. The clinical and histopathological findings in 26 children with non-Hodgkin's lymphoma without initial marrow involvement are reviewed. A marked male predominance similar to that observed in previous series was noted. Biopsy material was classified according to the recommendations of Rappaport in 22 cases. All have diffuse lymphomas, and 16 of 22 patients had involvement of the mediastinum as part of their initial presentation. Of these 12, 5 developed lymphomatous involvement of the central nervous system prior to the development of leukemic transformation of the bone marrow. This observation suggests that prophylactic therapy against CNS relapse be considered for children with mediastinal non-Hodgkin's lymphoma, even in the absence of initial marrow involvement.


Studies of trachoma in families on Taiwan. This study was undertaken to clarify the natural history and pathogenesis of trachoma. A group of families who live in a formerly trachoma hyperendemic area of Southern Taiwan were placed under continuous surveillance. The development in recent years of the micro immunofluorescence test for trachoma antibody, along with improved cell culture isolation methods, have allowed this surveillance to include repeated effective laboratory studies in addition to clinical observations. After four years' study  of one group of families and three years of another, a number of interesting findings have been obtained. Evidence is presented supporting our hypothesis that trachoma is a disease of immumopathology and results from repeated reinfections with the trachoma organisms. The clinical findings of papillae, especially those of an acute nature, has been the clinical finding most closely associated with the isolation of the organism and the demonstration of antibody. Evidence is presented that transmission of the organism is usually within the family group. Although only trachoma immunotypes B and C previously had been associated  with trachoma infection on Taiwan, data is presented from one family in which type D infections occurred. While a series of new and reinfections with trachoma organisms were demonstrated in some of the families under observation, the majority of the families not only showed no new infections but showed spontaneous healing or disappearance of clinical and laboratory evidence of trachoma infection. This tendency of active trachoma infection to disappear from a family in the absence of transmission of the organism parallels the rapid fall and prevalence of active trachoma on Taiwan during the past decade.


Indirect hemagglutination test of Rickettsia orientalis: its specificity for reference strains, Karp, Gilliam and Kato. Amberlite XE-64 and bovine serum albumin-treated rickettsia suspension, which was prepared from the chicken yolk sacs infected with each of 3 reference strains of Rickettsia orientalis, Karp, Gilliam and Kato, was sonicated at 10 KC for 15 min at 4 degrees C and centrifuged at 10,000 rpm for 40 min at 0 degrees C. The supernatant was used to sensitize the formalinized and tanned sheep red blood cells (SFTSRC). This antigen (2.5%) could be preserved for at least 1 wk at 4-8 degrees C and at least a month, if merthiolate (1:10,000) was added. Each SFTSRCP of 3 reference strains was found to be specific in indirect hemagglutination (IHA) reaction with each homologous immune serum and there was little cross reaction with the heterologous one. This minor cross reaction might be due to the presence of a small amount of soluble antigen in SFTSRC. No cross IHA reaction with the typhus fever immune serum was observed. The IHA test was considered to be useful for the diagnosis of scrub typhus.


Scanning electron microscopic studies on the external morphology of Azotobacter vinelandii during encystment and germination. Aspects of the external morphology of Azotobacter vinelandii cells during encystment and germination processes were observed with scanning electron microscopy. Most of the vegetative cells have a smooth surface but some have warty surfaces. The intact cysts have wrinkled surfaces and occasional small heaves. Mucoid materials are present on the surface of the cysts. During the encystment process, an extensive peeling-off of coat materials was noted, then the excretion and aggregation of new capsular materials was immediately followed. The germination process was initiated by an expansion of the central body (the cell), then the emerging of this cell from the cyst coats was observed.


Studies on the Monascus isolated from the startor of Kaoliang Brandy. Seven strains of Monascus spp. were isolated from the startors of Kaoliang Brandy in Taiwan and Kinmen. Their morphological, physiological, and biochemical characteristics were examined. Shape of colony, length of conidial chain, production of pigment and tolerance to NaCl were considered to be suitable keys to the classification of these isolates. It was found that there were at least 6 species of Monascus in the startors of Kaoliang Brandy, 2 from Kinmen and 4 from Taiwan.


Parasitological studies at a new breeding area of Oncomelania hupensis chiui in Taipei county, Taiwan. Oncomelania hupensis chiui was found at the Jui-Ping area, Linkow District, Taipei County, Taiwan, which is located on the north coast of the island approximately 10 km of the mouth of the Tamasui River. The habitat of the snails at this area is similar to the type locality at Alilao, on the slope of the hills along of coast. The snails from this new breeding area, are similar to the Alilao snails, and are highly susceptible to the infection with geographic strains of Schistosoma japonicum including the Changhua, Ilan, Japanese, Philippine and Chinese strains. Examinations of 7,758 snails and intradermal tests on 736 inhabitants along with stool examinations of 622 people indicated that there was no evidence of the presence of Schistosoma japonicum at this area. Results obtained from stool examination demonstrated high prevalence of hookworm infection (53.4%) and relatively low infection rates of Asearis lumbricoides (37.0%) and Trichuris trichiura (14.1%). The protozoan infections were low in general. A single Scotch-tape technique for Enterobius vermicularis among 499 school children yielded a 55.7% infection rate.


Trachoma organisms: technical advances in laboratory diagnosis. New knowledge of the microbiology and immunology of Chlamydia is reviewed. New serological and isolation methods for diagnosis of Trachoma infection are described. Results of studies of ocular and genital Trachoma infection utilizing these new techniques are presented.


The genital mycoplasmas: serological inquiries. Serological studies on the genital mycoplasmas (U. urealyticum and M. hominis) are briefly reviewed. Newly developed serological tests from our laboratory have been applied to the studies of mycoplasma strains and antibody responses in patients. The data indicate that genital mycoplasmas are serologically diverse, with at least 11 serotypes of U. urealyticum and 7 of M. hominis. No one serotype predominates in relation to any known association with illness. However, serological and cultural data indicate a strong link between genital mycoplasmas and perinatal morbidity and mortality.


Inhibition of measles virus replication and enhancement of cellular DNA synthesis in vero cells by ribavirin, an antiviral and antineoplastic drug. Excellent in vitro inhibition of measles virus infectivity by ribavirin was detectable by a tube method allowing prolonged maintenance which makes possible the evaluation of efficiency at daily intervals. Optimal efficiency occurred on day 5 to 7, depending on the drug dose. Although syntheses of cellular RNA and protein were inhibited by low drug dosage, the de novo DNA synthesis was enhanced. Peak 4-fold enhancement resulted with 320 mug/ml after 2 days treatment.


Histopathological and immunological studies of nasopharyngeal carcinoma. From 1968 to 1973, 793 cases of nasopharyngeal malignancies in Japan were examined histopathologically and immunologically. The majority of the carcinomas were undifferentiated squamous cell carcinomas, including transitional cell carcinoma and lymphoepithelioma. These findings correspond well with those of other countries. There were more well differentiated carcinomas in the old than in the young age groups. The positive rate (80%) and the geometric mean of the anti-VCA-antibody titers (more than 1:750) were remarkably high in the lymphoepithelioma group. These two factors seem to be very important to the study of oncogenesis of nasopharyngeal carcinoma (NPC). The relationship between subpopulations of peripheral lymphocytes in NPC and histopathological classification was investigated. The lymphoepithelioma group had a higher proportion of B cells (complement receptor cells) to T cells (erythrocyte rosette forming cells) than healthy persons throughout the clinical course, and its prognosis was not good.


An electron microscopic study of the structural polymorphism of hepatitis B antigen from human sera. The physical features of hepatitis B antigen (HBAg) particles from human sera are investigated with electron microscopy and immune electron microscopic technique. All the virus-like particles are pleomorphic in structure; although they are classified into two categories: HBsAg and HBcAg by immunological technique. The small, spherical particles measured in a range of 16 to 30 nm in diameter, mostly 20 to 22 nm,are populous in the positive serum. The tubular particles have the width of 18 to 22 nm and the length of 50 to 230 nm or even longer. Sometimes these particles contain a larger end and become the tadpole shape. The large particles or Dane particles measured mainly 42 nm in diameter have an inner core and the outer coats. The inner core of 27 nm in diameter can expose spontaneously. It can be released from the coats by heating at 56 degrees C for 30 min or by treatment of Tween 80 (1%) at room temperature. When specific antibody is added in the positive sample, the aggregate of the antigen-antibody clumping can be revealed with electron microscope. The core antigen of the large particles may attach to the molecular protein of the antibody and show the spike-like structure. This polymorphism of HBAg particles seems unique in animal virology. The roles of these particles played in medical and virological fields are discussed.


Blindness in Mentally Retarded Children. A survey of the causes of blindness in 201 notified patients. A preliminary survey of the causes of blindness in mentally retarded children in Denmark showed that 50% of the children had optic atrophy, 12.5% had cataract while tapeto-retinal degenerations, other malformation and retrolental fibroplasia each represents 8-9% of the causes of blindness. The survey, was done through written notification and some patients with tapeto-retinal degenerations might have been wrongly diagnosed.


Venereal disease prevention and a selected group of college students. This study was designed to discover the knowledge, attitudes, and practices of a selected group of undergraduate college students relative to individual venereal disease protective/preventive measures. A population of 373 students were drawn from two large, state-supported universities in the midwest. The investigation was conducted to provide base line data for medical personnel and health educators to consider when educating young adults about the prevention of venereal disease infection. The findings revealed the existence of desirable, as well as undesirable knowledge, attitudes, and practices with implications for education.


[Research on the modalities and mechanisms of toxic action of organochlorine insecticides. II. Long term toxicity effects of DDT in hamsters]. 18 months DDT feeding showed no carcinogenic potentiality in hamster even with the dose of 1 g/kg of DDT in the diet.


A venereal disease knowledge evaluation instrument. The purpose of this study was to develop a valid, reliable test to measure the knowledge of elementary school teachers about venereal disease. Recommended scientific test construction procedures were carefully followed. These included the development of a content outline and a table of specification; submitting potential test items to a review panel; revision of items and initial administration of the test; item analysis, revision, and a second administration; and the item analysis and revision which resulted in the Schmidt VD Knowlege Evaluator. This test consists of 45 multiple-choice items related primarily to syphilis and gonorrhea with some items related to the other venereal diseases. Test construction procedures assure face validity and the Kuder-Richardson formula estimates reliability to be 0.79. The instrument would be useful as a pre-test and/or post-test for inservice programs, workshops, and seminars for teachers, school nurses, or any similar group.


Effect of fermented (butter milk) food on fibrinolytic activity. Effect of one day fermented milk (butter milk) was studied in 18 medical students between 18 to 20 years of age. Results showed that there is a significant decrease in fibrinolytic activity two hours after giving butter milk and the effect persists even at the end of six hours.


Early childhood psychosis and bleeding during pregnancy. A prospective study of gravid women and their offspring. Children with infantile autism and childhood psychoses were identified in the National Institute of Neurological Diseases and Stroke Collaborative Perinatal Study. They were matched with two control groups one of normal-IQ and the other of low-IQ children. Perinatal data, which had been collected prospectively, were then rated blindly. The relationship between uterine bleeding in mothers and their subsequently delivered children, who developed the syndromes of autism and childhood psychosis, was found to be significant. Mid-trimester bleeding was especially prevalent. The bleeding was usually minor and was not considered to be clinically significant at the time of occurrence. The results tend to corroborate 12 previously published retrospective reports indicating more perinatal complications in children who develop autism and childhood psychosis.


Minor physical anomalies in normal, neurotic, learning disabled, and severely disturbed children. A high incidence of minor physical anomalies in a childhood schizophrenic population has been previously reported by Goldfarb. In the present study, 108 boys from four different clinical populations were examined, utilizing a standardized anomaly scoring system for which a high interrater reliability was obtained. The patient populations were: general pediatric ward patients (n = 31), psychoneurotic outpatients at a university child guidance clinic (n = 26), learning diabled children (n = 23), and autistic, borderline, and atypical children (n = 28) from two residential treatment centers. Both the learning disabled and residential treatment populations had higher mean anomaly scores than did the first two groups, but did not differ significantly from each other. There was a trend for patients with multiple anomalies to have had more frequent history of prenatal insults or paternal psychopathology. These results indicate that the development of these minor anatomical anomalies which are formed in the first three months of fetal development may parallel early developmental deviation of the central nervous system. The finding of high anomalies in the residential treatment groups supports the idea that some of these patients share a common etiology with the other early developmental deviations, such as speech delay or mental retardation, for which high anomaly scores have also been reported.


Prognostic antecedents and outcome in a follow-up study of children with a diagnosis of childhood psychosis. Records of the initial period of observation and the early history of 59 children with a diagnosis of childhood psychosis during the preschool years were examined for possible predictive variables. The children, now age 10 years or older, were divided into two groups--those that are presently successful and those that are presently unsuccessful, according to the criteria of this study. A cluster of 23 items was found significantly to differentiate the two groups.


Language patterns of adolescent autistics. The language samples of seven verbal autistic adolescents were analyzed. Linguistic deficits were compared to characteristics reported for preteen autistics and described structurally. Only four subjects demonstrated linguistic impairments. These clustered primarily in the area of prosodic features, semantic cooccurrence constraints and general disfluency. No such clustering had been reported for the preteen population. No correlation between linguistic deficits, IQ, and age was found. However, performance on the Seashore Test for Musical Ability correlated highly with linguistic performance. Results suggest that (a) autism includes liguistically, and possibly etiologically, distinct subtroups; (b) the basic linguistic deficits in autism may be more specific than thought previously; and (c) perception of prosodic features may be crucial for decoding and encoding linguistic signals. Autistic children may be lacking in this ability.


Systematic observation of play behavior in autistic children. The play behavior, defined as interaction with peers and objects, of five autistic children was systematically observed in four environments, i.e., a stark environment, a theraplay unit, a playroom, and an outside play deck. The preliminary results suggested that (1) with some children environment has little or no effect on their play behavior; (2) with multiple objects, autistic children frequently related to the objects rather than to their peers; (3) object play was most frequently at the manipulative stage and often included repetitive and negative behavior; (4) within a confined space with no objects present, autistic children frequently engaged in solitary repetitive behavior; and (5) within a confined space designed to facilitate a movement flow (theraplay), autistic children modeled and imitated and were involved in gross motor play together.


Serum diiodotyrosine.

Serum diiodotyrosine. Serum diiodotyrosine (DIT) was measured by radioimmunoassay in healthy subjects patients with thyroid disease and a variety of laboratorty animals. Ninety-two healthy adults had a mean level of 101 ng/100 ml. There was no sex difference in DIT  levels but DIT fell with aging. There was no change with short term oral SSKI administration. Athyrotic subjects had measurable but reduced levels (mean = 52 ng/100 ml). Hyperthyroid subjects had levels slightly, but not significantly, higher than controls (mean = 149 ng/100 ml). Treatment of hyperthyroidism was followed by a small but significant fall in DIT levels, but there was no change in DIT levels with thyroid hormone therapy of hypothyroidism. A large species variation in serum DIT levels was found among laboratory animals with mean levels ranging from 17 ng/100 ml in mice to 428 ng/100 ml in dogs.


Convenient, simplified preparation of less commonly used media. A method is described for the preparation of some less commonly used media. This approach should encourage use of these media.


Analysis of the role of endogenous prolactin on fluid and sodium chloride absorption by the rat jejunum. Intestinal absorption of fluid and NaCl in rats is significantly decreased after hypophysectomy and increased in rats with pituitary implants. Oestrogen and reserpine significantly stimulate mucosal fluid and NaCl transfer in both normal and adrenalectomized rats, comparable to the effects of administration of prolactin. In intact rats, ergocryptine enhanced intestinal absorption of fluid and NaCl; however, it failed to exert any effects in adrenalectomized rats. Adrenalectomy alone had no adverse effects on intestinal absorption in saline-compensated rats. The administration of corticosterone alone or together with prolactin significantly enhanced intestinal absorption, although the effect of corticosterone alone was more variable. These data strongly suggest that increased endogenous prolactin levels produce stimulatory effects on intestinal absorption of fluid and NaCl by the rat jejunum.


Influence of reproductive state on intestinal fluid and ion transport by the rat jejunum, in relation to the possible contribution of prolactin. Mucosal fluid, sodium and chloride transfer by the rat jejunum was higher at pro-oestrus and oestrus than at dioestrus. Prolactin enhanced intestinal absorption in dioestrous but not in oestrous rats. Ovariectomy had no significant effect on fluid and sodium absorption but resulted in increased chloride absorption. Oestrogen treatment, however, stimulated fluid and sodium transport without affecting chloride absorption in ovariectomized rats. In contrast, progesterone had no influence on fluid and sodium transport but inhibited chloride absorption. Intestinal absorption of fluid, sodium chloride, potassium, calcium and magnesium was significantly increased during pregnancy and lactation. The limited effect of 2-Br-alpha-ergocryptine in depressing intestinal absorption of fluid and NaCl in both pregnant and lactating rats suggests that hormones other than prolactin are also involved. Lactating rats not suckled for 24 h, or subjected to reduction in the number of pups from eight to three, did not show major changes in intestinal absorption of fluid and NaCl. The present data suggest that increases in intestinal transport during oestrus, pregnancy and lactation are attributable to hormonal changes to which prolactin may make an important contribution.


The incorporation of carbon dioxide into the major classes of RNA during culture of the preimplantation mouse embryo. The fixation of CO2 into major classes of RNA in the mouse embryo was studied in culture. Total fixation of CO2 was low at the two-cell stage and no label was found in RNA. Between the eight-cell and morula/early blastocyst stages of development, total fixation increased markedly but decreased again at the late blastocyst stage. On a per cell basis, the level of incorporation of CO2 decreased steadily throughout the preimplantation period. A significant acceleration in the accumulation of 14CO2 into all classes of RNA occurred between eight-celled embryos and morulae/early blastocysts, and this effect was more evident when results were calculated in relation to cell number. At the late blastocyst stage, incorporation of label into RNA decreased on a per embryo and a per cell basis. Most of the label from CO2 was incorporated into the r-RNA fraction at all stages of development and incorporation into s-RNA was always less. The pattern of labelling of RNA with 14CO2 was similar to that previously obtained for the incorporation of [3H]uridine into embryonic RNA, suggesting that most of the CO2 entering the RNA pool may be incorporated into nucleotide bases. The s-RNA and r-RNA fractions were susceptible to digestion with both pancreatic ribonuclease and 0-3 M alkali. Approximately 31% of the label in the TD-RNA fraction remained after hydrolysis with ribonuclease and a similar proportion of the TD-RNA was resistant to alkali treatment. Incorporation of CO2 by morulae/early blastocysts was substantial during culture in substrate-free medium but was increased significantly in medium containing lactate plus pyruvate. Carbon dioxide fixation into RNA was decreased by preculture for 48 hr before incubation in radioactive medium. When compared with freshly collected morulae/early blastocysts, the proportion of the total label in the s-RNA fraction of precultured embryos was low, and a correspondingly greater proportion of the total label was found in the TD-RNA fraction.


A technique for obtaining scanning electron micrographs in colour. A digital electronic unit is described which, by modifying the video signal of the scanning electron microscope (SEM), permits the selection of images in separate tonal or grey-scale levels. By the sequential exposure of these grey levels onto colour film with the intervention of colour filters, coloured scanning electron micrographs have been obtained. Full details of the procedure are given. The process is applicable to any normal image capable of being displayed at the scanning electron microscope.


Aspects of scanning microdensitometry. III. The monochromator system. Microdensitometric errors can result from various factors associated with the monochromator system, including imperfect monochromaticity of the light, incorrect setting of the wavelength, and non-uniform illumination of either the microscopic field or the objective aperture. Certain types of potential error are characteristic of particular instruments. Thus in the Vickers M85 microdensitometer, where the flying spot is the reduced image of a hole situated at the monochromator exit aperture, the interpretation of results obtained with different spot sizes is complicated by the fact that the hole size affects both the spatial resolution and the spectral bandwidth of the system. Similarly, in instruments in which the monochromator exit slit lies in an aperture plane the numerical aperture of the whole system may be affected by the spectral bandwidth and vice versa. Overall instrumental sensitivity is mainly limited at the blue and red ends of the spectrum respectively by the lamp output and the photomultiplier tube sensitivity. Quartz-iodine lamps are slightly brighter than conventional tungsten sources, especially at short wavelengths, but tend to be less stable photometrically and are more expensive. Simple refracting monochromators and graded-spectrum interference filters in general pass more light, in the visible spectrum, than do grating monochromators of similar bandwidth. Most errors of wavelength setting can be avoided by routinely measuring at that wavelength, lambda(max), found empirically to give the maximum absorbance or integrated absorbance. Off-peak wavelengths can be set reproducibly with the aid of an eyepiece spectroscope, or by adjusting the wavelength so that the absorbance of a given specimen is some precise fraction of that at lambda(max).


The relationship of plastic deformation in freeze-etching to the orientation of a protein particle. Freeze-fracturing of face-centered, cubically packed, intracellular crystals of fraction 1 protein result in two distinct fracture responses of the constituent particles, according to their orientation relative to the plane of fracture. If a square-packed plane is revealed, fracture occurs either between particles or the particles plastically deform. Conversely, if a hexagonally-packed plane is revealed, fracture occurs either betwen particles or cleanly at internal planes of the particles, without any plastic deformation. It is proposed that this information may be of value in determining the arrangement of the axes of the covalently bound polypeptide protomer chains which constitute the oligomer.


Determination of the principal distance and the location of the perspective centre in low magnification SEM photogrammetry. The principal distance, D, from the centre of perspective in the SEM optical projection to the tilt axis of the specimen stage must be accurately determined before photogrammetric evaluation of stereoscopic pairs of micrographs can proceed. A precise procedure for measuring D is described in which the specimen stage X micrometer is used to measure the width of the field scanned for a particular width of the CRT, when the specimen stage is moved along the electron beam axis by amounts measured with the stage Z micrometer. The Z micrometer is calibrated with an external dial gauge. A plot of field width against Z extrapolated to zero gives the location of the perspective centre. In SEM photogrammetry, it is usual to leave the lens currents unchanged whilst recording the stereo-pairs. The values of D measured with a constant final lens current show that the perspective centre is located close to the final aperture in its conventional position. Previous determinations of D for Stereoscans have used a changing lens current to keep the specimen in focus at varying Z, and found a virtual centre several millimetres above the final aperture. The value of D so obtained should only be used if the micrographs were recorded with dynamic or automatic focusing systems.


[Are lysosomal enzymes involved in regulation of cell proliferation? (AUTHOR'S TRANSL)]. An activation of cell growth is affected by the addition of proteolytic enzymes to cultures of normal cells. A stimulation of integration of thymidine or guanosine into the nucleic acids, and a phosphorylation of histones resulted after protease treatment of cells and also of resulted after protease treatment of cells and also of isolated nuclei. Proteases are present in the lysosomes, among them also some whose maximal activity is in the region of pH 7. Lysosome preparations cause a stimulation of incorporation of nucleotides into the nucleic acids of cells in vitro and an increase in proliferation. It has been possible to demonstrate that the blastic transformation of lymphocytes can be activated by proteolytic enzymes, and that various inhibitors of proteolytic enzymes can check the activation, independent of the kind of blastogenic factor used. All blastogenic factors seem to produce an extrusion of lysosomal enzymes. Various authors reported an inhibition of lymphocyte-transformation by substances which stabilize the membrane of lysosomes. During the past 50 years reports were repeatedly published stating that malignant tumors yield proteolytic enzymes, which also may induce fibrinolysis. An increasing number of publications have recently been reported about the emission of a plasminogen-activating factor originating from virally transformed cells. Although the dependence of this effect on virus-infections could not be confirmed in all cases, it seems to be established that malignant or transformed cells release considerably more enzymes out of the lysosomes into the plasma and into the surrounding fluid than the corresponding normal cells. One should take into consideration that leakage of lysosomal membranes could be one of the causes of the increased proliferation of the majority of malignant cells.


[The diagnostic and prognostic significance of epithelial blood group isoantigens in carcinomas and polyps of the colon (author's transl)]. Blood group isoantigens (BG) were detected in carcinomas and polyps of the colon and were related to the degree of differentiation, the histologic type, the age of the patients and the histologic signs of malignancy. 1. BG were found in 60-70% of colon carcinomas regardless of their differentiation. 2. BG-positive carcinomas were less often surrounded by lymphocytes and plasma cells than BG-negative ones. 3. BG were present in colon polyps as mucusassociated and as membrane-associated antigens depending on the differentiation of the cells. Hence, BG-activity can be regarded as additional criterium to assess objectively the differentiation of the tumor cells in a polyp. 4. The percentage of BG-positive polyps increased with dedifferentiation. 5. Polyps with foci of malignant degeneration were consistently BG-positive. 6. Villous polyps contained BG more often than the adenomatous ones. 7. The results support the concept that both villous and adenomatous polyps of the colon are precancerous lesions.


Investigation of cell-vitality in tumor specimen after cryosurgical operations. Carcinomas of the gastro-intestinal tract were resected in 6 patients either by cryosurgery or in the usual, conventional manner without freezing the tumor. Cells from the tumorsections in each case were isolated by the use of enzymes and were examined for vitality following trypan-blue vital staining. In 5 out of 6 cryosurgical cases fewer than 10% of the cells were vital compared with sections from nonfrozen specimen. In one case the freezing method (cryosurgery) did not have any influence on the cell vitality. The cell-damaging effect of cryosurgical procedures proven in vitro suggests possible additional therapeutic effects in tumor-patients. Cryosurgery has proven useful in the treatment of hypertrophic prostates, when an unusual risk was involved. Recently it has also been used in the surgical treatment of carcinomas of the skin, the bladder and the cervix (1; 2, 3, 6). Approximately a year ago we started to use cryosurgery in our hospital in inoperable abdominal tumors. After freezing the primary tumor or its metastases a massive breakdown of the remaining tumor in-situ occurs, which might produce a palliative effect. As a result of freezing the tumor before resection, we expect a decrease in the spread of tumor cells during surgery and a stimulation and mobilization of specific immune response against the tumor (5). In order to increase our knowledge of the biological behaviour of cryosurgically treated tumors, we investigated in the present study teh cell-vitality in tumor tissues before and after cryosurgery.


[The effect of various solvents (benzene, toluene, acetone) used with carcinogens on the collagen content of the mouse dorsal skin]. Benzene, toluene and acetone--frequently used as solvents of skin carcinogens--have different effects on the skin collagen of mice: Benzene and toluene lower the collagen content significantly whereas acetone does not. Methylcholanthrene solved in acetone causes a slower collagen decrease and a longer latency period of tumor development as can be observed, when solved in benzene or toluene. This leads to the conclusion, that benzene and toluene have a cocarcinogenic potency.


[Smoking habits and epidemiology of lung cancer in Austria. III. Changes in lung cancer mortality in men]. It has been possible to show that the international trend of a reduced mortality rate in lung cancer of men can also be demonstrated in the Austrian population. By means of cohort-analysis this trend has been attributed mainly to a reduced mortality in younger male population. The improvement in the quality of cigarettes, namely the reduction in the amount of carcinogens and its relation to the reduction of lung cancer death rates will be discussed. At the present time, it is impossible to decide whether or not this reduced mortality rate will remain constant in the future or whether these results may be interpreted as expressing an increased period of latency in pulmonary carcinoma.


Carcinogen and smoke induced early alterations in the Syrian golden hamster respiratory epithelium as revealed by electron microscopy. Syrian golden hamsters were treated once weekly with 0.63 mg B(a)P administered intratrracheally. Another group of hamsters was exposed once daily for one year to the smoke of research cigarettes by means of a smoking machine (Type Hamburg II). Trachea, lobar and segmental bronchi of the animals were examined electron microscopically. The smoke induced epithelial alterations resembled, in many aspects, those caused by a ten week B(a)P treatment.


[Halo Nevus (Morbus Sutton): model of an immunological tumor regression]. Spontaneous regressions of malignant tumors are rare in the history of malignant disease. In malignant melanoma immunological mechanisms were accounted for the regressions observed. By the clinical phenomenon called Halo nevus a benign pigment-cell-tumor is described which shows spontaneous involution. The characteristic feature is the depigmentation of the surrounding uninvolved skin and a centripetal progression of the tumor-regression-phenomenon. In the present study it is demonstrated by histopathological and immunological investigations that lymphocytes are responsible for this tumor-regression. Lymphocyte-reactivity of 16 patients with Sutton's disease in different stages were investigated in the microcytotoxicity-assay against culture-grown melanomatargetcells. In 11 patients a specific cell-mediated immunity against the melanoma cells could be demonstrated in vitro. 5 patients did not show any reactivity, the Halo nevus had been removed by surgery 2 years earlier. The results of the immunological assay are confirmed by histopathological light- and electron-microscopic incestigations and documented by typical examples.


[Results of cisternoscintigraphy. A proscpective and retrospective study]. In a retrospective and prospective study the scintigraphically measured kinetics of intrathecally injected tracers are classified and compared with the final clinical diagnoses confirmed by additional examinations and clinical course. The results of the studies show characteristic dynamics of the tracer in patients without neurological diseases, whereas typically abnormal images are demonstrated in different neurological diseases.


Ergocryptine and pregnancy maintenance in hamsters. Ergocryptine (ECR) terminated pregnancy in hamsters when administered on Day 5; when ECR was given on Day 6 the response was diminished, and pregnancy continued after ECR treatment on Day 7. The abortifacient action of ECR in Day 5 pregnant hamsters was overcome by exogenous prolactin but not FSH and LH. When sera collected from hamsters on different days of gestation were examined for their ability to neutralize the effect of ECR in Day 5 pregnant hamsters, a peak of luteotrophic activity was observed in sera collected on Days 10 and 11. The results of these studies suggest that in hamsters the role of hypophyseal prolactin in luteal support is diminished by Day 7 of pregnancy, and the appearance of luteotrophic activity in sera collected on Days 10 and 11 may be indicative of a placental luteotrophin.


The possible mode of action of prostaglandins IX-prostaglandin F2alpha involvement in the reversal of ovulation blockade by ergocornine in rats. A single injection of 1 mg ergocornine methanesulphonate to semispayed rat on day 3 of the cycle was found to block ovulation. However, the animals showed regular compensatory hypertrophy of the remaining ovary. Prostaglandin F2alpha (PGF2alpha) of 2.0 mg/kg bw on days 3 and 4 in the ergocornine-blocked semispayed rats consistently reversed the blocking effect and the animals showed compensatory ovulation and ovarian hypertrophy. It was moreover observed that the ergocornine-treated mated animals did not become either pregnant or pseudopregnant, but returned to normal cycle as usual. Conversely, the animals which had combined regimen of ergocornine and PGF2alpha became pregnant and the number of embryonic swellings in a single horn and their average weight were statistically identical to their experimental controls. The possible involvement of PGF2alpha in the mechanism of follicular rupture has been discussed.


Prevalence of respiratory symptoms in towns with different air pollution. An epidemiologic study was carried out for the estimation of air pollution as a risk factor for chronic obstructive lung disease. The whole male population aged 40 to 60 years was investigated in a polluted and a non-polluted control town. The subjects with occupational exposure to dusts, gases and irritant vapours were discarded from the study. The prevalence of respiratory symptoms and of chronic bronchitis in the polluted town was twice that in the control (non-polluted) one. These results are discussed in the light of some previous investigations of the authors and of the available data in the literature.